Clinical trial NCT04642638
Conditions: Coronavirus Infection Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) COVID-19 Disease
Keywords: DNA vaccine Electroporation Healthy COVID-19
Sponsor: Inovio Pharmaceuticals
Start date: 2020-11-30; Completion date: 2022-09-13
Enrollment: 1307 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 2/3, randomized, placebo-controlled, multi-center trial to evaluate the safety, immunogenicity and efficacy of INO-4800 administered by intradermal (ID) injection followed by electroporation (EP) using CELLECTRA® 2000 device to prevent coronavirus disease 2019 (COVID-19) in participants at high risk of exposure to severe acute respiratory syndrome coronavirus - 2 (SARS-CoV-2).

The Phase 2 segment will evaluate immunogenicity and safety in approximately 400 participants at two dose levels across three age groups. Safety and immunogenicity information from the Phase 2 segment will be used to determine the dose level for the Phase 3 efficacy segment of the study involving approximately 7116 participants.

Detailed description:

Arms: arm 1: Participants received one ID injection of 1.0 milligram (mg) of INO-4800 followed by EP using the CELLECTRA® 2000 device on Day 0 and Day 28. arm 2: Participants received two ID injections of 1.0 mg (total 2.0 mg per dosing visit) of INO-4800 followed by EP using the CELLECTRA® 2000 device on Day 0 and Day 28. arm 3: Participants received one ID injection of placebo followed by EP using the CELLECTRA® 2000 device on Day 0 and Day 28. arm 4: Participants received 2 ID injections of placebo followed by EP using the CELLECTRA® 2000 device on Day 0 and Day 28. arm 5: Participants received two 1.0 mg ID injections of INO-4800, each followed by EP using the CELLECTRA® 2000 device on Day 0 and Day 28. arm 6: Participants received 2 ID injections of placebo per dosing visit, each followed by EP using the CELLECTRA® 2000 device on Day 0 and Day 28.
Interventions: intervention 1: INO-4800 intervention 2: CELLECTRA® 2000 intervention 3: Placebo intervention 4: CELLECTRA® 2000
Intervention descriptions: intervention 1: INO-4800 was administered ID on Day 0 and Day 28. intervention 2: EP using the CELLECTRA® 2000 device was administered following ID delivery of INO-4800 on Day 0 and Day 28. intervention 3: Sterile saline sodium citrate (SSC) buffer (SSC-0001) was administered ID on Day 0 and Day 28. intervention 4: EP using the CELLECTRA® 2000 device was administered following ID delivery of sterile saline sodium citrate (SSC) buffer (SSC-0001) on Day 0 and Day 28.

Protocol documents:
Prot_000.pdf: 
Official Title: 
NCT Number: 
NCT04642638
Document Dates:
Protocol Version 7.0: 08 March 2022 
Protocol Version 6.0: 30 April 2021 
Protocol Version 5.0: 02 April 2021 
Protocol Version 4.0: 13 November 2020
Protocol Version 3.0: 19 August 2020 
Protocol Version 2.0: 15 June 2020
Protocol Version 2.0 (US): 08 October 2021 
Protocol Version 1.0: 22 May 2020
Protocol Version 1.0 (US): 30 July 2021
Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the Safety, 
Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine Against 
COVID-19 Disease, Administered Intradermally Followed by Electroporation in 
Adults at High Risk of SARS-CoV-2 Exposure


Inovio Pharmaceuticals, Inc. 
Clinical Study Report for Protocol COVID19-311 
 
 
CONFIDENTIAL 
 
 
 
16.1 
Study Information 
Page 1 of 768


Inovio Pharmaceuticals, Inc. 
Clinical Study Report for Protocol COVID19-311 
 
 
CONFIDENTIAL 
 
 
 
 
16.1.1 Protocol and Protocol Amendments 
Original Protocol Version 1.0, dated 22 May 2020 
Protocol Version 2.0, dated 15 Jun 2020 
Protocol Version 3.0, dated 18 Aug 2020 
Protocol Version 4.0, dated 13 Nov 2020 
Protocol Version 5.0, dated 02 Apr 2021 
Protocol Version 6.0, dated 30 Apr 2021 
Protocol Version 7.0, dated 08 Mar 2022 
The Sponsor terminated the study while the clinical trial operated under Protocol Version 6.0. 
Protocol Version 7.0 was not implemented into the study. 
Regional Protocols 
Protocol Version 1.0 (US), dated 30 Jul 2021 
Protocol Version 2.0 (US), dated 08 Oct 2021 
 
 
Page 2 of 768


CONFIDENTIAL 
 
Page 1 of 67 
 
 
 
 
 
 
 
 
 
 
COVID19-311 
 
Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the 
Safety, Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against 
COVID-19 Disease, Administered Intradermally Followed by Electroporation in 
Healthy Adults at High Risk of SARS-CoV-2 Exposure   
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
IND #: 19690 
 
Protocol Version: 1.0 
 
Protocol Version Date: 22-May-2020 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 22-May-2020 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 2 of 67 
 
 
Medical Monitor Approval Page 
 
Drug:  
INO-4800 
 
Sponsor: 
Inovio Pharmaceuticals, Inc. 
 
660 W. Germantown Pike, Suite 110 
 
Plymouth Meeting, PA 19462 
 
Medical Monitor: 
 M.D., Ph.D. 
 
 
 
Inovio Pharmaceuticals, Inc. 
 
Approval Signature: 
 
[Electronically Signed] 
  
M.D., Ph.D. 
Inovio Pharmaceuticals, Inc. 
 Date (ddMmmyyyy) 
 
 
 
 
CONFIDENTIAL 
The information in this document is considered privileged and confidential by Inovio 
Pharmaceuticals Inc. (INOVIO) and may not be disclosed to others except to the extent 
necessary to obtain Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics 
Committee (EC) approval and informed consent, or as required by local regulatory 
authorities. Persons to whom this information is disclosed must be informed that this 
information is privileged and confidential and that it should not be further disclosed 
without the written permission of INOVIO. Any supplemental information added to this 
document is also confidential and proprietary information of INOVIO and must be kept in 
confidence in the same manner as the contents of this document. 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 22-May-2020 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 3 of 67 
 
 
Principal Investigator Acknowledgement 
 
I have read and understood this Protocol and agree that it contains all details necessary to 
conduct the clinical trial. I understand that it must be reviewed by the Institutional Review Board 
(IRB)/Research Ethics Board (REB)/Ethics Committee (EC) overseeing the conduct of the 
clinical trial and approved or given favorable opinion before implementation. 
 
The Principal Investigator’s (PI’s) signature constitutes the PI’s approval of this Protocol and 
provides the necessary assurances that this clinical trial will be conducted in accordance with 
International Council for Harmonization (ICH)/Good Clinical Practice (GCP), local legal and 
regulatory requirements, and all stipulations of the Protocol. 
 
 
Principal Investigator Signature: 
 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
Principal Investigator Signature 
 
Date (ddMmmyyyy) 
 
 
 
Clinical Trial Site Number: 
 
Clinical Trial Site Name: 
 
 
 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 22-May-2020 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 4 of 67 
 
TABLE OF CONTENTS 
 
Table of Contents ....................................................................................................................... 4 
Clinical Protocol Synopsis .......................................................................................................... 8 
Table 2 - Schedule of Events ....................................................................................................14 
1.0 
Introduction .................................................................................................................16 
1.1 
Background and Scientific Rationale ........................................................................... 16 
1.2 
Background Information .............................................................................................. 16 
1.2.1 
Clinical Presentation, Transmission and Immune Response .................................17 
1.2.2 
Current Treatment and Unmet Need .....................................................................18 
1.3 
Rationale for prophylactic vaccine development ......................................................... 19 
1.3.1 
Dose and Regimen Rationale ...............................................................................19 
1.3.2 
DNA Vaccines.......................................................................................................19 
1.3.3 
Use of Electroporation with DNA Vaccines ...........................................................20 
1.4 
Potential Benefits and Risks ....................................................................................... 21 
2.0 
Objectives and Purpose ..............................................................................................21 
2.1 
Hypothesis .................................................................................................................. 21 
3.0 
Clinical Trial Design and Endpoints ............................................................................21 
3.1 
Primary Objectives ...................................................................................................... 22 
3.2 
Primary Endpoints....................................................................................................... 22 
3.3 
Secondary Objectives ................................................................................................. 23 
3.4 
Secondary Endpoints .................................................................................................. 23 
3.5 
Exploratory Objective .................................................................................................. 24 
3.6 
Exploratory Endpoint ................................................................................................... 24 
3.7 
Efficacy Assessment ................................................................................................... 24 
3.7.1 
Case definition for laboratory-confirmed COVID-19 disease: ................................24 
3.7.2 
Case Definition of “Laboratory-Confirmed SARS-CoV-2 Infection”; SARS-CoV-2 
infection without symptoms ...................................................................................26 
3.8 
Safety Assessment ..................................................................................................... 26 
3.9 
Immunogenicity Assessment ...................................................................................... 26 
4.0 
Clinical Trial Population ..............................................................................................26 
4.1 
Inclusion Criteria ......................................................................................................... 26 
4.2 
Exclusion Criteria ........................................................................................................ 27 
4.3 
Discontinuation/Withdrawal of Clinical Trial Subjects .................................................. 28 
5.0 
Clinical Trial Investigational Product Information .........................................................29 
5.1 
Investigational Product (IP) and Study Device ............................................................ 29 
5.1.1 
INO-4800 and Placebo .........................................................................................29 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 22-May-2020 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 5 of 67 
 
5.1.2 
CELLECTRA® 2000 ..............................................................................................29 
5.2 
Dosing Regimens ....................................................................................................... 30 
5.2.1 
Blinding .................................................................................................................30 
5.3 
Packaging and Labeling .............................................................................................. 30 
5.3.1 
INO-4800 or Placebo ............................................................................................30 
5.3.2 
CELLECTRA® 2000 ..............................................................................................31 
5.4 
Handling and Storage ................................................................................................. 31 
5.4.1 
INO-4800 and Placebo .........................................................................................31 
5.4.2 
CELLECTRA® 2000 ..............................................................................................31 
5.5 
Preparation and Dispensing ........................................................................................ 31 
5.6 
Use of Study Device ................................................................................................... 31 
5.7 
Investigational Drug and Study Device Accountability ................................................. 32 
5.7.1 
Investigational Product (IP) Accountability ............................................................32 
5.7.2 
CELLECTRA® 2000 Accountability .......................................................................32 
5.8 
Return and Destruction of Investigational Drug and Study Device .............................. 32 
5.8.1 
INO-4800 and Placebo .........................................................................................32 
5.8.2 
Return of CELLECTRA® 2000...............................................................................32 
6.0 
Clinical Trial Procedures and Schedule ......................................................................33 
6.1 
Procedure by Visit ....................................................................................................... 33 
6.1.1 
Clinical Trial Screening Evaluations ......................................................................33 
6.1.1.1 Medical History .....................................................................................................34 
6.1.2 
Clinical Trial Evaluations and Procedures .............................................................34 
6.1.2.1 Day 0 and Day 28 (Dosing Visits) .........................................................................34 
6.1.2.2 Day 7 and Day 42 (post-dose visits) .....................................................................34 
6.1.2.3 Phone calls (Days 35, 70, 98, 112, 126, 140, 168, 182, 196, 224, 238, 252, 280, 
294, 308, 336, 350, 364, and 378) ........................................................................35 
6.1.2.4 Day 56 Visit ..........................................................................................................35 
6.1.2.5 Days 84, 154, 210, 266, 322 Visits and Day 393 Visit ...........................................35 
6.1.2.6 Suspected COVID-19 Assessment Visit................................................................36 
6.2 
Informed Consent ....................................................................................................... 36 
6.3 
Assignment of Subject Identification Numbers ............................................................ 37 
6.4 
Safety Evaluations ...................................................................................................... 37 
6.4.1 
Injection and EP ....................................................................................................38 
6.4.2 
Management of Pain Due to Electroporation (EP) Procedures ..............................38 
6.4.3 
Assessment of Laboratory Abnormalities ..............................................................38 
6.4.4 
Assessment of Clinical Trial Adverse Events (AEs) ..............................................38 
6.4.5 
Assessment of Injection Site Reactions ................................................................39 
6.4.6 
Peripheral Blood Immunogenicity Assessments ....................................................39 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 22-May-2020 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 6 of 67 
 
6.4.7 
Concomitant Medications/Treatments ...................................................................40 
6.4.8 
Restrictions ...........................................................................................................40 
6.4.9 
SARS-CoV-2 Testing ............................................................................................40 
6.4.10 COVID-19 Disease Monitoring ..............................................................................41 
7.0 
Evaluation of Safety and Management of Toxicity ......................................................41 
7.1 
Safety Parameters ...................................................................................................... 41 
7.2 
Adverse Events (AEs) ................................................................................................. 42 
7.2.1 
Laboratory-Confirmed COVID-19 Disease and Severe COVID-19 Disease ..........42 
7.3 
Adverse Drug Reaction (ADR) .................................................................................... 42 
7.4 
Serious Adverse Events (SAEs) .................................................................................. 42 
7.5 
Unexpected Adverse Drug Reaction ........................................................................... 43 
7.6 
Unanticipated (Serious) Adverse Device Effect (UADE) .............................................. 43 
7.7 
Device Deficiency ....................................................................................................... 44 
7.8 
Safety and Toxicity Management ................................................................................ 44 
7.8.1 
Adverse Event of Special Interest (AESI) ..............................................................44 
7.8.2 
Medically Attended Adverse Event (MAAE) ..........................................................44 
7.8.3 
Abnormal Laboratory Value ..................................................................................44 
7.8.4 
Clinical Trial Stopping Rules .................................................................................44 
7.9 
Safety Data Reporting Period, Method of Collection and Submission ......................... 45 
7.10 
Adverse Event Reporting ............................................................................................ 46 
7.10.1 Submitting the Initial Serious Adverse Event (SAE) Report Form..........................46 
7.10.2 Recording the Event .............................................................................................46 
7.10.3 Assessing Severity (Intensity) ...............................................................................46 
7.10.4 Causal Relationship of Clinical Material to Adverse Events (AEs) .........................47 
7.11 
Reporting Pregnancy During the Clinical Trial ............................................................. 47 
7.12 
Reporting Device-Related Complaints or Deficiencies ................................................ 48 
7.13 
Notifying Regulatory Authorities and Institutional Review Boards (IRBs)/Research 
Ethics Boards (REBs)/Ethics Committees (ECs) of Safety Information ....................... 48 
7.13.1 Sponsor Responsibilities .......................................................................................48 
7.13.2 Principal Investigator (PI) Responsibilities ............................................................49 
7.14 
Post-Trial Reporting Requirements ............................................................................. 49 
7.15 
Clinical Trial Discontinuation ....................................................................................... 49 
8.0 
Statistical Considerations ...........................................................................................49 
8.1 
Statistical and Analytical Plan ..................................................................................... 49 
8.2 
General Considerations .............................................................................................. 49 
8.3 
Statistical Hypotheses ................................................................................................. 50 
8.4 
Analytical Populations ................................................................................................. 50 
8.5 
Description of Statistical Methods ............................................................................... 50 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 22-May-2020 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 7 of 67 
 
8.5.1 
Primary efficacy Analysis ......................................................................................50 
8.5.2 
secondary Analyses ..............................................................................................51 
8.5.3 
Safety Analyses ....................................................................................................51 
8.5.4 
Disposition ............................................................................................................52 
8.5.5 
Demographic and Other Baseline Characteristics .................................................52 
8.5.6 
Interim Analyses ...................................................................................................53 
8.5.7 
Multiplicity .............................................................................................................53 
8.5.8 
Missing Values......................................................................................................53 
8.5.9 
Exploratory Analyses ............................................................................................53 
8.6 
Sample Size/Power ..................................................................................................... 54 
8.7 
Randomization and Blinding ....................................................................................... 54 
9.0 
Ethics .........................................................................................................................54 
9.1 
Investigator and Sponsor Responsibilities ................................................................... 54 
9.2 
Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics Committee (EC)
 ................................................................................................................................... 55 
9.3 
Protection of Human Subjects ..................................................................................... 55 
9.3.1 
Compliance with Informed Consent Regulations ...................................................55 
9.3.2 
Compliance with Institutional Review Board (IRB)/Research Ethics Board 
(REB)/Ethics Committee (EC) Requirements ........................................................56 
9.3.3 
Compliance with Good Clinical Practice ................................................................56 
9.3.4 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11) .....56 
9.3.5 
Compliance with Protocol .....................................................................................56 
9.3.6 
Changes to the Protocol .......................................................................................56 
10.0 
Data Collection, Monitoring and Reporting ..................................................................56 
10.1 
Confidentiality and Privacy .......................................................................................... 56 
11.0 
Source Documents .....................................................................................................57 
11.1 
Records Retention ...................................................................................................... 57 
12.0 
Safety and Quality Monitoring .....................................................................................57 
12.1 
Safety Review ............................................................................................................. 57 
12.2 
Clinical Monitoring....................................................................................................... 58 
13.0 
Financing and Insurance ............................................................................................59 
14.0 
Publication Policy .......................................................................................................59 
15.0 
List of Abbreviations ...................................................................................................60 
16.0 
References .................................................................................................................62 
17.0 
Appendices .................................................................................................................65 
17.1 
APPENDIX A: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trial ............................................................... 65 
17.2 
APPENDIX B: Adverse Events of Special Interest ...................................................... 67 
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INO-4800 
COVID19-311 
Inovio Pharmaceuticals, Inc. 
Clinical Protocol 
Protocol Version Date: 22-May-2020 
CONFIDENTIAL 
Protocol Version: 1.0 
Page 8 of 67 
CLINICAL PROTOCOL SYNOPSIS 
Protocol Title: Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the 
Safety, Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-19 
Disease, Administered Intradermally Followed by Electroporation in Healthy Adults at High 
Risk of SARS-CoV-2 Exposure 
Protocol Number: COVID19-311 
Clinical Trial Phase: 3 
Estimated Number of Clinical Trial Centers and Countries/Regions: Up to 30 centers in 
the US 
Background:   
INO-4800 is a prophylactic vaccine under development against SARS-CoV-2, the causative 
agent of COVID-19. INO-4800 contains the plasmid pGX9501, which encodes for the full 
length of the Spike glycoprotein of SARS-CoV-2. The goal of this trial is to assess the safety, 
immunogenicity and efficacy of INO-4800 to prevent COVID-19 disease in subjects at high 
risk of exposure to SARS-CoV-2.  
Clinical Trial Design:  
This is a Phase 3, randomized, placebo-controlled, multi-center trial to evaluate the safety, 
immunogenicity, and efficacy of INO-4800 (1.0mg), administered by intradermal (ID) injection 
followed immediately by electroporation (EP) using CELLECTRA® 2000 device using a 2-
dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-2 exposure. The 
primary objective of this trial is to evaluate the efficacy of INO-4800 in seronegative subjects.  
Approximately 3438 seronegative subjects and 100 seropositive subjects 18 years of age or 
older are expected to be enrolled and will be randomized at a 1:1 ratio to receive either 
investigational product (1.0mg INO-4800) or placebo (SSC-0001). See Table 1.    
Table 1: COVID19-311 Dose Groups 
Study 
Group 
Expected 
Number of 
Seronegative 
Subjects 
Number of 
Seropositive 
Subjects 
Dosing 
Days 
Number of  
Injections + 
EP per Dosing 
Visit 
INO-4800 
(mg) per 
injection 
Total 
Dose 
INO-4800 
1719 
50 
0, 28 
1 
1.0 mg 
2.0 mg 
Placebo 
1719 
50 
0, 28 
1 
0 
0 
Total 
3438 
100 
Grand 
Total 
3538 
The trial is case-driven. Among seronegative subjects, a total of 89 observed cases will be 
required for 90% power to declare the vaccine efficacious (>15%), assuming a true efficacy 
of 60%.  A sample size of 3438 seronegative subjects is expected to be required to achieve 
this number of cases assuming an underlying attack rate of 3.7%. The sample size may be 
increased if the underlying attack rate is lower than projected. 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 6-
months post-dose 2. Subjects will be followed for 12 months post-dose 2. 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 22-May-2020 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 9 of 67 
 
All subjects, investigating site staff (excluding site pharmacy staff) and the Sponsor will be 
blinded throughout the trial. A group-level unblinding will occur when all subjects’ data is 
complete for the primary efficacy timeframe. 
 
A Data Safety Monitoring Board (DSMB) will convene regularly throughout the trial to review 
unblinded safety data and adjudicate the cases of COVID-19 disease. Details of its scope will 
be provided in a charter.  
Criteria for Evaluation:  
 
Research Hypothesis:  
INO-4800 delivered ID followed by EP using CELLECTRA® 2000 will provide protection 
against laboratory-confirmed COVID-19 in subjects at high risk of SARS-CoV-2 exposure.  
 
Primary Objective 
Associated Primary Endpoints 
1. Evaluate the efficacy of INO-4800 in 
subjects who are SARS-CoV-2 
seronegative at baseline 
 
1. Incidence of laboratory-confirmed COVID-19 
disease starting 14 days after completion of the 2-
dose regimen until 6 months post-dose 2 in 
subjects who are SARS-CoV-2 seronegative at 
baseline 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of 
INO-4800    
 
1a. Incidence of injection site reactions 
1b. Incidence of systemic adverse events (AEs) by 
system organ class (SOC), preferred term (PT), 
severity and relationship to investigational 
product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of injection site reactions, systemic AEs 
by SOC, PT, severity and relationship to 
investigational product, SAEs, and AESIs in 
subjects who are SARS-CoV-2 seropositive at 
baseline 
 
2. Evaluate the efficacy of INO-4800 of 
laboratory-confirmed severe or critical 
COVID-19 cases for 6 months post-
dose 2 in subjects who are SARS-
CoV-2 seronegative at baseline     
 
2a. Incidence of severe or critical COVID-19 disease 
in SARS-CoV-2 seronegative subjects starting 14 
days after completion of the 2-dose regimen until 
6 months post-dose 2 
2b. Incidence of COVID-19 disease in SARS-CoV-2 
seronegative subjects requiring mechanical 
ventilation, ECMO, noninvasive ventilation, or 
high-flow nasal cannula oxygen delivery starting 
14 days after completion of the 2-dose regimen 
until 6 months post-dose 2 
2c. Incidence of deaths due to COVID-19 disease in 
SARS-CoV-2 seronegative subjects starting 14 
days after completion of the 2-dose regimen until 
6 months post-dose 2 
3. Evaluate the efficacy of INO-4800 
with respect to SARS-CoV-2 
infections who are SARS-CoV-2 
seronegative at baseline 
3.   Incidence of laboratory-confirmed SARS-CoV-2 
infections in SARS-CoV-2 seronegative subjects 
starting 14 days after completion of the 2-dose 
regimen until 6 months post-dose 2 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 22-May-2020 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 10 of 67 
 
4. Evaluate efficacy of INO-4800 for 12 
months post-dose 2 in subjects who 
are SARS-CoV-2 seronegative at 
baseline   
4a.  Incidence of laboratory-confirmed COVID-19 
disease starting 14 days after completion of the 2-
dose regimen until End of Study (EOS) in subjects 
who are SARS-CoV-2 seronegative at baseline 
4b. Incidence of severe or critical COVID-19 disease  
in SARS-CoV-2 seronegative subjects starting 14 
days after completion of the 2-dose regimen until 
EOS 
4c. Incidence of COVID-19 disease in SARS-CoV-2 
seronegative subjects requiring mechanical 
ventilation, ECMO, noninvasive ventilation, or 
high-flow nasal cannula oxygen delivery starting 
14 days after completion of the 2-dose regimen 
until EOS 
4d. Incidence of deaths due to COVID-19 disease in 
SARS-CoV-2 seronegative subjects starting 14 
days after completion of the 2-dose regimen until 
EOS 
4e. Incidence of laboratory-confirmed SARS-CoV-2 
infections in SARS-CoV-2 seronegative subjects 
starting 14 days after completion of the 2-dose 
regimen until EOS 
5. Evaluate the short-term efficacy of 
INO-4800 following one dose in 
subjects who are SARS-CoV-2 
seronegative at baseline 
5.  Incidence of COVID-19 disease in SARS-CoV-2 
seronegative subjects starting 14 days post-dose 
1 until 14 days post-dose 2 
6. Evaluate the timing of symptom 
resolution in subjects who develop 
COVID-19 illness who are SARS-
CoV-2 seronegative at baseline 
6.  Days to symptom resolution in SARS-CoV-2 
seronegative subjects who develop COVID-19 
disease. 
 
7.  Evaluate the humoral immune 
response to INO-4800 in subjects 
who are SARS-CoV-2 seronegative 
at baseline 
7a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody titers in subjects who are SARS-
CoV-2 seronegative at baseline 
7b. Incidence of seroconversion by SARS-CoV-2 
Spike glycoprotein antigen specific binding 
antibody assay in subjects who are SARS-CoV-2 
seronegative at baseline 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Evaluate the expanded 
immunological profile by assessing 
both T and B cell immune responses 
1a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot. 
1b. T cell phenotype (i.e., Th1/Th2/Th17) analysis by 
mRNA expression levels or flow cytometry may 
be conducted. The humoral response may also 
be interrogated by such assays as neutralization, 
ADCC or B cell ELISpot to further delineate the 
functional nature of the humoral response.  
 
 
Efficacy Assessment:  
Subjects will receive either investigational product (1.0mg INO-4800) or placebo (SSC-0001) 
in a 2-dose regimen administered on Days 0 and 28 intradermally followed immediately by 
EP. Subjects will be monitored through regularly scheduled clinic visits and phone calls 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 22-May-2020 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 11 of 67 
 
throughout the study. Subjects will be regularly tested for SARS-CoV-2 infection using saliva 
and serologic testing. If COVID-19 disease is suspected based on symptoms and laboratory 
testing, site personnel will arrange for a clinic visit. Subjects with symptoms that begin on or 
after 14 days post-dose 2 with laboratory confirmation will contribute to the case count for 
the primary endpoint analysis. 
Safety Assessment:  
Subjects will be followed for safety during the entire duration of trial participation. AEs, 
regardless of relationship to study drug, will be collected from the time of consent until 28 
days post-dose 2. SAEs, Medically Attended Adverse Events (MAAEs) and AESIs will be 
collected from time of consent until EOS. SAEs, AESIs and treatment-related AEs will be 
followed to resolution or stabilization.  
Baseline and serial laboratory blood and urine samples will be drawn according to the 
Schedule of Events (Table 2). Subjects will report any potential symptoms of COVID-19 in 
real time during the trial and will be followed bi-weekly through clinic visits or phone calls.  
Immunogenicity Assessment:  
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 2).  Binding ELISA will be evaluated at serial timepoints. All subjects will be tested for 
seroconversion as indicative of vaccine-take. Furthermore, the Spike-Binding ELISA results 
will be assessed in order to determine antibody correlates of protection. In addition, immune 
assessments will be conducted to determine additional correlates of protection. The correlate 
can either be mechanistic or non-mechanistic. Determination of assays, timepoints and 
number of subjects tested will be based on current literature and reagent availability. 
Clinical Trial Population: 
Healthy subjects at high risk for SARS-CoV-2 exposure who are 18 years or older. 
Inclusion Criteria: 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, physical 
examination and vital signs performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working, visiting or residing in an environment with high risk of exposure to SARS-
CoV-2 (e.g., civilian and military health care workers or emergency response personnel 
having direct interactions with patients or providing direct care to patients, nursing 
home staff);   
f. Screening laboratory results within normal limits for testing laboratory or deemed not 
clinically significant by the Investigator; 
g. Body Mass Index of 18-30 kg/m2 at Screening; 
h. Negative serological tests for Hepatitis B surface antigen (HBsAg), Hepatitis C antibody 
and Human Immunodeficiency Virus (HIV) antibody or rapid test at screening (subjects 
who are positive for Hepatitis C antibody but are in remission as defined by 
undetectable HCV RNA level ≥ 12 weeks after completion of HCV therapy may be 
enrolled) 
i. 
Must meet one of the following criteria with respect to reproductive capacity: 
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
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Protocol Version: 1.0 
 
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• 
Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or 
tubal ligation, absence of ovaries and/or uterus in females). In the case of 
vasectomy, subjects should wait six (6) months post-vasectomy prior to 
enrolling;  
• 
Use of medically effective contraception with a failure rate of < 1% per year 
when used consistently and correctly from screening until 3 months following 
last dose. Acceptable methods include:  
o hormonal contraception including implants, injections or oral; 
o two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
o abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Exclusion Criteria: 
a. Acute febrile illness with temperature > 100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat); 
b. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the screening visit until 3 
months following the last dose; 
c. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
d. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0; 
e. Previous receipt of an investigational vaccine for prevention or treatment of COVID-19, 
MERS or SARS; 
f. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring medical evaluation and/or treatment within the past 5 years; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, resting systolic blood pressure >150 mm Hg or a 
resting diastolic blood pressure >95 mm Hg at Screening; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 7.0%); 
• 
Malignancy within the past 5 years, with the exception of superficial skin 
cancers that only required local excision; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring medical 
evaluation and/or treatment within the past 5 years; 
• 
History of seizures within the past 5 years with the use of no more than a 
single antiepileptic agent; 
g. Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies; 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed); 
• 
Current or anticipated use of disease modifying doses of anti-rheumatic drugs 
(e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic 
disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, adalimumab 
or etanercept); 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
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CONFIDENTIAL 
Protocol Version: 1.0 
 
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• 
History of solid organ or bone marrow transplantation; 
• 
History of receipt of any other clinically significant immunosuppressive drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the 
subject or require therapy that would interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results. 
h. Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation 
site; 
i. 
Blood donation within 1 month prior to Day 0; 
j. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
k. Reported ongoing smoking or vaping; 
l. 
Reported alcohol or substance abuse/dependence within the past 5 years; 
m. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
Clinical Trial Treatment: 
Investigational Product: A single 1.0mg ID injection of INO-4800 (~0.1mL dose volume) 
followed immediately by EP administered at Day 0 and Day 28 (±3 days) 
Placebo: A single ID injection of SSC-0001 (~0.1mL) followed immediately by EP administered 
at Day 0 and Day 28 (±3 days) 
Formulation: 
INO-4800 is formulated in sodium chloride and sodium citrate (SSC) buffer, refrigerated.  
 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 22-May-2020 
CONFIDENTIAL 
Protocol Version: 1.0 
 
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TABLE 2 - SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Wk
1 
Wk 
4 
Tel
#1 
Wk 
6 
Wk
8 
Tel
#2 
Wk
12 
Tel 
#3-
6 
Wk 
22 
Tel 
#7-
9 
Wk 
30 
Tel 
#10
-12 
Wk
38 
Tel 
#13-
15 
Wk
46 
Tel 
#16
-19 
Wk 
56 
Illness 
Screena 
Day 0 
Day 7 (±3d) 
Day 28 
(±3d) 
Phone call - Day 35 (±3d) 
Day 42 (±3d) 
Day 56 (±3d) 
Phone call - Day 70 (±5d) 
Day 84 (±5d) 
Phone calls  
Days 98, 112, 126, 140  ±5d) 
Day 154 (±5d) 
Phone calls 
Days 168, 182, 196 (±5d) 
Day 210 (± 10d) 
Phone calls 
Days 224, 238, 252 (±5d) 
Day 266 (± 10d) 
Phone calls 
Days 280, 294, 308) (±5d) 
Day 322 (± 10d) 
Phone calls 
Days 336, 350, 364, 378 (±5d) 
Day 393 (± 10d) 
Suspected 
COVID-19 assessment visitn 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Vital Signs 
X 
X 
 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Chemistryc 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
SARS-CoV-2 Serologyd 
X 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
HIV, HBV, HCV Serology  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis Routinee 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Pregnancy Testf 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
INO-4800 or Placebo + EPg 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Download EP Datah 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Eventsi  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Responsesj 
 
X 
 
 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Humoral Responsesk 
 
X 
 
 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
SARS-CoV-2 RT-PCR 
(Saliva) l 
X 
X 
 
X 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Xm 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0.   
b. 
Full physical examination only at screening and Day 393 (or any study discontinuation visit). Targeted physical exam at all other visits. 
c. 
Includes Na, K, Cl, HCO3, Ca, PO4, glucose, BUN, Cr, alkaline phosphatase, AST, ALT, LDH, total bilirubin, and hemoglobin A1c (hemoglobin A1c collected at screening only). 
d. 
SARS-CoV-2 antibody.   
e. 
Dipstick for glucose, protein, and hematuria. Microscopic examination should be performed if dipstick is abnormal.  
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Clinical Protocol 
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CONFIDENTIAL 
Protocol Version: 1.0 
 
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f. 
Serum pregnancy test at screening. Urine pregnancy test at other visits.  
g. 
An intradermal injection in skin preferably over deltiod muscle followed by EP at Day 0 and Day 28. 
h. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
i. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
j. 
Cellular responses utilizing ELIspot assay requires 34 mL of whole blood; collect 8.5 mL of whole blood in each of four 10 mL Acid Citrate Dextrose (ACD, Yellow top) tubes per time point. 
Note: Collect a total of 68 mL whole blood prior to 1st dose. 
k. 
Humoral responses utilizing the S-Binding ELISA, NP-Binding ELISA and SARS-CoV-2 neutralization assays require a total of 8.5 mL of serum collected in a 10-mL red top serum 
collection tube per time point. Note: Collect four aliquots of 1 mL each (total 4 mL) serum at each time point prior to 1st dose (Screening and prior to Day 0 dosing). 
l. 
SARS-CoV-2 RT-PCR with saliva specimen; The Day 0 and Day 28 RT-PCR results will not be required prior to dosing on that day.  
m. 
Nasopharyngeal, oropharyngeal swabs and saliva specimens.  
n. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The laboratory-confirmation of a case will be based on SARS-CoV-2 RT-PCR. 
Additional safety testing will be collected to understand the impact on various organ systems. Additional diagnostic testing (e.g., influenza diagnostics) may be ordered at the discretion 
of the Investigator. 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 22-May-2020 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 16 of 67 
 
1.0 
INTRODUCTION 
This document is a protocol for a human research trial to be conducted according to US 
and international standards of Good Clinical Practice (GCP) (FDA Title 21 part 312, 812 
and International Conference on Harmonization (ICH) guidelines), applicable government 
regulations and Institutional research policies and procedures. 
1.1 
BACKGROUND AND SCIENTIFIC RATIONALE 
The lack of available therapy in conjunction with increasing numbers of global cases 
indicate that SARS-CoV-2 infection remains a serious unmet medical concern. 
Appropriate measures to prevent, control and treat existing and future infections are in 
dire need. 
1.2 
BACKGROUND INFORMATION 
In late 2019, a cluster of cases of pneumonia of unknown etiology was reported in Wuhan, 
Hubei province, China [1-3]. These cases were announced on January 6, 2020 as testing 
negative for influenza, SARS, and MERS. On January 7, 2020 a novel virus was isolated 
by the Chinese Center for Disease Control and Prevention (CDC) from the throat swab 
sample of a patient, and the isolate was named “Wuhan-Hu-1.” The gene sequence of 
that isolate was then generated and determined to be of a novel coronavirus[4, 5]. That 
gene sequence was publically posted on January 10, and the novel coronavirus was 
preliminarily named 2019-nCoV. Subsequently, on February 11, 2020, the virus was 
named SARS-CoV-2 by the International Committee on Taxonomy of Viruses (ICTV) [6, 
7], due to its similarity with the original SARS virus. That same day, the World Health 
Organization (WHO) announced a specific name of the disease, “COVID-19,” associated 
with infection by this novel coronavirus, as based on the novel coronavirus origin and year 
of first reported cases. The cluster of human cases first identified pneumonia of unknown 
origin infections was comprised people who worked, visited, or lived around the local 
Huanan seafood wholesale market in Wuhan, where live animals and fresh meat and fish 
were on sale, suggesting an animal as the source of the novel virus transmission to 
humans. 
The first U.S. case of COVID-19 was detected in Washington State, confirmed on and as 
announced January 21, 2020 by the Washington State Department of Health and the U.S. 
Centers for Disease Control and Prevention (US CDC) [8].  That was a case of a traveler 
who had returned from Wuhan, China. Since that case detection, human-to-human local 
transmission began (or continued from previously undetected infections) in the U.S., and 
as of May 17, 2020, nearly 1.5 million lab-confirmed US COVID-19 cases and nearly 
90,000 US deaths due to COVID-19 have been reported [9]. COVID-19 cases have been 
reported from all 50 states and several territories.  
SARS-CoV-2 infection rapidly emerged as a global threat to public health, joining severe 
acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) 
infectious agents in a growing number of coronaviruses which have evolved to infect 
humans. COVID-19 was declared a Public Health Emergency of International Concern 
(PHEIC) by the WHO on January 20, 2020, and then progressed to be declared on March 
11, 2020 as a pandemic [10], associated with substantial morbidity and mortality [11].   The 
pandemic of COVID-19 includes scope of lab-confirmed cases reported by virtually all 
countries and COVID-19 deaths reported by many of those countries.  As of May 17, 2020, 
a total of over 4.7 million lab-confirmed COVID-19 cases have been reported 
internationally, including nearly 315,000 deaths [9]. However, and very importantly, 
because this is from a new pathogen and thus lab testing and reporting are not widely 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 22-May-2020 
CONFIDENTIAL 
Protocol Version: 1.0 
 
Page 17 of 67 
 
available and thus incomplete, the true number of cases of COVID-19 is likely far higher 
than reported, and the true number of SARS-CoV-2 infections – regardless of disease – 
is thought to be many (perhaps dozens of) times the number of detected infections and 
reported COVID-19 cases. 
An article in JAMA by Wu and McGoogan [12] provided a summary of a major report by 
the Chinese Center for Disease Control and Prevention (China CDC) [13].  That report 
found that among a total of 72,314 case records, 44,672 were classified as confirmed 
cases of SARS-CoV-2 infection (62%; diagnosis based on positive viral nucleic acid test 
result on throat swab samples), 16,186 as suspected cases (22%; diagnosis based on 
symptoms and exposures only, no test was performed because testing capacity was 
insufficient to meet current needs), 10,567 as clinically diagnosed cases (15%; this 
designation is being used in Hubei Province only; in these cases, no test was performed 
but diagnosis was made based on symptoms, exposures, and presence of lung imaging 
features consistent with coronavirus pneumonia), and 889 as asymptomatic cases (1%; 
diagnosis by positive viral nucleic acid test result but lacking typical symptoms including 
fever, dry cough, and fatigue) [14]. The overall case-fatality ratio (CFR) was 2.3% (1023 
deaths among 44,672 confirmed cases). No deaths occurred in the group aged 9 years 
and younger, but cases in those aged 70 to 79 years had an 8.0% CFR and cases in those 
aged 80 years and older had a 14.8% CFR. The CFR was 49.0% among critical cases. 
CFR was elevated among those with preexisting comorbid conditions - 10.5% for 
cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease, 6.0% for 
hypertension, and 5.6% for cancer [14]. These initial reports of the CFR documented the 
level of seriousness of COVID-19.  
Because of the novelty of SARS-CoV, the COVID-19 it causes and the serious outcomes 
in some patients, and the speed of propagation worldwide, unsurprisingly there has been 
an explosion of epidemiological, clinical, virological, and other data have emerged from 
China, the United States, and many other countries about this new virus and disease.  
These data in summary have further established that 1) SARS-CoV-2 is transmitted 
person-to-person [15], even from those asymptomatic or presymptomatic [16-18], 2) the 
virus is very infectious, with estimates of the R0 (Reproductive number) ranging from 1.5 
to 6.49, with a mean average of 3.28 and a median average of 2.79 [19], 3) the 
constellation of symptoms, signs, and an incubation period range of 2 to 14 days [20], and 
4)  the asymptomatic proportion of those infected being substantial, perhaps 50% or even 
up to 80% [15, 21, 22]. Further, research has found that the risk of death from COVID-19 
increases with age and for those with serious, comorbid conditions including hypertension, 
diabetes, cardiovascular disease, obesity, etc.   
Finally, although much has been learned very quickly about SARS-CoV-2 and COVID-19, 
much more is still to be determined. The aforementioned case-fatality ratio and similar 
estimates are from crude analyses that have only or largely been of moderate to serious 
cases and not included minor cases that did not present to health care. Therefore, the true 
CFR is likely significantly lower. Further, the infection-fatality ratio (IFR), which is the 
proportion who die among all those infected regardless of any symptomology, is likely still 
even lower than the CFR, but both the CFR and IFR will not be known with certainty until 
well-designed and controlled seroepidemiology surveys have been conducted using well-
validated antibody assays and thorough questionnaires to obtain symptom history.  Also, 
the presence of natural immunity of those infected who survive and the durability of such 
natural immunity is to be determined. Thus the existence and possibility of reinfection and 
recurrent infection is unknown. 
1.2.1 CLINICAL PRESENTATION, TRANSMISSION AND IMMUNE RESPONSE 
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A study in The Lancet by Huang and colleagues [3] reported the epidemiological, clinical, 
laboratory, and radiological characteristics, as well as treatment and clinical outcomes, of 
patients with laboratory-confirmed COVID-19 pneumonia. Common symptoms at onset of 
illness were fever (n=40, 98% of 41 patients), cough (n=31, 76%), and myalgia or fatigue  
(n=18, 44%);  less  common  symptoms  were  sputum  production  (n=11, 28%  of  39 
patients),  headache  (n=3, 8%  of  38 patients), hemoptysis (n=2, 5% of 39 patients), and 
diarrhea (n=1, 3% of 38 patients). Dyspnea developed in 22 (55%) of 40 patients (median 
time from illness onset to dyspnea was 8 days [Interquartile range 5 - 13 days]). Twenty 
six (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal 
findings on chest CT scan. Complications included acute respiratory distress syndrome 
(n=12, 29%), RNAaemia (n=6, 15%), acute cardiac injury (n=5 12%) and secondary 
infection (n=4, 10%).  
Transmission of SARS-CoV-2 occurred mainly after days of illness [23] and was 
associated with modest viral loads in the respiratory tract early in the illness, with viral 
loads peaking approximately 10 days after symptom onset [24]. Higher viral loads were 
detected soon after symptom onset, with higher viral loads detected in the nose than in 
the throat. Analysis of these samples suggested that the viral nucleic acid shedding 
pattern of patients infected with SARS-CoV-2 resembles that of patients with influenza 
[25] and appears different from that seen in patients infected with SARS-CoV [24]. The 
viral load that was detected in the asymptomatic patient was similar to that in the 
symptomatic patients, which suggests the transmission potential of asymptomatic or 
minimally symptomatic patients [11]. The SARS-CoV-2 transmission time window from 
COVID-19 patients is perhaps 2 days before symptom onset up to 37 days after symptom 
onset [18]. 
T cells play a critical role in antiviral immunity but their numbers and functional state in 
SARS-CoV-2 infected patients remain largely unclear. Diao and colleagues performed a 
retrospective review of the counts of total T cells, and CD4+and CD8+ T cell subsets, as 
well as serum cytokine concentration based on inpatient data from 522 patients with 
laboratory-confirmed SARS-CoV-2 infection, admitted into two hospitals in Wuhan from 
December 2019 to January 2020, and 40 healthy controls in the same two hospitals 
receiving routine physical examination. The number of total T cells, and CD4+ and CD8+ 
T cells were dramatically reduced in COVID-19 infected patients, especially among elderly 
patients (≥60 years of age) and in patients requiring Intensive Care Unit (ICU) care. Counts 
of total T cells, CD8+ T cells or CD4+ T cells lower than 800/μL, 300/μL, or 400/μL, 
respectively, are negatively correlated with patient survival [26]. 
1.2.2 CURRENT TREATMENT AND UNMET NEED 
Hospitals can provide supportive care for infected people. Currently, no licensed 
preventative vaccine or anti-viral therapy is available as indicated for SARS-CoV-2 
infection or COVID-19, except for Emergency Use Authorization (EUA). Clinical 
management includes prompt implementation of recommended infection prevention and 
control measures and supportive management of complications, including advanced 
organ support if indicated. Remdesivir has received Emergency Use Authorization for 
treatment of suspected or laboratory confirmed COVID-19 in adults and children 
hospitalized with severe disease [27]. Chloroquine Phosphate also has received EUA for 
treatment of adults and adolescents who are hospitalized with COVID-19 for whom a 
clinical trial is not available [28]. Hydyroxychloroquine, with and without azithromycin, is 
being investigated in multiple clinical trials, as is plasma-derived polyclonal antibodies and 
immune globulin, among other therapies.  
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
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CONFIDENTIAL 
Protocol Version: 1.0 
 
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1.3 
RATIONALE FOR PROPHYLACTIC VACCINE DEVELOPMENT 
SARS-CoV-2 has become a pandemic resulting in substantial morbidity and mortality. No 
specific treatment for COVID-19 is currently available, thus highlighting the need for 
effective therapeutic and preventive solutions. Due to rapid spread of SARS-CoV-2 
infections even from asymptomatic and mildly infected patients, there is an urgent need 
for appropriate measures to prevent, control and treat existing and future infections.  
To address this critical need for a medical countermeasure for prevention of further 
dissemination of SARS-CoV-2, we have employed our synthetic DNA-based vaccine 
technology. This technology is highly amenable to accelerated developmental timelines, 
due to the ability to rapidly design multiple test constructs, manufacture large quantities of 
the drug product, and the possibility of leveraging established regulatory pathways to the 
clinic. Furthermore, this technology has demonstrated proof of concept efficacy and safety 
in humans in a phase 2b randomized, double-blind, placebo-controlled study [29], for 
human papillomavirus (HPV) associated cervical pre-cancer and is currently in two 
multinational phase 3 trials for that indication (NCT03185013 and NCT03721978) and 
several phase 2 trials for related and other indications. For the development of a SARS-
COV-2 vaccine candidate, we have built upon our prior experience in developing a MERS 
coronavirus (MERS-CoV) vaccine. In a phase 1 clinical study, the MERS-CoV coronavirus 
vaccine was well tolerated and immune response was induced in more than 85% of 
participants after two vaccinations, and durable through 1 year of follow-up [30]. 
1.3.1 DOSE AND REGIMEN RATIONALE 
The intended use for INO-4800 is for both routine prophylaxis and use during an outbreak 
situation. As such, there is a desire to demonstrate the ability of the vaccine to drive 
immune responses within 4-8 weeks of administration, which supports evaluation of a 
dose regimen that includes Day 0 and Day 28. 
In this study, 1.0 mg of vaccine is administered by ID injection and followed by EP at Day 
0 and Day 28. The dose selection is supported by the well tolerated safety profile in the 
phase 1 trial of INO-4800 (COVID19-001, NCT04336410) as well as our prior experience 
in developing a MERS coronavirus (MERS-CoV) vaccine (INO-4700) [16, 17].  
In the ongoing phase 1 study of INO-4800, as of May 18, 2020, a total of 40 subjects has 
been enrolled into the phase 1 study, 20 subjects each in 1.0 mg and 2.0 mg groups. All 
subjects received at least one dose of INO-4800 while nine subjects in 1.0 mg group 
completed two doses of vaccination. A total of six adverse events (AEs) has bene reported 
as shown in Table 2. All of the AEs are grade 1 AEs. No serious adverse events (SAEs) 
or adverse event of special interest (AESIs) have been reported. Two meetings of the 
DSMB have been convened. After thorough review of available safety laboratory data and 
AE list, the DSMB did not find any safety concerning and recommended the trial continue 
without modification. 
Seropositive subjects are also included in the study to assess safety of INO-4800 in those 
with prior exposure to SARS-CoV-2 infection. 
1.3.2 DNA VACCINES 
Since the 1990s, a novel approach to vaccination against a broad array of target antigens 
and diseases has been in development. This involves the direct introduction of plasmid 
deoxyribonucleic acid (DNA) containing the gene encoding the immunogen against which 
an immune response is sought into appropriate host tissues and the in situ production of 
the target immunogen(s). This approach offers a combination of potential advantages, 
including the stimulation of both B and T-cell responses, stability of the vaccine across a 
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broad temperature range, absence of infectivity of the immunogen itself, the speed with 
which the vaccine can be constructed (for example in the face of an epidemic or pandemic 
as it is the case here with SARS-CoV-2), and the relative ease and generic nature of large-
scale manufacture. Many scientific publications have addressed the potential of DNA 
vaccination [31-40]. Immune responses in animal models have been obtained using genes 
from a variety of infectious agents including influenza viruses, hepatitis B virus, human 
immunodeficiency virus, human papillomaviruses, Marburg virus, Middle East Respiratory 
Syndrome (MERS) coronavirus, rabies virus, Severe Acute Respiratory Syndrome 
(SARS) coronavirus, West Nile virus (WNV), Zika virus, and other infectious agents as 
plasmodium, mycoplasma, and many more [39, 41]. In many cases, protection from 
disease in animal models has also been demonstrated.  
DNA vaccines are able to generate both CD4+ and CD8+ T cell responses. The ability to 
generate MHC-Class I restricted CD8+ T cells (cytolytic T lymphocytes), which generally 
are not made following administration of inactivated viruses, proteins or peptides, may be 
important for key responses against certain pathogens, as well as enabling cross-strain 
specific responses when many antibody responses are strain-specific. Because the 
encoded protein is synthesized in vivo by the host following administration, DNA vaccines 
can encode membrane-bound proteins instead of solely the soluble versions [42]. This 
can be important because key neutralizing epitopes are located in regions that would be 
excluded, or not formed in a monomeric truncated soluble version. Some early research 
in COVID-19 control has already suggested that neutralizing antibodies may not be 
sufficient and that cell-mediated immunity may be necessary [43]. 
Unlike certain other vectors (such as heterologous viral vectors), DNA vaccines do not 
stimulate adaptive immune responses against themselves, although the DNA itself does 
stimulate certain innate immune responses [44]. In other words, they do not generate anti-
vector immunity that could stunt antigen-specific responses following multiple exposures. 
1.3.3 USE OF ELECTROPORATION WITH DNA VACCINES 
Electroporation (EP) enhances gene expression of plasmid DNA delivered by the 
intramuscular (IM) or intradermal (ID) routes of administration (Figure 1). Following IM or 
ID delivery of a DNA vaccine or therapeutic product, EP facilitates entry of the DNA into 
the target site: muscle or dermal cells. Following cellular uptake, there is efficient 
production of the proteins encoded by the DNA expression plasmid system. The different 
EP devices, each with varying electrical parameters and protocols, have been reviewed 
[45]. EP has been extensively tested in animal species such as dogs, pigs, cattle, and 
NHPs to deliver therapeutic genes that encode for a variety of hormones, cytokines, 
enzymes or antigens [45] for the activation of both cellular and humoral responses [46, 
47]. Importantly, immune responses generated by DNA vaccines delivered with EP are far 
superior to responses to the same vaccines delivered without EP [47]. IM and ID delivery 
of DNA vaccines with EP has been studied extensively, and optimum conditions for 
plasmid uptake and expression have been described for therapeutic indications, vaccines 
and tumor animal model systems [48, 49].  
The Inovio Pharmaceuticals’ constant current EP device [45] referred to as the 
CELLECTRA® 2000 for ID administration (3P-ID) device will be used in this clinical trial. 
The ID route of delivery has been selected for INO-4800 based on recent findings from 
multiple DNA vaccine development programs where ID delivery has driven equivalent if 
not superior humoral and cellular responses while improving tolerability (clinicaltrials.gov 
NCT02464670, clinicaltrials.gov NCT02431767) [50]. 
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Figure 1: How Electroporation Works in the Body 
 
1.4 
POTENTIAL BENEFITS AND RISKS 
As of May 18, 2020, a total of 40 subjects have been dosed with INO-4800 ID. In the 
ongoing phase 1 study of INO-4800 administered ID followed by EP using CELLECTRA™ 
2000 devices in healthy volunteers the most frequently reported AE has been injection site 
reactions, and all AEs have been Grade 1.  
No specific AE has been identified as a risk. There may be potential benefit for prevention 
of COVID-19 disease, but efficacy is still unknown.  Data gathered in this trial will be useful 
for future development of this prophylactic vaccine against SARS-CoV-2 infection. 
Additional details regarding the benefits and risks for subjects participating in this clinical 
trial may be found in the Investigator’s Brochure (IB). 
2.0 
OBJECTIVES AND PURPOSE 
The overall purpose of this clinical trial is to evaluate the safety and efficacy of INO-4800 
for future development. 
2.1 
HYPOTHESIS 
INO-4800 delivered ID followed immediately by EP using CELLECTRA® 2000 will provide 
protection against laboratory-confirmed COVID-19 in subjects at high risk of SARS-CoV-
2 exposure.  
3.0 
CLINICAL TRIAL DESIGN AND ENDPOINTS 
This is a Phase 3, randomized, placebo-controlled, multi-center trial to evaluate the 
safety, immunogenicity, and efficacy of INO-4800 (1.0mg), administered by intradermal 
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(ID) injection followed immediately by electroporation (EP) using CELLECTRA® 2000 
device using a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-
CoV-2 exposure. The primary objective of this trial is to evaluate the efficacy of INO-4800 
in seronegative subjects.  
 
Approximately 3438 seronegative subjects and 100 seropositive subjects 18 years of age 
or older are expected to be enrolled and will be randomized at a 1:1 ratio to receive either 
investigational product (1.0mg INO-4800) or placebo (SSC-0001). See Table 1.   
 
Table 2: COVID19-311 Dose Groups 
Study 
Group 
Expected 
Number of 
Seronegative 
Subjects 
Number of 
Seropositive 
Subjects 
Dosing 
Days 
Number of  
Injections + 
EP per Dosing 
Visit 
INO-4800 
(mg) per 
injection 
Total 
Dose 
INO-4800 
1719 
50 
0, 28 
1 
1.0 mg 
2.0 mg 
Placebo 
1719 
50 
0, 28 
1 
0 
0 
Total 
3438 
100 
 
 
 
 
Grand 
Total 
3538 
 
 
 
 
 
The trial is case-driven. Among seronegative subjects, a total of 89 observed cases will 
be required for 90% power to declare the vaccine efficacious (>15%), assuming a true 
efficacy of 60%.  A sample size of 3438 seronegative subjects is expected to be required 
to achieve this number of cases assuming an underlying attack rate of 3.7%.  The sample 
size may be increased if the underlying attack rate is lower than projected.  
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 6-
months post-dose 2. Subjects will be followed for 12 months post-dose 2. 
 
All subjects, investigating site staff (excluding site pharmacy staff) and the Sponsor will 
be blinded throughout the trial. A group-level unblinding will occur when all subjects’ data 
is complete for the primary efficacy timeframe. 
 
A Data Safety Monitoring Board (DSMB) will convene regularly throughout the trial to 
review unblinded safety data and adjudicate the cases of COVID-19 disease. Details of 
its scope will be provided in a charter. 
3.1 
PRIMARY OBJECTIVES 
See Table 3. 
3.2 
PRIMARY ENDPOINTS 
Table 3: Primary Objective and Associated Endpoints 
Primary Objective 
Associated Primary Endpoints 
1. Evaluate the efficacy of INO-4800 in 
subjects who are SARS-CoV-2 
seronegative at baseline 
1. Incidence of laboratory-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 6 months post-dose 2 in 
subjects who are SARS-CoV-2 seronegative at 
baseline  
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3.3 
SECONDARY OBJECTIVES 
See Table 4. 
3.4 
SECONDARY ENDPOINTS 
Table 4: Secondary Objectives and Associated Endpoints 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability 
of INO-4800    
 
1a. Incidence of Injection site reactions 
1b. Incidence of systemic adverse events (AEs) by 
system organ class (SOC), preferred term (PT), 
severity and relationship to investigational 
product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of injection site reactions, systemic 
AEs by SOC, PT, severity and relationship to 
investigational product, SAEs, and AESIs in 
subjects who are SARS-CoV-2 seropositive at 
baseline 
 
2. Evaluate the efficacy of INO-4800 of 
laboratory-confirmed severe or 
critical COVID-19 cases for 6 
months post-dose 2 in subjects who 
are SARS-CoV-2 seronegative at 
baseline    
 
2a. Incidence of severe or critical COVID-19 disease 
in SARS-CoV-2 seronegative subjects starting 
14 days after completion of the 2-dose regimen 
until 6 months post-dose 2 
2b. Incidence of COVID-19 disease in SARS-CoV-2 
seronegative subjects requiring mechanical 
ventilation, ECMO, noninvasive ventilation, or 
high-flow nasal cannula oxygen delivery starting 
14 days after completion of the 2-dose regimen 
until 6 months post-dose 2 
2c. Incidence of deaths due to COVID-19 disease in 
SARS-CoV-2 seronegative subjects starting 14 
days after completion of the 2-dose regimen until 
6 months post-dose 2 
3.   Evaluate the efficacy of INO-4800 
with respect to SARS-CoV-2 
infections who are SARS-CoV-2 
seronegative at baseline  
3.   Incidence of laboratory-confirmed SARS-CoV-2 
infections in SARS-CoV-2 seronegative 
subjects starting 14 days after completion of the 
2-dose regimen until 6 months post-dose 2 
4.   Evaluate efficacy of INO-4800 for 12 
months post-dose 2 in subjects who 
are SARS-CoV-2 seronegative at 
baseline  
4a.   Incidence of COVID-19 disease in SARS-CoV-
2 seronegative subjects starting 14 days post-
dose 1 until Day 42 
4b. Incidence of severe or critical COVID-19 disease  
in SARS-CoV-2 seronegative subjects starting 
14 days after completion of the 2-dose regimen 
until End of Study (EOS) 
4c. Incidence of COVID-19 disease in SARS-CoV-2 
seronegative subjects requiring mechanical 
ventilation, ECMO, noninvasive ventilation, or 
high-flow nasal cannula oxygen delivery starting 
14 days after completion of the 2-dose regimen 
until EOS 
4d. Incidence of deaths due to COVID-19 disease in 
SARS-CoV-2 seronegative subjects starting 14 
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days after completion of the 2-dose regimen until 
EOS 
4e. Incidence of laboratory-confirmed SARS-CoV-2 
infections in SARS-CoV-2 seronegative subjects 
starting 14 days after completion of the 2-dose 
regimen until EOS 
5.   Evaluate the short-term efficacy of 
INO-4800 following one dose in 
subjects who are SARS-CoV-2 
seronegative at baseline 
5.  Incidence of COVID-19 disease in SARS-CoV-2 
seronegative subjects starting 14 days post-
dose 1 until 14 days post-dose 2 
6.   Evaluate the timing of symptom 
resolution in subjects who develop 
COVID-19 illness who are SARS-
CoV-2 seronegative at baseline 
6.  Days to symptom resolution in SARS-CoV-2 
seronegative subjects who develop COVID-19 
disease. 
7.   Evaluate the humoral immune 
response to INO-4800 in subjects 
who are SARS-CoV-2 seronegative 
at baseline 
 
7a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody titers in subjects who are SARS-
CoV-2 seronegative at baseline 
7b. Incidence of seroconversion by SARS-CoV-2 
Spike glycoprotein antigen specific binding 
antibody assay in subjects who are SARS-CoV-
2 seronegative at baseline 
3.5 
EXPLORATORY OBJECTIVE 
See Table 5. 
3.6 
EXPLORATORY ENDPOINT 
Table 5: Exploratory Objectives and Associated Endpoints 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Evaluate the expanded 
immunological profile by assessing 
both T and B cell immune 
responses 
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot. 
1b. T cell phenotype (i.e., Th1/Th2/Th17) analysis 
by mRNA expression levels or flow cytometry 
may be conducted. The humoral response may 
also be interrogated by such assays as 
neutralization, ADCC or B cell ELISpot to 
further delineate the functional nature of the 
humoral response.  
3.7 
EFFICACY ASSESSMENT 
Subjects will receive either investigational product (1.0mg INO-4800) or placebo (SSC-
0001) in a 2-dose regimen administered on Days 0 and 28 intradermally followed 
immediately by EP. Subjects will be followed for the duration of the trial by regularly 
scheduled clinic visits and phone calls. Subjects will be routinely tested for SARS-CoV-2 
using saliva and serologic testing. If COVID-19 disease is suspected based on symptoms 
or testing, site personnel will arrange for a clinic visit. Subjects with symptoms that begin 
on or after 14 days post-dose 2 with laboratory confirmation will contribute to the case 
count for the primary endpoint analysis. The DSMB will adjudicate each case of laboratory-
confirmed COVID-19 disease for inclusion in the primary efficacy analysis (see Section 
12.1). 
3.7.1 CASE DEFINITION FOR LABORATORY-CONFIRMED COVID-19 DISEASE: 
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Protocol Version: 1.0 
 
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Case Definition for Mild COVID-19  
• Positive testing by standard RT-PCR assay;  
• Symptoms of mild illness with COVID-19 that could include fever, cough, chills, 
sore throat, malaise, headache, muscle pain, gastrointestinal symptoms such as 
diarrhea, vomiting, and abdominal pain, new loss of taste or smell, without 
shortness of breath or dyspnea; 
• No clinical signs indicative of Moderate, Severe, or Critical Severity (see below).  
Case Definition for Moderate COVID-19   
• Positive testing by standard RT-PCR assay;  
• Symptoms of moderate illness with COVID-19, which could include any symptom 
of mild illness or shortness of breath with exertion;  
• Clinical signs suggestive of moderate illness with COVID-19, such as respiratory 
rate ≥ 20 but < 30 breaths per minute, saturation of oxygen (SpO2) > 93% on 
room air at sea level, heart rate ≥ 90 but < 125 beats per minute;  
• No clinical signs indicative of Severe or Critical Illness Severity.  
Case Definition for Severe COVID-19 
• Positive testing by standard RT-PCR assay;  
• Symptoms suggestive of severe systemic illness with COVID-19, which could 
include any symptom of moderate illness or shortness of breath at rest, or 
respiratory distress;  
• Clinical signs indicative of severe systemic illness with COVID-19, such as 
respiratory rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on 
room air at sea level or PaO2/FiO2 < 300;   
• No criteria for Critical Severity.  
Case Definition for Critical COVID-19  
• Positive testing by standard RT-PCR assay;  
• Evidence of critical illness, defined by at least one of the following:   
o Respiratory failure defined based on resource utilization requiring at least 
one of the following:  
- 
Endotracheal intubation and mechanical ventilation, oxygen 
delivered by high-flow nasal cannula (heated, humidified, oxygen 
delivered via reinforced nasal cannula at flow rates > 20 L/min with 
fraction of delivered oxygen ≥ 0.5), noninvasive positive pressure 
ventilation, ECMO, or clinical diagnosis of respiratory failure (i.e., 
clinical need for one of the preceding therapies, but preceding 
therapies not able to be administered in setting of resource 
limitation)  
o Shock (defined by systolic blood pressure < 90 mm Hg, or diastolic blood 
pressure < 60 mm Hg or requiring vasopressors);  
o Multi-organ dysfunction/failure.  
Case Definition for Suspected COVID-19 Disease  
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• Unavailable, inclusive or negative testing by standard RT-PCR assay without an 
opportunity for testing or retesting; 
• Recent seroconversion by NP-Binding ELISA or CT scan evidence of COVID-19; 
• Clinical symptoms and signs indicative of mild, moderate, severe or critical COVID-19. 
3.7.2 CASE DEFINITION OF “LABORATORY-CONFIRMED SARS-COV-2 INFECTION”; SARS-COV-2 
INFECTION WITHOUT SYMPTOMS  
• Positive testing by standard RT-PCR assay;  
• No clinical signs and symptoms.  
3.8 
SAFETY ASSESSMENT 
Subjects will be followed for safety during the entire duration of trial participation. AEs, 
regardless of relationship to study drug, will be collected from the time of consent until 28 
days post-dose 2. SAEs, MAAEs and AESIs will be collected from time of consent until 
EOS. SAEs, AESIs, and treatment-related AEs will be followed to resolution or 
stabilization.  
Baseline and serial laboratory blood and urine samples will be drawn according to the 
Schedule of Events (Table 2). Subjects will report any potential symptoms of COVID-19 
in real time during the trial and subjects will be followed bi-weekly by visit or phone call.  
3.9 
IMMUNOGENICITY ASSESSMENT 
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 2).  Binding ELISA will be evaluated at serial timepoints.  All subjects will be tested 
for seroconversion as indicative of vaccine-take. Furthermore, the Spike-Binding ELISA 
results will be assessed in order to determine antibody correlates of protection. In addition, 
immune assessments will be conducted to determine additional correlates of protection. 
The correlate can either be mechanistic or non-mechanistic.  Determination of assays, 
timepoints and number of subjects tested will be based on current literature and reagent 
availability. 
4.0 
CLINICAL TRIAL POPULATION 
4.1 
INCLUSION CRITERIA 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, physical 
examination and vital signs performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working, visiting or residing in an environment with high risk of exposure to SARS-
CoV-2 (e.g., civilian and military health care workers or emergency response 
personnel having direct interactions with patients or providing direct care to patients, 
nursing home staff);   
f. Screening laboratory results within normal limits for testing laboratory or deemed not 
clinically significant by the Investigator; 
g. Body Mass Index of 18-30 kg/m2 at Screening; 
h. Negative serological tests for Hepatitis B surface antigen (HBsAg), Hepatitis C 
antibody and Human Immunodeficiency Virus (HIV) antibody or rapid test at 
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screening (subjects who are positive for Hepatitis C antibody but are in remission as 
defined by undetectable HCV RNA level ≥ 12 weeks after completion of HCV therapy 
may be enrolled) 
i. 
Must meet one of the following criteria with respect to reproductive capacity: 
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or tubal 
ligation, absence of ovaries and/or uterus in females). In the case of vasectomy, 
subjects should wait six (6) months post-vasectomy prior to enrolling;  
• 
Use of medically effective contraception with a failure rate of < 1% per year when 
used consistently and correctly from screening until 3 months following last dose. 
Acceptable methods include:  
o hormonal contraception including implants, injections or oral; 
o two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
‒ 
abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
4.2 
EXCLUSION CRITERIA 
a. Acute febrile illness with temperature > 100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat);  
b. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the screening visit until 
3 months following the last dose; 
c. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
d. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0; 
e. Previous receipt of an investigational vaccine for prevention or treatment of COVID-
19, MERS or SARS; 
f. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring medical evaluation and/or treatment within the past 5 years; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, resting systolic blood pressure >150 mm Hg or a 
resting diastolic blood pressure >95 mm Hg at Screening; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 7.0%); 
• 
Malignancy within the past 5 years, with the exception of superficial skin cancers 
that only required local excision; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring medical evaluation 
and/or treatment within the past 5 years; 
• 
History of seizures within the past 5 years with the use of no more than a single 
antiepileptic agent; 
g. Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies; 
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• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed); 
• 
Current or anticipated use of disease modifying doses of anti-rheumatic drugs 
(e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic 
disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, adalimumab or 
etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of receipt of any other clinically significant immunosuppressive drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the subject 
or require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
h. Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation site; 
i. 
Blood donation within 1 month prior to Day 0; 
j. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
k. Reported ongoing smoking or vaping; 
l. 
Reported alcohol or substance abuse/dependence within the past 5 years; 
m. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
4.3 
DISCONTINUATION/WITHDRAWAL OF CLINICAL TRIAL SUBJECTS 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the Investigator should any untoward effect occur. In addition, the 
Investigator or the Sponsor has the right to discontinue a subject from the trial at any time. 
The Investigator must notify the Sponsor immediately when a subject has been 
discontinued/withdrawn due to an Adverse Event (AE). If a subject withdraws from the trial 
or is discontinued from the trial prior to trial completion, all applicable activities scheduled 
for the final trial visit (i.e., Day 393) should be performed at the time of 
discontinuation/withdrawal. Any related AEs, AESIs, and/or Serious Adverse Events 
(SAEs) present at the time of discontinuation/withdrawal should be followed in accordance 
with the safety requirements outlined in Section 7.9. 
Unless a subject refuses to continue participation, all follow-up visits and procedures 
should be completed as indicated in the Schedule of Events (Table 2) following the second 
dose whether or not the subject has completed both doses. 
 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. In cases where 
the subject does not return for the rescheduled visit or cannot be reached to reschedule 
the missed visit, the site should make every effort to regain contact with the subject (3 
telephone calls and if that fails, then a certified letter to the subject’s last known mailing 
address) so that the subject’s disposition can be considered as withdrawn from the study 
(i.e. lost to follow-up). If the contact with subject is re-established, site should contact 
medical monitor to discuss whether subject can continue study treatment or follow-up 
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visits for the study. For all other subjects withdrawing from the study, an alternative reason 
for discontinuation should be recorded in the eCRF. 
 
Reasons for discontinuation/withdrawal from the trial may include but are not limited to the 
following: 
• 
Subject withdrawal of consent at any time; 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardize the 
subject’s safety if he or she continues in the trial; 
• 
Investigator, DSMB or Sponsor determines it is in the best interest of the subject; 
• 
Subject non-compliance. 
Every effort should be made to obtain information on subjects who withdraw from the trial. 
The primary reason for withdrawal from the trial should be documented on the appropriate 
CRF. However, subjects will not be followed for any reason after consent has been 
withdrawn. Data and/or samples collected prior to withdrawal of consent will be analyzed.  
 
Reasons for discontinuing subject dosing may include but are not limited to the following: 
• 
Adverse Event (Adverse Reaction); 
o The Investigator or trial coordinator must notify the Sponsor immediately 
when a subject has been discontinued/withdrawn due to an Adverse Event 
(AE). 
• 
Any medical condition that may jeopardize the subject’s safety if he or she 
continues on trial; 
• 
Pregnancy. 
5.0 
CLINICAL TRIAL INVESTIGATIONAL PRODUCT INFORMATION 
5.1 
INVESTIGATIONAL PRODUCT (IP) AND STUDY DEVICE 
5.1.1 INO-4800 AND PLACEBO 
Investigational product is defined as a pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in the study, whether blinded or unblinded. 
INO-4800 is the active investigational product to be used in this study. The INO-4800 drug 
product contains 10 mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM 
sodium chloride and 15 mM sodium citrate). pGX9501 is a DNA plasmid expressing a 
synthetic consensus (SynCon®) sequence of the SARS-CoV-2 full length Spike 
glycoprotein. 
A volume of 0.4 mL will be filled into 2-mL glass vials that are fitted with rubber stoppers 
and sealed aluminum caps. 
Sterile saline sodium citrate (SSC) buffer (SSC-0001), which contains sterile 150 mM 
sodium chloride and 15 mM sodium citrate in 10-mL glass vials, stoppered, and sealed 
with aluminum caps, will be used as the placebo. 
 
5.1.2 CELLECTRA® 2000 
The CELLECTRA® 2000 is a portable, battery-powered medical device designed to 
generate a minimally-controlled, electric field which temporarily and reversibly increases 
cellular membrane permeability without damaging the tissue. During the period of 
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increased permeability an indicated injected plasmid DNA formulation can be introduced 
into the cells. 
The CELLECTRA® 2000 device is indicated to enhance the uptake and expression of DNA 
plasmid-based biologics in order to enhance vaccine efficacy. The DNA plasmid is 
delivered separately via needle and syringe injection immediately prior to the 
electroporation. The electroporation is accomplished through a sterile, disposable needle 
Array attached to an Applicator delivering current controlled electrical pulses as follows: 
• 
An EP treatment consists of four pulses. 
• 
An Array of three stainless steel electrode needles is used to deliver the electrical 
pulses into the tissue. 
• 
Voltage levels are limited to 200 volts (V) for patient safety.  
• 
The specified current is constantly maintained through voltage modulation using 
an analog feedback loop. Measurements of voltage and current are processed for 
error reporting and collected for data logging. 
The CELLECTRA® 2000 device for ID administration is comprised of three components: 
(1) A battery-powered Pulse Generator, (2) an ID Applicator that is connected to the pulse 
generator, and (3) a three-point sterile disposable ID Array of stainless steel needles. 
5.2 
DOSING REGIMENS 
• 
Investigational Product: A single 1.0mg ID injection of INO-4800 (~0.1mL dose 
volume) followed immediately by EP administered at Day 0 and Day 28 (±3 days) 
• 
Placebo: A single ID injection of SSC-0001 (~0.1mL) followed immediately by EP 
administered at Day 0 and Day 28 (±3 days) 
5.2.1 BLINDING 
This study is double-blinded. The Sponsor, subjects and clinical site staff, with the 
exception of the site’s pharmacy personnel will be blinded throughout the trial. There is no 
difference in appearance for both the INO-4800 product and the placebo; however, they 
are packaged in different sized vials. To maintain the blind, vials will only be handled by 
designated unblinded personnel (site pharmacist) at the site. 
The PI may request to unblind a subject’s dose assignment in case of an emergency or 
serious medical condition when knowledge of the study product or dose is essential for 
proper clinical management of the subject, as judged by the PI. It is preferred, but not 
required, that the PI first contact the Medical Monitor (MM) to discuss options before 
unblinding the subject’s dose assignment. In case of non-emergency, PI must contact MM 
to discuss the options before unblinding the subject’s dose assignment. 
The Sponsor’s pharmacovigilance staff may unblind a subject’s dose assignment for an 
SAE, unanticipated adverse device effect (UADE), or adverse event of special interest 
(AESI) when the event is assessed as related and unexpected. If expedited regulatory 
reporting is required for an event, the report may be submitted to regulatory authorities 
with the subject’s dose assignment, in accordance with local regulations. 
5.3 
PACKAGING AND LABELING 
5.3.1 INO-4800 OR PLACEBO 
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Each vial of INO-4800 or placebo will be labeled consistent with the example product label 
provided in the Investigator’s Brochure (IB).  
5.3.2 CELLECTRA® 2000 
Please see shipping box for shipping documents and contents. 
The CELLECTRA® 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer. The CELLECTRA® 2000 User Manual 
describes all relevant contraindications, hazards, potential risks and adverse effects, 
interfering substances or devices, warnings, and precautions. Each Pulse Generator has 
a unique serial number, and each ID Applicator has a unique serial number. Each ID Array 
has a Lot Number and Expiration Date. Examples of device labels are provided in the IB. 
The CELLECTRA® 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. 
5.4 
HANDLING AND STORAGE 
5.4.1 INO-4800 AND PLACEBO 
INO-4800 and Placebo will be shipped at 2–8°C. If the temperature monitoring devices in 
the shipping container(s) denote temperatures outside this 2–8°C (36-46°F) range, the 
Sponsor, or its designee, should be contacted immediately. 
Upon arrival, it must be transferred from the shipping container into 2–8°C (36-46°F) 
storage, in a secure area, in accordance with local regulations by designated personnel 
(e.g., pharmacy personnel). The Sponsor must be notified of any deviations from this 
storage condition. Refrigerator temperature logs must be maintained at the clinical site 
and temperatures must be recorded and monitored regularly. For further details see 
Pharmacy Manual and IB. 
5.4.2 CELLECTRA® 2000 
See User Manual for operating and storage conditions. 
5.5 
PREPARATION AND DISPENSING 
INO-4800 is supplied in 2-mL vials at a concentration of 10 mg/mL at a minimum volume 
of 0.4 mL. SSC-0001 is supplied in 10-mL vials at a minimum volume of 2 mL.  
Blinded staff involved in the clinical execution of the study should not come in contact with 
vials of INO-4800 or SSC-0001. Vials will only be handled by designated unblinded 
personnel (e.g., pharmacy) at the site. When a participant is eligible for enrollment, 
unblinded personnel will draw INO-4800 or SSC-0001 into a blinded syringe in accordance 
with the subject’s randomized treatment assignment according to a randomization 
schedule. The syringe will be transferred to blinded site personnel for administration.  
Each INO-4800 and placebo vial will contain a volume of product sufficient to dose multiple 
subjects. The preparation and dispensing information will be provided in the Pharmacy 
Manual. 
5.6 
USE OF STUDY DEVICE 
The instructions for use of the CELLECTRA® 2000 device are provided in the User 
Manual. Each clinical site will receive training for use of the CELLECTRA® 2000 device 
prior to first dose.  
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The EP procedure must be performed by qualified personnel. Any individual designated 
to perform the procedure should be permitted by the relevant local authorities to administer 
parenteral injections to patients (e.g., MD, DO, RN) in addition to successfully completing 
device training from Sponsor personnel.  
5.7 
INVESTIGATIONAL DRUG AND STUDY DEVICE ACCOUNTABILITY 
5.7.1 INVESTIGATIONAL PRODUCT (IP) ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current accountability record of 
investigational products (INO-4800 or placebo) is maintained at the study site. The 
investigational products must have full traceability from the receipt of the products through 
subject use, disposal or return of the products. Records or logs must comply with 
applicable regulations and guidelines. The accountability information is provided in the 
Pharmacy Manual. 
5.7.2 CELLECTRA® 2000 ACCOUNTABILITY 
The investigative site is responsible for maintaining device accountability logs. The device 
must have full traceability from the receipt of the products through subject use, disposal 
or return of the products. The site must document acknowledgement of receipt and notify 
Inovio upon receipt of study devices. This includes the content shipped and condition upon 
receipt. 
For each subject administration, there must be a record of each product used for that 
subject, i.e., Pulse Generator serial number, ID Applicator serial number, and ID Array lot 
number. The ID Applicator is reusable with a new ID Array and sheath for each procedure. 
The sterile ID Array and sheath are single use only and must be discarded after use in 
accordance with institutional policy regarding disposal of sharp needles/instruments. 
5.8 
RETURN AND DESTRUCTION OF INVESTIGATIONAL DRUG AND STUDY DEVICE 
5.8.1 INO-4800 AND PLACEBO 
Upon completion or termination of the study, all unused vials of INO-4800 or placebo must 
be destroyed at the study site in accordance with institution policy or returned to Inovio 
Pharmaceuticals, Inc., or its designee if the site cannot destroy IP. 
The used vials of INO-4800 and placebo will be discarded in accordance with the site’s 
used IP disposal procedure. It is the Investigator’s responsibility to arrange for disposal of 
all empty vials, provided that procedures for proper disposal have been established in 
accordance with applicable national, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. If requested by the Sponsor, the 
return of unused IP vials should be arranged by the responsible Inovio Representative. 
The unused IP vials should only be destroyed after being inspected and reconciled by the 
responsible Inovio Pharmaceuticals, Inc., personnel or designated Clinical Monitor. If IP 
vials are returned to Inovio Pharmaceuticals, Inc., or its designee, the IP must be 
accompanied by the appropriate documentation. The return of unused IP(s) should be 
arranged with the responsible Inovio personnel and/or Clinical Monitor. 
5.8.2 RETURN OF CELLECTRA® 2000 
Upon completion or termination of the study, an Inovio Representative will provide 
instructions regarding the component(s) to be returned to Inovio Pharmaceuticals, Inc., 
destroyed onsite or shipped to a destruction vendor. 
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All product returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original containers. 
The return of all product identified above should be arranged by the Inovio Representative. 
The ID Arrays should be discarded in the sharps container immediately after use. The 
used ID Applicators can either be destroyed at the site, shipped to a destruction vendor, 
or returned to Inovio. If the used ID Applicators are destroyed on site, it is the Investigator’s 
responsibility to ensure that arrangements have been made for the disposal, written 
authorization has been granted by Inovio Pharmaceuticals, Inc., or its designee, 
procedures for proper disposal have been established in accordance with applicable 
regulation and guidelines and institutional procedures, and appropriate records of the 
disposal have been documented. 
6.0 
CLINICAL TRIAL PROCEDURES AND SCHEDULE 
The Schedule of Events (36TTable 236T) in the Clinical Protocol Synopsis summarizes the 
procedures to be performed at each visit. Individual procedures are described in detail 
below. It may be necessary to perform these procedures at unscheduled time points if 
deemed clinically necessary by the Investigator. A subject will be required to provide 
informed consent (Section 6.2) prior to any study procedure being performed. Protocol 
waivers or exemptions will not be granted. Therefore, adherence to the study design and 
assessments are essential and required for study conduct. 
6.1 
PROCEDURE BY VISIT 
Refer to Sections 6.1.1 and 6.1.2 for trial procedures and the times at which they are to 
be performed. 
6.1.1 CLINICAL TRIAL SCREENING EVALUATIONS 
The assessments performed during Screening will determine the subject’s eligibility for 
the study and also their ability to comply with protocol requirements by completing all 
screening assessments. Subjects’ post-menopausal status must meet requirements as 
specified in the inclusion criteria. The following screening evaluations will be performed 
within 30 days prior to dosing on Day 0. All screening assessment values must be 
reviewed prior to the first Study IP administration.  
If a subject does not meet an inclusion or exclusion criterion due to a transient and non-
clinically significant event at Screening, relevant Screening evaluations may be repeated 
within the same 30 day Screening period. If the subject fails twice, they will be considered 
a screen failure. 
• 
Signed and dated informed consent (Section 6.2); 
• 
Review and confirm all inclusion/exclusion criteria (Section 4.1 and 4.2); 
• 
Obtain and document complete medical history, surgical history (including all 
clinically significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Section 6.1.1.1); 
• 
Collect demographics and document any ongoing, pre-existing conditions; 
• 
Collect adverse events (Section 6.4.4); 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Full physical examinations (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Record height and weight (Section 6.4); 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
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• 
Collect blood for serum pregnancy test (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing, HIV, Hepatitis B surface antigen 
(HBsAg) and Hepatitis C serology (Section 6.4) per national guidelines; 
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.9). 
6.1.1.1 
Medical History 
A medical history will be obtained by the Investigator or qualified designee at the time of 
Screening. Medical history will include all active conditions, and any other past conditions, 
as well as surgical procedures, that are considered to be clinically significant by the 
Investigator and/or occurred within the 12 weeks prior to Screening. Illnesses first 
occurring or detected after the signing of the informed consent, or during the study and/or 
worsening of an existing illness in severity, frequency or nature after signing of the 
informed consent are to be documented as AEs on the CRF. Prior treatments, defined as 
administered up to 12 weeks prior to the time of informed consent and stopped prior to 
dosing on Day 0, should be recorded in the CRF as prior medications. Concomitant 
treatments, defined as continuing on Day 0 or new treatments taken at or after Day 0, 
should be recorded in the CRF as concomitant medications. 
6.1.2 CLINICAL TRIAL EVALUATIONS AND PROCEDURES 
Once eligibility has been confirmed, the subject will be randomized to receive a treatment 
assignment (investigational product or placebo). Visit dates and windows must be 
calculated from Day 0, unless otherwise noted. All subjects will be followed until the Day 
393 Visit. All subjects will be followed in accordance with assessments outlined below. 
6.1.2.1 
Day 0 and Day 28 (Dosing Visits) 
The following evaluations will be performed on Day 0 and Day 28 prior to dose 
administration: 
• 
Collect all present and/or new or ongoing adverse events (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect urine for urine pregnancy test (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6); 
• 
Review restrictions for injection and EP (Section 6.4.8); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.9); 
• 
Randomize subject (instructions to be provided under separate cover). 
 
The following evaluations will be performed on Day 0 and Day 28 after IP plus EP 
administration: 
• 
Collect any new adverse events (Section 6.4.4); 
• 
Download EP Data (Section 6.4.1.1). 
6.1.2.2 
Day 7 and Day 42 (post-dose visits) 
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing adverse events (Section 6.4.4); 
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• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.9); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6). 
6.1.2.3 
Phone calls (Days 35, 70, 98, 112, 126, 140, 168, 182, 196, 224, 238, 252, 
280, 294, 308, 336, 350, 364, and 378) 
Phone calls to subjects have been spaced bi-weekly between study visits for the 
duration of the trial.  The following evaluations will be performed during the phone call: 
• 
Collect all present and/or new or ongoing adverse events (Section 6.4.4); only 
SAEs, AESIs and MAAEs will be collected after the Day 56 Visit; 
• 
Arrange on-site visit if there are any signs and symptoms of COVID-19 disease; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Remind subject to self-collect saliva sample and ship to designated laboratory 
(Section 6.4.9). 
6.1.2.4 
Day 56 Visit 
The following evaluations will be performed at this visits: 
• 
Collect all present and/or new or ongoing adverse events (Section 6.4.4);  
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.9); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6); 
6.1.2.5 
Days 84, 154, 210, 266, 322 Visits and Day 393 Visit 
The following evaluations will be performed at these visits: 
• 
Collect all present and/or new or ongoing adverse events (Section 6.4.4); SAEs, 
AESIs, and MAAEs will be collected at these visits. 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Days 84, 154, 210, 266, 322) or full physical 
examination (Day 393, EOS) (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect urine pregnancy test at Day 393 visit only (Section 6.4); 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
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• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.9); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6); 
6.1.2.6 
Suspected COVID-19 Assessment Visit 
Subjects will be evaluated during a “Suspected COVID-19 assessment visit” when acute 
COVID-19 is suspected based on symptoms or positive SARS-CoV-2 testing. The 
laboratory-confirmation of a case will be based on SARS-CoV-2 RT-PCR. Additional 
safety testing will be collected to understand the impact on various organ systems. 
Additional diagnostic testing (e.g., influenza diagnostics) may be ordered at the discretion 
of the Investigator. The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing adverse events (Section 6.4.4); Only 
SAEs, AESIs and MAAEs will be collected at visits after Day 56; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record clinical signs and symptoms; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect nasopharyngeal, oropharyngeal swabs and saliva for SARS-CoV-2 RT-
PCR detection. 
6.2 
INFORMED CONSENT 
All subjects must sign the informed consent prior to participating in any clinical trial-related 
procedures. The informed consent documentation must be in compliance with applicable 
regulations and GCP. Qualified clinical trial personnel will: 
• 
Meet with prospective clinical trial subjects 
• 
Explain the clinical trial 
• 
Provide clinical trial subjects with an Informed Consent Form (ICF) that includes the 
following in a language that is understandable to the subject: 
• 
Screening test(s) description 
• 
Eligibility criteria for entering the clinical trial 
• 
Clinical trial treatments and follow-up procedures description 
• 
Explanation of the clinical trial, including but is not limited to: 
• 
Clinical trial objectives 
• 
Potential benefits and risks 
• 
Discomforts/inconveniences 
• 
Subject’s rights and responsibilities 
The subject or subject’s legally authorized representative is then requested to sign and 
date the ICF. A copy of the signed informed consent documentation must be provided to 
the subject or subject’s legally authorized representative. The qualified clinical trial 
personnel will document the process of obtaining informed consent within the source 
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record. Signed ICFs are maintained in the subject’s source records and must be 
accessible for verification at any time. Signing of the ICF begins the 30 day screening 
period. 
6.3 
ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number (SID), 
which identifies the subject for all clinical trial-related procedures. SIDs are a combination 
of a four digit site code and a four digit subject number starting with 0001. After SIDs are 
assigned, they cannot be reused or reassigned for any reason. Information regarding the 
SID and screen date will be documented on a screening and enrollment log/system and 
in the Case Report Form (CRF). 
6.4 
SAFETY EVALUATIONS 
PHYSICAL AND TARGETED PHYSICAL EXAM  
A full physical examination will be conducted during Screening and at study 
discharge/EOS (e.g. Day 393). A targeted physical assessment will be performed at other 
visits as determined by the Investigator or directed per subject complaints. 
VITAL SIGNS 
Vital signs including temperature, respiration rate, blood pressure and heart rate will be 
measured at Screening and at visits specified in the Schedule of Events (36TTable 236T).  
HEIGHT AND WEIGHT 
Weight (kg) and height (cm) will be collected at Screening. 
LABORATORY EVALUATIONS 
At Screening and at visits specified in the Schedule of Events (36TTable 236T), blood samples 
will be collected for safety assessments. Approximately 680 mL of blood will be drawn 
from each subject over the course of the study. Subjects may be asked to return for 
additional blood draws if collected blood sample is lost or unevaluable for any reason. 
Hematology [Complete blood count (CBC) with automated differential]: 
White blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit and 
platelet count will be measured at Screening and at visits specified in the Schedule of 
Events (36TTable 236T). 
Serum chemistry: 
Electrolytes [Sodium (Na), Potassium (K), Chloride (Cl), Bicarbonate (HCO3), Calcium 
(Ca), Phosphate (PO4)], glucose, BUN (blood urea nitrogen), Creatinine (Cr),  alkaline 
phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), LDH,  
total bilirubin (TBili), and hemoglobin A1c at Screening and at visits specified in the 
Schedule of Events (36TTable 236T). Hemoglobin A1c will only be performed at Screening. 
Urinalysis:  
Urine samples will be tested by dipstick for glucose, protein, and hematuria at Screening 
and at visits specified in the Schedule of Events (36TTable 236T). If abnormal (presence of 
protein, hematuria, or glucose ≥ 1+), a microscopic examination should be performed.  
Serology: 
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Antibodies to Hepatitis B surface antigen (HBsAg), Hepatitis C antibody and HIV antibody 
or rapid test will be measured at Screening only. Antibodies to SARS-CoV-2 will be 
measured at Screening and at visits specified in the Schedule of Events (Table 2). 
Pregnancy Testing:  
For women of child bearing potential (WOCBP), a serum pregnancy test will be obtained 
at Screening and a urine pregnancy test will be performed immediately prior to any dosing 
and at the subject’s last visit. A negative result for urine β-HCG (test must have a sensitivity 
of at least 25 mIU/mL) must be available prior to each administration of IP. If the β-HCG 
test is positive, indicating that the subject is pregnant prior to completing the specified 
dose regimen, then no further IP will be administered. Every attempt should be made to 
follow pregnant subjects for the remainder of the study and to determine the outcome of 
the pregnancy. 
6.4.1 INJECTION AND EP  
Subjects will receive a two-dose regimen of INO-4800 or placebo by ID injection in a 
volume of ~0.1 mL in an acceptable skin location for injection and subsequently followed 
immediately by EP with CELLECTRA® 2000 at Day 0 and Day 28.  
 
Only if the deltoid area is not a suitable location (see exclusion criterion ‘f’), the ID injection 
can then be administered above the lateral quadriceps followed immediately by EP. IP 
must not be given within 2 cm of a tattoo, scar, keloid, or active lesion/rash. Also, ID 
injection followed immediately by EP must not be performed on the skin of an extremity 
which has any metal implants or implantable medical device (e.g., surgical rods, pins or 
joint replacements). If a subject has an implanted cardiac defibrillator or pacemaker, ID 
injection/EP must not be performed above the deltoid muscle on the same side of the body 
where the device is located. 
6.4.2 MANAGEMENT OF PAIN DUE TO ELECTROPORATION (EP) PROCEDURES 
In case of pain, subjects may be treated with a non-narcotic analgesic (e.g., 
acetaminophen) after injection/EP.  
Medication taken for pain management will be documented as concomitant medications. 
6.4.3 ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry and hematology and urinalysis will be performed 
at the visits listed in the Schedule of Events (36TTable 236T) and as listed in Section 6.4.  
Laboratory AEs will be assessed and graded in accordance with the “Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials”, issued in September 2007 (Appendix A). Laboratory values that are not clinically 
significant (NCS) in the Investigator’s opinion will not be reported as adverse events. 
6.4.4 ASSESSMENT OF CLINICAL TRIAL ADVERSE EVENTS (AES) 
Subjects will be queried regarding the occurrence of any adverse events including adverse 
events related to injection site reactions, concomitant medications and new onset illness or 
disease during their study visits and phone calls. Subjects will be reminded to contact study 
personnel and immediately report any event for the duration of the study. All adverse events will 
be captured from the time of the informed consent until 28 days post-dose 2. Following the Day 
56 visit, only SAEs, AESIs and MAAEs will be collected. All related AEs, AESIs and SAEs will 
be followed to resolution or stabilization. These events will be recorded on the subject’s CRF. 
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6.4.5 ASSESSMENT OF INJECTION SITE REACTIONS  
The IP administration procedure consists of an ID injection (formation of a wheal) of IP 
followed by insertion of the ID Array needles (electrodes) through the skin and into the 
wheal followed by delivery of the electroporation pulses. This procedure is broadly 
described as administration because it involves more than the injection of a drug. 
Consequently, reactions arising from the IP administration procedure may be reported as 
administration site or injection site reactions. When evaluating administration (injection) 
site reactions throughout the study, it is most important to be as specific as possible by 
selecting the most appropriate term (see Table 6 below) and use the grading scale as 
listed in the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials, issued September 2007 (Appendix A). Administration 
(injection) site reactions and administration site pain will be evaluated starting 30 minutes 
following injection/EP. In addition, other events associated with administration (injection) 
site reactions (e.g., hematoma, infection or necrosis) should also be reported with 
preferred terms specific for administration (injection) site reactions.  
Table 6: Grading Scale for Injection Site Reactions 
Local Reaction to 
Injectable Product 
(Grade) 
Mild (1) 
Moderate (2) 
Severe (3) 
Potentially 
Life 
Threatening 
(4) 
Pain 
Does not 
interfere with 
activity 
Repeated use 
of non-
narcotic pain 
reliever >24 
hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency 
room visit or 
hospitalization 
Tenderness 
Mild 
discomfort to 
touch 
Discomfort 
with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/Rednessa 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swellingb 
2.5-5 cm and 
no 
interference 
w/ activity 
5.1-10 cm or 
interferes with 
activity 
>10 cm or 
prevents daily 
activity 
Necrosis 
September 2007 “FDA Guidance for Industry-Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
a In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable 
b Should be evaluated and graded using the functional scale as well as the actual measurement. 
6.4.6 PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at specified in the Schedule of Events 
(36TTable 236T) for cellular and humoral immunology assessments. Baseline (Day 0) 
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immunology samples are required to enable all immunology testing. Therefore a total of 
68mL whole blood and 8mL serum is required prior to 1st dose. Details of the immunology 
sample collection and shipment information will be provided in the Laboratory Manual. The 
T and B cell immune responses to INO-4800 will be measured using assays that include 
but are not limited to ELISA, neutralization, assessment of immunological gene 
expression, assessment of immunological protein expression, flow cytometry and 
ELISPOT. In addition, humoral responses to SARS-CoV-2 Nucleocapsid Protein (NP) may 
also be assessed to rule out potential infection by wild-type SARS-CoV-2 post INO-4800 
treatment during the trial. Determination of analysis of collected samples for 
immunological endpoints will be determined on an ongoing basis throughout the trial. 
6.4.7 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken at the time of Screening and 
ongoing from signing of the informed consent to study discharge that do not affect a 
subject’s eligibility for participation (see Section 4.2) must be recorded on CRFs. 
Actual or estimated start and stop dates must be provided. This information will be 
obtained from the subject and abstracted from any available medical records. The 
indication for the medication, dose, and dose regimen will be documented.  
Therapy considered necessary for the subject’s welfare may be given at the discretion of 
the Investigator. If the permissibility of a specific medication/treatment is in question, 
please contact the Sponsor. 
The decision to administer a prohibited medication/treatment (Section 6.4.8) is made with 
the safety of the clinical trial subject as the primary consideration. When possible, the 
Sponsor should be notified before the prohibited medication/treatment is administered. 
6.4.8 RESTRICTIONS  
Subjects should refrain from becoming pregnant until 3 months following the last dose of 
investigational product by using appropriate contraceptive measures (see Section 4.1). 
Subjects must not receive any non-study related vaccine (e.g., influenza vaccine) within 2 
weeks prior to the first dose of IP, or within 2 weeks of (before or after) any subsequent 
dose of IP.  
Subjects must not have fever (oral temperature >38.0 degrees Celsius or 100.4 degrees 
Fahrenheit) within 72 hours prior to each dosing. 
Subjects should refrain from donating blood from Screening visit through the duration of 
the trial. 
Subjects must not receive disease modifying doses of anti-rheumatic drugs (e.g., 
azathioprine, cyclophosphamide, cyclosporine, methotrexate), biologic disease modifying 
drugs such as TNF-α inhibitors (e.g., infliximab, adalimumab or etanercept) and long term 
use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of prednisone 
equivalent (use of inhaled, topical, nasal, otic, and ophthalmic corticosteroids are allowed).  
6.4.9 SARS-COV-2 TESTING 
Serology SARS-CoV-2 antibody testing will be used during screening to test for previous 
SARS-CoV-2 infection and during each subsequent visit (see Table 2: Schedule of 
Events) to identify SARS-CoV-2 infections that may occur regardless of symptoms 
between study visits. 
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SARS-CoV-2 RT-PCR testing will be conducted on saliva specimens collected at 
Screening and during study visits (see Table 2: Schedule of Events) with bi-weekly home 
self-collections, when possible, between study visits. The Day 0 and Day 28 RT-PCR 
results will not be required prior to dosing on that day. 
If either the SARS-CoV-2 antibody or RT-PCR test result is positive during the trial, the 
subject will be notified of the result and will be requested to come to the clinic for an 
evaluation.  During that visit, a blood sample will be collected for serologic testing and 3 
specimens (nasopharyngeal swab, oropharyngeal swab and saliva) will be collected to 
detect SARS-CoV-2 using the RT-PCR assay. If acute SARS-CoV-2 infection is 
diagnosed regardless of symptoms, serial saliva samples will be collected every 2 days 
for 20 days for quantitative SARS-CoV-2 RT-PCR testing to assess the viral load..  
6.4.10 COVID-19 DISEASE MONITORING 
All subjects will be monitored through regularly scheduled clinic visits and phone calls for 
the development of symptoms suggestive of COVID-19 disease. Site personnel will 
arrange for a clinic visit for subjects reporting symptoms suggestive of COVID-19 (e.g., 
fever, cough, chills, sore throat, malaise, headache, muscle pain, gastrointestinal 
symptoms such as diarrhea, vomiting, and abdominal pain, shortness of breath or 
dyspnea, New loss of taste or smell)) at any time during the study. During that visit, a 
blood sample will be collected for serologic testing and 3 specimens (nasopharyngeal 
swab, oropharyngeal swab and saliva) will be collected to detect SARS-CoV-2 using the 
RT-PCR assay. Diagnosis of COVID-19 will be made by the investigator according to the 
case definitions (See Section 3.7.1) and recorded on the CRF.  
If the specimens are RT-PCR negative, a diagnosis of influenza has been ruled out, and 
COVID-19 remains a possible diagnosis, the RT-PCR assay may be repeated. 
Furthermore, SARS-CoV-2 RT-PCR detection may be performed on sputum, 
endotracheal aspirate or bronchoalveolar lavage samples, if available. Pulmonary CT 
scan findings showing typical interstitial pneumonia including ground-glass opacities may 
corroborate the diagnosis of COVID-19 disease. The formal radiologist’s interpretation of 
the CT scan should be included as a source document. Diagnosis of COVID-19 will be 
made by the investigator according to the case definitions (See Section 3.7.1) and 
recorded on the CRF. If SARS-CoV-2 infection or COVID-19 is diagnosed, saliva samples 
will be collected every 2 days for 20 days for SARS-CoV-2 RT-PCR testing. 
Subjects with a confirmed COVID-19 diagnosis after dose 1 will be discontinued from 
further dosing and will be followed until EOS for safety and resolution of COVID-19. 
Recovery from  COVID-19 disease requires resolution of clinical symptoms and a 
minimum of two consecutive negative nasopharyngeal swabs collected at least 24 hrs 
apart..    
7.0 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
The safety of INO-4800 will be measured and graded in accordance with the “Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials”, issued September 2007 (Appendix A). 
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7.2 
ADVERSE EVENTS (AES) 
Any untoward medical occurrence in a patient or clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.  
Adverse Events (AEs) include the following: 
• Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (before the administration of clinical trial drug) 
• Any pre-existing condition that increases in severity, or changes in nature during or as 
a consequence of the clinical trial drug administration phase 
• Complications of pregnancy (refer to Section 7.11) 
Adverse Events (AEs) do not include the following: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; however, the condition that leads to the procedure is an AE 
• Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the Screening Visit that do not worsen 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions) 
• Overdose without clinical sequelae 
• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed, is not an AE; it is considered to be pre-existing and will be 
documented on the medical history CRF 
• Uncomplicated pregnancy 
• An induced elective abortion to terminate a pregnancy without medical reason 
• Laboratory-confirmed COVID-19 disease  
7.2.1 LABORATORY-CONFIRMED COVID-19 DISEASE AND SEVERE COVID-19 DISEASE 
The DSMB will adjudicate COVID-19 cases. Details are provided in the DSMB Charter. 
The endpoint of laboratory-confirmed COVID-19 disease and severe COVID-19 disease is 
recorded in the CRF. The endpoint is not recorded as an AE or SAE. 
7.3 
ADVERSE DRUG REACTION (ADR) 
All noxious and unintended responses to a medicinal product related to any dose. This 
means that a causal relationship between the medicinal product and an adverse event is 
at least a reasonable possibility (i.e., the relationship cannot be ruled out). 
7.4 
SERIOUS ADVERSE EVENTS (SAES) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death  
• Is life-threatening 
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o Refers to an event in which the subject was at risk of death at the time of the event. 
It does not refer to an event which hypothetically might have caused death if it 
were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
o Includes any hospitalization in which the subject has been admitted to the hospital 
regardless the length of stay, even if the hospitalization is only a precautionary 
measure to allow continued observation. However, hospitalization (including 
hospitalization for an elective procedure) for a pre-existing condition that has not 
worsened, does not constitute an SAE. 
• Results in persistent or significant disability/incapacity 
o A substantial disruption of a person's ability to conduct normal life functions (i.e., 
the adverse event resulted in a significant, persistent or permanent change, 
impairment, damage or disruption in the subject’s body function/structure, physical 
activities and/or quality of life). 
• Results in congenital anomaly or birth defect and/or 
• An important medical event  
o An event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
Clarification of Serious Adverse Events (SAEs) 
• Death in itself is not an AE. Death is an outcome of an AE, but when the cause of death 
has not been provided, use the event term: death of unknown cause. 
• COVID-19 disease with an outcome of death is recorded as an endpoint, and not 
recorded as an SAE. 
• The subject may not have been receiving an investigational medicinal product at the 
occurrence of the event. 
• Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is an SAE. 
7.5 
UNEXPECTED ADVERSE DRUG REACTION 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator’s Brochure [IB] for an unapproved investigational 
product, package insert/summary of product characteristics for an approved product). 
7.6 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects.  
A UADE is a type of SAE that requires reporting to the Sponsor in accordance with Section 
7.9. 
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7.7 
DEVICE DEFICIENCY 
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance. 
Note: Device deficiencies include malfunctions, use errors and inadequate labelling. 
7.8 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor is responsible for the overall safety monitoring of the clinical trial. 
Safety monitoring assessments include but are not limited to:  
• Incidence of all adverse events classified by system organ class, preferred term, 
severity and causal relationship to clinical trial treatment 
• Changes in laboratory parameters 
• Local and systemic injection site review; special attention will be paid to the examination 
of the injection site 
7.8.1 ADVERSE EVENT OF SPECIAL INTEREST (AESI)  
An adverse event of special interest (serious or non-serious) is one of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the PI to the Sponsor can be appropriate.  
For the purpose of this clinical trial, the AESIs listed in Appendix B are to be reported to 
the Sponsor in accordance with Section 7.9. 
7.8.2 MEDICALLY ATTENDED ADVERSE EVENT (MAAE) 
A medically attended adverse event (serious or non-serious) is defined as an adverse 
event that leads to an unplanned contact with a health care provider. 
7.8.3 ABNORMAL LABORATORY VALUE 
The PI will annotate each abnormal lab value as clinically significant (CS) or not clinically 
significant (NCS). 
Laboratory values that are NCS in the PI’s opinion should not be reported as an adverse 
event. 
Any abnormal laboratory value that is new in onset or worsened in severity or frequency 
from the baseline condition and meets one of the following criteria will be recorded as an 
AE: 
• 
Requires therapeutic intervention or diagnostic tests 
• 
Leads to discontinuation of further administration of the investigational product in 
the clinical trial 
• 
Has accompanying or inducing symptoms or signs 
• 
Is judged by the PI as clinically significant (CS) 
Abnormal laboratory values that meet the criteria of an AE or SAE should be reported in 
accordance with Section 7.9. 
7.8.4 CLINICAL TRIAL STOPPING RULES 
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The investigator is to immediately notify the Medical Monitor if the following are observed: 
• 
Any SAE related to study treatment. 
• 
Any Grade 4 adverse events related to study treatment. 
• 
Any report of anaphylaxis related to study treatment. 
The Medical Monitor, in consultation with the Safety Review Committee members when 
necessary, will make a determination as to whether to temporarily halt dosing until a more 
formal review of the case(s) is made. Such a formal review may include an emergency 
meeting of the DSMB, after consultation with the DSMB Chair. Following such a meeting, 
the DSMB chair will render a recommendation to the Medical Monitor of the Sponsor. The 
Sponsor will independently investigate the case(s) and, after review of the DSMB 
recommendations, will communicate a final decision as to whether to lift the dosing 
suspension or whether to continue dosing. These deliberations will be documented and 
will be provided to the IRBs and FDA.   
7.9 
SAFETY DATA REPORTING PERIOD, METHOD OF COLLECTION AND SUBMISSION 
All AEs will be collected from the time informed consent is obtained through Day 56. 
MAAEs, AESIs and SAEs only will continue to be collected after the Day 56 visit and will 
be followed to resolution or stabilization. This information will be captured in the CRF. 
If the PI determines that the AE meets serious criteria, then the AE will be recorded as an 
SAE. 
SAEs and AESIs will be reported to the Sponsor from the time the subject signs the 
informed consent until the last visit. 
All SAEs (regardless of causal relationship) and AESIs will be reported on the SAE Report 
Form and submitted to the Sponsor within 24 hours of becoming aware of the event. The 
SAE Report Form will be either emailed tosafety.inovio@apcerls.co or faxed to
. The original SAE Report Form must be kept at the clinical trial site. 
The event will be data entered into the CRF. 
 
For the events that are considered an AESI, the PI will contact the Sponsor within 24 hours 
of becoming aware of the event to discuss whether dosing should continue. 
Table 4: SAE Contact Information 
Sponsor Safety Email: safety.inovio@apcerls.com  
Sponsor Safety Fax: 
Sponsor Safety Phone: 
 
Table 5: Medical Monitor Direct contact Information 
Medical Monitor: 
, M.D., Ph.D. 
Email: 
 
Cell Phone: 
 
 
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All SAEs, treatment-related AEs and AESIs must be followed by the PI until resolution or 
return to baseline status, stabilization of the event (i.e., the expectation that it will remain 
chronic), even if it extends beyond the clinical trial reporting period or until it is determined 
that the subject is lost to follow up. 
Follow-up information is to be submitted to the Sponsor on an SAE Report Form and within 
24 hours of becoming aware of the information. 
If medical records are submitted to the Sponsor with the SAE Report Form, the clinical 
trial site must: 
• Redact the medical records of all personal data (e.g., confidential subject data, 
Personal Identifying Information [PII]) 
• Provide the subject’s assigned identification number (SID) on the records 
7.10 ADVERSE EVENT REPORTING 
This section provides details on reporting the safety information. 
7.10.1 SUBMITTING THE INITIAL SERIOUS ADVERSE EVENT (SAE) REPORT FORM 
The PI should include as much safety information as possible when submitting the initial 
report, but the report must include the following at a minimum:  
• 
The adverse event 
• 
The subject’s assigned identification number (SID) 
• 
Investigational product(s) (IP) and/or study device 
• 
Investigator causal relationship to the IP(s) and/or study device 
• 
Serious criteria 
• 
Reporter name and contact information 
If a case is submitted to the Sponsor with only the “minimum” information, a more detailed 
or updated follow-up report will be sent to the Sponsor as soon as possible but no later 
than three (3) calendar days after the date of the initial report. 
7.10.2 RECORDING THE EVENT 
Principal Investigators (PIs) should use correct medical terminology/concepts when 
recording adverse events on the EDC and SAE Report Form. The use of colloquialisms 
and abbreviations should be avoided. 
A medical diagnosis, if known, should be recorded rather than individual signs and 
symptoms. However, if the signs and/or symptoms cannot be medically characterized as 
a single diagnosis or syndrome, each individual sign and/or symptom should be recorded. 
If a diagnosis is subsequently established, all previous signs and/or symptoms will be 
subsumed and replaced with a single medical diagnosis. 
7.10.3 ASSESSING SEVERITY (INTENSITY) 
Severity is used to describe the intensity of a specific event (e.g., mild, moderate, severe). 
The PI will assess and grade clinical AEs or SAEs (based on discussions with clinical trial 
subjects) in accordance with Toxicity Grading Scale for Healthy Adult and Adolescent 
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Volunteers Enrolled in Preventive Vaccine Clinical Trials (Food and Drug Administration 
[FDA] Guidance for Industry) (Appendix A). 
7.10.4 CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS (AES) 
A causally related AE is one judged to have a possible, probable or definite relationship 
to the administration of the IP and/or the study device. An AE may also be assessed as 
not related to the IP and/or the study device. Because the PI is knowledgeable about the 
subject (e.g., medical history, concomitant medications), administers the IP, and monitors 
the subject’s response to the IP, the PI is responsible for reporting AEs and judging the 
relationship between the administration of the IP and EP and a subsequent AE. The PI is 
aware of the subject’s clinical state and may have observed the event, and thus may be 
sensitive to distinctions between events due to the underlying disease process versus 
events that may be product-related.  
Principal Investigators (PIs) should use their knowledge of the clinical trial subject, the 
circumstances surrounding the event, and an evaluation of any potential alternative 
causes to determine whether an AE is considered to be related to the IP and/or the study 
device and the causal relationship reported as "Yes" or "No" accordingly. Causality should 
be assessed by the PI as related to drug, related to device, or related to both drug and 
device (i.e., related to both or indiscernible) by the following criteria: 
• 
Yes – there is a reasonable possibility that administration of the clinical trial 
treatment (drug or device or both drug and device) contributed to the event 
• 
No – there is no reasonable possibility that administration of the clinical trial 
treatment contributed to the event and there are more likely causes 
The following guidance should also be taken into consideration: 
• 
Temporal relationship of event to administration of IP and/or EP 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable) 
• 
Known association of the event with the IP, EP or with similar treatments 
• 
Known association of the event with the disease under trial 
• 
Presence of risk factors in the clinical trial subject or use of concomitant 
medications known to increase the occurrence of the event 
The rationale for the PI’s causal assessment is to be recorded on the SAE Report Form. 
The Sponsor will assess the overall safety of the IP delivered by EP and determine 
whether to report expeditiously to the regulatory authority(ies). 
7.11 REPORTING PREGNANCY DURING THE CLINICAL TRIAL 
Subjects who are pregnant or expect to become pregnant prior to 3 months following the 
last dose will be excluded from participation in the clinical trial.  
All pregnancies that occur from the time of first administration of clinical trial treatment 
through study completion (i.e., Day 393) will be reported to the Sponsor. If clinical trial site 
staff become aware that a subject becomes pregnant after the first dose in the clinical trial, 
she will not be given any additional treatments with the IP. A Pregnancy Form will be 
completed by the PI and submitted to the Sponsor within 24 hours after becoming aware 
of the pregnancy. 
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The PI will report this event to their IRB/REB/EC in accordance with their policies and 
procedures.  
The clinical trial site must request the subject’s permission to query pregnancy outcome 
and follow the subject for outcome of the pregnancy. The subject will continue to be 
followed for safety assessments without receiving additional IP until clinical trial discharge 
in accordance with this protocol. Procedures that are contraindicated during pregnancy, 
including additional dose administrations, must not be performed. The PI should use 
clinical judgment regarding subsequent clinical trial-related blood collection based on the 
presence or absence of anemia in each subject.  
Male subjects will be instructed through the ICF to immediately inform the PI if their partner 
becomes pregnant until study completion. A Pregnancy Form will be completed by the PI 
and submitted to the Sponsor within 24 hours after becoming aware of the pregnancy. The 
pregnant partner will be asked to sign an Authorization for Use and Disclosure of 
Pregnancy Health Information to allow for follow-up on her pregnancy. If the authorization 
has been signed, the PI will collect and report details of the course and outcome of the 
pregnancy in the partner of a male subject exposed to IP. The PI will update the Pregnancy 
Form with additional information on the course and outcome of the pregnancy and submit 
the form to the Sponsor.  
If a PI is contacted by the male subject or his pregnant partner, the PI may provide 
information on the risks of the pregnancy and the possible effects on the fetus to support 
an informed decision in cooperation with the treating physician and/or obstetrician. 
If the end of the pregnancy occurs after the clinical trial has been completed, the outcome 
will be reported directly to the Sponsor. 
7.12 REPORTING DEVICE-RELATED COMPLAINTS OR DEFICIENCIES 
All product complaints that meet the definition of device deficiency must be reported to the 
Sponsor within 10 days of discovery, with the exception of SAEs which require 24-hour 
reporting. The error reporting or complaint form must be completed and emailed to the 
Sponsor at clinicalcomplaint@inovio.com. 
Device deficiencies include malfunctions, misuse or use errors and inadequate labeling. 
A malfunction is defined as the failure of a device to meet its performance specifications 
or otherwise perform as intended. The intended performance of a device refers to the 
intended use for which the device is labeled or marketed. 
Any problems experienced during the treatment procedure including malfunctions of the 
device, error messages displayed on the device screen following treatment, or errors that 
occur during the treatment procedure must immediately be reported to the Sponsor or its 
designee for evaluation.  
7.13 NOTIFYING REGULATORY AUTHORITIES AND INSTITUTIONAL REVIEW BOARDS 
(IRBS)/RESEARCH ETHICS BOARDS (REBS)/ETHICS COMMITTEES (ECS) OF SAFETY 
INFORMATION 
7.13.1 SPONSOR RESPONSIBILITIES 
• 
Determine whether the safety information meets the requirements for expedited 
reporting to the applicable regulatory authorities 
• 
Prepare and submit the safety report to the applicable regulatory authorities 
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• 
Send all participating PIs a safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) that will include a statement if there is or is not any significant new 
safety information that might influence the risk-benefit assessment of the IP and/or 
study device, sufficient to consider changes in product administration or overall 
conduct of the clinical investigation 
7.13.2 PRINCIPAL INVESTIGATOR (PI) RESPONSIBILITIES 
• 
Forward a copy of the safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) to their IRB/REB/EC as soon as practical in accordance with the 
governing policy and/or procedures 
• 
Notify their IRB/REB/EC of safety information (i.e., SAEs, pregnancies, and AESIs) 
that occur at their clinical trial site in accordance with their local institutional policy 
7.14 POST-TRIAL REPORTING REQUIREMENTS 
PIs are not obligated to actively seek AEs or SAEs beyond the clinical trial reporting period. 
However, if the PI becomes aware of an AE or SAE that occurs after the Completion or 
Termination Visit and the event is deemed by the PI to be related to the clinical trial 
treatment, the PI should promptly document and report the event to the Sponsor. 
7.15 CLINICAL TRIAL DISCONTINUATION  
INOVIO reserves the right to discontinue the clinical trial at a site or at multiple sites for 
safety or administrative reasons at any time. In particular, a clinical trial site that does not 
recruit at a reasonable rate may be discontinued. Additionally, the clinical trial may be 
discontinued at any time by an IRB/REB/EC, INOVIO, or a regulatory authority as part of 
their duties to ensure that clinical trial subjects are protected.  
If the clinical trial is discontinued and/or the clinical trial site closed for any 
reason, all IP and devices must be returned to INOVIO or its 
representative. The PI should ensure that their site file documents are complete 
prior to archiving, and provide copies of any requested documents to INOVIO 
for its Trial Master File (TMF). 
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
STATISTICAL AND ANALYTICAL PLAN 
The formal Statistical Analysis Plan is contained in the sections that follow. 
8.2 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is a two-arm, multi-center, placebo-controlled, blinded, and randomized clinical trial 
in subjects at high risk of SARS-CoV-2 exposure. The study’s primary endpoint is the 
incidence of laboratory-confirmed COVID-19 disease starting 14 days after completion of 
the 2-dose regimen until 6 months post-dose 2.  The primary hypothesis is that INO-4800 
will be efficacious relative to placebo (relative efficacy > 15%).  Secondary efficacy 
analyses involve severe cases, cases requiring mechanical ventilation, cases resulting in 
death, long-term efficacy (disease starting 14 days after completion of the 2-dose regimen 
until 12 months post-dose 2), short-term efficacy (disease starting 14 days after 1 dose 
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until 14 days post-dose 2), and timing of symptom resolution.  Other secondary analyses 
concern safety and humoral immunological measures.  Exploratory analyses concern 
cellular immunological measures. 
8.3 
STATISTICAL HYPOTHESES 
Among baseline seronegative subjects, the primary hypothesis of relative efficacy greater 
than 15% will be tested with H0: p ≥ .85/(.85+k) vs. H1: p < .85/(.85+k), where p is the true 
proportion of subjects with disease who receive INO-4800 relative to the total number of 
subjects with disease, and k is the total amount of follow-up time in the placebo group 
divided by the total amount of follow-up time in the INO-4800 group. There are no other 
formal hypotheses. 
8.4 
ANALYTICAL POPULATIONS 
Analysis populations will be: 
The per-protocol (PP) population includes all baseline seronegative subjects who receive 
all doses of Study Treatments and have no protocol violations. Subjects with disease 
occurring prior to 14 days post-dose 2 will be excluded from the PP population.  Subjects 
in the PP population will be grouped to treatment arms as randomized.  Subjects excluded 
from the PP population will be identified and documented prior to unblinding of the trial 
database.  Analyses on the PP population will be primary for the analysis of efficacy in this 
trial. 
The modified intention to treat (mITT) population includes all baseline seronegative 
subjects who receive at least one dose of Study Treatment. Subjects in this population will 
be grouped to treatment arms as randomized.  Analysis of the mITT population will be 
considered supportive for the corresponding PP population for the analysis of efficacy. 
The intention to treat (ITT) population includes all baseline seronegative subjects who are 
randomized. Subjects in this sample will be grouped to treatment arms as randomized.  
Analysis of the ITT population will be considered supportive for the corresponding PP 
population for the analysis of efficacy. 
The safety analysis population includes all subjects who receive at least one dose of Study 
Treatment. Subjects will be analyzed according to the treatments received. 
8.5 
DESCRIPTION OF STATISTICAL METHODS 
8.5.1 PRIMARY EFFICACY ANALYSIS 
Among baseline seronegative subjects, the primary hypothesis of relative efficacy greater 
than 15% will be tested with H0: p ≥ 0.85/(0.85+k) vs. H1: p < 0.85/(0.85+k), where p is the 
true proportion of subjects with disease who receive INO-4800 relative to the total number 
of subjects with disease, and k is the total amount of follow-up time in the placebo group 
divided by the total amount of follow-up time in the INO-4800 group. 
A p-value for this hypothesis test and corresponding 95% confidence interval will be 
computed based on the exact binomial method of Clopper-Pearson. Success will be 
concluded if the one-sided p-value is <0.025 and the corresponding lower bound of the 
two-sided 95% CI for efficacy exceeds 15%. 
For calculating k, an individual subject’s follow-up time is either: 
a) the date of first disease diagnosis – date of the start of surveillance 
period +1 (for subjects who are cases), or 
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b) the date of last follow-up – date of the start of surveillance period 
+1 (for subjects who are non-cases). 
This methodology is based on the following. Assuming that the number of subjects who 
are cases in the INO-4800 group follows a Poisson distribution with parameter λv and the 
number of subjects who are cases in the placebo group follows a Poisson distribution with 
parameter λc, then conditional on total number of subjects with cases, t, the number of 
subjects who are cases in the INO-4800 group follows a binomial distribution with 
parameters (t, p=λv/(λv+λc)).  The relationship between p and efficacy is: efficacy = (1-
(1+k)p)/(1-p).  Therefore, testing efficacy > 15% corresponds to testing p < 0.85/(0.85+k).  
Similarly, the confidence interval for efficacy is (1-(1+k)UBp)/(1-UBp), (1-(1+k)LBp)/(1-LBp), 
where UB and LB are the Clopper-Pearson upper and lower limits for the proportion. 
The efficacy time frame is defined by symptoms beginning at any time starting from 14 
days after Dose 2 and ending 6 months after Dose 2.  Subjects identified as cases based 
on symptoms starting prior to this time point will be excluded.  Subjects with multiple 
instances meeting the case definition will be counted only once, using the first such 
instance.    
The PP population will be primary for the analysis of efficacy in this trial. Efficacy analysis 
using the mITT population will also be conducted counting cases from 14 days postdose 
1 as a supportive analysis.  The ITT population will also be used for a supportive analysis 
counting cases starting from randomization. 
8.5.2 SECONDARY ANALYSES 
8.5.2.1 Efficacy 
The secondary efficacy incidence endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values. The efficacy timeframe is 
different for the long-term efficacy endpoint and for the short-term efficacy endpoint.  For 
the long-term endpoint, the end of the timeframe is 12 months postdose 2, and for the 
short-term endpoint, the start of the timeframe is 14 days postdose 1 and the end of the 
timeframe is 14 days postdose 2. 
The secondary efficacy endpoint regarding timing of symptom resolution will be 
analyzed with Kaplan-Meier plots by treatment group. 
8.5.2.2 Immunogenicity 
Among baseline seronegative subjects, post-baseline antibody titers from ELISA will be 
compared between treatment groups using ratios of geometric mean titers and 
associated 95% CIs. 
 
Among baseline seronegative subjects, post-baseline seroconversion from ELISA will 
be compared between treatment groups using differences in proportions and associated 
Miettinen and Nurminen 95% CIs. 
 
The summaries listed above will be stratified according to disease status of the subjects. 
 
Valid samples for statistical analysis purposes will be those collected within the days of 
the specified visit according to the Schedule of Events. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
8.5.3 SAFETY ANALYSES 
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8.5.3.1 Adverse Events 
All AEs including injection-site reactions will be summarized among the Safety 
Population by frequency per treatment arm. These frequencies will be presented overall 
and separately by dose, and will depict overall, by system organ class and by preferred 
term, the percentage of subjects affected. Additional frequencies will be presented with 
respect to maximum severity and to strongest relationship to Study Treatment. Multiple 
occurrences of the same AE will be counted only once following a worst-case approach 
with respect to severity and relationship to Study Treatment. All serious AEs will also be 
summarized as above. 
The main summary of safety data will be based on events occurring within 30 days of 
any dose. For this summary, the frequency of preferred term events will be compared 
between study arms with risk differences and 95% confidence intervals, using the 
method of Miettinen and Nurminen. As this analysis will use many event categories, and 
produce many confidence intervals, caution should be exercised when interpreting these 
confidence intervals.  Separate summaries will be based on events occurring within 7 
days of any dose and regardless of when they occurred. 
The analyses listed above will also be stratified by baseline seronegative versus 
seropositive status. 
For AE data, partial start dates will be imputed to the date of treatment to conservatively 
report the event as treatment-emergent, whenever the portion of the date is consistent 
with that of the study treatment.  Otherwise, it will be imputed to the earliest date 
consistent with the partial date. A completely missing onset date will be imputed as the 
day of treatment. Partial stop dates will be assumed to be the latest possible day 
consistent with the partial date. 
AE duration will be calculated as (Stop Date – Start Date) + 1. 
8.5.3.2 Vital Signs 
Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean, standard deviation, minimum, median, and maximum 
values by time point and treatment arm, for the Safety population. Baseline is defined 
as the last measurement prior to the first treatment administration.  These summaries 
will also be stratified by baseline seronegative versus seropositive status. 
8.5.3.3 Physical Examination 
The percentage of subjects with abnormal physical examination findings at each time 
point will be summarized by treatment arm and by body system, for the Safety 
population.  These summaries will also be stratified by baseline seronegative versus 
seropositive status. 
8.5.4 DISPOSITION 
Disposition will be summarized by treatment arm for the ITT population and will include 
the number and percentage randomized, the number and percentage who received each 
dose and the number who completed the trial.  The number and percentage of subjects 
who discontinued will be summarized overall and by reason.  The number in each analysis 
population will also be presented.  These summaries will also be stratified by baseline 
seronegative versus seropositive status. 
8.5.5 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
8.5.5.1 Demographics 
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Demographic data will be summarized with descriptive statistics: mean standard 
deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables, by treatment arm, for the ITT and PP populations. 
These summaries will also be stratified by baseline seronegative versus seropositive 
status. 
8.5.5.2 Medical History 
The percentage of subjects with abnormal medical history findings will be summarized 
by body system, by treatment arm, for the ITT and PP populations. These summaries 
will also be stratified by baseline seronegative versus seropositive status. 
8.5.5.3 Prior Medications 
Prior medications are those that were used before the start of the trial (prior to Day 0). 
Partial stop dates of prior medications will be assumed to be the latest possible date 
consistent with the partial date; start dates will not be imputed. Data for all prior 
medications will be summarized with percentages by treatment arm, for the Mitt and PP 
populations. These summaries will also be stratified by baseline seronegative versus 
seropositive status. 
8.5.6 INTERIM ANALYSES  
For reasons of futility (early evidence of poor efficacy) or safety issues, the DSMB could 
recommend stopping enrollment at any time; no formal interim analysis will be performed 
for this purpose. The two-sided type I error of 0.05 will not be adjusted for possible early 
stopping due to futility. 
A group-level unblinded (INO-4800, Placebo) summary and analysis of efficacy will be 
produced once the primary endpoint data are completed for all subjects; subject-level 
blinding will be maintained. Long-term follow-up data will continue to be collected for all 
subjects with remaining visits through the final Week 56 visit. The summary and analysis 
will allow the Sponsor to have results with respect to the primary endpoint on which to 
make decisions regarding the INO-4800 program, while still gathering long-term data 
through the final Week 56 visit. This summary/analysis will not be provided if the total 
count of subjects who experience the event of interest is greater than 0 and the count for 
a treatment group relative to this total count is less than 3%. The group-level unblinded 
(INO-4800, Placebo) production of the summary and analysis will not include anyone 
directly involved with the trial or any additional unblinded personnel; only the external 
Contract Research Organization (CRO), which will also be providing unblinded 
summaries for the Data Safety Monitoring Board, will be utilized.  Thus, the trial will 
remain blinded with respect to subject treatment assignment throughout the trial.  The 
type I error of 0.05 will not be adjusted for this procedure.  
8.5.7 MULTIPLICITY 
Not applicable; there is one hypothesis that will be tested. 
8.5.8 MISSING VALUES 
Missing data will not be imputed. 
For the ITT analyses of efficacy, subjects with missing or unevaluable data regarding case 
definition will be considered cases (failures). 
8.5.9 EXPLORATORY ANALYSES  
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  8.5.9.1 Immunogenicity 
Among baseline seronegative subjects, post-baseline Increases from baseline in 
interferon-γ ELISpot response magnitudes will be compared between treatment groups 
using a difference in medians and associated non-parametric 95% CIs. 
Among baseline seronegative subjects, T cell phenotype and functional nature of the 
humoral response results will be compared between treatment groups using a 
difference in medians and associated non-parametric 95% CIs. 
The summaries listed above will be stratified according to disease status of the 
subjects. 
 
Valid samples for statistical analysis purposes will be those collected within the days of 
the specified visit according to the Schedule of Events. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
8.5.9.2 Concomitant Medications 
Concomitant medications are those used during the course of the trial (on or after Day 
0). Partial stop dates of concomitant medications will be assumed to be the latest 
possible date consistent with the partial date; start dates will not be imputed. Data for 
all concomitant medications will be summarized with percentages by treatment arm, for 
the ITT and PP populations.  These summaries will also be stratified by baseline 
seronegative versus seropositive status.   
8.6 
SAMPLE SIZE/POWER 
The trial is case-driven. Among baseline seronegative subjects, a total of 89 observed 
cases will be required to provide 90% power to declare the vaccine efficacious (>15%), 
utilizing the methodology described in Section 8.5.1 and assuming a true efficacy of 60%.  
A sample size of 3438 seronegative subjects will be required to achieve this number of 
cases assuming an underlying attack rate of 3.7%.   
A group of 100 baseline seropositive subjects will also be enrolled. 
8.7 
RANDOMIZATION AND BLINDING  
Subjects will be randomized (1 INO-4800:1 Placebo) in a stratified manner according to 
baseline serostatus. 
The study is double-blinded. Randomization and blinding will avoid bias in the assignment 
of participants to treatment, increase the likelihood that known and unknown subject 
attributes (e.g., demographics and other baseline characteristics) are evenly balanced 
between treatment groups, and enable valid statistical comparisons between treatment 
groups. 
9.0 
ETHICS 
9.1 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical trial is 
performed in accordance with the protocol, the principles of the Declaration of Helsinki, 
Good Clinical Practice (GCP) and applicable regulatory requirements. 
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9.2 
INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD (REB)/ETHICS 
COMMITTEE (EC) 
The Investigator will commence the clinical trial after full approval of the protocol and 
adjunctive materials (e.g., ICF, advertising) has been obtained from the applicable 
IRB/REB/EC and a copy of IRB/REB/EC approval documentation has been received by 
the Sponsor. 
Investigator responsibilities relevant to the IRB/REB/EC include the following: 
• Submit progress reports to the IRB/REB/EC as required, and request re-review 
and approval of the clinical trial at least once a year during the conduct of the 
clinical trial 
• Notify the Sponsor immediately of any suspected unexpected adverse drug or 
device events/effects 
• Notify the IRB/REB/EC immediately if the Sponsor notifies the Investigator about 
any reportable safety events 
• Obtain approval from the IRB/REB/EC for protocol amendments and for revisions 
to the consent form or subject recruitment advertisements, as required 
• Submit reports on, and reviews of, the clinical trial and its progress to the 
IRB/REB/EC at intervals stipulated in their guidelines and in accordance with 
pertinent regulations and guidelines 
• Maintain a file of clinical trial-related information (refer to clinical trial files) that 
includes all correspondence with the IRB/REB/EC 
• Notify the IRB/REB/EC when the clinical trial is completed (i.e., after the last clinical 
trial visit of the final clinical trial subject) 
• After clinical trial completion (within three [3] months is recommended), provide the 
IRB/REB/EC with a final report on the clinical trial 
Institutional Biosafety Committee (IBC) 
The Investigator will undertake the trial after full approval of the protocol and adjunctive 
materials (e.g., pharmacy manual) has been obtained from the applicable IBC and a copy 
of this approval has been received by the Sponsor. 
Investigator responsibilities relevant to the IBC include the following: 
• 
Notify the Sponsor, IBC and NIH OSP within 30 days of any: 
o Substantial problems or violation of the NIH Guidelines 
o Significant research related accidents or illnesses 
• 
Notify the IBC to any changes to the research (dosage, procedure, etc.) or facility 
(new space, remodeling, etc.).   
9.3 
PROTECTION OF HUMAN SUBJECTS 
9.3.1 COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent must be obtained from each subject, and/or from the subject’s 
legally authorized representative, prior to the subject’s enrollment in the clinical trial. The 
process for obtaining informed consent must be documented in the subject’s medical 
record (also refer to Section 6.2). 
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9.3.2 COMPLIANCE WITH INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD 
(REB)/ETHICS COMMITTEE (EC) REQUIREMENTS 
This clinical trial is to be conducted in accordance with applicable IRB/REB/EC 
regulations. The Investigator must obtain approval from a properly constituted 
IRB/REB/EC prior to initiating the clinical trial and obtain re-approval or review at least 
annually. The Sponsor is to be notified immediately if the responsible IRB/REB/EC has 
been disqualified or if proceedings leading to disqualification have begun. Copies of all 
IRB/REB/EC correspondence with the Investigator should be provided to the Sponsor. 
9.3.3 COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.3.4 COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS (21CFR 
PART 11) 
When applicable, this clinical trial is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.3.5 COMPLIANCE WITH PROTOCOL 
Subjects are not required to follow special instructions specific to the IP used in this clinical 
trial. Subjects will be provided with Investigator emergency contact information and 
advised to report all AEs. While every effort should be made to avoid protocol deviations, 
should an important deviation be discovered, the Sponsor must be informed immediately. 
Any protocol deviation impacting subject safety must be reported to the Medical Monitor 
immediately. 
9.3.6 CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from, or changes to, the protocol 
without Sponsor approval and prior review and documented approval/favorable opinion of 
the protocol amendment from the IRB/REB/EC, except where necessary to eliminate 
immediate hazards to clinical trial subjects, or when the changes involve only logistical or 
administrative aspects of the clinical trial (e.g., change in monitors, change of telephone 
numbers).  
10.0 DATA COLLECTION, MONITORING AND REPORTING 
10.1 CONFIDENTIALITY AND PRIVACY 
A report of the results of this clinical trial may be published or sent to the appropriate 
regulatory authorities in any country in which the clinical trial products are legally marketed 
or may ultimately be marketed, but the subject’s name/identity will not be disclosed in 
these documents. The clinical trial Sponsor, its agents, the IRB/REB/EC and regulatory 
authorities will have direct access to the subjects’ medical records for the purposes of trial-
related monitoring, auditing and inspection. Appropriate precautions will be taken to 
maintain confidentiality of medical records and personal information. 
Written Authorization and other documentation are to be obtained from each subject, 
and/or from the subject’s legally authorized representative, prior to enrollment in the 
clinical trial, in accordance with all applicable laws, regulations and/or directives relating 
to privacy and data protection. 
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11.0 SOURCE DOCUMENTS 
Source data is all information, electronic or hardcopy original records or clinical findings, 
laboratory results, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the clinical trial. 
Examples of original source data records may include:  
• Hospital records 
• Clinical and office charts 
• Laboratory notes 
• Memoranda 
• Pharmacy dispensing records 
• Recorded data from automated instruments 
• Copies of electronic medical records (EMR) certified after verification as being 
accurate and complete 
• X-rays 
• Subject files and records kept at the pharmacy, at the laboratories, at the medical 
records facility and within information technology (IT) systems that are involved in 
the clinical trial  
The Investigator/institution will permit clinical trial-related monitoring, audits, IRB/REB/EC 
review and regulatory inspections by providing direct access to source data/documents 
related to this clinical trial. 
11.1 RECORDS RETENTION 
Upon request of the Clinical Monitor, Sponsor or its agent(s), auditor, IRB/REB/EC or 
regulatory authority, the Investigator/institution should make available for direct access all 
requested clinical trial-related records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
It is the Investigator’s responsibility to retain clinical trial essential documents for at least 
two (2) years after the last approval of a marketing application in their country and until 
there are no pending or contemplated marketing applications in their country or at least 
two (2) years have elapsed since the formal discontinuation of clinical development of the 
IP. This retention period may be superseded by local requirements. The Sponsor will 
inform the Investigator/institution when these documents are no longer needed to be 
retained. 
If the Records Retention requirements are addressed in a governing clinical trial 
agreement, it is the Investigator’s responsibility to retain clinical trial essential documents 
in accordance with the governing clinical trial agreement and applicable local 
requirements. 
12.0 SAFETY AND QUALITY MONITORING 
12.1 SAFETY REVIEW 
The Sponsor’s Safety Review Committee (SRC), composed of the Sponsor’s Medical 
Monitor and 2 additional physicians, will review blinded safety and tolerability data on a 
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regular basis throughout the trial until the trial is unblinded. The SRC will meet 
approximately once per month, at a minimum.  
The DSMB will review unblinded safety and tolerability data, including AEs of clinical 
significance, AESIs and SAEs, as well as safety laboratory data for all enrolled subjects. 
The DSMB will advise regarding any safety concerns and will make recommendations 
regarding continued enrollment, safety pause and trial suspension. If the safety data is 
considered unfavorable during any safety review, the DSMB may recommend a trial pause 
or trial termination at which time further enrollment and administration of IP to subjects will 
be paused. The Sponsor will perform an investigation and consult with the DSMB and 
other experts, if needed, to determine whether to resume dosing of the remainder of the 
subjects. For further details, see the DSMB Charter.  
12.2 CLINICAL MONITORING 
Clinical Monitoring will be performed by qualified Clinical Monitors who will report to the 
Sponsor or the Sponsor’s designee. The following clinical trial site monitoring tasks will be 
performed at all clinical trial sites: 
• 
Prior to subject screening at the site, a Site Initiation Visit will be conducted to 
review all relevant forms and documentation, and ensure that the clinical trial site 
staff are qualified and compliant with all applicable requirements 
• 
All clinical trial site monitoring visits will be documented 
• 
Periodic clinical trial site visits will be performed throughout the clinical trial 
• 
The Clinical Monitor will address and document the following trial conduct activities 
and obligations: 
o Assure that the trial is being conducted in accordance with the protocol, 
applicable regulatory agency regulations, and IRB/REB/EC policies. 
o Discuss trial conduct issues and incidents of noncompliance with the 
Investigator and/or trial personnel and document them on the resolution trip 
report. Report any significant unresolved problems immediately to the 
Sponsor. 
o Remind the Investigator as necessary of the obligation to immediately report 
all SAEs and provide subsequent follow-up report of the final outcome to the 
IRB. 
o Throughout the trial, inspect source documents to ensure they are complete, 
logical, consistent, attributable, legible, contemporaneous, original, accurate 
and complete (ALCOA-C). 
o Assure that the trial facilities, including the pharmacy, continue to be 
acceptable. 
o Compare the trial CRFs with source documents to assure that the data are 
accurate and complete and that the protocol is being followed. 
o Assure that investigational drug and device accountability and reconciliation of 
records are complete and accurate. 
o Assure that all subject specimens are being stored and forwarded properly for 
testing in accordance with laboratory manual requirements. 
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13.0 FINANCING AND INSURANCE 
Inovio Pharmaceuticals is the Sponsor. Clinical trial insurance has been taken out 
according to the laws of the countries where the study will be conducted. The investigative 
site is being compensated for the conduct of this study and will follow the terms described 
in the clinical trial agreement. This agreement was executed separately from this clinical 
trial protocol. The Investigators will be required to provide full financial disclosure 
information per 21 CFR Part 54. 
14.0 PUBLICATION POLICY 
Publication of the results of this clinical trial in its entirety will be allowed. The proposed 
presentation, abstract and/or manuscript must be made available to the Sponsor for 
review and approval in accordance with the governing clinical trial agreement. 
 
 
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15.0 LIST OF ABBREVIATIONS 
ADE 
Adverse Device Effect 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALCOA-C 
Attributable, Legible, Contemporaneous, Original, Accurate and Complete 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
bGH polyA 
Bovine growth hormone 3’ end poly-adenylation signal 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CBC 
Complete Blood Count 
Cl 
Chloride 
COVID-19 
Coronavirus Disease 2019 
Cr 
Creatinine 
CRF 
Case Report Form 
CS 
Clinically Significant 
DNA 
Deoxyribonucleic Acid 
DLT 
Dose Limiting Toxicity  
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EP 
Electroporation 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B Surface Antigen 
HCO3 
Biocarbonate 
hCMV  
Human CMV 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICD 
Implantable-Cardioverter-defibrillator 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
ID 
Intradermal 
IM 
Intramuscular 
Inovio 
Inovio Pharmaceuticals Inc. 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
K 
Potassium 
KanR 
Kanamycin resistance gene 
MAAE 
Medically Attended Adverse Event 
mITT 
modified Intent to Treat 
MM 
Medical Monitor 
MERS 
Middle East Respiratory Syndrome  
MERS-CoV 
Middle East Respiratory Syndrome Coronavirus 
mRNA 
Messenger RNA 
Na 
Sodium 
NCS 
Not Clinically Significant 
NIAID 
National Institute for Allergy and Infectious Disease 
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NHP 
Non-human Primates 
NP 
Nucleocapsid Protein 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PII 
Personal Identifying Information 
PO4 
Potassium 
PT 
Preferred Term 
pUC ori 
Plasmid origin of replication 
RBC 
Red blood cell 
REB 
Research Ethics Board 
RR 
Respiratory Rate 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SARS 
Severe Acute Respiratory Syndrome  
SARS-CoV 
Severe Acute Respiratory Syndrome Coronavirus 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus - 2 
SID 
Subject Identification Number 
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
SynCon 
Synthetic consensus 
TBili 
Total Bilirubin 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of Child Bearing Potential 
 
 
 
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16.0 REFERENCES 
 
1. 
Lu H, Stratton CW, Tang YW. Outbreak of pneumonia of unknown etiology in Wuhan, 
China: The mystery and the miracle. J Med Virol 2020,92:401-402. 
2. 
Hui DS, E IA, Madani TA, Ntoumi F, Kock R, Dar O, et al. The continuing 2019-nCoV 
epidemic threat of novel coronaviruses to global health - The latest 2019 novel 
coronavirus outbreak in Wuhan, China. Int J Infect Dis 2020,91:264-266. 
3. 
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected 
with 2019 novel coronavirus in Wuhan, China. Lancet 2020,395:497-506. 
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GenBank. Severe acute respiratory syndrome coronavirus 2 isolate Wuhan-Hu-1, 
complete genome. In; 2020. 
5. 
Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al. Author Correction: A new 
coronavirus associated with human respiratory disease in China. Nature 2020,580:E7. 
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World Health Organization. Clinical Management of Sever Acute Respiratory Infection 
When Novel Coronavirus (2016-nCoV) Infection is Suspected. Interim Guidance. In; 
2020. 
7. 
World Health Organization. Novel Coronavirus (2019-nCoV) Situation Report. In; 2020. 
8. 
Centers for Disease Control and Prevention. First Travel-related Case of 2019 Novel 
Coronavirus Detected in United States. In; January 21, 2020. 
9. 
Center for Systems Science and Engineering at Johns Hopkins University. COVID-19 
Dashboard. In; 2020. 
10. 
World Health Organization. WHO Director-General's opening remarks at the media 
briefing on COVID-19 - 11 March 2020. In; March 11, 2020. 
11. 
Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, et al. SARS-CoV-2 Viral Load in 
Upper Respiratory Specimens of Infected Patients. N Engl J Med 2020. 
12. 
Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus 
Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases 
From the Chinese Center for Disease Control and Prevention. JAMA 2020. 
13. 
The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The 
epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases 
(COVID-19) in China. Chin J Epidemiol 2020,41. 
14. 
The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. Vital 
Surveillances: The Epidemiological Characteristics of an Outbreak of 2019 Novel 
Coronavirus Diseases (COVID-19) — China, 2020. China CDC Weekly 2020,2:113-122. 
15. 
Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J, et al. A familial cluster of pneumonia 
associated with the 2019 novel coronavirus indicating person-to-person transmission: a 
study of a family cluster. Lancet 2020,395:514-523. 
16. 
Rothe C, Schunk M, Sothmann P, Bretzel G, Froeschl G, Wallrauch C, et al. 
Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany. N 
Engl J Med 2020,382:970-971. 
17. 
Ganyani T, Kremer C, Chen D, Torneri A, Faes C, Wallinga J, et al. Estimating the 
generation interval for coronavirus disease (COVID-19) based on symptom onset data, 
March 2020. Euro Surveill 2020,25. 
18. 
He X, Lau EHY, Wu P, Deng X, Wang J, Hao X, et al. Temporal dynamics in viral 
shedding and transmissibility of COVID-19. Nat Med 2020,26:672-675. 
19. 
Liu Y, Gayle AA, Wilder-Smith A, Rocklov J. The reproductive number of COVID-19 is 
higher compared to SARS coronavirus. J Travel Med 2020,27. 
20. 
Centers for Disease Control and Prevention. Symptoms of Coronavirus. In; 2020. 
21. 
Gudbjartsson DF, Helgason A, Jonsson H, Magnusson OT, Melsted P, Norddahl GL, et 
al. Spread of SARS-CoV-2 in the Icelandic Population. N Engl J Med 2020. 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 22-May-2020 
CONFIDENTIAL 
Protocol Version: 1.0 
 
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22. 
Day M. Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ 
2020,369:m1375. 
23. 
Lipsitch M, Cohen T, Cooper B, Robins JM, Ma S, James L, et al. Transmission 
dynamics and control of severe acute respiratory syndrome. Science 2003,300:1966-
1970. 
24. 
Peiris JS, Chu CM, Cheng VC, Chan KS, Hung IF, Poon LL, et al. Clinical progression 
and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a 
prospective study. Lancet 2003,361:1767-1772. 
25. 
Tsang TK, Cowling BJ, Fang VJ, Chan KH, Ip DK, Leung GM, et al. Influenza A Virus 
Shedding and Infectivity in Households. J Infect Dis 2015,212:1420-1428. 
26. 
Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. Reduction and Functional 
Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19). Front 
Immunol 2020,11:827. 
27. 
US FDA. Fact Sheet For Health Care Providers Emergency Use Authorization (EUA) Of 
Remdesivir (Gs-5734™). In; 2020. 
28. 
US FDA. Fact Sheet For Health Care Providers Emergency Use Authorization (EUA) Of 
Chloroquine Phosphate Supplied From The Strategic National Stockpile For Treatment 
Of Covid-19 In Certain Hospitalized Patients. In; 2020. 
29. 
Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, et al. Safety, efficacy, 
and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human 
papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a 
randomised, double-blind, placebo-controlled phase 2b trial. Lancet 2015,386:2078-
2088. 
30. 
Modjarrad K, Roberts CC, Mills KT, Castellano AR, Paolino K, Muthumani K, et al. 
Safety and immunogenicity of an anti-Middle East respiratory syndrome coronavirus 
DNA vaccine: a phase 1, open-label, single-arm, dose-escalation trial. Lancet Infect Dis 
2019,19:1013-1022. 
31. 
Suschak JJ, Williams JA, Schmaljohn CS. Advancements in DNA vaccine vectors, non-
mechanical delivery methods, and molecular adjuvants to increase immunogenicity. 
Hum Vaccin Immunother 2017,13:2837-2848. 
32. 
Manickan E, Karem KL, Rouse BT. DNA Vaccines - A Modern Gimmick or a Boon to 
Vaccinology? Crit Rev Immunol 2017,37:483-498. 
33. 
Porter KR, Raviprakash K. DNA Vaccine Delivery and Improved Immunogenicity. Curr 
Issues Mol Biol 2017,22:129-138. 
34. 
Li L, Petrovsky N. Molecular mechanisms for enhanced DNA vaccine immunogenicity. 
Expert Rev Vaccines 2016,15:313-329. 
35. 
Marc MA, Dominguez-Alvarez E, Gamazo C. Nucleic acid vaccination strategies against 
infectious diseases. Expert Opin Drug Deliv 2015,12:1851-1865. 
36. 
Grunwald T, Ulbert S. Improvement of DNA vaccination by adjuvants and sophisticated 
delivery devices: vaccine-platforms for the battle against infectious diseases. Clin Exp 
Vaccine Res 2015,4:1-10. 
37. 
Tregoning JS, Kinnear E. Using Plasmids as DNA Vaccines for Infectious Diseases. 
Microbiol Spectr 2014,2. 
38. 
Williams JA. Improving DNA vaccine performance through vector design. Curr Gene 
Ther 2014,14:170-189. 
39. 
Liu MA. DNA vaccines: an historical perspective and view to the future. Immunol Rev 
2011,239:62-84. 
40. 
Wahren B, Liu MA. DNA Vaccines: Recent Developments and the Future. Vaccines 
(Basel) 2014,2:785-796wahren. 
41. 
Ledgerwood JE, Graham BS. DNA vaccines: a safe and efficient platform technology for 
responding to emerging infectious diseases. Hum Vaccin 2009,5:623-626. 
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Clinical Protocol 
Protocol Version Date: 22-May-2020 
CONFIDENTIAL 
Protocol Version: 1.0 
 
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42. 
Keefer MC, Graham BS, Belshe RB, Schwartz D, Corey L, Bolognesi DP, et al. Studies 
of high doses of a human immunodeficiency virus type 1 recombinant glycoprotein 160 
candidate vaccine in HIV type 1-seronegative humans. The AIDS Vaccine Clinical Trials 
Network. AIDS Res Hum Retroviruses 1994,10:1713-1723. 
43. 
Wu F, Wang A, Liu M, Wang Q, Chen J, Xia S, et al. Neutralizing antibody responses to 
SARS-CoV-2 in a COVID-19 recovered patient cohort and their implications. Medrxiv 
Preprint 2020. 
44. 
Martin JE, Sullivan NJ, Enama ME, Gordon IJ, Roederer M, Koup RA, et al. A DNA 
vaccine for Ebola virus is safe and immunogenic in a phase I clinical trial. Clin Vaccine 
Immunol 2006,13:1267-1277. 
45. 
Prud'homme GJ, Glinka Y, Khan AS, Draghia-Akli R. Electroporation-enhanced nonviral 
gene transfer for the prevention or treatment of immunological, endocrine and neoplastic 
diseases. Curr Gene Ther 2006,6:243-273. 
46. 
Hirao LA, Wu L, Khan AS, Hokey DA, Yan J, Dai A, et al. Combined effects of IL-12 and 
electroporation enhances the potency of DNA vaccination in macaques. Vaccine 
2008,26:3112-3120. 
47. 
Rosati M, Valentin A, Jalah R, Patel V, von Gegerfelt A, Bergamaschi C, et al. Increased 
immune responses in rhesus macaques by DNA vaccination combined with 
electroporation. Vaccine 2008,26:5223-5229. 
48. 
Curcio C, Khan AS, Amici A, Spadaro M, Quaglino E, Cavallo F, et al. DNA 
immunization using constant-current electroporation affords long-term protection from 
autochthonous mammary carcinomas in cancer-prone transgenic mice. Cancer Gene 
Ther. 2008,15:108-114. 
49. 
Ugen KE, Kutzler MA, Marrero B, Westover J, Coppola D, Weiner DB, et al. Regression 
of subcutaneous B16 melanoma tumors after intratumoral delivery of an IL-15-
expressing plasmid followed by in vivo electroporation. Cancer Gene Ther. 2006,13:969-
974. 
50. 
Tebas P, Roberts CC, Muthumani K, Reuschel EL, Kudchodkar SB, Zaidi FI, et al. 
Safety and Immunogenicity of an Anti-Zika Virus DNA Vaccine - Preliminary Report. N 
Engl J Med 2017. 
 
 
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17.0 APPENDICES 
17.1 APPENDIX A: TOXICITY GRADING SCALE FOR HEALTHY ADULT AND ADOLESCENT 
VOLUNTEERS ENROLLED IN PREVENTIVE VACCINE CLINICAL TRIAL  
 
Table for Clinical Abnormalities 
Local Reaction to 
Injectable Product 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
Does not interfere 
with activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency 
room (ER) visit 
or 
hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/Rednessa 
2.5-5 cm 
5.1-10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swellingb 
2.5-5 cm and 
does not interfere 
with activity 
5.1-10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
Vital Signsc 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Fever   (°C)d 
            (°F)d 
38.0-38.4 
100.4-101.1 
38.5-38.9 
101.2-102.0 
39.0-40.0 
102.1-104.0 
> 40.0 
> 104.0 
Tachycardia - beats 
per minute 
101-115 
116-130 
> 130 
ER visit or 
hospitalization 
for arrhythmia 
Bradycardia - beats 
per minutee 
50-54 
45-49 
< 45 
ER visit or 
hospitalization 
for arrhythmia 
Hypertension 
(systolic) - mm Hg 
141-150 
151-155 
> 155 
ER visit or 
hospitalization 
for malignant 
hypertension 
Hypertension 
(diastolic) - mm Hg 
91-95 
96-100 
> 100 
ER visit or 
hospitalization 
for malignant 
hypertension 
Hypotension 
(systolic) - mm Hg 
85-89 
80-84 
< 80 
ER visit or 
hospitalization 
for hypotensive 
shock 
Respiratory Rate - 
breaths per minute 
17-20 
21-25 
> 25 
Intubation 
a In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable. 
b Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
c Subject should be at rest for all vital sign measurements. 
d Oral temperature; no recent hot or cold beverages or smoking. 
e When resting heart rate is between 60-100 beats per minute. Use clinical judgement when characterizing bradycardia among 
some healthy subject populations, for example, conditioned athletes. 
 
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Systemic 
(General) 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Nausea/Vomiting 
No interference 
with activity or 1-2 
episodes/24 
hours 
Some interference 
with activity or > 2 
episodes/24 hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
for hypotensive 
shock 
Diarrhea 
2-3 loose stools 
or < 400 gms/24 
hours 
4-5 loose stools or 
400-800 gms/24 
hours 
6 or more watery 
stools or > 800 
gms/24 hours or 
requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache 
No interference 
with activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or some 
interference with 
activity 
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Fatigue 
No interference 
with activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
No interference 
with activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Systemic Illness 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Illness or clinical 
adverse event (as 
defined according 
to applicable 
regulations) 
No interference 
with activity 
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily 
activity and 
requires medical 
intervention 
ER visit or 
hospitalization 
U.S. Department of Health and Human Services, Food and Drug Administration, and Center for Biologics Evaluation and 
Research. Guidance for industry: Toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive 
vaccine clinical trials. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/toxicity-grading-scale-healthy-
adult-and-adolescent-volunteers-enrolled-preventive-vaccine-clinical 2007 Sep; 3-5 
 
 
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17.2 APPENDIX B: ADVERSE EVENTS OF SPECIAL INTEREST  
For the purpose of standardization across multiple vaccine platforms, including those substantially 
different from Inovio’s platform, the below table lists adverse events of special interest (AESIs) 
relevant to COVID-19 vaccine development.  
Body System 
AESI 
Respiratory 
Acute respiratory distress syndrome (ARDS) 
Pneumonitis/Pneumonia 
Neurologic 
Generalized convulsion 
Aseptic meningitis 
Guillain-Barré Syndrome (GBS) 
Encephalitis/Myelitis 
Acute disseminated encephalomyelitis (ADEM) 
CNS vasculopathy (stroke) 
Hematologic 
Thrombocytopenia 
Disseminated intravascular coagulation (DIC) 
Immunologic 
Anaphylaxis 
Vasculitides 
Other 
Acute cardiac failure 
Acute kidney failure 
Septic shock-like syndrome 
 
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Signature Page for VV-TMF-00448 v1.0
Signature Page for VV-TMF-00448 v1.0
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 22-May-2020 16:03:32 GMT+0000
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CONFIDENTIAL 
 
Page 1 of 70 
 
 
 
 
 
 
 
 
 
 
COVID19-311 
 
Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the 
Safety, Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against 
COVID-19 Disease, Administered Intradermally Followed by Electroporation in 
Healthy Adults at High Risk of SARS-CoV-2 Exposure   
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
IND #: 19690 
 
Protocol Version: 2.0 
 
Protocol Version Date: 15-Jun-2020 
 
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Page 2 of 70 
 
 
Medical Monitor Approval Page 
 
Drug:  
INO-4800 
 
Sponsor: 
Inovio Pharmaceuticals, Inc. 
 
660 W. Germantown Pike, Suite 110 
 
Plymouth Meeting, PA 19462 
 
Medical Monitor: 
 
Jr., M.D., FACP, FIDSA 
, 
 
Inovio Pharmaceuticals, Inc. 
 
 
Approval Signature: 
 
 
[Electronically signed] 
  
Jr., M.D., FACP, FIDSA 
 
Inovio Pharmaceuticals, Inc. 
 
 Date (ddMmmyyyy) 
 
 
CONFIDENTIAL 
The information in this document is considered privileged and confidential by Inovio 
Pharmaceuticals Inc. (INOVIO) and may not be disclosed to others except to the extent 
necessary to obtain Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics 
Committee (EC) approval and informed consent, or as required by local regulatory 
authorities. Persons to whom this information is disclosed must be informed that this 
information is privileged and confidential and that it should not be further disclosed 
without the written permission of INOVIO. Any supplemental information added to this 
document is also confidential and proprietary information of INOVIO and must be kept in 
confidence in the same manner as the contents of this document. 
 
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Principal Investigator Acknowledgement 
 
I have read and understood this Protocol and agree that it contains all details necessary to 
conduct the clinical trial. I understand that it must be reviewed by the Institutional Review Board 
(IRB)/Research Ethics Board (REB)/Ethics Committee (EC) overseeing the conduct of the 
clinical trial and approved or given favorable opinion before implementation. 
 
The Principal Investigator’s (PI’s) signature constitutes the PI’s approval of this Protocol and 
provides the necessary assurances that this clinical trial will be conducted in accordance with 
International Council for Harmonization (ICH)/Good Clinical Practice (GCP), local legal and 
regulatory requirements, and all stipulations of the Protocol. 
 
 
Principal Investigator Signature: 
 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
Principal Investigator Signature 
 
Date (ddMmmyyyy) 
 
 
 
Clinical Trial Site Number: 
 
Clinical Trial Site Name: 
 
 
 
 
 
 
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SUMMARY OF CHANGES 
The following is a list of significant changes from Version 1.0, dated 22May2020, to Version 2.0, 
dated 15Jun2020. All other changes are administrative and do not significantly affect the safety 
of subjects, trial scope, or scientific integrity of the protocol. 
 
1. The trial design has been modified as follows: 
a. The expected sample size of the trial has been increased to 6178 subjects. This is 
based on a revision of the lower bound of the two-sided 95% confidence interval 
for vaccine efficacy which has been increased from >15% to >30% in order to apply 
a more stringent criterion requiring the product to be more than modestly effective. 
b. The trial design has been modified to utilize a staggered approach to enrollment 
by initiating dosing in the 18-50 year old subjects and to expand enrollment to 
include subjects older than 50 years of age when safety and immunogenicity in 
this older age group has been confirmed using data due to be available from the 
ongoing COVID19-001 clinical trial.  
i. Additionally, minimum targets of 15% of the total sample size of subjects in 
the 51-64 age category and 5% of the total sample size of subjects in the 
65 years and older category have been included.  Stipulating a minimum 
enrollment of subjects 51 years of age or older will ensure that those who 
bear disproportionate risk for COVID-19 disease will contribute towards the 
primary endpoint. 
c. The enrollment of 100 seropositive subjects has been removed, as the likelihood 
of generating meaningful efficacy data from that group is low.  
i. Based on this modification, an exclusion criterion has been added to 
exclude subjects with positive SARS-CoV-2 test at Screening. 
2. The endpoints for the trial have been revised as follows: 
a. The primary endpoint surveillance period has been extended from 6 months to 12 
months post-dose 2. This will allow a longer surveillance period to detect COVID-
19 disease cases that will contribute to the primary endpoint. 
b. Secondary endpoints with the surveillance time period starting 14 days post-dose 
2 through 6 months post-dose 2 have been removed for consistency with the 
update to the primary endpoint surveillance period. 
c. A secondary endpoint of all-cause mortality has been added which will 
complement evaluation of COVID-19 disease-specific mortality.  
d. The secondary endpoint related to short term efficacy period has been removed 
as it is unlikely to observe an effect within the short timeframe specified in the 
endpoint. 
e. The definition of seroconversion in the secondary endpoint has been included as 
“at least fourfold rise over baseline”. 
3. The eligibility criteria for the trial has been revised as follows: 
a. Additional description of the target study population has been included in the 
inclusion criteria to provide clarity related to enrollment of subjects “with high risk 
of exposure to SARS-CoV-2”.  The revision to the inclusion criterion will provide 
clarity to the investigator regarding the types of subjects to be recruited. 
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b. We will no longer exclude subjects based on BMI given that vaccines will be 
administered intradermally and should not be influenced by BMI.  
c. The exclusion criterion related to medical conditions has been modified to be more 
inclusive, to permit subjects who may be at greater risk for Severe COVID-19 
disease due to their chronic medical conditions and thereby be more likely to 
benefit from an effective vaccine. 
d. The exclusion criterion that includes a restriction of blood donation has been 
revised to include a restriction for receipt of a blood transfusion within 1 month prior 
to Day 0, which could be an indication of a medical concern that has not been 
identified within other criteria. 
e. The exclusion criterion related to alcohol or substance abuse/dependence has 
been expanded to exclude current illicit drug use but allow for marijuana use. 
4. The Schedule of Events has been revised as follows: 
a. The number of in-person visits has been reduced in favor of phone call visits.  This 
is intended to reduce the need for subjects to travel to the study site for frequent 
visits. The visit and phone call frequency has remained bi-weekly through Day 210 
of the study and has been revised to approximately monthly after Day 210. 
b. A COVID-19 convalescent visit has been added to the Schedule of Events with the 
intent of re-evaluating subjects approximately 28 days after symptom onset for 
subjects with virologically-confirmed COVID-19 infection during the trial. 
c. Collection of safety labs (CBC with differential, Chemistry, routine urinalysis) post-
screening will only be collected in a subset of subjects at selected sites given that 
that there is no requirement for safety laboratory testing for Phase 3 trials as per 
FDA and that there have been no safety concerns identified from earlier studies 
that would require extensive safety laboratory monitoring.  
d. Collection of saliva samples for SAR-CoV-2 RT-PCR testing has been clarified to 
indicate that in-office collection time points for Screening, Day 0, Day 28, EOS and 
COVID-19 visits will be tested at the time of collection. All other saliva specimens 
will be stored frozen and will be selectively tested if a SARS-CoV-2 serology test 
becomes positive.   
e. A subject diary has been added to collect temperature, solicited injection site 
reactions and solicited systemic adverse events for 7 days following each dose in 
a subset of subjects. 
5. Preliminary safety data from the COVID19-001 study has been removed and a reference to 
the INO-4800 Investigator’s Brochure has been added.  The Investigator’s Brochure is the 
standard location for safety and immunogenicity information related to Inovio products. 
6. The case definitions have been revised as follows: 
a. The case definition for virologically-confirmed COVID-19 disease has been 
updated within the protocol to align with the CDC definition. 
b. Case definitions for non-severe and severe COVID-19 disease have been included 
to replace previous definitions for mild, moderate, severe and critical COVID-19 
disease.  The revised case definitions are aligned with CDC definitions. 
c. The case definition for suspected COVID-19 disease has been removed as it is no 
longer needed for the protocol. 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 15-Jun-2020 
CONFIDENTIAL 
Protocol Version: 2.0 
 
Page 6 of 70 
 
7. An Endpoint Adjudication Committee has been added for the purpose of adjudication of 
suspected COVID-19 cases in the trial and clarification has been made to the protocol that 
the adjudication of cases will not be performed by the DSMB. 
8. The requirement to collect serial saliva samples every 2 days for 20 days in the event of acute 
SARS-CoV-2 infection has been removed as this collection did not support any of the study 
endpoints and may be too onerous on subjects when they are ill.   
9. Instruction has been added regarding subjects taking their temperature daily at home starting 
on the Day 0 visit for the duration of the trial and contacting the site in the event of a fever 
higher than 100.4°F/38°C.  This will aid in proactive identification of COVID-19 cases. 
10. The text has been clarified to indicate that during assessment for suspected COVID-19 
disease, the investigator may perform additional diagnostic testing to rule out other possible 
etiologies (e.g. influenza). 
11. Additional procedures were added to help identify vaccine-enhanced disease.  A stopping rule 
was added to reflect that the investigator should notify the Medical Monitor immediately in the 
event of any suspected Severe COVID-19 disease case(s). The sequential steps triggered by 
this notification are delineated to include the possible convening of the DSMB to evaluate the 
unblinded data for signals of vaccine-enhanced disease and render a recommendation 
whether to halt the trial. 
12. Medical Monitor contact information was added to facilitate appropriate communication 
pathways for sites. 
13. The funding source of the trial was clarified to indicate that Inovio Pharmaceuticals is the 
Sponsor and Department of Defense, Joint Program Executive Office is providing funding for 
the study.  
 
 
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INO-4800 
COVID19-311 
Inovio Pharmaceuticals, Inc. 
Clinical Protocol 
Protocol Version Date: 15-Jun-2020 
CONFIDENTIAL 
Protocol Version: 2.0 
Page 7 of 70 
TABLE OF CONTENTS 
Summary of Changes ................................................................................................................ 4 
Table of Contents ....................................................................................................................... 7 
Clinical Protocol Synopsis .........................................................................................................12 
Table 2 - Schedule of Events ....................................................................................................18 
Introduction .................................................................................................................20 
Background and Scientific Rationale ........................................................................... 20 
Background Information .............................................................................................. 20 
Clinical Presentation, Transmission and Immune Response .................................22 
Current Treatment and Unmet Need .....................................................................22 
Rationale for prophylactic vaccine development ......................................................... 23 
Dose and Regimen Rationale ...............................................................................23 
DNA Vaccines.......................................................................................................23 
Use of Electroporation with DNA Vaccines ...........................................................24 
Potential Benefits and Risks ....................................................................................... 25 
Objectives and Purpose ..............................................................................................25 
Hypothesis .................................................................................................................. 25 
Clinical Trial Design and Endpoints ............................................................................25 
Primary Objectives ...................................................................................................... 26 
Primary Endpoints....................................................................................................... 26 
Secondary Objectives ................................................................................................. 26 
Secondary Endpoints .................................................................................................. 26 
Exploratory Objective .................................................................................................. 27 
Exploratory Endpoint ................................................................................................... 27 
Efficacy Assessment ................................................................................................... 27 
Case Definition for Virologically-confirmed COVID-19 Disease: ............................28 
Case Definition for Virologically-confirmed SARS-CoV-2 Infection ........................28 
Safety Assessment ..................................................................................................... 28 
Immunogenicity Assessment ...................................................................................... 29 
Clinical Trial Population ..............................................................................................29 
Inclusion Criteria ......................................................................................................... 29 
Exclusion Criteria ........................................................................................................ 30 
Discontinuation/Withdrawal of Clinical Trial Subjects .................................................. 31 
Clinical Trial Investigational Product Information .........................................................32 
Investigational Product (IP) and Study Device ............................................................ 32 
INO-4800 and Placebo .........................................................................................32 
CELLECTRA® 2000 ..............................................................................................32 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 15-Jun-2020 
CONFIDENTIAL 
Protocol Version: 2.0 
 
Page 8 of 70 
 
 
Dosing Regimens ....................................................................................................... 33 
 
Blinding .................................................................................................................33 
 
Packaging and Labeling .............................................................................................. 33 
 
INO-4800 or Placebo ............................................................................................33 
 
CELLECTRA® 2000 ..............................................................................................33 
 
Handling and Storage ................................................................................................. 34 
 
INO-4800 and Placebo .........................................................................................34 
 
CELLECTRA® 2000 ..............................................................................................34 
 
Preparation and Dispensing ........................................................................................ 34 
 
Use of Study Device ................................................................................................... 34 
 
Investigational Drug and Study Device Accountability ................................................. 34 
 
Investigational Product (IP) Accountability ............................................................34 
 
CELLECTRA® 2000 Accountability .......................................................................35 
 
Return and Destruction of Investigational Drug and Study Device .............................. 35 
 
INO-4800 and Placebo .........................................................................................35 
 
Return of CELLECTRA® 2000...............................................................................35 
 
Clinical Trial Procedures and Schedule ......................................................................36 
 
Procedure by Visit ....................................................................................................... 36 
 
Clinical Trial Screening Evaluations ......................................................................36 
6.1.1.1 Medical History .....................................................................................................36 
 
Clinical Trial Evaluations and Procedures .............................................................37 
6.1.2.1 Day 0 and Day 28 (Dosing Visits) .........................................................................37 
6.1.2.2 Day 7 and Day 35 phone calls (post-dose phone calls) .........................................37 
6.1.2.3 Day 56 Visit ..........................................................................................................38 
6.1.2.4 Phone calls (Days 70, 84, 98, 112, 140, 154, 168, 182, 196, 238, 266, 322, 350, 
and 378) ...............................................................................................................38 
6.1.2.5 Days 126, 210 and 294 Visits ...............................................................................38 
6.1.2.6 Day 393 Visit or EOS ............................................................................................38 
6.1.2.7 COVID-19 Assessment Visit .................................................................................39 
6.1.2.8 COVID-19 Convalescent Visit ...............................................................................39 
 
Informed Consent ....................................................................................................... 40 
 
Assignment of Subject Identification Numbers ............................................................ 40 
 
Safety Evaluations ...................................................................................................... 40 
 
Injection and EP ....................................................................................................42 
 
Management of Pain Due to Electroporation (EP) Procedures ..............................42 
 
Assessment of Laboratory Abnormalities ..............................................................42 
 
Assessment of Clinical Trial Adverse Events (AEs) ..............................................42 
 
Assessment of Injection Site Reactions ................................................................42 
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Clinical Protocol 
Protocol Version Date: 15-Jun-2020 
CONFIDENTIAL 
Protocol Version: 2.0 
 
Page 9 of 70 
 
 
Immunogenicity Assessments ...............................................................................43 
 
Concomitant Medications/Treatments ...................................................................44 
 
Restrictions ...........................................................................................................44 
 
SARS-CoV-2 Testing ............................................................................................44 
 COVID-19 Disease Monitoring ..............................................................................45 
 
Evaluation of Safety and Management of Toxicity ......................................................45 
 
Safety Parameters ...................................................................................................... 45 
 
Adverse Events (AEs) ................................................................................................. 46 
 
Adverse Drug Reaction (ADR) .................................................................................... 46 
 
Serious Adverse Events (SAEs) .................................................................................. 46 
 
Unexpected Adverse Drug Reaction ........................................................................... 47 
 
Unanticipated (Serious) Adverse Device Effect (UADE) .............................................. 47 
 
Device Deficiency ....................................................................................................... 47 
 
Safety and Toxicity Management ................................................................................ 48 
 
Adverse Event of Special Interest (AESI) ..............................................................48 
 
Medically Attended Adverse Event (MAAE) ..........................................................48 
 
Abnormal Laboratory Value ..................................................................................48 
 
Clinical Trial Stopping Rules .................................................................................48 
 
Safety Data Reporting Period, Method of Collection and Submission ......................... 49 
 
Adverse Event Reporting ............................................................................................ 50 
 Submitting the Initial Serious Adverse Event (SAE) Report Form..........................50 
 Recording the Event .............................................................................................50 
 Assessing Severity (Intensity) ...............................................................................50 
 Causal Relationship of Clinical Material to Adverse Events (AEs) .........................51 
 
Reporting Suspected COVID-19 Disease Cases During the Trial ............................... 51 
 
Reporting Pregnancy During the Clinical Trial ............................................................. 52 
 
Reporting Device-Related Complaints or Deficiencies ................................................ 52 
 
Notifying Regulatory Authorities and Institutional Review Boards (IRBs)/Research 
Ethics Boards (REBs)/Ethics Committees (ECs) of Safety Information ....................... 53 
 Sponsor Responsibilities .......................................................................................53 
 Principal Investigator (PI) Responsibilities ............................................................53 
 
Post-Trial Reporting Requirements ............................................................................. 53 
 
Clinical Trial Discontinuation ....................................................................................... 53 
 
Statistical Considerations ...........................................................................................54 
 
Statistical and Analytical Plan ..................................................................................... 54 
 
General Considerations .............................................................................................. 54 
 
Statistical Hypotheses ................................................................................................. 54 
 
Analytical Populations ................................................................................................. 54 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 15-Jun-2020 
CONFIDENTIAL 
Protocol Version: 2.0 
 
Page 10 of 70 
 
 
Description of Statistical Methods ............................................................................... 54 
 
Primary efficacy Analysis ......................................................................................54 
 
secondary Analyses ..............................................................................................55 
 
Safety Analyses ....................................................................................................56 
 
Disposition ............................................................................................................56 
 
Demographic and Other Baseline Characteristics .................................................56 
 
Interim Analyses ...................................................................................................57 
 
Multiplicity .............................................................................................................57 
 
Missing Values......................................................................................................57 
 
Exploratory Analyses ............................................................................................57 
 
Sample Size/Power ..................................................................................................... 58 
 
Randomization and Blinding ....................................................................................... 58 
 
Ethics .........................................................................................................................58 
 
Investigator and Sponsor Responsibilities ................................................................... 58 
 
Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics Committee (EC)
 ................................................................................................................................... 58 
 
Protection of Human Subjects ..................................................................................... 59 
 
Compliance with Informed Consent Regulations ...................................................59 
 
Compliance with Institutional Review Board (IRB)/Research Ethics Board 
(REB)/Ethics Committee (EC) Requirements ........................................................59 
 
Compliance with Good Clinical Practice ................................................................59 
 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11) .....59 
 
Compliance with Protocol .....................................................................................59 
 
Changes to the Protocol .......................................................................................60 
 
Data Collection, Monitoring and Reporting ..................................................................60 
 
Confidentiality and Privacy .......................................................................................... 60 
 
Source Documents .....................................................................................................60 
 
Records Retention ...................................................................................................... 61 
 
Safety and Quality Monitoring .....................................................................................61 
 
Safety Review ............................................................................................................. 61 
 
Clinical Monitoring....................................................................................................... 61 
 
Financing and Insurance ............................................................................................62 
 
Publication Policy .......................................................................................................62 
 
List of Abbreviations ...................................................................................................63 
 
References .................................................................................................................65 
 
Appendices .................................................................................................................68 
 
APPENDIX A: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trial ............................................................... 68 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 15-Jun-2020 
CONFIDENTIAL 
Protocol Version: 2.0 
 
Page 11 of 70 
 
 
APPENDIX B: Adverse Events of Special Interest ...................................................... 70 
 
 
 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 15-Jun-2020 
CONFIDENTIAL 
Protocol Version: 2.0 
 
Page 12 of 70 
 
CLINICAL PROTOCOL SYNOPSIS 
Protocol Title: Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the 
Safety, Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-19 
Disease, Administered Intradermally Followed by Electroporation in Healthy Adults at High 
Risk of SARS-CoV-2 Exposure 
Protocol Number: COVID19-311 
Clinical Trial Phase: 3 
Estimated Number of Clinical Trial Centers and Countries/Regions: Up to 30 centers in 
the US 
Background:   
INO-4800 is a prophylactic vaccine under development against SARS-CoV-2, the causative 
agent of COVID-19. INO-4800 contains the plasmid pGX9501, which encodes for the full 
length of the Spike glycoprotein of SARS-CoV-2. The goal of this trial is to assess the safety, 
immunogenicity and efficacy of INO-4800 to prevent COVID-19 disease in subjects at high 
risk of exposure to SARS-CoV-2.  
 
Clinical Trial Design:  
This is a Phase 3, randomized, placebo-controlled, multi-center trial to evaluate the safety, 
immunogenicity, and efficacy of INO-4800 (1.0mg), administered by intradermal (ID) injection 
followed immediately by electroporation (EP) using CELLECTRA® 2000 device using a 2-
dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-2 exposure. The 
primary objective of this trial is to evaluate the efficacy of INO-4800 in seronegative subjects.  
 
Approximately 6178 seronegative subjects 18 years of age or older are expected to be 
enrolled and will be randomized at a 1:1 ratio to receive either investigational product (1.0mg 
INO-4800) or placebo (SSC-0001). See Table 1.  Enrollment at the start of the trial will be 
initiated in subjects 18-50 years of age. Following confirmation that the COVID19-001 Phase 
1 trial’s safety and immunogenicity data is acceptable in subjects older than 50 years of age, 
the trial will expand enrollment to include subjects older than 50 years of age.  A minimum of 
15% of the total sample size of subjects will be 51-64 years of age, and a minimum of 5% of 
the total sample size of subjects will be 65 years of age and older. 
 
 
Table 1: COVID19-311 Dose Groups 
Study 
Group 
Expected 
Number of 
Subjects 
Dosing 
Days 
Number of  
Injections + 
EP per Dosing 
Visit 
INO-4800 
(mg) per 
injection 
Total 
Dose  
INO-4800 
3089 
0, 28 
1 
1.0 mg 
2.0 mg  
Placebo 
3089 
0, 28 
1 
0 
0 
Total 
6178 
 
 
 
 
 
The trial is case-driven. Among seronegative subjects, a total of 160 observed cases will be 
required for 90% power to declare the vaccine efficacious (>30%), assuming a true efficacy 
of 60%.  A sample size of 6178 seronegative subjects is expected to be required to achieve 
the 160 cases assuming an underlying attack rate of 3.7%. The sample size may be 
increased if the underlying attack rate is lower than projected.   
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 15-Jun-2020 
CONFIDENTIAL 
Protocol Version: 2.0 
 
Page 13 of 70 
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12-
months post-dose 2.  
 
All subjects, investigating site staff (excluding site pharmacy staff) and the Sponsor will be 
blinded throughout the trial. A group-level unblinding will occur when all subjects’ data is 
complete for the primary efficacy timeframe. 
 
A Data Safety Monitoring Board (DSMB) will convene regularly throughout the trial to review 
unblinded safety data. An independent, blinded Endpoint Adjudication Committee (EAC) will 
review and confirm COVID-19 cases. Details of each committee’s scope will be provided in 
charters.  
Criteria for Evaluation:  
 
Research Hypothesis:  
INO-4800 delivered ID followed by EP using CELLECTRA® 2000 will provide protection 
against virologically-confirmed COVID-19 in subjects at high risk of SARS-CoV-2 
exposure.  
 
Primary Objective 
Associated Primary Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease  
 
1. Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 2-
dose regimen until 12 months post-dose 2 (End of 
Study (EOS))  
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of 
INO-4800    
 
1a. Incidence of solicited and unsolicited injection site 
reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality 
 
2. Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of disease severity  
2a.  Incidence of non-severe COVID-19 disease 
starting 14 days after completion of the 2-dose 
regimen until EOS  
2b. Incidence of severe COVID-19 disease starting 14 
days after completion of the 2-dose regimen until 
EOS 
2c. Incidence of deaths due to COVID-19 starting 14 
days after completion of the 2-dose regimen until 
EOS 
3.   Evaluate the efficacy of INO-4800 in the 
prevention of SARS-CoV-2 infection  
3.   Incidence of virologically-confirmed SARS-CoV-2 
infections starting 14 days after completion of the 
2-dose regimen until EOS 
4. Evaluate the timing of symptom 
resolution in subjects who develop 
COVID-19 disease  
4.   Days to symptom resolution in subjects developing 
COVID-19 disease 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 15-Jun-2020 
CONFIDENTIAL 
Protocol Version: 2.0 
 
Page 14 of 70 
 
5.   Evaluate the binding antibody 
response to INO-4800  
5a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody titers  
5b. Incidence of seroconversion (at least fourfold rise 
over baseline) by SARS-CoV-2 Spike glycoprotein 
antigen specific binding antibody assay  
Exploratory Objective 
Associated Exploratory Endpoint 
1. Evaluate the expanded immunological 
profile by assessing both neutralizing 
antibody response and T cell immune 
responses 
1a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot 
1b. Neutralizing antibody response measured by live 
virus neutralizing or pseudovirus assays  
 
 
Efficacy Assessment:  
Subjects will receive either investigational product (1.0mg INO-4800) or placebo (SSC-0001) 
in a 2-dose regimen administered on Days 0 and 28 intradermally followed immediately by 
EP. Subjects will be monitored through regularly scheduled clinic visits and phone calls 
throughout the trial. Subjects will be regularly tested for SARS-CoV-2 infection using 
serologic testing. If COVID-19 disease is suspected based on symptoms or laboratory 
testing, site personnel will arrange for a clinic visit. Subjects with symptom(s) or a positive 
virologic test result confirmation will be reviewed by the EAC.  
Safety Assessment:  
Subjects will be followed for safety during the entire duration of trial participation through 
scheduled clinic visits and phone calls. AEs, regardless of relationship to study drug, will be 
collected from the time of consent until 28 days post-dose 2. Solicited local and systemic 
AEs will be collected for 7 days following each dose. SAEs, Medically Attended Adverse 
Events (MAAEs) and AESIs will be collected from time of consent until EOS. SAEs, AESIs 
and treatment-related AEs will be followed to resolution or stabilization.  
Please refer to the Schedule of Events (Table 2) for safety assessments to be performed.  
Immunogenicity Assessment:  
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 2).  Assays such as Binding ELISA, neutralizing antibody, and ELISpot will be evaluated 
at serial timepoints. 
Clinical Trial Population: 
Healthy subjects at high risk for SARS-CoV-2 exposure who are 18 years or older. 
Inclusion Criteria: 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, physical 
examination and vital signs performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working in an environment with high risk of exposure to SARS-CoV-2 for whom 
exposure may be relatively prolonged or for whom personal protective equipment 
(PPE) may be inconsistently used:  
1. Retail/service workers (restaurant waitresses/waiters and bar workers, store 
cashiers, hairdressers and barbers, veterinary staff, daycare workers, 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 15-Jun-2020 
CONFIDENTIAL 
Protocol Version: 2.0 
 
Page 15 of 70 
 
Transportation Security Administration screening staff, and elementary school 
teachers) 
2. Factory workers (when working in confined settings with large numbers of 
employees) 
3. Nursing home staff or correctional facility staff  
4. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) 
5. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists but not necessarily physicians unless they are 
assigned to dedicated COVID-19 treatment wards or other settings with 
prolonged exposure) 
6. Others, if approved by the medical monitor.   
f. Screening laboratory results within normal limits for testing laboratory or deemed not 
clinically significant by the Investigator; 
g. Negative serological tests for Hepatitis B surface antigen (HBsAg), Hepatitis C antibody 
and Human Immunodeficiency Virus (HIV) antibody or rapid test at screening (subjects 
who are positive for Hepatitis C antibody but are in remission as defined by 
undetectable HCV RNA level ≥ 12 weeks after completion of HCV therapy may be 
enrolled) 
h. Must meet one of the following criteria with respect to reproductive capacity: 
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or 
tubal ligation, absence of ovaries and/or uterus in females). In the case of 
vasectomy, subjects should wait six (6) months post-vasectomy prior to 
enrolling;  
• 
Use of medically effective contraception with a failure rate of < 1% per year 
when used consistently and correctly from screening until 3 months following 
last dose. Acceptable methods include:  
o hormonal contraception including implants, injections or oral; 
o two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
o abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Exclusion Criteria: 
a. Acute febrile illness with temperature >100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat); 
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the screening visit until 3 
months following the last dose; 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0; 
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Clinical Protocol 
Protocol Version Date: 15-Jun-2020 
CONFIDENTIAL 
Protocol Version: 2.0 
 
Page 16 of 70 
 
f. Previous receipt of an investigational vaccine for prevention or treatment of COVID-19, 
MERS or SARS; documented receipt of placebo in previous trial would be permissible 
for trial eligibility. 
g. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg at Screening; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin 
cancers that only required local excision; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in 
therapy or hospitalization for worsening disease during the 6 weeks prior to 
enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a 
single antiepileptic agent; 
h. Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies; 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed); 
• 
Current or anticipated use of disease modifying doses of anti-rheumatic drugs 
(e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic 
disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, adalimumab 
or etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of receipt of any other clinically significant immunosuppressive drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the 
subject or require therapy that would interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results. 
i. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation 
site; 
j. 
Blood donation or transfusion within 1 month prior to Day 0; 
k. Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
l. 
Reported ongoing smoking or vaping; 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the past 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 15-Jun-2020 
CONFIDENTIAL 
Protocol Version: 2.0 
 
Page 17 of 70 
 
Clinical Trial Treatment: 
Investigational Product: A single 1.0mg ID injection of INO-4800 (~0.1mL dose volume) 
followed immediately by EP administered at Day 0 and Day 28 (±3 days) 
Placebo: A single ID injection of saline sodium citrate buffer (SSC-0001) (~0.1mL) followed 
immediately by EP administered at Day 0 and Day 28 (±3 days) 
Formulation: 
INO-4800 is formulated in sodium chloride and sodium citrate (SSC) buffer, refrigerated.  
 
 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
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TABLE 2 - SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Tel 
#1 
Wk 
4 
Tel 
#2 
Wk
8 
Tel 
#3-
6 
Wk 
18 
Tel 
#7-
11 
Wk 
30 
Tel 
#12
-13 
Wk
42 
Tel 
#14
-16 
Wk 
56 
Illness 
Illness  
Screena 
Day 0 
Phone call - Day 7 (±3d) 
Day 28 
(±3d) 
Phone call - Day 35 (±3d) 
Day 56 (±5d) 
Phone call - Days 70, 84, 98, 
112 (±5d) 
Day  126 (±5d) 
Phone calls - Days 140, 154 
168, 182, 196 (±5d) 
Day 210 (±5d) 
Phone calls - Days 238, 266 
(±5d) 
Day 294 (±5d) 
Phone calls 
Days 322, 350, 378 (±5d) 
Day 393 (± 5d) 
COVID-19 assessment visitn  
COVID-19 convalescent visito 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Vital Signs 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
X 
Xp 
 
 
Xp 
 
 
Xp 
 
 
 
 
 
 
 
X 
X 
 
Chemistryc 
X 
Xp 
 
 
Xp 
 
 
Xp 
 
 
 
 
 
 
 
X 
X 
 
HIV, HBV, HCV Serology  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis Routined 
X 
Xp 
 
 
Xp 
 
 
Xp 
 
 
 
 
 
 
 
X 
X 
 
Pregnancy Teste 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
INO-4800 or Placebo + EPf 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Download EP Datag 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Eventsh  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Samplesi 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
Humoral Samplesj 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
SARS-CoV-2 Serologyk 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
SARS-CoV-2 RT-PCR 
(Saliva) l 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xm 
Distribute Diaryp 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review/Collect Diaryp,q 
 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0.   
b. 
Full physical examination only at screening and Day 393 (or EOS). Targeted physical exam at all other visits. 
c. 
Includes Na, K, Cl, HCO3, Ca, PO4, glucose, BUN, Cr, alkaline phosphatase, AST, ALT, LDH, total bilirubin, and hemoglobin A1c (hemoglobin A1c collected at screening only). 
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d. 
Dipstick for glucose, protein, and hematuria. Microscopic examination should be performed if dipstick is abnormal.  
e. 
Serum pregnancy test at screening. Urine pregnancy test at other visits.  
f. 
An intradermal injection in skin preferably over deltiod muscle followed by EP at Day 0 and Day 28. 
g. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
h. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
i. 
Cellular responses utilizing ELIspot assay requires 34 mL of whole blood; collect 8.5 mL of whole blood in each of four 10 mL Acid Citrate Dextrose (ACD, Yellow top) tubes per time point. 
Note: Collect a total of 68 mL whole blood on Day 0 prior to 1st dose. 
j. 
Humoral responses utilizing the S-Binding ELISA, NP-Binding ELISA and SARS-CoV-2 neutralization assays require a total of 8.5 mL of serum collected in a 10-mL red top serum 
collection tube per time point. Note: Collect four aliquots of 1 mL each (total 4 mL) prior to dosing on Day 0 and at each time point. 
k. 
SARS-CoV-2 antibody.   
l. 
Saliva will be collected at study visits and bi-weekly at home between office visits.  In-office collection time points for Screening, Day 0, Day 28, EOS and COVID-19 visits will be 
tested at the time of collection. All other saliva specimens will be stored frozen and will be selectively tested if a SARS-CoV-2 serology test becomes positive. The Day 0 and Day 28 
RT-PCR results will not be required prior to dosing on that day. 
m. 
Nasopharyngeal, oropharyngeal swabs and saliva specimens.  
n. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The virologic confirmation of a case will be based on SARS-CoV-2 RT-PCR. 
Additional safety testing will be collected to understand the impact on various organ systems. Additional diagnostic testing (e.g., influenza diagnostics) may be ordered at the discretion 
of the Investigator.  
o. 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of 
symptoms, the date of positive SARS-CoV-2 test.  
p. 
Implemented in approximately 500 subjects from selected sites.  
q. 
Diary should be reviewed at the 7 day post-dose phone call and collected at the next in-office visit. 
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Inovio Pharmaceuticals, Inc. 
 
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Protocol Version Date: 15-Jun-2020 
CONFIDENTIAL 
Protocol Version: 2.0 
 
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INTRODUCTION 
This document is a protocol for a human research trial to be conducted according to US 
and international standards of Good Clinical Practice (GCP) (FDA Title 21 part 312, 812 
and International Conference on Harmonization (ICH) guidelines), applicable government 
regulations and Institutional research policies and procedures. 
 
BACKGROUND AND SCIENTIFIC RATIONALE 
The lack of available therapy in conjunction with increasing numbers of global cases 
indicate that SARS-CoV-2 infection remains a serious unmet medical concern. 
Appropriate measures to prevent, control and treat existing and future infections are in 
dire need. 
 
BACKGROUND INFORMATION 
In late 2019, a cluster of cases of pneumonia of unknown etiology was reported in Wuhan, 
Hubei province, China [1-3]. These cases were announced on January 6, 2020 as testing 
negative for influenza, SARS, and MERS. On January 7, 2020 a novel virus was isolated 
by the Chinese Center for Disease Control and Prevention (CDC) from the throat swab 
sample of a patient, and the isolate was named “Wuhan-Hu-1.” The gene sequence of 
that isolate was then generated and determined to be of a novel coronavirus [4, 5]. That 
gene sequence was publically posted on January 10, and the novel coronavirus was 
preliminarily named 2019-nCoV. Subsequently, on February 11, 2020, the virus was 
named SARS-CoV-2 by the International Committee on Taxonomy of Viruses (ICTV) [6, 
7], due to its similarity with the original SARS virus. That same day, the World Health 
Organization (WHO) announced a specific name of the disease, “COVID-19,” associated 
with infection by this novel coronavirus, as based on the novel coronavirus origin and year 
of first reported cases. The cluster of human cases first identified pneumonia of unknown 
origin infections was comprised people who worked, visited, or lived around the local 
Huanan seafood wholesale market in Wuhan, where live animals and fresh meat and fish 
were on sale, suggesting an animal as the source of the novel virus transmission to 
humans. 
The first U.S. case of COVID-19 was detected in Washington State, confirmed on and as 
announced January 21, 2020 by the Washington State Department of Health and the U.S. 
Centers for Disease Control and Prevention (US CDC) [8].  That was a case of a traveler 
who had returned from Wuhan, China. Since that case detection, human-to-human local 
transmission began (or continued from previously undetected infections) in the U.S., and 
as of May 17, 2020, nearly 1.5 million lab-confirmed US COVID-19 cases and nearly 
90,000 US deaths due to COVID-19 have been reported [9]. COVID-19 cases have been 
reported from all 50 states and several territories.  
SARS-CoV-2 infection rapidly emerged as a global threat to public health, joining severe 
acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) 
infectious agents in a growing number of coronaviruses which have evolved to infect 
humans. COVID-19 was declared a Public Health Emergency of International Concern 
(PHEIC) by the WHO on January 20, 2020, and then progressed to be declared on March 
11, 2020 as a pandemic [10], associated with substantial morbidity and mortality [11].   The 
pandemic of COVID-19 includes scope of lab-confirmed cases reported by virtually all 
countries and COVID-19 deaths reported by many of those countries.  As of May 17, 2020, 
a total of over 4.7 million lab-confirmed COVID-19 cases have been reported 
internationally, including nearly 315,000 deaths [9]. However, and very importantly, 
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because this is from a new pathogen and thus lab testing and reporting are not widely 
available and thus incomplete, the true number of cases of COVID-19 is likely far higher 
than reported, and the true number of SARS-CoV-2 infections – regardless of disease – 
is thought to be many (perhaps dozens of) times the number of detected infections and 
reported COVID-19 cases. 
An article in JAMA by Wu and McGoogan [12] provided a summary of a major report by 
the Chinese Center for Disease Control and Prevention (China CDC) [13].  That report 
found that among a total of 72,314 case records, 44,672 were classified as confirmed 
cases of SARS-CoV-2 infection (62%; diagnosis based on positive viral nucleic acid test 
result on throat swab samples), 16,186 as suspected cases (22%; diagnosis based on 
symptoms and exposures only, no test was performed because testing capacity was 
insufficient to meet current needs), 10,567 as clinically diagnosed cases (15%; this 
designation is being used in Hubei Province only; in these cases, no test was performed 
but diagnosis was made based on symptoms, exposures, and presence of lung imaging 
features consistent with coronavirus pneumonia), and 889 as asymptomatic cases (1%; 
diagnosis by positive viral nucleic acid test result but lacking typical symptoms including 
fever, dry cough, and fatigue) [14]. The overall case-fatality ratio (CFR) was 2.3% (1023 
deaths among 44,672 confirmed cases). No deaths occurred in the group aged 9 years 
and younger, but cases in those aged 70 to 79 years had an 8.0% CFR and cases in those 
aged 80 years and older had a 14.8% CFR. The CFR was 49.0% among critical cases. 
CFR was elevated among those with preexisting comorbid conditions - 10.5% for 
cardiovascular disease, 7.3% for diabetes, 6.3% for chronic respiratory disease, 6.0% for 
hypertension, and 5.6% for cancer [14]. These initial reports of the CFR documented the 
level of seriousness of COVID-19.  
Because of the novelty of SARS-CoV, the COVID-19 it causes and the serious outcomes 
in some patients, and the speed of propagation worldwide, unsurprisingly there has been 
an explosion of epidemiological, clinical, virological, and other data have emerged from 
China, the United States, and many other countries about this new virus and disease.  
These data in summary have further established that 1) SARS-CoV-2 is transmitted 
person-to-person [15], even from those asymptomatic or presymptomatic [16-18], 2) the 
virus is very infectious, with estimates of the R0 (Reproductive number) ranging from 1.5 
to 6.49, with a mean average of 3.28 and a median average of 2.79 [19], 3) the 
constellation of symptoms, signs, and an incubation period range of 2 to 14 days [20], and 
4)  the asymptomatic proportion of those infected being substantial, perhaps 50% or even 
up to 80% [15, 21, 22]. Further, research has found that the risk of death from COVID-19 
increases with age and for those with serious, comorbid conditions including hypertension, 
diabetes, cardiovascular disease, obesity, etc.   
Finally, although much has been learned very quickly about SARS-CoV-2 and COVID-19, 
much more is still to be determined. The aforementioned case-fatality ratio and similar 
estimates are from crude analyses that have only or largely been of moderate to serious 
cases and not included minor cases that did not present to health care. Therefore, the true 
CFR is likely significantly lower. Further, the infection-fatality ratio (IFR), which is the 
proportion who die among all those infected regardless of any symptomology, is likely still 
even lower than the CFR, but both the CFR and IFR will not be known with certainty until 
well-designed and controlled seroepidemiology surveys have been conducted using well-
validated antibody assays and thorough questionnaires to obtain symptom history.  Also, 
the presence of natural immunity of those infected who survive and the durability of such 
natural immunity is to be determined. Thus the existence and possibility of reinfection and 
recurrent infection is unknown. 
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Protocol Version: 2.0 
 
Page 22 of 70 
 
 CLINICAL PRESENTATION, TRANSMISSION AND IMMUNE RESPONSE 
A study in The Lancet by Huang and colleagues [3] reported the epidemiological, clinical, 
laboratory, and radiological characteristics, as well as treatment and clinical outcomes, of 
patients with laboratory-confirmed COVID-19 pneumonia. Common symptoms at onset of 
illness were fever (n=40, 98% of 41 patients), cough (n=31, 76%), and myalgia or fatigue  
(n=18, 44%);  less  common  symptoms  were  sputum  production  (n=11, 28%  of  39 
patients),  headache  (n=3, 8%  of  38 patients), hemoptysis (n=2, 5% of 39 patients), and 
diarrhea (n=1, 3% of 38 patients). Dyspnea developed in 22 (55%) of 40 patients (median 
time from illness onset to dyspnea was 8 days [Interquartile range 5 - 13 days]). Twenty 
six (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal 
findings on chest CT scan. Complications included acute respiratory distress syndrome 
(n=12, 29%), RNAaemia (n=6, 15%), acute cardiac injury (n=5 12%) and secondary 
infection (n=4, 10%).  
Transmission of SARS-CoV-2 occurred mainly after days of illness [23] and was 
associated with modest viral loads in the respiratory tract early in the illness, with viral 
loads peaking approximately 10 days after symptom onset [24]. Higher viral loads were 
detected soon after symptom onset, with higher viral loads detected in the nose than in 
the throat. Analysis of these samples suggested that the viral nucleic acid shedding 
pattern of patients infected with SARS-CoV-2 resembles that of patients with influenza 
[25] and appears different from that seen in patients infected with SARS-CoV [24]. The 
viral load that was detected in the asymptomatic patient was similar to that in the 
symptomatic patients, which suggests the transmission potential of asymptomatic or 
minimally symptomatic patients [11]. The SARS-CoV-2 transmission time window from 
COVID-19 patients is perhaps 2 days before symptom onset up to 37 days after symptom 
onset [18]. 
T cells play a critical role in antiviral immunity but their numbers and functional state in 
SARS-CoV-2 infected patients remain largely unclear. Diao and colleagues performed a 
retrospective review of the counts of total T cells, and CD4+and CD8+ T cell subsets, as 
well as serum cytokine concentration based on inpatient data from 522 patients with 
laboratory-confirmed SARS-CoV-2 infection, admitted into two hospitals in Wuhan from 
December 2019 to January 2020, and 40 healthy controls in the same two hospitals 
receiving routine physical examination. The number of total T cells, and CD4+ and CD8+ 
T cells were dramatically reduced in COVID-19 infected patients, especially among elderly 
patients (≥60 years of age) and in patients requiring Intensive Care Unit (ICU) care. Counts 
of total T cells, CD8+ T cells or CD4+ T cells lower than 800/μL, 300/μL, or 400/μL, 
respectively, are negatively correlated with patient survival [26]. 
 CURRENT TREATMENT AND UNMET NEED 
Hospitals can provide supportive care for infected people. Currently, no licensed 
preventative vaccine or anti-viral therapy is available as indicated for SARS-CoV-2 
infection or COVID-19, except for Emergency Use Authorization (EUA). Clinical 
management includes prompt implementation of recommended infection prevention and 
control measures and supportive management of complications, including advanced 
organ support if indicated. Remdesivir has received Emergency Use Authorization for 
treatment of suspected or laboratory confirmed COVID-19 in adults and children 
hospitalized with severe disease [27]. Chloroquine Phosphate also has received EUA for 
treatment of adults and adolescents who are hospitalized with COVID-19 for whom a 
clinical trial is not available [28]. Hydyroxychloroquine, with and without azithromycin, is 
being investigated in multiple clinical trials, as is plasma-derived polyclonal antibodies and 
immune globulin, among other therapies.  
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Clinical Protocol 
Protocol Version Date: 15-Jun-2020 
CONFIDENTIAL 
Protocol Version: 2.0 
 
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RATIONALE FOR PROPHYLACTIC VACCINE DEVELOPMENT 
SARS-CoV-2 has become a pandemic resulting in substantial morbidity and mortality. No 
specific treatment for COVID-19 is currently available, thus highlighting the need for 
effective therapeutic and preventive solutions. Due to rapid spread of SARS-CoV-2 
infections even from asymptomatic and mildly infected patients, there is an urgent need 
for appropriate measures to prevent, control and treat existing and future infections.  
To address this critical need for a medical countermeasure for prevention of further 
dissemination of SARS-CoV-2, we have employed our synthetic DNA-based vaccine 
technology. This technology is highly amenable to accelerated developmental timelines, 
due to the ability to rapidly design multiple test constructs, manufacture large quantities of 
the drug product, and the possibility of leveraging established regulatory pathways to the 
clinic. Furthermore, this technology has demonstrated proof of concept efficacy and safety 
in humans in a phase 2b randomized, double-blind, placebo-controlled study [29], for 
human papillomavirus (HPV) associated cervical pre-cancer and is currently in two 
multinational phase 3 trials for that indication (NCT03185013 and NCT03721978) and 
several phase 2 trials for related and other indications. For the development of a SARS-
COV-2 vaccine candidate, we have built upon our prior experience in developing a MERS 
coronavirus (MERS-CoV) vaccine. In a phase 1 clinical study, the MERS-CoV coronavirus 
vaccine was well tolerated and immune response was induced in more than 85% of 
participants after two vaccinations, and durable through 1 year of follow-up [30]. 
 DOSE AND REGIMEN RATIONALE 
The intended use for INO-4800 is for both routine prophylaxis and use during an outbreak 
situation. As such, there is a desire to demonstrate the ability of the vaccine to drive 
immune responses within 4-8 weeks of administration, which supports evaluation of a 
dose regimen that includes Day 0 and Day 28. 
In this study, 1.0 mg of vaccine is administered by ID injection and followed by EP at Day 
0 and Day 28. The dose selection is supported by the well tolerated safety profile in the 
phase 1 trial of INO-4800 (COVID19-001, NCT04336410) as well as our prior experience 
in developing a MERS coronavirus (MERS-CoV) vaccine (INO-4700) [16, 17].  
Safety data for INO-4800 is provided in the Investigator’s Brochure.   
 DNA VACCINES 
Since the 1990s, a novel approach to vaccination against a broad array of target antigens 
and diseases has been in development. This involves the direct introduction of plasmid 
deoxyribonucleic acid (DNA) containing the gene encoding the immunogen against which 
an immune response is sought into appropriate host tissues and the in situ production of 
the target immunogen(s). This approach offers a combination of potential advantages, 
including the stimulation of both B and T-cell responses, stability of the vaccine across a 
broad temperature range, absence of infectivity of the immunogen itself, the speed with 
which the vaccine can be constructed (for example in the face of an epidemic or pandemic 
as it is the case here with SARS-CoV-2), and the relative ease and generic nature of large-
scale manufacture. Many scientific publications have addressed the potential of DNA 
vaccination [31-40]. Immune responses in animal models have been obtained using genes 
from a variety of infectious agents including influenza viruses, hepatitis B virus, human 
immunodeficiency virus, human papillomaviruses, Marburg virus, Middle East Respiratory 
Syndrome (MERS) coronavirus, rabies virus, Severe Acute Respiratory Syndrome 
(SARS) coronavirus, West Nile virus (WNV), Zika virus, and other infectious agents as 
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Protocol Version: 2.0 
 
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plasmodium, mycoplasma, and many more [39, 41]. In many cases, protection from 
disease in animal models has also been demonstrated.  
DNA vaccines are able to generate both CD4+ and CD8+ T cell responses. The ability to 
generate MHC-Class I restricted CD8+ T cells (cytolytic T lymphocytes), which generally 
are not made following administration of inactivated viruses, proteins or peptides, may be 
important for key responses against certain pathogens, as well as enabling cross-strain 
specific responses when many antibody responses are strain-specific. Because the 
encoded protein is synthesized in vivo by the host following administration, DNA vaccines 
can encode membrane-bound proteins instead of solely the soluble versions [42]. This 
can be important because key neutralizing epitopes are located in regions that would be 
excluded, or not formed in a monomeric truncated soluble version. Some early research 
in COVID-19 control has already suggested that neutralizing antibodies may not be 
sufficient and that cell-mediated immunity may be necessary [43]. 
Unlike certain other vectors (such as heterologous viral vectors), DNA vaccines do not 
stimulate adaptive immune responses against themselves, although the DNA itself does 
stimulate certain innate immune responses [44]. In other words, they do not generate anti-
vector immunity that could stunt antigen-specific responses following multiple exposures. 
 USE OF ELECTROPORATION WITH DNA VACCINES 
Electroporation (EP) enhances gene expression of plasmid DNA delivered by the 
intramuscular (IM) or intradermal (ID) routes of administration (Figure 1). Following IM or 
ID delivery of a DNA vaccine or therapeutic product, EP facilitates entry of the DNA into 
the target site: muscle or dermal cells. Following cellular uptake, there is efficient 
production of the proteins encoded by the DNA expression plasmid system. The different 
EP devices, each with varying electrical parameters and protocols, have been reviewed 
[45]. EP has been extensively tested in animal species such as dogs, pigs, cattle, and 
NHPs to deliver therapeutic genes that encode for a variety of hormones, cytokines, 
enzymes or antigens [45] for the activation of both cellular and humoral responses [46, 
47]. Importantly, immune responses generated by DNA vaccines delivered with EP are far 
superior to responses to the same vaccines delivered without EP [47]. IM and ID delivery 
of DNA vaccines with EP has been studied extensively, and optimum conditions for 
plasmid uptake and expression have been described for therapeutic indications, vaccines 
and tumor animal model systems [48, 49].  
The Inovio Pharmaceuticals’ constant current EP device [45] referred to as the 
CELLECTRA® 2000 for ID administration (3P-ID) device will be used in this clinical trial. 
The ID route of delivery has been selected for INO-4800 based on recent findings from 
multiple DNA vaccine development programs where ID delivery has driven equivalent if 
not superior humoral and cellular responses while improving tolerability (clinicaltrials.gov 
NCT02464670, clinicaltrials.gov NCT02431767) [50]. 
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Protocol Version: 2.0 
 
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Figure 1: How Electroporation Works in the Body 
 
 
POTENTIAL BENEFITS AND RISKS 
No specific AE has been identified as a risk. There may be potential benefit for prevention 
of COVID-19 disease, but efficacy is still unknown.  Data gathered in this trial will be useful 
for future development of this prophylactic vaccine against SARS-CoV-2 infection. 
Additional details regarding the benefits and risks for subjects participating in this clinical 
trial may be found in the Investigator’s Brochure (IB). 
 
OBJECTIVES AND PURPOSE 
The overall purpose of this clinical trial is to evaluate the safety and efficacy of INO-4800 
for future development. 
 
HYPOTHESIS 
INO-4800 delivered ID followed immediately by EP using CELLECTRA® 2000 will provide 
protection against virologically-confirmed COVID-19 in subjects at high risk of SARS-CoV-
2 exposure.  
 
CLINICAL TRIAL DESIGN AND ENDPOINTS 
This is a Phase 3, randomized, placebo-controlled, multi-center trial to evaluate the 
safety, immunogenicity, and efficacy of INO-4800 (1.0mg), administered by intradermal 
(ID) injection followed immediately by electroporation (EP) using CELLECTRA® 2000 
device using a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-
CoV-2 exposure. The primary objective of this trial is to evaluate the efficacy of INO-4800 
in seronegative subjects.  
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Approximately 6178 seronegative subjects 18 years of age or older are expected to be 
enrolled and will be randomized at a 1:1 ratio to receive either investigational product 
(1.0mg INO-4800) or placebo (SSC-0001). See Table 1. Enrollment at the start of the trial 
will be initiated in subjects 18-50 years of age. Following confirmation that the COVID19-
001 Phase 1 trial’s safety and immunogenicity data is acceptable in subjects older than 
50 years of age, the trial will expand enrollment to include subjects older than 50 years 
of age.  A minimum of 15% of the total sample size of subjects will be 51-64 years of age, 
and a minimum of 5% of the total sample size of subjects will be 65 years of age and 
older. 
 
The trial is case-driven. Among the 6178 subjects, a total of 160 observed cases will be 
required for 90% power to declare the vaccine efficacious (>30%), assuming a true 
efficacy of 60%.  A sample size of 6178 seronegative subjects is expected to be required 
to achieve the 160 cases assuming an underlying attack rate of 3.7%.  The sample size 
may be increased if the underlying attack rate is lower than projected.  
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12-
months post-dose 2.  
 
All subjects, investigating site staff (excluding site pharmacy staff) and the Sponsor will 
be blinded throughout the trial. A group-level unblinding will occur when all subjects’ data 
is complete for the primary efficacy timeframe. 
A Data Safety Monitoring Board (DSMB) will convene regularly throughout the trial to 
review unblinded safety data. An independent, blinded EAC will review and confirm 
COVID-19 cases. Details of each committee’s scope will be provided in charters. 
 
PRIMARY OBJECTIVES 
See Table 3. 
 
PRIMARY ENDPOINTS 
Table 3: Primary Objective and Associated Endpoints 
Primary Objective 
Associated Primary Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease  
1. Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 
(End of Study (EOS))  
 
SECONDARY OBJECTIVES 
See Table 4. 
 
SECONDARY ENDPOINTS 
Table 4: Secondary Objectives and Associated Endpoints 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability 
of INO-4800    
 
1a. Incidence of solicited and unsolicited injection 
site reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
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(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality  
 
2. Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of disease 
severity     
2a.  Incidence of non-severe COVID-19 disease 
starting 14 days after completion of the 2-dose 
regimen until EOS  
2b. Incidence of severe COVID-19 disease starting 
14 days after completion of the 2-dose regimen 
until EOS 
2c. Incidence of deaths due to COVID-19 starting 14 
days after completion of the 2-dose regimen until 
EOS 
3.   Evaluate the efficacy of INO-4800 in 
the prevention of SARS-CoV-2 
infection 
3.   Incidence of virologically-confirmed SARS-CoV-
2 infections starting 14 days after completion of 
the 2-dose regimen until EOS 
4.   Evaluate the timing of symptom 
resolution in subjects who develop 
COVID-19 disease  
4.  Days to symptom resolution in subjects 
developing COVID-19 disease. 
5.   Evaluate the binding antibody 
response to INO-4800  
5a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody titers  
5b. Incidence of seroconversion (at least fourfold 
rise over baseline) by SARS-CoV-2 Spike 
glycoprotein antigen specific binding antibody 
assay  
 
EXPLORATORY OBJECTIVE 
See Table 5. 
 
EXPLORATORY ENDPOINT 
Table 5: Exploratory Objectives and Associated Endpoints 
Exploratory Objective 
Associated Exploratory Endpoints 
1. Evaluate the expanded 
immunological profile by assessing 
both neutralizing antibody 
response and T cell immune 
responses 
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot. 
1b. Neutralizing antibody response measured by live 
virus neutralizing or pseudovirus assays  
 
EFFICACY ASSESSMENT 
Subjects will receive either investigational product (1.0mg INO-4800) or placebo (SSC-
0001) in a 2-dose regimen administered on Days 0 and 28 intradermally followed 
immediately by EP. Subjects will be monitored through regularly scheduled clinic visits 
and phone calls throughout the trial. Subjects will be regularly tested for SARS-CoV-2 
infection using serologic testing. If COVID-19 disease is suspected based on symptoms 
or laboratory testing, site personnel will arrange for a clinic visit. Subjects with symptom(s) 
or a positive virologic test result will be reviewed by the independent blinded EAC. The 
mechanism for review and confirmation of cases will be outlined in an EAC Charter. 
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 CASE DEFINITION FOR VIROLOGICALLY-CONFIRMED COVID-19 DISEASE: 
• Positive testing by RT-PCR assay (any source) with any of the following COVID-
19 related symptoms: 
• 
Fever or chills  
• 
Cough  
• 
Shortness of breath or difficulty breathing  
• 
Fatigue  
• 
Muscle or body aches  
• 
Headache  
• 
New loss of taste or smell  
• 
Sore throat  
• 
Congestion or runny nose  
• 
Nausea or vomiting  
• 
Diarrhea 
3.7.1.1 Case Definition for Non-Severe COVID-19  
• Confirmed COVID-19 disease (per Section 3.7.1);   
• Does not meet the case definition of Severe COVID-19 disease (Section 
3.7.1.2).   
3.7.1.2 Case Definition for Severe COVID-19 
• Confirmed COVID-19 disease (per Section 3.7.1) with any of the following:  
a. Clinical signs at rest indicative of severe systemic illness (respiratory 
rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room 
air at sea level or PaO2/FiO2 < 300 mm Hg),  
b. Respiratory failure (defined as needing high-flow oxygen, noninvasive 
ventilation, mechanical ventilation or ECMO),  
c. Evidence of shock (SBP < 90 mm Hg, DBP < 60 mm Hg, or requiring 
vasopressors),  
d. Significant acute renal, hepatic, or neurologic dysfunction,  
e. Admission to an ICU, or  
f. Death.  
 CASE DEFINITION FOR VIROLOGICALLY-CONFIRMED SARS-COV-2 INFECTION  
• Positive testing by RT-PCR assay (any source);  
• Irrespective of clinical signs and symptoms.  
 
SAFETY ASSESSMENT 
Subjects will be followed for safety during the entire duration of trial participation through 
scheduled clinic visits and phone calls. AEs, regardless of relationship to study drug, will 
be collected from the time of consent until 28 days post-dose 2. Solicited local and 
systemic AEs will be collected for 7 days following each dose. SAEs, MAAEs and AESIs 
will be collected from time of consent until EOS. SAEs, AESIs, and treatment-related AEs 
will be followed to resolution or stabilization.  
Please refer to the Schedule of Events (Table 2) for safety assessments to be performed.   
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IMMUNOGENICITY ASSESSMENT 
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 2). Assays such as Binding ELISA, neutralizing antibody, and ELISpot will be 
evaluated at serial timepoints. 
 
CLINICAL TRIAL POPULATION 
 
INCLUSION CRITERIA 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, physical 
examination and vital signs performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working in an environment with high risk of exposure to SARS-CoV-2 for whom 
exposure may be relatively prolonged or for whom personal protective equipment 
(PPE) may be inconsistently used:  
1. Retail/service workers (restaurant waitresses/waiters and bar workers, store 
cashiers, hairdressers and barbers, veterinary staff, daycare workers, 
Transportation Security Administration screening staff, and elementary school 
teachers) 
2. Factory workers (when working in confined settings with large numbers of 
employees) 
3. Nursing home staff or correctional facility staff  
4. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) 
5. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists but not necessarily physicians unless they are 
assigned to dedicated COVID-19 treatment wards or other settings with prolonged 
exposure) 
6. Others, if approved by the medical monitor;   
f. Screening laboratory results within normal limits for testing laboratory or deemed not 
clinically significant by the Investigator; 
g. Negative serological tests for Hepatitis B surface antigen (HBsAg), Hepatitis C 
antibody and Human Immunodeficiency Virus (HIV) antibody or rapid test at 
screening (subjects who are positive for Hepatitis C antibody but are in remission as 
defined by undetectable HCV RNA level ≥ 12 weeks after completion of HCV therapy 
may be enrolled) 
h. Must meet one of the following criteria with respect to reproductive capacity: 
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or tubal 
ligation, absence of ovaries and/or uterus in females). In the case of vasectomy, 
subjects should wait six (6) months post-vasectomy prior to enrolling;  
• 
Use of medically effective contraception with a failure rate of < 1% per year when 
used consistently and correctly from screening until 3 months following last dose. 
Acceptable methods include:  
o hormonal contraception including implants, injections or oral; 
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o two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
‒ 
abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 
EXCLUSION CRITERIA 
a. Acute febrile illness with temperature > 100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat);  
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the screening visit until 
3 months following the last dose; 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0; 
f. Previous receipt of an investigational vaccine for prevention or treatment of COVID-
19, MERS or SARS; documented receipt of placebo in previous trial would be 
permissible for trial eligibility. 
g. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg at Screening; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin cancers 
that only required local excision; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in therapy 
or hospitalization for worsening disease during the 6 weeks prior to enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a single 
antiepileptic agent; 
h. Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies; 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed); 
• 
Current or anticipated use of disease modifying doses of anti-rheumatic drugs 
(e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and biologic 
disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, adalimumab or 
etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of receipt of any other clinically significant immunosuppressive drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the subject 
or require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
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i. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation site; 
j. 
Blood donation or transfusion within 1 month prior to Day 0; 
k. Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
l. 
Reported ongoing smoking or vaping; 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the past 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
 
DISCONTINUATION/WITHDRAWAL OF CLINICAL TRIAL SUBJECTS 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the Investigator should any untoward effect occur. In addition, the 
Investigator or the Sponsor has the right to discontinue a subject from the trial at any time. 
The Investigator must notify the Sponsor immediately when a subject has been 
discontinued/withdrawn due to an Adverse Event (AE). If a subject withdraws from the trial 
or is discontinued from the trial prior to trial completion, all applicable activities scheduled 
for the final trial visit (i.e., Day 393) should be performed at the time of 
discontinuation/withdrawal if the subject agrees. Any related AEs, AESIs, and/or Serious 
Adverse Events (SAEs) present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.9. 
Unless a subject refuses to continue participation, all follow-up visits and procedures 
should be completed as indicated in the Schedule of Events (Table 2) following the second 
dose whether or not the subject has completed both doses. 
 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. In cases where 
the subject does not return for the rescheduled visit or cannot be reached to reschedule 
the missed visit, the site should make every effort to regain contact with the subject (3 
telephone calls and if that fails, then a certified letter to the subject’s last known mailing 
address) so that the subject’s disposition can be considered as withdrawn from the study 
(i.e. lost to follow-up). If the contact with subject is re-established, site should contact 
medical monitor to discuss whether subject can continue study treatment or follow-up 
visits for the study. For all other subjects withdrawing from the study, an alternative reason 
for discontinuation should be recorded in the eCRF. 
 
Reasons for discontinuation/withdrawal from the trial may include but are not limited to the 
following: 
• 
Subject withdrawal of consent at any time; 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardize the 
subject’s safety if he or she continues in the trial; 
• 
Investigator, DSMB or Sponsor determines it is in the best interest of the subject; 
• 
Subject non-compliance. 
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Every effort should be made to obtain information on subjects who withdraw from the trial. 
The primary reason for withdrawal from the trial should be documented on the appropriate 
CRF. However, subjects will not be followed for any reason after consent has been 
withdrawn. Data and/or samples collected prior to withdrawal of consent will be analyzed.  
 
Reasons for discontinuing subject dosing may include but are not limited to the following: 
• 
Adverse Event (Adverse Reaction); 
o The Investigator or trial coordinator must notify the Sponsor immediately 
when a subject has been discontinued/withdrawn due to an Adverse Event 
(AE). 
• 
Any medical condition that may jeopardize the subject’s safety if he or she 
continues on trial; 
• 
Pregnancy. 
 
CLINICAL TRIAL INVESTIGATIONAL PRODUCT INFORMATION 
 
INVESTIGATIONAL PRODUCT (IP) AND STUDY DEVICE 
 INO-4800 AND PLACEBO 
Investigational product is defined as a pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in the study, whether blinded or unblinded. 
INO-4800 is the active investigational product to be used in this study. The INO-4800 drug 
product contains 10 mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM 
sodium chloride and 15 mM sodium citrate). pGX9501 is a DNA plasmid expressing a 
synthetic consensus (SynCon®) sequence of the SARS-CoV-2 full length Spike 
glycoprotein. 
A volume of 0.4 mL will be filled into 2-mL glass vials that are fitted with rubber stoppers 
and sealed aluminum caps. 
Sterile saline sodium citrate (SSC) buffer (SSC-0001), which contains sterile 150 mM 
sodium chloride and 15 mM sodium citrate in 10-mL glass vials, stoppered, and sealed 
with aluminum caps, will be used as the placebo. 
 CELLECTRA® 2000 
The CELLECTRA® 2000 is a portable, battery-powered medical device designed to 
generate a minimally-controlled, electric field which temporarily and reversibly increases 
cellular membrane permeability without damaging the tissue. During the period of 
increased permeability an indicated injected plasmid DNA formulation can be introduced 
into the cells. 
The CELLECTRA® 2000 device is indicated to enhance the uptake and expression of DNA 
plasmid-based biologics in order to enhance vaccine efficacy. The DNA plasmid is 
delivered separately via needle and syringe injection immediately prior to the 
electroporation. The electroporation is accomplished through a sterile, disposable needle 
Array attached to an Applicator delivering current controlled electrical pulses as follows: 
• 
An EP treatment consists of four pulses. 
• 
An Array of three stainless steel electrode needles is used to deliver the electrical 
pulses into the tissue. 
• 
Voltage levels are limited to 200 volts (V) for patient safety.  
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• 
The specified current is constantly maintained through voltage modulation using 
an analog feedback loop. Measurements of voltage and current are processed for 
error reporting and collected for data logging. 
The CELLECTRA® 2000 device for ID administration is comprised of three components: 
(1) A battery-powered Pulse Generator, (2) an ID Applicator that is connected to the pulse 
generator, and (3) a three-point sterile disposable ID Array of stainless steel needles. 
 
DOSING REGIMENS 
• 
Investigational Product: A single 1.0mg ID injection of INO-4800 (~0.1mL dose 
volume) followed immediately by EP administered at Day 0 and Day 28 (±3 days) 
• 
Placebo: A single ID injection of SSC-0001 (~0.1mL) followed immediately by EP 
administered at Day 0 and Day 28 (±3 days) 
 BLINDING 
This study is double-blinded. The Sponsor, subjects and clinical site staff, with the 
exception of the site’s pharmacy personnel will be blinded throughout the trial. There is no 
difference in appearance for both the INO-4800 product and the placebo; however, they 
are packaged in different sized vials. To maintain the blind, vials will only be handled by 
designated unblinded personnel (site pharmacist) at the site. 
The PI may request to unblind a subject’s dose assignment in case of an emergency or 
serious medical condition when knowledge of the study product or dose is essential for 
proper clinical management of the subject, as judged by the PI. It is preferred, but not 
required, that the PI first contact the Medical Monitor (MM) to discuss options before 
unblinding the subject’s dose assignment. In case of non-emergency, PI must contact MM 
to discuss the options before unblinding the subject’s dose assignment. 
The Sponsor’s pharmacovigilance staff may unblind a subject’s dose assignment for an 
SAE, unanticipated adverse device effect (UADE), or adverse event of special interest 
(AESI) when the event is assessed as related and unexpected. If expedited regulatory 
reporting is required for an event, the report may be submitted to regulatory authorities 
with the subject’s dose assignment, in accordance with local regulations. 
 
PACKAGING AND LABELING 
 INO-4800 OR PLACEBO 
Each vial of INO-4800 or placebo will be labeled consistent with the example product label 
provided in the Investigator’s Brochure (IB).  
 CELLECTRA® 2000 
Please see shipping box for shipping documents and contents. 
The CELLECTRA® 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer. The CELLECTRA® 2000 User Manual 
describes all relevant contraindications, hazards, potential risks and adverse effects, 
interfering substances or devices, warnings, and precautions. Each Pulse Generator has 
a unique serial number, and each ID Applicator has a unique serial number. Each ID Array 
has a Lot Number and Expiration Date. Examples of device labels are provided in the IB. 
The CELLECTRA® 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. 
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HANDLING AND STORAGE 
 INO-4800 AND PLACEBO 
INO-4800 and Placebo will be shipped at 2–8°C. If the temperature monitoring devices in 
the shipping container(s) denote temperatures outside this 2–8°C (36-46°F) range, the 
Sponsor, or its designee, should be contacted immediately. 
Upon arrival, it must be transferred from the shipping container into 2–8°C (36-46°F) 
storage, in a secure area, in accordance with local regulations by designated personnel 
(e.g., pharmacy personnel). The Sponsor must be notified of any deviations from this 
storage condition. Refrigerator temperature logs must be maintained at the clinical site 
and temperatures must be recorded and monitored regularly. For further details see 
Pharmacy Manual and IB. 
 CELLECTRA® 2000 
See User Manual for operating and storage conditions. 
 
PREPARATION AND DISPENSING 
INO-4800 is supplied in 2-mL vials at a concentration of 10 mg/mL at a minimum volume 
of 0.4 mL. SSC-0001 is supplied in 10-mL vials at a minimum volume of 2 mL.  
Blinded staff involved in the clinical execution of the study should not come in contact with 
vials of INO-4800 or SSC-0001. Vials will only be handled by designated unblinded 
personnel (e.g., pharmacy) at the site. When a participant is eligible for enrollment, 
unblinded personnel will draw INO-4800 or SSC-0001 into a blinded syringe in accordance 
with the subject’s randomized treatment assignment according to a randomization 
schedule. The syringe will be transferred to blinded site personnel for administration.  
Each INO-4800 and placebo vial will contain a volume of product sufficient to dose multiple 
subjects. The preparation and dispensing information will be provided in the Pharmacy 
Manual. 
 
USE OF STUDY DEVICE 
The instructions for use of the CELLECTRA® 2000 device are provided in the User 
Manual. Each clinical site will receive training for use of the CELLECTRA® 2000 device 
prior to first dose.  
The EP procedure must be performed by qualified personnel. Any individual designated 
to perform the procedure should be permitted by the relevant local authorities to administer 
parenteral injections to patients (e.g., MD, DO, RN) in addition to successfully completing 
device training from Sponsor personnel.  
 
INVESTIGATIONAL DRUG AND STUDY DEVICE ACCOUNTABILITY 
 INVESTIGATIONAL PRODUCT (IP) ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current accountability record of 
investigational products (INO-4800 or placebo) is maintained at the study site. The 
investigational products must have full traceability from the receipt of the products through 
subject use, disposal or return of the products. Records or logs must comply with 
applicable regulations and guidelines. The accountability information is provided in the 
Pharmacy Manual. 
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 CELLECTRA® 2000 ACCOUNTABILITY 
The investigative site is responsible for maintaining device accountability logs. The device 
must have full traceability from the receipt of the products through subject use, disposal 
or return of the products. The site must document acknowledgement of receipt and notify 
Inovio upon receipt of study devices. This includes the content shipped and condition upon 
receipt. 
For each subject administration, there must be a record of each product used for that 
subject, i.e., Pulse Generator serial number, ID Applicator serial number, and ID Array lot 
number. The ID Applicator is reusable with a new ID Array and sheath for each procedure. 
The sterile ID Array and sheath are single use only and must be discarded after use in 
accordance with institutional policy regarding disposal of sharp needles/instruments. 
 
RETURN AND DESTRUCTION OF INVESTIGATIONAL DRUG AND STUDY DEVICE 
 INO-4800 AND PLACEBO 
Upon completion or termination of the study, all unused vials of INO-4800 or placebo must 
be destroyed at the study site in accordance with institution policy or returned to Inovio 
Pharmaceuticals, Inc., or its designee if the site cannot destroy IP. 
The used vials of INO-4800 and placebo will be discarded in accordance with the site’s 
used IP disposal procedure. It is the Investigator’s responsibility to arrange for disposal of 
all empty vials, provided that procedures for proper disposal have been established in 
accordance with applicable national, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. If requested by the Sponsor, the 
return of unused IP vials should be arranged by the responsible Inovio Representative. 
The unused IP vials should only be destroyed after being inspected and reconciled by the 
responsible Inovio Pharmaceuticals, Inc., personnel or designated Clinical Monitor. If IP 
vials are returned to Inovio Pharmaceuticals, Inc., or its designee, the IP must be 
accompanied by the appropriate documentation. The return of unused IP(s) should be 
arranged with the responsible Inovio personnel and/or Clinical Monitor. 
 RETURN OF CELLECTRA® 2000 
Upon completion or termination of the study, an Inovio Representative will provide 
instructions regarding the component(s) to be returned to Inovio Pharmaceuticals, Inc., 
destroyed onsite or shipped to a destruction vendor. 
All product returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original containers. 
The return of all product identified above should be arranged by the Inovio Representative. 
The ID Arrays should be discarded in the sharps container immediately after use. The 
used ID Applicators can either be destroyed at the site, shipped to a destruction vendor, 
or returned to Inovio. If the used ID Applicators are destroyed on site, it is the Investigator’s 
responsibility to ensure that arrangements have been made for the disposal, written 
authorization has been granted by Inovio Pharmaceuticals, Inc., or its designee, 
procedures for proper disposal have been established in accordance with applicable 
regulation and guidelines and institutional procedures, and appropriate records of the 
disposal have been documented. 
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CLINICAL TRIAL PROCEDURES AND SCHEDULE 
The Schedule of Events (36TTable 236T) in the Clinical Protocol Synopsis summarizes the 
procedures to be performed at each visit. Individual procedures are described in detail 
below. It may be necessary to perform these procedures at unscheduled time points if 
deemed clinically necessary by the Investigator. A subject will be required to provide 
informed consent (Section 6.2) prior to any study procedure being performed. Protocol 
waivers or exemptions will not be granted. Therefore, adherence to the study design and 
assessments are essential and required for study conduct. 
 
PROCEDURE BY VISIT 
Refer to Sections 6.1.1 and 6.1.2 for trial procedures and the times at which they are to 
be performed. 
 CLINICAL TRIAL SCREENING EVALUATIONS 
The assessments performed during Screening will determine the subject’s eligibility for 
the study and also their ability to comply with protocol requirements by completing all 
screening assessments. The following screening evaluations will be performed within 30 
days prior to dosing on Day 0. All screening assessment values must be reviewed prior to 
the first Study IP administration.  
If a subject does not meet an inclusion or exclusion criterion due to a transient and non-
clinically significant event at Screening, relevant Screening evaluations may be repeated 
within the same 30 day Screening period. If the subject fails twice, they will be considered 
a screen failure. 
• 
Signed and dated informed consent (Section 6.2); 
• 
Review and confirm all inclusion/exclusion criteria (Section 4.1 and 4.2); 
• 
Obtain and document complete medical history, surgical history (including all 
clinically significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Section 6.1.1.1); 
• 
Collect demographics and document any ongoing, pre-existing conditions; 
• 
Collect adverse events (Section 6.4.4); 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Record height and weight (Section 6.4); 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect blood for serum pregnancy test (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9);  
• 
Collect serum for HIV, Hepatitis B surface antigen (HBsAg) and Hepatitis C 
serology (Section 6.4) per national guidelines; 
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.9). 
6.1.1.1 
Medical History 
A medical history will be obtained by the Investigator or qualified designee at the time of 
Screening. Medical history will include all active conditions, and any other past conditions, 
as well as surgical procedures, that are considered to be clinically significant by the 
Investigator and/or occurred within the 12 weeks prior to Screening. Illnesses first 
occurring or detected after the signing of the informed consent, or during the study and/or 
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worsening of an existing illness in severity, frequency or nature after signing of the 
informed consent are to be documented as AEs on the CRF. Prior treatments, defined as 
administered up to 12 weeks prior to the time of informed consent and stopped prior to 
dosing on Day 0, should be recorded in the CRF as prior medications. Concomitant 
treatments, defined as continuing on Day 0 or new treatments taken at or after Day 0, 
should be recorded in the CRF as concomitant medications. 
 CLINICAL TRIAL EVALUATIONS AND PROCEDURES 
Once eligibility has been confirmed, the subject will be randomized to receive a treatment 
assignment (investigational product or placebo). Visit dates and windows must be 
calculated from Day 0, unless otherwise noted. All subjects will be followed until the Day 
393 Visit. All subjects will be followed in accordance with assessments outlined below. 
6.1.2.1 
Day 0 and Day 28 (Dosing Visits) 
The following evaluations will be performed on Day 0 and Day 28 prior to dose 
administration: 
• 
Collect all present and/or new or ongoing adverse events (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect blood for CBC with differential and serum chemistry (will be implemented 
in approximately 500 subjects from selected sites) (Section 6.4); 
• 
Collect urine for routine urinalysis (will be implemented in approximately 500 
subjects from selected sites) (Section 6.4); 
• 
Collect urine for urine pregnancy test (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6); 
• 
Review restrictions for injection and EP (Section 6.4.8); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.9); 
• 
Randomize subject (instructions to be provided under separate cover) (Day 0 visit 
only). 
 
The following evaluations will be performed on Day 0 and Day 28 after IP plus EP 
administration: 
• 
Collect any new adverse events (Section 6.4.4); 
• 
Download EP Data (Section 6.4.1.1); 
• 
Distribute diaries and provide supplies for subject to use at home, as required (e.g. 
thermometer, wound guide). 
6.1.2.2 
Day 7 and Day 35 phone calls (post-dose phone calls) 
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing adverse events (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Review diary (Section 6.4). 
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6.1.2.3 
Day 56 Visit 
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing adverse events (Section 6.4.4);  
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect blood for CBC with differential and serum chemistry (will be implemented 
in approximately 500 subjects from selected sites) (Section 6.4); 
• 
Collect urine for routine urinalysis (will be implemented in approximately 500 
subjects from selected sites) (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect saliva for SARS-CoV-2 RT-PCR and store in freezer (Section 6.4.9); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6);  
• 
Provide supplies for subject to use at home, as required (e.g. saliva collection kit). 
6.1.2.4 
Phone calls (Days 70, 84, 98, 112, 140, 154, 168, 182, 196, 238, 266, 322, 
350, and 378) 
Phone calls to subjects have been spaced bi-weekly between study visits through Day 
210, and approximately monthly between visits from Day 210 to Day 393.  Guidelines for 
information to be collected during the phone call can be found in the Phone Script. The 
following evaluations will be performed during the phone call: 
• 
Collect all present and/or new or ongoing adverse events (Section 6.4.4); only 
SAEs, AESIs and MAAEs will be reported after the Day 56 Visit; 
• 
Ask about any symptoms of COVID-19 disease; Arrange on-site visit if any signs 
and symptoms of COVID-19 disease are present (Section 6.4.10); 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Remind subject to self-collect saliva sample and store in freezer (Section 6.4.9). 
6.1.2.5 
Days 126, 210 and 294 Visits 
The following evaluations will be performed at these visits: 
• 
Collect all present and/or new or ongoing adverse events (Section 6.4.4); SAEs, 
AESIs, and MAAEs will be reported after the Day 56 Visit. 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect saliva for SARS-CoV-2 RT-PCR and store in freezer; (Section 6.4.9); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(except Day 294 visit) (Section 6.4.6); 
• 
Provide supplies for subject to use at home, as required (e.g. saliva collection kit). 
6.1.2.6 
Day 393 Visit or EOS 
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• 
Collect all present and/or new or ongoing adverse events (Section 6.4.4); SAEs, 
AESIs, and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect urine pregnancy test (Section 6.4); 
• 
Collect blood for CBC with differential and serum chemistry(Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect saliva for SARS-CoV-2 RT-PCR (will be tested at the time of collection) 
(Section 6.4.9); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6). 
6.1.2.7 
COVID-19 Assessment Visit 
Subjects will be evaluated during a COVID-19 assessment visit when acute COVID-19 is 
suspected based on symptoms or positive SARS-CoV-2 testing. The virologic-
confirmation of a case will be based on SARS-CoV-2 RT-PCR. Additional safety testing 
will be collected to understand the impact on various organ systems. Additional diagnostic 
testing (e.g., influenza diagnostics) may be ordered at the discretion of the Investigator. 
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing adverse events (Section 6.4.4); Only 
SAEs, AESIs and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect nasopharyngeal, oropharyngeal swabs and saliva for SARS-CoV-2 RT-
PCR detection (Section 6.4.9). 
6.1.2.8 
COVID-19 Convalescent Visit 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit 
should be scheduled approximately 28 days after symptom onset, or in the absence of 
symptoms, the date of positive SARS-CoV-2 test. The following evaluations will be 
performed at this visit: 
• 
Collect all present and/or new or ongoing adverse events (Section 6.4.4); Only 
SAEs, AESIs and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6); 
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• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect nasopharyngeal, oropharyngeal swabs and saliva for SARS-CoV-2 RT-
PCR detection (Section 6.4.9). 
 
INFORMED CONSENT 
All subjects must sign the informed consent prior to participating in any clinical trial-related 
procedures. The informed consent documentation must be in compliance with applicable 
regulations and GCP. Qualified clinical trial personnel will: 
• 
Meet with prospective clinical trial subjects 
• 
Explain the clinical trial 
• 
Provide clinical trial subjects with an Informed Consent Form (ICF) that includes the 
following in a language that is understandable to the subject: 
• 
Screening test(s) description 
• 
Eligibility criteria for entering the clinical trial 
• 
Clinical trial treatments and follow-up procedures description 
• 
Explanation of the clinical trial, including but is not limited to: 
• 
Clinical trial objectives 
• 
Potential benefits and risks 
• 
Discomforts/inconveniences 
• 
Subject’s rights and responsibilities 
The subject is then requested to sign and date the ICF. A copy of the signed informed 
consent documentation must be provided to the subject. The qualified clinical trial 
personnel will document the process of obtaining informed consent within the source 
record. Signed ICFs are maintained in the subject’s source records and must be 
accessible for verification at any time. Signing of the ICF begins the 30 day screening 
period. 
 
ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number (SID), 
which identifies the subject for all clinical trial-related procedures. SIDs are a combination 
of a four digit site code and a three digit subject number starting with 001. After SIDs are 
assigned, they cannot be reused or reassigned for any reason. Information regarding the 
SID and screen date will be documented on a screening and enrollment log/system and 
in the Case Report Form (CRF). 
 
SAFETY EVALUATIONS 
PHYSICAL AND TARGETED PHYSICAL EXAM  
A full physical examination will be conducted during Screening and at study 
discharge/EOS (e.g. Day 393). A targeted physical assessment will be performed at other 
visits as determined by the Investigator or directed per subject complaints. 
VITAL SIGNS 
Vital signs including temperature, respiration rate, blood pressure and heart rate will be 
measured at Screening and at visits specified in the Schedule of Events (36TTable 236T).  
HEIGHT AND WEIGHT 
Weight (kg) and height (cm) will be collected at Screening. 
LABORATORY EVALUATIONS 
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At Screening and at visits specified in the Schedule of Events (36TTable 236T), blood samples 
will be collected for safety assessments. Approximately 375-450 mL of blood will be drawn 
from each subject over the course of the study. Subjects may be asked to return for 
additional blood draws if collected blood sample is lost or unevaluable for any reason. 
Hematology [Complete blood count (CBC) with automated differential]: 
White blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit and 
platelet count will be measured at Screening and at visits specified in the Schedule of 
Events (36TTable 236T). 
Serum chemistry: 
Electrolytes [Sodium (Na), Potassium (K), Chloride (Cl), Bicarbonate (HCO3), Calcium 
(Ca), Phosphate (PO4)], glucose, BUN (blood urea nitrogen), Creatinine (Cr),  alkaline 
phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), LDH,  
total bilirubin (TBili), and hemoglobin A1c at Screening and at visits specified in the 
Schedule of Events (36TTable 236T). Hemoglobin A1c will only be performed at Screening. 
Urinalysis:  
Urine samples will be tested by dipstick for glucose, protein, and hematuria at Screening 
and at visits specified in the Schedule of Events (36TTable 236T). If abnormal (presence of 
protein, hematuria, or glucose ≥ 1+), a microscopic examination should be performed.  
Serology: 
Antibodies to Hepatitis B surface antigen (HBsAg), Hepatitis C antibody and HIV antibody 
or rapid test will be measured at Screening only. Antibodies to SARS-CoV-2 will be 
measured at Screening and at visits specified in the Schedule of Events (Table 2). 
Pregnancy Testing:  
For women of child bearing potential (WOCBP), a serum pregnancy test will be obtained 
at Screening and a urine pregnancy test will be performed immediately prior to any dosing 
and at the subject’s last visit. A negative result for urine β-HCG (test must have a sensitivity 
of at least 25 mIU/mL) must be available prior to each administration of IP. If the β-HCG 
test is positive, indicating that the subject is pregnant prior to completing the specified 
dose regimen, then no further IP will be administered. Every attempt should be made to 
follow pregnant subjects for the remainder of the study and to determine the outcome of 
the pregnancy. 
DIARY 
Diaries will be implemented in approximately 500 subjects from selected sites. Subjects 
will be provided a diary to record the following solicited local and systemic adverse 
events: 
• 
Oral temperature and time taken (each daily entry before 11:59 pm) 
• 
Solicited systemic systems 
• 
Solicited local injection site symptoms 
• 
Concomitant medications 
The diary should be completed once daily starting the evening of each study dose through 
6 days post-dose. The completed diary will be reviewed with the subject by the study staff 
during the phone calls on Day 7 and Day 35. The study staff will review the diary with the 
subject to assess for temperature, solicited systemic symptoms (unusually tired/feeling 
unwell, muscle aches, headache, nausea, joint pain) and solicited injection site symptoms 
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(pain, itching, redness, swelling, bruising). In addition, unsolicited symptoms and 
concomitant medications will be collected.  
Any diary entry determined to meet the CTCAE criteria for a Grade 1 or higher adverse 
event should be documented as an adverse event unless deemed part of the subject’s 
ongoing medical history. If the diary entry does not meet the criteria of a Grade 1 or higher 
AE as per the CTCAE guidelines, Investigator clinical judgment can be used to determine 
whether the entry should be recorded as an AE and documented accordingly in the site’s 
source. For cases where the diary entry and final AE reporting (i.e. grading) do not agree, 
the reasoning should be recorded in the source documents. 
 INJECTION AND EP  
Subjects will receive a two-dose regimen of INO-4800 or placebo by ID injection in a 
volume of ~0.1 mL in an acceptable skin location for injection and subsequently followed 
immediately by EP with CELLECTRA® 2000 at Day 0 and Day 28.  
 
Only if the deltoid area is not a suitable location (see exclusion criterion ‘i’), the ID injection 
can then be administered above the lateral quadriceps followed immediately by EP. IP 
must not be given within 2 cm of a tattoo, scar, keloid, or active lesion/rash. Also, ID 
injection followed immediately by EP must not be performed on the skin of an extremity 
which has any metal implants or implantable medical device (e.g., surgical rods, pins or 
joint replacements). If a subject has an implanted cardiac defibrillator or pacemaker, ID 
injection/EP must not be performed above the deltoid muscle on the same side of the body 
where the device is located. 
 MANAGEMENT OF PAIN DUE TO ELECTROPORATION (EP) PROCEDURES 
In case of pain, subjects may be treated with a non-narcotic analgesic (e.g., 
acetaminophen) after injection/EP.  
Medication taken for pain management will be documented as concomitant medications. 
 ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry and hematology and urinalysis will be performed 
at the visits listed in the Schedule of Events (36TTable 236T) and as listed in Section 6.4.  
Laboratory AEs will be assessed and graded in accordance with the “Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical 
Trials”, issued in September 2007 (Appendix A). Laboratory values that are not clinically 
significant (NCS) in the Investigator’s opinion will not be reported as adverse events. 
 ASSESSMENT OF CLINICAL TRIAL ADVERSE EVENTS (AES) 
Subjects will be queried regarding the occurrence of any adverse events including adverse 
events related to injection site reactions, concomitant medications and new onset illness or 
disease during their study visits and phone calls. Subjects will be reminded to contact study 
personnel and immediately report any event for the duration of the study. All adverse events will 
be captured from the time of the informed consent until 28 days post-dose 2. Following the Day 
56 visit, only SAEs, AESIs and MAAEs will be collected. All related AEs, AESIs and SAEs will 
be followed to resolution or stabilization. These events will be recorded on the subject’s CRF. 
 ASSESSMENT OF INJECTION SITE REACTIONS  
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The IP administration procedure consists of an ID injection (formation of a wheal) of IP 
followed by insertion of the ID Array needles (electrodes) through the skin and into the 
wheal followed by delivery of the electroporation pulses. This procedure is broadly 
described as administration because it involves more than the injection of a drug. 
Consequently, reactions arising from the IP administration procedure may be reported as 
administration site or injection site reactions. When evaluating administration (injection) 
site reactions throughout the study, it is most important to be as specific as possible by 
selecting the most appropriate term (see Table 6 below) and use the grading scale as 
listed in the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials, issued September 2007 (Appendix A). Administration 
(injection) site reactions and administration site pain will be evaluated starting 30 minutes 
following injection/EP. In addition, other events associated with administration (injection) 
site reactions (e.g., hematoma, infection or necrosis) should also be reported with 
preferred terms specific for administration (injection) site reactions.  
Table 6: Grading Scale for Injection Site Reactions 
Local Reaction to 
Injectable Product 
(Grade) 
Mild (1) 
Moderate (2) 
Severe (3) 
Potentially 
Life 
Threatening 
(4) 
Pain 
Does not 
interfere with 
activity 
Repeated use 
of non-
narcotic pain 
reliever >24 
hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency 
room visit or 
hospitalization 
Tenderness 
Mild 
discomfort to 
touch 
Discomfort 
with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/Rednessa 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swellingb 
2.5-5 cm and 
no 
interference 
w/ activity 
5.1-10 cm or 
interferes with 
activity 
>10 cm or 
prevents daily 
activity 
Necrosis 
September 2007 “FDA Guidance for Industry-Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
a In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable 
b Should be evaluated and graded using the functional scale as well as the actual measurement. 
 IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at visits specified in the Schedule of 
Events (36TTable 236T) for cellular and humoral immunology assessments. Binding ELISA will 
be evaluated at serial timepoints. Baseline (Day 0) immunology samples are required to 
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enable all immunology testing. Therefore a total of 68mL whole blood and 4mL serum is 
required prior to 1st dose. Details of the immunology sample collection and shipment 
information will be provided in the Laboratory Manual.  
The additional immune responses to INO-4800 will be measured using assays that include 
neutralization, flow cytometry and ELIspot. Determination of additional analysis using 
assays not specified, such as assessment of immunological gene expression, assessment 
of immunological protein expression on collected samples for immunological endpoints 
will be made on an ongoing basis throughout the trial. 
 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken at the time of Screening and 
ongoing from signing of the informed consent to study discharge that do not affect a 
subject’s eligibility for participation (see Section 4.2) must be recorded on CRFs. 
Actual or estimated start and stop dates must be provided. This information will be 
obtained from the subject and abstracted from any available medical records. The 
indication for the medication, dose, and dose regimen will be documented.  
Therapy considered necessary for the subject’s welfare may be given at the discretion of 
the Investigator or medical provider. If the permissibility of a specific medication/treatment 
is in question, please contact the Sponsor. 
The decision to administer a prohibited medication/treatment (Section 6.4.8) is made with 
the safety of the clinical trial subject as the primary consideration. When possible, the 
Sponsor should be notified before the prohibited medication/treatment is administered. 
 RESTRICTIONS  
Subjects should refrain from becoming pregnant until 3 months following the last dose of 
investigational product by using appropriate contraceptive measures (see Section 4.1). 
Subjects must not receive any non-study related vaccine (e.g., influenza vaccine) within 2 
weeks prior to the first dose of IP, or within 2 weeks of (before or after) any subsequent 
dose of IP.  
Subjects must not have fever (oral temperature >38.0 degrees Celsius or 100.4 degrees 
Fahrenheit) within 72 hours prior to each dosing. 
Subjects should refrain from donating blood from Screening visit through the duration of 
the trial. 
Subjects must not receive disease modifying doses of anti-rheumatic drugs (e.g., 
azathioprine, cyclophosphamide, cyclosporine, methotrexate), biologic disease modifying 
drugs such as TNF-α inhibitors (e.g., infliximab, adalimumab or etanercept) and long term 
use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of prednisone 
equivalent (use of inhaled, topical, nasal, otic, and ophthalmic corticosteroids are allowed).  
 SARS-COV-2 TESTING 
Serology SARS-CoV-2 antibody testing will be used during screening to test for previous 
SARS-CoV-2 infection and during each subsequent visit (see Table 2: Schedule of 
Events) to identify SARS-CoV-2 infections that may occur regardless of symptoms 
between study visits. 
SARS-CoV-2 RT-PCR testing will be conducted on saliva specimens collected at 
Screening, Day 0, Day 28 and Day 393 or EOS visit. During other in-office study visits 
(see Table 2: Schedule of Events), saliva samples will be collected and stored frozen on 
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site. Bi-weekly home self-collections will be done by subjects, when possible, between 
study visits and stored frozen at the subject’s home. The subject will be encouraged to 
document any symptoms present at the time of saliva collection and report them to the 
site. Testing may be selectively performed on the frozen saliva samples if the subject’s 
SARS-CoV-2 serology test becomes positive. 
The Day 0 and Day 28 RT-PCR results will not be required prior to dosing on that day. 
If either the SARS-CoV-2 antibody or RT-PCR test result is positive during the trial, the 
subject will be notified of the result and will be requested to come to the clinic for an 
evaluation.  During that visit, a blood sample will be collected for serologic testing and 3 
specimens (nasopharyngeal swab, oropharyngeal swab and saliva) will be collected to 
detect SARS-CoV-2 using the RT-PCR assay.  
 COVID-19 DISEASE MONITORING 
All subjects will be monitored through regularly scheduled clinic visits and phone calls for 
the development of symptoms suggestive of COVID-19 disease. Subjects should be 
instructed to take their temperature daily at home starting on the Day 0 visit for the duration 
of the trial and contact the site in the event of a fever higher than 100.4°F/38°C. Site 
personnel will arrange for a clinic visit for subjects reporting symptoms suggestive of 
COVID-19 (e.g., fever or chills, cough, shortness of breath or difficulty breathing, fatigue, 
muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or 
runny nose, nausea or vomiting, diarrhea) at any time during the study. During that visit, 
a blood sample will be collected for serologic testing and 3 specimens (nasopharyngeal 
swab, oropharyngeal swab and saliva) will be collected to detect SARS-CoV-2 using the 
RT-PCR assay, and additional diagnostic testing (e.g., influenza diagnostics) may be 
ordered at the discretion of the Investigator. All suspected COVID-19 disease cases 
should be entered into the Suspected COVID-19 Clinical Event CRF within 24 hours of 
awareness.  
If the specimen(s) are RT-PCR negative, the RT-PCR assay may be repeated if other 
possible etiologies such as influenza have been ruled out and a diagnosis of COVID-19 
remains a possible diagnosis. Furthermore, SARS-CoV-2 RT-PCR detection may be 
performed on sputum, endotracheal aspirate, bronchoalveolar lavage samples or rectal 
samples, if available. Pulmonary CT scan findings showing typical interstitial pneumonia 
including ground-glass opacities may corroborate the diagnosis of COVID-19 disease. The 
formal radiologist’s interpretation of the CT scan should be included as a source 
document.  
Subjects with a confirmed COVID-19 diagnosis prior to dose 2 will be discontinued from 
further dosing and will be followed until EOS for safety and resolution of COVID-19. 
Subjects with confirmed SARS-CoV-2 infection will return for a convalescent visit 
approximately 28 days after symptom onset, or in the absence of symptoms, 
approximately 28 days after the date the positive SARS-CoV-2 sample was collected. 
Recovery from COVID-19 disease requires resolution of clinical symptoms and follow up 
testing according to Institutional policy.    
 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
 
SAFETY PARAMETERS 
The safety of INO-4800 will be measured and graded in accordance with the “Toxicity 
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials”, issued September 2007 (Appendix A). 
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ADVERSE EVENTS (AES) 
Any untoward medical occurrence in a patient or clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.  
Adverse Events (AEs) include the following: 
• Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (before the administration of clinical trial drug) 
• Any pre-existing condition that increases in severity, or changes in nature during or as 
a consequence of the clinical trial drug administration phase 
• Complications of pregnancy (refer to Section 7.11) 
Adverse Events (AEs) do not include the following: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; however, the condition that leads to the procedure is an AE 
• Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the Screening Visit that do not worsen 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions) 
• Overdose without clinical sequelae 
• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed, is not an AE; it is considered to be pre-existing and will be 
documented on the medical history CRF 
• Uncomplicated pregnancy 
• An induced elective abortion to terminate a pregnancy without medical reason 
• Confirmed COVID-19 disease  
 
ADVERSE DRUG REACTION (ADR) 
All noxious and unintended responses to a medicinal product related to any dose. This 
means that a causal relationship between the medicinal product and an adverse event is 
at least a reasonable possibility (i.e., the relationship cannot be ruled out). 
 
SERIOUS ADVERSE EVENTS (SAES) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death  
• Is life-threatening 
o Refers to an event in which the subject was at risk of death at the time of the event. 
It does not refer to an event which hypothetically might have caused death if it 
were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
o Includes any hospitalization in which the subject has been admitted to the hospital 
regardless the length of stay, even if the hospitalization is only a precautionary 
measure to allow continued observation. However, hospitalization (including 
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hospitalization for an elective procedure) for a pre-existing condition that has not 
worsened, does not constitute an SAE. 
• Results in persistent or significant disability/incapacity 
o A substantial disruption of a person's ability to conduct normal life functions (i.e., 
the adverse event resulted in a significant, persistent or permanent change, 
impairment, damage or disruption in the subject’s body function/structure, physical 
activities and/or quality of life). 
• Results in congenital anomaly or birth defect and/or 
• An important medical event  
o An event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
Clarification of Serious Adverse Events (SAEs) 
• Death in itself is not an AE. Death is an outcome of an AE, but when the cause of death 
has not been provided, use the event term: death of unknown cause. 
• Confirmed COVID-19 disease that requires hospitalization is recorded as an endpoint, 
and not recorded as an SAE. 
• COVID-19 disease with an outcome of death is recorded as an endpoint, and not 
recorded as an SAE. 
• The subject may not have been receiving an investigational medicinal product at the 
occurrence of the event. 
• Complications associated with COVID-19 disease that occur or prolong 
hospitalization are recorded on the Suspected COVID-19 Clinical Event CRF. 
 
UNEXPECTED ADVERSE DRUG REACTION 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator’s Brochure [IB] for an unapproved investigational 
product, package insert/summary of product characteristics for an approved product). 
 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects.  
A UADE is a type of SAE that requires reporting to the Sponsor in accordance with Section 
7.9. 
 
DEVICE DEFICIENCY 
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance. 
Note: Device deficiencies include malfunctions, use errors and inadequate labelling. 
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SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor is responsible for the overall safety monitoring of the clinical trial. 
Safety monitoring assessments include but are not limited to:  
• Incidence of all adverse events classified by system organ class, preferred term, 
severity and causal relationship to clinical trial treatment 
• Changes in laboratory parameters 
• Local and systemic injection site review; special attention will be paid to the examination 
of the injection site 
 ADVERSE EVENT OF SPECIAL INTEREST (AESI)  
An adverse event of special interest (serious or non-serious) is one of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the PI to the Sponsor can be appropriate.  
For the purpose of this clinical trial, the AESIs listed in Appendix B are to be reported to 
the Sponsor in accordance with Section 7.9. 
 MEDICALLY ATTENDED ADVERSE EVENT (MAAE) 
A medically attended adverse event (serious or non-serious) is defined as an adverse 
event that leads to an unplanned contact with a health care provider. 
 ABNORMAL LABORATORY VALUE 
The PI will annotate each abnormal lab value as clinically significant (CS) or not clinically 
significant (NCS). 
Laboratory values that are NCS in the PI’s opinion should not be reported as an adverse 
event. 
Any abnormal laboratory value that is new in onset or worsened in severity or frequency 
from the baseline condition and meets one of the following criteria will be recorded as an 
AE: 
• 
Requires therapeutic intervention or diagnostic tests 
• 
Leads to discontinuation of further administration of the investigational product in 
the clinical trial 
• 
Has accompanying or inducing symptoms or signs 
• 
Is judged by the PI as clinically significant (CS) 
Abnormal laboratory values that meet the criteria of an AE or SAE should be reported in 
accordance with Section 7.9. 
 CLINICAL TRIAL STOPPING RULES 
The investigator is to immediately notify the Medical Monitor if the following are observed: 
• 
Any SAE related to study treatment. 
• 
Any Grade 4 adverse events related to study treatment. 
• 
Any report of anaphylaxis related to study treatment. 
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• 
Any suspected Severe COVID-19 disease case (per Sections 3.7.1.1 and Section 
3.7.1.2). 
The Medical Monitor will notify the Chair of the Safety Review Committee, who will make 
a determination as to whether to temporarily halt dosing until a more formal review of the 
case(s) is made. Such a formal review may include an ad hoc meeting of the DSMB, after 
consultation with the DSMB Chair. Following such a meeting, the DSMB chair will render 
a recommendation to the Medical Monitor regarding continuation of trial dosing. The 
Sponsor will independently investigate the case(s) and, after review of the DSMB 
recommendations, will communicate a final decision as to whether to lift the dosing 
suspension or whether to continue dosing. These deliberations will be documented and 
will be provided to the IRBs and FDA, where required.   
 
SAFETY DATA REPORTING PERIOD, METHOD OF COLLECTION AND SUBMISSION 
All AEs will be collected from the time informed consent is obtained through Day 56. 
MAAEs, AESIs and SAEs only will continue to be collected after the Day 56 visit and will 
be followed to resolution or stabilization. This information will be captured in the CRF. 
If the PI determines that the AE meets serious criteria, then the AE will be recorded as an 
SAE. 
SAEs and AESIs will be reported to the Sponsor from the time the subject signs the 
informed consent until the last visit. 
All SAEs (regardless of causal relationship) and AESIs will be reported on the SAE Report 
Form and submitted to the Sponsor within 24 hours of becoming aware of the event. The 
SAE Report Form will be either emailed to safety.inovio@apcerls.com or faxed to
The original SAE Report Form must be kept at the clinical trial site. 
The event will be data entered into the CRF. 
 
For the events that are considered an AESI, the PI will contact the Sponsor within 24 hours 
of becoming aware of the event to discuss whether dosing should continue. 
Table 7: SAE Contact Information 
Sponsor Safety Email: safety.inovio@apcerls.com  
Sponsor Safety Fax: 
Sponsor Safety Phone: 
 
Table 8: Medical Monitor Direct contact Information 
Primary point of contact, ICON Medical Monitor: 
M.D.  
Email: 
 
Cell Phone: 
 
Inovio Medical Monitor: 
Jr., M.D., FACP, FIDSA 
Email: 
 
Cell Phone: 
 
 
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All SAEs, treatment-related AEs and AESIs must be followed by the PI until resolution or 
return to baseline status, stabilization of the event (i.e., the expectation that it will remain 
chronic), even if it extends beyond the clinical trial reporting period or until it is determined 
that the subject is lost to follow up. 
Follow-up information is to be submitted to the Sponsor on an SAE Report Form and within 
24 hours of becoming aware of the information. 
If medical records are submitted to the Sponsor with the SAE Report Form, the clinical 
trial site must: 
• Redact the medical records of all personal data (e.g., confidential subject data, 
Personal Identifying Information [PII]) 
• Provide the subject’s assigned identification number (SID) on the records 
 ADVERSE EVENT REPORTING 
This section provides details on reporting the safety information. 
 SUBMITTING THE INITIAL SERIOUS ADVERSE EVENT (SAE) REPORT FORM 
The PI should include as much safety information as possible when submitting the initial 
report, but the report must include the following at a minimum:  
• 
The adverse event 
• 
The subject’s assigned identification number (SID) 
• 
Investigational product(s) (IP) and/or study device 
• 
Investigator causal relationship to the IP(s) and/or study device 
• 
Serious criteria 
• 
Reporter name and contact information 
If a case is submitted to the Sponsor with only the “minimum” information, a more detailed 
or updated follow-up report will be sent to the Sponsor as soon as possible but no later 
than three (3) calendar days after the date of the initial report. 
 RECORDING THE EVENT 
Principal Investigators (PIs) should use correct medical terminology/concepts when 
recording adverse events on the EDC and SAE Report Form. The use of colloquialisms 
and abbreviations should be avoided. 
A medical diagnosis, if known, should be recorded rather than individual signs and 
symptoms. However, if the signs and/or symptoms cannot be medically characterized as 
a single diagnosis or syndrome, each individual sign and/or symptom should be recorded. 
If a diagnosis is subsequently established, all previous signs and/or symptoms will be 
subsumed and replaced with a single medical diagnosis. 
 ASSESSING SEVERITY (INTENSITY) 
Severity is used to describe the intensity of a specific event (e.g., mild, moderate, severe). 
The PI will assess and grade clinical AEs or SAEs (based on discussions with clinical trial 
subjects) in accordance with Toxicity Grading Scale for Healthy Adult and Adolescent 
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Volunteers Enrolled in Preventive Vaccine Clinical Trials (Food and Drug Administration 
[FDA] Guidance for Industry) (Appendix A). 
 CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS (AES) 
A causally related AE is one judged to have a possible, probable or definite relationship 
to the administration of the IP and/or the study device. An AE may also be assessed as 
not related to the IP and/or the study device. Because the PI is knowledgeable about the 
subject (e.g., medical history, concomitant medications), administers the IP, and monitors 
the subject’s response to the IP, the PI is responsible for reporting AEs and judging the 
relationship between the administration of the IP and EP and a subsequent AE. The PI is 
aware of the subject’s clinical state and may have observed the event, and thus may be 
sensitive to distinctions between events due to the underlying disease process versus 
events that may be product-related.  
Principal Investigators (PIs) should use their knowledge of the clinical trial subject, the 
circumstances surrounding the event, and an evaluation of any potential alternative 
causes to determine whether an AE is considered to be related to the IP and/or the study 
device and the causal relationship reported as "Yes" or "No" accordingly. Causality should 
be assessed by the PI as related to drug, related to device, or related to both drug and 
device (i.e., related to both or indiscernible) by the following criteria: 
• 
Yes – there is a reasonable possibility that administration of the clinical trial 
treatment (drug or device or both drug and device) contributed to the event 
• 
No – there is no reasonable possibility that administration of the clinical trial 
treatment contributed to the event and there are more likely causes 
The following guidance should also be taken into consideration: 
• 
Temporal relationship of event to administration of IP and/or EP 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable) 
• 
Known association of the event with the IP, EP or with similar treatments 
• 
Known association of the event with the disease under trial 
• 
Presence of risk factors in the clinical trial subject or use of concomitant 
medications known to increase the occurrence of the event 
The rationale for the PI’s causal assessment is to be recorded on the SAE Report Form. 
The Sponsor will assess the overall safety of the IP delivered by EP and determine 
whether to report expeditiously to the regulatory authority(ies). 
 REPORTING SUSPECTED COVID-19 DISEASE CASES DURING THE TRIAL 
All suspected COVID-19 disease cases based on reported COVID-19 symptoms and/or 
SARS-CoV-2 test results should be entered into the Suspected COVID-19 Clinical Event 
CRF within 24 hours of awareness. Cases will be tracked until final determination of 
whether the case meets criteria of a confirmed COVID-19 disease case, per the case 
definition, by the EAC. 
If the COVID-19 disease case reported is later determined not to be a confirmed case, the 
event (e.g. symptoms or other diagnosis), if serious, would be reported as an SAE within 
24 hours following notification of the determination by the EAC.  
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If the COVID-19 disease case reported is later determined not to be a confirmed case, the 
event (e.g. symptoms or other diagnosis), if non-serious and if occurring from the time of 
consent until 28 days post-dose 2, would be reported as an AE following notification of the 
determination by the EAC. 
 REPORTING PREGNANCY DURING THE CLINICAL TRIAL 
Subjects who are pregnant or expect to become pregnant prior to 3 months following the 
last dose will be excluded from participation in the clinical trial.  
All pregnancies that occur from the time of first administration of clinical trial treatment 
through study completion (i.e., Day 393) will be reported to the Sponsor. If clinical trial site 
staff become aware that a subject becomes pregnant after the first dose in the clinical trial, 
she will not be given any additional treatments with the IP. A Pregnancy Form will be 
completed by the PI and submitted to the Sponsor within 24 hours after becoming aware 
of the pregnancy. 
The PI will report this event to their IRB/REB/EC in accordance with their policies and 
procedures.  
The clinical trial site must request the subject’s permission to query pregnancy outcome 
and follow the subject for outcome of the pregnancy. The subject will continue to be 
followed for safety assessments without receiving additional IP until clinical trial discharge 
in accordance with this protocol. Procedures that are contraindicated during pregnancy, 
including additional dose administrations, must not be performed. The PI should use 
clinical judgment regarding subsequent clinical trial-related blood collection based on the 
presence or absence of anemia in each subject.  
Male subjects will be instructed through the ICF to immediately inform the PI if their partner 
becomes pregnant until study completion. A Pregnancy Form will be completed by the PI 
and submitted to the Sponsor within 24 hours after becoming aware of the pregnancy. The 
pregnant partner will be asked to sign a Pregnancy Information Collection Consent Form 
to allow for follow-up on her pregnancy. If the authorization has been signed, the PI will 
collect and report details of the course and outcome of the pregnancy in the partner of a 
male subject exposed to IP. The PI will update the Pregnancy Form with additional 
information on the course and outcome of the pregnancy and submit the form to the 
Sponsor.  
If a PI is contacted by the male subject or his pregnant partner, the PI may provide 
information on the risks of the pregnancy and the possible effects on the fetus to support 
an informed decision in cooperation with the treating physician and/or obstetrician. 
If the end of the pregnancy occurs after the clinical trial has been completed, the outcome 
will be reported directly to the Sponsor. 
 REPORTING DEVICE-RELATED COMPLAINTS OR DEFICIENCIES 
All product complaints that meet the definition of device deficiency must be reported to the 
Sponsor within 10 days of discovery, with the exception of SAEs which require 24-hour 
reporting. The error reporting or complaint form must be completed and emailed to the 
Sponsor at clinicalcomplaint@inovio.com. 
Device deficiencies include malfunctions, misuse or use errors and inadequate labeling. 
A malfunction is defined as the failure of a device to meet its performance specifications 
or otherwise perform as intended. The intended performance of a device refers to the 
intended use for which the device is labeled or marketed. 
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Any problems experienced during the treatment procedure including malfunctions of the 
device, error messages displayed on the device screen following treatment, or errors that 
occur during the treatment procedure must immediately be reported to the Sponsor or its 
designee for evaluation.  
 NOTIFYING REGULATORY AUTHORITIES AND INSTITUTIONAL REVIEW BOARDS 
(IRBS)/RESEARCH ETHICS BOARDS (REBS)/ETHICS COMMITTEES (ECS) OF SAFETY 
INFORMATION 
 SPONSOR RESPONSIBILITIES 
• 
Determine whether the safety information meets the requirements for expedited 
reporting to the applicable regulatory authorities 
• 
Prepare and submit the safety report to the applicable regulatory authorities 
• 
Send all participating PIs a safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) that will include a statement if there is or is not any significant new 
safety information that might influence the risk-benefit assessment of the IP and/or 
study device, sufficient to consider changes in product administration or overall 
conduct of the clinical investigation 
 PRINCIPAL INVESTIGATOR (PI) RESPONSIBILITIES 
• 
Forward a copy of the safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) to their IRB/REB/EC as soon as practical in accordance with the 
governing policy and/or procedures 
• 
Notify their IRB/REB/EC of safety information (i.e., SAEs, pregnancies, and AESIs) 
that occur at their clinical trial site in accordance with their local institutional policy 
 POST-TRIAL REPORTING REQUIREMENTS 
PIs are not obligated to actively seek AEs or SAEs beyond the clinical trial reporting period. 
However, if the PI becomes aware of an AE or SAE that occurs after the Completion or 
Termination Visit and the event is deemed by the PI to be related to the clinical trial 
treatment, the PI should promptly document and report the event to the Sponsor. 
 CLINICAL TRIAL DISCONTINUATION  
INOVIO reserves the right to discontinue the clinical trial at a site or at multiple sites for 
safety or administrative reasons at any time. In particular, a clinical trial site that does not 
recruit at a reasonable rate may be discontinued. Additionally, the clinical trial may be 
discontinued at any time by an IRB/REB/EC, INOVIO, or a regulatory authority as part of 
their duties to ensure that clinical trial subjects are protected.  
If the clinical trial is discontinued and/or the clinical trial site closed for any 
reason, all IP and devices must be returned to INOVIO or its 
representative. The PI should ensure that their site file documents are complete 
prior to archiving, and provide copies of any requested documents to INOVIO 
for its Trial Master File (TMF). 
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STATISTICAL CONSIDERATIONS 
 
STATISTICAL AND ANALYTICAL PLAN 
The formal Statistical Analysis Plan is contained in the sections that follow. 
 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is a two-arm, multi-center, placebo-controlled, blinded, and randomized clinical trial 
in subjects at high risk of SARS-CoV-2 exposure. The study’s primary endpoint is the 
incidence of virologically-confirmed COVID-19 disease starting 14 days after completion 
of the 2-dose regimen until 12 months post-dose 2.  The primary hypothesis is that INO-
4800 will be efficacious relative to placebo (relative efficacy > 30%).  Secondary efficacy 
analyses involve non-severe cases, severe cases, cases resulting in death, infection, and 
timing of symptom resolution.  Other secondary analyses concern safety and binding 
antibody response.  Exploratory analyses concern cellular immunological measures. 
 
STATISTICAL HYPOTHESES 
The primary hypothesis of relative efficacy greater than 30% will be tested with H0: p ≥ 
.70/(.70+k) vs. H1: p < .70/(.70+k), where p is the true proportion of subjects with disease 
who receive INO-4800 relative to the total number of subjects with disease, and k is the 
total amount of follow-up time in the placebo group divided by the total amount of follow-
up time in the INO-4800 group. There are no other formal hypotheses. 
 
ANALYTICAL POPULATIONS 
Analysis populations will be: 
The per-protocol (PP) population includes all subjects who receive all doses of Study 
Treatments and have no protocol violations. Subjects with disease occurring prior to 14 
days post-dose 2 will be excluded from the PP population.  Subjects in the PP population 
will be grouped to treatment arms as randomized.  Subjects excluded from the PP 
population will be identified and documented prior to unblinding of the trial database.  
Analyses on the PP population will be primary for the analysis of efficacy in this trial. 
The modified intention to treat (mITT) population includes all subjects who receive at least 
one dose of Study Treatment. Subjects in this population will be grouped to treatment 
arms as randomized.  Analysis of the mITT population will be considered supportive for 
the corresponding PP population for the analysis of efficacy. 
The intention to treat (ITT) population includes all subjects who are randomized. Subjects 
in this sample will be grouped to treatment arms as randomized.  Analysis of the ITT 
population will be considered supportive for the corresponding PP population for the 
analysis of efficacy. 
The safety analysis population includes all subjects who receive at least one dose of Study 
Treatment. Subjects will be analyzed according to the treatments received. 
 
DESCRIPTION OF STATISTICAL METHODS 
 PRIMARY EFFICACY ANALYSIS 
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The primary hypothesis of relative efficacy greater than 30% will be tested with H0: p ≥ 
0.70/(0.70+k) vs. H1: p < 0.705/(0.70+k), where p is the true proportion of subjects with 
disease who receive INO-4800 relative to the total number of subjects with disease, and 
k is the total amount of follow-up time in the placebo group divided by the total amount of 
follow-up time in the INO-4800 group. 
A p-value for this hypothesis test and corresponding 95% confidence interval will be 
computed based on the exact binomial method of Clopper-Pearson. Success will be 
concluded if the one-sided p-value is <0.025 and the corresponding lower bound of the 
two-sided 95% CI for efficacy exceeds 30%. 
For calculating k, an individual subject’s follow-up time is either: 
a) the date of first disease diagnosis – date of the start of surveillance period +1 (for 
subjects who are cases), or 
b) the date of last follow-up – date of the start of surveillance period +1 (for subjects 
who are non-cases). 
This methodology is based on the following. Assuming that the number of subjects who 
are cases in the INO-4800 group follows a Poisson distribution with parameter λv and the 
number of subjects who are cases in the placebo group follows a Poisson distribution with 
parameter λc, then conditional on total number of subjects with cases, t, the number of 
subjects who are cases in the INO-4800 group follows a binomial distribution with 
parameters (t, p=λv/(λv+λc)).  The relationship between p and efficacy is: efficacy = (1-
(1+k)p)/(1-p).  Therefore, testing efficacy > 30% corresponds to testing p < 0.70/(0.70+k).  
Similarly, the confidence interval for efficacy is (1-(1+k)UBp)/(1-UBp), (1-(1+k)LBp)/(1-LBp), 
where UB and LB are the Clopper-Pearson upper and lower limits for the proportion. 
The efficacy time frame is defined by symptoms beginning at any time starting from 14 
days after Dose 2 and ending 12 months after Dose 2.  Subjects identified as cases that 
started prior to this time point will be excluded.  Subjects with multiple instances meeting 
the case definition will be counted only once, using the first such instance.    
The PP population will be primary for the analysis of efficacy in this trial. Efficacy analysis 
using the mITT population will also be conducted counting cases from 14 days postdose 
1 as a supportive analysis.  The ITT population will also be used for a supportive analysis 
counting cases starting from randomization. 
 SECONDARY ANALYSES 
8.5.2.1 Efficacy 
The secondary efficacy incidence endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values.  
The secondary efficacy endpoint regarding timing of symptom resolution will be 
analyzed with Kaplan-Meier plots by treatment group. 
8.5.2.2 Immunogenicity 
Post-baseline antibody titers from ELISA will be compared between treatment groups 
using ratios of geometric mean titers and associated 95% CIs. 
 
Post-baseline seroconversion from ELISA will be compared between treatment groups 
using differences in proportions and associated Miettinen and Nurminen 95% CIs. 
 
The summaries listed above will be stratified according to disease status of the subjects. 
 
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Valid samples for statistical analysis purposes will be those collected within the days of 
the specified visit according to the Schedule of Events. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
 SAFETY ANALYSES 
8.5.3.1 Adverse Events 
All AEs including injection-site reactions will be summarized among the Safety 
Population by frequency per treatment arm. These frequencies will be presented overall 
and separately by dose, and will depict overall, by system organ class and by preferred 
term, the percentage of subjects affected. Additional frequencies will be presented with 
respect to maximum severity and to strongest relationship to Study Treatment. Multiple 
occurrences of the same AE will be counted only once following a worst-case approach 
with respect to severity and relationship to Study Treatment. All serious AEs will also be 
summarized as above. 
The main summary of safety data will be based on events occurring within 30 days of 
any dose. For this summary, the frequency of preferred term events will be compared 
between study arms with risk differences and 95% confidence intervals, using the 
method of Miettinen and Nurminen. As this analysis will use many event categories, and 
produce many confidence intervals, caution should be exercised when interpreting these 
confidence intervals.  Separate summaries will be based on events occurring within 7 
days of any dose and regardless of when they occurred. 
The analyses listed above will also be performed on the subset who are assigned to 
complete the 7-day post-dose diary. For AE data, partial start dates will be imputed to 
the date of treatment to conservatively report the event as treatment-emergent, 
whenever the portion of the date is consistent with that of the study treatment. Otherwise, 
it will be imputed to the earliest date consistent with the partial date. A completely 
missing onset date will be imputed as the day of treatment. Partial stop dates will be 
assumed to be the latest possible day consistent with the partial date. 
AE duration will be calculated as (Stop Date – Start Date) + 1. 
8.5.3.2 Vital Signs 
Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean, standard deviation, minimum, median, and maximum 
values by time point and treatment arm, for the Safety population. Baseline is defined 
as the last measurement prior to the first treatment administration.   
 DISPOSITION 
Disposition will be summarized by treatment arm for the ITT population and will include 
the number and percentage randomized, the number and percentage who received each 
dose and the number who completed the trial.  The number and percentage of subjects 
who discontinued will be summarized overall and by reason.  The number in each analysis 
population will also be presented.   
 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
8.5.5.1 Demographics 
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Demographic data will be summarized with descriptive statistics: mean standard 
deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables, by treatment arm, for the ITT and PP populations.  
8.5.5.2 Medical History 
The percentage of subjects with abnormal medical history findings will be summarized 
by body system, by treatment arm, for the ITT and PP populations.  
8.5.5.3 Prior Medications 
Prior medications are those that were used before the start of the trial (prior to Day 0). 
Partial stop dates of prior medications will be assumed to be the latest possible date 
consistent with the partial date; start dates will not be imputed. Data for all prior 
medications will be summarized with percentages by treatment arm, for the ITT and PP 
populations.  
 INTERIM ANALYSES  
For safety issues or evidence of poor efficacy, the DSMB could recommend stopping 
enrollment at any time; no formal interim analysis will be performed for this purpose. The 
two-sided type I error of 0.05 will not be adjusted for possible early stopping due to 
futility. 
 MULTIPLICITY 
Not applicable; there is one hypothesis that will be tested. 
 MISSING VALUES 
Missing data will not be imputed. 
For the ITT analyses of efficacy, subjects with missing or unevaluable data regarding case 
definition will be considered cases (failures). 
 EXPLORATORY ANALYSES  
  8.5.9.1 Immunogenicity 
Post-baseline increases from baseline in interferon-γ ELISpot response magnitudes will 
be compared between treatment groups using a difference in medians and associated 
non-parametric 95% CIs. 
Post-baseline decreases from baseline in neutralizing antibody response magnitudes 
will be compared between treatment groups using a difference in medians and 
associated non-parametric 95% Cis. 
 
The summaries listed above will be stratified according to disease status of the 
subjects. 
Valid samples for statistical analysis purposes will be those collected within the days of 
the specified visit according to the Schedule of Events. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
8.5.9.1 Concomitant Medications 
Concomitant medications are those used during the course of the trial (on or after Day 
0). Partial stop dates of concomitant medications will be assumed to be the latest 
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possible date consistent with the partial date; start dates will not be imputed. Data for 
all concomitant medications will be summarized with percentages by treatment arm, for 
the ITT and PP populations.   
 
SAMPLE SIZE/POWER 
The trial is case-driven. A total of 160 observed cases will be required to provide 90% 
power to declare the vaccine efficacious (>30%), utilizing the methodology described in 
Section 8.5.1 and assuming a true efficacy of 60%.  A sample size of 6178 subjects will 
be required to achieve this number of cases assuming an underlying attack rate of 3.7%.   
 
RANDOMIZATION AND BLINDING  
Subjects will be randomized (1 INO-4800:1 Placebo). 
The study is double-blinded. Randomization and blinding will avoid bias in the assignment 
of participants to treatment, increase the likelihood that known and unknown subject 
attributes (e.g., demographics and other baseline characteristics) are evenly balanced 
between treatment groups, and enable valid statistical comparisons between treatment 
groups. 
 
ETHICS 
 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical trial is 
performed in accordance with the protocol, the principles of the Declaration of Helsinki, 
Good Clinical Practice (GCP) and applicable regulatory requirements. 
 
INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD (REB)/ETHICS 
COMMITTEE (EC) 
The Investigator will commence the clinical trial after full approval of the protocol and 
adjunctive materials (e.g., ICF, advertising) has been obtained from the applicable 
IRB/REB/EC and a copy of IRB/REB/EC approval documentation has been received by 
the Sponsor. 
Investigator responsibilities relevant to the IRB/REB/EC include the following: 
• Submit continuing review reports to the IRB/REB/EC as required, and request re-
review and approval of the clinical trial at least once a year during the conduct of 
the clinical trial 
• Notify the Sponsor immediately of any suspected unexpected adverse drug or 
device events/effects 
• Notify the IRB/REB/EC immediately if the Sponsor notifies the Investigator about 
any reportable safety events 
• Obtain approval from the IRB/REB/EC for protocol amendments and for revisions 
to the consent form or subject recruitment advertisements, as required 
• Submit reports on, and reviews of, the clinical trial and its progress to the 
IRB/REB/EC at intervals stipulated in their guidelines and in accordance with 
pertinent regulations and guidelines 
• Maintain a file of clinical trial-related information (refer to clinical trial files) that 
includes all correspondence with the IRB/REB/EC 
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• Notify the IRB/REB/EC when the clinical trial is completed (i.e., after the last clinical 
trial visit of the final clinical trial subject) 
• After clinical trial completion (within three [3] months is recommended), provide the 
IRB/REB/EC with a final report on the clinical trial 
Institutional Biosafety Committee (IBC) 
The Investigator will undertake the trial after full approval of the protocol and adjunctive 
materials (e.g., pharmacy manual) has been obtained from the applicable IBC and a copy 
of this approval has been received by the Sponsor. 
Investigator responsibilities relevant to the IBC include the following: 
• 
Notify the Sponsor, IBC and NIH OSP within 30 days of any: 
o Substantial problems or violation of the NIH Guidelines 
o Significant research related accidents or illnesses 
• 
Notify the IBC to any changes to the research (dosage, procedure, etc.) or facility 
(new space, remodeling, etc.).   
 
PROTECTION OF HUMAN SUBJECTS 
 COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent must be obtained from each subject prior to the subject’s 
enrollment in the clinical trial. The process for obtaining informed consent must be 
documented in the subject’s medical record (also refer to Section 6.2). 
 COMPLIANCE WITH INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD 
(REB)/ETHICS COMMITTEE (EC) REQUIREMENTS 
This clinical trial is to be conducted in accordance with applicable IRB/REB/EC 
regulations. The Investigator must obtain approval from a properly constituted 
IRB/REB/EC prior to initiating the clinical trial and obtain re-approval or review at least 
annually. The Sponsor is to be notified immediately if the responsible IRB/REB/EC has 
been disqualified or if proceedings leading to disqualification have begun. Copies of all 
IRB/REB/EC correspondence with the Investigator should be provided to the Sponsor. 
 COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
 COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS (21CFR 
PART 11) 
When applicable, this clinical trial is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
 COMPLIANCE WITH PROTOCOL 
Subjects are not required to follow special instructions specific to the IP used in this clinical 
trial. Subjects will be provided with Investigator emergency contact information and 
advised to report all AEs. While every effort should be made to avoid protocol deviations, 
should an important deviation be discovered, the Sponsor must be informed immediately. 
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Any protocol deviation impacting subject safety must be reported to the Medical Monitor 
immediately. 
 CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from, or changes to, the protocol 
without Sponsor approval and prior review and documented approval/favorable opinion of 
the protocol amendment from the IRB/REB/EC, except where necessary to eliminate 
immediate hazards to clinical trial subjects, or when the changes involve only logistical or 
administrative aspects of the clinical trial (e.g., change in monitors, change of telephone 
numbers).  
 DATA COLLECTION, MONITORING AND REPORTING 
 CONFIDENTIALITY AND PRIVACY 
A report of the results of this clinical trial may be published or sent to the appropriate 
regulatory authorities in any country in which the clinical trial products are legally marketed 
or may ultimately be marketed, but the subject’s name/identity will not be disclosed in 
these documents. The clinical trial Sponsor, its agents, the IRB/REB/EC and regulatory 
authorities will have direct access to the subjects’ medical records for the purposes of trial-
related monitoring, auditing and inspection. Appropriate precautions will be taken to 
maintain confidentiality of medical records and personal information. 
Written Authorization and other documentation are to be obtained from each subject, 
and/or from the subject’s legally authorized representative, prior to enrollment in the 
clinical trial, in accordance with all applicable laws, regulations and/or directives relating 
to privacy and data protection. 
 SOURCE DOCUMENTS 
Source data is all information, electronic or hardcopy original records or clinical findings, 
laboratory results, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the clinical trial. 
Examples of original source data records may include:  
• Hospital records 
• Clinical and office charts 
• Laboratory notes 
• Memoranda 
• Pharmacy dispensing records 
• Recorded data from automated instruments 
• Copies of electronic medical records (EMR) certified after verification as being 
accurate and complete 
• X-rays 
• Subject files and records kept at the pharmacy, at the laboratories, at the medical 
records facility and within information technology (IT) systems that are involved in 
the clinical trial  
The Investigator/institution will permit clinical trial-related monitoring, audits, IRB/REB/EC 
review and regulatory inspections by providing direct access to source data/documents 
related to this clinical trial. 
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 RECORDS RETENTION 
Upon request of the Clinical Monitor, Sponsor or its agent(s), auditor, IRB/REB/EC or 
regulatory authority, the Investigator/institution should make available for direct access all 
requested clinical trial-related records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
It is the Investigator’s responsibility to retain clinical trial essential documents for at least 
two (2) years after the last approval of a marketing application in their country and until 
there are no pending or contemplated marketing applications in their country or at least 
two (2) years have elapsed since the formal discontinuation of clinical development of the 
IP. This retention period may be superseded by local requirements. The Sponsor will 
inform the Investigator/institution when these documents are no longer needed to be 
retained. 
If the Records Retention requirements are addressed in a governing clinical trial 
agreement, it is the Investigator’s responsibility to retain clinical trial essential documents 
in accordance with the governing clinical trial agreement and applicable local 
requirements. 
 SAFETY AND QUALITY MONITORING 
 SAFETY REVIEW 
The Sponsor’s Safety Review Committee (SRC), composed of the Sponsor’s Medical 
Monitor, the ICON Medical Monitor and 1 additional physician, will review blinded safety 
and tolerability data on a regular basis throughout the trial. The SRC will meet 
approximately once per month, at a minimum. The SRC will refer any of the events listed 
in Section 7.8.4 or any other safety concerns to the DSMB Chair. 
The DSMB will review unblinded safety and tolerability data, including AEs of clinical 
significance, AESIs and SAEs, as well as safety laboratory data for all enrolled subjects. 
The DSMB will also evaluate the data for signals of vaccine-enhanced disease and in the 
event of a signal, advise whether to halt the trial. The DSMB will advise regarding any 
safety concerns and will make recommendations regarding continued enrollment, safety 
pause and trial suspension. If the safety data is considered unfavorable during any safety 
review, the DSMB may recommend a trial pause or trial termination at which time further 
enrollment and administration of IP to subjects will be paused. The Sponsor will perform 
an investigation and consult with the DSMB and other experts, if needed, to determine 
whether to resume dosing of the remainder of the subjects. For further details, see the 
DSMB Charter.  
 CLINICAL MONITORING 
Clinical Monitoring will be performed by qualified Clinical Monitors who will report to the 
Sponsor or the Sponsor’s designee. The following clinical trial site monitoring tasks will be 
performed at all clinical trial sites: 
• 
Prior to subject screening at the site, a Site Initiation Visit will be conducted to 
review all relevant forms and documentation, and ensure that the clinical trial site 
staff are qualified and compliant with all applicable requirements 
• 
All clinical trial site monitoring visits will be documented 
• 
Periodic clinical trial site visits will be performed throughout the clinical trial 
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• 
The Clinical Monitor will address and document the following trial conduct activities 
and obligations: 
o Assure that the trial is being conducted in accordance with the protocol, 
applicable regulatory agency regulations, and IRB/REB/EC policies. 
o Discuss trial conduct issues and incidents of noncompliance with the 
Investigator and/or trial personnel and document them on the resolution trip 
report. Report any significant unresolved problems immediately to the 
Sponsor. 
o Remind the Investigator as necessary of the obligation to immediately report 
all SAEs and provide subsequent follow-up report of the final outcome to the 
IRB. 
o Throughout the trial, inspect source documents to ensure they are complete, 
logical, consistent, attributable, legible, contemporaneous, original, accurate 
and complete (ALCOA-C). 
o Assure that the trial facilities, including the pharmacy, continue to be 
acceptable. 
o Compare the trial CRFs with source documents to assure that the data are 
accurate and complete and that the protocol is being followed. 
o Assure that investigational drug and device accountability and reconciliation of 
records are complete and accurate. 
o Assure that all subject specimens are being stored and forwarded properly for 
testing in accordance with laboratory manual requirements. 
 FINANCING AND INSURANCE 
Inovio Pharmaceuticals is the Sponsor and Department of Defense, Joint Program 
Executive Office is providing funding for the study. Clinical trial insurance has been taken 
out according to the laws of the countries where the study will be conducted. The 
investigative site is being compensated for the conduct of this study and will follow the 
terms described in the clinical trial agreement. This agreement was executed separately 
from this clinical trial protocol. The Investigators will be required to provide full financial 
disclosure information per 21 CFR Part 54. 
 PUBLICATION POLICY 
Publication of the results of this clinical trial in its entirety will be allowed. The proposed 
presentation, abstract and/or manuscript must be made available to the Sponsor for 
review and approval in accordance with the governing clinical trial agreement. 
 
 
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 LIST OF ABBREVIATIONS 
ADE 
Adverse Device Effect 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALCOA-C 
Attributable, Legible, Contemporaneous, Original, Accurate and Complete 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
bGH polyA 
Bovine growth hormone 3’ end poly-adenylation signal 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CBC 
Complete Blood Count 
Cl 
Chloride 
COVID-19 
Coronavirus Disease 2019 
Cr 
Creatinine 
CRF 
Case Report Form 
CS 
Clinically Significant 
DNA 
Deoxyribonucleic Acid 
DLT 
Dose Limiting Toxicity  
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EP 
Electroporation 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B Surface Antigen 
HCO3 
Biocarbonate 
hCMV  
Human CMV 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICD 
Implantable-Cardioverter-defibrillator 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
ID 
Intradermal 
IM 
Intramuscular 
Inovio 
Inovio Pharmaceuticals Inc. 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
K 
Potassium 
KanR 
Kanamycin resistance gene 
MAAE 
Medically Attended Adverse Event 
mITT 
modified Intent to Treat 
MM 
Medical Monitor 
MERS 
Middle East Respiratory Syndrome  
MERS-CoV 
Middle East Respiratory Syndrome Coronavirus 
mRNA 
Messenger RNA 
Na 
Sodium 
NCS 
Not Clinically Significant 
NIAID 
National Institute for Allergy and Infectious Disease 
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NHP 
Non-human Primates 
NP 
Nucleocapsid Protein 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PII 
Personal Identifying Information 
PO4 
Potassium 
PT 
Preferred Term 
pUC ori 
Plasmid origin of replication 
RBC 
Red blood cell 
REB 
Research Ethics Board 
RR 
Respiratory Rate 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SARS 
Severe Acute Respiratory Syndrome  
SARS-CoV 
Severe Acute Respiratory Syndrome Coronavirus 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus - 2 
SID 
Subject Identification Number 
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
SynCon 
Synthetic consensus 
TBili 
Total Bilirubin 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of Child Bearing Potential 
 
 
 
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Curcio C, Khan AS, Amici A, Spadaro M, Quaglino E, Cavallo F, et al. DNA 
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Ugen KE, Kutzler MA, Marrero B, Westover J, Coppola D, Weiner DB, et al. Regression 
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Tebas P, Roberts CC, Muthumani K, Reuschel EL, Kudchodkar SB, Zaidi FI, et al. 
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 APPENDICES 
 APPENDIX A: TOXICITY GRADING SCALE FOR HEALTHY ADULT AND ADOLESCENT 
VOLUNTEERS ENROLLED IN PREVENTIVE VACCINE CLINICAL TRIAL  
 
Table for Clinical Abnormalities 
Local Reaction to 
Injectable Product 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Pain 
Does not interfere 
with activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency 
room (ER) visit 
or 
hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/Rednessa 
2.5-5 cm 
5.1-10 cm 
> 10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swellingb 
2.5-5 cm and 
does not interfere 
with activity 
5.1-10 cm or 
interferes with 
activity 
> 10 cm or 
prevents daily 
activity 
Necrosis 
Vital Signsc 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Fever   (°C)d 
            (°F)d 
38.0-38.4 
100.4-101.1 
38.5-38.9 
101.2-102.0 
39.0-40.0 
102.1-104.0 
> 40.0 
> 104.0 
Tachycardia - beats 
per minute 
101-115 
116-130 
> 130 
ER visit or 
hospitalization 
for arrhythmia 
Bradycardia - beats 
per minutee 
50-54 
45-49 
< 45 
ER visit or 
hospitalization 
for arrhythmia 
Hypertension 
(systolic) - mm Hg 
141-150 
151-155 
> 155 
ER visit or 
hospitalization 
for malignant 
hypertension 
Hypertension 
(diastolic) - mm Hg 
91-95 
96-100 
> 100 
ER visit or 
hospitalization 
for malignant 
hypertension 
Hypotension 
(systolic) - mm Hg 
85-89 
80-84 
< 80 
ER visit or 
hospitalization 
for hypotensive 
shock 
Respiratory Rate - 
breaths per minute 
17-20 
21-25 
> 25 
Intubation 
a In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable. 
b Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
c Subject should be at rest for all vital sign measurements. 
d Oral temperature; no recent hot or cold beverages or smoking. 
e When resting heart rate is between 60-100 beats per minute. Use clinical judgement when characterizing bradycardia among 
some healthy subject populations, for example, conditioned athletes. 
 
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Protocol Version: 2.0 
 
Page 69 of 70 
 
 
Systemic 
(General) 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Nausea/Vomiting 
No interference 
with activity or 1-2 
episodes/24 
hours 
Some interference 
with activity or > 2 
episodes/24 hours 
Prevents daily 
activity, requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
for hypotensive 
shock 
Diarrhea 
2-3 loose stools 
or < 400 gms/24 
hours 
4-5 loose stools or 
400-800 gms/24 
hours 
6 or more watery 
stools or > 800 
gms/24 hours or 
requires 
outpatient IV 
hydration 
ER visit or 
hospitalization 
Headache 
No interference 
with activity 
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or some 
interference with 
activity 
Significant; any 
use of narcotic 
pain reliever or 
prevents daily 
activity 
ER visit or 
hospitalization 
Fatigue 
No interference 
with activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Myalgia 
No interference 
with activity 
Some interference 
with activity 
Significant; 
prevents daily 
activity 
ER visit or 
hospitalization 
Systemic Illness 
Mild (Grade 1) 
Moderate (Grade 
2) 
Severe (Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
Illness or clinical 
adverse event (as 
defined according 
to applicable 
regulations) 
No interference 
with activity 
Some interference 
with activity not 
requiring medical 
intervention 
Prevents daily 
activity and 
requires medical 
intervention 
ER visit or 
hospitalization 
U.S. Department of Health and Human Services, Food and Drug Administration, and Center for Biologics Evaluation and 
Research. Guidance for industry: Toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive 
vaccine clinical trials. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/toxicity-grading-scale-healthy-
adult-and-adolescent-volunteers-enrolled-preventive-vaccine-clinical 2007 Sep; 3-5 
 
 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 15-Jun-2020 
CONFIDENTIAL 
Protocol Version: 2.0 
 
Page 70 of 70 
 
 APPENDIX B: ADVERSE EVENTS OF SPECIAL INTEREST  
For the purpose of standardization across multiple vaccine platforms, including those substantially 
different from Inovio’s platform, the below table lists adverse events of special interest (AESIs) 
relevant to COVID-19 vaccine development.  
Body System 
AESI 
Respiratory 
Acute respiratory distress syndrome (ARDS) 
Pneumonitis/Pneumonia 
Neurologic 
Generalized convulsion 
Aseptic meningitis 
Guillain-Barré Syndrome (GBS) 
Encephalitis/Myelitis 
Acute disseminated encephalomyelitis (ADEM) 
CNS vasculopathy (stroke) 
Hematologic 
Thrombocytopenia 
Disseminated intravascular coagulation (DIC) 
Immunologic 
Anaphylaxis 
Vasculitides 
Other 
Acute cardiac failure 
Acute kidney failure 
Septic shock-like syndrome 
 
Page 140 of 768


CONFIDENTIAL 
 
Page 1 of 80 
COVID19-311 
Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the Safety, 
Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-
19 Disease, Administered Intradermally Followed by Electroporation in Healthy 
Seronegative Adults at High Risk of SARS-CoV-2 Exposure   
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
IND #: 19690 
Protocol Version: 3.0 
Protocol Version Date: 18-Aug-2020 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 2 of 80 
 
 
Medical Monitor Approval Page 
 
Drug:  
INO-4800 
 
Sponsor: 
Inovio Pharmaceuticals, Inc. 
 
660 W. Germantown Pike, Suite 110 
 
Plymouth Meeting, PA 19462 
 
Medical Monitor: 
 
Jr., M.D., FACP, FIDSA 
Inovio Pharmaceuticals, Inc. 
 
 
Approval Signature: 
 
 
[Electronically signed] 
  
r., M.D., FACP, FIDSA 
Inovio Pharmaceuticals, Inc. 
 
 Date (ddMmmyyyy) 
 
 
CONFIDENTIAL 
The information in this document is considered privileged and confidential by Inovio 
Pharmaceuticals Inc. (INOVIO) and may not be disclosed to others except to the extent 
necessary to obtain Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics 
Committee (EC) approval and informed consent, or as required by local regulatory 
authorities. Persons to whom this information is disclosed must be informed that this 
information is privileged and confidential and that it should not be further disclosed 
without the written permission of INOVIO. Any supplemental information added to this 
document is also confidential and proprietary information of INOVIO and must be kept in 
confidence in the same manner as the contents of this document. 
 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 3 of 80 
 
 
Principal Investigator Acknowledgement 
 
I have read and understood this Protocol and agree that it contains all details necessary to 
conduct the clinical trial. I understand that it must be reviewed by the Institutional Review Board 
(IRB)/Research Ethics Board (REB)/Ethics Committee (EC) overseeing the conduct of the clinical 
trial and approved or given favorable opinion before implementation. 
 
The Principal Investigator’s (PI’s) signature constitutes the PI’s approval of this Protocol and 
provides the necessary assurances that this clinical trial will be conducted in accordance with 
International Council for Harmonization (ICH)/Good Clinical Practice (GCP), local legal and 
regulatory requirements, and all stipulations of the Protocol. 
 
 
Principal Investigator Signature: 
 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
Principal Investigator Signature 
 
Date (ddMmmyyyy) 
 
 
 
Clinical Trial Site Number: 
 
Clinical Trial Site Name: 
 
 
 
 
 
 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 4 of 80 
 
SUMMARY OF CHANGES 
The following is a list of significant changes from Version 2.0, dated 15Jun2020, to Version 3.0, 
dated 18-Aug-2020. All other changes are administrative and do not significantly affect the safety 
of subjects, trial scope, or scientific integrity of the protocol. 
 
1. The trial design has been modified as follows: 
a. A Phase 2 segment has been added to the study which will evaluate 
immunogenicity and safety in 400 subjects at two dose levels across three age 
groups. Safety and immunogenicity information from the Phase 2 segment will be 
used to determine the dose level for the Phase 3 segment of the study.  The 
Phase 3 segment of the study has remained largely unchanged from the 
previous version of the protocol (v2.0). 
b. Relevant sections of the protocol have been updated to specify procedures for 
the Phase 2 segment of the study if they differ from the established procedures 
for the Phase 3 segment. 
2. The eligibility criteria for the trial has been revised as follows: 
a. Additional description of the target study population has been included in the 
inclusion criteria to provide clarity related to enrollment of subjects “with high risk 
of exposure to SARS-CoV-2”.  The revision to the inclusion criterion will provide 
clarity to the investigator regarding the types of subjects to be recruited. 
b. The inclusion criterion that discusses reproductive capacity has been modified to 
include Intrauterine device or system under medically effective contraception with 
a failure rate of < 1% per year. 
c. Several eligibility criteria have been modified to be more inclusive: 
i. The exclusion of subjects with Hepatitis B, Hepatitis C and HIV has been 
modified to limit exclusion to subjects with a known history of uncontrolled 
HIV.  
ii. The exclusion criterion related to medical conditions has been modified to 
permit subjects who have had non-metastatic prostate cancer not requiring 
treatment. 
iii. The exclusion criterion related to primary immunodeficiencies has been 
modified to permit subjects with conditions including hypothyroidism, 
Hashimoto’s thyroiditis and vitiligo. 
iv. The exclusion of ongoing smoking or vaping has been removed as per 
the recommendation of the DSMB chair, as these patients may be at 
higher risk for severe COVID-19 and may benefit from a future efficacious 
vaccine. 
3. The schedule of events has been revised as follows: 
a. A separate Schedule of Events has been added for the Phase 2 segment of the 
study. 
b. Collection of safety blood samples (complete blood count, serum chemistry, 
urinalysis) has been moved from the Phase 3 segment of the study, where they 
were originally proposed by Inovio to be performed on a subset of subjects, to 
the Phase 2 segment of the study. 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 5 of 80 
 
c. Implementation of a diary for collection of solicited AEs and injection site 
reactions has been moved from the Phase 3 segment of the study, where they 
were intended to be collected on a subset of subjects, to the Phase 2 segment of 
the study. 
d. The timepoints for collection of cellular and humoral samples have been revised 
and it has been clarified that cellular samples will be collected in Cell Preparation 
Tubes (CPT) vacutainers. 
e. The timeframes for performing the COVID-19 assessment and convalescent 
visits have been clarified. 
f. Vital signs to be performed at the acute COVID-19 assessment and convalescent 
visits have been revised to enable the visit to be performed from the subject’s 
vehicle or via telemedicine, if appropriate and allowable per site procedures. 
g. The post-dose 2 in person visit has been modified to occur on Day 42 as 
opposed to Day 56, as Day 42 is the preferred immunogenicity collection 
timepoint.  A phone call will occur on Day 56. 
4. Background information has been updated based on current disease statistics and to 
provide additional rationale for the trial design.  Additional safety data has been included 
from the Phase 1 study and additional information has been included related to risks of 
INO-4800 and the CELLECTRA® 2000 device. 
5. Additional description of the investigational product, active (INO-4800) and placebo 
(SSC-0001), to be used for the Phase 2 and Phase 3 segments was provided.  The 
description of the product within the protocol remains current for the Phase 2 segment of 
the study.  The Phase 3 segment product will be matched product, both in 2 mL vials 
with 1.1 mL fill volumes. 
6. Additional description has been provided regarding the device’s essential performance 
requirements and administration procedure. Text clarifying that readministration is not 
permitted has been included. 
7. The protocol has been revised to include the allowance of telemedicine for regularly 
scheduled visits should a subject have suspected or confirmed COVID-19 in order to 
make the visits more convenient to subjects and safe for site staff.  
8. Clarification around rescreening of previously screen failed subjects has been included. 
9. A restriction around receipt of hydroxychloroquine as prophylaxis has been added. 
10. In the Phase 3 segment of the study, an additional at-home saliva collection has been 
added in the case where a subject develops a fever or experiences any symptoms 
suggestive of COVID-19. Clarification has also been included regarding storage of saliva 
collected at home. 
11. Detail has been provided regarding referral of subjects to a primary care physician or 
medical treatment facility for treatment of COVID-19 disease as well as the expectations 
around obtaining test results, treatments, diagnostics, etc. from said facility. 
12. The protocol has been clarified to reflect that, aside from grading of injection site 
reactions, the assessment of AE and laboratory abnormalities will be performed using 
the Common Terminology Criteria for Adverse Events, version 5.0. This has been 
removed as an Appendix from the document. 
 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
Page 6 of 80 
TABLE OF CONTENTS 
Summary of Changes ................................................................................................................ 4 
Table of Contents ....................................................................................................................... 6 
Clinical Protocol Synopsis .........................................................................................................11 
Table 3 – Phase 2 Segment Schedule of Events ......................................................................19 
Table 4 – Phase 3 Segment Schedule of Events ......................................................................21 
1.0 
Introduction .................................................................................................................23 
1.1 
Background and Scientific Rationale ........................................................................... 23 
1.2 
Background Information .............................................................................................. 23 
1.2.1 
Clinical Presentation, Transmission and Immune Response .................................24 
1.2.2 
Current Treatment and Unmet Need .....................................................................26 
1.3 
Rationale for prophylactic vaccine development ......................................................... 26 
1.3.1 
DNA Vaccines.......................................................................................................26 
1.3.2 
Use of Electroporation with DNA Vaccines ...........................................................27 
1.3.3 
Inovio’s Proprietary Technology Against COVID-19 Disease ................................27 
1.3.4 
Nonhuman Primate (NHP) Challenge Studies with INO-4800 ...............................28 
1.3.5 
First-In-Human Phase 1 Trial of INO-4800 ............................................................29 
1.3.6 
Proposed Phase 2/3 Trial of INO-4800 .................................................................29 
1.3.7 
Dose and Regimen Rationale ...............................................................................29 
1.4 
Potential Benefits and Risks ....................................................................................... 30 
2.0 
Objectives and Purpose ..............................................................................................31 
2.1 
Hypothesis .................................................................................................................. 31 
3.0 
Clinical Trial Design and Endpoints ............................................................................31 
3.1 
Primary Objectives ...................................................................................................... 32 
3.2 
Primary Endpoints....................................................................................................... 32 
3.3 
Secondary Objectives ................................................................................................. 32 
3.4 
Secondary Endpoints .................................................................................................. 32 
3.5 
Exploratory Objective .................................................................................................. 33 
3.6 
Exploratory Endpoint ................................................................................................... 33 
3.7 
Efficacy Assessment (Phase 3 Segment Only) ........................................................... 34 
3.7.1 
Case Definition for Virologically-confirmed COVID-19 Disease: ............................34 
3.7.2 
Case Definition for Virologically-confirmed SARS-CoV-2 Infection ........................35 
3.8 
Safety Assessment ..................................................................................................... 35 
3.9 
Immunogenicity Assessment ...................................................................................... 35 
4.0 
Clinical Trial Population ..............................................................................................35 
4.1 
Inclusion Criteria ......................................................................................................... 35 
4.2 
Exclusion Criteria ........................................................................................................ 36 
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Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 7 of 80 
 
4.3 
Discontinuation/Withdrawal of Clinical Trial Subjects .................................................. 37 
5.0 
Clinical Trial Investigational Product Information .........................................................38 
5.1 
Investigational Product (IP) and Study Device ............................................................ 38 
5.1.1 
INO-4800 and Placebo .........................................................................................38 
5.1.2 
CELLECTRA® 2000 ..............................................................................................39 
5.2 
Dosing Regimens ....................................................................................................... 39 
5.2.1 
Blinding .................................................................................................................40 
5.3 
Packaging and Labeling .............................................................................................. 40 
5.3.1 
INO-4800 or Placebo ............................................................................................40 
5.3.2 
CELLECTRA® 2000 ..............................................................................................40 
5.4 
Handling and Storage ................................................................................................. 41 
5.4.1 
INO-4800 and Placebo .........................................................................................41 
5.4.2 
CELLECTRA® 2000 ..............................................................................................41 
5.5 
Preparation and Dispensing ........................................................................................ 41 
5.6 
Use of Study Device ................................................................................................... 41 
5.7 
Investigational Drug and Study Device Accountability ................................................. 41 
5.7.1 
Investigational Product (IP) Accountability ............................................................41 
5.7.2 
CELLECTRA® 2000 Accountability .......................................................................42 
5.8 
Return and Destruction of Investigational Drug and Study Device .............................. 42 
5.8.1 
INO-4800 and Placebo .........................................................................................42 
5.8.2 
Return of CELLECTRA® 2000...............................................................................42 
6.0 
Clinical Trial Procedures and Schedule ......................................................................43 
6.1 
Procedure by Visit ....................................................................................................... 43 
6.1.1 
Clinical Trial Screening Evaluations ......................................................................43 
6.1.1.1 Medical History .....................................................................................................43 
6.1.2 
Clinical Trial Evaluations and Procedures .............................................................44 
6.1.2.1 Day 0 and Day 28 (Dosing Visits) .........................................................................44 
6.1.2.2 Post-dose phone calls ...........................................................................................45 
6.1.2.3 Day 42 Visit ..........................................................................................................45 
6.1.2.4 Phone calls ...........................................................................................................46 
6.1.2.5 Follow up clinic visits.............................................................................................46 
6.1.2.6 Day 393 Visit or EOS ............................................................................................46 
6.1.2.7 COVID-19 Assessment Visit .................................................................................47 
6.1.2.8 COVID-19 Convalescent Visit ...............................................................................47 
6.2 
Informed Consent ....................................................................................................... 48 
6.3 
Assignment of Subject Identification Numbers ............................................................ 48 
6.4 
Safety Evaluations ...................................................................................................... 48 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 8 of 80 
 
6.4.1 
Intradermal Injection and EP .................................................................................50 
6.4.2 
Management of Pain Due to Electroporation (EP) Procedures ..............................51 
6.4.3 
Assessment of Laboratory Abnormalities ..............................................................51 
6.4.4 
Assessment of Clinical Trial Adverse Events (AEs) ..............................................52 
6.4.5 
Assessment of Injection Site Reactions ................................................................52 
6.4.6 
Immunogenicity Assessments ...............................................................................52 
6.4.7 
Concomitant Medications/Treatments ...................................................................53 
6.4.8 
Restrictions ...........................................................................................................53 
6.4.9 
SARS-CoV-2 Testing ............................................................................................53 
6.4.10 COVID-19 Disease Monitoring ..............................................................................54 
7.0 
Evaluation of Safety and Management of Toxicity ......................................................55 
7.1 
Safety Parameters ...................................................................................................... 55 
7.2 
Adverse Events (AEs) ................................................................................................. 55 
7.3 
Adverse Drug Reaction (ADR) .................................................................................... 56 
7.4 
Serious Adverse Events (SAEs) .................................................................................. 56 
7.5 
Unexpected Adverse Drug Reaction ........................................................................... 57 
7.6 
Unanticipated (Serious) Adverse Device Effect (UADE) .............................................. 57 
7.7 
Device Deficiency ....................................................................................................... 57 
7.8 
Safety and Toxicity Management ................................................................................ 57 
7.8.1 
Adverse Event of Special Interest (AESI) ..............................................................57 
7.8.2 
Medically Attended Adverse Event (MAAE) ..........................................................58 
7.8.3 
Abnormal Laboratory Value ..................................................................................58 
7.8.4 
Clinical Trial Stopping Rules .................................................................................58 
7.9 
Safety Data Reporting Period, Method of Collection and Submission ......................... 58 
7.10 
Adverse Event Reporting ............................................................................................ 59 
7.10.1 Submitting the Initial Serious Adverse Event (SAE) Report Form..........................60 
7.10.2 Recording the Event .............................................................................................60 
7.10.3 Assessing Severity (Intensity) ...............................................................................60 
7.10.4 Causal Relationship of Clinical Material to Adverse Events (AEs) .........................60 
7.11 
Reporting Suspected COVID-19 Disease Cases During the Trial ............................... 61 
7.12 
Reporting Pregnancy During the Clinical Trial ............................................................. 61 
7.13 
Reporting Device-Related Complaints or Deficiencies ................................................ 62 
7.14 
Notifying Regulatory Authorities and Institutional Review Boards (IRBs)/Research 
Ethics Boards (REBs)/Ethics Committees (ECs) of Safety Information ....................... 62 
7.14.1 Sponsor Responsibilities .......................................................................................62 
7.14.2 Principal Investigator (PI) Responsibilities ............................................................63 
7.15 
Post-Trial Reporting Requirements ............................................................................. 63 
7.16 
Clinical Trial Discontinuation ....................................................................................... 63 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 9 of 80 
 
8.0 
Statistical Considerations ...........................................................................................63 
8.1 
Statistical and Analytical Plan ..................................................................................... 63 
8.2 
General Considerations .............................................................................................. 63 
8.3 
Statistical Hypotheses ................................................................................................. 64 
8.4 
Analytical Populations ................................................................................................. 64 
8.5 
Description of Statistical Methods ............................................................................... 64 
8.5.1 
Primary Analysis ...................................................................................................64 
8.5.2 
Secondary Analyses .............................................................................................65 
8.5.3 
Safety Analyses ....................................................................................................66 
8.5.4 
Disposition ............................................................................................................67 
8.5.5 
Demographic and Other Baseline Characteristics .................................................67 
8.5.6 
Interim Analyses ...................................................................................................67 
8.5.7 
Multiplicity .............................................................................................................67 
8.5.8 
Missing Values......................................................................................................67 
8.5.9 
Exploratory Analyses ............................................................................................67 
8.6 
Sample Size/Power ..................................................................................................... 68 
8.7 
Randomization and Blinding ....................................................................................... 68 
9.0 
Ethics .........................................................................................................................69 
9.1 
Investigator and Sponsor Responsibilities ................................................................... 69 
9.2 
Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics Committee (EC)
 ................................................................................................................................... 69 
9.3 
Protection of Human Subjects ..................................................................................... 70 
9.3.1 
Compliance with Informed Consent Regulations ...................................................70 
9.3.2 
Compliance with Institutional Review Board (IRB)/Research Ethics Board 
(REB)/Ethics Committee (EC) Requirements ........................................................70 
9.3.3 
Compliance with Good Clinical Practice ................................................................70 
9.3.4 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11) .....70 
9.3.5 
Compliance with Protocol .....................................................................................70 
9.3.6 
Changes to the Protocol .......................................................................................70 
10.0 
Data Collection, Monitoring and Reporting ..................................................................71 
10.1 
Confidentiality and Privacy .......................................................................................... 71 
11.0 
Source Documents .....................................................................................................71 
11.1 
Records Retention ...................................................................................................... 71 
12.0 
Safety and Quality Monitoring .....................................................................................72 
12.1 
Safety Review ............................................................................................................. 72 
12.2 
Clinical Monitoring....................................................................................................... 72 
13.0 
Financing and Insurance ............................................................................................73 
14.0 
Publication Policy .......................................................................................................73 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 10 of 80 
 
15.0 
List of Abbreviations ...................................................................................................74 
16.0 
References .................................................................................................................76 
17.0 
Appendices .................................................................................................................80 
17.1 
APPENDIX A: Adverse Events of Special Interest ...................................................... 80 
 
 
 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 11 of 80 
 
CLINICAL PROTOCOL SYNOPSIS 
Protocol Title: Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the 
Safety, Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-19 
Disease, Administered Intradermally Followed by Electroporation in Healthy Seronegative 
Adults at High Risk of SARS-CoV-2 Exposure 
Protocol Number: COVID19-311 
Clinical Trial Phase: 2/3 
Estimated Number of Clinical Trial Centers and Countries/Regions: Approximately 40 
centers in the US 
Background:   
INO-4800 is a prophylactic vaccine under development against SARS-CoV-2, the causative 
agent of COVID-19. INO-4800 contains the plasmid pGX9501, which encodes for the full 
length of the Spike glycoprotein of SARS-CoV-2. The goal of this trial is to assess the safety, 
immunogenicity and efficacy of INO-4800 to prevent COVID-19 disease in subjects at high risk 
of exposure to SARS-CoV-2.  
 
Clinical Trial Design:  
This is an operationally seamless Phase 2/3, randomized, placebo-controlled, multi-center trial 
to evaluate the safety, immunogenicity, and efficacy of INO-4800, administered by intradermal 
(ID) injection followed immediately by electroporation (EP) using the CELLECTRA® 2000 
device, in a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-2 
exposure. The primary objectives of this trial are to identify in seronegative subjects an optimal 
age-related dose of INO-4800 in the Phase 2 segment for a subsequent efficacy evaluation in 
the Phase 3 segment.  
 
Approximately 6578 seronegative subjects 18 years of age and older are expected to be 
enrolled across two (2) segments of this study. The subjects and data from Phase 2 are 
independent from that of Phase 3. 
 
Phase 2 Segment – Dose Selection 
In the Phase 2 segment, approximately 400 subjects 18 years of age and older will be 
evaluated across four (4) dose groups (Table 1, Figure 1). Subjects will be randomized at a 
3:3:1:1 ratio to receive either active investigational product (INO-4800) or placebo (SSC-0001) 
according to Table 1 below. Dose groups receiving INO-4800 will enroll approximately 150 
subjects per group. Dose groups receiving placebo will enroll approximately 50 subjects per 
group. Randomization will be such that approximately 240 subjects aged 18-50 years, 120 
subjects aged 51-64 years and 40 subjects aged ≥ 65 years will be enrolled. Initial enrollment 
will include subjects aged 18-50 years. Initiation of enrollment of older subjects 51-64 years of 
age and elderly subjects 65 years and older will depend on review of safety and 
immunogenicity data from those age groups generated in the Phase 1 study (COVID19-001).   
 
Table 1: Phase 2 Segment Dose Groups 
Study  
Group 
Expected 
Number of 
Subjects 
Dosing 
Days 
Number of 
Injections + EP 
per Dosing Visit 
INO-4800 
(mg) per 
injection 
INO-4800 
(mg) per 
Dosing Visit 
Total Dose 
(mg) 
INO-4800 
150 
0, 28 
1 
1.0 
1.0 
2.0 
INO-4800 
150 
0, 28 
2a 
1.0 
2.0 
4.0 
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Clinical Protocol 
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CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 12 of 80 
 
Placebo 
50 
0, 28 
1 
0 
0 
0 
Placebo 
50 
0, 28 
2a 
0 
0 
0 
Total 
400 
 
 
 
 
 
aINO-4800 or placebo will be injected ID followed immediately by EP in an acceptable location on two different limbs at each 
dosing visit. 
 
Dose selection for evaluation of efficacy in the Phase 3 segment will be based on Week 6 
immunogenicity data and Week 8 safety data from the Phase 2 segment. Group-level unblinded 
summaries and analyses of safety will be produced once the Week 8 phone call visit data are 
completed for all subjects in the Phase 2 segment. Group-level unblinded summaries and 
analyses of immunogenicity will be produced once the Week 6 visit data are completed for all 
subjects in the Phase 2 segment.  
 
Phase 3 Segment – Efficacy 
In the Phase 3 segment, approximately 6178 subjects 18 years of age and older will be 
randomized at a 1:1 ratio to receive either active investigational product (INO-4800, dose 
selected from the Phase 2 segment) or placebo (SSC-0001). See Table 2 and Figure 1.  A 
minimum of 15% of the total sample size of subjects will be 51-64 years of age, and a minimum 
of 5% of the total sample size of subjects will be ≥ 65 years of age. 
 
Table 2: Phase 3 Segment Dose Groups 
Study 
Group 
Expected 
Number of 
Subjects 
Dosing 
Days 
Number of 
Injections + 
EP per 
Dosing Visit 
INO-4800 
(mg) per 
injection 
Total 
Dose 
(mg)  
INO-4800 
3089 
0, 28 
TBD 
TBD 
TBD 
Placebo 
3089 
0, 28 
TBD 
0 
0 
Total 
6178 
 
 
 
 
TBD, to be determined based on the Phase 2 segment optimal dose selection 
 
This segment of the trial is case-driven. Among seronegative subjects, a total of 160 observed 
cases will be required for 90% power to declare the vaccine efficacious (>30%), assuming a 
true efficacy of 60%. A sample size of 6178 seronegative subjects is expected to be required 
to achieve the 160 cases assuming an underlying attack rate of 3.7%. The actual sample size 
may differ if the observed attack rate is different than projected.   
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12-months 
post-dose 2. All Phase 3 segment subjects will be followed for 56 weeks from the Day 0 dosing 
[i.e., Week 56 will be the planned End of Study (EOS) visit for this segment of the trial]. 
 
Figure 1: Enrollment and Dose Group Design 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 13 of 80 
 
 
 
External Committee Reviews 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will convene 
regularly to review all available unblinded safety data. For the Phase 3 segment, an 
independent, blinded Endpoint Adjudication Committee (EAC) will review and confirm COVID-
19 cases.  
 
Details of each committee’s scope will be provided in the respective charters. 
  
Criteria for Evaluation:  
 
Research Hypothesis:  
INO-4800 delivered ID followed immediately by EP will be well-tolerated, exhibit an acceptable 
safety profile, result in generation of cellular and humoral immune responses to SARS-CoV-2 
Spike glycoprotein and provide protection against virologically-confirmed COVID-19 disease in 
subjects at high risk of SARS-CoV-2 exposure.  
 
Phase 2 Segment Objectives and Endpoints: 
 
Primary Objective 
Primary Endpoint 
1.  Evaluate the cellular and humoral 
immune response to INO-4800 
administered by ID injection followed 
immediately by EP  
  
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot 
1b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
Secondary Objective 
Secondary Endpoints 
1.  Evaluate the safety and tolerability of 
INO-4800 administered by ID injection 
followed immediately by EP    
  
1a. Incidence of solicited and unsolicited injection site 
reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)   
Exploratory Objective 
Exploratory Endpoint 
1.  Evaluate the expanded immunological 
profile of antibody response and T cell 
immune response 
1a.  Antigen-specific cellular immune response 
measured by flow cytometry 
1b. Expanded immunological profile which may 
include additional assessments of T and B cell 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 14 of 80 
 
numbers and molecular changes by measuring 
immunologic proteins and mRNA levels of genes 
of interest as determined by sample availability 
 
Phase 3 Segment Objectives and Endpoints: 
 
Primary Objective 
Primary Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease  
 
1.   Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 (End 
of Study (EOS))  
Secondary Objectives 
Secondary Endpoints 
1. Evaluate the safety and tolerability of 
INO-4800    
 
1a. Incidence of solicited and unsolicited injection site 
reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality 
 
2.  Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of severity   
2a.  Incidence of non-severe COVID-19 disease 
starting 14 days after completion of the 2-dose 
regimen until EOS  
2b. Incidence of severe COVID-19 disease starting 14 
days after completion of the 2-dose regimen until 
EOS 
2c. Incidence of deaths due to COVID-19 starting 14 
days after completion of the 2-dose regimen until 
EOS 
3.  Evaluate the efficacy of INO-4800 in the 
prevention of SARS-CoV-2 infection  
3.   Incidence of virologically-confirmed SARS-CoV-2 
infections starting 14 days after completion of the 
2-dose regimen until EOS 
4. Evaluate the time to symptom 
resolution in subjects who develop 
COVID-19 disease  
4.   Days to symptom resolution in subjects developing 
COVID-19 disease 
 
5.  Evaluate the cellular and humoral 
immune response to INO-4800 
5a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot 
5b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay 
 
Exploratory Objective 
Exploratory Endpoint 
1.  Evaluate the immunological profile by 
assessing both antibody response and 
T cell immune response 
1a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels  
1b. Antigen-specific cellular immune response 
measured by flow cytometry 
 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 15 of 80 
 
Immunogenicity Assessment:  
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 3 and Table 4).  Assays such as Binding ELISA, pseudovirus-based neutralization 
assay, and ELISpot will be evaluated at serial timepoints. 
Safety Assessment:  
Subjects will be followed for safety during the trial through scheduled clinic visits and phone 
calls. Adverse events (AEs), regardless of relationship to study drug, will be collected from 
the time of consent until 28 days post-dose 2 (i.e., Day 56). SAEs, Medically Attended Adverse 
Events (MAAEs) and AESIs will be collected from time of consent until EOS. SAEs, AESIs 
and treatment-related AEs will be followed to resolution or stabilization. For the Phase 2 
segment, solicited local and systemic AEs will be collected for 7 days following each dose 
using a Participant Diary. 
Subjects will also be monitored for COVID-19 disease.  
Please refer to the Schedule of Events (Table 3 and Table 4) for safety assessments to be 
performed.  
Efficacy Assessment (Phase 3 segment only):  
Subjects will receive either active investigational product (INO-4800) or placebo (SSC-0001) 
in a 2-dose regimen administered on Days 0 and 28 intradermally followed immediately by 
EP. Subjects will be monitored through regularly scheduled clinic visits and phone calls 
throughout the trial. Subjects will be regularly tested for SARS-CoV-2 infection using serologic 
testing and RT-PCR. If COVID-19 disease is suspected based on symptoms or laboratory 
testing, site personnel will arrange for a clinic visit. Subjects with symptom(s) or a positive 
SARS-CoV-2 test result will be reviewed by the EAC. 
Clinical Trial Population: 
Healthy subjects at high risk for SARS-CoV-2 exposure who are 18 years and older. 
Inclusion Criteria: 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, vital signs and 
physical examination performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar 
workers, store cashiers, hairdressers and barbers, veterinary staff, daycare 
workers, Transportation Security Administration screening staff, school 
teachers and college professors teaching in-person classes) 
2. Factory workers (when working in confined settings with large numbers of 
employees) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) 
4. User of public transportation (e.g., bus, train, subway) at least 3 times weekly 
5. Nursing home staff or correctional facility staff  
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 16 of 80 
 
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists.) Physicians should not be enrolled unless they 
are assigned to dedicated COVID-19 treatment wards or other settings with 
prolonged exposure 
10. Others, if approved by the medical monitor.   
f. Screening laboratory results within normal limits for testing laboratory or are deemed 
not clinically significant by the Investigator; 
g. Must meet one of the following criteria with respect to reproductive capacity: 
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or 
tubal ligation, absence of ovaries and/or uterus in females). In the case of 
vasectomy, subjects should wait six (6) months post-vasectomy prior to 
enrolling;  
• 
Use of medically effective contraception with a failure rate of < 1% per year 
when used consistently and correctly from screening until 3 months following 
last dose. Acceptable methods include:  
o hormonal contraception including implants, injections or oral; 
o two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
o intrauterine device or intrauterine system; 
o abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Exclusion Criteria: 
a. Acute febrile illness with temperature >100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat); 
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the Screening visit until 3 
months following the last dose; 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or a 
detectable viral load within the past 3 months; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 17 of 80 
 
g. Previous receipt of an investigational vaccine for prevention or treatment of COVID-19, 
MERS or SARS (documented receipt of placebo in previous trial would be permissible 
for trial eligibility); 
h. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg at Screening; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin 
cancers that only required local excision and non-metastatic prostate cancer 
not requiring treatment; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in 
therapy or hospitalization for worsening disease during the 6 weeks prior to 
enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a 
single antiepileptic agent; 
i. 
Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed); 
• 
Current or anticipated use of disease modifying doses of systemic anti-
rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, 
cyclosporine, 
methotrexate) and biologic disease modifying drugs such as TNF-α inhibitors 
(e.g., infliximab, adalimumab or etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the 
subject or require therapy that would interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results. 
j. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation 
site; 
k. Blood donation or transfusion within 1 month prior to Day 0; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the past 2 years; 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 18 of 80 
 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
Clinical Trial Treatment: 
Phase 2 Segment 
Active Investigational Product: One or two 1.0mg ID injection(s) of INO-4800 (~0.1mL dose 
volume) followed immediately by EP administered on Day 0 and Day 28 (±3 days)  
Placebo: One or two ID injection(s) of saline sodium citrate buffer (SSC-0001) (~0.1mL) 
followed immediately by EP administered on Day 0 and Day 28 (±3 days) 
Phase 3 Segment 
Active Investigational Product: Dose level to be determined, each ID injection(s) of INO-4800 
followed immediately by EP administered at Day 0 and Day 28 (±3 days) 
Placebo: Number of injections to be determined, each ID injection(s) of SSC-0001 followed 
immediately by EP administered at Day 0 and Day 28 (±3 days) 
Formulation: 
INO-4800 is formulated in sodium chloride and sodium citrate buffer, refrigerated. Placebo 
[sterile saline sodium citrate buffer (SSC-0001)], refrigerated. 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 19 of 80 
 
TABLE 3 – PHASE 2 SEGMENT SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Tel 
#1 
Wk 
4 
Tel 
#2 
Wk
6 
Tel 
#3 
Wk 
30 
Wk 
56 
Illness 
Illness  
Screena 
Day 0 
Phone call - Day 7 (±3d) 
Day 28 
(±3d) 
Phone call - Day 35 (±3d) 
Day 42 (±5d) 
Phone Call - Day 56 (±5d) 
Day 210 (±5d) 
Day 393 (± 5d) 
COVID-19 assessment visitm  
COVID-19 convalescent visitn 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behavioral Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
Vital Signs 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
Xp 
Xp 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differentialc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Chemistryc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
HIV Serology  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis Routined 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Pregnancy Teste 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
INO-4800 or Placebo + EPf 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Download EP Datag 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Adverse Eventsh  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Samplesi 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
Humoral Samplesj 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
SARS-CoV-2 Serologyk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 RT-PCR (Saliva and Swab) 
Xl 
 
 
 
 
 
 
 
 
 
 
Xl 
Xl 
Distribute Diary 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Review/Collect Diaryo 
 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 20 of 80 
 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0.   
b. 
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits. The targeted physical exam is optional at the COVID-19 
assessment visit if the visit is conducted via telemedicine. 
c. 
Hemoglobin A1c collected at screening only. Chemistry includes Na, K, Cl, HCO3, Ca, PO4, glucose, BUN, Cr, alkaline phosphatase, AST, ALT, LDH, total bilirubin.  
d. 
Dipstick for glucose, protein, and hematuria. Microscopic examination should be performed if dipstick is abnormal.  
e. 
Serum pregnancy test at Screening. Urine pregnancy test at other visits.  
f. 
Intradermal injection(s) in skin preferably over deltiod muscle, or alternately over anterolateral quadriceps muscle, followed by EP at Day 0 and Day 28. 
g. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
h. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
i. 
On Day 0, cellular sampling requires 64 mL of whole blood (8 Cell Preparation Tubes (CPT), each 8 mL of whole blood) prior to 1st dose. At all other time points, collect 32 mL of 
whole blood (4 CPT tubes, each 8 mL of whole blood).   
j. 
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce eight serum aliquots of 1 
mL each). At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce four serum aliquots of 1 mL each.  
k. 
SARS-CoV-2 antibody.   
l. 
Saliva specimen at Screening; Nasal swab and saliva specimens at COVID-19 assessment and convalescent visits.  
m. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The assessment visit may be performed in the clinic, subject’s vehicle, or via 
telemedicine and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test. Additional instructions for this visit will be provided 
in a separate study manual.  
n. 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of 
symptoms, the date of positive SARS-CoV-2 test. If acute symptoms are ongoing, the site should follow up with the subject via phone call or an unscheduled visit after symptom 
resolution or stabilization.   
o. 
Diary should be reviewed at the 7-day post-dose phone call and collected at the next in-office visit. 
p. 
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation. 
 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 21 of 80 
 
TABLE 4 – PHASE 3 SEGMENT SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Tel 
#1 
Wk 
4 
Wk
6 
Tel 
#2-
6 
Wk 
18 
Tel 
#7-
11 
Wk 
30 
Tel 
#12
-13 
Wk
42 
Tel 
#14
-16 
Wk 
56 
Illness 
Illness  
Screena 
Day 0 
Phone call - Day 14 (±3d) 
Day 28 
(±3d) 
Day 42 (±5d) 
Phone call - Days 56, 70, 84, 
98, 112 (±5d) 
Day 126 (±5d) 
Phone calls - Days 140, 154 
168, 182, 196 (±5d) 
Day 210 (±5d) 
Phone calls - Days 238, 266 
(±5d) 
Day 294 (±5d) 
Phone calls 
Days 322, 350, 378 (±5d) 
Day 393 (± 5d) 
COVID-19 assessment visitn  
COVID-19 convalescent visito 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behavioral Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Vital Signs 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Xp 
Xp 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differentialc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Chemistryc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
HIV Serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis Routined 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Pregnancy Teste 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
INO-4800 or Placebo + EPf 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Download EP Datag 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Eventsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Samplesi 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
Humoral Samplesj 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
SARS-CoV-2 Serologyl 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
SARS-CoV-2 RT-PCR  
(Saliva) l 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xm 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0.   
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 18-Aug-2020 
CONFIDENTIAL 
Protocol Version: 3.0 
 
Page 22 of 80 
 
b. 
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits. The targeted physical exam is optional at the COVID-19 assessment 
visit if the visit is conducted via telemedicine. 
c. 
Hemoglobin A1c collected at screening only. Chemistry includes Na, K, Cl, HCO3, Ca, PO4, glucose, BUN, Cr, alkaline phosphatase, AST, ALT, LDH, total bilirubin.  
d. 
Dipstick for glucose, protein, and hematuria. Microscopic examination should be performed if dipstick is abnormal.  
e. 
Serum pregnancy test at Screening. Urine pregnancy test at other visits.  
f. 
Intradermal injection(s) in skin preferably over deltiod muscle, or alternately over anterolateral quadriceps muscle, followed by EP at Day 0 and Day 28. 
g. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
h. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
i. 
On Day 0, cellular sampling requires 64 mL of whole blood (8 CPT tubes, each 8 mL of whole blood) prior to 1st dose. At all other time points, collect 32 mL of whole blood (4 CPT tubes, 
each 8 mL of whole blood). Cellular samples collected for all subjects at Day 0 pre-dose and Week 6; collected for approximately 10% of subjects at other indicated visits.  
j. 
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce eight serum aliquots of 1 
mL each). At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce four serum aliquots of 1 mL each.  
k. 
SARS-CoV-2 antibody.   
l. 
Saliva will be collected at study visits and bi-weekly at home between office visits.  In-office collection time points for Screening, Day 0, Day 28, EOS and COVID-19 visits will be 
tested at the time of collection. All other stored saliva specimens will be selectively tested if a SARS-CoV-2 serology test becomes positive. The Day 0 and Day 28 RT-PCR results 
will not be required prior to dosing on that day. 
m. 
Nasal swab and saliva specimens.  
n. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The assessment visit may be performed in the clinic, subject’s vehicle, or via 
telemedicine and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test. Additional instructions for this visit will be provided 
in a separate study manual.  
o. 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of 
symptoms, the date of positive SARS-CoV-2 test. If acute symptoms are ongoing the site should follow up with the subject via phone call or unscheduled visit after symptom resolution 
or stabilization. 
p. 
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation. 
 
 
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1.0 
INTRODUCTION 
This document is a protocol for a human research trial to be conducted according to U.S. 
and international standards of Good Clinical Practice (GCP) (FDA Title 21 part 312, 812 
and International Conference on Harmonization (ICH) guidelines), applicable government 
regulations and Institutional research policies and procedures. 
1.1 
BACKGROUND AND SCIENTIFIC RATIONALE 
The lack of available therapy in conjunction with increasing numbers of global cases 
indicate that SARS-CoV-2 infection remains a serious unmet medical concern. 
Appropriate measures to prevent, control and treat existing and future infections are in 
dire need. 
1.2 
BACKGROUND INFORMATION 
In late 2019, a cluster of cases of pneumonia of unknown etiology was reported in Wuhan, 
Hubei province, China [1-3]. These cases were announced on January 6, 2020 as testing 
negative for influenza, severe acute respiratory syndrome (SARS), and Middle East 
respiratory syndrome (MERS). On January 7, 2020 a novel virus was isolated by the 
Chinese Center for Disease Control and Prevention (CDC) from the throat swab sample 
of a patient, and the isolate was named “Wuhan-Hu-1.” The gene sequence of that isolate 
was then generated and determined to be of a novel coronavirus [4, 5]. That gene 
sequence was publicly posted on January 10, and the novel coronavirus was preliminarily 
named 2019-nCoV. Subsequently, on February 11, 2020, the virus was named SARS-
CoV-2 by the International Committee on Taxonomy of Viruses (ICTV) [6, 7], due to its 
similarity with the original SARS virus. That same day, the World Health Organization 
(WHO) announced a specific name of the disease, “COVID-19,” associated with infection 
by this novel coronavirus, as based on the novel coronavirus origin and year of first 
reported cases. The first cluster of human cases identified comprised people who worked, 
visited, or lived around the local Huanan seafood wholesale market in Wuhan, where live 
animals and fresh meat and fish were on sale, suggesting that an animal was the source 
of the novel respiratory virus being transmitted to humans.  
The first case of COVID-19 in the U.S. was announced in Washington State on January 
21, 2020 by the Washington State Department of Health and the U.S. Centers for Disease 
Control and Prevention (US CDC) [8].  It was a case of a traveler who had returned from 
Wuhan, China. Since that case was detected, human-to-human local transmission began 
(or continued from previously undetected infections) in the U.S., and as of July 27, 2020, 
over 4 million laboratory-confirmed US COVID-19 cases and nearly 150,000 US deaths 
due to COVID-19 have been reported in all 50 states and its territories [9]. Epidemiologic 
data suggest that droplets expelled during face-to-face exposure during talking, coughing, 
or sneezing is the most common mode of transmission while contact surface spread 
remains yet another possible mode of transmission [10].  
SARS-CoV-2 infection rapidly emerged as a global threat to public health, joining other 
coronavirus-related diseases, such as SARS and MERS. COVID-19 was declared a 
Public Health Emergency of International Concern (PHEIC) by the WHO on January 20, 
2020, and was declared a pandemic on March 11, 2020 [11], associated with substantial 
morbidity and mortality [12]. As of July 25, 2020, a total of nearly 16 million laboratory-
confirmed COVID-19 cases have been reported internationally, including over 643,000 
deaths [9]. However, given the lack of widespread testing, the true number of cases of 
COVID-19 is likely far higher than reported. Preliminary results from large U.S.-based 
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seroepidemiological surveys indicate an estimated incidence rate of SARS-CoV-2 
infections to be 6 to 24 times that of the number of reported cases of COVID-19 [13].  
An article in JAMA by Wu and McGoogan [14] provided a summary of a major report by 
the Chinese Center for Disease Control and Prevention (China CDC) [15]. Of a total of 
72,314 case records, 44,672 (62%) were confirmed as SARS-CoV-2 infections based on 
positive viral nucleic acid test results on throat swabs, 16,186 (22%) as suspected cases 
based on symptoms and exposures only, 10,567 (15%) as clinically diagnosed based on 
symptoms, exposures, and presence of lung imaging features consistent with coronavirus 
pneumonia, and 889 (1%) as asymptomatic cases based on a positive viral nucleic acid 
test result but lacking typical symptoms including fever, dry cough, and fatigue [16]. The 
overall case-fatality ratio (CFR) was 2.3% (1023 deaths among 44,672 confirmed cases). 
No deaths occurred in the group aged 9 years and younger, but cases in those aged 70 
to 79 years had an 8.0% CFR and cases in those aged 80 years and older had a 14.8% 
CFR. The CFR was 49.0% among critical cases. CFR was elevated among those with 
preexisting comorbid conditions - 10.5% for cardiovascular disease, 7.3% for diabetes, 
6.3% for chronic respiratory disease, 6.0% for hypertension, and 5.6% for cancer [16]. 
These initial reports of the CFR documented the level of seriousness of COVID-19.  
Given the novelty of SARS-CoV-2, its rapid spread among humans and its associated 
morbidity and mortality, there has been an explosion of epidemiological, clinical, virologic, 
and other scientific data regarding the propagation of effects of this virus emerging from 
China, the United States, and many other countries. These data have established that 1) 
SARS-CoV-2 is transmitted person-to-person [17], even from those who are asymptomatic 
or presymptomatic [18-20], 2) the virus is very infectious, with estimates of the R0 
(Reproductive number) ranging from 1.50 to 6.49, with a mean average of 3.28 and a 
median average of 2.79 [21], 3) the constellation of symptoms, signs, and an incubation 
period ranging between  2 and 14 days [22], and 4)  the asymptomatic proportion of those 
infected being substantial, perhaps as high as  80% [17, 23-25]. Further, research has 
found that the risk of death from COVID-19 increases with age and with serious, comorbid 
conditions including hypertension, diabetes, cardiovascular disease, obesity, etc.   
Finally, although much has been learned very quickly about SARS-CoV-2 and COVID-19, 
much more is still to be determined. The aforementioned CFR and similar estimates are 
from crude analyses that have only accounted for moderate to serious cases. Therefore, 
the true CFR is likely significantly lower. Further, the infection-fatality ratio (IFR), which is 
the proportion who die among all those infected regardless of any symptomology, is likely 
still even lower than the CFR, but both the CFR and IFR will not be known with certainty 
until well-designed and controlled seroepidemiology surveys have been conducted using 
well-validated antibody assays and thorough questionnaires to obtain symptom history. 
Also, the presence of natural immunity of those infected who survive and the durability of 
such natural immunity is to be determined. Thus, the existence and possibility of 
reinfection and recurrent infection is unknown. 
1.2.1 CLINICAL PRESENTATION, TRANSMISSION AND IMMUNE RESPONSE 
A study in The Lancet by Huang and colleagues [3] reported the epidemiological, clinical, 
laboratory, and radiological characteristics, as well as treatment and clinical outcomes, of 
patients with laboratory-confirmed COVID-19 pneumonia. Common symptoms at onset of 
illness were fever (n=40, 98% of 41 patients), cough (n=31, 76%), and myalgia or fatigue  
(n=18, 44%);  less  common  symptoms  were  sputum  production  (n=11, 28%  of  39 
patients),  headache  (n=3, 8%  of  38 patients), hemoptysis (n=2, 5% of 39 patients), and 
diarrhea (n=1, 3% of 38 patients). Dyspnea developed in 22 (55%) of 40 patients (median 
time from illness onset to dyspnea was 8 days [Interquartile range 5 - 13 days]). Twenty 
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six (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal 
findings on chest CT scan. Complications included acute respiratory distress syndrome 
(n=12, 29%), RNAaemia (n=6, 15%), acute cardiac injury (n=5, 12%) and secondary 
infection (n=4, 10%).  
Wiersinga, et al, summarized the common symptoms of COVID-19 in hospitalized patients 
as fever (70-90%), dry cough (60-86%), shortness of breath (53-80%), fatigue (38%), 
myalgias (15-44%), nausea/vomiting or diarrhea (15-39%), headache, weakness (25%) 
and rhinorrhea (7%). Anosmia and ageusia may be the sole presenting symptom in 
approximately 3% of individuals with COVID-19. Common laboratory abnormalities 
include lymphopenia (83%), elevated inflammatory markers (e.g., erythrocyte 
sedimentation rate, C-reactive protein, ferritin, tumor necrosis factor-alpha, IL-1, IL-6) and 
abnormal coagulation parameters (e.g., prolonged prothrombin time, thrombocytopenia, 
elevated D-dimer and low fibrinogen). Common radiographic findings include bilateral, 
lower lobe infiltrates on chest radiographic imaging and bilateral, peripheral, lower-lobe 
ground-glass opacities and/or consolidation on chest computed tomographic imaging [10].  
Transmission of SARS-CoV-2 occurred mainly after days of illness [26] and was 
associated with modest viral loads in the respiratory tract early in the illness, with viral 
loads peaking approximately 10 days after symptom onset [27]. Higher viral loads were 
detected soon after symptom onset, with higher viral loads detected in the nose than in 
the throat. Analysis of these samples suggested that the viral nucleic acid shedding 
pattern of patients infected with SARS-CoV-2 resembles that of patients with influenza 
[28] and appears different from that seen in patients infected with SARS-CoV [27]. The 
viral load that was detected in the asymptomatic patient was similar to that in the 
symptomatic patients, which suggests the transmission potential of asymptomatic or 
minimally symptomatic patients [12]. The SARS-CoV-2 transmission time window from 
COVID-19 patients is perhaps 2 days before symptom onset up to 37 days after symptom 
onset [20]. It is estimated that 48% to 62% of transmission may occur via presymptomatic 
carriers [10].  
Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10-15 
days following the onset of COVID-19 symptoms. Seow, et al observed seroconversion in 
>95% with neutralizing antibody responses when sampled beyond 8 days after onset of 
symptoms [29]. However, declining neutralizing antibody titers were observed during the 
follow-up period. Long, et al, when following 37 asymptomatic individuals and 37 
symptomatic patients into the early convalescent phase, observed that the IgG levels in 
93.3% of the asymptomatic group and 96.8% of the symptomatic group declined during 
the early convalescent phase [30]. T cells play a critical role in antiviral immunity but their 
numbers and functional state in SARS-CoV-2 infected patients remain largely unclear. 
Diao and colleagues performed a retrospective review of total T cell counts, and CD4+ and 
CD8+ T cell subsets based on inpatient data from 522 patients with laboratory-confirmed 
SARS-CoV-2 infection and 40 healthy controls in Wuhan from December 2019 to January 
2020. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe and 
critical disease groups as well as those who died were significantly lower than in the 
mild/moderate disease group. Most importantly, the numbers of total T cells, CD8+ T cells 
and CD4+ T cells in severe COVID-19 cases, including those who died, were lower 
suggesting that there is a profound T cell loss in COVID-19 disease. Counts of total T 
cells, CD8+ T cells or CD4+ T cells were negatively correlated with patient survival [31]. 
It is quite likely that CD4+ T cell, CD8+ T cell, and neutralizing antibody all contribute to 
clearance of the acute infection. There is an ongoing need to understand the magnitude 
and composition of the human CD4+ and CD8+ T cell responses to SARS-CoV-2. If 
natural infection with SARS-CoV-2 elicits potent CD4+ and CD8+ T cell responses 
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commonly associated with protective antiviral immunity, COVID-19 is a strong candidate 
for rapid vaccine development [32].  
1.2.2 CURRENT TREATMENT AND UNMET NEED 
Currently, there is no licensed prophylactic vaccine against COVID-19. Numerous vaccine 
efforts are underway. Given the growing concerns regarding the emergence of a dominant 
SARS-CoV-2 variant G614, which now comprises more than 80% of circulating global viral 
strains, and is reportedly associated with increased infectivity and spread [33], an effective 
prophylactic vaccine should ideally induce immunity against not only the D614 virus but 
also the G614 variants. 
Hospitals can provide supportive care for those who are infected and develop severe 
illness. Clinical management includes prompt implementation of recommended infection 
prevention and control measures and supportive management of complications, including 
advanced organ support if indicated.  
The CDC recommends that dexamethasone be used in the treatment of COVID-19 in 
patients who are mechanically ventilated and in patients who require supplemental oxygen 
but who are not mechanically ventilated based on a preliminary report from the 
Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial [34].  
Remdesivir has received Emergency Use Authorization (EUA) for the treatment of 
hospitalized patients with COVID-19 who require supplemental oxygen but who are not 
on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal 
membrane oxygenation (ECMO) [35]. 
1.3 
RATIONALE FOR PROPHYLACTIC VACCINE DEVELOPMENT 
SARS-CoV-2 has become a pandemic resulting in substantial morbidity and mortality. Due 
to rapid spread of SARS-CoV-2 infections even from asymptomatic and mildly infected 
patients, there is an urgent need for appropriate measures to prevent, control and treat 
SARS-CoV-2 infections.  
To address this critical need for a medical countermeasure for prevention of COVID-19 
disease, we at Inovio Pharmaceuticals have employed our synthetic DNA-based vaccine 
technology. This technology is highly amenable to accelerated developmental timelines, 
due to the ability to rapidly design multiple test constructs, manufacture large quantities of 
the drug product, and leverage established regulatory pathways to the clinic. Furthermore, 
this technology platform has demonstrated proof of concept efficacy and safety in humans 
in a phase 2b randomized, double-blind, placebo-controlled study for human 
papillomavirus (HPV) associated cervical pre-cancer [31] and is currently in two 
multinational phase 3 trials for that indication (NCT03185013 and NCT03721978) and 
several phase 2 trials for related and other indications. We have built upon our prior 
experience in developing a MERS coronavirus (MERS-CoV) vaccine to accelerate the 
development of a SARS-CoV-2 vaccine candidate. In a phase 1 clinical study, the MERS-
CoV coronavirus vaccine was safe and well tolerated, eliciting immune responses in more 
than 85% of participants after two vaccinations that were durable through 1 year of follow-
up [36].   
1.3.1 DNA VACCINES 
Since the 1990s, a novel approach to vaccination against a broad array of target antigens 
and diseases has been in development. This involves the direct introduction of plasmid 
deoxyribonucleic acid (DNA) containing the gene encoding the immunogen against which 
an immune response is sought into appropriate host tissues and the in situ production of 
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the target immunogen(s). This approach offers a combination of potential advantages, 
including the stimulation of both B- and T-cell responses, stability of the vaccine across a 
broad temperature range, absence of infectivity of the immunogen itself, the speed with 
which the vaccine can be constructed (for example in the face of an epidemic or pandemic 
as it is the case here with SARS-CoV-2), and the relative ease and generic nature of large-
scale manufacture. Many scientific publications have addressed the potential of DNA 
vaccination [37-46]. Immune responses in animal models have been obtained using genes 
from a variety of infectious agents including influenza viruses, hepatitis B virus, human 
immunodeficiency virus, human papillomaviruses, Marburg virus, MERS coronavirus, 
rabies virus, SARS coronavirus, West Nile virus (WNV), Zika virus, and other infectious 
agents as plasmodium, mycoplasma, and many more [45, 47]. In many cases, protection 
from disease in animal models has also been demonstrated.  
DNA vaccines are able to generate both CD4+ and CD8+ T cell responses. The ability to 
generate MHC-Class I restricted CD8+ T cells (cytolytic T lymphocytes), which generally 
are not made following administration of inactivated viruses, proteins or peptides, may be 
important for key responses against certain pathogens, as well as enabling cross-strain 
specific responses when many antibody responses are strain-specific. Because the 
encoded protein is synthesized in vivo by the host following administration, DNA vaccines 
can encode membrane-bound proteins instead of solely the soluble versions [48]. This 
can be important because key neutralizing epitopes are located in regions that would be 
excluded, or not formed in a monomeric truncated soluble version. Some early research 
in COVID-19 control has already suggested that neutralizing antibodies may not be 
sufficient and that cell-mediated immunity may be necessary [49]. 
Unlike certain other vectors (such as heterologous viral vectors), DNA vaccines do not 
stimulate adaptive immune responses against themselves, although the DNA itself does 
stimulate certain innate immune responses [50]. In other words, they do not generate anti-
vector immunity that could stunt antigen-specific responses following multiple exposures. 
1.3.2 USE OF ELECTROPORATION WITH DNA VACCINES 
Electroporation (EP) enhances gene expression of plasmid DNA delivered by the 
intramuscular (IM) or intradermal (ID) routes of administration (Figure 2). Following IM or 
ID delivery of a DNA vaccine or therapeutic product, EP facilitates entry of the DNA into 
the target site: muscle or dermal cells. Following cellular uptake, there is efficient 
production of the proteins encoded by the DNA expression plasmid system. The different 
EP devices, each with varying electrical parameters and protocols, have been reviewed 
[51]. EP has been extensively tested in animal species such as dogs, pigs, cattle, and 
NHPs to deliver therapeutic genes that encode for a variety of hormones, cytokines, 
enzymes or antigens [51] for the activation of both cellular and humoral responses [52, 
53]. Importantly, immune responses generated by DNA vaccines delivered with EP are far 
superior to responses to the same vaccines delivered without EP [53]. IM and ID delivery 
of DNA vaccines with EP has been studied extensively, and optimum conditions for 
plasmid uptake and expression have been described for therapeutic indications, vaccines 
and tumor animal model systems [54, 55].  
1.3.3 INOVIO’S PROPRIETARY TECHNOLOGY AGAINST COVID-19 DISEASE 
Inovio Pharmaceuticals has developed INO-4800 as a DNA vaccine that contains 10 
mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM sodium chloride and 15 
mM sodium citrate). pGX9501 is a DNA plasmid expressing a synthetic consensus 
(SynCon®) sequence of the SARS-CoV-2 full length Spike glycoprotein. The ID route of 
delivery has been selected for INO-4800 based on recent findings from multiple DNA 
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vaccine development programs where ID delivery has driven equivalent if not superior 
humoral and cellular responses to IM delivery while improving tolerability (clinicaltrials.gov 
NCT02464670, clinicaltrials.gov NCT02431767) [56-58]. 
Following intradermal injection, the Inovio Pharmaceuticals’ constant current EP device 
[51] referred to as the CELLECTRA® 2000 for ID administration (3P-ID) device is used to 
facilitate DNA entry into the cells.  
Figure 2: The Potential Mechanism of Action Underlying Electroporation 
 
1.3.4 NONHUMAN PRIMATE (NHP) CHALLENGE STUDIES WITH INO-4800 
NHPs are a valuable model in the development of COVID-19 vaccines and therapeutics 
as they can be infected with wild-type SARS-CoV-2, and present with early infection that 
mimics aspects of human disease [59].  Rhesus macaques (n=5) received two 
immunizations of INO-4800 (1.0 mg), at Week 0 and Week 4.  Naïve control animals (n=5) 
did not receive vaccine.  Humoral and cellular immune responses were monitored for 15 
weeks (~4 months) following prime immunization for memory responses. All animals 
seroconverted following a single INO-4800 immunization, with serum IgG titers detected 
against the full-length S1+S2 extracellular domain (ECD), S1, S2, and receptor binding 
domain (RBD) regions of the SARS-CoV-2 S protein.  
INO-4800 immunized macaques and unvaccinated controls were challenged with SARS-
CoV-2 13 weeks (~3 months) post-final immunization. NHPs received a challenge dose of 
1.1x104 PFU of SARS-CoV-2 by intranasal and intratracheal inoculation. Peak viral RNA 
loads in the BAL were significantly lower in the INO-4800 vaccinated group, along with 
significantly lower viral RNA loads at day 7 post-challenge, indicating protection from lower 
respiratory disease. While RNA was detected in the nasal swabs of both the control and 
INO-4800 vaccinated animals, viral mRNA levels trended downwards in INO-4800 
vaccinated animals by more than 2 logs and were achieved sooner on average. Overall, 
the reduced viral loads following exposure to SARS-CoV-2 infection at 17 weeks after 
immunization show an important durable impact mediated by the vaccine [60].  
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1.3.5 FIRST-IN-HUMAN PHASE 1 TRIAL OF INO-4800 
In the open-label, Phase 1 clinical trial, we initially evaluated the safety and 
immunogenicity of INO-4800 in 40 healthy participants, 18-50 years of age.  There were 
two groups of 20 participants each who received either 1.0 mg or 2.0 mg of INO-4800 
intradermally followed by EP at 0 and 4 weeks. In the first 40 subjects, by Week 8, 11 
adverse events were reported of which all were Grade 1 in severity of which 6 were related 
to study drug. The frequency of AEs did not increase with the second administration.  
From the immunogenicity analysis of the initial 40 subjects enrolled, two subjects were 
excluded from the analysis, one due to early discontinuation prior to the Week 4 dose for 
non-study reasons and the other due to suspected exposure to SARS-CoV-2 before the 
first dose of INO-4800 was administered based on a baseline positive SARS-CoV-2 
serology. Thirty-eight (38) evaluable subjects had cellular and/or humoral immune 
responses following the second dose of INO-4800. Assessment of data from both Week 
6 and Week 8 ELISpot revealed that 74% and 100% of the subjects generated T cell 
responses in the 1.0 mg and 2.0 mg groups, respectively. By Week 6, 95% (36 of 38) of 
the participants seroconverted by generating binding and/or neutralizing antibodies. 
Overall, INO-4800 elicited antigen-specific humoral and cellular immune responses 
against the SARS-CoV-2 Spike protein while demonstrating favorable safety and 
tolerability. 
The protocol was amended to include an additional 80 healthy participants to evaluate 
safety and immunogenicity of INO-4800 in older and elderly age populations. A lower dose 
level (0.5 mg) was also added for evaluation of dose-sparing potential. A total of 40 
participants were enrolled into three dose levels (0.5 mg, 1.0 mg and 2.0 mg), such that 
each Group included 20 participants 18-50 years of age, 10 participants 51-64 years of 
age, and 10 participants 65 years of age and older. Doses were delivered intradermally 
followed by EP at 0 and 4 weeks. As of July 29, 2020, 17 related adverse events were 
reported cumulatively, of which all but one (Grade 2 injection site pruritus) was Grade 1 in 
severity. 
Please refer to the Investigator’s Brochure, which will include future updates through the 
life of the study. 
1.3.6 PROPOSED PHASE 2/3 TRIAL OF INO-4800 
Based on the review of the immunogenicity data from its Phase 1 trial in its initial cohort 
of 40 subjects 18-50 years of age, Inovio has determined that while the 1.0 mg and 2.0 mg 
doses of INO-4800 generate encouraging neutralizing antibody responses, the 2.0 mg 
dose appears to offer superior T-cell responses over the 1.0 mg dose as measured by 
INF-gamma responses in the initial Phase 1 cohort. Therefore, this Phase 2/3 trial is 
designed to begin with a Phase 2 segment to evaluate both the 1.0 mg and 2.0 mg doses 
in approximately 400 subjects, including in the older (51 to 64 years of age) and elderly 
subjects (65 years of age and older), before selecting a dose or age-related doses for an 
efficacy evaluation in a subsequent Phase 3 segment involving >6000 subjects.  
1.3.7 DOSE AND REGIMEN RATIONALE 
The intent is to evaluate INO-4800 as a prophylactic vaccine against COVID-19 disease. 
As such, there is a desire to demonstrate the ability of the vaccine to drive immune 
responses primarily within the first 6 weeks of the first dose, which supports evaluation of 
a 2-dose regimen (Days 0 and 28). 
In this study, 1.0 mg and 2.0 mg of vaccine is administered by ID injection and followed 
immediately by EP at Day 0 and Day 28. The dose selection is supported by the safety 
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profile in the Phase 1 trial of INO-4800 (COVID19-001, NCT04336410) as well as our 
prior experience in developing a MERS coronavirus (MERS-CoV) vaccine (INO-4700) [16, 
17]. The safety data for INO-4800 is provided in the Investigator’s Brochure (IB). 
The objective of the Phase 2 segment of the Phase 2/3 trial is to further down-select the 
1.0mg and 2.0mg doses of INO-4800 for each age group in order to evaluate the optimal 
dose(s) in the efficacy Phase 3 segment.  
1.4 
POTENTIAL BENEFITS AND RISKS 
As of July 29, 2020, no treatment related serious adverse events have been reported for 
INO-4800. There may be side effects and discomforts that are not yet known. There may 
be potential benefits for prevention of COVID-19 disease, although efficacy remains 
unknown.   
In accordance with the International Council for Harmonisation (ICH), Inovio-sponsored 
studies have been designed to minimize risk to study participants. Expected risks of INO-
4800 in combination with the CELLECTRA® 2000 device are listed below in Table5. 
Table 5: Expected Risks of INO-4800 Delivered ID with EP using the CELLECTRA® 
2000 Devicea 
Frequencyb 
Event 
Very Common 
(≥10%) 
• 
Injection site pruritus 
• 
Injection site erythema or redness 
• 
Injection site pain or tenderness  
Common 
(≥1% to <10%) 
• 
Injection site bruising 
• 
Injection site swelling or induration 
 
Uncommon or Rare 
(<1%) 
• 
Administration site lesions or bleeding  
• 
Severe administration site pain or tenderness 
a Investigator’s Brochure v2.0, dated 10-Apr-2020 
b EU commission guideline on the SmPC September 2009 [61] 
Additionally, the following potential risks are noted for use with the CELLECTRA® 2000 
device (as per CELLECTRA® 2000 User Manual): 
• 
Brief muscle contractions which may be uncomfortable. 
• 
Injection site reactions: erythema, hematoma, pruritus, swelling, induration, 
tenderness, bruising/ecchymosis, laceration, or scab. 
• 
Pain or soreness at the administration site. 
• 
Temporary bleeding at the administration site. 
• 
Anxiety related to the administration procedure. 
• 
Vasovagal reaction/lightheadedness/dizziness related to the administration 
procedure. 
• 
Muscle damage resulting in transient changes in creatine phosphokinase. 
As of June 30, 2020, there have been no AEs associated with EP errors or failures.  
Please refer to the Investigator’s Brochure and User Manual, which will include future 
updates through the life of the study. 
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2.0 
OBJECTIVES AND PURPOSE 
The overall purpose of this clinical trial is to evaluate the safety, immunogenicity and 
efficacy of INO-4800. 
2.1 
HYPOTHESIS 
INO-4800 delivered ID followed immediately by EP will be well-tolerated, exhibit an 
acceptable safety profile, result in generation of cellular and humoral immune responses 
to SARS-CoV-2 Spike glycoprotein and provide protection against virologically-confirmed 
COVID-19 disease in subjects at high risk of SARS-CoV-2 exposure.  
3.0 
CLINICAL TRIAL DESIGN AND ENDPOINTS 
This is an operationally seamless Phase 2/3, randomized, placebo-controlled, multi-
center trial to evaluate the safety, immunogenicity, and efficacy of INO-4800, 
administered by ID injection followed immediately by EP using the CELLECTRA® 2000 
device, in a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-
2 exposure. Approximately 6578 seronegative subjects 18 years of age and older are 
expected to be enrolled across two (2) segments of this study, a Phase 2 segment and a 
Phase 3 segment. The subjects and data from Phase 2 are independent from that of 
Phase 3.  The primary objectives of this trial are to identify in seronegative subjects an 
optimal age-related dose (Phase 2 segment) for subsequent evaluation for efficacy 
(Phase 3 segment).  
 
Phase 2 Segment – Dose Selection 
 
In the Phase 2 segment, approximately 400 subjects 18 years of age and older will be 
evaluated across four (4) dose groups (Table 1, Figure 1). Subjects will be randomized 
at a 3:3:1:1 ratio to receive either 1.0 mg or 2.0 mg of active investigational product (INO-
4800) or 1 or 2 injections of placebo (SSC-0001). Dose groups receiving INO-4800 will 
enroll approximately 150 subjects per group. Dose groups receiving placebo will enroll 
approximately 50 subjects per group. Randomization will be such that approximately 240 
subjects aged 18-50 years, 120 subjects aged 51-64 years and 40 subjects aged ≥ 65 
years will be enrolled. Initial enrollment will include subjects aged 18-50 years. Initiation 
of enrollment of older subjects 51-64 years of age and elderly subjects 65 years and older 
will depend on review of safety and immunogenicity data from those age groups 
generated in the Phase 1 study (COVID19-001). 
 
Dose selection for evaluation of efficacy in the Phase 3 segment will be based on Week 
6 immunogenicity data and Week 8 safety data from the Phase 2 segment. Group-level 
unblinded summaries and analyses of safety will be produced once the Week 8 phone 
call visit data are completed for all subjects in the Phase 2 segment. 
 
Phase 3 Segment – Efficacy 
In the Phase 3 segment, approximately 6178 subjects 18 years of age and older will be 
randomized at a 1:1 ratio to receive either active investigational product (INO-4800, dose 
selected from the Phase 2 segment) or placebo (SSC-0001). A minimum of 15% of the 
total sample size of subjects will be 51-64 years of age, and a minimum of 5% of the total 
sample size of subjects will be ≥ 65 years of age. 
This segment of the trial is case-driven. Among seronegative subjects, a total of 160 
observed cases will be required for 90% power to declare the vaccine efficacious (>30%), 
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assuming a true efficacy of 60%. A sample size of 6178 subjects is expected to be 
required to achieve the 160 cases assuming an underlying attack rate of 3.7%. The actual 
sample size may differ if the observed attack rate is different than projected. 
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12-
months post-dose 2. All Phase 3 segment subjects will be followed for 56 weeks from the 
Day 0 dosing [i.e., Week 56 will be the planned End of Study (EOS) visit for this segment 
of the trial]. 
 
External Committee Reviews 
 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will 
convene regularly to review all available unblinded safety data, and additionally upon 
completion of the Week 8 phone call visit for all subjects enrolled during the Phase 2 
segment. For the Phase 3 segment, an independent, blinded Endpoint Adjudication 
Committee (EAC) will review and confirm COVID-19 cases.  
 
Details of each committee’s scope will be provided in the respective charters. 
3.1 
PRIMARY OBJECTIVES 
See Table 6. 
3.2 
PRIMARY ENDPOINTS 
Table 6: Primary Objectives and Associated Endpoints 
Phase 2 Primary Objective 
Phase 2 Primary Endpoints 
1.  Evaluate the cellular and humoral 
immune response to INO-4800 
administered by ID injection followed 
immediately by EP  
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot assay 
1b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay 
Phase 3 Primary Objective 
Phase 3 Associated Primary Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease  
1.   Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 
(End of Study (EOS))  
3.3 
SECONDARY OBJECTIVES 
See Table 7. 
3.4 
SECONDARY ENDPOINTS 
Table 7: Secondary Objectives and Associated Endpoints 
Phase 2 Secondary Objectives 
Phase 2 Secondary Endpoints 
1.  Evaluate the safety and tolerability of 
INO-4800 administered by ID 
injection followed immediately by EP  
 
1a. Incidence of solicited and unsolicited injection 
site reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
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 1d. Incidence of adverse events of special interest 
(AESIs)   
Phase 3 Secondary Objectives 
Phase 3 Secondary Endpoints 
1. Evaluate the safety and tolerability 
of INO-4800    
 
1a. Incidence of solicited and unsolicited injection 
site reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality  
 
2. Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of disease 
severity     
2a.  Incidence of non-severe COVID-19 disease 
starting 14 days after completion of the 2-dose 
regimen until EOS  
2b. Incidence of severe COVID-19 disease starting 
14 days after completion of the 2-dose regimen 
until EOS 
2c. Incidence of deaths due to COVID-19 starting 14 
days after completion of the 2-dose regimen until 
EOS 
3.   Evaluate the efficacy of INO-4800 in 
the prevention of SARS-CoV-2 
infection 
3.   Incidence of virologically-confirmed SARS-CoV-
2 infections starting 14 days after completion of 
the 2-dose regimen until EOS 
4.   Evaluate the timing of symptom 
resolution in subjects who develop 
COVID-19 disease  
4.  Days to symptom resolution in subjects 
developing COVID-19 disease. 
5.   Evaluate the cellular and humoral 
immune response to INO-4800 
5a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot 
5b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay 
 
3.5 
EXPLORATORY OBJECTIVE 
See Table 8. 
3.6 
EXPLORATORY ENDPOINT 
Table 8: Exploratory Objectives and Associated Endpoints 
Phase 2 Exploratory Objective 
Phase 2 Exploratory Endpoints 
1.  Evaluate the expanded 
immunological profile of antibody 
response and T cell immune 
response 
1a.  Antigen-specific cellular immune response 
measured by flow cytometry. 
1b. Expanded immunological profile which may 
include additional assessments of T and B cell 
numbers and molecular changes by measuring 
immunologic proteins and mRNA levels of genes 
of interest as determined by sample availability 
Phase 3 Exploratory Objective 
Phase 3 Exploratory Endpoints 
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1.
Evaluate the immunological profile
by assessing both antibody
response and T cell immune
response
1a.  SARS-CoV-2 Spike glycoprotein antigen-
specific binding antibody levels 
1b.  Antigen-specific cellular immune response 
measured by flow cytometry 
3.7 
EFFICACY ASSESSMENT (PHASE 3 SEGMENT ONLY) 
Subjects will receive either active investigational product (INO-4800, dose selected from 
the Phase 2 segment) or placebo (SSC-0001) in a 2-dose regimen administered 
intradermally followed immediately by EP on Days 0 and 28. Subjects will be monitored 
through regularly scheduled clinic visits and phone calls throughout the trial. Subjects will 
be regularly tested for SARS-CoV-2 infection using serologic testing and RT-PCR. If 
COVID-19 disease is suspected based on symptoms or laboratory testing, site personnel 
will arrange for a clinic visit. Subjects with symptom(s) or a positive SARS-Cov-2 test result 
will be reviewed by the independent blinded EAC. The mechanism for review and 
confirmation of cases will be outlined in an EAC Charter.  
3.7.1 CASE DEFINITION FOR VIROLOGICALLY-CONFIRMED COVID-19 DISEASE: 
•
Positive testing by SARS-CoV-2 RT-PCR assay (any source) with fever
(temperature of 100.4ºF/38.0ºC or higher), or
•
Positive testing by SARS-CoV-2 RT-PCR assay (any source) with any of the
following COVID-19 related symptoms:
•
Feeling feverish or chills
•
Cough
•
Shortness of breath or difficulty breathing
•
Fatigue
•
Muscle or body aches
•
Headache
•
New loss of taste or smell
•
Sore throat
•
Congestion or runny nose
•
Nausea or vomiting
•
Diarrhea
3.7.1.1 Case Definition for Severe COVID-19 
• Confirmed COVID-19 disease (per Section 3.7.1) with any of the following:
a.
Clinical signs at rest indicative of severe systemic illness (respiratory
rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room
air at sea level or PaO2/FiO2 < 300 mm Hg),
b.
Respiratory failure (defined as needing high-flow oxygen, noninvasive
ventilation, mechanical ventilation or ECMO),
c.
Evidence of shock (SBP < 90 mm Hg, DBP < 60 mm Hg, or requiring
vasopressors),
d.
Significant acute renal, hepatic, or neurologic dysfunction,
e.
Admission to an ICU, or
f.
Death.
3.7.1.2 Case Definition for Non-Severe COVID-19 
• Confirmed COVID-19 disease (per Section 3.7.1);
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• Does not meet the case definition of Severe COVID-19 disease (Section 
3.7.1.1) 
3.7.2 CASE DEFINITION FOR VIROLOGICALLY-CONFIRMED SARS-COV-2 INFECTION  
• Positive testing by SARS-CoV-2 RT-PCR assay (any source);  
• With or without clinical signs or symptoms of COVID-19 disease.  
3.8 
SAFETY ASSESSMENT 
Subjects will be followed for safety during the trial through scheduled clinic visits and 
phone calls. AEs, regardless of relationship to study drug, will be collected from the time 
of consent until 28 days post-dose 2. SAEs, MAAEs and AESIs will be collected from time 
of consent until EOS. SAEs, AESIs, and treatment-related AEs will be followed to 
resolution or stabilization. For the Phase 2 segment, solicited local and systemic AEs will 
be collected for 7 days following each dose. 
Subjects will also be monitored for COVID-19 disease. 
Please refer to the Schedule of Events (Table 3 and Table 4) for safety assessments to 
be performed.   
3.9 
IMMUNOGENICITY ASSESSMENT 
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 3 and Table 4). Assays such as Binding ELISA, pseudovirus-based neutralization 
assay, and ELISpot will be evaluated at serial timepoints. 
4.0 
CLINICAL TRIAL POPULATION 
4.1 
INCLUSION CRITERIA 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, vital signs and 
physical examination performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar workers, 
store cashiers, hairdressers and barbers, veterinary staff, daycare workers, 
Transportation Security Administration screening staff, school teachers and 
college professors teaching in-person classes) 
2. Factory workers (when working in confined settings with large numbers of 
employees) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) 
4. User of public transportation (e.g., bus, train, subway) at least 3 times weekly 
5. Nursing home staff or correctional facility staff  
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
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8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol. Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field) 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists.) Physicians should not be enrolled unless they are 
assigned to dedicated COVID-19 treatment wards or other settings with prolonged 
exposure) 
10. Others, if approved by the medical monitor;   
f. Screening laboratory results within normal limits for testing laboratory or are deemed 
not clinically significant by the Investigator; 
g. Must meet one of the following criteria with respect to reproductive capacity: 
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or tubal 
ligation, absence of ovaries and/or uterus in females). In the case of vasectomy, 
subjects should wait six (6) months post-vasectomy prior to enrolling;  
• 
Use of medically effective contraception with a failure rate of < 1% per year when 
used consistently and correctly from screening until 3 months following last dose. 
Acceptable methods include:  
o hormonal contraception including implants, injections or oral; 
o two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
o intrauterine device or intrauterine system; 
o abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
4.2 
EXCLUSION CRITERIA 
a. Acute febrile illness with temperature > 100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat);  
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the Screening visit until 
3 months following the last dose; 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or 
a detectable viral load within the past 3 months; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0 (documented receipt of placebo in a previous trial 
would be permissible for trial eligibility); 
g. Previous receipt of an investigational vaccine for prevention or treatment of COVID-
19, MERS or SARS (documented receipt of placebo in previous trial would be 
permissible for trial eligibility). 
h. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
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• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg at Screening; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin cancers 
that only required local excision and non-metastatic prostate cancer not requiring 
treatment; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in therapy 
or hospitalization for worsening disease during the 6 weeks prior to enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a single 
antiepileptic agent; 
i. 
Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed); 
• 
Current or anticipated use of disease modifying doses of systemic anti-rheumatic 
drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and 
biologic disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, 
adalimumab or etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the subject 
or require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
j. 
Lack of acceptable sites for ID injection and EP considering the skin above the 
deltoid and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
ICD or pacemaker (to prevent a life-threatening arrhythmia) that is located 
ipsilateral to the deltoid injection site (unless deemed acceptable by a 
cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation site; 
k. Blood donation or transfusion within 1 month prior to Day 0; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the past 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
4.3 
DISCONTINUATION/WITHDRAWAL OF CLINICAL TRIAL SUBJECTS 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the Investigator should any untoward effect occur. In addition, the 
Investigator or the Sponsor has the right to discontinue a subject from the trial at any time. 
The Investigator must notify the Sponsor immediately when a subject has been 
discontinued/withdrawn due to an Adverse Event (AE). If a subject withdraws from the trial 
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or is discontinued from the trial prior to trial completion, all applicable activities scheduled 
for the final trial visit (i.e., Day 393) should be performed at the time of 
discontinuation/withdrawal if the subject agrees. Any related AEs, AESIs, and/or Serious 
Adverse Events (SAEs) present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.9. 
Unless a subject refuses to continue participation, all follow-up visits and procedures 
should be completed as indicated in the Schedule of Events (Table 3 and Table 4) 
following the second dose whether or not the subject has completed both doses. 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. In cases where 
the subject does not return for the rescheduled visit or cannot be reached to reschedule 
the missed visit, the site should make every effort to regain contact with the subject (3 
telephone calls and if that fails, then a certified letter to the subject’s last known mailing 
address) so that the subject’s disposition can be considered as withdrawn from the study 
(i.e. lost to follow-up). If the contact with subject is re-established, site should contact 
medical monitor to discuss whether subject can continue study treatment or follow-up 
visits for the study. For all other subjects withdrawing from the study, an alternative reason 
for discontinuation should be recorded in the eCRF. 
Reasons for discontinuation/withdrawal from the trial may include but are not limited to the 
following: 
• 
Subject withdrawal of consent at any time; 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardize the 
subject’s safety if he or she continues in the trial; 
• 
Investigator, DSMB or Sponsor determines it is in the best interest of the subject; 
• 
Subject non-compliance. 
Every effort should be made to obtain information on subjects who withdraw from the trial. 
The primary reason for withdrawal from the trial should be documented on the appropriate 
CRF. However, subjects will not be followed for any reason after consent has been 
withdrawn. Data and/or samples collected prior to withdrawal of consent will be analyzed.  
Reasons for discontinuing subject dosing may include but are not limited to the following: 
• 
Adverse Event (Adverse Reaction); 
o The Investigator or trial coordinator must notify the Sponsor immediately when a 
subject has been discontinued/withdrawn due to an Adverse Event (AE). 
• 
Any medical condition that may jeopardize the subject’s safety if he or she continues 
on trial; 
• 
Pregnancy. 
5.0 
CLINICAL TRIAL INVESTIGATIONAL PRODUCT INFORMATION 
5.1 
INVESTIGATIONAL PRODUCT (IP) AND STUDY DEVICE 
5.1.1 INO-4800 AND PLACEBO 
Investigational product is defined as a pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in the study, whether blinded or unblinded. 
INO-4800 is the active investigational product to be used in this study. The INO-4800 drug 
product contains 10 mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM 
sodium chloride and 15 mM sodium citrate). pGX9501 is a DNA plasmid expressing a 
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synthetic consensus (SynCon®) sequence of the SARS-CoV-2 full length Spike 
glycoprotein. 
Phase 2 segment: 
Active Investigational Product (INO-4800): A volume of 0.4 mL will be filled into 2-mL glass 
vials that are fitted with rubber stoppers and sealed aluminum caps. 
Placebo (SSC-0001): Sterile saline sodium citrate (SSC) buffer, which contains sterile 150 
mM sodium chloride and 15 mM sodium citrate in 10-mL glass vials, stoppered, and 
sealed with aluminum caps. 
Phase 3 segment: 
Active Investigational Product (INO-4800): A volume of 1.1 mL will be filled into 2-mL glass 
vials that are fitted with rubber stoppers and sealed aluminum caps. 
Placebo (SSC-0001): Sterile saline sodium citrate (SSC) buffer, which contains sterile 150 
mM sodium chloride and 15 mM sodium citrate at a volume of 1.1 mL in 2-mL glass vials, 
stoppered, and sealed with aluminum caps. 
5.1.2 CELLECTRA® 2000 
Electroporation is a procedure used to enhance cellular DNA uptake within host cells 
following DNA vaccine ID delivery. This study will use the CELLECTRA® 2000, a portable, 
battery-powered medical device designed to generate a minimally-controlled, electric field 
which temporarily and reversibly increases cellular membrane permeability without 
damaging the tissue. During the period of increased permeability, injected plasmid DNA 
can be introduced into the cells. 
As mentioned above, the CELLECTRA® 2000 device is intended to enhance the uptake 
and expression of DNA plasmid-based biologics in order to enhance vaccine efficacy. The 
DNA plasmid is delivered separately via needle and syringe ID injection immediately prior 
to the electroporation. The electroporation is accomplished through a sterile, disposable 
needle Array attached to an Applicator delivering controlled electrical pulses as follows: 
• 
An EP treatment consists of four pulses. 
• 
An Array of three stainless steel electrode needles is used to deliver the electrical 
pulses into the tissue. The needle length that penetrates into the skin and tissue is 
approximately 3 mm. 
• 
The CELLECTRA® 2000 generates four 52ms electrical current controlled DC 
pulses. The nominal current is set to 200mA ±10% by modulating voltage, or 
capped at 200V ±5%, determined by patient tissue impedance  
• 
The specified current is constantly maintained through voltage modulation using 
an analog feedback loop. Measurements of voltage and current are processed for 
error reporting and collected for data logging. 
The CELLECTRA® 2000 device for ID administration is comprised of three components: 
(1) A battery-powered Pulse Generator, (2) an ID Applicator that is connected to the pulse 
generator, and (3) a three-point sterile disposable ID Array of stainless steel needles. 
5.2 
DOSING REGIMENS 
Phase 2 Segment 
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• 
Active Investigational Product: One or two 1.0mg ID injection(s) of INO-4800 (~0.1mL 
dose volume each) followed immediately by EP administered on Day 0 and Day 28 
(±3 days) 
• 
Placebo: One or two ID injection(s) of SSC-0001 (~0.1mL) followed immediately by 
EP administered on Day 0 and Day 28 (±3 days) 
Phase 3 Segment 
• 
Active Investigational Product: Dose level to be determined, each ID injection(s) of 
INO-4800 (~0.1mL dose volume) followed immediately by EP administered on Day 0 
and Day 28 (±3 days) 
• 
Placebo: Dose level to be determined, each ID injection(s) of SSC-0001 (~0.1mL) 
followed immediately by EP administered on Day 0 and Day 28 (±3 days) 
5.2.1 BLINDING 
This study is blinded. The Sponsor, subjects and clinical site staff, with the exception of 
the site’s pharmacy personnel, will be blinded throughout the trial. There is no difference 
in appearance between INO-4800 and the placebo; however, they are distinguishable 
based on the vial size and/or labelling on the vials. In the Phase 2 segment, the vials will 
be of different sizes and have unblinded labelling. In the Phase 3 segment, the vials will 
be the same size but will have unblinded labelling. To maintain the blind, vials will only be 
handled by designated unblinded personnel (site pharmacist) at the site. 
Under exceptional circumstances, the PI may desire to unblind a subject’s dose 
assignment in case of an emergency or serious medical condition when knowledge of the 
study product or dose is deemed by the PI to be absolutely essential for proper clinical 
management of the subject. Under such emergency circumstances, the Sponsor urges 
the PI to first contact the Medical Monitor (MM) to review options before unblinding the 
subject’s dose assignment. In case of non-emergency, PI must contact MM to discuss the 
options before unblinding the subject’s dose assignment. 
The Sponsor’s pharmacovigilance staff may unblind a subject’s dose assignment for an 
SAE, unanticipated adverse device effect (UADE), or adverse event of special interest 
(AESI) when the event is assessed as related and unexpected. If expedited regulatory 
reporting is required for an event, the report may be submitted to regulatory authorities 
with the subject’s dose assignment, in accordance with local regulations. 
5.3 
PACKAGING AND LABELING 
5.3.1 INO-4800 OR PLACEBO 
Each vial of INO-4800 or placebo will be labeled consistent with the example product label 
provided in the IB.  
5.3.2 CELLECTRA® 2000 
Please see shipping box for shipping documents and contents. 
The CELLECTRA® 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer. The CELLECTRA® 2000 User Manual 
describes all relevant contraindications, hazards, potential risks and adverse effects, 
interfering substances or devices, warnings, and precautions. Each Pulse Generator has 
a unique serial number, and each ID Applicator has a unique serial number. Each ID Array 
has a Lot Number and Expiration Date. Examples of device labels are provided in the IB. 
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The CELLECTRA® 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. 
5.4 
HANDLING AND STORAGE 
5.4.1 INO-4800 AND PLACEBO 
INO-4800 and Placebo will be shipped at 2–8°C. If the temperature monitoring devices in 
the shipping container(s) denote temperatures outside this 2–8°C (36-46°F) range, the 
Sponsor, or its designee, should be contacted immediately. 
Upon arrival, the INO-4800 and placebo must be transferred from the shipping container 
into 2–8°C (36-46°F) storage, in a secure area, in accordance with local regulations by 
designated personnel (e.g., pharmacy personnel). The Sponsor must be notified of any 
deviations from this storage condition. Refrigerator temperature logs must be maintained 
at the clinical site and temperatures must be recorded and monitored regularly. For further 
details see Pharmacy Manual and IB. 
5.4.2 CELLECTRA® 2000 
See User Manual for operating and storage conditions. 
5.5 
PREPARATION AND DISPENSING 
In the Phase 2 segment, INO-4800 is supplied in 2-mL vials at a concentration of 10 
mg/mL at a minimum volume of 0.4 mL. SSC-0001 is supplied in 10-mL vials at a minimum 
volume of 2 mL.  
In the Phase 3 segment, INO-4800 is supplied in 2-mL vials at a concentration of 10 
mg/mL at a minimum volume of 1.1 mL.  SSC-0001 is supplied in 2-mL vials at a minimum 
volume of 1.1 mL. 
Blinded staff involved in the clinical execution of the study should not come in contact with 
vials of INO-4800 or SSC-0001. Vials will only be handled by designated unblinded 
personnel (e.g., pharmacy) at the site. When a subject is eligible for enrollment, unblinded 
personnel will draw INO-4800 or SSC-0001 into a blinded syringe in accordance with the 
subject’s randomized treatment assignment according to a randomization schedule. The 
syringe will be transferred to blinded site personnel for administration.  
Each INO-4800 and placebo vial will contain a volume of product sufficient to dose multiple 
subjects. The preparation and dispensing information will be provided in the Pharmacy 
Manual. 
5.6 
USE OF STUDY DEVICE 
The instructions for use of the CELLECTRA® 2000 device are provided in the User 
Manual. Each clinical site will receive training for use of the CELLECTRA® 2000 device 
prior to first dose. The EP procedure must be performed by qualified personnel. Any 
individual designated to perform the procedure should be permitted by the relevant local 
authorities to administer parenteral injections to patients (e.g., MD, DO, RN) in addition to 
successfully completing device training provided by Sponsor personnel.  
5.7 
INVESTIGATIONAL DRUG AND STUDY DEVICE ACCOUNTABILITY 
5.7.1 INVESTIGATIONAL PRODUCT (IP) ACCOUNTABILITY 
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It is the responsibility of the Investigator to ensure that a current accountability record of 
investigational products (INO-4800 or placebo) is maintained at the study site. The 
investigational products must have full traceability from the receipt of the products through 
subject use, disposal or return of the products. Records or logs must comply with 
applicable regulations and guidelines. The accountability information is provided in the 
Pharmacy Manual. 
5.7.2 CELLECTRA® 2000 ACCOUNTABILITY 
The investigational site is responsible for maintaining device accountability logs. The 
device must have full traceability from the receipt of the products through subject use, 
disposal or return of the products. The site must document acknowledgement of receipt 
and notify Inovio upon receipt of study devices. This includes the content shipped and 
condition upon receipt. 
For each subject administration, there must be a record of each product used for that 
subject, i.e., Pulse Generator serial number, ID Applicator serial number, and ID Array lot 
number. The ID Applicator is reusable with a new ID Array and sheath for each procedure. 
The sterile ID Array and sheath are single use only and must be discarded after use in 
accordance with institutional policy regarding disposal of sharp needles/instruments. 
5.8 
RETURN AND DESTRUCTION OF INVESTIGATIONAL DRUG AND STUDY DEVICE 
5.8.1 INO-4800 AND PLACEBO 
Upon completion or termination of the study, all unused vials of INO-4800 or placebo must 
be destroyed at the study site in accordance with institution policy or returned to Inovio 
Pharmaceuticals, Inc., or its designee if the site cannot destroy IP. 
The used vials of INO-4800 and placebo will be discarded in accordance with the site’s 
used IP disposal procedure. It is the Investigator’s responsibility to arrange for disposal of 
all empty vials, provided that procedures for proper disposal have been established in 
accordance with applicable national, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. If requested by the Sponsor, the 
return of unused IP vials should be arranged by the responsible Inovio Representative. 
The unused IP vials should only be destroyed after being inspected and reconciled by the 
responsible Inovio Pharmaceuticals, Inc., personnel or designated Clinical Monitor. If IP 
vials are returned to Inovio Pharmaceuticals, Inc., or its designee, the IP must be 
accompanied by the appropriate documentation. The return of unused IP(s) should be 
arranged with the responsible Inovio personnel and/or Clinical Monitor. 
5.8.2 RETURN OF CELLECTRA® 2000 
Upon completion or termination of the study, an Inovio Representative will provide 
instructions regarding the component(s) to be returned to Inovio Pharmaceuticals, Inc., 
destroyed onsite or shipped to a destruction vendor. 
All products returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original containers. 
The return of all products identified above should be arranged by the Inovio 
Representative. The ID Arrays should be discarded in the sharps container immediately 
after use. The used ID Applicators can either be destroyed at the site, shipped to a 
destruction vendor, or returned to Inovio. If the used ID Applicators are destroyed on site, 
it is the Investigator’s responsibility to ensure that arrangements have been made for the 
disposal, written authorization has been granted by Inovio Pharmaceuticals, Inc., or its 
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designee, procedures for proper disposal have been established in accordance with 
applicable regulation and guidelines and institutional procedures, and appropriate records 
of the disposal have been documented. 
6.0 
CLINICAL TRIAL PROCEDURES AND SCHEDULE 
The Schedule of Events (36TTables 3 and 436T) in the Clinical Protocol Synopsis summarizes 
the procedures to be performed at each visit. Individual procedures are described in detail 
below. It may be necessary to perform these procedures at unscheduled time points if 
deemed clinically necessary by the Investigator. A subject will be required to provide 
informed consent (Section 6.2) prior to any study procedure being performed. Protocol 
waivers or exemptions will not be granted. Therefore, adherence to the study design and 
assessments are essential and required for study conduct. 
6.1 
PROCEDURE BY VISIT 
Refer to Sections 6.1.1 and 6.1.2 for trial procedures and the times at which they are to 
be performed. 
6.1.1 CLINICAL TRIAL SCREENING EVALUATIONS 
The assessments performed during Screening will determine the subject’s eligibility for 
the study and also their ability to comply with protocol requirements by completing all 
screening assessments. The following screening evaluations will be performed for both 
Phase 2 and Phase 3 segments within 30 days prior to dosing on Day 0. All screening 
assessment values must be reviewed prior to the first Study IP administration.  
If a subject does not meet an inclusion or exclusion criterion due to a transient and non-
clinically significant event at Screening, relevant Screening evaluations may be repeated 
within the same 30-day Screening period. If the subject fails twice, they will be considered 
a screen failure. 
• 
Signed and dated informed consent (Section 6.2); 
• 
Review and confirm all inclusion/exclusion criteria (Section 4.1 and 4.2); 
• 
Obtain and document complete medical history, surgical history (including all 
clinically significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Section 6.1.1.1); 
• 
Collect demographics and document any ongoing, pre-existing conditions; 
• 
Collect socio-behavioral assessment information (Section 6.4); 
• 
Collect AEs (Section 6.4.4); 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Record height and weight (Section 6.4); 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect blood for serum pregnancy test (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9);  
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.9). 
6.1.1.1 
Medical History 
A medical history will be obtained by the Investigator or qualified designee at the time of 
Screening. Medical history will include all active conditions, and any other past conditions, 
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as well as surgical procedures, that are considered to be clinically significant by the 
Investigator and/or occurred within the 12 weeks prior to Screening. Subjects should be 
queried about any history of Hepatitis B and Hepatitis C.  Any subject with a self-reported 
history of Hepatitis B or C who has clinically significant elevated liver enzymes at 
Screening will be excluded from the study based on inclusion criterion f. Subjects with self-
reported HIV must provide documentation of controlled HIV infection based on a CD4 
count greater than 200 cells/mm3 and an undetectable viral load within the past 3 months. 
If a recent CD4 count and/or viral load is not available, this testing should be performed at 
Screening. 
Illnesses first occurring or detected after the signing of the informed consent, or during the 
study and/or worsening of an existing illness in severity, frequency or nature after signing 
of the informed consent are to be documented as AEs on the Case Report Forms (CRF). 
Prior treatments, defined as administered up to 12 weeks prior to the time of informed 
consent and stopped prior to dosing on Day 0, should be recorded in the CRF as prior 
medications. Concomitant treatments, defined as continuing on Day 0 or new treatments 
taken at or after Day 0, should be recorded in the CRF as concomitant medications. 
6.1.2 CLINICAL TRIAL EVALUATIONS AND PROCEDURES 
Once eligibility has been confirmed, the subject will be randomized to receive a treatment 
assignment (INO-4800 or placebo). Visit dates and windows must be calculated from Day 
0, unless otherwise noted. All subjects will be followed until the Day 393 Visit. All subjects 
will be followed in accordance with assessments outlined below. 
Study visits occurring within 3 weeks of an acute COVID-19 visit with confirmed SARS-
CoV-2 RT-PCR test may be conducted via telemedicine. 
6.1.2.1 
Day 0 and Day 28 (Dosing Visits) 
The following evaluations will be performed on Day 0 and Day 28 prior to dose 
administration: 
Both Phase 2 and Phase 3 segments: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Obtain any updates to medical history, surgical history (including all clinically 
significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Section 6.1.1.1); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect urine for urine pregnancy test (Section 6.4); 
• 
Collect blood for HIV serology (Day 0 visit only) (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6); 
• 
Review restrictions for injection and EP (Section 6.4.8); 
• 
Randomize subject (instructions to be provided under separate cover) (Day 0 visit 
only). 
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
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• 
Collect diary from Day 0 dose (Day 28 visit only). 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect saliva for SARS-CoV-2 RT-PCR and send to lab for testing (Section 6.4.9); 
 
The following evaluations will be performed on Day 0 and Day 28 after IP plus EP 
administration: 
• 
Collect any new AEs (Section 6.4.4); 
• 
Download EP Data (Section 6.4.1.1); 
• 
Provide supplies for subject to use at home, as required (e.g. thermometer, wound 
guide, saliva collection kit) 
• 
Phase 2 segment only: Distribute diary 
6.1.2.2 
Post-dose phone calls 
Phase 2 segment: Day 7 and Day 35 
Phase 3 segment: Day 14  
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
 
Phase 2 segment only: 
• 
Review diary (Section 6.4). 
 
Phase 3 segment only: 
• 
Remind subject to perform at-home saliva collection (Section 6.4.9). 
6.1.2.3 
Day 42 Visit 
Both Phase 2 and Phase 3 segments: The following evaluations will be performed at this 
visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4);  
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6);  
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect diary from Day 28 visit. 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
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• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.9); 
• 
Provide supplies for subject to use at home, as required (e.g. saliva collection kit). 
6.1.2.4 
Phone calls  
Phase 2 segment: Day 56 
Phase 3 segment: Days 56, 70, 84, 98, 112, 140, 154, 168, 182, 196, 238, 266, 322, 
350, and 378 
In the Phase 3 segment, phone calls to subjects have been spaced bi-weekly 
between study visits through Day 210, and approximately monthly between visits 
from Day 210 to Day 393.   
 
Guidelines for information to be collected during the phone call can be found in the 
Phone Script. The following evaluations will be performed during the phone call: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Ask about any symptoms of COVID-19 disease; Arrange on-site visit if any signs 
and symptoms of COVID-19 disease are present (Section 6.4.10); 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Phase 3 segment only: Remind subject to perform at-home saliva collection 
(Section 6.4.9). 
6.1.2.5 
Follow up clinic visits 
Phase 2 segment: Day 210 
Phase 3 segment: Days 126, 210 and 294 Visits 
Both Phase 2 and Phase 3 segments: The following evaluations will be performed at these 
visits: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); SAEs, AESIs, and 
MAAEs will be reported after the Day 56 Visit. 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(except Day 294 visit) (Section 6.4.6); 
 
Phase 3 segment: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect saliva for SARS-CoV-2 RT-PCR; (Section 6.4.9); 
• 
Provide supplies for subject to use at home, as required (e.g. saliva collection kit). 
6.1.2.6 
Day 393 Visit or EOS 
Phase 2 and Phase 3 segments: The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); SAEs, AESIs, and 
MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Ask about any symptoms of COVID-19 disease; 
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• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect urine pregnancy test (Section 6.4); 
• 
Collect blood for CBC with differential and serum chemistry(Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6). 
 
Phase 3 segment: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.9); 
6.1.2.7 
COVID-19 Assessment Visit 
For both the Phase 2 and Phase 3 segments of the study, subjects will be evaluated during 
a COVID-19 assessment visit when acute COVID-19 is suspected based on symptoms or 
positive SARS-CoV-2 testing. The assessment visit may be performed in the clinic, 
subject’s vehicle, or via telemedicine and should be performed within 3 days of a positive 
SARS-CoV-2 test or site knowledge of COVID-19 symptom onset. The virologic-
confirmation of a case will be based on SARS-CoV-2 RT-PCR. Additional instructions will 
be provided to sites in a separate study manual. 
Phase 2 and Phase 3 segments: The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); Only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Optional targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect nasal swab and saliva for SARS-CoV-2 RT-PCR detection (Section 6.4.9). 
6.1.2.8 
COVID-19 Convalescent Visit 
Phase 2 and Phase 3 segments: For subjects with confirmed SARS-CoV-2 infection 
during the trial, a convalescent visit should be scheduled approximately 28 days after 
symptom onset, or in the absence of symptoms, after the collection date of a positive 
SARS-CoV-2 test. If symptoms are ongoing at 28 days after symptom onset, the site 
should follow up with the subject via phone call or unscheduled visit after symptom 
resolution or stabilization.  
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); Only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6); 
• 
Collect nasal swab and saliva for SARS-CoV-2 RT-PCR detection (Section 6.4.9). 
 
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Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9). 
6.2 
INFORMED CONSENT 
All subjects must sign the informed consent prior to participating in any clinical trial-related 
procedures. The informed consent documentation must be in compliance with applicable 
regulations and GCP. Qualified clinical trial personnel will: 
• 
Meet with prospective clinical trial subjects 
• 
Explain the clinical trial 
• 
Provide clinical trial subjects with an Informed Consent Form (ICF) that includes the 
following in a language that is understandable to the subject: 
• 
Screening test(s) description 
• 
Eligibility criteria for entering the clinical trial 
• 
Clinical trial treatments and follow-up procedures description 
• 
Explanation of the clinical trial, including but is not limited to: 
• 
Clinical trial objectives 
• 
Potential benefits and risks 
• 
Discomforts/inconveniences 
• 
Subject’s rights and responsibilities 
The subject is then requested to sign and date the ICF. A copy of the signed informed 
consent documentation must be provided to the subject. The qualified clinical trial 
personnel will document the process of obtaining informed consent within the source 
record. Signed ICFs are maintained in the subject’s source records and must be 
accessible for verification at any time. Signing of the ICF begins the 30-day screening 
period. 
6.3 
ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number (SID), 
which identifies the subject for all clinical trial-related procedures. SIDs are a combination 
of a 4-digit site code and a 4-digit subject number. After SIDs are assigned, they cannot 
be reused or reassigned for any reason. Information regarding the SID and screen date 
will be documented on a screening and enrollment log/system and in the CRF.   
Previously screen failed subjects may be rescreened provided there is a valid documented 
reason for rescreening (i.e. changes to the person’s health or situation that would make 
them possibly eligible at this later time). If rescreening occurs, the subject will keep their 
original Subject ID.  
6.4 
SAFETY EVALUATIONS 
PHYSICAL AND TARGETED PHYSICAL EXAM  
A full physical examination will be conducted during Screening and at study 
discharge/EOS (e.g. Day 393). A targeted physical assessment will be performed at other 
visits as determined by the Investigator based on subject symptoms. The targeted physical 
exam is optional at the COVID-19 assessment visit if the visit is conducted via 
telemedicine. 
VITAL SIGNS 
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Vital signs including temperature, respiration rate, blood pressure and heart rate will be 
measured at Screening and at visits specified in the Schedule of Events (36TTables 3 and 
436T).  
At the COVID-19 Assessment and Convalescent visits, temperature, respiration rate, 
heart rate and oxygen saturation should be performed.   
HEIGHT AND WEIGHT 
Weight and height will be collected at Screening. 
SOCIO-BEHAVIORAL ASSESSMENT  
A Socio-behavioral Assessment, including self-reported smoking and vaping history, and 
self-reported history of exposure to second-hand smoke will be obtained at Screening. 
LABORATORY EVALUATIONS 
At Screening and at visits specified in the Schedule of Events (36TTables 3 and 436T), blood 
samples will be collected for safety assessments. Approximately mL 270-360 of blood will 
be drawn from each subject over the course of the study. Subjects may be asked to return 
for additional blood draws if collected blood sample is lost or unevaluable for any reason. 
Hematology [Complete blood count (CBC) with automated differential]: 
White blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit and 
platelet count will be measured at Screening and at visits specified in the Schedule of 
Events (36TTables 3 and 436T). Hemoglobin A1c will additionally be performed at Screening. 
Serum chemistry: 
Electrolytes [Sodium (Na), Potassium (K), Chloride (Cl), Bicarbonate (HCO3), Calcium 
(Ca), Phosphate (PO4)], glucose, Blood Urea Nitrogen (BUN), Creatinine (Cr),  alkaline 
phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), LDH,  
and total bilirubin (TBili) at Screening and at visits specified in the Schedule of Events 
(36TTables 3 and 436T).  
Urinalysis:  
Urine samples will be tested by dipstick for glucose, protein, and hematuria at Screening 
and at visits specified in the Schedule of Events (36TTables 3 and 436T). If abnormal (presence 
of protein, hematuria, or glucose ≥ 1+), a microscopic examination should be performed.  
Serology: 
HIV antibody or rapid test will be measured at Day 0 only.  
Antibodies to SARS-CoV-2 will be measured at Screening and at visits specified in the 
Schedule of Events (Tables 3 and 4). 
Pregnancy Testing:  
For women of childbearing potential (WOCBP), a serum pregnancy test will be obtained 
at Screening and a urine pregnancy test will be performed immediately prior to any dosing 
and at the subject’s last visit. A negative result for urine β-HCG (test must have a sensitivity 
of at least 25 mIU/mL) must be available prior to each administration of IP. If the β-HCG 
test is positive, indicating that the subject is pregnant prior to completing the specified 
dose regimen, then no further IP will be administered. Every attempt should be made to 
follow pregnant subjects for the remainder of the study and to determine the outcome of 
the pregnancy (see Section 7.12). 
DIARY 
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Diaries will be implemented in the Phase 2 segment of the protocol only.  Subjects will 
be provided a diary to record the following solicited local and systemic AEs: 
• 
Oral temperature and time taken (each daily entry before 11:59 pm) 
• 
Solicited systemic symptoms 
• 
Solicited local injection site symptoms 
• 
Concomitant medications 
The diary should be completed once daily starting the evening of each study dose through 
6 days post-dose. The completed diary post-dose 1 and post-dose 2 will be reviewed with 
the subject by the study staff during the phone calls on Day 7 and Day 35, respectively. 
The study staff will review the diary with the subject to assess for temperature, solicited 
systemic symptoms (unusually tired/feeling unwell, muscle aches, headache, nausea, 
joint pain) and solicited injection site symptoms (pain, itching, redness, swelling, bruising). 
In addition, unsolicited symptoms and concomitant medications will be collected.  
Any diary entry determined to meet the Common Terminology Criteria for Adverse Events 
version 5.0 (CTCAE) criteria for a Grade 1 or higher adverse event should be documented 
as an adverse event unless deemed part of the subject’s ongoing medical history. Injection 
site reactions should be graded per the Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, issued September 
2007 (See Section 6.4.5). If the diary entry does not meet the criteria of a Grade 1 or 
higher AE as per the relevant guidelines, Investigator clinical judgment can be used to 
determine whether the entry should be recorded as an AE and documented accordingly 
in the site’s source. For cases where the diary entry and final AE reporting (i.e. grading) 
do not agree, the reasoning should be recorded in the source documents. 
6.4.1 INTRADERMAL INJECTION AND EP  
Phase 2 and Phase 3 segments: 
A complete administration procedure is defined as an ID injection (formation of a wheal) 
of IP followed by insertion of the ID Array needles (electrodes) through the skin and into 
the wheal followed by delivery of four electroporation pulses. This procedure is broadly 
described as administration because it involves more than the injection of a drug. 
Only if the deltoid area is not a suitable location for administration (see exclusion criterion 
‘j’), the ID injection can then be administered above the lateral quadriceps followed 
immediately by EP. IP must not be given within 2 cm of a tattoo, scar, keloid, or active 
lesion/rash. Also, ID injection followed immediately by EP must not be performed on the 
skin of an extremity which has any metal implants or implantable medical device (e.g., 
surgical rods, pins or joint replacements). If a subject has an implanted cardiac defibrillator 
or pacemaker, ID injection/EP must not be performed above the deltoid muscle on the 
same side of the body where the device is located. 
There are three steps that must be performed as part of the administration procedure: 
- 
Injection of IP (INO-4800 or placebo) 
- 
Insertion of the array into the subject’s skin 
- 
Pressing the trigger button on the EP applicator  
Table 9 below is provided as guidance on how to appropriately complete the procedure 
when injection of IP has occurred, but the subject did not receive EP. 
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Table 9: Guidance for how to manage an incomplete administration after drug has 
been administered 
Was IP 
injected? 
Was the array 
inserted into skin? 
Was trigger button 
pressed (i.e. EP 
given)? 
Action 
Yes 
Yes (if array gets 
dislodged before 
the trigger button 
is pressed, the 
same array may 
be re-inserted) 
No 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
Yes 
No 
Yes 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
Yes 
No 
No 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
 
Readministration of drug (i.e. protocol-specified drug has already been delivered) is not 
permitted. 
Training will be provided by the Sponsor on use of the device. 
Phase 2 segment: 
Subjects will receive a two-dose regimen of one or two 1.0mg ID injections of INO-4800 
or placebo in a volume of ~0.1 mL in an acceptable skin location for injection and 
subsequently followed immediately by EP with CELLECTRA® 2000 at Day 0 and Day 28.  
Phase 3 segment: 
Subjects will receive a two-dose regimen of either one or two 1.0mg ID injections of INO-
4800 or placebo in a volume of ~0.1 mL in an acceptable skin location for injection and 
subsequently followed immediately by EP with CELLECTRA® 2000 at Day 0 and Day 28. 
The dose level will be determined based on results of the study’s Phase 2 segment. 
6.4.2 MANAGEMENT OF PAIN DUE TO ELECTROPORATION (EP) PROCEDURES 
In case of pain, subjects may be treated with a non-narcotic analgesic (e.g., 
acetaminophen) after injection/EP.  
Medication taken for pain management will be documented as concomitant medications. 
6.4.3 ASSESSMENT OF LABORATORY ABNORMALITIES 
Samples will be collected for serum chemistry, hematology, and urinalysis at the visits 
listed in the Schedule of Events (36TTables 3 and 436T) and as listed in Section 6.4.  
Laboratory AEs will be assessed and graded in accordance with the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. Laboratory values that are 
not clinically significant (NCS) in the Investigator’s opinion will not be reported as AEs. 
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6.4.4 ASSESSMENT OF CLINICAL TRIAL ADVERSE EVENTS (AES) 
Subjects will be queried regarding the occurrence of any AEs including AEs related to 
injection site reactions, concomitant medications and new onset illness or disease during 
their study visits and phone calls. Subjects will be reminded to contact study personnel 
and immediately report any event for the duration of the study. All AEs will be captured 
from the time of the informed consent until 28 days post-dose 2 (Day 56). Following the 
Day 56 visit, only SAEs, AESIs and MAAEs will be collected. All related AEs, AESIs and 
SAEs will be followed to resolution or stabilization. These events will be recorded on the 
subject’s CRF. 
6.4.5 ASSESSMENT OF INJECTION SITE REACTIONS  
Reactions arising from the IP administration procedure may be reported as administration 
site or injection site reactions. When evaluating administration (injection) site reactions 
throughout the study, it is most important to be as specific as possible by selecting the 
most appropriate term (see Table 10 below) and using the grading scale as listed in the 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, issued September 2007. Administration (injection) site reactions 
and administration site pain will be evaluated starting 30 minutes following injection/EP. 
In addition, other events associated with administration (injection) site reactions (e.g., 
hematoma, infection or necrosis) should also be reported with preferred terms specific for 
administration (injection) site reactions.  
Table 10: Grading Scale for Injection Site Reactions 
Local Reaction to 
Injectable Product 
(Grade) 
Mild (1) 
Moderate (2) 
Severe (3) 
Potentially 
Life 
Threatening 
(4) 
Pain 
Does not 
interfere with 
activity 
Repeated use 
of non-
narcotic pain 
reliever >24 
hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency 
room visit or 
hospitalization 
Tenderness 
Mild 
discomfort to 
touch 
Discomfort 
with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/Rednessa 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swellingb 
2.5-5 cm and 
no 
interference 
w/ activity 
5.1-10 cm or 
interferes with 
activity 
>10 cm or 
prevents daily 
activity 
Necrosis 
September 2007 “FDA Guidance for Industry-Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
a In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable 
b Should be evaluated and graded using the functional scale as well as the actual measurement. 
6.4.6 IMMUNOGENICITY ASSESSMENTS 
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Whole blood and serum samples will be obtained at visits specified in the Schedule of 
Events (36TTables 3 and 436T) for cellular and humoral immunology assessments. Binding 
ELISA will be evaluated at serial timepoints. Cellular sampling requires, 32 mL of whole 
blood (4 CPT tubes, each 8 mL of whole blood) be collected at each visit. Humoral 
sampling requires collection of 8.5 mL of whole blood in a single 10-mL red top serum 
collection tube to produce four serum aliquots of 1 mL each. However, baseline (Day 0) 
immunology samples are required to serve as a baseline for all subsequent immunology 
testing. Therefore, a total of 68 mL whole blood and 8 mL serum is required on Day 0 prior 
to 1st dose. Details of the immunology sample collection and shipment information will be 
provided in the Laboratory Manual.  
The additional immune responses to INO-4800 will be measured using assays that include 
a pseudovirus-based neutralization assay, flow cytometry and ELISpot. Determination of 
additional analyses using assays not specified, such as assessment of immunological 
gene expression, assessment of immunological protein expression on collected samples 
for immunological endpoints will be made on an ongoing basis throughout the trial. 
6.4.7 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken at the time of Screening and 
ongoing from signing of the informed consent to study discharge that do not affect a 
subject’s eligibility for participation (see Section 4.2) must be recorded on CRFs. 
Actual or estimated start and stop dates must be provided. This information will be 
obtained from the subject and/or any available medical records. The indication for the 
medication, dose, and dose regimen will be documented.  
Therapy considered necessary for the subject’s welfare may be given at the discretion of 
the Investigator or medical provider. If the permissibility of a specific medication/treatment 
is in question, please contact the Medical Monitor. 
The decision to administer a prohibited medication/treatment (Section 6.4.8) is made with 
the safety of the clinical trial subject as the primary consideration. When possible, the 
Sponsor should be notified before the prohibited medication/treatment is administered. 
6.4.8 RESTRICTIONS  
Subjects should refrain from becoming pregnant until 3 months following the last dose of 
investigational product by using appropriate contraceptive measures (see Section 4.1). 
Subjects must not receive any non-study related vaccine (e.g., influenza vaccine) within 2 
weeks prior to the first dose of IP, or within 2 weeks of (before or after) any subsequent 
dose of IP.  
Subjects must not have fever (oral temperature >38.0 degrees Celsius or 100.4o 
Fahrenheit) within 72 hours prior to each dosing. 
Subjects should not receive hydroxychloroquine for any condition, or any other drug 
intended as COVID-19 prophylaxis during the trial, or as supplementary COVID-19 
prophylaxis post-dose.  
Subjects must not receive disease modifying doses of anti-rheumatic drugs (e.g., 
azathioprine, cyclophosphamide, cyclosporine, methotrexate), biologic disease modifying 
drugs such as TNF-α inhibitors (e.g., infliximab, adalimumab or etanercept) and long term 
use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of prednisone 
equivalent (use of inhaled, topical, nasal, otic, and ophthalmic corticosteroids are allowed).  
6.4.9 SARS-COV-2 TESTING 
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Phase 2 segment: 
SARS-CoV-2 antibody and RT-PCR testing will be used during screening to test for 
previous or current SARS-CoV-2 infection. During the trial, subjects who report symptoms 
suggestive of COVID-19 will be assessed at a COVID-19 assessment visit in the clinic, 
subject’s vehicle, or via telemedicine. During this visit, a nasal swab and saliva will be 
collected to detect SARS-CoV-2 using the RT-PCR assay. For a remote visit, the subject 
will self-collect the nasal and saliva samples and the site will provide instructions to 
properly handle the samples (e.g. transport of samples to the clinic, shipment of samples 
to the testing laboratory, etc). If the subject is confirmed to be COVID-19 positive, a follow-
up nasal swab and saliva will be collected to detect SARS-CoV-2 using the RT-PCR assay 
at the COVID-19 convalescent visit. 
Phase 3 segment: 
SARS-CoV-2 antibody testing will be used during screening to test for previous SARS-
CoV-2 infection and during each subsequent visit (see Table 4: Schedule of Events) to 
identify SARS-CoV-2 infections that may occur regardless of symptoms between study 
visits. 
SARS-CoV-2 RT-PCR testing will be conducted on saliva specimens collected at 
Screening, Day 0, Day 28 and Day 393 or EOS visit. During other in-office study visits 
(see Table 4: Schedule of Events), saliva samples will be collected by clinical personnel 
and stored on site until further instruction. Bi-weekly home self-collections of saliva will be 
done by subjects, between study visits according to the Schedule of Events. Subjects will 
be provided instructions to properly handle these specimens (e.g. transport of samples to 
the clinic at the next in-person visit, shipment of samples directly to the testing laboratory, 
etc). Testing will be performed on selected saliva samples if the subject’s SARS-CoV-2 
serology test becomes positive. 
The Day 0 and Day 28 SARS-CoV-2 RT-PCR results will not be required prior to dosing 
on that day. 
If, at any time during the trial, either the SARS-CoV-2 antibody or RT-PCR test result is 
positive, the subject will be notified of the result and will be evaluated at a COVID-19 
assessment visit. During that visit, which may be conducted in the clinic, from the subject’s 
vehicle, or via telemedicine, a nasal swab and saliva will be collected to detect SARS-
CoV-2 using the RT-PCR assay.  
6.4.10 COVID-19 DISEASE MONITORING 
During both the Phase 2 and Phase 3 segments of the trial, all subjects will be monitored 
for the development of symptoms suggestive of COVID-19 disease. For the Phase 3 
segment, frequent (approximately bi-weekly) scheduled clinic visits or phone calls will 
occur.  
All subjects in the trial should be instructed to do the following: 
• 
Take their temperature daily at home starting on the Day 0 visit for the duration of 
the trial.     
• 
Monitor for symptoms suggestive of COVID-19 (e.g., feeling feverish or chills, 
cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, 
headache, new loss of taste or smell, sore throat, congestion or runny nose, 
nausea or vomiting, diarrhea) starting on the Day 0 visit for the duration of the trial.  
If at any time during the study, the subject experiences a fever of higher than 100.4°F/38°C 
or symptoms suggestive of COVID-19, the subject should contact the site. The site staff 
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should arrange for a clinic visit (COVID-19 assessment visit) within 3 days of the site being 
aware of either a positive SARS-CoV-2 test or COVID-19 symptom onset. For subjects in 
the Phase 3 segment, a home saliva sample should be self-collected each day for up to 3 
days by the subject until the COVID-19 assessment visit. The COVID-19 assessment visit 
may be performed either at the clinic, in the subject’s vehicle or via telemedicine. 
Procedures to be performed during this visit will be specified in a separate study manual. 
Subjects with a confirmed COVID-19 diagnosis prior to dose 2 will be discontinued from 
further dosing and will be followed until EOS for safety and resolution of COVID-19. 
Subjects with confirmed SARS-CoV-2 infection will return for a convalescent visit 
approximately 28 days after symptom onset, or in the absence of symptoms, after the 
collection date of the positive SARS-CoV-2 sample. If symptoms are ongoing at 28 days 
after symptom onset, the site should follow up with the subject via phone call or 
unscheduled visit after symptom resolution or stabilization. Recovery from COVID-19 
disease requires either resolution of clinical symptoms except for loss of taste/smell or 
stabilization of symptoms and follow up testing according to Institutional policy.    
Subjects who require medical care for COVID-19 disease (or any other suspected 
condition) will be referred to their primary health care provider or a medical treatment 
facility if the Investigator believes that the subject should be managed beyond routine care 
that can be provided by the study site. Subjects referred for treatment will continue study 
follow-up according to the protocol schedule. If subjects are treated or hospitalized due to 
their illness, the study team will request COVID-19 specific test results, treatments, 
treatment outcomes and diagnostics from medical treatment facilities with the subject’s 
written permission. These results and diagnostics will be recorded in the study and/or 
safety database consistent with protocol reporting requirements. 
7.0 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
The safety of INO-4800 will be measured and graded in accordance with the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. 
7.2 
ADVERSE EVENTS (AES) 
Any untoward medical occurrence in a patient or clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.  
Adverse Events (AEs) include the following: 
• Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (before the administration of clinical trial drug) 
• Any pre-existing condition that increases in severity, or changes in nature during or as 
a consequence of the clinical trial drug administration phase 
• Complications of pregnancy (refer to Section 7.11) 
Adverse Events (AEs) do not include the following: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; however, the condition that leads to the procedure is an AE 
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• Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the Screening Visit that do not worsen 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions) 
• Overdose without clinical sequelae 
• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed, is not an AE; it is considered to be pre-existing and will be 
documented on the medical history CRF 
• Uncomplicated pregnancy 
• An induced elective abortion to terminate a pregnancy without medical reason 
• Confirmed COVID-19 disease  
7.3 
ADVERSE DRUG REACTION (ADR) 
All noxious and unintended responses to a medicinal product related to any dose. This 
means that a causal relationship between the medicinal product and an adverse event is 
at least a reasonable possibility (i.e., the relationship cannot be ruled out). 
7.4 
SERIOUS ADVERSE EVENTS (SAES) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death  
• Is life-threatening 
o Refers to an event in which the subject was at risk of death at the time of the event. 
It does not refer to an event which hypothetically might have caused death if it 
were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
o Includes any hospitalization in which the subject has been admitted to the hospital 
regardless the length of stay, even if the hospitalization is only a precautionary 
measure to allow continued observation. However, hospitalization (including 
hospitalization for an elective procedure) for a pre-existing condition that has not 
worsened, does not constitute an SAE. 
• Results in persistent or significant disability/incapacity 
o A substantial disruption of a person's ability to conduct normal life functions (i.e., 
the adverse event resulted in a significant, persistent or permanent change, 
impairment, damage or disruption in the subject’s body function/structure, physical 
activities and/or quality of life). 
• Results in congenital anomaly or birth defect and/or 
• An important medical event  
o An event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
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Clarification of Serious Adverse Events (SAEs) 
• Death itself is not an AE. Death is an outcome of an AE, but when the cause of death 
has not been provided, use the event term: death of unknown cause. 
• Confirmed COVID-19 disease that requires hospitalization is recorded on the 
Suspected COVID-19 Clinical Event CRF, and not recorded as an SAE.. 
• COVID-19 disease with an outcome of death is recorded on the Suspected COVID-19 
Clinical Event CRF, and not recorded as an SAE. 
• The subject may not have been receiving an investigational medicinal product at the 
occurrence of the event. 
• Complications associated with COVID-19 disease that occur or prolong 
hospitalization are recorded on the Suspected COVID-19 Clinical Event CRF. 
7.5 
UNEXPECTED ADVERSE DRUG REACTION 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator’s Brochure [IB] for an unapproved investigational 
product, package insert/summary of product characteristics for an approved product). 
7.6 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects.  
A UADE is a type of SAE that requires reporting to the Sponsor in accordance with Section 
7.9. 
7.7 
DEVICE DEFICIENCY 
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance. 
Note: Device deficiencies include malfunctions, use errors and inadequate labelling. 
7.8 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor is responsible for the overall safety monitoring of the clinical trial. 
Safety monitoring assessments include but are not limited to:  
• Incidence of all AEs classified by system organ class, preferred term, severity and 
causal relationship to clinical trial treatment 
• Changes in laboratory parameters 
• Local and systemic injection site review; special attention will be paid to the examination 
of the injection site 
7.8.1 ADVERSE EVENT OF SPECIAL INTEREST (AESI)  
An adverse event of special interest (serious or non-serious) is one of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the PI to the Sponsor can be appropriate.  
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For the purpose of this clinical trial, the AESIs listed in Appendix A are to be reported to 
the Sponsor in accordance with Section 7.9. 
7.8.2 MEDICALLY ATTENDED ADVERSE EVENT (MAAE) 
A medically attended adverse event (serious or non-serious) is defined as an adverse 
event that leads to an unplanned contact with a health care provider. 
7.8.3 ABNORMAL LABORATORY VALUE 
The PI will annotate each abnormal lab value as clinically significant (CS) or not clinically 
significant (NCS). 
Laboratory values that are NCS in the PI’s opinion should not be reported as an adverse 
event. 
Any abnormal laboratory value that is new in onset or worsened in severity or frequency 
from the baseline condition and meets one of the following criteria will be recorded as an 
AE: 
• 
Requires therapeutic intervention or diagnostic tests 
• 
Leads to discontinuation of further administration of the investigational product in 
the clinical trial 
• 
Has accompanying or inducing symptoms or signs 
• 
Is judged by the PI as clinically significant (CS) 
Abnormal laboratory values that meet the criteria of an AE or SAE should be reported in 
accordance with Section 7.9. 
7.8.4 CLINICAL TRIAL STOPPING RULES 
The investigator is to immediately notify the Medical Monitor if the following are observed: 
• 
Any SAE related to study treatment. 
• 
Any Grade 4 AEs related to study treatment. 
• 
Any report of anaphylaxis related to study treatment. 
• 
Any suspected Severe COVID-19 disease case (per Sections 3.7.1.1 and Section 
3.7.1.2). 
The Medical Monitor will notify the Chair of the Safety Review Committee, who will make 
a determination as to whether to temporarily halt dosing until a more formal review of the 
case(s) is made. Such a formal review may include an ad hoc meeting of the DSMB, after 
consultation with the DSMB Chair. Following such a meeting, the DSMB chair will render 
a recommendation to the Medical Monitor regarding continuation of trial dosing. The 
Sponsor will independently investigate the case(s) and, after review of the DSMB 
recommendations, will communicate a final decision as to whether to lift the dosing 
suspension or whether to continue dosing. These deliberations will be documented and 
will be provided to the IRBs and FDA, where required.   
7.9 
SAFETY DATA REPORTING PERIOD, METHOD OF COLLECTION AND SUBMISSION 
All AEs will be collected from the time informed consent is obtained through Day 56. 
MAAEs, AESIs and SAEs only will continue to be collected after the Day 56 visit and will 
be followed to resolution or stabilization. This information will be captured in the CRF. 
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If the PI determines that the AE meets serious criteria, then the AE will be recorded as an 
SAE. 
SAEs and AESIs will be reported to the Sponsor from the time the subject signs the 
informed consent until the last visit. 
All SAEs (regardless of causal relationship) and AESIs will be reported on the SAE Report 
Form and submitted to the Sponsor within 24 hours of becoming aware of the event. The 
SAE Report Form will be either emailed to safety.inovio@apcerls.com or faxed to
The original SAE Report Form must be kept at the clinical trial site. 
The event will be data entered into the CRF. 
 
For the events that are considered an AESI, the PI will contact the Sponsor within 24 hours 
of becoming aware of the event to discuss whether dosing should continue. 
Table 11: SAE Contact Information 
Sponsor Safety Email: safety.inovio@apcerls.com  
Sponsor Safety Fax: 
Sponsor Safety Phone: 
 
Table 12: Medical Monitor Direct Contact Information 
Primary point of contact, ICON Medical Monitor: 
, M.D.  
Email: 
 
Cell Phone: 
 
Inovio Medical Monitor: 
Jr., M.D., FACP, FIDSA 
Email: 
 
Cell Phone: 
 
 
All SAEs, treatment-related AEs, MAAEs and AESIs must be followed by the PI until 
resolution or return to baseline status, stabilization of the event (i.e., the expectation that 
it will remain chronic), even if it extends beyond the clinical trial reporting period or until it 
is determined that the subject is lost to follow up. 
Follow-up information is to be submitted to the Sponsor on an SAE Report Form and within 
24 hours of becoming aware of the information. 
If medical records are submitted to the Sponsor with the SAE Report Form, the clinical 
trial site must: 
• Redact the medical records of all personal data (e.g., confidential subject data, 
Personal Identifying Information [PII]) 
• Provide the subject’s assigned identification number (SID) on the records 
7.10 ADVERSE EVENT REPORTING 
This section provides details on reporting the safety information. 
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7.10.1 SUBMITTING THE INITIAL SERIOUS ADVERSE EVENT (SAE) REPORT FORM 
The PI should include as much safety information as possible when submitting the initial 
report, but the report must include the following at a minimum:  
• 
The adverse event 
• 
The subject’s assigned identification number (SID) 
• 
Investigational product(s) (IP) and/or study device 
• 
Investigator causal relationship to the IP(s) and/or study device 
• 
Serious criteria 
• 
Reporter name and contact information 
If a case is submitted to the Sponsor with only the “minimum” information, a more detailed 
or updated follow-up report will be sent to the Sponsor as soon as possible but no later 
than three (3) calendar days after the date of the initial report. 
7.10.2 RECORDING THE EVENT 
Principal Investigators (PIs) should use correct medical terminology/concepts when 
recording AEs on the EDC and SAE Report Form. The use of colloquialisms and 
abbreviations should be avoided. 
A medical diagnosis, if known, should be recorded rather than individual signs and 
symptoms. However, if the signs and/or symptoms cannot be medically characterized as 
a single diagnosis or syndrome, each individual sign and/or symptom should be recorded. 
If a diagnosis is subsequently established, all previous signs and/or symptoms will be 
subsumed and replaced with a single medical diagnosis. 
7.10.3 ASSESSING SEVERITY (INTENSITY) 
Severity is used to describe the intensity of a specific event (e.g., mild, moderate, severe). 
The PI will assess and grade clinical AEs or SAEs (based on discussions with clinical trial 
subjects) in accordance with CTCAE. 
7.10.4 CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS (AES) 
A causally related AE is one judged to have a possible, probable or definite relationship 
to the administration of the IP and/or the study device. An AE may also be assessed as 
not related to the IP and/or the study device. Because the PI is knowledgeable about the 
subject (e.g., medical history, concomitant medications), administers the IP, and monitors 
the subject’s response to the IP, the PI is responsible for reporting AEs and judging the 
relationship between the administration of the IP and EP and a subsequent AE. The PI is 
aware of the subject’s clinical state and may have observed the event, and thus may be 
sensitive to distinctions between events due to the underlying disease process versus 
events that may be product-related.  
Principal Investigators (PIs) should use their knowledge of the clinical trial subject, the 
circumstances surrounding the event, and an evaluation of any potential alternative 
causes to determine whether an AE is considered to be related to the IP and/or the study 
device and the causal relationship reported as "Yes" or "No" accordingly. Causality should 
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be assessed by the PI as related to drug, related to device, or related to both drug and 
device (i.e., related to both or indiscernible) by the following criteria: 
• 
Yes – there is a reasonable possibility that administration of the clinical trial 
treatment (drug or device or both drug and device) contributed to the event 
• 
No – there is no reasonable possibility that administration of the clinical trial 
treatment contributed to the event and there are more likely causes 
The following guidance should also be taken into consideration: 
• 
Temporal relationship of event to administration of IP and/or EP 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable) 
• 
Known association of the event with the IP, EP or with similar treatments 
• 
Known association of the event with the disease under trial 
• 
Presence of risk factors in the clinical trial subject or use of concomitant 
medications known to increase the occurrence of the event 
The rationale for the PI’s causal assessment is to be recorded on the SAE Report Form. 
The Sponsor will assess the overall safety of the IP delivered by EP and determine 
whether to report expeditiously to the regulatory authority(ies). 
7.11 REPORTING SUSPECTED COVID-19 DISEASE CASES DURING THE TRIAL 
For both Phase 2 and Phase 3 segments of the trial, all suspected COVID-19 disease 
cases based on reported COVID-19 symptoms and/or SARS-CoV-2 test results should be 
entered into the Suspected COVID-19 Clinical Event CRF within 24 hours of awareness. 
Cases will be tracked until final determination of whether the case meets criteria of a 
confirmed COVID-19 disease case, per the case definition. For the Phase 2 segment of 
the trial, this determination will be made by the PI. For the Phase 3 segment, this 
determination will be made by the EAC. 
If the reported COVID-19 disease case is later determined not to be a confirmed COVID-
19 case, the event (e.g. symptoms or other diagnosis), if serious, would be reported as an 
SAE within 24 hours following determination by the PI (Phase 2 segment) or notification 
by EAC (Phase 3 segment).  
If the reported COVID-19 disease case is later determined not to be a confirmed COVID-
19 case, the event (e.g. symptoms or other diagnosis), if non-serious and if occurring from 
the time of consent until 28 days post-dose 2, would be reported as an AE following 
determination by the PI (Phase 2 segment) or notification by EAC (Phase 3 segment). 
7.12 REPORTING PREGNANCY DURING THE CLINICAL TRIAL 
Subjects who are pregnant or expect to become pregnant prior to 3 months following the 
last dose will be excluded from participation in the clinical trial.  
All pregnancies that occur from the time of first administration of clinical trial treatment 
through study completion (i.e., Day 393) will be reported to the Sponsor. If clinical trial site 
staff become aware that a subject becomes pregnant after the first dose in the clinical trial, 
she will not be given any additional treatments with the IP. A Pregnancy Form will be 
completed by the PI and submitted to the Sponsor within 24 hours after becoming aware 
of the pregnancy. 
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The PI will report this event to their IRB/REB/EC in accordance with their policies and 
procedures.  
The clinical trial site must request the subject’s permission to query pregnancy outcome 
and follow the subject for outcome of the pregnancy. The subject will continue to be 
followed for safety assessments without receiving additional IP until clinical trial discharge 
in accordance with this protocol. Procedures that are contraindicated during pregnancy, 
including additional dose administrations, must not be performed. The PI should use 
clinical judgment regarding subsequent clinical trial-related blood collection based on the 
presence or absence of anemia in each subject.  
Male subjects will be instructed through the ICF to immediately inform the PI if their partner 
becomes pregnant until study completion. A Pregnancy Form will be completed by the PI 
and submitted to the Sponsor within 24 hours after becoming aware of the pregnancy. The 
pregnant partner will be asked to sign a Pregnancy Information Collection Consent Form 
to allow for follow-up on her pregnancy. If the authorization has been signed, the PI will 
collect and report details of the course and outcome of the pregnancy in the partner of a 
male subject exposed to IP. The PI will update the Pregnancy Form with additional 
information on the course and outcome of the pregnancy and submit the form to the 
Sponsor.  
If a PI is contacted by the male subject or his pregnant partner, the PI may provide 
information on the risks of the pregnancy and the possible effects on the fetus to support 
an informed decision in cooperation with the treating physician and/or obstetrician. 
If the end of the pregnancy occurs after the clinical trial has been completed, the outcome 
will be reported directly to the Sponsor. 
7.13 REPORTING DEVICE-RELATED COMPLAINTS OR DEFICIENCIES 
All product complaints that meet the definition of device deficiency must be reported to the 
Sponsor within 10 days of discovery, with the exception of SAEs which require 24-hour 
reporting. The error reporting or complaint form must be completed and emailed to the 
Sponsor at clinicalcomplaint@inovio.com. 
Device deficiencies include malfunctions, misuse or use errors and inadequate labeling. 
A malfunction is defined as the failure of a device to meet its performance specifications 
or otherwise perform as intended. The intended performance of a device refers to the 
intended use for which the device is labeled or marketed. 
Any problems experienced during the treatment procedure including malfunctions of the 
device, error messages displayed on the device screen following treatment, or errors that 
occur during the treatment procedure must immediately be reported to the Sponsor or its 
designee for evaluation.  
7.14 NOTIFYING REGULATORY AUTHORITIES AND INSTITUTIONAL REVIEW BOARDS 
(IRBS)/RESEARCH ETHICS BOARDS (REBS)/ETHICS COMMITTEES (ECS) OF SAFETY 
INFORMATION 
7.14.1 SPONSOR RESPONSIBILITIES 
• 
Determine whether the safety information meets the requirements for expedited 
reporting to the applicable regulatory authorities 
• 
Prepare and submit the safety report to the applicable regulatory authorities 
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• 
Send all participating PIs a safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) that will include a statement if there is or is not any significant new 
safety information that might influence the risk-benefit assessment of the IP and/or 
study device, sufficient to consider changes in product administration or overall 
conduct of the clinical investigation 
7.14.2 PRINCIPAL INVESTIGATOR (PI) RESPONSIBILITIES 
• 
Forward a copy of the safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) to their IRB/REB/EC as soon as practical in accordance with the 
governing policy and/or procedures 
• 
Notify their IRB/REB/EC of safety information (i.e., SAEs, pregnancies, and AESIs) 
that occur at their clinical trial site in accordance with their local institutional policy 
7.15 POST-TRIAL REPORTING REQUIREMENTS 
PIs are not obligated to actively seek AEs or SAEs beyond the clinical trial reporting period. 
However, if the PI becomes aware of an AE or SAE that occurs after the Completion or 
Termination Visit and the event is deemed by the PI to be related to the clinical trial 
treatment, the PI should promptly document and report the event to the Sponsor. 
7.16 CLINICAL TRIAL DISCONTINUATION  
INOVIO reserves the right to discontinue the clinical trial at a site or at multiple sites for 
safety or administrative reasons at any time. In particular, a clinical trial site that does not 
recruit at a reasonable rate may be discontinued. Additionally, the clinical trial may be 
discontinued at any time by an IRB/REB/EC, INOVIO, or a regulatory authority as part of 
their duties to ensure that clinical trial subjects are protected.  
If the clinical trial is discontinued and/or the clinical trial site closed for any 
reason, all IP and devices must be returned to INOVIO or its 
representative. The PI should ensure that their site file documents are complete 
prior to archiving, and provide copies of any requested documents to INOVIO 
for its Trial Master File (TMF). 
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
STATISTICAL AND ANALYTICAL PLAN 
The formal Statistical Analysis Plan is contained in the sections that follow. 
8.2 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is an operationally seamless Phase 2/3 trial.  The subjects and data from Phase 2 
are independent from that of Phase 3.   
Phase 2 Segment:  This is a four-arm, multi-center, placebo-controlled, blinded, and 
randomized clinical trial in subjects at high risk of SARS-CoV-2 exposure. The trial’s 
primary endpoints are antigen-specific cellular immune response measured by IFN-
gamma ELISpot and neutralizing antibody responses. Secondary efficacy endpoints are 
safety measures.  Exploratory endpoints are antigen-specific cellular immune response 
measured by flow cytometry and other T and B cell measures.  
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Phase 3 Segment: This is a two-arm, multi-center, placebo-controlled, double-blinded, and 
randomized clinical trial in subjects at high risk of SARS-CoV-2 exposure. The study’s 
primary endpoint is the incidence of virologically-confirmed COVID-19 disease starting 14 
days after completion of the 2-dose regimen until 12 months post-dose 2.  The primary 
hypothesis is that INO-4800 will be efficacious relative to placebo (relative efficacy > 30%). 
Secondary efficacy analyses involve non-severe cases, severe cases, cases resulting in 
death, infection, and timing of symptom resolution. Other secondary analyses concern 
safety and cellular and neutralizing antibody response. Exploratory analyses concern 
binding antibody and cellular immunological measures. 
8.3 
STATISTICAL HYPOTHESES 
Phase 2 Segment: This is an estimation segment pertaining to immunogenicity and safety.  
There are no hypotheses. 
Phase 3 Segment: The primary hypothesis of relative efficacy greater than 30% will be 
tested with H0: p ≥ .70/(.70+k) vs. H1: p < .70/(.70+k), where p is the true proportion of 
subjects with disease who receive INO-4800 relative to the total number of subjects with 
disease, and k is the total amount of follow-up time in the placebo group divided by the 
total amount of follow-up time in the INO-4800 group. There are no other formal 
hypotheses. 
8.4 
ANALYTICAL POPULATIONS 
Analysis populations will be: 
The per-protocol (PP) population includes all subjects who receive all doses of Study 
Treatments and have no protocol violations. Subjects in the PP population will be grouped 
to treatment arms as randomized.  Subjects excluded from the PP population will be 
identified and documented prior to unblinding of the trial database.  Analyses on the PP 
population will be primary for the analysis of efficacy in the Phase 3 segment of this trial. 
The modified intention to treat (mITT) population includes all subjects who receive at least 
one dose of Study Treatment. Subjects in this population will be grouped to treatment 
arms as randomized.  Analysis of the mITT population will be considered supportive for 
the corresponding PP population for the analysis of efficacy in the Phase 3 segment of 
this trial. 
The intention to treat (ITT) population includes all subjects who are randomized. Subjects 
in this sample will be grouped to treatment arms as randomized.  Analysis of the ITT 
population will be considered supportive for the corresponding PP population for the 
analysis of efficacy in the Phase 3 segment of this trial. 
The safety analysis population includes all subjects who receive at least one dose of Study 
Treatment. Subjects will be analyzed according to the treatments received. 
8.5 
DESCRIPTION OF STATISTICAL METHODS 
8.5.1 PRIMARY ANALYSIS 
Phase 2 Segment 
Post-baseline increases from baseline in interferon-γ ELISpot response magnitudes will 
be compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
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Post-baseline increases from baseline in neutralizing antibody response magnitudes will 
be compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
Valid samples for statistical analysis purposes will be those collected within the days of 
the specified visit according to the Schedule of Events. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for these immunogenicity analyses. 
Phase 3 Segment 
The primary hypothesis of relative efficacy greater than 30% will be tested with H0: p ≥ 
0.70/(0.70+k) vs. H1: p < 0.70/(0.70+k), where p is the true proportion of subjects with 
disease who receive INO-4800 relative to the total number of subjects with disease, and 
k is the total amount of follow-up time in the placebo group divided by the total amount of 
follow-up time in the INO-4800 group. 
A p-value for this hypothesis test and corresponding 95% confidence interval will be 
computed based on the exact binomial method of Clopper-Pearson. Success will be 
concluded if the one-sided p-value is <0.025 and the corresponding lower bound of the 
two-sided 95% CI for efficacy exceeds 30%, and the point estimate for efficacy exceeds 
50%. 
For calculating k, an individual subject’s follow-up time is either: 
o the date of first disease diagnosis – date of the start of surveillance period +1 (for 
subjects who are cases), or 
o the date of last follow-up – date of the start of surveillance period +1 (for subjects who 
are non-cases). 
This methodology is based on the following. Assuming that the number of subjects who 
are cases in the INO-4800 group follows a Poisson distribution with parameter λv and the 
number of subjects who are cases in the placebo group follows a Poisson distribution with 
parameter λc, then conditional on total number of subjects with cases, t, the number of 
subjects who are cases in the INO-4800 group follows a binomial distribution with 
parameters (t, p=λv/(λv+λc)).  The relationship between p and efficacy is: efficacy = (1-
(1+k)p)/(1-p).  Therefore, testing efficacy > 30% corresponds to testing p < 0.70/(0.70+k).  
Similarly, the confidence interval for efficacy is (1-(1+k)UBp)/(1-UBp), (1-(1+k)LBp)/(1-LBp), 
where UB and LB are the Clopper-Pearson upper and lower limits for the proportion. 
The efficacy time frame is defined by symptoms beginning at any time starting from 14 
days after Dose 2 and ending 12 months after Dose 2.  Subjects identified as cases that 
started prior to this time point will be excluded.  Subjects with multiple instances meeting 
the case definition will be counted only once, using the first such instance.    
The PP population will be primary for the analysis of efficacy in this trial. Efficacy analysis 
using the mITT population will also be conducted counting cases from 14 days postdose 
1 as a supportive analysis.  The ITT population will also be used for a supportive analysis 
counting cases starting from randomization. 
8.5.2 SECONDARY ANALYSES 
8.5.2.1 Efficacy 
Phase 3 Segment 
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The secondary efficacy incidence endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values.  
The secondary efficacy endpoint regarding timing of symptom resolution will be 
analyzed with Kaplan-Meier plots by treatment group. 
8.5.2.2 Immunogenicity 
 
   Phase 3 Segment 
Post-baseline increases from baseline in interferon-γ ELISpot response magnitudes will 
be compared between treatment groups using differences in medians and associated 
non-parametric 95% CIs. 
Post-baseline increases from baseline in neutralizing antibody response magnitudes will 
be compared between treatment groups using differences in medians and associated 
non-parametric 95% CIs. 
The summaries listed above will be stratified according to disease status of the subjects. 
Valid samples for statistical analysis purposes will be those collected within the days of 
the specified visit according to the Schedule of Events. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for these immunogenicity analyses. 
8.5.3 SAFETY ANALYSES 
8.5.3.1 Adverse Events 
All AEs including injection-site reactions will be summarized among the Safety 
Population by frequency per treatment arm. These frequencies will be presented overall 
and separately by dose, and will depict overall, by system organ class and by preferred 
term, the percentage of subjects affected. Additional frequencies will be presented with 
respect to maximum severity and to strongest relationship to Study Treatment. Multiple 
occurrences of the same AE will be counted only once following a worst-case approach 
with respect to severity and relationship to Study Treatment. All serious AEs will also be 
summarized as above. 
The main summary of safety data will be based on events occurring within 30 days of 
any dose. For this summary, the frequency of preferred term events will be compared 
between study arms with risk differences and 95% confidence intervals, using the 
method of Miettinen and Nurminen. As this analysis will use many event categories, and 
produce many confidence intervals, caution should be exercised when interpreting these 
confidence intervals.  Separate summaries will be based on events occurring within 7 
days of any dose and regardless of when they occurred. 
The analyses listed above will be performed according to Phase.  
For AE data, partial start dates will be imputed to the date of treatment to conservatively 
report the event as treatment-emergent, whenever the portion of the date is consistent 
with that of the study treatment. Otherwise, it will be imputed to the earliest date 
consistent with the partial date. A completely missing onset date will be imputed as the 
day of treatment. Partial stop dates will be assumed to be the latest possible day 
consistent with the partial date. AE duration will be calculated as (Stop Date – Start 
Date) + 1. 
8.5.3.2 Vital Signs 
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Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean, standard deviation, minimum, median, and maximum 
values by time point and treatment arm, for the Safety population. Baseline is defined 
as the last measurement prior to the first treatment administration. These summaries 
will be performed according to Phase. 
8.5.4 DISPOSITION 
Disposition will be summarized by treatment arm for the ITT population and will include 
the number and percentage randomized, the number and percentage who received each 
dose and the number who completed the trial.  The number and percentage of subjects 
who discontinued will be summarized overall and by reason.  The number in each analysis 
population will also be presented. These summaries will be performed according to Phase.  
8.5.5 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
8.5.5.1 Demographics 
Demographic data will be summarized with descriptive statistics: mean standard 
deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables, by treatment arm, for the ITT and PP populations. 
These summaries will be performed according to Phase. 
8.5.5.2 Prior Medications 
Prior medications are those that were used before the start of the trial (prior to Day 0). 
Partial stop dates of prior medications will be assumed to be the latest possible date 
consistent with the partial date; start dates will not be imputed. Data for all prior 
medications will be summarized with percentages by treatment arm, for the ITT and PP 
populations. These summaries will be performed according to Phase. 
8.5.6 INTERIM ANALYSES  
For safety issues or evidence of poor efficacy, the DSMB could recommend stopping 
enrollment at any time; no formal interim analysis will be performed for this purpose. The 
two-sided type I error of 0.05 will not be adjusted for possible early stopping due to 
futility. 
8.5.7 MULTIPLICITY 
Not applicable; there is one hypothesis that will be tested. 
8.5.8 MISSING VALUES 
Missing data will not be imputed. 
For the ITT analyses of efficacy in the Phase 3 segment, subjects with missing or 
unevaluable data regarding case definition will be considered cases (failures). 
8.5.9 EXPLORATORY ANALYSES  
  8.5.9.1 Immunogenicity 
Phase 2 segment 
Post-baseline increases from baseline in cellular response magnitudes will be 
compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
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Valid samples for statistical analysis purposes will be those collected within the days of 
the specified visit according to the Schedule of Events. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
Phase 3 Segment 
Post-baseline antibody titers from ELISA will be compared between treatment groups 
using ratios of geometric mean titers and associated 95% t-distribution based CIs. 
Post-baseline increases from baseline in cellular response magnitudes will be 
compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
The summaries listed above will be stratified according to disease status of the 
subjects. 
Valid samples for statistical analysis purposes will be those collected within the days of 
the specified visit according to the Schedule of Events. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
8.5.9.2 Concomitant Medications 
Concomitant medications are those used during the course of the trial (on or after Day 
0). Partial stop dates of concomitant medications will be assumed to be the latest 
possible date consistent with the partial date; start dates will not be imputed. Data for 
all concomitant medications will be summarized with percentages by treatment arm, for 
the ITT and PP populations. These summaries will be performed according to Phase. 
8.6 
SAMPLE SIZE/POWER 
Phase 3 segment: The trial is case-driven. A total of 160 observed cases will be required 
to provide 90% power to declare the vaccine efficacious (>30%), utilizing the methodology 
described in Section 8.5.1 and assuming a true efficacy of 60%.  A sample size of 6178 
subjects will be required to achieve this number of cases assuming an underlying attack 
rate of 3.7%.   
8.7 
RANDOMIZATION AND BLINDING  
Phase 2 Segment 
Subjects will be randomized (3 INO-4800 1.0 mg, one injection: 3 INO-4800 2.0 mg, two 
injections:1 Placebo, one injection: 1 Placebo, two injections). 
The study is blinded. It is double-blinded within dose group.  Randomization and blinding 
will avoid bias in the assignment of subjects to treatment, increase the likelihood that 
known and unknown subject attributes (e.g., demographics and other baseline 
characteristics) are evenly balanced between treatment groups, and enable valid 
statistical comparisons between treatment groups. 
Phase 3 Segment 
Subjects will be randomized (1 INO-4800:1 Placebo). 
The study is double-blinded. Randomization and blinding will avoid bias in the assignment 
of subjects to treatment, increase the likelihood that known and unknown subject attributes 
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(e.g., demographics and other baseline characteristics) are evenly balanced between 
treatment groups, and enable valid statistical comparisons between treatment groups. 
9.0 
ETHICS 
9.1 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical trial is 
performed in accordance with the protocol, the principles of the Declaration of Helsinki, 
Good Clinical Practice (GCP) and applicable regulatory requirements. 
9.2 
INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD (REB)/ETHICS 
COMMITTEE (EC) 
The Investigator will commence the clinical trial after full approval of the protocol and 
adjunctive materials (e.g., ICF, advertising) has been obtained from the applicable 
IRB/REB/EC and a copy of IRB/REB/EC approval documentation has been received by 
the Sponsor. 
Investigator responsibilities relevant to the IRB/REB/EC include the following: 
• Submit continuing review reports to the IRB/REB/EC as required, and request re-
review and approval of the clinical trial at least once a year during the conduct of 
the clinical trial 
• Notify the Sponsor immediately of any suspected unexpected adverse drug or 
device events/effects 
• Notify the IRB/REB/EC immediately if the Sponsor notifies the Investigator about 
any reportable safety events 
• Obtain approval from the IRB/REB/EC for protocol amendments and for revisions 
to the consent form or subject recruitment advertisements, as required 
• Submit reports on, and reviews of, the clinical trial and its progress to the 
IRB/REB/EC at intervals stipulated in their guidelines and in accordance with 
pertinent regulations and guidelines 
• Maintain a file of clinical trial-related information (refer to clinical trial files) that 
includes all correspondence with the IRB/REB/EC 
• Notify the IRB/REB/EC when the clinical trial is completed (i.e., after the last clinical 
trial visit of the final clinical trial subject) 
• After clinical trial completion (within three [3] months is recommended), provide the 
IRB/REB/EC with a final report on the clinical trial 
Institutional Biosafety Committee (IBC) 
The Investigator will undertake the trial after full approval of the protocol and adjunctive 
materials (e.g., pharmacy manual) has been obtained from the applicable IBC and a copy 
of this approval has been received by the Sponsor. 
Investigator responsibilities relevant to the IBC include the following: 
• 
Notify the Sponsor, IBC and NIH OSP within 30 days of any: 
o Substantial problems or violation of the NIH Guidelines 
o Significant research related accidents or illnesses 
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• 
Notify the IBC to any changes to the research (dosage, procedure, etc.) or facility 
(new space, remodeling, etc.).   
9.3 
PROTECTION OF HUMAN SUBJECTS 
9.3.1 COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent must be obtained from each subject prior to the subject’s 
enrollment in the clinical trial. The process for obtaining informed consent must be 
documented in the subject’s medical record (also refer to Section 6.2). 
9.3.2 COMPLIANCE WITH INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD 
(REB)/ETHICS COMMITTEE (EC) REQUIREMENTS 
This clinical trial is to be conducted in accordance with applicable IRB/REB/EC 
regulations. The Investigator must obtain approval from a properly constituted 
IRB/REB/EC prior to initiating the clinical trial and obtain re-approval or review at least 
annually. The Sponsor is to be notified immediately if the responsible IRB/REB/EC has 
been disqualified or if proceedings leading to disqualification have begun. Copies of all 
IRB/REB/EC correspondence with the Investigator should be provided to the Sponsor. 
9.3.3 COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.3.4 COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS (21CFR 
PART 11) 
When applicable, this clinical trial is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.3.5 COMPLIANCE WITH PROTOCOL 
Subjects are not required to follow special instructions specific to the IP used in this clinical 
trial. Subjects will be provided with Investigator emergency contact information and 
advised to report all AEs. While every effort should be made to avoid protocol deviations, 
should an important deviation be discovered, the Sponsor must be informed immediately. 
Any protocol deviation impacting subject safety must be reported to the Medical Monitor 
immediately. 
9.3.6 CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from, or changes to, the protocol 
without Sponsor approval and prior review and documented approval/favorable opinion of 
the protocol amendment from the IRB/REB/EC, except where necessary to eliminate 
immediate hazards to clinical trial subjects, or when the changes involve only logistical or 
administrative aspects of the clinical trial (e.g., change in monitors, change of telephone 
numbers).  
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10.0 DATA COLLECTION, MONITORING AND REPORTING 
10.1 CONFIDENTIALITY AND PRIVACY 
A report of the results of this clinical trial may be published or sent to the appropriate 
regulatory authorities in any country in which the clinical trial products are legally marketed 
or may ultimately be marketed, but the subject’s name/identity will not be disclosed in 
these documents. The clinical trial Sponsor, its agents, the IRB/REB/EC and regulatory 
authorities will have direct access to the subjects’ medical records for the purposes of trial-
related monitoring, auditing and inspection. Appropriate precautions will be taken to 
maintain confidentiality of medical records and personal information. 
Written Authorization and other documentation are to be obtained from each subject, 
and/or from the subject’s legally authorized representative, prior to enrollment in the 
clinical trial, in accordance with all applicable laws, regulations and/or directives relating 
to privacy and data protection. 
11.0 SOURCE DOCUMENTS 
Source data is all information, electronic or hardcopy original records or clinical findings, 
laboratory results, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the clinical trial. 
Examples of original source data records may include:  
• Hospital records 
• Clinical and office charts 
• Laboratory notes 
• Memoranda 
• Pharmacy dispensing records 
• Recorded data from automated instruments 
• Copies of electronic medical records (EMR) certified after verification as being 
accurate and complete 
• X-rays 
• Subject files and records kept at the pharmacy, at the laboratories, at the medical 
records facility and within information technology (IT) systems that are involved in 
the clinical trial  
The Investigator/institution will permit clinical trial-related monitoring, audits, IRB/REB/EC 
review and regulatory inspections by providing direct access to source data/documents 
related to this clinical trial. 
11.1 RECORDS RETENTION 
Upon request of the Clinical Monitor, Sponsor or its agent(s), auditor, IRB/REB/EC or 
regulatory authority, the Investigator/institution should make available for direct access all 
requested clinical trial-related records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
It is the Investigator’s responsibility to retain clinical trial essential documents for at least 
two (2) years after the last approval of a marketing application in their country and until 
there are no pending or contemplated marketing applications in their country or at least 
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two (2) years have elapsed since the formal discontinuation of clinical development of 
INO-4800. This retention period may be superseded by local requirements. The Sponsor 
will inform the Investigator/institution when these documents are no longer needed to be 
retained. 
If the Records Retention requirements are addressed in a governing clinical trial 
agreement, it is the Investigator’s responsibility to retain clinical trial essential documents 
in accordance with the governing clinical trial agreement and applicable local 
requirements. 
12.0 SAFETY AND QUALITY MONITORING 
12.1 SAFETY REVIEW 
The Sponsor’s Safety Review Committee (SRC), composed of the Sponsor’s Medical 
Monitor, the ICON Medical Monitor and 1 additional physician, will review blinded safety 
and tolerability data on a regular basis throughout the trial. The SRC will meet 
approximately once per month, at a minimum. The SRC will refer any of the events listed 
in Section 7.8.4 or any other safety concerns to the DSMB Chair. 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will 
convene regularly to review all available unblinded safety data, and additionally upon 
completion of the Week 8 phone call visit for all subjects enrolled during the Phase 2 
segment. The DSMB will review unblinded safety and tolerability data, including AEs of 
clinical significance, AESIs and SAEs, as well as safety laboratory data for all enrolled 
subjects. The DSMB will also evaluate the data for signals of vaccine-enhanced disease 
and in the event of a signal, advise whether to halt the trial. The DSMB will advise 
regarding any safety concerns and will make recommendations regarding continued 
enrollment, safety pause and trial suspension. If the safety data is considered unfavorable 
during any safety review, the DSMB may recommend a trial pause or trial termination at 
which time further enrollment and administration of IP to subjects will be paused. The 
Sponsor will perform an investigation and consult with the DSMB and other experts, if 
needed, to determine whether to resume dosing of the remainder of the subjects. For 
further details, see the DSMB Charter.  
12.2 CLINICAL MONITORING 
Clinical Monitoring will be performed by qualified Clinical Monitors who will report to the 
Sponsor or the Sponsor’s designee. The following clinical trial site monitoring tasks will be 
performed at all clinical trial sites: 
• 
Prior to subject screening at the site, a Site Initiation Visit will be conducted to 
review all relevant forms and documentation, and ensure that the clinical trial site 
staff are qualified and compliant with all applicable requirements 
• 
All clinical trial site monitoring visits will be documented 
• 
Periodic clinical trial site visits will be performed throughout the clinical trial 
• 
The Clinical Monitor will address and document the following trial conduct activities 
and obligations: 
o Assure that the trial is being conducted in accordance with the protocol, 
applicable regulatory agency regulations, and IRB/REB/EC policies. 
o Discuss trial conduct issues and incidents of noncompliance with the 
Investigator and/or trial personnel and document them on the resolution trip 
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report. Report any significant unresolved problems immediately to the 
Sponsor. 
o Remind the Investigator as necessary of the obligation to immediately report 
all SAEs and provide subsequent follow-up report of the final outcome to the 
IRB. 
o Throughout the trial, inspect source documents to ensure they are complete, 
logical, consistent, attributable, legible, contemporaneous, original, accurate 
and complete (ALCOA-C). 
o Assure that the trial facilities, including the pharmacy, continue to be 
acceptable. 
o Compare the trial CRFs with source documents to assure that the data are 
accurate and complete and that the protocol is being followed. 
o Assure that investigational drug and device accountability and reconciliation of 
records are complete and accurate. 
o Assure that all subject specimens are being stored and forwarded properly for 
testing in accordance with laboratory manual requirements. 
13.0 FINANCING AND INSURANCE 
Inovio Pharmaceuticals is the Sponsor and Department of Defense, Joint Program 
Executive Office is providing funding for the study. Clinical trial insurance has been taken 
out according to the laws of the countries where the study will be conducted. The 
investigative site is being compensated for the conduct of this study and will follow the 
terms described in the clinical trial agreement. This agreement was executed separately 
from this clinical trial protocol. The Investigators will be required to provide full financial 
disclosure information per 21 CFR Part 54. 
14.0 PUBLICATION POLICY 
Publication of the results of this clinical trial in its entirety will be allowed. The proposed 
presentation, abstract and/or manuscript must be made available to the Sponsor for 
review and approval in accordance with the governing clinical trial agreement. 
 
 
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15.0 LIST OF ABBREVIATIONS 
ADE 
Adverse Device Effect 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALCOA-C 
Attributable, Legible, Contemporaneous, Original, Accurate and Complete 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CBC 
Complete Blood Count 
Cl 
Chloride 
COVID-19 
Coronavirus Disease 2019 
Cr 
Creatinine 
CRF 
Case Report Form 
CS 
Clinically Significant 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
EP 
Electroporation 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCO3 
Biocarbonate 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICD 
Implantable-Cardioverter-defibrillator 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
ID 
Intradermal 
IM 
Intramuscular 
Inovio 
Inovio Pharmaceuticals Inc. 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
K 
Potassium 
MAAE 
Medically Attended Adverse Event 
mITT 
modified Intent to Treat 
MM 
Medical Monitor 
MERS 
Middle East Respiratory Syndrome  
MERS-CoV 
Middle East Respiratory Syndrome Coronavirus 
mRNA 
Messenger RNA 
Na 
Sodium 
NCS 
Not Clinically Significant 
NHP 
Non-human Primates 
NP 
Nucleocapsid Protein 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PII 
Personal Identifying Information 
PO4 
Potassium 
PT 
Preferred Term 
RBC 
Red blood cell 
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REB 
Research Ethics Board 
RR 
Respiratory Rate 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SARS 
Severe Acute Respiratory Syndrome  
SARS-CoV 
Severe Acute Respiratory Syndrome Coronavirus 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus - 2 
SID 
Subject Identification Number 
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
SynCon 
Synthetic consensus 
TBili 
Total Bilirubin 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
 
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2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223):497-506. 
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Spread of SARS-CoV-2 in the Icelandic Population. The New England journal of medicine 
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T Cells in Patients With Coronavirus Disease 2019 (COVID-19). Front Immunol 2020; 11:827. 
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33. Korber B, Fischer WM, Gnanakaran S, Yoon H, Theiler J, Abfalterer W, et al. Tracking 
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Hospitalized Patients with Covid-19 - Preliminary Report. The New England journal of 
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Spectr 2014; 2(6). 
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53. Rosati M, Valentin A, Jalah R, Patel V, von Gegerfelt A, Bergamaschi C, et al. Increased 
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54. Curcio C, Khan AS, Amici A, Spadaro M, Quaglino E, Cavallo F, et al. DNA immunization 
using constant-current electroporation affords long-term protection from autochthonous 
mammary carcinomas in cancer-prone transgenic mice. Cancer Gene Ther 2008; 15(2):108-
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55. Ugen KE, Kutzler MA, Marrero B, Westover J, Coppola D, Weiner DB, et al. Regression of 
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56. Tebas P, Roberts CC, Muthumani K, Reuschel EL, Kudchodkar SB, Zaidi FI, et al. Safety and 
Immunogenicity of an Anti-Zika Virus DNA Vaccine - Preliminary Report. The New England 
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57. Tebas P, Kraynyak KA, Patel A, Maslow JN, Morrow MP, Sylvester AJ, et al. Intradermal 
SynCon(R) Ebola GP DNA Vaccine is Temperature Stable and Safely Demonstrates Cellular 
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cellular responses induced by DNA-only vaccination for HIV. JCI Insight 2020; 5(13). 
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infection protects against rechallenge in rhesus macaques. Science 2020. 
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61. European Commission. Directorate-General: A Guideline on Summary of Product 
Characteristics (SmPC). In: EMA; 2009. 
 
 
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17.0 APPENDICES 
17.1 APPENDIX A: ADVERSE EVENTS OF SPECIAL INTEREST  
For the purpose of standardization across multiple vaccine platforms, including those substantially 
different from Inovio’s platform, the below table lists AEs of special interest (AESIs) relevant to 
COVID-19 vaccine development.  
Body System 
AESI 
Respiratory 
Acute respiratory distress syndrome (ARDS) 
Pneumonitis/Pneumonia 
Neurologic 
Generalized convulsion 
Aseptic meningitis 
Guillain-Barré Syndrome (GBS) 
Encephalitis/Myelitis 
Acute disseminated encephalomyelitis (ADEM) 
CNS vasculopathy (stroke) 
Hematologic 
Thrombocytopenia 
Disseminated intravascular coagulation (DIC) 
Immunologic 
Anaphylaxis 
Vasculitides 
Other 
Acute cardiac failure 
Acute kidney failure 
Septic shock-like syndrome 
 
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Signature Page for VV-TMF-00448 v3.0
Signature Page for VV-TMF-00448 v3.0
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 19-Aug-2020 03:39:54 GMT+0000
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CONFIDENTIAL 
Page 1 of 81 
COVID19-311 
Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the Safety, 
Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-
19 Disease, Administered Intradermally Followed by Electroporation in Healthy 
Seronegative Adults at High Risk of SARS-CoV-2 Exposure   
INNOVATE 
(Inovio INO-4800 Vaccine Trial for Efficacy) 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
IND #: 19690 
Protocol Version: 4.0 
Protocol Version Date: 13-Nov-2020 
10 
POWERING DNA MEDICINES™ 
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Page 2 of 81 
 
 
Medical Monitor Approval Page 
 
Drug:  
INO-4800 
 
Sponsor: 
Inovio Pharmaceuticals, Inc. 
 
660 W. Germantown Pike, Suite 110 
 
Plymouth Meeting, PA 19462 
 
Medical Monitor: 
 
Jr., M.D., FACP, FIDSA 
Inovio Pharmaceuticals, Inc. 
 
 
Approval Signature: 
 
 
[Electronically signed] 
  
Jr., M.D., FACP, FIDSA 
Inovio Pharmaceuticals, Inc. 
 
 Date (ddMmmyyyy) 
 
 
CONFIDENTIAL 
The information in this document is considered privileged and confidential by Inovio 
Pharmaceuticals Inc. (INOVIO) and may not be disclosed to others except to the extent 
necessary to obtain Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics 
Committee (EC) approval and informed consent, or as required by local regulatory 
authorities. Persons to whom this information is disclosed must be informed that this 
information is privileged and confidential and that it should not be further disclosed 
without the written permission of INOVIO. Any supplemental information added to this 
document is also confidential and proprietary information of INOVIO and must be kept in 
confidence in the same manner as the contents of this document. 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 3 of 81 
 
 
Principal Investigator Acknowledgement 
 
I have read and understood this Protocol and agree that it contains all details necessary to 
conduct the clinical trial. I understand that it must be reviewed by the Institutional Review Board 
(IRB)/Research Ethics Board (REB)/Ethics Committee (EC) overseeing the conduct of the clinical 
trial and approved or given favorable opinion before implementation. 
 
The Principal Investigator’s (PI’s) signature constitutes the PI’s approval of this Protocol and 
provides the necessary assurances that this clinical trial will be conducted in accordance with 
International Council for Harmonization (ICH)/Good Clinical Practice (GCP), local legal and 
regulatory requirements, and all stipulations of the Protocol. 
 
 
Principal Investigator Signature: 
 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
Principal Investigator Signature 
 
Date (ddMmmyyyy) 
 
 
 
Clinical Trial Site Number: 
 
Clinical Trial Site Name: 
 
 
 
 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 4 of 81 
 
SUMMARY OF CHANGES 
 
The following is a list of significant changes from Version 3.0, dated 18Aug2020, to Version 4.0, 
dated 13-Nov-2020. All other changes are administrative and do not significantly affect the safety 
of subjects, trial scope, or scientific integrity of the protocol. 
 
1. The following device information has been clarified in the protocol, upon request from the 
United States Food and Drug Administration (U.S. FDA): 
a. Risks of INO-4800 Delivered ID followed by EP using the CELLECTRA® 2000 device 
have been expanded to include theoretical risks, especially as related to the device. 
b. Discussions regarding the needle depth and total maximum energy delivered during 
electroporation have been added. 
c. The description of the administration procedure has been updated to clarify that 
reinjection of the IP or delivery of a second EP in tissue is not permitted. 
2. The restrictions have been updated to limit subjects from participating in any other 
interventional trials while they are enrolled in this trial. 
 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 5 of 81 
 
TABLE OF CONTENTS 
Summary of Changes ................................................................................................................ 4 
Table of Contents ....................................................................................................................... 5 
Clinical Protocol Synopsis .........................................................................................................10 
Table 3 – Phase 2 Segment Schedule of Events ......................................................................18 
Table 4 – Phase 3 Segment Schedule of Events ......................................................................20 
 
Introduction .................................................................................................................22 
 
Background and Scientific Rationale ........................................................................... 22 
 
Background Information .............................................................................................. 22 
 
Clinical Presentation, Transmission and Immune Response .................................23 
 
Current Treatment and Unmet Need .....................................................................25 
 
Rationale for prophylactic vaccine development ......................................................... 25 
 
DNA Vaccines.......................................................................................................25 
 
Use of Electroporation with DNA Vaccines ...........................................................26 
 
Inovio’s Proprietary Technology Against COVID-19 Disease ................................26 
 
Nonhuman Primate (NHP) Challenge Studies with INO-4800 ...............................27 
 
First-In-Human Phase 1 Trial of INO-4800 ............................................................28 
 
Proposed Phase 2/3 Trial of INO-4800 .................................................................28 
 
Dose and Regimen Rationale ...............................................................................28 
 
Risks and Potential Benefits  ...................................................................................... 29 
 
Potential Benefits ..................................................................................................29 
 
Product Risks........................................................................................................29 
 
Overall Benefit/Risk Conclusion ............................................................................31 
 
Objectives and Purpose ..............................................................................................31 
 
Hypothesis .................................................................................................................. 31 
 
Clinical Trial Design and Endpoints ............................................................................31 
 
Primary Objectives ...................................................................................................... 32 
 
Primary Endpoints....................................................................................................... 33 
 
Secondary Objectives ................................................................................................. 33 
 
Secondary Endpoints .................................................................................................. 33 
 
Exploratory Objective .................................................................................................. 34 
 
Exploratory Endpoint ................................................................................................... 34 
 
Efficacy Assessment (Phase 3 Segment Only) ........................................................... 34 
 
Case Definition for Virologically-confirmed COVID-19 Disease: ............................34 
 
Case Definition for Virologically-confirmed SARS-CoV-2 Infection ........................35 
 
Safety Assessment ..................................................................................................... 35 
 
Immunogenicity Assessment ...................................................................................... 36 
1.0 
1.1 
1.2 
1.2.1 
1.2.2 
1.3 
1.3.1 
1.3.2 
1.3.3 
1.3.4 
1.3.5 
1.3.6 
1.3.7 
1.4 
1.4.1 
1.4.2 
1.4.3 
2.0 
2.1 
3.0 
3.1 
3.2 
3.3 
3.4 
3.5 
3.6 
3.7 
3.7.1 
3.7.2 
3.8 
3.9 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 6 of 81 
 
 
Clinical Trial Population ..............................................................................................36 
 
Inclusion Criteria ......................................................................................................... 36 
 
Exclusion Criteria ........................................................................................................ 37 
 
Discontinuation/Withdrawal of Clinical Trial Subjects .................................................. 38 
 
Clinical Trial Investigational Product Information .........................................................39 
 
Investigational Product (IP) and Study Device ............................................................ 39 
 
INO-4800 and Placebo .........................................................................................39 
 
CELLECTRA® 2000 ..............................................................................................40 
 
Dosing Regimens ....................................................................................................... 41 
 
Blinding .................................................................................................................41 
 
Packaging and Labeling .............................................................................................. 41 
 
INO-4800 or Placebo ............................................................................................41 
 
CELLECTRA® 2000 ..............................................................................................42 
 
Handling and Storage ................................................................................................. 42 
 
INO-4800 and Placebo .........................................................................................42 
 
CELLECTRA® 2000 ..............................................................................................42 
 
Preparation and Dispensing ........................................................................................ 42 
 
Use of Study Device ................................................................................................... 42 
 
Investigational Drug and Study Device Accountability ................................................. 43 
 
Investigational Product (IP) Accountability ............................................................43 
 
CELLECTRA® 2000 Accountability .......................................................................43 
 
Return and Destruction of Investigational Drug and Study Device .............................. 43 
 
INO-4800 and Placebo .........................................................................................43 
 
Return of CELLECTRA® 2000...............................................................................43 
 
Clinical Trial Procedures and Schedule ......................................................................44 
 
Procedure by Visit ....................................................................................................... 44 
 
Clinical Trial Screening Evaluations ......................................................................44 
6.1.1.1 Medical History .....................................................................................................45 
 
Clinical Trial Evaluations and Procedures .............................................................45 
6.1.2.1 Day 0 and Day 28 (Dosing Visits) .........................................................................45 
6.1.2.2 Post-dose phone calls ...........................................................................................46 
6.1.2.3 Day 42 Visit ..........................................................................................................46 
6.1.2.4 Phone calls ...........................................................................................................47 
6.1.2.5 Follow up clinic visits.............................................................................................47 
6.1.2.6 Day 393 Visit or EOS ............................................................................................47 
6.1.2.7 COVID-19 Assessment Visit .................................................................................48 
6.1.2.8 COVID-19 Convalescent Visit ...............................................................................48 
4.0 
4.1 
4.2 
4.3 
5.0 
5.1 
5.1.1 
5.1.2 
5.2 
5.2.1 
5.3 
5.3.1 
5.3.2 
5.4 
5.4.1 
5.4.2 
5.5 
5.6 
5.7 
5.7.1 
5.7.2 
5.8 
5.8.1 
5.8.2 
6.0 
6.1 
6.1.1 
6.1.2 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 7 of 81 
 
 
Informed Consent ....................................................................................................... 49 
 
Assignment of Subject Identification Numbers ............................................................ 49 
 
Safety Evaluations ...................................................................................................... 49 
 
Intradermal Injection and EP .................................................................................51 
 
Management of Pain Due to Electroporation (EP) Procedures ..............................52 
 
Assessment of Laboratory Abnormalities ..............................................................52 
 
Assessment of Clinical Trial Adverse Events (AEs) ..............................................53 
 
Assessment of Injection Site Reactions ................................................................53 
 
Immunogenicity Assessments ...............................................................................54 
 
Concomitant Medications/Treatments ...................................................................54 
 
Restrictions ...........................................................................................................54 
 
SARS-CoV-2 Testing ............................................................................................55 
 COVID-19 Disease Monitoring ..............................................................................55 
 
Evaluation of Safety and Management of Toxicity ......................................................56 
 
Safety Parameters ...................................................................................................... 56 
 
Adverse Events (AEs) ................................................................................................. 56 
 
Adverse Drug Reaction (ADR) .................................................................................... 57 
 
Serious Adverse Events (SAEs) .................................................................................. 57 
 
Unexpected Adverse Drug Reaction ........................................................................... 58 
 
Unanticipated (Serious) Adverse Device Effect (UADE) .............................................. 58 
 
Device Deficiency ....................................................................................................... 58 
 
Safety and Toxicity Management ................................................................................ 58 
 
Adverse Event of Special Interest (AESI) ..............................................................59 
 
Medically Attended Adverse Event (MAAE) ..........................................................59 
 
Abnormal Laboratory Value ..................................................................................59 
 
Clinical Trial Stopping Rules .................................................................................59 
 
Safety Data Reporting Period, Method of Collection and Submission ......................... 60 
 
Adverse Event Reporting ............................................................................................ 61 
 Submitting the Initial Serious Adverse Event (SAE) Report Form..........................61 
 Recording the Event .............................................................................................61 
 Assessing Severity (Intensity) ...............................................................................61 
 Causal Relationship of Clinical Material to Adverse Events (AEs) .........................61 
 
Reporting Suspected COVID-19 Disease Cases During the Trial ............................... 62 
 
Reporting Pregnancy During the Clinical Trial ............................................................. 63 
 
Reporting Device-Related Complaints or Deficiencies ................................................ 63 
 
Notifying Regulatory Authorities and Institutional Review Boards (IRBs)/Research 
Ethics Boards (REBs)/Ethics Committees (ECs) of Safety Information ....................... 64 
 Sponsor Responsibilities .......................................................................................64 
6.2 
6.3 
6.4 
6.4.1 
6.4.2 
6.4.3 
6.4.4 
6.4.5 
6.4.6 
6.4.7 
6.4.8 
6.4.9 
6.4.10 
7.0 
7.1 
7.2 
7.3 
7.4 
7.5 
7.6 
7.7 
7.8 
7.8.1 
7.8.2 
7.8.3 
7.8.4 
7.9 
7.10 
7.10.1 
7.10.2 
7.10.3 
7.10.4 
7.11 
7.12 
7.13 
7.14 
7.14.1 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 8 of 81 
 
 Principal Investigator (PI) Responsibilities ............................................................64 
 
Post-Trial Reporting Requirements ............................................................................. 64 
 
Clinical Trial Discontinuation ....................................................................................... 64 
 
Statistical Considerations ...........................................................................................64 
 
Statistical and Analytical Plan ..................................................................................... 64 
 
General Considerations .............................................................................................. 65 
 
Statistical Hypotheses ................................................................................................. 65 
 
Analytical Populations ................................................................................................. 65 
 
Description of Statistical Methods ............................................................................... 66 
 
Primary Analysis ...................................................................................................66 
 
Secondary Analyses .............................................................................................67 
 
Safety Analyses ....................................................................................................67 
 
Disposition ............................................................................................................68 
 
Demographic and Other Baseline Characteristics .................................................68 
 
Interim Analyses ...................................................................................................68 
 
Multiplicity .............................................................................................................68 
 
Missing Values......................................................................................................68 
 
Exploratory Analyses ............................................................................................69 
 
Sample Size/Power ..................................................................................................... 69 
 
Randomization and Blinding ....................................................................................... 69 
 
Ethics .........................................................................................................................70 
 
Investigator and Sponsor Responsibilities ................................................................... 70 
 
Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics Committee 
(EC) ............................................................................................................................ 70 
 
Protection of Human Subjects ..................................................................................... 71 
 
Compliance with Informed Consent Regulations ...................................................71 
 
Compliance with Institutional Review Board (IRB)/Research Ethics Board 
(REB)/Ethics Committee (EC) Requirements ........................................................71 
 
Compliance with Good Clinical Practice ................................................................71 
 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11) .....71 
 
Compliance with Protocol .....................................................................................71 
 
Changes to the Protocol .......................................................................................71 
 
Data Collection, Monitoring and Reporting ..................................................................72 
 
Confidentiality and Privacy .......................................................................................... 72 
 
Source Documents .....................................................................................................72 
 
Records Retention ...................................................................................................... 72 
 
Safety and Quality Monitoring .....................................................................................73 
 
Safety Review ............................................................................................................. 73 
7.14.2 
7.15 
7.16 
8.0 
8.1 
8.2 
8.3 
8.4 
8.5 
8.5.1 
8.5.2 
8.5.3 
8.5.4 
8.5.5 
8.5.6 
8.5.7 
8.5.8 
8.5.9 
8.6 
8.7 
9.0 
9.1 
9.2 
9.3 
9.3.1 
9.3.2 
9.3.3 
9.3.4 
9.3.5 
9.3.6 
10.0 
10.1 
11.0 
11.1 
12.0 
12.1 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 9 of 81 
 
 
Clinical Monitoring....................................................................................................... 73 
 
Financing and Insurance ............................................................................................74 
 
Publication Policy .......................................................................................................74 
 
List of Abbreviations ...................................................................................................75 
 
References .................................................................................................................77 
 
Appendices .................................................................................................................81 
 
APPENDIX A: Adverse Events of Special Interest ...................................................... 81 
 
 
 
 
12.2 
13.0 
14.0 
15.0 
16.0 
17.0 
17.1 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 10 of 81 
 
CLINICAL PROTOCOL SYNOPSIS 
Protocol Title: Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the 
Safety, Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-19 
Disease, Administered Intradermally Followed by Electroporation in Healthy Seronegative 
Adults at High Risk of SARS-CoV-2 Exposure 
Protocol Number: COVID19-311 
Clinical Trial Phase: 2/3 
Estimated Number of Clinical Trial Centers and Countries/Regions: Approximately 40 
centers in the US 
Background:   
INO-4800 is a prophylactic vaccine under development against SARS-CoV-2, the causative 
agent of COVID-19. INO-4800 contains the plasmid pGX9501, which encodes for the full 
length of the Spike glycoprotein of SARS-CoV-2. The goal of this trial is to assess the safety, 
immunogenicity and efficacy of INO-4800 to prevent COVID-19 disease in subjects at high risk 
of exposure to SARS-CoV-2.  
 
Clinical Trial Design:  
This is an operationally seamless Phase 2/3, randomized, placebo-controlled, multi-center trial 
to evaluate the safety, immunogenicity, and efficacy of INO-4800, administered by intradermal 
(ID) injection followed immediately by electroporation (EP) using the CELLECTRA® 2000 
device, in a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-2 
exposure. The primary objectives of this trial are to identify in seronegative subjects an optimal 
age-related dose of INO-4800 in the Phase 2 segment for a subsequent efficacy evaluation in 
the Phase 3 segment.  
 
Approximately 6578 seronegative subjects 18 years of age and older are expected to be 
enrolled across two (2) segments of this study. The subjects and data from Phase 2 are 
independent from that of Phase 3. 
 
Phase 2 Segment – Dose Selection 
In the Phase 2 segment, approximately 400 subjects 18 years of age and older will be 
evaluated across four (4) dose groups (Table 1, Figure 1). Subjects will be randomized at a 
3:3:1:1 ratio to receive either active investigational product (INO-4800) or placebo (SSC-0001) 
according to Table 1 below. Dose groups receiving INO-4800 will enroll approximately 150 
subjects per group. Dose groups receiving placebo will enroll approximately 50 subjects per 
group. Randomization will be such that approximately 240 subjects aged 18-50 years, 120 
subjects aged 51-64 years and 40 subjects aged ≥ 65 years will be enrolled. Initial enrollment 
will include subjects aged 18-50 years. Initiation of enrollment of older subjects 51-64 years of 
age and elderly subjects 65 years and older will depend on review of safety and 
immunogenicity data from those age groups generated in the Phase 1 study (COVID19-001).   
 
Table 1: Phase 2 Segment Dose Groups 
Study  
Group 
Expected 
Number of 
Subjects 
Dosing 
Days 
Number of 
Injections + EP 
per Dosing Visit 
INO-4800 
(mg) per 
injection 
INO-4800 
(mg) per 
Dosing Visit 
Total Dose 
(mg) 
INO-4800 
150 
0, 28 
1 
1.0 
1.0 
2.0 
INO-4800 
150 
0, 28 
2a 
1.0 
2.0 
4.0 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 11 of 81 
 
Placebo 
50 
0, 28 
1 
0 
0 
0 
Placebo 
50 
0, 28 
2a 
0 
0 
0 
Total 
400 
 
 
 
 
 
aINO-4800 or placebo will be injected ID followed immediately by EP in an acceptable location on two different limbs at each 
dosing visit. 
 
Dose selection for evaluation of efficacy in the Phase 3 segment will be based on Week 6 
immunogenicity data and Week 8 safety data from the Phase 2 segment. Group-level unblinded 
summaries and analyses of safety will be produced once the Week 8 phone call visit data are 
completed for all subjects in the Phase 2 segment. Group-level unblinded summaries and 
analyses of immunogenicity will be produced once the Week 6 visit data are completed for all 
subjects in the Phase 2 segment.  
 
Phase 3 Segment – Efficacy 
In the Phase 3 segment, approximately 6178 subjects 18 years of age and older will be 
randomized at a 1:1 ratio to receive either active investigational product (INO-4800, dose 
selected from the Phase 2 segment) or placebo (SSC-0001). See Table 2 and Figure 1.  A 
minimum of 15% of the total sample size of subjects will be 51-64 years of age, and a minimum 
of 5% of the total sample size of subjects will be ≥ 65 years of age. 
 
Table 2: Phase 3 Segment Dose Groups 
Study 
Group 
Expected 
Number of 
Subjects 
Dosing 
Days 
Number of 
Injections + 
EP per 
Dosing Visit 
INO-4800 
(mg) per 
injection 
Total 
Dose 
(mg)  
INO-4800 
3089 
0, 28 
TBD 
TBD 
TBD 
Placebo 
3089 
0, 28 
TBD 
0 
0 
Total 
6178 
 
 
 
 
TBD, to be determined based on the Phase 2 segment optimal dose selection 
 
This segment of the trial is case-driven. Among seronegative subjects, a total of 160 observed 
cases will be required for 90% power to declare the vaccine efficacious (>30%), assuming a 
true efficacy of 60%. A sample size of 6178 seronegative subjects is expected to be required 
to achieve the 160 cases assuming an underlying attack rate of 3.7%. The actual sample size 
may differ if the observed attack rate is different than projected.   
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12-months 
post-dose 2. All Phase 3 segment subjects will be followed for 56 weeks from the Day 0 dosing 
[i.e., Week 56 will be the planned End of Study (EOS) visit for this segment of the trial]. 
 
Figure 1: Enrollment and Dose Group Design 
 
Phase 2 Segment: Dose Selection 
Active (INO-4800) 
1.0 mg, 1 injection + EP 
N = 150 
Placebo (SSC-0001) 
1 injection + EP 
N = 50 
Active (INO-4800) 
2.0 mg, 2 injections + EP 
N = 150 
Placebo (SSC-0001) 
2 injections + EP 
N= 50 
Phase 3 Segment: Efficacy 
Active (INO-4800) 
Selected Dose 
N = 3089 
Placebo (SSC-0001) 
Matched lnjection(s) 
N = 3089 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 12 of 81 
 
 
External Committee Reviews 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will convene 
regularly to review all available unblinded safety data. For the Phase 3 segment, an 
independent, blinded Endpoint Adjudication Committee (EAC) will review and confirm COVID-
19 cases.  
 
Details of each committee’s scope will be provided in the respective charters. 
  
Criteria for Evaluation:  
 
Research Hypothesis:  
INO-4800 delivered ID followed immediately by EP will be well-tolerated, exhibit an acceptable 
safety profile, result in generation of cellular and humoral immune responses to SARS-CoV-2 
Spike glycoprotein and provide protection against virologically-confirmed COVID-19 disease in 
subjects at high risk of SARS-CoV-2 exposure.  
 
Phase 2 Segment Objectives and Endpoints: 
 
Primary Objective 
Primary Endpoint 
1.  Evaluate the cellular and humoral 
immune response to INO-4800 
administered by ID injection followed 
immediately by EP  
  
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot 
1b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
Secondary Objective 
Secondary Endpoints 
1.  Evaluate the safety and tolerability of 
INO-4800 administered by ID injection 
followed immediately by EP    
  
1a. Incidence of solicited and unsolicited injection site 
reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)   
Exploratory Objective 
Exploratory Endpoint 
1.  Evaluate the expanded immunological 
profile of antibody response and T cell 
immune response 
 
 
1a.  Antigen-specific cellular immune response 
measured by flow cytometry 
1b. Expanded immunological profile which may 
include additional assessments of T and B cell 
numbers and molecular changes by measuring 
immunologic proteins and mRNA levels of genes 
of interest as determined by sample availability 
 
Phase 3 Segment Objectives and Endpoints: 
 
Primary Objective 
Primary Endpoint 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 13 of 81 
 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease  
 
1.   Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 (End 
of Study (EOS))  
Secondary Objectives 
Secondary Endpoints 
1. Evaluate the safety and tolerability of 
INO-4800    
 
1a. Incidence of solicited and unsolicited injection site 
reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality 
 
2.  Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of severity   
2a.  Incidence of non-severe COVID-19 disease 
starting 14 days after completion of the 2-dose 
regimen until EOS  
2b. Incidence of severe COVID-19 disease starting 14 
days after completion of the 2-dose regimen until 
EOS 
2c. Incidence of deaths due to COVID-19 starting 14 
days after completion of the 2-dose regimen until 
EOS 
3.  Evaluate the efficacy of INO-4800 in the 
prevention of SARS-CoV-2 infection  
3.   Incidence of virologically-confirmed SARS-CoV-2 
infections starting 14 days after completion of the 
2-dose regimen until EOS 
4. Evaluate the time to symptom 
resolution in subjects who develop 
COVID-19 disease  
4.   Days to symptom resolution in subjects developing 
COVID-19 disease 
 
5.  Evaluate the cellular and humoral 
immune response to INO-4800 
5a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot 
5b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay 
 
Exploratory Objective 
Exploratory Endpoint 
1.  Evaluate the immunological profile by 
assessing both antibody response and 
T cell immune response 
1a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels  
1b. Antigen-specific cellular immune response 
measured by flow cytometry 
 
 
 
Immunogenicity Assessment:  
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 3 and Table 4).  Assays such as binding enzyme-linked immunosorbent assay (ELISA), 
pseudovirus-based neutralization assay, and enzyme-linked immunosorbent spot (ELISpot) 
will be evaluated at serial timepoints. 
Safety Assessment:  
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 14 of 81 
 
Subjects will be followed for safety during the trial through scheduled clinic visits and phone 
calls. Adverse events (AEs), regardless of relationship to study drug, will be collected from 
the time of consent until 28 days post-dose 2 (i.e., Day 56). SAEs, Medically Attended Adverse 
Events (MAAEs) and AESIs will be collected from time of consent until EOS. SAEs, AESIs 
and treatment-related AEs will be followed to resolution or stabilization. For the Phase 2 
segment, solicited local and systemic AEs will be collected for 7 days following each dose 
using a Participant Diary. 
Subjects will also be monitored for COVID-19 disease.  
Please refer to the Schedule of Events (Table 3 and Table 4) for safety assessments to be 
performed.  
Efficacy Assessment (Phase 3 segment only):  
Subjects will receive either active investigational product (INO-4800) or placebo (SSC-0001) 
in a 2-dose regimen administered on Days 0 and 28 intradermally followed immediately by 
EP. Subjects will be monitored through regularly scheduled clinic visits and phone calls 
throughout the trial. Subjects will be regularly tested for SARS-CoV-2 infection using serologic 
testing and RT-PCR. If COVID-19 disease is suspected based on symptoms or laboratory 
testing, site personnel will arrange for a clinic visit. Subjects with symptom(s) or a positive 
SARS-CoV-2 test result will be reviewed by the EAC. 
Clinical Trial Population: 
Healthy subjects at high risk for SARS-CoV-2 exposure who are 18 years and older. 
Inclusion Criteria: 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, vital signs and 
physical examination performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar 
workers, store cashiers, hairdressers and barbers, veterinary staff, daycare 
workers, Transportation Security Administration screening staff, school 
teachers and college professors teaching in-person classes) 
2. Factory workers (when working in confined settings with large numbers of 
employees) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) 
4. User of public transportation (e.g., bus, train, subway) at least 3 times weekly 
5. Nursing home staff or correctional facility staff  
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
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9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists.) Physicians should not be enrolled unless they 
are assigned to dedicated COVID-19 treatment wards or other settings with 
prolonged exposure 
10. Others, if approved by the medical monitor.   
f. Screening laboratory results within normal limits for testing laboratory or are deemed 
not clinically significant by the Investigator; 
g. Must meet one of the following criteria with respect to reproductive capacity: 
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or 
tubal ligation, absence of ovaries and/or uterus in females). In the case of 
vasectomy, subjects should wait six (6) months post-vasectomy prior to 
enrolling;  
• 
Use of medically effective contraception with a failure rate of < 1% per year 
when used consistently and correctly from screening until 3 months following 
last dose. Acceptable methods include:  
o hormonal contraception including implants, injections or oral; 
o two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
o intrauterine device or intrauterine system; 
o abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Exclusion Criteria: 
a. Acute febrile illness with temperature >100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat); 
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the Screening visit until 3 
months following the last dose; 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or a 
detectable viral load within the past 3 months; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous receipt of an investigational vaccine for prevention or treatment of COVID-19, 
MERS or SARS (documented receipt of placebo in previous trial would be permissible 
for trial eligibility); 
h. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
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Page 16 of 81 
 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg at Screening; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin 
cancers that only required local excision and non-metastatic prostate cancer 
not requiring treatment; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in 
therapy or hospitalization for worsening disease during the 6 weeks prior to 
enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a 
single antiepileptic agent; 
i. 
Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed); 
• 
Current or anticipated use of disease modifying doses of systemic anti-
rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, 
cyclosporine, 
methotrexate) and biologic disease modifying drugs such as TNF-α inhibitors 
(e.g., infliximab, adalimumab or etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the 
subject or require therapy that would interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results. 
j. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation 
site; 
k. Blood donation or transfusion within 1 month prior to Day 0; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the past 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
Clinical Trial Treatment: 
Phase 2 Segment 
Active Investigational Product: One or two 1.0mg ID injection(s) of INO-4800 (~0.1mL dose 
volume) followed immediately by EP administered on Day 0 and Day 28 (±3 days)  
Placebo: One or two ID injection(s) of saline sodium citrate buffer (SSC-0001) (~0.1mL) 
followed immediately by EP administered on Day 0 and Day 28 (±3 days) 
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Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 17 of 81 
 
Phase 3 Segment 
Active Investigational Product: Dose level to be determined, each ID injection(s) of INO-4800 
followed immediately by EP administered at Day 0 and Day 28 (±3 days) 
Placebo: Number of injections to be determined, each ID injection(s) of SSC-0001 followed 
immediately by EP administered at Day 0 and Day 28 (±3 days) 
Formulation: 
INO-4800 is formulated in sodium chloride and sodium citrate buffer, refrigerated. Placebo 
[sterile saline sodium citrate buffer (SSC-0001)], refrigerated. 
 
 
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Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 18 of 81 
 
TABLE 3 – PHASE 2 SEGMENT SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Tel 
#1 
Wk 
4 
Tel 
#2 
Wk
6 
Tel 
#3 
Wk 
30 
Wk 
56 
Illness 
Illness  
Screena 
Day 0 
Phone call - Day 7 (±3d) 
Day 28 
(±3d) 
Phone call - Day 35 (±3d) 
Day 42 (±5d) 
Phone Call - Day 56 (±5d) 
Day 210 (±5d) 
Day 393 (± 5d) 
COVID-19 assessment visitm  
COVID-19 convalescent visitn 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behavioral Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
Vital Signs 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
Xp 
Xp 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differentialc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Chemistryc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
HIV Serology  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis Routined 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Pregnancy Teste 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
INO-4800 or Placebo + EPf 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Download EP Datag 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Adverse Eventsh  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Samplesi 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
Humoral Samplesj 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
SARS-CoV-2 Serologyk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 RT-PCR (Saliva and Swab) 
Xl 
 
 
 
 
 
 
 
 
 
 
Xl 
Xl 
Distribute Diary 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Review/Collect Diaryo 
 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
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Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 19 of 81 
 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0.   
b. 
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits. The targeted physical exam is optional at the COVID-19 
assessment visit if the visit is conducted via telemedicine. 
c. 
Hemoglobin A1c collected at screening only. Chemistry includes Na, K, Cl, HCO3, Ca, PO4, glucose, BUN, Cr, alkaline phosphatase, AST, ALT, LDH, total bilirubin.  
d. 
Dipstick for glucose, protein, and hematuria. Microscopic examination should be performed if dipstick is abnormal.  
e. 
Serum pregnancy test at Screening. Urine pregnancy test at other visits.  
f. 
Intradermal injection(s) in skin preferably over deltiod muscle, or alternately over anterolateral quadriceps muscle, followed by EP at Day 0 and Day 28. 
g. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
h. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
i. 
On Day 0, cellular sampling requires 64 mL of whole blood (8 Cell Preparation Tubes (CPT), each 8 mL of whole blood) prior to 1st dose. At all other time points, collect 32 mL of 
whole blood (4 CPT tubes, each 8 mL of whole blood).   
j. 
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce eight serum aliquots of 1 
mL each). At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce four serum aliquots of 1 mL each.  
k. 
SARS-CoV-2 antibody.   
l. 
Saliva specimen at Screening; Nasal swab and saliva specimens at COVID-19 assessment and convalescent visits.  
m. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The assessment visit may be performed in the clinic, subject’s vehicle, or via 
telemedicine and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test.  
n. 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of 
symptoms, the date of positive SARS-CoV-2 test. If acute symptoms are ongoing, the site should follow up with the subject via phone call or an unscheduled visit after symptom 
resolution or stabilization.   
o. 
Diary should be reviewed at the 7-day post-dose phone call and collected at the next in-office visit. 
p. 
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation. 
 
 
 
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Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 20 of 81 
 
TABLE 4 – PHASE 3 SEGMENT SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Tel 
#1 
Wk 
4 
Wk
6 
Tel 
#2-
6 
Wk 
18 
Tel 
#7-
11 
Wk 
30 
Tel 
#12
-13 
Wk
42 
Tel 
#14
-16 
Wk 
56 
Illness 
Illness  
Screena 
Day 0 
Phone call - Day 14 (±3d) 
Day 28 
(±3d) 
Day 42 (±5d) 
Phone call - Days 56, 70, 84, 
98, 112 (±5d) 
Day 126 (±5d) 
Phone calls - Days 140, 154 
168, 182, 196 (±5d) 
Day 210 (±5d) 
Phone calls - Days 238, 266 
(±5d) 
Day 294 (±5d) 
Phone calls 
Days 322, 350, 378 (±5d) 
Day 393 (± 5d) 
COVID-19 assessment visitn  
COVID-19 convalescent visito 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behavioral Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Vital Signs 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Xp 
Xp 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differentialc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Chemistryc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
HIV Serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis Routined 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Pregnancy Teste 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
INO-4800 or Placebo + EPf 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Download EP Datag 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Eventsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Samplesi 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
Humoral Samplesj 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
SARS-CoV-2 Serologyl 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
SARS-CoV-2 RT-PCR  
(Saliva) l 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xm 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0.   
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Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 21 of 81 
 
b. 
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits. The targeted physical exam is optional at the COVID-19 assessment 
visit if the visit is conducted via telemedicine. 
c. 
Hemoglobin A1c collected at screening only. Chemistry includes Na, K, Cl, HCO3, Ca, PO4, glucose, BUN, Cr, alkaline phosphatase, AST, ALT, LDH, total bilirubin.  
d. 
Dipstick for glucose, protein, and hematuria. Microscopic examination should be performed if dipstick is abnormal.  
e. 
Serum pregnancy test at Screening. Urine pregnancy test at other visits.  
f. 
Intradermal injection(s) in skin preferably over deltiod muscle, or alternately over anterolateral quadriceps muscle, followed by EP at Day 0 and Day 28. 
g. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
h. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
i. 
On Day 0, cellular sampling requires 64 mL of whole blood (8 CPT tubes, each 8 mL of whole blood) prior to 1st dose. At all other time points, collect 32 mL of whole blood (4 CPT tubes, 
each 8 mL of whole blood). Cellular samples collected for all subjects at Day 0 pre-dose and Week 6; collected for approximately 10% of subjects at other indicated visits.  
j. 
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce eight serum aliquots of 1 
mL each). At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce four serum aliquots of 1 mL each.  
k. 
SARS-CoV-2 antibody.   
l. 
Saliva will be collected at study visits and bi-weekly at home between office visits.  In-office collection time points for Screening, Day 0, Day 28, EOS and COVID-19 visits will be 
tested at the time of collection. All other stored saliva specimens will be selectively tested if a SARS-CoV-2 serology test becomes positive. The Day 0 and Day 28 RT-PCR results 
will not be required prior to dosing on that day. 
m. 
Nasal swab and saliva specimens.  
n. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The assessment visit may be performed in the clinic, subject’s vehicle, or via 
telemedicine and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test.  
o. 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of 
symptoms, the date of positive SARS-CoV-2 test. If acute symptoms are ongoing the site should follow up with the subject via phone call or unscheduled visit after symptom resolution 
or stabilization. 
p. 
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation. 
 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 22 of 81 
 
 
INTRODUCTION 
This document is a protocol for a human research trial to be conducted according to U.S. 
and international standards of Good Clinical Practice (GCP) (FDA Title 21 part 312, 812 
and International Conference on Harmonization (ICH) guidelines), applicable government 
regulations and Institutional research policies and procedures. 
 
BACKGROUND AND SCIENTIFIC RATIONALE 
The lack of available therapy in conjunction with increasing numbers of global cases 
indicate that SARS-CoV-2 infection remains a serious unmet medical concern. 
Appropriate measures to prevent, control and treat existing and future infections are in 
dire need. 
 
BACKGROUND INFORMATION 
In late 2019, a cluster of cases of pneumonia of unknown etiology was reported in Wuhan, 
Hubei province, China [1-3]. These cases were announced on January 6, 2020 as testing 
negative for influenza, severe acute respiratory syndrome (SARS), and Middle East 
respiratory syndrome (MERS). On January 7, 2020 a novel virus was isolated by the 
Chinese Center for Disease Control and Prevention (CDC) from the throat swab sample 
of a patient, and the isolate was named “Wuhan-Hu-1.” The gene sequence of that isolate 
was then generated and determined to be of a novel coronavirus [4, 5]. That gene 
sequence was publicly posted on January 10, and the novel coronavirus was preliminarily 
named 2019-nCoV. Subsequently, on February 11, 2020, the virus was named SARS-
CoV-2 by the International Committee on Taxonomy of Viruses (ICTV) [6, 7], due to its 
similarity with the original SARS virus. That same day, the World Health Organization 
(WHO) announced a specific name of the disease, “COVID-19,” associated with infection 
by this novel coronavirus, as based on the novel coronavirus origin and year of first 
reported cases. The first cluster of human cases identified comprised people who worked, 
visited, or lived around the local Huanan seafood wholesale market in Wuhan, where live 
animals and fresh meat and fish were on sale, suggesting that an animal was the source 
of the novel respiratory virus being transmitted to humans.  
The first case of COVID-19 in the U.S. was announced in Washington State on January 
21, 2020 by the Washington State Department of Health and the U.S. Centers for Disease 
Control and Prevention (US CDC) [8].  It was a case of a traveler who had returned from 
Wuhan, China. Since that case was detected, human-to-human local transmission began 
(or continued from previously undetected infections) in the U.S., and as of July 27, 2020, 
over 4 million laboratory-confirmed US COVID-19 cases and nearly 150,000 US deaths 
due to COVID-19 have been reported in all 50 states and its territories [9]. Epidemiologic 
data suggest that droplets expelled during face-to-face exposure during talking, coughing, 
or sneezing is the most common mode of transmission while contact surface spread 
remains yet another possible mode of transmission [10].  
SARS-CoV-2 infection rapidly emerged as a global threat to public health, joining other 
coronavirus-related diseases, such as SARS and MERS. COVID-19 was declared a 
Public Health Emergency of International Concern (PHEIC) by the WHO on January 20, 
2020, and was declared a pandemic on March 11, 2020 [11], associated with substantial 
morbidity and mortality [12]. As of July 25, 2020, a total of nearly 16 million laboratory-
confirmed COVID-19 cases have been reported internationally, including over 643,000 
deaths [9]. However, given the lack of widespread testing, the true number of cases of 
COVID-19 is likely far higher than reported. Preliminary results from large U.S.-based 
1.0 
1.1 
1.2 
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Clinical Protocol 
Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 23 of 81 
 
seroepidemiological surveys indicate an estimated incidence rate of SARS-CoV-2 
infections to be 6 to 24 times that of the number of reported cases of COVID-19 [13].  
An article in JAMA by Wu and McGoogan [14] provided a summary of a major report by 
the Chinese Center for Disease Control and Prevention (China CDC) [15]. Of a total of 
72,314 case records, 44,672 (62%) were confirmed as SARS-CoV-2 infections based on 
positive viral nucleic acid test results on throat swabs, 16,186 (22%) as suspected cases 
based on symptoms and exposures only, 10,567 (15%) as clinically diagnosed based on 
symptoms, exposures, and presence of lung imaging features consistent with coronavirus 
pneumonia, and 889 (1%) as asymptomatic cases based on a positive viral nucleic acid 
test result but lacking typical symptoms including fever, dry cough, and fatigue [16]. The 
overall case-fatality ratio (CFR) was 2.3% (1023 deaths among 44,672 confirmed cases). 
No deaths occurred in the group aged 9 years and younger, but cases in those aged 70 
to 79 years had an 8.0% CFR and cases in those aged 80 years and older had a 14.8% 
CFR. The CFR was 49.0% among critical cases. CFR was elevated among those with 
preexisting comorbid conditions - 10.5% for cardiovascular disease, 7.3% for diabetes, 
6.3% for chronic respiratory disease, 6.0% for hypertension, and 5.6% for cancer [16]. 
These initial reports of the CFR documented the level of seriousness of COVID-19.  
Given the novelty of SARS-CoV-2, its rapid spread among humans and its associated 
morbidity and mortality, there has been an explosion of epidemiological, clinical, virologic, 
and other scientific data regarding the propagation of effects of this virus emerging from 
China, the United States, and many other countries. These data have established that 1) 
SARS-CoV-2 is transmitted person-to-person [17], even from those who are asymptomatic 
or presymptomatic [18-20], 2) the virus is very infectious, with estimates of the R0 
(Reproductive number) ranging from 1.50 to 6.49, with a mean average of 3.28 and a 
median average of 2.79 [21], 3) the constellation of symptoms, signs, and an incubation 
period ranging between  2 and 14 days [22], and 4)  the asymptomatic proportion of those 
infected being substantial, perhaps as high as  80% [17, 23-25]. Further, research has 
found that the risk of death from COVID-19 increases with age and with serious, comorbid 
conditions including hypertension, diabetes, cardiovascular disease, obesity, etc.   
Finally, although much has been learned very quickly about SARS-CoV-2 and COVID-19, 
much more is still to be determined. The aforementioned CFR and similar estimates are 
from crude analyses that have only accounted for moderate to serious cases. Therefore, 
the true CFR is likely significantly lower. Further, the infection-fatality ratio (IFR), which is 
the proportion who die among all those infected regardless of any symptomology, is likely 
still even lower than the CFR, but both the CFR and IFR will not be known with certainty 
until well-designed and controlled seroepidemiology surveys have been conducted using 
well-validated antibody assays and thorough questionnaires to obtain symptom history. 
Also, the presence of natural immunity of those infected who survive and the durability of 
such natural immunity is to be determined. Thus, the existence and possibility of 
reinfection and recurrent infection is unknown. 
 CLINICAL PRESENTATION, TRANSMISSION AND IMMUNE RESPONSE 
A study in The Lancet by Huang and colleagues [3] reported the epidemiological, clinical, 
laboratory, and radiological characteristics, as well as treatment and clinical outcomes, of 
patients with laboratory-confirmed COVID-19 pneumonia. Common symptoms at onset of 
illness were fever (n=40, 98% of 41 patients), cough (n=31, 76%), and myalgia or fatigue  
(n=18, 44%);  less  common  symptoms  were  sputum  production  (n=11, 28%  of  39 
patients),  headache  (n=3, 8%  of  38 patients), hemoptysis (n=2, 5% of 39 patients), and 
diarrhea (n=1, 3% of 38 patients). Dyspnea developed in 22 (55%) of 40 patients (median 
time from illness onset to dyspnea was 8 days [Interquartile range 5 - 13 days]). Twenty-
1.2.1 
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Protocol Version Date: 13-Nov-2020 
CONFIDENTIAL 
Protocol Version: 4.0 
 
Page 24 of 81 
 
six (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal 
findings on chest CT scan. Complications included acute respiratory distress syndrome 
(n=12, 29%), RNAaemia (n=6, 15%), acute cardiac injury (n=5, 12%) and secondary 
infection (n=4, 10%).  
Wiersinga et al. summarized the common symptoms of COVID-19 in hospitalized patients 
as fever (70-90%), dry cough (60-86%), shortness of breath (53-80%), fatigue (38%), 
myalgias (15-44%), nausea/vomiting or diarrhea (15-39%), headache, weakness (25%) 
and rhinorrhea (7%). Anosmia and ageusia may be the sole presenting symptom in 
approximately 3% of individuals with COVID-19. Common laboratory abnormalities 
include lymphopenia (83%), elevated inflammatory markers (e.g., erythrocyte 
sedimentation rate, C-reactive protein, ferritin, tumor necrosis factor-alpha, IL-1, IL-6) and 
abnormal coagulation parameters (e.g., prolonged prothrombin time, thrombocytopenia, 
elevated D-dimer and low fibrinogen). Common radiographic findings include bilateral, 
lower lobe infiltrates on chest radiographic imaging and bilateral, peripheral, lower-lobe 
ground-glass opacities and/or consolidation on chest computed tomographic imaging [10].  
Transmission of SARS-CoV-2 occurred mainly after days of illness [26] and was 
associated with modest viral loads in the respiratory tract early in the illness, with viral 
loads peaking approximately 10 days after symptom onset [27]. Higher viral loads were 
detected soon after symptom onset, with higher viral loads detected in the nose than in 
the throat. Analysis of these samples suggested that the viral nucleic acid shedding 
pattern of patients infected with SARS-CoV-2 resembles that of patients with influenza 
[28] and appears different from that seen in patients infected with SARS-CoV [27]. The 
viral load that was detected in the asymptomatic patient was similar to that in the 
symptomatic patients, which suggests the transmission potential of asymptomatic or 
minimally symptomatic patients [12]. The SARS-CoV-2 transmission time window from 
COVID-19 patients is perhaps 2 days before symptom onset up to 37 days after symptom 
onset [20]. It is estimated that 48% to 62% of transmission may occur via presymptomatic 
carriers [10].  
Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10-15 
days following the onset of COVID-19 symptoms. Seow et al. observed seroconversion in 
>95% with neutralizing antibody responses when sampled beyond 8 days after onset of 
symptoms [29]. However, declining neutralizing antibody titers were observed during the 
follow-up period. Long, et al, when following 37 asymptomatic individuals and 37 
symptomatic patients into the early convalescent phase, observed that the IgG levels in 
93.3% of the asymptomatic group and 96.8% of the symptomatic group declined during 
the early convalescent phase [30]. T cells play a critical role in antiviral immunity but their 
numbers and functional state in SARS-CoV-2 infected patients remain largely unclear. 
Diao and colleagues performed a retrospective review of total T cell counts, and CD4+ and 
CD8+ T cell subsets based on inpatient data from 522 patients with laboratory-confirmed 
SARS-CoV-2 infection and 40 healthy controls in Wuhan from December 2019 to January 
2020. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe and 
critical disease groups as well as those who died were significantly lower than in the 
mild/moderate disease group. Most importantly, the numbers of total T cells, CD8+ T cells 
and CD4+ T cells in severe COVID-19 cases, including those who died, were lower 
suggesting that there is a profound T cell loss in COVID-19 disease. Counts of total T 
cells, CD8+ T cells or CD4+ T cells were negatively correlated with patient survival [31]. 
It is quite likely that CD4+ T cell, CD8+ T cell, and neutralizing antibody all contribute to 
clearance of the acute infection. There is an ongoing need to understand the magnitude 
and composition of the human CD4+ and CD8+ T cell responses to SARS-CoV-2. If 
natural infection with SARS-CoV-2 elicits potent CD4+ and CD8+ T cell responses 
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commonly associated with protective antiviral immunity, COVID-19 is a strong candidate 
for rapid vaccine development [32].  
 CURRENT TREATMENT AND UNMET NEED 
Currently, there is no licensed prophylactic vaccine against COVID-19. Numerous vaccine 
efforts are underway. Given the growing concerns regarding the emergence of a dominant 
SARS-CoV-2 variant G614, which now comprises more than 80% of circulating global viral 
strains, and is reportedly associated with increased infectivity and spread [33], an effective 
prophylactic vaccine should ideally induce immunity against not only the D614 virus but 
also the G614 variants. 
Hospitals can provide supportive care for those who are infected and develop severe 
illness. Clinical management includes prompt implementation of recommended infection 
prevention and control measures and supportive management of complications, including 
advanced organ support if indicated.  
The CDC recommends that dexamethasone be used in the treatment of COVID-19 in 
patients who are mechanically ventilated and in patients who require supplemental oxygen 
but who are not mechanically ventilated based on a preliminary report from the 
Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial [34].  
Remdesivir has received Emergency Use Authorization (EUA) for the treatment of 
hospitalized patients with COVID-19 who require supplemental oxygen but who are not 
on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal 
membrane oxygenation (ECMO) [35]. 
 
RATIONALE FOR PROPHYLACTIC VACCINE DEVELOPMENT 
SARS-CoV-2 has become a pandemic resulting in substantial morbidity and mortality. Due 
to rapid spread of SARS-CoV-2 infections even from asymptomatic and mildly infected 
patients, there is an urgent need for appropriate measures to prevent, control and treat 
SARS-CoV-2 infections.  
To address this critical need for a medical countermeasure for prevention of COVID-19 
disease, we at Inovio Pharmaceuticals have employed our synthetic DNA-based vaccine 
technology. This technology is highly amenable to accelerated developmental timelines, 
due to the ability to rapidly design multiple test constructs, manufacture large quantities of 
the drug product, and leverage established regulatory pathways to the clinic. Furthermore, 
this technology platform has demonstrated proof of concept efficacy and safety in humans 
in a Phase 2b randomized, double-blind, placebo-controlled study for human 
papillomavirus (HPV) associated cervical pre-cancer [36] and is currently in two 
multinational Phase 3 trials for that indication (NCT03185013 and NCT03721978) and 
several Phase 2 trials for related and other indications. We have built upon our prior 
experience in developing a MERS coronavirus (MERS-CoV) vaccine to accelerate the 
development of a SARS-CoV-2 vaccine candidate. In a Phase 1 clinical study, the MERS-
CoV coronavirus vaccine was safe and well tolerated, eliciting immune responses in more 
than 85% of participants after two vaccinations that were durable through 1 year of follow-
up [37].   
 DNA VACCINES 
Since the 1990s, a novel approach to vaccination against a broad array of target antigens 
and diseases has been in development. This involves the direct introduction of plasmid 
deoxyribonucleic acid (DNA) containing the gene encoding the immunogen against which 
an immune response is sought into appropriate host tissues and the in situ production of 
1.2.2 
1.3 
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the target immunogen(s). This approach offers a combination of potential advantages, 
including the stimulation of both B- and T-cell responses, stability of the vaccine across a 
broad temperature range, absence of infectivity of the immunogen itself, the speed with 
which the vaccine can be constructed (for example in the face of an epidemic or pandemic 
as it is the case here with SARS-CoV-2), and the relative ease and generic nature of large-
scale manufacture. Many scientific publications have addressed the potential of DNA 
vaccination [38-47]. Immune responses in animal models have been obtained using genes 
from a variety of infectious agents including influenza viruses, hepatitis B virus, human 
immunodeficiency virus, human papillomaviruses, Marburg virus, MERS coronavirus, 
rabies virus, SARS coronavirus, West Nile virus (WNV), Zika virus, and other infectious 
agents as plasmodium, mycoplasma, and many more [46, 48]. In many cases, protection 
from disease in animal models has also been demonstrated.  
DNA vaccines are able to generate both CD4+ and CD8+ T cell responses. The ability to 
generate MHC-Class I restricted CD8+ T cells (cytolytic T lymphocytes), which generally 
are not made following administration of inactivated viruses, proteins or peptides, may be 
important for key responses against certain pathogens, as well as enabling cross-strain 
specific responses when many antibody responses are strain-specific. Because the 
encoded protein is synthesized in vivo by the host following administration, DNA vaccines 
can encode membrane-bound proteins instead of solely the soluble versions [49]. This 
can be important because key neutralizing epitopes are located in regions that would be 
excluded, or not formed in a monomeric truncated soluble version. Some early research 
in COVID-19 control has already suggested that neutralizing antibodies may not be 
sufficient and that cell-mediated immunity may be necessary [50]. 
Unlike certain other vectors (such as heterologous viral vectors), DNA vaccines do not 
stimulate adaptive immune responses against themselves, although the DNA itself does 
stimulate certain innate immune responses [51]. In other words, they do not generate anti-
vector immunity that could stunt antigen-specific responses following multiple exposures. 
 USE OF ELECTROPORATION WITH DNA VACCINES 
Electroporation (EP) enhances gene expression of plasmid DNA delivered by the 
intramuscular (IM) or intradermal (ID) routes of administration (Figure 2). Following IM or 
ID delivery of a DNA vaccine or therapeutic product, EP facilitates entry of the DNA into 
the target site: muscle or dermal cells. Following cellular uptake, there is efficient 
production of the proteins encoded by the DNA expression plasmid system. The different 
EP devices, each with varying electrical parameters and protocols, have been reviewed 
[52]. EP has been extensively tested in animal species such as dogs, pigs, cattle, and 
NHPs to deliver therapeutic genes that encode for a variety of hormones, cytokines, 
enzymes or antigens [52] for the activation of both cellular and humoral responses [53, 
54]. Importantly, immune responses generated by DNA vaccines delivered with EP are far 
superior to responses to the same vaccines delivered without EP [54]. IM and ID delivery 
of DNA vaccines with EP has been studied extensively, and optimum conditions for 
plasmid uptake and expression have been described for therapeutic indications, vaccines 
and tumor animal model systems [55, 56].  
 INOVIO’S PROPRIETARY TECHNOLOGY AGAINST COVID-19 DISEASE 
Inovio Pharmaceuticals has developed INO-4800 as a DNA vaccine that contains 10 
mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM sodium chloride and 15 
mM sodium citrate). pGX9501 is a DNA plasmid expressing a synthetic consensus 
(SynCon®) sequence of the SARS-CoV-2 full length Spike glycoprotein. The ID route of 
delivery has been selected for INO-4800 based on recent findings from multiple DNA 
1.3.2 
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vaccine development programs where ID delivery has driven equivalent if not superior 
humoral and cellular responses to IM delivery while improving tolerability (clinicaltrials.gov 
NCT02464670, clinicaltrials.gov NCT02431767) [57-59]. 
Following ID injection, the Inovio Pharmaceuticals’ constant current EP device [52] 
referred to as the CELLECTRA® 2000 for ID administration (3P-ID) device is used to 
facilitate DNA entry into the cells.  
Figure 2: The Potential Mechanism of Action Underlying Electroporation 
 
 NONHUMAN PRIMATE (NHP) CHALLENGE STUDIES WITH INO-4800 
NHPs are a valuable model in the development of COVID-19 vaccines and therapeutics 
as they can be infected with wild-type SARS-CoV-2, and present with early infection that 
mimics aspects of human disease [60].  Rhesus macaques (n=5) received two 
immunizations of INO-4800 (1.0 mg), at Week 0 and Week 4.  Naïve control animals (n=5) 
did not receive vaccine.  Humoral and cellular immune responses were monitored for 15 
weeks (~4 months) following prime immunization for memory responses. All animals 
seroconverted following a single INO-4800 immunization, with serum IgG titers detected 
against the full-length S1+S2 extracellular domain (ECD), S1, S2, and receptor binding 
domain (RBD) regions of the SARS-CoV-2 S protein.  
INO-4800 immunized macaques and unvaccinated controls were challenged with SARS-
CoV-2 13 weeks (~3 months) post-final immunization. NHPs received a challenge dose of 
1.1x104 PFU of SARS-CoV-2 by intranasal and intratracheal inoculation. Peak viral RNA 
loads in the BAL were significantly lower in the INO-4800 vaccinated group, along with 
significantly lower viral RNA loads at day 7 post-challenge, indicating protection from lower 
respiratory disease. While RNA was detected in the nasal swabs of both the control and 
INO-4800 vaccinated animals, viral mRNA levels trended downwards in INO-4800 
vaccinated animals by more than 2 logs and were achieved sooner on average. Overall, 
the reduced viral loads following exposure to SARS-CoV-2 infection at 17 weeks after 
immunization show an important durable impact mediated by the vaccine [61].  
<D 
muscle or skin. 
Cell membrane reseals. 
C llular machinery uses the 
ONA code to produce one or 
more of the disease an gens 
~d by the DNA va«lne. 
1.3.4 
Electroporation: millisecond 
electrical fields applied. 
Antigen-presenting cells 
eng\Jlf the antigens and carry 
them to lymph nodes. 
Tempcrary pares in cell 
membrane; s gnlficant cellular 
upt 
of vaccine. 
Antibodies or killer T-cells 
that can eliminate cancerous 
or infected cells are produced. 
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 FIRST-IN-HUMAN PHASE 1 TRIAL OF INO-4800 
In the open-label, Phase 1 clinical trial, we initially evaluated the safety and 
immunogenicity of INO-4800 in 40 healthy participants, 18-50 years of age.  There were 
two groups of 20 participants each who received either 1.0 mg or 2.0 mg of INO-4800 
intradermally followed by EP at 0 and 4 weeks. In the first 40 subjects, by Week 8, 11 
adverse events were reported of which all were Grade 1 in severity of which 6 were related 
to study drug. The frequency of AEs did not increase with the second administration.  
From the immunogenicity analysis of the initial 40 subjects enrolled, two subjects were 
excluded from the analysis, one due to early discontinuation prior to the Week 4 dose for 
non-study reasons and the other due to suspected exposure to SARS-CoV-2 before the 
first dose of INO-4800 was administered based on a baseline positive SARS-CoV-2 
serology. Thirty-eight (38) evaluable subjects had cellular and/or humoral immune 
responses following the second dose of INO-4800. Assessment of data from both Week 
6 and Week 8 ELISpot revealed that 74% and 100% of the subjects generated T cell 
responses in the 1.0 mg and 2.0 mg groups, respectively. By Week 6, 95% (36 of 38) of 
the participants seroconverted by generating binding and/or neutralizing antibodies. 
Overall, INO-4800 elicited antigen-specific humoral and cellular immune responses 
against the SARS-CoV-2 Spike protein while demonstrating favorable safety and 
tolerability. 
The protocol was amended to include an additional 80 healthy participants to evaluate 
safety and immunogenicity of INO-4800 in older and elderly age populations. A lower dose 
level (0.5 mg) was also added for evaluation of dose-sparing potential. A total of 40 
participants were enrolled into three dose levels (0.5 mg, 1.0 mg and 2.0 mg), such that 
each Group included 20 participants 18-50 years of age, 10 participants 51-64 years of 
age, and 10 participants 65 years of age and older. Doses were delivered intradermally 
followed by EP at 0 and 4 weeks. As of July 29, 2020, 17 related adverse events were 
reported cumulatively, of which all but one (Grade 2 injection site pruritus) was Grade 1 in 
severity. 
Please refer to the Investigator’s Brochure, which will include future updates through the 
life of the study. 
 PROPOSED PHASE 2/3 TRIAL OF INO-4800 
Based on the review of the immunogenicity data from its Phase 1 trial in its initial cohort 
of 40 subjects 18-50 years of age, Inovio has determined that while the 1.0 mg and 2.0 mg 
doses of INO-4800 generate encouraging neutralizing antibody responses, the 2.0 mg 
dose appears to offer superior T-cell responses over the 1.0 mg dose as measured by 
INF-gamma responses in the initial Phase 1 cohort. Therefore, this Phase 2/3 trial is 
designed to begin with a Phase 2 segment to evaluate both the 1.0 mg and 2.0 mg doses 
in approximately 400 subjects, including in the older (51 to 64 years of age) and elderly 
subjects (65 years of age and older), before selecting a dose or age-related doses for an 
efficacy evaluation in a subsequent Phase 3 segment involving >6000 subjects.  
 DOSE AND REGIMEN RATIONALE 
The intent is to evaluate INO-4800 as a prophylactic vaccine against COVID-19 disease. 
As such, there is a desire to demonstrate the ability of the vaccine to drive immune 
responses primarily within the first 6 weeks of the first dose, which supports evaluation of 
a 2-dose regimen (Days 0 and 28). 
In this study, 1.0 mg and 2.0 mg of vaccine is administered by ID injection and followed 
immediately by EP at Day 0 and Day 28. The dose selection is supported by the safety 
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profile in the Phase 1 trial of INO-4800 (COVID19-001, NCT04336410) as well as our 
prior experience in developing a MERS coronavirus (MERS-CoV) vaccine (INO-4700) [16, 
17]. The safety data for INO-4800 is provided in the Investigator’s Brochure (IB). 
The objective of the Phase 2 segment of the Phase 2/3 trial is to further down-select the 
1.0mg and 2.0mg doses of INO-4800 for each age group in order to evaluate the optimal 
dose(s) in the efficacy Phase 3 segment.  
 
RISKS AND POTENTIAL BENEFITS  
As of October 9, 2020, no treatment related serious adverse events have been reported 
for INO-4800. There may be side effects and discomforts that are not yet known.  
Please refer to the Investigator’s Brochure and User Manual, which will include future 
updates of the risk profile through the duration of the study. 
 POTENTIAL BENEFITS 
There may be potential benefits for prevention of COVID-19 disease, although efficacy of 
INO-4800 remains unknown.   
 PRODUCT RISKS 
1.4.2.1. 
Expected Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Device 
In accordance with the International Council for Harmonisation (ICH), Inovio-sponsored 
studies have been designed to minimize risk to study participants. Expected risks of INO-
4800 delivered ID followed by EP with the CELLECTRA® 2000 device are listed below in 
Table5. 
Table 5: Expected Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Devicea  
Frequency among subjectsb 
Event 
Very Common 
(≥10%) 
• 
Injection site pruritus 
• 
Injection site erythema or redness 
• 
Injection site painc or tenderness  
Common 
(≥1% to <10%) 
• 
Injection site bruising 
• 
Injection site swelling or induration 
Uncommon or Rare (<1%) 
• 
Administration site lesions or bleeding  
• 
Temporary severe injection site pain or 
tenderness 
a Investigator’s Brochure v3.0, dated 25-Aug-2020 
b EU commission guideline on the SmPC September 2009 [62] 
c Brief muscle contractions may occur and could be uncomfortable 
1.4.2.2  
Theoretical Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Device 
The following adverse events have been observed at least once, as of June 30, 2020, 
across all clinical trials with Inovio DNA products delivered intradermally followed by EP 
using the CELLECTRA® 2000 device: 
1.4 
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•
Allergic reaction
•
Anxiety
•
Creatine phosphokinase (CPK) elevations that are transient
•
Injection site infection, paresthesia, hypoesthesia, hematoma, or scab
•
Vasovagal reaction, lightheadedness or dizziness.
The following events have not been observed, as of June 30, 2020, in any subject or any 
clinical trials with Inovio DNA products delivered intradermally followed by EP using the 
CELLECTRA® 2000 device. While considered theoretical and unlikely to occur, any 
occurrence of these events should be reported to the Sponsor during this trial: 
•
Antibody-dependent enhancement of disease (i.e., potential for greater respiratory
disease upon exposure to SARS-CoV-2 due to priming of immune cells from prior
vaccination. Although observed in nonclinical models for vaccines against other
viruses such as SARS, the occurrence or observation of antibody-dependent
enhancement of the disease with COVID-19 vaccines in humans remains
unknown)
•
Cardiac arrhythmias (product-related); Please note that “ICD or pacemaker (to
prevent a life-threatening arrhythmia) that is located ipsilateral to the deltoid
injection site (unless deemed acceptable by a cardiologist)” is an exclusion
criterion (‘j’) in this protocol;
•
Death (product-related);
•
Disruption of function of implanted electronic medical device(s); Please note that
“ICD or pacemaker (to prevent a life-threatening arrhythmia) that is located
ipsilateral to the deltoid injection site (unless deemed acceptable by a cardiologist)”
is an exclusion criterion (‘j’) in this protocol;
•
Effects on fetus and/or pregnancy; Please note inclusion criterion ‘g’ in this protocol
which requires use of medically effective contraception in women of childbearing
potential;
•
Electrical injury (e.g. electrocution); Please note warning within the device User
Manual (Section 7). Since the device is not connected to any power supply during
the EP procedure of a subject, this theoretical event is unlikely but has the potential
to occur to the user of the device (e.g., study site staff). This will be mitigated
through device training and user qualification prior to use;
•
Fire hazard to the facility; This theoretical event is unlikely but has the potential to
occur to the clinical trial site. The possibility of this event has been mitigated
through device design;
•
Hearing damage (product-related); The possibility of this event has been mitigated
through the device design. The audio is limited in volume and is of very short
duration.
•
Inaccurate energy delivery, the result of which is covered in other events listed
here (e.g., tissue damage);
•
Injection site laceration; This has not been observed but would be theoretically
possible with any needle;
•
Major injury to deeper tissue and/or bone; This event is not foreseeable given the
array needle length is limited to 3.2 mm;
•
Muscle damage; This event is not foreseeable given the array needle length is
limited to 3.2 mm;
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• 
Paresis or paralysis with possible loss of nerve function; There are minor nerves 
innervating the skin and subcutaneous tissues that may be disrupted, but are 
extremely unlikely to result in serious injury; 
• 
Radiation hazard to eyes and skin; This theoretical event is unlikely but has the 
potential to occur to the user of the device (e.g., study site staff). The possibility of 
this event has been mitigated through the device design; 
• 
Tissue injury/burn;  
• 
User/subject unaware that treatment was incomplete; 
• 
Worsening of unstable cardiac disease; Please note that “Cardiovascular diseases 
(e.g., myocardial infarction, congestive heart failure, cardiomyopathy or clinically 
significant arrhythmias) requiring changes in therapy or hospitalization for 
worsening disease during the 6 weeks prior to enrollment” is an exclusion criterion 
(‘h’) in this protocol. 
There have been no AEs associated with EP errors or failures. 
 OVERALL BENEFIT/RISK CONCLUSION 
In the context of the ongoing COVID-19 pandemic resulting in substantial morbidity and 
mortality, the overall cumulative safety profile of Inovio’s DNA platform across all of its 
products, and INO-4800’s Phase 1 adverse events being generally limited to local injection 
site reactions, the benefit risk profile justifies participation in the Phase 2/3 trial. 
 
OBJECTIVES AND PURPOSE 
The overall purpose of this clinical trial is to evaluate the safety, immunogenicity and 
efficacy of INO-4800. 
 
HYPOTHESIS 
INO-4800 delivered ID followed immediately by EP will be well-tolerated, exhibit an 
acceptable safety profile, result in generation of cellular and humoral immune responses 
to SARS-CoV-2 Spike glycoprotein and provide protection against virologically-confirmed 
COVID-19 disease in subjects at high risk of SARS-CoV-2 exposure.  
 
CLINICAL TRIAL DESIGN AND ENDPOINTS 
This is an operationally seamless Phase 2/3, randomized, placebo-controlled, multi-
center trial to evaluate the safety, immunogenicity, and efficacy of INO-4800, 
administered by ID injection followed immediately by EP using the CELLECTRA® 2000 
device, in a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-
2 exposure. Approximately 6578 seronegative subjects 18 years of age and older are 
expected to be enrolled across two (2) segments of this study, a Phase 2 segment and a 
Phase 3 segment. The subjects and data from Phase 2 are independent from that of 
Phase 3.  The primary objectives of this trial are to identify in seronegative subjects an 
optimal age-related dose (Phase 2 segment) for subsequent evaluation for efficacy 
(Phase 3 segment).  
 
Phase 2 Segment – Dose Selection 
 
In the Phase 2 segment, approximately 400 subjects 18 years of age and older will be 
evaluated across four (4) dose groups (Table 1, Figure 1). Subjects will be randomized 
at a 3:3:1:1 ratio to receive either 1.0 mg or 2.0 mg of active investigational product (INO-
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4800) or 1 or 2 injections of placebo (SSC-0001). Dose groups receiving INO-4800 will 
enroll approximately 150 subjects per group. Dose groups receiving placebo will enroll 
approximately 50 subjects per group. Randomization will be such that approximately 240 
subjects aged 18-50 years, 120 subjects aged 51-64 years and 40 subjects aged ≥ 65 
years will be enrolled. Initial enrollment will include subjects aged 18-50 years. Initiation 
of enrollment of older subjects 51-64 years of age and elderly subjects 65 years and older 
will depend on review of safety and immunogenicity data from those age groups 
generated in the Phase 1 study (COVID19-001). 
 
Dose selection for evaluation of efficacy in the Phase 3 segment will be based on Week 
6 immunogenicity data and Week 8 safety data from the Phase 2 segment. Group-level 
unblinded summaries and analyses of safety will be produced once the Week 8 phone 
call visit data are completed for all subjects in the Phase 2 segment. 
 
Phase 3 Segment – Efficacy 
In the Phase 3 segment, approximately 6178 subjects 18 years of age and older will be 
randomized at a 1:1 ratio to receive either active investigational product (INO-4800, dose 
selected from the Phase 2 segment) or placebo (SSC-0001). A minimum of 15% of the 
total sample size of subjects will be 51-64 years of age, and a minimum of 5% of the total 
sample size of subjects will be ≥ 65 years of age. 
This segment of the trial is case-driven. Among seronegative subjects, a total of 160 
observed cases will be required for 90% power to declare the vaccine efficacious (>30%), 
assuming a true efficacy of 60%. A sample size of 6178 subjects is expected to be 
required to achieve the 160 cases assuming an underlying attack rate of 3.7%. The actual 
sample size may differ if the observed attack rate is different than projected. 
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12-
months post-dose 2. All Phase 3 segment subjects will be followed for 56 weeks from the 
Day 0 dosing [i.e., Week 56 will be the planned End of Study (EOS) visit for this segment 
of the trial]. 
 
External Committee Reviews 
 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will 
convene regularly to review all available unblinded safety data, and additionally upon 
completion of the Week 8 phone call visit for all subjects enrolled during the Phase 2 
segment. For the Phase 3 segment, an independent, blinded Endpoint Adjudication 
Committee (EAC) will review and confirm COVID-19 cases.  
 
Details of each committee’s scope will be provided in the respective charters. 
 
PRIMARY OBJECTIVES 
See Table 6. 
3.1 
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PRIMARY ENDPOINTS 
Table 6: Primary Objectives and Associated Endpoints 
Phase 2 Primary Objective 
Phase 2 Primary Endpoints 
1.  Evaluate the cellular and humoral 
immune response to INO-4800 
administered by ID injection followed 
immediately by EP  
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot assay 
1b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay 
Phase 3 Primary Objective 
Phase 3 Associated Primary Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease  
1.   Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 
(End of Study (EOS))  
 
SECONDARY OBJECTIVES 
See Table 7. 
 
SECONDARY ENDPOINTS 
Table 7: Secondary Objectives and Associated Endpoints 
Phase 2 Secondary Objectives 
Phase 2 Secondary Endpoints 
1.  Evaluate the safety and tolerability of 
INO-4800 administered by ID 
injection followed immediately by EP  
 
1a. Incidence of solicited and unsolicited injection 
site reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
 1d. Incidence of adverse events of special interest 
(AESIs)   
Phase 3 Secondary Objectives 
Phase 3 Secondary Endpoints 
1. Evaluate the safety and tolerability 
of INO-4800    
 
1a. Incidence of solicited and unsolicited injection 
site reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality  
 
2. Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of disease 
severity     
2a.  Incidence of non-severe COVID-19 disease 
starting 14 days after completion of the 2-dose 
regimen until EOS  
2b. Incidence of severe COVID-19 disease starting 
14 days after completion of the 2-dose regimen 
until EOS 
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2c. Incidence of deaths due to COVID-19 starting 14 
days after completion of the 2-dose regimen until 
EOS 
3.   Evaluate the efficacy of INO-4800 in 
the prevention of SARS-CoV-2 
infection 
3.   Incidence of virologically-confirmed SARS-CoV-
2 infections starting 14 days after completion of 
the 2-dose regimen until EOS 
4.   Evaluate the timing of symptom 
resolution in subjects who develop 
COVID-19 disease  
4.  Days to symptom resolution in subjects 
developing COVID-19 disease. 
5.   Evaluate the cellular and humoral 
immune response to INO-4800 
5a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot 
5b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay 
 
 
EXPLORATORY OBJECTIVE 
See Table 8. 
 
EXPLORATORY ENDPOINT 
Table 8: Exploratory Objectives and Associated Endpoints 
Phase 2 Exploratory Objective 
Phase 2 Exploratory Endpoints 
1.  Evaluate the expanded 
immunological profile of antibody 
response and T cell immune 
response 
1a.  Antigen-specific cellular immune response 
measured by flow cytometry. 
1b. Expanded immunological profile which may 
include additional assessments of T and B cell 
numbers and molecular changes by measuring 
immunologic proteins and mRNA levels of genes 
of interest as determined by sample availability 
Phase 3 Exploratory Objective 
Phase 3 Exploratory Endpoints 
1. Evaluate the immunological profile 
by assessing both antibody 
response and T cell immune 
response 
1a.  SARS-CoV-2 Spike glycoprotein antigen-
specific binding antibody levels 
1b.  Antigen-specific cellular immune response 
measured by flow cytometry 
 
EFFICACY ASSESSMENT (PHASE 3 SEGMENT ONLY) 
Subjects will receive either active investigational product (INO-4800, dose selected from 
the Phase 2 segment) or placebo (SSC-0001) in a 2-dose regimen administered 
intradermally followed immediately by EP on Days 0 and 28. Subjects will be monitored 
through regularly scheduled clinic visits and phone calls throughout the trial. Subjects will 
be regularly tested for SARS-CoV-2 infection using serologic testing and RT-PCR. If 
COVID-19 disease is suspected based on symptoms or laboratory testing, site personnel 
will arrange for a clinic visit. Subjects with symptom(s) or a positive SARS-Cov-2 test result 
will be reviewed by the independent blinded EAC. The mechanism for review and 
confirmation of cases will be outlined in an EAC Charter.  
 CASE DEFINITION FOR VIROLOGICALLY-CONFIRMED COVID-19 DISEASE: 
•  Positive testing by SARS-CoV-2 RT-PCR assay (any source) with fever 
(temperature of 100.4ºF/38.0ºC or higher), or  
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• 
Positive testing by SARS-CoV-2 RT-PCR assay (any source) with any of the 
following COVID-19 related symptoms: 
• 
Feeling feverish or chills  
• 
Cough  
• 
Shortness of breath or difficulty breathing  
• 
Fatigue  
• 
Muscle or body aches  
• 
Headache  
• 
New loss of taste or smell  
• 
Sore throat  
• 
Congestion or runny nose  
• 
Nausea or vomiting  
• 
Diarrhea  
3.7.1.1 Case Definition for Severe COVID-19 
• Confirmed COVID-19 disease (per Section 3.7.1) with any of the following:  
a. Clinical signs at rest indicative of severe systemic illness (respiratory 
rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room 
air at sea level or PaO2/FiO2 < 300 mm Hg),  
b. Respiratory failure (defined as needing high-flow oxygen, noninvasive 
ventilation, mechanical ventilation or ECMO),  
c. Evidence of shock (SBP < 90 mm Hg, DBP < 60 mm Hg, or requiring 
vasopressors),  
d. Significant acute renal, hepatic, or neurologic dysfunction,  
e. Admission to an ICU, or  
f. Death.  
3.7.1.2 Case Definition for Non-Severe COVID-19  
• Confirmed COVID-19 disease (per Section 3.7.1);   
• Does not meet the case definition of Severe COVID-19 disease (Section 
3.7.1.1) 
 CASE DEFINITION FOR VIROLOGICALLY-CONFIRMED SARS-COV-2 INFECTION  
• Positive testing by SARS-CoV-2 RT-PCR assay (any source);  
• With or without clinical signs or symptoms of COVID-19 disease.  
 
SAFETY ASSESSMENT 
Subjects will be followed for safety during the trial through scheduled clinic visits and 
phone calls. AEs, regardless of relationship to study drug, will be collected from the time 
of consent until 28 days post-dose 2. SAEs, MAAEs and AESIs will be collected from time 
of consent until EOS. SAEs, AESIs, and treatment-related AEs will be followed to 
resolution or stabilization. For the Phase 2 segment, solicited local and systemic AEs will 
be collected for 7 days following each dose. 
Subjects will also be monitored for COVID-19 disease. 
Please refer to the Schedule of Events (Table 3 and Table 4) for safety assessments to 
be performed.   
3.7.2 
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IMMUNOGENICITY ASSESSMENT 
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 3 and Table 4). Assays such as Binding ELISA, pseudovirus-based neutralization 
assay, and ELISpot will be evaluated at serial timepoints. 
 
CLINICAL TRIAL POPULATION 
 
INCLUSION CRITERIA 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, vital signs and 
physical examination performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar workers, 
store cashiers, hairdressers and barbers, veterinary staff, daycare workers, 
Transportation Security Administration screening staff, school teachers and 
college professors teaching in-person classes) 
2. Factory workers (when working in confined settings with large numbers of 
employees) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) 
4. User of public transportation (e.g., bus, train, subway) at least 3 times weekly 
5. Nursing home staff or correctional facility staff  
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol. Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field) 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists.) Physicians should not be enrolled unless they are 
assigned to dedicated COVID-19 treatment wards or other settings with prolonged 
exposure) 
10. Others, if approved by the medical monitor;   
f. Screening laboratory results within normal limits for testing laboratory or are deemed 
not clinically significant by the Investigator; 
g. Must meet one of the following criteria with respect to reproductive capacity: 
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or tubal 
ligation, absence of ovaries and/or uterus in females). In the case of vasectomy, 
subjects should wait six (6) months post-vasectomy prior to enrolling;  
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• 
Use of medically effective contraception with a failure rate of < 1% per year when 
used consistently and correctly from screening until 3 months following last dose. 
Acceptable methods include:  
o hormonal contraception including implants, injections or oral; 
o two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
o intrauterine device or intrauterine system; 
o abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 
EXCLUSION CRITERIA 
a. Acute febrile illness with temperature > 100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat);  
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the Screening visit until 
3 months following the last dose; 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or 
a detectable viral load within the past 3 months; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0 (documented receipt of placebo in a previous trial 
would be permissible for trial eligibility); 
g. Previous receipt of an investigational vaccine for prevention or treatment of COVID-
19, MERS or SARS (documented receipt of placebo in previous trial would be 
permissible for trial eligibility). 
h. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg at Screening; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin cancers 
that only required local excision and non-metastatic prostate cancer not requiring 
treatment; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in therapy 
or hospitalization for worsening disease during the 6 weeks prior to enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a single 
antiepileptic agent; 
i. 
Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
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• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed); 
• 
Current or anticipated use of disease modifying doses of systemic anti-rheumatic 
drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and 
biologic disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, 
adalimumab or etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the subject 
or require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
j. 
Lack of acceptable sites for ID injection and EP considering the skin above the 
deltoid and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
ICD or pacemaker (to prevent a life-threatening arrhythmia) that is located 
ipsilateral to the deltoid injection site (unless deemed acceptable by a 
cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation site; 
k. Blood donation or transfusion within 1 month prior to Day 0; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the past 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
 
DISCONTINUATION/WITHDRAWAL OF CLINICAL TRIAL SUBJECTS 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the Investigator should any untoward effect occur. In addition, the 
Investigator or the Sponsor has the right to discontinue a subject from the trial at any time. 
The Investigator must notify the Sponsor immediately when a subject has been 
discontinued/withdrawn due to an Adverse Event (AE). If a subject withdraws from the trial 
or is discontinued from the trial prior to trial completion, all applicable activities scheduled 
for the final trial visit (i.e., Day 393) should be performed at the time of 
discontinuation/withdrawal if the subject agrees. Any related AEs, AESIs, and/or Serious 
Adverse Events (SAEs) present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.9. 
Unless a subject refuses to continue participation, all follow-up visits and procedures 
should be completed as indicated in the Schedule of Events (Table 3 and Table 4) 
following the second dose whether or not the subject has completed both doses. 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. In cases where 
the subject does not return for the rescheduled visit or cannot be reached to reschedule 
the missed visit, the site should make every effort to regain contact with the subject (3 
telephone calls and if that fails, then a certified letter to the subject’s last known mailing 
address) so that the subject’s disposition can be considered as withdrawn from the study 
(i.e. lost to follow-up). If the contact with subject is re-established, site should contact 
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medical monitor to discuss whether subject can continue study treatment or follow-up 
visits for the study. For all other subjects withdrawing from the study, an alternative reason 
for discontinuation should be recorded in the eCRF. 
Reasons for discontinuation/withdrawal from the trial may include but are not limited to the 
following: 
• 
Subject withdrawal of consent at any time; 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardize the 
subject’s safety if he or she continues in the trial; 
• 
Investigator, DSMB or Sponsor determines it is in the best interest of the subject; 
• 
Subject non-compliance. 
Every effort should be made to obtain information on subjects who withdraw from the trial. 
The primary reason for withdrawal from the trial should be documented on the appropriate 
CRF. However, subjects will not be followed for any reason after consent has been 
withdrawn. Data and/or samples collected prior to withdrawal of consent will be analyzed.  
Reasons for discontinuing subject dosing may include but are not limited to the following: 
• 
Adverse Event (Adverse Reaction); 
• 
The Investigator or trial coordinator must notify the Sponsor immediately when a 
subject has been discontinued/withdrawn due to an Adverse Event (AE). 
• 
Any medical condition that may jeopardize the subject’s safety if he or she continues 
on trial; 
• 
Pregnancy. 
 
CLINICAL TRIAL INVESTIGATIONAL PRODUCT INFORMATION 
 
INVESTIGATIONAL PRODUCT (IP) AND STUDY DEVICE 
 INO-4800 AND PLACEBO 
Investigational product is defined as a pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in the study, whether blinded or unblinded. 
INO-4800 is the active investigational product to be used in this study. The INO-4800 drug 
product contains 10 mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM 
sodium chloride and 15 mM sodium citrate). pGX9501 is a DNA plasmid expressing a 
synthetic consensus (SynCon®) sequence of the SARS-CoV-2 full length Spike 
glycoprotein. 
Phase 2 segment: 
Active Investigational Product (INO-4800): A volume of 0.4 mL will be filled into 2-mL glass 
vials that are fitted with rubber stoppers and sealed aluminum caps. 
Placebo (SSC-0001): Sterile saline sodium citrate (SSC) buffer, which contains sterile 150 
mM sodium chloride and 15 mM sodium citrate in 10-mL glass vials, stoppered, and 
sealed with aluminum caps. 
Phase 3 segment: 
Active Investigational Product (INO-4800): A volume of 1.1 mL will be filled into 2-mL glass 
vials that are fitted with rubber stoppers and sealed aluminum caps. 
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Placebo (SSC-0001): Sterile saline sodium citrate (SSC) buffer, which contains sterile 150 
mM sodium chloride and 15 mM sodium citrate at a volume of 1.1 mL in 2-mL glass vials, 
stoppered, and sealed with aluminum caps. 
 CELLECTRA® 2000 
Electroporation is a procedure used to enhance cellular DNA uptake within host cells 
following DNA vaccine ID delivery. This study will use the CELLECTRA® 2000, a portable, 
battery-powered medical device designed to generate a controlled, electric field that 
temporarily and reversibly increases cellular membrane permeability without clinically 
damaging the tissue. During the period of increased permeability, injected plasmid DNA 
can be introduced into the cells. 
As mentioned above, the CELLECTRA® 2000 device is intended to enhance the uptake 
and expression of DNA plasmid-based biologics in order to enhance vaccine efficacy. The 
DNA plasmid is delivered separately via needle and syringe ID injection immediately prior 
to the electroporation. The electroporation is accomplished through a sterile, disposable 
needle Array attached to an Applicator delivering controlled electrical pulses as follows: 
• 
An EP administration consists of four pulses. 
• 
An array of three stainless steel electrode needles is used to deliver the electrical 
pulses into the tissue. The Array needle length that penetrates into the skin and 
tissue is approximately 3.2 mm. To date, we have not had any safety concerns 
associated with the depth of the array electrode needles. Within the Array needle 
depth of 3.2 mm, there are no major blood vessels (arteries, veins) or nerve 
structures at the authorized sites of administration overlying the deltoid or the 
anterolateral quadricep muscle. There are superficial capillaries and minor nerves 
innervating the skin, including subcutaneous tissues that may be disrupted by 
needle insertion, but are extremely unlikely to result in serious injury; intradermal 
injection followed by EP of these structures poses no significant risk to the subject 
except for possibly injection site reactions. 
• 
The CELLECTRA® 2000 generates four 52ms ±1ms electrical current controlled 
DC pulses. The nominal current is set to 0.2A ±10% by modulating voltage, or 
capped at 200V ±5%, determined by patient tissue impedance. 
• 
The total energy delivered by the device is determined by the combination of four 
device parameters: Pulse Current, Pulse Voltage, Number of Pulses, and Pulse 
Width. The parameters are pre-set by Inovio to be a pulse current of 0.2A, a pulse 
voltage of 200V, and 4 pulses at 52ms pulse width. The parameters are verified 
prior to shipment and cannot be changed by the user.  
• 
In eight clinical trials administering ID injection followed by EP using the 
CELLECTRA® 2000, total energy delivered ranged from 0.9J to 7.8J, which have 
been generally safe and well-tolerated. In addition, Inovio has calculated the total 
maximum energy delivered ID as 8.32J for normal use conditions. Higher energy 
pulses ranging from 10.7J to 11.7J were evaluated in a guinea pig model which 
induced erythema localized to the electrode insertion site. Taken together, these 
nonclinical data and Inovio’s clinical experience provide evidence that the total 
energy delivered by the CELLECTRA® 2000 device will not result in 
unacceptable risks when delivered to patients. Further, a published study 
evaluated the Visual Analog Scale (VAS) pain scores of normal use conditions 
(0.2A), and found ID injection followed by EP using  the CELLECTRA® 2000 
device to be safe and well tolerated [63]. 
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• 
The specified current is constantly maintained through voltage modulation using 
an analog feedback loop. Measurements of voltage and current are processed for 
error reporting and collected for data logging. 
The CELLECTRA® 2000 device is comprised of three components: (1) A battery-powered 
Pulse Generator, (2) an ID Applicator that is connected to the pulse generator, and (3) a 
three-point sterile disposable ID Array of stainless steel needles. 
 
DOSING REGIMENS 
Phase 2 Segment 
• 
Active Investigational Product: One or two 1.0mg ID injection(s) of INO-4800 (~0.1mL 
dose volume each) followed immediately by EP administered on Day 0 and Day 28 
(±3 days) 
• 
Placebo: One or two ID injection(s) of SSC-0001 (~0.1mL) followed immediately by 
EP administered on Day 0 and Day 28 (±3 days) 
Phase 3 Segment 
• 
Active Investigational Product: Dose level to be determined, each ID injection(s) of 
INO-4800 (~0.1mL dose volume) followed immediately by EP administered on Day 0 
and Day 28 (±3 days) 
• 
Placebo: Dose level to be determined, each ID injection(s) of SSC-0001 (~0.1mL) 
followed immediately by EP administered on Day 0 and Day 28 (±3 days) 
 BLINDING 
This study is blinded. The Sponsor, subjects and clinical site staff, with the exception of 
the site’s pharmacy personnel, will be blinded throughout the trial. There is no difference 
in appearance between INO-4800 and the placebo; however, they are distinguishable 
based on the vial size and/or labelling on the vials. In the Phase 2 segment, the vials will 
be of different sizes and have unblinded labelling. In the Phase 3 segment, the vials will 
be the same size but will have unblinded labelling. To maintain the blind, vials will only be 
handled by designated unblinded personnel (site pharmacist) at the site. 
Under exceptional circumstances, the PI may desire to unblind a subject’s dose 
assignment in case of an emergency or serious medical condition when knowledge of the 
study product or dose is deemed by the PI to be absolutely essential for proper clinical 
management of the subject. Under such emergency circumstances, the Sponsor urges 
the PI to first contact the Medical Monitor (MM) to review options before unblinding the 
subject’s dose assignment. In case of non-emergency, PI must contact MM to discuss the 
options before unblinding the subject’s dose assignment. 
The Sponsor’s pharmacovigilance staff may unblind a subject’s dose assignment for an 
SAE, unanticipated adverse device effect (UADE), or adverse event of special interest 
(AESI) when the event is assessed as related and unexpected. If expedited regulatory 
reporting is required for an event, the report may be submitted to regulatory authorities 
with the subject’s dose assignment, in accordance with local regulations. 
 
PACKAGING AND LABELING 
 INO-4800 OR PLACEBO 
Each vial of INO-4800 or placebo will be labeled consistent with the example product label 
provided in the IB.  
5.2 
5.2.1 
5.3 
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 CELLECTRA® 2000 
Please see shipping box for shipping documents and contents. 
The CELLECTRA® 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer. The CELLECTRA® 2000 User Manual 
describes all relevant contraindications, hazards, potential risks and adverse effects, 
interfering substances or devices, warnings, and precautions. Each Pulse Generator has 
a unique serial number, and each ID Applicator has a unique serial number. Each ID Array 
has a Lot Number and Expiration Date. Examples of device labels are provided in the IB. 
The CELLECTRA® 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. 
 
HANDLING AND STORAGE 
 INO-4800 AND PLACEBO 
INO-4800 and Placebo will be shipped at 2–8°C. If the temperature monitoring devices in 
the shipping container(s) denote temperatures outside this 2–8°C (36-46°F) range, the 
Sponsor, or its designee, should be contacted immediately. 
Upon arrival, the INO-4800 and placebo must be transferred from the shipping container 
into 2–8°C (36-46°F) storage, in a secure area, in accordance with local regulations by 
designated personnel (e.g., pharmacy personnel). The Sponsor must be notified of any 
deviations from this storage condition. Refrigerator temperature logs must be maintained 
at the clinical site and temperatures must be recorded and monitored regularly. For further 
details see Pharmacy Manual and IB. 
 CELLECTRA® 2000 
See User Manual for operating and storage conditions. 
 
PREPARATION AND DISPENSING 
In the Phase 2 segment, INO-4800 is supplied in 2-mL vials at a concentration of 10 
mg/mL at a minimum volume of 0.4 mL. SSC-0001 is supplied in 10-mL vials at a minimum 
volume of 2 mL.  
In the Phase 3 segment, INO-4800 is supplied in 2-mL vials at a concentration of 10 
mg/mL at a minimum volume of 1.1 mL.  SSC-0001 is supplied in 2-mL vials at a minimum 
volume of 1.1 mL. 
Blinded staff involved in the clinical execution of the study should not come in contact with 
vials of INO-4800 or SSC-0001. Vials will only be handled by designated unblinded 
personnel (e.g., pharmacy) at the site. When a subject is eligible for enrollment, unblinded 
personnel will draw INO-4800 or SSC-0001 into a blinded syringe in accordance with the 
subject’s randomized treatment assignment according to a randomization schedule. The 
syringe will be transferred to blinded site personnel for administration.  
Each INO-4800 and placebo vial will contain a volume of product sufficient to dose multiple 
subjects. The preparation and dispensing information will be provided in the Pharmacy 
Manual. 
 
USE OF STUDY DEVICE 
The instructions for use of the CELLECTRA® 2000 device are provided in the User 
Manual. Each clinical site will receive training for use of the CELLECTRA® 2000 device 
5.3.2 
5.4 
5.4.1 
5.4.2 
5.5 
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prior to first dose. The EP procedure must be performed by qualified personnel. Any 
individual designated to perform the procedure should be permitted by the relevant local 
authorities to administer parenteral injections to patients (e.g., MD, DO, RN) in addition to 
successfully completing device training provided by Sponsor personnel.  
 
INVESTIGATIONAL DRUG AND STUDY DEVICE ACCOUNTABILITY 
 INVESTIGATIONAL PRODUCT (IP) ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current accountability record of 
investigational products (INO-4800 or placebo) is maintained at the study site. The 
investigational products must have full traceability from the receipt of the products through 
subject use, disposal or return of the products. Records or logs must comply with 
applicable regulations and guidelines. The accountability information is provided in the 
Pharmacy Manual. 
 CELLECTRA® 2000 ACCOUNTABILITY 
The investigational site is responsible for maintaining device accountability logs. The 
device must have full traceability from the receipt of the products through subject use, 
disposal or return of the products. The site must document acknowledgement of receipt 
and notify Inovio upon receipt of study devices. This includes the content shipped and 
condition upon receipt. 
For each subject administration, there must be a record of each product used for that 
subject, i.e., Pulse Generator serial number, ID Applicator serial number, and ID Array lot 
number. The ID Applicator is reusable with a new ID Array and sheath for each procedure. 
The sterile ID Array and sheath are single use only and must be discarded after use in 
accordance with institutional policy regarding disposal of sharp needles/instruments. 
 
RETURN AND DESTRUCTION OF INVESTIGATIONAL DRUG AND STUDY DEVICE 
 INO-4800 AND PLACEBO 
Upon completion or termination of the study, all unused vials of INO-4800 or placebo must 
be destroyed at the study site in accordance with institution policy or returned to Inovio 
Pharmaceuticals, Inc., or its designee if the site cannot destroy IP. 
The used vials of INO-4800 and placebo will be discarded in accordance with the site’s 
used IP disposal procedure. It is the Investigator’s responsibility to arrange for disposal of 
all empty vials, provided that procedures for proper disposal have been established in 
accordance with applicable national, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. If requested by the Sponsor, the 
return of unused IP vials should be arranged by the responsible Inovio Representative. 
The unused IP vials should only be destroyed after being inspected and reconciled by the 
responsible Inovio Pharmaceuticals, Inc., personnel or designated Clinical Monitor. If IP 
vials are returned to Inovio Pharmaceuticals, Inc., or its designee, the IP must be 
accompanied by the appropriate documentation. The return of unused IP(s) should be 
arranged with the responsible Inovio personnel and/or Clinical Monitor. 
 RETURN OF CELLECTRA® 2000 
Upon completion or termination of the study, an Inovio Representative will provide 
instructions regarding the component(s) to be returned to Inovio Pharmaceuticals, Inc., 
destroyed onsite or shipped to a destruction vendor. 
5.7 
5.7.1 
5.7.2 
5.8 
5.8.1 
5.8.2 
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All products returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original containers. 
The return of all products identified above should be arranged by the Inovio 
Representative. The ID Arrays should be discarded in the sharps container immediately 
after use. The used ID Applicators can either be destroyed at the site, shipped to a 
destruction vendor, or returned to Inovio. If the used ID Applicators are destroyed on site, 
it is the Investigator’s responsibility to ensure that arrangements have been made for the 
disposal, written authorization has been granted by Inovio Pharmaceuticals, Inc., or its 
designee, procedures for proper disposal have been established in accordance with 
applicable regulation and guidelines and institutional procedures, and appropriate records 
of the disposal have been documented. 
 
CLINICAL TRIAL PROCEDURES AND SCHEDULE 
The Schedule of Events (36TTables 3 and 436T) in the Clinical Protocol Synopsis summarizes 
the procedures to be performed at each visit. Individual procedures are described in detail 
below. It may be necessary to perform these procedures at unscheduled time points if 
deemed clinically necessary by the Investigator. A subject will be required to provide 
informed consent (Section 6.2) prior to any study procedure being performed. Protocol 
waivers or exemptions will not be granted. Therefore, adherence to the study design and 
assessments are essential and required for study conduct. 
 
PROCEDURE BY VISIT 
Refer to Sections 6.1.1 and 6.1.2 for trial procedures and the times at which they are to 
be performed. 
 CLINICAL TRIAL SCREENING EVALUATIONS 
The assessments performed during Screening will determine the subject’s eligibility for 
the study and also their ability to comply with protocol requirements by completing all 
screening assessments. The following screening evaluations will be performed for both 
Phase 2 and Phase 3 segments within 30 days prior to dosing on Day 0. All screening 
assessment values must be reviewed prior to the first Study IP administration.  
If a subject does not meet an inclusion or exclusion criterion due to a transient and non-
clinically significant event at Screening, relevant Screening evaluations may be repeated 
within the same 30-day Screening period. If the subject fails twice, they will be considered 
a screen failure. 
• 
Signed and dated informed consent (Section 6.2); 
• 
Review and confirm all inclusion/exclusion criteria (Section 4.1 and 4.2); 
• 
Obtain and document complete medical history, surgical history (including all 
clinically significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Section 6.1.1.1); 
• 
Collect demographics and document any ongoing, pre-existing conditions; 
• 
Collect socio-behavioral assessment information (Section 6.4); 
• 
Collect AEs (Section 6.4.4); 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Record height and weight (Section 6.4); 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
6.0 
6.1 
6.1.1 
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• 
Collect blood for serum pregnancy test (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9);  
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.9). 
6.1.1.1 
Medical History 
A medical history will be obtained by the Investigator or qualified designee at the time of 
Screening. Medical history will include all active conditions, and any other past conditions, 
as well as surgical procedures, that are considered to be clinically significant by the 
Investigator and/or occurred within the 12 weeks prior to Screening. Subjects should be 
queried about any history of Hepatitis B and Hepatitis C.  Any subject with a self-reported 
history of Hepatitis B or C who has clinically significant elevated liver enzymes at 
Screening will be excluded from the study based on inclusion criterion f. Subjects with self-
reported HIV must provide documentation of controlled HIV infection based on a CD4 
count greater than 200 cells/mm3 and an undetectable viral load within the past 3 months. 
If a recent CD4 count and/or viral load is not available, this testing should be performed at 
Screening. 
Illnesses first occurring or detected after the signing of the informed consent, or during the 
study and/or worsening of an existing illness in severity, frequency or nature after signing 
of the informed consent are to be documented as AEs on the Case Report Forms (CRF). 
Prior treatments, defined as administered up to 12 weeks prior to the time of informed 
consent and stopped prior to dosing on Day 0, should be recorded in the CRF as prior 
medications. Concomitant treatments, defined as continuing on Day 0 or new treatments 
taken at or after Day 0, should be recorded in the CRF as concomitant medications. 
 CLINICAL TRIAL EVALUATIONS AND PROCEDURES 
Once eligibility has been confirmed, the subject will be randomized to receive a treatment 
assignment (INO-4800 or placebo). Visit dates and windows must be calculated from Day 
0, unless otherwise noted. All subjects will be followed until the Day 393 Visit. All subjects 
will be followed in accordance with assessments outlined below. 
Study visits occurring within 3 weeks of an acute COVID-19 visit with confirmed SARS-
CoV-2 RT-PCR test may be conducted via telemedicine. 
6.1.2.1 
Day 0 and Day 28 (Dosing Visits) 
The following evaluations will be performed on Day 0 and Day 28 prior to dose 
administration: 
Both Phase 2 and Phase 3 segments: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Obtain any updates to medical history, surgical history (including all clinically 
significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Day 0 visit only) (Section 6.1.1.1); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect urine for urine pregnancy test (Section 6.4); 
• 
Collect blood for HIV serology (Day 0 visit only) (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Day 0 visit only) (Section 6.4.6); 
6.1.2 
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• 
Review restrictions for injection and EP (Section 6.4.8); 
• 
Randomize subject (instructions to be provided under separate cover) (Day 0 visit 
only). 
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect diary from Day 0 dose (Day 28 visit only). 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect saliva for SARS-CoV-2 RT-PCR and send to lab for testing (Section 6.4.9); 
 
The following evaluations will be performed on Day 0 and Day 28 after IP plus EP 
administration: 
• 
Collect any new AEs (Section 6.4.4); 
• 
Download EP Data; 
• 
Provide supplies for subject to use at home, as required (e.g. thermometer, wound 
guide, saliva collection kit) 
• 
Phase 2 segment only: Distribute diary 
6.1.2.2 
Post-dose phone calls 
Phase 2 segment: Day 7 and Day 35 
Phase 3 segment: Day 14  
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
 
Phase 2 segment only: 
• 
Review diary (Section 6.4). 
 
Phase 3 segment only: 
• 
Remind subject to perform at-home saliva collection (Section 6.4.9). 
6.1.2.3 
Day 42 Visit 
Both Phase 2 and Phase 3 segments: The following evaluations will be performed at this 
visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4);  
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6);  
 
Phase 2 segment only: 
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• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect diary from Day 28 visit. 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.9); 
• 
Provide supplies for subject to use at home, as required (e.g. saliva collection kit). 
6.1.2.4 
Phone calls  
Phase 2 segment: Day 56 
Phase 3 segment: Days 56, 70, 84, 98, 112, 140, 154, 168, 182, 196, 238, 266, 322, 
350, and 378 
In the Phase 3 segment, phone calls to subjects have been spaced bi-weekly 
between study visits through Day 210, and approximately monthly between visits 
from Day 210 to Day 393.   
 
Guidelines for information to be collected during the phone call can be found in the 
Phone Script. The following evaluations will be performed during the phone call: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Ask about any symptoms of COVID-19 disease; Arrange on-site visit if any signs 
and symptoms of COVID-19 disease are present (Section 6.4.10); 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Phase 3 segment only: Remind subject to perform at-home saliva collection 
(Section 6.4.9). 
6.1.2.5 
Follow up clinic visits 
Phase 2 segment: Day 210 
Phase 3 segment: Days 126, 210 and 294 Visits 
Both Phase 2 and Phase 3 segments: The following evaluations will be performed at these 
visits: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); SAEs, AESIs, and 
MAAEs will be reported after the Day 56 Visit. 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(except Day 294 visit) (Section 6.4.6); 
 
Phase 3 segment: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect saliva for SARS-CoV-2 RT-PCR; (Section 6.4.9); 
• 
Provide supplies for subject to use at home, as required (e.g. saliva collection kit). 
6.1.2.6 
Day 393 Visit or EOS 
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Phase 2 and Phase 3 segments: The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); SAEs, AESIs, and 
MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect urine pregnancy test (Section 6.4); 
• 
Collect blood for CBC with differential and serum chemistry(Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6). 
 
Phase 3 segment: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9); 
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.9); 
6.1.2.7 
COVID-19 Assessment Visit 
For both the Phase 2 and Phase 3 segments of the study, subjects will be evaluated during 
a COVID-19 assessment visit when acute COVID-19 is suspected based on symptoms or 
positive SARS-CoV-2 testing. The assessment visit may be performed in the clinic, 
subject’s vehicle, or via telemedicine and should be performed within 3 days of a positive 
SARS-CoV-2 test or site knowledge of COVID-19 symptom onset. The virologic-
confirmation of a case will be based on SARS-CoV-2 RT-PCR. 
Phase 2 and Phase 3 segments: The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); Only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Optional targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect nasal swab and saliva for SARS-CoV-2 RT-PCR detection (Section 6.4.9). 
6.1.2.8 
COVID-19 Convalescent Visit 
Phase 2 and Phase 3 segments: For subjects with confirmed SARS-CoV-2 infection 
during the trial, a convalescent visit should be scheduled approximately 28 days after 
symptom onset, or in the absence of symptoms, after the collection date of a positive 
SARS-CoV-2 test. If symptoms are ongoing at 28 days after symptom onset, the site 
should follow up with the subject via phone call or unscheduled visit after symptom 
resolution or stabilization.  
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); Only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.7); 
• 
Targeted physical examination (Section 6.4); 
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• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6); 
• 
Collect nasal swab and saliva for SARS-CoV-2 RT-PCR detection (Section 6.4.9). 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.9). 
 
INFORMED CONSENT 
All subjects must sign the informed consent prior to participating in any clinical trial-related 
procedures. The informed consent documentation must be in compliance with applicable 
regulations and GCP. Qualified clinical trial personnel will: 
• 
Meet with prospective clinical trial subjects; 
• 
Explain the clinical trial; 
• 
Provide clinical trial subjects with an Informed Consent Form (ICF) that includes the 
following in a language that is understandable to the subject: 
• 
Screening test(s) description; 
• 
Eligibility criteria for entering the clinical trial; 
• 
Clinical trial treatments and follow-up procedures description; 
• 
Explanation of the clinical trial, including but is not limited to: 
• 
Clinical trial objectives; 
• 
Potential benefits and risks; 
• 
Discomforts/inconveniences; 
• 
Subject’s rights and responsibilities. 
The subject is then requested to sign and date the ICF. A copy of the signed informed 
consent documentation must be provided to the subject. The qualified clinical trial 
personnel will document the process of obtaining informed consent within the source 
record. Signed ICFs are maintained in the subject’s source records and must be 
accessible for verification at any time. Signing of the ICF begins the 30-day screening 
period. 
 
ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number (SID), 
which identifies the subject for all clinical trial-related procedures. SIDs are a combination 
of a 4-digit site code and a 4-digit subject number. After SIDs are assigned, they cannot 
be reused or reassigned for any reason. Information regarding the SID and screen date 
will be documented on a screening and enrollment log/system and in the CRF.   
Previously screen failed subjects may be rescreened provided there is a valid documented 
reason for rescreening (i.e. changes to the person’s health or situation that would make 
them possibly eligible at this later time). If rescreening occurs, the subject will keep their 
original Subject ID.  
 
SAFETY EVALUATIONS 
PHYSICAL AND TARGETED PHYSICAL EXAM  
A full physical examination will be conducted during Screening and at study 
discharge/EOS (e.g. Day 393). A targeted physical assessment will be performed at other 
visits as determined by the Investigator based on subject symptoms. The targeted physical 
6.2 
6.3 
6.4 
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exam is optional at the COVID-19 assessment visit if the visit is conducted via 
telemedicine. 
VITAL SIGNS 
Vital signs including temperature, respiration rate, blood pressure and heart rate will be 
measured at Screening and at visits specified in the Schedule of Events (36TTables 3 and 
436T).  
At the COVID-19 Assessment and Convalescent visits, temperature, respiration rate, 
heart rate and oxygen saturation should be performed.   
HEIGHT AND WEIGHT 
Weight and height will be collected at Screening. 
SOCIO-BEHAVIORAL ASSESSMENT  
A Socio-behavioral Assessment, including self-reported smoking and vaping history, and 
self-reported history of exposure to second-hand smoke will be obtained at Screening. 
LABORATORY EVALUATIONS 
At Screening and at visits specified in the Schedule of Events (36TTables 3 and 436T), blood 
samples will be collected for safety assessments. Approximately mL 270-360 of blood will 
be drawn from each subject over the course of the study. Subjects may be asked to return 
for additional blood draws if collected blood sample is lost or unevaluable for any reason. 
Hematology [Complete blood count (CBC) with automated differential]: 
White blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit and 
platelet count will be measured at Screening and at visits specified in the Schedule of 
Events (36TTables 3 and 436T). Hemoglobin A1c will additionally be performed at Screening. 
Serum chemistry: 
Electrolytes [Sodium (Na), Potassium (K), Chloride (Cl), Bicarbonate (HCO3), Calcium 
(Ca), Phosphate (PO4)], glucose, Blood Urea Nitrogen (BUN), Creatinine (Cr),  alkaline 
phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), LDH,  
and total bilirubin (TBili) at Screening and at visits specified in the Schedule of Events 
(36TTables 3 and 436T).  
Urinalysis:  
Urine samples will be tested by dipstick for glucose, protein, and hematuria at Screening 
and at visits specified in the Schedule of Events (36TTables 3 and 436T). If abnormal (presence 
of protein, hematuria, or glucose ≥ 1+), a microscopic examination should be performed.  
Serology: 
HIV antibody or rapid test will be measured at Day 0 only.  
Antibodies to SARS-CoV-2 will be measured at Screening and at visits specified in the 
Schedule of Events (Tables 3 and 4). 
Pregnancy Testing:  
For women of childbearing potential (WOCBP), a serum pregnancy test will be obtained 
at Screening and a urine pregnancy test will be performed immediately prior to any dosing 
and at the subject’s last visit. A negative result for urine β-HCG (test must have a sensitivity 
of at least 25 mIU/mL) must be available prior to each administration of IP. If the β-HCG 
test is positive, indicating that the subject is pregnant prior to completing the specified 
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dose regimen, then no further IP will be administered. Every attempt should be made to 
follow pregnant subjects for the remainder of the study and to determine the outcome of 
the pregnancy (see Section 7.12). 
DIARY 
Diaries will be implemented in the Phase 2 segment of the protocol only.  Subjects will 
be provided a diary to record the following solicited local and systemic AEs: 
• 
Oral temperature and time taken (each daily entry before 11:59 pm) 
• 
Solicited systemic symptoms 
• 
Solicited local injection site symptoms 
• 
Concomitant medications 
The diary should be completed once daily starting the evening of each study dose through 
6 days post-dose. The completed diary post-dose 1 and post-dose 2 will be reviewed with 
the subject by the study staff during the phone calls on Day 7 and Day 35, respectively. 
The study staff will review the diary with the subject to assess for temperature, solicited 
systemic symptoms (unusually tired/feeling unwell, muscle aches, headache, nausea, 
joint pain) and solicited injection site symptoms (pain, itching, redness, swelling, bruising). 
In addition, unsolicited symptoms and concomitant medications will be collected.  
Any diary entry determined to meet the Common Terminology Criteria for Adverse Events 
version 5.0 (CTCAE) criteria for a Grade 1 or higher adverse event should be documented 
as an adverse event unless deemed part of the subject’s ongoing medical history. Injection 
site reactions should be graded per the Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, issued September 
2007 (See Section 6.4.5). If the diary entry does not meet the criteria of a Grade 1 or 
higher AE as per the relevant guidelines, Investigator clinical judgment can be used to 
determine whether the entry should be recorded as an AE and documented accordingly 
in the site’s source. For cases where the diary entry and final AE reporting (i.e. grading) 
do not agree, the reasoning should be recorded in the source documents. 
 INTRADERMAL INJECTION AND EP  
Phase 2 and Phase 3 segments: 
A complete administration procedure is defined as an ID injection (formation of a wheal) 
of IP followed by insertion of the ID Array needles (electrodes) through the skin and into 
the wheal followed by delivery of four electroporation pulses. This procedure is broadly 
described as administration because it involves more than the injection of a drug. 
Only if the deltoid area is not a suitable location for administration (see exclusion criterion 
‘j’), the ID injection can then be administered above the lateral quadriceps followed 
immediately by EP. IP must not be given within 2 cm of a tattoo, scar, keloid, or active 
lesion/rash. Also, ID injection followed immediately by EP must not be performed on the 
skin of an extremity which has any metal implants or implantable medical device (e.g., 
surgical rods, pins or joint replacements). If a subject has an implanted cardiac defibrillator 
or pacemaker, ID injection/EP must not be performed above the deltoid muscle on the 
same side of the body where the device is located. 
There are three steps that must be performed as part of the administration procedure: 
1. Injection of IP (INO-4800 or placebo) 
2. Insertion of the array into the subject’s skin 
3. Pressing the trigger button on the EP applicator  
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Table 9 below is provided as guidance on how to appropriately complete the procedure 
when injection of IP has occurred, but the subject did not receive EP. 
Table 9: Guidance for how to manage an incomplete administration after IP has 
been injected 
Was IP 
injected? 
Was the array 
inserted into skin? 
Was trigger button 
pressed? 
Action 
Yes 
Yes (if array gets 
dislodged before 
the trigger button 
is pressed, the 
same array may 
be re-inserted) 
No 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
Yes 
No 
Yes 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
Yes 
No 
No 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
 
Reinjection of IP (i.e. protocol-specified IP has already been delivered) is not permitted. 
Delivery of a second electroporation in tissue is not permitted. 
Training will be provided by the Sponsor on use of the device. 
Phase 2 segment: 
Subjects will receive a two-dose regimen of one or two 1.0mg ID injections of INO-4800 
or placebo in a volume of ~0.1 mL in an acceptable skin location for injection and 
subsequently followed immediately by EP with CELLECTRA® 2000 at Day 0 and Day 28. 
For subjects assigned to receive two injections + EP at each dosing visit, the two 
injections should be performed in acceptable locations on two different limbs. 
Phase 3 segment: 
Subjects will receive a two-dose regimen of either one or two 1.0mg ID injections of INO-
4800 or placebo in a volume of ~0.1 mL in an acceptable skin location for injection and 
subsequently followed immediately by EP with CELLECTRA® 2000 at Day 0 and Day 28. 
The dose level will be determined based on results of the study’s Phase 2 segment. 
 MANAGEMENT OF PAIN DUE TO ELECTROPORATION (EP) PROCEDURES 
In case of pain, subjects may be treated with a non-narcotic analgesic (e.g., 
acetaminophen) after injection/EP.  
Medication taken for pain management will be documented as concomitant medications. 
 ASSESSMENT OF LABORATORY ABNORMALITIES 
Samples will be collected for serum chemistry, hematology, and urinalysis at the visits 
listed in the Schedule of Events (36TTables 3 and 436T) and as listed in Section 6.4.  
6.4.2 
6.4.3 
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Laboratory AEs will be assessed and graded in accordance with the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. Laboratory values that are 
not clinically significant (NCS) in the Investigator’s opinion will not be reported as AEs. 
 ASSESSMENT OF CLINICAL TRIAL ADVERSE EVENTS (AES) 
Subjects will be queried regarding the occurrence of any AEs including AEs related to 
injection site reactions, concomitant medications and new onset illness or disease during 
their study visits and phone calls. Subjects will be reminded to contact study personnel 
and immediately report any event for the duration of the study. All AEs will be captured 
from the time of the informed consent until 28 days post-dose 2 (Day 56). Following the 
Day 56 visit, only SAEs, AESIs and MAAEs will be collected. All related AEs, AESIs and 
SAEs will be followed to resolution or stabilization. These events will be recorded on the 
subject’s CRF. 
 ASSESSMENT OF INJECTION SITE REACTIONS  
Reactions arising from the IP administration procedure may be reported as administration 
site or injection site reactions. When evaluating administration (injection) site reactions 
throughout the study, it is most important to be as specific as possible by selecting the 
most appropriate term (see Table 10 below) and using the grading scale as listed in the 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, issued September 2007. Administration (injection) site reactions 
and administration site pain will be evaluated starting 30 minutes following injection/EP. 
In addition, other events associated with administration (injection) site reactions (e.g., 
hematoma, infection or necrosis) should also be reported with preferred terms specific for 
administration (injection) site reactions.  
Table 10: Grading Scale for Injection Site Reactions 
Local Reaction to 
Injectable Product 
(Grade) 
Mild (1) 
Moderate (2) 
Severe (3) 
Potentially 
Life 
Threatening 
(4) 
Pain 
Does not 
interfere with 
activity 
Repeated use 
of non-
narcotic pain 
reliever >24 
hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency 
room visit or 
hospitalization 
Tenderness 
Mild 
discomfort to 
touch 
Discomfort 
with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/Rednessa 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swellingb 
2.5-5 cm and 
no 
interference 
w/ activity 
5.1-10 cm or 
interferes with 
activity 
>10 cm or 
prevents daily 
activity 
Necrosis 
September 2007 “FDA Guidance for Industry-Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
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a In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable 
b Should be evaluated and graded using the functional scale as well as the actual measurement. 
 IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at visits specified in the Schedule of 
Events (36TTables 3 and 436T) for cellular and humoral immunology assessments. Binding 
ELISA will be evaluated at serial timepoints. Cellular sampling requires, 32 mL of whole 
blood (4 CPT tubes, each 8 mL of whole blood) be collected at each visit. Humoral 
sampling requires collection of 8.5 mL of whole blood in a single 10-mL red top serum 
collection tube to produce four serum aliquots of 1 mL each. However, baseline (Day 0) 
immunology samples are required to serve as a baseline for all subsequent immunology 
testing. Therefore, a total of 68 mL whole blood and 8 mL serum is required on Day 0 prior 
to 1st dose. Details of the immunology sample collection and shipment information will be 
provided in the Laboratory Manual.  
The additional immune responses to INO-4800 will be measured using assays that include 
a pseudovirus-based neutralization assay, flow cytometry and ELISpot. Determination of 
additional analyses using assays not specified, such as assessment of immunological 
gene expression, assessment of immunological protein expression on collected samples 
for immunological endpoints will be made on an ongoing basis throughout the trial. 
 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken at the time of Screening and 
ongoing from signing of the informed consent to study discharge that do not affect a 
subject’s eligibility for participation (see Section 4.2) must be recorded on CRFs. 
Actual or estimated start and stop dates must be provided. This information will be 
obtained from the subject and/or any available medical records. The indication for the 
medication, dose, and dose regimen will be documented.  
Therapy considered necessary for the subject’s welfare may be given at the discretion of 
the Investigator or medical provider. If the permissibility of a specific medication/treatment 
is in question, please contact the Medical Monitor. 
The decision to administer a prohibited medication/treatment (Section 6.4.8) is made with 
the safety of the clinical trial subject as the primary consideration. When possible, the 
Sponsor should be notified before the prohibited medication/treatment is administered. 
 RESTRICTIONS  
Subjects should refrain from becoming pregnant until 3 months following the last dose of 
investigational product by using appropriate contraceptive measures (see Section 4.1). 
Subjects must not receive any non-study related vaccine (e.g., influenza vaccine) within 2 
weeks prior to the first dose of IP, or within 2 weeks of (before or after) any subsequent 
dose of IP.  
Subjects must not have fever (oral temperature >38.0 degrees Celsius or 100.4o 
Fahrenheit) within 72 hours prior to each dosing. 
Subjects should not receive hydroxychloroquine for any condition, or any other 
drug/vaccine intended as COVID-19 prophylaxis during the trial, or as supplementary 
COVID-19 prophylaxis post-dose.  
Subjects should not participate in any other interventional trials for the duration of this trial. 
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6.4.7 
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Subjects must not receive disease modifying doses of anti-rheumatic drugs (e.g., 
azathioprine, cyclophosphamide, cyclosporine, methotrexate), biologic disease modifying 
drugs such as TNF-α inhibitors (e.g., infliximab, adalimumab or etanercept) and long term 
use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of prednisone 
equivalent (use of inhaled, topical, nasal, otic, and ophthalmic corticosteroids are allowed).  
 SARS-COV-2 TESTING 
Phase 2 segment: 
SARS-CoV-2 antibody and RT-PCR testing will be used during screening to test for 
previous or current SARS-CoV-2 infection. During the trial, subjects who report symptoms 
suggestive of COVID-19 will be assessed at a COVID-19 assessment visit in the clinic, 
subject’s vehicle, or via telemedicine. During this visit, a nasal swab and saliva will be 
collected to detect SARS-CoV-2 using the RT-PCR assay. For a remote visit, the subject 
will self-collect the nasal and saliva samples and the site will provide instructions to 
properly handle the samples (e.g. transport of samples to the clinic, shipment of samples 
to the testing laboratory, etc). If the subject is confirmed to be COVID-19 positive, a follow-
up nasal swab and saliva will be collected to detect SARS-CoV-2 using the RT-PCR assay 
at the COVID-19 convalescent visit. 
Phase 3 segment: 
SARS-CoV-2 antibody testing will be used during screening to test for previous SARS-
CoV-2 infection and during each subsequent visit (see Table 4: Schedule of Events) to 
identify SARS-CoV-2 infections that may occur regardless of symptoms between study 
visits. 
SARS-CoV-2 RT-PCR testing will be conducted on saliva specimens collected at 
Screening, Day 0, Day 28 and Day 393 or EOS visit. During other in-office study visits 
(see Table 4: Schedule of Events), saliva samples will be collected by clinical personnel 
and stored on site until further instruction. Bi-weekly home self-collections of saliva will be 
done by subjects, between study visits according to the Schedule of Events. Subjects will 
be provided instructions to properly handle these specimens (e.g. transport of samples to 
the clinic at the next in-person visit, shipment of samples directly to the testing laboratory, 
etc). Testing will be performed on selected saliva samples if the subject’s SARS-CoV-2 
serology test becomes positive. 
The Day 0 and Day 28 SARS-CoV-2 RT-PCR results will not be required prior to dosing 
on that day. 
If, at any time during the trial, either the SARS-CoV-2 antibody or RT-PCR test result is 
positive, the subject will be notified of the result and will be evaluated at a COVID-19 
assessment visit. During that visit, which may be conducted in the clinic, from the subject’s 
vehicle, or via telemedicine, a nasal swab and saliva will be collected to detect SARS-
CoV-2 using the RT-PCR assay.  
 COVID-19 DISEASE MONITORING 
During both the Phase 2 and Phase 3 segments of the trial, all subjects will be monitored 
for the development of symptoms suggestive of COVID-19 disease. For the Phase 3 
segment, frequent (approximately bi-weekly) scheduled clinic visits or phone calls will 
occur.  
All subjects in the trial should be instructed to do the following: 
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• 
Take their temperature daily at home starting on the Day 0 visit for the duration of 
the trial.     
• 
Monitor for symptoms suggestive of COVID-19 (e.g., feeling feverish or chills, 
cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, 
headache, new loss of taste or smell, sore throat, congestion or runny nose, 
nausea or vomiting, diarrhea) starting on the Day 0 visit for the duration of the trial.  
If at any time during the study, the subject experiences a fever of higher than 100.4°F/38°C 
or symptoms suggestive of COVID-19, the subject should contact the site. The site staff 
should arrange for a clinic visit (COVID-19 assessment visit) within 3 days of the site being 
aware of either a positive SARS-CoV-2 test or COVID-19 symptom onset. For subjects in 
the Phase 3 segment, a home saliva sample should be self-collected each day for up to 3 
days by the subject until the COVID-19 assessment visit. The COVID-19 assessment visit 
may be performed either at the clinic, in the subject’s vehicle or via telemedicine. 
Subjects with a confirmed COVID-19 diagnosis prior to dose 2 will be discontinued from 
further dosing and will be followed until EOS for safety and resolution of COVID-19. 
Subjects with confirmed SARS-CoV-2 infection will return for a convalescent visit 
approximately 28 days after symptom onset, or in the absence of symptoms, after the 
collection date of the positive SARS-CoV-2 sample. If symptoms are ongoing at 28 days 
after symptom onset, the site should follow up with the subject via phone call or 
unscheduled visit after symptom resolution or stabilization. Recovery from COVID-19 
disease requires either resolution of clinical symptoms except for loss of taste/smell or 
stabilization of symptoms and follow up testing according to Institutional policy.    
Subjects who require medical care for COVID-19 disease (or any other suspected 
condition) will be referred to their primary health care provider or a medical treatment 
facility if the Investigator believes that the subject should be managed beyond routine care 
that can be provided by the study site. Subjects referred for treatment will continue study 
follow-up according to the protocol schedule. If subjects are treated or hospitalized due to 
their illness, the study team will request COVID-19 specific test results, treatments, 
treatment outcomes and diagnostics from medical treatment facilities with the subject’s 
written permission. These results and diagnostics will be recorded in the study and/or 
safety database consistent with protocol reporting requirements. 
 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
 
SAFETY PARAMETERS 
The safety of INO-4800 will be measured and graded in accordance with the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. 
 
ADVERSE EVENTS (AES) 
Any untoward medical occurrence in a patient or clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.  
Adverse Events (AEs) include the following: 
• Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (before the administration of clinical trial drug); 
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• Any pre-existing condition that increases in severity, or changes in nature during or as 
a consequence of the clinical trial drug administration phase; 
• Complications of pregnancy (refer to Section 7.11). 
Adverse Events (AEs) do not include the following: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; however, the condition that leads to the procedure is an AE; 
• Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the Screening Visit that do not worsen; 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions); 
• Overdose without clinical sequelae; 
• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed, is not an AE; it is considered to be pre-existing and will be 
documented on the medical history CRF; 
• Uncomplicated pregnancy; 
• An induced elective abortion to terminate a pregnancy without medical reason; 
• Confirmed COVID-19 disease.  
 
ADVERSE DRUG REACTION (ADR) 
All noxious and unintended responses to a medicinal product related to any dose. This 
means that a causal relationship between the medicinal product and an adverse event is 
at least a reasonable possibility (i.e., the relationship cannot be ruled out). 
 
SERIOUS ADVERSE EVENTS (SAES) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death;  
• Is life-threatening; 
o Refers to an event in which the subject was at risk of death at the time of the event. 
It does not refer to an event which hypothetically might have caused death if it 
were more severe 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
o Includes any hospitalization in which the subject has been admitted to the hospital 
regardless the length of stay, even if the hospitalization is only a precautionary 
measure to allow continued observation. However, hospitalization (including 
hospitalization for an elective procedure) for a pre-existing condition that has not 
worsened, does not constitute an SAE 
• Results in persistent or significant disability/incapacity; 
o A substantial disruption of a person's ability to conduct normal life functions (i.e., 
the adverse event resulted in a significant, persistent or permanent change, 
impairment, damage or disruption in the subject’s body function/structure, physical 
activities and/or quality of life) 
• Results in congenital anomaly or birth defect and/or; 
• An important medical event.  
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7.4 
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o An event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse 
Clarification of Serious Adverse Events (SAEs) 
• Death itself is not an AE. Death is an outcome of an AE, but when the cause of death 
has not been provided, use the event term: death of unknown cause; 
• Confirmed COVID-19 disease that requires hospitalization is recorded on the 
Suspected COVID-19 Clinical Event CRF, and not recorded as an SAE; 
• COVID-19 disease with an outcome of death is recorded on the Suspected COVID-19 
Clinical Event CRF, and not recorded as an SAE; 
• The subject may not have been receiving an investigational medicinal product at the 
occurrence of the event; 
• Complications associated with COVID-19 disease that occur or prolong 
hospitalization are recorded on the Suspected COVID-19 Clinical Event CRF. 
 
UNEXPECTED ADVERSE DRUG REACTION 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator’s Brochure [IB] for an unapproved investigational 
product, package insert/summary of product characteristics for an approved product). 
 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects.  
A UADE is a type of SAE that requires reporting to the Sponsor in accordance with Section 
7.9. 
 
DEVICE DEFICIENCY 
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance. 
Note: Device deficiencies include malfunctions, use errors and inadequate labelling. 
 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor is responsible for the overall safety monitoring of the clinical trial. 
Safety monitoring assessments include but are not limited to:  
• Incidence of all AEs classified by system organ class, preferred term, severity and 
causal relationship to clinical trial treatment; 
• Changes in laboratory parameters; 
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• Local and systemic injection site review; special attention will be paid to the examination 
of the injection site. 
 ADVERSE EVENT OF SPECIAL INTEREST (AESI)  
An adverse event of special interest (serious or non-serious) is one of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the PI to the Sponsor can be appropriate.  
For the purpose of this clinical trial, the AESIs listed in Appendix A are to be reported to 
the Sponsor in accordance with Section 7.9. 
 MEDICALLY ATTENDED ADVERSE EVENT (MAAE) 
A medically attended adverse event (serious or non-serious) is defined as an adverse 
event that leads to an unplanned contact with a health care provider. 
 ABNORMAL LABORATORY VALUE 
The PI will annotate each abnormal lab value as clinically significant (CS) or not clinically 
significant (NCS). 
Laboratory values that are NCS in the PI’s opinion should not be reported as an adverse 
event. 
Any abnormal laboratory value that is new in onset or worsened in severity or frequency 
from the baseline condition and meets one of the following criteria will be recorded as an 
AE: 
• 
Requires therapeutic intervention or diagnostic tests; 
• 
Leads to discontinuation of further administration of the investigational product in 
the clinical trial; 
• 
Has accompanying or inducing symptoms or signs; 
• 
Is judged by the PI as clinically significant (CS). 
Abnormal laboratory values that meet the criteria of an AE or SAE should be reported in 
accordance with Section 7.9. 
 CLINICAL TRIAL STOPPING RULES 
The investigator is to immediately notify the Medical Monitor if the following are observed: 
• 
Any SAE related to study treatment; 
• 
Any Grade 4 AEs related to study treatment; 
• 
Any report of anaphylaxis related to study treatment; 
• 
Any suspected Severe COVID-19 disease case (per Sections 3.7.1.1 and Section 
3.7.1.2). 
The Medical Monitor will notify the Chair of the Safety Review Committee, who will make 
a determination as to whether to temporarily halt dosing until a more formal review of the 
case(s) is made. Such a formal review may include an ad hoc meeting of the DSMB, after 
consultation with the DSMB Chair. Following such a meeting, the DSMB chair will render 
a recommendation to the Medical Monitor regarding continuation of trial dosing. The 
Sponsor will independently investigate the case(s) and, after review of the DSMB 
7.8.1 
7.8.2 
7.8.3 
7.8.4 
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recommendations, will communicate a final decision as to whether to lift the dosing 
suspension or whether to continue dosing. These deliberations will be documented and 
will be provided to the IRBs and FDA, where required.   
 
SAFETY DATA REPORTING PERIOD, METHOD OF COLLECTION AND SUBMISSION 
All AEs will be collected from the time informed consent is obtained through Day 56. 
MAAEs, AESIs and SAEs only will continue to be collected after the Day 56 visit and will 
be followed to resolution or stabilization. This information will be captured in the CRF. 
If the PI determines that the AE meets serious criteria, then the AE will be recorded as an 
SAE. 
SAEs and AESIs will be reported to the Sponsor from the time the subject signs the 
informed consent until the last visit. 
All SAEs (regardless of causal relationship) and AESIs will be reported on the SAE Report 
Form and submitted to the Sponsor within 24 hours of becoming aware of the event. The 
SAE Report Form will be either emailed to safety.inovio@apcerls.com or faxed to
The original SAE Report Form must be kept at the clinical trial site. 
The event will be data entered into the CRF. 
 
For the events that are considered an AESI, the PI will contact the Sponsor within 24 hours 
of becoming aware of the event to discuss whether dosing should continue. 
Table 11: SAE Contact Information 
Sponsor Safety Email: safety.inovio@apcerls.com  
Sponsor Safety Fax: 
Sponsor Safety Phone: 
 
Table 12: Medical Monitor Direct Contact Information 
Primary point of contact, ICON Medical Monitor: 
, M.D.  
Email: 
 
Phone: 
 
Inovio Medical Monitor:  
 Jr., M.D., FACP, FIDSA 
Email: 
 
Cell Phone: 
 
 
All SAEs, treatment-related AEs, MAAEs and AESIs must be followed by the PI until 
resolution or return to baseline status, stabilization of the event (i.e., the expectation that 
it will remain chronic), even if it extends beyond the clinical trial reporting period or until it 
is determined that the subject is lost to follow up. 
Follow-up information is to be submitted to the Sponsor on an SAE Report Form and within 
24 hours of becoming aware of the information. 
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If medical records are submitted to the Sponsor with the SAE Report Form, the clinical 
trial site must: 
• Redact the medical records of all personal data (e.g., confidential subject data, 
Personal Identifying Information [PII]) 
• Provide the subject’s assigned identification number (SID) on the records 
 ADVERSE EVENT REPORTING 
This section provides details on reporting the safety information. 
 SUBMITTING THE INITIAL SERIOUS ADVERSE EVENT (SAE) REPORT FORM 
The PI should include as much safety information as possible when submitting the initial 
report, but the report must include the following at a minimum:  
• 
The adverse event; 
• 
The subject’s assigned identification number (SID); 
• 
Investigational product(s) (IP) and/or study device; 
• 
Investigator causal relationship to the IP(s) and/or study device; 
• 
Serious criteria; 
• 
Reporter name and contact information. 
If a case is submitted to the Sponsor with only the “minimum” information, a more detailed 
or updated follow-up report will be sent to the Sponsor as soon as possible but no later 
than three (3) calendar days after the date of the initial report. 
 RECORDING THE EVENT 
Principal Investigators (PIs) should use correct medical terminology/concepts when 
recording AEs on the EDC and SAE Report Form. The use of colloquialisms and 
abbreviations should be avoided. 
A medical diagnosis, if known, should be recorded rather than individual signs and 
symptoms. However, if the signs and/or symptoms cannot be medically characterized as 
a single diagnosis or syndrome, each individual sign and/or symptom should be recorded. 
If a diagnosis is subsequently established, all previous signs and/or symptoms will be 
subsumed and replaced with a single medical diagnosis. 
 ASSESSING SEVERITY (INTENSITY) 
Severity is used to describe the intensity of a specific event (e.g., mild, moderate, severe). 
The PI will assess and grade clinical AEs or SAEs (based on discussions with clinical trial 
subjects) in accordance with CTCAE. 
 CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS (AES) 
A causally related AE is one judged to have a possible, probable or definite relationship 
to the administration of the IP and/or the study device. An AE may also be assessed as 
not related to the IP and/or the study device. Because the PI is knowledgeable about the 
subject (e.g., medical history, concomitant medications), administers the IP, and monitors 
the subject’s response to the IP, the PI is responsible for reporting AEs and judging the 
7.10 
7.10.1 
7.10.2 
7.10.3 
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relationship between the administration of the IP and EP and a subsequent AE. The PI is 
aware of the subject’s clinical state and may have observed the event, and thus may be 
sensitive to distinctions between events due to the underlying disease process versus 
events that may be product-related.  
Principal Investigators (PIs) should use their knowledge of the clinical trial subject, the 
circumstances surrounding the event, and an evaluation of any potential alternative 
causes to determine whether an AE is considered to be related to the IP and/or the study 
device and the causal relationship reported as "Yes" or "No" accordingly. Causality should 
be assessed by the PI as related to drug, related to device, or related to both drug and 
device (i.e., related to both or indiscernible) by the following criteria: 
• 
Yes – there is a reasonable possibility that administration of the clinical trial 
treatment (drug or device or both drug and device) contributed to the event 
• 
No – there is no reasonable possibility that administration of the clinical trial 
treatment contributed to the event and there are more likely causes 
The following guidance should also be taken into consideration: 
• 
Temporal relationship of event to administration of IP and/or EP; 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
• 
Known association of the event with the IP, EP or with similar treatments; 
• 
Known association of the event with the disease under trial; 
• 
Presence of risk factors in the clinical trial subject or use of concomitant 
medications known to increase the occurrence of the event. 
The rationale for the PI’s causal assessment is to be recorded on the SAE Report Form. 
The Sponsor will assess the overall safety of the IP delivered by EP and determine 
whether to report expeditiously to the regulatory authority(ies). 
 REPORTING SUSPECTED COVID-19 DISEASE CASES DURING THE TRIAL 
For both Phase 2 and Phase 3 segments of the trial, all suspected COVID-19 disease 
cases based on reported COVID-19 symptoms and/or SARS-CoV-2 test results should be 
entered into the Suspected COVID-19 Clinical Event CRF within 24 hours of awareness. 
Cases will be tracked until final determination of whether the case meets criteria of a 
confirmed COVID-19 disease case, per the case definition. For the Phase 2 segment of 
the trial, this determination will be made by the PI. For the Phase 3 segment, this 
determination will be made by the EAC. 
If the reported COVID-19 disease case is later determined not to be a confirmed COVID-
19 case, the event (e.g. symptoms or other diagnosis), if serious, would be reported as an 
SAE within 24 hours following determination by the PI (Phase 2 segment) or notification 
by EAC (Phase 3 segment).  
If the reported COVID-19 disease case is later determined not to be a confirmed COVID-
19 case, the event (e.g. symptoms or other diagnosis), if non-serious and if occurring from 
the time of consent until 28 days post-dose 2, would be reported as an AE following 
determination by the PI (Phase 2 segment) or notification by EAC (Phase 3 segment). 
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 REPORTING PREGNANCY DURING THE CLINICAL TRIAL 
Subjects who are pregnant or expect to become pregnant prior to 3 months following the 
last dose will be excluded from participation in the clinical trial.  
All pregnancies that occur from the time of first administration of clinical trial treatment 
through study completion (i.e., Day 393) will be reported to the Sponsor. If clinical trial site 
staff become aware that a subject becomes pregnant after the first dose in the clinical trial, 
she will not be given any additional treatments with the IP. A Pregnancy Form will be 
completed by the PI and submitted to the Sponsor within 24 hours after becoming aware 
of the pregnancy. 
The PI will report this event to their IRB/REB/EC in accordance with their policies and 
procedures.  
The clinical trial site must request the subject’s permission to query pregnancy outcome 
and follow the subject for outcome of the pregnancy. The subject will continue to be 
followed for safety assessments without receiving additional IP until clinical trial discharge 
in accordance with this protocol. Procedures that are contraindicated during pregnancy, 
including additional dose administrations, must not be performed. The PI should use 
clinical judgment regarding subsequent clinical trial-related blood collection based on the 
presence or absence of anemia in each subject.  
Male subjects will be instructed through the ICF to immediately inform the PI if their partner 
becomes pregnant until study completion. A Pregnancy Form will be completed by the PI 
and submitted to the Sponsor within 24 hours after becoming aware of the pregnancy. The 
pregnant partner will be asked to sign a Pregnancy Information Collection Consent Form 
to allow for follow-up on her pregnancy. If the authorization has been signed, the PI will 
collect and report details of the course and outcome of the pregnancy in the partner of a 
male subject exposed to IP. The PI will update the Pregnancy Form with additional 
information on the course and outcome of the pregnancy and submit the form to the 
Sponsor.  
If a PI is contacted by the male subject or his pregnant partner, the PI may provide 
information on the risks of the pregnancy and the possible effects on the fetus to support 
an informed decision in cooperation with the treating physician and/or obstetrician. 
If the end of the pregnancy occurs after the clinical trial has been completed, the outcome 
will be reported directly to the Sponsor. 
 REPORTING DEVICE-RELATED COMPLAINTS OR DEFICIENCIES 
All product complaints that meet the definition of device deficiency must be reported to the 
Sponsor within 10 days of discovery, with the exception of SAEs which require 24-hour 
reporting. The error reporting or complaint form must be completed and emailed to the 
Sponsor at clinicalcomplaint@inovio.com. 
Device deficiencies include malfunctions, misuse or use errors and inadequate labeling. 
A malfunction is defined as the failure of a device to meet its performance specifications 
or otherwise perform as intended. The intended performance of a device refers to the 
intended use for which the device is labeled or marketed. 
Any problems experienced during the treatment procedure including malfunctions of the 
device, error messages displayed on the device screen following treatment, or errors that 
occur during the treatment procedure must immediately be reported to the Sponsor or its 
designee for evaluation.  
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 NOTIFYING REGULATORY AUTHORITIES AND INSTITUTIONAL REVIEW BOARDS 
(IRBS)/RESEARCH ETHICS BOARDS (REBS)/ETHICS COMMITTEES (ECS) OF SAFETY 
INFORMATION 
 SPONSOR RESPONSIBILITIES 
• 
Determine whether the safety information meets the requirements for expedited 
reporting to the applicable regulatory authorities; 
• 
Prepare and submit the safety report to the applicable regulatory authorities; 
• 
Send all participating PIs a safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) that will include a statement if there is or is not any significant new 
safety information that might influence the risk-benefit assessment of the IP and/or 
study device, sufficient to consider changes in product administration or overall 
conduct of the clinical investigation. 
 PRINCIPAL INVESTIGATOR (PI) RESPONSIBILITIES 
• 
Forward a copy of the safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) to their IRB/REB/EC as soon as practical in accordance with the 
governing policy and/or procedures; 
• 
Notify their IRB/REB/EC of safety information (i.e., SAEs, pregnancies, and AESIs) 
that occur at their clinical trial site in accordance with their local institutional policy. 
 POST-TRIAL REPORTING REQUIREMENTS 
PIs are not obligated to actively seek AEs or SAEs beyond the clinical trial reporting period. 
However, if the PI becomes aware of an AE or SAE that occurs after the Completion or 
Termination Visit and the event is deemed by the PI to be related to the clinical trial 
treatment, the PI should promptly document and report the event to the Sponsor. 
 CLINICAL TRIAL DISCONTINUATION  
INOVIO reserves the right to discontinue the clinical trial at a site or at multiple sites for 
safety or administrative reasons at any time. In particular, a clinical trial site that does not 
recruit at a reasonable rate may be discontinued. Additionally, the clinical trial may be 
discontinued at any time by an IRB/REB/EC, INOVIO, or a regulatory authority as part of 
their duties to ensure that clinical trial subjects are protected.  
If the clinical trial is discontinued and/or the clinical trial site closed for any 
reason, all IP and devices must be returned to INOVIO or its 
representative. The PI should ensure that their site file documents are complete 
prior to archiving, and provide copies of any requested documents to INOVIO 
for its Trial Master File (TMF). 
 
STATISTICAL CONSIDERATIONS 
 
STATISTICAL AND ANALYTICAL PLAN 
The formal Statistical Analysis Plan is contained in the sections that follow. 
7.14 
7.15 
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GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is an operationally seamless Phase 2/3 trial.  The subjects and data from Phase 2 
are independent from that of Phase 3.   
Phase 2 Segment:  This is a four-arm, multi-center, placebo-controlled, blinded, and 
randomized clinical trial in subjects at high risk of SARS-CoV-2 exposure. The trial’s 
primary endpoints are antigen-specific cellular immune response measured by IFN-
gamma ELISpot and neutralizing antibody responses. Secondary efficacy endpoints are 
safety measures.  Exploratory endpoints are antigen-specific cellular immune response 
measured by flow cytometry and other T and B cell measures.  
Phase 3 Segment: This is a two-arm, multi-center, placebo-controlled, double-blinded, and 
randomized clinical trial in subjects at high risk of SARS-CoV-2 exposure. The study’s 
primary endpoint is the incidence of virologically-confirmed COVID-19 disease starting 14 
days after completion of the 2-dose regimen until 12 months post-dose 2.  The primary 
hypothesis is that INO-4800 will be efficacious relative to placebo (relative efficacy > 30%). 
Secondary efficacy analyses involve non-severe cases, severe cases, cases resulting in 
death, infection, and timing of symptom resolution. Other secondary analyses concern 
safety and cellular and neutralizing antibody response. Exploratory analyses concern 
binding antibody and cellular immunological measures. 
 
STATISTICAL HYPOTHESES 
Phase 2 Segment: This is an estimation segment pertaining to immunogenicity and safety.  
There are no hypotheses. 
Phase 3 Segment: The primary hypothesis of relative efficacy greater than 30% will be 
tested with H0: p ≥ .70/(.70+k) vs. H1: p < .70/(.70+k), where p is the true proportion of 
subjects with disease who receive INO-4800 relative to the total number of subjects with 
disease, and k is the total amount of follow-up time in the placebo group divided by the 
total amount of follow-up time in the INO-4800 group. There are no other formal 
hypotheses. 
 
ANALYTICAL POPULATIONS 
Analysis populations will be: 
The per-protocol (PP) population includes all subjects who receive all doses of Study 
Treatments and have no protocol violations. Subjects in the PP population will be grouped 
to treatment arms as randomized.  Subjects excluded from the PP population will be 
identified and documented prior to unblinding of the trial database.  Analyses on the PP 
population will be primary for the analysis of efficacy in the Phase 3 segment of this trial. 
The modified intention to treat (mITT) population includes all subjects who receive at least 
one dose of Study Treatment. Subjects in this population will be grouped to treatment 
arms as randomized.  Analysis of the mITT population will be considered supportive for 
the corresponding PP population for the analysis of efficacy in the Phase 3 segment of 
this trial. 
The intention to treat (ITT) population includes all subjects who are randomized. Subjects 
in this sample will be grouped to treatment arms as randomized.  Analysis of the ITT 
population will be considered supportive for the corresponding PP population for the 
analysis of efficacy in the Phase 3 segment of this trial. 
8.2 
8.3 
8.4 
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The safety analysis population includes all subjects who receive at least one dose of Study 
Treatment. Subjects will be analyzed according to the treatments received. 
 
DESCRIPTION OF STATISTICAL METHODS 
 PRIMARY ANALYSIS 
Phase 2 Segment 
Post-baseline increases from baseline in interferon-γ ELISpot response magnitudes will 
be compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
Post-baseline increases from baseline in neutralizing antibody response magnitudes will 
be compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
Valid samples for statistical analysis purposes will be those collected within the days of 
the specified visit according to the Schedule of Events. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for these immunogenicity analyses. 
Phase 3 Segment 
The primary hypothesis of relative efficacy greater than 30% will be tested with H0: p ≥ 
0.70/(0.70+k) vs. H1: p < 0.70/(0.70+k), where p is the true proportion of subjects with 
disease who receive INO-4800 relative to the total number of subjects with disease, and 
k is the total amount of follow-up time in the placebo group divided by the total amount of 
follow-up time in the INO-4800 group. 
A p-value for this hypothesis test and corresponding 95% confidence interval will be 
computed based on the exact binomial method of Clopper-Pearson. Success will be 
concluded if the one-sided p-value is <0.025 and the corresponding lower bound of the 
two-sided 95% CI for efficacy exceeds 30%, and the point estimate for efficacy exceeds 
50%. 
For calculating k, an individual subject’s follow-up time is either: 
o the date of first disease diagnosis – date of the start of surveillance period +1 (for 
subjects who are cases), or 
o the date of last follow-up – date of the start of surveillance period +1 (for subjects who 
are non-cases). 
This methodology is based on the following. Assuming that the number of subjects who 
are cases in the INO-4800 group follows a Poisson distribution with parameter λv and the 
number of subjects who are cases in the placebo group follows a Poisson distribution with 
parameter λc, then conditional on total number of subjects with cases, t, the number of 
subjects who are cases in the INO-4800 group follows a binomial distribution with 
parameters (t, p=λv/(λv+λc)).  The relationship between p and efficacy is: efficacy = (1-
(1+k)p)/(1-p).  Therefore, testing efficacy > 30% corresponds to testing p < 0.70/(0.70+k).  
Similarly, the confidence interval for efficacy is (1-(1+k)UBp)/(1-UBp), (1-(1+k)LBp)/(1-LBp), 
where UB and LB are the Clopper-Pearson upper and lower limits for the proportion. 
The efficacy time frame is defined by symptoms beginning at any time starting from 14 
days after Dose 2 and ending 12 months after Dose 2.  Subjects identified as cases that 
started prior to this time point will be excluded.  Subjects with multiple instances meeting 
the case definition will be counted only once, using the first such instance.    
8.5 
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The PP population will be primary for the analysis of efficacy in this trial. Efficacy analysis 
using the mITT population will also be conducted counting cases from 14 days postdose 
1 as a supportive analysis.  The ITT population will also be used for a supportive analysis 
counting cases starting from randomization. 
 SECONDARY ANALYSES 
8.5.2.1 Efficacy 
Phase 3 Segment 
The secondary efficacy incidence endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-values.  
The secondary efficacy endpoint regarding timing of symptom resolution will be 
analyzed with Kaplan-Meier plots by treatment group. 
8.5.2.2 Immunogenicity 
 
   Phase 3 Segment 
Post-baseline increases from baseline in interferon-γ ELISpot response magnitudes will 
be compared between treatment groups using differences in medians and associated 
non-parametric 95% CIs. 
Post-baseline increases from baseline in neutralizing antibody response magnitudes will 
be compared between treatment groups using differences in medians and associated 
non-parametric 95% CIs. 
The summaries listed above will be stratified according to disease status of the subjects. 
Valid samples for statistical analysis purposes will be those collected within the days of 
the specified visit according to the Schedule of Events. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for these immunogenicity analyses. 
 SAFETY ANALYSES 
8.5.3.1 Adverse Events 
All AEs including injection-site reactions will be summarized among the Safety 
Population by frequency per treatment arm. These frequencies will be presented overall 
and separately by dose, and will depict overall, by system organ class and by preferred 
term, the percentage of subjects affected. Additional frequencies will be presented with 
respect to maximum severity and to strongest relationship to Study Treatment. Multiple 
occurrences of the same AE will be counted only once following a worst-case approach 
with respect to severity and relationship to Study Treatment. All serious AEs will also be 
summarized as above. 
The main summary of safety data will be based on events occurring within 30 days of 
any dose. For this summary, the frequency of preferred term events will be compared 
between study arms with risk differences and 95% confidence intervals, using the 
method of Miettinen and Nurminen. As this analysis will use many event categories, and 
produce many confidence intervals, caution should be exercised when interpreting these 
confidence intervals.  Separate summaries will be based on events occurring within 7 
days of any dose and regardless of when they occurred. 
The analyses listed above will be performed according to Phase.  
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For AE data, partial start dates will be imputed to the date of treatment to conservatively 
report the event as treatment-emergent, whenever the portion of the date is consistent 
with that of the study treatment. Otherwise, it will be imputed to the earliest date 
consistent with the partial date. A completely missing onset date will be imputed as the 
day of treatment. Partial stop dates will be assumed to be the latest possible day 
consistent with the partial date. AE duration will be calculated as (Stop Date – Start 
Date) + 1. 
8.5.3.2 Vital Signs 
Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean, standard deviation, minimum, median, and maximum 
values by time point and treatment arm, for the Safety population. Baseline is defined 
as the last measurement prior to the first treatment administration. These summaries 
will be performed according to Phase. 
 DISPOSITION 
Disposition will be summarized by treatment arm for the ITT population and will include 
the number and percentage randomized, the number and percentage who received each 
dose and the number who completed the trial.  The number and percentage of subjects 
who discontinued will be summarized overall and by reason.  The number in each analysis 
population will also be presented. These summaries will be performed according to Phase.  
 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
8.5.5.1 Demographics 
Demographic data will be summarized with descriptive statistics: mean standard 
deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables, by treatment arm, for the ITT and PP populations. 
These summaries will be performed according to Phase. 
8.5.5.2 Prior Medications 
Prior medications are those that were used before the start of the trial (prior to Day 0). 
Partial stop dates of prior medications will be assumed to be the latest possible date 
consistent with the partial date; start dates will not be imputed. Data for all prior 
medications will be summarized with percentages by treatment arm, for the ITT and PP 
populations. These summaries will be performed according to Phase. 
 INTERIM ANALYSES  
For safety issues or evidence of poor efficacy, the DSMB could recommend stopping 
enrollment at any time; no formal interim analysis will be performed for this purpose. The 
two-sided type I error of 0.05 will not be adjusted for possible early stopping due to 
futility. 
 MULTIPLICITY 
Not applicable; there is one hypothesis that will be tested. 
 MISSING VALUES 
Missing data will not be imputed. 
For the ITT analyses of efficacy in the Phase 3 segment, subjects with missing or 
unevaluable data regarding case definition will be considered cases (failures). 
8.5.4 
8.5.5 
8.5.6 
8.5.7 
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 EXPLORATORY ANALYSES  
  8.5.9.1 Immunogenicity 
Phase 2 segment 
Post-baseline increases from baseline in cellular response magnitudes will be 
compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
Valid samples for statistical analysis purposes will be those collected within the days of 
the specified visit according to the Schedule of Events. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
Phase 3 Segment 
Post-baseline antibody titers from ELISA will be compared between treatment groups 
using ratios of geometric mean titers and associated 95% t-distribution based CIs. 
Post-baseline increases from baseline in cellular response magnitudes will be 
compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
The summaries listed above will be stratified according to disease status of the 
subjects. 
Valid samples for statistical analysis purposes will be those collected within the days of 
the specified visit according to the Schedule of Events. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
8.5.9.2 Concomitant Medications 
Concomitant medications are those used during the course of the trial (on or after Day 
0). Partial stop dates of concomitant medications will be assumed to be the latest 
possible date consistent with the partial date; start dates will not be imputed. Data for 
all concomitant medications will be summarized with percentages by treatment arm, for 
the ITT and PP populations. These summaries will be performed according to Phase. 
 
SAMPLE SIZE/POWER 
Phase 3 segment: The trial is case-driven. A total of 160 observed cases will be required 
to provide 90% power to declare the vaccine efficacious (>30%), utilizing the methodology 
described in Section 8.5.1 and assuming a true efficacy of 60%.  A sample size of 6178 
subjects will be required to achieve this number of cases assuming an underlying attack 
rate of 3.7%.   
 
RANDOMIZATION AND BLINDING  
Phase 2 Segment 
Subjects will be randomized (3 INO-4800 1.0 mg, one injection: 3 INO-4800 2.0 mg, two 
injections:1 Placebo, one injection: 1 Placebo, two injections). 
The study is blinded. It is double-blinded within dose group.  Randomization and blinding 
will avoid bias in the assignment of subjects to treatment, increase the likelihood that 
known and unknown subject attributes (e.g., demographics and other baseline 
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8.6 
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characteristics) are evenly balanced between treatment groups, and enable valid 
statistical comparisons between treatment groups. 
Phase 3 Segment 
Subjects will be randomized (1 INO-4800:1 Placebo). 
The study is double-blinded. Randomization and blinding will avoid bias in the assignment 
of subjects to treatment, increase the likelihood that known and unknown subject attributes 
(e.g., demographics and other baseline characteristics) are evenly balanced between 
treatment groups, and enable valid statistical comparisons between treatment groups. 
 
ETHICS 
 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical trial is 
performed in accordance with the protocol, the principles of the Declaration of Helsinki, 
Good Clinical Practice (GCP) and applicable regulatory requirements. 
 
INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD (REB)/ETHICS 
COMMITTEE (EC) 
The Investigator will commence the clinical trial after full approval of the protocol and 
adjunctive materials (e.g., ICF, advertising) has been obtained from the applicable 
IRB/REB/EC and a copy of IRB/REB/EC approval documentation has been received by 
the Sponsor. 
Investigator responsibilities relevant to the IRB/REB/EC include the following: 
• Submit continuing review reports to the IRB/REB/EC as required, and request re-
review and approval of the clinical trial at least once a year during the conduct of 
the clinical trial; 
• Notify the Sponsor immediately of any suspected unexpected adverse drug or 
device events/effects; 
• Notify the IRB/REB/EC immediately if the Sponsor notifies the Investigator about 
any reportable safety events; 
• Obtain approval from the IRB/REB/EC for protocol amendments and for revisions 
to the consent form or subject recruitment advertisements, as required; 
• Submit reports on, and reviews of, the clinical trial and its progress to the 
IRB/REB/EC at intervals stipulated in their guidelines and in accordance with 
pertinent regulations and guidelines; 
• Maintain a file of clinical trial-related information (refer to clinical trial files) that 
includes all correspondence with the IRB/REB/EC; 
• Notify the IRB/REB/EC when the clinical trial is completed (i.e., after the last clinical 
trial visit of the final clinical trial subject); 
• After clinical trial completion (within three [3] months is recommended), provide the 
IRB/REB/EC with a final report on the clinical trial. 
Institutional Biosafety Committee (IBC) 
The Investigator will undertake the trial after full approval of the protocol and adjunctive 
materials (e.g., pharmacy manual) has been obtained from the applicable IBC and a copy 
of this approval has been received by the Sponsor. 
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Investigator responsibilities relevant to the IBC include the following: 
• 
Notify the Sponsor, IBC and NIH OSP within 30 days of any: 
o Substantial problems or violation of the NIH Guidelines 
o Significant research related accidents or illnesses 
• 
Notify the IBC to any changes to the research (dosage, procedure, etc.) or facility 
(new space, remodeling, etc.).   
 
PROTECTION OF HUMAN SUBJECTS 
 COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent must be obtained from each subject prior to the subject’s 
enrollment in the clinical trial. The process for obtaining informed consent must be 
documented in the subject’s medical record (also refer to Section 6.2). 
 COMPLIANCE WITH INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD 
(REB)/ETHICS COMMITTEE (EC) REQUIREMENTS 
This clinical trial is to be conducted in accordance with applicable IRB/REB/EC 
regulations. The Investigator must obtain approval from a properly constituted 
IRB/REB/EC prior to initiating the clinical trial and obtain re-approval or review at least 
annually. The Sponsor is to be notified immediately if the responsible IRB/REB/EC has 
been disqualified or if proceedings leading to disqualification have begun. Copies of all 
IRB/REB/EC correspondence with the Investigator should be provided to the Sponsor. 
 COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
 COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS (21CFR 
PART 11) 
When applicable, this clinical trial is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
 COMPLIANCE WITH PROTOCOL 
Subjects are not required to follow special instructions specific to the IP used in this clinical 
trial. Subjects will be provided with Investigator emergency contact information and 
advised to report all AEs. While every effort should be made to avoid protocol deviations, 
should an important deviation be discovered, the Sponsor must be informed immediately. 
Any protocol deviation impacting subject safety must be reported to the Medical Monitor 
immediately. 
 CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from, or changes to, the protocol 
without Sponsor approval and prior review and documented approval/favorable opinion of 
the protocol amendment from the IRB/REB/EC, except where necessary to eliminate 
immediate hazards to clinical trial subjects, or when the changes involve only logistical or 
administrative aspects of the clinical trial (e.g., change in monitors, change of telephone 
numbers).  
9.3 
9.3.1 
9.3.2 
9.3.3 
9.3.4 
9.3.5 
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 DATA COLLECTION, MONITORING AND REPORTING 
 CONFIDENTIALITY AND PRIVACY 
A report of the results of this clinical trial may be published or sent to the appropriate 
regulatory authorities in any country in which the clinical trial products are legally marketed 
or may ultimately be marketed, but the subject’s name/identity will not be disclosed in 
these documents. The clinical trial Sponsor, its agents, the IRB/REB/EC and regulatory 
authorities will have direct access to the subjects’ medical records for the purposes of trial-
related monitoring, auditing and inspection. Appropriate precautions will be taken to 
maintain confidentiality of medical records and personal information. 
Written Authorization and other documentation are to be obtained from each subject, 
and/or from the subject’s legally authorized representative, prior to enrollment in the 
clinical trial, in accordance with all applicable laws, regulations and/or directives relating 
to privacy and data protection. 
 SOURCE DOCUMENTS 
Source data is all information, electronic or hardcopy original records or clinical findings, 
laboratory results, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the clinical trial. 
Examples of original source data records may include:  
• Hospital records 
• Clinical and office charts 
• Laboratory notes 
• Memoranda 
• Pharmacy dispensing records 
• Recorded data from automated instruments 
• Copies of electronic medical records (EMR) certified after verification as being 
accurate and complete 
• X-rays 
• Subject files and records kept at the pharmacy, at the laboratories, at the medical 
records facility and within information technology (IT) systems that are involved in 
the clinical trial  
The Investigator/institution will permit clinical trial-related monitoring, audits, IRB/REB/EC 
review and regulatory inspections by providing direct access to source data/documents 
related to this clinical trial. 
 RECORDS RETENTION 
Upon request of the Clinical Monitor, Sponsor or its agent(s), auditor, IRB/REB/EC or 
regulatory authority, the Investigator/institution should make available for direct access all 
requested clinical trial-related records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
It is the Investigator’s responsibility to retain clinical trial essential documents for at least 
two (2) years after the last approval of a marketing application in their country and until 
there are no pending or contemplated marketing applications in their country or at least 
10.0 
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two (2) years have elapsed since the formal discontinuation of clinical development of 
INO-4800. This retention period may be superseded by local requirements. The Sponsor 
will inform the Investigator/institution when these documents are no longer needed to be 
retained. 
If the Records Retention requirements are addressed in a governing clinical trial 
agreement, it is the Investigator’s responsibility to retain clinical trial essential documents 
in accordance with the governing clinical trial agreement and applicable local 
requirements. 
 SAFETY AND QUALITY MONITORING 
 SAFETY REVIEW 
The Sponsor’s Safety Review Committee (SRC), composed of the Sponsor’s Medical 
Monitor, the ICON Medical Monitor and 1 additional physician, will review blinded safety 
and tolerability data on a regular basis throughout the trial. The SRC will meet 
approximately once per month, at a minimum. The SRC will refer any of the events listed 
in Section 7.8.4 or any other safety concerns to the DSMB Chair. 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will 
convene regularly to review all available unblinded safety data, and additionally upon 
completion of the Week 8 phone call visit for all subjects enrolled during the Phase 2 
segment. The DSMB will review unblinded safety and tolerability data, including AEs of 
clinical significance, AESIs and SAEs, as well as safety laboratory data for all enrolled 
subjects. The DSMB will also evaluate the data for signals of vaccine-enhanced disease 
and in the event of a signal, advise whether to halt the trial. The DSMB will advise 
regarding any safety concerns and will make recommendations regarding continued 
enrollment, safety pause and trial suspension. If the safety data is considered unfavorable 
during any safety review, the DSMB may recommend a trial pause or trial termination at 
which time further enrollment and administration of IP to subjects will be paused. The 
Sponsor will perform an investigation and consult with the DSMB and other experts, if 
needed, to determine whether to resume dosing of the remainder of the subjects. For 
further details, see the DSMB Charter.  
 CLINICAL MONITORING 
Clinical Monitoring will be performed by qualified Clinical Monitors who will report to the 
Sponsor or the Sponsor’s designee. The following clinical trial site monitoring tasks will be 
performed at all clinical trial sites: 
• 
Prior to subject screening at the site, a Site Initiation Visit will be conducted to 
review all relevant forms and documentation, and ensure that the clinical trial site 
staff are qualified and compliant with all applicable requirements 
• 
All clinical trial site monitoring visits will be documented 
• 
Periodic clinical trial site visits will be performed throughout the clinical trial 
• 
The Clinical Monitor will address and document the following trial conduct activities 
and obligations: 
o Assure that the trial is being conducted in accordance with the protocol, 
applicable regulatory agency regulations, and IRB/REB/EC policies. 
o Discuss trial conduct issues and incidents of noncompliance with the 
Investigator and/or trial personnel and document them on the resolution trip 
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report. Report any significant unresolved problems immediately to the 
Sponsor. 
o Remind the Investigator as necessary of the obligation to immediately report 
all SAEs and provide subsequent follow-up report of the final outcome to the 
IRB. 
o Throughout the trial, inspect source documents to ensure they are complete, 
logical, consistent, attributable, legible, contemporaneous, original, accurate 
and complete (ALCOA-C). 
o Assure that the trial facilities, including the pharmacy, continue to be 
acceptable. 
o Compare the trial CRFs with source documents to assure that the data are 
accurate and complete and that the protocol is being followed. 
o Assure that investigational drug and device accountability and reconciliation of 
records are complete and accurate. 
o Assure that all subject specimens are being stored and forwarded properly for 
testing in accordance with laboratory manual requirements. 
 FINANCING AND INSURANCE 
Inovio Pharmaceuticals is the Sponsor and Department of Defense, Joint Program 
Executive Office is providing funding for the study. Clinical trial insurance has been taken 
out according to the laws of the countries where the study will be conducted. The 
investigative site is being compensated for the conduct of this study and will follow the 
terms described in the clinical trial agreement. This agreement was executed separately 
from this clinical trial protocol. The Investigators will be required to provide full financial 
disclosure information per 21 CFR Part 54. 
 PUBLICATION POLICY 
Publication of the results of this clinical trial in its entirety will be allowed. The proposed 
presentation, abstract and/or manuscript must be made available to the Sponsor for 
review and approval in accordance with the governing clinical trial agreement. 
 
 
13.0 
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 LIST OF ABBREVIATIONS 
ADE 
Adverse Device Effect 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALCOA-C 
Attributable, Legible, Contemporaneous, Original, Accurate and Complete 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CBC 
Complete Blood Count 
Cl 
Chloride 
COVID-19 
Coronavirus Disease 2019 
Cr 
Creatinine 
CRF 
Case Report Form 
CS 
Clinically Significant 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELISpot 
Enzyme-linked immunosorbent spot 
EP 
Electroporation 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCO3 
Biocarbonate 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICD 
Implantable-Cardioverter-defibrillator 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
ID 
Intradermal 
IM 
Intramuscular 
Inovio 
Inovio Pharmaceuticals Inc. 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
K 
Potassium 
MAAE 
Medically Attended Adverse Event 
mITT 
modified Intent to Treat 
MM 
Medical Monitor 
MERS 
Middle East Respiratory Syndrome  
MERS-CoV 
Middle East Respiratory Syndrome Coronavirus 
mRNA 
Messenger RNA 
Na 
Sodium 
NCS 
Not Clinically Significant 
NHP 
Non-human Primates 
NP 
Nucleocapsid Protein 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PII 
Personal Identifying Information 
PO4 
Potassium 
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PT 
Preferred Term 
RBC 
Red blood cell 
REB 
Research Ethics Board 
RR 
Respiratory Rate 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SARS 
Severe Acute Respiratory Syndrome  
SARS-CoV 
Severe Acute Respiratory Syndrome Coronavirus 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus - 2 
SID 
Subject Identification Number 
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
SynCon 
Synthetic consensus 
TBili 
Total Bilirubin 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
 
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3.  Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 
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CONFIDENTIAL 
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T Cells in Patients With Coronavirus Disease 2019 (COVID-19). Front Immunol 2020; 11:827. 
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Virus. Cell 2020. 
34. Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. Dexamethasone in 
Hospitalized Patients with Covid-19 - Preliminary Report. The New England journal of 
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(EUA) Of Veklury® (remdesivir) For Coronavirus Disease 2019 (COVID-19) In; 2020. 
36. Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, et al. Safety, efficacy, and 
immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human 
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randomised, double-blind, placebo-controlled phase 2b trial. Lancet 2015; 386(10008):2078-
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38. Suschak JJ, Williams JA, Schmaljohn CS. Advancements in DNA vaccine vectors, non-
mechanical delivery methods, and molecular adjuvants to increase immunogenicity. Hum 
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delivery devices: vaccine-platforms for the battle against infectious diseases. Clin Exp 
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Spectr 2014; 2(6). 
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2014; 14(3):170-189. 
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239(1):62-84. 
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2014; 2(4):785-796wahren. 
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responding to emerging infectious diseases. Hum Vaccin 2009; 5(9):623-626. 
49. Keefer MC, Graham BS, Belshe RB, Schwartz D, Corey L, Bolognesi DP, et al. Studies of 
high doses of a human immunodeficiency virus type 1 recombinant glycoprotein 160 
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50. Wu F, Wang A, Liu M, Wang Q, Chen J, Xia S, et al. Neutralizing antibody responses to 
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51. Martin JE, Sullivan NJ, Enama ME, Gordon IJ, Roederer M, Koup RA, et al. A DNA vaccine 
for Ebola virus is safe and immunogenic in a phase I clinical trial. Clin Vaccine Immunol 2006; 
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52. Prud'homme GJ, Glinka Y, Khan AS, Draghia-Akli R. Electroporation-enhanced nonviral gene 
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Curr Gene Ther 2006; 6(2):243-273. 
53. Hirao LA, Wu L, Khan AS, Hokey DA, Yan J, Dai A, et al. Combined effects of IL-12 and 
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54. Rosati M, Valentin A, Jalah R, Patel V, von Gegerfelt A, Bergamaschi C, et al. Increased 
immune responses in rhesus macaques by DNA vaccination combined with electroporation. 
Vaccine 2008; 26(40):5223-5229. 
55. Curcio C, Khan AS, Amici A, Spadaro M, Quaglino E, Cavallo F, et al. DNA immunization 
using constant-current electroporation affords long-term protection from autochthonous 
mammary carcinomas in cancer-prone transgenic mice. Cancer Gene Ther 2008; 15(2):108-
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56. Ugen KE, Kutzler MA, Marrero B, Westover J, Coppola D, Weiner DB, et al. Regression of 
subcutaneous B16 melanoma tumors after intratumoral delivery of an IL-15-expressing 
plasmid followed by in vivo electroporation. Cancer Gene Ther 2006; 13(10):969-974. 
57. Tebas P, Roberts CC, Muthumani K, Reuschel EL, Kudchodkar SB, Zaidi FI, et al. Safety and 
Immunogenicity of an Anti-Zika Virus DNA Vaccine - Preliminary Report. The New England 
journal of medicine 2017. 
58. Tebas P, Kraynyak KA, Patel A, Maslow JN, Morrow MP, Sylvester AJ, et al. Intradermal 
SynCon(R) Ebola GP DNA Vaccine is Temperature Stable and Safely Demonstrates Cellular 
and Humoral Immunogenicity Advantages in Healthy Volunteers. J Infect Dis 2019. 
59. De Rosa SC, Edupuganti S, Huang Y, Han X, Elizaga M, Swann E, et al. Robust antibody 
and cellular responses induced by DNA-only vaccination for HIV. JCI Insight 2020; 5(13). 
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60. Chandrashekar A, Liu J, Martinot AJ, McMahan K, Mercado NB, Peter L, et al. SARS-CoV-2 
infection protects against rechallenge in rhesus macaques. Science 2020. 
61. Patel A, Walters J, Reuschel EL, Schultheis K, Parzych E, Gary EN, et al. Intradermal-
delivered DNA vaccine provides anamnestic protection in a rhesus macaque SARS-CoV-2 
challenge model. bioRxiv 2020:2020.2007.2028.225649. 
62. European Commission. Directorate-General: A Guideline on Summary of Product 
Characteristics (SmPC). In: EMA; 2009. 
63. Diehl MC, Lee JC, Daniels SE, Tebas P, Khan AS, Giffear M, et al. Tolerability of intramuscular 
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device in healthy volunteers. Hum Vaccin Immunother 2013; 9(10):2246-2252. 
 
 
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 APPENDICES 
 APPENDIX A: ADVERSE EVENTS OF SPECIAL INTEREST  
For the purpose of standardization across multiple vaccine platforms, including those substantially 
different from Inovio’s platform, the below table lists AEs of special interest (AESIs) relevant to 
COVID-19 vaccine development.  
Body System 
AESI 
Respiratory 
Acute respiratory distress syndrome (ARDS) 
Pneumonitis/Pneumonia 
Neurologic 
Generalized convulsion 
Aseptic meningitis 
Guillain-Barré Syndrome (GBS) 
Encephalitis/Myelitis 
Acute disseminated encephalomyelitis (ADEM) 
CNS vasculopathy (stroke) 
Hematologic 
Thrombocytopenia 
Disseminated intravascular coagulation (DIC) 
Immunologic 
Anaphylaxis 
Vasculitides 
Other 
Acute cardiac failure 
Acute kidney failure 
Septic shock-like syndrome 
 
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COVID19-311 
 
Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the Safety, 
Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-
19 Disease, Administered Intradermally Followed by Electroporation in Adults at 
High Risk of SARS-CoV-2 Exposure   
 
 
 
INNOVATE 
(Inovio INO-4800 Vaccine Trial for Efficacy) 
 
 
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
IND #: 19690 
 
Protocol Version: 5.0 
 
Protocol Version Date: 2-Apr-2021 
 
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Page 2 of 91 
 
 
 
Medical Monitor Approval Page 
 
Drug:  
INO-4800 
 
Sponsor: 
Inovio Pharmaceuticals, Inc. 
 
660 W. Germantown Pike, Suite 110 
 
Plymouth Meeting, PA 19462 
 
Medical Monitor: 
 
Jr., M.D., FACP, FIDSA 
Inovio Pharmaceuticals, Inc. 
 
 
Approval Signature: 
 
 
[Electronically signed] 
  
Jr., M.D., FACP, FIDSA 
Inovio Pharmaceuticals, Inc. 
 
 Date (ddMmmyyyy) 
 
 
CONFIDENTIAL 
The information in this document is considered privileged and confidential by Inovio 
Pharmaceuticals Inc. (INOVIO) and may not be disclosed to others except to the extent 
necessary to obtain Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics 
Committee (EC) approval and informed consent, or as required by local regulatory 
authorities. Persons to whom this information is disclosed must be informed that this 
information is privileged and confidential and that it should not be further disclosed 
without the written permission of INOVIO. Any supplemental information added to this 
document is also confidential and proprietary information of INOVIO and must be kept in 
confidence in the same manner as the contents of this document. 
 
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Principal Investigator Acknowledgement 
 
I have read and understood this Protocol and agree that it contains all details necessary to 
conduct the clinical trial. I understand that it must be reviewed by the Institutional Review Board 
(IRB)/Research Ethics Board (REB)/Ethics Committee (EC) overseeing the conduct of the clinical 
trial and approved or given favorable opinion before implementation. 
 
The Principal Investigator’s (PI’s) signature constitutes the PI’s approval of this Protocol and 
provides the necessary assurances that this clinical trial will be conducted in accordance with 
International Council for Harmonization (ICH)/Good Clinical Practice (GCP), local legal and 
regulatory requirements, and all stipulations of the Protocol. 
 
 
Principal Investigator Signature: 
 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
Principal Investigator Signature 
 
Date (ddMmmyyyy) 
 
 
 
Clinical Trial Site Number: 
 
Clinical Trial Site Name: 
 
 
 
 
 
 
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SUMMARY OF CHANGES 
 
The following is a list of significant changes from Version 4.0, dated 13-Nov-2020, to Version 5.0, 
dated 2-Apr-2021. All other changes are administrative and do not significantly affect the safety 
of subjects, trial scope, or scientific integrity of the protocol. 
 
1. The approximate number of sites and regions has been updated; 
2. The number of subjects to be enrolled in the Phase 3 segment has been increased to a total 
of 7116 subjects, inclusive of 6714 SARS-CoV-2 seronegative and 402 SARS-CoV-2 
seropositive subjects. The randomization ratio of active to placebo was increased from 1:1 to 
2:1 in the Phase 3 segment of the trial in order to increase the likelihood that subjects will 
receive INO-4800. This resulted in a change to the sample size, which was increased to 6714 
seronegative subjects in the Phase 3 segment, and a change in the number of COVID-19 
cases needed for the primary endpoint analysis to 149; 
a. The seropositive group of 402 subjects was added to evaluate primarily the safety of 
INO-4800 in those who have been previously infected with SARS-CoV-2 in order that 
future vaccinations under Emergency Use Authorization or post-licensure can be 
administered INO-4800 without the requirement of prior testing for serostatus; 
b. Two age groups will be evaluated in the Phase 3 segment: 18-50 years of age and 51 
years or older. A minimum of 10% of the overall enrollment will be subjects ≥65 years 
of age. Age has been added as a stratification factor to the Phase 3 segment of the 
trial; 
3. For the Phase 3 segment, two formal interim analyses were added and are planned for when 
50% and 75% of the COVID-19 cases accrue, respectively, and criteria were added for 
crossing subjects over from placebo to active product; 
4. The following secondary objectives have been removed for the Phase 3 segment of the trial: 
a. Time to symptom resolution in subjects developing COVID-19; 
b. Evaluation of efficacy in prevention of SARS-CoV-2 infection. 
i. Bi-weekly self-collection of saliva samples by subjects has also been 
removed from the protocol as this will no longer be necessary to support 
this objective. 
5. The following secondary and exploratory endpoints have been added for the Phase 3 segment 
of the trial: 
a. Secondary objective to assess vaccine efficacy in subjects with prior SARS-CoV-2 
infection; 
b. Exploratory endpoint to monitor vaccine efficacy against SARS-CoV-2 variants; 
c. Exploratory objective to evaluate the prevention of SARS-CoV-2 asymptomatic 
infection.  
d. Exploratory objective to assess antibody persistence;  
6. In the Phase 3 segment of the trial, the requirement for use of medically effective 
contraception will be required only during the 1-month dosing period. Urine pregnancy testing 
for women of childbearing potential will be required at Screening and prior to each dose to 
ensure that pregnant women are not dosed during the trial; 
7. The inclusion criterion that defines the target population at high risk of SARS-CoV-2 was 
refined to include additional examples and allows for the judgment of the Investigator in 
determining whether a subject falls into this high risk category for SARS-CoV-2 exposure; 
8. The subject eligibility criteria for the Phase 3 segment have been further modified to include 
those with selected medical conditions that place them at higher risk for severe COVID-
19. The protocol will allow subjects with cancer, chronic kidney disease, chronic lung 
diseases, including chronic obstructive pulmonary disease (COPD), asthma (moderate-to-
severe), interstitial lung disease, cystic fibrosis, pulmonary hypertension, neurologic 
conditions including stroke or cerebrovascular disease that do not impact cognition, diabetes 
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(type 1 or 2), hypertension, heart conditions, such as heart failure, coronary artery disease, or 
cardiomyopathies, HIV infection (CD4 count > 200 cells/mm3 or undetectable viral load), liver 
disease, obesity (BMI ≥ 30 kg/m2), sickle cell disease or thalassemia, smoking (current or 
former smoker) as long as these conditions have been stable without requiring hospitalization 
or significant medication changes within 3 months prior to planned dosing. This has also been 
added to the Phase 3 segment of the study as a stratification factor at randomization;  
9. The dose of INO-4800 for the Phase 3 segment of the study has been preliminarily indicated
as 1.0 mg. However, upon review of the Phase 2 data by age group, if the immunogenicity of
the 2.0 mg dose of INO-4800 is substantially superior to that of 1.0 mg dose, then the clinical
protocol will be updated accordingly;
10. Safety labs at Screening and Day 393 for the Phase 3 segment were removed based on safety
data from the Phase 1 study and the blinded safety data from the Phase 2 segment of the
current study. Consequently, the requirement for safety labs within the normal range or
deemed not clinically significant by the Investigator were removed from the inclusion criteria;
11. SARS-CoV-2 PCR testing specimen will be collected on Day 0 instead of at Screening. Any
subject who is suspected to have COVID-19 at Day 0 will not be dosed. If a subject’s Day 0
specimen subsequently tests positive, they will not receive the second dose of Investigational
Product (IP). Additional PCR testing timepoints have been removed, as SARS-CoV-2 infection
in seronegative subjects will be determined based on serology sample collection at in-office
visits throughout the trial;
12. The cellular immunology sample collection timepoints have been modified and will be
collected at only selected Phase 3 sites. Further details regarding the testing plan have been
included;
13. The primary endpoint for Phase 3 will be assessed using nasopharyngeal swabs.
Furthermore, the language has been updated to disallow subject self-collection of SARS-CoV-
2 RT-PCR samples that contribute to the primary endpoint. The case definition has been
revised to indicate that specimens contributing to the primary endpoint will be tested at a
central laboratory, with the exception when a subject is hospitalized, at which testing at a local
lab is permissible if obtaining a specimen for central laboratory testing is not possible.
14. Genotyping has been added to the SARS-CoV-2 testing at the COVID-19 assessment visit to
attempt to detect infection with potential SARS-CoV-2 variants;
15. It has been clarified that for the Phase 3 segment, the DSMB will also review efficacy in an
unblinded fashion. A pausing rule has been added to pause the trial based on a vaccine-to-
placebo case split of 8:0 for severe COVID-19 disease, as confirmed by the DSMB;
16. Collection of solicited injection site reactions and systemic AEs using a diary in the Phase 3
segment has been added to be administered at selected sites to further establish the safety
and tolerability of INO-4800;
17. Instructions related to cleaning and disinfecting the CELLECTRA® 2000 Pulse Generators
and ID Applicators have been included in Section 5.1.2;
18. The exclusion criterion and restrictions around receipt of investigational (including EUA or
local equivalent authorization) or licensed COVID-19 vaccine have been clarified. Selective
unblinding for the purposes of supporting any decision to receive EUA vaccine will not be
permitted;
19. A description of the Phase 2 group level unblinded analysis details has been added;
20. The IP information has been updated to include INO-4800 vials with a fill volume of 0.4 mL;
21. Additional Adverse Events of Special Interest (AESI) have been added to the table in
Appendix A.
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Inovio Pharmaceuticals, Inc. 
 
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Protocol Version: 5.0 
 
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TABLE OF CONTENTS 
Summary of Changes ................................................................................................................ 4 
Table of Contents ....................................................................................................................... 6 
Clinical Protocol Synopsis .........................................................................................................11 
Table 3 – Phase 2 Segment Schedule of Events ......................................................................22 
Table 4 – Phase 3 Segment Schedule of Events ......................................................................24 
1.0 
Introduction .................................................................................................................26 
1.1 
Background and Scientific Rationale ........................................................................... 26 
1.2 
Background Information .............................................................................................. 26 
1.2.1 
Clinical Presentation, Transmission and Immune Response .................................27 
1.2.2 
Current Treatment and Unmet Need .....................................................................28 
1.3 
Rationale for prophylactic vaccine development ......................................................... 29 
1.3.1 
DNA Vaccines.......................................................................................................29 
1.3.2 
Use of Electroporation with DNA Vaccines ...........................................................30 
1.3.3 
Inovio’s Proprietary Technology Against COVID-19 ..............................................30 
1.3.4 
Nonhuman Primate (NHP) Challenge Studies Following Vaccination with INO-4800
 .............................................................................................................................31 
1.3.5 
First-In-Human Phase 1 Trial of INO-4800 ............................................................31 
1.3.6 
Proposed Phase 2/3 Trial of INO-4800 .................................................................32 
1.3.7 
Dose and Regimen Rationale ...............................................................................32 
1.4 
Risks and Potential Benefits ....................................................................................... 33 
1.4.1 
Potential Benefits ..................................................................................................33 
1.4.2 
Product Risks........................................................................................................33 
1.4.3 
Overall Benefit/Risk Conclusion ............................................................................35 
2.0 
Objectives and Purpose ..............................................................................................35 
2.1 
Hypothesis .................................................................................................................. 35 
3.0 
Clinical Trial Design and Endpoints ............................................................................35 
3.1 
Primary Objectives ...................................................................................................... 37 
3.2 
Primary Endpoints....................................................................................................... 37 
3.3 
Secondary Objectives ................................................................................................. 37 
3.4 
Secondary Endpoints .................................................................................................. 37 
3.5 
Exploratory Objective .................................................................................................. 38 
3.6 
Exploratory Endpoints ................................................................................................. 38 
3.7 
Efficacy Assessment (Phase 3 Segment Only) ........................................................... 39 
3.7.1 
Case Definition for Virologically-confirmed COVID-19 Disease: ............................39 
3.7.2 
Case Definition for SARS-CoV-2 Asymptomatic Infection .....................................40 
3.8 
Safety Assessment ..................................................................................................... 40 
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Inovio Pharmaceuticals, Inc. 
 
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Protocol Version: 5.0 
 
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3.9 
Immunogenicity Assessment ...................................................................................... 40 
4.0 
Clinical Trial Population ..............................................................................................41 
4.1 
Inclusion Criteria ......................................................................................................... 41 
4.1.1 
Phase 2 Segment .................................................................................................41 
4.1.2 
Phase 3 Segment .................................................................................................42 
4.2 
Exclusion Criteria ........................................................................................................ 43 
4.2.1 
Phase 2 Segment .................................................................................................43 
4.2.2 
Phase 3 Segment .................................................................................................44 
4.3 
Discontinuation/Withdrawal of Clinical Trial Subjects .................................................. 45 
5.0 
Clinical Trial Investigational Product Information .........................................................46 
5.1 
Investigational Product (IP) and Study Device ............................................................ 46 
5.1.1 
INO-4800 and Placebo .........................................................................................46 
5.1.2 
CELLECTRA® 2000 ..............................................................................................47 
5.2 
Dosing Regimens ....................................................................................................... 48 
5.2.1 
Blinding .................................................................................................................48 
5.3 
Packaging and Labeling .............................................................................................. 49 
5.3.1 
INO-4800 or Placebo ............................................................................................49 
5.3.2 
CELLECTRA® 2000 ..............................................................................................49 
5.4 
Handling and Storage ................................................................................................. 49 
5.4.1 
INO-4800 and Placebo .........................................................................................49 
5.4.2 
CELLECTRA® 2000 ..............................................................................................49 
5.5 
Preparation and Dispensing ........................................................................................ 49 
5.6 
Use of Study Device ................................................................................................... 50 
5.7 
Investigational Drug and Study Device Accountability ................................................. 50 
5.7.1 
Investigational Product (IP) Accountability ............................................................50 
5.7.2 
CELLECTRA® 2000 Accountability .......................................................................50 
5.8 
Return and Destruction of Investigational Drug and Study Device .............................. 50 
5.8.1 
INO-4800 and Placebo .........................................................................................50 
5.8.2 
Return of CELLECTRA® 2000...............................................................................51 
6.0 
Clinical Trial Procedures and Schedule ......................................................................51 
6.1 
Procedure by Visit ....................................................................................................... 51 
6.1.1 
Clinical Trial Screening Evaluations ......................................................................51 
6.1.1.1 Medical History .....................................................................................................52 
6.1.2 
Clinical Trial Evaluations and Procedures .............................................................53 
6.1.2.1 Day 0 and Day 28 (Dosing Visits) .........................................................................53 
6.1.2.2 Post-dose phone calls ...........................................................................................54 
6.1.2.3 Day 42 Visit ..........................................................................................................54 
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Inovio Pharmaceuticals, Inc. 
 
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Protocol Version: 5.0 
 
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6.1.2.4 Phone calls ...........................................................................................................54 
6.1.2.5 Follow up clinic visits.............................................................................................55 
6.1.2.6 Day 393 Visit or EOS ............................................................................................55 
6.1.2.7 COVID-19 Assessment Visit .................................................................................56 
6.1.2.8 COVID-19 Convalescent Visit ...............................................................................56 
6.2 
Informed Consent ....................................................................................................... 57 
6.3 
Assignment of Subject Identification Numbers ............................................................ 57 
6.4 
Safety Evaluations ...................................................................................................... 57 
6.4.1 
Intradermal Injection and EP .................................................................................59 
6.4.2 
Management of Pain Due to Electroporation (EP) Procedures ..............................61 
6.4.3 
Assessment of Laboratory Abnormalities ..............................................................61 
6.4.4 
Assessment of Clinical Trial Adverse Events (AEs) ..............................................61 
6.4.5 
Assessment of Injection Site Reactions ................................................................61 
6.4.6 
Concomitant Medications/Treatments ...................................................................62 
6.4.7 
Restrictions ...........................................................................................................62 
6.4.8 
SARS-CoV-2 Testing ............................................................................................63 
6.4.9 
COVID-19 Disease Monitoring ..............................................................................63 
6.5 
Immunogenicity Assessments ..................................................................................... 64 
7.0 
Evaluation of Safety and Management of Toxicity ......................................................65 
7.1 
Safety Parameters ...................................................................................................... 65 
7.2 
Adverse Events (AEs) ................................................................................................. 65 
7.3 
Adverse Drug Reaction (ADR) .................................................................................... 66 
7.4 
Serious Adverse Events (SAEs) .................................................................................. 66 
7.5 
Unexpected Adverse Drug Reaction ........................................................................... 67 
7.6 
Unanticipated (Serious) Adverse Device Effect (UADE) .............................................. 67 
7.7 
Device Deficiency ....................................................................................................... 67 
7.8 
Safety and Toxicity Management ................................................................................ 67 
7.8.1 
Adverse Event of Special Interest (AESI) ..............................................................67 
7.8.2 
Medically Attended Adverse Event (MAAE) ..........................................................67 
7.8.3 
Abnormal Laboratory Value ..................................................................................67 
7.8.4 
Clinical Trial Stopping Rules .................................................................................68 
7.9 
Safety Data Reporting Period, Method of Collection and Submission ......................... 68 
7.10 
Adverse Event Reporting ............................................................................................ 69 
7.10.1 Submitting the Initial Serious Adverse Event (SAE) Report Form..........................69 
7.10.2 Recording the Event .............................................................................................70 
7.10.3 Assessing Severity (Intensity) ...............................................................................70 
7.10.4 Causal Relationship of Clinical Material to Adverse Events (AEs) .........................70 
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7.11 
Reporting Suspected COVID-19 Disease Cases During the Trial ............................... 71 
7.12 
Reporting Pregnancy During the Clinical Trial ............................................................. 71 
7.13 
Reporting Device-Related Complaints or Deficiencies ................................................ 72 
7.14 
Notifying Regulatory Authorities and Institutional Review Boards (IRBs)/Research 
Ethics Boards (REBs)/Ethics Committees (ECs) of Safety Information ....................... 72 
7.14.1 Sponsor Responsibilities .......................................................................................72 
7.14.2 Principal Investigator (PI) Responsibilities ............................................................73 
7.15 
Post-Trial Reporting Requirements ............................................................................. 73 
7.16 
Clinical Trial Discontinuation ....................................................................................... 73 
8.0 
Statistical Considerations ...........................................................................................73 
8.1 
Statistical and Analytical Plan ..................................................................................... 73 
8.2 
General Considerations .............................................................................................. 73 
8.3 
Statistical Hypotheses ................................................................................................. 74 
8.4 
Analytical Populations ................................................................................................. 74 
8.5 
Description of Statistical Methods ............................................................................... 74 
8.5.1 
Primary Analysis ...................................................................................................74 
8.5.2 
Secondary Analyses .............................................................................................75 
8.5.3 
Safety Analyses ....................................................................................................76 
8.5.4 
Disposition ............................................................................................................77 
8.5.5 
Demographic and Other Baseline Characteristics .................................................77 
8.5.6 
Interim Analyses ...................................................................................................77 
8.5.7 
Multiplicity .............................................................................................................78 
8.5.8 
Missing Values......................................................................................................78 
8.5.9 
Exploratory Analyses ............................................................................................78 
8.6 
Sample Size/Power ..................................................................................................... 79 
8.7 
Randomization and Blinding ....................................................................................... 80 
9.0 
Ethics .........................................................................................................................80 
9.1 
Investigator and Sponsor Responsibilities ................................................................... 80 
9.2 
Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics Committee (EC)
 ................................................................................................................................... 80 
9.3 
Protection of Human Subjects ..................................................................................... 81 
9.3.1 
Compliance with Informed Consent Regulations ...................................................81 
9.3.2 
Compliance with Institutional Review Board (IRB)/Research Ethics Board 
(REB)/Ethics Committee (EC) Requirements ........................................................81 
9.3.3 
Compliance with Good Clinical Practice ................................................................81 
9.3.4 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11) .....81 
9.3.5 
Compliance with Protocol .....................................................................................81 
9.3.6 
Changes to the Protocol .......................................................................................82 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 2-Apr-2021 
CONFIDENTIAL 
Protocol Version: 5.0 
 
Page 10 of 91 
 
10.0 
Data Collection, Monitoring and Reporting ..................................................................82 
10.1 
Confidentiality and Privacy .......................................................................................... 82 
11.0 
Source Documents .....................................................................................................82 
11.1 
Records Retention ...................................................................................................... 83 
12.0 
Safety and Quality Monitoring .....................................................................................83 
12.1 
Safety Review ............................................................................................................. 83 
12.2 
Clinical Monitoring....................................................................................................... 84 
13.0 
Financing and Insurance ............................................................................................84 
14.0 
Publication Policy .......................................................................................................85 
15.0 
List of Abbreviations ...................................................................................................86 
16.0 
References .................................................................................................................88 
17.0 
Appendices .................................................................................................................91 
17.1 
APPENDIX A: Adverse Events of Special Interest ...................................................... 91 
 
 
 
 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 2-Apr-2021 
CONFIDENTIAL 
Protocol Version: 5.0 
 
Page 11 of 91 
 
CLINICAL PROTOCOL SYNOPSIS 
Protocol Title: Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the 
Safety, Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-19 
Disease, Administered Intradermally Followed by Electroporation in Adults at High Risk of 
SARS-CoV-2 Exposure 
Protocol Number: COVID19-311 
Clinical Trial Phase: 2/3 
Estimated Number of Clinical Trial Centers and Countries/Regions: Approximately 50 
centers globally. Final country list to be determined. 
Background:   
INO-4800 is a prophylactic vaccine under development against SARS-CoV-2, the causative 
agent of COVID-19. INO-4800 contains the plasmid pGX9501, which encodes for the full 
length of the Spike glycoprotein of SARS-CoV-2. The goal of this trial is to assess the safety, 
immunogenicity and efficacy of INO-4800 to prevent COVID-19 in subjects at high risk of 
exposure to SARS-CoV-2.  
 
Clinical Trial Design:  
This is an operationally seamless Phase 2/3, randomized, placebo-controlled, multi-center trial 
to evaluate the safety, immunogenicity, and efficacy of INO-4800, administered by intradermal 
(ID) injection followed immediately by electroporation (EP) using the CELLECTRA® 2000 
device, in a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-2 
exposure. The primary objectives of this trial are to identify in seronegative subjects an optimal 
age-related dose of INO-4800 in the Phase 2 segment for a subsequent efficacy evaluation in 
the Phase 3 segment.  
 
Subjects 18 years of age and older are expected to be enrolled across two (2) segments of 
this study. In the Phase 2 segment, approximately 400 seronegative subjects will be enrolled. 
In the Phase 3 segment, approximately 6714 seronegative subjects are expected to be 
enrolled, and 402 seropositive subjects will be enrolled. The subjects and data from Phase 2 
are independent from that of Phase 3. 
 
Phase 2 Segment – Dose Selection 
In the Phase 2 segment, approximately 400 subjects 18 years of age and older will be 
evaluated across four (4) dose groups (Table 1, Figure 1). Subjects will be randomized at a 
3:3:1:1 ratio to receive either active investigational product (INO-4800) or placebo (SSC-0001) 
according to Table 1 below. Dose groups receiving INO-4800 will enroll approximately 150 
subjects per group. Dose groups receiving placebo will enroll approximately 50 subjects per 
group. Randomization will be such that approximately 240 subjects aged 18-50 years, 120 
subjects aged 51-64 years and 40 subjects aged ≥ 65 years will be enrolled. Initial enrollment 
will include subjects aged 18-50 years. Initiation of enrollment of older subjects 51-64 years of 
age and elderly subjects 65 years and older will depend on review of safety and 
immunogenicity data from those age groups generated in the Phase 1 study (COVID19-001).   
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
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CONFIDENTIAL 
Protocol Version: 5.0 
 
Page 12 of 91 
 
Table 1: Phase 2 Segment Dose Groups 
Study  
Group 
Expected 
Number of 
Subjects 
Dosing 
Days 
Number of 
Injections + EP 
per Dosing Visit 
INO-4800 
(mg) per 
injection 
INO-4800 
(mg) per 
Dosing Visit 
Total Dose 
(mg) 
INO-4800 
150 
0, 28 
1 
1.0 
1.0 
2.0 
INO-4800 
150 
0, 28 
2a 
1.0 
2.0 
4.0 
Placebo 
50 
0, 28 
1 
0 
0 
0 
Placebo 
50 
0, 28 
2a 
0 
0 
0 
Total 
400 
 
 
 
 
 
aINO-4800 or placebo will be injected ID followed immediately by EP in an acceptable location on two different limbs at each 
dosing visit. 
 
Dose selection for evaluation of efficacy in the Phase 3 segment will be based on Week 6 
immunogenicity data and Week 8 safety data from the Phase 2 segment. Group-level unblinded 
summaries and analyses of safety will be produced once the Week 8 phone call visit data are 
completed for all subjects in the Phase 2 segment. Group-level unblinded summaries and 
analyses of immunogenicity will be produced once the Week 6 visit data are completed for all 
subjects in the Phase 2 segment.  
 
Phase 3 Segment – Efficacy 
In the Phase 3 segment, approximately 6714 seronegative and 402 seropositive subjects 18 
years of age and older will be randomized at a 2:1 ratio to receive either active investigational 
product (INO-4800, 1.0 mg) or placebo (SSC-0001). See Table 2 and Figure 1.  Approximately 
half of seronegative subjects and approximately half of seropositive subjects will be 18-50 
years of age, and the other half will be ≥51 years of age. Also, a minimum of 10% of the total 
sample size will be ≥65 years of age. 
 
Subjects will be randomized in a stratified manner according to (a) age category (18-50 years 
vs. ≥51 years) on Day 0, and (b) presence or absence on Day 0 of any of the following 
underlying medical conditions that increase risk of severe COVID-19 disease, per U.S. Center 
for Disease Control (CDC) criteria [1], as listed below: 
• 
Cancer 
• 
Chronic kidney disease 
• 
Chronic lung diseases, including Chronic obstructive pulmonary disease (COPD), 
asthma (moderate-to-severe), interstitial lung disease, cystic fibrosis, pulmonary 
hypertension 
• 
Neurologic conditions including stroke or cerebrovascular disease that do not impact 
cognition 
• 
Diabetes (type 1 or type 2) 
• 
Hypertension 
• 
Heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies 
• 
HIV infection (CD4 count >200 cells/mm3 or undetectable viral load) 
• 
Liver disease 
• 
Obesity (BMI ≥ 30 kg/m2) 
• 
Sickle cell disease or thalassemia, or 
• 
Smoking (current or former smoker). 
 
 
 
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Protocol Version: 5.0 
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Table 2: Phase 3 Segment 
Treatment 
Arm 
Sero 
status 
Expected 
Number 
of 
Subjects 
Expected 
Number of 
Subjects by 
Age Group 
Dosing 
Days 
Number of 
Injections + 
EP per 
Dosing Visit 
INO-4800 
(mg) per 
injection 
INO-4800 
(mg) per 
Dosing Visit 
Total Dose 
of 
INO-4800 
(mg) 
18-50
51+b
INO-4800 
Seroneg 
4476 
2238 
2238 
0, 28 
1 
1.0 
1.0a 
2.0a 
Seropos 
268 
134 
134 
Placebo 
Seroneg 
2238 
1119 
1119 
0, 28 
1 
0 
0 
0 
Seropos 
134 
67 
67 
Total 
Seroneg 
6714 
3357 
3357 
Seropos 
402 
201 
201 
Total 
7116 
a1.0mg is the presumed dose for Phase 3 
bat least 711 subjects will be ≥65 years of age 
This segment of the trial is case-driven. Among seronegative subjects, a total of 149 observed 
cases will be required for 90% power to declare the vaccine efficacious (>30%), assuming a 
true efficacy of 60%. A sample size of 6714 seronegative subjects is expected to be required 
to achieve the 149 cases assuming an underlying attack rate of 3.7%. The actual sample size 
may differ if the observed attack rate is different than projected.  There are two formal interim 
analyses of efficacy; one when 50% of the cases accrue and one when 75% of the cases 
accrue. If the prespecified criteria for efficacy are met at either interim analysis, then enrollment 
will continue until 4500 subjects have been enrolled, and blinded follow-up will continue until 
at least those 4500 subjects have a minimum of 6 months of safety follow-up. At that point, the 
trial would be unblinded and placebo-recipients will be offered the active product.    
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12 months 
post-dose 2. All Phase 3 segment subjects will be followed for 56 weeks from the Day 0 dosing 
[i.e., Week 56 will be the planned End of Study (EOS) visit for this segment of the trial]. 
Figure 1: Enrollment and Dose Group Design 
External Committee Reviews 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will convene 
regularly to review all available unblinded safety data. For the Phase 3 segment, the DSMB 
will also review efficacy in an unblinded fashion. Additionally, for the Phase 3 segment, an 
independent, blinded Endpoint Adjudication Committee (EAC) will review and confirm COVID-
19 cases.  
Details of each committee’s scope will be provided in the respective charters. 
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Criteria for Evaluation:  
 
Research Hypothesis:  
INO-4800 delivered ID followed immediately by EP will be well-tolerated, exhibit an acceptable 
safety profile, result in generation of cellular and humoral immune responses to SARS-CoV-2 
Spike glycoprotein and provide protection against virologically-confirmed COVID-19 disease in 
subjects at high risk of SARS-CoV-2 exposure.  
 
Phase 2 Segment Objectives and Endpoints: 
 
Primary Objective 
Primary Endpoint 
1.  Evaluate the cellular and humoral 
immune response to INO-4800 
administered by ID injection followed 
immediately by EP  
  
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot 
1b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
Secondary Objective 
Secondary Endpoints 
1.  Evaluate the safety and tolerability of 
INO-4800 administered by ID injection 
followed immediately by EP    
  
1a. Incidence of solicited and unsolicited injection site 
reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)   
Exploratory Objective 
Exploratory Endpoint 
1.  Evaluate the expanded immunological 
profile of antibody response and T cell 
immune response 
  
1a.  Antigen-specific cellular immune response 
measured by flow cytometry 
1b. Expanded immunological profile which may 
include additional assessments of T and B cell 
numbers and molecular changes by measuring 
immunologic proteins and mRNA levels of genes 
of interest as determined by sample availability 
 
Phase 3 Segment Objectives and Endpoints: 
 
Primary Objective 
Primary Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease in 
subjects who are SARS-CoV-2 
negative at baseline  
 
1.   Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 (End 
of Study (EOS)) in subjects who are SARS-CoV-2 
seronegative at baseline 
Secondary Objectives 
Secondary Endpoints 
1. Evaluate the safety and tolerability of 
INO-4800    
 
1a. Incidence of solicited and unsolicited injection site 
reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
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Inovio Pharmaceuticals, Inc. 
 
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(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality 
 
2.  Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of severity in 
subjects who are SARS-CoV-2 
seronegative at baseline       
2a.  Incidence of non-severe COVID-19 disease in 
SARS-CoV-2 seronegative subjects starting 14 
days after completion of the 2-dose regimen until 
EOS  
2b. Incidence of severe COVID-19 disease in SARS-
CoV-2 seronegative subjects starting 14 days after 
completion of the 2-dose regimen until EOS 
2c. Incidence of deaths due to COVID-19 in SARS-
CoV-2 seronegative subjects starting 14 days after 
completion of the 2-dose regimen until EOS 
3.  Evaluate the cellular and humoral 
immune response to INO-4800  
3a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot  
3b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
 
4. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease in 
subjects who are SARS-CoV-2 
seropositive at baseline  
 
4.  Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 (End 
of Study (EOS)) in subjects who are SARS-CoV-
2 seropositive at baseline 
Exploratory Objective 
Exploratory Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease 
from SARS-CoV-2 variants in subjects 
who are SARS-CoV-2 seronegative at 
baseline 
1. Incidence of virologically-confirmed COVID-19 
disease from a SARS-CoV-2 variant starting 14 
days after completion of the 2-dose regimen until 
12 months post-dose 2 (End of Study (EOS)) in 
subjects who are SARS-CoV-2 seronegative at 
baseline 
2. Evaluate the efficacy of INO-4800 in 
the prevention of SARS-CoV-2 
asymptomatic infection in subjects 
who are SARS-CoV-2 seronegative at 
baseline     
2. Incidence of SARS-CoV-2 asymptomatic 
infections in SARS-CoV-2 seronegative subjects 
starting 14 days after completion of the 2-dose 
regimen until EOS 
3.  Evaluate the immunological profile by 
assessing both antibody response and 
T cell immune response  
3a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels  
3b. Antigen-specific cellular immune response such as 
measured by flow cytometry  
4. Evaluate antibody persistence  
4a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels at Week 30 or later.  
4b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay at Week 
30 or later 
 
 
Immunogenicity Assessment:  
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 2-Apr-2021 
CONFIDENTIAL 
Protocol Version: 5.0 
 
Page 16 of 91 
 
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 3 and Table 4).  Assays such as binding enzyme-linked immunosorbent assay (ELISA), 
pseudovirus-based neutralization assay, and enzyme-linked immunosorbent spot-forming 
assay (ELISpot) will be evaluated at serial timepoints. 
Safety Assessment:  
Subjects will be followed for safety during the trial through scheduled clinic visits and phone 
calls. Adverse events (AEs), regardless of relationship to study drug, will be collected from 
the time of consent until 28 days post-dose 2 (i.e., Day 56). SAEs, Medically Attended Adverse 
Events (MAAEs) and AESIs will be collected from time of consent until EOS. SAEs, AESIs 
and treatment-related AEs will be followed to resolution or stabilization. For the Phase 2 
segment and at selected sites in the Phase 3 segment, solicited local and systemic AEs will 
be collected for 7 days following each dose using a participant diary. 
Subjects will also be monitored for COVID-19.  
Please refer to the Schedule of Events (Table 3 and Table 4) for safety assessments to be 
performed.  
Efficacy Assessment (Phase 3 segment only):  
Subjects will receive either active investigational product (INO-4800) or placebo (SSC-0001) 
in a 2-dose regimen administered on Days 0 and 28 intradermally followed immediately by 
EP. Subjects will be monitored through regularly scheduled clinic visits and phone calls 
throughout the trial. Subjects will be regularly tested for SARS-CoV-2 infection using serologic 
testing. If COVID-19 disease is suspected based on symptoms per the case definition or 
laboratory testing, site personnel will arrange for a clinic visit. Subjects with symptom(s) or a 
positive SARS-CoV-2 test result will be reviewed by the EAC. 
Clinical Trial Population: 
Phase 2 segment: Healthy subjects at high risk for SARS-CoV-2 exposure who are 18 years 
and older. 
Phase 3 segment: Subjects at high risk for SARS-CoV-2 exposure including subjects at high 
risk for severe COVID-19 who are 18 years and older. 
Inclusion Criteria: Phase 2 segment 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, vital signs and 
physical examination performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar 
workers, store cashiers, hairdressers and barbers, veterinary staff, daycare 
workers, Transportation Security Administration screening staff, school 
teachers and college professors teaching in-person classes) 
2. Factory workers (when working in confined settings with large numbers of 
employees) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) 
4. User of public transportation (e.g., bus, train, subway) at least 3 times weekly 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 2-Apr-2021 
CONFIDENTIAL 
Protocol Version: 5.0 
 
Page 17 of 91 
 
5. Nursing home staff or correctional facility staff  
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists.) Physicians should not be enrolled unless they 
are assigned to dedicated COVID-19 treatment wards or other settings with 
prolonged exposure 
10. Others, if approved by the medical monitor.   
f. Screening laboratory results within normal limits for testing laboratory or are deemed 
not clinically significant by the Investigator; 
g. Must meet one of the following criteria with respect to reproductive capacity: 
1. Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
2. Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or 
tubal ligation, absence of ovaries and/or uterus in females). In the case of 
vasectomy, subjects should wait six (6) months post-vasectomy prior to 
enrolling;  
3. Use of medically effective contraception with a failure rate of < 1% per year 
when used consistently and correctly from screening until 3 months following 
last dose. Acceptable methods include:  
i. hormonal contraception including implants, injections or oral; 
ii. two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
iii. intrauterine device or intrauterine system; 
iv. abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Inclusion Criteria: Phase 3 segment 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Per investigator judgment, healthy or stable with pre-existing medical conditions that 
do not require significant change in medication or have led to a hospitalization in the 3 
months prior to enrollment or who, in the judgment of the investigator, are unlikely to 
require a significant change in therapy or hospitalization for worsening disease through 
Day 56; 
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings. Examples 
include:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar 
workers, street vendors, store cashiers, hairdressers and barbers, veterinary 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 2-Apr-2021 
CONFIDENTIAL 
Protocol Version: 5.0 
 
Page 18 of 91 
 
staff, daycare workers, airport screening staff, school teachers and college 
professors teaching in-person classes, college students attending in-person 
classes, office workers and volunteers who have multiple brief exposures to 
people regularly) 
2. Factory workers (when working in confined settings with large numbers of 
employees, meat-packing facilities) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) and delivery 
services  
4. User of public transportation (e.g., bus, train, subway) or public facilities (e.g. 
gyms) at least 3 times weekly 
5. Nursing home staff or correctional facility staff 
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, medical assistants and technicians, respiratory therapists, 
physical therapists, social workers, dentists and dental hygienists)  
10. Others, if in the opinion of the PI, the risk of COVID-19 exposure is comparable 
to the examples above.   
f. Must meet one of the following criteria with respect to reproductive capacity: 
1. Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
2. Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or 
tubal ligation, absence of ovaries and/or uterus in females). In the case of 
vasectomy, subjects should wait six (6) months post-vasectomy prior to 
enrolling;  
3. Use of medically effective contraception with a failure rate of < 1% per year 
when used consistently and correctly from screening until last dose. Acceptable 
methods include:  
i. hormonal contraception including implants, injections or oral; 
ii. two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
iii. intrauterine device or intrauterine system; 
iv. abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 
Exclusion Criteria: Phase 2 segment 
a. Acute febrile illness with temperature >100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat); 
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the Screening visit until 3 
months following the last dose; 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 2-Apr-2021 
CONFIDENTIAL 
Protocol Version: 5.0 
 
Page 19 of 91 
 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or a 
detectable viral load within the past 3 months; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous receipt of an investigational vaccine for prevention or treatment of COVID-19, 
MERS or SARS (documented receipt of placebo in previous trial would be permissible 
for trial eligibility); 
h. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg prior to first dose; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin 
cancers that only required local excision and non-metastatic prostate cancer 
not requiring treatment; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in 
therapy or hospitalization for worsening disease during the 6 weeks prior to 
enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a 
single antiepileptic agent; 
i. 
Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed); 
• 
Current or anticipated use of disease modifying doses of systemic anti-
rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, 
cyclosporine, 
methotrexate) and biologic disease modifying drugs such as TNF-α inhibitors 
(e.g., infliximab, adalimumab or etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the 
subject or require therapy that would interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results. 
j. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 2-Apr-2021 
CONFIDENTIAL 
Protocol Version: 5.0 
 
Page 20 of 91 
 
• 
Any metal implants or implantable medical device within the electroporation 
site; 
k. Blood donation or transfusion within 1 month prior to Day 0; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the past 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
 
Exclusion Criteria: Phase 3 segment 
a. Acute febrile illness with temperature ≥100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat) on Day 
0 prior to dosing; 
b. Positive serologic test for SARS-CoV-2 at Screening (this criterion only applies after 
approximately 402 subjects positive for SARS-CoV-2 serologic test are randomized, 
after which this criterion will apply to all remaining subjects); 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children starting from the Screening visit until the last dose; 
d. Positive urine pregnancy test during screening or immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or a 
detectable viral load within 3 months prior to screening; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days prior to Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous or planned receipt of an investigational (including Emergency Use 
Authorization (EUA) or local equivalent authorization) or licensed vaccine for 
prevention or treatment of COVID-19, MERS or SARS (documented receipt of placebo 
in previous trial would be permissible for trial eligibility); 
h. Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed) in the past 6 months; 
• 
Current or anticipated use of disease modifying doses of systemic anti-
rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, 
cyclosporine, 
methotrexate) and biologic disease modifying drugs such as TNF-α inhibitors 
(e.g., infliximab, adalimumab or etanercept) or others; 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the 
subject or require therapy that would interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results. 
i. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 2-Apr-2021 
CONFIDENTIAL 
Protocol Version: 5.0 
 
Page 21 of 91 
 
• 
Any metal implants or implantable medical device within the electroporation 
site; 
j. 
Blood donation or transfusion within 1 month prior to Day 0; 
k. People who work remotely or in a socially distanced setting with minimal risk of 
exposure to SARS-CoV-2; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the prior 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
Clinical Trial Treatment: 
Phase 2 Segment 
Active Investigational Product: One or two 1.0mg ID injection(s) of INO-4800 (~0.1mL dose 
volume) followed immediately by EP administered on Day 0 and Day 28 (±3 days)  
Placebo: One or two ID injection(s) of saline sodium citrate buffer (SSC-0001) (~0.1mL) 
followed immediately by EP administered on Day 0 and Day 28 (±3 days) 
Phase 3 Segment 
Active Investigational Product: One 1.0mg ID injection of INO-4800 followed immediately by 
EP administered at Day 0 and Day 28 (±3 days) 
Placebo: One ID injection of SSC-0001 followed immediately by EP administered at Day 0 
and Day 28 (±3 days) 
Formulation: 
INO-4800 is formulated in sodium chloride and sodium citrate buffer, refrigerated. Placebo 
[sterile saline sodium citrate buffer (SSC-0001)], refrigerated. 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 2-Apr-2021 
CONFIDENTIAL 
Protocol Version: 5.0 
 
Page 22 of 91 
 
TABLE 3 – PHASE 2 SEGMENT SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Tel 
#1 
Wk 
4 
Tel 
#2 
Wk
6 
Tel 
#3 
Wk 
30 
Wk 
56 
Illness 
Illness  
Screena 
Day 0 
Phone call - Day 7 (±3d) 
Day 28 
(±3d) 
Phone call - Day 35 (±3d) 
Day 42 (±5d) 
Phone Call - Day 56 (±5d) 
Day 210 (±5d) 
Day 393 (± 5d) 
COVID-19 assessment visitm  
COVID-19 convalescent visitn 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behavioral Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
Vital Signs 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
Xp 
Xp 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differentialc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Chemistryc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
HIV Serology  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis Routined 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Pregnancy Teste 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
INO-4800 or Placebo + EPf 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Download EP Datag 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Adverse Eventsh  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Samplesi 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
Humoral Samplesj 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
SARS-CoV-2 Serologyk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 RT-PCR (Saliva and Swabs) 
Xl 
 
 
 
 
 
 
 
 
 
 
Xl 
Xl 
Distribute Diary 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Review/Collect Diaryo 
 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 2-Apr-2021 
CONFIDENTIAL 
Protocol Version: 5.0 
 
Page 23 of 91 
 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0.   
b. 
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits.  
c. 
Hemoglobin A1c collected at screening only. Chemistry includes Na, K, Cl, HCO3, Ca, PO4, glucose, BUN, Cr, alkaline phosphatase, AST, ALT, LDH, total bilirubin.  
d. 
Dipstick for glucose, protein, and hematuria. Microscopic examination should be performed if dipstick is abnormal.  
e. 
Serum pregnancy test at Screening. Urine pregnancy test at other visits.  
f. 
Intradermal injection(s) in skin preferably over deltoid muscle, or alternately over anterolateral quadriceps muscle, followed by EP at Day 0 and Day 28. 
g. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
h. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
i. 
On Day 0, cellular sampling requires 64 mL of whole blood (8 Cell Preparation Tubes (CPT), each 8 mL of whole blood) prior to 1st dose. At all other time points, collect 32 mL of 
whole blood (4 CPT tubes, each 8 mL of whole blood).   
j. 
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce eight serum aliquots of 1 
mL each). At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce four serum aliquots of 1 mL each.  
k. 
SARS-CoV-2 antibody.   
l. 
Saliva specimen at Screening; Nasal swabs and saliva specimens at COVID-19 assessment and convalescent visits. Genotyping may also be performed on sample(s) collected at 
the COVID-19 assessment visit. 
m. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The assessment visit may be performed in the clinic, in the subject’s vehicle 
or at the subject’s home and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test.  
n. 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of 
symptoms, the date of positive SARS-CoV-2 test. If acute symptoms are ongoing, the site should follow up with the subject via phone call or an unscheduled visit after symptom 
resolution or stabilization.   
o. 
Diary should be reviewed at the 7-day post-dose phone call and collected at the next in-office visit. 
p. 
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation. 
 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 2-Apr-2021 
CONFIDENTIAL 
Protocol Version: 5.0 
 
Page 24 of 91 
 
TABLE 4 – PHASE 3 SEGMENT SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Tel 
#1 
Wk 
4 
Wk
6 
Tel 
#2-6 
Wk 
18 
Tel 
#7-11 
Wk 
30 
Tel 
#12-13 
Wk
42 
Tel 
#14-16 
Wk 
56 
Illness 
Illness 
Screena 
Day 0 
Phone call - Day 14 (±3d) 
Day 28 
(±3d) 
Day 42 (±5d)k 
Phone call - Days 56, 70, 84, 
98, 112 (±5d) 
Day 126 (±5d) 
Phone calls - Days 140, 154 
168, 182, 196 (±5d) 
Day 210 (±5d) 
Phone calls - Days 238, 266 
(±5d) 
Day 294 (±5d) 
Phone calls 
Days 322, 350, 378 (±5d) 
Day 393 (± 5d) 
COVID-19 assessment visitl  
COVID-19 convalescent visitm 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behavioral Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Vital Signs 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Xn 
Xn 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testc 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
INO-4800 or Placebo + EPd 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Download EP Datae 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Eventsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Samplesg 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
X 
Humoral Samplesh 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
X 
SARS-CoV-2 Serologyi 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
SARS-CoV-2 RT-PCR 
(Nasopharyngeal swabs) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
 
Distribute Diaryp 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Review/Collect Diaryq 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0. Screening and Day 0 visits may be combined if eligibility is able to be confirmed prior to dosing. If so, all assessments 
for Screening and Day 0 must be performed at the combined visit.  
b. 
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits.  
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 2-Apr-2021 
CONFIDENTIAL 
Protocol Version: 5.0 
 
Page 25 of 91 
 
c. 
In women of childbearing potential. Urine pregnancy test at all indicated visits.  
d. 
Intradermal injection(s) in skin preferably over deltoid region, or alternately over anterolateral quadriceps region, followed by EP at Day 0 and Day 28. 
e. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
f. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
g. 
On Day 0, cellular sampling requires 64 mL of whole blood prior to 1st dose. At all other time points, collect 32 mL of whole blood. Cellular samples will be collected at selected clinical sites 
(estimated to include 711 subjects) 
h. 
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce four serum aliquots of 2 mL 
each). At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce two serum aliquots of 2 mL each.  
i. 
SARS-CoV-2 antibody. 
j. 
The Day 0 RT-PCR results will not be required prior to dosing on that day. 
k. 
Day 42 visit must occur at least 10 days after Day 28 visit. 
l. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The assessment visit may be performed in the clinic, subject’s vehicle, or at a 
home visit and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test.  
m. 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of 
symptoms, the date of positive SARS-CoV-2 test. If acute symptoms are ongoing the site should follow up with the subject via phone call or unscheduled visit after symptom resolution 
or stabilization 
n. 
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation.   
o. 
Genotyping may also be performed on sample(s) collected at the COVID-19 assessment visit.  
p. 
Diaries to be used at selected sites only (estimated to include 711 subjects). 
q. 
Diary should be reviewed at the 14-day post-dose phone call or visit and collected at the next in-office visit. 
r. 
When possible, cellular and humoral immunology samples will be collected. Cellular samples will be collected at selected sites only. 
 
 
 
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1.0 
INTRODUCTION 
This document is a protocol for a human research trial to be conducted according to U.S. 
and international standards of Good Clinical Practice (GCP) (FDA Title 21 part 312, 812 
and International Conference on Harmonization (ICH) guidelines), applicable government 
regulations and Institutional research policies and procedures. 
1.1 
BACKGROUND AND SCIENTIFIC RATIONALE 
Given the continued number of cases globally, SARS-CoV-2 infections remain a serious 
unmet medical concern. Appropriate measures to prevent SARS-CoV-2 infections, 
including its variants, are not yet widely available. 
1.2 
BACKGROUND INFORMATION 
In late 2019, a cluster of cases of pneumonia of unknown etiology was reported in Wuhan, 
Hubei province, China [2-4]. These cases were announced on January 6, 2020 as testing 
negative for influenza, severe acute respiratory syndrome (SARS), and Middle East 
respiratory syndrome (MERS). On January 7, 2020 a novel virus was isolated by the 
Chinese Center for Disease Control and Prevention (CDC) from the throat swab sample 
of a patient, and the isolate was named “Wuhan-Hu-1.” The gene sequence of that isolate 
was then generated and determined to be of a novel coronavirus [5, 6]. That gene 
sequence was publicly posted on January 10, and the novel coronavirus was preliminarily 
named 2019-nCoV. Subsequently, on February 11, 2020, the virus was named SARS-
CoV-2 by the International Committee on Taxonomy of Viruses (ICTV) [7, 8], due to its 
similarity with the original SARS virus. That same day, the World Health Organization 
(WHO) announced a specific name of the disease, “COVID-19,” associated with infection 
by this novel coronavirus, as based on the novel coronavirus origin and year of first 
reported cases. The first cluster of human cases identified comprised people who worked, 
visited, or lived around the local Huanan seafood wholesale market in Wuhan, where live 
animals and fresh meat and fish were on sale, suggesting that an animal was the source 
of the novel respiratory virus being transmitted to humans.  
Epidemiologic data suggest that droplets expelled during face-to-face exposure during 
talking, coughing, or sneezing is the most common mode of transmission while contact 
surface spread remains yet another possible mode of transmission [9].  
SARS-CoV-2 infection rapidly emerged as a global threat to public health, joining other 
coronavirus-related diseases, such as SARS and MERS. COVID-19 was declared a 
Public Health Emergency of International Concern (PHEIC) by the WHO on January 20, 
2020, and was declared a pandemic on March 11, 2020 [10], associated with substantial 
morbidity and mortality [11]. As of July 25, 2020, a total of nearly 16 million laboratory-
confirmed COVID-19 cases have been reported internationally, including over 643,000 
deaths [12]. However, given the lack of widespread testing, the true number of cases of 
COVID-19 is likely far higher than reported. Preliminary results from large U.S.-based 
seroepidemiological surveys indicate an estimated incidence rate of SARS-CoV-2 
infections to be 6 to 24 times that of the number of reported cases of COVID-19 [13].  
An article in JAMA by Wu and McGoogan [14] provided a summary of a major report by 
the Chinese Center for Disease Control and Prevention (China CDC) [15]. Of a total of 
72,314 case records, 44,672 (62%) were confirmed as SARS-CoV-2 infections based on 
positive viral nucleic acid test results on throat swabs, 16,186 (22%) as suspected cases 
based on symptoms and exposures only, 10,567 (15%) as clinically diagnosed based on 
symptoms, exposures, and presence of lung imaging features consistent with coronavirus 
pneumonia, and 889 (1%) as asymptomatic cases based on a positive viral nucleic acid 
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test result but lacking typical symptoms including fever, dry cough, and fatigue [16]. The 
overall case-fatality ratio (CFR) was 2.3% (1023 deaths among 44,672 confirmed cases). 
No deaths occurred in the group aged 9 years and younger, but cases in those aged 70 
to 79 years had an 8.0% CFR and cases in those aged 80 years and older had a 14.8% 
CFR. The CFR was 49.0% among critical cases. CFR was elevated among those with 
preexisting comorbid conditions - 10.5% for cardiovascular disease, 7.3% for diabetes, 
6.3% for chronic respiratory disease, 6.0% for hypertension, and 5.6% for cancer [16]. 
These initial reports of the CFR documented the level of seriousness of COVID-19.  
Given the novelty of SARS-CoV-2, its rapid spread among humans and its associated 
morbidity and mortality, there has been an explosion of epidemiological, clinical, virologic, 
and other scientific data regarding the propagation of effects of this virus emerging from 
China, the United States, and many other countries. These data have established that 1) 
SARS-CoV-2 is transmitted person-to-person [17], even from those who are asymptomatic 
or presymptomatic [18-20], 2) the virus is very infectious, with estimates of the R0 
(Reproductive number) ranging from 1.50 to 6.49, with a mean average of 3.28 and a 
median average of 2.79 [21], 3) the constellation of symptoms, signs, and an incubation 
period ranging between  2 and 14 days [22], and 4)  the asymptomatic proportion of those 
infected being substantial, perhaps as high as  80% [17, 23-25]. Further, research has 
found that the risk of death from COVID-19 increases with age and with serious, comorbid 
conditions including hypertension, diabetes, cardiovascular disease, obesity, etc.   
Finally, although much has been learned very quickly about SARS-CoV-2 and COVID-19, 
much more is still to be determined. The aforementioned CFR and similar estimates are 
from crude analyses that have only accounted for moderate to serious cases. Therefore, 
the true CFR is likely significantly lower. Further, the infection-fatality ratio (IFR), which is 
the proportion who die among all those infected regardless of any symptomology, is likely 
still even lower than the CFR, but both the CFR and IFR will not be known with certainty 
until well-designed and controlled seroepidemiology surveys have been conducted using 
well-validated antibody assays and thorough questionnaires to obtain symptom history. 
Also, the presence of natural immunity of those infected who survive and the durability of 
such natural immunity is to be determined. Thus, the existence and possibility of 
reinfection and recurrent infection is unknown. 
1.2.1 CLINICAL PRESENTATION, TRANSMISSION AND IMMUNE RESPONSE 
A study in The Lancet by Huang and colleagues [4] reported the epidemiological, clinical, 
laboratory, and radiological characteristics, as well as treatment and clinical outcomes, of 
patients with laboratory-confirmed COVID-19 pneumonia. Common symptoms at onset of 
illness were fever (n=40, 98% of 41 patients), cough (n=31, 76%), and myalgia or fatigue  
(n=18, 44%);  less  common  symptoms  were  sputum  production  (n=11, 28%  of  39 
patients),  headache  (n=3, 8%  of  38 patients), hemoptysis (n=2, 5% of 39 patients), and 
diarrhea (n=1, 3% of 38 patients). Dyspnea developed in 22 (55%) of 40 patients (median 
time from illness onset to dyspnea was 8 days [Interquartile range 5 - 13 days]). Twenty-
six (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal 
findings on chest CT scan. Complications included acute respiratory distress syndrome 
(n=12, 29%), RNAaemia (n=6, 15%), acute cardiac injury (n=5, 12%) and secondary 
infection (n=4, 10%).  
Wiersinga et al. summarized the common symptoms of COVID-19 in hospitalized patients 
as fever (70-90%), dry cough (60-86%), shortness of breath (53-80%), fatigue (38%), 
myalgias (15-44%), nausea/vomiting or diarrhea (15-39%), headache, weakness (25%) 
and rhinorrhea (7%). Anosmia and ageusia may be the sole presenting symptom in 
approximately 3% of individuals with COVID-19. Common laboratory abnormalities 
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include lymphopenia (83%), elevated inflammatory markers (e.g., erythrocyte 
sedimentation rate, C-reactive protein, ferritin, tumor necrosis factor-alpha, IL-1, IL-6) and 
abnormal coagulation parameters (e.g., prolonged prothrombin time, thrombocytopenia, 
elevated D-dimer and low fibrinogen). Common radiographic findings include bilateral, 
lower lobe infiltrates on chest radiographic imaging and bilateral, peripheral, lower-lobe 
ground-glass opacities and/or consolidation on chest computed tomographic imaging [9].  
Transmission of SARS-CoV-2 occurred mainly after days of illness [26] and was 
associated with modest viral loads in the respiratory tract early in the illness, with viral 
loads peaking approximately 10 days after symptom onset [27]. Higher viral loads were 
detected soon after symptom onset, with higher viral loads detected in the nose than in 
the throat. Analysis of these samples suggested that the viral nucleic acid shedding 
pattern of patients infected with SARS-CoV-2 resembles that of patients with influenza 
[28] and appears different from that seen in patients infected with SARS-CoV [27]. The 
viral load that was detected in the asymptomatic patient was similar to that in the 
symptomatic patients, which suggests the transmission potential of asymptomatic or 
minimally symptomatic patients [11]. The SARS-CoV-2 transmission time window from 
COVID-19 patients is perhaps 2 days before symptom onset up to 37 days after symptom 
onset [20]. It is estimated that 48% to 62% of transmission may occur via presymptomatic 
carriers [9].  
Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10-15 
days following the onset of COVID-19 symptoms. Seow et al. observed seroconversion in 
>95% with neutralizing antibody responses when sampled beyond 8 days after onset of 
symptoms [29]. However, declining neutralizing antibody titers were observed during the 
follow-up period. Long, et al, when following 37 asymptomatic individuals and 37 
symptomatic patients into the early convalescent phase, observed that the IgG levels in 
93.3% of the asymptomatic group and 96.8% of the symptomatic group declined during 
the early convalescent phase [30]. T cells play a critical role in antiviral immunity but their 
numbers and functional state in SARS-CoV-2 infected patients remain largely unclear. 
Diao and colleagues performed a retrospective review of total T cell counts, and CD4+ and 
CD8+ T cell subsets based on inpatient data from 522 patients with laboratory-confirmed 
SARS-CoV-2 infection and 40 healthy controls in Wuhan from December 2019 to January 
2020. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe and 
critical disease groups as well as those who died were significantly lower than in the 
mild/moderate disease group. Most importantly, the numbers of total T cells, CD8+ T cells 
and CD4+ T cells in severe COVID-19 cases, including those who died, were lower 
suggesting that there is a profound T cell loss in COVID-19 disease. Counts of total T 
cells, CD8+ T cells or CD4+ T cells were negatively correlated with patient survival [31]. 
It is quite likely that CD4+ T cell, CD8+ T cell, and neutralizing antibody all contribute to 
clearance of the acute infection. There is an ongoing need to understand the magnitude 
and composition of the human CD4+ and CD8+ T cell responses to SARS-CoV-2. If 
natural infection with SARS-CoV-2 elicits potent CD4+ and CD8+ T cell responses 
commonly associated with protective antiviral immunity, COVID-19 is a strong candidate 
for rapid vaccine development [32].  
1.2.2 CURRENT TREATMENT AND UNMET NEED 
Currently, there is no licensed prophylactic vaccine against COVID-19, however there are 
several vaccines that are available under Emergency Use Authorization (EUA) in the 
United States and other countries. Numerous vaccine efforts are underway. Given the 
growing concerns regarding the emergence of new strains of SARS-CoV-2, an effective 
prophylactic vaccine ideally induces immunity against not only SARS-CoV-2 Wuhan-Hu-
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1 but also its variants. Due to rapid spread of SARS-CoV-2 infections even from 
asymptomatic and mildly infected patients, there is an urgent need for additional vaccines 
for prevention of SARS-CoV-2 infections. 
1.3 
RATIONALE FOR PROPHYLACTIC VACCINE DEVELOPMENT 
SARS-CoV-2 has become a pandemic resulting in substantial morbidity and mortality. Due 
to rapid spread of SARS-CoV-2 infections even from asymptomatic and mildly infected 
patients, there is an urgent need for appropriate measures to prevent, control and treat 
SARS-CoV-2 infections.  
To address this critical need for a medical countermeasure for prevention of COVID-19 
disease, we at Inovio Pharmaceuticals have employed our synthetic DNA-based vaccine 
technology. This technology is highly amenable to accelerated developmental timelines, 
due to the ability to rapidly design multiple test constructs, manufacture large quantities of 
the drug product, and leverage established regulatory pathways to the clinic. Furthermore, 
this technology platform has demonstrated proof of concept efficacy and safety in humans 
in a Phase 3 (REVEAL1) randomized, double-blind, placebo-controlled study for human 
papillomavirus (HPV) associated cervical pre-cancer (NCT03185013) and several Phase 
2 trials for related and other indications and several Phase 2 trials for related and other 
indications. We have additionally built upon our prior experience in developing a MERS 
coronavirus (MERS-CoV) vaccine to accelerate the development of a SARS-CoV-2 
vaccine candidate. In a Phase 1 clinical study, the MERS-CoV vaccine candidate was safe 
and well tolerated, eliciting immune responses in more than 85% of participants after two 
vaccinations that were durable through 1 year of follow-up [33].   
1.3.1 DNA VACCINES 
Since the 1990s, a novel approach to vaccination against a broad array of target antigens 
and diseases has been in development. This involves the direct introduction of plasmid 
deoxyribonucleic acid (DNA) containing the gene encoding the immunogen against which 
an immune response is sought into appropriate host tissues and the in situ production of 
the target immunogen(s). This approach offers a combination of potential advantages, 
including the stimulation of both B- and T-cell responses, stability of the vaccine across a 
broad temperature range, absence of infectivity of the immunogen itself, the speed with 
which the vaccine can be constructed (for example in the face of an epidemic or pandemic 
as it is the case here with SARS-CoV-2), and the relative ease and generic nature of large-
scale manufacture. Many scientific publications have addressed the potential of DNA 
vaccination [34-43]. Immune responses in animal models have been obtained using genes 
from a variety of infectious agents including influenza viruses, hepatitis B virus, human 
immunodeficiency virus, human papillomaviruses, Marburg virus, MERS coronavirus, 
rabies virus, SARS coronavirus, West Nile virus (WNV), Zika virus, and other infectious 
agents as plasmodium, mycoplasma, and many more [42, 44]. In many cases, protection 
from disease in animal models has also been demonstrated.  
DNA vaccines are able to generate both CD4+ and CD8+ T cell responses. The ability to 
generate MHC-Class I restricted CD8+ T cells (cytolytic T lymphocytes), which generally 
are not made following administration of inactivated viruses, proteins or peptides, may be 
important for key responses against certain pathogens, as well as enabling cross-strain 
specific responses when many antibody responses are strain-specific. Because the 
encoded protein is synthesized in vivo by the host following administration, DNA vaccines 
can encode membrane-bound proteins instead of solely the soluble versions [45]. This 
can be important because key neutralizing epitopes are located in regions that would be 
excluded, or not formed in a monomeric truncated soluble version. Some early research 
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in COVID-19 control has already suggested that neutralizing antibodies may not be 
sufficient and that cell-mediated immunity may be necessary [46]. 
Unlike certain other vectors (such as heterologous viral vectors), DNA vaccines do not 
stimulate adaptive immune responses against themselves, although the DNA itself does 
stimulate certain innate immune responses [47]. In other words, they do not generate anti-
vector immunity that could stunt antigen-specific responses following multiple exposures. 
1.3.2 USE OF ELECTROPORATION WITH DNA VACCINES 
Electroporation (EP) enhances gene expression of plasmid DNA delivered by the 
intramuscular (IM) or intradermal (ID) routes of administration (Figure 2). Following IM or 
ID delivery of a DNA vaccine or therapeutic product, EP facilitates entry of the DNA into 
the target site: muscle or dermal cells. Following cellular uptake, there is efficient 
production of the proteins encoded by the DNA expression plasmid system. The different 
EP devices, each with varying electrical parameters and protocols, have been reviewed 
[48]. EP has been extensively tested in animal species such as dogs, pigs, cattle, and 
NHPs to deliver therapeutic genes that encode for a variety of hormones, cytokines, 
enzymes or antigens  for the activation of both cellular and humoral responses [49, 50]. 
Importantly, immune responses generated by DNA vaccines delivered with EP are far 
superior to responses to the same vaccines delivered without EP [50]. IM and ID delivery 
of DNA vaccines with EP has been studied extensively, and optimum conditions for 
plasmid uptake and expression have been described for therapeutic indications, vaccines 
and tumor animal model systems [51, 52].  
1.3.3 INOVIO’S PROPRIETARY TECHNOLOGY AGAINST COVID-19  
Inovio Pharmaceuticals has developed INO-4800 as a DNA vaccine that contains 10 
mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM sodium chloride and 15 
mM sodium citrate). pGX9501 is a DNA plasmid expressing a synthetic consensus 
(SynCon®) sequence of the SARS-CoV-2 Wuhan-Hu-1 full length Spike glycoprotein. The 
ID route of delivery has been selected for INO-4800 based on recent findings from multiple 
DNA vaccine development programs where ID delivery has driven equivalent if not 
superior humoral and cellular responses to IM delivery while improving tolerability 
(clinicaltrials.gov NCT02464670, clinicaltrials.gov NCT02431767) [53-55]. 
Following ID injection, the Inovio Pharmaceuticals’ EP device [48] referred to as the 
CELLECTRA® 2000 for ID administration (3P-ID) device is used to facilitate DNA entry 
into the cells.  
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Figure 2: The Potential Mechanism of Action Underlying Electroporation 
 
1.3.4 NONHUMAN PRIMATE (NHP) CHALLENGE STUDIES FOLLOWING VACCINATION WITH 
INO-4800 
NHPs are a valuable model in the development of COVID-19 vaccines and therapeutics 
as they can be infected with wild-type SARS-CoV-2, and present with early infection that 
mimics aspects of human disease [56].  Rhesus macaques (n=5) received two 
immunizations of INO-4800 (1.0 mg), at Week 0 and Week 4.  Naïve control animals (n=5) 
did not receive vaccine.  Humoral and cellular immune responses were monitored for 15 
weeks (~4 months) following prime immunization for memory responses. All animals 
seroconverted following a single INO-4800 immunization, with serum IgG titers detected 
against the full-length S1+S2 extracellular domain (ECD), S1, S2, and receptor binding 
domain (RBD) regions of the SARS-CoV-2 S protein.  
INO-4800 immunized macaques and unvaccinated controls were challenged with SARS-
CoV-2 13 weeks (~3 months) post-final immunization. NHPs received a challenge dose of 
1.1x104 PFU of SARS-CoV-2 by intranasal and intratracheal inoculation. Peak viral RNA 
loads in the BAL were significantly lower in the INO-4800 vaccinated group, along with 
significantly lower viral RNA loads at day 7 post-challenge, indicating protection from lower 
respiratory disease. While RNA was detected in the nasal swabs of both the control and 
INO-4800 vaccinated animals, viral mRNA levels trended downwards in INO-4800 
vaccinated animals by more than 2 logs and were achieved sooner on average. Overall, 
the reduced viral loads following exposure to SARS-CoV-2 infection at 17 weeks after 
immunization show an important durable impact mediated by the vaccine [57].  
1.3.5 FIRST-IN-HUMAN PHASE 1 TRIAL OF INO-4800 
In the open-label, Phase 1 clinical trial, we initially evaluated the safety and 
immunogenicity of INO-4800 in 40 healthy participants, 18-50 years of age.  There were 
two groups of 20 participants each who received either 1.0 mg or 2.0 mg of INO-4800 
intradermally followed by EP at 0 and 4 weeks. In the first 40 subjects, by Week 8, 11 
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adverse events were reported of which all were Grade 1 in severity of which 6 were related 
to study drug. The frequency of AEs did not increase with the second administration.  
From the immunogenicity analysis of the initial 40 subjects enrolled, two subjects were 
excluded from the analysis, one due to early discontinuation prior to the Week 4 dose for 
non-study reasons and the other due to suspected exposure to SARS-CoV-2 before the 
first dose of INO-4800 was administered based on a baseline positive SARS-CoV-2 
serology. Thirty-eight (38) evaluable subjects had cellular and/or humoral immune 
responses following the second dose of INO-4800. Assessment of data from both Week 
6 and Week 8 ELISpot revealed that 74% and 100% of the subjects generated T cell 
responses in the 1.0 mg and 2.0 mg groups, respectively. By Week 6, 95% (36 of 38) of 
the participants seroconverted by generating binding and/or neutralizing antibodies. 
Overall, INO-4800 elicited antigen-specific humoral and cellular immune responses 
against the SARS-CoV-2 Spike protein while demonstrating favorable safety and 
tolerability. 
The protocol was amended to include an additional 80 healthy participants to evaluate 
safety and immunogenicity of INO-4800 in older and elderly age populations. A lower dose 
level (0.5 mg) was also added for evaluation of dose-sparing potential. A total of 40 
participants were enrolled into three dose levels (0.5 mg, 1.0 mg and 2.0 mg), such that 
each Group included 20 participants 18-50 years of age, 10 participants 51-64 years of 
age, and 10 participants 65 years of age and older. Doses were delivered intradermally 
followed by EP at 0 and 4 weeks. As of July 29, 2020, 17 related adverse events were 
reported cumulatively, of which all but one (Grade 2 injection site pruritus) was Grade 1 in 
severity. 
Please refer to the Investigator’s Brochure, which will include future updates through the 
duration of the study. 
1.3.6 PROPOSED PHASE 2/3 TRIAL OF INO-4800 
This Phase 2/3 trial is designed to begin with a Phase 2 segment to evaluate both the 1.0 
mg and 2.0 mg doses in approximately 400 subjects, including in the older (51 to 64 years 
of age) and elderly subjects (65 years of age and older), to enable selection of a dose or 
age-related doses for an efficacy evaluation in a subsequent Phase 3 segment involving 
>7000 subjects.  
1.3.7 DOSE AND REGIMEN RATIONALE 
The intent is to evaluate INO-4800 as a prophylactic vaccine against COVID-19 disease. 
Based on Inovio’s extensive experience developing vaccine candidates against infectious 
diseases via the ID route ([54], [33]), a 2-dose regimen was considered to be optimal, 
based on the balanced humoral and cellular responses obtained 2 weeks post-dose 2, 
which supports evaluation of a 2-dose regimen (Days 0 and 28). 
In this study, 1.0 mg and 2.0 mg of vaccine is administered by ID injection and followed 
immediately by EP at Day 0 and Day 28. The selection of the doses to test in Phase 2 is 
supported by the safety profile in the Phase 1 trial of INO-4800 (COVID19-001, 
NCT04336410) as well as our prior experience in developing a MERS coronavirus 
(MERS-CoV) vaccine (INO-4700) [16, 17]. The safety data for INO-4800 is provided in the 
Investigator’s Brochure (IB). 
The objective of the Phase 2 segment of the Phase 2/3 trial is to further select the 1.0 mg 
and 2.0 mg doses of INO-4800 for each age group in order to evaluate the optimal 
vaccination regimen in the efficacy Phase 3 segment. The final decision between the two 
doses by age group relies on safety, immunogenicity as well as the practicality of 
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administration. The 1.0 mg and 2.0 mg doses in the Phase 1 study had a similar safety 
profile. The available blinded Phase 2 data has not revealed any significant safety signals. 
The 1.0 mg dose is favored over the 2.0 mg dose based on the greater convenience of a 
single injection per day. Therefore, unless the 2.0 mg dose provides substantially superior 
immunogenicity when compared to the 1.0 mg dose by age group in Phase 2, we 
anticipate that the 1.0 mg dose will offer the better balance of safety, immunogenicity and 
ease of administration.    
1.4 
RISKS AND POTENTIAL BENEFITS  
As of Dec 31, 2020, no treatment related serious adverse events have been reported for 
INO-4800. There may be side effects and discomforts that are not yet known.  
Please refer to the Investigator’s Brochure and User Manual, which will include future 
updates of the risk profile through the duration of the study. 
1.4.1 POTENTIAL BENEFITS 
The efficacy of INO-4800 remains unknown.   
1.4.2 PRODUCT RISKS 
1.4.2.1. 
Expected Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Device 
In accordance with the International Council for Harmonisation (ICH), Inovio-sponsored 
studies have been designed to minimize risk to study participants. Expected risks of INO-
4800 delivered ID followed by EP with the CELLECTRA® 2000 device are listed below in 
Table5. 
Table 5: Expected Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Devicea  
Frequency among subjectsb 
Event 
Very Common 
(≥10%) 
• 
Injection site pruritus 
• 
Injection site erythema or redness 
• 
Injection site painc or tenderness  
Common 
(≥1% to <10%) 
• 
Injection site bruising 
• 
Injection site swelling or induration 
Uncommon or Rare (<1%) 
• 
Administration site lesions or bleeding  
• 
Temporary severe injection site pain or 
tenderness 
a Investigator’s Brochure v3.0, dated 25-Aug-2020 
b EU commission guideline on the SmPC September 2009 [58] 
c Brief muscle contractions may occur and could be uncomfortable 
1.4.2.2  
Theoretical Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Device 
The following adverse events have been observed at least once, as of June 30, 2020, 
across all clinical trials with Inovio DNA products delivered intradermally followed by EP 
using the CELLECTRA® 2000 device: 
• 
Allergic reaction 
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• 
Anxiety 
• 
Creatine phosphokinase (CPK) elevations that are transient 
• 
Injection site infection, paresthesia, hypoesthesia, hematoma, or scab 
• 
Vasovagal reaction, lightheadedness or dizziness. 
The following events have not been observed, as of June 30, 2020, in any subject or any 
clinical trials with Inovio DNA products delivered intradermally followed by EP using the 
CELLECTRA® 2000 device. While considered theoretical and unlikely to occur, any 
occurrence of these events should be reported to the Sponsor during this trial: 
• 
Antibody-dependent enhancement of disease (i.e., potential for greater respiratory 
disease upon exposure to SARS-CoV-2 due to priming of immune cells from prior 
vaccination. Although observed in nonclinical models for vaccines against other 
viruses such as SARS, the occurrence or observation of antibody-dependent 
enhancement of the disease with COVID-19 vaccines in humans remains 
unknown) 
• 
Cardiac arrhythmias (product-related); Please note that “ICD or pacemaker (to 
prevent a life-threatening arrhythmia) that is located ipsilateral to the deltoid 
injection site (unless deemed acceptable by a cardiologist)” is an exclusion 
criterion (‘j’) in this protocol; 
• 
Death (product-related); 
• 
Disruption of function of implanted electronic medical device(s); Please note that 
“ICD or pacemaker (to prevent a life-threatening arrhythmia) that is located 
ipsilateral to the deltoid injection site (unless deemed acceptable by a cardiologist)” 
is an exclusion criterion (‘j’) in this protocol; 
• 
Effects on fetus and/or pregnancy; Please note inclusion criterion in this protocol 
which requires use of medically effective contraception in women of childbearing 
potential; 
• 
Electrical injury (e.g., electrocution); Please note warning within the device User 
Manual (Section 7). Since the device is not connected to any power supply during 
the EP procedure of a subject, this theoretical event is unlikely but has the potential 
to occur to the user of the device (e.g., study site staff). This will be mitigated 
through device training and user qualification prior to use; 
• 
Fire hazard to the facility; This theoretical event is unlikely but has the potential to 
occur to the clinical trial site. The possibility of this event has been mitigated 
through device design; 
• 
Hearing damage (product-related); The possibility of this event has been mitigated 
through the device design. The audio is limited in volume and is of very short 
duration. 
• 
Inaccurate energy delivery, the result of which is covered in other events listed 
here (e.g., tissue damage); 
• 
Injection site laceration; This has not been observed but would be theoretically 
possible with any needle; 
• 
Major injury to deeper tissue and/or bone; This event is not foreseeable given the 
array needle length is limited to 3.2 mm;  
• 
Muscle damage; This event is not foreseeable given the array needle length is 
limited to 3.2 mm; 
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• 
Paresis or paralysis with possible loss of nerve function; There are minor nerves 
innervating the skin and subcutaneous tissues that may be disrupted, but are 
extremely unlikely to result in serious injury; 
• 
Radiation hazard to eyes and skin; This theoretical event is unlikely but has the 
potential to occur to the user of the device (e.g., study site staff). The possibility of 
this event has been mitigated through the device design; 
• 
Tissue injury/burn;  
• 
User/subject unaware that treatment was incomplete; 
• 
Worsening of unstable cardiac disease; Please note that “Cardiovascular diseases 
(e.g., myocardial infarction, congestive heart failure, cardiomyopathy or clinically 
significant arrhythmias) requiring changes in therapy or hospitalization for 
worsening disease during the 6 weeks prior to enrollment” is an exclusion criterion 
(‘h’) in this protocol. 
There have been no AEs associated with EP errors or failures. 
1.4.3 OVERALL BENEFIT/RISK CONCLUSION 
While EUA vaccines are currently becoming available in many countries, the global 
availability to the general population remains limited. In the context of the ongoing COVID-
19 pandemic resulting in substantial morbidity and mortality, the overall cumulative safety 
profile of Inovio’s DNA platform across all of its products, and INO-4800’s Phase 1 adverse 
events being generally limited to local injection site reactions, the benefit risk profile 
justifies the conduct of the Phase 2/3 trial. 
2.0 
OBJECTIVES AND PURPOSE 
The overall purpose of this clinical trial is to evaluate the safety, immunogenicity and 
efficacy of INO-4800. 
2.1 
HYPOTHESIS 
INO-4800 delivered ID followed immediately by EP will be well-tolerated, exhibit an 
acceptable safety profile, result in generation of cellular and humoral immune responses 
to SARS-CoV-2 Spike glycoprotein and provide protection against virologically-confirmed 
COVID-19 disease in subjects at high risk of SARS-CoV-2 exposure.  
3.0 
CLINICAL TRIAL DESIGN AND ENDPOINTS 
This is an operationally seamless Phase 2/3, randomized, placebo-controlled, multi-
center trial to evaluate the safety, immunogenicity, and efficacy of INO-4800, 
administered by ID injection followed immediately by EP using the CELLECTRA® 2000 
device, in a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-
2 exposure. Subjects 18 years of age and older are expected to be enrolled across two 
(2) segments of this study. In the Phase 2 segment, approximately 400 seronegative 
subjects will be enrolled. In the Phase 3 segment, approximately 6714 seronegative 
subjects are expected to be enrolled, and 402 seropositive subjects will be enrolled. The 
subjects and data from Phase 2 are independent from that of Phase 3.  The primary 
objectives of this trial are to identify in seronegative subjects an optimal age-related dose 
(Phase 2 segment) for subsequent evaluation for efficacy (Phase 3 segment).  
 
Phase 2 Segment – Dose Selection 
 
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In the Phase 2 segment, approximately 400 subjects 18 years of age and older will be 
evaluated across four (4) dose groups (Table 1, Figure 1). Subjects will be randomized 
at a 3:3:1:1 ratio to receive either 1.0 mg or 2.0 mg of active investigational product (INO-
4800) or 1 or 2 injections of placebo (SSC-0001). Dose groups receiving INO-4800 will 
enroll approximately 150 subjects per group. Dose groups receiving placebo will enroll 
approximately 50 subjects per group. Randomization will be such that approximately 240 
subjects aged 18-50 years, 120 subjects aged 51-64 years and 40 subjects aged ≥ 65 
years will be enrolled. Initial enrollment will include subjects aged 18-50 years. Initiation 
of enrollment of older subjects 51-64 years of age and elderly subjects 65 years and older 
will depend on review of safety and immunogenicity data from those age groups 
generated in the Phase 1 study (COVID19-001). 
 
Dose selection for evaluation of efficacy in the Phase 3 segment will be based on Week 
6 immunogenicity data and Week 8 safety data from the Phase 2 segment. Group-level 
unblinded summaries and analyses of safety will be produced once the Week 8 phone 
call visit data are completed for all subjects in the Phase 2 segment. Group-level 
unblinded summaries and analyses of immunogenicity will be produced once the Week 
6 visit data are completed for all subjects in the Phase 2 segment. 
 
Phase 3 Segment – Efficacy 
In the Phase 3 segment, approximately 6714 seronegative and 402 seropositive subjects 
18 years of age and older will be randomized at a 2:1 ratio to receive either active 
investigational product (INO-4800, 1mg) or placebo (SSC-0001).  Approximately half of 
seronegative subjects and approximately half of seropositive subjects will be 18-50 years 
of age, and the other half will be ≥ 51 years of age. Also, a minimum of 10% of the total 
sample size will be ≥65 years of age. 
Subjects will be randomized in a stratified manner according to (a) age category (18-50 
years vs. ≥51 years) on Day 0, and (b) presence of or absence on Day 0 of any of the 
following underlying medical conditions that increase risk of severe COVID-19 disease, 
per CDC criteria [1], as listed below: 
• 
Cancer 
• 
Chronic kidney disease 
• 
Chronic lung diseases, including Chronic obstructive pulmonary disease (COPD), 
asthma (moderate-to-severe), interstitial lung disease, cystic fibrosis, pulmonary 
hypertension 
• 
Neurologic conditions including stroke or cerebrovascular disease, that do not impact 
cognition 
• 
Diabetes (type 1 or type 2) 
• 
Hypertension 
• 
Heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies 
• 
HIV infection (CD4 count >200 cells/mm3 or undetectable viral load) 
• 
Liver disease 
• 
Obesity (BMI ≥ 30 kg/m2) 
• 
Sickle cell disease or thalassemia, or 
• 
Smoking (current or former smoker). 
This segment of the trial is case-driven. Among seronegative subjects, a total of 149 
observed cases will be required for 90% power to declare the vaccine efficacious (>30%), 
assuming a true efficacy of 60%. A sample size of 6714 seronegative subjects is expected 
to be required to achieve the 149 cases assuming an underlying attack rate of 3.7%. The 
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actual sample size may differ if the observed attack rate is different than projected.  There 
are two formal interim analyses of efficacy; one when 50% of the cases accrue and one 
when 75% of the cases accrue. If the prespecified criteria for efficacy are met at either 
interim analysis, then enrollment will continue until 4500 subjects have been enrolled, 
and blinded follow-up will continue until at least those 4500 subjects have a minimum of 
6 months of safety follow-up. At that point, the trial would be unblinded and placebo-
recipients will be offered the active product.    
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12 
months post-dose 2. All Phase 3 segment subjects will be followed for 56 weeks from the 
Day 0 dosing [i.e., Week 56 will be the planned End of Study (EOS) visit for this segment 
of the trial]. 
 
External Committee Reviews 
 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will 
convene regularly to review all available unblinded safety data, and additionally upon 
completion of the Week 8 phone call visit for all subjects enrolled during the Phase 2 
segment. For the Phase 3 segment, the DSMB will also review efficacy in an unblinded 
fashion. Additionally, for Phase 3, an independent, blinded Endpoint Adjudication 
Committee (EAC) will review and confirm COVID-19 cases. 
 
Details of each committee’s scope will be provided in the respective charters. 
3.1 
PRIMARY OBJECTIVES 
See Table 6. 
3.2 
PRIMARY ENDPOINTS 
Table 6: Primary Objectives and Associated Endpoints 
Phase 2 Primary Objective 
Phase 2 Primary Endpoints 
1.  Evaluate the cellular and humoral 
immune response to INO-4800 
administered by ID injection followed 
immediately by EP  
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot assay 
1b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay 
Phase 3 Primary Objective 
Phase 3 Associated Primary Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease 
in subjects who are SARS-CoV-2 
negative at baseline  
1.   Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 
(End of Study (EOS)) in subjects who are SARS-
CoV-2 seronegative at baseline  
3.3 
SECONDARY OBJECTIVES 
See Table 7. 
3.4 
SECONDARY ENDPOINTS 
Table 7: Secondary Objectives and Associated Endpoints 
Phase 2 Secondary Objectives 
Phase 2 Secondary Endpoints 
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1.  Evaluate the safety and tolerability of 
INO-4800 administered by ID 
injection followed immediately by EP  
 
1a. Incidence of solicited and unsolicited injection 
site reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
 1d. Incidence of adverse events of special interest 
(AESIs)   
Phase 3 Secondary Objectives 
Phase 3 Secondary Endpoints 
1. Evaluate the safety and tolerability 
of INO-4800    
 
1a. Incidence of solicited and unsolicited injection 
site reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality  
2. Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of disease 
severity in subjects who are SARS-
CoV-2 seronegative at baseline    
2a.  Incidence of non-severe COVID-19 disease in 
SARS-CoV-2 seronegative subjects starting 14 
days after completion of the 2-dose regimen until 
EOS  
2b. Incidence of severe COVID-19 disease in SARS-
CoV-2 seronegative subjects starting 14 days 
after completion of the 2-dose regimen until EOS 
2c. Incidence of deaths due to COVID-19 in SARS-
CoV-2 seronegative subjects starting 14 days 
after completion of the 2-dose regimen until EOS 
3.   Evaluate the cellular and humoral 
immune response to INO-4800  
3a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot  
3b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
4. Evaluate the efficacy of INO-4800 
in the prevention of COVID-19 
disease in subjects who are SARS-
CoV-2 seropositive at baseline  
 
4.  Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 
(End of Study (EOS)) in subjects who are SARS-
CoV-2 seropositive at baseline 
3.5 
EXPLORATORY OBJECTIVE 
See Table 8. 
3.6 
EXPLORATORY ENDPOINTS 
Table 8: Exploratory Objectives and Associated Endpoints 
Phase 2 Exploratory Objective 
Phase 2 Exploratory Endpoints 
1.  Evaluate the expanded 
immunological profile of antibody 
1a.  Antigen-specific cellular immune response 
measured by flow cytometry. 
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response and T cell immune 
response 
1b. Expanded immunological profile which may 
include additional assessments of T and B cell 
numbers and molecular changes by measuring 
immunologic proteins and mRNA levels of genes 
of interest as determined by sample availability 
Phase 3 Exploratory Objective 
Phase 3 Exploratory Endpoints 
1. Evaluate the efficacy of INO-4800 
in the prevention of COVID-19 
disease from SARS-CoV-2 variants 
in subjects who are SARS-CoV-2 
seronegative at baseline 
1. Incidence of virologically-confirmed COVID-19 
disease from a SARS-CoV-2 variant starting 14 
days after completion of the 2-dose regimen until 
12 months post-dose 2 (End of Study (EOS)) in 
subjects who are SARS-CoV-2 seronegative at 
baseline 
2. Evaluate the efficacy of INO-4800 
in the prevention of SARS-CoV-2 
asymptomatic infection in subjects 
who are SARS-CoV-2 seronegative 
at baseline     
2. Incidence of SARS-CoV-2 asymptomatic 
infections in SARS-CoV-2 seronegative subjects 
starting 14 days after completion of the 2-dose 
regimen until EOS 
3. Evaluate the immunological profile 
by assessing both antibody 
response and T cell immune 
response  
3a.  SARS-CoV-2 Spike glycoprotein antigen-
specific binding antibody levels  
3b.  Antigen-specific cellular immune response 
measured by flow cytometry  
4. Evaluate antibody persistence  
4a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels at Week 30 or later.  
4b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay at Week 
30 or later 
3.7 
EFFICACY ASSESSMENT (PHASE 3 SEGMENT ONLY) 
Subjects will receive either active investigational product (INO-4800, dose selected from 
the Phase 2 segment) or placebo (SSC-0001) in a 2-dose regimen administered 
intradermally followed immediately by EP on Days 0 and 28. Subjects will be monitored 
through regularly scheduled clinic visits and phone calls throughout the trial. Subjects will 
be regularly tested for SARS-CoV-2 infection using serologic testing. If COVID-19 disease 
is suspected based on symptoms or laboratory testing, site personnel will arrange for a 
clinic visit. Subjects with symptom(s) or a positive SARS-CoV-2 test result will be reviewed 
by the independent blinded EAC.  
The mechanism for review and confirmation of cases will be outlined in an EAC Charter.  
3.7.1 CASE DEFINITION FOR VIROLOGICALLY-CONFIRMED COVID-19 DISEASE: 
•  Positive testing by SARS-CoV-2 RT-PCR assay (performed at central lab*) 
with fever (temperature of 100.4ºF/38.0ºC or higher), or  
• 
Positive testing by SARS-CoV-2 RT-PCR assay (performed at central lab*) 
with any of the following COVID-19 related symptoms: 
• 
Feeling feverish or chills  
• 
Cough  
• 
Shortness of breath or difficulty breathing  
• 
Fatigue  
• 
Muscle or body aches  
• 
Headache  
• 
New loss of taste or smell  
• 
Sore throat  
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• 
Congestion or runny nose  
• 
Nausea or vomiting  
• 
Diarrhea  
*Local lab results will be accepted if the subject is hospitalized and a sample is 
not able to be obtained for analysis at central lab. 
3.7.1.1 Case Definition for Severe COVID-19 
• Confirmed COVID-19 disease (per Section 3.7.1) with any of the following:  
a. Clinical signs at rest indicative of severe systemic illness (respiratory 
rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room 
air at sea level or PaO2/FiO2 < 300 mm Hg),  
b. Respiratory failure (defined as needing high-flow oxygen, noninvasive 
ventilation, mechanical ventilation or ECMO),  
c. Evidence of shock (SBP < 90 mm Hg, DBP < 60 mm Hg, or requiring 
vasopressors),  
d. Significant acute renal, hepatic, or neurologic dysfunction,  
e. Admission to an ICU, or  
f. 
Death.  
3.7.1.2 Case Definition for Non-Severe COVID-19  
• Confirmed COVID-19 disease (per Section 3.7.1);   
• Does not meet the case definition of Severe COVID-19 disease (Section 
3.7.1.1) 
3.7.2 CASE DEFINITION FOR SARS-COV-2 ASYMPTOMATIC INFECTION  
Positive testing by SARS-CoV-2 serologic assay (performed at central lab);  
• Without clinical signs or symptoms of COVID-19 disease since the previous 
negative serologic test.  
 
3.8 
SAFETY ASSESSMENT 
Subjects will be followed for safety during the trial through scheduled clinic visits and 
phone calls. AEs, regardless of relationship to study drug, will be collected from the time 
of consent until 28 days post-dose 2 (i.e., Day 56). SAEs, MAAEs and AESIs will be 
collected from time of consent until EOS. SAEs, AESIs, and treatment-related AEs will be 
followed to resolution or stabilization. For the Phase 2 segment and at selected sites in 
the Phase 3 segment, solicited local and systemic AEs will be collected for 7 days following 
each dose using a participant diary. 
Subjects will also be monitored for COVID-19 disease. 
Please refer to the Schedule of Events (Table 3 and Table 4) for safety assessments to 
be performed.   
3.9 
IMMUNOGENICITY ASSESSMENT 
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 3 and Table 4). Assays such as binding ELISA, pseudovirus-based neutralization 
assay, and ELISpot will be evaluated at serial timepoints. 
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4.0 
CLINICAL TRIAL POPULATION 
4.1 
INCLUSION CRITERIA 
4.1.1 PHASE 2 SEGMENT 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, vital signs and 
physical examination performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar workers, 
store cashiers, hairdressers and barbers, veterinary staff, daycare workers, 
Transportation Security Administration screening staff, school teachers and 
college professors teaching in-person classes) 
2. Factory workers (when working in confined settings with large numbers of 
employees) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) 
4. User of public transportation (e.g., bus, train, subway) at least 3 times weekly 
5. Nursing home staff or correctional facility staff  
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol. Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field) 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists.) Physicians should not be enrolled unless they are 
assigned to dedicated COVID-19 treatment wards or other settings with prolonged 
exposure) 
10. Others, if approved by the medical monitor;   
f. Screening laboratory results within normal limits for testing laboratory or are deemed 
not clinically significant by the Investigator; 
g. Must meet one of the following criteria with respect to reproductive capacity: 
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or tubal 
ligation, absence of ovaries and/or uterus in females). In the case of vasectomy, 
subjects should wait six (6) months post-vasectomy prior to enrolling;  
• 
Use of medically effective contraception with a failure rate of < 1% per year when 
used consistently and correctly from screening until 3 months following last dose. 
Acceptable methods include:  
o hormonal contraception including implants, injections or oral; 
o two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
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o intrauterine device or intrauterine system; 
o abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
4.1.2 PHASE 3 SEGMENT 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Per investigator judgment, healthy or stable with pre-existing medical conditions that 
do not require significant change in medication or have led to a hospitalization in the 
3 months prior to enrollment or who, in the judgment of the investigator, are unlikely 
to require a significant change in therapy or hospitalization for worsening disease 
through Day 56;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings. 
Examples include:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar workers, 
street vendors, store cashiers, hairdressers and barbers, veterinary staff, daycare 
workers, airport screening staff, school teachers and college professors teaching 
in-person classes, college students attending in-person classes, office workers 
and volunteers who have multiple brief exposures to people regularly) 
2. Factory workers (when working in confined settings with large numbers of 
employees, meat-packing facilities) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) and delivery 
services  
4. User of public transportation (e.g., bus, train, subway) or public facilities (e.g. 
gyms) at least 3 times weekly 
5. Nursing home staff or correctional facility staff 
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, medical assistants and technicians, respiratory therapists, 
physical therapists, social workers, dentists and dental hygienists)  
10. Others, if in the opinion of the PI, the risk of COVID-19 exposure is comparable 
to the examples above. 
f. Must meet one of the following criteria with respect to reproductive capacity: 
1. Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
2. Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or tubal 
ligation, absence of ovaries and/or uterus in females). In the case of vasectomy, 
subjects should wait six (6) months post-vasectomy prior to enrolling;  
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3. Use of medically effective contraception with a failure rate of < 1% per year when 
used consistently and correctly from screening until last dose. Acceptable 
methods include:  
i. hormonal contraception including implants, injections or oral; 
ii. two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
iii. intrauterine device or intrauterine system; 
iv. abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
4.2 
EXCLUSION CRITERIA 
4.2.1 PHASE 2 SEGMENT 
a. Acute febrile illness with temperature > 100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat);  
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the Screening visit until 
3 months following the last dose; 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or 
a detectable viral load within the past 3 months; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0 (documented receipt of placebo in a previous trial 
would be permissible for trial eligibility); 
g. Previous receipt of an investigational vaccine for prevention or treatment of COVID-
19, MERS or SARS (documented receipt of placebo in previous trial would be 
permissible for trial eligibility). 
h. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg prior to first dose; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin cancers 
that only required local excision and non-metastatic prostate cancer not requiring 
treatment; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in therapy 
or hospitalization for worsening disease during the 6 weeks prior to enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a single 
antiepileptic agent; 
i. 
Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
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• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed) in the prior 6 months; 
• 
Current or anticipated use of disease modifying doses of systemic anti-rheumatic 
drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and 
biologic disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, 
adalimumab or etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the subject 
or require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
j. 
Lack of acceptable sites for ID injection and EP considering the skin above the 
deltoid and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
ICD or pacemaker (to prevent a life-threatening arrhythmia) that is located 
ipsilateral to the deltoid injection site (unless deemed acceptable by a 
cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation site; 
k. Blood donation or transfusion within 1 month prior to Day 0; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the prior 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
4.2.2 PHASE 3 SEGMENT 
a. Acute febrile illness with temperature ≥100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat) on 
Day 0 prior to dosing; 
b. Positive serologic test for SARS-CoV-2 at Screening (after approximately 402 
subjects positive for SARS-CoV-2 serologic test are randomized, this criterion will 
apply to all remaining subjects); 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children starting from the Screening visit until the last dose; 
d. Positive urine pregnancy test during screening or  immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or 
a detectable viral load within 3 months prior to screening; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days prior to Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous or planned receipt of an investigational (including Emergency Use 
Authorization (EUA) or local equivalent authorization) or licensed vaccine for 
prevention or treatment of COVID-19, MERS or SARS (documented receipt of 
placebo in previous trial would be permissible for trial eligibility); 
h. Immunosuppression as a result of underlying illness or treatment including: 
 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
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• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed) in the past 6 months; 
• 
Current or anticipated use of disease modifying doses of systemic anti-rheumatic 
drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and 
biologic disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, 
adalimumab or etanercept) or others; 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the subject 
or require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
i. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation site; 
j. 
Blood donation or transfusion within 1 month prior to Day 0; 
k. People who work remotely or in a socially distanced setting with minimal risk of 
exposure to SARS-CoV-2; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the prior 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
4.3 
DISCONTINUATION/WITHDRAWAL OF CLINICAL TRIAL SUBJECTS 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the Investigator should any untoward effect occur. In addition, the 
Investigator or the Sponsor has the right to discontinue a subject from the trial at any time. 
The Investigator must notify the Sponsor immediately when a subject has been 
discontinued/withdrawn due to an Adverse Event (AE). If a subject withdraws from the trial 
or is discontinued from the trial prior to trial completion, all applicable activities scheduled 
for the final trial visit (i.e., Day 393) should be performed at the time of 
discontinuation/withdrawal if the subject agrees. Any related AEs, AESIs, and/or Serious 
Adverse Events (SAEs) present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.9. 
Unless a subject refuses to continue participation, all follow-up visits and procedures 
should be completed as indicated in the Schedule of Events (Table 3 and Table 4) 
following the second dose whether or not the subject has completed both doses. 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. In cases where 
the subject does not return for the rescheduled visit or cannot be reached to reschedule 
the missed visit, the site should make every effort to regain contact with the subject (3 
telephone calls and if that fails, then a certified letter to the subject’s last known mailing 
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address) so that the subject’s disposition can be considered as withdrawn from the study 
(i.e. lost to follow-up). If the contact with subject is re-established, site should contact 
medical monitor to discuss whether subject can continue study treatment or follow-up 
visits for the study. For all other subjects withdrawing from the study, an alternative reason 
for discontinuation should be recorded in the eCRF. 
Reasons for discontinuation/withdrawal from the trial may include but are not limited to the 
following: 
• 
Subject withdrawal of consent at any time; 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardize the 
subject’s safety if he or she continues in the trial; 
• 
Investigator, DSMB or Sponsor determines it is in the best interest of the subject; 
• 
Subject non-compliance. 
Every effort should be made to obtain information on subjects who withdraw from the trial. 
The primary reason for withdrawal from the trial should be documented on the appropriate 
CRF. However, subjects will not be followed for any reason after consent has been 
withdrawn. Data and/or samples collected prior to withdrawal of consent will be analyzed.  
Reasons for discontinuing subject dosing may include but are not limited to the following: 
• 
Adverse Event (Adverse Reaction); 
• 
The Investigator or trial coordinator must notify the Sponsor immediately when a 
subject has been discontinued/withdrawn due to an Adverse Event (AE). 
• 
Any medical condition that may jeopardize the subject’s safety if he or she continues 
on trial; 
• 
Pregnancy. 
5.0 
CLINICAL TRIAL INVESTIGATIONAL PRODUCT INFORMATION 
5.1 
INVESTIGATIONAL PRODUCT (IP) AND STUDY DEVICE 
5.1.1 INO-4800 AND PLACEBO 
Investigational product is defined as a pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in the study, whether blinded or unblinded. 
INO-4800 is the active investigational product to be used in this study. The INO-4800 drug 
product contains 10 mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM 
sodium chloride and 15 mM sodium citrate). pGX9501 is a DNA plasmid expressing a 
synthetic consensus (SynCon®) sequence of the SARS-CoV-2 full length Spike 
glycoprotein. 
Phase 2 segment: 
Active Investigational Product (INO-4800): A volume of 0.4 mL will be filled into 2-mL glass 
vials that are fitted with rubber stoppers and sealed aluminum caps. 
Placebo (SSC-0001): Sterile saline sodium citrate (SSC) buffer, which contains sterile 150 
mM sodium chloride and 15 mM sodium citrate in 10-mL glass vials, stoppered, and 
sealed with aluminum caps. 
Phase 3 segment: 
Active Investigational Product (INO-4800): A volume of 0.4 mL or 1.1 mL will be filled into 
2-mL glass vials that are fitted with rubber stoppers and sealed aluminum caps. 
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Placebo (SSC-0001): Sterile saline sodium citrate (SSC) buffer, which contains sterile 150 
mM sodium chloride and 15 mM sodium citrate at a volume of 1.1 mL in 2-mL glass vials, 
stoppered, and sealed with aluminum caps. 
5.1.2 CELLECTRA® 2000 
Electroporation is a procedure used to enhance cellular DNA uptake within host cells 
following DNA vaccine ID delivery. This study will use the CELLECTRA® 2000, a portable, 
battery-powered medical device designed to generate a controlled, electric field that 
temporarily and reversibly increases cellular membrane permeability without clinically 
damaging the tissue. During the period of increased permeability, injected plasmid DNA 
can be introduced into the cells. 
As mentioned above, the CELLECTRA® 2000 device is intended to enhance the uptake 
and expression of DNA plasmid-based biologics in order to enhance vaccine efficacy. The 
DNA plasmid is delivered separately via needle and syringe ID injection immediately prior 
to the electroporation. The electroporation is accomplished through a sterile, disposable 
needle Array attached to an Applicator delivering controlled electrical pulses as follows: 
• 
An EP administration consists of four pulses. 
• 
An array of three stainless steel electrode needles is used to deliver the electrical 
pulses into the tissue. The Array needle length that penetrates into the skin and 
tissue is approximately 3.2 mm. To date, we have not had any safety concerns 
associated with the depth of the array electrode needles. Within the Array needle 
depth of 3.2 mm, there are no major blood vessels (arteries, veins) or nerve 
structures at the authorized sites of administration overlying the deltoid or the 
anterolateral quadricep muscle. There are superficial capillaries and minor nerves 
innervating the skin, including subcutaneous tissues that may be disrupted by 
needle insertion, but are extremely unlikely to result in serious injury; intradermal 
injection followed by EP of these structures poses no significant risk to the subject 
except for possibly injection site reactions. 
• 
The CELLECTRA® 2000 generates four 52ms ±1ms electrical current controlled 
DC pulses. The nominal current is set to 0.2A ±10% by modulating voltage, or 
capped at 200V ±5%, determined by patient tissue impedance. 
• 
The total energy delivered by the device is determined by the combination of four 
device parameters: Pulse Current, Pulse Voltage, Number of Pulses, and Pulse 
Width. The parameters are pre-set by Inovio to be a pulse current of 0.2A, a pulse 
voltage of 200V, and 4 pulses at 52ms pulse width. The parameters are verified 
prior to shipment and cannot be changed by the user.  
• 
In eight clinical trials administering ID injection followed by EP using the 
CELLECTRA® 2000, total energy delivered ranged from 0.9J to 7.8J, which have 
been generally safe and well-tolerated. In addition, Inovio has calculated the total 
maximum energy delivered ID as 8.32J for normal use conditions. Higher energy 
pulses ranging from 10.7J to 11.7J were evaluated in a guinea pig model which 
induced erythema localized to the electrode insertion site. Taken together, these 
nonclinical data and Inovio’s clinical experience provide evidence that the total 
energy delivered by the CELLECTRA® 2000 device will not result in 
unacceptable risks when delivered to patients. Further, a published study 
evaluated the Visual Analog Scale (VAS) pain scores of normal use conditions 
(0.2A), and found ID injection followed by EP using  the CELLECTRA® 2000 
device to be safe and well tolerated [59]. 
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• 
The specified current is constantly maintained through voltage modulation using 
an analog feedback loop. Measurements of voltage and current are processed for 
error reporting and collected for data logging. 
The CELLECTRA® 2000 device is comprised of three components: (1) A battery-powered 
Pulse Generator, (2) an ID Applicator that is connected to the pulse generator, and (3) a 
three-point sterile disposable ID Array of stainless steel needles. The Pulse Generator 
and ID Applicator are reusable components. These components should be cleaned and 
disinfected prior to each subject’s use according to the Cleaning and Maintenance 
procedure in the User Manual. The Pulse Generator and ID Applicator have been 
validated for up to 30 cleaning and disinfection cycles based on a maximum of 30 subjects 
being treated in a day. Therefore, the Pulse Generator and ID Applicator’s use should be 
limited to 30 subjects in a day. Any potential risk of damage to the device due to cleaning 
and disinfection for more than 30 cycles has not been validated. Always inspect the device 
before use according to the instructions in the Maintenance section of the User Manual. 
5.2 
DOSING REGIMENS 
Phase 2 Segment 
• 
Active Investigational Product: One or two 1.0mg ID injection(s) of INO-4800 (~0.1mL 
dose volume each) followed immediately by EP administered on Day 0 and Day 28 
(±3 days) 
• 
Placebo: One or two ID injection(s) of SSC-0001 (~0.1mL) followed immediately by 
EP administered on Day 0 and Day 28 (±3 days) 
Phase 3 Segment 
• 
Active Investigational Product: One 1.0mg ID injection of INO-4800 (~0.1mL dose 
volume) followed immediately by EP administered on Day 0 and Day 28 (±3 days) 
• 
Placebo: One ID injection of SSC-0001 (~0.1mL) followed immediately by EP 
administered on Day 0 and Day 28 (±3 days) 
5.2.1 BLINDING 
This study is blinded. The Sponsor, subjects and clinical site staff, with the exception of 
the site’s pharmacy personnel, will be blinded throughout the trial. There is no difference 
in appearance between INO-4800 and the placebo; however, they are distinguishable 
based on the vial size and/or labelling on the vials. In the Phase 2 segment, the vials will 
be of different sizes and have unblinded labelling. In the Phase 3 segment, the vials will 
be the same size but will have unblinded labelling. To maintain the blind, vials will only be 
handled by designated unblinded personnel (site pharmacist) at the site. 
Under exceptional circumstances, the PI may desire to unblind a subject’s dose 
assignment in case of an emergency or serious medical condition when knowledge of the 
study product or dose is deemed by the PI to be absolutely essential for proper clinical 
management of the subject. Under such emergency circumstances, the Sponsor urges 
the PI to first contact the Medical Monitor (MM) to review options before unblinding the 
subject’s dose assignment. In case of non-emergency, PI must contact MM to discuss the 
options before unblinding the subject’s dose assignment.  
It is not deemed appropriate to unblind a subject’s treatment assignment for the purpose 
of assisting the subject in making a decision regarding receipt a different COVID-19 
vaccine (emergency use or licensed vaccine).  Subjects should be advised that without 
efficacy data, INO-4800 has not been proven to be more protective than placebo in the 
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prevention of COVID-19 and SARS-CoV-2 infection. Therefore, unblinding will not provide 
any meaningful information to inform a decision of receiving a different COVID-19 vaccine. 
The Sponsor’s pharmacovigilance staff may unblind a subject’s dose assignment for an 
SAE, unanticipated adverse device effect (UADE), or adverse event of special interest 
(AESI) when the event is assessed as related and unexpected. If expedited regulatory 
reporting is required for such an event, the report may be submitted to regulatory 
authorities with the subject’s dose assignment, in accordance with local regulations. 
5.3 
PACKAGING AND LABELING 
5.3.1 INO-4800 OR PLACEBO 
Each vial of INO-4800 or placebo will be labeled consistent with the example product label 
provided in the IB.  
5.3.2 CELLECTRA® 2000 
Please see shipping box for shipping documents and contents. 
The CELLECTRA® 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer. The CELLECTRA® 2000 User Manual 
describes all relevant contraindications, hazards, potential risks and adverse effects, 
interfering substances or devices, warnings, and precautions. Each Pulse Generator has 
a unique serial number, and each ID Applicator has a unique serial number. Each ID Array 
has a Lot Number and Expiration Date. Examples of device labels are provided in the IB. 
The CELLECTRA® 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. 
5.4 
HANDLING AND STORAGE 
5.4.1 INO-4800 AND PLACEBO 
INO-4800 and Placebo will be shipped at 2–8°C. If the temperature monitoring devices in 
the shipping container(s) denote temperatures outside this 2–8°C (36-46°F) range, the 
Sponsor, or its designee, should be contacted immediately. 
Upon arrival, the INO-4800 and placebo must be transferred from the shipping container 
into 2–8°C (36-46°F) storage, in a secure area, in accordance with local regulations by 
designated personnel (e.g., pharmacy personnel). The Sponsor must be notified of any 
deviations from this storage condition. Refrigerator temperature logs must be maintained 
at the clinical site and temperatures must be recorded and monitored regularly. For further 
details see Pharmacy Manual and IB. 
5.4.2 CELLECTRA® 2000 
See User Manual for operating and storage conditions. 
5.5 
PREPARATION AND DISPENSING 
In the Phase 2 segment, INO-4800 is supplied in 2-mL vials at a concentration of 10 
mg/mL at a minimum volume of 0.4 mL. SSC-0001 is supplied in 10-mL vials at a minimum 
volume of 2 mL.  
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In the Phase 3 segment, INO-4800 is supplied in 2-mL vials at a concentration of 10 
mg/mL at a minimum volume of 0.4 or 1.1 mL.  SSC-0001 is supplied in 2-mL vials at a 
minimum volume of 1.1 mL. 
Blinded staff involved in the clinical execution of the study should not come in contact with 
vials of INO-4800 or SSC-0001. Vials will only be handled by designated unblinded 
personnel (e.g., pharmacy) at the site. When a subject is eligible for enrollment, unblinded 
personnel will draw INO-4800 or SSC-0001 into a blinded syringe in accordance with the 
subject’s randomized treatment assignment according to a randomization schedule. The 
syringe will be transferred to blinded site personnel for administration.  
Each INO-4800 and placebo vial will contain a volume of product sufficient to dose multiple 
subjects. The preparation and dispensing information will be provided in the Pharmacy 
Manual. 
5.6 
USE OF STUDY DEVICE 
The instructions for use of the CELLECTRA® 2000 device are provided in the User 
Manual. Each clinical site will receive training for use of the CELLECTRA® 2000 device 
prior to first dose. The EP procedure must be performed by qualified personnel. Any 
individual designated to perform the procedure should be permitted by the relevant local 
authorities to administer parenteral injections to patients (e.g., MD, DO, RN) in addition to 
successfully completing device training provided by Sponsor personnel.  
5.7 
INVESTIGATIONAL DRUG AND STUDY DEVICE ACCOUNTABILITY 
5.7.1 INVESTIGATIONAL PRODUCT (IP) ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current accountability record of 
investigational products (INO-4800 or placebo) is maintained at the study site. The 
investigational products must have full traceability from the receipt of the products through 
subject use, disposal or return of the products. Records or logs must comply with 
applicable regulations and guidelines. The accountability information is provided in the 
Pharmacy Manual. 
5.7.2 CELLECTRA® 2000 ACCOUNTABILITY 
The investigational site is responsible for maintaining device accountability logs. The 
device must have full traceability from the receipt of the products through subject use, 
disposal or return of the products. The site must document acknowledgement of receipt 
and notify Inovio upon receipt of study devices. This includes the content shipped and 
condition upon receipt. 
For each subject administration, there must be a record of each product used for that 
subject, i.e., Pulse Generator serial number, ID Applicator serial number, and ID Array lot 
number. The ID Applicator is reusable with a new ID Array and sheath for each procedure. 
The sterile ID Array and sheath are single use only and must be discarded after use in 
accordance with institutional policy regarding disposal of sharp needles/instruments. 
5.8 
RETURN AND DESTRUCTION OF INVESTIGATIONAL DRUG AND STUDY DEVICE 
5.8.1 INO-4800 AND PLACEBO 
Upon completion or termination of the study, all unused vials of INO-4800 or placebo must 
be destroyed at the study site in accordance with institution policy or returned to Inovio 
Pharmaceuticals, Inc., or its designee if the site cannot destroy IP. 
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The used vials of INO-4800 and placebo will be discarded in accordance with the site’s 
used IP disposal procedure. It is the Investigator’s responsibility to arrange for disposal of 
all empty vials, provided that procedures for proper disposal have been established in 
accordance with applicable national, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. If requested by the Sponsor, the 
return of unused IP vials should be arranged by the responsible Inovio Representative. 
The unused IP vials should only be destroyed after being inspected and reconciled by the 
responsible Inovio Pharmaceuticals, Inc., personnel or designated Clinical Monitor. If IP 
vials are returned to Inovio Pharmaceuticals, Inc., or its designee, the IP must be 
accompanied by the appropriate documentation. The return of unused IP(s) should be 
arranged with the responsible Inovio personnel and/or Clinical Monitor. 
5.8.2 RETURN OF CELLECTRA® 2000 
Upon completion or termination of the study, an Inovio Representative will provide 
instructions regarding the component(s) to be returned to Inovio Pharmaceuticals, Inc., 
destroyed onsite or shipped to a destruction vendor. 
All products returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original containers. 
The return of all products identified above should be arranged by the Inovio 
Representative. The ID Arrays should be discarded in the sharps container immediately 
after use. The used ID Applicators can either be destroyed at the site, shipped to a 
destruction vendor, or returned to Inovio. If the used ID Applicators are destroyed on site, 
it is the Investigator’s responsibility to ensure that arrangements have been made for the 
disposal, written authorization has been granted by Inovio Pharmaceuticals, Inc., or its 
designee, procedures for proper disposal have been established in accordance with 
applicable regulation and guidelines and institutional procedures, and appropriate records 
of the disposal have been documented. 
6.0 
CLINICAL TRIAL PROCEDURES AND SCHEDULE 
The Schedule of Events (36TTables 3 and 436T) in the Clinical Protocol Synopsis summarizes 
the procedures to be performed at each visit. Individual procedures are described in detail 
below. It may be necessary to perform these procedures at unscheduled time points if 
deemed clinically necessary by the Investigator. A subject will be required to provide 
informed consent (Section 6.2) prior to any study procedure being performed. Protocol 
waivers or exemptions will not be granted. Therefore, adherence to the study design and 
assessments are essential and required for study conduct. 
6.1 
PROCEDURE BY VISIT 
Refer to Sections 6.1.1 and 6.1.2 for trial procedures and the times at which they are to 
be performed. 
6.1.1 CLINICAL TRIAL SCREENING EVALUATIONS 
The assessments performed during Screening will determine the subject’s eligibility for 
the study and also their ability to comply with protocol requirements by completing all 
screening assessments. The following screening evaluations will be performed for both 
Phase 2 and Phase 3 segments within 30 days prior to dosing on Day 0. All screening 
assessment values must be reviewed prior to the first Study IP administration. Screening 
and Day 0 visits may be on the same day if eligibility is able to be confirmed prior to 
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randomization. If so, all assessments for Screening and Day 0 must be performed at the 
combined visit. 
If a subject does not meet an inclusion or exclusion criterion due to a transient and non-
clinically significant event at Screening, relevant Screening evaluations may be repeated 
within the same 30-day Screening period. If the subject fails twice, they will be considered 
a screen failure. 
• 
Signed and dated informed consent (Section 6.2); 
• 
Review and confirm all inclusion/exclusion criteria (Section 4.1 and 4.2); 
• 
Obtain and document complete medical history, surgical history (including all 
clinically significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Section 6.1.1.1); 
• 
Collect demographics; 
• 
Collect socio-behavioral assessment information (Section 6.4); 
• 
Collect AEs (Section 6.4.4); 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Record height and weight (Section 6.4); 
• 
Collect urine for pregnancy test (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8).  
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.8). 
 
6.1.1.1 
Medical History 
A medical history will be obtained by the Investigator or qualified designee at the time of 
Screening. Medical history will include all active conditions, and any other past conditions, 
as well as surgical procedures, that are considered to be clinically significant by the 
Investigator and/or having occurred within 3 months prior to Screening. Subjects should 
be queried about any history of Hepatitis B, Hepatitis C and HIV.   
In the Phase 3 segment, subjects with a self-reported history of Hepatitis B or C must 
provide documentation of liver enzymes that are not significantly elevated within the past 
3 months. If such a report of liver enzyme testing is not available, this testing should be 
performed at Screening. Subjects with a history of Hepatitis C without cirrhosis who have 
completed treatment and have proof of an undetectable viral load at least 12 weeks 
following treatment may be enrolled and do not require liver enzymes within the past  
months. 
Subjects with self-reported HIV must provide documentation of controlled HIV infection 
based on a CD4 count greater than 200 cells/mm3 or an undetectable viral load within the 
past 3 months. If a recent CD4 count and/or viral load is not available, this testing should 
be performed at Screening. 
Illnesses first occurring or detected after the signing of the informed consent, or during the 
study and/or worsening of an existing illness in severity, frequency or nature after signing 
of the informed consent are to be documented as AEs on the Case Report Forms (CRF). 
Prior treatments, defined as administered up to 12 weeks prior to the time of informed 
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consent and stopped prior to dosing on Day 0, should be recorded in the CRF as prior 
medications. Concomitant treatments, defined as continuing on Day 0 or new treatments 
taken at or after Day 0, should be recorded in the CRF as concomitant medications. 
6.1.2 CLINICAL TRIAL EVALUATIONS AND PROCEDURES 
Once eligibility has been confirmed, the subject will be randomized to receive a treatment 
assignment (INO-4800 or placebo). Visit dates and windows must be calculated from Day 
0, unless otherwise noted. All subjects will be followed until the Day 393 Visit. All subjects 
will be followed in accordance with assessments outlined below. 
6.1.2.1 
Day 0 and Day 28 (Dosing Visits) 
The following evaluations will be performed on Day 0 and Day 28 prior to dose 
administration: 
Both Phase 2 and Phase 3 segments: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Obtain any updates to medical history, surgical history (including all clinically 
significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Day 0 visit only) (Section 6.1.1.1); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect urine for urine pregnancy test (Section 6.4); 
• 
Collect blood for HIV serology (Day 0 visit only) (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Day 0 visit only) (Phase 3 cellular immunology collection at selected sites only) 
(Section 6.5); 
• 
Review restrictions for injection and EP (Section 6.4.7); 
• 
Randomize subject (instructions to be provided under separate cover) (Day 0 visit 
only). 
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect diary from Day 0 dose (Day 28 visit only). 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8); 
• 
Collect nasopharyngeal swabs for SARS-CoV-2 RT-PCR (Day 0 only) (Section 
6.4.8); 
• 
Collect diary from Day 0 dose during Day 28 visit only(for selected sites only). 
 
The following evaluations will be performed on Day 0 and Day 28 after IP plus EP 
administration: 
• 
Collect any new AEs (Section 6.4.4); 
• 
Download EP Data; 
• 
Provide supplies for subject to use at home, as required (e.g. thermometer, wound 
guide); 
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• 
Phase 2 segment: Distribute diary; 
• 
Phase 3 segment, for selected sites: Distribute diary. 
6.1.2.2 
Post-dose phone calls 
Phase 2 segment: Day 7 and Day 35 
Phase 3 segment: Day 14  
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
 
Phase 2 segment only: 
• 
Review diary (Section 6.4). 
 
Phase 3 segment only: 
• 
Review diary (for selected sites)(Section 6.4); 
6.1.2.3 
Day 42 Visit 
Both Phase 2 and Phase 3 segments: The following evaluations will be performed at this 
visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4);  
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 cellular immunology collection at selected sites only)(Section 6.5);  
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect diary from Day 28 visit. 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8); 
• 
Collect diary from Day 28 visit (for selected sites only); 
• 
Ensure subject has necessary supplies at home (e.g. thermometer). 
6.1.2.4 
Phone calls  
Phase 2 segment: Day 56 
Phase 3 segment: Days 56, 70, 84, 98, 112, 140, 154, 168, 182, 196, 238, 266, 322, 
350, and 378 
In the Phase 3 segment, phone calls to subjects have been spaced bi-weekly 
between study visits through Day 210, and approximately monthly between visits 
from Day 210 to Day 393.   
 
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Guidelines for information to be collected during the phone call can be found in the 
Phone Script. The following evaluations will be performed during the phone call: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Ask about any symptoms of COVID-19 disease; Arrange on-site visit if any signs 
and symptoms of COVID-19 disease are present (Section 6.4.9); 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
6.1.2.5 
Follow up clinic visits 
Phase 2 segment: Day 210 
Phase 3 segment: Days 126, 210 and 294 Visits 
Both Phase 2 and Phase 3 segments: The following evaluations will be performed at these 
visits: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); SAEs, AESIs, and 
MAAEs will be reported after the Day 56 Visit. 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 Day 201 visit only; Phase 3 cellular immunology collection at selected 
sites only) (Section 6.5); 
 
Phase 3 segment: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8);  
• 
Ensure subject has necessary supplies at home (e.g. thermometer). 
6.1.2.6 
Day 393 Visit or EOS 
Phase 2 and Phase 3 segments: The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); SAEs, AESIs, and 
MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect urine pregnancy test (Section 6.4); 
 
Phase 2 segment: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6). 
 
Phase 3 segment: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8); 
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• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 cellular immunology collection at selected sites only)(Section 6.5). 
6.1.2.7 
COVID-19 Assessment Visit 
For both the Phase 2 and Phase 3 segments of the study, subjects will be evaluated 
during a COVID-19 assessment visit when acute COVID-19 is suspected based on 
symptoms or positive SARS-CoV-2 testing. The assessment visit may be performed in 
the clinic, subject’s vehicle, or at a home visit and should be performed within 3 days of 
a positive SARS-CoV-2 test or site knowledge of COVID-19 symptom onset. The 
virologic-confirmation of a case will be based on SARS-CoV-2 RT-PCR testing from the 
central lab. A local RT-PCR result will be considered acceptable in the case where a 
subject is hospitalized and a sample for central lab analysis is not able to be obtained, if 
it was obtained using. an assay performed by a laboratory accredited according to 
standards set by a national or regional accreditation body.  
If a local lab is used to confirm the case, the report from the laboratory must be provided.  
Phase 2 and Phase 3 segments: The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); Only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Optional targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
 
Phase 2 only: 
• 
Collect nasal swabs and saliva for SARS-CoV-2 RT-PCR detection (Section 6.4.8). 
Phase 3 only: 
• 
Collect whole blood and serum for cellular and humoral immunology assessment, 
where possible (Phase 3 cellular immunology collection at selected sites 
only)(Section 6.5) 
• 
Collect nasopharyngeal swabs for SARS-CoV-2 RT-PCR testing (Section 6.4.8). 
6.1.2.8 
COVID-19 Convalescent Visit 
Phase 2 and Phase 3 segments: For subjects with confirmed SARS-CoV-2 infection 
during the trial, a convalescent visit should be scheduled approximately 28 days after 
symptom onset, or in the absence of symptoms, after the collection date of a positive 
SARS-CoV-2 test. If symptoms are ongoing at 28 days after symptom onset, the site 
should follow up with the subject via phone call or unscheduled visit after symptom 
resolution or stabilization.  
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); Only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
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• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 cellular immunology collection at selected sites only) (Section 6.5); 
 
Phase 2 segment only: 
• 
Collect nasal swabs and saliva for SARS-CoV-2 RT-PCR detection (Section 6.4.8). 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8). 
6.2 
INFORMED CONSENT 
All subjects must sign the informed consent prior to participating in any clinical trial-related 
procedures. The informed consent documentation must be in compliance with applicable 
regulations and GCP. Qualified clinical trial personnel will: 
• 
Meet with prospective clinical trial subjects; 
• 
Explain the clinical trial; 
• 
Provide clinical trial subjects with an Informed Consent Form (ICF) that includes the 
following in a language that is understandable to the subject: 
• 
Screening test(s) description; 
• 
Eligibility criteria for entering the clinical trial; 
• 
Clinical trial treatments and follow-up procedures description; 
• 
Explanation of the clinical trial, including but is not limited to: 
• 
Clinical trial objectives; 
• 
Potential benefits and risks; 
• 
Discomforts/inconveniences; 
• 
Subject’s rights and responsibilities. 
The subject is then requested to sign and date the ICF. A copy of the signed informed 
consent documentation must be provided to the subject. The qualified clinical trial 
personnel will document the process of obtaining informed consent within the source 
record. Signed ICFs are maintained in the subject’s source records and must be 
accessible for verification at any time. Signing of the ICF begins the 30-day screening 
period. 
6.3 
ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number (SID), 
which identifies the subject for all clinical trial-related procedures. SIDs are a combination 
of a 4-digit site code and a 4-digit subject number. After SIDs are assigned, they cannot 
be reused or reassigned for any reason. Information regarding the SID and screen date 
will be documented on a screening and enrollment log/system and in the CRF.   
Previously screen failed subjects may be rescreened provided there is a valid documented 
reason for rescreening (i.e. changes to the person’s health or situation that would make 
them possibly eligible at this later time). If rescreening occurs, the subject will keep their 
original Subject ID.  
6.4 
SAFETY EVALUATIONS 
PHYSICAL AND TARGETED PHYSICAL EXAM  
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A full physical examination will be conducted during Screening and at study 
discharge/EOS (e.g. Day 393). A targeted physical assessment will be performed at other 
visits as determined by the Investigator based on subject symptoms.  
VITAL SIGNS 
Vital signs including temperature, respiration rate, blood pressure and heart rate will be 
measured at Screening and at visits specified in the Schedule of Events (36TTables 3 and 
436T).  
At the COVID-19 assessment and convalescent visits, temperature, respiration rate, 
heart rate and oxygen saturation should be performed.   
HEIGHT AND WEIGHT 
Weight and height will be collected at Screening. 
SOCIO-BEHAVIORAL ASSESSMENT  
A Socio-behavioral Assessment, including self-reported smoking and vaping history, and 
self-reported history of exposure to second-hand smoke will be obtained at Screening. 
LABORATORY EVALUATIONS 
Blood samples will be collected at visits specified in the Schedule of Events (36TTables 3 and 
436T). A total of approximately mL 245-330mL of blood will be drawn from each subject over 
the course of the study (inclusive of relevant safety and immunology samples at regular 
study visits per Tables 3 and 4). If the subjects is evaluated at COVID-19 visits, an 
additional volume of approximately 85-120mL will be collected. Subjects may be asked to 
return for additional blood draws if collected blood sample is lost or unevaluable for any 
reason. 
Hematology [Complete blood count (CBC) with automated differential]: 
White blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit and 
platelet count will be measured at Screening (Phase 2 segment only) and at visits specified 
in the Schedule of Events (36TTables 3 and 436T). Hemoglobin A1c will additionally be performed 
at Screening (Phase 2 segment only). 
Serum chemistry: 
Electrolytes [Sodium (Na), Potassium (K), Chloride (Cl), Bicarbonate (HCO3), Calcium 
(Ca), Phosphate (PO4)], glucose, Blood Urea Nitrogen (BUN), Creatinine (Cr),  alkaline 
phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), LDH,  
and total bilirubin (TBili) at Screening (Phase 2 segment only) and at visits specified in the 
Schedule of Events (36TTables 3 and 436T).  
Urinalysis:  
Urine samples will be tested by dipstick for glucose, protein, and hematuria at Screening 
(Phase 2 segment only) and at visits specified in the Schedule of Events (36TTables 3 and 
436T). If abnormal (presence of protein, hematuria, or glucose ≥ 1+), a microscopic 
examination should be performed.  
Serology: 
HIV antibody or rapid test will be measured at Day 0 only.  
Antibodies to SARS-CoV-2 will be measured at Screening and at visits specified in the 
Schedule of Events (Tables 3 and 4). 
Pregnancy Testing:  
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Pregnancy testing will be performed on women of childbearing potential (WOCBP). All 
women will be assumed to be of childbearing potential unless they are:  
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Women who are surgically sterile or have a partner who is sterile (i.e., vasectomy 
in males or tubal ligation, absence of ovaries and/or uterus in females). In the 
case of a vasectomy, subjects should wait six (6) months post-vasectomy to be 
considered sterile. 
Phase 2: For WOCBP, a serum pregnancy test will be obtained at Screening and a urine 
pregnancy test will be performed immediately prior to any dosing and at the subject’s last 
visit.  
Phase 3: For WOCBP, a urine pregnancy test will be obtained at Screening and will be 
performed immediately prior to any dosing. 
A negative result for urine β-HCG (test must have a sensitivity of at least 25 mIU/mL) must 
be available prior to each administration of IP. If the β-HCG test is positive, indicating that 
the subject is pregnant prior to completing the specified dose regimen, then no further IP 
will be administered. Every attempt should be made to follow pregnant subjects for the 
remainder of the study and to determine the outcome of the pregnancy (see Section 7.12). 
DIARY 
Diaries will be implemented in the Phase 2 segment of the protocol and at selected sites 
(estimated to include 711 subjects) in the Phase 3 segment.  Subjects will be provided a 
diary to record the following solicited local and systemic AEs: 
• 
Oral temperature and time taken (each daily entry before 11:59 pm) 
• 
Solicited systemic symptoms 
• 
Solicited local injection site symptoms 
• 
Concomitant medications 
The diary should be completed once daily starting the evening of each study dose through 
6 days post-dose. The completed diary post-dose 1 and post-dose 2 will be reviewed with 
the subject by the study staff during the next study phone call or visit and collected at the 
next in-person study visit. The study staff will review the diary with the subject to assess 
for temperature, solicited systemic symptoms (unusually tired/feeling unwell, muscle 
aches, headache, nausea, joint pain) and solicited injection site symptoms (pain, itching, 
redness, swelling, bruising). In addition, unsolicited symptoms and concomitant 
medications will be assessed.  
Any diary entry determined to meet the Common Terminology Criteria for Adverse Events 
version 5.0 (CTCAE) criteria for a Grade 1 or higher adverse event should be documented 
as an adverse event unless deemed part of the subject’s ongoing medical history. Injection 
site reactions should be graded per the Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, issued September 
2007 (See Section 6.4.5). If the diary entry does not meet the criteria of a Grade 1 or 
higher AE as per the relevant guidelines, Investigator clinical judgment can be used to 
determine whether the entry should be recorded as an AE and documented accordingly 
in the site’s source. For cases where the diary entry and final AE reporting (i.e. grading) 
do not agree, the reasoning should be recorded in the source documents. 
6.4.1 INTRADERMAL INJECTION AND EP  
Phase 2 and Phase 3 segments: 
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A complete administration procedure is defined as an ID injection (formation of a wheal) 
of IP followed by insertion of the ID Array needles (electrodes) through the skin and into 
the wheal followed by delivery of four electroporation pulses. This procedure is broadly 
described as administration because it involves more than the injection of a drug. 
Only if the deltoid area is not a suitable location for administration (see exclusion criterion 
‘j’), the ID injection can then be administered above the lateral quadriceps followed 
immediately by EP. IP must not be given within 2 cm of a tattoo, scar, keloid, or active 
lesion/rash. Also, ID injection followed immediately by EP must not be performed on the 
skin of an extremity which has any metal implants or implantable medical device (e.g., 
surgical rods, pins or joint replacements). If a subject has an implanted cardiac defibrillator 
or pacemaker, ID injection/EP must not be performed above the deltoid muscle on the 
same side of the body where the device is located. 
There are three steps that must be performed as part of the administration procedure: 
1. Injection of IP (INO-4800 or placebo) 
2. Insertion of the array into the subject’s skin 
3. Pressing the trigger button on the EP applicator  
Table 9 below is provided as guidance on how to appropriately complete the procedure 
when injection of IP has occurred, but the subject did not receive EP. 
Table 9: Guidance for how to manage an incomplete administration after IP has 
been injected 
Was IP 
injected? 
Was the array 
inserted into skin? 
Was trigger button 
pressed? 
Action 
Yes 
Yes (if array gets 
dislodged before 
the trigger button 
is pressed, the 
same array may 
be re-inserted) 
No 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
Yes 
No 
Yes 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
Yes 
No 
No 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
 
Reinjection of IP (i.e. protocol-specified IP has already been delivered) is not permitted. 
Delivery of a second electroporation in tissue is not permitted. 
Training will be provided by the Sponsor on use of the device. 
Phase 2 segment: 
Subjects will receive a two-dose regimen of one or two 1.0 mg ID injections of INO-4800 
or placebo in a volume of ~0.1 mL in an acceptable skin location for injection and 
subsequently followed immediately by EP of each injection site with CELLECTRA® 2000 
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at Day 0 and Day 28. For subjects assigned to receive two injections + EP at each dosing 
visit, the two injections must be performed in acceptable locations on two different limbs. 
Phase 3 segment: 
Subjects will receive a two-dose regimen of 1.0 mg ID injections of INO-4800 or placebo 
in a volume of ~0.1 mL in an acceptable skin location for injection and subsequently 
followed immediately by EP of the injection site with CELLECTRA® 2000 at Day 0 and 
Day 28. The dose level will be determined based on results of the study’s Phase 2 
segment. 
6.4.2 MANAGEMENT OF PAIN DUE TO ELECTROPORATION (EP) PROCEDURES 
In case of pain, subjects may be treated with a non-narcotic analgesic (e.g., 
acetaminophen) after injection/EP.  
Medication taken for pain management will be documented as concomitant medications. 
6.4.3 ASSESSMENT OF LABORATORY ABNORMALITIES 
In Phase 2, samples will be collected for serum chemistry, hematology, and urinalysis at 
the visits listed in the Schedule of Events (36TTables 3 and 436T) and as listed in Section 6.4.  
Laboratory AEs will be assessed and graded in accordance with the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. Laboratory values that are 
not clinically significant (NCS) in the Investigator’s opinion will not be reported as AEs. 
6.4.4 ASSESSMENT OF CLINICAL TRIAL ADVERSE EVENTS (AES) 
Subjects will be queried regarding the occurrence of any AEs including AEs related to 
injection site reactions, concomitant medications and new onset illness or disease during 
their study visits and phone calls. Subjects will be reminded to contact study personnel 
and immediately report any event for the duration of the study. All AEs will be captured 
from the time of the informed consent until 28 days post-dose 2 (Day 56). Following the 
Day 56 visit, only SAEs, AESIs and MAAEs will be collected. All related AEs, AESIs and 
SAEs will be followed to resolution or stabilization. These events will be recorded on the 
subject’s CRF. 
6.4.5 ASSESSMENT OF INJECTION SITE REACTIONS  
Reactions arising from the IP administration procedure may be reported as administration 
site or injection site reactions. When evaluating administration (injection) site reactions 
throughout the study, it is most important to be as specific as possible by selecting the 
most appropriate term (see Table 10 below) and using the grading scale as listed in the 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, issued September 2007. All subjects will be observed for 30 
minutes following the IP administration procedure for immediate AEs.  In addition, other 
events associated with administration (injection) site reactions (e.g., hematoma, infection 
or necrosis) should also be reported with preferred terms specific for administration 
(injection) site reactions.  
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Table 10: Grading Scale for Injection Site Reactions 
Local Reaction to 
Injectable Product 
(Grade) 
Mild (1) 
Moderate (2) 
Severe (3) 
Potentially 
Life 
Threatening 
(4) 
Pain 
Does not 
interfere with 
activity 
Repeated use 
of non-
narcotic pain 
reliever >24 
hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency 
room visit or 
hospitalization 
Tenderness 
Mild 
discomfort to 
touch 
Discomfort 
with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/Rednessa 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swellingb 
2.5-5 cm and 
no 
interference 
w/ activity 
5.1-10 cm or 
interferes with 
activity 
>10 cm or 
prevents daily 
activity 
Necrosis 
September 2007 “FDA Guidance for Industry-Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
a In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable 
b Should be evaluated and graded using the functional scale as well as the actual measurement. 
6.4.6 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken at the time of Screening and 
ongoing from signing of the informed consent to study discharge that do not affect a 
subject’s eligibility for participation (see Section 4.2) must be recorded on CRFs. 
Actual or estimated start and stop dates must be provided. This information will be 
obtained from the subject and/or any available medical records. The indication for the 
medication, dose, and dose regimen will be documented.  
Therapy considered necessary for the subject’s welfare may be given at the discretion of 
the Investigator or medical provider. If the permissibility of a specific medication/treatment 
is in question, please contact the Medical Monitor. 
The decision to administer a prohibited medication/treatment (Section 6.4.7) is made with 
the safety of the clinical trial subject as the primary consideration. When possible, the 
Sponsor should be notified before the prohibited medication/treatment is administered. 
6.4.7 RESTRICTIONS  
In the Phase 2 segment of the trial, subjects should refrain from becoming pregnant until 
3 months following the last dose of investigational product by using appropriate 
contraceptive measures (see Section 4.1.1). In the Phase 3 segment of the trial, subjects 
should refrain from becoming pregnant until receipt of the last dose of investigation 
product by using appropriate contraceptive measures (See Section 4.1). 
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Subjects must not receive any non-study related vaccine (e.g., influenza vaccine) within 2 
weeks prior to the first dose of IP, or within 2 weeks of (before or after) any subsequent 
dose of IP.  
Subjects must not have fever (oral temperature ≥38.0 degrees Celsius or 100.4o 
Fahrenheit) within 72 hours prior to each dosing. 
Subjects should not receive hydroxychloroquine or any other drug/vaccine intended as 
COVID-19 prophylaxis during the trial. If a subject informs the site of their intent to receive 
another COVID-19 vaccine (emergency use or licensed vaccine), the subject should be 
informed that the safety and effectiveness of receiving INO-4800 followed by another 
COVID-19 vaccine has not been studied. In the Phase 3 segment, subjects should be 
reminded that if and when appropriate, the Sponsor would provide INO-4800 to those who 
received placebo in the trial. 
Subjects should not participate in any other interventional trials for the duration of this trial. 
Subjects must not receive disease modifying doses of anti-rheumatic drugs (e.g., 
azathioprine, cyclophosphamide, cyclosporine, methotrexate), biologic disease modifying 
drugs such as TNF-α inhibitors (e.g., infliximab, adalimumab or etanercept) and long term 
use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of prednisone 
equivalent (use of inhaled, topical, nasal, otic, and ophthalmic corticosteroids are allowed).  
6.4.8 SARS-COV-2 TESTING 
Phase 2 segment: 
SARS-CoV-2 antibody and RT-PCR testing will be used during screening to test for 
previous or current SARS-CoV-2 infection. During the trial, subjects who report symptoms 
suggestive of COVID-19 will be assessed at a COVID-19 assessment visit in the clinic or 
subject’s vehicle or at the subject’s home. During this visit, nasal swabs and saliva will be 
collected to detect SARS-CoV-2 using the RT-PCR assay. Genotyping may also be 
performed. If the subject is confirmed to be COVID-19 positive, a follow-up nasal swab 
and saliva will be collected to detect SARS-CoV-2 using the RT-PCR assay at the COVID-
19 convalescent visit. 
Phase 3 segment: 
SARS-CoV-2 antibody testing will be used during screening to test for previous SARS-
CoV-2 infection and during each subsequent visit (see Table 4: Schedule of Events) to 
identify SARS-CoV-2 infections that may occur regardless of symptoms between study 
visits. 
SARS-CoV-2 RT-PCR testing will be conducted on nasopharyngeal specimens collected 
at Day 0. The Day 0 SARS-CoV-2 RT-PCR results will not be required prior to dosing on 
that day. 
If, at any time during the trial, either the SARS-CoV-2 antibody or an RT-PCR test result 
is positive, the subject will be notified of the result and will be evaluated at a COVID-19 
assessment visit. During that visit, which may be conducted in the clinic, from the subject’s 
vehicle, or in the subject’s home, nasopharyngeal swabs will be collected to detect SARS-
CoV-2 using the RT-PCR assay. Genotyping may also be performed on the sample(s) 
collected at the COVID-19 assessment visit.  
6.4.9 COVID-19 DISEASE MONITORING 
During both the Phase 2 and Phase 3 segments of the trial, all subjects will be monitored 
for the development of symptoms suggestive of COVID-19 disease. For the Phase 3 
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segment, frequent (approximately bi-weekly) scheduled clinic visits or phone calls will 
occur.  
All subjects in the trial should be instructed to do the following: 
• 
Take their temperature daily at home starting on the Day 0 visit for the duration of 
the trial.     
• 
Monitor for symptoms suggestive of COVID-19 (e.g., feeling feverish or chills, 
cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, 
headache, new loss of taste or smell, sore throat, congestion or runny nose, 
nausea or vomiting, diarrhea) starting on the Day 0 visit for the duration of the trial.  
If at any time during the study, the subject experiences a fever of ≥ 100.4°F/38°C or 
symptoms suggestive of COVID-19, the subject should contact the site. The site staff 
should arrange for a clinic visit (COVID-19 assessment visit) within 3 days of the site being 
aware of either a positive SARS-CoV-2 test or COVID-19 symptom onset. The COVID-19 
assessment visit may be performed either at the clinic, in the subject’s vehicle or in the 
subject’s home. 
Subjects with a confirmed COVID-19 diagnosis, per the case definition outlined in Section 
3.7, prior to dose 2 or who have a positive SARS-CoV-2 PCR test at Day 0 will be 
discontinued from further dosing and will be followed until EOS for safety and resolution 
of COVID-19. Subjects with confirmed SARS-CoV-2 infection will return for a convalescent 
visit approximately 28 days after symptom onset, or in the absence of symptoms, after the 
collection date of the positive SARS-CoV-2 sample. If symptoms are ongoing at 28 days 
after symptom onset, the site should follow up with the subject via phone call or 
unscheduled visit after symptom resolution or stabilization. Recovery from COVID-19 
disease requires either resolution of clinical symptoms except for loss of taste/smell, or 
with sequelae that appear to be permanent.     
Subjects who require medical care for COVID-19 (or any other suspected condition) will 
be referred to their primary health care provider or a medical treatment facility if the 
Investigator believes that the subject should be managed beyond routine care that can be 
provided by the study site. Subjects referred for treatment will continue study follow-up 
according to the protocol schedule. If subjects are treated or hospitalized due to their 
illness, the study team will request COVID-19 specific test results, treatments, treatment 
outcomes and diagnostics from medical treatment facilities with the subject’s written 
permission. These results and diagnostics will be recorded in the study and/or safety 
database consistent with protocol reporting requirements. 
6.5 
IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at visits specified in the Schedule of 
Events (36TTables 3 and 436T) for cellular and humoral immunology assessments. Binding 
ELISA will be evaluated at serial timepoints. Cellular sampling requires 32 mL of whole 
blood be collected at each visit. Humoral sampling requires collection of 8.5 mL of whole 
blood in a single 10-mL red top serum collection tube to produce two serum aliquots of 2 
mL each. However, baseline (Day 0) immunology samples are required to serve as a 
baseline for all subsequent immunology testing. Therefore, a total of 68 mL whole blood 
for cellular sampling and 8 mL serum for humoral sampling is required on Day 0 prior to 
1st dose. Subjects may be asked to return for additional blood draws if collected blood 
sample is lost or unevaluable for any reason. Details of the immunology sample collection 
and shipment information will be provided in the Laboratory Manual.  
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Humoral samples will be collected on all subjects and cellular samples will be collected at 
selected sites (from approximately 711 subjects). Both humoral and cellular analysis will 
be conducted in the first 102 subjects age 18-50 and in the first 102 subjects age 51 and 
older enrolled at the sites that are selected for cellular sample collection. In addition, 
cellular and humoral samples will be analyzed on all subjects with COVID-19 when 
samples are available. 
The immune responses to INO-4800 will be measured using assays that include a 
pseudovirus-based neutralization assay and ELISpot. Determination of additional 
analyses using assays not specified, such as assessment of immunological gene 
expression or flow cytometry, assessment of immunological protein expression on 
collected samples for immunological endpoints will be made on an ongoing basis 
throughout the trial. 
7.0 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
The safety of INO-4800 will be measured and graded in accordance with the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. 
7.2 
ADVERSE EVENTS (AES) 
Any untoward medical occurrence in a patient or clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.  
Adverse Events (AEs) include the following: 
• Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (before the administration of clinical trial drug); 
• Any pre-existing condition that increases in severity, or changes in nature during or as 
a consequence of the clinical trial drug administration phase; 
• Complications of pregnancy (refer to Section 7.11). 
Adverse Events (AEs) do not include the following: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; however, the condition that leads to the procedure is an AE; 
• Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the Screening Visit that do not worsen; 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions); 
• Overdose without clinical sequelae; 
• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed, is not an AE; it is considered to be pre-existing and will be 
documented on the medical history CRF; 
• Uncomplicated pregnancy; 
• An induced elective abortion to terminate a pregnancy without medical reason; 
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• Confirmed COVID-19 disease.  
7.3 
ADVERSE DRUG REACTION (ADR) 
All noxious and unintended responses to a medicinal product related to any dose. This 
means that a causal relationship between the medicinal product and an adverse event is 
at least a reasonable possibility (i.e., the relationship cannot be ruled out). 
7.4 
SERIOUS ADVERSE EVENTS (SAES) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death;  
• Is life-threatening; 
o Refers to an event in which the subject was at risk of death at the time of the event. 
It does not refer to an event which hypothetically might have caused death if it 
were more severe 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
o Includes any hospitalization in which the subject has been admitted to the hospital 
regardless the length of stay, even if the hospitalization is only a precautionary 
measure to allow continued observation. However, hospitalization (including 
hospitalization for an elective procedure) for a pre-existing condition that has not 
worsened, does not constitute an SAE 
• Results in persistent or significant disability/incapacity; 
o A substantial disruption of a person's ability to conduct normal life functions (i.e., 
the adverse event resulted in a significant, persistent or permanent change, 
impairment, damage or disruption in the subject’s body function/structure, physical 
activities and/or quality of life) 
• Results in congenital anomaly or birth defect and/or; 
• An important medical event.  
o An event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse 
Clarification of Serious Adverse Events (SAEs) 
• Death itself is not an AE. Death is an outcome of an AE, but when the cause of death 
has not been provided, use the event term: death of unknown cause; 
• Confirmed COVID-19 disease that requires hospitalization is recorded on the 
Suspected COVID-19 Clinical Event CRF, and not recorded as an SAE; 
• COVID-19 disease with an outcome of death is recorded on the Suspected COVID-19 
Clinical Event CRF, and not recorded as an SAE; 
• The subject may not have been receiving an investigational medicinal product at the 
occurrence of the event; 
• Complications associated with COVID-19 disease that occur or prolong 
hospitalization are recorded on the Suspected COVID-19 Clinical Event CRF. 
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7.5 
UNEXPECTED ADVERSE DRUG REACTION 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator’s Brochure [IB] for an unapproved investigational 
product, package insert/summary of product characteristics for an approved product). 
7.6 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects.  
A UADE is a type of SAE that requires reporting to the Sponsor in accordance with Section 
7.9. 
7.7 
DEVICE DEFICIENCY 
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance. 
Note: Device deficiencies include malfunctions, use errors and inadequate labelling. 
7.8 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor is responsible for the overall safety monitoring of the clinical trial. 
Safety monitoring assessments include but are not limited to:  
• Incidence of all AEs classified by system organ class, preferred term, severity and 
causal relationship to clinical trial treatment; 
• Changes in laboratory parameters; 
• Local and systemic injection site review; special attention will be paid to the examination 
of the injection site. 
7.8.1 ADVERSE EVENT OF SPECIAL INTEREST (AESI)  
An adverse event of special interest (serious or non-serious) is one of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor can be 
appropriate.  
For the purpose of this clinical trial, the AESIs listed in Appendix A are to be reported to 
the Sponsor in accordance with Section 7.9. 
7.8.2 MEDICALLY ATTENDED ADVERSE EVENT (MAAE) 
A medically attended adverse event (serious or non-serious) is defined as an adverse 
event that leads to an unplanned contact with a health care provider. 
7.8.3 ABNORMAL LABORATORY VALUE 
The Investigator will annotate each abnormal lab value as clinically significant (CS) or not 
clinically significant (NCS). 
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Laboratory values that are NCS in the Investigator’s opinion should not be reported as an 
adverse event. 
Any abnormal laboratory value that is new in onset or worsened in severity or frequency 
from the baseline condition and meets one of the following criteria will be recorded as an 
AE: 
• 
Requires therapeutic intervention or diagnostic tests; 
• 
Leads to discontinuation of further administration of the investigational product in 
the clinical trial; 
• 
Has accompanying or inducing symptoms or signs; 
• 
Is judged by the Investigator as clinically significant (CS). 
Abnormal laboratory values that meet the criteria of an AE or SAE should be reported in 
accordance with Section 7.9. 
7.8.4 CLINICAL TRIAL STOPPING RULES 
The Investigator is to immediately notify the Medical Monitor if the following are observed: 
• 
Any SAE related to study treatment; 
• 
Any Grade 4 AEs related to study treatment; 
• 
Any report of anaphylaxis related to study treatment; 
• 
Any suspected Severe COVID-19 disease case (per Sections 3.7.1.1 and Section 
3.7.1.2). 
The Medical Monitor will notify the Chair of the Safety Review Committee, who will make 
a determination as to whether to temporarily halt dosing until a more formal review of the 
case(s) is made. Such a formal review may include an ad hoc meeting of the DSMB, after 
consultation with the DSMB Chair. Following such a meeting, the DSMB chair will render 
a recommendation to the Medical Monitor regarding continuation of trial dosing. The 
Sponsor will independently investigate the case(s) and, after review of the DSMB 
recommendations, will communicate a final decision as to whether to lift the dosing 
suspension or whether to continue dosing. These deliberations will be documented and 
will be provided to the IRBs and FDA, where required.   
In the case of suspected Severe COVID-19 cases, the trial will be paused if a vaccine-to-
placebo case split yields a relative risk with a 90% confidence interval lower bound >1.  
The minimum case split corresponding to this criterion is 8:0. In this scenario, the trial will 
pause until at least one additional case is accrued and the DSMB can review the data and 
make a recommendation regarding continued enrollment in the trial. 
7.9 
SAFETY DATA REPORTING PERIOD, METHOD OF COLLECTION AND SUBMISSION 
All AEs will be collected from the time informed consent is obtained through Day 56. 
MAAEs, AESIs and SAEs only will continue to be collected after the Day 56 visit and will 
be followed to resolution or stabilization. This information will be captured in the CRF. 
If the Investigator determines that the AE meets serious criteria, then the AE will be 
recorded as an SAE. 
SAEs and AESIs will be reported to the Sponsor from the time the subject signs the 
informed consent until the last visit. 
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All SAEs (regardless of causal relationship) and AESIs will be reported on the SAE Report 
Form and submitted to the Sponsor within 24 hours of becoming aware of the event. The 
SAE Report Form will be either emailed to safety.inovio@apcerls.com or faxed to
The original SAE Report Form must be kept at the clinical trial site.
The event will be data entered into the CRF. 
For the events that are considered an AESI, the Investigator will contact the Sponsor within 
24 hours of becoming aware of the event to discuss whether dosing should continue. 
Table 11: SAE Contact Information 
Sponsor Safety Email: safety.inovio@apcerls.com 
Sponsor Safety Fax: 
Sponsor Safety Phone: 
Table 12: Medical Monitor Direct Contact Information 
Primary point of contact, ICON Medical Monitor: 
, M.D. 
Email: 
 
Phone: 
 
Inovio Medical Monitor:  
, Jr., M.D., FACP, FIDSA 
Email: 
 
Cell Phone: 
 
All SAEs, treatment-related AEs, MAAEs and AESIs must be followed by the Investigator 
until resolution or return to baseline status, stabilization of the event (i.e., the expectation 
that it will remain chronic), even if it extends beyond the clinical trial reporting period or 
until it is determined that the subject is lost to follow up. 
Follow-up information is to be submitted to the Sponsor on an SAE Report Form and within 
24 hours of becoming aware of the information. 
If medical records are submitted to the Sponsor with the SAE Report Form, the clinical 
trial site must: 
• Redact the medical records of all personal data (e.g., confidential subject data,
Personal Identifying Information [PII])
• Provide the subject’s assigned identification number (SID) on the records
7.10 ADVERSE EVENT REPORTING 
This section provides details on reporting the safety information. 
7.10.1 SUBMITTING THE INITIAL SERIOUS ADVERSE EVENT (SAE) REPORT FORM 
The Investigator should include as much safety information as possible when submitting 
the initial report, but the report must include the following at a minimum:  
•
The adverse event;
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• 
The subject’s assigned identification number (SID); 
• 
Investigational product(s) (IP) and/or study device; 
• 
Investigator causal relationship to the IP(s) and/or study device; 
• 
Serious criteria; 
• 
Reporter name and contact information. 
If a case is submitted to the Sponsor with only the “minimum” information, a more detailed 
or updated follow-up report will be sent to the Sponsor as soon as possible but no later 
than three (3) calendar days after the date of the initial report. 
7.10.2 RECORDING THE EVENT 
Investigators should use correct medical terminology/concepts when recording AEs on the 
EDC and SAE Report Form. The use of colloquialisms and abbreviations should be 
avoided. 
A medical diagnosis, if known, should be recorded rather than individual signs and 
symptoms. However, if the signs and/or symptoms cannot be medically characterized as 
a single diagnosis or syndrome, each individual sign and/or symptom should be recorded. 
If a diagnosis is subsequently established, all previous signs and/or symptoms will be 
subsumed and replaced with a single medical diagnosis. 
7.10.3 ASSESSING SEVERITY (INTENSITY) 
Severity is used to describe the intensity of a specific event (e.g., mild, moderate, severe). 
The Investigator will assess and grade clinical AEs or SAEs (based on discussions with 
clinical trial subjects) in accordance with CTCAE. 
7.10.4 CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS (AES) 
A causally related AE is one judged to have a possible, probable or definite relationship 
to the administration of the IP and/or the study device. An AE may also be assessed as 
not related to the IP and/or the study device. Because the Investigator is knowledgeable 
about the subject (e.g., medical history, concomitant medications), administers the IP, and 
monitors the subject’s response to the IP, the Investigator is responsible for reporting AEs 
and judging the relationship between the administration of the IP and EP and a 
subsequent AE. The Investigator is aware of the subject’s clinical state and may have 
observed the event, and thus may be sensitive to distinctions between events due to the 
underlying disease process versus events that may be product-related.  
Investigators should use their knowledge of the clinical trial subject, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to determine 
whether an AE is considered to be related to the IP and/or the study device and the causal 
relationship reported as "Yes" or "No" accordingly. Causality should be assessed by the 
Investigator as related to drug, related to device, or related to both drug and device (i.e., 
related to both or indiscernible) by the following criteria: 
• 
Yes – there is a reasonable possibility that administration of the clinical trial 
treatment (drug or device or both drug and device) contributed to the event 
• 
No – there is no reasonable possibility that administration of the clinical trial 
treatment contributed to the event and there are more likely causes 
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The following guidance should also be taken into consideration: 
• 
Temporal relationship of event to administration of IP and/or EP; 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
• 
Known association of the event with the IP, EP or with similar treatments; 
• 
Known association of the event with the disease under trial; 
• 
Presence of risk factors in the clinical trial subject or use of concomitant 
medications known to increase the occurrence of the event. 
The rationale for the Investigator’s causal assessment is to be recorded on the SAE Report 
Form. 
The Sponsor will assess the overall safety of the IP delivered by EP and determine 
whether to report expeditiously to the regulatory authority(ies). 
7.11 REPORTING SUSPECTED COVID-19 DISEASE CASES DURING THE TRIAL 
For both Phase 2 and Phase 3 segments of the trial, all suspected COVID-19 disease 
cases based on reported COVID-19 symptoms and/or SARS-CoV-2 test results should be 
entered into the Suspected COVID-19 Clinical Event CRF within 24 hours of awareness. 
Cases will be tracked until final determination of whether the case meets criteria of a 
confirmed COVID-19 disease case, per the case definition. For the Phase 2 segment of 
the trial, this determination will be made by the Investigator. For the Phase 3 segment, this 
determination will be made by the EAC. 
If the reported COVID-19 disease case is later determined not to be a confirmed COVID-
19 case, the event (e.g. symptoms or other diagnosis), if serious, would be reported as an 
SAE within 24 hours following determination by the Investigator (Phase 2 segment) or 
notification by EAC (Phase 3 segment).  
If the reported COVID-19 disease case is later determined not to be a confirmed COVID-
19 case, the event (e.g. symptoms or other diagnosis), if non-serious and if occurring from 
the time of consent until 28 days post-dose 2, would be reported as an AE following 
determination by the Investigator (Phase 2 segment) or notification by EAC (Phase 3 
segment). 
7.12 REPORTING PREGNANCY DURING THE CLINICAL TRIAL 
Subjects in Phase 2 who are pregnant or expect to become pregnant prior to 3 months 
following the last dose will be excluded from participation in the clinical trial.  
Subjects in Phase 3 who are pregnant or expect to become pregnant prior to the last dose 
will be excluded from participation in the clinical trial.  
All pregnancies that occur from the time of first administration of clinical trial treatment 
through study completion (i.e., Day 393) will be reported to the Sponsor. If clinical trial site 
staff become aware that a subject becomes pregnant after the first dose in the clinical trial, 
she will not be given any additional treatments with the IP. A Pregnancy Form will be 
completed by the site and submitted to the Sponsor within 24 hours after becoming aware 
of the pregnancy. 
The Investigator will report this event to their IRB/REB/EC in accordance with their policies 
and procedures.  
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The clinical trial site must request the subject’s permission to query pregnancy outcome 
and follow the subject for outcome of the pregnancy. The subject will continue to be 
followed for safety assessments without receiving additional IP until clinical trial discharge 
in accordance with this protocol. Procedures that are contraindicated during pregnancy, 
including additional dose administrations, must not be performed. The Investigator should 
use clinical judgment regarding subsequent clinical trial-related blood collection based on 
the presence or absence of anemia in each subject.  
Male subjects will be instructed through the ICF to immediately inform the Investigator if 
their partner becomes pregnant until study completion. A Pregnancy Form will be 
completed by the site and submitted to the Sponsor within 24 hours after becoming aware 
of the pregnancy. The pregnant partner will be asked to sign a Pregnancy Information 
Collection Consent Form to allow for follow-up on her pregnancy. If the authorization has 
been signed, the Investigator will collect and report details of the course and outcome of 
the pregnancy in the partner of a male subject exposed to IP. The site will update the 
Pregnancy Form with additional information on the course and outcome of the pregnancy 
and submit the form to the Sponsor.  
If an Investigator is contacted by the male subject or his pregnant partner, the Investigator 
may provide information on the risks of the pregnancy and the possible effects on the fetus 
to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
If the end of the pregnancy occurs after the clinical trial has been completed, the outcome 
will be reported directly to the Sponsor. 
7.13 REPORTING DEVICE-RELATED COMPLAINTS OR DEFICIENCIES 
All product complaints that meet the definition of device deficiency must be reported to the 
Sponsor within 10 days of discovery, with the exception of SAEs which require 24-hour 
reporting. The error reporting or complaint form must be completed and emailed to the 
Sponsor at clinicalcomplaint@inovio.com. 
Device deficiencies include malfunctions, misuse or use errors and inadequate labeling. 
A malfunction is defined as the failure of a device to meet its performance specifications 
or otherwise perform as intended. The intended performance of a device refers to the 
intended use for which the device is labeled or marketed. 
Any problems experienced during the treatment procedure including malfunctions of the 
device, error messages displayed on the device screen following treatment, or errors that 
occur during the treatment procedure must immediately be reported to the Sponsor or its 
designee for evaluation.  
7.14 NOTIFYING REGULATORY AUTHORITIES AND INSTITUTIONAL REVIEW BOARDS 
(IRBS)/RESEARCH ETHICS BOARDS (REBS)/ETHICS COMMITTEES (ECS) OF SAFETY 
INFORMATION 
7.14.1 SPONSOR RESPONSIBILITIES 
• 
Determine whether the safety information meets the requirements for expedited 
reporting to the applicable regulatory authorities; 
• 
Prepare and submit the safety report to the applicable regulatory authorities; 
• 
Send all participating PIs a safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) that will include a statement if there is or is not any significant new 
safety information that might influence the risk-benefit assessment of the IP and/or 
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study device, sufficient to consider changes in product administration or overall 
conduct of the clinical investigation. 
7.14.2 PRINCIPAL INVESTIGATOR (PI) RESPONSIBILITIES 
• 
Forward a copy of the safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) to their IRB/REB/EC as soon as practical in accordance with the 
governing policy and/or procedures; 
• 
Notify their IRB/REB/EC of safety information (i.e., SAEs, pregnancies, and AESIs) 
that occur at their clinical trial site in accordance with their local institutional policy. 
7.15 POST-TRIAL REPORTING REQUIREMENTS 
PIs are not obligated to actively seek AEs or SAEs beyond the clinical trial reporting period. 
However, if the PI becomes aware of an AE or SAE that occurs after the Completion or 
Termination Visit and the event is deemed by the PI to be related to the clinical trial 
treatment, the PI should promptly document and report the event to the Sponsor. 
7.16 CLINICAL TRIAL DISCONTINUATION  
INOVIO reserves the right to discontinue the clinical trial at a site or at multiple sites for 
safety or administrative reasons at any time. In particular, a clinical trial site that does not 
recruit at a reasonable rate may be discontinued. Additionally, the clinical trial may be 
discontinued at any time by an IRB/REB/EC, INOVIO, or a regulatory authority as part of 
their duties to ensure that clinical trial subjects are protected.  
If the clinical trial is discontinued and/or the clinical trial site closed for any 
reason, all IP and devices must be returned to INOVIO or its 
representative. The PI should ensure that their site file documents are complete 
prior to archiving, and provide copies of any requested documents to INOVIO 
for its Trial Master File (TMF). 
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
STATISTICAL AND ANALYTICAL PLAN 
The formal Statistical Analysis Plan is contained in the sections that follow. 
8.2 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is an operationally seamless Phase 2/3 trial.  The subjects and data from Phase 2 
are independent from that of Phase 3.   
Phase 2 Segment:  This is a four-arm, multi-center, placebo-controlled, blinded, and 
randomized clinical trial in subjects at high risk of SARS-CoV-2 exposure. The trial’s 
primary endpoints are antigen-specific cellular immune response measured by IFN-
gamma ELISpot and neutralizing antibody responses. Secondary efficacy endpoints are 
safety measures.  Exploratory endpoints are antigen-specific cellular immune response 
measured by flow cytometry and other T and B cell measures.  
Phase 3 Segment: This is a two-arm, multi-center, placebo-controlled, double-blinded, and 
randomized clinical trial in subjects at high risk of SARS-CoV-2 exposure. The study’s 
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primary endpoint is the incidence of virologically-confirmed COVID-19 disease in subjects 
who are SARS-CoV-2 seronegative at baseline starting 14 days after completion of the 2-
dose regimen until 12 months post-dose 2.  The primary hypothesis is that INO-4800 will 
be efficacious relative to placebo (relative efficacy > 30%). Secondary efficacy analyses 
involve non-severe cases, severe cases, cases resulting in death, and cases among 
baseline SARS-CoV-2 seropositive subjects. Other secondary analyses concern safety 
and cellular and neutralizing antibody response. Exploratory analyses concern efficacy 
against variants, efficacy against asymptomatic infection, and binding antibody and 
cellular immunological measures. 
8.3 
STATISTICAL HYPOTHESES 
Phase 2 Segment: This is an estimation segment pertaining to immunogenicity and safety.  
There are no hypotheses. 
Phase 3 Segment: The primary hypothesis of relative efficacy greater than 30% among 
baseline SARS-CoV-2 seronegative subjects will be tested with H0: p ≥ .70/(.70+k) vs. H1: 
p < .70/(.70+k), where p is the true proportion of subjects with disease who receive INO-
4800 relative to the total number of subjects with disease, and k is the total amount of 
follow-up time in the placebo group divided by the total amount of follow-up time in the 
INO-4800 group. There are no other formal hypotheses. 
8.4 
ANALYTICAL POPULATIONS 
Analysis populations will be: 
The per-protocol (PP) population includes all subjects who receive all doses of Study 
Treatments and have no protocol violations. Subjects in the PP population will be grouped 
to treatment arms as randomized.  Subjects excluded from the PP population will be 
identified and documented prior to unblinding of the trial database.  Analyses on the PP 
population among those who are baseline SARS-CoV-2 seronegative will be primary for 
the analyses of efficacy in the Phase 3 segment of this trial. 
The modified intention to treat (mITT) population includes all subjects who receive at least 
one dose of Study Treatment. Subjects in this population will be grouped to treatment 
arms as randomized.  Analysis of the mITT population will be considered supportive for 
the corresponding PP population for the analyses of efficacy in the Phase 3 segment of 
this trial. 
The intention to treat (ITT) population includes all subjects who are randomized. Subjects 
in this sample will be grouped to treatment arms as randomized.  Analysis of the ITT 
population will be considered supportive for the corresponding PP population for the 
analyses of efficacy in the Phase 3 segment of this trial. 
The safety analysis population includes all subjects who receive at least one dose of Study 
Treatment. Subjects will be analyzed according to the treatments received. 
8.5 
DESCRIPTION OF STATISTICAL METHODS 
8.5.1 PRIMARY ANALYSIS 
Phase 2 Segment 
Post-baseline increases from baseline in interferon-γ ELISpot response magnitudes will 
be compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
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Post-baseline increases from baseline in neutralizing antibody response titers will be 
compared between treatment groups using ratios of geometric mean fold-rises and 
associated t-distribution based 95% CIs. 
The summaries listed above will be stratified according to NP positive/negative status of 
the subjects. Valid samples for statistical analysis purposes will be those collected: at least 
6 and no more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no 
more than 198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more 
than 380 days after Dose 2 for the Week 56 timepoint. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for these immunogenicity analyses. 
Phase 3 Segment 
Among subjects who are SARS-CoV-2 seronegative at baseline, the primary hypothesis 
of relative efficacy greater than 30% will be tested with H0: p ≥ 0.70/(0.70+k) vs. H1: p < 
0.70/(0.70+k), where p is the true proportion of subjects with disease who receive INO-
4800 relative to the total number of subjects with disease, and k is the total amount of 
follow-up time in the placebo group divided by the total amount of follow-up time in the 
INO-4800 group. 
A p-value for this hypothesis test and corresponding confidence interval will be computed 
based on the exact binomial method of Clopper-Pearson. Success will be concluded if the 
one-sided p-value is <0.022 and the corresponding lower bound of the two-sided 95.6% 
CI for efficacy exceeds 30% (alpha-level adjusted for interim analyses, see Section 8.5.6), 
and the point estimate for efficacy exceeds 50%. 
For calculating k, an individual subject’s follow-up time is either: 
o the date of first disease diagnosis – date of the start of surveillance period +1 (for 
subjects who are cases), or 
o the date of last follow-up – date of the start of surveillance period +1 (for subjects who 
are non-cases). 
This methodology is based on the following. Assuming that the number of subjects who 
are cases in the INO-4800 group follows a Poisson distribution with parameter λv and the 
number of subjects who are cases in the placebo group follows a Poisson distribution with 
parameter λc, then conditional on total number of subjects with cases, t, the number of 
subjects who are cases in the INO-4800 group follows a binomial distribution with 
parameters (t, p=λv/(λv+λc)).  The relationship between p and efficacy is: efficacy = (1-
(1+k)p)/(1-p).  Therefore, testing efficacy > 30% corresponds to testing p < 0.70/(0.70+k).  
Similarly, the confidence interval for efficacy is (1-(1+k)UBp)/(1-UBp), (1-(1+k)LBp)/(1-LBp), 
where UB and LB are the Clopper-Pearson upper and lower limits for the proportion. 
The efficacy time frame is defined by symptoms beginning at any time starting from 14 
days after Dose 2 and ending 12 months after Dose 2.  Subjects identified as cases that 
started prior to this time point will be excluded.  Subjects with multiple instances meeting 
the case definition will be counted only once, using the first such instance.    
The PP population will be primary for the analysis of efficacy in this trial. Efficacy analysis 
using the mITT population will also be conducted counting cases from 14 days postdose 
1 as a supportive analysis.  The ITT population will also be used for a supportive analysis 
counting cases starting from randomization. 
8.5.2 SECONDARY ANALYSES 
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8.5.2.1 Efficacy 
Phase 3 Segment 
The secondary efficacy incidence endpoints will be analyzed in the same manner as the 
primary hypothesis, but with 95% CIs and without the hypothesis test p-value.  
8.5.2.2 Immunogenicity 
 
   Phase 3 Segment 
Post-baseline increases from baseline in interferon-γ ELISpot response magnitudes will 
be compared between treatment groups using differences in medians and associated 
non-parametric 95% CIs. 
Post-baseline increases from baseline in neutralizing antibody response titers will be 
compared between treatment groups using ratios of geometric mean fold-rises and 
associated t-distribution based 95% CIs. 
The summaries listed above will be stratified according to disease status of the subjects 
and by baseline SARS-CoV-2 serostatus. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more than 
198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more than 
380 days after Dose 2 for the Week 56 timepoint.. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for these immunogenicity analyses. 
8.5.3 SAFETY ANALYSES 
8.5.3.1 Adverse Events 
All AEs including injection-site reactions will be summarized among the Safety 
Population by frequency per treatment arm. These frequencies will be presented overall 
and separately by dose, and will depict overall, by system organ class and by preferred 
term, the percentage of subjects affected. Additional frequencies will be presented with 
respect to maximum severity and to strongest relationship to Study Treatment. Multiple 
occurrences of the same AE will be counted only once following a worst-case approach 
with respect to severity and relationship to Study Treatment. All serious AEs will also be 
summarized as above. 
The main summary of safety data will be based on events occurring within 30 days of 
any dose. For this summary, the frequency of preferred term events will be compared 
between study arms with risk differences and 95% confidence intervals, using the 
method of Miettinen and Nurminen. As this analysis will use many event categories, and 
produce many confidence intervals, caution should be exercised when interpreting these 
confidence intervals.  Separate summaries will be based on events occurring within 7 
days of any dose and regardless of when they occurred. 
The analyses listed above will be performed according to Phase. For the Phase 3 
segment, the analyses listed above will also be performed according to SARS-CoV-2 
serostatus at baseline. 
For AE data, partial start dates will be imputed to the date of treatment to conservatively 
report the event as treatment-emergent, whenever the portion of the date is consistent 
with that of the study treatment. Otherwise, it will be imputed to the earliest date 
consistent with the partial date. A completely missing onset date will be imputed as the 
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day of treatment. Partial stop dates will be assumed to be the latest possible day 
consistent with the partial date. AE duration will be calculated as (Stop Date – Start 
Date) + 1. 
8.5.3.2 Vital Signs 
Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean, standard deviation, minimum, median, and maximum 
values by time point and treatment arm, for the Safety population. Baseline is defined 
as the last measurement prior to the first treatment administration. These summaries 
will be performed according to Phase. For the Phase 3 segment, the analyses listed 
above will also be performed according to SARS-CoV-2 serostatus at baseline. 
8.5.4 DISPOSITION 
Disposition will be summarized by treatment arm for the ITT population and will include 
the number and percentage randomized, the number and percentage who received each 
dose and the number who completed the trial.  The number and percentage of subjects 
who discontinued will be summarized overall and by reason.  The number in each analysis 
population will also be presented. These summaries will be performed according to Phase. 
For the Phase 3 segment, the analyses listed above will also be performed according to 
SARS-CoV-2 serostatus at baseline. 
8.5.5 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
8.5.5.1 Demographics 
Demographic data will be summarized with descriptive statistics: mean standard 
deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables, by treatment arm, for the ITT and PP populations. 
These summaries will be performed according to Phase. For the Phase 3 segment, the 
analyses listed above will also be performed according to SARS-CoV-2 serostatus at 
baseline. 
8.5.5.2 Prior Medications 
Prior medications are those that were used before the start of the trial (prior to Day 0). 
Partial stop dates of prior medications will be assumed to be the latest possible date 
consistent with the partial date; start dates will not be imputed. Data for all prior 
medications will be summarized with percentages by treatment arm, for the ITT and PP 
populations. These summaries will be performed according to Phase. For the Phase 3 
segment, the analyses listed above will also be performed according to SARS-CoV-2 
serostatus at baseline. 
8.5.6 INTERIM ANALYSES  
For safety issues, the DSMB could recommend stopping enrollment at any time; no 
formal interim analysis will be performed for this purpose. The two-sided type I error of 
0.05 will not be adjusted for possible early stopping due to this aspect. 
 
For the Phase 2 segment, group-level unblinded summaries of the immunogenicity and 
safety data will be produced once Week 6 visit immunology data and Week 8 visit safety 
data are complete for all subjects who have not discontinued, while maintaining subject-
level blinding.  Long-term follow-up data will continue to be collected for all subjects who 
have not discontinued with remaining visits through the final visit.  These summaries will 
allow the Sponsor to have results for the purposes of dose selection for the Phase 3 
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portion.  No subject-level immunogenicity data will be produced, and subject-level 
immunogenicity data will not be available in the clinical trial database until all other clinical 
trial data are finalized at the end of the trial.  No safety summary will be provided if the 
total number of subjects who experience the event of interest is greater than 0 and the 
count of the number of subjects with the event in a given treatment group relative to the 
total produces a percentage less than 3%, for a given summary.  The group-level 
unblinded production of the summaries will not include anyone directly involved with the 
trial or any additional unblinded personnel; only the external Contract Research 
Organization (CRO), ICON, which will already be providing unblinded summaries for the 
Data Safety Monitoring Board, will be utilized.  Thus, the trial will remain blinded to the 
Sponsor with respect to subject treatment assignment.  
 
For the Phase 3 segment, there are two planned formal interim efficacy analyses: one at 
50% (75 cases) and one at 75% (112 cases) of the total required for the primary endpoint 
(149 cases).  The Lan-DeMets O’Brien-Fleming approximate alpha-spending function will 
be used for the efficacy and futility boundaries.  As such, the first interim analysis will utilize 
a one-sided nominal alpha of 0.0016, and the second interim analysis will utilize a one-
sided nominal alpha of 0.0092.  The final analysis will utilize a one-sided nominal alpha of 
0.022.  The DSMB will be responsible for the interim evaluations. The unblinded interim 
analyses will not include anyone directly involved with the trial or any additional unblinded 
personnel; only the external Contract Research Organization (CRO), ICON, which will 
already be providing unblinded summaries for the Data Safety Monitoring Board, will be 
utilized.  Thus, the trial will remain blinded to the Sponsor with respect to subject treatment 
assignment.  
 
If the prespecified criteria for efficacy above are met at either interim analysis, then 
enrollment will continue until 4500 subjects have been enrolled, and blinded follow-up will 
continue until 4500 subjects have 6 months of safety follow-up.  At that point, the trial 
would be unblinded, and subjects who received placebo will be offered the active product. 
8.5.7 MULTIPLICITY 
There is one primary hypothesis that will be tested.  As there are two interim analyses of 
the primary endpoint, the type I error rate will be controlled at two-sided 0.05 by using the 
Lan-DeMets O’Brien-Fleming approximate alpha-spending function (see Section 8.5.6).  
8.5.8 MISSING VALUES 
Missing data will not be imputed. 
For the ITT analyses of efficacy in the Phase 3 segment, subjects with missing or 
unevaluable data regarding case definition will be considered cases (failures). 
8.5.9 EXPLORATORY ANALYSES  
8.5.9.1 Efficacy 
Phase 3 segment 
The exploratory efficacy endpoints will be analyzed in the same manner as the primary 
hypothesis, but with a 95% CI and without the hypothesis test p-value.   
8.5.9.2 Immunogenicity 
Phase 2 segment 
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Post-baseline increases from baseline in cellular response magnitudes will be 
compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
The summaries listed above will be stratified according to NP positive/negative status 
of the subjects. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more 
than 198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more 
than 380 days after Dose 2 for the Week 56 timepoint. . Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
Phase 3 Segment 
Post-baseline increases in antibody titers from ELISA will be compared between 
treatment groups using ratios of geometric mean fold-rises and associated 95% t-
distribution based CIs. 
Post-baseline increases from baseline in cellular response magnitudes will be 
compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
Post-baseline increases from baseline in neutralizing antibody response titers will be 
compared between treatment groups using ratios of geometric mean fold-rises and 
associated t-distribution based 95% CIs. 
The summaries listed above will be stratified according to disease status of the 
subjects. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more 
than 198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more 
than 380 days after Dose 2 for the Week 56 timepoint. . Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
8.5.9.3 Concomitant Medications 
Concomitant medications are those used during the course of the trial (on or after Day 
0). Partial stop dates of concomitant medications will be assumed to be the latest 
possible date consistent with the partial date; start dates will not be imputed. Data for 
all concomitant medications will be summarized with percentages by treatment arm, for 
the ITT and PP populations. These summaries will be performed according to Phase. 
For the Phase 3 segment, the analyses listed above will also be performed according 
to SARS-CoV-2 serostatus at baseline. 
8.6 
SAMPLE SIZE/POWER 
Phase 3 segment: The trial is case-driven. A total of  149 observed cases among baseline 
SARS-CoV-2 seronegative subjects will be required to provide 90% power to declare the 
vaccine efficacious (>30%), assuming a true efficacy of 60% and utilizing the methodology 
described in Section 8.5.1 and Section 8.5.6 .  A sample size of 6714 baseline SARS-
CoV-2 seronegative subjects will be required to achieve this number of cases assuming 
an underlying attack rate of 3.7%.   
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8.7 
RANDOMIZATION AND BLINDING  
Phase 2 Segment 
Subjects will be randomized (3 INO-4800 1.0 mg, one injection: 3 INO-4800 2.0 mg, two 
injections:1 Placebo, one injection: 1 Placebo, two injections). 
The study is blinded. It is double-blinded within dose group.  Randomization and blinding 
will avoid bias in the assignment of subjects to treatment, increase the likelihood that 
known and unknown subject attributes (e.g., demographics and other baseline 
characteristics) are evenly balanced between treatment groups, and enable valid 
statistical comparisons between treatment groups. 
Phase 3 Segment 
Subjects will be randomized (2 INO-4800:1 Placebo).  Randomization will be stratified 
according to two factors, each with two levels: a) age-group age category (18-50 years vs. 
≥51 years) on Day 0, and b) presence or absence on Day 0 of underlying medical 
conditions that increase risk of severe COVID-19 disease, per US CDC criteria. 
The study is double-blinded. Randomization and blinding will avoid bias in the assignment 
of subjects to treatment, increase the likelihood that known and unknown subject attributes 
(e.g., demographics and other baseline characteristics) are evenly balanced between 
treatment groups, and enable valid statistical comparisons between treatment groups. 
9.0 
ETHICS 
9.1 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical trial is 
performed in accordance with the protocol, the principles of the Declaration of Helsinki, 
Good Clinical Practice (GCP) and applicable regulatory requirements. 
9.2 
INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD (REB)/ETHICS 
COMMITTEE (EC) 
The Investigator will commence the clinical trial after full approval of the protocol and 
adjunctive materials (e.g., ICF, advertising) has been obtained from the applicable 
IRB/REB/EC and a copy of IRB/REB/EC approval documentation has been received by 
the Sponsor. 
Investigator responsibilities relevant to the IRB/REB/EC include the following: 
• Submit continuing review reports to the IRB/REB/EC as required, and request re-
review and approval of the clinical trial at least once a year during the conduct of 
the clinical trial; 
• Notify the Sponsor immediately of any suspected unexpected adverse drug or 
device events/effects; 
• Notify the IRB/REB/EC immediately if the Sponsor notifies the Investigator about 
any reportable safety events; 
• Obtain approval from the IRB/REB/EC for protocol amendments and for revisions 
to the consent form or subject recruitment advertisements, as required; 
• Submit reports on, and reviews of, the clinical trial and its progress to the 
IRB/REB/EC at intervals stipulated in their guidelines and in accordance with 
pertinent regulations and guidelines; 
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• Maintain a file of clinical trial-related information (refer to clinical trial files) that 
includes all correspondence with the IRB/REB/EC; 
• Notify the IRB/REB/EC when the clinical trial is completed (i.e., after the last clinical 
trial visit of the final clinical trial subject); 
• After clinical trial completion (within three [3] months is recommended), provide the 
IRB/REB/EC with a final report on the clinical trial. 
Institutional Biosafety Committee (IBC) 
The Investigator will undertake the trial after full approval of the protocol and adjunctive 
materials (e.g., pharmacy manual) has been obtained from the applicable IBC and a copy 
of this approval has been received by the Sponsor. 
Investigator responsibilities relevant to the IBC include the following: 
• 
Notify the Sponsor, IBC and NIH OSP within 30 days of any: 
o Substantial problems or violation of the NIH Guidelines 
o Significant research related accidents or illnesses 
• 
Notify the IBC to any changes to the research (dosage, procedure, etc.) or facility 
(new space, remodeling, etc.).   
9.3 
PROTECTION OF HUMAN SUBJECTS 
9.3.1 COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent must be obtained from each subject prior to the subject’s 
enrollment in the clinical trial. The process for obtaining informed consent must be 
documented in the subject’s medical record (also refer to Section 6.2). 
9.3.2 COMPLIANCE WITH INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD 
(REB)/ETHICS COMMITTEE (EC) REQUIREMENTS 
This clinical trial is to be conducted in accordance with applicable IRB/REB/EC 
regulations. The Investigator must obtain approval from a properly constituted 
IRB/REB/EC prior to initiating the clinical trial and obtain re-approval or review at least 
annually. The Sponsor is to be notified immediately if the responsible IRB/REB/EC has 
been disqualified or if proceedings leading to disqualification have begun. Copies of all 
IRB/REB/EC correspondence with the Investigator should be provided to the Sponsor. 
9.3.3 COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
9.3.4 COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS (21CFR 
PART 11) 
When applicable, this clinical trial is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
9.3.5 COMPLIANCE WITH PROTOCOL 
Subjects are not required to follow special instructions specific to the IP used in this clinical 
trial. Subjects will be provided with Investigator emergency contact information and 
advised to report all AEs. While every effort should be made to avoid protocol deviations, 
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should an important deviation be discovered, the Sponsor must be informed immediately. 
Any protocol deviation impacting subject safety must be reported to the Medical Monitor 
immediately. 
9.3.6 CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from, or changes to, the protocol 
without Sponsor approval and prior review and documented approval/favorable opinion of 
the protocol amendment from the IRB/REB/EC, except where necessary to eliminate 
immediate hazards to clinical trial subjects, or when the changes involve only logistical or 
administrative aspects of the clinical trial (e.g., change in monitors, change of telephone 
numbers).  
10.0 DATA COLLECTION, MONITORING AND REPORTING 
10.1 CONFIDENTIALITY AND PRIVACY 
A report of the results of this clinical trial may be published or sent to the appropriate 
regulatory authorities in any country in which the clinical trial products are legally marketed 
or may ultimately be marketed, but the subject’s name/identity will not be disclosed in 
these documents. The clinical trial Sponsor, its agents, the IRB/REB/EC and regulatory 
authorities will have direct access to the subjects’ medical records for the purposes of trial-
related monitoring, auditing and inspection. Appropriate precautions will be taken to 
maintain confidentiality of medical records and personal information. 
Written Authorization and other documentation are to be obtained from each subject, 
and/or from the subject’s legally authorized representative, prior to enrollment in the 
clinical trial, in accordance with all applicable laws, regulations and/or directives relating 
to privacy and data protection. 
11.0 SOURCE DOCUMENTS 
Source data is all information, electronic or hardcopy original records or clinical findings, 
laboratory results, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the clinical trial. 
Examples of original source data records may include:  
• Hospital records 
• Clinical and office charts 
• Laboratory notes 
• Memoranda 
• Pharmacy dispensing records 
• Recorded data from automated instruments 
• Copies of electronic medical records (EMR) certified after verification as being 
accurate and complete 
• X-rays 
• Subject files and records kept at the pharmacy, at the laboratories, at the medical 
records facility and within information technology (IT) systems that are involved in 
the clinical trial  
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The Investigator/institution will permit clinical trial-related monitoring, audits, IRB/REB/EC 
review and regulatory inspections by providing direct access to source data/documents 
related to this clinical trial. 
11.1 RECORDS RETENTION 
Upon request of the Clinical Monitor, Sponsor or its agent(s), auditor, IRB/REB/EC or 
regulatory authority, the Investigator/institution should make available for direct access all 
requested clinical trial-related records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
It is the Investigator’s responsibility to retain clinical trial essential documents for at least 
two (2) years after the last approval of a marketing application in their country and until 
there are no pending or contemplated marketing applications in their country or at least 
two (2) years have elapsed since the formal discontinuation of clinical development of 
INO-4800. This retention period may be superseded by local requirements. The Sponsor 
will inform the Investigator/institution when these documents are no longer needed to be 
retained. 
If the Records Retention requirements are addressed in a governing clinical trial 
agreement, it is the Investigator’s responsibility to retain clinical trial essential documents 
in accordance with the governing clinical trial agreement and applicable local 
requirements. 
12.0 SAFETY AND QUALITY MONITORING 
12.1 SAFETY REVIEW 
The Sponsor’s Safety Review Committee (SRC), composed of the Sponsor’s Medical 
Monitor, the ICON Medical Monitor and 1 additional physician, will review blinded safety 
and tolerability data on a regular basis throughout the trial. The SRC will refer any of the 
events listed in Section 7.8.4 or any other safety concerns to the DSMB Chair. 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will 
convene regularly to review all available unblinded safety data, and additionally upon 
completion of the Week 8 phone call visit for all subjects enrolled during the Phase 2 
segment. The DSMB will review unblinded safety and tolerability data, including AEs of 
clinical significance, AESIs and SAEs, as well as safety laboratory data for all enrolled 
subjects. The DSMB will also evaluate the data for signals of vaccine-enhanced disease 
and in the event of a signal, advise whether to halt the trial. The DSMB will advise 
regarding any safety concerns and will make recommendations regarding continued 
enrollment, safety pause and trial suspension. For the Phase 3 segment, the DSMB will 
also review efficacy in an unblinded fashion. 
If the safety data is considered unfavorable during any safety review, the DSMB may 
recommend a trial pause or trial termination at which time further enrollment and 
administration of IP to subjects will be paused. The Sponsor will perform an investigation 
and consult with the DSMB and other experts, if needed, to determine whether to resume 
dosing of the remainder of the subjects. For further details, see the DSMB Charter.  
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12.2 CLINICAL MONITORING 
Clinical Monitoring will be performed by qualified Clinical Monitors who will report to the 
Sponsor or the Sponsor’s designee. The following clinical trial site monitoring tasks will be 
performed at all clinical trial sites: 
• 
Prior to subject screening at the site, a Site Initiation Visit will be conducted to 
review all relevant forms and documentation, and ensure that the clinical trial site 
staff are qualified and compliant with all applicable requirements 
• 
All clinical trial site monitoring visits will be documented 
• 
Periodic clinical trial site visits will be performed throughout the clinical trial 
• 
The Clinical Monitor will address and document the following trial conduct activities 
and obligations: 
o Assure that the trial is being conducted in accordance with the protocol, 
applicable regulatory agency regulations, and IRB/REB/EC policies. 
o Discuss trial conduct issues and incidents of noncompliance with the 
Investigator and/or trial personnel and document them on the resolution trip 
report. Report any significant unresolved problems immediately to the 
Sponsor. 
o Remind the Investigator as necessary of the obligation to immediately report 
all SAEs and provide subsequent follow-up report of the final outcome to the 
IRB. 
o Throughout the trial, inspect source documents to ensure they are complete, 
logical, consistent, attributable, legible, contemporaneous, original, accurate 
and complete (ALCOA-C). 
o Assure that the trial facilities, including the pharmacy, continue to be 
acceptable. 
o Compare the trial CRFs with source documents to assure that the data are 
accurate and complete and that the protocol is being followed. 
o Assure that investigational drug and device accountability and reconciliation of 
records are complete and accurate. 
o Assure that all subject specimens are being stored and forwarded properly for 
testing in accordance with laboratory manual requirements. 
13.0 FINANCING AND INSURANCE 
Inovio Pharmaceuticals is the Sponsor and Department of Defense, Joint Program 
Executive Office is providing funding for the study. Clinical trial insurance has been taken 
out according to the laws of the countries where the study will be conducted. The 
investigative site is being compensated for the conduct of this study and will follow the 
terms described in the clinical trial agreement. This agreement was executed separately 
from this clinical trial protocol. The Investigators will be required to provide full financial 
disclosure information per 21 CFR Part 54. 
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14.0 PUBLICATION POLICY 
Publication of the results of this clinical trial in its entirety will be allowed. The proposed 
presentation, abstract and/or manuscript must be made available to the Sponsor for 
review and approval in accordance with the governing clinical trial agreement. 
 
 
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15.0 LIST OF ABBREVIATIONS 
ADE 
Adverse Device Effect 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALCOA-C 
Attributable, Legible, Contemporaneous, Original, Accurate and Complete 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CBC 
Complete Blood Count 
Cl 
Chloride 
COVID-19 
Coronavirus Disease 2019 
Cr 
Creatinine 
CRF 
Case Report Form 
CS 
Clinically Significant 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELISpot 
Enzyme-linked immunosorbent spot-forming assay 
EP 
Electroporation 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCO3 
Biocarbonate 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICD 
Implantable-Cardioverter-defibrillator 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
ID 
Intradermal 
IM 
Intramuscular 
Inovio 
Inovio Pharmaceuticals Inc. 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
K 
Potassium 
MAAE 
Medically Attended Adverse Event 
mITT 
modified Intent to Treat 
MM 
Medical Monitor 
MERS 
Middle East Respiratory Syndrome  
MERS-CoV 
Middle East Respiratory Syndrome Coronavirus 
mRNA 
Messenger RNA 
Na 
Sodium 
NCS 
Not Clinically Significant 
NHP 
Non-human Primates 
NP 
Nucleocapsid Protein 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PII 
Personal Identifying Information 
PO4 
Potassium 
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PT 
Preferred Term 
RBC 
Red blood cell 
REB 
Research Ethics Board 
RR 
Respiratory Rate 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SARS 
Severe Acute Respiratory Syndrome  
SARS-CoV 
Severe Acute Respiratory Syndrome Coronavirus 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus - 2 
SID 
Subject Identification Number 
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
SynCon 
Synthetic consensus 
TBili 
Total Bilirubin 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of Child-bearing Potential 
 
 
 
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16.0 REFERENCES 
1.
Centers for Disease Control and Prevention. People with Certain Medical Conditions.
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Lu, H., C.W. Stratton, and Y.W. Tang, Outbreak of pneumonia of unknown etiology in
Wuhan, China: The mystery and the miracle. J Med Virol, 2020. 92(4): p. 401-402.
3.
Hui, D.S., et al., The continuing 2019-nCoV epidemic threat of novel coronaviruses to
global health - The latest 2019 novel coronavirus outbreak in Wuhan, China. Int J Infect
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4.
Huang, C., et al., Clinical features of patients infected with 2019 novel coronavirus in
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GenBank. Severe acute respiratory syndrome coronavirus 2 isolate Wuhan-Hu-1,
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Smith, T.R.F., et al., Immunogenicity of a DNA vaccine candidate for COVID-19. Nat
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World Health Organization, Clinical Management of Sever Acute Respiratory Infection
When Novel Coronavirus (2016-nCoV) Infection is Suspected. Interim Guidance. 2020.
8.
World Health Organization, Novel Coronavirus (2019-nCoV) Situation Report. 2020.
9.
Wiersinga, W.J., et al., Pathophysiology, Transmission, Diagnosis, and Treatment of
Coronavirus Disease 2019 (COVID-19): A Review. JAMA, 2020.
10.
World Health Organization, WHO Director-General's opening remarks at the media
briefing on COVID-19 - 11 March 2020. March 11, 2020.
11.
Zou, L., et al., SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected
Patients. N Engl J Med, 2020.
12.
Center for Systems Science and Engineering at Johns Hopkins University, COVID-19
Dashboard. 2020.
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Havers, F.P., et al., Seroprevalence of Antibodies to SARS-CoV-2 in 10 Sites in the
United States, March 23-May 12, 2020. JAMA Intern Med, 2020.
14.
Wu, Z. and J.M. McGoogan, Characteristics of and Important Lessons From the
Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of
72314 Cases From the Chinese Center for Disease Control and Prevention. JAMA,
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The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, The
epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases
(COVID-19) in China. Chin J Epidemiol, 2020. 41(Epub ahead of print).
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The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, Vital
Surveillances: The Epidemiological Characteristics of an Outbreak of 2019 Novel
Coronavirus Diseases (COVID-19) — China, 2020. China CDC Weekly, 2020. 2(8): p.
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Chan, J.F., et al., A familial cluster of pneumonia associated with the 2019 novel
coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet,
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18.
Rothe, C., et al., Transmission of 2019-nCoV Infection from an Asymptomatic Contact in
Germany. N Engl J Med, 2020. 382(10): p. 970-971.
19.
Ganyani, T., et al., Estimating the generation interval for coronavirus disease (COVID-
19) based on symptom onset data, March 2020. Euro Surveill, 2020. 25(17).
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He, X., et al., Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat
Med, 2020. 26(5): p. 672-675.
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Protocol Version Date: 2-Apr-2021 
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21. 
Liu, Y., et al., The reproductive number of COVID-19 is higher compared to SARS 
coronavirus. J Travel Med, 2020. 27(2). 
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Centers for Disease Control and Prevention. Symptoms of Coronavirus. 2020  March 
2020]; Available from: https://www.cdc.gov/coronavirus/2019-ncov/symptoms-
testing/symptoms.html. 
23. 
Gudbjartsson, D.F., et al., Spread of SARS-CoV-2 in the Icelandic Population. N Engl J 
Med, 2020. 
24. 
Day, M., Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ, 
2020. 369: p. m1375. 
25. 
Centers for Disease Control and Prevention. COVID-19 Pandemic Planning Scenarios. 
July 10, 2020 July 20, 2020 July 27, 2020]; Available from: 
https://www.cdc.gov/coronavirus/2019-ncov/hcp/planning-scenarios.html. 
26. 
Lipsitch, M., et al., Transmission dynamics and control of severe acute respiratory 
syndrome. Science, 2003. 300(5627): p. 1966-70. 
27. 
Peiris, J.S., et al., Clinical progression and viral load in a community outbreak of 
coronavirus-associated SARS pneumonia: a prospective study. Lancet, 2003. 
361(9371): p. 1767-72. 
28. 
Tsang, T.K., et al., Influenza A Virus Shedding and Infectivity in Households. J Infect 
Dis, 2015. 212(9): p. 1420-8. 
29. 
Seow, J., et al., Longitudinal evaluation and decline of antibody responses in SARS-
CoV-2 infection. medRxiv, 2020: p. 2020.07.09.20148429. 
30. 
Long, Q.X., et al., Clinical and immunological assessment of asymptomatic SARS-CoV-2 
infections. Nat Med, 2020. 
31. 
Diao, B., et al., Reduction and Functional Exhaustion of T Cells in Patients With 
Coronavirus Disease 2019 (COVID-19). Front Immunol, 2020. 11: p. 827. 
32. 
Grifoni, A., et al., Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans 
with COVID-19 Disease and Unexposed Individuals. Cell, 2020. 181(7): p. 1489-1501 
e15. 
33. 
Modjarrad, K., et al., Safety and immunogenicity of an anti-Middle East respiratory 
syndrome coronavirus DNA vaccine: a phase 1, open-label, single-arm, dose-escalation 
trial. Lancet Infect Dis, 2019. 19(9): p. 1013-1022. 
34. 
Suschak, J.J., J.A. Williams, and C.S. Schmaljohn, Advancements in DNA vaccine 
vectors, non-mechanical delivery methods, and molecular adjuvants to increase 
immunogenicity. Hum Vaccin Immunother, 2017. 13(12): p. 2837-2848. 
35. 
Manickan, E., K.L. Karem, and B.T. Rouse, DNA Vaccines - A Modern Gimmick or a 
Boon to Vaccinology? Crit Rev Immunol, 2017. 37(2-6): p. 483-498. 
36. 
Porter, K.R. and K. Raviprakash, DNA Vaccine Delivery and Improved Immunogenicity. 
Curr Issues Mol Biol, 2017. 22: p. 129-138. 
37. 
Li, L. and N. Petrovsky, Molecular mechanisms for enhanced DNA vaccine 
immunogenicity. Expert Rev Vaccines, 2016. 15(3): p. 313-29. 
38. 
Marc, M.A., E. Dominguez-Alvarez, and C. Gamazo, Nucleic acid vaccination strategies 
against infectious diseases. Expert Opin Drug Deliv, 2015. 12(12): p. 1851-65. 
39. 
Grunwald, T. and S. Ulbert, Improvement of DNA vaccination by adjuvants and 
sophisticated delivery devices: vaccine-platforms for the battle against infectious 
diseases. Clin Exp Vaccine Res, 2015. 4(1): p. 1-10. 
40. 
Tregoning, J.S. and E. Kinnear, Using Plasmids as DNA Vaccines for Infectious 
Diseases. Microbiol Spectr, 2014. 2(6). 
41. 
Williams, J.A., Improving DNA vaccine performance through vector design. Curr Gene 
Ther, 2014. 14(3): p. 170-89. 
42. 
Liu, M.A., DNA vaccines: an historical perspective and view to the future. Immunol Rev, 
2011. 239(1): p. 62-84. 
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Protocol Version Date: 2-Apr-2021 
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43. 
Wahren, B. and M.A. Liu, DNA Vaccines: Recent Developments and the Future. 
Vaccines (Basel), 2014. 2(4): p. 785-796wahren. 
44. 
Ledgerwood, J.E. and B.S. Graham, DNA vaccines: a safe and efficient platform 
technology for responding to emerging infectious diseases. Hum Vaccin, 2009. 5(9): p. 
623-6. 
45. 
Keefer, M.C., et al., Studies of high doses of a human immunodeficiency virus type 1 
recombinant glycoprotein 160 candidate vaccine in HIV type 1-seronegative humans. 
The AIDS Vaccine Clinical Trials Network. AIDS Res Hum Retroviruses, 1994. 10(12): p. 
1713-23. 
46. 
Wu, F., et al., Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered 
patient cohort and their implications. Medrxiv Preprint, 2020. 
47. 
Martin, J.E., et al., A DNA vaccine for Ebola virus is safe and immunogenic in a phase I 
clinical trial. Clin Vaccine Immunol, 2006. 13(11): p. 1267-77. 
48. 
Prud'homme, G.J., et al., Electroporation-enhanced nonviral gene transfer for the 
prevention or treatment of immunological, endocrine and neoplastic diseases. Curr Gene 
Ther, 2006. 6(2): p. 243-73. 
49. 
Hirao, L.A., et al., Combined effects of IL-12 and electroporation enhances the potency 
of DNA vaccination in macaques. Vaccine, 2008. 26(25): p. 3112-20. 
50. 
Rosati, M., et al., Increased immune responses in rhesus macaques by DNA vaccination 
combined with electroporation. Vaccine, 2008. 26(40): p. 5223-9. 
51. 
Curcio, C., et al., DNA immunization using constant-current electroporation affords long-
term protection from autochthonous mammary carcinomas in cancer-prone transgenic 
mice. Cancer Gene Ther., 2008. 15(2): p. 108-114. 
52. 
Ugen, K.E., et al., Regression of subcutaneous B16 melanoma tumors after intratumoral 
delivery of an IL-15-expressing plasmid followed by in vivo electroporation. Cancer Gene 
Ther., 2006. 13(10): p. 969-974. 
53. 
Tebas, P., et al., Safety and Immunogenicity of an Anti-Zika Virus DNA Vaccine - 
Preliminary Report. N Engl J Med, 2017. 
54. 
Tebas, P., et al., Intradermal SynCon(R) Ebola GP DNA Vaccine is Temperature Stable 
and Safely Demonstrates Cellular and Humoral Immunogenicity Advantages in Healthy 
Volunteers. J Infect Dis, 2019. 
55. 
De Rosa, S.C., et al., Robust antibody and cellular responses induced by DNA-only 
vaccination for HIV. JCI Insight, 2020. 5(13). 
56. 
Chandrashekar, A., et al., SARS-CoV-2 infection protects against rechallenge in rhesus 
macaques. Science, 2020. 
57. 
Patel, A., et al., Intradermal-delivered DNA vaccine provides anamnestic protection in a 
rhesus macaque SARS-CoV-2 challenge model. bioRxiv, 2020: p. 2020.07.28.225649. 
58. 
European Commission, Directorate-General: A Guideline on Summary of Product 
Characteristics (SmPC). 2009, EMA. 
59. 
Diehl, M.C., et al., Tolerability of intramuscular and intradermal delivery by 
CELLECTRA((R)) adaptive constant current electroporation device in healthy volunteers. 
Hum Vaccin Immunother, 2013. 9(10): p. 2246-52. 
 
 
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17.0 APPENDICES 
17.1 APPENDIX A: ADVERSE EVENTS OF SPECIAL INTEREST  
For the purpose of standardization across multiple vaccine platforms, including those substantially 
different from Inovio’s platform, the below table lists AEs of special interest (AESIs) relevant to 
COVID-19 vaccine development.  
Body System 
AESI 
Respiratory 
Acute respiratory distress syndrome (ARDS) 
Pneumonitis/Pneumonia 
Neurologic 
Generalized convulsion 
Aseptic meningitis 
Guillain-Barré Syndrome (GBS) 
Encephalitis/Myelitis 
Acute disseminated encephalomyelitis (ADEM) 
CNS vasculopathy (stroke) 
Bell’s Palsy 
Transverse myelitis  
Narcolepsy 
Hematologic 
Thrombocytopenia 
Immune thrombocytopenia (ITP) 
Disseminated intravascular coagulation (DIC) 
Hemorrhagic stroke 
Non-hemorrhagic stroke 
Deep Vein Thrombosis (DVT) 
Pulmonary Embolism (PE) 
Immunologic 
Anaphylaxis 
Vasculitides 
Cardiac  
Acute cardiac failure 
Myocarditis/pericarditis 
Acute myocardial infarction 
Other 
Septic shock-like syndrome 
Appendicitis 
Multisystem Inflammatory Syndrome 
Acute kidney failure 
 
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Signature Page for VV-TMF-00448 v5.0
Signature Page for VV-TMF-00448 v5.0
Reason for signing: Approved
Name: 
Role: Approver
Date of signature: 02-Apr-2021 23:46:56 GMT+0000
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CONFIDENTIAL 
Page 1 of 93 
COVID19-311 
Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the Safety, 
Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-
19 Disease, Administered Intradermally Followed by Electroporation in Adults at 
High Risk of SARS-CoV-2 Exposure   
INNOVATE 
(Inovio INO-4800 Vaccine Trial for Efficacy) 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
IND #: 19690 
Protocol Version: 6.0 
Protocol Version Date: 30-Apr-2021 
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Page 2 of 93 
 
 
Medical Monitor Approval Page 
 
Drug:  
INO-4800 
 
Sponsor: 
Inovio Pharmaceuticals, Inc. 
 
660 W. Germantown Pike, Suite 110 
 
Plymouth Meeting, PA 19462 
 
Medical Monitor: 
 
 Jr., M.D., FACP, FIDSA 
Inovio Pharmaceuticals, Inc. 
 
 
Approval Signature: 
 
 
[Electronically signed] 
  
Jr., M.D., FACP, FIDSA 
Inovio Pharmaceuticals, Inc. 
 
 Date (ddMmmyyyy) 
 
 
CONFIDENTIAL 
The information in this document is considered privileged and confidential by Inovio 
Pharmaceuticals Inc. (INOVIO) and may not be disclosed to others except to the extent 
necessary to obtain Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics 
Committee (EC) approval and informed consent, or as required by local regulatory 
authorities. Persons to whom this information is disclosed must be informed that this 
information is privileged and confidential and that it should not be further disclosed 
without the written permission of INOVIO. Any supplemental information added to this 
document is also confidential and proprietary information of INOVIO and must be kept in 
confidence in the same manner as the contents of this document. 
 
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Page 3 of 93 
 
 
Principal Investigator Acknowledgement 
 
I have read and understood this Protocol and agree that it contains all details necessary to 
conduct the clinical trial. I understand that it must be reviewed by the Institutional Review Board 
(IRB)/Research Ethics Board (REB)/Ethics Committee (EC) overseeing the conduct of the clinical 
trial and approved or given favorable opinion before implementation. 
 
The Principal Investigator’s (PI’s) signature constitutes the PI’s approval of this Protocol and 
provides the necessary assurances that this clinical trial will be conducted in accordance with 
International Council for Harmonization (ICH)/Good Clinical Practice (GCP), local legal and 
regulatory requirements, and all stipulations of the Protocol. 
 
 
Principal Investigator Signature: 
 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
Principal Investigator Signature 
 
Date (ddMmmyyyy) 
 
 
 
Clinical Trial Site Number: 
 
Clinical Trial Site Name: 
 
 
 
 
 
 
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SUMMARY OF CHANGES 
 
The following is a list of significant changes from Version 5.0, dated 2-Apr-2021, to Version 6.0, 
dated 29-Apr-2021. All other changes are administrative and do not significantly affect the safety 
of subjects, trial scope, or scientific integrity of the protocol. 
 
1. Based upon the review of immunology data from Phase 2, the dose of INO-4800 for the Phase 
3 segment of the study has been updated to 2.0 mg. Additional background information has 
been included to justify the dose selection and the advancement of the trial into the Phase 3 
segment; 
2. Possible benefits of the trial have been added; 
3. It has been clarified that for subjects who are seropositive at Screening, a COVID-19 
Assessment Visit is not required to be performed based on further positive SARS-CoV-2 tests 
during the trial; 
4. The minimum fill volume of the SSC-0001 vials has been clarified to be 0.8mL. 
 
 
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Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 5 of 93 
 
TABLE OF CONTENTS 
Summary of Changes ................................................................................................................ 4 
Table of Contents ....................................................................................................................... 5 
Clinical Protocol Synopsis .........................................................................................................10 
Table 3 – Phase 2 Segment Schedule of Events ......................................................................21 
Table 4 – Phase 3 Segment Schedule of Events ......................................................................23 
 
Introduction .................................................................................................................25 
 
Background and Scientific Rationale ........................................................................... 25 
 
Background Information .............................................................................................. 25 
 
Clinical Presentation, Transmission and Immune Response .................................26 
 
Current Treatment and Unmet Need .....................................................................27 
 
Rationale for prophylactic vaccine development ......................................................... 28 
 
DNA Vaccines.......................................................................................................28 
 
Use of Electroporation with DNA Vaccines ...........................................................29 
 
Inovio’s Proprietary Technology Against COVID-19 ..............................................29 
 
Nonhuman Primate (NHP) Challenge Studies Following Vaccination with INO-4800
 .............................................................................................................................30 
 
First-In-Human Phase 1 Trial of INO-4800 ............................................................30 
 
Proposed Phase 2/3 Trial of INO-4800 .................................................................31 
1.3.6.1 Safety and tolerability of INO-4800 ....................................................................32 
1.3.6.2 Nonclinical INO-4800 Data in Support of Potential Efficacy ............................32 
1.3.6.3 Potential Role of INO-4800 as a Booster ...........................................................32 
1.3.6.4 Thermostability of INO-4800 ..............................................................................32 
 
Dose and Regimen Rationale ...............................................................................33 
1.3.7.1 Binding Antibody Response ..............................................................................33 
1.3.7.2 Neutralizing Antibody Response .......................................................................33 
1.3.7.3 ELISPOT analysis ...............................................................................................34 
 
Risks and Potential Benefits ....................................................................................... 34 
 
Potential Benefits ..................................................................................................34 
 
Product Risks........................................................................................................34 
 
Overall Benefit/Risk Conclusion ............................................................................36 
 
Objectives and Purpose ..............................................................................................36 
 
Hypothesis .................................................................................................................. 36 
 
Clinical Trial Design and Endpoints ............................................................................37 
 
Primary Objectives ...................................................................................................... 38 
 
Primary Endpoints....................................................................................................... 39 
 
Secondary Objectives ................................................................................................. 39 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 6 of 93 
 
 
Secondary Endpoints .................................................................................................. 39 
 
Exploratory Objective .................................................................................................. 40 
 
Exploratory Endpoints ................................................................................................. 40 
 
Efficacy Assessment (Phase 3 Segment Only) ........................................................... 41 
 
Case Definition for Virologically-confirmed COVID-19 Disease: ............................41 
 
Case Definition for SARS-CoV-2 Asymptomatic Infection .....................................42 
 
Safety Assessment ..................................................................................................... 42 
 
Immunogenicity Assessment ...................................................................................... 42 
 
Clinical Trial Population ..............................................................................................42 
 
Inclusion Criteria ......................................................................................................... 42 
 
Phase 2 Segment .................................................................................................42 
 
Phase 3 Segment .................................................................................................43 
 
Exclusion Criteria ........................................................................................................ 44 
 
Phase 2 Segment .................................................................................................44 
 
Phase 3 Segment .................................................................................................46 
 
Discontinuation/Withdrawal of Clinical Trial Subjects .................................................. 47 
 
Clinical Trial Investigational Product Information .........................................................48 
 
Investigational Product (IP) and Study Device ............................................................ 48 
 
INO-4800 and Placebo .........................................................................................48 
 
CELLECTRA® 2000 ..............................................................................................48 
 
Dosing Regimens ....................................................................................................... 49 
 
Blinding .................................................................................................................50 
 
Packaging and Labeling .............................................................................................. 50 
 
INO-4800 or Placebo ............................................................................................50 
 
CELLECTRA® 2000 ..............................................................................................50 
 
Handling and Storage ................................................................................................. 51 
 
INO-4800 and Placebo .........................................................................................51 
 
CELLECTRA® 2000 ..............................................................................................51 
 
Preparation and Dispensing ........................................................................................ 51 
 
Use of Study Device ................................................................................................... 51 
 
Investigational Drug and Study Device Accountability ................................................. 51 
 
Investigational Product (IP) Accountability ............................................................51 
 
CELLECTRA® 2000 Accountability .......................................................................52 
 
Return and Destruction of Investigational Drug and Study Device .............................. 52 
 
INO-4800 and Placebo .........................................................................................52 
 
Return of CELLECTRA® 2000...............................................................................52 
 
Clinical Trial Procedures and Schedule ......................................................................53 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 7 of 93 
 
 
Procedure by Visit ....................................................................................................... 53 
 
Clinical Trial Screening Evaluations ......................................................................53 
6.1.1.1 Medical History ...................................................................................................54 
 
Clinical Trial Evaluations and Procedures .............................................................54 
6.1.2.1 Day 0 and Day 28 (Dosing Visits) .......................................................................54 
6.1.2.2 Post-dose phone calls ........................................................................................55 
6.1.2.3 Day 42 Visit .........................................................................................................55 
6.1.2.4 Phone calls ..........................................................................................................56 
6.1.2.5 Follow up clinic visits .........................................................................................56 
6.1.2.6 Day 393 Visit or EOS ...........................................................................................57 
6.1.2.7 COVID-19 Assessment Visit ...............................................................................57 
6.1.2.8 COVID-19 Convalescent Visit .............................................................................58 
 
Informed Consent ....................................................................................................... 58 
 
Assignment of Subject Identification Numbers ............................................................ 59 
 
Safety Evaluations ...................................................................................................... 59 
 
Intradermal Injection and EP .................................................................................61 
 
Management of Pain Due to Electroporation (EP) Procedures ..............................62 
 
Assessment of Laboratory Abnormalities ..............................................................62 
 
Assessment of Clinical Trial Adverse Events (AEs) ..............................................62 
 
Assessment of Injection Site Reactions ................................................................63 
 
Concomitant Medications/Treatments ...................................................................63 
 
Restrictions ...........................................................................................................64 
 
SARS-CoV-2 Testing ............................................................................................64 
 
COVID-19 Disease Monitoring ..............................................................................65 
 
Immunogenicity Assessments ..................................................................................... 66 
 
Evaluation of Safety and Management of Toxicity ......................................................66 
 
Safety Parameters ...................................................................................................... 66 
 
Adverse Events (AEs) ................................................................................................. 66 
 
Adverse Drug Reaction (ADR) .................................................................................... 67 
 
Serious Adverse Events (SAEs) .................................................................................. 67 
 
Unexpected Adverse Drug Reaction ........................................................................... 68 
 
Unanticipated (Serious) Adverse Device Effect (UADE) .............................................. 68 
 
Device Deficiency ....................................................................................................... 68 
 
Safety and Toxicity Management ................................................................................ 68 
 
Adverse Event of Special Interest (AESI) ..............................................................68 
 
Medically Attended Adverse Event (MAAE) ..........................................................69 
 
Abnormal Laboratory Value ..................................................................................69 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 8 of 93 
 
 
Clinical Trial Stopping Rules .................................................................................69 
 
Safety Data Reporting Period, Method of Collection and Submission ......................... 70 
 
Adverse Event Reporting ............................................................................................ 71 
 Submitting the Initial Serious Adverse Event (SAE) Report Form..........................71 
 Recording the Event .............................................................................................71 
 Assessing Severity (Intensity) ...............................................................................71 
 Causal Relationship of Clinical Material to Adverse Events (AEs) .........................71 
 
Reporting Suspected COVID-19 Disease Cases During the Trial ............................... 72 
 
Reporting Pregnancy During the Clinical Trial ............................................................. 73 
 
Reporting Device-Related Complaints or Deficiencies ................................................ 73 
 
Notifying Regulatory Authorities and Institutional Review Boards (IRBs)/Research 
Ethics Boards (REBs)/Ethics Committees (ECs) of Safety Information ....................... 74 
 Sponsor Responsibilities .......................................................................................74 
 Principal Investigator (PI) Responsibilities ............................................................74 
 
Post-Trial Reporting Requirements ............................................................................. 74 
 
Clinical Trial Discontinuation ....................................................................................... 74 
 
Statistical Considerations ...........................................................................................74 
 
Statistical and Analytical Plan ..................................................................................... 74 
 
General Considerations .............................................................................................. 75 
 
Statistical Hypotheses ................................................................................................. 75 
 
Analytical Populations ................................................................................................. 75 
 
Description of Statistical Methods ............................................................................... 76 
 
Primary Analysis ...................................................................................................76 
 
Secondary Analyses .............................................................................................77 
 
Safety Analyses ....................................................................................................77 
 
Disposition ............................................................................................................78 
 
Demographic and Other Baseline Characteristics .................................................78 
 
Interim Analyses ...................................................................................................79 
 
Multiplicity .............................................................................................................79 
 
Missing Values......................................................................................................79 
 
Exploratory Analyses ............................................................................................80 
 
Sample Size/Power ..................................................................................................... 81 
 
Randomization and Blinding ....................................................................................... 81 
 
Ethics .........................................................................................................................81 
 
Investigator and Sponsor Responsibilities ................................................................... 81 
 
Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics Committee (EC)
 ................................................................................................................................... 81 
 
Protection of Human Subjects ..................................................................................... 82 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 9 of 93 
 
 
Compliance with Informed Consent Regulations ...................................................82 
 
Compliance with Institutional Review Board (IRB)/Research Ethics Board 
(REB)/Ethics Committee (EC) Requirements ........................................................82 
 
Compliance with Good Clinical Practice ................................................................83 
 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11) .....83 
 
Compliance with Protocol .....................................................................................83 
 
Changes to the Protocol .......................................................................................83 
 
Data Collection, Monitoring and Reporting ..................................................................83 
 
Confidentiality and Privacy .......................................................................................... 83 
 
Source Documents .....................................................................................................83 
 
Records Retention ...................................................................................................... 84 
 
Safety and Quality Monitoring .....................................................................................84 
 
Safety Review ............................................................................................................. 84 
 
Clinical Monitoring....................................................................................................... 85 
 
Financing and Insurance ............................................................................................85 
 
Publication Policy .......................................................................................................86 
 
List of Abbreviations ...................................................................................................87 
 
References .................................................................................................................89 
 
Appendices .................................................................................................................93 
 
APPENDIX A: Adverse Events of Special Interest ...................................................... 93 
 
 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 10 of 93 
 
CLINICAL PROTOCOL SYNOPSIS 
Protocol Title: Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the 
Safety, Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-19 
Disease, Administered Intradermally Followed by Electroporation in Adults at High Risk of 
SARS-CoV-2 Exposure 
Protocol Number: COVID19-311 
Clinical Trial Phase: 2/3 
Estimated Number of Clinical Trial Centers and Countries/Regions: Approximately 50 
centers globally. Final country list to be determined. 
Background:   
INO-4800 is a prophylactic vaccine under development against SARS-CoV-2, the causative 
agent of COVID-19. INO-4800 contains the plasmid pGX9501, which encodes for the full 
length of the Spike glycoprotein of SARS-CoV-2. The goal of this trial is to assess the safety, 
immunogenicity and efficacy of INO-4800 to prevent COVID-19 in subjects at high risk of 
exposure to SARS-CoV-2.  
 
Clinical Trial Design:  
This is an operationally seamless Phase 2/3, randomized, placebo-controlled, multi-center trial 
to evaluate the safety, immunogenicity, and efficacy of INO-4800, administered by intradermal 
(ID) injection followed immediately by electroporation (EP) using the CELLECTRA® 2000 
device, in a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-2 
exposure. The primary objectives of this trial are to identify in seronegative subjects an optimal 
age-related dose of INO-4800 in the Phase 2 segment for a subsequent efficacy evaluation in 
the Phase 3 segment.  
 
Subjects 18 years of age and older are expected to be enrolled across two (2) segments of 
this study. In the Phase 2 segment, approximately 400 seronegative subjects will be enrolled. 
In the Phase 3 segment, approximately 6714 seronegative subjects are expected to be 
enrolled, and 402 seropositive subjects will be enrolled. The subjects and data from Phase 2 
are independent from that of Phase 3. 
 
Phase 2 Segment – Dose Selection 
In the Phase 2 segment, approximately 400 subjects 18 years of age and older will be 
evaluated across four (4) dose groups (Table 1, Figure 1). Subjects will be randomized at a 
3:3:1:1 ratio to receive either active investigational product (INO-4800) or placebo (SSC-0001) 
according to Table 1 below. Dose groups receiving INO-4800 will enroll approximately 150 
subjects per group. Dose groups receiving placebo will enroll approximately 50 subjects per 
group. Randomization will be such that approximately 240 subjects aged 18-50 years, 120 
subjects aged 51-64 years and 40 subjects aged ≥ 65 years will be enrolled. Initial enrollment 
will include subjects aged 18-50 years. Initiation of enrollment of older subjects 51-64 years of 
age and elderly subjects 65 years and older will depend on review of safety and 
immunogenicity data from those age groups generated in the Phase 1 study (COVID19-001).   
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 11 of 93 
 
Table 1: Phase 2 Segment Dose Groups 
Study  
Group 
Expected 
Number of 
Subjects 
Dosing 
Days 
Number of 
Injections + EP 
per Dosing Visit 
INO-4800 
(mg) per 
injection 
INO-4800 
(mg) per 
Dosing Visit 
Total Dose 
(mg) 
INO-4800 
150 
0, 28 
1 
1.0 
1.0 
2.0 
INO-4800 
150 
0, 28 
2a 
1.0 
2.0 
4.0 
Placebo 
50 
0, 28 
1 
0 
0 
0 
Placebo 
50 
0, 28 
2a 
0 
0 
0 
Total 
400 
 
 
 
 
 
aINO-4800 or placebo will be injected ID followed immediately by EP in an acceptable location on two different limbs at each 
dosing visit. 
 
Dose selection for evaluation of efficacy in the Phase 3 segment will be based on Week 6 
immunogenicity data and Week 8 safety data from the Phase 2 segment. Group-level unblinded 
summaries and analyses of safety will be produced once the Week 8 phone call visit data are 
completed for all subjects in the Phase 2 segment. Group-level unblinded summaries and 
analyses of immunogenicity will be produced once the Week 6 visit data are completed for all 
subjects in the Phase 2 segment.  
 
Phase 3 Segment – Efficacy 
In the Phase 3 segment, approximately 6714 seronegative and 402 seropositive subjects 18 
years of age and older will be randomized at a 2:1 ratio to receive either active investigational 
product (INO-4800, 2.0 mg) or placebo (SSC-0001). See Table 2 and Figure 1.  Approximately 
half of seronegative subjects and approximately half of seropositive subjects will be 18-50 
years of age, and the other half will be ≥51 years of age as is operationally feasible. Also, 
approximately 711 subjects will be ≥65 years of age, if operationally feasible. 
 
Subjects will be randomized in a stratified manner according to (a) age category (18-50 years 
vs. ≥51 years) on Day 0, and (b) presence or absence on Day 0 of any of the following 
underlying medical conditions that increase risk of severe COVID-19 disease, per U.S. Center 
for Disease Control (CDC) criteria [1], as listed below: 
• 
Cancer 
• 
Chronic kidney disease 
• 
Chronic lung diseases, including Chronic obstructive pulmonary disease (COPD), 
asthma (moderate-to-severe), interstitial lung disease, cystic fibrosis, pulmonary 
hypertension 
• 
Neurologic conditions including stroke or cerebrovascular disease that do not impact 
cognition 
• 
Diabetes (type 1 or type 2) 
• 
Hypertension 
• 
Heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies 
• 
HIV infection (CD4 count >200 cells/mm3 or undetectable viral load) 
• 
Liver disease 
• 
Obesity (BMI ≥ 30 kg/m2) 
• 
Sickle cell disease or thalassemia, or 
• 
Smoking (current or former smoker). 
 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 12 of 93 
 
Table 2: Phase 3 Segment  
Treatment 
Arm 
Sero 
status 
Expected 
Number 
of 
Subjects 
Approx. 
Expected 
Number of 
Subjects by 
Age Group 
Dosing 
Days 
Number of 
Injections + 
EP per 
Dosing Visit 
INO-4800 
(mg) per 
injection 
INO-4800 
(mg) per 
Dosing Visit 
Total Dose 
of 
INO-4800 
(mg) 
18-50 
51+a 
INO-4800 
Seroneg 
4476 
2238 
2238 
0, 28 
2 
1.0 
2.0 
4.0 
Seropos 
268 
134 
134 
Placebo 
Seroneg 
2238 
1119 
1119 
0, 28 
2 
0 
0 
0 
Seropos 
134 
67 
67 
Total 
Seroneg 
6714 
3357 
3357 
 
 
 
 
 
Seropos 
402 
201 
201 
 
 
 
 
 
Total 
7116 
 
 
 
 
 
 
 
 
aat least 711 subjects will be ≥65 years of age 
 
This segment of the trial is case-driven. Among seronegative subjects, a total of 149 observed 
cases will be required for 90% power to declare the vaccine efficacious (>30%), assuming a 
true efficacy of 60%. A sample size of 6714 seronegative subjects is expected to be required 
to achieve the 149 cases assuming an underlying attack rate of 3.7%. The actual sample size 
may differ if the observed attack rate is different than projected.  There are two formal interim 
analyses of efficacy; one when 50% of the cases accrue and one when 75% of the cases 
accrue. If the prespecified criteria for efficacy are met at either interim analysis, then enrollment 
will continue until 4500 subjects have been enrolled, and blinded follow-up will continue until 
at least those 4500 subjects have a minimum of 6 months of safety follow-up. At that point, the 
trial would be unblinded and placebo-recipients will be offered the active product.    
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12 months 
post-dose 2. All Phase 3 segment subjects will be followed for 56 weeks from the Day 0 dosing 
[i.e., Week 56 will be the planned End of Study (EOS) visit for this segment of the trial]. 
 
Figure 1: Enrollment and Dose Group Design 
 
 
 
External Committee Reviews 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will convene 
regularly to review all available unblinded safety data. For the Phase 3 segment, the DSMB 
will also review efficacy in an unblinded fashion. Additionally, for the Phase 3 segment, an 
independent, blinded Endpoint Adjudication Committee (EAC) will review and confirm COVID-
19 cases.  
 
Details of each committee’s scope will be provided in the respective charters. 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 13 of 93 
 
  
Criteria for Evaluation:  
 
Research Hypothesis:  
INO-4800 delivered ID followed immediately by EP will be well-tolerated, exhibit an acceptable 
safety profile, result in generation of cellular and humoral immune responses to SARS-CoV-2 
Spike glycoprotein and provide protection against virologically-confirmed COVID-19 disease in 
subjects at high risk of SARS-CoV-2 exposure.  
 
Phase 2 Segment Objectives and Endpoints: 
 
Primary Objective 
Primary Endpoint 
1.  Evaluate the cellular and humoral 
immune response to INO-4800 
administered by ID injection followed 
immediately by EP  
  
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot 
1b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
Secondary Objective 
Secondary Endpoints 
1.  Evaluate the safety and tolerability of 
INO-4800 administered by ID injection 
followed immediately by EP    
  
1a. Incidence of solicited and unsolicited injection site 
reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)   
Exploratory Objective 
Exploratory Endpoint 
1.  Evaluate the expanded immunological 
profile of antibody response and T cell 
immune response 
  
1a.  Antigen-specific cellular immune response 
measured by flow cytometry 
1b. Expanded immunological profile which may 
include additional assessments of T and B cell 
numbers and molecular changes by measuring 
immunologic proteins and mRNA levels of genes 
of interest as determined by sample availability 
 
Phase 3 Segment Objectives and Endpoints: 
 
Primary Objective 
Primary Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease in 
subjects who are SARS-CoV-2 
negative at baseline  
 
1.   Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 (End 
of Study (EOS)) in subjects who are SARS-CoV-2 
seronegative at baseline 
Secondary Objectives 
Secondary Endpoints 
1. Evaluate the safety and tolerability of 
INO-4800    
 
1a. Incidence of solicited and unsolicited injection site 
reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 14 of 93 
 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality 
 
2.  Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of severity in 
subjects who are SARS-CoV-2 
seronegative at baseline       
2a.  Incidence of non-severe COVID-19 disease in 
SARS-CoV-2 seronegative subjects starting 14 
days after completion of the 2-dose regimen until 
EOS  
2b. Incidence of severe COVID-19 disease in SARS-
CoV-2 seronegative subjects starting 14 days after 
completion of the 2-dose regimen until EOS 
2c. Incidence of deaths due to COVID-19 in SARS-
CoV-2 seronegative subjects starting 14 days after 
completion of the 2-dose regimen until EOS 
3.  Evaluate the cellular and humoral 
immune response to INO-4800  
3a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot  
3b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
 
4. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease in 
subjects who are SARS-CoV-2 
seropositive at baseline  
 
4.  Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 (End 
of Study (EOS)) in subjects who are SARS-CoV-
2 seropositive at baseline 
Exploratory Objective 
Exploratory Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease 
from SARS-CoV-2 variants in subjects 
who are SARS-CoV-2 seronegative at 
baseline 
1. Incidence of virologically-confirmed COVID-19 
disease from a SARS-CoV-2 variant starting 14 
days after completion of the 2-dose regimen until 
12 months post-dose 2 (End of Study (EOS)) in 
subjects who are SARS-CoV-2 seronegative at 
baseline 
2. Evaluate the efficacy of INO-4800 in 
the prevention of SARS-CoV-2 
asymptomatic infection in subjects 
who are SARS-CoV-2 seronegative at 
baseline     
2. Incidence of SARS-CoV-2 asymptomatic 
infections in SARS-CoV-2 seronegative subjects 
starting 14 days after completion of the 2-dose 
regimen until EOS 
3.  Evaluate the immunological profile by 
assessing both antibody response and 
T cell immune response  
3a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels  
3b. Antigen-specific cellular immune response such as 
measured by flow cytometry  
4. Evaluate antibody persistence  
4a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels at Week 30 or later.  
4b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay at Week 
30 or later 
 
 
Immunogenicity Assessment:  
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INO-4800 
  
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 15 of 93 
 
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 3 and Table 4).  Assays such as binding enzyme-linked immunosorbent assay (ELISA), 
pseudovirus-based neutralization assay, and enzyme-linked immunosorbent spot-forming 
assay (ELISpot) will be evaluated at serial timepoints. 
Safety Assessment:  
Subjects will be followed for safety during the trial through scheduled clinic visits and phone 
calls. Adverse events (AEs), regardless of relationship to study drug, will be collected from 
the time of consent until 28 days post-dose 2 (i.e., Day 56). SAEs, Medically Attended Adverse 
Events (MAAEs) and AESIs will be collected from time of consent until EOS. SAEs, AESIs 
and treatment-related AEs will be followed to resolution or stabilization. For the Phase 2 
segment and at selected sites in the Phase 3 segment, solicited local and systemic AEs will 
be collected for 7 days following each dose using a participant diary. 
Subjects will also be monitored for COVID-19.  
Please refer to the Schedule of Events (Table 3 and Table 4) for safety assessments to be 
performed.  
Efficacy Assessment (Phase 3 segment only):  
Subjects will receive either active investigational product (INO-4800) or placebo (SSC-0001) 
in a 2-dose regimen administered on Days 0 and 28 intradermally followed immediately by 
EP. Subjects will be monitored through regularly scheduled clinic visits and phone calls 
throughout the trial. Subjects will be regularly tested for SARS-CoV-2 infection using serologic 
testing. If COVID-19 disease is suspected based on symptoms per the case definition or 
laboratory testing, site personnel will arrange for a clinic visit. Subjects with symptom(s) or a 
positive SARS-CoV-2 test result will be reviewed by the EAC. 
Clinical Trial Population: 
Phase 2 segment: Healthy subjects at high risk for SARS-CoV-2 exposure who are 18 years 
and older. 
Phase 3 segment: Subjects at high risk for SARS-CoV-2 exposure including subjects at high 
risk for severe COVID-19 who are 18 years and older. 
Inclusion Criteria: Phase 2 segment 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, vital signs and 
physical examination performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar 
workers, store cashiers, hairdressers and barbers, veterinary staff, daycare 
workers, Transportation Security Administration screening staff, school 
teachers and college professors teaching in-person classes) 
2. Factory workers (when working in confined settings with large numbers of 
employees) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) 
4. User of public transportation (e.g., bus, train, subway) at least 3 times weekly 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 16 of 93 
 
5. Nursing home staff or correctional facility staff  
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists.) Physicians should not be enrolled unless they 
are assigned to dedicated COVID-19 treatment wards or other settings with 
prolonged exposure 
10. Others, if approved by the medical monitor.   
f. Screening laboratory results within normal limits for testing laboratory or are deemed 
not clinically significant by the Investigator; 
g. Must meet one of the following criteria with respect to reproductive capacity: 
1. Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
2. Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or 
tubal ligation, absence of ovaries and/or uterus in females). In the case of 
vasectomy, subjects should wait six (6) months post-vasectomy prior to 
enrolling;  
3. Use of medically effective contraception with a failure rate of < 1% per year 
when used consistently and correctly from screening until 3 months following 
last dose. Acceptable methods include:  
i. hormonal contraception including implants, injections or oral; 
ii. two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
iii. intrauterine device or intrauterine system; 
iv. abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Inclusion Criteria: Phase 3 segment 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Per investigator judgment, healthy or stable with pre-existing medical conditions that 
do not require significant change in medication or have led to a hospitalization in the 3 
months prior to enrollment or who, in the judgment of the investigator, are unlikely to 
require a significant change in therapy or hospitalization for worsening disease through 
Day 56; 
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings. Examples 
include:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar 
workers, street vendors, store cashiers, hairdressers and barbers, veterinary 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 17 of 93 
 
staff, daycare workers, airport screening staff, school teachers and college 
professors teaching in-person classes, college students attending in-person 
classes, office workers and volunteers who have multiple brief exposures to 
people regularly) 
2. Factory workers (when working in confined settings with large numbers of 
employees, meat-packing facilities) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) and delivery 
services  
4. User of public transportation (e.g., bus, train, subway) or public facilities (e.g. 
gyms) at least 3 times weekly 
5. Nursing home staff or correctional facility staff 
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, medical assistants and technicians, respiratory therapists, 
physical therapists, social workers, dentists and dental hygienists)  
10. Others, if in the opinion of the PI, the risk of COVID-19 exposure is comparable 
to the examples above.   
f. Must meet one of the following criteria with respect to reproductive capacity: 
1. Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
2. Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or 
tubal ligation, absence of ovaries and/or uterus in females). In the case of 
vasectomy, subjects should wait six (6) months post-vasectomy prior to 
enrolling;  
3. Use of medically effective contraception with a failure rate of < 1% per year 
when used consistently and correctly from screening until last dose. Acceptable 
methods include:  
i. hormonal contraception including implants, injections or oral; 
ii. two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
iii. intrauterine device or intrauterine system; 
iv. abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 
Exclusion Criteria: Phase 2 segment 
a. Acute febrile illness with temperature >100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat); 
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the Screening visit until 3 
months following the last dose; 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 18 of 93 
 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or a 
detectable viral load within the past 3 months; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous receipt of an investigational vaccine for prevention or treatment of COVID-19, 
MERS or SARS (documented receipt of placebo in previous trial would be permissible 
for trial eligibility); 
h. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg prior to first dose; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin 
cancers that only required local excision and non-metastatic prostate cancer 
not requiring treatment; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in 
therapy or hospitalization for worsening disease during the 6 weeks prior to 
enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a 
single antiepileptic agent; 
i. 
Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed); 
• 
Current or anticipated use of disease modifying doses of systemic anti-
rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, 
cyclosporine, 
methotrexate) and biologic disease modifying drugs such as TNF-α inhibitors 
(e.g., infliximab, adalimumab or etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the 
subject or require therapy that would interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results. 
j. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 19 of 93 
 
• 
Any metal implants or implantable medical device within the electroporation 
site; 
k. Blood donation or transfusion within 1 month prior to Day 0; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the past 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
 
Exclusion Criteria: Phase 3 segment 
a. Acute febrile illness with temperature ≥100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat) on Day 
0 prior to dosing; 
b. Positive serologic test for SARS-CoV-2 at Screening (this criterion only applies after 
approximately 402 subjects positive for SARS-CoV-2 serologic test are randomized, 
after which this criterion will apply to all remaining subjects); 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children starting from the Screening visit until the last dose; 
d. Positive urine pregnancy test during screening or immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or a 
detectable viral load within 3 months prior to screening; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days prior to Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous or planned receipt of an investigational (including Emergency Use 
Authorization (EUA) or local equivalent authorization) or licensed vaccine for 
prevention or treatment of COVID-19, MERS or SARS (documented receipt of placebo 
in previous trial would be permissible for trial eligibility); 
h. Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed) in the past 6 months; 
• 
Current or anticipated use of disease modifying doses of systemic anti-
rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, 
cyclosporine, 
methotrexate) and biologic disease modifying drugs such as TNF-α inhibitors 
(e.g., infliximab, adalimumab or etanercept) or others; 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the 
subject or require therapy that would interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results. 
i. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 20 of 93 
 
• 
Any metal implants or implantable medical device within the electroporation 
site; 
j. 
Blood donation or transfusion within 1 month prior to Day 0; 
k. People who work remotely or in a socially distanced setting with minimal risk of 
exposure to SARS-CoV-2; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the prior 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
Clinical Trial Treatment: 
Phase 2 Segment 
Active Investigational Product: One or two 1.0mg ID injection(s) of INO-4800 (~0.1mL dose 
volume) followed immediately by EP administered on Day 0 and Day 28 (±3 days)  
Placebo: One or two ID injection(s) of saline sodium citrate buffer (SSC-0001) (~0.1mL) 
followed immediately by EP administered on Day 0 and Day 28 (±3 days) 
Phase 3 Segment 
Active Investigational Product: Two 1.0mg ID injections of INO-4800 followed immediately by 
EP administered in separate limbs at Day 0 and Day 28 (±3 days) 
Placebo: Two ID injections of SSC-0001 followed immediately by EP administered in separate 
limbs at Day 0 and Day 28 (±3 days) 
Formulation: 
INO-4800 is formulated in sodium chloride and sodium citrate buffer, refrigerated. Placebo 
[sterile saline sodium citrate buffer (SSC-0001)], refrigerated. 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 29-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 21 of 93 
 
TABLE 3 – PHASE 2 SEGMENT SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Tel 
#1 
Wk 
4 
Tel 
#2 
Wk
6 
Tel 
#3 
Wk 
30 
Wk 
56 
Illness 
Illness  
Screena 
Day 0 
Phone call - Day 7 (±3d) 
Day 28 
(±3d) 
Phone call - Day 35 (±3d) 
Day 42 (±5d) 
Phone Call - Day 56 (±5d) 
Day 210 (±5d) 
Day 393 (± 5d) 
COVID-19 assessment visitm  
COVID-19 convalescent visitn 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behavioral Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
Vital Signs 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
Xp 
Xp 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differentialc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Chemistryc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
HIV Serology  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis Routined 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Pregnancy Teste 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
INO-4800 or Placebo + EPf 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Download EP Datag 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Adverse Eventsh  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Samplesi 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
Humoral Samplesj 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
SARS-CoV-2 Serologyk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 RT-PCR (Saliva and Swabs) 
Xl 
 
 
 
 
 
 
 
 
 
 
Xl 
Xl 
Distribute Diary 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Review/Collect Diaryo 
 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 29-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 22 of 93 
 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0.   
b. 
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits.  
c. 
Hemoglobin A1c collected at screening only. Chemistry includes Na, K, Cl, HCO3, Ca, PO4, glucose, BUN, Cr, alkaline phosphatase, AST, ALT, LDH, total bilirubin.  
d. 
Dipstick for glucose, protein, and hematuria. Microscopic examination should be performed if dipstick is abnormal.  
e. 
Serum pregnancy test at Screening. Urine pregnancy test at other visits.  
f. 
Intradermal injection(s) in skin preferably over deltoid muscle, or alternately over anterolateral quadriceps muscle, followed by EP at Day 0 and Day 28. 
g. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
h. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
i. 
On Day 0, cellular sampling requires 64 mL of whole blood (8 Cell Preparation Tubes (CPT), each 8 mL of whole blood) prior to 1st dose. At all other time points, collect 32 mL of 
whole blood (4 CPT tubes, each 8 mL of whole blood).   
j. 
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce eight serum aliquots of 1 
mL each). At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce four serum aliquots of 1 mL each.  
k. 
SARS-CoV-2 antibody.   
l. 
Saliva specimen at Screening; Nasal swabs and saliva specimens at COVID-19 assessment and convalescent visits. Genotyping may also be performed on sample(s) collected at 
the COVID-19 assessment visit. 
m. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The assessment visit may be performed in the clinic, in the subject’s vehicle 
or at the subject’s home and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test.  
n. 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of 
symptoms, the date of positive SARS-CoV-2 test. If acute symptoms are ongoing, the site should follow up with the subject via phone call or an unscheduled visit after symptom 
resolution or stabilization.   
o. 
Diary should be reviewed at the 7-day post-dose phone call and collected at the next in-office visit. 
p. 
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation. 
 
 
 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 29-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 23 of 93 
 
TABLE 4 – PHASE 3 SEGMENT SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Tel 
#1 
Wk 
4 
Wk
6 
Tel 
#2-6 
Wk 
18 
Tel 
#7-11 
Wk 
30 
Tel 
#12-13 
Wk
42 
Tel 
#14-16 
Wk 
56 
Illness 
Illness 
Screena 
Day 0 
Phone call - Day 14 (±3d) 
Day 28 
(±3d) 
Day 42 (±5d)k 
Phone call - Days 56, 70, 84, 
98, 112 (±5d) 
Day 126 (±5d) 
Phone calls - Days 140, 154 
168, 182, 196 (±5d) 
Day 210 (±5d) 
Phone calls - Days 238, 266 
(±5d) 
Day 294 (±5d) 
Phone calls 
Days 322, 350, 378 (±5d) 
Day 393 (± 5d) 
COVID-19 assessment visitl  
COVID-19 convalescent visitm 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behavioral Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Vital Signs 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Xn 
Xn 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testc 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
INO-4800 or Placebo + EPd 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Download EP Datae 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Eventsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Samplesg 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
X 
Humoral Samplesh 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
X 
SARS-CoV-2 Serologyi 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
SARS-CoV-2 RT-PCR 
(Nasopharyngeal swabs) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
 
Distribute Diaryp 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Review/Collect Diaryq 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0. Screening and Day 0 visits may be combined if eligibility is able to be confirmed prior to dosing. If so, all assessments 
for Screening and Day 0 must be performed at the combined visit.  
b. 
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits.  
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 29-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 24 of 93 
 
c. 
In women of childbearing potential. Urine pregnancy test at all indicated visits.  
d. 
Intradermal injection(s) in skin preferably over deltoid region, or alternately over anterolateral quadriceps region, followed by EP at Day 0 and Day 28. 
e. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
f. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
g. 
On Day 0, cellular sampling requires 64 mL of whole blood prior to 1st dose. At all other time points, collect 32 mL of whole blood. Cellular samples will be collected at selected clinical sites 
(estimated to include 711 subjects) 
h. 
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce four serum aliquots of 2 mL 
each). At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce two serum aliquots of 2 mL each.  
i. 
SARS-CoV-2 antibody. 
j. 
The Day 0 RT-PCR results will not be required prior to dosing on that day. 
k. 
Day 42 visit must occur at least 10 days after Day 28 visit. 
l. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The assessment visit may be performed in the clinic, subject’s vehicle, or at a 
home visit and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test.  
m. 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of 
symptoms, the date of positive SARS-CoV-2 test. If acute symptoms are ongoing the site should follow up with the subject via phone call or unscheduled visit after symptom resolution 
or stabilization 
n. 
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation.   
o. 
Genotyping may also be performed on sample(s) collected at the COVID-19 assessment visit.  
p. 
Diaries to be used at selected sites only (estimated to include 711 subjects). 
q. 
Diary should be reviewed at the 14-day post-dose phone call or visit and collected at the next in-office visit. 
r. 
When possible, cellular and humoral immunology samples will be collected. Cellular samples will be collected at selected sites only. 
 
 
 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 25 of 93 
 
 
INTRODUCTION 
This document is a protocol for a human research trial to be conducted according to U.S. 
and international standards of Good Clinical Practice (GCP) (FDA Title 21 part 312, 812 
and International Conference on Harmonization (ICH) guidelines), applicable government 
regulations and Institutional research policies and procedures. 
 
BACKGROUND AND SCIENTIFIC RATIONALE 
Given the continued number of cases globally, SARS-CoV-2 infections remain a serious 
unmet medical concern. Appropriate measures to prevent SARS-CoV-2 infections, 
including its variants, are not yet widely available. 
 
BACKGROUND INFORMATION 
In late 2019, a cluster of cases of pneumonia of unknown etiology was reported in Wuhan, 
Hubei province, China [2-4]. These cases were announced on January 6, 2020 as testing 
negative for influenza, severe acute respiratory syndrome (SARS), and Middle East 
respiratory syndrome (MERS). On January 7, 2020 a novel virus was isolated by the 
Chinese Center for Disease Control and Prevention (CDC) from the throat swab sample 
of a patient, and the isolate was named “Wuhan-Hu-1.” The gene sequence of that isolate 
was then generated and determined to be of a novel coronavirus [5, 6]. That gene 
sequence was publicly posted on January 10, and the novel coronavirus was preliminarily 
named 2019-nCoV. Subsequently, on February 11, 2020, the virus was named SARS-
CoV-2 by the International Committee on Taxonomy of Viruses (ICTV) [7, 8], due to its 
similarity with the original SARS virus. That same day, the World Health Organization 
(WHO) announced a specific name of the disease, “COVID-19,” associated with infection 
by this novel coronavirus, as based on the novel coronavirus origin and year of first 
reported cases. The first cluster of human cases identified comprised people who worked, 
visited, or lived around the local Huanan seafood wholesale market in Wuhan, where live 
animals and fresh meat and fish were on sale, suggesting that an animal was the source 
of the novel respiratory virus being transmitted to humans.  
Epidemiologic data suggest that droplets expelled during face-to-face exposure during 
talking, coughing, or sneezing is the most common mode of transmission while contact 
surface spread remains yet another possible mode of transmission [9].  
SARS-CoV-2 infection rapidly emerged as a global threat to public health, joining other 
coronavirus-related diseases, such as SARS and MERS. COVID-19 was declared a 
Public Health Emergency of International Concern (PHEIC) by the WHO on January 20, 
2020, and was declared a pandemic on March 11, 2020 [10], associated with substantial 
morbidity and mortality [11]. As of July 25, 2020, a total of nearly 16 million laboratory-
confirmed COVID-19 cases have been reported internationally, including over 643,000 
deaths [12]. However, given the lack of widespread testing, the true number of cases of 
COVID-19 is likely far higher than reported. Preliminary results from large U.S.-based 
seroepidemiological surveys indicate an estimated incidence rate of SARS-CoV-2 
infections to be 6 to 24 times that of the number of reported cases of COVID-19 [13].  
An article in JAMA by Wu and McGoogan [14] provided a summary of a major report by 
the Chinese Center for Disease Control and Prevention (China CDC) [15]. Of a total of 
72,314 case records, 44,672 (62%) were confirmed as SARS-CoV-2 infections based on 
positive viral nucleic acid test results on throat swabs, 16,186 (22%) as suspected cases 
based on symptoms and exposures only, 10,567 (15%) as clinically diagnosed based on 
symptoms, exposures, and presence of lung imaging features consistent with coronavirus 
pneumonia, and 889 (1%) as asymptomatic cases based on a positive viral nucleic acid 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 26 of 93 
 
test result but lacking typical symptoms including fever, dry cough, and fatigue [16]. The 
overall case-fatality ratio (CFR) was 2.3% (1023 deaths among 44,672 confirmed cases). 
No deaths occurred in the group aged 9 years and younger, but cases in those aged 70 
to 79 years had an 8.0% CFR and cases in those aged 80 years and older had a 14.8% 
CFR. The CFR was 49.0% among critical cases. CFR was elevated among those with 
preexisting comorbid conditions - 10.5% for cardiovascular disease, 7.3% for diabetes, 
6.3% for chronic respiratory disease, 6.0% for hypertension, and 5.6% for cancer [16]. 
These initial reports of the CFR documented the level of seriousness of COVID-19.  
Given the novelty of SARS-CoV-2, its rapid spread among humans and its associated 
morbidity and mortality, there has been an explosion of epidemiological, clinical, virologic, 
and other scientific data regarding the propagation of effects of this virus emerging from 
China, the United States, and many other countries. These data have established that 1) 
SARS-CoV-2 is transmitted person-to-person [17], even from those who are asymptomatic 
or presymptomatic [18-20], 2) the virus is very infectious, with estimates of the R0 
(Reproductive number) ranging from 1.50 to 6.49, with a mean average of 3.28 and a 
median average of 2.79 [21], 3) the constellation of symptoms, signs, and an incubation 
period ranging between  2 and 14 days [22], and 4)  the asymptomatic proportion of those 
infected being substantial, perhaps as high as  80% [17, 23-25]. Further, research has 
found that the risk of death from COVID-19 increases with age and with serious, comorbid 
conditions including hypertension, diabetes, cardiovascular disease, obesity, etc.   
Finally, although much has been learned very quickly about SARS-CoV-2 and COVID-19, 
much more is still to be determined. The aforementioned CFR and similar estimates are 
from crude analyses that have only accounted for moderate to serious cases. Therefore, 
the true CFR is likely significantly lower. Further, the infection-fatality ratio (IFR), which is 
the proportion who die among all those infected regardless of any symptomology, is likely 
still even lower than the CFR, but both the CFR and IFR will not be known with certainty 
until well-designed and controlled seroepidemiology surveys have been conducted using 
well-validated antibody assays and thorough questionnaires to obtain symptom history. 
Also, the presence of natural immunity of those infected who survive and the durability of 
such natural immunity is to be determined. Thus, the existence and possibility of 
reinfection and recurrent infection is unknown. 
 CLINICAL PRESENTATION, TRANSMISSION AND IMMUNE RESPONSE 
A study in The Lancet by Huang and colleagues [4] reported the epidemiological, clinical, 
laboratory, and radiological characteristics, as well as treatment and clinical outcomes, of 
patients with laboratory-confirmed COVID-19 pneumonia. Common symptoms at onset of 
illness were fever (n=40, 98% of 41 patients), cough (n=31, 76%), and myalgia or fatigue  
(n=18, 44%);  less  common  symptoms  were  sputum  production  (n=11, 28%  of  39 
patients),  headache  (n=3, 8%  of  38 patients), hemoptysis (n=2, 5% of 39 patients), and 
diarrhea (n=1, 3% of 38 patients). Dyspnea developed in 22 (55%) of 40 patients (median 
time from illness onset to dyspnea was 8 days [Interquartile range 5 - 13 days]). Twenty-
six (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal 
findings on chest CT scan. Complications included acute respiratory distress syndrome 
(n=12, 29%), RNAaemia (n=6, 15%), acute cardiac injury (n=5, 12%) and secondary 
infection (n=4, 10%).  
Wiersinga et al. summarized the common symptoms of COVID-19 in hospitalized patients 
as fever (70-90%), dry cough (60-86%), shortness of breath (53-80%), fatigue (38%), 
myalgias (15-44%), nausea/vomiting or diarrhea (15-39%), headache, weakness (25%) 
and rhinorrhea (7%). Anosmia and ageusia may be the sole presenting symptom in 
approximately 3% of individuals with COVID-19. Common laboratory abnormalities 
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include lymphopenia (83%), elevated inflammatory markers (e.g., erythrocyte 
sedimentation rate, C-reactive protein, ferritin, tumor necrosis factor-alpha, IL-1, IL-6) and 
abnormal coagulation parameters (e.g., prolonged prothrombin time, thrombocytopenia, 
elevated D-dimer and low fibrinogen). Common radiographic findings include bilateral, 
lower lobe infiltrates on chest radiographic imaging and bilateral, peripheral, lower-lobe 
ground-glass opacities and/or consolidation on chest computed tomographic imaging [9].  
Transmission of SARS-CoV-2 occurred mainly after days of illness [26] and was 
associated with modest viral loads in the respiratory tract early in the illness, with viral 
loads peaking approximately 10 days after symptom onset [27]. Higher viral loads were 
detected soon after symptom onset, with higher viral loads detected in the nose than in 
the throat. Analysis of these samples suggested that the viral nucleic acid shedding 
pattern of patients infected with SARS-CoV-2 resembles that of patients with influenza 
[28] and appears different from that seen in patients infected with SARS-CoV [27]. The 
viral load that was detected in the asymptomatic patient was similar to that in the 
symptomatic patients, which suggests the transmission potential of asymptomatic or 
minimally symptomatic patients [11]. The SARS-CoV-2 transmission time window from 
COVID-19 patients is perhaps 2 days before symptom onset up to 37 days after symptom 
onset [20]. It is estimated that 48% to 62% of transmission may occur via presymptomatic 
carriers [9].  
Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10-15 
days following the onset of COVID-19 symptoms. Seow et al. observed seroconversion in 
>95% with neutralizing antibody responses when sampled beyond 8 days after onset of 
symptoms [29]. However, declining neutralizing antibody titers were observed during the 
follow-up period. Long, et al, when following 37 asymptomatic individuals and 37 
symptomatic patients into the early convalescent phase, observed that the IgG levels in 
93.3% of the asymptomatic group and 96.8% of the symptomatic group declined during 
the early convalescent phase [30]. T cells play a critical role in antiviral immunity but their 
numbers and functional state in SARS-CoV-2 infected patients remain largely unclear. 
Diao and colleagues performed a retrospective review of total T cell counts, and CD4+ and 
CD8+ T cell subsets based on inpatient data from 522 patients with laboratory-confirmed 
SARS-CoV-2 infection and 40 healthy controls in Wuhan from December 2019 to January 
2020. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe and 
critical disease groups as well as those who died were significantly lower than in the 
mild/moderate disease group. Most importantly, the numbers of total T cells, CD8+ T cells 
and CD4+ T cells in severe COVID-19 cases, including those who died, were lower 
suggesting that there is a profound T cell loss in COVID-19 disease. Counts of total T 
cells, CD8+ T cells or CD4+ T cells were negatively correlated with patient survival [31]. 
It is quite likely that CD4+ T cell, CD8+ T cell, and neutralizing antibody all contribute to 
clearance of the acute infection. There is an ongoing need to understand the magnitude 
and composition of the human CD4+ and CD8+ T cell responses to SARS-CoV-2. If 
natural infection with SARS-CoV-2 elicits potent CD4+ and CD8+ T cell responses 
commonly associated with protective antiviral immunity, COVID-19 is a strong candidate 
for rapid vaccine development [32].  
 CURRENT TREATMENT AND UNMET NEED 
Currently, there is no licensed prophylactic vaccine against COVID-19, however there are 
several vaccines that are available under Emergency Use Authorization (EUA) in the 
United States and other countries. Numerous vaccine efforts are underway. Given the 
growing concerns regarding the emergence of new strains of SARS-CoV-2, an effective 
prophylactic vaccine ideally induces immunity against not only SARS-CoV-2 Wuhan-Hu-
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1 but also its variants. Due to rapid spread of SARS-CoV-2 infections even from 
asymptomatic and mildly infected patients, there is an urgent need for additional vaccines 
for prevention of SARS-CoV-2 infections. 
 
RATIONALE FOR PROPHYLACTIC VACCINE DEVELOPMENT 
SARS-CoV-2 has become a pandemic resulting in substantial morbidity and mortality. Due 
to rapid spread of SARS-CoV-2 infections even from asymptomatic and mildly infected 
patients, there is an urgent need for appropriate measures to prevent, control and treat 
SARS-CoV-2 infections.  
To address this critical need for a medical countermeasure for prevention of COVID-19 
disease, we at Inovio Pharmaceuticals have employed our synthetic DNA-based vaccine 
technology. This technology is highly amenable to accelerated developmental timelines, 
due to the ability to rapidly design multiple test constructs, manufacture large quantities of 
the drug product, and leverage established regulatory pathways to the clinic. Furthermore, 
this technology platform has demonstrated proof of concept efficacy and safety in humans 
in a Phase 3 (REVEAL1) randomized, double-blind, placebo-controlled study for human 
papillomavirus (HPV) associated cervical pre-cancer (NCT03185013) and several Phase 
2 trials for related and other indications and several Phase 2 trials for related and other 
indications. We have additionally built upon our prior experience in developing a MERS 
coronavirus (MERS-CoV) vaccine to accelerate the development of a SARS-CoV-2 
vaccine candidate. In a Phase 1 clinical study, the MERS-CoV vaccine candidate was safe 
and well tolerated, eliciting immune responses in more than 85% of participants after two 
vaccinations that were durable through 1 year of follow-up [33].   
 DNA VACCINES 
Since the 1990s, a novel approach to vaccination against a broad array of target antigens 
and diseases has been in development. This involves the direct introduction of plasmid 
deoxyribonucleic acid (DNA) containing the gene encoding the immunogen against which 
an immune response is sought into appropriate host tissues and the in situ production of 
the target immunogen(s). This approach offers a combination of potential advantages, 
including the stimulation of both B- and T-cell responses, stability of the vaccine across a 
broad temperature range, absence of infectivity of the immunogen itself, the speed with 
which the vaccine can be constructed (for example in the face of an epidemic or pandemic 
as it is the case here with SARS-CoV-2), and the relative ease and generic nature of large-
scale manufacture. Many scientific publications have addressed the potential of DNA 
vaccination [34-43]. Immune responses in animal models have been obtained using genes 
from a variety of infectious agents including influenza viruses, hepatitis B virus, human 
immunodeficiency virus, human papillomaviruses, Marburg virus, MERS coronavirus, 
rabies virus, SARS coronavirus, West Nile virus (WNV), Zika virus, and other infectious 
agents as plasmodium, mycoplasma, and many more [42, 44]. In many cases, protection 
from disease in animal models has also been demonstrated.  
DNA vaccines are able to generate both CD4+ and CD8+ T cell responses. The ability to 
generate MHC-Class I restricted CD8+ T cells (cytolytic T lymphocytes), which generally 
are not made following administration of inactivated viruses, proteins or peptides, may be 
important for key responses against certain pathogens, as well as enabling cross-strain 
specific responses when many antibody responses are strain-specific. Because the 
encoded protein is synthesized in vivo by the host following administration, DNA vaccines 
can encode membrane-bound proteins instead of solely the soluble versions [45]. This 
can be important because key neutralizing epitopes are located in regions that would be 
excluded, or not formed in a monomeric truncated soluble version. Some early research 
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in COVID-19 control has already suggested that neutralizing antibodies may not be 
sufficient and that cell-mediated immunity may be necessary [46]. 
Unlike certain other vectors (such as heterologous viral vectors), DNA vaccines do not 
stimulate adaptive immune responses against themselves, although the DNA itself does 
stimulate certain innate immune responses [47]. In other words, they do not generate anti-
vector immunity that could stunt antigen-specific responses following multiple exposures. 
 USE OF ELECTROPORATION WITH DNA VACCINES 
Electroporation (EP) enhances gene expression of plasmid DNA delivered by the 
intramuscular (IM) or intradermal (ID) routes of administration (Figure 2). Following IM or 
ID delivery of a DNA vaccine or therapeutic product, EP facilitates entry of the DNA into 
the target site: muscle or dermal cells. Following cellular uptake, there is efficient 
production of the proteins encoded by the DNA expression plasmid system. The different 
EP devices, each with varying electrical parameters and protocols, have been reviewed 
[48]. EP has been extensively tested in animal species such as dogs, pigs, cattle, and 
NHPs to deliver therapeutic genes that encode for a variety of hormones, cytokines, 
enzymes or antigens  for the activation of both cellular and humoral responses [49, 50]. 
Importantly, immune responses generated by DNA vaccines delivered with EP are far 
superior to responses to the same vaccines delivered without EP [50]. IM and ID delivery 
of DNA vaccines with EP has been studied extensively, and optimum conditions for 
plasmid uptake and expression have been described for therapeutic indications, vaccines 
and tumor animal model systems [51, 52].  
 INOVIO’S PROPRIETARY TECHNOLOGY AGAINST COVID-19  
Inovio Pharmaceuticals has developed INO-4800 as a DNA vaccine that contains 10 
mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM sodium chloride and 15 
mM sodium citrate). pGX9501 is a DNA plasmid expressing a synthetic consensus 
(SynCon®) sequence of the SARS-CoV-2 Wuhan-Hu-1 full length Spike glycoprotein. The 
ID route of delivery has been selected for INO-4800 based on recent findings from multiple 
DNA vaccine development programs where ID delivery has driven equivalent if not 
superior humoral and cellular responses to IM delivery while improving tolerability 
(clinicaltrials.gov NCT02464670, clinicaltrials.gov NCT02431767) [53-55]. 
Following ID injection, the Inovio Pharmaceuticals’ EP device [48] referred to as the 
CELLECTRA® 2000 for ID administration (3P-ID) device is used to facilitate DNA entry 
into the cells.  
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Figure 2: The Potential Mechanism of Action Underlying Electroporation 
 
 NONHUMAN PRIMATE (NHP) CHALLENGE STUDIES FOLLOWING VACCINATION WITH 
INO-4800 
NHPs are a valuable model in the development of COVID-19 vaccines and therapeutics 
as they can be infected with wild-type SARS-CoV-2, and present with early infection that 
mimics aspects of human disease [56].  Rhesus macaques (n=5) received two 
immunizations of INO-4800 (1.0 mg), at Week 0 and Week 4.  Naïve control animals (n=5) 
did not receive vaccine.  Humoral and cellular immune responses were monitored for 15 
weeks (~4 months) following prime immunization for memory responses. All animals 
seroconverted following a single INO-4800 immunization, with serum IgG titers detected 
against the full-length S1+S2 extracellular domain (ECD), S1, S2, and receptor binding 
domain (RBD) regions of the SARS-CoV-2 S protein.  
INO-4800 immunized macaques and unvaccinated controls were challenged with SARS-
CoV-2 13 weeks (~3 months) post-final immunization. NHPs received a challenge dose of 
1.1x104 PFU of SARS-CoV-2 by intranasal and intratracheal inoculation. Peak viral RNA 
loads in the BAL were significantly lower in the INO-4800 vaccinated group, along with 
significantly lower viral RNA loads at day 7 post-challenge, indicating protection from lower 
respiratory disease. While RNA was detected in the nasal swabs of both the control and 
INO-4800 vaccinated animals, viral mRNA levels trended downwards in INO-4800 
vaccinated animals by more than 2 logs and were achieved sooner on average. Overall, 
the reduced viral loads following exposure to SARS-CoV-2 infection at 17 weeks after 
immunization show an important durable impact mediated by the vaccine [57].  
 FIRST-IN-HUMAN PHASE 1 TRIAL OF INO-4800 
In the open-label, Phase 1 clinical trial, we initially evaluated the safety and 
immunogenicity of INO-4800 in 40 healthy participants, 18-50 years of age.  There were 
two groups of 20 participants each who received either 1.0 mg or 2.0 mg of INO-4800 
intradermally followed by EP at 0 and 4 weeks. In the first 40 subjects, by Week 8, 11 
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adverse events were reported of which all were Grade 1 in severity of which 6 were related 
to study drug. The frequency of AEs did not increase with the second administration.  
From the immunogenicity analysis of the initial 40 subjects enrolled, two subjects were 
excluded from the analysis, one due to early discontinuation prior to the Week 4 dose for 
non-study reasons and the other due to suspected exposure to SARS-CoV-2 before the 
first dose of INO-4800 was administered based on a baseline positive SARS-CoV-2 
serology. Thirty-eight (38) evaluable subjects had cellular and/or humoral immune 
responses following the second dose of INO-4800. Assessment of data from both Week 
6 and Week 8 ELISpot revealed that 74% and 100% of the subjects generated T cell 
responses in the 1.0 mg and 2.0 mg groups, respectively. By Week 6, 95% (36 of 38) of 
the participants seroconverted by generating binding and/or neutralizing antibodies. 
Overall, INO-4800 elicited antigen-specific humoral and cellular immune responses 
against the SARS-CoV-2 Spike protein while demonstrating favorable safety and 
tolerability. 
The protocol was amended to include an additional 80 healthy participants to evaluate 
safety and immunogenicity of INO-4800 in older and elderly age populations. A lower dose 
level (0.5 mg) was also added for evaluation of dose-sparing potential. A total of 40 
participants were enrolled into three dose levels (0.5 mg, 1.0 mg and 2.0 mg), such that 
each Group included 20 participants 18-50 years of age, 10 participants 51-64 years of 
age, and 10 participants 65 years of age and older. Doses were delivered intradermally 
followed by EP at 0 and 4 weeks. As of March 10, 2021, 35 related adverse events were 
reported cumulatively, of which all but three (Grade 2 injection site pruritus, lethargy and 
abdominal pain) were Grade 1 in severity. 
Additional analyses showed that INO-4800 provides broad cross-reactive immune 
responses against variants of concern (VOC). Clinical samples, collected at varying 
timepoints post-immunization from subjects enrolled during Phase 1 INO-4800 clinical 
trial, were analyzed against the spike protein of different VOC (including UK variant 
B.1.1.7, South African variant B.1.351, and Brazilian variant P.1. strains) [58]. The results 
revealed neutralization activity against the P.1 variant (neutralizing antibodies levels 
comparable to those against wild-type) and reduced, but still measurable neutralization 
activity against the B.1.1.7 and B.1.351 variants. Additionally, it has been demonstrated 
that INO-4800 induces cross-reactive T cell responses against B.1.1.7, B.1.351, and P.1 
variants that are comparable to the wild-type strain. Taken together, these data 
demonstrate that INO-4800 maintains cellular and/or humoral immune responses against 
the major SARS-CoV-2 variants that are currently in circulation, which will likely be critical 
factors necessary to impact the ongoing COVID-19 pandemic. 
Please refer to the Investigator’s Brochure, which will include future updates through the 
duration of the study. 
 PROPOSED PHASE 2/3 TRIAL OF INO-4800 
This Phase 2/3 trial is designed to begin with a Phase 2 segment to evaluate both the 1.0 
mg and 2.0 mg doses in approximately 400 subjects, including in the older (51 to 64 years 
of age) and elderly subjects (65 years of age and older), to enable selection of a dose or 
age-related doses for an efficacy evaluation in a subsequent Phase 3 segment involving 
>7000 subjects.  
The safety and immunogenicity data from the Phase 2 segment strongly support the 
selection and advancement of the 2.0 mg dose of INO-4800 into the Phase 3 segment 
(see Section 1.3.7 for immunogenicity details). INO-4800’s competitive safety/tolerability 
profile, nonclinical data supporting its potential to confer durable protection against severe 
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disease, ability to serve as a safe and tolerable homologous booster, and thermostability 
profile collectively support its potential as an additional tool for COVID-19 prevention with 
distinct advantages to facilitate global distribution and uptake. 
1.3.6.1 
Safety and tolerability of INO-4800  
Safety and tolerability data collected on INO-4800 to date mirror the favorable safety 
profile of Inovio’s plasmid DNA vaccines against multiple targets and indications.  
Nonclinical studies have revealed no safety concerns. Clinical studies (Phase 1 and Phase 
2) have also not revealed any safety concerns as per reviews by independent Data Safety 
Monitoring Boards.   
1.3.6.2 
Nonclinical INO-4800 Data in Support of Potential Efficacy 
The efficacy of INO-4800 in protecting against SARS-CoV-2 disease has been 
demonstrated in multiple nonclinical models. In the AAV6 human ACE2-transduced 
mouse model challenged with SARS-CoV-2, complete protection against lung virus load 
was observed [59]. Applying clinically relevant dosing and CELLECTRA-ID delivery 
parameters, INO-4800 has been tested in multiple nonhuman primate models, the gold 
standard large animal model for COVID-19 vaccine testing. We demonstrated protection 
against lung disease and viral load in the lower and upper respiratory tract in the rhesus 
macaque model after one or two doses of INO-4800 [60][61]. Furthermore, the durability 
of the impact of INO-4800 in reducing lung viral load was demonstrated in a rhesus 
macaque challenged with SARS-CoV-2 several months after immunization [57]. In 
conclusion, multiple nonclinical models have demonstrated the efficacy of INO-4800.  
1.3.6.3 
Potential Role of INO-4800 as a Booster 
INO-4800 offers a potential role in serving as a booster to maintain protection against 
COVID-19 over time in the context of a potential endemic disease scenario. Unlike viral 
vectors, DNA elicits no anti-vector response and, therefore, can be repeatedly 
administered without a reduction in the generated immune responses. When subjects in 
the INO-4800 Phase 1 were provided a booster dose 6 to 10.5 months following the 2-
dose regimen, there was no appreciable change in reactogenicity when compared to the 
first two doses, indicating that repeat dosing with INO-4800, as with other vaccines in 
Inovio’s DNA platform, does not lead to an increase in reactogenicity. Inovio’s DNA 
platform experience with Oncology DNA-vaccine targets have established that more than 
10 sequential administrations of vaccine is capable of consistent re-boosting from an 
immunological perspective with no associated changes in safety and reactogenicity. 
1.3.6.4 
Thermostability of INO-4800  
INO-4800 offers thermostability that could facilitate vaccine distribution globally. The 
current shelf life applied to INO-4800 clinical supplies is 24 months when stored at its 
recommended refrigerated storage condition of 5 ± 3°C. A 24-month real-time study for 
INO-4800 under refrigerated conditions (5°C) is ongoing; current Month 9 results are all 
within specification. Percent supercoiled forms, which is the strongest indication of DNA 
plasmid stability, decreased by only 2% (T0 97%, M9 95%) over the duration of the study 
to date, while percent total circular forms remained at 99%.  
Inovio has a platform stability program with 12 different DNA plasmid products, all 
constructed with the same plasmid backbone and formulated in the same SSC buffer, at 
various DNA concentrations, and the stability data to date are all consistent with the 
excellent stability profile seen with INO-4800. 
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 DOSE AND REGIMEN RATIONALE 
The intent is to evaluate INO-4800 as a prophylactic vaccine against COVID-19 disease. 
Based on Inovio’s extensive experience developing vaccine candidates against infectious 
diseases via the ID route ([54], [33]), a 2-dose regimen was considered to be optimal, 
based on the balanced humoral and cellular responses obtained 2 weeks post-dose 2, 
which supports evaluation of a 2-dose regimen (Days 0 and 28). 
In the Phase 2 segment of this trial, 1.0 mg and 2.0 mg of vaccine were administered by 
ID injection and followed immediately by EP at Day 0 and Day 28. The selection of the 
doses to test in Phase 2 is supported by the safety profile in the Phase 1 trial of INO-4800 
(COVID19-001, NCT04336410) in addition to our prior experience in developing a MERS 
coronavirus (MERS-CoV) vaccine (INO-4700) [16, 17]. The safety data for INO-4800 is 
provided in the Investigator’s Brochure (IB). 
The objective of the Phase 2 segment of the Phase 2/3 trial was to further evaluate the 
1.0 mg and 2.0 mg doses of INO-4800 for each age group in order to select the optimal 
vaccination regimen in the Phase 3 efficacy segment. The final decision between the two 
doses by age group relies on safety and immunogenicity. The 1.0 mg and 2.0 mg doses 
in the Phase 1 study had a similar safety profile. The review of the Phase 2 data by the 
independent DSMB has not revealed any safety signals of concern. Furthermore, there 
were no differences in the safety profile between the 1.0 mg and 2.0 mg dosing groups to 
impact Phase 3 dose selection. However, the immunology data from the Phase 2 study 
revealed superior immunogenicity with the 2.0 mg dose over the 1.0 mg dose.    
The immune response was measured using binding (ELISA) and neutralizing antibodies 
(pseudoneutralization) as well as cells capable of secreting IFN-gamma in a vaccine 
specific manner (ELISPOT). Data were analyzed for two age groups:  ≥18 to ≤50 years of 
age and ≥51 years of age. The Phase 2 data illustrate that the 2.0 mg dose induced higher 
levels of SARS-CoV-2 spike specific antibodies as well as higher levels of IFN-gamma 
producing cells.   
1.3.7.1 
Binding Antibody Response 
The binding antibody response was measured for all Phase 2 subjects at Day 0 and Week 
6.  Across all ages, the geometric mean titer (GMT) for the 1.0 mg dose group was 123.3 
at Day 0 compared to 938.8 at Week 6. The geometric mean fold rise was 7.8. The GMT 
for the 2.0 mg dose group was 93.5 at baseline compared to 2210.0 at Week 6. The 
geometric mean fold rise was 23.5. 
Subjects 18-50 years old in the 1.0 mg dose group had a GMT that was 148.5 at Day 0 
compared to 1182.1 at Week 6.  The geometric mean fold rise in binding antibody titers 
was 7.9. The GMT for the 2.0 mg dose group was 99.5 at baseline compared to 2671.2 at 
Week 6. The geometric mean fold rise was 26.5. 
Subjects ≥51 years old in the 1.0 mg dose group had a GMT that was 87.5 at Day 0 
compared to 623.3 at Week 6. The geometric mean fold rise in titers was 7.6. The GMT 
for the 2.0 mg dose group was 84.0 at baseline compared to 1613.7 at Week 6. The 
geometric mean fold rise in binding antibodies was 19.2.  
1.3.7.2 
Neutralizing Antibody Response 
The neutralizing antibody response was measured for all Phase 2 subjects at Days 0 and 
Week 6.  Across all ages the geometric mean titer (GMT) for the 1.0 mg dose group was 
32.2 at Day 0 compared to 93.6 at Week 6.  The geometric mean fold rise in neutralizing 
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titers was 2.9. The GMT for the 2.0 mg dose group was 35.8 at baseline compared to 
150.6 at Week 6.  The geometric mean fold rise was 4.3. 
Subjects 18-50 years old in the 1.0 mg dose group had a GMT that was 34.5 at Day 0 
compared to 112.6 at Week 6.  The geometric mean fold rise in neutralizing titers was 3.3. 
The GMT for the 2.0 mg dose group was 32.2 at baseline compared to 159.9 at week 6. 
The geometric mean fold rise was 5.0. 
Subjects ≥51 years old in the 1.0 mg dose group had a GMT that was 28.4 at Day 0 
compared to 67.4 at Week 6. The geometric mean fold rise in neutralizing titers was 2.3. 
The GMT for the 2.0 mg dose group was 43.3 at baseline compared to 135.7 at Week 6. 
The geometric mean fold rise was 3.2. 
1.3.7.3 
ELISPOT analysis 
ELISPOT analysis was performed for all Phase 2 subjects at Day 0 and Week 6. Across 
all ages, the median for the 1.0 mg dose group was 0 at Day 0 compared to 6.7 at Week 
6. The median for the 2.0 mg dose group was 2.2 at baseline compared to 18.9 at Week 
6. Subjects 18-50 years old in the 1.0 mg dose group had a median of that was 1.1 at Day 
0 compared to 7.6 at Week 6. The median for the 2.0 mg dose group was 0.6 at baseline 
compared to 18.9 at Week 6.  Subjects ≥51 years old in the 1.0 mg dose group had a median that 
was 0 at Day 0 compared to 10 at Week 6. The median for the 2.0 mg dose group was 3.3 at 
baseline compared to 18.4 at Week 6.   
 
RISKS AND POTENTIAL BENEFITS  
As of Dec 31, 2020, no treatment related serious adverse events have been reported for 
INO-4800. There may be side effects and discomforts that are not yet known.  
Please refer to the Investigator’s Brochure and User Manual, which will include future 
updates of the risk profile delineated in this section through the duration of the study. 
 POTENTIAL BENEFITS 
As part of the trial, subjects will have access to COVID-19 diagnostic and antibody testing 
to which they might not otherwise have access. Additionally, subjects will have the benefit 
of contributing to research to help others in a time of a global pandemic.  Benefits related 
to receipt of INO-4800 and protection from COVID-19 disease are unknown because the 
efficacy of INO-4800 remains unknown.      
 PRODUCT RISKS 
1.4.2.1. 
Expected Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Device 
In accordance with the International Council for Harmonisation (ICH), Inovio-sponsored 
studies have been designed to minimize risk to study participants. Expected risks of INO-
4800 delivered ID followed by EP with the CELLECTRA® 2000 device are listed below in 
Table5. 
Table 5: Expected Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Devicea  
Frequency among subjectsb 
Event 
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Very Common 
(≥10%) 
• 
Injection site pruritus 
• 
Injection site erythema or redness 
• 
Injection site painc or tenderness  
Common 
(≥1% to <10%) 
• 
Injection site bruising 
• 
Injection site swelling or induration 
Uncommon or Rare (<1%) 
• 
Administration site lesions or bleeding  
• 
Temporary severe injection site pain or 
tenderness 
a Investigator’s Brochure v4.0, dated 16-Nov-2020 
b EU commission guideline on the SmPC September 2009 [62] 
c Brief muscle contractions may occur and could be uncomfortable 
1.4.2.2  
Theoretical Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Device 
The following adverse events have been observed at least once, as of Dec. 31, 2020, 
across all clinical trials with Inovio DNA products delivered intradermally followed by EP 
using the CELLECTRA® 2000 device: 
• 
Allergic reaction 
• 
Anxiety 
• 
Creatine phosphokinase (CPK) elevations that are transient 
• 
Injection site infection, paresthesia, hypoesthesia, hematoma, or scab 
• 
Vasovagal reaction, lightheadedness or dizziness. 
The following events have not been observed, as of Dec. 31, 2020, in any subject or any 
clinical trials with Inovio DNA products delivered intradermally followed by EP using the 
CELLECTRA® 2000 device. While considered theoretical and unlikely to occur, any 
occurrence of these events should be reported to the Sponsor during this trial: 
• 
Antibody-dependent enhancement of disease (i.e., potential for greater respiratory 
disease upon exposure to SARS-CoV-2 due to priming of immune cells from prior 
vaccination. Although observed in nonclinical models for vaccines against other 
viruses such as SARS, the occurrence or observation of antibody-dependent 
enhancement of the disease with COVID-19 vaccines in humans remains 
unknown) 
• 
Cardiac arrhythmias (product-related); Please note that “ICD or pacemaker (to 
prevent a life-threatening arrhythmia) that is located ipsilateral to the deltoid 
injection site (unless deemed acceptable by a cardiologist)” is an exclusion 
criterion (‘j’) in this protocol; 
• 
Death (product-related); 
• 
Disruption of function of implanted electronic medical device(s); Please note that 
“ICD or pacemaker (to prevent a life-threatening arrhythmia) that is located 
ipsilateral to the deltoid injection site (unless deemed acceptable by a cardiologist)” 
is an exclusion criterion (‘j’) in this protocol; 
• 
Effects on fetus and/or pregnancy; Please note inclusion criterion in this protocol 
which requires use of medically effective contraception in women of childbearing 
potential; 
• 
Electrical injury (e.g., electrocution); Please note warning within the device User 
Manual (Section 7). Since the device is not connected to any power supply during 
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the EP procedure of a subject, this theoretical event is unlikely but has the potential 
to occur to the user of the device (e.g., study site staff). This will be mitigated 
through device training and user qualification prior to use; 
• 
Fire hazard to the facility; This theoretical event is unlikely but has the potential to 
occur to the clinical trial site. The possibility of this event has been mitigated 
through device design; 
• 
Hearing damage (product-related); The possibility of this event has been mitigated 
through the device design. The audio is limited in volume and is of very short 
duration. 
• 
Inaccurate energy delivery, the result of which is covered in other events listed 
here (e.g., tissue damage); 
• 
Injection site laceration; This has not been observed but would be theoretically 
possible with any needle; 
• 
Major injury to deeper tissue and/or bone; This event is not foreseeable given the 
array needle length is limited to 3.2 mm;  
• 
Muscle damage; This event is not foreseeable given the array needle length is 
limited to 3.2 mm; 
• 
Paresis or paralysis with possible loss of nerve function; There are minor nerves 
innervating the skin and subcutaneous tissues that may be disrupted, but are 
extremely unlikely to result in serious injury; 
• 
Radiation hazard to eyes and skin; This theoretical event is unlikely but has the 
potential to occur to the user of the device (e.g., study site staff). The possibility of 
this event has been mitigated through the device design; 
• 
Tissue injury/burn;  
• 
User/subject unaware that treatment was incomplete; 
• 
Worsening of unstable cardiac disease; Please note that “Cardiovascular diseases 
(e.g., myocardial infarction, congestive heart failure, cardiomyopathy or clinically 
significant arrhythmias) requiring changes in therapy or hospitalization for 
worsening disease during the 6 weeks prior to enrollment” is an exclusion criterion 
(‘h’) in this protocol. 
There have been no AEs associated with EP errors or failures. 
 OVERALL BENEFIT/RISK CONCLUSION 
While EUA vaccines are currently becoming available in many countries, the global 
availability to the general population remains limited. In the context of the ongoing COVID-
19 pandemic resulting in substantial morbidity and mortality, the overall cumulative safety 
profile of Inovio’s DNA platform across all of its products, and INO-4800’s Phase 1 adverse 
events being generally limited to local injection site reactions, the benefit risk profile 
justifies the conduct of the Phase 2/3 trial. 
 
OBJECTIVES AND PURPOSE 
The overall purpose of this clinical trial is to evaluate the safety, immunogenicity and 
efficacy of INO-4800. 
 
HYPOTHESIS 
INO-4800 delivered ID followed immediately by EP will be well-tolerated, exhibit an 
acceptable safety profile, result in generation of cellular and humoral immune responses 
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to SARS-CoV-2 Spike glycoprotein and provide protection against virologically-confirmed 
COVID-19 disease in subjects at high risk of SARS-CoV-2 exposure.  
 
CLINICAL TRIAL DESIGN AND ENDPOINTS 
This is an operationally seamless Phase 2/3, randomized, placebo-controlled, multi-
center trial to evaluate the safety, immunogenicity, and efficacy of INO-4800, 
administered by ID injection followed immediately by EP using the CELLECTRA® 2000 
device, in a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-
2 exposure. Subjects 18 years of age and older are expected to be enrolled across two 
(2) segments of this study. In the Phase 2 segment, approximately 400 seronegative 
subjects will be enrolled. In the Phase 3 segment, approximately 6714 seronegative 
subjects are expected to be enrolled, and 402 seropositive subjects will be enrolled. The 
subjects and data from Phase 2 are independent from that of Phase 3.  The primary 
objectives of this trial are to identify in seronegative subjects an optimal age-related dose 
(Phase 2 segment) for subsequent evaluation for efficacy (Phase 3 segment).  
 
Phase 2 Segment – Dose Selection 
 
In the Phase 2 segment, approximately 400 subjects 18 years of age and older will be 
evaluated across four (4) dose groups (Table 1, Figure 1). Subjects will be randomized 
at a 3:3:1:1 ratio to receive either 1.0 mg or 2.0 mg of active investigational product (INO-
4800) or 1 or 2 injections of placebo (SSC-0001). Dose groups receiving INO-4800 will 
enroll approximately 150 subjects per group. Dose groups receiving placebo will enroll 
approximately 50 subjects per group. Randomization will be such that approximately 240 
subjects aged 18-50 years, 120 subjects aged 51-64 years and 40 subjects aged ≥ 65 
years will be enrolled. Initial enrollment will include subjects aged 18-50 years. Initiation 
of enrollment of older subjects 51-64 years of age and elderly subjects 65 years and older 
will depend on review of safety and immunogenicity data from those age groups 
generated in the Phase 1 study (COVID19-001). 
 
Dose selection for evaluation of efficacy in the Phase 3 segment will be based on Week 
6 immunogenicity data and Week 8 safety data from the Phase 2 segment. Group-level 
unblinded summaries and analyses of safety will be produced once the Week 8 phone 
call visit data are completed for all subjects in the Phase 2 segment. Group-level 
unblinded summaries and analyses of immunogenicity will be produced once the Week 
6 visit data are completed for all subjects in the Phase 2 segment. 
 
Phase 3 Segment – Efficacy 
In the Phase 3 segment, approximately 6714 seronegative and 402 seropositive subjects 
18 years of age and older will be randomized at a 2:1 ratio to receive either active 
investigational product (INO-4800, 2.0mg) or placebo (SSC-0001).  Approximately half of 
seronegative subjects and approximately half of seropositive subjects will be 18-50 years 
of age, and the other half will be ≥ 51 years of age as is operationally feasible. Also, 
approximately 711 subjects will be ≥65 years of age, if operationally feasible. 
Subjects will be randomized in a stratified manner according to (a) age category (18-50 
years vs. ≥51 years) on Day 0, and (b) presence of or absence on Day 0 of any of the 
following underlying medical conditions that increase risk of severe COVID-19 disease, 
per CDC criteria [1], as listed below: 
• 
Cancer 
• 
Chronic kidney disease 
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• 
Chronic lung diseases, including Chronic obstructive pulmonary disease (COPD), 
asthma (moderate-to-severe), interstitial lung disease, cystic fibrosis, pulmonary 
hypertension 
• 
Neurologic conditions including stroke or cerebrovascular disease, that do not impact 
cognition 
• 
Diabetes (type 1 or type 2) 
• 
Hypertension 
• 
Heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies 
• 
HIV infection (CD4 count >200 cells/mm3 or undetectable viral load) 
• 
Liver disease 
• 
Obesity (BMI ≥ 30 kg/m2) 
• 
Sickle cell disease or thalassemia, or 
• 
Smoking (current or former smoker). 
This segment of the trial is case-driven. Among seronegative subjects, a total of 149 
observed cases will be required for 90% power to declare the vaccine efficacious (>30%), 
assuming a true efficacy of 60%. A sample size of 6714 seronegative subjects is expected 
to be required to achieve the 149 cases assuming an underlying attack rate of 3.7%. The 
actual sample size may differ if the observed attack rate is different than projected.  There 
are two formal interim analyses of efficacy; one when 50% of the cases accrue and one 
when 75% of the cases accrue. If the prespecified criteria for efficacy are met at either 
interim analysis, then enrollment will continue until 4500 subjects have been enrolled, 
and blinded follow-up will continue until at least those 4500 subjects have a minimum of 
6 months of safety follow-up. At that point, the trial would be unblinded and placebo-
recipients will be offered the active product.    
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12 
months post-dose 2. All Phase 3 segment subjects will be followed for 56 weeks from the 
Day 0 dosing [i.e., Week 56 will be the planned End of Study (EOS) visit for this segment 
of the trial]. 
 
External Committee Reviews 
 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will 
convene regularly to review all available unblinded safety data, and additionally upon 
completion of the Week 8 phone call visit for all subjects enrolled during the Phase 2 
segment. For the Phase 3 segment, the DSMB will also review efficacy in an unblinded 
fashion. Additionally, for Phase 3, an independent, blinded Endpoint Adjudication 
Committee (EAC) will review and confirm COVID-19 cases. 
 
Details of each committee’s scope will be provided in the respective charters. 
 
PRIMARY OBJECTIVES 
See Table 6. 
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PRIMARY ENDPOINTS 
Table 6: Primary Objectives and Associated Endpoints 
Phase 2 Primary Objective 
Phase 2 Primary Endpoints 
1.  Evaluate the cellular and humoral 
immune response to INO-4800 
administered by ID injection followed 
immediately by EP  
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot assay 
1b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay 
Phase 3 Primary Objective 
Phase 3 Associated Primary Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease 
in subjects who are SARS-CoV-2 
negative at baseline  
1.   Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 
(End of Study (EOS)) in subjects who are SARS-
CoV-2 seronegative at baseline  
 
SECONDARY OBJECTIVES 
See Table 7. 
 
SECONDARY ENDPOINTS 
Table 7: Secondary Objectives and Associated Endpoints 
Phase 2 Secondary Objectives 
Phase 2 Secondary Endpoints 
1.  Evaluate the safety and tolerability of 
INO-4800 administered by ID 
injection followed immediately by EP  
 
1a. Incidence of solicited and unsolicited injection 
site reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
 1d. Incidence of adverse events of special interest 
(AESIs)   
Phase 3 Secondary Objectives 
Phase 3 Secondary Endpoints 
1. Evaluate the safety and tolerability 
of INO-4800    
 
1a. Incidence of solicited and unsolicited injection 
site reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality  
2. Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of disease 
severity in subjects who are SARS-
CoV-2 seronegative at baseline    
2a.  Incidence of non-severe COVID-19 disease in 
SARS-CoV-2 seronegative subjects starting 14 
days after completion of the 2-dose regimen until 
EOS  
2b. Incidence of severe COVID-19 disease in SARS-
CoV-2 seronegative subjects starting 14 days 
after completion of the 2-dose regimen until EOS 
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2c. Incidence of deaths due to COVID-19 in SARS-
CoV-2 seronegative subjects starting 14 days 
after completion of the 2-dose regimen until EOS 
3.   Evaluate the cellular and humoral 
immune response to INO-4800  
3a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot  
3b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
4. Evaluate the efficacy of INO-4800 
in the prevention of COVID-19 
disease in subjects who are SARS-
CoV-2 seropositive at baseline  
 
4.  Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 
(End of Study (EOS)) in subjects who are SARS-
CoV-2 seropositive at baseline 
 
EXPLORATORY OBJECTIVE 
See Table 8. 
 
EXPLORATORY ENDPOINTS 
Table 8: Exploratory Objectives and Associated Endpoints 
Phase 2 Exploratory Objective 
Phase 2 Exploratory Endpoints 
1.  Evaluate the expanded 
immunological profile of antibody 
response and T cell immune 
response 
1a.  Antigen-specific cellular immune response 
measured by flow cytometry. 
1b. Expanded immunological profile which may 
include additional assessments of T and B cell 
numbers and molecular changes by measuring 
immunologic proteins and mRNA levels of genes 
of interest as determined by sample availability 
Phase 3 Exploratory Objective 
Phase 3 Exploratory Endpoints 
1. Evaluate the efficacy of INO-4800 
in the prevention of COVID-19 
disease from SARS-CoV-2 variants 
in subjects who are SARS-CoV-2 
seronegative at baseline 
1. Incidence of virologically-confirmed COVID-19 
disease from a SARS-CoV-2 variant starting 14 
days after completion of the 2-dose regimen until 
12 months post-dose 2 (End of Study (EOS)) in 
subjects who are SARS-CoV-2 seronegative at 
baseline 
2. Evaluate the efficacy of INO-4800 
in the prevention of SARS-CoV-2 
asymptomatic infection in subjects 
who are SARS-CoV-2 seronegative 
at baseline     
2. Incidence of SARS-CoV-2 asymptomatic 
infections in SARS-CoV-2 seronegative subjects 
starting 14 days after completion of the 2-dose 
regimen until EOS 
3. Evaluate the immunological profile 
by assessing both antibody 
response and T cell immune 
response  
3a.  SARS-CoV-2 Spike glycoprotein antigen-
specific binding antibody levels  
3b.  Antigen-specific cellular immune response 
measured by flow cytometry  
4. Evaluate antibody persistence  
4a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels at Week 30 or later.  
4b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay at Week 
30 or later 
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EFFICACY ASSESSMENT (PHASE 3 SEGMENT ONLY) 
Subjects will receive either active investigational product (INO-4800, dose selected from 
the Phase 2 segment) or placebo (SSC-0001) in a 2-dose regimen administered 
intradermally followed immediately by EP on Days 0 and 28. Subjects will be monitored 
through regularly scheduled clinic visits and phone calls throughout the trial. Subjects will 
be regularly tested for SARS-CoV-2 infection using serologic testing. If COVID-19 disease 
is suspected based on symptoms or laboratory testing, site personnel will arrange for a 
clinic visit. Subjects with symptom(s) or a positive SARS-CoV-2 test result will be reviewed 
by the independent blinded EAC.  
The mechanism for review and confirmation of cases will be outlined in an EAC Charter.  
 CASE DEFINITION FOR VIROLOGICALLY-CONFIRMED COVID-19 DISEASE: 
•  Positive testing by SARS-CoV-2 RT-PCR assay (performed at central lab*) 
with fever (temperature of 100.4ºF/38.0ºC or higher), or  
• 
Positive testing by SARS-CoV-2 RT-PCR assay (performed at central lab*) 
with any of the following COVID-19 related symptoms: 
• 
Feeling feverish or chills  
• 
Cough  
• 
Shortness of breath or difficulty breathing  
• 
Fatigue  
• 
Muscle or body aches  
• 
Headache  
• 
New loss of taste or smell  
• 
Sore throat  
• 
Congestion or runny nose  
• 
Nausea or vomiting  
• 
Diarrhea  
*Local lab results will be accepted if the subject is hospitalized and a sample is 
not able to be obtained for analysis at central lab. 
3.7.1.1 Case Definition for Severe COVID-19 
• Confirmed COVID-19 disease (per Section 3.7.1) with any of the following:  
a. Clinical signs at rest indicative of severe systemic illness (respiratory 
rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room 
air at sea level or PaO2/FiO2 < 300 mm Hg),  
b. Respiratory failure (defined as needing high-flow oxygen, noninvasive 
ventilation, mechanical ventilation or ECMO),  
c. Evidence of shock (SBP < 90 mm Hg, DBP < 60 mm Hg, or requiring 
vasopressors),  
d. Significant acute renal, hepatic, or neurologic dysfunction,  
e. Admission to an ICU, or  
f. Death.  
3.7.1.2 Case Definition for Non-Severe COVID-19  
• Confirmed COVID-19 disease (per Section 3.7.1);   
• Does not meet the case definition of Severe COVID-19 disease (Section 
3.7.1.1) 
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 CASE DEFINITION FOR SARS-COV-2 ASYMPTOMATIC INFECTION  
Positive testing by SARS-CoV-2 serologic assay (performed at central lab);  
• Without clinical signs or symptoms of COVID-19 disease since the previous 
negative serologic test.  
 
SAFETY ASSESSMENT 
Subjects will be followed for safety during the trial through scheduled clinic visits and 
phone calls. AEs, regardless of relationship to study drug, will be collected from the time 
of consent until 28 days post-dose 2 (i.e., Day 56). SAEs, MAAEs and AESIs will be 
collected from time of consent until EOS. SAEs, AESIs, and treatment-related AEs will be 
followed to resolution or stabilization. For the Phase 2 segment and at selected sites in 
the Phase 3 segment, solicited local and systemic AEs will be collected for 7 days following 
each dose using a participant diary. 
Subjects will also be monitored for COVID-19 disease. 
Please refer to the Schedule of Events (Table 3 and Table 4) for safety assessments to 
be performed.   
 
IMMUNOGENICITY ASSESSMENT 
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 3 and Table 4). Assays such as binding ELISA, pseudovirus-based neutralization 
assay, and ELISpot will be evaluated at serial timepoints. 
 
CLINICAL TRIAL POPULATION 
 
INCLUSION CRITERIA 
 PHASE 2 SEGMENT 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, vital signs and 
physical examination performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar workers, 
store cashiers, hairdressers and barbers, veterinary staff, daycare workers, 
Transportation Security Administration screening staff, school teachers and 
college professors teaching in-person classes) 
2. Factory workers (when working in confined settings with large numbers of 
employees) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) 
4. User of public transportation (e.g., bus, train, subway) at least 3 times weekly 
5. Nursing home staff or correctional facility staff  
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
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7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol. Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field) 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists.) Physicians should not be enrolled unless they are 
assigned to dedicated COVID-19 treatment wards or other settings with prolonged 
exposure) 
10. Others, if approved by the medical monitor;   
f. Screening laboratory results within normal limits for testing laboratory or are deemed 
not clinically significant by the Investigator; 
g. Must meet one of the following criteria with respect to reproductive capacity: 
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or tubal 
ligation, absence of ovaries and/or uterus in females). In the case of vasectomy, 
subjects should wait six (6) months post-vasectomy prior to enrolling;  
• 
Use of medically effective contraception with a failure rate of < 1% per year when 
used consistently and correctly from screening until 3 months following last dose. 
Acceptable methods include:  
o hormonal contraception including implants, injections or oral; 
o two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
o intrauterine device or intrauterine system; 
o abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 PHASE 3 SEGMENT 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Per investigator judgment, healthy or stable with pre-existing medical conditions that 
do not require significant change in medication or have led to a hospitalization in the 
3 months prior to enrollment or who, in the judgment of the investigator, are unlikely 
to require a significant change in therapy or hospitalization for worsening disease 
through Day 56;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings. 
Examples include:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar workers, 
street vendors, store cashiers, hairdressers and barbers, veterinary staff, daycare 
workers, airport screening staff, school teachers and college professors teaching 
in-person classes, college students attending in-person classes, office workers 
and volunteers who have multiple brief exposures to people regularly) 
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2. Factory workers (when working in confined settings with large numbers of 
employees, meat-packing facilities) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) and delivery 
services  
4. User of public transportation (e.g., bus, train, subway) or public facilities (e.g. 
gyms) at least 3 times weekly 
5. Nursing home staff or correctional facility staff 
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, medical assistants and technicians, respiratory therapists, 
physical therapists, social workers, dentists and dental hygienists)  
10. Others, if in the opinion of the PI, the risk of COVID-19 exposure is comparable 
to the examples above. 
f. Must meet one of the following criteria with respect to reproductive capacity: 
1. Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
2. Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or tubal 
ligation, absence of ovaries and/or uterus in females). In the case of vasectomy, 
subjects should wait six (6) months post-vasectomy prior to enrolling;  
3. Use of medically effective contraception with a failure rate of < 1% per year when 
used consistently and correctly from screening until last dose. Acceptable 
methods include:  
i. hormonal contraception including implants, injections or oral; 
ii. two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
iii. intrauterine device or intrauterine system; 
iv. abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 
EXCLUSION CRITERIA 
 PHASE 2 SEGMENT 
a. Acute febrile illness with temperature > 100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat);  
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the Screening visit until 
3 months following the last dose; 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or 
a detectable viral load within the past 3 months; 
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f. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0 (documented receipt of placebo in a previous trial 
would be permissible for trial eligibility); 
g. Previous receipt of an investigational vaccine for prevention or treatment of COVID-
19, MERS or SARS (documented receipt of placebo in previous trial would be 
permissible for trial eligibility). 
h. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg prior to first dose; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin cancers 
that only required local excision and non-metastatic prostate cancer not requiring 
treatment; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in therapy 
or hospitalization for worsening disease during the 6 weeks prior to enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a single 
antiepileptic agent; 
i. 
Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed) in the prior 6 months; 
• 
Current or anticipated use of disease modifying doses of systemic anti-rheumatic 
drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and 
biologic disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, 
adalimumab or etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the subject 
or require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
j. 
Lack of acceptable sites for ID injection and EP considering the skin above the 
deltoid and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
ICD or pacemaker (to prevent a life-threatening arrhythmia) that is located 
ipsilateral to the deltoid injection site (unless deemed acceptable by a 
cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation site; 
k. Blood donation or transfusion within 1 month prior to Day 0; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the prior 2 years; 
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n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
 PHASE 3 SEGMENT 
a. Acute febrile illness with temperature ≥100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat) on 
Day 0 prior to dosing; 
b. Positive serologic test for SARS-CoV-2 at Screening (after approximately 402 
subjects positive for SARS-CoV-2 serologic test are randomized, this criterion will 
apply to all remaining subjects); 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children starting from the Screening visit until the last dose; 
d. Positive urine pregnancy test during screening or  immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or 
a detectable viral load within 3 months prior to screening; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days prior to Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous or planned receipt of an investigational (including Emergency Use 
Authorization (EUA) or local equivalent authorization) or licensed vaccine for 
prevention or treatment of COVID-19, MERS or SARS (documented receipt of 
placebo in previous trial would be permissible for trial eligibility); 
h. Immunosuppression as a result of underlying illness or treatment including: 
 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed) in the past 6 months; 
• 
Current or anticipated use of disease modifying doses of systemic anti-rheumatic 
drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and 
biologic disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, 
adalimumab or etanercept) or others; 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the subject 
or require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
i. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation site; 
j. 
Blood donation or transfusion within 1 month prior to Day 0; 
k. People who work remotely or in a socially distanced setting with minimal risk of 
exposure to SARS-CoV-2; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
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m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the prior 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
 
DISCONTINUATION/WITHDRAWAL OF CLINICAL TRIAL SUBJECTS 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the Investigator should any untoward effect occur. In addition, the 
Investigator or the Sponsor has the right to discontinue a subject from the trial at any time. 
The Investigator must notify the Sponsor immediately when a subject has been 
discontinued/withdrawn due to an Adverse Event (AE). If a subject withdraws from the trial 
or is discontinued from the trial prior to trial completion, all applicable activities scheduled 
for the final trial visit (i.e., Day 393) should be performed at the time of 
discontinuation/withdrawal if the subject agrees. Any related AEs, AESIs, and/or Serious 
Adverse Events (SAEs) present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.9. 
Unless a subject refuses to continue participation, all follow-up visits and procedures 
should be completed as indicated in the Schedule of Events (Table 3 and Table 4) 
following the second dose whether or not the subject has completed both doses. 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. In cases where 
the subject does not return for the rescheduled visit or cannot be reached to reschedule 
the missed visit, the site should make every effort to regain contact with the subject (3 
telephone calls and if that fails, then a certified letter to the subject’s last known mailing 
address) so that the subject’s disposition can be considered as withdrawn from the study 
(i.e. lost to follow-up). If the contact with subject is re-established, site should contact 
medical monitor to discuss whether subject can continue study treatment or follow-up 
visits for the study. For all other subjects withdrawing from the study, an alternative reason 
for discontinuation should be recorded in the eCRF. 
Reasons for discontinuation/withdrawal from the trial may include but are not limited to the 
following: 
• 
Subject withdrawal of consent at any time; 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardize the 
subject’s safety if he or she continues in the trial; 
• 
Investigator, DSMB or Sponsor determines it is in the best interest of the subject; 
• 
Subject non-compliance. 
Every effort should be made to obtain information on subjects who withdraw from the trial. 
The primary reason for withdrawal from the trial should be documented on the appropriate 
CRF. However, subjects will not be followed for any reason after consent has been 
withdrawn. Data and/or samples collected prior to withdrawal of consent will be analyzed.  
Reasons for discontinuing subject dosing may include but are not limited to the following: 
• 
Adverse Event (Adverse Reaction); 
• 
The Investigator or trial coordinator must notify the Sponsor immediately when a 
subject has been discontinued/withdrawn due to an Adverse Event (AE). 
• 
Any medical condition that may jeopardize the subject’s safety if he or she continues 
on trial; 
• 
Pregnancy. 
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CLINICAL TRIAL INVESTIGATIONAL PRODUCT INFORMATION 
 
INVESTIGATIONAL PRODUCT (IP) AND STUDY DEVICE 
 INO-4800 AND PLACEBO 
Investigational product is defined as a pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in the study, whether blinded or unblinded. 
INO-4800 is the active investigational product to be used in this study. The INO-4800 drug 
product contains 10 mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM 
sodium chloride and 15 mM sodium citrate). pGX9501 is a DNA plasmid expressing a 
synthetic consensus (SynCon®) sequence of the SARS-CoV-2 full length Spike 
glycoprotein. 
Phase 2 segment: 
Active Investigational Product (INO-4800): A volume of 0.4 mL will be filled into 2-mL glass 
vials that are fitted with rubber stoppers and sealed aluminum caps. 
Placebo (SSC-0001): Sterile saline sodium citrate (SSC) buffer, which contains sterile 150 
mM sodium chloride and 15 mM sodium citrate in 10-mL glass vials, stoppered, and 
sealed with aluminum caps. 
Phase 3 segment: 
Active Investigational Product (INO-4800): A volume of 0. mL or 0.8 mL will be filled into 
2-mL glass vials that are fitted with rubber stoppers and sealed aluminum caps. 
Placebo (SSC-0001): Sterile saline sodium citrate (SSC) buffer, which contains sterile 150 
mM sodium chloride and 15 mM sodium citrate at a volume of 0.8 mL in 2-mL glass vials, 
stoppered, and sealed with aluminum caps. 
 CELLECTRA® 2000 
Electroporation is a procedure used to enhance cellular DNA uptake within host cells 
following DNA vaccine ID delivery. This study will use the CELLECTRA® 2000, a portable, 
battery-powered medical device designed to generate a controlled, electric field that 
temporarily and reversibly increases cellular membrane permeability without clinically 
damaging the tissue. During the period of increased permeability, injected plasmid DNA 
can be introduced into the cells. 
As mentioned above, the CELLECTRA® 2000 device is intended to enhance the uptake 
and expression of DNA plasmid-based biologics in order to enhance vaccine efficacy. The 
DNA plasmid is delivered separately via needle and syringe ID injection immediately prior 
to the electroporation. The electroporation is accomplished through a sterile, disposable 
needle Array attached to an Applicator delivering controlled electrical pulses as follows: 
• 
An EP administration consists of four pulses. 
• 
An array of three stainless steel electrode needles is used to deliver the electrical 
pulses into the tissue. The Array needle length that penetrates into the skin and 
tissue is approximately 3.2 mm. To date, we have not had any safety concerns 
associated with the depth of the array electrode needles. Within the Array needle 
depth of 3.2 mm, there are no major blood vessels (arteries, veins) or nerve 
structures at the authorized sites of administration overlying the deltoid or the 
anterolateral quadricep muscle. There are superficial capillaries and minor nerves 
innervating the skin, including subcutaneous tissues that may be disrupted by 
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needle insertion, but are extremely unlikely to result in serious injury; intradermal 
injection followed by EP of these structures poses no significant risk to the subject 
except for possibly injection site reactions. 
• 
The CELLECTRA® 2000 generates four 52ms ±1ms electrical current controlled 
DC pulses. The nominal current is set to 0.2A ±10% by modulating voltage, or 
capped at 200V ±5%, determined by patient tissue impedance. 
• 
The total energy delivered by the device is determined by the combination of four 
device parameters: Pulse Current, Pulse Voltage, Number of Pulses, and Pulse 
Width. The parameters are pre-set by Inovio to be a pulse current of 0.2A, a pulse 
voltage of 200V, and 4 pulses at 52ms pulse width. The parameters are verified 
prior to shipment and cannot be changed by the user.  
• 
In eight clinical trials administering ID injection followed by EP using the 
CELLECTRA® 2000, total energy delivered ranged from 0.9J to 7.8J, which have 
been generally safe and well-tolerated. In addition, Inovio has calculated the total 
maximum energy delivered ID as 8.32J for normal use conditions. Higher energy 
pulses ranging from 10.7J to 11.7J were evaluated in a guinea pig model which 
induced erythema localized to the electrode insertion site. Taken together, these 
nonclinical data and Inovio’s clinical experience provide evidence that the total 
energy delivered by the CELLECTRA® 2000 device will not result in 
unacceptable risks when delivered to patients. Further, a published study 
evaluated the Visual Analog Scale (VAS) pain scores of normal use conditions 
(0.2A), and found ID injection followed by EP using  the CELLECTRA® 2000 
device to be safe and well tolerated [63]. 
• 
The specified current is constantly maintained through voltage modulation using 
an analog feedback loop. Measurements of voltage and current are processed for 
error reporting and collected for data logging. 
The CELLECTRA® 2000 device is comprised of three components: (1) A battery-powered 
Pulse Generator, (2) an ID Applicator that is connected to the pulse generator, and (3) a 
three-point sterile disposable ID Array of stainless steel needles. The Pulse Generator 
and ID Applicator are reusable components. These components should be cleaned and 
disinfected prior to each subject’s use according to the Cleaning and Maintenance 
procedure in the User Manual. The Pulse Generator and ID Applicator have been 
validated for up to 30 cleaning and disinfection cycles based on a maximum of 30 subjects 
being treated in a day. Therefore, the Pulse Generator and ID Applicator’s use should be 
limited to 30 subjects in a day. Any potential risk of damage to the device due to cleaning 
and disinfection for more than 30 cycles has not been validated. Always inspect the device 
before use according to the instructions in the Maintenance section of the User Manual. 
 
DOSING REGIMENS 
Phase 2 Segment 
• 
Active Investigational Product: One or two 1.0mg ID injection(s) of INO-4800 (~0.1mL 
dose volume each) followed immediately by EP administered on Day 0 and Day 28 
(±3 days) 
• 
Placebo: One or two ID injection(s) of SSC-0001 (~0.1mL) followed immediately by 
EP administered on Day 0 and Day 28 (±3 days) 
Phase 3 Segment 
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• 
Active Investigational Product: Two 1.0mg ID injections of INO-4800 (~0.1mL dose 
volume) followed immediately by EP administered in separate limbs on Day 0 and Day 
28 (±3 days) 
• 
Placebo: Two ID injections of SSC-0001 (~0.1mL) followed immediately by EP 
administered in separate limbs on Day 0 and Day 28 (±3 days) 
 BLINDING 
This study is blinded. The Sponsor, subjects and clinical site staff, with the exception of 
the site’s pharmacy personnel, will be blinded throughout the trial. There is no difference 
in appearance between INO-4800 and the placebo; however, they are distinguishable 
based on the vial size and/or labelling on the vials. In the Phase 2 segment, the vials will 
be of different sizes and have unblinded labelling. In the Phase 3 segment, the vials will 
be the same size but will have unblinded labelling. To maintain the blind, vials will only be 
handled by designated unblinded personnel (site pharmacist) at the site. 
Under exceptional circumstances, the PI may desire to unblind a subject’s dose 
assignment in case of an emergency or serious medical condition when knowledge of the 
study product or dose is deemed by the PI to be absolutely essential for proper clinical 
management of the subject. Under such emergency circumstances, the Sponsor urges 
the PI to first contact the Medical Monitor (MM) to review options before unblinding the 
subject’s dose assignment. In case of non-emergency, PI must contact MM to discuss the 
options before unblinding the subject’s dose assignment.  
It is not deemed appropriate to unblind a subject’s treatment assignment for the purpose 
of assisting the subject in making a decision regarding receipt a different COVID-19 
vaccine (emergency use or licensed vaccine).  Subjects should be advised that without 
efficacy data, INO-4800 has not been proven to be more protective than placebo in the 
prevention of COVID-19 and SARS-CoV-2 infection. Therefore, unblinding will not provide 
any meaningful information to inform a decision of receiving a different COVID-19 vaccine. 
The Sponsor’s pharmacovigilance staff may unblind a subject’s dose assignment for an 
SAE, unanticipated adverse device effect (UADE), or adverse event of special interest 
(AESI) when the event is assessed as related and unexpected. If expedited regulatory 
reporting is required for such an event, the report may be submitted to regulatory 
authorities with the subject’s dose assignment, in accordance with local regulations. 
 
PACKAGING AND LABELING 
 INO-4800 OR PLACEBO 
Each vial of INO-4800 or placebo will be labeled consistent with the example product label 
provided in the IB.  
 CELLECTRA® 2000 
Please see shipping box for shipping documents and contents. 
The CELLECTRA® 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer. The CELLECTRA® 2000 User Manual 
describes all relevant contraindications, hazards, potential risks and adverse effects, 
interfering substances or devices, warnings, and precautions. Each Pulse Generator has 
a unique serial number, and each ID Applicator has a unique serial number. Each ID Array 
has a Lot Number and Expiration Date. Examples of device labels are provided in the IB. 
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The CELLECTRA® 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. 
 
HANDLING AND STORAGE 
 INO-4800 AND PLACEBO 
INO-4800 and Placebo will be shipped at 2–8°C. If the temperature monitoring devices in 
the shipping container(s) denote temperatures outside this 2–8°C (36-46°F) range, the 
Sponsor, or its designee, should be contacted immediately. 
Upon arrival, the INO-4800 and placebo must be transferred from the shipping container 
into 2–8°C (36-46°F) storage, in a secure area, in accordance with local regulations by 
designated personnel (e.g., pharmacy personnel). The Sponsor must be notified of any 
deviations from this storage condition. Refrigerator temperature logs must be maintained 
at the clinical site and temperatures must be recorded and monitored regularly. For further 
details see Pharmacy Manual and IB. 
 CELLECTRA® 2000 
See User Manual for operating and storage conditions. 
 
PREPARATION AND DISPENSING 
In the Phase 2 segment, INO-4800 is supplied in 2-mL vials at a concentration of 10 
mg/mL at a minimum volume of 0.4 mL. SSC-0001 is supplied in 10-mL vials at a minimum 
volume of 2 mL.  
In the Phase 3 segment, INO-4800 is supplied in 2-mL vials at a concentration of 10 
mg/mL at a minimum volume of 0.4 or 0.8 mL.  SSC-0001 is supplied in 2-mL vials at a 
minimum volume of 0.8 mL. 
Blinded staff involved in the clinical execution of the study should not come in contact with 
vials of INO-4800 or SSC-0001. Vials will only be handled by designated unblinded 
personnel (e.g., pharmacy) at the site. When a subject is eligible for enrollment, unblinded 
personnel will draw INO-4800 or SSC-0001 into a blinded syringe in accordance with the 
subject’s randomized treatment assignment according to a randomization schedule. The 
syringe will be transferred to blinded site personnel for administration.  
Each INO-4800 and placebo vial will contain a volume of product sufficient to dose multiple 
subjects. The preparation and dispensing information will be provided in the Pharmacy 
Manual. 
 
USE OF STUDY DEVICE 
The instructions for use of the CELLECTRA® 2000 device are provided in the User 
Manual. Each clinical site will receive training for use of the CELLECTRA® 2000 device 
prior to first dose. The EP procedure must be performed by qualified personnel. Any 
individual designated to perform the procedure should be permitted by the relevant local 
authorities to administer parenteral injections to patients (e.g., MD, DO, RN) in addition to 
successfully completing device training provided by Sponsor personnel.  
 
INVESTIGATIONAL DRUG AND STUDY DEVICE ACCOUNTABILITY 
 INVESTIGATIONAL PRODUCT (IP) ACCOUNTABILITY 
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It is the responsibility of the Investigator to ensure that a current accountability record of 
investigational products (INO-4800 or placebo) is maintained at the study site. The 
investigational products must have full traceability from the receipt of the products through 
subject use, disposal or return of the products. Records or logs must comply with 
applicable regulations and guidelines. The accountability information is provided in the 
Pharmacy Manual. 
 CELLECTRA® 2000 ACCOUNTABILITY 
The investigational site is responsible for maintaining device accountability logs. The 
device must have full traceability from the receipt of the products through subject use, 
disposal or return of the products. The site must document acknowledgement of receipt 
and notify Inovio upon receipt of study devices. This includes the content shipped and 
condition upon receipt. 
For each subject administration, there must be a record of each product used for that 
subject, i.e., Pulse Generator serial number, ID Applicator serial number, and ID Array lot 
number. The ID Applicator is reusable with a new ID Array and sheath for each procedure. 
The sterile ID Array and sheath are single use only and must be discarded after use in 
accordance with institutional policy regarding disposal of sharp needles/instruments. 
 
RETURN AND DESTRUCTION OF INVESTIGATIONAL DRUG AND STUDY DEVICE 
 INO-4800 AND PLACEBO 
Upon completion or termination of the study, all unused vials of INO-4800 or placebo must 
be destroyed at the study site in accordance with institution policy or returned to Inovio 
Pharmaceuticals, Inc., or its designee if the site cannot destroy IP. 
The used vials of INO-4800 and placebo will be discarded in accordance with the site’s 
used IP disposal procedure. It is the Investigator’s responsibility to arrange for disposal of 
all empty vials, provided that procedures for proper disposal have been established in 
accordance with applicable national, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. If requested by the Sponsor, the 
return of unused IP vials should be arranged by the responsible Inovio Representative. 
The unused IP vials should only be destroyed after being inspected and reconciled by the 
responsible Inovio Pharmaceuticals, Inc., personnel or designated Clinical Monitor. If IP 
vials are returned to Inovio Pharmaceuticals, Inc., or its designee, the IP must be 
accompanied by the appropriate documentation. The return of unused IP(s) should be 
arranged with the responsible Inovio personnel and/or Clinical Monitor. 
 RETURN OF CELLECTRA® 2000 
Upon completion or termination of the study, an Inovio Representative will provide 
instructions regarding the component(s) to be returned to Inovio Pharmaceuticals, Inc., 
destroyed onsite or shipped to a destruction vendor. 
All products returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original containers. 
The return of all products identified above should be arranged by the Inovio 
Representative. The ID Arrays should be discarded in the sharps container immediately 
after use. The used ID Applicators can either be destroyed at the site, shipped to a 
destruction vendor, or returned to Inovio. If the used ID Applicators are destroyed on site, 
it is the Investigator’s responsibility to ensure that arrangements have been made for the 
disposal, written authorization has been granted by Inovio Pharmaceuticals, Inc., or its 
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designee, procedures for proper disposal have been established in accordance with 
applicable regulation and guidelines and institutional procedures, and appropriate records 
of the disposal have been documented. 
 
CLINICAL TRIAL PROCEDURES AND SCHEDULE 
The Schedule of Events (36TTables 3 and 436T) in the Clinical Protocol Synopsis summarizes 
the procedures to be performed at each visit. Individual procedures are described in detail 
below. It may be necessary to perform these procedures at unscheduled time points if 
deemed clinically necessary by the Investigator. A subject will be required to provide 
informed consent (Section 6.2) prior to any study procedure being performed. Protocol 
waivers or exemptions will not be granted. Therefore, adherence to the study design and 
assessments are essential and required for study conduct. 
 
PROCEDURE BY VISIT 
Refer to Sections 6.1.1 and 6.1.2 for trial procedures and the times at which they are to 
be performed. 
 CLINICAL TRIAL SCREENING EVALUATIONS 
The assessments performed during Screening will determine the subject’s eligibility for 
the study and also their ability to comply with protocol requirements by completing all 
screening assessments. The following screening evaluations will be performed for both 
Phase 2 and Phase 3 segments within 30 days prior to dosing on Day 0. All screening 
assessment values must be reviewed prior to the first Study IP administration. Screening 
and Day 0 visits may be on the same day if eligibility is able to be confirmed prior to 
randomization. If so, all assessments for Screening and Day 0 must be performed at the 
combined visit. 
If a subject does not meet an inclusion or exclusion criterion due to a transient and non-
clinically significant event at Screening, relevant Screening evaluations may be repeated 
within the same 30-day Screening period. If the subject fails twice, they will be considered 
a screen failure. 
• 
Signed and dated informed consent (Section 6.2); 
• 
Review and confirm all inclusion/exclusion criteria (Section 4.1 and 4.2); 
• 
Obtain and document complete medical history, surgical history (including all 
clinically significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Section 6.1.1.1); 
• 
Collect demographics; 
• 
Collect socio-behavioral assessment information (Section 6.4); 
• 
Collect AEs (Section 6.4.4); 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Record height and weight (Section 6.4); 
• 
Collect urine for pregnancy test (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8).  
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
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• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.8). 
 
6.1.1.1 
Medical History 
A medical history will be obtained by the Investigator or qualified designee at the time of 
Screening. Medical history will include all active conditions, and any other past conditions, 
as well as surgical procedures, that are considered to be clinically significant by the 
Investigator and/or having occurred within 3 months prior to Screening. Subjects should 
be queried about any history of Hepatitis B, Hepatitis C and HIV.   
In the Phase 3 segment, subjects with a self-reported history of Hepatitis B or C must 
provide documentation of liver enzymes that are not significantly elevated within the past 
3 months. If such a report of liver enzyme testing is not available, this testing should be 
performed at Screening. Subjects with a history of Hepatitis C without cirrhosis who have 
completed treatment and have proof of an undetectable viral load at least 12 weeks 
following treatment may be enrolled and do not require liver enzymes within the past  
months. 
Subjects with self-reported HIV must provide documentation of controlled HIV infection 
based on a CD4 count greater than 200 cells/mm3 or an undetectable viral load within the 
past 3 months. If a recent CD4 count and/or viral load is not available, this testing should 
be performed at Screening. 
Illnesses first occurring or detected after the signing of the informed consent, or during the 
study and/or worsening of an existing illness in severity, frequency or nature after signing 
of the informed consent are to be documented as AEs on the Case Report Forms (CRF). 
Prior treatments, defined as administered up to 12 weeks prior to the time of informed 
consent and stopped prior to dosing on Day 0, should be recorded in the CRF as prior 
medications. Concomitant treatments, defined as continuing on Day 0 or new treatments 
taken at or after Day 0, should be recorded in the CRF as concomitant medications. 
 CLINICAL TRIAL EVALUATIONS AND PROCEDURES 
Once eligibility has been confirmed, the subject will be randomized to receive a treatment 
assignment (INO-4800 or placebo). Visit dates and windows must be calculated from Day 
0, unless otherwise noted. All subjects will be followed until the Day 393 Visit. All subjects 
will be followed in accordance with assessments outlined below. 
6.1.2.1 
Day 0 and Day 28 (Dosing Visits) 
The following evaluations will be performed on Day 0 and Day 28 prior to dose 
administration: 
Both Phase 2 and Phase 3 segments: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Obtain any updates to medical history, surgical history (including all clinically 
significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Day 0 visit only) (Section 6.1.1.1); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect urine for urine pregnancy test (Section 6.4); 
• 
Collect blood for HIV serology (Day 0 visit only) (Section 6.4); 
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• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Day 0 visit only) (Phase 3 cellular immunology collection at selected sites only) 
(Section 6.5); 
• 
Review restrictions for injection and EP (Section 6.4.7); 
• 
Randomize subject (instructions to be provided under separate cover) (Day 0 visit 
only). 
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect diary from Day 0 dose (Day 28 visit only). 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8); 
• 
Collect nasopharyngeal swabs for SARS-CoV-2 RT-PCR (Day 0 only) (Section 
6.4.8); 
• 
Collect diary from Day 0 dose during Day 28 visit only(for selected sites only). 
 
The following evaluations will be performed on Day 0 and Day 28 after IP plus EP 
administration: 
• 
Collect any new AEs (Section 6.4.4); 
• 
Download EP Data; 
• 
Provide supplies for subject to use at home, as required (e.g. thermometer, wound 
guide); 
• 
Phase 2 segment: Distribute diary; 
• 
Phase 3 segment, for selected sites: Distribute diary. 
6.1.2.2 
Post-dose phone calls 
Phase 2 segment: Day 7 and Day 35 
Phase 3 segment: Day 14  
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
 
Phase 2 segment only: 
• 
Review diary (Section 6.4). 
 
Phase 3 segment only: 
• 
Review diary (for selected sites)(Section 6.4); 
6.1.2.3 
Day 42 Visit 
Both Phase 2 and Phase 3 segments: The following evaluations will be performed at this 
visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4);  
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Ask about any symptoms of COVID-19 disease; 
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• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 cellular immunology collection at selected sites only)(Section 6.5);  
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect diary from Day 28 visit. 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8); 
• 
Collect diary from Day 28 visit (for selected sites only); 
• 
Ensure subject has necessary supplies at home (e.g. thermometer). 
6.1.2.4 
Phone calls  
Phase 2 segment: Day 56 
Phase 3 segment: Days 56, 70, 84, 98, 112, 140, 154, 168, 182, 196, 238, 266, 322, 
350, and 378 
In the Phase 3 segment, phone calls to subjects have been spaced bi-weekly 
between study visits through Day 210, and approximately monthly between visits 
from Day 210 to Day 393.   
 
Guidelines for information to be collected during the phone call can be found in the 
Phone Script. The following evaluations will be performed during the phone call: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Ask about any symptoms of COVID-19 disease; Arrange on-site visit if any signs 
and symptoms of COVID-19 disease are present (Section 6.4.9); 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
6.1.2.5 
Follow up clinic visits 
Phase 2 segment: Day 210 
Phase 3 segment: Days 126, 210 and 294 Visits 
Both Phase 2 and Phase 3 segments: The following evaluations will be performed at these 
visits: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); SAEs, AESIs, and 
MAAEs will be reported after the Day 56 Visit. 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 Day 201 visit only; Phase 3 cellular immunology collection at selected 
sites only) (Section 6.5); 
 
Phase 3 segment: 
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• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8);  
• 
Ensure subject has necessary supplies at home (e.g. thermometer). 
6.1.2.6 
Day 393 Visit or EOS 
Phase 2 and Phase 3 segments: The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); SAEs, AESIs, and 
MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect urine pregnancy test (Section 6.4); 
 
Phase 2 segment: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6). 
 
Phase 3 segment: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 cellular immunology collection at selected sites only)(Section 6.5). 
6.1.2.7 
COVID-19 Assessment Visit 
For both the Phase 2 and Phase 3 segments of the study, subjects will be evaluated 
during a COVID-19 assessment visit when acute COVID-19 is suspected based on 
symptoms or positive SARS-CoV-2 testing. The assessment visit may be performed in 
the clinic, subject’s vehicle, or at a home visit and should be performed within 3 days of 
a positive SARS-CoV-2 test or site knowledge of COVID-19 symptom onset. The 
virologic-confirmation of a case will be based on SARS-CoV-2 RT-PCR testing from the 
central lab. A local RT-PCR result will be considered acceptable in the case where a 
subject is hospitalized and a sample for central lab analysis is not able to be obtained, if 
it was obtained using. an assay performed by a laboratory accredited according to 
standards set by a national or regional accreditation body.  
If a local lab is used to confirm the case, the report from the laboratory must be provided.  
Phase 2 and Phase 3 segments: The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); Only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Optional targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
 
Phase 2 only: 
• 
Collect nasal swabs and saliva for SARS-CoV-2 RT-PCR detection (Section 6.4.8). 
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Phase 3 only: 
• 
Collect whole blood and serum for cellular and humoral immunology assessment, 
where possible (Phase 3 cellular immunology collection at selected sites 
only)(Section 6.5) 
• 
Collect nasopharyngeal swabs for SARS-CoV-2 RT-PCR testing (Section 6.4.8). 
6.1.2.8 
COVID-19 Convalescent Visit 
Phase 2 and Phase 3 segments: For subjects with confirmed SARS-CoV-2 infection 
during the trial, a convalescent visit should be scheduled approximately 28 days after 
symptom onset, or in the absence of symptoms, after the collection date of a positive 
SARS-CoV-2 test. If symptoms are ongoing at 28 days after symptom onset, the site 
should follow up with the subject via phone call or unscheduled visit after symptom 
resolution or stabilization.  
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); Only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 cellular immunology collection at selected sites only) (Section 6.5); 
 
Phase 2 segment only: 
• 
Collect nasal swabs and saliva for SARS-CoV-2 RT-PCR detection (Section 6.4.8). 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8). 
 
INFORMED CONSENT 
All subjects must sign the informed consent prior to participating in any clinical trial-related 
procedures. The informed consent documentation must be in compliance with applicable 
regulations and GCP. Qualified clinical trial personnel will: 
• 
Meet with prospective clinical trial subjects; 
• 
Explain the clinical trial; 
• 
Provide clinical trial subjects with an Informed Consent Form (ICF) that includes the 
following in a language that is understandable to the subject: 
• 
Screening test(s) description; 
• 
Eligibility criteria for entering the clinical trial; 
• 
Clinical trial treatments and follow-up procedures description; 
• 
Explanation of the clinical trial, including but is not limited to: 
• 
Clinical trial objectives; 
• 
Potential benefits and risks; 
• 
Discomforts/inconveniences; 
• 
Subject’s rights and responsibilities. 
The subject is then requested to sign and date the ICF. A copy of the signed informed 
consent documentation must be provided to the subject. The qualified clinical trial 
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personnel will document the process of obtaining informed consent within the source 
record. Signed ICFs are maintained in the subject’s source records and must be 
accessible for verification at any time. Signing of the ICF begins the 30-day screening 
period. 
 
ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number (SID), 
which identifies the subject for all clinical trial-related procedures. SIDs are a combination 
of a site code and a subject number. After SIDs are assigned, they cannot be reused or 
reassigned for any reason. Information regarding the SID and screen date will be 
documented on a screening and enrollment log/system and in the CRF.   
Previously screen failed subjects may be rescreened provided there is a valid documented 
reason for rescreening (i.e. changes to the person’s health or situation that would make 
them possibly eligible at this later time). If rescreening occurs, the subject will keep their 
original Subject ID.  
 
SAFETY EVALUATIONS 
PHYSICAL AND TARGETED PHYSICAL EXAM  
A full physical examination will be conducted during Screening and at study 
discharge/EOS (e.g. Day 393). A targeted physical assessment will be performed at other 
visits as determined by the Investigator based on subject symptoms.  
VITAL SIGNS 
Vital signs including temperature, respiration rate, blood pressure and heart rate will be 
measured at Screening and at visits specified in the Schedule of Events (36TTables 3 and 
436T).  
At the COVID-19 assessment and convalescent visits, temperature, respiration rate, 
heart rate and oxygen saturation should be performed.   
HEIGHT AND WEIGHT 
Weight and height will be collected at Screening. 
SOCIO-BEHAVIORAL ASSESSMENT  
A Socio-behavioral Assessment, including self-reported smoking and vaping history, and 
self-reported history of exposure to second-hand smoke will be obtained at Screening. 
LABORATORY EVALUATIONS 
Blood samples will be collected at visits specified in the Schedule of Events (36TTables 3 and 
436T). A total of approximately mL 245-330mL of blood will be drawn from each subject over 
the course of the study (inclusive of relevant safety and immunology samples at regular 
study visits per Tables 3 and 4). If the subjects is evaluated at COVID-19 visits, an 
additional volume of approximately 85-120mL will be collected. Subjects may be asked to 
return for additional blood draws if collected blood sample is lost or unevaluable for any 
reason. 
Hematology [Complete blood count (CBC) with automated differential]: 
White blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit and 
platelet count will be measured at Screening (Phase 2 segment only) and at visits specified 
in the Schedule of Events (36TTables 3 and 436T). Hemoglobin A1c will additionally be performed 
at Screening (Phase 2 segment only). 
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Serum chemistry: 
Electrolytes [Sodium (Na), Potassium (K), Chloride (Cl), Bicarbonate (HCO3), Calcium 
(Ca), Phosphate (PO4)], glucose, Blood Urea Nitrogen (BUN), Creatinine (Cr),  alkaline 
phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), LDH,  
and total bilirubin (TBili) at Screening (Phase 2 segment only) and at visits specified in the 
Schedule of Events (36TTables 3 and 436T).  
Urinalysis:  
Urine samples will be tested by dipstick for glucose, protein, and hematuria at Screening 
(Phase 2 segment only) and at visits specified in the Schedule of Events (36TTables 3 and 
436T). If abnormal (presence of protein, hematuria, or glucose ≥ 1+), a microscopic 
examination should be performed.  
Serology: 
HIV antibody or rapid test will be measured at Day 0 only.  
Antibodies to SARS-CoV-2 will be measured at Screening and at visits specified in the 
Schedule of Events (Tables 3 and 4). 
Pregnancy Testing:  
Pregnancy testing will be performed on women of childbearing potential (WOCBP). All 
women will be assumed to be of childbearing potential unless they are:  
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Women who are surgically sterile or have a partner who is sterile (i.e., vasectomy 
in males or tubal ligation, absence of ovaries and/or uterus in females). In the 
case of a vasectomy, subjects should wait six (6) months post-vasectomy to be 
considered sterile. 
Phase 2: For WOCBP, a serum pregnancy test will be obtained at Screening and a urine 
pregnancy test will be performed immediately prior to any dosing and at the subject’s last 
visit.  
Phase 3: For WOCBP, a urine pregnancy test will be obtained at Screening and will be 
performed immediately prior to any dosing. 
A negative result for urine β-HCG (test must have a sensitivity of at least 25 mIU/mL) must 
be available prior to each administration of IP. If the β-HCG test is positive, indicating that 
the subject is pregnant prior to completing the specified dose regimen, then no further IP 
will be administered. Every attempt should be made to follow pregnant subjects for the 
remainder of the study and to determine the outcome of the pregnancy (see Section 7.12). 
DIARY 
Diaries will be implemented in the Phase 2 segment of the protocol and at selected sites 
(estimated to include 711 subjects) in the Phase 3 segment.  Subjects will be provided a 
diary to record the following solicited local and systemic AEs: 
• 
Oral temperature and time taken (each daily entry before 11:59 pm) 
• 
Solicited systemic symptoms 
• 
Solicited local injection site symptoms 
• 
Concomitant medications 
The diary should be completed once daily starting the evening of each study dose through 
6 days post-dose. The completed diary post-dose 1 and post-dose 2 will be reviewed with 
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the subject by the study staff during the next study phone call or visit and collected at the 
next in-person study visit. The study staff will review the diary with the subject to assess 
for temperature, solicited systemic symptoms (unusually tired/feeling unwell, muscle 
aches, headache, nausea, joint pain) and solicited injection site symptoms (pain, itching, 
redness, swelling, bruising). In addition, unsolicited symptoms and concomitant 
medications will be assessed.  
Any diary entry determined to meet the Common Terminology Criteria for Adverse Events 
version 5.0 (CTCAE) criteria for a Grade 1 or higher adverse event should be documented 
as an adverse event unless deemed part of the subject’s ongoing medical history. Injection 
site reactions should be graded per the Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, issued September 
2007 (See Section 6.4.5). If the diary entry does not meet the criteria of a Grade 1 or 
higher AE as per the relevant guidelines, Investigator clinical judgment can be used to 
determine whether the entry should be recorded as an AE and documented accordingly 
in the site’s source. For cases where the diary entry and final AE reporting (i.e. grading) 
do not agree, the reasoning should be recorded in the source documents. 
 INTRADERMAL INJECTION AND EP  
Phase 2 and Phase 3 segments: 
A complete administration procedure is defined as an ID injection (formation of a wheal) 
of IP followed by insertion of the ID Array needles (electrodes) through the skin and into 
the wheal followed by delivery of four electroporation pulses. This procedure is broadly 
described as administration because it involves more than the injection of a drug. 
Only if the deltoid area is not a suitable location for administration (see exclusion criterion 
‘j’), the ID injection can then be administered above the lateral quadriceps followed 
immediately by EP. IP must not be given within 2 cm of a tattoo, scar, keloid, or active 
lesion/rash. Also, ID injection followed immediately by EP must not be performed on the 
skin of an extremity which has any metal implants or implantable medical device (e.g., 
surgical rods, pins or joint replacements). If a subject has an implanted cardiac defibrillator 
or pacemaker, ID injection/EP must not be performed above the deltoid muscle on the 
same side of the body where the device is located. 
There are three steps that must be performed as part of the administration procedure: 
1. Injection of IP (INO-4800 or placebo) 
2. Insertion of the array into the subject’s skin 
3. Pressing the trigger button on the EP applicator  
Table 9 below is provided as guidance on how to appropriately complete the procedure 
when injection of IP has occurred, but the subject did not receive EP. 
Table 9: Guidance for how to manage an incomplete administration after IP has 
been injected 
Was IP 
injected? 
Was the array 
inserted into skin? 
Was trigger button 
pressed? 
Action 
Yes 
Yes (if array gets 
dislodged before 
the trigger button 
is pressed, the 
same array may 
be re-inserted) 
No 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
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Yes 
No 
Yes 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
Yes 
No 
No 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
 
Reinjection of IP (i.e. protocol-specified IP has already been delivered) is not permitted. 
Delivery of a second electroporation in tissue is not permitted. 
Training will be provided by the Sponsor on use of the device. 
Phase 2 segment: 
Subjects will receive a two-dose regimen of one or two 1.0 mg ID injections of INO-4800 
or placebo in a volume of ~0.1 mL in an acceptable skin location for injection and 
subsequently followed immediately by EP of each injection site with CELLECTRA® 2000 
at Day 0 and Day 28. For subjects assigned to receive two injections + EP at each dosing 
visit, the two injections must be performed in acceptable locations on two different limbs. 
Phase 3 segment: 
Subjects will receive a two-dose regimen of two 1.0 mg ID injections of INO-4800 or 
placebo in a volume of ~0.1 mL in an acceptable skin location for injection on different 
limbs and subsequently followed immediately by EP of the injection site with 
CELLECTRA® 2000 at Day 0 and Day 28. 
 MANAGEMENT OF PAIN DUE TO ELECTROPORATION (EP) PROCEDURES 
In case of pain, subjects may be treated with a non-narcotic analgesic (e.g., 
acetaminophen) after injection/EP.  
Medication taken for pain management will be documented as concomitant medications. 
 ASSESSMENT OF LABORATORY ABNORMALITIES 
In Phase 2, samples will be collected for serum chemistry, hematology, and urinalysis at 
the visits listed in the Schedule of Events (36TTables 3 and 436T) and as listed in Section 6.4.  
Laboratory AEs will be assessed and graded in accordance with the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. Laboratory values that are 
not clinically significant (NCS) in the Investigator’s opinion will not be reported as AEs. 
 ASSESSMENT OF CLINICAL TRIAL ADVERSE EVENTS (AES) 
Subjects will be queried regarding the occurrence of any AEs including AEs related to 
injection site reactions, concomitant medications and new onset illness or disease during 
their study visits and phone calls. Subjects will be reminded to contact study personnel 
and immediately report any event for the duration of the study. All AEs will be captured 
from the time of the informed consent until 28 days post-dose 2 (Day 56). Following the 
Day 56 visit, only SAEs, AESIs and MAAEs will be collected. All related AEs, AESIs and 
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SAEs will be followed to resolution or stabilization. These events will be recorded on the 
subject’s CRF. 
 ASSESSMENT OF INJECTION SITE REACTIONS  
Reactions arising from the IP administration procedure may be reported as administration 
site or injection site reactions. When evaluating administration (injection) site reactions 
throughout the study, it is most important to be as specific as possible by selecting the 
most appropriate term (see Table 10 below) and using the grading scale as listed in the 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, issued September 2007. All subjects will be observed for 30 
minutes following the IP administration procedure for immediate AEs.  In addition, other 
events associated with administration (injection) site reactions (e.g., hematoma, infection 
or necrosis) should also be reported with preferred terms specific for administration 
(injection) site reactions.  
Table 10: Grading Scale for Injection Site Reactions 
Local Reaction to 
Injectable Product 
(Grade) 
Mild (1) 
Moderate (2) 
Severe (3) 
Potentially 
Life 
Threatening 
(4) 
Pain 
Does not 
interfere with 
activity 
Repeated use 
of non-
narcotic pain 
reliever >24 
hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency 
room visit or 
hospitalization 
Tenderness 
Mild 
discomfort to 
touch 
Discomfort 
with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/Rednessa 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swellingb 
2.5-5 cm and 
no 
interference 
w/ activity 
5.1-10 cm or 
interferes with 
activity 
>10 cm or 
prevents daily 
activity 
Necrosis 
September 2007 “FDA Guidance for Industry-Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
a In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable 
b Should be evaluated and graded using the functional scale as well as the actual measurement. 
 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken at the time of Screening and 
ongoing from signing of the informed consent to study discharge that do not affect a 
subject’s eligibility for participation (see Section 4.2) must be recorded on CRFs. 
Actual or estimated start and stop dates must be provided. This information will be 
obtained from the subject and/or any available medical records. The indication for the 
medication, dose, and dose regimen will be documented.  
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Therapy considered necessary for the subject’s welfare may be given at the discretion of 
the Investigator or medical provider. If the permissibility of a specific medication/treatment 
is in question, please contact the Medical Monitor. 
The decision to administer a prohibited medication/treatment (Section 6.4.7) is made with 
the safety of the clinical trial subject as the primary consideration. When possible, the 
Sponsor should be notified before the prohibited medication/treatment is administered. 
 RESTRICTIONS  
In the Phase 2 segment of the trial, subjects should refrain from becoming pregnant until 
3 months following the last dose of investigational product by using appropriate 
contraceptive measures (see Section 4.1.1). In the Phase 3 segment of the trial, subjects 
should refrain from becoming pregnant until receipt of the last dose of investigation 
product by using appropriate contraceptive measures (See Section 4.1). 
Subjects must not receive any non-study related vaccine (e.g., influenza vaccine) within 2 
weeks prior to the first dose of IP, or within 2 weeks of (before or after) any subsequent 
dose of IP.  
Subjects must not have fever (oral temperature ≥38.0 degrees Celsius or 100.4o 
Fahrenheit) within 72 hours prior to each dosing. 
Subjects should not receive hydroxychloroquine or any other drug/vaccine intended as 
COVID-19 prophylaxis during the trial. If a subject informs the site of their intent to receive 
another COVID-19 vaccine (emergency use or licensed vaccine), the subject should be 
informed that the safety and effectiveness of receiving INO-4800 followed by another 
COVID-19 vaccine has not been studied. In the Phase 3 segment, subjects should be 
reminded that if and when appropriate, the Sponsor would provide INO-4800 to those who 
received placebo in the trial. 
Subjects should not participate in any other interventional trials for the duration of this trial. 
Subjects must not receive disease modifying doses of anti-rheumatic drugs (e.g., 
azathioprine, cyclophosphamide, cyclosporine, methotrexate), biologic disease modifying 
drugs such as TNF-α inhibitors (e.g., infliximab, adalimumab or etanercept) and long term 
use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of prednisone 
equivalent (use of inhaled, topical, nasal, otic, and ophthalmic corticosteroids are allowed).  
 SARS-COV-2 TESTING 
Phase 2 segment: 
SARS-CoV-2 antibody and RT-PCR testing will be used during screening to test for 
previous or current SARS-CoV-2 infection. During the trial, subjects who report symptoms 
suggestive of COVID-19 will be assessed at a COVID-19 assessment visit in the clinic or 
subject’s vehicle or at the subject’s home. During this visit, nasal swabs and saliva will be 
collected to detect SARS-CoV-2 using the RT-PCR assay. Genotyping may also be 
performed. If the subject is confirmed to be COVID-19 positive, a follow-up nasal swab 
and saliva will be collected to detect SARS-CoV-2 using the RT-PCR assay at the COVID-
19 convalescent visit. 
Phase 3 segment: 
SARS-CoV-2 antibody testing will be used during screening to test for previous SARS-
CoV-2 infection and during each subsequent visit (see Table 4: Schedule of Events) to 
identify SARS-CoV-2 infections that may occur regardless of symptoms between study 
visits. 
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SARS-CoV-2 RT-PCR testing will be conducted on nasopharyngeal specimens collected 
at Day 0. The Day 0 SARS-CoV-2 RT-PCR results will not be required prior to dosing on 
that day. 
For subjects who are seronegative at baseline, if at any time during the trial, either the 
SARS-CoV-2 antibody or an RT-PCR test result is positive, the subject will be notified of 
the result and will be evaluated at a COVID-19 assessment visit. During that visit, which 
may be conducted in the clinic, from the subject’s vehicle, or in the subject’s home, 
nasopharyngeal swabs will be collected to detect SARS-CoV-2 using the RT-PCR assay. 
Genotyping may also be performed on the sample(s) collected at the COVID-19 
assessment visit.  
 COVID-19 DISEASE MONITORING 
During both the Phase 2 and Phase 3 segments of the trial, all subjects will be monitored 
for the development of symptoms suggestive of COVID-19 disease. For the Phase 3 
segment, frequent (approximately bi-weekly) scheduled clinic visits or phone calls will 
occur.  
All subjects in the trial should be instructed to do the following: 
• 
Take their temperature daily at home starting on the Day 0 visit for the duration of 
the trial.     
• 
Monitor for symptoms suggestive of COVID-19 (e.g., feeling feverish or chills, 
cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, 
headache, new loss of taste or smell, sore throat, congestion or runny nose, 
nausea or vomiting, diarrhea) starting on the Day 0 visit for the duration of the trial.  
If at any time during the study, the subject experiences a fever of ≥ 100.4°F/38°C or 
symptoms suggestive of COVID-19, the subject should contact the site. The site staff 
should arrange for a clinic visit (COVID-19 assessment visit) within 3 days of the site being 
aware of either a positive SARS-CoV-2 test or COVID-19 symptom onset. The COVID-19 
assessment visit may be performed either at the clinic, in the subject’s vehicle or in the 
subject’s home. 
Subjects with a confirmed COVID-19 diagnosis, per the case definition outlined in Section 
3.7, prior to dose 2 or who have a positive SARS-CoV-2 PCR test at Day 0 will be 
discontinued from further dosing and will be followed until EOS for safety and resolution 
of COVID-19. Subjects with confirmed SARS-CoV-2 infection will return for a convalescent 
visit approximately 28 days after symptom onset, or in the absence of symptoms, after the 
collection date of the positive SARS-CoV-2 sample. If symptoms are ongoing at 28 days 
after symptom onset, the site should follow up with the subject via phone call or 
unscheduled visit after symptom resolution or stabilization. Recovery from COVID-19 
disease requires either resolution of clinical symptoms except for loss of taste/smell, or 
with sequelae that appear to be permanent.     
Subjects who require medical care for COVID-19 (or any other suspected condition) will 
be referred to their primary health care provider or a medical treatment facility if the 
Investigator believes that the subject should be managed beyond routine care that can be 
provided by the study site. Subjects referred for treatment will continue study follow-up 
according to the protocol schedule. If subjects are treated or hospitalized due to their 
illness, the study team will request COVID-19 specific test results, treatments, treatment 
outcomes and diagnostics from medical treatment facilities with the subject’s written 
permission. These results and diagnostics will be recorded in the study and/or safety 
database consistent with protocol reporting requirements. 
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IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at visits specified in the Schedule of 
Events (36TTables 3 and 436T) for cellular and humoral immunology assessments. Binding 
ELISA will be evaluated at serial timepoints. Cellular sampling requires 32 mL of whole 
blood be collected at each visit. Humoral sampling requires collection of 8.5 mL of whole 
blood in a single 10-mL red top serum collection tube to produce two serum aliquots of 2 
mL each. However, baseline (Day 0) immunology samples are required to serve as a 
baseline for all subsequent immunology testing. Therefore, a total of 68 mL whole blood 
for cellular sampling and 8 mL serum for humoral sampling is required on Day 0 prior to 
1st dose. Subjects may be asked to return for additional blood draws if collected blood 
sample is lost or unevaluable for any reason. Details of the immunology sample collection 
and shipment information will be provided in the Laboratory Manual.  
Humoral samples will be collected on all subjects and cellular samples will be collected at 
selected sites (from approximately 711 subjects). Both humoral and cellular analysis will 
be conducted in the first 102 subjects age 18-50 and in the first 102 subjects age 51 and 
older enrolled at the sites that are selected for cellular sample collection. In addition, 
cellular and humoral samples will be analyzed on all subjects with COVID-19 when 
samples are available. 
The immune responses to INO-4800 will be measured using assays that include a 
pseudovirus-based neutralization assay and ELISpot. Determination of additional 
analyses using assays not specified, such as assessment of immunological gene 
expression or flow cytometry, assessment of immunological protein expression on 
collected samples for immunological endpoints will be made on an ongoing basis 
throughout the trial. 
 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
 
SAFETY PARAMETERS 
The safety of INO-4800 will be measured and graded in accordance with the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. 
 
ADVERSE EVENTS (AES) 
Any untoward medical occurrence in a patient or clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.  
Adverse Events (AEs) include the following: 
• Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (before the administration of clinical trial drug); 
• Any pre-existing condition that increases in severity, or changes in nature during or as 
a consequence of the clinical trial drug administration phase; 
• Complications of pregnancy (refer to Section 7.11). 
Adverse Events (AEs) do not include the following: 
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• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; however, the condition that leads to the procedure is an AE; 
• Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the Screening Visit that do not worsen; 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions); 
• Overdose without clinical sequelae; 
• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed, is not an AE; it is considered to be pre-existing and will be 
documented on the medical history CRF; 
• Uncomplicated pregnancy; 
• An induced elective abortion to terminate a pregnancy without medical reason; 
• Confirmed COVID-19 disease.  
 
ADVERSE DRUG REACTION (ADR) 
All noxious and unintended responses to a medicinal product related to any dose. This 
means that a causal relationship between the medicinal product and an adverse event is 
at least a reasonable possibility (i.e., the relationship cannot be ruled out). 
 
SERIOUS ADVERSE EVENTS (SAES) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death;  
• Is life-threatening; 
o Refers to an event in which the subject was at risk of death at the time of the event. 
It does not refer to an event which hypothetically might have caused death if it 
were more severe 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
o Includes any hospitalization in which the subject has been admitted to the hospital 
regardless the length of stay, even if the hospitalization is only a precautionary 
measure to allow continued observation. However, hospitalization (including 
hospitalization for an elective procedure) for a pre-existing condition that has not 
worsened, does not constitute an SAE 
• Results in persistent or significant disability/incapacity; 
o A substantial disruption of a person's ability to conduct normal life functions (i.e., 
the adverse event resulted in a significant, persistent or permanent change, 
impairment, damage or disruption in the subject’s body function/structure, physical 
activities and/or quality of life) 
• Results in congenital anomaly or birth defect and/or; 
• An important medical event.  
o An event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse 
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Clarification of Serious Adverse Events (SAEs) 
• Death itself is not an AE. Death is an outcome of an AE, but when the cause of death 
has not been provided, use the event term: death of unknown cause; 
• Confirmed COVID-19 disease that requires hospitalization is recorded on the 
Suspected COVID-19 Clinical Event CRF, and not recorded as an SAE; 
• COVID-19 disease with an outcome of death is recorded on the Suspected COVID-19 
Clinical Event CRF, and not recorded as an SAE; 
• The subject may not have been receiving an investigational medicinal product at the 
occurrence of the event; 
• Complications associated with COVID-19 disease that occur or prolong 
hospitalization are recorded on the Suspected COVID-19 Clinical Event CRF; 
• The Pregnancy outcomes of spontaneous abortion (miscarriage), ectopic pregnancy, 
fetal demise/stillbirth in a subject or subject partner following exposure to study 
treatment is considered to be an SAE. 
 
UNEXPECTED ADVERSE DRUG REACTION 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator’s Brochure [IB] for an unapproved investigational 
product, package insert/summary of product characteristics for an approved product). 
 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects.  
A UADE is a type of SAE that requires reporting to the Sponsor in accordance with Section 
7.9. 
 
DEVICE DEFICIENCY 
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance. 
Note: Device deficiencies include malfunctions, use errors and inadequate labelling. 
 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor is responsible for the overall safety monitoring of the clinical trial. 
Safety monitoring assessments include but are not limited to:  
• Incidence of all AEs classified by system organ class, preferred term, severity and 
causal relationship to clinical trial treatment; 
• Changes in laboratory parameters; 
• Local and systemic injection site review; special attention will be paid to the examination 
of the injection site. 
 ADVERSE EVENT OF SPECIAL INTEREST (AESI)  
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An adverse event of special interest (serious or non-serious) is one of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor can be 
appropriate.  
For the purpose of this clinical trial, the AESIs listed in Appendix A are to be reported to 
the Sponsor in accordance with Section 7.9. 
 MEDICALLY ATTENDED ADVERSE EVENT (MAAE) 
A medically attended adverse event (serious or non-serious) is defined as an adverse 
event that leads to an unplanned contact with a health care provider. 
 ABNORMAL LABORATORY VALUE 
The Investigator will annotate each abnormal lab value as clinically significant (CS) or not 
clinically significant (NCS). 
Laboratory values that are NCS in the Investigator’s opinion should not be reported as an 
adverse event. 
Any abnormal laboratory value that is new in onset or worsened in severity or frequency 
from the baseline condition and meets one of the following criteria will be recorded as an 
AE: 
• 
Requires therapeutic intervention or diagnostic tests; 
• 
Leads to discontinuation of further administration of the investigational product in 
the clinical trial; 
• 
Has accompanying or inducing symptoms or signs; 
• 
Is judged by the Investigator as clinically significant (CS). 
Abnormal laboratory values that meet the criteria of an AE or SAE should be reported in 
accordance with Section 7.9. 
 CLINICAL TRIAL STOPPING RULES 
The Investigator is to immediately notify the Medical Monitor if the following are observed: 
• 
Any SAE related to study treatment; 
• 
Any Grade 4 AEs related to study treatment; 
• 
Any report of anaphylaxis related to study treatment; 
• 
Any suspected Severe COVID-19 disease case (per Sections 3.7.1.1 and Section 
3.7.1.2). 
The Medical Monitor will notify the Chair of the Safety Review Committee, who will make 
a determination as to whether to temporarily halt dosing until a more formal review of the 
case(s) is made. Such a formal review may include an ad hoc meeting of the DSMB, after 
consultation with the DSMB Chair. Following such a meeting, the DSMB chair will render 
a recommendation to the Medical Monitor regarding continuation of trial dosing. The 
Sponsor will independently investigate the case(s) and, after review of the DSMB 
recommendations, will communicate a final decision as to whether to lift the dosing 
suspension or whether to continue dosing. These deliberations will be documented and 
will be provided to the IRBs and FDA, where required.   
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In the case of suspected Severe COVID-19 cases, the trial will be paused if a vaccine-to-
placebo case split yields a relative risk with a 90% confidence interval lower bound >1.  
The minimum case split corresponding to this criterion is 8:0. In this scenario, the trial will 
pause until at least one additional case is accrued and the DSMB can review the data and 
make a recommendation regarding continued enrollment in the trial. 
 
SAFETY DATA REPORTING PERIOD, METHOD OF COLLECTION AND SUBMISSION 
All AEs will be collected from the time informed consent is obtained through Day 56. 
MAAEs, AESIs and SAEs only will continue to be collected after the Day 56 visit and will 
be followed to resolution or stabilization. This information will be captured in the CRF. 
If the Investigator determines that the AE meets serious criteria, then the AE will be 
recorded as an SAE. 
SAEs and AESIs will be reported to the Sponsor from the time the subject signs the 
informed consent until the last visit. 
All SAEs (regardless of causal relationship) and AESIs will be reported on the SAE Report 
Form and submitted to the Sponsor within 24 hours of becoming aware of the event. The 
SAE Report Form will be either emailed to safety.inovio@apcerls.com or faxed to
The original SAE Report Form must be kept at the clinical trial site. 
The event will be data entered into the CRF. 
 
For the events that are considered an AESI, the Investigator will contact the Sponsor within 
24 hours of becoming aware of the event to discuss whether dosing should continue. 
Table 11: SAE Contact Information 
Sponsor Safety Email: safety.inovio@apcerls.com  
Sponsor Safety Fax: 
Sponsor Safety Phone: 
 
Table 12: Medical Monitor Direct Contact Information 
Primary point of contact, ICON Medical Monitor: 
, M.D.  
Email: 
 
Phone: 
 
Inovio Medical Monitor:  
, Jr., M.D., FACP, FIDSA 
Email: 
 
Cell Phone: 
 
 
All SAEs, treatment-related AEs, MAAEs and AESIs must be followed by the Investigator 
until resolution or return to baseline status, stabilization of the event (i.e., the expectation 
that it will remain chronic), even if it extends beyond the clinical trial reporting period or 
until it is determined that the subject is lost to follow up. 
Follow-up information is to be submitted to the Sponsor on an SAE Report Form and within 
24 hours of becoming aware of the information. 
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If medical records are submitted to the Sponsor with the SAE Report Form, the clinical 
trial site must: 
• Redact the medical records of all personal data (e.g., confidential subject data, 
Personal Identifying Information [PII]) 
• Provide the subject’s assigned identification number (SID) on the records 
 ADVERSE EVENT REPORTING 
This section provides details on reporting the safety information. 
 SUBMITTING THE INITIAL SERIOUS ADVERSE EVENT (SAE) REPORT FORM 
The Investigator should include as much safety information as possible when submitting 
the initial report, but the report must include the following at a minimum:  
• 
The adverse event; 
• 
The subject’s assigned identification number (SID); 
• 
Investigational product(s) (IP) and/or study device; 
• 
Investigator causal relationship to the IP(s) and/or study device; 
• 
Serious criteria; 
• 
Reporter name and contact information. 
If a case is submitted to the Sponsor with only the “minimum” information, a more detailed 
or updated follow-up report will be sent to the Sponsor as soon as possible but no later 
than three (3) calendar days after the date of the initial report. 
 RECORDING THE EVENT 
Investigators should use correct medical terminology/concepts when recording AEs on the 
EDC and SAE Report Form. The use of colloquialisms and abbreviations should be 
avoided. 
A medical diagnosis, if known, should be recorded rather than individual signs and 
symptoms. However, if the signs and/or symptoms cannot be medically characterized as 
a single diagnosis or syndrome, each individual sign and/or symptom should be recorded. 
If a diagnosis is subsequently established, all previous signs and/or symptoms will be 
subsumed and replaced with a single medical diagnosis. 
 ASSESSING SEVERITY (INTENSITY) 
Severity is used to describe the intensity of a specific event (e.g., mild, moderate, severe). 
The Investigator will assess and grade clinical AEs or SAEs (based on discussions with 
clinical trial subjects) in accordance with CTCAE. 
 CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS (AES) 
A causally related AE is one judged to have a possible, probable or definite relationship 
to the administration of the IP and/or the study device. An AE may also be assessed as 
not related to the IP and/or the study device. Because the Investigator is knowledgeable 
about the subject (e.g., medical history, concomitant medications), administers the IP, and 
monitors the subject’s response to the IP, the Investigator is responsible for reporting AEs 
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and judging the relationship between the administration of the IP and EP and a 
subsequent AE. The Investigator is aware of the subject’s clinical state and may have 
observed the event, and thus may be sensitive to distinctions between events due to the 
underlying disease process versus events that may be product-related.  
Investigators should use their knowledge of the clinical trial subject, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to determine 
whether an AE is considered to be related to the IP and/or the study device and the causal 
relationship reported as "Yes" or "No" accordingly. Causality should be assessed by the 
Investigator as related to drug, related to device, or related to both drug and device (i.e., 
related to both or indiscernible) by the following criteria: 
• 
Yes – there is a reasonable possibility that administration of the clinical trial 
treatment (drug or device or both drug and device) contributed to the event 
• 
No – there is no reasonable possibility that administration of the clinical trial 
treatment contributed to the event and there are more likely causes 
The following guidance should also be taken into consideration: 
• 
Temporal relationship of event to administration of IP and/or EP; 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
• 
Known association of the event with the IP, EP or with similar treatments; 
• 
Known association of the event with the disease under trial; 
• 
Presence of risk factors in the clinical trial subject or use of concomitant 
medications known to increase the occurrence of the event. 
The rationale for the Investigator’s causal assessment is to be recorded on the SAE Report 
Form. 
The Sponsor will assess the overall safety of the IP delivered by EP and determine 
whether to report expeditiously to the regulatory authority(ies). 
 REPORTING SUSPECTED COVID-19 DISEASE CASES DURING THE TRIAL 
For both Phase 2 and Phase 3 segments of the trial, all suspected COVID-19 disease 
cases based on reported COVID-19 symptoms and/or SARS-CoV-2 test results should be 
entered into the Suspected COVID-19 Clinical Event CRF within 24 hours of awareness. 
Cases will be tracked until final determination of whether the case meets criteria of a 
confirmed COVID-19 disease case, per the case definition. For the Phase 2 segment of 
the trial, this determination will be made by the Investigator. For the Phase 3 segment, this 
determination will be made by the EAC. 
If the reported COVID-19 disease case is later determined not to be a confirmed COVID-
19 case, the event (e.g. symptoms or other diagnosis), if serious, would be reported as an 
SAE within 24 hours following determination by the Investigator (Phase 2 segment) or 
notification by EAC (Phase 3 segment).  
If the reported COVID-19 disease case is later determined not to be a confirmed COVID-
19 case, the event (e.g. symptoms or other diagnosis), if non-serious and if occurring from 
the time of consent until 28 days post-dose 2, would be reported as an AE following 
determination by the Investigator (Phase 2 segment) or notification by EAC (Phase 3 
segment). 
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 REPORTING PREGNANCY DURING THE CLINICAL TRIAL 
Subjects in Phase 2 who are pregnant or expect to become pregnant prior to 3 months 
following the last dose will be excluded from participation in the clinical trial.  
Subjects in Phase 3 who are pregnant or expect to become pregnant prior to the last dose 
will be excluded from participation in the clinical trial.  
All pregnancies that occur from the time of first administration of clinical trial treatment 
through study completion (i.e., Day 393) will be reported to the Sponsor. If clinical trial site 
staff become aware that a subject becomes pregnant after the first dose in the clinical trial, 
she will not be given any additional treatments with the IP. A Pregnancy Form will be 
completed by the site and submitted to the Sponsor within 24 hours after becoming aware 
of the pregnancy. 
The Investigator will report this event to their IRB/REB/EC in accordance with their policies 
and procedures.  
The clinical trial site must request the subject’s permission to query pregnancy outcome 
and follow the subject for outcome of the pregnancy. The subject will continue to be 
followed for safety assessments without receiving additional IP until clinical trial discharge 
in accordance with this protocol. Procedures that are contraindicated during pregnancy, 
including additional dose administrations, must not be performed. The Investigator should 
use clinical judgment regarding subsequent clinical trial-related blood collection based on 
the presence or absence of anemia in each subject.  
Male subjects will be instructed through the ICF to immediately inform the Investigator if 
their partner becomes pregnant until study completion. A Pregnancy Form will be 
completed by the site and submitted to the Sponsor within 24 hours after becoming aware 
of the pregnancy. The pregnant partner will be asked to sign a Pregnancy Information 
Collection Consent Form to allow for follow-up on her pregnancy. If the authorization has 
been signed, the Investigator will collect and report details of the course and outcome of 
the pregnancy in the partner of a male subject exposed to IP. The site will update the 
Pregnancy Form with additional information on the course and outcome of the pregnancy 
and submit the form to the Sponsor.  
If an Investigator is contacted by the male subject or his pregnant partner, the Investigator 
may provide information on the risks of the pregnancy and the possible effects on the fetus 
to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
If the end of the pregnancy occurs after the clinical trial has been completed, the outcome 
will be reported directly to the Sponsor. 
 REPORTING DEVICE-RELATED COMPLAINTS OR DEFICIENCIES 
All product complaints that meet the definition of device deficiency must be reported to the 
Sponsor within 10 days of discovery, with the exception of SAEs which require 24-hour 
reporting. The error reporting or complaint form must be completed and emailed to the 
Sponsor at clinicalcomplaint@inovio.com. 
Device deficiencies include malfunctions, misuse or use errors and inadequate labeling. 
A malfunction is defined as the failure of a device to meet its performance specifications 
or otherwise perform as intended. The intended performance of a device refers to the 
intended use for which the device is labeled or marketed. 
Any problems experienced during the treatment procedure including malfunctions of the 
device, error messages displayed on the device screen following treatment, or errors that 
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occur during the treatment procedure must immediately be reported to the Sponsor or its 
designee for evaluation.  
 NOTIFYING REGULATORY AUTHORITIES AND INSTITUTIONAL REVIEW BOARDS 
(IRBS)/RESEARCH ETHICS BOARDS (REBS)/ETHICS COMMITTEES (ECS) OF SAFETY 
INFORMATION 
 SPONSOR RESPONSIBILITIES 
• 
Determine whether the safety information meets the requirements for expedited 
reporting to the applicable regulatory authorities; 
• 
Prepare and submit the safety report to the applicable regulatory authorities; 
• 
Send all participating PIs a safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) that will include a statement if there is or is not any significant new 
safety information that might influence the risk-benefit assessment of the IP and/or 
study device, sufficient to consider changes in product administration or overall 
conduct of the clinical investigation. 
 PRINCIPAL INVESTIGATOR (PI) RESPONSIBILITIES 
• 
Forward a copy of the safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) to their IRB/REB/EC as soon as practical in accordance with the 
governing policy and/or procedures; 
• 
Notify their IRB/REB/EC of safety information (i.e., SAEs, pregnancies, and AESIs) 
that occur at their clinical trial site in accordance with their local institutional policy. 
 POST-TRIAL REPORTING REQUIREMENTS 
PIs are not obligated to actively seek AEs or SAEs beyond the clinical trial reporting period. 
However, if the PI becomes aware of an AE or SAE that occurs after the Completion or 
Termination Visit and the event is deemed by the PI to be related to the clinical trial 
treatment, the PI should promptly document and report the event to the Sponsor. 
 CLINICAL TRIAL DISCONTINUATION  
INOVIO reserves the right to discontinue the clinical trial at a site or at multiple sites for 
safety or administrative reasons at any time. In particular, a clinical trial site that does not 
recruit at a reasonable rate may be discontinued. Additionally, the clinical trial may be 
discontinued at any time by an IRB/REB/EC, INOVIO, or a regulatory authority as part of 
their duties to ensure that clinical trial subjects are protected.  
If the clinical trial is discontinued and/or the clinical trial site closed for any 
reason, all IP and devices must be returned to INOVIO or its 
representative. The PI should ensure that their site file documents are complete 
prior to archiving, and provide copies of any requested documents to INOVIO 
for its Trial Master File (TMF). 
 
STATISTICAL CONSIDERATIONS 
 
STATISTICAL AND ANALYTICAL PLAN 
The formal Statistical Analysis Plan is contained in the sections that follow. 
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GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is an operationally seamless Phase 2/3 trial.  The subjects and data from Phase 2 
are independent from that of Phase 3.   
Phase 2 Segment:  This is a four-arm, multi-center, placebo-controlled, blinded, and 
randomized clinical trial in subjects at high risk of SARS-CoV-2 exposure. The trial’s 
primary endpoints are antigen-specific cellular immune response measured by IFN-
gamma ELISpot and neutralizing antibody responses. Secondary efficacy endpoints are 
safety measures.  Exploratory endpoints are antigen-specific cellular immune response 
measured by flow cytometry and other T and B cell measures.  
Phase 3 Segment: This is a two-arm, multi-center, placebo-controlled, double-blinded, and 
randomized clinical trial in subjects at high risk of SARS-CoV-2 exposure. The study’s 
primary endpoint is the incidence of virologically-confirmed COVID-19 disease in subjects 
who are SARS-CoV-2 seronegative at baseline starting 14 days after completion of the 2-
dose regimen until 12 months post-dose 2.  The primary hypothesis is that INO-4800 will 
be efficacious relative to placebo (relative efficacy > 30%). Secondary efficacy analyses 
involve non-severe cases, severe cases, cases resulting in death, and cases among 
baseline SARS-CoV-2 seropositive subjects. Other secondary analyses concern safety 
and cellular and neutralizing antibody response. Exploratory analyses concern efficacy 
against variants, efficacy against asymptomatic infection, and binding antibody and 
cellular immunological measures. 
 
STATISTICAL HYPOTHESES 
Phase 2 Segment: This is an estimation segment pertaining to immunogenicity and safety.  
There are no hypotheses. 
Phase 3 Segment: The primary hypothesis of relative efficacy greater than 30% among 
baseline SARS-CoV-2 seronegative subjects will be tested with H0: p ≥ .70/(.70+k) vs. H1: 
p < .70/(.70+k), where p is the true proportion of subjects with disease who receive INO-
4800 relative to the total number of subjects with disease, and k is the total amount of 
follow-up time in the placebo group divided by the total amount of follow-up time in the 
INO-4800 group. There are no other formal hypotheses. 
 
ANALYTICAL POPULATIONS 
Analysis populations will be: 
The per-protocol (PP) population includes all subjects who receive all doses of Study 
Treatments and have no protocol violations. Subjects in the PP population will be grouped 
to treatment arms as randomized.  Subjects excluded from the PP population will be 
identified and documented prior to unblinding of the trial database.  Analyses on the PP 
population among those who are baseline SARS-CoV-2 seronegative will be primary for 
the analyses of efficacy in the Phase 3 segment of this trial. 
The modified intention to treat (mITT) population includes all subjects who receive at least 
one dose of Study Treatment. Subjects in this population will be grouped to treatment 
arms as randomized.  Analysis of the mITT population will be considered supportive for 
the corresponding PP population for the analyses of efficacy in the Phase 3 segment of 
this trial. 
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The intention to treat (ITT) population includes all subjects who are randomized. Subjects 
in this sample will be grouped to treatment arms as randomized.  Analysis of the ITT 
population will be considered supportive for the corresponding PP population for the 
analyses of efficacy in the Phase 3 segment of this trial. 
The safety analysis population includes all subjects who receive at least one dose of Study 
Treatment. Subjects will be analyzed according to the treatments received. 
 
DESCRIPTION OF STATISTICAL METHODS 
 PRIMARY ANALYSIS 
Phase 2 Segment 
Post-baseline increases from baseline in interferon-γ ELISpot response magnitudes will 
be compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
Post-baseline increases from baseline in neutralizing antibody response titers will be 
compared between treatment groups using ratios of geometric mean fold-rises and 
associated t-distribution based 95% CIs. 
The summaries listed above will be stratified according to NP positive/negative status of 
the subjects. Valid samples for statistical analysis purposes will be those collected: at least 
6 and no more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no 
more than 198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more 
than 380 days after Dose 2 for the Week 56 timepoint. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for these immunogenicity analyses. 
Phase 3 Segment 
Among subjects who are SARS-CoV-2 seronegative at baseline, the primary hypothesis 
of relative efficacy greater than 30% will be tested with H0: p ≥ 0.70/(0.70+k) vs. H1: p < 
0.70/(0.70+k), where p is the true proportion of subjects with disease who receive INO-
4800 relative to the total number of subjects with disease, and k is the total amount of 
follow-up time in the placebo group divided by the total amount of follow-up time in the 
INO-4800 group. 
A p-value for this hypothesis test and corresponding confidence interval will be computed 
based on the exact binomial method of Clopper-Pearson. Success will be concluded if the 
one-sided p-value is <0.022 and the corresponding lower bound of the two-sided 95.6% 
CI for efficacy exceeds 30% (alpha-level adjusted for interim analyses, see Section 8.5.6), 
and the point estimate for efficacy exceeds 50%. 
For calculating k, an individual subject’s follow-up time is either: 
o the date of first disease diagnosis – date of the start of surveillance period +1 (for 
subjects who are cases), or 
o the date of last follow-up – date of the start of surveillance period +1 (for subjects who 
are non-cases). 
This methodology is based on the following. Assuming that the number of subjects who 
are cases in the INO-4800 group follows a Poisson distribution with parameter λv and the 
number of subjects who are cases in the placebo group follows a Poisson distribution with 
parameter λc, then conditional on total number of subjects with cases, t, the number of 
subjects who are cases in the INO-4800 group follows a binomial distribution with 
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parameters (t, p=λv/(λv+λc)).  The relationship between p and efficacy is: efficacy = (1-
(1+k)p)/(1-p).  Therefore, testing efficacy > 30% corresponds to testing p < 0.70/(0.70+k).  
Similarly, the confidence interval for efficacy is (1-(1+k)UBp)/(1-UBp), (1-(1+k)LBp)/(1-LBp), 
where UB and LB are the Clopper-Pearson upper and lower limits for the proportion. 
The efficacy time frame is defined by symptoms beginning at any time starting from 14 
days after Dose 2 and ending 12 months after Dose 2.  Subjects identified as cases that 
started prior to this time point will be excluded.  Subjects with multiple instances meeting 
the case definition will be counted only once, using the first such instance.    
The PP population will be primary for the analysis of efficacy in this trial. Efficacy analysis 
using the mITT population will also be conducted counting cases from 14 days postdose 
1 as a supportive analysis.  The ITT population will also be used for a supportive analysis 
counting cases starting from randomization. 
 SECONDARY ANALYSES 
8.5.2.1 Efficacy 
Phase 3 Segment 
The secondary efficacy incidence endpoints will be analyzed in the same manner as the 
primary hypothesis, but with 95% CIs and without the hypothesis test p-value.  
8.5.2.2 Immunogenicity 
 
   Phase 3 Segment 
Post-baseline increases from baseline in interferon-γ ELISpot response magnitudes will 
be compared between treatment groups using differences in medians and associated 
non-parametric 95% CIs. 
Post-baseline increases from baseline in neutralizing antibody response titers will be 
compared between treatment groups using ratios of geometric mean fold-rises and 
associated t-distribution based 95% CIs. 
The summaries listed above will be stratified according to disease status of the subjects 
and by baseline SARS-CoV-2 serostatus. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more than 
198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more than 
380 days after Dose 2 for the Week 56 timepoint.. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for these immunogenicity analyses. 
 SAFETY ANALYSES 
8.5.3.1 Adverse Events 
All AEs including injection-site reactions will be summarized among the Safety 
Population by frequency per treatment arm. These frequencies will be presented overall 
and separately by dose, and will depict overall, by system organ class and by preferred 
term, the percentage of subjects affected. Additional frequencies will be presented with 
respect to maximum severity and to strongest relationship to Study Treatment. Multiple 
occurrences of the same AE will be counted only once following a worst-case approach 
with respect to severity and relationship to Study Treatment. All serious AEs will also be 
summarized as above. 
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The main summary of safety data will be based on events occurring within 30 days of 
any dose. For this summary, the frequency of preferred term events will be compared 
between study arms with risk differences and 95% confidence intervals, using the 
method of Miettinen and Nurminen. As this analysis will use many event categories, and 
produce many confidence intervals, caution should be exercised when interpreting these 
confidence intervals.  Separate summaries will be based on events occurring within 7 
days of any dose and regardless of when they occurred. 
The analyses listed above will be performed according to Phase. For the Phase 3 
segment, the analyses listed above will also be performed according to SARS-CoV-2 
serostatus at baseline. 
For AE data, partial start dates will be imputed to the date of treatment to conservatively 
report the event as treatment-emergent, whenever the portion of the date is consistent 
with that of the study treatment. Otherwise, it will be imputed to the earliest date 
consistent with the partial date. A completely missing onset date will be imputed as the 
day of treatment. Partial stop dates will be assumed to be the latest possible day 
consistent with the partial date. AE duration will be calculated as (Stop Date – Start 
Date) + 1. 
8.5.3.2 Vital Signs 
Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean, standard deviation, minimum, median, and maximum 
values by time point and treatment arm, for the Safety population. Baseline is defined 
as the last measurement prior to the first treatment administration. These summaries 
will be performed according to Phase. For the Phase 3 segment, the analyses listed 
above will also be performed according to SARS-CoV-2 serostatus at baseline. 
 DISPOSITION 
Disposition will be summarized by treatment arm for the ITT population and will include 
the number and percentage randomized, the number and percentage who received each 
dose and the number who completed the trial.  The number and percentage of subjects 
who discontinued will be summarized overall and by reason.  The number in each analysis 
population will also be presented. These summaries will be performed according to Phase. 
For the Phase 3 segment, the analyses listed above will also be performed according to 
SARS-CoV-2 serostatus at baseline. 
 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
8.5.5.1 Demographics 
Demographic data will be summarized with descriptive statistics: mean standard 
deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables, by treatment arm, for the ITT and PP populations. 
These summaries will be performed according to Phase. For the Phase 3 segment, the 
analyses listed above will also be performed according to SARS-CoV-2 serostatus at 
baseline. 
8.5.5.2 Prior Medications 
Prior medications are those that were used before the start of the trial (prior to Day 0). 
Partial stop dates of prior medications will be assumed to be the latest possible date 
consistent with the partial date; start dates will not be imputed. Data for all prior 
medications will be summarized with percentages by treatment arm, for the ITT and PP 
populations. These summaries will be performed according to Phase. For the Phase 3 
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segment, the analyses listed above will also be performed according to SARS-CoV-2 
serostatus at baseline. 
 INTERIM ANALYSES  
For safety issues, the DSMB could recommend stopping enrollment at any time; no 
formal interim analysis will be performed for this purpose. The two-sided type I error of 
0.05 will not be adjusted for possible early stopping due to this aspect. 
 
For the Phase 2 segment, group-level unblinded summaries of the immunogenicity and 
safety data will be produced once Week 6 visit immunology data and Week 8 visit safety 
data are complete for all subjects who have not discontinued, while maintaining subject-
level blinding.  Long-term follow-up data will continue to be collected for all subjects who 
have not discontinued with remaining visits through the final visit.  These summaries will 
allow the Sponsor to have results for the purposes of dose selection for the Phase 3 
portion.  No subject-level immunogenicity data will be produced, and subject-level 
immunogenicity data will not be available in the clinical trial database until all other clinical 
trial data are finalized at the end of the trial.  No safety summary will be provided if the 
total number of subjects who experience the event of interest is greater than 0 and the 
count of the number of subjects with the event in a given treatment group relative to the 
total produces a percentage less than 3%, for a given summary.  The group-level 
unblinded production of the summaries will not include anyone directly involved with the 
trial or any additional unblinded personnel; only the external Contract Research 
Organization (CRO), ICON, which will already be providing unblinded summaries for the 
Data Safety Monitoring Board, will be utilized.  Thus, the trial will remain blinded to the 
Sponsor with respect to subject treatment assignment.  
 
For the Phase 3 segment, there are two planned formal interim efficacy analyses: one at 
50% (75 cases) and one at 75% (112 cases) of the total required for the primary endpoint 
(149 cases).  The Lan-DeMets O’Brien-Fleming approximate alpha-spending function will 
be used for the efficacy and futility boundaries.  As such, the first interim analysis will utilize 
a one-sided nominal alpha of 0.0016, and the second interim analysis will utilize a one-
sided nominal alpha of 0.0092.  The final analysis will utilize a one-sided nominal alpha of 
0.022.  The DSMB will be responsible for the interim evaluations. The unblinded interim 
analyses will not include anyone directly involved with the trial or any additional unblinded 
personnel; only the external Contract Research Organization (CRO), ICON, which will 
already be providing unblinded summaries for the Data Safety Monitoring Board, will be 
utilized.  Thus, the trial will remain blinded to the Sponsor with respect to subject treatment 
assignment.  
 
If the prespecified criteria for efficacy above are met at either interim analysis, then 
enrollment will continue until 4500 subjects have been enrolled, and blinded follow-up will 
continue until 4500 subjects have 6 months of safety follow-up.  At that point, the trial 
would be unblinded, and subjects who received placebo will be offered the active product. 
 MULTIPLICITY 
There is one primary hypothesis that will be tested.  As there are two interim analyses of 
the primary endpoint, the type I error rate will be controlled at two-sided 0.05 by using the 
Lan-DeMets O’Brien-Fleming approximate alpha-spending function (see Section 8.5.6).  
 MISSING VALUES 
Missing data will not be imputed. 
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For the ITT analyses of efficacy in the Phase 3 segment, subjects with missing or 
unevaluable data regarding case definition will be considered cases (failures). 
 EXPLORATORY ANALYSES  
8.5.9.1 Efficacy 
Phase 3 segment 
The exploratory efficacy endpoints will be analyzed in the same manner as the primary 
hypothesis, but with a 95% CI and without the hypothesis test p-value.   
8.5.9.2 Immunogenicity 
Phase 2 segment 
Post-baseline increases from baseline in cellular response magnitudes will be 
compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
The summaries listed above will be stratified according to NP positive/negative status 
of the subjects. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more 
than 198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more 
than 380 days after Dose 2 for the Week 56 timepoint. . Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
Phase 3 Segment 
Post-baseline increases in antibody titers from ELISA will be compared between 
treatment groups using ratios of geometric mean fold-rises and associated 95% t-
distribution based CIs. 
Post-baseline increases from baseline in cellular response magnitudes will be 
compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
Post-baseline increases from baseline in neutralizing antibody response titers will be 
compared between treatment groups using ratios of geometric mean fold-rises and 
associated t-distribution based 95% CIs. 
The summaries listed above will be stratified according to disease status of the 
subjects. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more 
than 198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more 
than 380 days after Dose 2 for the Week 56 timepoint. . Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
8.5.9.3 Concomitant Medications 
Concomitant medications are those used during the course of the trial (on or after Day 
0). Partial stop dates of concomitant medications will be assumed to be the latest 
possible date consistent with the partial date; start dates will not be imputed. Data for 
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all concomitant medications will be summarized with percentages by treatment arm, for 
the ITT and PP populations. These summaries will be performed according to Phase. 
For the Phase 3 segment, the analyses listed above will also be performed according 
to SARS-CoV-2 serostatus at baseline. 
 
SAMPLE SIZE/POWER 
Phase 3 segment: The trial is case-driven. A total of  149 observed cases among baseline 
SARS-CoV-2 seronegative subjects will be required to provide 90% power to declare the 
vaccine efficacious (>30%), assuming a true efficacy of 60% and utilizing the methodology 
described in Section 8.5.1 and Section 8.5.6 .  A sample size of 6714 baseline SARS-
CoV-2 seronegative subjects will be required to achieve this number of cases assuming 
an underlying attack rate of 3.7%.   
 
RANDOMIZATION AND BLINDING  
Phase 2 Segment 
Subjects will be randomized (3 INO-4800 1.0 mg, one injection: 3 INO-4800 2.0 mg, two 
injections:1 Placebo, one injection: 1 Placebo, two injections). 
The study is blinded. It is double-blinded within dose group.  Randomization and blinding 
will avoid bias in the assignment of subjects to treatment, increase the likelihood that 
known and unknown subject attributes (e.g., demographics and other baseline 
characteristics) are evenly balanced between treatment groups, and enable valid 
statistical comparisons between treatment groups. 
Phase 3 Segment 
Subjects will be randomized (2 INO-4800:1 Placebo).  Randomization will be stratified 
according to two factors, each with two levels: a) age-group age category (18-50 years vs. 
≥51 years) on Day 0, and b) presence or absence on Day 0 of underlying medical 
conditions that increase risk of severe COVID-19 disease, per US CDC criteria. 
The study is double-blinded. Randomization and blinding will avoid bias in the assignment 
of subjects to treatment, increase the likelihood that known and unknown subject attributes 
(e.g., demographics and other baseline characteristics) are evenly balanced between 
treatment groups, and enable valid statistical comparisons between treatment groups. 
 
ETHICS 
 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical trial is 
performed in accordance with the protocol, the principles of the Declaration of Helsinki, 
Good Clinical Practice (GCP) and applicable regulatory requirements. 
 
INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD (REB)/ETHICS 
COMMITTEE (EC) 
The Investigator will commence the clinical trial after full approval of the protocol and 
adjunctive materials (e.g., ICF, advertising) has been obtained from the applicable 
IRB/REB/EC and a copy of IRB/REB/EC approval documentation has been received by 
the Sponsor. 
Investigator responsibilities relevant to the IRB/REB/EC include the following: 
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• Submit continuing review reports to the IRB/REB/EC as required, and request re-
review and approval of the clinical trial at least once a year during the conduct of 
the clinical trial; 
• Notify the Sponsor immediately of any suspected unexpected adverse drug or 
device events/effects; 
• Notify the IRB/REB/EC immediately if the Sponsor notifies the Investigator about 
any reportable safety events; 
• Obtain approval from the IRB/REB/EC for protocol amendments and for revisions 
to the consent form or subject recruitment advertisements, as required; 
• Submit reports on, and reviews of, the clinical trial and its progress to the 
IRB/REB/EC at intervals stipulated in their guidelines and in accordance with 
pertinent regulations and guidelines; 
• Maintain a file of clinical trial-related information (refer to clinical trial files) that 
includes all correspondence with the IRB/REB/EC; 
• Notify the IRB/REB/EC when the clinical trial is completed (i.e., after the last clinical 
trial visit of the final clinical trial subject); 
• After clinical trial completion (within three [3] months is recommended), provide the 
IRB/REB/EC with a final report on the clinical trial. 
Institutional Biosafety Committee (IBC) 
The Investigator will undertake the trial after full approval of the protocol and adjunctive 
materials (e.g., pharmacy manual) has been obtained from the applicable IBC and a copy 
of this approval has been received by the Sponsor. 
Investigator responsibilities relevant to the IBC include the following: 
• 
Notify the Sponsor, IBC and NIH OSP within 30 days of any: 
o Substantial problems or violation of the NIH Guidelines 
o Significant research related accidents or illnesses 
• 
Notify the IBC to any changes to the research (dosage, procedure, etc.) or facility 
(new space, remodeling, etc.).   
 
PROTECTION OF HUMAN SUBJECTS 
 COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent must be obtained from each subject prior to the subject’s 
enrollment in the clinical trial. The process for obtaining informed consent must be 
documented in the subject’s medical record (also refer to Section 6.2). 
 COMPLIANCE WITH INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD 
(REB)/ETHICS COMMITTEE (EC) REQUIREMENTS 
This clinical trial is to be conducted in accordance with applicable IRB/REB/EC 
regulations. The Investigator must obtain approval from a properly constituted 
IRB/REB/EC prior to initiating the clinical trial and obtain re-approval or review at least 
annually. The Sponsor is to be notified immediately if the responsible IRB/REB/EC has 
been disqualified or if proceedings leading to disqualification have begun. Copies of all 
IRB/REB/EC correspondence with the Investigator should be provided to the Sponsor. 
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 COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
 COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS (21CFR 
PART 11) 
When applicable, this clinical trial is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
 COMPLIANCE WITH PROTOCOL 
Subjects are not required to follow special instructions specific to the IP used in this clinical 
trial. Subjects will be provided with Investigator emergency contact information and 
advised to report all AEs. While every effort should be made to avoid protocol deviations, 
should an important deviation be discovered, the Sponsor must be informed immediately. 
Any protocol deviation impacting subject safety must be reported to the Medical Monitor 
immediately. 
 CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from, or changes to, the protocol 
without Sponsor approval and prior review and documented approval/favorable opinion of 
the protocol amendment from the IRB/REB/EC, except where necessary to eliminate 
immediate hazards to clinical trial subjects, or when the changes involve only logistical or 
administrative aspects of the clinical trial (e.g., change in monitors, change of telephone 
numbers).  
 DATA COLLECTION, MONITORING AND REPORTING 
 CONFIDENTIALITY AND PRIVACY 
A report of the results of this clinical trial may be published or sent to the appropriate 
regulatory authorities in any country in which the clinical trial products are legally marketed 
or may ultimately be marketed, but the subject’s name/identity will not be disclosed in 
these documents. The clinical trial Sponsor, its agents, the IRB/REB/EC and regulatory 
authorities will have direct access to the subjects’ medical records for the purposes of trial-
related monitoring, auditing and inspection. Appropriate precautions will be taken to 
maintain confidentiality of medical records and personal information. 
Written Authorization and other documentation are to be obtained from each subject, 
and/or from the subject’s legally authorized representative, prior to enrollment in the 
clinical trial, in accordance with all applicable laws, regulations and/or directives relating 
to privacy and data protection. 
 SOURCE DOCUMENTS 
Source data is all information, electronic or hardcopy original records or clinical findings, 
laboratory results, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the clinical trial. 
Examples of original source data records may include:  
• Hospital records 
• Clinical and office charts 
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• Laboratory notes 
• Memoranda 
• Pharmacy dispensing records 
• Recorded data from automated instruments 
• Copies of electronic medical records (EMR) certified after verification as being 
accurate and complete 
• X-rays 
• Subject files and records kept at the pharmacy, at the laboratories, at the medical 
records facility and within information technology (IT) systems that are involved in 
the clinical trial  
The Investigator/institution will permit clinical trial-related monitoring, audits, IRB/REB/EC 
review and regulatory inspections by providing direct access to source data/documents 
related to this clinical trial. 
 RECORDS RETENTION 
Upon request of the Clinical Monitor, Sponsor or its agent(s), auditor, IRB/REB/EC or 
regulatory authority, the Investigator/institution should make available for direct access all 
requested clinical trial-related records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
It is the Investigator’s responsibility to retain clinical trial essential documents for at least 
two (2) years after the last approval of a marketing application in their country and until 
there are no pending or contemplated marketing applications in their country or at least 
two (2) years have elapsed since the formal discontinuation of clinical development of 
INO-4800. This retention period may be superseded by local requirements. The Sponsor 
will inform the Investigator/institution when these documents are no longer needed to be 
retained. 
If the Records Retention requirements are addressed in a governing clinical trial 
agreement, it is the Investigator’s responsibility to retain clinical trial essential documents 
in accordance with the governing clinical trial agreement and applicable local 
requirements. 
 SAFETY AND QUALITY MONITORING 
 SAFETY REVIEW 
The Sponsor’s Safety Review Committee (SRC), composed of the Sponsor’s Medical 
Monitor, the ICON Medical Monitor and 1 additional physician, will review blinded safety 
and tolerability data on a regular basis throughout the trial. The SRC will refer any of the 
events listed in Section 7.8.4 or any other safety concerns to the DSMB Chair. 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will 
convene regularly to review all available unblinded safety data, and additionally upon 
completion of the Week 8 phone call visit for all subjects enrolled during the Phase 2 
segment. The DSMB will review unblinded safety and tolerability data, including AEs of 
clinical significance, AESIs and SAEs, as well as safety laboratory data for all enrolled 
subjects. The DSMB will also evaluate the data for signals of vaccine-enhanced disease 
and in the event of a signal, advise whether to halt the trial. The DSMB will advise 
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regarding any safety concerns and will make recommendations regarding continued 
enrollment, safety pause and trial suspension. For the Phase 3 segment, the DSMB will 
also review efficacy in an unblinded fashion. 
If the safety data is considered unfavorable during any safety review, the DSMB may 
recommend a trial pause or trial termination at which time further enrollment and 
administration of IP to subjects will be paused. The Sponsor will perform an investigation 
and consult with the DSMB and other experts, if needed, to determine whether to resume 
dosing of the remainder of the subjects. For further details, see the DSMB Charter.  
 CLINICAL MONITORING 
Clinical Monitoring will be performed by qualified Clinical Monitors who will report to the 
Sponsor or the Sponsor’s designee. The following clinical trial site monitoring tasks will be 
performed at all clinical trial sites: 
• 
Prior to subject screening at the site, a Site Initiation Visit will be conducted to 
review all relevant forms and documentation, and ensure that the clinical trial site 
staff are qualified and compliant with all applicable requirements 
• 
All clinical trial site monitoring visits will be documented 
• 
Periodic clinical trial site visits will be performed throughout the clinical trial 
• 
The Clinical Monitor will address and document the following trial conduct activities 
and obligations: 
o Assure that the trial is being conducted in accordance with the protocol, 
applicable regulatory agency regulations, and IRB/REB/EC policies. 
o Discuss trial conduct issues and incidents of noncompliance with the 
Investigator and/or trial personnel and document them on the resolution trip 
report. Report any significant unresolved problems immediately to the 
Sponsor. 
o Remind the Investigator as necessary of the obligation to immediately report 
all SAEs and provide subsequent follow-up report of the final outcome to the 
IRB. 
o Throughout the trial, inspect source documents to ensure they are complete, 
logical, consistent, attributable, legible, contemporaneous, original, accurate 
and complete (ALCOA-C). 
o Assure that the trial facilities, including the pharmacy, continue to be 
acceptable. 
o Compare the trial CRFs with source documents to assure that the data are 
accurate and complete and that the protocol is being followed. 
o Assure that investigational drug and device accountability and reconciliation of 
records are complete and accurate. 
o Assure that all subject specimens are being stored and forwarded properly for 
testing in accordance with laboratory manual requirements. 
 FINANCING AND INSURANCE 
Inovio Pharmaceuticals is the Sponsor of this study.  The Department of Defense, Joint 
Program Executive Office is providing funding for the Phase 2 segment of the study and 
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Page 86 of 93 
 
Inovio is providing funding for the Phase 3 segment. Clinical trial insurance has been taken 
out according to the laws of the countries where the study will be conducted. The 
investigative site is being compensated for the conduct of this study and will follow the 
terms described in the clinical trial agreement. This agreement was executed separately 
from this clinical trial protocol. The Investigators will be required to provide full financial 
disclosure information per ICH E6 R1. 
 PUBLICATION POLICY 
Publication of the results of this clinical trial in its entirety will be allowed. The proposed 
presentation, abstract and/or manuscript must be made available to the Sponsor for 
review and approval in accordance with the governing clinical trial agreement. 
 
 
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Page 87 of 93 
 
 LIST OF ABBREVIATIONS 
ADE 
Adverse Device Effect 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALCOA-C 
Attributable, Legible, Contemporaneous, Original, Accurate and Complete 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CBC 
Complete Blood Count 
Cl 
Chloride 
COVID-19 
Coronavirus Disease 2019 
Cr 
Creatinine 
CRF 
Case Report Form 
CS 
Clinically Significant 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELISpot 
Enzyme-linked immunosorbent spot-forming assay 
EP 
Electroporation 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCO3 
Biocarbonate 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICD 
Implantable-Cardioverter-defibrillator 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
ID 
Intradermal 
IM 
Intramuscular 
Inovio 
Inovio Pharmaceuticals Inc. 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
K 
Potassium 
MAAE 
Medically Attended Adverse Event 
mITT 
modified Intent to Treat 
MM 
Medical Monitor 
MERS 
Middle East Respiratory Syndrome  
MERS-CoV 
Middle East Respiratory Syndrome Coronavirus 
mRNA 
Messenger RNA 
Na 
Sodium 
NCS 
Not Clinically Significant 
NHP 
Non-human Primates 
NP 
Nucleocapsid Protein 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PII 
Personal Identifying Information 
PO4 
Potassium 
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Page 88 of 93 
 
PT 
Preferred Term 
RBC 
Red blood cell 
REB 
Research Ethics Board 
RR 
Respiratory Rate 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SARS 
Severe Acute Respiratory Syndrome  
SARS-CoV 
Severe Acute Respiratory Syndrome Coronavirus 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus - 2 
SID 
Subject Identification Number 
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
SynCon 
Synthetic consensus 
TBili 
Total Bilirubin 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of Child-bearing Potential 
 
 
 
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Page 89 of 93 
 
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Lu, H., C.W. Stratton, and Y.W. Tang, Outbreak of pneumonia of unknown etiology in 
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Hui, D.S., et al., The continuing 2019-nCoV epidemic threat of novel coronaviruses to 
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Huang, C., et al., Clinical features of patients infected with 2019 novel coronavirus in 
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The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, The 
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The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, Vital 
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Chan, J.F., et al., A familial cluster of pneumonia associated with the 2019 novel 
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Rothe, C., et al., Transmission of 2019-nCoV Infection from an Asymptomatic Contact in 
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Ganyani, T., et al., Estimating the generation interval for coronavirus disease (COVID-
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He, X., et al., Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
Page 90 of 93 
 
21. 
Liu, Y., et al., The reproductive number of COVID-19 is higher compared to SARS 
coronavirus. J Travel Med, 2020. 27(2). 
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testing/symptoms.html. 
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Gudbjartsson, D.F., et al., Spread of SARS-CoV-2 in the Icelandic Population. N Engl J 
Med, 2020. 
24. 
Day, M., Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ, 
2020. 369: p. m1375. 
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Centers for Disease Control and Prevention. COVID-19 Pandemic Planning Scenarios. 
July 10, 2020 July 20, 2020 July 27, 2020]; Available from: 
https://www.cdc.gov/coronavirus/2019-ncov/hcp/planning-scenarios.html. 
26. 
Lipsitch, M., et al., Transmission dynamics and control of severe acute respiratory 
syndrome. Science, 2003. 300(5627): p. 1966-70. 
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Peiris, J.S., et al., Clinical progression and viral load in a community outbreak of 
coronavirus-associated SARS pneumonia: a prospective study. Lancet, 2003. 
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28. 
Tsang, T.K., et al., Influenza A Virus Shedding and Infectivity in Households. J Infect 
Dis, 2015. 212(9): p. 1420-8. 
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Seow, J., et al., Longitudinal evaluation and decline of antibody responses in SARS-
CoV-2 infection. medRxiv, 2020: p. 2020.07.09.20148429. 
30. 
Long, Q.X., et al., Clinical and immunological assessment of asymptomatic SARS-CoV-2 
infections. Nat Med, 2020. 
31. 
Diao, B., et al., Reduction and Functional Exhaustion of T Cells in Patients With 
Coronavirus Disease 2019 (COVID-19). Front Immunol, 2020. 11: p. 827. 
32. 
Grifoni, A., et al., Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans 
with COVID-19 Disease and Unexposed Individuals. Cell, 2020. 181(7): p. 1489-1501 
e15. 
33. 
Modjarrad, K., et al., Safety and immunogenicity of an anti-Middle East respiratory 
syndrome coronavirus DNA vaccine: a phase 1, open-label, single-arm, dose-escalation 
trial. Lancet Infect Dis, 2019. 19(9): p. 1013-1022. 
34. 
Suschak, J.J., J.A. Williams, and C.S. Schmaljohn, Advancements in DNA vaccine 
vectors, non-mechanical delivery methods, and molecular adjuvants to increase 
immunogenicity. Hum Vaccin Immunother, 2017. 13(12): p. 2837-2848. 
35. 
Manickan, E., K.L. Karem, and B.T. Rouse, DNA Vaccines - A Modern Gimmick or a 
Boon to Vaccinology? Crit Rev Immunol, 2017. 37(2-6): p. 483-498. 
36. 
Porter, K.R. and K. Raviprakash, DNA Vaccine Delivery and Improved Immunogenicity. 
Curr Issues Mol Biol, 2017. 22: p. 129-138. 
37. 
Li, L. and N. Petrovsky, Molecular mechanisms for enhanced DNA vaccine 
immunogenicity. Expert Rev Vaccines, 2016. 15(3): p. 313-29. 
38. 
Marc, M.A., E. Dominguez-Alvarez, and C. Gamazo, Nucleic acid vaccination strategies 
against infectious diseases. Expert Opin Drug Deliv, 2015. 12(12): p. 1851-65. 
39. 
Grunwald, T. and S. Ulbert, Improvement of DNA vaccination by adjuvants and 
sophisticated delivery devices: vaccine-platforms for the battle against infectious 
diseases. Clin Exp Vaccine Res, 2015. 4(1): p. 1-10. 
40. 
Tregoning, J.S. and E. Kinnear, Using Plasmids as DNA Vaccines for Infectious 
Diseases. Microbiol Spectr, 2014. 2(6). 
41. 
Williams, J.A., Improving DNA vaccine performance through vector design. Curr Gene 
Ther, 2014. 14(3): p. 170-89. 
42. 
Liu, M.A., DNA vaccines: an historical perspective and view to the future. Immunol Rev, 
2011. 239(1): p. 62-84. 
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Protocol Version Date: 30-Apr-2021 
CONFIDENTIAL 
Protocol Version: 6.0 
 
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43. 
Wahren, B. and M.A. Liu, DNA Vaccines: Recent Developments and the Future. 
Vaccines (Basel), 2014. 2(4): p. 785-796wahren. 
44. 
Ledgerwood, J.E. and B.S. Graham, DNA vaccines: a safe and efficient platform 
technology for responding to emerging infectious diseases. Hum Vaccin, 2009. 5(9): p. 
623-6. 
45. 
Keefer, M.C., et al., Studies of high doses of a human immunodeficiency virus type 1 
recombinant glycoprotein 160 candidate vaccine in HIV type 1-seronegative humans. 
The AIDS Vaccine Clinical Trials Network. AIDS Res Hum Retroviruses, 1994. 10(12): p. 
1713-23. 
46. 
Wu, F., et al., Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered 
patient cohort and their implications. Medrxiv Preprint, 2020. 
47. 
Martin, J.E., et al., A DNA vaccine for Ebola virus is safe and immunogenic in a phase I 
clinical trial. Clin Vaccine Immunol, 2006. 13(11): p. 1267-77. 
48. 
Prud'homme, G.J., et al., Electroporation-enhanced nonviral gene transfer for the 
prevention or treatment of immunological, endocrine and neoplastic diseases. Curr Gene 
Ther, 2006. 6(2): p. 243-73. 
49. 
Hirao, L.A., et al., Combined effects of IL-12 and electroporation enhances the potency 
of DNA vaccination in macaques. Vaccine, 2008. 26(25): p. 3112-20. 
50. 
Rosati, M., et al., Increased immune responses in rhesus macaques by DNA vaccination 
combined with electroporation. Vaccine, 2008. 26(40): p. 5223-9. 
51. 
Curcio, C., et al., DNA immunization using constant-current electroporation affords long-
term protection from autochthonous mammary carcinomas in cancer-prone transgenic 
mice. Cancer Gene Ther., 2008. 15(2): p. 108-114. 
52. 
Ugen, K.E., et al., Regression of subcutaneous B16 melanoma tumors after intratumoral 
delivery of an IL-15-expressing plasmid followed by in vivo electroporation. Cancer Gene 
Ther., 2006. 13(10): p. 969-974. 
53. 
Tebas, P., et al., Safety and Immunogenicity of an Anti-Zika Virus DNA Vaccine - 
Preliminary Report. N Engl J Med, 2017. 
54. 
Tebas, P., et al., Intradermal SynCon(R) Ebola GP DNA Vaccine is Temperature Stable 
and Safely Demonstrates Cellular and Humoral Immunogenicity Advantages in Healthy 
Volunteers. J Infect Dis, 2019. 
55. 
De Rosa, S.C., et al., Robust antibody and cellular responses induced by DNA-only 
vaccination for HIV. JCI Insight, 2020. 5(13). 
56. 
Chandrashekar, A., et al., SARS-CoV-2 infection protects against rechallenge in rhesus 
macaques. Science, 2020. 
57. 
Patel, A., et al., Intradermal-delivered DNA vaccine provides anamnestic protection in a 
rhesus macaque SARS-CoV-2 challenge model. bioRxiv, 2020: p. 2020.07.28.225649. 
58. 
Andrade, V.M., et al., INO-4800 DNA Vaccine Induces Neutralizing Antibodies and T cell 
Activity Against Global SARS-CoV-2 Variants. bioRxiv, 2021: p. 2021.04.14.439719. 
59. 
Gary E., W.B.M., Parzych E.M., Griffin B.D., Zhu X., Tailor N., Tursi N.J., Chan M., 
Purwar M., Vendramelli R., Choi J., Frost K.L, Reeder S., Liaw K., Tello E., Ali A.R., Yun 
K., Pei Y.,Thomas S.,Rghei A.D.,  Guilleman M.M., Muthumani K., Smith T., Wootton 
S.K., Patel A., Weiner D.B., Kobasa D., A novel mouse AAV6 hACE2 transduction 
model of wild-type SARS-CoV-2 infection studied using synDNA immunogens. iScience, 
2021. 
60. 
Gooch, K., et al., One or two dose regimen of the SARS-CoV-2 synthetic DNA vaccine 
INO-4800 protects against respiratory tract disease burden in nonhuman primate 
challenge model. Research Square 2021. 
61. 
Trevor, S. Development of INO-4800, a DNA-vaccine for COVID-19. in Keystone 
Symposia Antibodies and Vaccines as Drugs for COVID-19. 2021. 
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European Commission, Directorate-General: A Guideline on Summary of Product 
Characteristics (SmPC). 2009, EMA. 
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Protocol Version Date: 30-Apr-2021 
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63. 
Diehl, M.C., et al., Tolerability of intramuscular and intradermal delivery by 
CELLECTRA((R)) adaptive constant current electroporation device in healthy volunteers. 
Hum Vaccin Immunother, 2013. 9(10): p. 2246-52. 
 
 
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Protocol Version: 6.0 
 
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 APPENDICES 
 APPENDIX A: ADVERSE EVENTS OF SPECIAL INTEREST  
For the purpose of standardization across multiple vaccine platforms, including those substantially 
different from Inovio’s platform, the below table lists AEs of special interest (AESIs) relevant to 
COVID-19 vaccine development.  
Body System 
AESI 
Respiratory 
Acute respiratory distress syndrome (ARDS) 
Pneumonitis/Pneumonia 
Neurologic 
Generalized convulsion 
Aseptic meningitis 
Guillain-Barré Syndrome (GBS) 
Encephalitis/Myelitis 
Acute disseminated encephalomyelitis (ADEM) 
CNS vasculopathy (stroke) 
Bell’s Palsy 
Transverse myelitis  
Narcolepsy 
Hematologic 
Thrombocytopenia 
Immune thrombocytopenia (ITP) 
Disseminated intravascular coagulation (DIC) 
Hemorrhagic stroke 
Non-hemorrhagic stroke 
Deep Vein Thrombosis (DVT) 
Pulmonary Embolism (PE) 
Immunologic 
Anaphylaxis 
Vasculitides 
Cardiac  
Acute cardiac failure 
Myocarditis/pericarditis 
Acute myocardial infarction 
Other 
Septic shock-like syndrome 
Appendicitis 
Multisystem Inflammatory Syndrome 
Acute kidney failure 
 
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CONFIDENTIAL 
 
Page 1 of 94 
 
 
 
 
 
 
 
 
COVID19-311 
 
Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the Safety, 
Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-
19 Disease, Administered Intradermally Followed by Electroporation in Adults at 
High Risk of SARS-CoV-2 Exposure   
 
 
 
INNOVATE 
(Inovio INO-4800 Vaccine Trial for Efficacy) 
 
 
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
IND #: 19690 
WHO UTN: U1111-1266-9952 
 
Protocol Version: 7.0 
 
Protocol Version Date: 8-Mar-2022 
 
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CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 2 of 94 
 
 
Medical Monitor Approval Page 
 
Drug:  
INO-4800 
 
Sponsor: 
Inovio Pharmaceuticals, Inc. 
 
660 W. Germantown Pike, Suite 110 
 
Plymouth Meeting, PA 19462 
 
Medical Monitor: 
 
Jr., M.D., FACP, FIDSA 
Inovio Pharmaceuticals, Inc. 
 
 
Approval Signature: 
 
 
[Electronically signed] 
  
Jr., M.D., FACP, FIDSA 
Inovio Pharmaceuticals, Inc. 
 
 Date (ddMmmyyyy) 
 
 
CONFIDENTIAL 
The information in this document is considered privileged and confidential by Inovio 
Pharmaceuticals Inc. (INOVIO) and may not be disclosed to others except to the extent 
necessary to obtain Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics 
Committee (EC) approval and informed consent, or as required by local regulatory 
authorities. Persons to whom this information is disclosed must be informed that this 
information is privileged and confidential and that it should not be further disclosed 
without the written permission of INOVIO. Any supplemental information added to this 
document is also confidential and proprietary information of INOVIO and must be kept in 
confidence in the same manner as the contents of this document. 
 
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Protocol Version: 7.0 
 
Page 3 of 94 
 
 
Principal Investigator Acknowledgement 
 
I have read and understood this Protocol and agree that it contains all details necessary to 
conduct the clinical trial. I understand that it must be reviewed by the Institutional Review Board 
(IRB)/Research Ethics Board (REB)/Ethics Committee (EC) overseeing the conduct of the clinical 
trial and approved or given favorable opinion before implementation. 
 
The Principal Investigator’s (PI’s) signature constitutes the PI’s approval of this Protocol and 
provides the necessary assurances that this clinical trial will be conducted in accordance with 
International Council for Harmonization (ICH)/Good Clinical Practice (GCP), local legal and 
regulatory requirements, and all stipulations of the Protocol. 
 
 
Principal Investigator Signature: 
 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
Principal Investigator Signature 
 
Date (ddMmmyyyy) 
 
 
 
Clinical Trial Site Number: 
 
Clinical Trial Site Name: 
 
 
 
 
 
 
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Protocol Version: 7.0 
 
Page 4 of 94 
 
SUMMARY OF CHANGES 
 
The following is a list of significant changes from Version 6.0, dated 30-Apr-2021, to Version 7.0, 
dated 8-Mar-2022. All other changes are administrative and do not significantly affect the safety 
of subjects, trial scope, or scientific integrity of the protocol. 
 
1. The endpoint of prevention of all COVID-19 disease has been moved from primary to 
secondary, and the endpoint of prevention of severe COVID-19 disease has been moved from 
secondary to primary. This change has been made in response to information pertaining to 
the SARS-CoV-2 B.1.1.529 (Omicron) strain, which suggests that current vaccines (including 
INO-4800) targeting SARS-CoV-2 will not protect against acquisition of SARS-CoV-2 
B.1.1.529 (Omicron) or symptomatic COVID-19 caused by B.1.1.529 (Omicron) but will 
protect against severe disease and hospitalization.   
2. Based on the revision of the primary endpoint, the required number of cases of disease to 
meet the primary endpoint of severe COVID-19 disease and sample size have changed. 
3. The interim analyses at 50% and 75% of cases have been removed. This is because the total 
number of cases of severe disease required to meet the primary endpoint is small, rendering 
any interim analysis of limited utility. 
4. The primary analysis population has been clarified that it will include “subjects who are SARS-
CoV-2 seronegative and RT-PCR negative at baseline”. 
5. All information previously clarified or corrected in protocol administrative memoranda and 
country-specific protocol amendments have been included in this amendment. 
 
 
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Page 5 of 94 
 
TABLE OF CONTENTS 
Summary of Changes ................................................................................................................ 4 
Table of Contents ....................................................................................................................... 5 
Clinical Protocol Synopsis .........................................................................................................10 
Table 3 – Phase 2 Segment Schedule of Events ......................................................................21 
Table 4 – Phase 3 Segment Schedule of Events ......................................................................23 
 
Introduction .................................................................................................................25 
 
Background and Scientific Rationale ........................................................................... 25 
 
Background Information .............................................................................................. 25 
 
Clinical Presentation, Transmission and Immune Response .................................26 
 
Current Treatment and Unmet Need .....................................................................27 
 
Rationale for prophylactic vaccine development ......................................................... 28 
 
DNA Vaccines.......................................................................................................28 
 
Use of Electroporation with DNA Vaccines ...........................................................29 
 
Inovio’s Proprietary Technology Against COVID-19 ..............................................29 
 
Nonhuman Primate (NHP) Challenge Studies Following Vaccination with INO-4800
 .............................................................................................................................30 
 
First-In-Human Phase 1 Trial of INO-4800 ............................................................30 
 
Proposed Phase 2/3 Trial of INO-4800 .................................................................31 
1.3.6.1 Safety and tolerability of INO-4800 .......................................................................32 
1.3.6.2 Nonclinical INO-4800 Data in Support of Potential Efficacy...................................32 
1.3.6.3 Potential Role of INO-4800 as a Booster ..............................................................32 
1.3.6.4 Thermostability of INO-4800 .................................................................................32 
 
Dose and Regimen Rationale ...............................................................................33 
1.3.7.1 Binding Antibody Response ..................................................................................34 
1.3.7.2 Neutralizing Antibody Response ...........................................................................34 
1.3.7.3 ELISPOT analysis .................................................................................................34 
 
Risks and Potential Benefits ....................................................................................... 34 
 
Potential Benefits ..................................................................................................34 
 
Product Risks........................................................................................................35 
 
Overall Benefit/Risk Conclusion ............................................................................37 
 
Objectives and Purpose ..............................................................................................37 
 
Hypothesis .................................................................................................................. 37 
 
Clinical Trial Design and Endpoints ............................................................................37 
 
Primary Objectives ...................................................................................................... 39 
 
Primary Endpoints....................................................................................................... 39 
 
Secondary Objectives ................................................................................................. 39 
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Secondary Endpoints .................................................................................................. 39 
 
Exploratory Objective .................................................................................................. 40 
 
Exploratory Endpoints ................................................................................................. 40 
 
Efficacy Assessment (Phase 3 Segment Only) ........................................................... 41 
 
Case Definition for Virologically-confirmed COVID-19 Disease: ............................41 
 
Case Definition for SARS-CoV-2 Asymptomatic Infection .....................................42 
 
Safety Assessment ..................................................................................................... 42 
 
Immunogenicity Assessment ...................................................................................... 42 
 
Clinical Trial Population ..............................................................................................42 
 
Inclusion Criteria ......................................................................................................... 42 
 
Phase 2 Segment .................................................................................................42 
 
Phase 3 Segment .................................................................................................43 
 
Exclusion Criteria ........................................................................................................ 45 
 
Phase 2 Segment .................................................................................................45 
 
Phase 3 Segment .................................................................................................46 
 
Discontinuation/Withdrawal of Clinical Trial Subjects .................................................. 47 
 
Clinical Trial Investigational Product Information .........................................................48 
 
Investigational Product (IP) and Study Device ............................................................ 48 
 
INO-4800 and Placebo .........................................................................................48 
 
CELLECTRA® 2000 ..............................................................................................49 
 
Dosing Regimens ....................................................................................................... 50 
 
Blinding .................................................................................................................50 
 
Packaging and Labeling .............................................................................................. 51 
 
INO-4800 or Placebo ............................................................................................51 
 
CELLECTRA® 2000 ..............................................................................................51 
 
Handling and Storage ................................................................................................. 51 
 
INO-4800 and Placebo .........................................................................................51 
 
CELLECTRA® 2000 ..............................................................................................51 
 
Preparation and Dispensing ........................................................................................ 52 
 
Use of Study Device ................................................................................................... 52 
 
Investigational Drug and Study Device Accountability ................................................. 52 
 
Investigational Product (IP) Accountability ............................................................52 
 
CELLECTRA® 2000 Accountability .......................................................................52 
 
Return and Destruction of Investigational Drug and Study Device .............................. 53 
 
INO-4800 and Placebo .........................................................................................53 
 
Return of CELLECTRA® 2000...............................................................................53 
 
Clinical Trial Procedures and Schedule ......................................................................53 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 7 of 94 
 
 
Procedure by Visit ....................................................................................................... 53 
 
Clinical Trial Screening Evaluations ......................................................................53 
6.1.1.1 Medical History .....................................................................................................54 
 
Clinical Trial Evaluations and Procedures .............................................................55 
6.1.2.1 Day 0 and Day 28 (Dosing Visits) .........................................................................55 
6.1.2.2 Post-dose phone calls ...........................................................................................56 
6.1.2.3 Day 42 Visit ..........................................................................................................56 
The Day 42 visit must occur at least 10 days after Day 28 visit. .........................................56 
6.1.2.4 Phone calls ...........................................................................................................57 
6.1.2.5 Follow up clinic visits.............................................................................................57 
6.1.2.6 Day 393 Visit or EOS ............................................................................................57 
6.1.2.7 COVID-19 Assessment Visit .................................................................................58 
6.1.2.8 COVID-19 Convalescent Visit ...............................................................................58 
 
Informed Consent ....................................................................................................... 59 
 
Assignment of Subject Identification Numbers ............................................................ 59 
 
Safety Evaluations ...................................................................................................... 60 
 
Intradermal Injection and EP .................................................................................62 
 
Management of Pain Due to Electroporation (EP) Procedures ..............................63 
 
Assessment of Laboratory Abnormalities ..............................................................63 
 
Assessment of Clinical Trial Adverse Events (AEs) ..............................................63 
 
Assessment of Injection Site Reactions ................................................................63 
 
Concomitant Medications/Treatments ...................................................................64 
 
Restrictions ...........................................................................................................64 
 
SARS-CoV-2 Testing ............................................................................................65 
 
COVID-19 Disease Monitoring ..............................................................................66 
 
Immunogenicity Assessments ..................................................................................... 67 
 
Evaluation of Safety and Management of Toxicity ......................................................67 
 
Safety Parameters ...................................................................................................... 67 
 
Adverse Events (AEs) ................................................................................................. 67 
 
Adverse Drug Reaction (ADR) .................................................................................... 68 
 
Serious Adverse Events (SAEs) .................................................................................. 68 
 
Unexpected Adverse Drug Reaction ........................................................................... 69 
 
Unanticipated (Serious) Adverse Device Effect (UADE) .............................................. 69 
 
Device Deficiency ....................................................................................................... 69 
 
Safety and Toxicity Management ................................................................................ 69 
 
Adverse Event of Special Interest (AESI) ..............................................................70 
 
Medically Attended Adverse Event (MAAE) ..........................................................70 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
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CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 8 of 94 
 
 
Abnormal Laboratory Value ..................................................................................70 
 
Clinical Trial Stopping Rules .................................................................................70 
 
Safety Data Reporting Period, Method of Collection and Submission ......................... 71 
 
Adverse Event Reporting ............................................................................................ 72 
 Submitting the Initial Serious Adverse Event (SAE) Report Form..........................72 
 Recording the Event .............................................................................................72 
 Assessing Severity (Intensity) ...............................................................................73 
 Causal Relationship of Clinical Material to Adverse Events (AEs) .........................73 
 
Reporting Suspected COVID-19 Disease Cases During the Trial ............................... 74 
 
Reporting Pregnancy During the Clinical Trial ............................................................. 74 
 
Reporting Device-Related Complaints or Deficiencies ................................................ 75 
 
Notifying Regulatory Authorities and Institutional Review Boards (IRBs)/Research 
Ethics Boards (REBs)/Ethics Committees (ECs) of Safety Information ....................... 75 
 Sponsor Responsibilities .......................................................................................75 
 Principal Investigator (PI) Responsibilities ............................................................75 
 
Post-Trial Reporting Requirements ............................................................................. 76 
 
Clinical Trial Discontinuation ....................................................................................... 76 
 
Statistical Considerations ...........................................................................................76 
 
Statistical and Analytical Plan ..................................................................................... 76 
 
General Considerations .............................................................................................. 76 
 
Statistical Hypotheses ................................................................................................. 77 
 
Analytical Populations ................................................................................................. 77 
 
Description of Statistical Methods ............................................................................... 77 
 
Primary Analysis ...................................................................................................77 
 
Secondary Analyses .............................................................................................78 
 
Safety Analyses ....................................................................................................79 
 
Disposition ............................................................................................................80 
 
Demographic and Other Baseline Characteristics .................................................80 
 
Interim Analyses ...................................................................................................80 
 
Multiplicity .............................................................................................................81 
 
Missing Values......................................................................................................81 
 
Exploratory Analyses ............................................................................................81 
 
Sample Size/Power ..................................................................................................... 82 
 
Randomization and Blinding ....................................................................................... 82 
 
Ethics .........................................................................................................................83 
 
Investigator and Sponsor Responsibilities ................................................................... 83 
 
Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics Committee (EC)
 ................................................................................................................................... 83 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 9 of 94 
 
 
Protection of Human Subjects ..................................................................................... 84 
 
Compliance with Informed Consent Regulations ...................................................84 
 
Compliance with Institutional Review Board (IRB)/Research Ethics Board 
(REB)/Ethics Committee (EC) Requirements ........................................................84 
 
Compliance with Good Clinical Practice ................................................................84 
 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11) .....84 
 
Compliance with Protocol .....................................................................................84 
 
Changes to the Protocol .......................................................................................84 
 
Data Collection, Monitoring and Reporting ..................................................................85 
 
Confidentiality and Privacy .......................................................................................... 85 
 
Source Documents .....................................................................................................85 
 
Records Retention ...................................................................................................... 85 
 
Safety and Quality Monitoring .....................................................................................86 
 
Safety Review ............................................................................................................. 86 
 
Clinical Monitoring....................................................................................................... 86 
 
Financing and Insurance ............................................................................................87 
 
Publication Policy .......................................................................................................87 
 
List of Abbreviations ...................................................................................................88 
 
References .................................................................................................................90 
 
Appendices .................................................................................................................94 
 
APPENDIX A: Adverse Events of Special Interest ...................................................... 94 
 
 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 10 of 94 
 
CLINICAL PROTOCOL SYNOPSIS 
Protocol Title: Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the 
Safety, Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-19 
Disease, Administered Intradermally Followed by Electroporation in Adults at High Risk of 
SARS-CoV-2 Exposure 
Protocol Number: COVID19-311 
Clinical Trial Phase: 2/3 
Estimated Number of Clinical Trial Centers and Countries/Regions: Approximately 70-
100 centers in Latin America, Asia Pacific, North America and Africa. 
Background:   
INO-4800 is a prophylactic vaccine under development against SARS-CoV-2, the causative 
agent of COVID-19. INO-4800 contains the plasmid pGX9501, which encodes for the full 
length of the Spike glycoprotein of SARS-CoV-2. The goal of this trial is to assess the safety, 
immunogenicity and efficacy of INO-4800 to prevent COVID-19 in subjects at high risk of 
exposure to SARS-CoV-2.  
 
Clinical Trial Design:  
This is an operationally seamless Phase 2/3, randomized, placebo-controlled, multi-center trial 
to evaluate the safety, immunogenicity, and efficacy of INO-4800, administered by intradermal 
(ID) injection followed immediately by electroporation (EP) using the CELLECTRA® 2000 
device, in a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-2 
exposure. The primary objectives of this trial are to identify in seronegative subjects an optimal 
age-related dose of INO-4800 in the Phase 2 segment for a subsequent efficacy evaluation in 
the Phase 3 segment.  
 
Subjects 18 years of age and older are expected to be enrolled across two (2) segments of 
this study. In the Phase 2 segment, approximately 400 seronegative subjects will be enrolled. 
In the Phase 3 segment, approximately 10,002 seronegative subjects are expected to be 
enrolled, and 402 seropositive subjects will be enrolled. The subjects and data from Phase 2 
are independent from that of Phase 3. 
 
Phase 2 Segment – Dose Selection 
In the Phase 2 segment, approximately 400 subjects 18 years of age and older will be 
evaluated across four (4) dose groups (Table 1, Figure 1). Subjects will be randomized at a 
3:3:1:1 ratio to receive either active investigational product (INO-4800) or placebo  according 
to Table 1 below. Dose groups receiving INO-4800 will enroll approximately 150 subjects per 
group. Dose groups receiving placebo will enroll approximately 50 subjects per group. 
Randomization will be such that approximately 240 subjects aged 18-50 years, 120 subjects 
aged 51-64 years and 40 subjects aged ≥ 65 years will be enrolled. Initial enrollment will 
include subjects aged 18-50 years. Initiation of enrollment of older subjects 51-64 years of age 
and elderly subjects 65 years and older will depend on review of safety and immunogenicity 
data from those age groups generated in the Phase 1 study (COVID19-001).   
 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 11 of 94 
 
Table 1: Phase 2 Segment Dose Groups 
Study  
Group 
Expected 
Number of 
Subjects 
Dosing 
Days 
Number of 
Injections + EP 
per Dosing Visit 
INO-4800 
(mg) per 
injection 
INO-4800 
(mg) per 
Dosing Visit 
Total Dose 
(mg) 
INO-4800 
150 
0, 28 
1 
1.0 
1.0 
2.0 
INO-4800 
150 
0, 28 
2a 
1.0 
2.0 
4.0 
Placebo 
50 
0, 28 
1 
0 
0 
0 
Placebo 
50 
0, 28 
2a 
0 
0 
0 
Total 
400 
 
 
 
 
 
aINO-4800 or placebo will be injected ID followed immediately by EP in an acceptable location on two different limbs at each 
dosing visit. 
 
Dose selection for evaluation of efficacy in the Phase 3 segment will be based on Week 6 
immunogenicity data and Week 8 safety data from the Phase 2 segment. Group-level unblinded 
summaries and analyses of safety will be produced once the Week 8 phone call visit data are 
completed for all subjects in the Phase 2 segment. Group-level unblinded summaries and 
analyses of immunogenicity will be produced once the Week 6 visit data are completed for all 
subjects in the Phase 2 segment. Subject treatment assignments will be unblinded after Phase 
2 subjects have reached the Week 30 visit. 
 
Phase 3 Segment – Efficacy 
In the Phase 3 segment, approximately 10,002 seronegative and 402 seropositive subjects 18 
years of age and older will be randomized at a 2:1 ratio to receive either active investigational 
product (INO-4800, 2.0 mg) or placebo. See Table 2 and Figure 1.  Approximately half of 
seronegative subjects and approximately half of seropositive subjects will be 18-50 years of 
age, and the other half will be ≥51 years of age as is operationally feasible. 
 
Subjects will be randomized in a stratified manner according to (a) age category (18-50 years 
vs. ≥51 years) on Day 0, and (b) presence or absence on Day 0 of any of the following 
underlying medical conditions that increase risk of severe COVID-19 disease, per U.S. Center 
for Disease Control (CDC) criteria [1], as listed below: 
• 
Cancer 
• 
Chronic kidney disease 
• 
Chronic lung diseases, including Chronic obstructive pulmonary disease (COPD), 
asthma (moderate-to-severe), interstitial lung disease, cystic fibrosis, pulmonary 
hypertension 
• 
Neurologic conditions including stroke or cerebrovascular disease that do not impact 
cognition 
• 
Diabetes (type 1 or type 2) 
• 
Hypertension 
• 
Heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies 
• 
HIV infection 
• 
Liver disease 
• 
Obesity (BMI ≥ 30 kg/m2) 
• 
Sickle cell disease or thalassemia, or 
• 
Smoking (current or former smoker). 
 
 
 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 12 of 94 
 
Table 2: Phase 3 Segment  
Treatment 
Arm 
Sero 
status 
Expected 
Number 
of 
Subjects 
Approx. 
Expected 
Number of 
Subjects by 
Age Group 
Dosing 
Days 
Number of 
Injections + 
EP per 
Dosing Visit 
INO-4800 
(mg) per 
injection 
INO-4800 
(mg) per 
Dosing Visit 
Total Dose 
of 
INO-4800 
(mg) 
18-50 
51+ 
INO-4800 
Seroneg 
6668 
3334 
3334 
0, 28 
2 
1.0 
2.0 
4.0 
Seropos 
268 
134 
134 
Placebo 
Seroneg 
3334 
1667 
1667 
0, 28 
2 
0 
0 
0 
Seropos 
134 
67 
67 
Total 
Seroneg 
10002 
5001 
5001 
 
 
 
 
 
Seropos 
402 
201 
201 
 
 
 
 
 
Total 
10404 
 
 
 
 
 
 
 
 
 
This segment of the trial is case-driven. Among subjects who are SARS-CoV-2 seronegative 
and RT-PCR negative at baseline, a total of 17 observed severe COVID-19 cases will be 
required for 90% power to declare the vaccine efficacious (>30%), assuming a true efficacy of 
90%. A sample size of 10,002 seronegative subjects is expected to be required to achieve the 
17 severe cases assuming an underlying attack rate of 0.4%. The actual sample size may 
differ if the observed attack rate is different than projected. If the criteria for efficacy are met, 
placebo-recipients will be offered the active product. 
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12 months 
post-dose 2. All Phase 3 segment subjects will be followed for 56 weeks from the Day 0 dosing 
[i.e., Week 56 will be the planned End of Study (EOS) visit for this segment of the trial]. 
 
Figure 1: Enrollment and Dose Group Design 
 
 
 
External Committee Reviews 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will convene 
regularly to review all available unblinded safety data. For the Phase 3 segment, the DSMB 
will also review efficacy in an unblinded fashion. Additionally, for the Phase 3 segment, an 
independent, blinded Endpoint Adjudication Committee (EAC) will review and confirm COVID-
19 cases.  
 
Details of each committee’s scope will be provided in the respective charters. 
  
Criteria for Evaluation:  
 
Research Hypothesis:  
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 13 of 94 
 
INO-4800 delivered ID followed immediately by EP will be well-tolerated, exhibit an acceptable 
safety profile, result in generation of cellular and humoral immune responses to SARS-CoV-2 
Spike glycoprotein and provide protection against virologically-confirmed severe COVID-19 
disease in subjects at high risk of SARS-CoV-2 exposure.  
 
Phase 2 Segment Objectives and Endpoints: 
 
Primary Objective 
Primary Endpoint 
1.  Evaluate the cellular and humoral 
immune response to INO-4800 
administered by ID injection followed 
immediately by EP  
  
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot 
1b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
Secondary Objective 
Secondary Endpoints 
1.  Evaluate the safety and tolerability of 
INO-4800 administered by ID injection 
followed immediately by EP    
  
1a. Incidence of solicited and unsolicited injection site 
reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)   
Exploratory Objective 
Exploratory Endpoint 
1.  Evaluate the expanded immunological 
profile of antibody response and T cell 
immune response 
  
1a.  Antigen-specific cellular immune response 
measured by flow cytometry 
1b. Expanded immunological profile which may 
include additional assessments of T and B cell 
numbers and molecular changes by measuring 
immunologic proteins and mRNA levels of genes 
of interest as determined by sample availability 
 
Phase 3 Segment Objectives and Endpoints: 
 
Primary Objective 
Primary Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of severe COVID-19 
disease in subjects who are SARS-
CoV-2 seronegative and RT-PCR 
negative at baseline  
 
1.   Incidence of virologically-confirmed severe 
COVID-19 disease starting 14 days after 
completion of the 2-dose regimen until 12 months 
post-dose 2 (End of Study (EOS)) in subjects who 
are SARS-CoV-2 seronegative and RT-PCR 
negative at baseline 
Secondary Objectives 
Secondary Endpoints 
1. Evaluate the safety and tolerability of 
INO-4800    
 
1a. Incidence of solicited and unsolicited injection site 
reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
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Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
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Protocol Version: 7.0 
 
Page 14 of 94 
 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality 
 
2.  Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of severity in 
subjects who are SARS-CoV-2 
seronegative and RT-PCR negative at 
baseline       
2a.  Incidence of non-severe COVID-19 disease in 
subjects who are SARS-CoV-2 seronegative and 
RT-PCR negative at baseline starting 14 days 
after completion of the 2-dose regimen until EOS  
2b. Incidence of COVID-19 disease in subjects who 
are SARS-CoV-2 seronegative and RT-PCR 
negative at baseline starting 14 days after 
completion of the 2-dose regimen until EOS 
2c. Incidence of deaths due to COVID-19 in subjects 
who are SARS-CoV-2 seronegative and RT-PCR 
negative at baseline starting 14 days after 
completion of the 2-dose regimen until EOS 
3.  Evaluate the cellular and humoral 
immune response to INO-4800  
3a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot  
3b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
 
4. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease in 
subjects who are SARS-CoV-2 
seropositive at baseline  
 
4.  Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 (End 
of Study (EOS)) in subjects who are SARS-CoV-
2 seropositive at baseline 
Exploratory Objective 
Exploratory Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease 
from SARS-CoV-2 variants in subjects 
who are SARS-CoV-2 seronegative 
and RT-PCR negative at baseline 
1. Incidence of virologically-confirmed COVID-19 
disease from a SARS-CoV-2 variant starting 14 
days after completion of the 2-dose regimen until 
12 months post-dose 2 (End of Study (EOS)) in 
subjects who are SARS-CoV-2 seronegative and 
RT-PCR negative at baseline 
2. Evaluate the efficacy of INO-4800 in 
the prevention of SARS-CoV-2 
asymptomatic infection in subjects 
who are SARS-CoV-2 seronegative 
and RT-PCR negative at baseline     
2. Incidence of SARS-CoV-2 asymptomatic 
infections in in subjects who are SARS-CoV-2 
seronegative and RT-PCR negative at baseline 
starting 14 days after completion of the 2-dose 
regimen until EOS 
3.  Evaluate the immunological profile by 
assessing both antibody response and 
T cell immune response  
3a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels  
3b. Antigen-specific cellular immune response such as 
measured by flow cytometry  
4. Evaluate antibody persistence  
4a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels at Week 30 or later.  
4b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay at Week 
30 or later 
 
 
Immunogenicity Assessment:  
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 3 and Table 4).  Assays such as binding enzyme-linked immunosorbent assay (ELISA), 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
Page 15 of 94 
pseudovirus-based neutralization assay, and enzyme-linked immunosorbent spot-forming 
assay (ELISpot) will be evaluated at serial timepoints. 
Safety Assessment: 
Subjects will be followed for safety during the trial through scheduled clinic visits and phone 
calls. Adverse events (AEs), regardless of relationship to study drug, will be collected from 
the time of consent until 28 days post-dose 2 (i.e., Day 56). SAEs, Medically Attended Adverse 
Events (MAAEs) and AESIs will be collected from time of consent until EOS. SAEs, AESIs 
and treatment-related AEs will be followed to resolution or stabilization. For the Phase 2 
segment and at selected sites in the Phase 3 segment, solicited local and systemic AEs will 
be collected for 7 days following each dose using a participant diary. 
Subjects will also be monitored for COVID-19. 
Please refer to the Schedule of Events (Table 3 and Table 4) for safety assessments to be 
performed.  
Efficacy Assessment (Phase 3 segment only): 
Subjects will receive either active investigational product (INO-4800) or placebo in a 2-dose 
regimen administered on Days 0 and 28 intradermally followed immediately by EP. Subjects 
will be monitored through regularly scheduled clinic visits and phone calls throughout the trial. 
Subjects will be regularly tested for SARS-CoV-2 infection using serologic testing. If COVID-
19 disease (including severe disease) is suspected based on symptoms per the case 
definition or laboratory testing, site personnel will arrange for a clinic visit. Subjects with 
symptom(s) or a positive SARS-CoV-2 test result will be reviewed by the EAC. The EAC will 
adjudicate all suspected COVID-19 events and determine whether cases meet the case 
definitions (per Section 3.7) for COVID-19 disease, severe COVID-19 or SARS-CoV-2 
asymptomatic infection. 
Clinical Trial Population: 
Phase 2 segment: Healthy subjects at high risk for SARS-CoV-2 exposure who are 18 years 
and older. 
Phase 3 segment: Subjects at high risk for SARS-CoV-2 exposure including subjects at high 
risk for severe COVID-19 who are 18 years and older. 
Inclusion Criteria: Phase 2 segment 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior
to screening procedures;
b. Men and non-pregnant women 18 years of age or older;
c.
Assessed by the Investigator to be healthy based on medical history, vital signs and
physical examination performed at Screening;
d. Able and willing to comply with all study procedures;
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for
whom exposure may be relatively prolonged or for whom personal protective
equipment (PPE) may be inconsistently used, especially in confined settings:
1. Retail/service workers/educators (restaurant waitresses/waiters and bar
workers, store cashiers, hairdressers and barbers, veterinary staff, daycare
workers, Transportation Security Administration screening staff, school
teachers and college professors teaching in-person classes)
2. Factory workers (when working in confined settings with large numbers of
employees)
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft)
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 16 of 94 
 
4. User of public transportation (e.g., bus, train, subway) at least 3 times weekly 
5. Nursing home staff or correctional facility staff  
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists.) Physicians should not be enrolled unless they 
are assigned to dedicated COVID-19 treatment wards or other settings with 
prolonged exposure 
10. Others, if approved by the medical monitor.   
f. Screening laboratory results within normal limits for testing laboratory or are deemed 
not clinically significant by the Investigator; 
g. Must meet one of the following criteria with respect to reproductive capacity: 
1. Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
2. Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or 
tubal ligation, absence of ovaries and/or uterus in females). In the case of 
vasectomy, subjects should wait six (6) months post-vasectomy prior to 
enrolling;  
3. Use of medically effective contraception with a failure rate of < 1% per year 
when used consistently and correctly from screening until 3 months following 
last dose. Acceptable methods include:  
i. hormonal contraception including implants, injections or oral; 
ii. two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
iii. intrauterine device or intrauterine system; 
iv. abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Inclusion Criteria: Phase 3 segment 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Per investigator judgment, healthy or stable with pre-existing medical conditions that 
do not require significant change in medication or have led to a hospitalization in the 3 
months prior to enrollment or who, in the judgment of the investigator, are unlikely to 
require a significant change in therapy or hospitalization for worsening disease through 
Day 56; 
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings. Examples 
include:  
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 17 of 94 
 
1. Retail/service workers/educators (restaurant waitresses/waiters and bar 
workers, street vendors, store cashiers, hairdressers and barbers, veterinary 
staff, daycare workers, airport screening staff, school teachers and college 
professors teaching in-person classes, college students attending in-person 
classes, office workers and volunteers who have multiple brief exposures to 
people regularly) 
2. Factory workers (when working in confined settings with large numbers of 
employees, meat-packing facilities) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) and delivery 
services  
4. User of public transportation (e.g., bus, train, subway) or public facilities (e.g. 
gyms) at least 3 times weekly 
5. Nursing home staff or correctional facility staff 
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, medical assistants and technicians, respiratory therapists, 
physical therapists, social workers, dentists and dental hygienists)  
10. Others, if in the opinion of the PI, the risk of COVID-19 exposure is comparable 
to the examples above.   
f. Must meet one of the following criteria with respect to reproductive capacity: 
1. Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
2. Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or 
tubal ligation, absence of ovaries and/or uterus in females). In the case of 
vasectomy, subjects should wait six (6) months post-vasectomy prior to 
enrolling;  
3. Use of medically effective contraception with a failure rate of < 1% per year 
when used consistently and correctly from screening until last dose. Acceptable 
methods include:  
i. hormonal contraception including implants, injections or oral; 
ii. two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
iii. intrauterine device or intrauterine system; 
iv. abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 
Exclusion Criteria: Phase 2 segment 
a. Acute febrile illness with temperature >100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat); 
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 18 of 94 
 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the Screening visit until 3 
months following the last dose; 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or a 
detectable viral load within the past 3 months; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous receipt of an investigational vaccine for prevention or treatment of COVID-19, 
MERS or SARS (documented receipt of placebo in previous trial would be permissible 
for trial eligibility); 
h. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg prior to first dose; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin 
cancers that only required local excision and non-metastatic prostate cancer 
not requiring treatment; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in 
therapy or hospitalization for worsening disease during the 6 weeks prior to 
enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a 
single antiepileptic agent; 
i. 
Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed); 
• 
Current or anticipated use of disease modifying doses of systemic anti-
rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, 
cyclosporine, 
methotrexate) and biologic disease modifying drugs such as TNF-α inhibitors 
(e.g., infliximab, adalimumab or etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the 
subject or require therapy that would interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results. 
j. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 19 of 94 
 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation 
site; 
k. Blood donation or transfusion within 1 month prior to Day 0; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the past 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
 
Exclusion Criteria: Phase 3 segment 
a. Acute febrile illness with temperature ≥100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat) within 
72 hours prior to Day 0 dosing; 
b. Positive serologic test for SARS-CoV-2 at Screening (this criterion only applies after 
approximately 402 subjects positive for SARS-CoV-2 serologic test are randomized, 
after which this criterion will apply to all remaining subjects); 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children starting from the Screening visit until the last dose; 
d. Positive urine pregnancy test during screening or immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or a 
detectable viral load within 3 months prior to screening; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days prior to Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous or planned receipt of an investigational (including Emergency Use 
Authorization (EUA) or local equivalent authorization) or licensed vaccine for 
prevention or treatment of COVID-19, MERS or SARS (documented receipt of placebo 
in previous trial would be permissible for trial eligibility); 
h. Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed) in the past 6 months; 
• 
Current or anticipated use of disease modifying doses of systemic anti-
rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, 
cyclosporine, 
methotrexate) and biologic disease modifying drugs such as TNF-α inhibitors 
(e.g., infliximab, adalimumab or etanercept) or others; 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the 
subject or require therapy that would interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results. 
i. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 20 of 94 
 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation 
site; 
j. 
Blood donation or transfusion within 1 month prior to Day 0; 
k. People who work remotely or in a socially distanced setting with minimal risk of 
exposure to SARS-CoV-2; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the prior 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
Clinical Trial Treatment: 
Phase 2 Segment 
Active Investigational Product: One or two 1.0mg ID injection(s) of INO-4800 (~0.1mL dose 
volume) followed immediately by EP administered on Day 0 and Day 28 (±3 days)  
Placebo: One or two ID injection(s) of Placebo (saline sodium citrate buffer or SSC) (~0.1mL) 
followed immediately by EP administered on Day 0 and Day 28 (±3 days) 
Phase 3 Segment 
Active Investigational Product: Two 1.0mg ID injections of INO-4800 followed immediately by 
EP administered in separate limbs at Day 0 and Day 28 (±3 days) 
Placebo: Two ID injections of Placebo followed immediately by EP administered in separate 
limbs at Day 0 and Day 28 (±3 days). Placebo may also be referred to as Placebo for INO-
4800 or Sterile SSC Buffer. 
Formulation: 
INO-4800 is formulated in sodium chloride and sodium citrate buffer, refrigerated. Placebo 
for INO-4800 (sterile saline sodium citrate (SSC) buffer), refrigerated. 
 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 21 of 94 
 
TABLE 3 – PHASE 2 SEGMENT SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Tel 
#1 
Wk 
4 
Tel 
#2 
Wk
6 
Tel 
#3 
Wk 
30 
Wk 
56 
Illness 
Illness  
Screena 
Day 0 
Phone call - Day 7 (±3d) 
Day 28 
(±3d) 
Phone call - Day 35 (±3d) 
Day 42 (±5d) 
Phone Call - Day 56 (±5d) 
Day 210 (±5d) 
Day 393 (± 5d) 
COVID-19 assessment visitm  
COVID-19 convalescent visitn 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behavioral Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
Vital Signs 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
Xp 
Xp 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differentialc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Chemistryc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
HIV Serology  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis Routined 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Pregnancy Teste 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
INO-4800 or Placebo + EPf 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Download EP Datag 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Adverse Eventsh  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Samplesi 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
Humoral Samplesj 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
SARS-CoV-2 Serologyk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 RT-PCR (Saliva and Swabs) 
Xl 
 
 
 
 
 
 
 
 
 
 
Xl 
Xl 
Distribute Diary 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Review/Collect Diaryo 
 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
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Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 22 of 94 
 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0.   
b. 
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits.  
c. 
Hemoglobin A1c collected at screening only. Chemistry includes Na, K, Cl, HCO3, Ca, PO4, glucose, BUN, Cr, alkaline phosphatase, AST, ALT, LDH, total bilirubin.  
d. 
Dipstick for glucose, protein, and hematuria. Microscopic examination should be performed if dipstick is abnormal.  
e. 
Serum pregnancy test at Screening. Urine pregnancy test at other visits.  
f. 
Intradermal injection(s) in skin preferably over deltoid muscle, or alternately over anterolateral quadriceps muscle, followed by EP at Day 0 and Day 28. 
g. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
h. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
i. 
On Day 0, cellular sampling requires 64 mL of whole blood (8 Cell Preparation Tubes (CPT), each 8 mL of whole blood) prior to 1st dose. At all other time points, collect 32 mL of 
whole blood (4 CPT tubes, each 8 mL of whole blood).   
j. 
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce eight serum aliquots of 1 
mL each). At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce four serum aliquots of 1 mL each.  
k. 
SARS-CoV-2 antibody.   
l. 
Saliva specimen at Screening; Nasal swabs and saliva specimens at COVID-19 assessment and convalescent visits. Genotyping may also be performed on sample(s) collected at 
the COVID-19 assessment visit. 
m. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The assessment visit may be performed in the clinic, in the subject’s vehicle 
or at the subject’s home and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test.  
n. 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of 
symptoms, the date of positive SARS-CoV-2 test. If acute symptoms are ongoing, the site should follow up with the subject via phone call or an unscheduled visit after symptom 
resolution or stabilization.   
o. 
Diary should be reviewed at the 7-day post-dose phone call and collected at the next in-office visit. 
p. 
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation. 
 
 
 
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Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 23 of 94 
 
TABLE 4 – PHASE 3 SEGMENT SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Tel 
#1 
Wk 
4 
Wk
6 
Tel 
#2-6 
Wk 
18 
Tel 
#7-11 
Wk 
30 
Tel 
#12-13 
Wk
42 
Tel 
#14-16 
Wk 
56 
Illness 
Illness 
Screena 
Day 0 
Phone call - Day 14 (±3d) 
Day 28 
(±3d) 
Day 42 (±5d)k 
Phone call - Days 56, 70, 84, 
98, 112 (±5d) 
Day 126 (±5d) 
Phone calls - Days 140, 154 
168, 182, 196 (±5d) 
Day 210 (±5d) 
Phone calls - Days 238, 266 
(±5d) 
Day 294 (±5d) 
Phone calls 
Days 322, 350, 378 (±5d) 
Day 393 (± 5d) 
COVID-19 assessment visitl  
COVID-19 convalescent visitm 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behavioral Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Vital Signs 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Xn 
Xn 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testc 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
INO-4800 or Placebo + EPd 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Download EP Datae 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Eventsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Samplesg 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
X 
Humoral Samplesh 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
X 
SARS-CoV-2 Serologyi 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
SARS-CoV-2 RT-PCR 
(Nasopharyngeal swabs) 
 
Xj 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
 
Distribute Diaryp 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Review/Collect Diaryq 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0. Screening and Day 0 visits may be combined if eligibility is able to be confirmed prior to dosing. If so, all assessments 
for Screening and Day 0 must be performed at the combined visit.  
b. 
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits.  
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 24 of 94 
 
c. 
In women of childbearing potential. Urine pregnancy test at all indicated visits.  
d. 
Intradermal injection(s) in skin preferably over deltoid region, or alternately over anterolateral quadriceps region, followed by EP at Day 0 and Day 28. 
e. 
Following administration of INO-4800 or placebo, a subset of sites will be required to download EP data from the CELLECTRA® 2000 device and provided to Inovio. 
f. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
g. 
On Day 0, cellular sampling requires 64 mL of whole blood prior to 1st dose. At all other time points, collect 32 mL of whole blood. Cellular samples will be collected at selected clinical sites 
(estimated to include 711 subjects) 
h. 
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce four serum aliquots of 2 mL 
each). At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce two serum aliquots of 2 mL each.  
i. 
SARS-CoV-2 antibody. Screening samples will be tested in the clinic via rapid test to detect antibodies against the Spike protein. Samples collected pre-dose Day 0 and at subsequent 
timepoints will be tested at a study-designated lab to detect antibodies against the Nucleocapsid protein. 
j. 
The Day 0 RT-PCR results will not be required prior to dosing on that day. 
k. 
Day 42 visit must occur at least 10 days after Day 28 visit. 
l. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The assessment visit may be performed in the clinic, subject’s vehicle, or at a 
home visit and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test.  
m. 
For subjects with virologically-confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the 
absence of symptoms, after the collection date of any specimen testing positive for SARS-CoV-2 RT-PCR. If acute symptoms are ongoing the site should follow up with the subject 
via phone call or unscheduled visit after symptom resolution or stabilization 
n. 
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation.   
o. 
Genotyping may also be performed on sample(s) collected at the COVID-19 assessment visit.  
p. 
Diaries to be used at selected sites only (estimated to include 711 subjects). 
q. 
Diary should be reviewed at the 14-day post-dose phone call or visit and collected at the next in-office visit. 
r. 
When possible, cellular and humoral immunology samples will be collected. Cellular samples will be collected at selected sites only. 
 
 
 
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Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 25 of 94 
 
 
INTRODUCTION 
This document is a protocol for a human research trial to be conducted according to U.S. 
and international standards of Good Clinical Practice (GCP) (FDA Title 21 part 312, 812 
and International Conference on Harmonization (ICH) guidelines), applicable government 
regulations and Institutional research policies and procedures. 
 
BACKGROUND AND SCIENTIFIC RATIONALE 
Given the continued number of cases globally, SARS-CoV-2 infections remain a serious 
unmet medical concern. Appropriate measures to prevent SARS-CoV-2 infections, 
including its variants, are not yet widely available. 
 
BACKGROUND INFORMATION 
In late 2019, a cluster of cases of pneumonia of unknown etiology was reported in Wuhan, 
Hubei province, China [2-4]. These cases were announced on January 6, 2020 as testing 
negative for influenza, severe acute respiratory syndrome (SARS), and Middle East 
respiratory syndrome (MERS). On January 7, 2020 a novel virus was isolated by the 
Chinese Center for Disease Control and Prevention (CDC) from the throat swab sample 
of a patient, and the isolate was named “Wuhan-Hu-1.” The gene sequence of that isolate 
was then generated and determined to be of a novel coronavirus [5, 6]. That gene 
sequence was publicly posted on January 10, and the novel coronavirus was preliminarily 
named 2019-nCoV. Subsequently, on February 11, 2020, the virus was named SARS-
CoV-2 by the International Committee on Taxonomy of Viruses (ICTV) [7, 8], due to its 
similarity with the original SARS virus. That same day, the World Health Organization 
(WHO) announced a specific name of the disease, “COVID-19,” associated with infection 
by this novel coronavirus, as based on the novel coronavirus origin and year of first 
reported cases. The first cluster of human cases identified comprised people who worked, 
visited, or lived around the local Huanan seafood wholesale market in Wuhan, where live 
animals and fresh meat and fish were on sale, suggesting that an animal was the source 
of the novel respiratory virus being transmitted to humans.  
Epidemiologic data suggest that droplets expelled during face-to-face exposure during 
talking, coughing, or sneezing is the most common mode of transmission while contact 
surface spread remains yet another possible mode of transmission [9].  
SARS-CoV-2 infection rapidly emerged as a global threat to public health, joining other 
coronavirus-related diseases, such as SARS and MERS. COVID-19 was declared a 
Public Health Emergency of International Concern (PHEIC) by the WHO on January 20, 
2020, and was declared a pandemic on March 11, 2020 [10], associated with substantial 
morbidity and mortality [11]. As of July 25, 2020, a total of nearly 16 million laboratory-
confirmed COVID-19 cases have been reported internationally, including over 643,000 
deaths [12]. However, given the lack of widespread testing, the true number of cases of 
COVID-19 is likely far higher than reported. Preliminary results from large U.S.-based 
seroepidemiological surveys indicate an estimated incidence rate of SARS-CoV-2 
infections to be 6 to 24 times that of the number of reported cases of COVID-19 [13].  
An article in JAMA by Wu and McGoogan [14] provided a summary of a major report by 
the Chinese Center for Disease Control and Prevention (China CDC) [15]. Of a total of 
72,314 case records, 44,672 (62%) were confirmed as SARS-CoV-2 infections based on 
positive viral nucleic acid test results on throat swabs, 16,186 (22%) as suspected cases 
based on symptoms and exposures only, 10,567 (15%) as clinically diagnosed based on 
symptoms, exposures, and presence of lung imaging features consistent with coronavirus 
pneumonia, and 889 (1%) as asymptomatic cases based on a positive viral nucleic acid 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 26 of 94 
 
test result but lacking typical symptoms including fever, dry cough, and fatigue [16]. The 
overall case-fatality ratio (CFR) was 2.3% (1023 deaths among 44,672 confirmed cases). 
No deaths occurred in the group aged 9 years and younger, but cases in those aged 70 
to 79 years had an 8.0% CFR and cases in those aged 80 years and older had a 14.8% 
CFR. The CFR was 49.0% among critical cases. CFR was elevated among those with 
preexisting comorbid conditions - 10.5% for cardiovascular disease, 7.3% for diabetes, 
6.3% for chronic respiratory disease, 6.0% for hypertension, and 5.6% for cancer [16]. 
These initial reports of the CFR documented the level of seriousness of COVID-19.  
Given the novelty of SARS-CoV-2, its rapid spread among humans and its associated 
morbidity and mortality, there has been an explosion of epidemiological, clinical, virologic, 
and other scientific data regarding the propagation of effects of this virus emerging from 
China, the United States, and many other countries. These data have established that 1) 
SARS-CoV-2 is transmitted person-to-person [17], even from those who are asymptomatic 
or presymptomatic [18-20], 2) the virus is very infectious, with estimates of the R0 
(Reproductive number) ranging from 1.50 to 6.49, with a mean average of 3.28 and a 
median average of 2.79 [21], 3) the constellation of symptoms, signs, and an incubation 
period ranging between  2 and 14 days [22], and 4)  the asymptomatic proportion of those 
infected being substantial, perhaps as high as  80% [17, 23-25]. Further, research has 
found that the risk of death from COVID-19 increases with age and with serious, comorbid 
conditions including hypertension, diabetes, cardiovascular disease, obesity, etc.   
Finally, although much has been learned very quickly about SARS-CoV-2 and COVID-19, 
much more is still to be determined. The aforementioned CFR and similar estimates are 
from crude analyses that have only accounted for moderate to serious cases. Therefore, 
the true CFR is likely significantly lower. Further, the infection-fatality ratio (IFR), which is 
the proportion who die among all those infected regardless of any symptomology, is likely 
still even lower than the CFR, but both the CFR and IFR will not be known with certainty 
until well-designed and controlled seroepidemiology surveys have been conducted using 
well-validated antibody assays and thorough questionnaires to obtain symptom history. 
Also, the presence of natural immunity of those infected who survive and the durability of 
such natural immunity is to be determined. Thus, the existence and possibility of 
reinfection and recurrent infection is unknown. 
 CLINICAL PRESENTATION, TRANSMISSION AND IMMUNE RESPONSE 
A study in The Lancet by Huang and colleagues [4] reported the epidemiological, clinical, 
laboratory, and radiological characteristics, as well as treatment and clinical outcomes, of 
patients with laboratory-confirmed COVID-19 pneumonia. Common symptoms at onset of 
illness were fever (n=40, 98% of 41 patients), cough (n=31, 76%), and myalgia or fatigue  
(n=18, 44%);  less  common  symptoms  were  sputum  production  (n=11, 28%  of  39 
patients),  headache  (n=3, 8%  of  38 patients), hemoptysis (n=2, 5% of 39 patients), and 
diarrhea (n=1, 3% of 38 patients). Dyspnea developed in 22 (55%) of 40 patients (median 
time from illness onset to dyspnea was 8 days [Interquartile range 5 - 13 days]). Twenty-
six (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal 
findings on chest CT scan. Complications included acute respiratory distress syndrome 
(n=12, 29%), RNAaemia (n=6, 15%), acute cardiac injury (n=5, 12%) and secondary 
infection (n=4, 10%).  
Wiersinga et al. summarized the common symptoms of COVID-19 in hospitalized patients 
as fever (70-90%), dry cough (60-86%), shortness of breath (53-80%), fatigue (38%), 
myalgias (15-44%), nausea/vomiting or diarrhea (15-39%), headache, weakness (25%) 
and rhinorrhea (7%). Anosmia and ageusia may be the sole presenting symptom in 
approximately 3% of individuals with COVID-19. Common laboratory abnormalities 
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include lymphopenia (83%), elevated inflammatory markers (e.g., erythrocyte 
sedimentation rate, C-reactive protein, ferritin, tumor necrosis factor-alpha, IL-1, IL-6) and 
abnormal coagulation parameters (e.g., prolonged prothrombin time, thrombocytopenia, 
elevated D-dimer and low fibrinogen). Common radiographic findings include bilateral, 
lower lobe infiltrates on chest radiographic imaging and bilateral, peripheral, lower-lobe 
ground-glass opacities and/or consolidation on chest computed tomographic imaging [9].  
Transmission of SARS-CoV-2 occurred mainly after days of illness [26] and was 
associated with modest viral loads in the respiratory tract early in the illness, with viral 
loads peaking approximately 10 days after symptom onset [27]. Higher viral loads were 
detected soon after symptom onset, with higher viral loads detected in the nose than in 
the throat. Analysis of these samples suggested that the viral nucleic acid shedding 
pattern of patients infected with SARS-CoV-2 resembles that of patients with influenza 
[28] and appears different from that seen in patients infected with SARS-CoV [27]. The 
viral load that was detected in the asymptomatic patient was similar to that in the 
symptomatic patients, which suggests the transmission potential of asymptomatic or 
minimally symptomatic patients [11]. The SARS-CoV-2 transmission time window from 
COVID-19 patients is perhaps 2 days before symptom onset up to 37 days after symptom 
onset [20]. It is estimated that 48% to 62% of transmission may occur via presymptomatic 
carriers [9].  
Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10-15 
days following the onset of COVID-19 symptoms. Seow et al. observed seroconversion in 
>95% with neutralizing antibody responses when sampled beyond 8 days after onset of 
symptoms [29]. However, declining neutralizing antibody titers were observed during the 
follow-up period. Long, et al, when following 37 asymptomatic individuals and 37 
symptomatic patients into the early convalescent phase, observed that the IgG levels in 
93.3% of the asymptomatic group and 96.8% of the symptomatic group declined during 
the early convalescent phase [30]. T cells play a critical role in antiviral immunity but their 
numbers and functional state in SARS-CoV-2 infected patients remain largely unclear. 
Diao and colleagues performed a retrospective review of total T cell counts, and CD4+ and 
CD8+ T cell subsets based on inpatient data from 522 patients with laboratory-confirmed 
SARS-CoV-2 infection and 40 healthy controls in Wuhan from December 2019 to January 
2020. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe and 
critical disease groups as well as those who died were significantly lower than in the 
mild/moderate disease group. Most importantly, the numbers of total T cells, CD8+ T cells 
and CD4+ T cells in severe COVID-19 cases, including those who died, were lower 
suggesting that there is a profound T cell loss in COVID-19 disease. Counts of total T 
cells, CD8+ T cells or CD4+ T cells were negatively correlated with patient survival [31]. 
It is quite likely that CD4+ T cell, CD8+ T cell, and neutralizing antibody all contribute to 
clearance of the acute infection. There is an ongoing need to understand the magnitude 
and composition of the human CD4+ and CD8+ T cell responses to SARS-CoV-2. If 
natural infection with SARS-CoV-2 elicits potent CD4+ and CD8+ T cell responses 
commonly associated with protective antiviral immunity, COVID-19 is a strong candidate 
for rapid vaccine development [32].  
 CURRENT TREATMENT AND UNMET NEED 
Currently, there is no licensed prophylactic vaccine against COVID-19, however there are 
several vaccines that are available under Emergency Use Authorization (EUA) in the 
United States and other countries. Numerous vaccine efforts are underway. Given the 
growing concerns regarding the emergence of new strains of SARS-CoV-2, an effective 
prophylactic vaccine ideally induces immunity against not only SARS-CoV-2 Wuhan-Hu-
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1 but also its variants. Due to rapid spread of SARS-CoV-2 infections even from 
asymptomatic and mildly infected patients, there is an urgent need for additional vaccines 
for prevention of SARS-CoV-2 infections. 
 
RATIONALE FOR PROPHYLACTIC VACCINE DEVELOPMENT 
SARS-CoV-2 has become a pandemic resulting in substantial morbidity and mortality. Due 
to rapid spread of SARS-CoV-2 infections even from asymptomatic and mildly infected 
patients, there is an urgent need for appropriate measures to prevent, control and treat 
SARS-CoV-2 infections.  
To address this critical need for a medical countermeasure for prevention of COVID-19 
disease, we at Inovio Pharmaceuticals have employed our synthetic DNA-based vaccine 
technology. This technology is highly amenable to accelerated developmental timelines, 
due to the ability to rapidly design multiple test constructs, manufacture large quantities of 
the drug product, and leverage established regulatory pathways to the clinic. Furthermore, 
this technology platform has demonstrated proof of concept efficacy and safety in humans 
in a Phase 3 (REVEAL1) randomized, double-blind, placebo-controlled study for human 
papillomavirus (HPV) associated cervical pre-cancer (NCT03185013) and several Phase 
2 trials for related and other indications and several Phase 2 trials for related and other 
indications. We have additionally built upon our prior experience in developing a MERS 
coronavirus (MERS-CoV) vaccine to accelerate the development of a SARS-CoV-2 
vaccine candidate. In a Phase 1 clinical study, the MERS-CoV vaccine candidate was safe 
and well tolerated, eliciting immune responses in more than 85% of participants after two 
vaccinations that were durable through 1 year of follow-up [33].   
 DNA VACCINES 
Since the 1990s, a novel approach to vaccination against a broad array of target antigens 
and diseases has been in development. This involves the direct introduction of plasmid 
deoxyribonucleic acid (DNA) containing the gene encoding the immunogen against which 
an immune response is sought into appropriate host tissues and the in situ production of 
the target immunogen(s). This approach offers a combination of potential advantages, 
including the stimulation of both B- and T-cell responses, stability of the vaccine across a 
broad temperature range, absence of infectivity of the immunogen itself, the speed with 
which the vaccine can be constructed (for example in the face of an epidemic or pandemic 
as it is the case here with SARS-CoV-2), and the relative ease and generic nature of large-
scale manufacture. Many scientific publications have addressed the potential of DNA 
vaccination [34-43]. Immune responses in animal models have been obtained using genes 
from a variety of infectious agents including influenza viruses, hepatitis B virus, human 
immunodeficiency virus, human papillomaviruses, Marburg virus, MERS coronavirus, 
rabies virus, SARS coronavirus, West Nile virus (WNV), Zika virus, and other infectious 
agents as plasmodium, mycoplasma, and many more [42, 44]. In many cases, protection 
from disease in animal models has also been demonstrated.  
DNA vaccines are able to generate both CD4+ and CD8+ T cell responses. The ability to 
generate MHC-Class I restricted CD8+ T cells (cytolytic T lymphocytes), which generally 
are not made following administration of inactivated viruses, proteins or peptides, may be 
important for key responses against certain pathogens, as well as enabling cross-strain 
specific responses when many antibody responses are strain-specific. Because the 
encoded protein is synthesized in vivo by the host following administration, DNA vaccines 
can encode membrane-bound proteins instead of solely the soluble versions [45]. This 
can be important because key neutralizing epitopes are located in regions that would be 
excluded, or not formed in a monomeric truncated soluble version. Some early research 
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in COVID-19 control has already suggested that neutralizing antibodies may not be 
sufficient and that cell-mediated immunity may be necessary [46]. 
Unlike certain other vectors (such as heterologous viral vectors), DNA vaccines do not 
stimulate adaptive immune responses against themselves, although the DNA itself does 
stimulate certain innate immune responses [47]. In other words, they do not generate anti-
vector immunity that could stunt antigen-specific responses following multiple exposures. 
 USE OF ELECTROPORATION WITH DNA VACCINES 
Electroporation (EP) enhances gene expression of plasmid DNA delivered by the 
intramuscular (IM) or intradermal (ID) routes of administration (Figure 2). Following IM or 
ID delivery of a DNA vaccine or therapeutic product, EP facilitates entry of the DNA into 
the target site: muscle or dermal cells. Following cellular uptake, there is efficient 
production of the proteins encoded by the DNA expression plasmid system. The different 
EP devices, each with varying electrical parameters and protocols, have been reviewed 
[48]. EP has been extensively tested in animal species such as dogs, pigs, cattle, and 
NHPs to deliver therapeutic genes that encode for a variety of hormones, cytokines, 
enzymes or antigens  for the activation of both cellular and humoral responses [49, 50]. 
Importantly, immune responses generated by DNA vaccines delivered with EP are far 
superior to responses to the same vaccines delivered without EP [50]. IM and ID delivery 
of DNA vaccines with EP has been studied extensively, and optimum conditions for 
plasmid uptake and expression have been described for therapeutic indications, vaccines 
and tumor animal model systems [51, 52].  
 INOVIO’S PROPRIETARY TECHNOLOGY AGAINST COVID-19  
Inovio Pharmaceuticals has developed INO-4800 as a DNA vaccine that contains 10 
mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM sodium chloride and 15 
mM sodium citrate). pGX9501 is a DNA plasmid expressing a synthetic consensus 
(SynCon®) sequence of the SARS-CoV-2 Wuhan-Hu-1 full length Spike glycoprotein. The 
ID route of delivery has been selected for INO-4800 based on recent findings from multiple 
DNA vaccine development programs where ID delivery has driven equivalent if not 
superior humoral and cellular responses to IM delivery while improving tolerability 
(clinicaltrials.gov NCT02464670, clinicaltrials.gov NCT02431767) [53-55]. 
Following ID injection, the Inovio Pharmaceuticals’ EP device [48] referred to as the 
CELLECTRA® 2000 for ID administration (3P-ID) device is used to facilitate DNA entry 
into the cells.  
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Figure 2: The Potential Mechanism of Action Underlying Electroporation 
 
 NONHUMAN PRIMATE (NHP) CHALLENGE STUDIES FOLLOWING VACCINATION WITH 
INO-4800 
NHPs are a valuable model in the development of COVID-19 vaccines and therapeutics 
as they can be infected with wild-type SARS-CoV-2, and present with early infection that 
mimics aspects of human disease [56].  Rhesus macaques (n=5) received two 
immunizations of INO-4800 (1.0 mg), at Week 0 and Week 4.  Naïve control animals (n=5) 
did not receive vaccine.  Humoral and cellular immune responses were monitored for 15 
weeks (~4 months) following prime immunization for memory responses. All animals 
seroconverted following a single INO-4800 immunization, with serum IgG titers detected 
against the full-length S1+S2 extracellular domain (ECD), S1, S2, and receptor binding 
domain (RBD) regions of the SARS-CoV-2 S protein.  
INO-4800 immunized macaques and unvaccinated controls were challenged with SARS-
CoV-2 13 weeks (~3 months) post-final immunization. NHPs received a challenge dose of 
1.1x104 PFU of SARS-CoV-2 by intranasal and intratracheal inoculation. Peak viral RNA 
loads in the BAL were significantly lower in the INO-4800 vaccinated group, along with 
significantly lower viral RNA loads at day 7 post-challenge, indicating protection from lower 
respiratory disease. While RNA was detected in the nasal swabs of both the control and 
INO-4800 vaccinated animals, viral mRNA levels trended downwards in INO-4800 
vaccinated animals by more than 2 logs and were achieved sooner on average. Overall, 
the reduced viral loads following exposure to SARS-CoV-2 infection at 17 weeks after 
immunization show an important durable impact mediated by the vaccine [57].  
 FIRST-IN-HUMAN PHASE 1 TRIAL OF INO-4800 
In the open-label, Phase 1 clinical trial, we initially evaluated the safety and 
immunogenicity of INO-4800 in 40 healthy participants, 18-50 years of age.  There were 
two groups of 20 participants each who received either 1.0 mg or 2.0 mg of INO-4800 
intradermally followed by EP at 0 and 4 weeks. In the first 40 subjects, by Week 8, 11 
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adverse events were reported of which all were Grade 1 in severity of which 6 were related 
to study drug. The frequency of AEs did not increase with the second administration.  
From the immunogenicity analysis of the initial 40 subjects enrolled, two subjects were 
excluded from the analysis, one due to early discontinuation prior to the Week 4 dose for 
non-study reasons and the other due to suspected exposure to SARS-CoV-2 before the 
first dose of INO-4800 was administered based on a baseline positive SARS-CoV-2 
serology. Thirty-eight (38) evaluable subjects had cellular and/or humoral immune 
responses following the second dose of INO-4800. Assessment of data from both Week 
6 and Week 8 ELISpot revealed that 74% and 100% of the subjects generated T cell 
responses in the 1.0 mg and 2.0 mg groups, respectively. By Week 6, 95% (36 of 38) of 
the participants seroconverted by generating binding and/or neutralizing antibodies. 
Overall, INO-4800 elicited antigen-specific humoral and cellular immune responses 
against the SARS-CoV-2 Spike protein while demonstrating favorable safety and 
tolerability. 
The protocol was amended to include an additional 80 healthy participants to evaluate 
safety and immunogenicity of INO-4800 in older and elderly age populations. A lower dose 
level (0.5 mg) was also added for evaluation of dose-sparing potential. A total of 40 
participants were enrolled into three dose levels (0.5 mg, 1.0 mg and 2.0 mg), such that 
each Group included 20 participants 18-50 years of age, 10 participants 51-64 years of 
age, and 10 participants 65 years of age and older. Doses were delivered intradermally 
followed by EP at 0 and 4 weeks. As of March 10, 2021, 35 related adverse events were 
reported cumulatively, of which all but three (Grade 2 injection site pruritus, lethargy and 
abdominal pain) were Grade 1 in severity. 
Additional analyses showed that INO-4800 provides broad cross-reactive immune 
responses against variants of concern (VOC). Clinical samples, collected at varying 
timepoints post-immunization from subjects enrolled during Phase 1 INO-4800 clinical 
trial, were analyzed against the spike protein of different VOC (including UK variant 
B.1.1.7, South African variant B.1.351, and Brazilian variant P.1. strains) [58]. The results 
revealed neutralization activity against the P.1 variant (neutralizing antibodies levels 
comparable to those against wild-type) and reduced, but still measurable neutralization 
activity against the B.1.1.7 and B.1.351 variants. Additionally, it has been demonstrated 
that INO-4800 induces cross-reactive T cell responses against B.1.1.7, B.1.351, and P.1 
variants that are comparable to the wild-type strain. Taken together, these data 
demonstrate that INO-4800 maintains cellular and/or humoral immune responses against 
the major SARS-CoV-2 variants that are currently in circulation, which will likely be critical 
factors necessary to impact the ongoing COVID-19 pandemic. 
Please refer to the Investigator’s Brochure, which will include future updates through the 
duration of the study. 
 PROPOSED PHASE 2/3 TRIAL OF INO-4800 
This Phase 2/3 trial is designed to begin with a Phase 2 segment to evaluate both the 1.0 
mg and 2.0 mg doses in approximately 400 subjects, including in the older (51 to 64 years 
of age) and elderly subjects (65 years of age and older), to enable selection of a dose or 
age-related doses for an efficacy evaluation in a subsequent Phase 3 segment involving 
>7000 subjects.  
The safety and immunogenicity data from the Phase 2 segment strongly support the 
selection and advancement of the 2.0 mg dose of INO-4800 into the Phase 3 segment 
(see Section 1.3.7 for immunogenicity details). INO-4800’s competitive safety/tolerability 
profile, nonclinical data supporting its potential to confer durable protection against severe 
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disease, ability to serve as a safe and tolerable homologous booster, and thermostability 
profile collectively support its potential as an additional tool for COVID-19 prevention with 
distinct advantages to facilitate global distribution and uptake. 
1.3.6.1 
Safety and tolerability of INO-4800  
Safety and tolerability data collected on INO-4800 to date mirror the favorable safety 
profile of Inovio’s plasmid DNA vaccines against multiple targets and indications.  
Nonclinical studies have revealed no safety concerns. Clinical studies (Phase 1 and Phase 
2) have also not revealed any safety concerns as per reviews by independent Data Safety 
Monitoring Boards.   
1.3.6.2 
Nonclinical INO-4800 Data in Support of Potential Efficacy 
The efficacy of INO-4800 in protecting against SARS-CoV-2 disease has been 
demonstrated in multiple nonclinical models. In the AAV6 human ACE2-transduced 
mouse model challenged with SARS-CoV-2, complete protection against lung virus load 
was observed [59]. Applying clinically relevant dosing and CELLECTRA-ID delivery 
parameters, INO-4800 has been tested in multiple nonhuman primate models, the gold 
standard large animal model for COVID-19 vaccine testing. We demonstrated protection 
against lung disease and viral load in the lower and upper respiratory tract in the rhesus 
macaque model after one or two doses of INO-4800 [60, 61]. Furthermore, the durability 
of the impact of INO-4800 in reducing lung viral load was demonstrated in a rhesus 
macaque challenged with SARS-CoV-2 several months after immunization [57]. In 
conclusion, multiple nonclinical models have demonstrated the efficacy of INO-4800.  
1.3.6.3 
Potential Role of INO-4800 as a Booster 
INO-4800 offers a potential role in serving as a booster to maintain protection against 
COVID-19 over time in the context of a potential endemic disease scenario. Unlike viral 
vectors, DNA elicits no anti-vector response and, therefore, can be repeatedly 
administered without a reduction in the generated immune responses. When subjects in 
the INO-4800 Phase 1 were provided a booster dose 6 to 10.5 months following the 2-
dose regimen, there was no appreciable change in reactogenicity when compared to the 
first two doses, indicating that repeat dosing with INO-4800, as with other vaccines in 
Inovio’s DNA platform, does not lead to an increase in reactogenicity. Inovio’s DNA 
platform experience with Oncology DNA-vaccine targets have established that more than 
10 sequential administrations of vaccine is capable of consistent re-boosting from an 
immunological perspective with no associated changes in safety and reactogenicity. 
1.3.6.4 
Thermostability of INO-4800  
INO-4800 offers thermostability that could facilitate vaccine distribution globally. The 
current shelf life applied to INO-4800 clinical supplies is 24 months when stored at its 
recommended refrigerated storage condition of 5 ± 3°C. A 24-month real-time study for 
INO-4800 under refrigerated conditions (5°C) is ongoing; current Month 9 results are all 
within specification. Percent supercoiled forms, which is the strongest indication of DNA 
plasmid stability, decreased by only 2% (T0 97%, M9 95%) over the duration of the study 
to date, while percent total circular forms remained at 99%.  
Inovio has a platform stability program with 12 different DNA plasmid products, all 
constructed with the same plasmid backbone and formulated in the same SSC buffer, at 
various DNA concentrations, and the stability data to date are all consistent with the 
excellent stability profile seen with INO-4800. 
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 DOSE AND REGIMEN RATIONALE 
The intent is to evaluate INO-4800 as a prophylactic vaccine against COVID-19 disease. 
Based on Inovio’s extensive experience developing vaccine candidates against infectious 
diseases via the ID route ([54], [33]), a 2-dose regimen was considered to be optimal, 
based on the balanced humoral and cellular responses obtained 2 weeks post-dose 2, 
which supports evaluation of a 2-dose regimen (Days 0 and 28). 
In the Phase 2 segment of this trial, 1.0 mg and 2.0 mg of vaccine were administered by 
ID injection and followed immediately by EP at Day 0 and Day 28. The selection of the 
doses to test in Phase 2 is supported by the safety profile in the Phase 1 trial of INO-4800 
(COVID19-001, NCT04336410) in addition to our prior experience in developing a MERS 
coronavirus (MERS-CoV) vaccine (INO-4700) [16, 17]. The safety data for INO-4800 is 
provided in the Investigator’s Brochure (IB). 
The objective of the Phase 2 segment of the Phase 2/3 trial was to further evaluate the 
1.0 mg and 2.0 mg doses of INO-4800 for each age group in order to select the optimal 
vaccination regimen in the Phase 3 efficacy segment. The final decision between the two 
doses by age group relies on safety and immunogenicity. The 1.0 mg and 2.0 mg doses 
in the Phase 1 study had a similar safety profile. The review of the Phase 2 data by the 
independent DSMB has not revealed any safety signals of concern to date. Furthermore, 
there have not been substantial differences in the safety profile between the 1.0 mg and 
2.0 mg dosing groups to impact Phase 3 dose selection. However, the interim immunology 
data from the Phase 2 study revealed superior immunogenicity with the 2.0 mg dose over 
the 1.0 mg dose.  Data were analyzed for two age groups:  ≥18 to ≤50 years of age and 
≥51 years of age. The results illustrate that the 2.0 mg dose induced higher levels of 
SARS-CoV-2 spike specific antibodies as well as higher levels of IFN-gamma producing 
cells.   
In November 2021, genotypic characterization identified a new VOC, Omicron, that has 
rapidly increased in prevalence. Omicron has acquired a large number of mutations, which 
not only gives it a growth advantage over the delta variant, but also allows it to evade the 
binding and neutralizing antibody responses generated by current COVID-19 vaccines or 
those of natural infection.  
As with other COVID-19 vaccines[62], INO-4800 exhibited significantly decreased levels 
of both neutralizing and binding antibodies against Omicron, relative to other VOCs. 
However, in vitro assessment of INO-4800 against Omicron showed full maintenance of 
T cell responses, including CD8+ responses. The maintenance and preservation of T cell 
responses remains a consistent observation for INO-4800 against the ancestral virus and 
across all VOCs tested, including Delta and Omicron. T cell responses are thought to play 
an important role in protection against severe disease and death and may be central to 
the durability of vaccine protection[63].  
The recognition of the importance of vaccine efficacy against severe disease is reflected 
in the January 2022 WHO Target Product Profiles for COVID-19 Vaccines. In light of this 
changing COVID-19 vaccine landscape and the maintenance of T cell responses against 
Omicron by INO-4800, Inovio Pharmaceuticals has amended the primary endpoint of this 
trial from “Incidence of virologically-confirmed COVID-19 disease starting 14 days after 
completion of the 2-dose regimen until 12 months post-dose 2 (End of Study (EOS)) in 
subjects who are SARS-CoV-2 seronegative at baseline” to “Incidence of virologically-
confirmed severe COVID-19 disease starting 14 days after completion of the 2-dose 
regimen until 12 months post-dose 2 (EOS) in subjects who are SARS-CoV-2 
seronegative and RT-PCR negative at baseline”. 
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1.3.7.1 
Binding Antibody Response 
The binding antibody response was measured for all Phase 2 subjects at Day 0 and Week 
6.  Across all ages, the geometric mean titer (GMT) for the 1.0 mg dose group was 123.3 
at Day 0 compared to 938.8 at Week 6. The geometric mean fold rise was 7.8. The GMT 
for the 2.0 mg dose group was 93.5 at baseline compared to 2210.0 at Week 6. The 
geometric mean fold rise was 23.5. 
Subjects 18-50 years old in the 1.0 mg dose group had a GMT that was 148.5 at Day 0 
compared to 1182.1 at Week 6.  The geometric mean fold rise in binding antibody titers 
was 7.9. The GMT for the 2.0 mg dose group was 99.5 at baseline compared to 2671.2 at 
Week 6. The geometric mean fold rise was 26.5. 
Subjects ≥51 years old in the 1.0 mg dose group had a GMT that was 87.5 at Day 0 
compared to 623.3 at Week 6. The geometric mean fold rise in titers was 7.6. The GMT 
for the 2.0 mg dose group was 84.0 at baseline compared to 1613.7 at Week 6. The 
geometric mean fold rise in binding antibodies was 19.2.  
1.3.7.2 
Neutralizing Antibody Response 
The neutralizing antibody response was measured for all Phase 2 subjects at Days 0 and 
Week 6.  Across all ages the geometric mean titer (GMT) for the 1.0 mg dose group was 
32.2 at Day 0 compared to 93.6 at Week 6.  The geometric mean fold rise in neutralizing 
titers was 2.9. The GMT for the 2.0 mg dose group was 35.8 at baseline compared to 
150.6 at Week 6.  The geometric mean fold rise was 4.3. 
Subjects 18-50 years old in the 1.0 mg dose group had a GMT that was 34.5 at Day 0 
compared to 112.6 at Week 6.  The geometric mean fold rise in neutralizing titers was 3.3. 
The GMT for the 2.0 mg dose group was 32.2 at baseline compared to 159.9 at week 6. 
The geometric mean fold rise was 5.0. 
Subjects ≥51 years old in the 1.0 mg dose group had a GMT that was 28.4 at Day 0 
compared to 67.4 at Week 6. The geometric mean fold rise in neutralizing titers was 2.3. 
The GMT for the 2.0 mg dose group was 43.3 at baseline compared to 135.7 at Week 6. 
The geometric mean fold rise was 3.2. 
1.3.7.3 
ELISPOT analysis 
ELISPOT analysis was performed for all Phase 2 subjects at Day 0 and Week 6. Across 
all ages, the median for the 1.0 mg dose group was 0 at Day 0 compared to 6.7 at Week 
6. The median for the 2.0 mg dose group was 2.2 at baseline compared to 18.9 at Week 
6. Subjects 18-50 years old in the 1.0 mg dose group had a median of 1.1 at Day 0 
compared to 7.6 at Week 6. The median for the 2.0 mg dose group was 0.6 at baseline compared 
to 18.9 at Week 6.  Subjects ≥51 years old in the 1.0 mg dose group had a median that was 0 at 
Day 0 compared to 10 at Week 6. The median for the 2.0 mg dose group was 3.3 at baseline 
compared to 18.4 at Week 6.   
 
RISKS AND POTENTIAL BENEFITS  
As of Dec 31, 2020, no treatment related serious adverse events have been reported for 
INO-4800. There may be side effects and discomforts that are not yet known.  
Please refer to the Investigator’s Brochure and User Manual, which will include future 
updates of the risk profile delineated in this section through the duration of the study. 
 POTENTIAL BENEFITS 
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As part of the trial, subjects will have access to COVID-19 diagnostic and antibody testing 
to which they might not otherwise have access. Additionally, subjects will have the benefit 
of contributing to research to help others in a time of a global pandemic.  Benefits related 
to receipt of INO-4800 and protection from COVID-19 disease are unknown because the 
efficacy of INO-4800 remains unknown.     
PRODUCT RISKS 
1.4.2.1. 
Expected Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Device 
In accordance with the International Council for Harmonisation (ICH), Inovio-sponsored 
studies have been designed to minimize risk to study participants. Expected risks of INO-
4800 delivered ID followed by EP with the CELLECTRA® 2000 device are listed below in 
Table5. 
Table 5: Expected Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Devicea 
Frequency among subjectsb 
Event 
Very Common 
(≥10%) 
•
Injection site pruritus
•
Injection site erythema or redness
•
Injection site painc or tenderness
Common 
(≥1% to <10%) 
•
Injection site bruising
•
Injection site swelling or induration
Uncommon or Rare (<1%) 
•
Administration site lesions or bleeding
•
Temporary severe injection site pain or
tenderness
a Investigator’s Brochure v4.0, dated 16-Nov-2020 
b EU commission guideline on the SmPC September 2009 [64] 
c Brief muscle contractions may occur and could be uncomfortable 
1.4.2.2 
Theoretical Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Device 
The following adverse events have been observed at least once, as of Dec. 31, 2020, 
across all clinical trials with Inovio DNA products delivered intradermally followed by EP 
using the CELLECTRA® 2000 device: 
•
Allergic reaction
•
Anxiety
•
Creatine phosphokinase (CPK) elevations that are transient
•
Injection site infection, paresthesia, hypoesthesia, hematoma, or scab
•
Vasovagal reaction, lightheadedness or dizziness.
The following events have not been observed, as of Dec. 31, 2020, in any subject or any 
clinical trials with Inovio DNA products delivered intradermally followed by EP using the 
CELLECTRA® 2000 device. While considered theoretical and unlikely to occur, any 
occurrence of these events should be reported to the Sponsor during this trial: 
•
Antibody-dependent enhancement of disease (i.e., potential for greater respiratory
disease upon exposure to SARS-CoV-2 due to priming of immune cells from prior
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vaccination. Although observed in nonclinical models for vaccines against other 
viruses such as SARS, the occurrence or observation of antibody-dependent 
enhancement of the disease with COVID-19 vaccines in humans remains 
unknown) 
• 
Cardiac arrhythmias (product-related); Please note that “ICD or pacemaker (to 
prevent a life-threatening arrhythmia) that is located ipsilateral to the deltoid 
injection site (unless deemed acceptable by a cardiologist)” is an exclusion 
criterion (‘j’) in this protocol; 
• 
Death (product-related); 
• 
Disruption of function of implanted electronic medical device(s); Please note that 
“ICD or pacemaker (to prevent a life-threatening arrhythmia) that is located 
ipsilateral to the deltoid injection site (unless deemed acceptable by a cardiologist)” 
is an exclusion criterion (‘j’) in this protocol; 
• 
Effects on fetus and/or pregnancy; Please note inclusion criterion in this protocol 
which requires use of medically effective contraception in women of childbearing 
potential; 
• 
Electrical injury (e.g., electrocution); Please note warning within the device User 
Manual (Section 7). Since the device is not connected to any power supply during 
the EP procedure of a subject, this theoretical event is unlikely but has the potential 
to occur to the user of the device (e.g., study site staff). This will be mitigated 
through device training and user qualification prior to use; 
• 
Fire hazard to the facility; This theoretical event is unlikely but has the potential to 
occur to the clinical trial site. The possibility of this event has been mitigated 
through device design; 
• 
Hearing damage (product-related); The possibility of this event has been mitigated 
through the device design. The audio is limited in volume and is of very short 
duration. 
• 
Inaccurate energy delivery, the result of which is covered in other events listed 
here (e.g., tissue damage); 
• 
Injection site laceration; This has not been observed but would be theoretically 
possible with any needle; 
• 
Major injury to deeper tissue and/or bone; This event is not foreseeable given the 
array needle length is limited to 3.2 mm;  
• 
Muscle damage; This event is not foreseeable given the array needle length is 
limited to 3.2 mm; 
• 
Paresis or paralysis with possible loss of nerve function; There are minor nerves 
innervating the skin and subcutaneous tissues that may be disrupted, but are 
extremely unlikely to result in serious injury; 
• 
Radiation hazard to eyes and skin; This theoretical event is unlikely but has the 
potential to occur to the user of the device (e.g., study site staff). The possibility of 
this event has been mitigated through the device design; 
• 
Tissue injury/burn;  
• 
User/subject unaware that treatment was incomplete; 
• 
Worsening of unstable cardiac disease; Please note that “Cardiovascular diseases 
(e.g., myocardial infarction, congestive heart failure, cardiomyopathy or clinically 
significant arrhythmias) requiring changes in therapy or hospitalization for 
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worsening disease during the 6 weeks prior to enrollment” is an exclusion criterion 
(‘h’) in this protocol. 
There have been no AEs associated with EP errors or failures. 
 OVERALL BENEFIT/RISK CONCLUSION 
While EUA vaccines are currently becoming available in many countries, the global 
availability to the general population remains limited. In the context of the ongoing COVID-
19 pandemic resulting in substantial morbidity and mortality, the overall cumulative safety 
profile of Inovio’s DNA platform across all of its products, and INO-4800’s Phase 1 adverse 
events being generally limited to local injection site reactions, the benefit risk profile 
justifies the conduct of the Phase 2/3 trial. 
 
OBJECTIVES AND PURPOSE 
The overall purpose of this clinical trial is to evaluate the safety, immunogenicity and 
efficacy of INO-4800. 
 
HYPOTHESIS 
INO-4800 delivered ID followed immediately by EP will be well-tolerated, exhibit an 
acceptable safety profile, result in generation of cellular and humoral immune responses 
to SARS-CoV-2 Spike glycoprotein and provide protection against virologically-confirmed 
severe COVID-19 disease in subjects at high risk of SARS-CoV-2 exposure.  
 
CLINICAL TRIAL DESIGN AND ENDPOINTS 
This is an operationally seamless Phase 2/3, randomized, placebo-controlled, multi-
center trial to evaluate the safety, immunogenicity, and efficacy of INO-4800, 
administered by ID injection followed immediately by EP using the CELLECTRA® 2000 
device, in a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-
2 exposure. Subjects 18 years of age and older are expected to be enrolled across two 
(2) segments of this study. In the Phase 2 segment, approximately 400 seronegative 
subjects will be enrolled. In the Phase 3 segment, approximately 10,002 seronegative 
subjects are expected to be enrolled, and 402 seropositive subjects will be enrolled. The 
subjects and data from Phase 2 are independent from that of Phase 3.  The primary 
objectives of this trial are to identify in seronegative subjects an optimal age-related dose 
(Phase 2 segment) for subsequent evaluation for efficacy (Phase 3 segment).  
 
Phase 2 Segment – Dose Selection 
 
In the Phase 2 segment, approximately 400 subjects 18 years of age and older will be 
evaluated across four (4) dose groups (Table 1, Figure 1). Subjects will be randomized 
at a 3:3:1:1 ratio to receive either 1.0 mg or 2.0 mg of active investigational product (INO-
4800) or 1 or 2 injections of placebo. Dose groups receiving INO-4800 will enroll 
approximately 150 subjects per group. Dose groups receiving placebo will enroll 
approximately 50 subjects per group. Randomization will be such that approximately 240 
subjects aged 18-50 years, 120 subjects aged 51-64 years and 40 subjects aged ≥ 65 
years will be enrolled. Initial enrollment will include subjects aged 18-50 years. Initiation 
of enrollment of older subjects 51-64 years of age and elderly subjects 65 years and older 
will depend on review of safety and immunogenicity data from those age groups 
generated in the Phase 1 study (COVID19-001). 
 
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Dose selection for evaluation of efficacy in the Phase 3 segment will be based on Week 
6 immunogenicity data and Week 8 safety data from the Phase 2 segment. Group-level 
unblinded summaries and analyses of safety will be produced once the Week 8 phone 
call visit data are completed for all subjects in the Phase 2 segment. Group-level 
unblinded summaries and analyses of immunogenicity will be produced once the Week 
6 visit data are completed for all subjects in the Phase 2 segment. Subject treatment 
assignments will be unblinded after Phase 2 subjects have reached the Week 30 visit. 
 
Phase 3 Segment – Efficacy 
In the Phase 3 segment, approximately 10,002 seronegative and 402 seropositive 
subjects 18 years of age and older will be randomized at a 2:1 ratio to receive either active 
investigational product (INO-4800, 2.0mg) or placebo. Approximately half of seronegative 
subjects and approximately half of seropositive subjects will be 18-50 years of age, and 
the other half will be ≥ 51 years of age as is operationally feasible.  
Subjects will be randomized in a stratified manner according to (a) age category (18-50 
years vs. ≥51 years) on Day 0, and (b) presence of or absence on Day 0 of any of the 
following underlying medical conditions that increase risk of severe COVID-19 disease, 
per CDC criteria [1], as listed below: 
• 
Cancer 
• 
Chronic kidney disease 
• 
Chronic lung diseases, including Chronic obstructive pulmonary disease (COPD), 
asthma (moderate-to-severe), interstitial lung disease, cystic fibrosis, pulmonary 
hypertension 
• 
Neurologic conditions including stroke or cerebrovascular disease, that do not impact 
cognition 
• 
Diabetes (type 1 or type 2) 
• 
Hypertension 
• 
Heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies 
• 
HIV infection  
• 
Liver disease 
• 
Obesity (BMI ≥ 30 kg/m2) 
• 
Sickle cell disease or thalassemia, or 
• 
Smoking (current or former smoker). 
This segment of the trial is case-driven. Among subjects who are seronegative and RT-
PCR negative at baseline, a total of 17 observed severe cases will be required for 90% 
power to declare the vaccine efficacious (>30%), assuming a true efficacy of 90%. A 
sample size of 10,002 seronegative subjects is expected to be required to achieve the 17 
severe cases assuming an underlying attack rate of 0.4%. The actual sample size may 
differ if the observed attack rate is different than projected. If the criteria for efficacy are 
met, placebo-recipients will be offered the active product.   
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12 
months post-dose 2. All Phase 3 segment subjects will be followed for 56 weeks from the 
Day 0 dosing [i.e., Week 56 will be the planned End of Study (EOS) visit for this segment 
of the trial]. 
 
External Committee Reviews 
 
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For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will 
convene regularly to review all available unblinded safety data, and additionally upon 
completion of the Week 8 phone call visit for all subjects enrolled during the Phase 2 
segment. For the Phase 3 segment, the DSMB will also review efficacy in an unblinded 
fashion. Additionally, for Phase 3, an independent, blinded Endpoint Adjudication 
Committee (EAC) will review and confirm COVID-19 cases. 
 
Details of each committee’s scope will be provided in the respective charters. 
 
PRIMARY OBJECTIVES 
See Table 6. 
 
PRIMARY ENDPOINTS 
Table 6: Primary Objectives and Associated Endpoints 
Phase 2 Primary Objective 
Phase 2 Primary Endpoints 
1.  Evaluate the cellular and humoral 
immune response to INO-4800 
administered by ID injection followed 
immediately by EP  
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot assay 
1b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay 
Phase 3 Primary Objective 
Phase 3 Associated Primary Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of severe COVID-19 
disease in subjects who are SARS-
CoV-2 seronegative and RT-PCR 
negative at baseline  
1.   Incidence of virologically-confirmed severe 
COVID-19 disease starting 14 days after 
completion of the 2-dose regimen until 12 
months post-dose 2 (End of Study (EOS)) in 
subjects who are SARS-CoV-2 seronegative and 
RT-PCR negative at baseline  
 
SECONDARY OBJECTIVES 
See Table 7. 
 
SECONDARY ENDPOINTS 
Table 7: Secondary Objectives and Associated Endpoints 
Phase 2 Secondary Objectives 
Phase 2 Secondary Endpoints 
1.  Evaluate the safety and tolerability of 
INO-4800 administered by ID 
injection followed immediately by EP  
 
1a. Incidence of solicited and unsolicited injection 
site reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
 1d. Incidence of adverse events of special interest 
(AESIs)   
Phase 3 Secondary Objectives 
Phase 3 Secondary Endpoints 
1. Evaluate the safety and tolerability 
of INO-4800    
 
1a. Incidence of solicited and unsolicited injection 
site reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
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(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality  
2. Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of disease 
severity in subjects who are SARS-
CoV-2 seronegative and RT-PCR 
negative at baseline    
2a.  Incidence of non-severe COVID-19 disease in 
subjects who are SARS-CoV-2 seronegative and 
RT-PCR negative at baseline starting 14 days 
after completion of the 2-dose regimen until EOS  
2b. Incidence of COVID-19 disease in subjects who 
are SARS-CoV-2 seronegative and RT-PCR 
negative at baseline starting 14 days after 
completion of the 2-dose regimen until EOS 
2c. Incidence of deaths due to COVID- in subjects 
who are SARS-CoV-2 seronegative and RT-
PCR negative at baseline starting 14 days after 
completion of the 2-dose regimen until EOS 
3.   Evaluate the cellular and humoral 
immune response to INO-4800  
3a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot  
3b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
4. Evaluate the efficacy of INO-4800 
in the prevention of COVID-19 
disease in subjects who are SARS-
CoV-2 seropositive at baseline  
 
4.  Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 
(End of Study (EOS)) in subjects who are SARS-
CoV-2 seropositive at baseline 
 
EXPLORATORY OBJECTIVE 
See Table 8. 
 
EXPLORATORY ENDPOINTS 
Table 8: Exploratory Objectives and Associated Endpoints 
Phase 2 Exploratory Objective 
Phase 2 Exploratory Endpoints 
1.  Evaluate the expanded 
immunological profile of antibody 
response and T cell immune 
response 
1a.  Antigen-specific cellular immune response 
measured by flow cytometry. 
1b. Expanded immunological profile which may 
include additional assessments of T and B cell 
numbers and molecular changes by measuring 
immunologic proteins and mRNA levels of genes 
of interest as determined by sample availability 
Phase 3 Exploratory Objective 
Phase 3 Exploratory Endpoints 
1. Evaluate the efficacy of INO-4800 
in the prevention of COVID-19 
disease from SARS-CoV-2 variants 
in subjects who are SARS-CoV-2 
seronegative and RT-PCR 
negative at baseline 
1. Incidence of virologically-confirmed COVID-19 
disease from a SARS-CoV-2 variant starting 14 
days after completion of the 2-dose regimen until 
12 months post-dose 2 (End of Study (EOS)) in 
subjects who are SARS-CoV-2 seronegative and 
RT-PCR negative at baseline 
2. Evaluate the efficacy of INO-4800 
in the prevention of SARS-CoV-2 
2. Incidence of SARS-CoV-2 asymptomatic 
infections in in subjects who are SARS-CoV-2 
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asymptomatic infection in subjects 
who are SARS-CoV-2 seronegative 
and RT-PCR negative at 
baseline     
seronegative and RT-PCR negative at baseline 
starting 14 days after completion of the 2-dose 
regimen until EOS 
3. Evaluate the immunological profile 
by assessing both antibody 
response and T cell immune 
response  
3a.  SARS-CoV-2 Spike glycoprotein antigen-
specific binding antibody levels  
3b.  Antigen-specific cellular immune response 
measured by flow cytometry  
4. Evaluate antibody persistence  
4a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels at Week 30 or later.  
4b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay at Week 
30 or later 
 
EFFICACY ASSESSMENT (PHASE 3 SEGMENT ONLY) 
Subjects will receive either active investigational product (INO-4800, dose selected from 
the Phase 2 segment) or placebo in a 2-dose regimen administered intradermally followed 
immediately by EP on Days 0 and 28. Subjects will be monitored through regularly 
scheduled clinic visits and phone calls throughout the trial. Subjects will be regularly tested 
for SARS-CoV-2 infection using serologic testing. If COVID-19 disease (including severe 
COVID-19) is suspected based on symptoms or laboratory testing, site personnel will 
arrange for a clinic visit. Subjects with symptom(s) or a positive SARS-CoV-2 test result 
will be reviewed by the independent blinded EAC. The EAC will adjudicate all suspected 
COVID-19 events and determine whether cases meet the case definitions for COVID-19 
disease, severe COVID-19 or SARS-CoV-2 asymptomatic infection. 
The mechanism for review and confirmation of cases will be outlined in an EAC Charter.  
 CASE DEFINITION FOR VIROLOGICALLY-CONFIRMED COVID-19 DISEASE: 
•  Positive testing by SARS-CoV-2 RT-PCR assay (performed at central lab*) 
with fever (temperature of 100.4ºF/38.0ºC or higher), or  
• 
Positive testing by SARS-CoV-2 RT-PCR assay (performed at central lab*) 
with any of the following COVID-19 related symptoms: 
• 
Feeling feverish or chills  
• 
Cough  
• 
Shortness of breath or difficulty breathing  
• 
Fatigue  
• 
Muscle or body aches  
• 
Headache  
• 
New loss of taste or smell  
• 
Sore throat  
• 
Congestion or runny nose  
• 
Nausea or vomiting  
• 
Diarrhea  
*Local lab results will be accepted if the subject is hospitalized and a sample is 
not able to be obtained for analysis at central lab. 
3.7.1.1 Case Definition for Severe COVID-19 
• Confirmed COVID-19 disease (per Section 3.7.1) with any of the following:  
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a. Clinical signs at rest indicative of severe systemic illness (respiratory 
rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room 
air at sea level or PaO2/FiO2 < 300 mm Hg),  
b. Respiratory failure (defined as needing high-flow oxygen, noninvasive 
ventilation, mechanical ventilation or ECMO),  
c. Evidence of shock (SBP < 90 mm Hg, DBP < 60 mm Hg, or requiring 
vasopressors),  
d. Significant acute renal, hepatic, or neurologic dysfunction,  
e. Admission to an ICU, or  
f. Death.  
3.7.1.2 Case Definition for Non-Severe COVID-19  
• Confirmed COVID-19 disease (per Section 3.7.1);   
• Does not meet the case definition of Severe COVID-19 disease (Section 
3.7.1.1) 
 CASE DEFINITION FOR SARS-COV-2 ASYMPTOMATIC INFECTION  
Positive testing by SARS-CoV-2 serologic assay detecting antibodies to the 
Nucleocapsid protein. 
• Without clinical signs or symptoms of COVID-19 disease since the previous 
negative serologic test.  
 
SAFETY ASSESSMENT 
Subjects will be followed for safety during the trial through scheduled clinic visits and 
phone calls. AEs, regardless of relationship to study drug, will be collected from the time 
of consent until 28 days post-dose 2 (i.e., Day 56). SAEs, MAAEs and AESIs will be 
collected from time of consent until EOS. SAEs, AESIs, and treatment-related AEs will be 
followed to resolution or stabilization. For the Phase 2 segment and at selected sites in 
the Phase 3 segment, solicited local and systemic AEs will be collected for 7 days following 
each dose using a participant diary. 
Subjects will also be monitored for COVID-19 disease. 
Please refer to the Schedule of Events (Table 3 and Table 4) for safety assessments to 
be performed.   
 
IMMUNOGENICITY ASSESSMENT 
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 3 and Table 4). Assays such as binding ELISA, pseudovirus-based neutralization 
assay, and ELISpot will be evaluated at serial timepoints. 
 
CLINICAL TRIAL POPULATION 
 
INCLUSION CRITERIA 
 PHASE 2 SEGMENT 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
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c. Assessed by the Investigator to be healthy based on medical history, vital signs and 
physical examination performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar workers, 
store cashiers, hairdressers and barbers, veterinary staff, daycare workers, 
Transportation Security Administration screening staff, school teachers and 
college professors teaching in-person classes) 
2. Factory workers (when working in confined settings with large numbers of 
employees) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) 
4. User of public transportation (e.g., bus, train, subway) at least 3 times weekly 
5. Nursing home staff or correctional facility staff  
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol. Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field) 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists.) Physicians should not be enrolled unless they are 
assigned to dedicated COVID-19 treatment wards or other settings with prolonged 
exposure) 
10. Others, if approved by the medical monitor;   
f. Screening laboratory results within normal limits for testing laboratory or are deemed 
not clinically significant by the Investigator; 
g. Must meet one of the following criteria with respect to reproductive capacity: 
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or tubal 
ligation, absence of ovaries and/or uterus in females). In the case of vasectomy, 
subjects should wait six (6) months post-vasectomy prior to enrolling;  
• 
Use of medically effective contraception with a failure rate of < 1% per year when 
used consistently and correctly from screening until 3 months following last dose. 
Acceptable methods include:  
o hormonal contraception including implants, injections or oral; 
o two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
o intrauterine device or intrauterine system; 
o abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 PHASE 3 SEGMENT 
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a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Per investigator judgment, healthy or stable with pre-existing medical conditions that 
do not require significant change in medication or have led to a hospitalization in the 
3 months prior to enrollment or who, in the judgment of the investigator, are unlikely 
to require a significant change in therapy or hospitalization for worsening disease 
through Day 56;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings. 
Examples include:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar workers, 
street vendors, store cashiers, hairdressers and barbers, veterinary staff, daycare 
workers, airport screening staff, school teachers and college professors teaching 
in-person classes, college students attending in-person classes, office workers 
and volunteers who have multiple brief exposures to people regularly) 
2. Factory workers (when working in confined settings with large numbers of 
employees, meat-packing facilities) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) and delivery 
services  
4. User of public transportation (e.g., bus, train, subway) or public facilities (e.g. 
gyms) at least 3 times weekly 
5. Nursing home staff or correctional facility staff 
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, medical assistants and technicians, respiratory therapists, 
physical therapists, social workers, dentists and dental hygienists)  
10. Others, if in the opinion of the PI, the risk of COVID-19 exposure is comparable 
to the examples above. 
f. Must meet one of the following criteria with respect to reproductive capacity: 
1. Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
2. Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or tubal 
ligation, absence of ovaries and/or uterus in females). In the case of vasectomy, 
subjects should wait six (6) months post-vasectomy prior to enrolling;  
3. Use of medically effective contraception with a failure rate of < 1% per year when 
used consistently and correctly from screening until last dose. Acceptable 
methods include:  
i. hormonal contraception including implants, injections or oral; 
ii. two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
iii. intrauterine device or intrauterine system; 
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iv. abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 
EXCLUSION CRITERIA 
 PHASE 2 SEGMENT 
a. Acute febrile illness with temperature > 100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat);  
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the Screening visit until 
3 months following the last dose; 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or 
a detectable viral load within the past 3 months; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0 (documented receipt of placebo in a previous trial 
would be permissible for trial eligibility); 
g. Previous receipt of an investigational vaccine for prevention or treatment of COVID-
19, MERS or SARS (documented receipt of placebo in previous trial would be 
permissible for trial eligibility). 
h. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg prior to first dose; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin cancers 
that only required local excision and non-metastatic prostate cancer not requiring 
treatment; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in therapy 
or hospitalization for worsening disease during the 6 weeks prior to enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a single 
antiepileptic agent; 
i. 
Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed) in the prior 6 months; 
• 
Current or anticipated use of disease modifying doses of systemic anti-rheumatic 
drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and 
biologic disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, 
adalimumab or etanercept); 
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• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the subject 
or require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
j. 
Lack of acceptable sites for ID injection and EP considering the skin above the 
deltoid and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
ICD or pacemaker (to prevent a life-threatening arrhythmia) that is located 
ipsilateral to the deltoid injection site (unless deemed acceptable by a 
cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation site; 
k. Blood donation or transfusion within 1 month prior to Day 0; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the prior 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
 PHASE 3 SEGMENT 
a. Acute febrile illness with temperature ≥100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat) within 
72 hours prior to Day 0 dosing; 
b. Positive serologic test for SARS-CoV-2 at Screening (after approximately 402 
subjects positive for SARS-CoV-2 serologic test are randomized, this criterion will 
apply to all remaining subjects); 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children starting from the Screening visit until the last dose; 
d. Positive urine pregnancy test during screening or  immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or 
a detectable viral load within 3 months prior to screening; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days prior to Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous or planned receipt of an investigational (including Emergency Use 
Authorization (EUA) or local equivalent authorization) or licensed vaccine for 
prevention or treatment of COVID-19, MERS or SARS (documented receipt of 
placebo in previous trial would be permissible for trial eligibility); 
h. Immunosuppression as a result of underlying illness or treatment including: 
 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed) in the past 6 months; 
• 
Current or anticipated use of disease modifying doses of systemic anti-rheumatic 
drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and 
biologic disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, 
adalimumab or etanercept) or others; 
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• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the subject 
or require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
i. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation site; 
j. 
Blood donation or transfusion within 1 month prior to Day 0; 
k. People who work remotely or in a socially distanced setting with minimal risk of 
exposure to SARS-CoV-2; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the prior 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
 
DISCONTINUATION/WITHDRAWAL OF CLINICAL TRIAL SUBJECTS 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the Investigator should any untoward effect occur. In addition, the 
Investigator or the Sponsor has the right to discontinue a subject from the trial at any time. 
If HIV testing performed at Day 0, in the setting of no prior HIV diagnosis, returns with a 
positive result after the subject has already received the Day 0 dose, the subject should 
be discontinued from further dosing and followed for safety.   
The Investigator must notify the Medical Monitor immediately when a subject has been 
discontinued/withdrawn due to an Adverse Event (AE). If a subject withdraws from the trial 
or is discontinued from the trial prior to trial completion, all applicable activities scheduled 
for the final trial visit (i.e., Day 393) should be performed at the time of 
discontinuation/withdrawal if the subject agrees. Any related AEs, AESIs, and/or Serious 
Adverse Events (SAEs) present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.9. 
Unless a subject refuses to continue participation, all follow-up visits and procedures 
should be completed as indicated in the Schedule of Events (Table 3 and Table 4) 
following the second dose whether or not the subject has completed both doses. 
If a subject receives a non-study COVID-19 vaccine either authorized under emergency 
use or licensed, during the trial, the subject should provide details of the vaccine to study 
staff and the Investigator should enter the details as a concomitant medication. The 
subject should be advised that there is inadequate information regarding the safety and 
effectiveness of other COVID-19 vaccines when received following the receipt of INO-
4800. Furthermore, the subject should be requested to remain in the trial (according to the 
Schedule of Events outlined in Tables 3 and 4).  
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. In cases where 
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the subject does not return for the rescheduled visit or cannot be reached to reschedule 
the missed visit, the site should make every effort to regain contact with the subject (3 
telephone calls and if that fails, then a certified letter to the subject’s last known mailing 
address) so that the subject’s disposition can be considered as withdrawn from the study 
(i.e. lost to follow-up). If the contact with subject is re-established, site should contact 
medical monitor to discuss whether subject can continue study treatment or follow-up 
visits for the study. For all other subjects withdrawing from the study, an alternative reason 
for discontinuation should be recorded in the eCRF. 
Reasons for discontinuation/withdrawal from the trial may include but are not limited to the 
following: 
• 
Subject withdrawal of consent at any time; 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardize the 
subject’s safety if he or she continues in the trial; 
• 
Investigator, DSMB or Sponsor determines it is in the best interest of the subject; 
• 
Subject non-compliance. 
Every effort should be made to obtain information on subjects who withdraw from the trial. 
The primary reason for withdrawal from the trial should be documented on the appropriate 
CRF. However, subjects will not be followed for any reason after consent has been 
withdrawn. Data and/or samples collected prior to withdrawal of consent will be analyzed.  
Reasons for discontinuing subject dosing may include but are not limited to the following: 
• 
Adverse Event (Adverse Reaction); 
• 
The Investigator or trial coordinator must notify the Sponsor immediately when a 
subject has been discontinued/withdrawn due to an Adverse Event (AE). 
• 
Any medical condition that may jeopardize the subject’s safety if he or she continues 
on trial; 
• 
Pregnancy. 
 
CLINICAL TRIAL INVESTIGATIONAL PRODUCT INFORMATION 
 
INVESTIGATIONAL PRODUCT (IP) AND STUDY DEVICE 
 INO-4800 AND PLACEBO 
Investigational product is defined as a pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in the study, whether blinded or unblinded. 
INO-4800 is the active investigational product to be used in this study. The INO-4800 drug 
product contains 10 mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM 
sodium chloride and 15 mM sodium citrate). pGX9501 is a DNA plasmid expressing a 
synthetic consensus (SynCon®) sequence of the SARS-CoV-2 full length Spike 
glycoprotein. 
Phase 2 segment: 
Active Investigational Product (INO-4800): A volume of 0.4 mL will be filled into 2-mL glass 
vials that are fitted with rubber stoppers and sealed aluminum caps. 
Placebo: Sterile saline sodium citrate (SSC) buffer, which contains sterile 150 mM sodium 
chloride and 15 mM sodium citrate in 10-mL glass vials, stoppered, and sealed with 
aluminum caps. 
Phase 3 segment: 
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Active Investigational Product (INO-4800): A volume of 0.4 mL, 0.8 mL, or 1.5 mL will be 
filled into 2R glass vials that are fitted with rubber stoppers and sealed aluminum caps. 
Placebo: Sterile saline sodium citrate (SSC) buffer, which contains sterile 150 mM sodium 
chloride and 15 mM sodium citrate at a volume of 0.8 mL or 1.5 mL in 2R glass vials, 
stoppered, and sealed with aluminum caps. Placebo may also be referred to as Placebo 
for INO-4800 or Sterile SSC Buffer. 
 CELLECTRA® 2000 
Electroporation is a procedure used to enhance cellular DNA uptake within host cells 
following DNA vaccine ID delivery. This study will use the CELLECTRA® 2000, a portable, 
battery-powered medical device designed to generate a controlled, electric field that 
temporarily and reversibly increases cellular membrane permeability without clinically 
damaging the tissue. During the period of increased permeability, injected plasmid DNA 
can be introduced into the cells. 
As mentioned above, the CELLECTRA® 2000 device is intended to enhance the uptake 
and expression of DNA plasmid-based biologics in order to enhance vaccine efficacy. The 
DNA plasmid is delivered separately via needle and syringe ID injection immediately prior 
to the electroporation. The electroporation is accomplished through a sterile, disposable 
needle Array attached to an Applicator delivering controlled electrical pulses as follows: 
• 
An EP administration consists of four pulses. 
• 
An array of three stainless steel electrode needles is used to deliver the electrical 
pulses into the tissue. The Array needle length that penetrates into the skin and 
tissue is approximately 3.2 mm. To date, we have not had any safety concerns 
associated with the depth of the array electrode needles. Within the Array needle 
depth of 3.2 mm, there are no major blood vessels (arteries, veins) or nerve 
structures at the authorized sites of administration overlying the deltoid or the 
anterolateral quadricep muscle. There are superficial capillaries and minor nerves 
innervating the skin, including subcutaneous tissues that may be disrupted by 
needle insertion, but are extremely unlikely to result in serious injury; intradermal 
injection followed by EP of these structures poses no significant risk to the subject 
except for possibly injection site reactions. 
• 
The CELLECTRA® 2000 generates four 52ms ±1ms electrical current controlled 
DC pulses. The nominal current is set to 0.2A ±10% by modulating voltage, or 
capped at 200V ±5%, determined by patient tissue impedance. 
• 
The total energy delivered by the device is determined by the combination of four 
device parameters: Pulse Current, Pulse Voltage, Number of Pulses, and Pulse 
Width. The parameters are pre-set by Inovio to be a pulse current of 0.2A, a pulse 
voltage of 200V, and 4 pulses at 52ms pulse width. The parameters are verified 
prior to shipment and cannot be changed by the user.  
• 
In eight clinical trials administering ID injection followed by EP using the 
CELLECTRA® 2000, total energy delivered ranged from 0.9J to 7.8J, which have 
been generally safe and well-tolerated. In addition, Inovio has calculated the total 
maximum energy delivered ID as 8.32J for normal use conditions. Higher energy 
pulses ranging from 10.7J to 11.7J were evaluated in a guinea pig model which 
induced erythema localized to the electrode insertion site. Taken together, these 
nonclinical data and Inovio’s clinical experience provide evidence that the total 
energy delivered by the CELLECTRA® 2000 device will not result in 
unacceptable risks when delivered to patients. Further, a published study 
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evaluated the Visual Analog Scale (VAS) pain scores of normal use conditions 
(0.2A), and found ID injection followed by EP using  the CELLECTRA® 2000 
device to be safe and well tolerated [65]. 
• 
The specified current is constantly maintained through voltage modulation using 
an analog feedback loop. Measurements of voltage and current are processed for 
error reporting and collected for data logging. 
The CELLECTRA® 2000 device is comprised of three components: (1) A battery-powered 
Pulse Generator, (2) an ID Applicator that is connected to the pulse generator, and (3) a 
three-point sterile disposable ID Array of stainless steel needles. The Pulse Generator 
and ID Applicator are reusable components. These components should be cleaned and 
disinfected prior to each subject’s use according to the Cleaning and Maintenance 
procedure in the User Manual. The Pulse Generator and ID Applicator have been 
validated for up to 30 cleaning and disinfection cycles based on a maximum of 30 subjects 
being treated in a day. Therefore, the Pulse Generator and ID Applicator’s use should be 
limited to 30 subjects in a day. Any potential risk of damage to the device due to cleaning 
and disinfection for more than 30 cycles has not been validated. Always inspect the device 
before use according to the instructions in the Maintenance section of the User Manual. 
 
DOSING REGIMENS 
Phase 2 Segment 
• 
Active Investigational Product: One or two 1.0mg ID injection(s) of INO-4800 (~0.1mL 
dose volume each) followed immediately by EP administered on Day 0 and Day 28 
(±3 days) 
• 
Placebo: One or two ID injection(s) of placebo (~0.1mL) followed immediately by EP 
administered on Day 0 and Day 28 (±3 days) 
Phase 3 Segment 
• 
Active Investigational Product: Two 1.0mg ID injections of INO-4800 (~0.1mL dose 
volume) followed immediately by EP administered in separate limbs on Day 0 and Day 
28 (±3 days) 
• 
Placebo: Two ID injections of placebo (~0.1mL) followed immediately by EP 
administered in separate limbs on Day 0 and Day 28 (±3 days) 
 BLINDING 
This study is blinded. The Sponsor, subjects and clinical site staff, with the exception of 
the site’s pharmacy personnel, will be blinded. There is no difference in appearance 
between INO-4800 and the placebo; however, they are distinguishable based on the vial 
size and/or labelling on the vials. In the Phase 2 segment, the vials will be of different sizes 
and have unblinded labelling. In the Phase 3 segment, the vials will be the same size but 
will have unblinded labelling. To maintain the blind, vials will only be handled by 
designated unblinded personnel (site pharmacist) at the site. 
Under exceptional circumstances, the PI may desire to unblind a subject’s dose 
assignment in case of an emergency or serious medical condition when knowledge of the 
study product or dose is deemed by the PI to be absolutely essential for proper clinical 
management of the subject. Under such emergency circumstances, the Sponsor urges 
the PI to first contact the Medical Monitor (MM) to review options before unblinding the 
subject’s dose assignment. In case of non-emergency, PI must contact MM to discuss the 
options before unblinding the subject’s dose assignment.  
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It is not deemed appropriate to unblind a subject’s treatment assignment for the purpose 
of assisting the subject in making a decision regarding receipt a different COVID-19 
vaccine (emergency use or licensed vaccine).  Subjects may be advised that without 
efficacy data, INO-4800 has not been proven to be more protective than placebo in the 
prevention of COVID-19 and SARS-CoV-2 infection. Therefore, unblinding will not provide 
any meaningful information to inform a decision of receiving a different COVID-19 vaccine. 
The Sponsor’s pharmacovigilance staff may unblind a subject’s dose assignment for an 
SAE, unanticipated adverse device effect (UADE), or adverse event of special interest 
(AESI) when the event is assessed as related and unexpected. If expedited regulatory 
reporting is required for such an event, the report may be submitted to regulatory 
authorities with the subject’s dose assignment, in accordance with local regulations. 
 
The Phase 2 segment of the trial will be unblinded following subjects reaching the Week 
30 visit. 
 
PACKAGING AND LABELING 
 INO-4800 OR PLACEBO 
Each vial of INO-4800 or placebo will be labeled consistent with the example product label 
provided in the IB.  
 CELLECTRA® 2000 
Please see shipping box for shipping documents and contents. 
The CELLECTRA® 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer. The CELLECTRA® 2000 User Manual 
describes all relevant contraindications, hazards, potential risks and adverse effects, 
interfering substances or devices, warnings, and precautions. Each Pulse Generator has 
a unique serial number, and each ID Applicator has a unique serial number. Each ID Array 
has a Lot Number and Expiration Date. Examples of device labels are provided in the IB. 
The CELLECTRA® 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. 
 
HANDLING AND STORAGE 
 INO-4800 AND PLACEBO 
INO-4800 and placebo will be shipped at 2–8°C. If the temperature monitoring devices in 
the shipping container(s) denote temperatures outside this 2–8°C (36-46°F) range, the 
Sponsor, or its designee, should be contacted immediately. 
Upon arrival, the INO-4800 and placebo must be transferred from the shipping container 
into 2–8°C (36-46°F) storage, in a secure area, in accordance with local regulations by 
designated personnel (e.g., pharmacy personnel). The Sponsor must be notified of any 
deviations from this storage condition. Refrigerator temperature logs must be maintained 
at the clinical site and temperatures must be recorded and monitored regularly. For further 
details see Pharmacy Manual and IB. 
 CELLECTRA® 2000 
See User Manual for operating and storage conditions. 
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PREPARATION AND DISPENSING 
In the Phase 2 segment, INO-4800 is supplied in 2-mL vials at a concentration of 10 
mg/mL at a minimum volume of 0.4 mL. Placebo is supplied in 10-mL vials at a minimum 
volume of 2 mL.  
In the Phase 3 segment, INO-4800 is supplied in 2-mL vials at a concentration of 10 
mg/mL at a minimum volume of 0.4 or 0.8 mL. Placebo is supplied in 2-mL vials at a 
minimum volume of 0.8 mL. 
Blinded staff involved in the clinical execution of the study should not come in contact with 
vials of INO-4800 or placebo. Vials will only be handled by designated unblinded 
personnel (e.g., pharmacy) at the site. When a subject is eligible for enrollment, unblinded 
personnel will draw INO-4800 or placebo into a blinded syringe in accordance with the 
subject’s randomized treatment assignment according to a randomization schedule. The 
syringe will be transferred to blinded site personnel for administration.  
Each INO-4800 and placebo vial will contain a volume of product sufficient to dose multiple 
subjects. The preparation and dispensing information will be provided in the Pharmacy 
Manual. 
 
USE OF STUDY DEVICE 
The instructions for use of the CELLECTRA® 2000 device are provided in the User 
Manual. Each clinical site will receive training for use of the CELLECTRA® 2000 device 
prior to first dose. The EP procedure must be performed by qualified personnel. Any 
individual designated to perform the procedure should be permitted by the relevant local 
authorities to administer parenteral injections to patients (e.g., MD, DO, RN) in addition to 
successfully completing device training provided by Sponsor personnel.  
 
INVESTIGATIONAL DRUG AND STUDY DEVICE ACCOUNTABILITY 
 INVESTIGATIONAL PRODUCT (IP) ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current accountability record of 
investigational products (INO-4800 or placebo) is maintained at the study site. The 
investigational products must have full traceability from the receipt of the products through 
subject use, disposal or return of the products. Records or logs must comply with 
applicable regulations and guidelines. The accountability information is provided in the 
Pharmacy Manual. 
 CELLECTRA® 2000 ACCOUNTABILITY 
The investigational site is responsible for maintaining device accountability logs. The 
device must have full traceability from the receipt of the products through subject use, 
disposal or return of the products. The site must document acknowledgement of receipt 
and notify Inovio upon receipt of study devices. This includes the content shipped and 
condition upon receipt. 
For each subject administration, there must be a record of each product used for that 
subject, i.e., Pulse Generator serial number, ID Applicator serial number, and ID Array lot 
number. The ID Applicator is reusable with a new ID Array and sheath for each procedure. 
The sterile ID Array and sheath are single use only and must be discarded after use in 
accordance with institutional policy regarding disposal of sharp needles/instruments. 
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RETURN AND DESTRUCTION OF INVESTIGATIONAL DRUG AND STUDY DEVICE 
 INO-4800 AND PLACEBO 
Upon completion or termination of the study, all unused vials of INO-4800 or placebo must 
be destroyed at the study site in accordance with institution policy or returned to Inovio 
Pharmaceuticals, Inc., or its designee if the site cannot destroy IP. 
The used vials of INO-4800 and placebo will be discarded in accordance with the site’s 
used IP disposal procedure. It is the Investigator’s responsibility to arrange for disposal of 
all empty vials, provided that procedures for proper disposal have been established in 
accordance with applicable national, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. If requested by the Sponsor, the 
return of unused IP vials should be arranged by the responsible Inovio Representative. 
The unused IP vials should only be destroyed after being inspected and reconciled by the 
responsible Inovio Pharmaceuticals, Inc., personnel or designated Clinical Monitor. If IP 
vials are returned to Inovio Pharmaceuticals, Inc., or its designee, the IP must be 
accompanied by the appropriate documentation. The return of unused IP(s) should be 
arranged with the responsible Inovio personnel and/or Clinical Monitor. 
 RETURN OF CELLECTRA® 2000 
Upon completion or termination of the study, an Inovio Representative will provide 
instructions regarding the component(s) to be returned to Inovio Pharmaceuticals, Inc., 
destroyed onsite or shipped to a destruction vendor. 
All products returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original containers. 
The return of all products identified above should be arranged by the Inovio 
Representative. The ID Arrays should be discarded in the sharps container immediately 
after use. The used ID Applicators can either be destroyed at the site, shipped to a 
destruction vendor, or returned to Inovio. If the used ID Applicators are destroyed on site, 
it is the Investigator’s responsibility to ensure that arrangements have been made for the 
disposal, written authorization has been granted by Inovio Pharmaceuticals, Inc., or its 
designee, procedures for proper disposal have been established in accordance with 
applicable regulation and guidelines and institutional procedures, and appropriate records 
of the disposal have been documented. 
 
CLINICAL TRIAL PROCEDURES AND SCHEDULE 
The Schedule of Events (36TTables 3 and 436T) in the Clinical Protocol Synopsis summarizes 
the procedures to be performed at each visit. Individual procedures are described in detail 
below. It may be necessary to perform these procedures at unscheduled time points if 
deemed clinically necessary by the Investigator. A subject will be required to provide 
informed consent (Section 6.2) prior to any study procedure being performed. Protocol 
waivers or exemptions will not be granted. Therefore, adherence to the study design and 
assessments are essential and required for study conduct. 
 
PROCEDURE BY VISIT 
Refer to Sections 6.1.1 and 6.1.2 for trial procedures and the times at which they are to 
be performed. 
 CLINICAL TRIAL SCREENING EVALUATIONS 
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The assessments performed during Screening will determine the subject’s eligibility for 
the study and also their ability to comply with protocol requirements by completing all 
screening assessments. The following screening evaluations will be performed for both 
Phase 2 and Phase 3 segments within 30 days prior to dosing on Day 0. All screening 
assessment values must be reviewed prior to the first Study IP administration. Screening 
and Day 0 visits may be on the same day if eligibility is able to be confirmed prior to 
randomization. If so, all assessments for Screening and Day 0 must be performed at the 
combined visit. 
If a subject does not meet an inclusion or exclusion criterion due to a transient and non-
clinically significant event at Screening, relevant Screening evaluations may be repeated 
within the same 30-day Screening period. If the subject fails twice, they will be considered 
a screen failure. 
• 
Signed and dated informed consent (Section 6.2); 
• 
Review and confirm all inclusion/exclusion criteria (Section 4.1 and 4.2); 
• 
Obtain and document complete medical history, surgical history (including all 
clinically significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Section 6.1.1.1); 
• 
Collect demographics; 
• 
Collect socio-behavioral assessment information (Section 6.4); 
• 
Collect AEs (Section 6.4.4); 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Record height and weight (Section 6.4); 
• 
Collect urine for pregnancy test (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8).  
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.8). 
 
6.1.1.1 
Medical History 
A medical history will be obtained by the Investigator or qualified designee at the time of 
Screening. Medical history will include all active conditions, and any other past conditions, 
as well as surgical procedures, that are considered to be clinically significant by the 
Investigator and/or having occurred within 3 months prior to Screening. Subjects should 
be queried about any history of Hepatitis B, Hepatitis C and HIV.   
In the Phase 3 segment, subjects with a self-reported history of Hepatitis B or C must 
provide documentation of liver enzymes that are not significantly elevated within the past 
3 months. If such a report of liver enzyme testing is not available, this testing should be 
performed at Screening. Subjects with a history of Hepatitis C without cirrhosis who have 
completed treatment and have proof of an undetectable viral load at least 12 weeks 
following treatment may be enrolled and do not require liver enzymes within the past 
months. 
Subjects with self-reported HIV must provide documentation of controlled HIV infection 
based on a CD4 count greater than 200 cells/mm3 or an undetectable viral load within the 
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past 3 months. If a recent CD4 count and/or viral load is not available, this testing should 
be performed at Screening.  
Illnesses first occurring or detected after the signing of the informed consent, or during the 
study and/or worsening of an existing illness in severity, frequency or nature after signing 
of the informed consent are to be documented as AEs on the Case Report Forms (CRF). 
Prior treatments, defined as administered up to 12 weeks prior to the time of informed 
consent and stopped prior to dosing on Day 0, should be recorded in the CRF as prior 
medications. Concomitant treatments, defined as continuing on Day 0 or new treatments 
taken at or after Day 0, should be recorded in the CRF as concomitant medications. 
 CLINICAL TRIAL EVALUATIONS AND PROCEDURES 
Once eligibility has been confirmed, the subject will be randomized to receive a treatment 
assignment (INO-4800 or placebo). Visit dates and windows must be calculated from Day 
0, unless otherwise noted. All subjects will be followed until the Day 393 Visit. All subjects 
will be followed in accordance with assessments outlined below. 
6.1.2.1 
Day 0 and Day 28 (Dosing Visits) 
The following evaluations will be performed on Day 0 and Day 28 prior to dose 
administration: 
Both Phase 2 and Phase 3 segments: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Obtain any updates to medical history, surgical history (including all clinically 
significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Day 0 visit only) (Section 6.1.1.1); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect urine for urine pregnancy test (Section 6.4); 
• 
Collect blood for HIV serology (Day 0 visit only) (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Day 0 visit only) (Phase 3 cellular immunology collection at selected sites only) 
(Section 6.5); 
• 
Review restrictions for injection and EP (Section 6.4.7); 
• 
Randomize subject (instructions to be provided under separate cover) (Day 0 visit 
only). 
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect diary from Day 0 dose (Day 28 visit only). 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8); 
• 
Collect nasopharyngeal swabs for SARS-CoV-2 RT-PCR (Day 0 only) (Section 
6.4.8); 
• 
Collect diary from Day 0 dose during Day 28 visit only (for selected sites only). 
 
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The following evaluations will be performed on Day 0 and Day 28 after IP plus EP 
administration: 
• 
Collect any new AEs (Section 6.4.4); 
• 
Download EP Data (for selected sites only); 
• 
Provide supplies for subject to use at home, as required (e.g. thermometer, wound 
guide); 
• 
Phase 2 segment: Distribute diary; 
• 
Phase 3 segment, for selected sites: Distribute diary. 
6.1.2.2 
Post-dose phone calls 
Phase 2 segment: Day 7 and Day 35 
Phase 3 segment: Day 14  
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
 
Phase 2 segment only: 
• 
Review diary (Section 6.4). 
 
Phase 3 segment only: 
• 
Review diary (for selected sites)(Section 6.4); 
6.1.2.3 
Day 42 Visit  
The Day 42 visit must occur at least 10 days after Day 28 visit. 
Both Phase 2 and Phase 3 segments: The following evaluations will be performed at this 
visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4);  
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 cellular immunology collection at selected sites only)(Section 6.5);  
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect diary from Day 28 visit. 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8); 
• 
Collect diary from Day 28 visit (for selected sites only); 
• 
Ensure subject has necessary supplies at home (e.g. thermometer). 
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6.1.2.4 
Phone calls  
Phase 2 segment: Day 56 
Phase 3 segment: Days 56, 70, 84, 98, 112, 140, 154, 168, 182, 196, 238, 266, 322, 
350, and 378 
In the Phase 3 segment, phone calls to subjects have been spaced bi-weekly 
between study visits through Day 210, and approximately monthly between visits 
from Day 210 to Day 393.   
 
Guidelines for information to be collected during the phone call can be found in the 
Phone Script. The following evaluations will be performed during the phone call: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Ask about any symptoms of COVID-19 disease; Arrange on-site visit if any signs 
and symptoms of COVID-19 disease are present (Section 6.4.9); 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
6.1.2.5 
Follow up clinic visits 
Phase 2 segment: Day 210 
Phase 3 segment: Days 126, 210 and 294 Visits 
Both Phase 2 and Phase 3 segments: The following evaluations will be performed at these 
visits: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); SAEs, AESIs, and 
MAAEs will be reported after the Day 56 Visit. 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 Day 201 visit only; Phase 3 cellular immunology collection at selected 
sites only) (Section 6.5); 
 
Phase 3 segment: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8);  
• 
Ensure subject has necessary supplies at home (e.g. thermometer). 
6.1.2.6 
Day 393 Visit or EOS 
Phase 2 and Phase 3 segments: The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); SAEs, AESIs, and 
MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
 
Phase 2 segment: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
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• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6); 
• 
Collect urine pregnancy test (Section 6.4). 
 
Phase 3 segment: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 cellular immunology collection at selected sites only) (Section 6.5). 
6.1.2.7 
COVID-19 Assessment Visit 
For both the Phase 2 and Phase 3 segments of the study, subjects will be evaluated 
during a COVID-19 assessment visit when acute COVID-19 is suspected based on 
symptoms or positive SARS-CoV-2 testing. The assessment visit may be performed in 
the clinic, subject’s vehicle, or at a home visit and should be performed within 3 days of 
a positive SARS-CoV-2 test or site knowledge of COVID-19 symptom onset. The 
virologic-confirmation of a case will be based on SARS-CoV-2 RT-PCR testing from the 
central lab. A local RT-PCR result will be considered acceptable in the case where a 
subject is hospitalized and a sample for central lab analysis is not able to be obtained, if 
it was obtained using. an assay performed by a laboratory accredited according to 
standards set by a national or regional accreditation body.  
If a local lab is used to confirm the case, the report from the laboratory must be provided.  
Phase 2 and Phase 3 segments: The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); Only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Optional targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
 
Phase 2 only: 
• 
Collect nasal swabs and saliva for SARS-CoV-2 RT-PCR detection (Section 6.4.8). 
Phase 3 only: 
• 
Collect whole blood and serum for cellular and humoral immunology assessment, 
where possible (Phase 3 cellular immunology collection at selected sites only) 
(Section 6.5) 
• 
Collect nasopharyngeal swabs for SARS-CoV-2 RT-PCR testing (Section 6.4.8). 
6.1.2.8 
COVID-19 Convalescent Visit 
Phase 2 and Phase 3 segments: For subjects with virologically confirmed SARS-CoV-2 
infection during the trial, a convalescent visit should be scheduled approximately 28 days 
after symptom onset, or in the absence of symptoms, after the collection date of any 
specimen testing positive for SARS-CoV-2 RT-PCR. If acute symptoms are ongoing at 28 
days after symptom onset, the site should follow up with the subject via phone call or 
unscheduled visit after symptom resolution or stabilization.  
The following evaluations will be performed at this visit: 
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• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); Only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
where possible (Phase 3 cellular immunology collection at selected sites only) 
(Section 6.5); 
 
Phase 2 segment only: 
• 
Collect nasal swabs and saliva for SARS-CoV-2 RT-PCR detection (Section 6.4.8). 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8). 
 
INFORMED CONSENT 
All subjects must sign the informed consent prior to participating in any clinical trial-related 
procedures. The informed consent documentation must be in compliance with applicable 
regulations and GCP. Qualified clinical trial personnel will: 
• 
Meet with prospective clinical trial subjects; 
• 
Explain the clinical trial; 
• 
Provide clinical trial subjects with an Informed Consent Form (ICF) that includes the 
following in a language that is understandable to the subject: 
• 
Screening test(s) description; 
• 
Eligibility criteria for entering the clinical trial; 
• 
Clinical trial treatments and follow-up procedures description; 
• 
Explanation of the clinical trial, including but is not limited to: 
• 
Clinical trial objectives; 
• 
Potential benefits and risks; 
• 
Discomforts/inconveniences; 
• 
Subject’s rights and responsibilities. 
The subject is then requested to sign and date the ICF. A copy of the signed informed 
consent documentation must be provided to the subject. The qualified clinical trial 
personnel will document the process of obtaining informed consent within the source 
record. Signed ICFs are maintained in the subject’s source records and must be 
accessible for verification at any time. Signing of the ICF begins the 30-day screening 
period. 
 
ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number (SID), 
which identifies the subject for all clinical trial-related procedures. SIDs are a combination 
of a site code and a subject number. After SIDs are assigned, they cannot be reused or 
reassigned for any reason. Information regarding the SID and screen date will be 
documented on a screening and enrollment log/system and in the CRF.   
Previously screen failed subjects may be rescreened provided there is a valid documented 
reason for rescreening (i.e. changes to the person’s health or situation that would make 
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them possibly eligible at this later time). If rescreening occurs, the subject will keep their 
original Subject ID.  
 
SAFETY EVALUATIONS 
PHYSICAL AND TARGETED PHYSICAL EXAM  
A full physical examination will be conducted during Screening and at study 
discharge/EOS (e.g. Day 393). A targeted physical assessment will be performed at other 
visits as determined by the Investigator based on subject symptoms.  
VITAL SIGNS 
Vital signs including temperature, respiration rate, blood pressure and heart rate will be 
measured at Screening and at visits specified in the Schedule of Events (36TTables 3 and 
436T).  
At the COVID-19 assessment and convalescent visits, temperature, respiration rate, 
heart rate and oxygen saturation should be performed.   
HEIGHT AND WEIGHT 
Weight and height will be collected at Screening. 
SOCIO-BEHAVIORAL ASSESSMENT  
A Socio-behavioral Assessment, including self-reported smoking and vaping history, and 
self-reported history of exposure to second-hand smoke will be obtained at Screening. 
LABORATORY EVALUATIONS 
Blood samples will be collected at visits specified in the Schedule of Events (36TTables 3 and 
436T). A total of approximately mL 245-330mL of blood will be drawn from each subject over 
the course of the study (inclusive of relevant safety and immunology samples at regular 
study visits per Tables 3 and 4). If the subject is evaluated at COVID-19 visits, an 
additional volume of approximately 85-120mL will be collected. Subjects may be asked to 
return for additional blood draws if collected blood sample is lost or unevaluable for any 
reason. 
Hematology [Complete blood count (CBC) with automated differential]: 
White blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit and 
platelet count will be measured at Screening (Phase 2 segment only) and at visits specified 
in the Schedule of Events (36TTables 3 and 436T). Hemoglobin A1c will additionally be performed 
at Screening (Phase 2 segment only). 
Serum chemistry: 
Electrolytes [Sodium (Na), Potassium (K), Chloride (Cl), Bicarbonate (HCO3), Calcium 
(Ca), Phosphate (PO4)], glucose, Blood Urea Nitrogen (BUN), Creatinine (Cr), alkaline 
phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), LDH, 
and total bilirubin (TBili) at Screening (Phase 2 segment only) and at visits specified in the 
Schedule of Events (36TTables 3 and 436T).  
Urinalysis:  
Urine samples will be tested by dipstick for glucose, protein, and hematuria at Screening 
(Phase 2 segment only) and at visits specified in the Schedule of Events (36TTables 3 and 
436T). If abnormal (presence of protein, hematuria, or glucose ≥ 1+), a microscopic 
examination should be performed.  
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Serology: 
HIV antibody or rapid test will be performed at Day 0 only.  
Antibodies to SARS-CoV-2 will be measured at Screening in the clinic using a rapid test 
which detects Spike protein antibodies and at pre-dose Day 0 and subsequent visits via 
testing at a study-designated lab which detects antibodies to Nucleocapsid protein. 
Timepoints are specified in the Schedule of Events (Tables 3 and 4). 
Pregnancy Testing:  
Pregnancy testing will be performed on women of childbearing potential (WOCBP). All 
women will be assumed to be of childbearing potential unless they are:  
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Women who are surgically sterile or have a partner who is sterile (i.e., vasectomy 
in males or tubal ligation, absence of ovaries and/or uterus in females). In the 
case of a vasectomy, subjects should wait six (6) months post-vasectomy to be 
considered sterile. 
Phase 2: For WOCBP, a serum pregnancy test will be obtained at Screening and a urine 
pregnancy test will be performed immediately prior to any dosing and at the subject’s last 
visit.  
Phase 3: For WOCBP, a urine pregnancy test will be obtained at Screening and will be 
performed immediately prior to any dosing. 
A negative result for urine β-HCG (test must have a sensitivity of at least 25 mIU/mL) must 
be available prior to each administration of IP. If the β-HCG test is positive, indicating that 
the subject is pregnant prior to completing the specified dose regimen, then no further IP 
will be administered. Every attempt should be made to follow pregnant subjects for the 
remainder of the study and to determine the outcome of the pregnancy (see Section 7.12). 
DIARY 
Diaries will be implemented in the Phase 2 segment of the protocol and at selected sites 
(estimated to include 711 subjects) in the Phase 3 segment.  Subjects will be provided a 
diary to record the following solicited local and systemic AEs: 
• 
Oral temperature and time taken (each daily entry before 11:59 pm) 
• 
Solicited systemic symptoms 
• 
Solicited local injection site symptoms 
• 
Concomitant medications 
The diary should be completed once daily starting the evening of each study dose through 
6 days post-dose. The completed diary post-dose 1 and post-dose 2 will be reviewed with 
the subject by the study staff during the next study phone call or visit and collected at the 
next in-person study visit. The study staff will review the diary with the subject to assess 
for temperature, solicited systemic symptoms (unusually tired/feeling unwell, muscle 
aches, headache, nausea, joint pain) and solicited injection site symptoms (pain, itching, 
redness, swelling, bruising). In addition, unsolicited symptoms and concomitant 
medications will be assessed.  
Any diary entry determined to meet the Common Terminology Criteria for Adverse Events 
version 5.0 (CTCAE) criteria for a Grade 1 or higher adverse event should be documented 
as an adverse event unless deemed part of the subject’s ongoing medical history. Injection 
site reactions should be graded per the Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, issued September 
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2007 (See Section 6.4.5). If the diary entry does not meet the criteria of a Grade 1 or 
higher AE as per the relevant guidelines, Investigator clinical judgment can be used to 
determine whether the entry should be recorded as an AE and documented accordingly 
in the site’s source. For cases where the diary entry and final AE reporting (i.e. grading) 
do not agree, the reasoning should be recorded in the source documents. 
 INTRADERMAL INJECTION AND EP  
Phase 2 and Phase 3 segments: 
A complete administration procedure is defined as an ID injection (formation of a wheal) 
of IP followed by insertion of the ID Array needles (electrodes) through the skin and into 
the wheal followed by delivery of four electroporation pulses. This procedure is broadly 
described as administration because it involves more than the injection of a drug. 
Only if the deltoid area is not a suitable location for administration (see exclusion criterion 
‘j’), the ID injection can then be administered above the lateral quadriceps followed 
immediately by EP. IP must not be given within 2 cm of a tattoo, scar, keloid, or active 
lesion/rash. Also, ID injection followed immediately by EP must not be performed on the 
skin of an extremity which has any metal implants or implantable medical device (e.g., 
surgical rods, pins or joint replacements). If a subject has an implanted cardiac defibrillator 
or pacemaker, ID injection/EP must not be performed above the deltoid muscle on the 
same side of the body where the device is located. 
There are three steps that must be performed as part of the administration procedure: 
1. Injection of IP (INO-4800 or placebo) 
2. Insertion of the array into the subject’s skin 
3. Pressing the trigger button on the EP applicator  
Table 9 below is provided as guidance on how to appropriately complete the procedure 
when injection of IP has occurred, but the subject did not receive EP. 
Table 9: Guidance for how to manage an incomplete administration after IP has 
been injected 
Was IP 
injected? 
Was the array 
inserted into skin? 
Was trigger button 
pressed? 
Action 
Yes 
Yes (if array gets 
dislodged before 
the trigger button 
is pressed, the 
same array may 
be re-inserted) 
No 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
Yes 
No 
Yes 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
Yes 
No 
No 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
 
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Reinjection of IP (i.e. protocol-specified IP has already been delivered) is not permitted. 
Delivery of a second electroporation in tissue is not permitted. 
Training will be provided by the Sponsor on use of the device. 
Phase 2 segment: 
Subjects will receive a two-dose regimen of one or two 1.0 mg ID injections of INO-4800 
or placebo in a volume of ~0.1 mL in an acceptable skin location for injection and 
subsequently followed immediately by EP of each injection site with CELLECTRA® 2000 
at Day 0 and Day 28. For subjects assigned to receive two injections + EP at each dosing 
visit, the two injections must be performed in acceptable locations on two different limbs. 
Phase 3 segment: 
Subjects will receive a two-dose regimen of two 1.0 mg ID injections of INO-4800 or 
placebo in a volume of ~0.1 mL in an acceptable skin location for injection on different 
limbs and subsequently followed immediately by EP of the injection site with 
CELLECTRA® 2000 at Day 0 and Day 28. 
 MANAGEMENT OF PAIN DUE TO ELECTROPORATION (EP) PROCEDURES 
In case of pain, subjects may be treated with a non-narcotic analgesic (e.g., 
acetaminophen) after injection/EP.  
Medication taken for pain management will be documented as concomitant medications. 
 ASSESSMENT OF LABORATORY ABNORMALITIES 
In Phase 2, samples will be collected for serum chemistry, hematology, and urinalysis at 
the visits listed in the Schedule of Events (36TTables 3 and 436T) and as listed in Section 6.4.  
Laboratory AEs will be assessed and graded in accordance with the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. Laboratory values that are 
not clinically significant (NCS) in the Investigator’s opinion will not be reported as AEs. 
 ASSESSMENT OF CLINICAL TRIAL ADVERSE EVENTS (AES) 
Subjects will be queried regarding the occurrence of any AEs including AEs related to 
injection site reactions, concomitant medications and new onset illness or disease during 
their study visits and phone calls. Subjects will be reminded to contact study personnel 
and immediately report any event for the duration of the study. All AEs will be captured 
from the time of the informed consent until 28 days post-dose 2 (Day 56). Following the 
Day 56 visit, only SAEs, AESIs and MAAEs will be collected. All related AEs, AESIs and 
SAEs will be followed to resolution or stabilization. These events will be recorded on the 
subject’s CRF. 
 ASSESSMENT OF INJECTION SITE REACTIONS  
Reactions arising from the IP administration procedure may be reported as administration 
site or injection site reactions. When evaluating administration (injection) site reactions 
throughout the study, it is most important to be as specific as possible by selecting the 
most appropriate term (see Table 10 below) and using the grading scale as listed in the 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, issued September 2007. All subjects will be observed for 30 
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minutes following the IP administration procedure for immediate AEs.  In addition, other 
events associated with administration (injection) site reactions (e.g., hematoma, infection 
or necrosis) should also be reported with preferred terms specific for administration 
(injection) site reactions.  
Table 10: Grading Scale for Injection Site Reactions 
Local Reaction to 
Injectable Product 
(Grade) 
Mild (1) 
Moderate (2) 
Severe (3) 
Potentially 
Life 
Threatening 
(4) 
Pain 
Does not 
interfere with 
activity 
Repeated use 
of non-
narcotic pain 
reliever >24 
hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency 
room visit or 
hospitalization 
Tenderness 
Mild 
discomfort to 
touch 
Discomfort 
with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/Rednessa 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swellingb 
2.5-5 cm and 
no 
interference 
w/ activity 
5.1-10 cm or 
interferes with 
activity 
>10 cm or 
prevents daily 
activity 
Necrosis 
September 2007 “FDA Guidance for Industry-Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
a In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable 
b Should be evaluated and graded using the functional scale as well as the actual measurement. 
 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription), including receipt of any non-study 
COVID-19 vaccine (authorized under emergency use or licensed) received between 
informed consent and study discharge (see Section 4.2) must be recorded on the CRFs. 
Actual or estimated start and stop dates must be provided. This information will be 
obtained from the subject and/or any available medical records. The indication for the 
medication, dose, and dose regimen will be documented.  
Therapy considered necessary for the subject’s welfare may be given at the discretion of 
the Investigator or medical provider. If the permissibility of a specific medication/treatment 
is in question, please contact the Medical Monitor. 
The decision to administer a prohibited medication/treatment (Section 6.4.7) is made with 
the safety of the clinical trial subject as the primary consideration. When possible, the 
Sponsor should be notified before the prohibited medication/treatment is administered. 
 RESTRICTIONS  
In the Phase 2 segment of the trial, subjects should refrain from becoming pregnant until 
3 months following the last dose of investigational product by using appropriate 
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contraceptive measures (see Section 4.1.1). In the Phase 3 segment of the trial, subjects 
should refrain from becoming pregnant until receipt of the last dose of investigation 
product by using appropriate contraceptive measures (See Section 4.1). 
Subjects must not receive any non-study related vaccine (e.g., influenza vaccine) within 2 
weeks prior to the first dose of IP, or within 2 weeks of (before or after) any subsequent 
dose of IP.  
Subjects must not have fever (oral temperature ≥38.0 degrees Celsius or 100.4o 
Fahrenheit) within 72 hours prior to each dosing. 
Subjects should not receive hydroxychloroquine during the trial. In the Phase 3 segment, 
subjects should not receive any other drug/vaccine intended as COVID-19 prophylaxis 
during the trial.  
For subjects in the Phase 2 segment of the trial, the receipt of any non-study prophylactic 
COVID-19 vaccine (authorized under emergency use or licensed) is no longer restricted, 
based upon increasing availability of EUA vaccine and completion of the Phase 2 data for 
purposes of Phase 3 dose selection. 
If a subject informs the site of their intent to receive a non-study prophylactic COVID-19 
vaccine (available either under emergency use or when licensed), the subject should be 
informed that the safety and effectiveness of receiving INO-4800 followed by receipt of 
another COVID-19 vaccine has not been studied.  
Subjects should not participate in any other interventional trials for the duration of this trial. 
Subjects must not receive disease modifying doses of anti-rheumatic drugs (e.g., 
azathioprine, cyclophosphamide, cyclosporine, methotrexate), biologic disease modifying 
drugs such as TNF-α inhibitors (e.g., infliximab, adalimumab or etanercept) and long term 
use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of prednisone 
equivalent (use of inhaled, topical, nasal, otic, and ophthalmic corticosteroids are allowed).  
 SARS-COV-2 TESTING 
Phase 2 segment: 
SARS-CoV-2 antibody and RT-PCR testing will be used during screening to test for 
previous or current SARS-CoV-2 infection. During the trial, subjects who report symptoms 
suggestive of COVID-19 will be assessed at a COVID-19 assessment visit in the clinic or 
subject’s vehicle or at the subject’s home. During this visit, nasal swabs and saliva will be 
collected to detect SARS-CoV-2 using the RT-PCR assay. Genotyping may also be 
performed. If the subject is confirmed to be COVID-19 positive, a follow-up nasal swab 
and saliva will be collected to detect SARS-CoV-2 using the RT-PCR assay at the COVID-
19 convalescent visit. 
Phase 3 segment: 
SARS-CoV-2 antibody testing for Spike protein antibodies will be performed via rapid test 
in the clinic during screening to identify previous SARS-CoV-2 infection. Serum samples 
will be collected prior to dosing at Day 0 and at each subsequent visit (see Table 4: 
Schedule of Events) and tested for nucleoprotein antibodies at the study-designated lab 
to identify any intervening SARS-CoV-2 infection that may occur, regardless of symptoms, 
between study visits.  
SARS-CoV-2 RT-PCR testing will be conducted on nasopharyngeal specimens collected 
at Day 0. The Day 0 SARS-CoV-2 RT-PCR results will not be required prior to dosing on 
that day. 
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A subject should be evaluated at a COVID-19 assessment visit if: 
- 
The SARS-CoV-2 serum antibody test by the study-designated lab (Nucleocapsid 
protein antibody assay) result becomes positive in subjects who tested seronegative 
at Day 0 (nucleoprotein antibody assay), with the exception of subjects who have a 
positive SARS-CoV-2 RT-PCR test result pre-dose on Day 0, or  
- 
A SARS-CoV-2 RT-PCR test result or results of any local rapid testing outside of the 
study are positive any time after the subject receives the first dose at Day 0, or 
- 
The subject has symptoms of COVID-19 (see Section 6.4.9). 
During that COVID-19 Assessment Visit, which may be conducted in the clinic, from the 
subject’s vehicle, or in the subject’s home, nasopharyngeal swabs will be collected to 
detect SARS-CoV-2 using the RT-PCR assay. Genotyping may also be performed on the 
sample(s) collected at the COVID-19 assessment visit.  
 COVID-19 DISEASE MONITORING 
During both the Phase 2 and Phase 3 segments of the trial, all subjects will be monitored 
for the development of symptoms suggestive of COVID-19 disease. For the Phase 3 
segment, frequent (approximately bi-weekly) scheduled clinic visits or phone calls will 
occur.  
All subjects in the trial should be instructed to do the following: 
• 
Take their temperature daily at home starting on the Day 0 visit for the duration of 
the trial.     
• 
Monitor for symptoms suggestive of COVID-19 (e.g., feeling feverish or chills, 
cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, 
headache, new loss of taste or smell, sore throat, congestion or runny nose, 
nausea or vomiting, diarrhea) starting on the Day 0 visit for the duration of the trial.  
If at any time during the study, the subject experiences a fever of ≥ 100.4°F/38°C or 
symptoms suggestive of COVID-19, the subject should contact the site. The site staff 
should arrange for a clinic visit (COVID-19 assessment visit) within 3 days of the site being 
aware of either a positive SARS-CoV-2 test or COVID-19 symptom onset. The COVID-19 
assessment visit may be performed either at the clinic, in the subject’s vehicle or in the 
subject’s home. 
Subjects with a confirmed COVID-19 diagnosis, per the case definition outlined in Section 
3.7, prior to dose 2 or who have a positive SARS-CoV-2 PCR test at Day 0 will be 
discontinued from further dosing and will be followed until EOS for safety and resolution 
of COVID-19. If a subject is due for Dose 2 but SARS-CoV-2 RT-PCR results are not yet 
available from either Day 0 or a Suspected COVID-19 Assessment Visit, they should be 
dosed on schedule as long as they are currently asymptomatic.  
Subjects with virologically confirmed SARS-CoV-2 infection will return for a convalescent 
visit approximately 28 days after symptom onset, or in the absence of symptoms, after the 
collection date of any specimen testing positive for SARS-CoV-2 RT-PCR. If symptoms 
are ongoing at 28 days after symptom onset, the site should follow up with the subject via 
phone call or unscheduled visit after symptom resolution or stabilization. Recovery from 
COVID-19 disease requires either resolution of clinical symptoms except for loss of 
taste/smell, or with sequelae that appear to be permanent.     
Subjects who require medical care for COVID-19 (or any other suspected condition) will 
be referred to their primary health care provider or a medical treatment facility if the 
Investigator believes that the subject should be managed beyond routine care that can be 
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provided by the study site. Subjects referred for treatment will continue study follow-up 
according to the protocol schedule. If subjects are treated or hospitalized due to their 
illness, the study team will request COVID-19 specific test results, treatments, treatment 
outcomes and diagnostics from medical treatment facilities with the subject’s written 
permission. These results and diagnostics will be recorded in the study and/or safety 
database consistent with protocol reporting requirements. 
 
IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at visits specified in the Schedule of 
Events (36TTables 3 and 436T) for cellular and humoral immunology assessments. Binding 
ELISA will be evaluated at serial timepoints. Cellular sampling requires 32 mL of whole 
blood be collected at each visit. Humoral sampling requires collection of 8.5 mL of whole 
blood in a single 10-mL red top serum collection tube to produce two serum aliquots of 2 
mL each. However, baseline (Day 0) immunology samples are required to serve as a 
baseline for all subsequent immunology testing. Therefore, a total of 68 mL whole blood 
for cellular sampling and 8 mL serum for humoral sampling is required on Day 0 prior to 
1st dose. Subjects may be asked to return for additional blood draws if collected blood 
sample is lost or unevaluable for any reason. Details of the immunology sample collection 
and shipment information will be provided in the Laboratory Manual.  
Humoral samples will be collected on all subjects and cellular samples will be collected at 
selected sites (from approximately 711 subjects). Both humoral and cellular analysis will 
be conducted in the first 102 subjects age 18-50 and in the first 102 subjects age 51 and 
older enrolled at the sites that are selected for cellular sample collection. In addition, 
cellular and humoral samples will be analyzed on all subjects with COVID-19 when 
samples are available. 
The immune responses to INO-4800 will be measured using assays that include a 
pseudovirus-based neutralization assay and ELISpot. Determination of additional 
analyses using assays not specified, such as assessment of immunological gene 
expression or flow cytometry, assessment of immunological protein expression on 
collected samples for immunological endpoints will be made on an ongoing basis 
throughout the trial. 
 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
 
SAFETY PARAMETERS 
The safety of INO-4800 will be measured and graded in accordance with the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. 
 
ADVERSE EVENTS (AES) 
Any untoward medical occurrence in a patient or clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.  
Adverse Events (AEs) include the following: 
• Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (before the administration of clinical trial drug); 
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• Any pre-existing condition that increases in severity, or changes in nature during or as 
a consequence of the clinical trial drug administration phase; 
• Complications of pregnancy (refer to Section 7.11). 
Adverse Events (AEs) do not include the following: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; however, the condition that leads to the procedure is an AE; 
• Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the Screening Visit that do not worsen; 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions); 
• Overdose without clinical sequelae; 
• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed, is not an AE; it is considered to be pre-existing and will be 
documented on the medical history CRF; 
• Uncomplicated pregnancy; 
• An induced elective abortion to terminate a pregnancy without medical reason; 
• Confirmed COVID-19 disease.  
 
ADVERSE DRUG REACTION (ADR) 
All noxious and unintended responses to a medicinal product related to any dose. This 
means that a causal relationship between the medicinal product and an adverse event is 
at least a reasonable possibility (i.e., the relationship cannot be ruled out). 
 
SERIOUS ADVERSE EVENTS (SAES) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death;  
• Is life-threatening; 
o Refers to an event in which the subject was at risk of death at the time of the event. 
It does not refer to an event which hypothetically might have caused death if it 
were more severe 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
o Includes any hospitalization in which the subject has been admitted to the hospital 
regardless the length of stay, even if the hospitalization is only a precautionary 
measure to allow continued observation. However, hospitalization (including 
hospitalization for an elective procedure) for a pre-existing condition that has not 
worsened, does not constitute an SAE 
• Results in persistent or significant disability/incapacity; 
o A substantial disruption of a person's ability to conduct normal life functions (i.e., 
the adverse event resulted in a significant, persistent or permanent change, 
impairment, damage or disruption in the subject’s body function/structure, physical 
activities and/or quality of life) 
• Results in congenital anomaly or birth defect and/or; 
• An important medical event.  
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o An event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse 
Clarification of Serious Adverse Events (SAEs) 
• Death itself is not an AE. Death is an outcome of an AE, but when the cause of death 
has not been provided, use the event term: death of unknown cause; 
• Confirmed COVID-19 disease that requires hospitalization is recorded on the 
Suspected COVID-19 Clinical Event CRF, and not recorded as an SAE; 
• COVID-19 disease with an outcome of death is recorded on the Suspected COVID-19 
Clinical Event CRF, and not recorded as an SAE; 
• The subject may not have been receiving an investigational medicinal product at the 
occurrence of the event; 
• Complications associated with COVID-19 disease that occur or prolong 
hospitalization are recorded on the Suspected COVID-19 Clinical Event CRF; 
• The Pregnancy outcomes of spontaneous abortion (miscarriage), ectopic pregnancy, 
fetal demise/stillbirth in a subject or subject partner following exposure to study 
treatment is considered to be an SAE. 
 
UNEXPECTED ADVERSE DRUG REACTION 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator’s Brochure [IB] for an unapproved investigational 
product, package insert/summary of product characteristics for an approved product). 
 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects.  
A UADE is a type of SAE that requires reporting to the Sponsor in accordance with Section 
7.9. 
 
DEVICE DEFICIENCY 
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance. 
Note: Device deficiencies include malfunctions, use errors and inadequate labelling. 
 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor is responsible for the overall safety monitoring of the clinical trial. 
Safety monitoring assessments include but are not limited to:  
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• Incidence of all AEs classified by system organ class, preferred term, severity and 
causal relationship to clinical trial treatment; 
• Changes in laboratory parameters; 
• Local and systemic injection site review; special attention will be paid to the examination 
of the injection site. 
 ADVERSE EVENT OF SPECIAL INTEREST (AESI)  
An adverse event of special interest (serious or non-serious) is one of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor can be 
appropriate.  
For the purpose of this clinical trial, the AESIs listed in Appendix A are to be reported to 
the Sponsor in accordance with Section 7.9. 
 MEDICALLY ATTENDED ADVERSE EVENT (MAAE) 
A medically attended adverse event (serious or non-serious) is defined as an adverse 
event that leads to an unplanned contact with a health care provider. 
 ABNORMAL LABORATORY VALUE 
The Investigator will annotate each abnormal lab value as clinically significant (CS) or not 
clinically significant (NCS). 
Laboratory values that are NCS in the Investigator’s opinion should not be reported as an 
adverse event. 
Any abnormal laboratory value that is new in onset or worsened in severity or frequency 
from the baseline condition and meets one of the following criteria will be recorded as an 
AE: 
• 
Requires therapeutic intervention or diagnostic tests; 
• 
Leads to discontinuation of further administration of the investigational product in 
the clinical trial; 
• 
Has accompanying or inducing symptoms or signs; 
• 
Is judged by the Investigator as clinically significant (CS). 
Abnormal laboratory values that meet the criteria of an AE or SAE should be reported in 
accordance with Section 7.9. 
 CLINICAL TRIAL STOPPING RULES 
The Investigator is to immediately notify the Medical Monitor if the following are observed: 
• 
Any SAE related to study treatment (i.e., IP and/or the study device); 
• 
Any Grade 4 AEs related to study treatment (i.e., IP and/or the study device); 
• 
Any report of anaphylaxis related to study treatment (i.e., IP and/or the study 
device); 
• 
Any suspected Severe COVID-19 disease case (per Sections 3.7.1.1 and Section 
3.7.1.2). 
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The Medical Monitor will notify the Chair of the Safety Review Committee (SRC), who will 
determine whether dosing should be temporarily halted until a more formal review of the 
case(s) is made. Such a formal review may include an ad hoc meeting of the SRC and/or 
a consultation with the DSMB Chair. If such a consultation occurs, the DSMB Chair and/or 
the SRC Chair may decide to convene an ad hoc meeting of the DSMB. Following such a 
meeting, the DSMB chair will render any recommendations to the SRC Chair. The 
Sponsor will independently investigate the case(s) and, after review of the DSMB 
recommendations, will make a final decision regarding continuation of trial dosing. These 
deliberations will be documented and will be provided to the IRBs and FDA, where 
required.   
 
In the case of suspected Severe COVID-19 cases, the trial will be paused if a vaccine-to-
placebo case split yields a relative risk with a 90% confidence interval lower bound >1.  
The minimum case split corresponding to this criterion is 8:0. In this scenario, the trial will 
pause until at least one additional case is accrued and the DSMB can review the data and 
make a recommendation regarding continued enrollment in the trial. 
 
SAFETY DATA REPORTING PERIOD, METHOD OF COLLECTION AND SUBMISSION 
All AEs will be collected from the time informed consent is obtained through Day 56. 
MAAEs, AESIs and SAEs only will continue to be collected after the Day 56 visit and will 
be followed to resolution or stabilization. This information will be captured in the CRF. 
If the Investigator determines that the AE meets serious criteria, then the AE will be 
recorded as an SAE. 
SAEs and AESIs will be reported to the Sponsor from the time the subject signs the 
informed consent until the last visit. 
All SAEs (regardless of causal relationship) and AESIs will be reported on the SAE CRF 
Form and submitted to the Sponsor via EDC within 24 hours of becoming aware of the 
event. In the event the EDC is unavailable, the SAE/AESI Report Form (paper) should be 
used and submitted to the Sponsor within 24 hours of becoming aware of the event. In 
that case, the SAE Report Form will be either emailed to safety.inovio@apcerls.com or 
faxed to
 The original SAE Report Form must be kept at the clinical trial 
site. 
The event will be data entered into the CRF. 
 
For the events that are considered an AESI, the Investigator will contact the Sponsor within 
24 hours of becoming aware of the event to discuss whether dosing should continue. 
Table 11: SAE Contact Information 
Sponsor Safety Email: safety.inovio@apcerls.com  
Sponsor Safety Fax: 
Sponsor Safety Phone: 
 
 
Table 12: Medical Monitor Direct Contact Information 
Primary point of contact, ICON Medical Monitor: 
, M.D.  
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Email: 
 
Phone: 
 
Inovio Medical Monitor:  
, Jr., M.D., FACP, FIDSA 
Email: 
 
Cell Phone: 
 
 
 
All SAEs, treatment-related AEs, MAAEs and AESIs must be followed by the Investigator 
until resolution or return to baseline status, stabilization of the event (i.e., the expectation 
that it will remain chronic), even if it extends beyond the clinical trial reporting period or 
until it is determined that the subject is lost to follow up. 
Follow-up information is to be submitted to the Sponsor on an SAE Report Form and within 
24 hours of becoming aware of the information. 
If medical records are submitted to the Sponsor with the SAE Report Form, the clinical 
trial site must: 
• Redact the medical records of all personal data (e.g., confidential subject data, 
Personal Identifying Information [PII]) 
• Provide the subject’s assigned identification number (SID) on the records 
 ADVERSE EVENT REPORTING 
This section provides details on reporting the safety information. 
 SUBMITTING THE INITIAL SERIOUS ADVERSE EVENT (SAE) REPORT FORM 
The Investigator should include as much safety information as possible when submitting 
the initial report, but the report must include the following at a minimum:  
• 
The adverse event; 
• 
The subject’s assigned identification number (SID); 
• 
Investigational product(s) (IP) and/or study device; 
• 
Investigator causal relationship to the IP(s) and/or study device; 
• 
Serious criteria; 
• 
Reporter name and contact information. 
If a case is submitted to the Sponsor with only the “minimum” information, a more detailed 
or updated follow-up report will be sent to the Sponsor as soon as possible but no later 
than three (3) calendar days after the date of the initial report. 
 RECORDING THE EVENT 
Investigators should use correct medical terminology/concepts when recording AEs on the 
EDC and SAE Report Form. The use of colloquialisms and abbreviations should be 
avoided. 
A medical diagnosis, if known, should be recorded rather than individual signs and 
symptoms. However, if the signs and/or symptoms cannot be medically characterized as 
a single diagnosis or syndrome, each individual sign and/or symptom should be recorded. 
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If a diagnosis is subsequently established, all previous signs and/or symptoms will be 
subsumed and replaced with a single medical diagnosis. 
 ASSESSING SEVERITY (INTENSITY) 
Severity is used to describe the intensity of a specific event (e.g., mild, moderate, severe). 
The Investigator will assess and grade clinical AEs or SAEs (based on discussions with 
clinical trial subjects) in accordance with CTCAE. 
 CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS (AES) 
A causally related AE is one judged to have a possible, probable or definite relationship 
to the administration of the IP and/or the study device. An AE may also be assessed as 
not related to the IP and/or the study device. Because the Investigator is knowledgeable 
about the subject (e.g., medical history, concomitant medications), administers the IP, and 
monitors the subject’s response to the IP, the Investigator is responsible for reporting AEs 
and judging the relationship between the administration of the IP and EP and a 
subsequent AE. The Investigator is aware of the subject’s clinical state and may have 
observed the event, and thus may be sensitive to distinctions between events due to the 
underlying disease process versus events that may be product-related.  
Investigators should use their knowledge of the clinical trial subject, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to determine 
whether an AE is considered to be related to the IP and/or the study device and the causal 
relationship reported as "Yes" or "No" accordingly. Causality should be assessed by the 
Investigator as related to drug, related to device, or related to both drug and device (i.e., 
related to both or indiscernible) by the following criteria: 
• 
Yes – there is a reasonable possibility that administration of the clinical trial 
treatment (drug or device or both drug and device) contributed to the event 
• 
No – there is no reasonable possibility that administration of the clinical trial 
treatment contributed to the event and there are more likely causes 
The following guidance should also be taken into consideration: 
• 
Temporal relationship of event to administration of IP and/or EP; 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
• 
Known association of the event with the IP, EP or with similar treatments; 
• 
Known association of the event with the disease under trial; 
• 
Presence of risk factors in the clinical trial subject or use of concomitant 
medications known to increase the occurrence of the event. 
The rationale for the Investigator’s causal assessment is to be recorded on the SAE Report 
Form. 
The Sponsor will assess the overall safety of the IP delivered by EP and determine 
whether to report expeditiously to the regulatory authority(ies). 
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 REPORTING SUSPECTED COVID-19 DISEASE CASES DURING THE TRIAL 
For both Phase 2 and Phase 3 segments of the trial, all suspected COVID-19 disease 
cases based on reported COVID-19 symptoms and/or SARS-CoV-2 test results should be 
entered into the Suspected COVID-19 Clinical Event CRF within 24 hours of awareness. 
Cases will be tracked until final determination of whether the case meets criteria of a 
confirmed COVID-19 disease case, per the case definition. For the Phase 2 segment of 
the trial, this determination will be made by the Investigator. For the Phase 3 segment, this 
determination will be made by the EAC. 
If the reported COVID-19 disease case is later determined not to be a confirmed COVID-
19 case, the event (e.g. symptoms or other diagnosis), if serious, would be reported as an 
SAE within 24 hours following determination by the Investigator (Phase 2 segment) or 
notification by EAC (Phase 3 segment).  
If the reported COVID-19 disease case is later determined not to be a confirmed COVID-
19 case, the event (e.g. symptoms or other diagnosis), if non-serious and if occurring from 
the time of consent until 28 days post-dose 2, would be reported as an AE following 
determination by the Investigator (Phase 2 segment) or notification by EAC (Phase 3 
segment). 
 REPORTING PREGNANCY DURING THE CLINICAL TRIAL 
Subjects in Phase 2 who are pregnant or expect to become pregnant prior to 3 months 
following the last dose will be excluded from participation in the clinical trial.  
Subjects in Phase 3 who are pregnant or expect to become pregnant prior to the last dose 
will be excluded from participation in the clinical trial.  
All pregnancies that occur from the time of first administration of clinical trial treatment 
through study completion (i.e., Day 393) will be reported to the Sponsor. If clinical trial site 
staff become aware that a subject becomes pregnant after the first dose in the clinical trial, 
she will not be given any additional treatments with the IP. A Pregnancy CRF Form will be 
completed by the site in EDC and submitted to the Sponsor within 24 hours after becoming 
aware of the pregnancy. In the event the EDC is unavailable, the Pregnancy and 
Pregnancy Outcome Report Form (paper) should be used and submitted to the Sponsor 
within 24 hours of becoming aware of the pregnancy. 
The Investigator will report this event to their IRB/REB/EC in accordance with their policies 
and procedures.  
The clinical trial site must request the subject’s permission to query pregnancy outcome 
and follow the subject for outcome of the pregnancy. The subject will continue to be 
followed for safety assessments without receiving additional IP until clinical trial discharge 
in accordance with this protocol. Procedures that are contraindicated during pregnancy, 
including additional dose administrations, must not be performed. The Investigator should 
use clinical judgment regarding subsequent clinical trial-related blood collection based on 
the presence or absence of anemia in each subject.  
Male subjects will be instructed through the ICF to immediately inform the Investigator if 
their partner becomes pregnant until study completion. A Pregnancy Form will be 
completed by the site and submitted to the Sponsor within 24 hours after becoming aware 
of the pregnancy. The pregnant partner will be asked to sign a Pregnancy Information 
Collection Consent Form to allow for follow-up on her pregnancy. If the authorization has 
been signed, the Investigator will collect and report details of the course and outcome of 
the pregnancy in the partner of a male subject exposed to IP. The site will update the 
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Pregnancy Form with additional information on the course and outcome of the pregnancy 
and submit the form to the Sponsor.  
If an Investigator is contacted by the male subject or his pregnant partner, the Investigator 
may provide information on the risks of the pregnancy and the possible effects on the fetus 
to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
If the end of the pregnancy occurs after the clinical trial has been completed, the outcome 
will be reported directly to the Sponsor. 
 REPORTING DEVICE-RELATED COMPLAINTS OR DEFICIENCIES 
All product complaints that meet the definition of device deficiency must be reported to the 
Sponsor within 10 days of discovery, with the exception of SAEs which require 24-hour 
reporting. The error reporting or complaint form must be completed and emailed to the 
Sponsor at clinicalcomplaint@inovio.com. 
Device deficiencies include malfunctions, misuse or use errors and inadequate labeling. 
A malfunction is defined as the failure of a device to meet its performance specifications 
or otherwise perform as intended. The intended performance of a device refers to the 
intended use for which the device is labeled or marketed. 
Any problems experienced during the treatment procedure including malfunctions of the 
device (e.g. significant device malfunction causing injury or resulting in a hazard which 
could cause injury to the subject or user), error messages displayed on the device screen 
following treatment, or errors that occur during the treatment procedure must immediately 
be reported to the Sponsor or its designee for evaluation. The Sponsor will review these 
reports for potential hazards that could cause an SAE. If Inovio determines that the 
malfunction could cause an SAE, the Inovio Medical Monitor will decide whether the Chair 
of the Safety Review Committee should be notified in accordance with Section 7.8.4. 
 NOTIFYING REGULATORY AUTHORITIES AND INSTITUTIONAL REVIEW BOARDS 
(IRBS)/RESEARCH ETHICS BOARDS (REBS)/ETHICS COMMITTEES (ECS) OF SAFETY 
INFORMATION 
 SPONSOR RESPONSIBILITIES 
• 
Determine whether the safety information meets the requirements for expedited 
reporting to the applicable regulatory authorities; 
• 
Prepare and submit the safety report to the applicable regulatory authorities; 
• 
Send all participating PIs a safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) that will include a statement if there is or is not any significant new 
safety information that might influence the risk-benefit assessment of the IP and/or 
study device, sufficient to consider changes in product administration or overall 
conduct of the clinical investigation. 
 PRINCIPAL INVESTIGATOR (PI) RESPONSIBILITIES 
• 
Forward a copy of the safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) to their IRB/REB/EC as soon as practical in accordance with the 
governing policy and/or procedures; 
• 
Notify their IRB/REB/EC of safety information (i.e., SAEs, pregnancies, and AESIs) 
that occur at their clinical trial site in accordance with their local institutional policy. 
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 POST-TRIAL REPORTING REQUIREMENTS 
PIs are not obligated to actively seek AEs or SAEs beyond the clinical trial reporting period. 
However, if the PI becomes aware of an AE or SAE that occurs after the Completion or 
Termination Visit and the event is deemed by the PI to be related to the clinical trial 
treatment, the PI should promptly document and report the event to the Sponsor. 
 CLINICAL TRIAL DISCONTINUATION  
INOVIO reserves the right to discontinue the clinical trial at a site or at multiple sites for 
safety or administrative reasons at any time. In particular, a clinical trial site that does not 
recruit at a reasonable rate may be discontinued. Additionally, the clinical trial may be 
discontinued at any time by an IRB/REB/EC, INOVIO, or a regulatory authority as part of 
their duties to ensure that clinical trial subjects are protected.  
If the clinical trial is discontinued and/or the clinical trial site closed for any 
reason, all IP and devices must be returned to INOVIO or its 
representative. The PI should ensure that their site file documents are complete 
prior to archiving, and provide copies of any requested documents to INOVIO 
for its Trial Master File (TMF). 
 
 
STATISTICAL CONSIDERATIONS 
 
STATISTICAL AND ANALYTICAL PLAN 
The formal Statistical Analysis Plan is contained in the sections that follow. 
 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is an operationally seamless Phase 2/3 trial.  The subjects and data from Phase 2 
are independent from that of Phase 3.   
Phase 2 Segment:  This is a four-arm, multi-center, placebo-controlled, blinded, and 
randomized clinical trial in subjects at high risk of SARS-CoV-2 exposure. The trial’s 
primary endpoints are antigen-specific cellular immune response measured by IFN-
gamma ELISpot and neutralizing antibody responses. Secondary efficacy endpoints are 
safety measures.  Exploratory endpoints are antigen-specific cellular immune response 
measured by flow cytometry and other T and B cell measures.  
Phase 3 Segment: This is a two-arm, multi-center, placebo-controlled, double-blinded, and 
randomized clinical trial in subjects at high risk of SARS-CoV-2 exposure. The study’s 
primary endpoint is the incidence of virologically-confirmed severe COVID-19 disease in 
subjects who are SARS-CoV-2 seronegative and RT-PCR negative at baseline starting 
14 days after completion of the 2-dose regimen until 12 months post-dose 2.  The primary 
hypothesis is that INO-4800 will be efficacious relative to placebo (relative efficacy > 30%). 
Secondary efficacy analyses involve non-severe cases, all cases, cases resulting in death, 
and cases among baseline SARS-CoV-2 seropositive subjects. Other secondary analyses 
concern safety and cellular and neutralizing antibody response. Exploratory analyses 
concern efficacy against variants, efficacy against asymptomatic infection, and binding 
antibody and cellular immunological measures. 
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STATISTICAL HYPOTHESES 
Phase 2 Segment: This is an estimation segment pertaining to immunogenicity and safety.  
There are no hypotheses. 
Phase 3 Segment: The primary hypothesis of relative efficacy greater than 30% among 
baseline SARS-CoV-2 seronegative and RT-PCR negative subjects will be tested with H0: 
p ≥ .70/(.70+k) vs. H1: p < .70/(.70+k), where p is the true proportion of subjects with severe 
disease who receive INO-4800 relative to the total number of subjects with severe 
disease, and k is the total amount of follow-up time in the placebo group divided by the 
total amount of follow-up time in the INO-4800 group. There are no other formal 
hypotheses. 
 
ANALYTICAL POPULATIONS 
Analysis populations will be: 
The per-protocol (PP) population includes all subjects who receive all doses of Study 
Treatments and have no protocol violations. Subjects in the PP population will be grouped 
to treatment arms as randomized.  Subjects excluded from the PP population will be 
identified and documented prior to unblinding of the trial database.  Analyses on the PP 
population among those who are baseline SARS-CoV-2 seronegative and RT-PCR 
negative will be primary for the analyses of efficacy in the Phase 3 segment of this trial. 
The modified intention to treat (mITT) population includes all subjects who receive at least 
one dose of Study Treatment. Subjects in this population will be grouped to treatment 
arms as randomized.  Analysis of the mITT population will be considered supportive for 
the corresponding PP population for the analyses of efficacy in the Phase 3 segment of 
this trial. 
The intention to treat (ITT) population includes all subjects who are randomized. Subjects 
in this sample will be grouped to treatment arms as randomized.  Analysis of the ITT 
population will be considered supportive for the corresponding PP population for the 
analyses of efficacy in the Phase 3 segment of this trial. 
The safety analysis population includes all subjects who receive at least one dose of Study 
Treatment. Subjects will be analyzed according to the treatments received. 
 
DESCRIPTION OF STATISTICAL METHODS 
 PRIMARY ANALYSIS 
Phase 2 Segment 
Post-baseline increases from baseline in interferon-γ ELISpot response magnitudes will 
be compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
Post-baseline increases from baseline in neutralizing antibody response titers will be 
compared between treatment groups using ratios of geometric mean fold-rises and 
associated t-distribution based 95% CIs. 
The summaries listed above will be stratified according to NP positive/negative status and 
according to prior receipt of any non-study prophylactic COVID-19 vaccine of the subjects. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more than 
198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more than 380 
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days after Dose 2 for the Week 56 timepoint. Baseline is defined as the last measurement 
prior to the first treatment administration. 
The PP population will be used for these immunogenicity analyses. 
Phase 3 Segment 
Among subjects who are SARS-CoV-2 seronegative and RT-PCR negative at baseline, 
the primary hypothesis of relative efficacy greater than 30% will be tested with H0: p ≥ 
0.70/(0.70+k) vs. H1: p < 0.70/(0.70+k), where p is the true proportion of subjects with 
severe disease who receive INO-4800 relative to the total number of subjects with severe 
disease, and k is the total amount of follow-up time in the placebo group divided by the 
total amount of follow-up time in the INO-4800 group. 
A p-value for this hypothesis test and corresponding confidence interval will be computed 
based on the exact binomial method of Clopper-Pearson. Success will be concluded if the 
one-sided p-value is <0.025 and the corresponding lower bound of the two-sided 95% CI 
for efficacy exceeds 30%. 
For calculating k, an individual subject’s follow-up time is either: 
o the date of first disease diagnosis – date of the start of surveillance period +1 (for 
subjects who are cases), or 
o the date of last follow-up – date of the start of surveillance period +1 (for subjects who 
are non-cases). 
This methodology is based on the following. Assuming that the number of subjects who 
are cases in the INO-4800 group follows a Poisson distribution with parameter λv and the 
number of subjects who are cases in the placebo group follows a Poisson distribution with 
parameter λc, then conditional on total number of subjects with cases, t, the number of 
subjects who are cases in the INO-4800 group follows a binomial distribution with 
parameters (t, p=λv/(λv+λc)).  The relationship between p and efficacy is: efficacy = (1-
(1+k)p)/(1-p).  Therefore, testing efficacy > 30% corresponds to testing p < 0.70/(0.70+k).  
Similarly, the confidence interval for efficacy is (1-(1+k)UBp)/(1-UBp), (1-(1+k)LBp)/(1-LBp), 
where UB and LB are the Clopper-Pearson upper and lower limits for the proportion. 
The efficacy time frame is defined by symptoms beginning at any time starting from 14 
days after Dose 2 and ending 12 months after Dose 2.  Subjects identified as cases that 
started prior to this time point will be excluded.  Subjects with multiple instances meeting 
the case definition will be counted only once, using the first such instance.    
The PP population will be primary for the analysis of efficacy in this trial. Efficacy analysis 
using the mITT population will also be conducted counting cases from 14 days postdose 
1 as a supportive analysis.  The ITT population will also be used for a supportive analysis 
counting cases starting from randomization. 
 SECONDARY ANALYSES 
8.5.2.1 Efficacy 
Phase 3 Segment 
The secondary efficacy incidence endpoints will be analyzed in the same manner as the 
primary hypothesis, but without the hypothesis test p-value.  
8.5.2.2 Immunogenicity 
 
   Phase 3 Segment 
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Post-baseline increases from baseline in interferon-γ ELISpot response magnitudes will 
be compared between treatment groups using differences in medians and associated 
non-parametric 95% CIs. 
Post-baseline increases from baseline in neutralizing antibody response titers will be 
compared between treatment groups using ratios of geometric mean fold-rises and 
associated t-distribution based 95% CIs. 
The summaries listed above will be stratified according to disease status of the subjects 
and by baseline SARS-CoV-2 serostatus. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more than 
198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more than 
380 days after Dose 2 for the Week 56 timepoint. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for these immunogenicity analyses. 
 SAFETY ANALYSES 
8.5.3.1 Adverse Events 
All AEs including injection-site reactions will be summarized among the Safety 
Population by frequency per treatment arm. These frequencies will be presented overall 
and separately by dose, and will depict overall, by system organ class and by preferred 
term, the percentage of subjects affected. Additional frequencies will be presented with 
respect to maximum severity and to strongest relationship to Study Treatment. Multiple 
occurrences of the same AE will be counted only once following a worst-case approach 
with respect to severity and relationship to Study Treatment. All serious AEs will also be 
summarized as above. 
The main summary of safety data will be based on events occurring within 30 days of 
any dose. For this summary, the frequency of preferred term events will be compared 
between study arms with risk differences and 95% confidence intervals, using the 
method of Miettinen and Nurminen. As this analysis will use many event categories, and 
produce many confidence intervals, caution should be exercised when interpreting these 
confidence intervals.  Separate summaries will be based on events occurring within 7 
days of any dose and regardless of when they occurred. 
The analyses listed above will be performed according to the Phase of the trial. For the 
Phase 2 segment, the analyses listed above will also be performed according to prior 
receipt of any non-study prophylactic COVID-19 vaccine. For the Phase 3 segment, the 
analyses listed above will also be performed according to SARS-CoV-2 serostatus at 
baseline. 
For AE data, partial start dates will be imputed to the date of treatment to conservatively 
report the event as treatment-emergent, whenever the portion of the date is consistent 
with that of the study treatment. Otherwise, it will be imputed to the earliest date 
consistent with the partial date. A completely missing onset date will be imputed as the 
day of treatment. Partial stop dates will be assumed to be the latest possible day 
consistent with the partial date. AE duration will be calculated as (Stop Date – Start 
Date) + 1. 
8.5.3.2 Vital Signs 
Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean, standard deviation, minimum, median, and maximum 
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values by time point and treatment arm, for the Safety population. Baseline is defined 
as the last measurement prior to the first treatment administration. These summaries 
will be performed according to Phase. For the Phase 2 segment, the analyses listed 
above will also be performed according to prior receipt of any non-study prophylactic 
COVID-19 vaccine. For the Phase 3 segment, the analyses listed above will also be 
performed according to SARS-CoV-2 serostatus at baseline. 
 DISPOSITION 
Disposition will be summarized by treatment arm for the ITT population and will include 
the number and percentage randomized, the number and percentage who received each 
dose and the number who completed the trial.  The number and percentage of subjects 
who discontinued will be summarized overall and by reason.  The number in each analysis 
population will also be presented. These summaries will be performed according to Phase. 
For the Phase 3 segment, the analyses listed above will also be performed according to 
SARS-CoV-2 serostatus at baseline. 
 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
8.5.5.1 Demographics 
Demographic data will be summarized with descriptive statistics: mean standard 
deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables, by treatment arm, for the ITT and PP populations. 
These summaries will be performed according to Phase. For the Phase 3 segment, the 
analyses listed above will also be performed according to SARS-CoV-2 serostatus at 
baseline. 
8.5.5.2 Prior Medications 
Prior medications are those that were used before the start of the trial (prior to Day 0). 
Partial stop dates of prior medications will be assumed to be the latest possible date 
consistent with the partial date; start dates will not be imputed. Data for all prior 
medications will be summarized with percentages by treatment arm, for the ITT and PP 
populations. These summaries will be performed according to Phase. For the Phase 3 
segment, the analyses listed above will also be performed according to SARS-CoV-2 
serostatus at baseline. 
 INTERIM ANALYSES  
For safety issues, the DSMB could recommend stopping enrollment at any time; no 
formal interim analysis will be performed for this purpose. The two-sided type I error of 
0.05 will not be adjusted for possible early stopping due to this aspect. 
 
For the Phase 2 segment, group-level unblinded summaries of the immunogenicity and 
safety data will be produced once Week 6 visit immunology data and Week 8 visit safety 
data are complete for all subjects who have not discontinued, while maintaining subject-
level blinding.  Long-term follow-up data will continue to be collected for all subjects who 
have not discontinued with remaining visits through the final visit.  These summaries will 
allow the Sponsor to have results for the purposes of dose selection for the Phase 3 
portion.  No subject-level immunogenicity data will be produced, and subject-level 
immunogenicity data will not be available in the clinical trial database until all other clinical 
trial data are finalized at the end of the trial.  No safety summary will be provided if the 
total number of subjects who experience the event of interest is greater than 0 and the 
count of the number of subjects with the event in a given treatment group relative to the 
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total produces a percentage less than 3%, for a given summary.  The group-level 
unblinded production of the summaries will not include anyone directly involved with the 
trial or any additional unblinded personnel; only the external Contract Research 
Organization (CRO), ICON, which will already be providing unblinded summaries for the 
Data Safety Monitoring Board, will be utilized.  Thus, the trial will remain blinded to the 
Sponsor with respect to subject treatment assignment.  
 
 MULTIPLICITY 
Not applicable; there is one primary hypothesis that will be tested.  
 MISSING VALUES 
Missing data will not be imputed. 
For the ITT analyses of efficacy in the Phase 3 segment, subjects with missing or 
unevaluable data regarding case definition will be considered cases (failures). 
 EXPLORATORY ANALYSES  
8.5.9.1 Efficacy 
Phase 3 segment 
The exploratory efficacy endpoints will be analyzed in the same manner as the primary 
hypothesis, but without the hypothesis test p-value.   
8.5.9.2 Immunogenicity 
Phase 2 segment 
Post-baseline increases from baseline in cellular response magnitudes will be 
compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
The summaries listed above will be stratified according to NP positive/negative status 
and according to prior receipt of any non-study prophylactic COVID-19 vaccine of the 
subjects. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more 
than 198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more 
than 380 days after Dose 2 for the Week 56 timepoint. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
Phase 3 Segment 
Post-baseline increases in antibody titers from ELISA will be compared between 
treatment groups using ratios of geometric mean fold-rises and associated 95% t-
distribution based CIs. 
Post-baseline increases from baseline in cellular response magnitudes will be 
compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
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Post-baseline increases from baseline in neutralizing antibody response titers will be 
compared between treatment groups using ratios of geometric mean fold-rises and 
associated t-distribution based 95% CIs. 
The summaries listed above will be stratified according to disease status of the 
subjects. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more 
than 198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more 
than 380 days after Dose 2 for the Week 56 timepoint. . Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
8.5.9.3 Concomitant Medications 
Concomitant medications are those used during the course of the trial (on or after Day 
0). Partial stop dates of concomitant medications will be assumed to be the latest 
possible date consistent with the partial date; start dates will not be imputed. Data for 
all concomitant medications will be summarized with percentages by treatment arm, for 
the ITT and PP populations. These summaries will be performed according to Phase. 
For the Phase 3 segment, the analyses listed above will also be performed according 
to SARS-CoV-2 serostatus at baseline. 
 
SAMPLE SIZE/POWER 
Phase 3 segment: The trial is case-driven. A total of 17 observed severe cases among 
baseline SARS-CoV-2 seronegative and RT-PCR negative subjects will be required to 
provide 90% power to declare the vaccine efficacious (>30%), assuming a true efficacy of 
90% and utilizing the methodology described in Section 8.5.1.  A sample size of 10,002 
baseline SARS-CoV-2 seronegative subjects is expected to be required to achieve this 
number of cases assuming an underlying attack rate of approximately 0.4%.   
 
RANDOMIZATION AND BLINDING  
Phase 2 Segment 
Subjects will be randomized (3 INO-4800 1.0 mg, one injection: 3 INO-4800 2.0 mg, two 
injections:1 Placebo, one injection: 1 Placebo, two injections). 
The study is blinded. It is double-blinded within dose group.  Randomization and blinding 
will avoid bias in the assignment of subjects to treatment, increase the likelihood that 
known and unknown subject attributes (e.g., demographics and other baseline 
characteristics) are evenly balanced between treatment groups, and enable valid 
statistical comparisons between treatment groups. Subject treatment assignments will be 
unblinded after Phase 2 subjects have reached the Week 30 visit. 
Phase 3 Segment 
Subjects will be randomized (2 INO-4800:1 Placebo).  Randomization will be stratified 
according to two factors, each with two levels: a) age-group age category (18-50 years vs. 
≥51 years) on Day 0, and b) presence or absence on Day 0 of underlying medical 
conditions that increase risk of severe COVID-19 disease, per US CDC criteria. 
The study is double-blinded. Randomization and blinding will avoid bias in the assignment 
of subjects to treatment, increase the likelihood that known and unknown subject attributes 
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(e.g., demographics and other baseline characteristics) are evenly balanced between 
treatment groups, and enable valid statistical comparisons between treatment groups. 
 
ETHICS 
 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical trial is 
performed in accordance with the protocol, the principles of the Declaration of Helsinki, 
Good Clinical Practice (GCP) and applicable regulatory requirements. 
 
INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD (REB)/ETHICS 
COMMITTEE (EC) 
The Investigator will commence the clinical trial after full approval of the protocol and 
adjunctive materials (e.g., ICF, advertising) has been obtained from the applicable 
IRB/REB/EC and a copy of IRB/REB/EC approval documentation has been received by 
the Sponsor. 
Investigator responsibilities relevant to the IRB/REB/EC include the following: 
• Submit continuing review reports to the IRB/REB/EC as required, and request re-
review and approval of the clinical trial at least once a year during the conduct of 
the clinical trial; 
• Notify the Sponsor immediately of any suspected unexpected adverse drug or 
device events/effects; 
• Notify the IRB/REB/EC immediately if the Sponsor notifies the Investigator about 
any reportable safety events; 
• Obtain approval from the IRB/REB/EC for protocol amendments and for revisions 
to the consent form or subject recruitment advertisements, as required; 
• Submit reports on, and reviews of, the clinical trial and its progress to the 
IRB/REB/EC at intervals stipulated in their guidelines and in accordance with 
pertinent regulations and guidelines; 
• Maintain a file of clinical trial-related information (refer to clinical trial files) that 
includes all correspondence with the IRB/REB/EC; 
• Notify the IRB/REB/EC when the clinical trial is completed (i.e., after the last clinical 
trial visit of the final clinical trial subject); 
• After clinical trial completion (within three [3] months is recommended), provide the 
IRB/REB/EC with a final report on the clinical trial. 
Institutional Biosafety Committee (IBC) 
The Investigator will undertake the trial after full approval of the protocol and adjunctive 
materials (e.g., pharmacy manual) has been obtained from the applicable IBC and a copy 
of this approval has been received by the Sponsor. 
Investigator responsibilities relevant to the IBC include the following: 
• 
Notify the Sponsor, IBC and NIH OSP within 30 days of any: 
o Substantial problems or violation of the NIH Guidelines 
o Significant research related accidents or illnesses 
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• 
Notify the IBC to any changes to the research (dosage, procedure, etc.) or facility 
(new space, remodeling, etc.).   
 
PROTECTION OF HUMAN SUBJECTS 
 COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent must be obtained from each subject prior to the subject’s 
enrollment in the clinical trial. The process for obtaining informed consent must be 
documented in the subject’s medical record (also refer to Section 6.2). 
 COMPLIANCE WITH INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD 
(REB)/ETHICS COMMITTEE (EC) REQUIREMENTS 
This clinical trial is to be conducted in accordance with applicable IRB/REB/EC 
regulations. The Investigator must obtain approval from a properly constituted 
IRB/REB/EC prior to initiating the clinical trial and obtain re-approval or review at least 
annually. The Sponsor is to be notified immediately if the responsible IRB/REB/EC has 
been disqualified or if proceedings leading to disqualification have begun. Copies of all 
IRB/REB/EC correspondence with the Investigator should be provided to the Sponsor. 
 COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
 COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS (21CFR 
PART 11) 
When applicable, this clinical trial is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
 COMPLIANCE WITH PROTOCOL 
Subjects are not required to follow special instructions specific to the IP used in this clinical 
trial. Subjects will be provided with Investigator emergency contact information and 
advised to report all AEs. While every effort should be made to avoid protocol deviations, 
should an important deviation be discovered, the Sponsor must be informed immediately. 
Any protocol deviation impacting subject safety must be reported to the Medical Monitor 
immediately. 
 CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from, or changes to, the protocol 
without Sponsor approval and prior review and documented approval/favorable opinion of 
the protocol amendment from the IRB/REB/EC, except where necessary to eliminate 
immediate hazards to clinical trial subjects, or when the changes involve only logistical or 
administrative aspects of the clinical trial (e.g., change in monitors, change of telephone 
numbers).  
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 DATA COLLECTION, MONITORING AND REPORTING 
 CONFIDENTIALITY AND PRIVACY 
A report of the results of this clinical trial may be published or sent to the appropriate 
regulatory authorities in any country in which the clinical trial products are legally marketed 
or may ultimately be marketed, but the subject’s name/identity will not be disclosed in 
these documents. The clinical trial Sponsor, its agents, the IRB/REB/EC and regulatory 
authorities will have direct access to the subjects’ medical records for the purposes of trial-
related monitoring, auditing and inspection. Appropriate precautions will be taken to 
maintain confidentiality of medical records and personal information. 
Written Authorization and other documentation are to be obtained from each subject, 
and/or from the subject’s legally authorized representative, prior to enrollment in the 
clinical trial, in accordance with all applicable laws, regulations and/or directives relating 
to privacy and data protection. 
 SOURCE DOCUMENTS 
Source data is all information, electronic or hardcopy original records or clinical findings, 
laboratory results, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the clinical trial. 
Examples of original source data records may include:  
• Hospital records 
• Clinical and office charts 
• Laboratory notes 
• Memoranda 
• Pharmacy dispensing records 
• Recorded data from automated instruments 
• Copies of electronic medical records (EMR) certified after verification as being 
accurate and complete 
• X-rays 
• Subject files and records kept at the pharmacy, at the laboratories, at the medical 
records facility and within information technology (IT) systems that are involved in 
the clinical trial  
The Investigator/institution will permit clinical trial-related monitoring, audits, IRB/REB/EC 
review and regulatory inspections by providing direct access to source data/documents 
related to this clinical trial. 
 RECORDS RETENTION 
Upon request of the Clinical Monitor, Sponsor or its agent(s), auditor, IRB/REB/EC or 
regulatory authority, the Investigator/institution should make available for direct access all 
requested clinical trial-related records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
It is the Investigator’s responsibility to retain clinical trial essential documents for at least 
two (2) years after the last approval of a marketing application in their country and until 
there are no pending or contemplated marketing applications in their country or at least 
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two (2) years have elapsed since the formal discontinuation of clinical development of 
INO-4800. This retention period may be superseded by local requirements. The Sponsor 
will inform the Investigator/institution when these documents are no longer needed to be 
retained. 
If the Records Retention requirements are addressed in a governing clinical trial 
agreement, it is the Investigator’s responsibility to retain clinical trial essential documents 
in accordance with the governing clinical trial agreement and applicable local 
requirements. 
 SAFETY AND QUALITY MONITORING 
 SAFETY REVIEW 
The Sponsor’s Safety Review Committee (SRC), composed of the Sponsor’s Medical 
Monitor, the ICON Medical Monitor and 1 additional physician, will review blinded safety 
and tolerability data on a regular basis throughout the trial. The SRC will refer any of the 
events listed in Section 7.8.4 or any other safety concerns to the DSMB Chair. 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will 
convene regularly to review all available unblinded safety data, and additionally upon 
completion of the Week 8 phone call visit for all subjects enrolled during the Phase 2 
segment. The DSMB will review unblinded safety and tolerability data, including AEs of 
clinical significance, AESIs and SAEs, as well as safety laboratory data for all enrolled 
subjects. The DSMB will also evaluate the data for signals of vaccine-enhanced disease 
and in the event of a signal, advise whether to halt the trial. The DSMB will advise 
regarding any safety concerns and will make recommendations regarding continued 
enrollment, safety pause and trial suspension. For the Phase 3 segment, the DSMB will 
also review efficacy in an unblinded fashion. 
If the safety data is considered unfavorable during any safety review, the DSMB may 
recommend a trial pause or trial termination at which time further enrollment and 
administration of IP to subjects will be paused. The Sponsor will perform an investigation 
and consult with the DSMB and other experts, if needed, to determine whether to resume 
dosing of the remainder of the subjects. For further details, see the DSMB Charter.  
 CLINICAL MONITORING 
Clinical Monitoring will be performed by qualified Clinical Monitors who will report to the 
Sponsor or the Sponsor’s designee. The following clinical trial site monitoring tasks will be 
performed at all clinical trial sites: 
• 
Prior to subject screening at the site, a Site Initiation Visit will be conducted to 
review all relevant forms and documentation, and ensure that the clinical trial site 
staff are qualified and compliant with all applicable requirements 
• 
All clinical trial site monitoring visits will be documented 
• 
Periodic clinical trial site visits will be performed throughout the clinical trial 
• 
The Clinical Monitor will address and document the following trial conduct activities 
and obligations: 
o Assure that the trial is being conducted in accordance with the protocol, 
applicable regulatory agency regulations, and IRB/REB/EC policies. 
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o Discuss trial conduct issues and incidents of noncompliance with the 
Investigator and/or trial personnel and document them on the resolution trip 
report. Report any significant unresolved problems immediately to the 
Sponsor. 
o Remind the Investigator as necessary of the obligation to immediately report 
all SAEs and provide subsequent follow-up report of the final outcome to the 
IRB. 
o Throughout the trial, inspect source documents to ensure they are complete, 
logical, consistent, attributable, legible, contemporaneous, original, accurate 
and complete (ALCOA-C). 
o Assure that the trial facilities, including the pharmacy, continue to be 
acceptable. 
o Compare the trial CRFs with source documents to assure that the data are 
accurate and complete and that the protocol is being followed. 
o Assure that investigational drug and device accountability and reconciliation of 
records are complete and accurate. 
o Assure that all subject specimens are being stored and forwarded properly for 
testing in accordance with laboratory manual requirements. 
 FINANCING AND INSURANCE 
Inovio Pharmaceuticals is the Sponsor of this study.  The Department of Defense, Joint 
Program Executive Office is providing funding for the Phase 2 segment of the study and 
Inovio is providing funding for the Phase 3 segment. Clinical trial insurance has been taken 
out according to the laws of the countries where the study will be conducted. The 
investigative site is being compensated for the conduct of this study and will follow the 
terms described in the clinical trial agreement. This agreement was executed separately 
from this clinical trial protocol. The Investigators will be required to provide full financial 
disclosure information per ICH E6 R1. 
 PUBLICATION POLICY 
Publication of the results of this clinical trial in its entirety will be allowed. The proposed 
presentation, abstract and/or manuscript must be made available to the Sponsor for 
review and approval in accordance with the governing clinical trial agreement. 
 
 
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 LIST OF ABBREVIATIONS 
ADE 
Adverse Device Effect 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALCOA-C 
Attributable, Legible, Contemporaneous, Original, Accurate and Complete 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CBC 
Complete Blood Count 
Cl 
Chloride 
COVID-19 
Coronavirus Disease 2019 
Cr 
Creatinine 
CRF 
Case Report Form 
CS 
Clinically Significant 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELISpot 
Enzyme-linked immunosorbent spot-forming assay 
EP 
Electroporation 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCO3 
Biocarbonate 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICD 
Implantable-Cardioverter-defibrillator 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
ID 
Intradermal 
IM 
Intramuscular 
Inovio 
Inovio Pharmaceuticals Inc. 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
K 
Potassium 
MAAE 
Medically Attended Adverse Event 
mITT 
modified Intent to Treat 
MM 
Medical Monitor 
MERS 
Middle East Respiratory Syndrome  
MERS-CoV 
Middle East Respiratory Syndrome Coronavirus 
mRNA 
Messenger RNA 
Na 
Sodium 
NCS 
Not Clinically Significant 
NHP 
Non-human Primates 
NP 
Nucleocapsid Protein 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PII 
Personal Identifying Information 
PO4 
Potassium 
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PT 
Preferred Term 
RBC 
Red blood cell 
REB 
Research Ethics Board 
RR 
Respiratory Rate 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SARS 
Severe Acute Respiratory Syndrome  
SARS-CoV 
Severe Acute Respiratory Syndrome Coronavirus 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus - 2 
SID 
Subject Identification Number 
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
SynCon 
Synthetic consensus 
TBili 
Total Bilirubin 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of Child-bearing Potential 
 
 
 
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Lu, H., C.W. Stratton, and Y.W. Tang, Outbreak of pneumonia of unknown etiology in 
Wuhan, China: The mystery and the miracle. J Med Virol, 2020. 92(4): p. 401-402. 
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Hui, D.S., et al., The continuing 2019-nCoV epidemic threat of novel coronaviruses to 
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Huang, C., et al., Clinical features of patients infected with 2019 novel coronavirus in 
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Smith, T.R.F., et al., Immunogenicity of a DNA vaccine candidate for COVID-19. Nat 
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Wiersinga, W.J., et al., Pathophysiology, Transmission, Diagnosis, and Treatment of 
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Chan, J.F., et al., A familial cluster of pneumonia associated with the 2019 novel 
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Rothe, C., et al., Transmission of 2019-nCoV Infection from an Asymptomatic Contact in 
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Ganyani, T., et al., Estimating the generation interval for coronavirus disease (COVID-
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He, X., et al., Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat 
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Protocol Version Date: 8-Mar-2022 
CONFIDENTIAL 
Protocol Version: 7.0 
 
Page 91 of 94 
 
21. 
Liu, Y., et al., The reproductive number of COVID-19 is higher compared to SARS 
coronavirus. J Travel Med, 2020. 27(2). 
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Centers for Disease Control and Prevention. Symptoms of Coronavirus. 2020  March 
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Gudbjartsson, D.F., et al., Spread of SARS-CoV-2 in the Icelandic Population. N Engl J 
Med, 2020. 
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Day, M., Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ, 
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Centers for Disease Control and Prevention. COVID-19 Pandemic Planning Scenarios. 
July 10, 2020 July 20, 2020 July 27, 2020]; Available from: 
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26. 
Lipsitch, M., et al., Transmission dynamics and control of severe acute respiratory 
syndrome. Science, 2003. 300(5627): p. 1966-70. 
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Peiris, J.S., et al., Clinical progression and viral load in a community outbreak of 
coronavirus-associated SARS pneumonia: a prospective study. Lancet, 2003. 
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Tsang, T.K., et al., Influenza A Virus Shedding and Infectivity in Households. J Infect 
Dis, 2015. 212(9): p. 1420-8. 
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Seow, J., et al., Longitudinal evaluation and decline of antibody responses in SARS-
CoV-2 infection. medRxiv, 2020: p. 2020.07.09.20148429. 
30. 
Long, Q.X., et al., Clinical and immunological assessment of asymptomatic SARS-CoV-2 
infections. Nat Med, 2020. 
31. 
Diao, B., et al., Reduction and Functional Exhaustion of T Cells in Patients With 
Coronavirus Disease 2019 (COVID-19). Front Immunol, 2020. 11: p. 827. 
32. 
Grifoni, A., et al., Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans 
with COVID-19 Disease and Unexposed Individuals. Cell, 2020. 181(7): p. 1489-1501 
e15. 
33. 
Modjarrad, K., et al., Safety and immunogenicity of an anti-Middle East respiratory 
syndrome coronavirus DNA vaccine: a phase 1, open-label, single-arm, dose-escalation 
trial. Lancet Infect Dis, 2019. 19(9): p. 1013-1022. 
34. 
Suschak, J.J., J.A. Williams, and C.S. Schmaljohn, Advancements in DNA vaccine 
vectors, non-mechanical delivery methods, and molecular adjuvants to increase 
immunogenicity. Hum Vaccin Immunother, 2017. 13(12): p. 2837-2848. 
35. 
Manickan, E., K.L. Karem, and B.T. Rouse, DNA Vaccines - A Modern Gimmick or a 
Boon to Vaccinology? Crit Rev Immunol, 2017. 37(2-6): p. 483-498. 
36. 
Porter, K.R. and K. Raviprakash, DNA Vaccine Delivery and Improved Immunogenicity. 
Curr Issues Mol Biol, 2017. 22: p. 129-138. 
37. 
Li, L. and N. Petrovsky, Molecular mechanisms for enhanced DNA vaccine 
immunogenicity. Expert Rev Vaccines, 2016. 15(3): p. 313-29. 
38. 
Marc, M.A., E. Dominguez-Alvarez, and C. Gamazo, Nucleic acid vaccination strategies 
against infectious diseases. Expert Opin Drug Deliv, 2015. 12(12): p. 1851-65. 
39. 
Grunwald, T. and S. Ulbert, Improvement of DNA vaccination by adjuvants and 
sophisticated delivery devices: vaccine-platforms for the battle against infectious 
diseases. Clin Exp Vaccine Res, 2015. 4(1): p. 1-10. 
40. 
Tregoning, J.S. and E. Kinnear, Using Plasmids as DNA Vaccines for Infectious 
Diseases. Microbiol Spectr, 2014. 2(6). 
41. 
Williams, J.A., Improving DNA vaccine performance through vector design. Curr Gene 
Ther, 2014. 14(3): p. 170-89. 
42. 
Liu, M.A., DNA vaccines: an historical perspective and view to the future. Immunol Rev, 
2011. 239(1): p. 62-84. 
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Protocol Version Date: 8-Mar-2022 
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43. 
Wahren, B. and M.A. Liu, DNA Vaccines: Recent Developments and the Future. 
Vaccines (Basel), 2014. 2(4): p. 785-796wahren. 
44. 
Ledgerwood, J.E. and B.S. Graham, DNA vaccines: a safe and efficient platform 
technology for responding to emerging infectious diseases. Hum Vaccin, 2009. 5(9): p. 
623-6. 
45. 
Keefer, M.C., et al., Studies of high doses of a human immunodeficiency virus type 1 
recombinant glycoprotein 160 candidate vaccine in HIV type 1-seronegative humans. 
The AIDS Vaccine Clinical Trials Network. AIDS Res Hum Retroviruses, 1994. 10(12): p. 
1713-23. 
46. 
Wu, F., et al., Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered 
patient cohort and their implications. Medrxiv Preprint, 2020. 
47. 
Martin, J.E., et al., A DNA vaccine for Ebola virus is safe and immunogenic in a phase I 
clinical trial. Clin Vaccine Immunol, 2006. 13(11): p. 1267-77. 
48. 
Prud'homme, G.J., et al., Electroporation-enhanced nonviral gene transfer for the 
prevention or treatment of immunological, endocrine and neoplastic diseases. Curr Gene 
Ther, 2006. 6(2): p. 243-73. 
49. 
Hirao, L.A., et al., Combined effects of IL-12 and electroporation enhances the potency 
of DNA vaccination in macaques. Vaccine, 2008. 26(25): p. 3112-20. 
50. 
Rosati, M., et al., Increased immune responses in rhesus macaques by DNA vaccination 
combined with electroporation. Vaccine, 2008. 26(40): p. 5223-9. 
51. 
Curcio, C., et al., DNA immunization using constant-current electroporation affords long-
term protection from autochthonous mammary carcinomas in cancer-prone transgenic 
mice. Cancer Gene Ther., 2008. 15(2): p. 108-114. 
52. 
Ugen, K.E., et al., Regression of subcutaneous B16 melanoma tumors after intratumoral 
delivery of an IL-15-expressing plasmid followed by in vivo electroporation. Cancer Gene 
Ther., 2006. 13(10): p. 969-974. 
53. 
Tebas, P., et al., Safety and Immunogenicity of an Anti-Zika Virus DNA Vaccine - 
Preliminary Report. N Engl J Med, 2017. 
54. 
Tebas, P., et al., Intradermal SynCon(R) Ebola GP DNA Vaccine is Temperature Stable 
and Safely Demonstrates Cellular and Humoral Immunogenicity Advantages in Healthy 
Volunteers. J Infect Dis, 2019. 
55. 
De Rosa, S.C., et al., Robust antibody and cellular responses induced by DNA-only 
vaccination for HIV. JCI Insight, 2020. 5(13). 
56. 
Chandrashekar, A., et al., SARS-CoV-2 infection protects against rechallenge in rhesus 
macaques. Science, 2020. 
57. 
Patel, A., et al., Intradermal-delivered DNA vaccine provides anamnestic protection in a 
rhesus macaque SARS-CoV-2 challenge model. bioRxiv, 2020: p. 2020.07.28.225649. 
58. 
Andrade, V.M., et al., INO-4800 DNA Vaccine Induces Neutralizing Antibodies and T cell 
Activity Against Global SARS-CoV-2 Variants. bioRxiv, 2021: p. 2021.04.14.439719. 
59. 
Gary E., W.B.M., Parzych E.M., Griffin B.D., Zhu X., Tailor N., Tursi N.J., Chan M., 
Purwar M., Vendramelli R., Choi J., Frost K.L, Reeder S., Liaw K., Tello E., Ali A.R., Yun 
K., Pei Y.,Thomas S.,Rghei A.D.,  Guilleman M.M., Muthumani K., Smith T., Wootton 
S.K., Patel A., Weiner D.B., Kobasa D., A novel mouse AAV6 hACE2 transduction 
model of wild-type SARS-CoV-2 infection studied using synDNA immunogens. iScience, 
2021. 
60. 
Gooch, K., et al., One or two dose regimen of the SARS-CoV-2 synthetic DNA vaccine 
INO-4800 protects against respiratory tract disease burden in nonhuman primate 
challenge model. Research Square 2021. 
61. 
Trevor, S. Development of INO-4800, a DNA-vaccine for COVID-19. in Keystone 
Symposia Antibodies and Vaccines as Drugs for COVID-19. 2021. 
62. 
Andrews, N., et al., Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) 
Variant. New England Journal of Medicine, 2022. 
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63. 
Keeton, R., et al., T cell responses to SARS-CoV-2 spike cross-recognize Omicron. 
Nature, 2022. 
64. 
European Commission, Directorate-General: A Guideline on Summary of Product 
Characteristics (SmPC). 2009, EMA. 
65. 
Diehl, M.C., et al., Tolerability of intramuscular and intradermal delivery by 
CELLECTRA((R)) adaptive constant current electroporation device in healthy volunteers. 
Hum Vaccin Immunother, 2013. 9(10): p. 2246-52. 
 
 
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APPENDICES 
APPENDIX A: ADVERSE EVENTS OF SPECIAL INTEREST
For the purpose of standardization across multiple vaccine platforms, including those substantially 
different from Inovio’s platform, the below table lists AEs of special interest (AESIs) relevant to 
COVID-19 vaccine development.  
Body System 
AESI 
Respiratory 
Acute respiratory distress syndrome (ARDS) 
Pneumonitis/Pneumonia 
Neurologic 
Generalized convulsion 
Aseptic meningitis 
Guillain-Barré Syndrome (GBS) 
Encephalitis/Myelitis 
Acute disseminated encephalomyelitis (ADEM) 
CNS vasculopathy (stroke) 
Bell’s Palsy 
Transverse myelitis 
Narcolepsy 
Hematologic 
Thrombocytopenia 
Immune thrombocytopenia (ITP) 
Disseminated intravascular coagulation (DIC) 
Hemorrhagic stroke 
Non-hemorrhagic stroke 
Deep Vein Thrombosis (DVT) 
Pulmonary Embolism (PE) 
Immunologic 
Anaphylaxis 
Vasculitides 
Cardiac 
Acute cardiac failure 
Myocarditis/pericarditis 
Acute myocardial infarction 
Other 
Septic shock-like syndrome 
Appendicitis 
Multisystem Inflammatory Syndrome 
Acute kidney failure 
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Page 1 of 93 
COVID19-311 
Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the Safety, 
Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-
19 Disease, Administered Intradermally Followed by Electroporation in Adults at 
High Risk of SARS-CoV-2 Exposure   
INNOVATE 
(Inovio INO-4800 Vaccine Trial for Efficacy) 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
IND #: 19690 
WHO UTN: U1111-1266-9952 
Protocol Version: 1.0USA 
Protocol Version Date: 30-Jul-2021 
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Protocol Version: 1.0USA 
 
Page 2 of 93 
 
 
Medical Monitor Approval Page 
 
Drug:  
INO-4800 
 
Sponsor: 
Inovio Pharmaceuticals, Inc. 
 
660 W. Germantown Pike, Suite 110 
 
Plymouth Meeting, PA 19462 
 
Medical Monitor: 
 
Jr., M.D., FACP, FIDSA 
Inovio Pharmaceuticals, Inc. 
 
 
Approval Signature: 
 
 
[Electronically signed] 
  
Jr., M.D., FACP, FIDSA 
Inovio Pharmaceuticals, Inc. 
 
 Date (ddMmmyyyy) 
 
 
CONFIDENTIAL 
The information in this document is considered privileged and confidential by Inovio 
Pharmaceuticals Inc. (INOVIO) and may not be disclosed to others except to the extent 
necessary to obtain Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics 
Committee (EC) approval and informed consent, or as required by local regulatory 
authorities. Persons to whom this information is disclosed must be informed that this 
information is privileged and confidential and that it should not be further disclosed 
without the written permission of INOVIO. Any supplemental information added to this 
document is also confidential and proprietary information of INOVIO and must be kept in 
confidence in the same manner as the contents of this document. 
 
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Page 3 of 93 
 
 
Principal Investigator Acknowledgement 
 
I have read and understood this Protocol and agree that it contains all details necessary to 
conduct the clinical trial. I understand that it must be reviewed by the Institutional Review Board 
(IRB)/Research Ethics Board (REB)/Ethics Committee (EC) overseeing the conduct of the clinical 
trial and approved or given favorable opinion before implementation. 
 
The Principal Investigator’s (PI’s) signature constitutes the PI’s approval of this Protocol and 
provides the necessary assurances that this clinical trial will be conducted in accordance with 
International Council for Harmonization (ICH)/Good Clinical Practice (GCP), local legal and 
regulatory requirements, and all stipulations of the Protocol. 
 
 
Principal Investigator Signature: 
 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
Principal Investigator Signature 
 
Date (ddMmmyyyy) 
 
 
 
Clinical Trial Site Number: 
 
Clinical Trial Site Name: 
 
 
 
 
 
 
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Page 4 of 93 
 
SUMMARY OF CHANGES 
 
The following is a list of significant changes from Version 6.0, dated 30-Apr-2021, to Version 
1.0USA, dated 30-Jul-2021. All other changes are administrative and do not significantly affect 
the safety of subjects, trial scope, or scientific integrity of the protocol. 
 
Based upon the increasing availability of EUA vaccine in the US and completion of the Phase 3 
dose selection from the Phase 2 data, the Sponsor recognizes that subjects may want to receive 
a non-study prophylactic COVID-19 vaccine (either authorized under emergency use  or when 
licensed). Therefore, the following change has been implemented: 
 
- 
Receipt of a non-study prophylactic COVID-19 vaccine (authorized under emergency use 
or when licensed), for subjects in the Phase 2 segment of the trial, is removed from the 
restricted concomitant medications (see Section 6.4.7). 
 
 
  
 
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TABLE OF CONTENTS 
Summary of Changes ..................................................................................................................... 4 
Table of Contents ............................................................................................................................ 5 
Clinical Protocol Synopsis ............................................................................................................ 10 
Table 3 – Phase 2 Segment Schedule of Events ........................................................................ 21 
Table 4 – Phase 3 Segment Schedule of Events ........................................................................ 23 
 
Introduction .................................................................................................................... 25 
 
Background and Scientific Rationale ............................................................................. 25 
 
Background Information ................................................................................................. 25 
 
Clinical Presentation, Transmission and Immune Response ................................. 26 
 
Current Treatment and Unmet Need ....................................................................... 27 
 
Rationale for prophylactic vaccine development ........................................................... 28 
 
DNA Vaccines .......................................................................................................... 28 
 
Use of Electroporation with DNA Vaccines ............................................................. 29 
 
Inovio’s Proprietary Technology Against COVID-19 ............................................... 29 
 
Nonhuman Primate (NHP) Challenge Studies Following Vaccination with INO-4800
.................................................................................................................................. 30 
 
First-In-Human Phase 1 Trial of INO-4800 ............................................................. 30 
 
Proposed Phase 2/3 Trial of INO-4800 ................................................................... 31 
1.3.6.1 Safety and tolerability of INO-4800 ......................................................................... 32 
1.3.6.2 Nonclinical INO-4800 Data in Support of Potential Efficacy ................................... 32 
1.3.6.3 Potential Role of INO-4800 as a Booster ................................................................ 32 
1.3.6.4 Thermostability of INO-4800 .................................................................................... 32 
 
Dose and Regimen Rationale .................................................................................. 33 
1.3.7.1 Binding Antibody Response .................................................................................... 33 
1.3.7.2 Neutralizing Antibody Response ............................................................................. 33 
1.3.7.3 ELISPOT analysis .................................................................................................... 34 
 
Risks and Potential Benefits .......................................................................................... 34 
 
Potential Benefits ..................................................................................................... 34 
 
Product Risks ........................................................................................................... 34 
 
Overall Benefit/Risk Conclusion .............................................................................. 36 
 
Objectives and Purpose ................................................................................................. 36 
 
Hypothesis ...................................................................................................................... 36 
 
Clinical Trial Design and Endpoints ............................................................................... 37 
 
Primary Objectives ......................................................................................................... 38 
 
Primary Endpoints .......................................................................................................... 39 
 
Secondary Objectives .................................................................................................... 39 
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Secondary Endpoints ..................................................................................................... 39 
 
Exploratory Objective ..................................................................................................... 40 
 
Exploratory Endpoints .................................................................................................... 40 
 
Efficacy Assessment (Phase 3 Segment Only) ............................................................. 41 
 
Case Definition for Virologically-confirmed COVID-19 Disease: ............................ 41 
 
Case Definition for SARS-CoV-2 Asymptomatic Infection ...................................... 42 
 
Safety Assessment ........................................................................................................ 42 
 
Immunogenicity Assessment ......................................................................................... 42 
 
Clinical Trial Population ................................................................................................. 42 
 
Inclusion Criteria............................................................................................................. 42 
 
Phase 2 Segment .................................................................................................... 42 
 
Phase 3 Segment .................................................................................................... 43 
 
Exclusion Criteria ........................................................................................................... 44 
 
Phase 2 Segment .................................................................................................... 44 
 
Phase 3 Segment .................................................................................................... 46 
 
Discontinuation/Withdrawal of Clinical Trial Subjects.................................................... 47 
 
Clinical Trial Investigational Product Information .......................................................... 48 
 
Investigational Product (IP) and Study Device .............................................................. 48 
 
INO-4800 and Placebo ............................................................................................ 48 
 
CELLECTRA® 2000 ................................................................................................. 48 
 
Dosing Regimens ........................................................................................................... 50 
 
Blinding .................................................................................................................... 50 
 
Packaging and Labeling ................................................................................................. 50 
 
INO-4800 or Placebo ............................................................................................... 50 
 
CELLECTRA® 2000 ................................................................................................. 51 
 
Handling and Storage .................................................................................................... 51 
 
INO-4800 and Placebo ............................................................................................ 51 
 
CELLECTRA® 2000 ................................................................................................. 51 
 
Preparation and Dispensing ........................................................................................... 51 
 
Use of Study Device ....................................................................................................... 52 
 
Investigational Drug and Study Device Accountability .................................................. 52 
 
Investigational Product (IP) Accountability .............................................................. 52 
 
CELLECTRA® 2000 Accountability ......................................................................... 52 
 
Return and Destruction of Investigational Drug and Study Device ............................... 52 
 
INO-4800 and Placebo ............................................................................................ 52 
 
Return of CELLECTRA® 2000 ................................................................................. 52 
 
Clinical Trial Procedures and Schedule ........................................................................ 53 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 7 of 93 
 
 
Procedure by Visit .......................................................................................................... 53 
 
Clinical Trial Screening Evaluations ........................................................................ 53 
6.1.1.1 Medical History ........................................................................................................ 54 
 
Clinical Trial Evaluations and Procedures ............................................................... 54 
6.1.2.1 Day 0 and Day 28 (Dosing Visits)............................................................................ 54 
6.1.2.2 Post-dose phone calls ............................................................................................. 55 
6.1.2.3 Day 42 Visit .............................................................................................................. 56 
6.1.2.4 Phone calls ............................................................................................................... 56 
6.1.2.5 Follow up clinic visits................................................................................................ 56 
6.1.2.6 Day 393 Visit or EOS ............................................................................................... 57 
6.1.2.7 COVID-19 Assessment Visit .................................................................................... 57 
6.1.2.8 COVID-19 Convalescent Visit ................................................................................. 58 
 
Informed Consent ........................................................................................................... 58 
 
Assignment of Subject Identification Numbers .............................................................. 59 
 
Safety Evaluations ......................................................................................................... 59 
 
Intradermal Injection and EP ................................................................................... 61 
 
Management of Pain Due to Electroporation (EP) Procedures .............................. 62 
 
Assessment of Laboratory Abnormalities ................................................................ 62 
 
Assessment of Clinical Trial Adverse Events (AEs) ................................................ 63 
 
Assessment of Injection Site Reactions .................................................................. 63 
 
Concomitant Medications/Treatments ..................................................................... 64 
 
Restrictions .............................................................................................................. 64 
 
SARS-CoV-2 Testing ............................................................................................... 65 
 
COVID-19 Disease Monitoring ................................................................................ 65 
 
Immunogenicity Assessments ....................................................................................... 66 
 
Evaluation of Safety and Management of Toxicity ........................................................ 67 
 
Safety Parameters.......................................................................................................... 67 
 
Adverse Events (AEs) .................................................................................................... 67 
 
Adverse Drug Reaction (ADR) ....................................................................................... 67 
 
Serious Adverse Events (SAEs) .................................................................................... 68 
 
Unexpected Adverse Drug Reaction ............................................................................. 68 
 
Unanticipated (Serious) Adverse Device Effect (UADE) ............................................... 69 
 
Device Deficiency ........................................................................................................... 69 
 
Safety and Toxicity Management .................................................................................. 69 
 
Adverse Event of Special Interest (AESI)................................................................ 69 
 
Medically Attended Adverse Event (MAAE) ............................................................ 69 
 
Abnormal Laboratory Value ..................................................................................... 69 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 8 of 93 
 
 
Clinical Trial Stopping Rules .................................................................................... 70 
 
Safety Data Reporting Period, Method of Collection and Submission .......................... 70 
 
Adverse Event Reporting ............................................................................................... 71 
 Submitting the Initial Serious Adverse Event (SAE) Report Form .......................... 71 
 Recording the Event ................................................................................................ 72 
 Assessing Severity (Intensity) ................................................................................. 72 
 Causal Relationship of Clinical Material to Adverse Events (AEs) ......................... 72 
 
Reporting Suspected COVID-19 Disease Cases During the Trial ................................ 73 
 
Reporting Pregnancy During the Clinical Trial .............................................................. 73 
 
Reporting Device-Related Complaints or Deficiencies ................................................. 74 
 
Notifying Regulatory Authorities and Institutional Review Boards (IRBs)/Research 
Ethics Boards (REBs)/Ethics Committees (ECs) of Safety Information ....................... 74 
 Sponsor Responsibilities ......................................................................................... 74 
 Principal Investigator (PI) Responsibilities .............................................................. 74 
 
Post-Trial Reporting Requirements ............................................................................... 75 
 
Clinical Trial Discontinuation .......................................................................................... 75 
 
Statistical Considerations .............................................................................................. 75 
 
Statistical and Analytical Plan ........................................................................................ 75 
 
General Considerations ................................................................................................. 75 
 
Statistical Hypotheses .................................................................................................... 76 
 
Analytical Populations .................................................................................................... 76 
 
Description of Statistical Methods .................................................................................. 76 
 
Primary Analysis ...................................................................................................... 76 
 
Secondary Analyses ................................................................................................ 77 
 
Safety Analyses ....................................................................................................... 78 
 
Disposition ................................................................................................................ 79 
 
Demographic and Other Baseline Characteristics .................................................. 79 
 
Interim Analyses ...................................................................................................... 79 
 
Multiplicity ................................................................................................................. 80 
 
Missing Values ......................................................................................................... 80 
 
Exploratory Analyses ............................................................................................... 80 
 
Sample Size/Power ........................................................................................................ 81 
 
Randomization and Blinding .......................................................................................... 81 
 
Ethics.............................................................................................................................. 82 
 
Investigator and Sponsor Responsibilities ..................................................................... 82 
 
Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics Committee (EC)
........................................................................................................................................ 82 
 
Protection of Human Subjects ....................................................................................... 83 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 9 of 93 
 
 
Compliance with Informed Consent Regulations .................................................... 83 
 
Compliance with Institutional Review Board (IRB)/Research Ethics Board 
(REB)/Ethics Committee (EC) Requirements ......................................................... 83 
 
Compliance with Good Clinical Practice.................................................................. 83 
 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11) .... 83 
 
Compliance with Protocol ........................................................................................ 83 
 
Changes to the Protocol .......................................................................................... 84 
 
Data Collection, Monitoring and Reporting ................................................................... 84 
 
Confidentiality and Privacy ............................................................................................. 84 
 
Source Documents ........................................................................................................ 84 
 
Records Retention ......................................................................................................... 85 
 
Safety and Quality Monitoring ....................................................................................... 85 
 
Safety Review ................................................................................................................ 85 
 
Clinical Monitoring .......................................................................................................... 85 
 
Financing and Insurance ............................................................................................... 86 
 
Publication Policy ........................................................................................................... 86 
 
List of Abbreviations....................................................................................................... 87 
 
References ..................................................................................................................... 89 
 
Appendices .................................................................................................................... 93 
 
APPENDIX A: Adverse Events of Special Interest ........................................................ 93 
 
 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 10 of 93 
 
CLINICAL PROTOCOL SYNOPSIS 
Protocol Title: Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the 
Safety, Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-19 
Disease, Administered Intradermally Followed by Electroporation in Adults at High Risk of 
SARS-CoV-2 Exposure 
Protocol Number: COVID19-311 
Clinical Trial Phase: 2/3 
Estimated Number of Clinical Trial Centers and Countries/Regions: Approximately 50 
centers globally. Final country list to be determined. 
Background:   
INO-4800 is a prophylactic vaccine under development against SARS-CoV-2, the causative 
agent of COVID-19. INO-4800 contains the plasmid pGX9501, which encodes for the full 
length of the Spike glycoprotein of SARS-CoV-2. The goal of this trial is to assess the safety, 
immunogenicity and efficacy of INO-4800 to prevent COVID-19 in subjects at high risk of 
exposure to SARS-CoV-2.  
 
Clinical Trial Design:  
This is an operationally seamless Phase 2/3, randomized, placebo-controlled, multi-center trial 
to evaluate the safety, immunogenicity, and efficacy of INO-4800, administered by intradermal 
(ID) injection followed immediately by electroporation (EP) using the CELLECTRA® 2000 
device, in a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-2 
exposure. The primary objectives of this trial are to identify in seronegative subjects an optimal 
age-related dose of INO-4800 in the Phase 2 segment for a subsequent efficacy evaluation in 
the Phase 3 segment.  
 
Subjects 18 years of age and older are expected to be enrolled across two (2) segments of 
this study. In the Phase 2 segment, approximately 400 seronegative subjects will be enrolled. 
In the Phase 3 segment, approximately 6714 seronegative subjects are expected to be 
enrolled, and 402 seropositive subjects will be enrolled. The subjects and data from Phase 2 
are independent from that of Phase 3. 
 
Phase 2 Segment – Dose Selection 
In the Phase 2 segment, approximately 400 subjects 18 years of age and older will be 
evaluated across four (4) dose groups (Table 1, Figure 1). Subjects will be randomized at a 
3:3:1:1 ratio to receive either active investigational product (INO-4800) or placebo (placebo for 
INO-4800) according to Table 1 below. Dose groups receiving INO-4800 will enroll 
approximately 150 subjects per group. Dose groups receiving placebo will enroll approximately 
50 subjects per group. Randomization will be such that approximately 240 subjects aged 18-
50 years, 120 subjects aged 51-64 years and 40 subjects aged ≥ 65 years will be enrolled. 
Initial enrollment will include subjects aged 18-50 years. Initiation of enrollment of older 
subjects 51-64 years of age and elderly subjects 65 years and older will depend on review of 
safety and immunogenicity data from those age groups generated in the Phase 1 study 
(COVID19-001).   
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 11 of 93 
 
Table 1: Phase 2 Segment Dose Groups 
Study  
Group 
Expected 
Number of 
Subjects 
Dosing 
Days 
Number of 
Injections + EP 
per Dosing Visit 
INO-4800 
(mg) per 
injection 
INO-4800 
(mg) per 
Dosing Visit 
Total Dose 
(mg) 
INO-4800 
150 
0, 28 
1 
1.0 
1.0 
2.0 
INO-4800 
150 
0, 28 
2a 
1.0 
2.0 
4.0 
Placebo 
50 
0, 28 
1 
0 
0 
0 
Placebo 
50 
0, 28 
2a 
0 
0 
0 
Total 
400 
 
 
 
 
 
aINO-4800 or placebo will be injected ID followed immediately by EP in an acceptable location on two different limbs at each 
dosing visit. 
 
Dose selection for evaluation of efficacy in the Phase 3 segment will be based on Week 6 
immunogenicity data and Week 8 safety data from the Phase 2 segment. Group-level unblinded 
summaries and analyses of safety will be produced once the Week 8 phone call visit data are 
completed for all subjects in the Phase 2 segment. Group-level unblinded summaries and 
analyses of immunogenicity will be produced once the Week 6 visit data are completed for all 
subjects in the Phase 2 segment.  
 
Phase 3 Segment – Efficacy 
In the Phase 3 segment, approximately 6714 seronegative and 402 seropositive subjects 18 
years of age and older will be randomized at a 2:1 ratio to receive either active investigational 
product (INO-4800, 2.0 mg) or placebo (placebo for INO-4800). See Table 2 and Figure 1.  
Approximately half of seronegative subjects and approximately half of seropositive subjects 
will be 18-50 years of age, and the other half will be ≥51 years of age as is operationally 
feasible. Also, approximately 711 subjects will be ≥65 years of age, if operationally feasible. 
 
Subjects will be randomized in a stratified manner according to (a) age category (18-50 years 
vs. ≥51 years) on Day 0, and (b) presence or absence on Day 0 of any of the following 
underlying medical conditions that increase risk of severe COVID-19 disease, per U.S. Center 
for Disease Control (CDC) criteria [1], as listed below: 
• 
Cancer 
• 
Chronic kidney disease 
• 
Chronic lung diseases, including Chronic obstructive pulmonary disease (COPD), 
asthma (moderate-to-severe), interstitial lung disease, cystic fibrosis, pulmonary 
hypertension 
• 
Neurologic conditions including stroke or cerebrovascular disease that do not impact 
cognition 
• 
Diabetes (type 1 or type 2) 
• 
Hypertension 
• 
Heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies 
• 
HIV infection (CD4 count >200 cells/mm3 or undetectable viral load) 
• 
Liver disease 
• 
Obesity (BMI ≥ 30 kg/m2) 
• 
Sickle cell disease or thalassemia, or 
• 
Smoking (current or former smoker). 
 
 
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 12 of 93 
 
Table 2: Phase 3 Segment  
Treatment 
Arm 
Sero 
status 
Expected 
Number 
of 
Subjects 
Approx. 
Expected 
Number of 
Subjects by 
Age Group 
Dosing 
Days 
Number of 
Injections + 
EP per 
Dosing Visit 
INO-4800 
(mg) per 
injection 
INO-4800 
(mg) per 
Dosing Visit 
Total Dose 
of 
INO-4800 
(mg) 
18-50 
51+a 
INO-4800 
Seroneg 
4476 
2238 
2238 
0, 28 
2 
1.0 
2.0 
4.0 
Seropos 
268 
134 
134 
Placebo 
Seroneg 
2238 
1119 
1119 
0, 28 
2 
0 
0 
0 
Seropos 
134 
67 
67 
Total 
Seroneg 
6714 
3357 
3357 
 
 
 
 
 
Seropos 
402 
201 
201 
 
 
 
 
 
Total 
7116 
 
 
 
 
 
 
 
 
aat least 711 subjects will be ≥65 years of age 
 
This segment of the trial is case-driven. Among seronegative subjects, a total of 149 observed 
cases will be required for 90% power to declare the vaccine efficacious (>30%), assuming a 
true efficacy of 60%. A sample size of 6714 seronegative subjects is expected to be required 
to achieve the 149 cases assuming an underlying attack rate of 3.7%. The actual sample size 
may differ if the observed attack rate is different than projected.  There are two formal interim 
analyses of efficacy; one when 50% of the cases accrue and one when 75% of the cases 
accrue. If the prespecified criteria for efficacy are met at either interim analysis, then enrollment 
will continue until 4500 subjects have been enrolled, and blinded follow-up will continue until 
at least those 4500 subjects have a minimum of 6 months of safety follow-up. At that point, the 
trial would be unblinded and placebo-recipients will be offered the active product.    
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12 months 
post-dose 2. All Phase 3 segment subjects will be followed for 56 weeks from the Day 0 dosing 
[i.e., Week 56 will be the planned End of Study (EOS) visit for this segment of the trial]. 
 
Figure 1: Enrollment and Dose Group Design 
 
 
 
External Committee Reviews 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will convene 
regularly to review all available unblinded safety data. For the Phase 3 segment, the DSMB 
will also review efficacy in an unblinded fashion. Additionally, for the Phase 3 segment, an 
independent, blinded Endpoint Adjudication Committee (EAC) will review and confirm COVID-
19 cases.  
 
Details of each committee’s scope will be provided in the respective charters. 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 13 of 93 
 
  
Criteria for Evaluation:  
 
Research Hypothesis:  
INO-4800 delivered ID followed immediately by EP will be well-tolerated, exhibit an acceptable 
safety profile, result in generation of cellular and humoral immune responses to SARS-CoV-2 
Spike glycoprotein and provide protection against virologically-confirmed COVID-19 disease in 
subjects at high risk of SARS-CoV-2 exposure.  
 
Phase 2 Segment Objectives and Endpoints: 
 
Primary Objective 
Primary Endpoint 
1.  Evaluate the cellular and humoral 
immune response to INO-4800 
administered by ID injection followed 
immediately by EP  
  
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot 
1b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
Secondary Objective 
Secondary Endpoints 
1.  Evaluate the safety and tolerability of 
INO-4800 administered by ID injection 
followed immediately by EP    
  
1a. Incidence of solicited and unsolicited injection site 
reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)   
Exploratory Objective 
Exploratory Endpoint 
1.  Evaluate the expanded immunological 
profile of antibody response and T cell 
immune response 
  
1a.  Antigen-specific cellular immune response 
measured by flow cytometry 
1b. Expanded immunological profile which may 
include additional assessments of T and B cell 
numbers and molecular changes by measuring 
immunologic proteins and mRNA levels of genes 
of interest as determined by sample availability 
 
Phase 3 Segment Objectives and Endpoints: 
 
Primary Objective 
Primary Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease in 
subjects who are SARS-CoV-2 
negative at baseline  
 
1.   Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 (End 
of Study (EOS)) in subjects who are SARS-CoV-2 
seronegative at baseline 
Secondary Objectives 
Secondary Endpoints 
1. Evaluate the safety and tolerability of 
INO-4800    
 
1a. Incidence of solicited and unsolicited injection site 
reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 14 of 93 
 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality 
 
2.  Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of severity in 
subjects who are SARS-CoV-2 
seronegative at baseline       
2a.  Incidence of non-severe COVID-19 disease in 
SARS-CoV-2 seronegative subjects starting 14 
days after completion of the 2-dose regimen until 
EOS  
2b. Incidence of severe COVID-19 disease in SARS-
CoV-2 seronegative subjects starting 14 days after 
completion of the 2-dose regimen until EOS 
2c. Incidence of deaths due to COVID-19 in SARS-
CoV-2 seronegative subjects starting 14 days after 
completion of the 2-dose regimen until EOS 
3.  Evaluate the cellular and humoral 
immune response to INO-4800  
3a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot  
3b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
 
4. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease in 
subjects who are SARS-CoV-2 
seropositive at baseline  
 
4.  Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 (End 
of Study (EOS)) in subjects who are SARS-CoV-
2 seropositive at baseline 
Exploratory Objective 
Exploratory Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease 
from SARS-CoV-2 variants in subjects 
who are SARS-CoV-2 seronegative at 
baseline 
1. Incidence of virologically-confirmed COVID-19 
disease from a SARS-CoV-2 variant starting 14 
days after completion of the 2-dose regimen until 
12 months post-dose 2 (End of Study (EOS)) in 
subjects who are SARS-CoV-2 seronegative at 
baseline 
2. Evaluate the efficacy of INO-4800 in 
the prevention of SARS-CoV-2 
asymptomatic infection in subjects 
who are SARS-CoV-2 seronegative at 
baseline     
2. Incidence of SARS-CoV-2 asymptomatic 
infections in SARS-CoV-2 seronegative subjects 
starting 14 days after completion of the 2-dose 
regimen until EOS 
3.  Evaluate the immunological profile by 
assessing both antibody response and 
T cell immune response  
3a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels  
3b. Antigen-specific cellular immune response such as 
measured by flow cytometry  
4. Evaluate antibody persistence  
4a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels at Week 30 or later.  
4b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay at Week 
30 or later 
 
 
Immunogenicity Assessment:  
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 15 of 93 
 
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 3 and Table 4).  Assays such as binding enzyme-linked immunosorbent assay (ELISA), 
pseudovirus-based neutralization assay, and enzyme-linked immunosorbent spot-forming 
assay (ELISpot) will be evaluated at serial timepoints. 
Safety Assessment:  
Subjects will be followed for safety during the trial through scheduled clinic visits and phone 
calls. Adverse events (AEs), regardless of relationship to study drug, will be collected from 
the time of consent until 28 days post-dose 2 (i.e., Day 56). SAEs, Medically Attended Adverse 
Events (MAAEs) and AESIs will be collected from time of consent until EOS. SAEs, AESIs 
and treatment-related AEs will be followed to resolution or stabilization. For the Phase 2 
segment and at selected sites in the Phase 3 segment, solicited local and systemic AEs will 
be collected for 7 days following each dose using a participant diary. 
Subjects will also be monitored for COVID-19.  
Please refer to the Schedule of Events (Table 3 and Table 4) for safety assessments to be 
performed.  
Efficacy Assessment (Phase 3 segment only):  
Subjects will receive either active investigational product (INO-4800) or placebo (placebo for 
INO-4800) in a 2-dose regimen administered on Days 0 and 28 intradermally followed 
immediately by EP. Subjects will be monitored through regularly scheduled clinic visits and 
phone calls throughout the trial. Subjects will be regularly tested for SARS-CoV-2 infection 
using serologic testing. If COVID-19 disease is suspected based on symptoms per the case 
definition or laboratory testing, site personnel will arrange for a clinic visit. Subjects with 
symptom(s) or a positive SARS-CoV-2 test result will be reviewed by the EAC. 
Clinical Trial Population: 
Phase 2 segment: Healthy subjects at high risk for SARS-CoV-2 exposure who are 18 years 
and older. 
Phase 3 segment: Subjects at high risk for SARS-CoV-2 exposure including subjects at high 
risk for severe COVID-19 who are 18 years and older. 
Inclusion Criteria: Phase 2 segment 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, vital signs and 
physical examination performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar 
workers, store cashiers, hairdressers and barbers, veterinary staff, daycare 
workers, Transportation Security Administration screening staff, school 
teachers and college professors teaching in-person classes) 
2. Factory workers (when working in confined settings with large numbers of 
employees) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) 
4. User of public transportation (e.g., bus, train, subway) at least 3 times weekly 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 16 of 93 
 
5. Nursing home staff or correctional facility staff  
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists.) Physicians should not be enrolled unless they 
are assigned to dedicated COVID-19 treatment wards or other settings with 
prolonged exposure 
10. Others, if approved by the medical monitor.   
f. Screening laboratory results within normal limits for testing laboratory or are deemed 
not clinically significant by the Investigator; 
g. Must meet one of the following criteria with respect to reproductive capacity: 
1. Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
2. Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or 
tubal ligation, absence of ovaries and/or uterus in females). In the case of 
vasectomy, subjects should wait six (6) months post-vasectomy prior to 
enrolling;  
3. Use of medically effective contraception with a failure rate of < 1% per year 
when used consistently and correctly from screening until 3 months following 
last dose. Acceptable methods include:  
i. hormonal contraception including implants, injections or oral; 
ii. two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
iii. intrauterine device or intrauterine system; 
iv. abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Inclusion Criteria: Phase 3 segment 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Per investigator judgment, healthy or stable with pre-existing medical conditions that 
do not require significant change in medication or have led to a hospitalization in the 3 
months prior to enrollment or who, in the judgment of the investigator, are unlikely to 
require a significant change in therapy or hospitalization for worsening disease through 
Day 56; 
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings. Examples 
include:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar 
workers, street vendors, store cashiers, hairdressers and barbers, veterinary 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 17 of 93 
 
staff, daycare workers, airport screening staff, school teachers and college 
professors teaching in-person classes, college students attending in-person 
classes, office workers and volunteers who have multiple brief exposures to 
people regularly) 
2. Factory workers (when working in confined settings with large numbers of 
employees, meat-packing facilities) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) and delivery 
services  
4. User of public transportation (e.g., bus, train, subway) or public facilities (e.g. 
gyms) at least 3 times weekly 
5. Nursing home staff or correctional facility staff 
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, medical assistants and technicians, respiratory therapists, 
physical therapists, social workers, dentists and dental hygienists)  
10. Others, if in the opinion of the PI, the risk of COVID-19 exposure is comparable 
to the examples above.   
f. Must meet one of the following criteria with respect to reproductive capacity: 
1. Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
2. Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or 
tubal ligation, absence of ovaries and/or uterus in females). In the case of 
vasectomy, subjects should wait six (6) months post-vasectomy prior to 
enrolling;  
3. Use of medically effective contraception with a failure rate of < 1% per year 
when used consistently and correctly from screening until last dose. Acceptable 
methods include:  
i. hormonal contraception including implants, injections or oral; 
ii. two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
iii. intrauterine device or intrauterine system; 
iv. abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 
Exclusion Criteria: Phase 2 segment 
a. Acute febrile illness with temperature >100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat); 
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the Screening visit until 3 
months following the last dose; 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
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Protocol Version: 1.0USA 
 
Page 18 of 93 
 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or a 
detectable viral load within the past 3 months; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous receipt of an investigational vaccine for prevention or treatment of COVID-19, 
MERS or SARS (documented receipt of placebo in previous trial would be permissible 
for trial eligibility); 
h. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg prior to first dose; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin 
cancers that only required local excision and non-metastatic prostate cancer 
not requiring treatment; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in 
therapy or hospitalization for worsening disease during the 6 weeks prior to 
enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a 
single antiepileptic agent; 
i. 
Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed); 
• 
Current or anticipated use of disease modifying doses of systemic anti-
rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, 
cyclosporine, 
methotrexate) and biologic disease modifying drugs such as TNF-α inhibitors 
(e.g., infliximab, adalimumab or etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the 
subject or require therapy that would interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results. 
j. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 19 of 93 
 
• 
Any metal implants or implantable medical device within the electroporation 
site; 
k. Blood donation or transfusion within 1 month prior to Day 0; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the past 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
 
Exclusion Criteria: Phase 3 segment 
a. Acute febrile illness with temperature ≥100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat) on Day 
0 prior to dosing; 
b. Positive serologic test for SARS-CoV-2 at Screening (this criterion only applies after 
approximately 402 subjects positive for SARS-CoV-2 serologic test are randomized, 
after which this criterion will apply to all remaining subjects); 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children starting from the Screening visit until the last dose; 
d. Positive urine pregnancy test during screening or immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or a 
detectable viral load within 3 months prior to screening; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days prior to Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous or planned receipt of an investigational (including Emergency Use 
Authorization (EUA) or local equivalent authorization) or licensed vaccine for 
prevention or treatment of COVID-19, MERS or SARS (documented receipt of placebo 
in previous trial would be permissible for trial eligibility); 
h. Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed) in the past 6 months; 
• 
Current or anticipated use of disease modifying doses of systemic anti-
rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, 
cyclosporine, 
methotrexate) and biologic disease modifying drugs such as TNF-α inhibitors 
(e.g., infliximab, adalimumab or etanercept) or others; 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the 
subject or require therapy that would interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results. 
i. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 20 of 93 
 
• 
Any metal implants or implantable medical device within the electroporation 
site; 
j. 
Blood donation or transfusion within 1 month prior to Day 0; 
k. People who work remotely or in a socially distanced setting with minimal risk of 
exposure to SARS-CoV-2; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the prior 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
Clinical Trial Treatment: 
Phase 2 Segment 
Active Investigational Product: One or two 1.0mg ID injection(s) of INO-4800 (~0.1mL dose 
volume) followed immediately by EP administered on Day 0 and Day 28 (±3 days)  
Placebo: One or two ID injection(s) of saline sodium citrate buffer (SSC-0001) (~0.1mL) 
followed immediately by EP administered on Day 0 and Day 28 (±3 days) 
Phase 3 Segment 
Active Investigational Product: Two 1.0mg ID injections of INO-4800 followed immediately by 
EP administered in separate limbs at Day 0 and Day 28 (±3 days) 
Placebo: Two ID injections of placebo for INO-4800 followed immediately by EP administered 
in separate limbs at Day 0 and Day 28 (±3 days) 
Formulation: 
INO-4800 is formulated in sodium chloride and sodium citrate buffer, refrigerated. Placebo 
[sterile saline sodium citrate buffer (placebo for INO-4800)], refrigerated. 
 
 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
 
 
 
Protocol Version: 1.0USA 
 
Page 21 of 93 
 
TABLE 3 – PHASE 2 SEGMENT SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Tel 
#1 
Wk 
4 
Tel 
#2 
Wk
6 
Tel 
#3 
Wk 
30 
Wk 
56 
Illness 
Illness  
Screena 
Day 0 
Phone call - Day 7 (±3d) 
Day 28 
(±3d) 
Phone call - Day 35 (±3d) 
Day 42 (±5d) 
Phone Call - Day 56 (±5d) 
Day 210 (±5d) 
Day 393 (± 5d) 
COVID-19 assessment visitm  
COVID-19 convalescent visitn 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behavioral Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
Vital Signs 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
Xp 
Xp 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differentialc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Chemistryc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
HIV Serology  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis Routined 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Pregnancy Teste 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
INO-4800 or Placebo + EPf 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Download EP Datag 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Adverse Eventsh  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Samplesi 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
Humoral Samplesj 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
SARS-CoV-2 Serologyk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 RT-PCR (Saliva and Swabs) 
Xl 
 
 
 
 
 
 
 
 
 
 
Xl 
Xl 
Distribute Diary 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Review/Collect Diaryo 
 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
 
 
 
Protocol Version: 1.0USA 
 
Page 22 of 93 
 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0.   
b. 
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits.  
c. 
Hemoglobin A1c collected at screening only. Chemistry includes Na, K, Cl, HCO3, Ca, PO4, glucose, BUN, Cr, alkaline phosphatase, AST, ALT, LDH, total bilirubin.  
d. 
Dipstick for glucose, protein, and hematuria. Microscopic examination should be performed if dipstick is abnormal.  
e. 
Serum pregnancy test at Screening. Urine pregnancy test at other visits.  
f. 
Intradermal injection(s) in skin preferably over deltoid muscle, or alternately over anterolateral quadriceps muscle, followed by EP at Day 0 and Day 28. 
g. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
h. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
i. 
On Day 0, cellular sampling requires 64 mL of whole blood (8 Cell Preparation Tubes (CPT), each 8 mL of whole blood) prior to 1st dose. At all other time points, collect 32 mL of 
whole blood (4 CPT tubes, each 8 mL of whole blood).   
j. 
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce eight serum aliquots of 1 
mL each). At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce four serum aliquots of 1 mL each.  
k. 
SARS-CoV-2 antibody.   
l. 
Saliva specimen at Screening; Nasal swabs and saliva specimens at COVID-19 assessment and convalescent visits. Genotyping may also be performed on sample(s) collected at 
the COVID-19 assessment visit. 
m. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The assessment visit may be performed in the clinic, in the subject’s vehicle 
or at the subject’s home and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test.  
n. 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of 
symptoms, the date of positive SARS-CoV-2 test. If acute symptoms are ongoing, the site should follow up with the subject via phone call or an unscheduled visit after symptom 
resolution or stabilization.   
o. 
Diary should be reviewed at the 7-day post-dose phone call and collected at the next in-office visit. 
p. 
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation. 
 
 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
 
 
 
Protocol Version: 1.0USA 
 
Page 23 of 93 
 
TABLE 4 – PHASE 3 SEGMENT SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Tel 
#1 
Wk 
4 
Wk
6 
Tel 
#2-6 
Wk 
18 
Tel 
#7-11 
Wk 
30 
Tel 
#12-13 
Wk
42 
Tel 
#14-16 
Wk 
56 
Illness 
Illness 
Screena 
Day 0 
Phone call - Day 14 (±3d) 
Day 28 
(±3d) 
Day 42 (±5d)k 
Phone call - Days 56, 70, 84, 
98, 112 (±5d) 
Day 126 (±5d) 
Phone calls - Days 140, 154 
168, 182, 196 (±5d) 
Day 210 (±5d) 
Phone calls - Days 238, 266 
(±5d) 
Day 294 (±5d) 
Phone calls 
Days 322, 350, 378 (±5d) 
Day 393 (± 5d) 
COVID-19 assessment visitl  
COVID-19 convalescent visitm 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behavioral Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Vital Signs 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Xn 
Xn 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testc 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
INO-4800 or Placebo + EPd 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Download EP Datae 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Eventsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Samplesg 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
X 
Humoral Samplesh 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
X 
SARS-CoV-2 Serologyi 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
SARS-CoV-2 RT-PCR 
(Nasopharyngeal swabs) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
 
Distribute Diaryp 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Review/Collect Diaryq 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0. Screening and Day 0 visits may be combined if eligibility is able to be confirmed prior to dosing. If so, all assessments 
for Screening and Day 0 must be performed at the combined visit.  
b. 
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits.  
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 30-Jul-2021 
CONFIDENTIAL 
 
 
 
Protocol Version: 1.0USA 
 
Page 24 of 93 
 
c. 
In women of childbearing potential. Urine pregnancy test at all indicated visits.  
d. 
Intradermal injection(s) in skin preferably over deltoid region, or alternately over anterolateral quadriceps region, followed by EP at Day 0 and Day 28. 
e. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
f. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
g. 
On Day 0, cellular sampling requires 64 mL of whole blood prior to 1st dose. At all other time points, collect 32 mL of whole blood. Cellular samples will be collected at selected clinical sites 
(estimated to include 711 subjects) 
h. 
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce four serum aliquots of 2 mL 
each). At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce two serum aliquots of 2 mL each.  
i. 
SARS-CoV-2 antibody. 
j. 
The Day 0 RT-PCR results will not be required prior to dosing on that day. 
k. 
Day 42 visit must occur at least 10 days after Day 28 visit. 
l. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The assessment visit may be performed in the clinic, subject’s vehicle, or at a 
home visit and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test.  
m. 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of 
symptoms, the date of positive SARS-CoV-2 test. If acute symptoms are ongoing the site should follow up with the subject via phone call or unscheduled visit after symptom resolution 
or stabilization 
n. 
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation.   
o. 
Genotyping may also be performed on sample(s) collected at the COVID-19 assessment visit.  
p. 
Diaries to be used at selected sites only (estimated to include 711 subjects). 
q. 
Diary should be reviewed at the 14-day post-dose phone call or visit and collected at the next in-office visit. 
r. 
When possible, cellular and humoral immunology samples will be collected. Cellular samples will be collected at selected sites only. 
 
 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 25 of 93 
 
 
INTRODUCTION 
This document is a protocol for a human research trial to be conducted according to U.S. 
and international standards of Good Clinical Practice (GCP) (FDA Title 21 part 312, 812 
and International Conference on Harmonization (ICH) guidelines), applicable government 
regulations and Institutional research policies and procedures. 
 
BACKGROUND AND SCIENTIFIC RATIONALE 
Given the continued number of cases globally, SARS-CoV-2 infections remain a serious 
unmet medical concern. Appropriate measures to prevent SARS-CoV-2 infections, 
including its variants, are not yet widely available. 
 
BACKGROUND INFORMATION 
In late 2019, a cluster of cases of pneumonia of unknown etiology was reported in Wuhan, 
Hubei province, China [2-4]. These cases were announced on January 6, 2020 as testing 
negative for influenza, severe acute respiratory syndrome (SARS), and Middle East 
respiratory syndrome (MERS). On January 7, 2020 a novel virus was isolated by the 
Chinese Center for Disease Control and Prevention (CDC) from the throat swab sample 
of a patient, and the isolate was named “Wuhan-Hu-1.” The gene sequence of that isolate 
was then generated and determined to be of a novel coronavirus [5, 6]. That gene 
sequence was publicly posted on January 10, and the novel coronavirus was preliminarily 
named 2019-nCoV. Subsequently, on February 11, 2020, the virus was named SARS-
CoV-2 by the International Committee on Taxonomy of Viruses (ICTV) [7, 8], due to its 
similarity with the original SARS virus. That same day, the World Health Organization 
(WHO) announced a specific name of the disease, “COVID-19,” associated with infection 
by this novel coronavirus, as based on the novel coronavirus origin and year of first 
reported cases. The first cluster of human cases identified comprised people who worked, 
visited, or lived around the local Huanan seafood wholesale market in Wuhan, where live 
animals and fresh meat and fish were on sale, suggesting that an animal was the source 
of the novel respiratory virus being transmitted to humans.  
Epidemiologic data suggest that droplets expelled during face-to-face exposure during 
talking, coughing, or sneezing is the most common mode of transmission while contact 
surface spread remains yet another possible mode of transmission [9].  
SARS-CoV-2 infection rapidly emerged as a global threat to public health, joining other 
coronavirus-related diseases, such as SARS and MERS. COVID-19 was declared a 
Public Health Emergency of International Concern (PHEIC) by the WHO on January 20, 
2020, and was declared a pandemic on March 11, 2020 [10], associated with substantial 
morbidity and mortality [11]. As of July 25, 2020, a total of nearly 16 million laboratory-
confirmed COVID-19 cases have been reported internationally, including over 643,000 
deaths [12]. However, given the lack of widespread testing, the true number of cases of 
COVID-19 is likely far higher than reported. Preliminary results from large U.S.-based 
seroepidemiological surveys indicate an estimated incidence rate of SARS-CoV-2 
infections to be 6 to 24 times that of the number of reported cases of COVID-19 [13].  
An article in JAMA by Wu and McGoogan [14] provided a summary of a major report by 
the Chinese Center for Disease Control and Prevention (China CDC) [15]. Of a total of 
72,314 case records, 44,672 (62%) were confirmed as SARS-CoV-2 infections based on 
positive viral nucleic acid test results on throat swabs, 16,186 (22%) as suspected cases 
based on symptoms and exposures only, 10,567 (15%) as clinically diagnosed based on 
symptoms, exposures, and presence of lung imaging features consistent with coronavirus 
pneumonia, and 889 (1%) as asymptomatic cases based on a positive viral nucleic acid 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 26 of 93 
 
test result but lacking typical symptoms including fever, dry cough, and fatigue [16]. The 
overall case-fatality ratio (CFR) was 2.3% (1023 deaths among 44,672 confirmed cases). 
No deaths occurred in the group aged 9 years and younger, but cases in those aged 70 
to 79 years had an 8.0% CFR and cases in those aged 80 years and older had a 14.8% 
CFR. The CFR was 49.0% among critical cases. CFR was elevated among those with 
preexisting comorbid conditions - 10.5% for cardiovascular disease, 7.3% for diabetes, 
6.3% for chronic respiratory disease, 6.0% for hypertension, and 5.6% for cancer [16]. 
These initial reports of the CFR documented the level of seriousness of COVID-19.  
Given the novelty of SARS-CoV-2, its rapid spread among humans and its associated 
morbidity and mortality, there has been an explosion of epidemiological, clinical, virologic, 
and other scientific data regarding the propagation of effects of this virus emerging from 
China, the United States, and many other countries. These data have established that 1) 
SARS-CoV-2 is transmitted person-to-person [17], even from those who are asymptomatic 
or presymptomatic [18-20], 2) the virus is very infectious, with estimates of the R0 
(Reproductive number) ranging from 1.50 to 6.49, with a mean average of 3.28 and a 
median average of 2.79 [21], 3) the constellation of symptoms, signs, and an incubation 
period ranging between  2 and 14 days [22], and 4)  the asymptomatic proportion of those 
infected being substantial, perhaps as high as  80% [17, 23-25]. Further, research has 
found that the risk of death from COVID-19 increases with age and with serious, comorbid 
conditions including hypertension, diabetes, cardiovascular disease, obesity, etc.   
Finally, although much has been learned very quickly about SARS-CoV-2 and COVID-19, 
much more is still to be determined. The aforementioned CFR and similar estimates are 
from crude analyses that have only accounted for moderate to serious cases. Therefore, 
the true CFR is likely significantly lower. Further, the infection-fatality ratio (IFR), which is 
the proportion who die among all those infected regardless of any symptomology, is likely 
still even lower than the CFR, but both the CFR and IFR will not be known with certainty 
until well-designed and controlled seroepidemiology surveys have been conducted using 
well-validated antibody assays and thorough questionnaires to obtain symptom history. 
Also, the presence of natural immunity of those infected who survive and the durability of 
such natural immunity is to be determined. Thus, the existence and possibility of 
reinfection and recurrent infection is unknown. 
 CLINICAL PRESENTATION, TRANSMISSION AND IMMUNE RESPONSE 
A study in The Lancet by Huang and colleagues [4] reported the epidemiological, clinical, 
laboratory, and radiological characteristics, as well as treatment and clinical outcomes, of 
patients with laboratory-confirmed COVID-19 pneumonia. Common symptoms at onset of 
illness were fever (n=40, 98% of 41 patients), cough (n=31, 76%), and myalgia or fatigue  
(n=18, 44%);  less  common  symptoms  were  sputum  production  (n=11, 28%  of  39 
patients),  headache  (n=3, 8%  of  38 patients), hemoptysis (n=2, 5% of 39 patients), and 
diarrhea (n=1, 3% of 38 patients). Dyspnea developed in 22 (55%) of 40 patients (median 
time from illness onset to dyspnea was 8 days [Interquartile range 5 - 13 days]). Twenty-
six (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal 
findings on chest CT scan. Complications included acute respiratory distress syndrome 
(n=12, 29%), RNAaemia (n=6, 15%), acute cardiac injury (n=5, 12%) and secondary 
infection (n=4, 10%).  
Wiersinga et al. summarized the common symptoms of COVID-19 in hospitalized patients 
as fever (70-90%), dry cough (60-86%), shortness of breath (53-80%), fatigue (38%), 
myalgias (15-44%), nausea/vomiting or diarrhea (15-39%), headache, weakness (25%) 
and rhinorrhea (7%). Anosmia and ageusia may be the sole presenting symptom in 
approximately 3% of individuals with COVID-19. Common laboratory abnormalities 
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INO-4800 
  
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Inovio Pharmaceuticals, Inc. 
 
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include lymphopenia (83%), elevated inflammatory markers (e.g., erythrocyte 
sedimentation rate, C-reactive protein, ferritin, tumor necrosis factor-alpha, IL-1, IL-6) and 
abnormal coagulation parameters (e.g., prolonged prothrombin time, thrombocytopenia, 
elevated D-dimer and low fibrinogen). Common radiographic findings include bilateral, 
lower lobe infiltrates on chest radiographic imaging and bilateral, peripheral, lower-lobe 
ground-glass opacities and/or consolidation on chest computed tomographic imaging [9].  
Transmission of SARS-CoV-2 occurred mainly after days of illness [26] and was 
associated with modest viral loads in the respiratory tract early in the illness, with viral 
loads peaking approximately 10 days after symptom onset [27]. Higher viral loads were 
detected soon after symptom onset, with higher viral loads detected in the nose than in 
the throat. Analysis of these samples suggested that the viral nucleic acid shedding 
pattern of patients infected with SARS-CoV-2 resembles that of patients with influenza 
[28] and appears different from that seen in patients infected with SARS-CoV [27]. The 
viral load that was detected in the asymptomatic patient was similar to that in the 
symptomatic patients, which suggests the transmission potential of asymptomatic or 
minimally symptomatic patients [11]. The SARS-CoV-2 transmission time window from 
COVID-19 patients is perhaps 2 days before symptom onset up to 37 days after symptom 
onset [20]. It is estimated that 48% to 62% of transmission may occur via presymptomatic 
carriers [9].  
Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10-15 
days following the onset of COVID-19 symptoms. Seow et al. observed seroconversion in 
>95% with neutralizing antibody responses when sampled beyond 8 days after onset of 
symptoms [29]. However, declining neutralizing antibody titers were observed during the 
follow-up period. Long, et al, when following 37 asymptomatic individuals and 37 
symptomatic patients into the early convalescent phase, observed that the IgG levels in 
93.3% of the asymptomatic group and 96.8% of the symptomatic group declined during 
the early convalescent phase [30]. T cells play a critical role in antiviral immunity but their 
numbers and functional state in SARS-CoV-2 infected patients remain largely unclear. 
Diao and colleagues performed a retrospective review of total T cell counts, and CD4+ and 
CD8+ T cell subsets based on inpatient data from 522 patients with laboratory-confirmed 
SARS-CoV-2 infection and 40 healthy controls in Wuhan from December 2019 to January 
2020. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe and 
critical disease groups as well as those who died were significantly lower than in the 
mild/moderate disease group. Most importantly, the numbers of total T cells, CD8+ T cells 
and CD4+ T cells in severe COVID-19 cases, including those who died, were lower 
suggesting that there is a profound T cell loss in COVID-19 disease. Counts of total T 
cells, CD8+ T cells or CD4+ T cells were negatively correlated with patient survival [31]. 
It is quite likely that CD4+ T cell, CD8+ T cell, and neutralizing antibody all contribute to 
clearance of the acute infection. There is an ongoing need to understand the magnitude 
and composition of the human CD4+ and CD8+ T cell responses to SARS-CoV-2. If 
natural infection with SARS-CoV-2 elicits potent CD4+ and CD8+ T cell responses 
commonly associated with protective antiviral immunity, COVID-19 is a strong candidate 
for rapid vaccine development [32].  
 CURRENT TREATMENT AND UNMET NEED 
Currently, there is no licensed prophylactic vaccine against COVID-19, however there are 
several vaccines that are available under Emergency Use Authorization (EUA) in the 
United States and other countries. Numerous vaccine efforts are underway. Given the 
growing concerns regarding the emergence of new strains of SARS-CoV-2, an effective 
prophylactic vaccine ideally induces immunity against not only SARS-CoV-2 Wuhan-Hu-
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1 but also its variants. Due to rapid spread of SARS-CoV-2 infections even from 
asymptomatic and mildly infected patients, there is an urgent need for additional vaccines 
for prevention of SARS-CoV-2 infections. 
 
RATIONALE FOR PROPHYLACTIC VACCINE DEVELOPMENT 
SARS-CoV-2 has become a pandemic resulting in substantial morbidity and mortality. Due 
to rapid spread of SARS-CoV-2 infections even from asymptomatic and mildly infected 
patients, there is an urgent need for appropriate measures to prevent, control and treat 
SARS-CoV-2 infections.  
To address this critical need for a medical countermeasure for prevention of COVID-19 
disease, we at Inovio Pharmaceuticals have employed our synthetic DNA-based vaccine 
technology. This technology is highly amenable to accelerated developmental timelines, 
due to the ability to rapidly design multiple test constructs, manufacture large quantities of 
the drug product, and leverage established regulatory pathways to the clinic. Furthermore, 
this technology platform has demonstrated proof of concept efficacy and safety in humans 
in a Phase 3 (REVEAL1) randomized, double-blind, placebo-controlled study for human 
papillomavirus (HPV) associated cervical pre-cancer (NCT03185013) and several Phase 
2 trials for related and other indications and several Phase 2 trials for related and other 
indications. We have additionally built upon our prior experience in developing a MERS 
coronavirus (MERS-CoV) vaccine to accelerate the development of a SARS-CoV-2 
vaccine candidate. In a Phase 1 clinical study, the MERS-CoV vaccine candidate was safe 
and well tolerated, eliciting immune responses in more than 85% of participants after two 
vaccinations that were durable through 1 year of follow-up [33].   
 DNA VACCINES 
Since the 1990s, a novel approach to vaccination against a broad array of target antigens 
and diseases has been in development. This involves the direct introduction of plasmid 
deoxyribonucleic acid (DNA) containing the gene encoding the immunogen against which 
an immune response is sought into appropriate host tissues and the in situ production of 
the target immunogen(s). This approach offers a combination of potential advantages, 
including the stimulation of both B- and T-cell responses, stability of the vaccine across a 
broad temperature range, absence of infectivity of the immunogen itself, the speed with 
which the vaccine can be constructed (for example in the face of an epidemic or pandemic 
as it is the case here with SARS-CoV-2), and the relative ease and generic nature of large-
scale manufacture. Many scientific publications have addressed the potential of DNA 
vaccination [34-43]. Immune responses in animal models have been obtained using genes 
from a variety of infectious agents including influenza viruses, hepatitis B virus, human 
immunodeficiency virus, human papillomaviruses, Marburg virus, MERS coronavirus, 
rabies virus, SARS coronavirus, West Nile virus (WNV), Zika virus, and other infectious 
agents as plasmodium, mycoplasma, and many more [42, 44]. In many cases, protection 
from disease in animal models has also been demonstrated.  
DNA vaccines are able to generate both CD4+ and CD8+ T cell responses. The ability to 
generate MHC-Class I restricted CD8+ T cells (cytolytic T lymphocytes), which generally 
are not made following administration of inactivated viruses, proteins or peptides, may be 
important for key responses against certain pathogens, as well as enabling cross-strain 
specific responses when many antibody responses are strain-specific. Because the 
encoded protein is synthesized in vivo by the host following administration, DNA vaccines 
can encode membrane-bound proteins instead of solely the soluble versions [45]. This 
can be important because key neutralizing epitopes are located in regions that would be 
excluded, or not formed in a monomeric truncated soluble version. Some early research 
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in COVID-19 control has already suggested that neutralizing antibodies may not be 
sufficient and that cell-mediated immunity may be necessary [46]. 
Unlike certain other vectors (such as heterologous viral vectors), DNA vaccines do not 
stimulate adaptive immune responses against themselves, although the DNA itself does 
stimulate certain innate immune responses [47]. In other words, they do not generate anti-
vector immunity that could stunt antigen-specific responses following multiple exposures. 
 USE OF ELECTROPORATION WITH DNA VACCINES 
Electroporation (EP) enhances gene expression of plasmid DNA delivered by the 
intramuscular (IM) or intradermal (ID) routes of administration (Figure 2). Following IM or 
ID delivery of a DNA vaccine or therapeutic product, EP facilitates entry of the DNA into 
the target site: muscle or dermal cells. Following cellular uptake, there is efficient 
production of the proteins encoded by the DNA expression plasmid system. The different 
EP devices, each with varying electrical parameters and protocols, have been reviewed 
[48]. EP has been extensively tested in animal species such as dogs, pigs, cattle, and 
NHPs to deliver therapeutic genes that encode for a variety of hormones, cytokines, 
enzymes or antigens  for the activation of both cellular and humoral responses [49, 50]. 
Importantly, immune responses generated by DNA vaccines delivered with EP are far 
superior to responses to the same vaccines delivered without EP [50]. IM and ID delivery 
of DNA vaccines with EP has been studied extensively, and optimum conditions for 
plasmid uptake and expression have been described for therapeutic indications, vaccines 
and tumor animal model systems [51, 52].  
 INOVIO’S PROPRIETARY TECHNOLOGY AGAINST COVID-19  
Inovio Pharmaceuticals has developed INO-4800 as a DNA vaccine that contains 10 
mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM sodium chloride and 15 
mM sodium citrate). pGX9501 is a DNA plasmid expressing a synthetic consensus 
(SynCon®) sequence of the SARS-CoV-2 Wuhan-Hu-1 full length Spike glycoprotein. The 
ID route of delivery has been selected for INO-4800 based on recent findings from multiple 
DNA vaccine development programs where ID delivery has driven equivalent if not 
superior humoral and cellular responses to IM delivery while improving tolerability 
(clinicaltrials.gov NCT02464670, clinicaltrials.gov NCT02431767) [53-55]. 
Following ID injection, the Inovio Pharmaceuticals’ EP device [48] referred to as the 
CELLECTRA® 2000 for ID administration (3P-ID) device is used to facilitate DNA entry 
into the cells.  
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Figure 2: The Potential Mechanism of Action Underlying Electroporation 
 
 NONHUMAN PRIMATE (NHP) CHALLENGE STUDIES FOLLOWING VACCINATION WITH 
INO-4800 
NHPs are a valuable model in the development of COVID-19 vaccines and therapeutics 
as they can be infected with wild-type SARS-CoV-2, and present with early infection that 
mimics aspects of human disease [56].  Rhesus macaques (n=5) received two 
immunizations of INO-4800 (1.0 mg), at Week 0 and Week 4.  Naïve control animals (n=5) 
did not receive vaccine.  Humoral and cellular immune responses were monitored for 15 
weeks (~4 months) following prime immunization for memory responses. All animals 
seroconverted following a single INO-4800 immunization, with serum IgG titers detected 
against the full-length S1+S2 extracellular domain (ECD), S1, S2, and receptor binding 
domain (RBD) regions of the SARS-CoV-2 S protein.  
INO-4800 immunized macaques and unvaccinated controls were challenged with SARS-
CoV-2 13 weeks (~3 months) post-final immunization. NHPs received a challenge dose of 
1.1x104 PFU of SARS-CoV-2 by intranasal and intratracheal inoculation. Peak viral RNA 
loads in the BAL were significantly lower in the INO-4800 vaccinated group, along with 
significantly lower viral RNA loads at day 7 post-challenge, indicating protection from lower 
respiratory disease. While RNA was detected in the nasal swabs of both the control and 
INO-4800 vaccinated animals, viral mRNA levels trended downwards in INO-4800 
vaccinated animals by more than 2 logs and were achieved sooner on average. Overall, 
the reduced viral loads following exposure to SARS-CoV-2 infection at 17 weeks after 
immunization show an important durable impact mediated by the vaccine [57].  
 FIRST-IN-HUMAN PHASE 1 TRIAL OF INO-4800 
In the open-label, Phase 1 clinical trial, we initially evaluated the safety and 
immunogenicity of INO-4800 in 40 healthy participants, 18-50 years of age.  There were 
two groups of 20 participants each who received either 1.0 mg or 2.0 mg of INO-4800 
intradermally followed by EP at 0 and 4 weeks. In the first 40 subjects, by Week 8, 11 
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adverse events were reported of which all were Grade 1 in severity of which 6 were related 
to study drug. The frequency of AEs did not increase with the second administration.  
From the immunogenicity analysis of the initial 40 subjects enrolled, two subjects were 
excluded from the analysis, one due to early discontinuation prior to the Week 4 dose for 
non-study reasons and the other due to suspected exposure to SARS-CoV-2 before the 
first dose of INO-4800 was administered based on a baseline positive SARS-CoV-2 
serology. Thirty-eight (38) evaluable subjects had cellular and/or humoral immune 
responses following the second dose of INO-4800. Assessment of data from both Week 
6 and Week 8 ELISpot revealed that 74% and 100% of the subjects generated T cell 
responses in the 1.0 mg and 2.0 mg groups, respectively. By Week 6, 95% (36 of 38) of 
the participants seroconverted by generating binding and/or neutralizing antibodies. 
Overall, INO-4800 elicited antigen-specific humoral and cellular immune responses 
against the SARS-CoV-2 Spike protein while demonstrating favorable safety and 
tolerability. 
The protocol was amended to include an additional 80 healthy participants to evaluate 
safety and immunogenicity of INO-4800 in older and elderly age populations. A lower dose 
level (0.5 mg) was also added for evaluation of dose-sparing potential. A total of 40 
participants were enrolled into three dose levels (0.5 mg, 1.0 mg and 2.0 mg), such that 
each Group included 20 participants 18-50 years of age, 10 participants 51-64 years of 
age, and 10 participants 65 years of age and older. Doses were delivered intradermally 
followed by EP at 0 and 4 weeks. As of March 10, 2021, 35 related adverse events were 
reported cumulatively, of which all but three (Grade 2 injection site pruritus, lethargy and 
abdominal pain) were Grade 1 in severity. 
Additional analyses showed that INO-4800 provides broad cross-reactive immune 
responses against variants of concern (VOC). Clinical samples, collected at varying 
timepoints post-immunization from subjects enrolled during Phase 1 INO-4800 clinical 
trial, were analyzed against the spike protein of different VOC (including UK variant 
B.1.1.7, South African variant B.1.351, and Brazilian variant P.1. strains) [58]. The results 
revealed neutralization activity against the P.1 variant (neutralizing antibodies levels 
comparable to those against wild-type) and reduced, but still measurable neutralization 
activity against the B.1.1.7 and B.1.351 variants. Additionally, it has been demonstrated 
that INO-4800 induces cross-reactive T cell responses against B.1.1.7, B.1.351, and P.1 
variants that are comparable to the wild-type strain. Taken together, these data 
demonstrate that INO-4800 maintains cellular and/or humoral immune responses against 
the major SARS-CoV-2 variants that are currently in circulation, which will likely be critical 
factors necessary to impact the ongoing COVID-19 pandemic. 
Please refer to the Investigator’s Brochure, which will include future updates through the 
duration of the study. 
 PROPOSED PHASE 2/3 TRIAL OF INO-4800 
This Phase 2/3 trial is designed to begin with a Phase 2 segment to evaluate both the 1.0 
mg and 2.0 mg doses in approximately 400 subjects, including in the older (51 to 64 years 
of age) and elderly subjects (65 years of age and older), to enable selection of a dose or 
age-related doses for an efficacy evaluation in a subsequent Phase 3 segment involving 
>7000 subjects.  
The current safety and immunogenicity data from the Phase 2 segment strongly support 
the selection and advancement of the 2.0 mg dose of INO-4800 into the Phase 3 segment 
(see Section 1.3.7 for immunogenicity details). INO-4800’s competitive safety/tolerability 
profile, nonclinical data supporting its potential to confer durable protection against severe 
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disease, ability to serve as a safe and tolerable homologous booster, and thermostability 
profile collectively support its potential as an additional tool for COVID-19 prevention with 
distinct advantages to facilitate global distribution and uptake. 
1.3.6.1 
Safety and tolerability of INO-4800  
Safety and tolerability data collected on INO-4800 to date mirror the favorable safety 
profile of Inovio’s plasmid DNA vaccines against multiple targets and indications.  
Nonclinical studies have revealed no safety concerns. Clinical studies (Phase 1 and Phase 
2) have also not revealed any safety concerns as per reviews by independent Data Safety 
Monitoring Boards.   
1.3.6.2 
Nonclinical INO-4800 Data in Support of Potential Efficacy 
The efficacy of INO-4800 in protecting against SARS-CoV-2 disease has been 
demonstrated in multiple nonclinical models. In the AAV6 human ACE2-transduced 
mouse model challenged with SARS-CoV-2, complete protection against lung virus load 
was observed [59]. Applying clinically relevant dosing and CELLECTRA-ID delivery 
parameters, INO-4800 has been tested in multiple nonhuman primate models, the gold 
standard large animal model for COVID-19 vaccine testing. We demonstrated protection 
against lung disease and viral load in the lower and upper respiratory tract in the rhesus 
macaque model after one or two doses of INO-4800 [60][61]. Furthermore, the durability 
of the impact of INO-4800 in reducing lung viral load was demonstrated in a rhesus 
macaque challenged with SARS-CoV-2 several months after immunization [57]. In 
conclusion, multiple nonclinical models have demonstrated the efficacy of INO-4800.  
1.3.6.3 
Potential Role of INO-4800 as a Booster 
INO-4800 offers a potential role in serving as a booster to maintain protection against 
COVID-19 over time in the context of a potential endemic disease scenario. Unlike viral 
vectors, DNA elicits no anti-vector response and, therefore, can be repeatedly 
administered without a reduction in the generated immune responses. When subjects in 
the INO-4800 Phase 1 were provided a booster dose 6 to 10.5 months following the 2-
dose regimen, there was no appreciable change in reactogenicity when compared to the 
first two doses, indicating that repeat dosing with INO-4800, as with other vaccines in 
Inovio’s DNA platform, does not lead to an increase in reactogenicity. Inovio’s DNA 
platform experience with Oncology DNA-vaccine targets have established that more than 
10 sequential administrations of vaccine is capable of consistent re-boosting from an 
immunological perspective with no associated changes in safety and reactogenicity. 
1.3.6.4 
Thermostability of INO-4800  
INO-4800 offers thermostability that could facilitate vaccine distribution globally. The 
current shelf life applied to INO-4800 clinical supplies is 24 months when stored at its 
recommended refrigerated storage condition of 5 ± 3°C. A 24-month real-time study for 
INO-4800 under refrigerated conditions (5°C) is ongoing; current Month 9 results are all 
within specification. Percent supercoiled forms, which is the strongest indication of DNA 
plasmid stability, decreased by only 2% (T0 97%, M9 95%) over the duration of the study 
to date, while percent total circular forms remained at 99%.  
Inovio has a platform stability program with 12 different DNA plasmid products, all 
constructed with the same plasmid backbone and formulated in the same SSC buffer, at 
various DNA concentrations, and the stability data to date are all consistent with the 
excellent stability profile seen with INO-4800. 
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 DOSE AND REGIMEN RATIONALE 
The intent is to evaluate INO-4800 as a prophylactic vaccine against COVID-19 disease. 
Based on Inovio’s extensive experience developing vaccine candidates against infectious 
diseases via the ID route ([54], [33]), a 2-dose regimen was considered to be optimal, 
based on the balanced humoral and cellular responses obtained 2 weeks post-dose 2, 
which supports evaluation of a 2-dose regimen (Days 0 and 28). 
In the Phase 2 segment of this trial, 1.0 mg and 2.0 mg of vaccine were administered by 
ID injection and followed immediately by EP at Day 0 and Day 28. The selection of the 
doses to test in Phase 2 is supported by the safety profile in the Phase 1 trial of INO-4800 
(COVID19-001, NCT04336410) in addition to our prior experience in developing a MERS 
coronavirus (MERS-CoV) vaccine (INO-4700) [16, 17]. The safety data for INO-4800 is 
provided in the Investigator’s Brochure (IB). 
The objective of the Phase 2 segment of the Phase 2/3 trial was to further evaluate the 
1.0 mg and 2.0 mg doses of INO-4800 for each age group in order to select the optimal 
vaccination regimen in the Phase 3 efficacy segment. The final decision between the two 
doses by age group relies on safety and immunogenicity. The 1.0 mg and 2.0 mg doses 
in the Phase 1 study had a similar safety profile. The review of the Phase 2 data by the 
independent DSMB has not revealed any safety signals of concern to date. Furthermore, 
there have not been substantial differences in the safety profile between the 1.0 mg and 
2.0 mg dosing groups to impact Phase 3 dose selection. However, the interim immunology 
data from the Phase 2 study revealed favorable immunogenicity with the 2.0 mg dose over 
the 1.0 mg dose. Data were analyzed for two age groups:  ≥18 to ≤50 years of age and 
≥51 years of age. The results illustrate that the 2.0 mg dose induced higher levels of 
SARS-CoV-2 spike specific antibodies as well as higher levels of IFN-gamma producing 
cells.    
   
1.3.7.1 
Binding Antibody Response 
The binding antibody response was measured for all Phase 2 subjects at Day 0 and Week 
6.  Across all ages, the geometric mean titer (GMT) for the 1.0 mg dose group was 123.3 
at Day 0 compared to 938.8 at Week 6. The geometric mean fold rise was 7.8. The GMT 
for the 2.0 mg dose group was 93.5 at baseline compared to 2210.0 at Week 6. The 
geometric mean fold rise was 23.5. 
Subjects 18-50 years old in the 1.0 mg dose group had a GMT that was 148.5 at Day 0 
compared to 1182.1 at Week 6.  The geometric mean fold rise in binding antibody titers 
was 7.9. The GMT for the 2.0 mg dose group was 99.5 at baseline compared to 2671.2 at 
Week 6. The geometric mean fold rise was 26.5. 
Subjects ≥51 years old in the 1.0 mg dose group had a GMT that was 87.5 at Day 0 
compared to 623.3 at Week 6. The geometric mean fold rise in titers was 7.6. The GMT 
for the 2.0 mg dose group was 84.0 at baseline compared to 1613.7 at Week 6. The 
geometric mean fold rise in binding antibodies was 19.2.  
1.3.7.2 
Neutralizing Antibody Response 
The neutralizing antibody response was measured for all Phase 2 subjects at Days 0 and 
Week 6.  Across all ages the geometric mean titer (GMT) for the 1.0 mg dose group was 
32.2 at Day 0 compared to 93.6 at Week 6.  The geometric mean fold rise in neutralizing 
titers was 2.9. The GMT for the 2.0 mg dose group was 35.8 at baseline compared to 
150.6 at Week 6.  The geometric mean fold rise was 4.3. 
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Subjects 18-50 years old in the 1.0 mg dose group had a GMT that was 34.5 at Day 0 
compared to 112.6 at Week 6.  The geometric mean fold rise in neutralizing titers was 3.3. 
The GMT for the 2.0 mg dose group was 32.2 at baseline compared to 159.9 at week 6. 
The geometric mean fold rise was 5.0. 
Subjects ≥51 years old in the 1.0 mg dose group had a GMT that was 28.4 at Day 0 
compared to 67.4 at Week 6. The geometric mean fold rise in neutralizing titers was 2.3. 
The GMT for the 2.0 mg dose group was 43.3 at baseline compared to 135.7 at Week 6. 
The geometric mean fold rise was 3.2. 
1.3.7.3 
ELISPOT analysis 
ELISPOT analysis was performed for all Phase 2 subjects at Day 0 and Week 6. Across 
all ages, the median for the 1.0 mg dose group was 0 at Day 0 compared to 6.7 at Week 
6. The median for the 2.0 mg dose group was 2.2 at baseline compared to 18.9 at Week 
6. Subjects 18-50 years old in the 1.0 mg dose group had a median of that was 1.1 at Day 
0 compared to 7.6 at Week 6. The median for the 2.0 mg dose group was 0.6 at baseline 
compared to 18.9 at Week 6.  Subjects ≥51 years old in the 1.0 mg dose group had a median that 
was 0 at Day 0 compared to 10 at Week 6. The median for the 2.0 mg dose group was 3.3 at 
baseline compared to 18.4 at Week 6.   
 
RISKS AND POTENTIAL BENEFITS  
As of Dec 31, 2020, no treatment related serious adverse events have been reported for 
INO-4800. There may be side effects and discomforts that are not yet known.  
Please refer to the Investigator’s Brochure and User Manual, which will include future 
updates of the risk profile delineated in this section through the duration of the study. 
 POTENTIAL BENEFITS 
As part of the trial, subjects will have access to COVID-19 diagnostic and antibody testing 
to which they might not otherwise have access. Additionally, subjects will have the benefit 
of contributing to research to help others in a time of a global pandemic.  Benefits related 
to receipt of INO-4800 and protection from COVID-19 disease are unknown because the 
efficacy of INO-4800 remains unknown.      
 PRODUCT RISKS 
1.4.2.1. 
Expected Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Device 
In accordance with the International Council for Harmonisation (ICH), Inovio-sponsored 
studies have been designed to minimize risk to study participants. Expected risks of INO-
4800 delivered ID followed by EP with the CELLECTRA® 2000 device are listed below in 
TableTableTable5. 
Table 5: Expected Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Devicea  
Frequency among subjectsb 
Event 
Very Common 
(≥10%) 
• 
Injection site pruritus 
• 
Injection site erythema or redness 
• 
Injection site painc or tenderness  
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Common 
(≥1% to <10%) 
• 
Injection site bruising 
• 
Injection site swelling or induration 
Uncommon or Rare (<1%) 
• 
Administration site lesions or bleeding  
• 
Temporary severe injection site pain or 
tenderness 
a Investigator’s Brochure v4.0, dated 16-Nov-2020 
b EU commission guideline on the SmPC September 2009 [62] 
c Brief muscle contractions may occur and could be uncomfortable 
1.4.2.2  
Theoretical Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Device 
The following adverse events have been observed at least once, as of Dec. 31, 2020, 
across all clinical trials with Inovio DNA products delivered intradermally followed by EP 
using the CELLECTRA® 2000 device: 
• 
Allergic reaction 
• 
Anxiety 
• 
Creatine phosphokinase (CPK) elevations that are transient 
• 
Injection site infection, paresthesia, hypoesthesia, hematoma, or scab 
• 
Vasovagal reaction, lightheadedness or dizziness. 
The following events have not been observed, as of Dec. 31, 2020, in any subject or any 
clinical trials with Inovio DNA products delivered intradermally followed by EP using the 
CELLECTRA® 2000 device. While considered theoretical and unlikely to occur, any 
occurrence of these events should be reported to the Sponsor during this trial: 
• 
Antibody-dependent enhancement of disease (i.e., potential for greater respiratory 
disease upon exposure to SARS-CoV-2 due to priming of immune cells from prior 
vaccination. Although observed in nonclinical models for vaccines against other 
viruses such as SARS, the occurrence or observation of antibody-dependent 
enhancement of the disease with COVID-19 vaccines in humans remains 
unknown) 
• 
Cardiac arrhythmias (product-related); Please note that “ICD or pacemaker (to 
prevent a life-threatening arrhythmia) that is located ipsilateral to the deltoid 
injection site (unless deemed acceptable by a cardiologist)” is an exclusion 
criterion (‘j’) in this protocol; 
• 
Death (product-related); 
• 
Disruption of function of implanted electronic medical device(s); Please note that 
“ICD or pacemaker (to prevent a life-threatening arrhythmia) that is located 
ipsilateral to the deltoid injection site (unless deemed acceptable by a cardiologist)” 
is an exclusion criterion (‘j’) in this protocol; 
• 
Effects on fetus and/or pregnancy; Please note inclusion criterion in this protocol 
which requires use of medically effective contraception in women of childbearing 
potential; 
• 
Electrical injury (e.g., electrocution); Please note warning within the device User 
Manual (Section 7). Since the device is not connected to any power supply during 
the EP procedure of a subject, this theoretical event is unlikely but has the potential 
to occur to the user of the device (e.g., study site staff). This will be mitigated 
through device training and user qualification prior to use; 
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• 
Fire hazard to the facility; This theoretical event is unlikely but has the potential to 
occur to the clinical trial site. The possibility of this event has been mitigated 
through device design; 
• 
Hearing damage (product-related); The possibility of this event has been mitigated 
through the device design. The audio is limited in volume and is of very short 
duration. 
• 
Inaccurate energy delivery, the result of which is covered in other events listed 
here (e.g., tissue damage); 
• 
Injection site laceration; This has not been observed but would be theoretically 
possible with any needle; 
• 
Major injury to deeper tissue and/or bone; This event is not foreseeable given the 
array needle length is limited to 3.2 mm;  
• 
Muscle damage; This event is not foreseeable given the array needle length is 
limited to 3.2 mm; 
• 
Paresis or paralysis with possible loss of nerve function; There are minor nerves 
innervating the skin and subcutaneous tissues that may be disrupted, but are 
extremely unlikely to result in serious injury; 
• 
Radiation hazard to eyes and skin; This theoretical event is unlikely but has the 
potential to occur to the user of the device (e.g., study site staff). The possibility of 
this event has been mitigated through the device design; 
• 
Tissue injury/burn;  
• 
User/subject unaware that treatment was incomplete; 
• 
Worsening of unstable cardiac disease; Please note that “Cardiovascular diseases 
(e.g., myocardial infarction, congestive heart failure, cardiomyopathy or clinically 
significant arrhythmias) requiring changes in therapy or hospitalization for 
worsening disease during the 6 weeks prior to enrollment” is an exclusion criterion 
(‘h’) in this protocol. 
There have been no AEs associated with EP errors or failures. 
 OVERALL BENEFIT/RISK CONCLUSION 
While EUA vaccines are currently becoming available in many countries, the global 
availability to the general population remains limited. In the context of the ongoing COVID-
19 pandemic resulting in substantial morbidity and mortality, the overall cumulative safety 
profile of Inovio’s DNA platform across all of its products, and INO-4800’s Phase 1 adverse 
events being generally limited to local injection site reactions, the benefit risk profile 
justifies the conduct of the Phase 2/3 trial. 
 
OBJECTIVES AND PURPOSE 
The overall purpose of this clinical trial is to evaluate the safety, immunogenicity and 
efficacy of INO-4800. 
 
HYPOTHESIS 
INO-4800 delivered ID followed immediately by EP will be well-tolerated, exhibit an 
acceptable safety profile, result in generation of cellular and humoral immune responses 
to SARS-CoV-2 Spike glycoprotein and provide protection against virologically-confirmed 
COVID-19 disease in subjects at high risk of SARS-CoV-2 exposure.  
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Protocol Version: 1.0USA 
 
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CLINICAL TRIAL DESIGN AND ENDPOINTS 
This is an operationally seamless Phase 2/3, randomized, placebo-controlled, multi-
center trial to evaluate the safety, immunogenicity, and efficacy of INO-4800, 
administered by ID injection followed immediately by EP using the CELLECTRA® 2000 
device, in a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-
2 exposure. Subjects 18 years of age and older are expected to be enrolled across two 
(2) segments of this study. In the Phase 2 segment, approximately 400 seronegative 
subjects will be enrolled. In the Phase 3 segment, approximately 6714 seronegative 
subjects are expected to be enrolled, and 402 seropositive subjects will be enrolled. The 
subjects and data from Phase 2 are independent from that of Phase 3.  The primary 
objectives of this trial are to identify in seronegative subjects an optimal age-related dose 
(Phase 2 segment) for subsequent evaluation for efficacy (Phase 3 segment).  
 
Phase 2 Segment – Dose Selection 
 
In the Phase 2 segment, approximately 400 subjects 18 years of age and older will be 
evaluated across four (4) dose groups (Table 1, Figure 1). Subjects will be randomized 
at a 3:3:1:1 ratio to receive either 1.0 mg or 2.0 mg of active investigational product (INO-
4800) or 1 or 2 injections of placebo (placebo for INO-4800). Dose groups receiving INO-
4800 will enroll approximately 150 subjects per group. Dose groups receiving placebo will 
enroll approximately 50 subjects per group. Randomization will be such that 
approximately 240 subjects aged 18-50 years, 120 subjects aged 51-64 years and 40 
subjects aged ≥ 65 years will be enrolled. Initial enrollment will include subjects aged 18-
50 years. Initiation of enrollment of older subjects 51-64 years of age and elderly subjects 
65 years and older will depend on review of safety and immunogenicity data from those 
age groups generated in the Phase 1 study (COVID19-001). 
 
Dose selection for evaluation of efficacy in the Phase 3 segment will be based on Week 
6 immunogenicity data and Week 8 safety data from the Phase 2 segment. Group-level 
unblinded summaries and analyses of safety will be produced once the Week 8 phone 
call visit data are completed for all subjects in the Phase 2 segment. Group-level 
unblinded summaries and analyses of immunogenicity will be produced once the Week 
6 visit data are completed for all subjects in the Phase 2 segment. 
 
Phase 3 Segment – Efficacy 
In the Phase 3 segment, approximately 6714 seronegative and 402 seropositive subjects 
18 years of age and older will be randomized at a 2:1 ratio to receive either active 
investigational product (INO-4800, 2.0mg) or placebo (placebo for INO-4800).  
Approximately half of seronegative subjects and approximately half of seropositive 
subjects will be 18-50 years of age, and the other half will be ≥ 51 years of age as is 
operationally feasible. Also, approximately 711 subjects will be ≥65 years of age, if 
operationally feasible. 
Subjects will be randomized in a stratified manner according to (a) age category (18-50 
years vs. ≥51 years) on Day 0, and (b) presence of or absence on Day 0 of any of the 
following underlying medical conditions that increase risk of severe COVID-19 disease, 
per CDC criteria [1], as listed below: 
• 
Cancer 
• 
Chronic kidney disease 
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Clinical Protocol 
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• 
Chronic lung diseases, including Chronic obstructive pulmonary disease (COPD), 
asthma (moderate-to-severe), interstitial lung disease, cystic fibrosis, pulmonary 
hypertension 
• 
Neurologic conditions including stroke or cerebrovascular disease, that do not impact 
cognition 
• 
Diabetes (type 1 or type 2) 
• 
Hypertension 
• 
Heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies 
• 
HIV infection (CD4 count >200 cells/mm3 or undetectable viral load) 
• 
Liver disease 
• 
Obesity (BMI ≥ 30 kg/m2) 
• 
Sickle cell disease or thalassemia, or 
• 
Smoking (current or former smoker). 
This segment of the trial is case-driven. Among seronegative subjects, a total of 149 
observed cases will be required for 90% power to declare the vaccine efficacious (>30%), 
assuming a true efficacy of 60%. A sample size of 6714 seronegative subjects is expected 
to be required to achieve the 149 cases assuming an underlying attack rate of 3.7%. The 
actual sample size may differ if the observed attack rate is different than projected.  There 
are two formal interim analyses of efficacy; one when 50% of the cases accrue and one 
when 75% of the cases accrue. If the prespecified criteria for efficacy are met at either 
interim analysis, then enrollment will continue until 4500 subjects have been enrolled, 
and blinded follow-up will continue until at least those 4500 subjects have a minimum of 
6 months of safety follow-up. At that point, the trial would be unblinded and placebo-
recipients will be offered the active product.    
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12 
months post-dose 2. All Phase 3 segment subjects will be followed for 56 weeks from the 
Day 0 dosing [i.e., Week 56 will be the planned End of Study (EOS) visit for this segment 
of the trial]. 
 
External Committee Reviews 
 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will 
convene regularly to review all available unblinded safety data, and additionally upon 
completion of the Week 8 phone call visit for all subjects enrolled during the Phase 2 
segment. For the Phase 3 segment, the DSMB will also review efficacy in an unblinded 
fashion. Additionally, for Phase 3, an independent, blinded Endpoint Adjudication 
Committee (EAC) will review and confirm COVID-19 cases. 
 
Details of each committee’s scope will be provided in the respective charters. 
 
PRIMARY OBJECTIVES 
See Table 6. 
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Page 39 of 93 
 
 
PRIMARY ENDPOINTS 
Table 6: Primary Objectives and Associated Endpoints 
Phase 2 Primary Objective 
Phase 2 Primary Endpoints 
1.  Evaluate the cellular and humoral 
immune response to INO-4800 
administered by ID injection followed 
immediately by EP  
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot assay 
1b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay 
Phase 3 Primary Objective 
Phase 3 Associated Primary Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease 
in subjects who are SARS-CoV-2 
negative at baseline  
1.   Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 
(End of Study (EOS)) in subjects who are SARS-
CoV-2 seronegative at baseline  
 
SECONDARY OBJECTIVES 
See Table 7. 
 
SECONDARY ENDPOINTS 
Table 7: Secondary Objectives and Associated Endpoints 
Phase 2 Secondary Objectives 
Phase 2 Secondary Endpoints 
1.  Evaluate the safety and tolerability of 
INO-4800 administered by ID 
injection followed immediately by EP  
 
1a. Incidence of solicited and unsolicited injection 
site reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
 1d. Incidence of adverse events of special interest 
(AESIs)   
Phase 3 Secondary Objectives 
Phase 3 Secondary Endpoints 
1. Evaluate the safety and tolerability 
of INO-4800    
 
1a. Incidence of solicited and unsolicited injection 
site reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality  
2. Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of disease 
severity in subjects who are SARS-
CoV-2 seronegative at baseline    
2a.  Incidence of non-severe COVID-19 disease in 
SARS-CoV-2 seronegative subjects starting 14 
days after completion of the 2-dose regimen until 
EOS  
2b. Incidence of severe COVID-19 disease in SARS-
CoV-2 seronegative subjects starting 14 days 
after completion of the 2-dose regimen until EOS 
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2c. Incidence of deaths due to COVID-19 in SARS-
CoV-2 seronegative subjects starting 14 days 
after completion of the 2-dose regimen until EOS 
3.   Evaluate the cellular and humoral 
immune response to INO-4800  
3a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot  
3b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
4. Evaluate the efficacy of INO-4800 
in the prevention of COVID-19 
disease in subjects who are SARS-
CoV-2 seropositive at baseline  
 
4.  Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 
(End of Study (EOS)) in subjects who are SARS-
CoV-2 seropositive at baseline 
 
EXPLORATORY OBJECTIVE 
See Table 8. 
 
EXPLORATORY ENDPOINTS 
Table 8: Exploratory Objectives and Associated Endpoints 
Phase 2 Exploratory Objective 
Phase 2 Exploratory Endpoints 
1.  Evaluate the expanded 
immunological profile of antibody 
response and T cell immune 
response 
1a.  Antigen-specific cellular immune response 
measured by flow cytometry. 
1b. Expanded immunological profile which may 
include additional assessments of T and B cell 
numbers and molecular changes by measuring 
immunologic proteins and mRNA levels of genes 
of interest as determined by sample availability 
Phase 3 Exploratory Objective 
Phase 3 Exploratory Endpoints 
1. Evaluate the efficacy of INO-4800 
in the prevention of COVID-19 
disease from SARS-CoV-2 variants 
in subjects who are SARS-CoV-2 
seronegative at baseline 
1. Incidence of virologically-confirmed COVID-19 
disease from a SARS-CoV-2 variant starting 14 
days after completion of the 2-dose regimen until 
12 months post-dose 2 (End of Study (EOS)) in 
subjects who are SARS-CoV-2 seronegative at 
baseline 
2. Evaluate the efficacy of INO-4800 
in the prevention of SARS-CoV-2 
asymptomatic infection in subjects 
who are SARS-CoV-2 seronegative 
at baseline     
2. Incidence of SARS-CoV-2 asymptomatic 
infections in SARS-CoV-2 seronegative subjects 
starting 14 days after completion of the 2-dose 
regimen until EOS 
3. Evaluate the immunological profile 
by assessing both antibody 
response and T cell immune 
response  
3a.  SARS-CoV-2 Spike glycoprotein antigen-
specific binding antibody levels  
3b.  Antigen-specific cellular immune response 
measured by flow cytometry  
4. Evaluate antibody persistence  
4a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels at Week 30 or later.  
4b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay at Week 
30 or later 
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EFFICACY ASSESSMENT (PHASE 3 SEGMENT ONLY) 
Subjects will receive either active investigational product (INO-4800, dose selected from 
the Phase 2 segment) or placebo (placebo for INO-4800) in a 2-dose regimen 
administered intradermally followed immediately by EP on Days 0 and 28. Subjects will 
be monitored through regularly scheduled clinic visits and phone calls throughout the trial. 
Subjects will be regularly tested for SARS-CoV-2 infection using serologic testing. If 
COVID-19 disease is suspected based on symptoms or laboratory testing, site personnel 
will arrange for a clinic visit. Subjects with symptom(s) or a positive SARS-CoV-2 test 
result will be reviewed by the independent blinded EAC.  
The mechanism for review and confirmation of cases will be outlined in an EAC Charter.  
 CASE DEFINITION FOR VIROLOGICALLY-CONFIRMED COVID-19 DISEASE: 
•  Positive testing by SARS-CoV-2 RT-PCR assay (performed at central lab*) 
with fever (temperature of 100.4ºF/38.0ºC or higher), or  
• 
Positive testing by SARS-CoV-2 RT-PCR assay (performed at central lab*) 
with any of the following COVID-19 related symptoms: 
• 
Feeling feverish or chills  
• 
Cough  
• 
Shortness of breath or difficulty breathing  
• 
Fatigue  
• 
Muscle or body aches  
• 
Headache  
• 
New loss of taste or smell  
• 
Sore throat  
• 
Congestion or runny nose  
• 
Nausea or vomiting  
• 
Diarrhea  
*Local lab results will be accepted if the subject is hospitalized and a sample is 
not able to be obtained for analysis at central lab. 
3.7.1.1 Case Definition for Severe COVID-19 
• Confirmed COVID-19 disease (per Section 3.7.1) with any of the following:  
a. Clinical signs at rest indicative of severe systemic illness (respiratory 
rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room 
air at sea level or PaO2/FiO2 < 300 mm Hg),  
b. Respiratory failure (defined as needing high-flow oxygen, noninvasive 
ventilation, mechanical ventilation or ECMO),  
c. Evidence of shock (SBP < 90 mm Hg, DBP < 60 mm Hg, or requiring 
vasopressors),  
d. Significant acute renal, hepatic, or neurologic dysfunction,  
e. Admission to an ICU, or  
f. Death.  
3.7.1.2 Case Definition for Non-Severe COVID-19  
• Confirmed COVID-19 disease (per Section 3.7.1);   
• Does not meet the case definition of Severe COVID-19 disease (Section 
3.7.1.1) 
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Protocol Version: 1.0USA 
 
Page 42 of 93 
 
 CASE DEFINITION FOR SARS-COV-2 ASYMPTOMATIC INFECTION  
Positive testing by SARS-CoV-2 serologic assay (performed at central lab);  
• Without clinical signs or symptoms of COVID-19 disease since the previous 
negative serologic test.  
 
SAFETY ASSESSMENT 
Subjects will be followed for safety during the trial through scheduled clinic visits and 
phone calls. AEs, regardless of relationship to study drug, will be collected from the time 
of consent until 28 days post-dose 2 (i.e., Day 56). SAEs, MAAEs and AESIs will be 
collected from time of consent until EOS. SAEs, AESIs, and treatment-related AEs will be 
followed to resolution or stabilization. For the Phase 2 segment and at selected sites in 
the Phase 3 segment, solicited local and systemic AEs will be collected for 7 days following 
each dose using a participant diary. 
Subjects will also be monitored for COVID-19 disease. 
Please refer to the Schedule of Events (Table 3 and Table 4) for safety assessments to 
be performed.   
 
IMMUNOGENICITY ASSESSMENT 
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 3 and Table 4). Assays such as binding ELISA, pseudovirus-based neutralization 
assay, and ELISpot will be evaluated at serial timepoints. 
 
CLINICAL TRIAL POPULATION 
 
INCLUSION CRITERIA 
 PHASE 2 SEGMENT 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, vital signs and 
physical examination performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar workers, 
store cashiers, hairdressers and barbers, veterinary staff, daycare workers, 
Transportation Security Administration screening staff, school teachers and 
college professors teaching in-person classes) 
2. Factory workers (when working in confined settings with large numbers of 
employees) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) 
4. User of public transportation (e.g., bus, train, subway) at least 3 times weekly 
5. Nursing home staff or correctional facility staff  
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
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7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol. Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field) 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists.) Physicians should not be enrolled unless they are 
assigned to dedicated COVID-19 treatment wards or other settings with prolonged 
exposure) 
10. Others, if approved by the medical monitor;   
f. Screening laboratory results within normal limits for testing laboratory or are deemed 
not clinically significant by the Investigator; 
g. Must meet one of the following criteria with respect to reproductive capacity: 
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or tubal 
ligation, absence of ovaries and/or uterus in females). In the case of vasectomy, 
subjects should wait six (6) months post-vasectomy prior to enrolling;  
• 
Use of medically effective contraception with a failure rate of < 1% per year when 
used consistently and correctly from screening until 3 months following last dose. 
Acceptable methods include:  
o hormonal contraception including implants, injections or oral; 
o two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
o intrauterine device or intrauterine system; 
o abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 PHASE 3 SEGMENT 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Per investigator judgment, healthy or stable with pre-existing medical conditions that 
do not require significant change in medication or have led to a hospitalization in the 
3 months prior to enrollment or who, in the judgment of the investigator, are unlikely 
to require a significant change in therapy or hospitalization for worsening disease 
through Day 56;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings. 
Examples include:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar workers, 
street vendors, store cashiers, hairdressers and barbers, veterinary staff, daycare 
workers, airport screening staff, school teachers and college professors teaching 
in-person classes, college students attending in-person classes, office workers 
and volunteers who have multiple brief exposures to people regularly) 
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2. Factory workers (when working in confined settings with large numbers of 
employees, meat-packing facilities) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) and delivery 
services  
4. User of public transportation (e.g., bus, train, subway) or public facilities (e.g. 
gyms) at least 3 times weekly 
5. Nursing home staff or correctional facility staff 
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, medical assistants and technicians, respiratory therapists, 
physical therapists, social workers, dentists and dental hygienists)  
10. Others, if in the opinion of the PI, the risk of COVID-19 exposure is comparable 
to the examples above. 
f. Must meet one of the following criteria with respect to reproductive capacity: 
1. Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
2. Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or tubal 
ligation, absence of ovaries and/or uterus in females). In the case of vasectomy, 
subjects should wait six (6) months post-vasectomy prior to enrolling;  
3. Use of medically effective contraception with a failure rate of < 1% per year when 
used consistently and correctly from screening until last dose. Acceptable 
methods include:  
i. hormonal contraception including implants, injections or oral; 
ii. two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
iii. intrauterine device or intrauterine system; 
iv. abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 
EXCLUSION CRITERIA 
 PHASE 2 SEGMENT 
a. Acute febrile illness with temperature > 100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat);  
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the Screening visit until 
3 months following the last dose; 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or 
a detectable viral load within the past 3 months; 
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f. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0 (documented receipt of placebo in a previous trial 
would be permissible for trial eligibility); 
g. Previous receipt of an investigational vaccine for prevention or treatment of COVID-
19, MERS or SARS (documented receipt of placebo in previous trial would be 
permissible for trial eligibility). 
h. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg prior to first dose; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin cancers 
that only required local excision and non-metastatic prostate cancer not requiring 
treatment; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in therapy 
or hospitalization for worsening disease during the 6 weeks prior to enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a single 
antiepileptic agent; 
i. 
Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed) in the prior 6 months; 
• 
Current or anticipated use of disease modifying doses of systemic anti-rheumatic 
drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and 
biologic disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, 
adalimumab or etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the subject 
or require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
j. 
Lack of acceptable sites for ID injection and EP considering the skin above the 
deltoid and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
ICD or pacemaker (to prevent a life-threatening arrhythmia) that is located 
ipsilateral to the deltoid injection site (unless deemed acceptable by a 
cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation site; 
k. Blood donation or transfusion within 1 month prior to Day 0; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the prior 2 years; 
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n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
 PHASE 3 SEGMENT 
a. Acute febrile illness with temperature ≥100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat) on 
Day 0 prior to dosing; 
b. Positive serologic test for SARS-CoV-2 at Screening (after approximately 402 
subjects positive for SARS-CoV-2 serologic test are randomized, this criterion will 
apply to all remaining subjects); 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children starting from the Screening visit until the last dose; 
d. Positive urine pregnancy test during screening or  immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or 
a detectable viral load within 3 months prior to screening; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days prior to Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous or planned receipt of an investigational (including Emergency Use 
Authorization (EUA) or local equivalent authorization) or licensed vaccine for 
prevention or treatment of COVID-19, MERS or SARS (documented receipt of 
placebo in previous trial would be permissible for trial eligibility); 
h. Immunosuppression as a result of underlying illness or treatment including: 
 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed) in the past 6 months; 
• 
Current or anticipated use of disease modifying doses of systemic anti-rheumatic 
drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and 
biologic disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, 
adalimumab or etanercept) or others; 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the subject 
or require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
i. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation site; 
j. 
Blood donation or transfusion within 1 month prior to Day 0; 
k. People who work remotely or in a socially distanced setting with minimal risk of 
exposure to SARS-CoV-2; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
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Clinical Protocol 
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m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the prior 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
 
DISCONTINUATION/WITHDRAWAL OF CLINICAL TRIAL SUBJECTS 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the Investigator should any untoward effect occur. In addition, the 
Investigator or the Sponsor has the right to discontinue a subject from the trial at any time. 
The Investigator must notify the Sponsor immediately when a subject has been 
discontinued/withdrawn due to an Adverse Event (AE). If a subject withdraws from the trial 
or is discontinued from the trial prior to trial completion, all applicable activities scheduled 
for the final trial visit (i.e., Day 393) should be performed at the time of 
discontinuation/withdrawal if the subject agrees. Any related AEs, AESIs, and/or Serious 
Adverse Events (SAEs) present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.9. 
Unless a subject refuses to continue participation, all follow-up visits and procedures 
should be completed as indicated in the Schedule of Events (Table 3 and Table 4) 
following the second dose whether or not the subject has completed both doses. 
If a subject decides to be vaccinated  with a non-study prophylactic COVID-19 vaccine, 
either authorized under emergency use or licensed,during the trial, subjects should 
provide details of the non-study COVID-19 vaccine received to study staff  and subjects 
should be requested to remain in the trial until the last visit. Additionally, subjects should 
also be advised that we do not have adequate information about the safety and 
effectiveness of another prophylactic COVID-19 vaccine when received following the 
receipt of INO-4800. As is already the case, if a subject is enrolled and receives a non-
study prophylactic COVID-19 vaccine, either authorized under emergency use or licensed, 
while on study, the Investigator should enter the details as a concomitant medication. The 
subject should be followed (according to the Schedule of Events outlined in Table 3 of the 
Protocol). 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. In cases where 
the subject does not return for the rescheduled visit or cannot be reached to reschedule 
the missed visit, the site should make every effort to regain contact with the subject (3 
telephone calls and if that fails, then a certified letter to the subject’s last known mailing 
address) so that the subject’s disposition can be considered as withdrawn from the study 
(i.e. lost to follow-up). If the contact with subject is re-established, site should contact 
medical monitor to discuss whether subject can continue study treatment or follow-up 
visits for the study. For all other subjects withdrawing from the study, an alternative reason 
for discontinuation should be recorded in the eCRF. 
Reasons for discontinuation/withdrawal from the trial may include but are not limited to the 
following: 
• 
Subject withdrawal of consent at any time; 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardize the 
subject’s safety if he or she continues in the trial; 
• 
Investigator, DSMB or Sponsor determines it is in the best interest of the subject; 
• 
Subject non-compliance. 
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Every effort should be made to obtain information on subjects who withdraw from the trial. 
The primary reason for withdrawal from the trial should be documented on the appropriate 
CRF. However, subjects will not be followed for any reason after consent has been 
withdrawn. Data and/or samples collected prior to withdrawal of consent will be analyzed.  
Reasons for discontinuing subject dosing may include but are not limited to the following: 
• 
Adverse Event (Adverse Reaction); 
• 
The Investigator or trial coordinator must notify the Sponsor immediately when a 
subject has been discontinued/withdrawn due to an Adverse Event (AE). 
• 
Any medical condition that may jeopardize the subject’s safety if he or she continues 
on trial; 
• 
Pregnancy. 
 
CLINICAL TRIAL INVESTIGATIONAL PRODUCT INFORMATION 
 
INVESTIGATIONAL PRODUCT (IP) AND STUDY DEVICE 
 INO-4800 AND PLACEBO 
Investigational product is defined as a pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in the study, whether blinded or unblinded. 
INO-4800 is the active investigational product to be used in this study. The INO-4800 drug 
product contains 10 mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM 
sodium chloride and 15 mM sodium citrate). pGX9501 is a DNA plasmid expressing a 
synthetic consensus (SynCon®) sequence of the SARS-CoV-2 full length Spike 
glycoprotein. 
Phase 2 segment: 
Active Investigational Product (INO-4800): A volume of 0.4 mL will be filled into 2-mL glass 
vials that are fitted with rubber stoppers and sealed aluminum caps. 
Placebo (placebo for INO-4800): Sterile saline sodium citrate (SSC) buffer, which contains 
sterile 150 mM sodium chloride and 15 mM sodium citrate in 10-mL glass vials, stoppered, 
and sealed with aluminum caps. 
Phase 3 segment: 
Active Investigational Product (INO-4800): A volume of 0.4 mL or 0.8 mL will be filled into 
2-mL glass vials that are fitted with rubber stoppers and sealed aluminum caps. 
Placebo (placebo for INO-4800): Sterile saline sodium citrate (SSC) buffer, which contains 
sterile 150 mM sodium chloride and 15 mM sodium citrate at a volume of 0.8 mL in 2-mL 
glass vials, stoppered, and sealed with aluminum caps. 
 CELLECTRA® 2000 
Electroporation is a procedure used to enhance cellular DNA uptake within host cells 
following DNA vaccine ID delivery. This study will use the CELLECTRA® 2000, a portable, 
battery-powered medical device designed to generate a controlled, electric field that 
temporarily and reversibly increases cellular membrane permeability without clinically 
damaging the tissue. During the period of increased permeability, injected plasmid DNA 
can be introduced into the cells. 
As mentioned above, the CELLECTRA® 2000 device is intended to enhance the uptake 
and expression of DNA plasmid-based biologics in order to enhance vaccine efficacy. The 
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Clinical Protocol 
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Protocol Version: 1.0USA 
 
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DNA plasmid is delivered separately via needle and syringe ID injection immediately prior 
to the electroporation. The electroporation is accomplished through a sterile, disposable 
needle Array attached to an Applicator delivering controlled electrical pulses as follows: 
• 
An EP administration consists of four pulses. 
• 
An array of three stainless steel electrode needles is used to deliver the electrical 
pulses into the tissue. The Array needle length that penetrates into the skin and 
tissue is approximately 3.2 mm. To date, we have not had any safety concerns 
associated with the depth of the array electrode needles. Within the Array needle 
depth of 3.2 mm, there are no major blood vessels (arteries, veins) or nerve 
structures at the authorized sites of administration overlying the deltoid or the 
anterolateral quadricep muscle. There are superficial capillaries and minor nerves 
innervating the skin, including subcutaneous tissues that may be disrupted by 
needle insertion, but are extremely unlikely to result in serious injury; intradermal 
injection followed by EP of these structures poses no significant risk to the subject 
except for possibly injection site reactions. 
• 
The CELLECTRA® 2000 generates four 52ms ±1ms electrical current controlled 
DC pulses. The nominal current is set to 0.2A ±10% by modulating voltage, or 
capped at 200V ±5%, determined by patient tissue impedance. 
• 
The total energy delivered by the device is determined by the combination of four 
device parameters: Pulse Current, Pulse Voltage, Number of Pulses, and Pulse 
Width. The parameters are pre-set by Inovio to be a pulse current of 0.2A, a pulse 
voltage of 200V, and 4 pulses at 52ms pulse width. The parameters are verified 
prior to shipment and cannot be changed by the user.  
• 
In eight clinical trials administering ID injection followed by EP using the 
CELLECTRA® 2000, total energy delivered ranged from 0.9J to 7.8J, which have 
been generally safe and well-tolerated. In addition, Inovio has calculated the total 
maximum energy delivered ID as 8.32J for normal use conditions. Higher energy 
pulses ranging from 10.7J to 11.7J were evaluated in a guinea pig model which 
induced erythema localized to the electrode insertion site. Taken together, these 
nonclinical data and Inovio’s clinical experience provide evidence that the total 
energy delivered by the CELLECTRA® 2000 device will not result in 
unacceptable risks when delivered to patients. Further, a published study 
evaluated the Visual Analog Scale (VAS) pain scores of normal use conditions 
(0.2A), and found ID injection followed by EP using  the CELLECTRA® 2000 
device to be safe and well tolerated [63]. 
• 
The specified current is constantly maintained through voltage modulation using 
an analog feedback loop. Measurements of voltage and current are processed for 
error reporting and collected for data logging. 
The CELLECTRA® 2000 device is comprised of three components: (1) A battery-powered 
Pulse Generator, (2) an ID Applicator that is connected to the pulse generator, and (3) a 
three-point sterile disposable ID Array of stainless steel needles. The Pulse Generator 
and ID Applicator are reusable components. These components should be cleaned and 
disinfected prior to each subject’s use according to the Cleaning and Maintenance 
procedure in the User Manual. The Pulse Generator and ID Applicator have been 
validated for up to 30 cleaning and disinfection cycles based on a maximum of 30 subjects 
being treated in a day. Therefore, the Pulse Generator and ID Applicator’s use should be 
limited to 30 subjects in a day. Any potential risk of damage to the device due to cleaning 
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Clinical Protocol 
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CONFIDENTIAL 
Protocol Version: 1.0USA 
 
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and disinfection for more than 30 cycles has not been validated. Always inspect the device 
before use according to the instructions in the Maintenance section of the User Manual. 
 
DOSING REGIMENS 
Phase 2 Segment 
• 
Active Investigational Product: One or two 1.0mg ID injection(s) of INO-4800 (~0.1mL 
dose volume each) followed immediately by EP administered on Day 0 and Day 28 
(±3 days) 
• 
Placebo: One or two ID injection(s) of placebo for INO-4800 (~0.1mL) followed 
immediately by EP administered on Day 0 and Day 28 (±3 days) 
Phase 3 Segment 
• 
Active Investigational Product: Two 1.0mg ID injections of INO-4800 (~0.1mL dose 
volume) followed immediately by EP administered in separate limbs on Day 0 and Day 
28 (±3 days) 
• 
Placebo: Two ID injections of  placebo for INO-4800 (~0.1mL) followed immediately 
by EP administered in separate limbs on Day 0 and Day 28 (±3 days) 
 BLINDING 
This study is blinded. The Sponsor, subjects and clinical site staff, with the exception of 
the site’s pharmacy personnel, will be blinded throughout the trial. There is no difference 
in appearance between INO-4800 and the placebo; however, they are distinguishable 
based on the vial size and/or labelling on the vials. In the Phase 2 segment, the vials will 
be of different sizes and have unblinded labelling. In the Phase 3 segment, the vials will 
be the same size but will have unblinded labelling. To maintain the blind, vials will only be 
handled by designated unblinded personnel (site pharmacist) at the site. 
Under exceptional circumstances, the PI may desire to unblind a subject’s dose 
assignment in case of an emergency or serious medical condition when knowledge of the 
study product or dose is deemed by the PI to be absolutely essential for proper clinical 
management of the subject. Under such emergency circumstances, the Sponsor urges 
the PI to first contact the Medical Monitor (MM) to review options before unblinding the 
subject’s dose assignment. In case of non-emergency, PI must contact MM to discuss the 
options before unblinding the subject’s dose assignment.  
It is not deemed appropriate to unblind a subject’s treatment assignment for the purpose 
of assisting the subject in making a decision regarding receipt a different COVID-19 
vaccine (emergency use or licensed vaccine).  Subjects should be advised that without 
efficacy data, INO-4800 has not been proven to be more protective than placebo in the 
prevention of COVID-19 and SARS-CoV-2 infection. Therefore, unblinding will not provide 
any meaningful information to inform a decision of receiving a different COVID-19 vaccine. 
The Sponsor’s pharmacovigilance staff may unblind a subject’s dose assignment for an 
SAE, unanticipated adverse device effect (UADE), or adverse event of special interest 
(AESI) when the event is assessed as related and unexpected. If expedited regulatory 
reporting is required for such an event, the report may be submitted to regulatory 
authorities with the subject’s dose assignment, in accordance with local regulations. 
 
 
PACKAGING AND LABELING 
 INO-4800 OR PLACEBO 
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Each vial of INO-4800 or placebo will be labeled consistent with the example product label 
provided in the IB.  
 CELLECTRA® 2000 
Please see shipping box for shipping documents and contents. 
The CELLECTRA® 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer. The CELLECTRA® 2000 User Manual 
describes all relevant contraindications, hazards, potential risks and adverse effects, 
interfering substances or devices, warnings, and precautions. Each Pulse Generator has 
a unique serial number, and each ID Applicator has a unique serial number. Each ID Array 
has a Lot Number and Expiration Date. Examples of device labels are provided in the IB. 
The CELLECTRA® 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. 
 
HANDLING AND STORAGE 
 INO-4800 AND PLACEBO 
INO-4800 and Placebo will be shipped at 2–8°C. If the temperature monitoring devices in 
the shipping container(s) denote temperatures outside this 2–8°C (36-46°F) range, the 
Sponsor, or its designee, should be contacted immediately. 
Upon arrival, the INO-4800 and placebo must be transferred from the shipping container 
into 2–8°C (36-46°F) storage, in a secure area, in accordance with local regulations by 
designated personnel (e.g., pharmacy personnel). The Sponsor must be notified of any 
deviations from this storage condition. Refrigerator temperature logs must be maintained 
at the clinical site and temperatures must be recorded and monitored regularly. For further 
details see Pharmacy Manual and IB. 
 CELLECTRA® 2000 
See User Manual for operating and storage conditions. 
 
PREPARATION AND DISPENSING 
In the Phase 2 segment, INO-4800 is supplied in 2-mL vials at a concentration of 10 
mg/mL at a minimum volume of 0.4 mL.  placebo for INO-4800 is supplied in 10-mL vials 
at a minimum volume of 2 mL.  
In the Phase 3 segment, INO-4800 is supplied in 2-mL vials at a concentration of 10 
mg/mL at a minimum volume of 0.4 or 0.8 mL.  placebo for INO-4800 is supplied in 2-mL 
vials at a minimum volume of 0.8 mL. 
Blinded staff involved in the clinical execution of the study should not come in contact with 
vials of INO-4800 or placebo for INO-4800. Vials will only be handled by designated 
unblinded personnel (e.g., pharmacy) at the site. When a subject is eligible for enrollment, 
unblinded personnel will draw INO-4800 or placebo for INO-4800 into a blinded syringe in 
accordance with the subject’s randomized treatment assignment according to a 
randomization schedule. The syringe will be transferred to blinded site personnel for 
administration.  
Each INO-4800 and placebo vial will contain a volume of product sufficient to dose multiple 
subjects. The preparation and dispensing information will be provided in the Pharmacy 
Manual. 
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USE OF STUDY DEVICE 
The instructions for use of the CELLECTRA® 2000 device are provided in the User 
Manual. Each clinical site will receive training for use of the CELLECTRA® 2000 device 
prior to first dose. The EP procedure must be performed by qualified personnel. Any 
individual designated to perform the procedure should be permitted by the relevant local 
authorities to administer parenteral injections to patients (e.g., MD, DO, RN) in addition to 
successfully completing device training provided by Sponsor personnel.  
 
INVESTIGATIONAL DRUG AND STUDY DEVICE ACCOUNTABILITY 
 INVESTIGATIONAL PRODUCT (IP) ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current accountability record of 
investigational products (INO-4800 or placebo) is maintained at the study site. The 
investigational products must have full traceability from the receipt of the products through 
subject use, disposal or return of the products. Records or logs must comply with 
applicable regulations and guidelines. The accountability information is provided in the 
Pharmacy Manual. 
 CELLECTRA® 2000 ACCOUNTABILITY 
The investigational site is responsible for maintaining device accountability logs. The 
device must have full traceability from the receipt of the products through subject use, 
disposal or return of the products. The site must document acknowledgement of receipt 
and notify Inovio upon receipt of study devices. This includes the content shipped and 
condition upon receipt. 
For each subject administration, there must be a record of each product used for that 
subject, i.e., Pulse Generator serial number, ID Applicator serial number, and ID Array lot 
number. The ID Applicator is reusable with a new ID Array and sheath for each procedure. 
The sterile ID Array and sheath are single use only and must be discarded after use in 
accordance with institutional policy regarding disposal of sharp needles/instruments. 
 
RETURN AND DESTRUCTION OF INVESTIGATIONAL DRUG AND STUDY DEVICE 
 INO-4800 AND PLACEBO 
Upon completion or termination of the study, all unused vials of INO-4800 or placebo must 
be destroyed at the study site in accordance with institution policy or returned to Inovio 
Pharmaceuticals, Inc., or its designee if the site cannot destroy IP. 
The used vials of INO-4800 and placebo will be discarded in accordance with the site’s 
used IP disposal procedure. It is the Investigator’s responsibility to arrange for disposal of 
all empty vials, provided that procedures for proper disposal have been established in 
accordance with applicable national, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. If requested by the Sponsor, the 
return of unused IP vials should be arranged by the responsible Inovio Representative. 
The unused IP vials should only be destroyed after being inspected and reconciled by the 
responsible Inovio Pharmaceuticals, Inc., personnel or designated Clinical Monitor. If IP 
vials are returned to Inovio Pharmaceuticals, Inc., or its designee, the IP must be 
accompanied by the appropriate documentation. The return of unused IP(s) should be 
arranged with the responsible Inovio personnel and/or Clinical Monitor. 
 RETURN OF CELLECTRA® 2000 
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Upon completion or termination of the study, an Inovio Representative will provide 
instructions regarding the component(s) to be returned to Inovio Pharmaceuticals, Inc., 
destroyed onsite or shipped to a destruction vendor. 
All products returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original containers. 
The return of all products identified above should be arranged by the Inovio 
Representative. The ID Arrays should be discarded in the sharps container immediately 
after use. The used ID Applicators can either be destroyed at the site, shipped to a 
destruction vendor, or returned to Inovio. If the used ID Applicators are destroyed on site, 
it is the Investigator’s responsibility to ensure that arrangements have been made for the 
disposal, written authorization has been granted by Inovio Pharmaceuticals, Inc., or its 
designee, procedures for proper disposal have been established in accordance with 
applicable regulation and guidelines and institutional procedures, and appropriate records 
of the disposal have been documented. 
 
CLINICAL TRIAL PROCEDURES AND SCHEDULE 
The Schedule of Events (36TTables 3 and 4 36T) in the Clinical Protocol Synopsis summarizes 
the procedures to be performed at each visit. Individual procedures are described in detail 
below. It may be necessary to perform these procedures at unscheduled time points if 
deemed clinically necessary by the Investigator. A subject will be required to provide 
informed consent (Section 6.2) prior to any study procedure being performed. Protocol 
waivers or exemptions will not be granted. Therefore, adherence to the study design and 
assessments are essential and required for study conduct. 
 
PROCEDURE BY VISIT 
Refer to Sections 6.1.1 and 6.1.2 for trial procedures and the times at which they are to 
be performed. 
 CLINICAL TRIAL SCREENING EVALUATIONS 
The assessments performed during Screening will determine the subject’s eligibility for 
the study and also their ability to comply with protocol requirements by completing all 
screening assessments. The following screening evaluations will be performed for both 
Phase 2 and Phase 3 segments within 30 days prior to dosing on Day 0. All screening 
assessment values must be reviewed prior to the first Study IP administration. Screening 
and Day 0 visits may be on the same day if eligibility is able to be confirmed prior to 
randomization. If so, all assessments for Screening and Day 0 must be performed at the 
combined visit. 
If a subject does not meet an inclusion or exclusion criterion due to a transient and non-
clinically significant event at Screening, relevant Screening evaluations may be repeated 
within the same 30-day Screening period. If the subject fails twice, they will be considered 
a screen failure. 
• 
Signed and dated informed consent (Section 6.2); 
• 
Review and confirm all inclusion/exclusion criteria (Section 4.1 and 4.2); 
• 
Obtain and document complete medical history, surgical history (including all 
clinically significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Section 6.1.1.1); 
• 
Collect demographics; 
• 
Collect socio-behavioral assessment information (Section 6.4); 
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• 
Collect AEs (Section 6.4.4); 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Record height and weight (Section 6.4); 
• 
Collect urine for pregnancy test (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8).  
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.8). 
 
6.1.1.1 
Medical History 
A medical history will be obtained by the Investigator or qualified designee at the time of 
Screening. Medical history will include all active conditions, and any other past conditions, 
as well as surgical procedures, that are considered to be clinically significant by the 
Investigator and/or having occurred within 3 months prior to Screening. Subjects should 
be queried about any history of Hepatitis B, Hepatitis C and HIV.   
In the Phase 3 segment, subjects with a self-reported history of Hepatitis B or C must 
provide documentation of liver enzymes that are not significantly elevated within the past 
3 months. If such a report of liver enzyme testing is not available, this testing should be 
performed at Screening. Subjects with a history of Hepatitis C without cirrhosis who have 
completed treatment and have proof of an undetectable viral load at least 12 weeks 
following treatment may be enrolled and do not require liver enzymes within the past  
months. 
Subjects with self-reported HIV must provide documentation of controlled HIV infection 
based on a CD4 count greater than 200 cells/mm3 or an undetectable viral load within the 
past 3 months. If a recent CD4 count and/or viral load is not available, this testing should 
be performed at Screening. 
Illnesses first occurring or detected after the signing of the informed consent, or during the 
study and/or worsening of an existing illness in severity, frequency or nature after signing 
of the informed consent are to be documented as AEs on the Case Report Forms (CRF). 
Prior treatments, defined as administered up to 12 weeks prior to the time of informed 
consent and stopped prior to dosing on Day 0, should be recorded in the CRF as prior 
medications. Concomitant treatments, defined as continuing on Day 0 or new treatments 
taken at or after Day 0, should be recorded in the CRF as concomitant medications. 
 CLINICAL TRIAL EVALUATIONS AND PROCEDURES 
Once eligibility has been confirmed, the subject will be randomized to receive a treatment 
assignment (INO-4800 or placebo). Visit dates and windows must be calculated from Day 
0, unless otherwise noted. All subjects will be followed until the Day 393 Visit. All subjects 
will be followed in accordance with assessments outlined below. 
6.1.2.1 
Day 0 and Day 28 (Dosing Visits) 
The following evaluations will be performed on Day 0 and Day 28 prior to dose 
administration: 
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Both Phase 2 and Phase 3 segments: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Obtain any updates to medical history, surgical history (including all clinically 
significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Day 0 visit only) (Section 6.1.1.1); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect urine for urine pregnancy test (Section 6.4); 
• 
Collect blood for HIV serology (Day 0 visit only) (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Day 0 visit only) (Phase 3 cellular immunology collection at selected sites only) 
(Section 6.5); 
• 
Review restrictions for injection and EP (Section 6.4.7); 
• 
Randomize subject (instructions to be provided under separate cover) (Day 0 visit 
only). 
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect diary from Day 0 dose (Day 28 visit only). 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8); 
• 
Collect nasopharyngeal swabs for SARS-CoV-2 RT-PCR (Day 0 only) (Section 
6.4.8); 
• 
Collect diary from Day 0 dose during Day 28 visit only(for selected sites only). 
 
The following evaluations will be performed on Day 0 and Day 28 after IP plus EP 
administration: 
• 
Collect any new AEs (Section 6.4.4); 
• 
Download EP Data; 
• 
Provide supplies for subject to use at home, as required (e.g. thermometer, wound 
guide); 
• 
Phase 2 segment: Distribute diary; 
• 
Phase 3 segment, for selected sites: Distribute diary. 
6.1.2.2 
Post-dose phone calls 
Phase 2 segment: Day 7 and Day 35 
Phase 3 segment: Day 14  
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
 
Phase 2 segment only: 
• 
Review diary (Section 6.4). 
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Phase 3 segment only: 
• 
Review diary (for selected sites)(Section 6.4); 
6.1.2.3 
Day 42 Visit 
Both Phase 2 and Phase 3 segments: The following evaluations will be performed at this 
visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4);  
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 cellular immunology collection at selected sites only)(Section 6.5);  
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect diary from Day 28 visit. 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8); 
• 
Collect diary from Day 28 visit (for selected sites only); 
• 
Ensure subject has necessary supplies at home (e.g. thermometer). 
6.1.2.4 
Phone calls  
Phase 2 segment: Day 56 
Phase 3 segment: Days 56, 70, 84, 98, 112, 140, 154, 168, 182, 196, 238, 266, 322, 
350, and 378 
In the Phase 3 segment, phone calls to subjects have been spaced bi-weekly 
between study visits through Day 210, and approximately monthly between visits 
from Day 210 to Day 393.   
 
Guidelines for information to be collected during the phone call can be found in the 
Phone Script. The following evaluations will be performed during the phone call: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Ask about any symptoms of COVID-19 disease; Arrange on-site visit if any signs 
and symptoms of COVID-19 disease are present (Section 6.4.9); 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
6.1.2.5 
Follow up clinic visits 
Phase 2 segment: Day 210 
Phase 3 segment: Days 126, 210 and 294 Visits 
Both Phase 2 and Phase 3 segments: The following evaluations will be performed at these 
visits: 
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• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); SAEs, AESIs, and 
MAAEs will be reported after the Day 56 Visit. 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 Day 201 visit only; Phase 3 cellular immunology collection at selected 
sites only) (Section 6.5); 
 
Phase 3 segment: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8);  
• 
Ensure subject has necessary supplies at home (e.g. thermometer). 
6.1.2.6 
Day 393 Visit or EOS 
Phase 2 and Phase 3 segments: The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); SAEs, AESIs, and 
MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
 
Phase 2 segment: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6); 
• 
Collect urine pregnancy test (Section 6.4). 
 
Phase 3 segment: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 cellular immunology collection at selected sites only) (Section 6.5). 
6.1.2.7 
COVID-19 Assessment Visit 
For both the Phase 2 and Phase 3 segments of the study, subjects will be evaluated 
during a COVID-19 assessment visit when acute COVID-19 is suspected based on 
symptoms or positive SARS-CoV-2 testing. The assessment visit may be performed in 
the clinic, subject’s vehicle, or at a home visit and should be performed within 3 days of 
a positive SARS-CoV-2 test or site knowledge of COVID-19 symptom onset. The 
virologic-confirmation of a case will be based on SARS-CoV-2 RT-PCR testing from the 
central lab. A local RT-PCR result will be considered acceptable in the case where a 
subject is hospitalized and a sample for central lab analysis is not able to be obtained, if 
it was obtained using. an assay performed by a laboratory accredited according to 
standards set by a national or regional accreditation body.  
If a local lab is used to confirm the case, the report from the laboratory must be provided.  
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Phase 2 and Phase 3 segments: The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); Only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Optional targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
 
Phase 2 only: 
• 
Collect nasal swabs and saliva for SARS-CoV-2 RT-PCR detection (Section 6.4.8). 
Phase 3 only: 
• 
Collect whole blood and serum for cellular and humoral immunology assessment, 
where possible (Phase 3 cellular immunology collection at selected sites only) 
(Section 6.5) 
• 
Collect nasopharyngeal swabs for SARS-CoV-2 RT-PCR testing (Section 6.4.8). 
6.1.2.8 
COVID-19 Convalescent Visit 
Phase 2 and Phase 3 segments: For subjects with confirmed SARS-CoV-2 infection 
during the trial, a convalescent visit should be scheduled approximately 28 days after 
symptom onset, or in the absence of symptoms, after the collection date of a positive 
SARS-CoV-2 test. If symptoms are ongoing at 28 days after symptom onset, the site 
should follow up with the subject via phone call or unscheduled visit after symptom 
resolution or stabilization.  
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); Only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 cellular immunology collection at selected sites only) (Section 6.5); 
 
Phase 2 segment only: 
• 
Collect nasal swabs and saliva for SARS-CoV-2 RT-PCR detection (Section 6.4.8). 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8). 
 
INFORMED CONSENT 
All subjects must sign the informed consent prior to participating in any clinical trial-related 
procedures. The informed consent documentation must be in compliance with applicable 
regulations and GCP. Qualified clinical trial personnel will: 
• 
Meet with prospective clinical trial subjects; 
• 
Explain the clinical trial; 
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• 
Provide clinical trial subjects with an Informed Consent Form (ICF) that includes the 
following in a language that is understandable to the subject: 
• 
Screening test(s) description; 
• 
Eligibility criteria for entering the clinical trial; 
• 
Clinical trial treatments and follow-up procedures description; 
• 
Explanation of the clinical trial, including but is not limited to: 
• 
Clinical trial objectives; 
• 
Potential benefits and risks; 
• 
Discomforts/inconveniences; 
• 
Subject’s rights and responsibilities. 
The subject is then requested to sign and date the ICF. A copy of the signed informed 
consent documentation must be provided to the subject. The qualified clinical trial 
personnel will document the process of obtaining informed consent within the source 
record. Signed ICFs are maintained in the subject’s source records and must be 
accessible for verification at any time. Signing of the ICF begins the 30-day screening 
period. 
 
ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number (SID), 
which identifies the subject for all clinical trial-related procedures. SIDs are a combination 
of a site code and a subject number. After SIDs are assigned, they cannot be reused or 
reassigned for any reason. Information regarding the SID and screen date will be 
documented on a screening and enrollment log/system and in the CRF.   
Previously screen failed subjects may be rescreened provided there is a valid documented 
reason for rescreening (i.e. changes to the person’s health or situation that would make 
them possibly eligible at this later time). If rescreening occurs, the subject will keep their 
original Subject ID.  
 
SAFETY EVALUATIONS 
PHYSICAL AND TARGETED PHYSICAL EXAM  
A full physical examination will be conducted during Screening and at study 
discharge/EOS (e.g. Day 393). A targeted physical assessment will be performed at other 
visits as determined by the Investigator based on subject symptoms.  
VITAL SIGNS 
Vital signs including temperature, respiration rate, blood pressure and heart rate will be 
measured at Screening and at visits specified in the Schedule of Events (36TTables 3 and 
436T).  
At the COVID-19 assessment and convalescent visits, temperature, respiration rate, 
heart rate and oxygen saturation should be performed.   
HEIGHT AND WEIGHT 
Weight and height will be collected at Screening. 
SOCIO-BEHAVIORAL ASSESSMENT  
A Socio-behavioral Assessment, including self-reported smoking and vaping history, and 
self-reported history of exposure to second-hand smoke will be obtained at Screening. 
LABORATORY EVALUATIONS 
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Blood samples will be collected at visits specified in the Schedule of Events (36TTables 3 and 
436T). A total of approximately mL 245-330mL of blood will be drawn from each subject over 
the course of the study (inclusive of relevant safety and immunology samples at regular 
study visits per Tables 3 and 4). If the subject is evaluated at COVID-19 visits, an 
additional volume of approximately 85-120mL will be collected. Subjects may be asked to 
return for additional blood draws if collected blood sample is lost or unevaluable for any 
reason. 
Hematology [Complete blood count (CBC) with automated differential]: 
White blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit and 
platelet count will be measured at Screening (Phase 2 segment only) and at visits specified 
in the Schedule of Events (36TTables 3 and 436T). Hemoglobin A1c will additionally be performed 
at Screening (Phase 2 segment only). 
Serum chemistry: 
Electrolytes [Sodium (Na), Potassium (K), Chloride (Cl), Bicarbonate (HCO3), Calcium 
(Ca), Phosphate (PO4)], glucose, Blood Urea Nitrogen (BUN), Creatinine (Cr),  alkaline 
phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), LDH,  
and total bilirubin (TBili) at Screening (Phase 2 segment only) and at visits specified in the 
Schedule of Events (36TTables 3 and 436T).  
Urinalysis:  
Urine samples will be tested by dipstick for glucose, protein, and hematuria at Screening 
(Phase 2 segment only) and at visits specified in the Schedule of Events (36TTables 3 and 
436T). If abnormal (presence of protein, hematuria, or glucose ≥ 1+), a microscopic 
examination should be performed.  
Serology: 
HIV antibody or rapid test will be measured at Day 0 only.  
Antibodies to SARS-CoV-2 will be measured at Screening and at visits specified in the 
Schedule of Events (Tables 3 and 4). 
Pregnancy Testing:  
Pregnancy testing will be performed on women of childbearing potential (WOCBP). All 
women will be assumed to be of childbearing potential unless they are:  
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Women who are surgically sterile or have a partner who is sterile (i.e., vasectomy 
in males or tubal ligation, absence of ovaries and/or uterus in females). In the 
case of a vasectomy, subjects should wait six (6) months post-vasectomy to be 
considered sterile. 
Phase 2: For WOCBP, a serum pregnancy test will be obtained at Screening and a urine 
pregnancy test will be performed immediately prior to any dosing and at the subject’s last 
visit.  
Phase 3: For WOCBP, a urine pregnancy test will be obtained at Screening and will be 
performed immediately prior to any dosing. 
A negative result for urine β-HCG (test must have a sensitivity of at least 25 mIU/mL) must 
be available prior to each administration of IP. If the β-HCG test is positive, indicating that 
the subject is pregnant prior to completing the specified dose regimen, then no further IP 
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will be administered. Every attempt should be made to follow pregnant subjects for the 
remainder of the study and to determine the outcome of the pregnancy (see Section 7.12). 
DIARY 
Diaries will be implemented in the Phase 2 segment of the protocol and at selected sites 
(estimated to include 711 subjects) in the Phase 3 segment.  Subjects will be provided a 
diary to record the following solicited local and systemic AEs: 
• 
Oral temperature and time taken (each daily entry before 11:59 pm) 
• 
Solicited systemic symptoms 
• 
Solicited local injection site symptoms 
• 
Concomitant medications 
The diary should be completed once daily starting the evening of each study dose through 
6 days post-dose. The completed diary post-dose 1 and post-dose 2 will be reviewed with 
the subject by the study staff during the next study phone call or visit and collected at the 
next in-person study visit. The study staff will review the diary with the subject to assess 
for temperature, solicited systemic symptoms (unusually tired/feeling unwell, muscle 
aches, headache, nausea, joint pain) and solicited injection site symptoms (pain, itching, 
redness, swelling, bruising). In addition, unsolicited symptoms and concomitant 
medications will be assessed.  
Any diary entry determined to meet the Common Terminology Criteria for Adverse Events 
version 5.0 (CTCAE) criteria for a Grade 1 or higher adverse event should be documented 
as an adverse event unless deemed part of the subject’s ongoing medical history. Injection 
site reactions should be graded per the Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, issued September 
2007 (See Section 6.4.5). If the diary entry does not meet the criteria of a Grade 1 or 
higher AE as per the relevant guidelines, Investigator clinical judgment can be used to 
determine whether the entry should be recorded as an AE and documented accordingly 
in the site’s source. For cases where the diary entry and final AE reporting (i.e. grading) 
do not agree, the reasoning should be recorded in the source documents. 
 INTRADERMAL INJECTION AND EP  
Phase 2 and Phase 3 segments: 
A complete administration procedure is defined as an ID injection (formation of a wheal) 
of IP followed by insertion of the ID Array needles (electrodes) through the skin and into 
the wheal followed by delivery of four electroporation pulses. This procedure is broadly 
described as administration because it involves more than the injection of a drug. 
Only if the deltoid area is not a suitable location for administration (see exclusion criterion 
‘j’), the ID injection can then be administered above the lateral quadriceps followed 
immediately by EP. IP must not be given within 2 cm of a tattoo, scar, keloid, or active 
lesion/rash. Also, ID injection followed immediately by EP must not be performed on the 
skin of an extremity which has any metal implants or implantable medical device (e.g., 
surgical rods, pins or joint replacements). If a subject has an implanted cardiac defibrillator 
or pacemaker, ID injection/EP must not be performed above the deltoid muscle on the 
same side of the body where the device is located. 
There are three steps that must be performed as part of the administration procedure: 
1. Injection of IP (INO-4800 or placebo) 
2. Insertion of the array into the subject’s skin 
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3. Pressing the trigger button on the EP applicator  
Table 9 below is provided as guidance on how to appropriately complete the procedure 
when injection of IP has occurred, but the subject did not receive EP. 
Table 9: Guidance for how to manage an incomplete administration after IP has 
been injected 
Was IP 
injected? 
Was the array 
inserted into skin? 
Was trigger button 
pressed? 
Action 
Yes 
Yes (if array gets 
dislodged before 
the trigger button 
is pressed, the 
same array may 
be re-inserted) 
No 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
Yes 
No 
Yes 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
Yes 
No 
No 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
 
Reinjection of IP (i.e. protocol-specified IP has already been delivered) is not permitted. 
Delivery of a second electroporation in tissue is not permitted. 
Training will be provided by the Sponsor on use of the device. 
Phase 2 segment: 
Subjects will receive a two-dose regimen of one or two 1.0 mg ID injections of INO-4800 
or placebo in a volume of ~0.1 mL in an acceptable skin location for injection and 
subsequently followed immediately by EP of each injection site with CELLECTRA® 2000 
at Day 0 and Day 28. For subjects assigned to receive two injections + EP at each dosing 
visit, the two injections must be performed in acceptable locations on two different limbs. 
Phase 3 segment: 
Subjects will receive a two-dose regimen of two 1.0 mg ID injections of INO-4800 or 
placebo in a volume of ~0.1 mL in an acceptable skin location for injection on different 
limbs and subsequently followed immediately by EP of the injection site with 
CELLECTRA® 2000 at Day 0 and Day 28. 
 MANAGEMENT OF PAIN DUE TO ELECTROPORATION (EP) PROCEDURES 
In case of pain, subjects may be treated with a non-narcotic analgesic (e.g., 
acetaminophen) after injection/EP.  
Medication taken for pain management will be documented as concomitant medications. 
 ASSESSMENT OF LABORATORY ABNORMALITIES 
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In Phase 2, samples will be collected for serum chemistry, hematology, and urinalysis at 
the visits listed in the Schedule of Events (36TTables 3 and 436T) and as listed in Section 6.4.  
Laboratory AEs will be assessed and graded in accordance with the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. Laboratory values that are 
not clinically significant (NCS) in the Investigator’s opinion will not be reported as AEs. 
 ASSESSMENT OF CLINICAL TRIAL ADVERSE EVENTS (AES) 
Subjects will be queried regarding the occurrence of any AEs including AEs related to 
injection site reactions, concomitant medications and new onset illness or disease during 
their study visits and phone calls. Subjects will be reminded to contact study personnel 
and immediately report any event for the duration of the study. All AEs will be captured 
from the time of the informed consent until 28 days post-dose 2 (Day 56). Following the 
Day 56 visit, only SAEs, AESIs and MAAEs will be collected. All related AEs, AESIs and 
SAEs will be followed to resolution or stabilization. These events will be recorded on the 
subject’s CRF. 
 ASSESSMENT OF INJECTION SITE REACTIONS  
Reactions arising from the IP administration procedure may be reported as administration 
site or injection site reactions. When evaluating administration (injection) site reactions 
throughout the study, it is most important to be as specific as possible by selecting the 
most appropriate term (see Table 10 below) and using the grading scale as listed in the 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, issued September 2007. All subjects will be observed for 30 
minutes following the IP administration procedure for immediate AEs.  In addition, other 
events associated with administration (injection) site reactions (e.g., hematoma, infection 
or necrosis) should also be reported with preferred terms specific for administration 
(injection) site reactions.  
Table 10: Grading Scale for Injection Site Reactions 
Local Reaction to 
Injectable Product 
(Grade) 
Mild (1) 
Moderate (2) 
Severe (3) 
Potentially 
Life 
Threatening 
(4) 
Pain 
Does not 
interfere with 
activity 
Repeated use 
of non-
narcotic pain 
reliever >24 
hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency 
room visit or 
hospitalization 
Tenderness 
Mild 
discomfort to 
touch 
Discomfort 
with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/Rednessa 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swellingb 
2.5-5 cm and 
no 
5.1-10 cm or 
interferes with 
activity 
>10 cm or 
prevents daily 
activity 
Necrosis 
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interference 
w/ activity 
September 2007 “FDA Guidance for Industry-Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
a In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable 
b Should be evaluated and graded using the functional scale as well as the actual measurement. 
 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription, including receipt of any non-study 
COVID-19 vaccine (authorized under emergency use or licensed)) taken between 
informed consent and study discharge (see Section 4.2) must be recorded on the CRFs. 
Actual or estimated start and stop dates must be provided. This information will be 
obtained from the subject and/or any available medical records. The indication for the 
medication, dose, and dose regimen will be documented.  
Therapy considered necessary for the subject’s welfare may be given at the discretion of 
the Investigator or medical provider. If the permissibility of a specific medication/treatment 
is in question, please contact the Medical Monitor. 
The decision to administer a prohibited medication/treatment (Section 6.4.7) is made with 
the safety of the clinical trial subject as the primary consideration. When possible, the 
Sponsor should be notified before the prohibited medication/treatment is administered. 
 RESTRICTIONS  
In the Phase 2 segment of the trial, subjects should refrain from becoming pregnant until 
3 months following the last dose of investigational product by using appropriate 
contraceptive measures (see Section 4.1.1). In the Phase 3 segment of the trial, subjects 
should refrain from becoming pregnant until receipt of the last dose of investigation 
product by using appropriate contraceptive measures (See Section 4.1). 
Subjects must not receive any non-study related vaccine (e.g., influenza vaccine) within 2 
weeks prior to the first dose of IP, or within 2 weeks of (before or after) any subsequent 
dose of IP.  
Subjects must not have fever (oral temperature ≥38.0 degrees Celsius or 100.4o 
Fahrenheit) within 72 hours prior to each dosing. 
Subjects should not receive hydroxychloroquine during the trial. In the Phase 3 segment, 
subjects should not receive any other drug/vaccine intended as COVID-19 prophylaxis 
during the trial. Subjects should be reminded that if and when appropriate, the Sponsor 
would offer INO-4800 to those who received placebo in the trial if INO-4800 is 
demonstrated to be efficacious.  
 
For subjects in the Phase 2 segment of the trial, the receipt of any non-study prophylactic 
COVID-19 vaccine (authorized under emergency use or licensed) is not restricted, based 
upon increasing availability of EUA vaccine in the US and completion of the Phase 3 dose 
selection from the Phase 2 data.  
If a subject informs the site of their intent to receive a non-study prophylactic COVID-19 
vaccine available either authorized under emergency use or when licensed, the subject 
should be informed that the safety and effectiveness of receiving INO-4800 followed by 
another COVID-19 vaccine has not been studied. 
 
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Subjects should not participate in any other interventional trials for the duration of this trial. 
Subjects must not receive disease modifying doses of anti-rheumatic drugs (e.g., 
azathioprine, cyclophosphamide, cyclosporine, methotrexate), biologic disease modifying 
drugs such as TNF-α inhibitors (e.g., infliximab, adalimumab or etanercept) and long term 
use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of prednisone 
equivalent (use of inhaled, topical, nasal, otic, and ophthalmic corticosteroids are allowed).  
 SARS-COV-2 TESTING 
Phase 2 segment: 
SARS-CoV-2 antibody and RT-PCR testing will be used during screening to test for 
previous or current SARS-CoV-2 infection. During the trial, subjects who report symptoms 
suggestive of COVID-19 will be assessed at a COVID-19 assessment visit in the clinic or 
subject’s vehicle or at the subject’s home. During this visit, nasal swabs and saliva will be 
collected to detect SARS-CoV-2 using the RT-PCR assay. Genotyping may also be 
performed. If the subject is confirmed to be COVID-19 positive, a follow-up nasal swab 
and saliva will be collected to detect SARS-CoV-2 using the RT-PCR assay at the COVID-
19 convalescent visit. 
Phase 3 segment: 
SARS-CoV-2 antibody testing will be used during screening to test for previous SARS-
CoV-2 infection and during each subsequent visit (see Table 4: Schedule of Events) to 
identify SARS-CoV-2 infections that may occur regardless of symptoms between study 
visits. 
SARS-CoV-2 RT-PCR testing will be conducted on nasopharyngeal specimens collected 
at Day 0. The Day 0 SARS-CoV-2 RT-PCR results will not be required prior to dosing on 
that day. 
For subjects who are seronegative at baseline, if at any time during the trial, either the 
SARS-CoV-2 antibody or an RT-PCR test result is positive, the subject will be notified of 
the result and will be evaluated at a COVID-19 assessment visit. During that visit, which 
may be conducted in the clinic, from the subject’s vehicle, or in the subject’s home, 
nasopharyngeal swabs will be collected to detect SARS-CoV-2 using the RT-PCR assay. 
Genotyping may also be performed on the sample(s) collected at the COVID-19 
assessment visit.  
 COVID-19 DISEASE MONITORING 
During both the Phase 2 and Phase 3 segments of the trial, all subjects will be monitored 
for the development of symptoms suggestive of COVID-19 disease. For the Phase 3 
segment, frequent (approximately bi-weekly) scheduled clinic visits or phone calls will 
occur.  
All subjects in the trial should be instructed to do the following: 
• 
Take their temperature daily at home starting on the Day 0 visit for the duration of 
the trial.     
• 
Monitor for symptoms suggestive of COVID-19 (e.g., feeling feverish or chills, 
cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, 
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headache, new loss of taste or smell, sore throat, congestion or runny nose, 
nausea or vomiting, diarrhea) starting on the Day 0 visit for the duration of the trial.  
If at any time during the study, the subject experiences a fever of ≥ 100.4°F/38°C or 
symptoms suggestive of COVID-19, the subject should contact the site. The site staff 
should arrange for a clinic visit (COVID-19 assessment visit) within 3 days of the site being 
aware of either a positive SARS-CoV-2 test or COVID-19 symptom onset. The COVID-19 
assessment visit may be performed either at the clinic, in the subject’s vehicle or in the 
subject’s home. 
Subjects with a confirmed COVID-19 diagnosis, per the case definition outlined in Section 
3.7, prior to dose 2 or who have a positive SARS-CoV-2 PCR test at Day 0 will be 
discontinued from further dosing and will be followed until EOS for safety and resolution 
of COVID-19. Subjects with confirmed SARS-CoV-2 infection will return for a convalescent 
visit approximately 28 days after symptom onset, or in the absence of symptoms, after the 
collection date of the positive SARS-CoV-2 sample. If symptoms are ongoing at 28 days 
after symptom onset, the site should follow up with the subject via phone call or 
unscheduled visit after symptom resolution or stabilization. Recovery from COVID-19 
disease requires either resolution of clinical symptoms except for loss of taste/smell, or 
with sequelae that appear to be permanent.     
Subjects who require medical care for COVID-19 (or any other suspected condition) will 
be referred to their primary health care provider or a medical treatment facility if the 
Investigator believes that the subject should be managed beyond routine care that can be 
provided by the study site. Subjects referred for treatment will continue study follow-up 
according to the protocol schedule. If subjects are treated or hospitalized due to their 
illness, the study team will request COVID-19 specific test results, treatments, treatment 
outcomes and diagnostics from medical treatment facilities with the subject’s written 
permission. These results and diagnostics will be recorded in the study and/or safety 
database consistent with protocol reporting requirements. 
 
IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at visits specified in the Schedule of 
Events (36TTables 3 and 436T) for cellular and humoral immunology assessments. Binding 
ELISA will be evaluated at serial timepoints. Cellular sampling requires 32 mL of whole 
blood be collected at each visit. Humoral sampling requires collection of 8.5 mL of whole 
blood in a single 10-mL red top serum collection tube to produce two serum aliquots of 2 
mL each. However, baseline (Day 0) immunology samples are required to serve as a 
baseline for all subsequent immunology testing. Therefore, a total of 68 mL whole blood 
for cellular sampling and 8 mL serum for humoral sampling is required on Day 0 prior to 
1st dose. Subjects may be asked to return for additional blood draws if collected blood 
sample is lost or unevaluable for any reason. Details of the immunology sample collection 
and shipment information will be provided in the Laboratory Manual.  
Humoral samples will be collected on all subjects and cellular samples will be collected at 
selected sites (from approximately 711 subjects). Both humoral and cellular analysis will 
be conducted in the first 102 subjects age 18-50 and in the first 102 subjects age 51 and 
older enrolled at the sites that are selected for cellular sample collection. In addition, 
cellular and humoral samples will be analyzed on all subjects with COVID-19 when 
samples are available. 
The immune responses to INO-4800 will be measured using assays that include a 
pseudovirus-based neutralization assay and ELISpot. Determination of additional 
analyses using assays not specified, such as assessment of immunological gene 
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expression or flow cytometry, assessment of immunological protein expression on 
collected samples for immunological endpoints will be made on an ongoing basis 
throughout the trial. 
 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
 
SAFETY PARAMETERS 
The safety of INO-4800 will be measured and graded in accordance with the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. 
 
ADVERSE EVENTS (AES) 
Any untoward medical occurrence in a patient or clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.  
Adverse Events (AEs) include the following: 
• Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (before the administration of clinical trial drug); 
• Any pre-existing condition that increases in severity, or changes in nature during or as 
a consequence of the clinical trial drug administration phase; 
• Complications of pregnancy (refer to Section 7.11). 
Adverse Events (AEs) do not include the following: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; however, the condition that leads to the procedure is an AE; 
• Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the Screening Visit that do not worsen; 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions); 
• Overdose without clinical sequelae; 
• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed, is not an AE; it is considered to be pre-existing and will be 
documented on the medical history CRF; 
• Uncomplicated pregnancy; 
• An induced elective abortion to terminate a pregnancy without medical reason; 
• Confirmed COVID-19 disease.  
 
ADVERSE DRUG REACTION (ADR) 
All noxious and unintended responses to a medicinal product related to any dose. This 
means that a causal relationship between the medicinal product and an adverse event is 
at least a reasonable possibility (i.e., the relationship cannot be ruled out). 
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SERIOUS ADVERSE EVENTS (SAES) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death;  
• Is life-threatening; 
o Refers to an event in which the subject was at risk of death at the time of the event. 
It does not refer to an event which hypothetically might have caused death if it 
were more severe 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
o Includes any hospitalization in which the subject has been admitted to the hospital 
regardless the length of stay, even if the hospitalization is only a precautionary 
measure to allow continued observation. However, hospitalization (including 
hospitalization for an elective procedure) for a pre-existing condition that has not 
worsened, does not constitute an SAE 
• Results in persistent or significant disability/incapacity; 
o A substantial disruption of a person's ability to conduct normal life functions (i.e., 
the adverse event resulted in a significant, persistent or permanent change, 
impairment, damage or disruption in the subject’s body function/structure, physical 
activities and/or quality of life) 
• Results in congenital anomaly or birth defect and/or; 
• An important medical event.  
o An event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse 
Clarification of Serious Adverse Events (SAEs) 
• Death itself is not an AE. Death is an outcome of an AE, but when the cause of death 
has not been provided, use the event term: death of unknown cause; 
• Confirmed COVID-19 disease that requires hospitalization is recorded on the 
Suspected COVID-19 Clinical Event CRF, and not recorded as an SAE; 
• COVID-19 disease with an outcome of death is recorded on the Suspected COVID-19 
Clinical Event CRF, and not recorded as an SAE; 
• The subject may not have been receiving an investigational medicinal product at the 
occurrence of the event; 
• Complications associated with COVID-19 disease that occur or prolong 
hospitalization are recorded on the Suspected COVID-19 Clinical Event CRF; 
• The Pregnancy outcomes of spontaneous abortion (miscarriage), ectopic pregnancy, 
fetal demise/stillbirth in a subject or subject partner following exposure to study 
treatment is considered to be an SAE. 
 
UNEXPECTED ADVERSE DRUG REACTION 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator’s Brochure [IB] for an unapproved investigational 
product, package insert/summary of product characteristics for an approved product). 
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UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects.  
A UADE is a type of SAE that requires reporting to the Sponsor in accordance with Section 
7.9. 
 
DEVICE DEFICIENCY 
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance. 
Note: Device deficiencies include malfunctions, use errors and inadequate labelling. 
 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor is responsible for the overall safety monitoring of the clinical trial. 
Safety monitoring assessments include but are not limited to:  
• Incidence of all AEs classified by system organ class, preferred term, severity and 
causal relationship to clinical trial treatment; 
• Changes in laboratory parameters; 
• Local and systemic injection site review; special attention will be paid to the examination 
of the injection site. 
 ADVERSE EVENT OF SPECIAL INTEREST (AESI)  
An adverse event of special interest (serious or non-serious) is one of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor can be 
appropriate.  
For the purpose of this clinical trial, the AESIs listed in Appendix A are to be reported to 
the Sponsor in accordance with Section 7.9. 
 MEDICALLY ATTENDED ADVERSE EVENT (MAAE) 
A medically attended adverse event (serious or non-serious) is defined as an adverse 
event that leads to an unplanned contact with a health care provider. 
 ABNORMAL LABORATORY VALUE 
The Investigator will annotate each abnormal lab value as clinically significant (CS) or not 
clinically significant (NCS). 
Laboratory values that are NCS in the Investigator’s opinion should not be reported as an 
adverse event. 
Any abnormal laboratory value that is new in onset or worsened in severity or frequency 
from the baseline condition and meets one of the following criteria will be recorded as an 
AE: 
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• 
Requires therapeutic intervention or diagnostic tests; 
• 
Leads to discontinuation of further administration of the investigational product in 
the clinical trial; 
• 
Has accompanying or inducing symptoms or signs; 
• 
Is judged by the Investigator as clinically significant (CS). 
Abnormal laboratory values that meet the criteria of an AE or SAE should be reported in 
accordance with Section 7.9. 
 CLINICAL TRIAL STOPPING RULES 
The Investigator is to immediately notify the Medical Monitor if the following are observed: 
• 
Any SAE related to study treatment; 
• 
Any Grade 4 AEs related to study treatment; 
• 
Any report of anaphylaxis related to study treatment; 
• 
Any suspected Severe COVID-19 disease case (per Sections 3.7.1.1 and Section 
3.7.1.2). 
The Medical Monitor will notify the Chair of the Safety Review Committee, who will make 
a determination as to whether to temporarily halt dosing until a more formal review of the 
case(s) is made. Such a formal review may include an ad hoc meeting of the DSMB, after 
consultation with the DSMB Chair. Following such a meeting, the DSMB chair will render 
a recommendation to the Medical Monitor regarding continuation of trial dosing. The 
Sponsor will independently investigate the case(s) and, after review of the DSMB 
recommendations, will communicate a final decision as to whether to lift the dosing 
suspension or whether to continue dosing. These deliberations will be documented and 
will be provided to the IRBs and FDA, where required.   
In the case of suspected Severe COVID-19 cases, the trial will be paused if a vaccine-to-
placebo case split yields a relative risk with a 90% confidence interval lower bound >1.  
The minimum case split corresponding to this criterion is 8:0. In this scenario, the trial will 
pause until at least one additional case is accrued and the DSMB can review the data and 
make a recommendation regarding continued enrollment in the trial. 
 
SAFETY DATA REPORTING PERIOD, METHOD OF COLLECTION AND SUBMISSION 
All AEs will be collected from the time informed consent is obtained through Day 56. 
MAAEs, AESIs and SAEs only will continue to be collected after the Day 56 visit and will 
be followed to resolution or stabilization. This information will be captured in the CRF. 
If the Investigator determines that the AE meets serious criteria, then the AE will be 
recorded as an SAE. 
SAEs and AESIs will be reported to the Sponsor from the time the subject signs the 
informed consent until the last visit. 
All SAEs (regardless of causal relationship) and AESIs will be reported on the SAE Report 
Form and submitted to the Sponsor within 24 hours of becoming aware of the event. The 
SAE Report Form will be either emailed to safety.inovio@apcerls.com or faxed to
The original SAE Report Form must be kept at the clinical trial site. 
The event will be data entered into the CRF. 
 
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For the events that are considered an AESI, the Investigator will contact the Sponsor within 
24 hours of becoming aware of the event to discuss whether dosing should continue. 
Table 11: SAE Contact Information 
Sponsor Safety Email: safety.inovio@apcerls.com 
Sponsor Safety Fax: 
 
Sponsor Safety Phone: 
 
Table 12: Medical Monitor Direct Contact Information 
Primary point of contact, ICON Medical Monitor: 
, M.D. 
Email: 
 
Phone: 
Inovio Medical Monitor:  
, Jr., M.D., FACP, FIDSA 
Email: 
 
Cell Phone: 
All SAEs, treatment-related AEs, MAAEs and AESIs must be followed by the Investigator 
until resolution or return to baseline status, stabilization of the event (i.e., the expectation 
that it will remain chronic), even if it extends beyond the clinical trial reporting period or 
until it is determined that the subject is lost to follow up. 
Follow-up information is to be submitted to the Sponsor on an SAE Report Form and within 
24 hours of becoming aware of the information. 
If medical records are submitted to the Sponsor with the SAE Report Form, the clinical 
trial site must: 
• Redact the medical records of all personal data (e.g., confidential subject data,
Personal Identifying Information [PII])
• Provide the subject’s assigned identification number (SID) on the records
ADVERSE EVENT REPORTING 
This section provides details on reporting the safety information. 
SUBMITTING THE INITIAL SERIOUS ADVERSE EVENT (SAE) REPORT FORM 
The Investigator should include as much safety information as possible when submitting 
the initial report, but the report must include the following at a minimum:  
•
The adverse event;
•
The subject’s assigned identification number (SID);
•
Investigational product(s) (IP) and/or study device;
•
Investigator causal relationship to the IP(s) and/or study device;
•
Serious criteria;
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• 
Reporter name and contact information. 
If a case is submitted to the Sponsor with only the “minimum” information, a more detailed 
or updated follow-up report will be sent to the Sponsor as soon as possible but no later 
than three (3) calendar days after the date of the initial report. 
 RECORDING THE EVENT 
Investigators should use correct medical terminology/concepts when recording AEs on the 
EDC and SAE Report Form. The use of colloquialisms and abbreviations should be 
avoided. 
A medical diagnosis, if known, should be recorded rather than individual signs and 
symptoms. However, if the signs and/or symptoms cannot be medically characterized as 
a single diagnosis or syndrome, each individual sign and/or symptom should be recorded. 
If a diagnosis is subsequently established, all previous signs and/or symptoms will be 
subsumed and replaced with a single medical diagnosis. 
 ASSESSING SEVERITY (INTENSITY) 
Severity is used to describe the intensity of a specific event (e.g., mild, moderate, severe). 
The Investigator will assess and grade clinical AEs or SAEs (based on discussions with 
clinical trial subjects) in accordance with CTCAE. 
 CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS (AES) 
A causally related AE is one judged to have a possible, probable or definite relationship 
to the administration of the IP and/or the study device. An AE may also be assessed as 
not related to the IP and/or the study device. Because the Investigator is knowledgeable 
about the subject (e.g., medical history, concomitant medications), administers the IP, and 
monitors the subject’s response to the IP, the Investigator is responsible for reporting AEs 
and judging the relationship between the administration of the IP and EP and a 
subsequent AE. The Investigator is aware of the subject’s clinical state and may have 
observed the event, and thus may be sensitive to distinctions between events due to the 
underlying disease process versus events that may be product-related.  
Investigators should use their knowledge of the clinical trial subject, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to determine 
whether an AE is considered to be related to the IP and/or the study device and the causal 
relationship reported as "Yes" or "No" accordingly. Causality should be assessed by the 
Investigator as related to drug, related to device, or related to both drug and device (i.e., 
related to both or indiscernible) by the following criteria: 
• 
Yes – there is a reasonable possibility that administration of the clinical trial 
treatment (drug or device or both drug and device) contributed to the event 
• 
No – there is no reasonable possibility that administration of the clinical trial 
treatment contributed to the event and there are more likely causes 
The following guidance should also be taken into consideration: 
• 
Temporal relationship of event to administration of IP and/or EP; 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
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• 
Known association of the event with the IP, EP or with similar treatments; 
• 
Known association of the event with the disease under trial; 
• 
Presence of risk factors in the clinical trial subject or use of concomitant 
medications known to increase the occurrence of the event. 
The rationale for the Investigator’s causal assessment is to be recorded on the SAE Report 
Form. 
The Sponsor will assess the overall safety of the IP delivered by EP and determine 
whether to report expeditiously to the regulatory authority(ies). 
 REPORTING SUSPECTED COVID-19 DISEASE CASES DURING THE TRIAL 
For both Phase 2 and Phase 3 segments of the trial, all suspected COVID-19 disease 
cases based on reported COVID-19 symptoms and/or SARS-CoV-2 test results should be 
entered into the Suspected COVID-19 Clinical Event CRF within 24 hours of awareness. 
Cases will be tracked until final determination of whether the case meets criteria of a 
confirmed COVID-19 disease case, per the case definition. For the Phase 2 segment of 
the trial, this determination will be made by the Investigator. For the Phase 3 segment, this 
determination will be made by the EAC. 
If the reported COVID-19 disease case is later determined not to be a confirmed COVID-
19 case, the event (e.g. symptoms or other diagnosis), if serious, would be reported as an 
SAE within 24 hours following determination by the Investigator (Phase 2 segment) or 
notification by EAC (Phase 3 segment).  
If the reported COVID-19 disease case is later determined not to be a confirmed COVID-
19 case, the event (e.g. symptoms or other diagnosis), if non-serious and if occurring from 
the time of consent until 28 days post-dose 2, would be reported as an AE following 
determination by the Investigator (Phase 2 segment) or notification by EAC (Phase 3 
segment). 
 REPORTING PREGNANCY DURING THE CLINICAL TRIAL 
Subjects in Phase 2 who are pregnant or expect to become pregnant prior to 3 months 
following the last dose will be excluded from participation in the clinical trial.  
Subjects in Phase 3 who are pregnant or expect to become pregnant prior to the last dose 
will be excluded from participation in the clinical trial.  
All pregnancies that occur from the time of first administration of clinical trial treatment 
through study completion (i.e., Day 393) will be reported to the Sponsor. If clinical trial site 
staff become aware that a subject becomes pregnant after the first dose in the clinical trial, 
she will not be given any additional treatments with the IP. A Pregnancy Form will be 
completed by the site and submitted to the Sponsor within 24 hours after becoming aware 
of the pregnancy. 
The Investigator will report this event to their IRB/REB/EC in accordance with their policies 
and procedures.  
The clinical trial site must request the subject’s permission to query pregnancy outcome 
and follow the subject for outcome of the pregnancy. The subject will continue to be 
followed for safety assessments without receiving additional IP until clinical trial discharge 
in accordance with this protocol. Procedures that are contraindicated during pregnancy, 
including additional dose administrations, must not be performed. The Investigator should 
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use clinical judgment regarding subsequent clinical trial-related blood collection based on 
the presence or absence of anemia in each subject.  
Male subjects will be instructed through the ICF to immediately inform the Investigator if 
their partner becomes pregnant until study completion. A Pregnancy Form will be 
completed by the site and submitted to the Sponsor within 24 hours after becoming aware 
of the pregnancy. The pregnant partner will be asked to sign a Pregnancy Information 
Collection Consent Form to allow for follow-up on her pregnancy. If the authorization has 
been signed, the Investigator will collect and report details of the course and outcome of 
the pregnancy in the partner of a male subject exposed to IP. The site will update the 
Pregnancy Form with additional information on the course and outcome of the pregnancy 
and submit the form to the Sponsor.  
If an Investigator is contacted by the male subject or his pregnant partner, the Investigator 
may provide information on the risks of the pregnancy and the possible effects on the fetus 
to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
If the end of the pregnancy occurs after the clinical trial has been completed, the outcome 
will be reported directly to the Sponsor. 
 REPORTING DEVICE-RELATED COMPLAINTS OR DEFICIENCIES 
All product complaints that meet the definition of device deficiency must be reported to the 
Sponsor within 10 days of discovery, with the exception of SAEs which require 24-hour 
reporting. The error reporting or complaint form must be completed and emailed to the 
Sponsor at clinicalcomplaint@inovio.com. 
Device deficiencies include malfunctions, misuse or use errors and inadequate labeling. 
A malfunction is defined as the failure of a device to meet its performance specifications 
or otherwise perform as intended. The intended performance of a device refers to the 
intended use for which the device is labeled or marketed. 
Any problems experienced during the treatment procedure including malfunctions of the 
device, error messages displayed on the device screen following treatment, or errors that 
occur during the treatment procedure must immediately be reported to the Sponsor or its 
designee for evaluation.  
 NOTIFYING REGULATORY AUTHORITIES AND INSTITUTIONAL REVIEW BOARDS 
(IRBS)/RESEARCH ETHICS BOARDS (REBS)/ETHICS COMMITTEES (ECS) OF SAFETY 
INFORMATION 
 SPONSOR RESPONSIBILITIES 
• 
Determine whether the safety information meets the requirements for expedited 
reporting to the applicable regulatory authorities; 
• 
Prepare and submit the safety report to the applicable regulatory authorities; 
• 
Send all participating PIs a safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) that will include a statement if there is or is not any significant new 
safety information that might influence the risk-benefit assessment of the IP and/or 
study device, sufficient to consider changes in product administration or overall 
conduct of the clinical investigation. 
 PRINCIPAL INVESTIGATOR (PI) RESPONSIBILITIES 
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• 
Forward a copy of the safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) to their IRB/REB/EC as soon as practical in accordance with the 
governing policy and/or procedures; 
• 
Notify their IRB/REB/EC of safety information (i.e., SAEs, pregnancies, and AESIs) 
that occur at their clinical trial site in accordance with their local institutional policy. 
 POST-TRIAL REPORTING REQUIREMENTS 
PIs are not obligated to actively seek AEs or SAEs beyond the clinical trial reporting period. 
However, if the PI becomes aware of an AE or SAE that occurs after the Completion or 
Termination Visit and the event is deemed by the PI to be related to the clinical trial 
treatment, the PI should promptly document and report the event to the Sponsor. 
 CLINICAL TRIAL DISCONTINUATION  
INOVIO reserves the right to discontinue the clinical trial at a site or at multiple sites for 
safety or administrative reasons at any time. In particular, a clinical trial site that does not 
recruit at a reasonable rate may be discontinued. Additionally, the clinical trial may be 
discontinued at any time by an IRB/REB/EC, INOVIO, or a regulatory authority as part of 
their duties to ensure that clinical trial subjects are protected.  
If the clinical trial is discontinued and/or the clinical trial site closed for any 
reason, all IP and devices must be returned to INOVIO or its 
representative. The PI should ensure that their site file documents are complete 
prior to archiving, and provide copies of any requested documents to INOVIO 
for its Trial Master File (TMF). 
 
STATISTICAL CONSIDERATIONS 
 
STATISTICAL AND ANALYTICAL PLAN 
The formal Statistical Analysis Plan is contained in the sections that follow. 
 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is an operationally seamless Phase 2/3 trial.  The subjects and data from Phase 2 
are independent from that of Phase 3.   
Phase 2 Segment:  This is a four-arm, multi-center, placebo-controlled, blinded, and 
randomized clinical trial in subjects at high risk of SARS-CoV-2 exposure. The trial’s 
primary endpoints are antigen-specific cellular immune response measured by IFN-
gamma ELISpot and neutralizing antibody responses. Secondary efficacy endpoints are 
safety measures.  Exploratory endpoints are antigen-specific cellular immune response 
measured by flow cytometry and other T and B cell measures.  
Phase 3 Segment: This is a two-arm, multi-center, placebo-controlled, double-blinded, and 
randomized clinical trial in subjects at high risk of SARS-CoV-2 exposure. The study’s 
primary endpoint is the incidence of virologically-confirmed COVID-19 disease in subjects 
who are SARS-CoV-2 seronegative at baseline starting 14 days after completion of the 2-
dose regimen until 12 months post-dose 2.  The primary hypothesis is that INO-4800 will 
be efficacious relative to placebo (relative efficacy > 30%). Secondary efficacy analyses 
involve non-severe cases, severe cases, cases resulting in death, and cases among 
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baseline SARS-CoV-2 seropositive subjects. Other secondary analyses concern safety 
and cellular and neutralizing antibody response. Exploratory analyses concern efficacy 
against variants, efficacy against asymptomatic infection, and binding antibody and 
cellular immunological measures. 
 
STATISTICAL HYPOTHESES 
Phase 2 Segment: This is an estimation segment pertaining to immunogenicity and safety.  
There are no hypotheses. 
Phase 3 Segment: The primary hypothesis of relative efficacy greater than 30% among 
baseline SARS-CoV-2 seronegative subjects will be tested with H0: p ≥ .70/(.70+k) vs. H1: 
p < .70/(.70+k), where p is the true proportion of subjects with disease who receive INO-
4800 relative to the total number of subjects with disease, and k is the total amount of 
follow-up time in the placebo group divided by the total amount of follow-up time in the 
INO-4800 group. There are no other formal hypotheses. 
 
ANALYTICAL POPULATIONS 
Analysis populations will be: 
The per-protocol (PP) population includes all subjects who receive all doses of Study 
Treatments and have no protocol violations. Subjects in the PP population will be grouped 
to treatment arms as randomized.  Subjects excluded from the PP population will be 
identified and documented prior to unblinding of the trial database.  Analyses on the PP 
population among those who are baseline SARS-CoV-2 seronegative will be primary for 
the analyses of efficacy in the Phase 3 segment of this trial. 
The modified intention to treat (mITT) population includes all subjects who receive at least 
one dose of Study Treatment. Subjects in this population will be grouped to treatment 
arms as randomized.  Analysis of the mITT population will be considered supportive for 
the corresponding PP population for the analyses of efficacy in the Phase 3 segment of 
this trial. 
The intention to treat (ITT) population includes all subjects who are randomized. Subjects 
in this sample will be grouped to treatment arms as randomized.  Analysis of the ITT 
population will be considered supportive for the corresponding PP population for the 
analyses of efficacy in the Phase 3 segment of this trial. 
The safety analysis population includes all subjects who receive at least one dose of Study 
Treatment. Subjects will be analyzed according to the treatments received. 
 
DESCRIPTION OF STATISTICAL METHODS 
 PRIMARY ANALYSIS 
Phase 2 Segment 
Post-baseline increases from baseline in interferon-γ ELISpot response magnitudes will 
be compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
Post-baseline increases from baseline in neutralizing antibody response titers will be 
compared between treatment groups using ratios of geometric mean fold-rises and 
associated t-distribution based 95% CIs. 
The summaries listed above will be stratified according to NP positive/negative status and 
according to prior receipt of any non-study prophylactic COVID-19 vaccine of the subjects. 
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Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more than 
198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more than 380 
days after Dose 2 for the Week 56 timepoint. Baseline is defined as the last measurement 
prior to the first treatment administration. 
The PP population will be used for these immunogenicity analyses. 
Phase 3 Segment 
Among subjects who are SARS-CoV-2 seronegative at baseline, the primary hypothesis 
of relative efficacy greater than 30% will be tested with H0: p ≥ 0.70/(0.70+k) vs. H1: p < 
0.70/(0.70+k), where p is the true proportion of subjects with disease who receive INO-
4800 relative to the total number of subjects with disease, and k is the total amount of 
follow-up time in the placebo group divided by the total amount of follow-up time in the 
INO-4800 group. 
A p-value for this hypothesis test and corresponding confidence interval will be computed 
based on the exact binomial method of Clopper-Pearson. Success will be concluded if the 
one-sided p-value is <0.022 and the corresponding lower bound of the two-sided 95.6% 
CI for efficacy exceeds 30% (alpha-level adjusted for interim analyses, see Section 8.5.6), 
and the point estimate for efficacy exceeds 50%. 
For calculating k, an individual subject’s follow-up time is either: 
o the date of first disease diagnosis – date of the start of surveillance period +1 (for 
subjects who are cases), or 
o the date of last follow-up – date of the start of surveillance period +1 (for subjects who 
are non-cases). 
This methodology is based on the following. Assuming that the number of subjects who 
are cases in the INO-4800 group follows a Poisson distribution with parameter λv and the 
number of subjects who are cases in the placebo group follows a Poisson distribution with 
parameter λc, then conditional on total number of subjects with cases, t, the number of 
subjects who are cases in the INO-4800 group follows a binomial distribution with 
parameters (t, p=λv/(λv+λc)).  The relationship between p and efficacy is: efficacy = (1-
(1+k)p)/(1-p).  Therefore, testing efficacy > 30% corresponds to testing p < 0.70/(0.70+k).  
Similarly, the confidence interval for efficacy is (1-(1+k)UBp)/(1-UBp), (1-(1+k)LBp)/(1-LBp), 
where UB and LB are the Clopper-Pearson upper and lower limits for the proportion. 
The efficacy time frame is defined by symptoms beginning at any time starting from 14 
days after Dose 2 and ending 12 months after Dose 2.  Subjects identified as cases that 
started prior to this time point will be excluded.  Subjects with multiple instances meeting 
the case definition will be counted only once, using the first such instance.    
The PP population will be primary for the analysis of efficacy in this trial. Efficacy analysis 
using the mITT population will also be conducted counting cases from 14 days postdose 
1 as a supportive analysis.  The ITT population will also be used for a supportive analysis 
counting cases starting from randomization. 
 SECONDARY ANALYSES 
8.5.2.1 Efficacy 
Phase 3 Segment 
The secondary efficacy incidence endpoints will be analyzed in the same manner as the 
primary hypothesis, but with 95% CIs and without the hypothesis test p-value.  
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8.5.2.2 Immunogenicity 
 
   Phase 3 Segment 
Post-baseline increases from baseline in interferon-γ ELISpot response magnitudes will 
be compared between treatment groups using differences in medians and associated 
non-parametric 95% CIs. 
Post-baseline increases from baseline in neutralizing antibody response titers will be 
compared between treatment groups using ratios of geometric mean fold-rises and 
associated t-distribution based 95% CIs. 
The summaries listed above will be stratified according to disease status of the subjects 
and by baseline SARS-CoV-2 serostatus. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more than 
198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more than 
380 days after Dose 2 for the Week 56 timepoint.. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for these immunogenicity analyses. 
 SAFETY ANALYSES 
8.5.3.1 Adverse Events 
All AEs including injection-site reactions will be summarized among the Safety 
Population by frequency per treatment arm. These frequencies will be presented overall 
and separately by dose, and will depict overall, by system organ class and by preferred 
term, the percentage of subjects affected. Additional frequencies will be presented with 
respect to maximum severity and to strongest relationship to Study Treatment. Multiple 
occurrences of the same AE will be counted only once following a worst-case approach 
with respect to severity and relationship to Study Treatment. All serious AEs will also be 
summarized as above. 
The main summary of safety data will be based on events occurring within 30 days of 
any dose. For this summary, the frequency of preferred term events will be compared 
between study arms with risk differences and 95% confidence intervals, using the 
method of Miettinen and Nurminen. As this analysis will use many event categories, and 
produce many confidence intervals, caution should be exercised when interpreting these 
confidence intervals.  Separate summaries will be based on events occurring within 7 
days of any dose and regardless of when they occurred. 
The analyses listed above will be performed according to the Phase of the trial. For the 
Phase 2 segment, the analyses listed above will also be performed according to prior 
receipt of any non-study prophylactic COVID-19 vaccine.  For the Phase 3 segment, the 
analyses listed above will also be performed according to SARS-CoV-2 serostatus at 
baseline. 
For AE data, partial start dates will be imputed to the date of treatment to conservatively 
report the event as treatment-emergent, whenever the portion of the date is consistent 
with that of the study treatment. Otherwise, it will be imputed to the earliest date 
consistent with the partial date. A completely missing onset date will be imputed as the 
day of treatment. Partial stop dates will be assumed to be the latest possible day 
consistent with the partial date. AE duration will be calculated as (Stop Date – Start 
Date) + 1. 
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8.5.3.2 Vital Signs 
Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean, standard deviation, minimum, median, and maximum 
values by time point and treatment arm, for the Safety population. Baseline is defined 
as the last measurement prior to the first treatment administration. These summaries 
will be performed according to Phase. For the Phase 2 segment, the analyses listed 
above will also be performed according to prior receipt of any non-study prophylactic 
COVID-19 vaccine.  For the Phase 3 segment, the analyses listed above will also be 
performed according to SARS-CoV-2 serostatus at baseline. 
 DISPOSITION 
Disposition will be summarized by treatment arm for the ITT population and will include 
the number and percentage randomized, the number and percentage who received each 
dose and the number who completed the trial.  The number and percentage of subjects 
who discontinued will be summarized overall and by reason.  The number in each analysis 
population will also be presented. These summaries will be performed according to Phase. 
For the Phase 3 segment, the analyses listed above will also be performed according to 
SARS-CoV-2 serostatus at baseline. 
 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
8.5.5.1 Demographics 
Demographic data will be summarized with descriptive statistics: mean standard 
deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables, by treatment arm, for the ITT and PP populations. 
These summaries will be performed according to Phase. For the Phase 3 segment, the 
analyses listed above will also be performed according to SARS-CoV-2 serostatus at 
baseline. 
8.5.5.2 Prior Medications 
Prior medications are those that were used before the start of the trial (prior to Day 0). 
Partial stop dates of prior medications will be assumed to be the latest possible date 
consistent with the partial date; start dates will not be imputed. Data for all prior 
medications will be summarized with percentages by treatment arm, for the ITT and PP 
populations. These summaries will be performed according to Phase. For the Phase 3 
segment, the analyses listed above will also be performed according to SARS-CoV-2 
serostatus at baseline. 
 INTERIM ANALYSES  
For safety issues, the DSMB could recommend stopping enrollment at any time; no 
formal interim analysis will be performed for this purpose. The two-sided type I error of 
0.05 will not be adjusted for possible early stopping due to this aspect. 
 
For the Phase 2 segment, group-level unblinded summaries of the immunogenicity and 
safety data will be produced once Week 6 visit immunology data and Week 8 visit safety 
data are complete for all subjects who have not discontinued, while maintaining subject-
level blinding.  Long-term follow-up data will continue to be collected for all subjects who 
have not discontinued with remaining visits through the final visit.  These summaries will 
allow the Sponsor to have results for the purposes of dose selection for the Phase 3 
portion.  No subject-level immunogenicity data will be produced, and subject-level 
immunogenicity data will not be available in the clinical trial database until all other clinical 
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trial data are finalized at the end of the trial.  No safety summary will be provided if the 
total number of subjects who experience the event of interest is greater than 0 and the 
count of the number of subjects with the event in a given treatment group relative to the 
total produces a percentage less than 3%, for a given summary.  The group-level 
unblinded production of the summaries will not include anyone directly involved with the 
trial or any additional unblinded personnel; only the external Contract Research 
Organization (CRO), ICON, which will already be providing unblinded summaries for the 
Data Safety Monitoring Board, will be utilized.  Thus, the trial will remain blinded to the 
Sponsor with respect to subject treatment assignment.  
 
For the Phase 3 segment, there are two planned formal interim efficacy analyses: one at 
50% (75 cases) and one at 75% (112 cases) of the total required for the primary endpoint 
(149 cases).  The Lan-DeMets O’Brien-Fleming approximate alpha-spending function will 
be used for the efficacy and futility boundaries.  As such, the first interim analysis will utilize 
a one-sided nominal alpha of 0.0016, and the second interim analysis will utilize a one-
sided nominal alpha of 0.0092.  The final analysis will utilize a one-sided nominal alpha of 
0.022.  The DSMB will be responsible for the interim evaluations. The unblinded interim 
analyses will not include anyone directly involved with the trial or any additional unblinded 
personnel; only the external Contract Research Organization (CRO), ICON, which will 
already be providing unblinded summaries for the Data Safety Monitoring Board, will be 
utilized.  Thus, the trial will remain blinded to the Sponsor with respect to subject treatment 
assignment.  
 
If the prespecified criteria for efficacy above are met at either interim analysis, then 
enrollment will continue until 4500 subjects have been enrolled, and blinded follow-up will 
continue until 4500 subjects have 6 months of safety follow-up.  At that point, the trial 
would be unblinded, and subjects who received placebo will be offered the active product. 
 MULTIPLICITY 
There is one primary hypothesis that will be tested.  As there are two interim analyses of 
the primary endpoint, the type I error rate will be controlled at two-sided 0.05 by using the 
Lan-DeMets O’Brien-Fleming approximate alpha-spending function (see Section 8.5.6).  
 MISSING VALUES 
Missing data will not be imputed. 
For the ITT analyses of efficacy in the Phase 3 segment, subjects with missing or 
unevaluable data regarding case definition will be considered cases (failures). 
 EXPLORATORY ANALYSES  
8.5.9.1 Efficacy 
Phase 3 segment 
The exploratory efficacy endpoints will be analyzed in the same manner as the primary 
hypothesis, but with a 95% CI and without the hypothesis test p-value.   
8.5.9.2 Immunogenicity 
Phase 2 segment 
Post-baseline increases from baseline in cellular response magnitudes will be 
compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
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The summaries listed above will be stratified according to NP positive/negative status 
and according to prior receipt of any non-study prophylactic COVID-19 vaccine of the 
subjects. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more 
than 198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more 
than 380 days after Dose 2 for the Week 56 timepoint. . Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
Phase 3 Segment 
Post-baseline increases in antibody titers from ELISA will be compared between 
treatment groups using ratios of geometric mean fold-rises and associated 95% t-
distribution based CIs. 
Post-baseline increases from baseline in cellular response magnitudes will be 
compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
Post-baseline increases from baseline in neutralizing antibody response titers will be 
compared between treatment groups using ratios of geometric mean fold-rises and 
associated t-distribution based 95% CIs. 
The summaries listed above will be stratified according to disease status of the 
subjects. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more 
than 198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more 
than 380 days after Dose 2 for the Week 56 timepoint. . Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
8.5.9.3 Concomitant Medications 
Concomitant medications are those used during the course of the trial (on or after Day 
0). Partial stop dates of concomitant medications will be assumed to be the latest 
possible date consistent with the partial date; start dates will not be imputed. Data for 
all concomitant medications will be summarized with percentages by treatment arm, for 
the ITT and PP populations. These summaries will be performed according to Phase. 
For the Phase 3 segment, the analyses listed above will also be performed according 
to SARS-CoV-2 serostatus at baseline. 
 
SAMPLE SIZE/POWER 
Phase 3 segment: The trial is case-driven. A total of  149 observed cases among baseline 
SARS-CoV-2 seronegative subjects will be required to provide 90% power to declare the 
vaccine efficacious (>30%), assuming a true efficacy of 60% and utilizing the methodology 
described in Section 8.5.1 and Section 8.5.6 .  A sample size of 6714 baseline SARS-
CoV-2 seronegative subjects will be required to achieve this number of cases assuming 
an underlying attack rate of 3.7%.   
 
RANDOMIZATION AND BLINDING  
Phase 2 Segment 
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Subjects will be randomized (3 INO-4800 1.0 mg, one injection: 3 INO-4800 2.0 mg, two 
injections:1 Placebo, one injection: 1 Placebo, two injections). 
The study is blinded. It is double-blinded within dose group.  Randomization and blinding 
will avoid bias in the assignment of subjects to treatment, increase the likelihood that 
known and unknown subject attributes (e.g., demographics and other baseline 
characteristics) are evenly balanced between treatment groups, and enable valid 
statistical comparisons between treatment groups. 
Phase 3 Segment 
Subjects will be randomized (2 INO-4800:1 Placebo).  Randomization will be stratified 
according to two factors, each with two levels: a) age-group age category (18-50 years vs. 
≥51 years) on Day 0, and b) presence or absence on Day 0 of underlying medical 
conditions that increase risk of severe COVID-19 disease, per US CDC criteria. 
The study is double-blinded. Randomization and blinding will avoid bias in the assignment 
of subjects to treatment, increase the likelihood that known and unknown subject attributes 
(e.g., demographics and other baseline characteristics) are evenly balanced between 
treatment groups, and enable valid statistical comparisons between treatment groups. 
 
ETHICS 
 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical trial is 
performed in accordance with the protocol, the principles of the Declaration of Helsinki, 
Good Clinical Practice (GCP) and applicable regulatory requirements. 
 
INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD (REB)/ETHICS 
COMMITTEE (EC) 
The Investigator will commence the clinical trial after full approval of the protocol and 
adjunctive materials (e.g., ICF, advertising) has been obtained from the applicable 
IRB/REB/EC and a copy of IRB/REB/EC approval documentation has been received by 
the Sponsor. 
Investigator responsibilities relevant to the IRB/REB/EC include the following: 
• Submit continuing review reports to the IRB/REB/EC as required, and request re-
review and approval of the clinical trial at least once a year during the conduct of 
the clinical trial; 
• Notify the Sponsor immediately of any suspected unexpected adverse drug or 
device events/effects; 
• Notify the IRB/REB/EC immediately if the Sponsor notifies the Investigator about 
any reportable safety events; 
• Obtain approval from the IRB/REB/EC for protocol amendments and for revisions 
to the consent form or subject recruitment advertisements, as required; 
• Submit reports on, and reviews of, the clinical trial and its progress to the 
IRB/REB/EC at intervals stipulated in their guidelines and in accordance with 
pertinent regulations and guidelines; 
• Maintain a file of clinical trial-related information (refer to clinical trial files) that 
includes all correspondence with the IRB/REB/EC; 
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• Notify the IRB/REB/EC when the clinical trial is completed (i.e., after the last clinical 
trial visit of the final clinical trial subject); 
• After clinical trial completion (within three [3] months is recommended), provide the 
IRB/REB/EC with a final report on the clinical trial. 
Institutional Biosafety Committee (IBC) 
The Investigator will undertake the trial after full approval of the protocol and adjunctive 
materials (e.g., pharmacy manual) has been obtained from the applicable IBC and a copy 
of this approval has been received by the Sponsor. 
Investigator responsibilities relevant to the IBC include the following: 
• 
Notify the Sponsor, IBC and NIH OSP within 30 days of any: 
o Substantial problems or violation of the NIH Guidelines 
o Significant research related accidents or illnesses 
• 
Notify the IBC to any changes to the research (dosage, procedure, etc.) or facility 
(new space, remodeling, etc.).   
 
PROTECTION OF HUMAN SUBJECTS 
 COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent must be obtained from each subject prior to the subject’s 
enrollment in the clinical trial. The process for obtaining informed consent must be 
documented in the subject’s medical record (also refer to Section 6.2). 
 COMPLIANCE WITH INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD 
(REB)/ETHICS COMMITTEE (EC) REQUIREMENTS 
This clinical trial is to be conducted in accordance with applicable IRB/REB/EC 
regulations. The Investigator must obtain approval from a properly constituted 
IRB/REB/EC prior to initiating the clinical trial and obtain re-approval or review at least 
annually. The Sponsor is to be notified immediately if the responsible IRB/REB/EC has 
been disqualified or if proceedings leading to disqualification have begun. Copies of all 
IRB/REB/EC correspondence with the Investigator should be provided to the Sponsor. 
 COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
 COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS (21CFR 
PART 11) 
When applicable, this clinical trial is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
 COMPLIANCE WITH PROTOCOL 
Subjects are not required to follow special instructions specific to the IP used in this clinical 
trial. Subjects will be provided with Investigator emergency contact information and 
advised to report all AEs. While every effort should be made to avoid protocol deviations, 
should an important deviation be discovered, the Sponsor must be informed immediately. 
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Any protocol deviation impacting subject safety must be reported to the Medical Monitor 
immediately. 
 CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from, or changes to, the protocol 
without Sponsor approval and prior review and documented approval/favorable opinion of 
the protocol amendment from the IRB/REB/EC, except where necessary to eliminate 
immediate hazards to clinical trial subjects, or when the changes involve only logistical or 
administrative aspects of the clinical trial (e.g., change in monitors, change of telephone 
numbers).  
 DATA COLLECTION, MONITORING AND REPORTING 
 CONFIDENTIALITY AND PRIVACY 
A report of the results of this clinical trial may be published or sent to the appropriate 
regulatory authorities in any country in which the clinical trial products are legally marketed 
or may ultimately be marketed, but the subject’s name/identity will not be disclosed in 
these documents. The clinical trial Sponsor, its agents, the IRB/REB/EC and regulatory 
authorities will have direct access to the subjects’ medical records for the purposes of trial-
related monitoring, auditing and inspection. Appropriate precautions will be taken to 
maintain confidentiality of medical records and personal information. 
Written Authorization and other documentation are to be obtained from each subject, 
and/or from the subject’s legally authorized representative, prior to enrollment in the 
clinical trial, in accordance with all applicable laws, regulations and/or directives relating 
to privacy and data protection. 
 SOURCE DOCUMENTS 
Source data is all information, electronic or hardcopy original records or clinical findings, 
laboratory results, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the clinical trial. 
Examples of original source data records may include:  
• Hospital records 
• Clinical and office charts 
• Laboratory notes 
• Memoranda 
• Pharmacy dispensing records 
• Recorded data from automated instruments 
• Copies of electronic medical records (EMR) certified after verification as being 
accurate and complete 
• X-rays 
• Subject files and records kept at the pharmacy, at the laboratories, at the medical 
records facility and within information technology (IT) systems that are involved in 
the clinical trial  
The Investigator/institution will permit clinical trial-related monitoring, audits, IRB/REB/EC 
review and regulatory inspections by providing direct access to source data/documents 
related to this clinical trial. 
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 RECORDS RETENTION 
Upon request of the Clinical Monitor, Sponsor or its agent(s), auditor, IRB/REB/EC or 
regulatory authority, the Investigator/institution should make available for direct access all 
requested clinical trial-related records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
It is the Investigator’s responsibility to retain clinical trial essential documents for at least 
two (2) years after the last approval of a marketing application in their country and until 
there are no pending or contemplated marketing applications in their country or at least 
two (2) years have elapsed since the formal discontinuation of clinical development of 
INO-4800. This retention period may be superseded by local requirements. The Sponsor 
will inform the Investigator/institution when these documents are no longer needed to be 
retained. 
If the Records Retention requirements are addressed in a governing clinical trial 
agreement, it is the Investigator’s responsibility to retain clinical trial essential documents 
in accordance with the governing clinical trial agreement and applicable local 
requirements. 
 SAFETY AND QUALITY MONITORING 
 SAFETY REVIEW 
The Sponsor’s Safety Review Committee (SRC), composed of the Sponsor’s Medical 
Monitor, the ICON Medical Monitor and 1 additional physician, will review blinded safety 
and tolerability data on a regular basis throughout the trial. The SRC will refer any of the 
events listed in Section 7.8.4 or any other safety concerns to the DSMB Chair. 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will 
convene regularly to review all available unblinded safety data, and additionally upon 
completion of the Week 8 phone call visit for all subjects enrolled during the Phase 2 
segment. The DSMB will review unblinded safety and tolerability data, including AEs of 
clinical significance, AESIs and SAEs, as well as safety laboratory data for all enrolled 
subjects. The DSMB will also evaluate the data for signals of vaccine-enhanced disease 
and in the event of a signal, advise whether to halt the trial. The DSMB will advise 
regarding any safety concerns and will make recommendations regarding continued 
enrollment, safety pause and trial suspension. For the Phase 3 segment, the DSMB will 
also review efficacy in an unblinded fashion. 
If the safety data is considered unfavorable during any safety review, the DSMB may 
recommend a trial pause or trial termination at which time further enrollment and 
administration of IP to subjects will be paused. The Sponsor will perform an investigation 
and consult with the DSMB and other experts, if needed, to determine whether to resume 
dosing of the remainder of the subjects. For further details, see the DSMB Charter.  
 CLINICAL MONITORING 
Clinical Monitoring will be performed by qualified Clinical Monitors who will report to the 
Sponsor or the Sponsor’s designee. The following clinical trial site monitoring tasks will be 
performed at all clinical trial sites: 
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• 
Prior to subject screening at the site, a Site Initiation Visit will be conducted to 
review all relevant forms and documentation, and ensure that the clinical trial site 
staff are qualified and compliant with all applicable requirements 
• 
All clinical trial site monitoring visits will be documented 
• 
Periodic clinical trial site visits will be performed throughout the clinical trial 
• 
The Clinical Monitor will address and document the following trial conduct activities 
and obligations: 
o Assure that the trial is being conducted in accordance with the protocol, 
applicable regulatory agency regulations, and IRB/REB/EC policies. 
o Discuss trial conduct issues and incidents of noncompliance with the 
Investigator and/or trial personnel and document them on the resolution trip 
report. Report any significant unresolved problems immediately to the 
Sponsor. 
o Remind the Investigator as necessary of the obligation to immediately report 
all SAEs and provide subsequent follow-up report of the final outcome to the 
IRB. 
o Throughout the trial, inspect source documents to ensure they are complete, 
logical, consistent, attributable, legible, contemporaneous, original, accurate 
and complete (ALCOA-C). 
o Assure that the trial facilities, including the pharmacy, continue to be 
acceptable. 
o Compare the trial CRFs with source documents to assure that the data are 
accurate and complete and that the protocol is being followed. 
o Assure that investigational drug and device accountability and reconciliation of 
records are complete and accurate. 
o Assure that all subject specimens are being stored and forwarded properly for 
testing in accordance with laboratory manual requirements. 
 FINANCING AND INSURANCE 
Inovio Pharmaceuticals is the Sponsor of this study.  The Department of Defense, Joint 
Program Executive Office is providing funding for the Phase 2 segment of the study and 
Inovio is providing funding for the Phase 3 segment. Clinical trial insurance has been taken 
out according to the laws of the countries where the study will be conducted. The 
investigative site is being compensated for the conduct of this study and will follow the 
terms described in the clinical trial agreement. This agreement was executed separately 
from this clinical trial protocol. The Investigators will be required to provide full financial 
disclosure information per ICH E6 R1. 
 PUBLICATION POLICY 
Publication of the results of this clinical trial in its entirety will be allowed. The proposed 
presentation, abstract and/or manuscript must be made available to the Sponsor for 
review and approval in accordance with the governing clinical trial agreement. 
 
 
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 LIST OF ABBREVIATIONS 
ADE 
Adverse Device Effect 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALCOA-C 
Attributable, Legible, Contemporaneous, Original, Accurate and Complete 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CBC 
Complete Blood Count 
Cl 
Chloride 
COVID-19 
Coronavirus Disease 2019 
Cr 
Creatinine 
CRF 
Case Report Form 
CS 
Clinically Significant 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELISpot 
Enzyme-linked immunosorbent spot-forming assay 
EP 
Electroporation 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCO3 
Biocarbonate 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICD 
Implantable-Cardioverter-defibrillator 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
ID 
Intradermal 
IM 
Intramuscular 
Inovio 
Inovio Pharmaceuticals Inc. 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
K 
Potassium 
MAAE 
Medically Attended Adverse Event 
mITT 
modified Intent to Treat 
MM 
Medical Monitor 
MERS 
Middle East Respiratory Syndrome  
MERS-CoV 
Middle East Respiratory Syndrome Coronavirus 
mRNA 
Messenger RNA 
Na 
Sodium 
NCS 
Not Clinically Significant 
NHP 
Non-human Primates 
NP 
Nucleocapsid Protein 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PII 
Personal Identifying Information 
PO4 
Potassium 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 88 of 93 
 
PT 
Preferred Term 
RBC 
Red blood cell 
REB 
Research Ethics Board 
RR 
Respiratory Rate 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SARS 
Severe Acute Respiratory Syndrome  
SARS-CoV 
Severe Acute Respiratory Syndrome Coronavirus 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus - 2 
SID 
Subject Identification Number 
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
SynCon 
Synthetic consensus 
TBili 
Total Bilirubin 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of Child-bearing Potential 
 
 
 
Page 669 of 768


INO-4800 
COVID19-311 
Inovio Pharmaceuticals, Inc. 
Clinical Protocol 
Protocol Version Date:30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
Page 89 of 93 
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Centers for Disease Control and Prevention. People with Certain Medical Conditions.
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Lu, H., C.W. Stratton, and Y.W. Tang, Outbreak of pneumonia of unknown etiology in
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Hui, D.S., et al., The continuing 2019-nCoV epidemic threat of novel coronaviruses to
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Huang, C., et al., Clinical features of patients infected with 2019 novel coronavirus in
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World Health Organization, Clinical Management of Sever Acute Respiratory Infection
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Wiersinga, W.J., et al., Pathophysiology, Transmission, Diagnosis, and Treatment of
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The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, The
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The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, Vital
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17.
Chan, J.F., et al., A familial cluster of pneumonia associated with the 2019 novel
coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet,
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Rothe, C., et al., Transmission of 2019-nCoV Infection from an Asymptomatic Contact in
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Ganyani, T., et al., Estimating the generation interval for coronavirus disease (COVID-
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He, X., et al., Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 90 of 93 
 
21. 
Liu, Y., et al., The reproductive number of COVID-19 is higher compared to SARS 
coronavirus. J Travel Med, 2020. 27(2). 
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Centers for Disease Control and Prevention. Symptoms of Coronavirus. 2020  March 
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Gudbjartsson, D.F., et al., Spread of SARS-CoV-2 in the Icelandic Population. N Engl J 
Med, 2020. 
24. 
Day, M., Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ, 
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Centers for Disease Control and Prevention. COVID-19 Pandemic Planning Scenarios. 
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Lipsitch, M., et al., Transmission dynamics and control of severe acute respiratory 
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Peiris, J.S., et al., Clinical progression and viral load in a community outbreak of 
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Tsang, T.K., et al., Influenza A Virus Shedding and Infectivity in Households. J Infect 
Dis, 2015. 212(9): p. 1420-8. 
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Seow, J., et al., Longitudinal evaluation and decline of antibody responses in SARS-
CoV-2 infection. medRxiv, 2020: p. 2020.07.09.20148429. 
30. 
Long, Q.X., et al., Clinical and immunological assessment of asymptomatic SARS-CoV-2 
infections. Nat Med, 2020. 
31. 
Diao, B., et al., Reduction and Functional Exhaustion of T Cells in Patients With 
Coronavirus Disease 2019 (COVID-19). Front Immunol, 2020. 11: p. 827. 
32. 
Grifoni, A., et al., Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans 
with COVID-19 Disease and Unexposed Individuals. Cell, 2020. 181(7): p. 1489-1501 
e15. 
33. 
Modjarrad, K., et al., Safety and immunogenicity of an anti-Middle East respiratory 
syndrome coronavirus DNA vaccine: a phase 1, open-label, single-arm, dose-escalation 
trial. Lancet Infect Dis, 2019. 19(9): p. 1013-1022. 
34. 
Suschak, J.J., J.A. Williams, and C.S. Schmaljohn, Advancements in DNA vaccine 
vectors, non-mechanical delivery methods, and molecular adjuvants to increase 
immunogenicity. Hum Vaccin Immunother, 2017. 13(12): p. 2837-2848. 
35. 
Manickan, E., K.L. Karem, and B.T. Rouse, DNA Vaccines - A Modern Gimmick or a 
Boon to Vaccinology? Crit Rev Immunol, 2017. 37(2-6): p. 483-498. 
36. 
Porter, K.R. and K. Raviprakash, DNA Vaccine Delivery and Improved Immunogenicity. 
Curr Issues Mol Biol, 2017. 22: p. 129-138. 
37. 
Li, L. and N. Petrovsky, Molecular mechanisms for enhanced DNA vaccine 
immunogenicity. Expert Rev Vaccines, 2016. 15(3): p. 313-29. 
38. 
Marc, M.A., E. Dominguez-Alvarez, and C. Gamazo, Nucleic acid vaccination strategies 
against infectious diseases. Expert Opin Drug Deliv, 2015. 12(12): p. 1851-65. 
39. 
Grunwald, T. and S. Ulbert, Improvement of DNA vaccination by adjuvants and 
sophisticated delivery devices: vaccine-platforms for the battle against infectious 
diseases. Clin Exp Vaccine Res, 2015. 4(1): p. 1-10. 
40. 
Tregoning, J.S. and E. Kinnear, Using Plasmids as DNA Vaccines for Infectious 
Diseases. Microbiol Spectr, 2014. 2(6). 
41. 
Williams, J.A., Improving DNA vaccine performance through vector design. Curr Gene 
Ther, 2014. 14(3): p. 170-89. 
42. 
Liu, M.A., DNA vaccines: an historical perspective and view to the future. Immunol Rev, 
2011. 239(1): p. 62-84. 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 91 of 93 
 
43. 
Wahren, B. and M.A. Liu, DNA Vaccines: Recent Developments and the Future. 
Vaccines (Basel), 2014. 2(4): p. 785-796wahren. 
44. 
Ledgerwood, J.E. and B.S. Graham, DNA vaccines: a safe and efficient platform 
technology for responding to emerging infectious diseases. Hum Vaccin, 2009. 5(9): p. 
623-6. 
45. 
Keefer, M.C., et al., Studies of high doses of a human immunodeficiency virus type 1 
recombinant glycoprotein 160 candidate vaccine in HIV type 1-seronegative humans. 
The AIDS Vaccine Clinical Trials Network. AIDS Res Hum Retroviruses, 1994. 10(12): p. 
1713-23. 
46. 
Wu, F., et al., Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered 
patient cohort and their implications. Medrxiv Preprint, 2020. 
47. 
Martin, J.E., et al., A DNA vaccine for Ebola virus is safe and immunogenic in a phase I 
clinical trial. Clin Vaccine Immunol, 2006. 13(11): p. 1267-77. 
48. 
Prud'homme, G.J., et al., Electroporation-enhanced nonviral gene transfer for the 
prevention or treatment of immunological, endocrine and neoplastic diseases. Curr Gene 
Ther, 2006. 6(2): p. 243-73. 
49. 
Hirao, L.A., et al., Combined effects of IL-12 and electroporation enhances the potency 
of DNA vaccination in macaques. Vaccine, 2008. 26(25): p. 3112-20. 
50. 
Rosati, M., et al., Increased immune responses in rhesus macaques by DNA vaccination 
combined with electroporation. Vaccine, 2008. 26(40): p. 5223-9. 
51. 
Curcio, C., et al., DNA immunization using constant-current electroporation affords long-
term protection from autochthonous mammary carcinomas in cancer-prone transgenic 
mice. Cancer Gene Ther., 2008. 15(2): p. 108-114. 
52. 
Ugen, K.E., et al., Regression of subcutaneous B16 melanoma tumors after intratumoral 
delivery of an IL-15-expressing plasmid followed by in vivo electroporation. Cancer Gene 
Ther., 2006. 13(10): p. 969-974. 
53. 
Tebas, P., et al., Safety and Immunogenicity of an Anti-Zika Virus DNA Vaccine - 
Preliminary Report. N Engl J Med, 2017. 
54. 
Tebas, P., et al., Intradermal SynCon(R) Ebola GP DNA Vaccine is Temperature Stable 
and Safely Demonstrates Cellular and Humoral Immunogenicity Advantages in Healthy 
Volunteers. J Infect Dis, 2019. 
55. 
De Rosa, S.C., et al., Robust antibody and cellular responses induced by DNA-only 
vaccination for HIV. JCI Insight, 2020. 5(13). 
56. 
Chandrashekar, A., et al., SARS-CoV-2 infection protects against rechallenge in rhesus 
macaques. Science, 2020. 
57. 
Patel, A., et al., Intradermal-delivered DNA vaccine provides anamnestic protection in a 
rhesus macaque SARS-CoV-2 challenge model. bioRxiv, 2020: p. 2020.07.28.225649. 
58. 
Andrade, V.M., et al., INO-4800 DNA Vaccine Induces Neutralizing Antibodies and T cell 
Activity Against Global SARS-CoV-2 Variants. bioRxiv, 2021: p. 2021.04.14.439719. 
59. 
Gary E., W.B.M., Parzych E.M., Griffin B.D., Zhu X., Tailor N., Tursi N.J., Chan M., 
Purwar M., Vendramelli R., Choi J., Frost K.L, Reeder S., Liaw K., Tello E., Ali A.R., Yun 
K., Pei Y.,Thomas S.,Rghei A.D.,  Guilleman M.M., Muthumani K., Smith T., Wootton 
S.K., Patel A., Weiner D.B., Kobasa D., A novel mouse AAV6 hACE2 transduction 
model of wild-type SARS-CoV-2 infection studied using synDNA immunogens. iScience, 
2021. 
60. 
Gooch, K., et al., One or two dose regimen of the SARS-CoV-2 synthetic DNA vaccine 
INO-4800 protects against respiratory tract disease burden in nonhuman primate 
challenge model. Research Square 2021. 
61. 
Trevor, S. Development of INO-4800, a DNA-vaccine for COVID-19. in Keystone 
Symposia Antibodies and Vaccines as Drugs for COVID-19. 2021. 
62. 
European Commission, Directorate-General: A Guideline on Summary of Product 
Characteristics (SmPC). 2009, EMA. 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 92 of 93 
 
63. 
Diehl, M.C., et al., Tolerability of intramuscular and intradermal delivery by 
CELLECTRA((R)) adaptive constant current electroporation device in healthy volunteers. 
Hum Vaccin Immunother, 2013. 9(10): p. 2246-52. 
 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:30-Jul-2021 
CONFIDENTIAL 
Protocol Version: 1.0USA 
 
Page 93 of 93 
 
 APPENDICES 
 APPENDIX A: ADVERSE EVENTS OF SPECIAL INTEREST  
For the purpose of standardization across multiple vaccine platforms, including those substantially 
different from Inovio’s platform, the below table lists AEs of special interest (AESIs) relevant to 
COVID-19 vaccine development.  
Body System 
AESI 
Respiratory 
Acute respiratory distress syndrome (ARDS) 
Pneumonitis/Pneumonia 
Neurologic 
Generalized convulsion 
Aseptic meningitis 
Guillain-Barré Syndrome (GBS) 
Encephalitis/Myelitis 
Acute disseminated encephalomyelitis (ADEM) 
CNS vasculopathy (stroke) 
Bell’s Palsy 
Transverse myelitis  
Narcolepsy 
Hematologic 
Thrombocytopenia 
Immune thrombocytopenia (ITP) 
Disseminated intravascular coagulation (DIC) 
Hemorrhagic stroke 
Non-hemorrhagic stroke 
Deep Vein Thrombosis (DVT) 
Pulmonary Embolism (PE) 
Immunologic 
Anaphylaxis 
Vasculitides 
Cardiac  
Acute cardiac failure 
Myocarditis/pericarditis 
Acute myocardial infarction 
Other 
Septic shock-like syndrome 
Appendicitis 
Multisystem Inflammatory Syndrome 
Acute kidney failure 
 
Page 674 of 768


 
 
CONFIDENTIAL 
 
Page 1 of 94 
 
 
 
 
 
 
 
 
COVID19-311 
 
Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the Safety, 
Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-
19 Disease, Administered Intradermally Followed by Electroporation in Adults at 
High Risk of SARS-CoV-2 Exposure   
 
 
 
INNOVATE 
(Inovio INO-4800 Vaccine Trial for Efficacy) 
 
 
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
IND #: 19690 
WHO UTN: U1111-1266-9952 
 
 
Protocol Version: 2.0USA 
 
Protocol Version Date: 08-Oct-2021 
 
Page 675 of 768


INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 2 of 94 
 
 
Medical Monitor Approval Page 
 
Drug:  
INO-4800 
 
Sponsor: 
Inovio Pharmaceuticals, Inc. 
 
660 W. Germantown Pike, Suite 110 
 
Plymouth Meeting, PA 19462 
 
Medical Monitor: 
 
, Jr., M.D., FACP, FIDSA 
Inovio Pharmaceuticals, Inc. 
 
 
Approval Signature: 
 
 
[Electronically signed] 
  
Jr., M.D., FACP, FIDSA 
Inovio Pharmaceuticals, Inc. 
 
 Date (ddMmmyyyy) 
 
 
CONFIDENTIAL 
The information in this document is considered privileged and confidential by Inovio 
Pharmaceuticals Inc. (INOVIO) and may not be disclosed to others except to the extent 
necessary to obtain Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics 
Committee (EC) approval and informed consent, or as required by local regulatory 
authorities. Persons to whom this information is disclosed must be informed that this 
information is privileged and confidential and that it should not be further disclosed 
without the written permission of INOVIO. Any supplemental information added to this 
document is also confidential and proprietary information of INOVIO and must be kept in 
confidence in the same manner as the contents of this document. 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 3 of 94 
 
 
Principal Investigator Acknowledgement 
 
I have read and understood this Protocol and agree that it contains all details necessary to 
conduct the clinical trial. I understand that it must be reviewed by the Institutional Review Board 
(IRB)/Research Ethics Board (REB)/Ethics Committee (EC) overseeing the conduct of the clinical 
trial and approved or given favorable opinion before implementation. 
 
The Principal Investigator’s (PI’s) signature constitutes the PI’s approval of this Protocol and 
provides the necessary assurances that this clinical trial will be conducted in accordance with 
International Council for Harmonization (ICH)/Good Clinical Practice (GCP), local legal and 
regulatory requirements, and all stipulations of the Protocol. 
 
 
Principal Investigator Signature: 
 
 
 
 
Principal Investigator Printed Name 
 
 
 
 
 
Principal Investigator Signature 
 
Date (ddMmmyyyy) 
 
 
 
Clinical Trial Site Number: 
 
Clinical Trial Site Name: 
 
 
 
 
 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 4 of 94 
 
SUMMARY OF CHANGES 
 
The following is a list of significant changes from Version 1.0USA, dated 30-Jul-2021, to Version 
2.0USA, dated 08-Oct-2021. All other changes are administrative and do not significantly affect 
the safety of subjects, trial scope, or scientific integrity of the protocol. 
 
- 
Based upon the wide availability of EUA and licensed vaccines in the US and completion 
of the data collection towards the Phase 3 dose selection, the Sponsor recognizes that 
subjects may want to know whether they received INO-4800 or placebo in order to make 
fully informed choices about receiving a non-study prophylactic COVID-19 vaccine (either 
authorized under emergency use or when licensed). Therefore, the Phase 2 segment of 
the study will be unblinded after all subjects have reached the Week 30 Visit timepoint. 
- 
Clarifications have been included within the stopping rules (Section 7.8.4) to clarify that 
stopping rules apply to both IP and device related events. 
- 
Clarifications have been included within the instructions for reporting of device-related 
complaints or deficiencies (Section 7.13) to clarify that the Sponsor will review any 
reported device complaints for potential hazards that could cause an SAE and determine 
whether the Safety Review Committee (SRC) Chair should be notified. 
 
 
 
  
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 5 of 94 
 
TABLE OF CONTENTS 
Summary of Changes ................................................................................................................ 4 
Table of Contents ....................................................................................................................... 5 
Clinical Protocol Synopsis .........................................................................................................10 
Table 3 – Phase 2 Segment Schedule of Events ......................................................................21 
Table 4 – Phase 3 Segment Schedule of Events ......................................................................23 
 
Introduction .................................................................................................................25 
 
Background and Scientific Rationale ........................................................................... 25 
 
Background Information .............................................................................................. 25 
 
Clinical Presentation, Transmission and Immune Response .................................26 
 
Current Treatment and Unmet Need .....................................................................27 
 
Rationale for prophylactic vaccine development ......................................................... 28 
 
DNA Vaccines.......................................................................................................28 
 
Use of Electroporation with DNA Vaccines ...........................................................29 
 
Inovio’s Proprietary Technology Against COVID-19 ..............................................29 
 
Nonhuman Primate (NHP) Challenge Studies Following Vaccination with INO-4800
 .............................................................................................................................30 
 
First-In-Human Phase 1 Trial of INO-4800 ............................................................30 
 
Proposed Phase 2/3 Trial of INO-4800 .................................................................31 
1.3.6.1 Safety and tolerability of INO-4800 .......................................................................32 
1.3.6.2 Nonclinical INO-4800 Data in Support of Potential Efficacy...................................32 
1.3.6.3 Potential Role of INO-4800 as a Booster ..............................................................32 
1.3.6.4 Thermostability of INO-4800 .................................................................................32 
 
Dose and Regimen Rationale ...............................................................................33 
1.3.7.1 Binding Antibody Response ..................................................................................33 
1.3.7.2 Neutralizing Antibody Response ...........................................................................33 
1.3.7.3 ELISPOT analysis .................................................................................................34 
 
Risks and Potential Benefits ....................................................................................... 34 
 
Potential Benefits ..................................................................................................34 
 
Product Risks........................................................................................................34 
 
Overall Benefit/Risk Conclusion ............................................................................36 
 
Objectives and Purpose ..............................................................................................36 
 
Hypothesis .................................................................................................................. 36 
 
Clinical Trial Design and Endpoints ............................................................................37 
 
Primary Objectives ...................................................................................................... 38 
 
Primary Endpoints....................................................................................................... 39 
 
Secondary Objectives ................................................................................................. 39 
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Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
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Protocol Version: 2.0USA 
 
Page 6 of 94 
 
 
Secondary Endpoints .................................................................................................. 39 
 
Exploratory Objective .................................................................................................. 40 
 
Exploratory Endpoints ................................................................................................. 40 
 
Efficacy Assessment (Phase 3 Segment Only) ........................................................... 41 
 
Case Definition for Virologically-confirmed COVID-19 Disease: ............................41 
 
Case Definition for SARS-CoV-2 Asymptomatic Infection .....................................42 
 
Safety Assessment ..................................................................................................... 42 
 
Immunogenicity Assessment ...................................................................................... 42 
 
Clinical Trial Population ..............................................................................................42 
 
Inclusion Criteria ......................................................................................................... 42 
 
Phase 2 Segment .................................................................................................42 
 
Phase 3 Segment .................................................................................................43 
 
Exclusion Criteria ........................................................................................................ 44 
 
Phase 2 Segment .................................................................................................44 
 
Phase 3 Segment .................................................................................................46 
 
Discontinuation/Withdrawal of Clinical Trial Subjects .................................................. 47 
 
Clinical Trial Investigational Product Information .........................................................48 
 
Investigational Product (IP) and Study Device ............................................................ 48 
 
INO-4800 and Placebo .........................................................................................48 
 
CELLECTRA® 2000 ..............................................................................................48 
 
Dosing Regimens ....................................................................................................... 50 
 
Blinding .................................................................................................................50 
 
Packaging and Labeling .............................................................................................. 50 
 
INO-4800 or Placebo ............................................................................................50 
 
CELLECTRA® 2000 ..............................................................................................51 
 
Handling and Storage ................................................................................................. 51 
 
INO-4800 and Placebo .........................................................................................51 
 
CELLECTRA® 2000 ..............................................................................................51 
 
Preparation and Dispensing ........................................................................................ 51 
 
Use of Study Device ................................................................................................... 52 
 
Investigational Drug and Study Device Accountability ................................................. 52 
 
Investigational Product (IP) Accountability ............................................................52 
 
CELLECTRA® 2000 Accountability .......................................................................52 
 
Return and Destruction of Investigational Drug and Study Device .............................. 52 
 
INO-4800 and Placebo .........................................................................................52 
 
Return of CELLECTRA® 2000...............................................................................52 
 
Clinical Trial Procedures and Schedule ......................................................................53 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 7 of 94 
 
 
Procedure by Visit ....................................................................................................... 53 
 
Clinical Trial Screening Evaluations ......................................................................53 
6.1.1.1 Medical History .....................................................................................................54 
 
Clinical Trial Evaluations and Procedures .............................................................54 
6.1.2.1 Day 0 and Day 28 (Dosing Visits) .........................................................................54 
6.1.2.2 Post-dose phone calls ...........................................................................................55 
6.1.2.3 Day 42 Visit ..........................................................................................................56 
6.1.2.4 Phone calls ...........................................................................................................56 
6.1.2.5 Follow up clinic visits.............................................................................................56 
6.1.2.6 Day 393 Visit or EOS ............................................................................................57 
6.1.2.7 COVID-19 Assessment Visit .................................................................................57 
6.1.2.8 COVID-19 Convalescent Visit ...............................................................................58 
 
Informed Consent ....................................................................................................... 58 
 
Assignment of Subject Identification Numbers ............................................................ 59 
 
Safety Evaluations ...................................................................................................... 59 
 
Intradermal Injection and EP .................................................................................61 
 
Management of Pain Due to Electroporation (EP) Procedures ..............................62 
 
Assessment of Laboratory Abnormalities ..............................................................62 
 
Assessment of Clinical Trial Adverse Events (AEs) ..............................................63 
 
Assessment of Injection Site Reactions ................................................................63 
 
Concomitant Medications/Treatments ...................................................................64 
 
Restrictions ...........................................................................................................64 
 
SARS-CoV-2 Testing ............................................................................................65 
 
COVID-19 Disease Monitoring ..............................................................................65 
 
Immunogenicity Assessments ..................................................................................... 66 
 
Evaluation of Safety and Management of Toxicity ......................................................67 
 
Safety Parameters ...................................................................................................... 67 
 
Adverse Events (AEs) ................................................................................................. 67 
 
Adverse Drug Reaction (ADR) .................................................................................... 67 
 
Serious Adverse Events (SAEs) .................................................................................. 68 
 
Unexpected Adverse Drug Reaction ........................................................................... 68 
 
Unanticipated (Serious) Adverse Device Effect (UADE) .............................................. 69 
 
Device Deficiency ....................................................................................................... 69 
 
Safety and Toxicity Management ................................................................................ 69 
 
Adverse Event of Special Interest (AESI) ..............................................................69 
 
Medically Attended Adverse Event (MAAE) ..........................................................69 
 
Abnormal Laboratory Value ..................................................................................69 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 8 of 94 
 
 
Clinical Trial Stopping Rules .................................................................................70 
 
Safety Data Reporting Period, Method of Collection and Submission ......................... 70 
 
Adverse Event Reporting ............................................................................................ 71 
 Submitting the Initial Serious Adverse Event (SAE) Report Form..........................71 
 Recording the Event .............................................................................................72 
 Assessing Severity (Intensity) ...............................................................................72 
 Causal Relationship of Clinical Material to Adverse Events (AEs) .........................72 
 
Reporting Suspected COVID-19 Disease Cases During the Trial ............................... 73 
 
Reporting Pregnancy During the Clinical Trial ............................................................. 73 
 
Reporting Device-Related Complaints or Deficiencies ................................................ 74 
 
Notifying Regulatory Authorities and Institutional Review Boards (IRBs)/Research 
Ethics Boards (REBs)/Ethics Committees (ECs) of Safety Information ....................... 74 
 Sponsor Responsibilities .......................................................................................74 
 Principal Investigator (PI) Responsibilities ............................................................75 
 
Post-Trial Reporting Requirements ............................................................................. 75 
 
Clinical Trial Discontinuation ....................................................................................... 75 
 
Statistical Considerations ...........................................................................................75 
 
Statistical and Analytical Plan ..................................................................................... 75 
 
General Considerations .............................................................................................. 75 
 
Statistical Hypotheses ................................................................................................. 76 
 
Analytical Populations ................................................................................................. 76 
 
Description of Statistical Methods ............................................................................... 76 
 
Primary Analysis ...................................................................................................76 
 
Secondary Analyses .............................................................................................77 
 
Safety Analyses ....................................................................................................78 
 
Disposition ............................................................................................................79 
 
Demographic and Other Baseline Characteristics .................................................79 
 
Interim Analyses ...................................................................................................79 
 
Multiplicity .............................................................................................................80 
 
Missing Values......................................................................................................80 
 
Exploratory Analyses ............................................................................................80 
 
Sample Size/Power ..................................................................................................... 81 
 
Randomization and Blinding ....................................................................................... 82 
 
Ethics .........................................................................................................................82 
 
Investigator and Sponsor Responsibilities ................................................................... 82 
 
Institutional Review Board (IRB)/Research Ethics Board (REB)/Ethics Committee (EC)
 ................................................................................................................................... 82 
 
Protection of Human Subjects ..................................................................................... 83 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 9 of 94 
 
 
Compliance with Informed Consent Regulations ...................................................83 
 
Compliance with Institutional Review Board (IRB)/Research Ethics Board 
(REB)/Ethics Committee (EC) Requirements ........................................................83 
 
Compliance with Good Clinical Practice ................................................................83 
 
Compliance with Electronic Records/Signatures Regulations (21CFR Part 11) .....83 
 
Compliance with Protocol .....................................................................................84 
 
Changes to the Protocol .......................................................................................84 
 
Data Collection, Monitoring and Reporting ..................................................................84 
 
Confidentiality and Privacy .......................................................................................... 84 
 
Source Documents .....................................................................................................84 
 
Records Retention ...................................................................................................... 85 
 
Safety and Quality Monitoring .....................................................................................85 
 
Safety Review ............................................................................................................. 85 
 
Clinical Monitoring....................................................................................................... 86 
 
Financing and Insurance ............................................................................................86 
 
Publication Policy .......................................................................................................87 
 
List of Abbreviations ...................................................................................................88 
 
References .................................................................................................................90 
 
Appendices .................................................................................................................94 
 
APPENDIX A: Adverse Events of Special Interest ...................................................... 94 
 
 
 
 
Page 683 of 768


INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 10 of 94 
 
CLINICAL PROTOCOL SYNOPSIS 
Protocol Title: Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the 
Safety, Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine against COVID-19 
Disease, Administered Intradermally Followed by Electroporation in Adults at High Risk of 
SARS-CoV-2 Exposure 
Protocol Number: COVID19-311 
Clinical Trial Phase: 2/3 
Estimated Number of Clinical Trial Centers and Countries/Regions: Approximately 50 
centers globally. Final country list to be determined. 
Background:   
INO-4800 is a prophylactic vaccine under development against SARS-CoV-2, the causative 
agent of COVID-19. INO-4800 contains the plasmid pGX9501, which encodes for the full 
length of the Spike glycoprotein of SARS-CoV-2. The goal of this trial is to assess the safety, 
immunogenicity and efficacy of INO-4800 to prevent COVID-19 in subjects at high risk of 
exposure to SARS-CoV-2.  
 
Clinical Trial Design:  
This is an operationally seamless Phase 2/3, randomized, placebo-controlled, multi-center trial 
to evaluate the safety, immunogenicity, and efficacy of INO-4800, administered by intradermal 
(ID) injection followed immediately by electroporation (EP) using the CELLECTRA® 2000 
device, in a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-2 
exposure. The primary objectives of this trial are to identify in seronegative subjects an optimal 
age-related dose of INO-4800 in the Phase 2 segment for a subsequent efficacy evaluation in 
the Phase 3 segment.  
 
Subjects 18 years of age and older are expected to be enrolled across two (2) segments of 
this study. In the Phase 2 segment, approximately 400 seronegative subjects will be enrolled. 
In the Phase 3 segment, approximately 6714 seronegative subjects are expected to be 
enrolled, and 402 seropositive subjects will be enrolled. The subjects and data from Phase 2 
are independent from that of Phase 3. 
 
Phase 2 Segment – Dose Selection 
In the Phase 2 segment, approximately 400 subjects 18 years of age and older will be 
evaluated across four (4) dose groups (Table 1, Figure 1). Subjects will be randomized at a 
3:3:1:1 ratio to receive either active investigational product (INO-4800) or placebo (placebo for 
INO-4800) according to Table 1 below. Dose groups receiving INO-4800 will enroll 
approximately 150 subjects per group. Dose groups receiving placebo will enroll approximately 
50 subjects per group. Randomization will be such that approximately 240 subjects aged 18-
50 years, 120 subjects aged 51-64 years and 40 subjects aged ≥ 65 years will be enrolled. 
Initial enrollment will include subjects aged 18-50 years. Initiation of enrollment of older 
subjects 51-64 years of age and elderly subjects 65 years and older will depend on review of 
safety and immunogenicity data from those age groups generated in the Phase 1 study 
(COVID19-001).   
 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 11 of 94 
 
Table 1: Phase 2 Segment Dose Groups 
Study  
Group 
Expected 
Number of 
Subjects 
Dosing 
Days 
Number of 
Injections + EP 
per Dosing Visit 
INO-4800 
(mg) per 
injection 
INO-4800 
(mg) per 
Dosing Visit 
Total Dose 
(mg) 
INO-4800 
150 
0, 28 
1 
1.0 
1.0 
2.0 
INO-4800 
150 
0, 28 
2a 
1.0 
2.0 
4.0 
Placebo 
50 
0, 28 
1 
0 
0 
0 
Placebo 
50 
0, 28 
2a 
0 
0 
0 
Total 
400 
 
 
 
 
 
aINO-4800 or placebo will be injected ID followed immediately by EP in an acceptable location on two different limbs at each 
dosing visit. 
 
Dose selection for evaluation of efficacy in the Phase 3 segment will be based on Week 6 
immunogenicity data and Week 8 safety data from the Phase 2 segment. Group-level unblinded 
summaries and analyses of safety will be produced once the Week 8 phone call visit data are 
completed for all subjects in the Phase 2 segment. Group-level unblinded summaries and 
analyses of immunogenicity will be produced once the Week 6 visit data are completed for all 
subjects in the Phase 2 segment. Subject treatment assignments will be unblinded after Phase 
2 subjects have reached the Week 30 visit. 
 
Phase 3 Segment – Efficacy 
In the Phase 3 segment, approximately 6714 seronegative and 402 seropositive subjects 18 
years of age and older will be randomized at a 2:1 ratio to receive either active investigational 
product (INO-4800, 2.0 mg) or placebo (placebo for INO-4800). See Table 2 and Figure 1.  
Approximately half of seronegative subjects and approximately half of seropositive subjects 
will be 18-50 years of age, and the other half will be ≥51 years of age as is operationally 
feasible. Also, approximately 711 subjects will be ≥65 years of age, if operationally feasible. 
 
Subjects will be randomized in a stratified manner according to (a) age category (18-50 years 
vs. ≥51 years) on Day 0, and (b) presence or absence on Day 0 of any of the following 
underlying medical conditions that increase risk of severe COVID-19 disease, per U.S. Center 
for Disease Control (CDC) criteria [1], as listed below: 
• 
Cancer 
• 
Chronic kidney disease 
• 
Chronic lung diseases, including Chronic obstructive pulmonary disease (COPD), 
asthma (moderate-to-severe), interstitial lung disease, cystic fibrosis, pulmonary 
hypertension 
• 
Neurologic conditions including stroke or cerebrovascular disease that do not impact 
cognition 
• 
Diabetes (type 1 or type 2) 
• 
Hypertension 
• 
Heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies 
• 
HIV infection (CD4 count >200 cells/mm3 or undetectable viral load) 
• 
Liver disease 
• 
Obesity (BMI ≥ 30 kg/m2) 
• 
Sickle cell disease or thalassemia, or 
• 
Smoking (current or former smoker). 
 
 
 
Page 685 of 768


INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 12 of 94 
 
Table 2: Phase 3 Segment  
Treatment 
Arm 
Sero 
status 
Expected 
Number 
of 
Subjects 
Approx. 
Expected 
Number of 
Subjects by 
Age Group 
Dosing 
Days 
Number of 
Injections + 
EP per 
Dosing Visit 
INO-4800 
(mg) per 
injection 
INO-4800 
(mg) per 
Dosing Visit 
Total Dose 
of 
INO-4800 
(mg) 
18-50 
51+a 
INO-4800 
Seroneg 
4476 
2238 
2238 
0, 28 
2 
1.0 
2.0 
4.0 
Seropos 
268 
134 
134 
Placebo 
Seroneg 
2238 
1119 
1119 
0, 28 
2 
0 
0 
0 
Seropos 
134 
67 
67 
Total 
Seroneg 
6714 
3357 
3357 
 
 
 
 
 
Seropos 
402 
201 
201 
 
 
 
 
 
Total 
7116 
 
 
 
 
 
 
 
 
aat least 711 subjects will be ≥65 years of age 
 
This segment of the trial is case-driven. Among seronegative subjects, a total of 149 observed 
cases will be required for 90% power to declare the vaccine efficacious (>30%), assuming a 
true efficacy of 60%. A sample size of 6714 seronegative subjects is expected to be required 
to achieve the 149 cases assuming an underlying attack rate of 3.7%. The actual sample size 
may differ if the observed attack rate is different than projected.  There are two formal interim 
analyses of efficacy; one when 50% of the cases accrue and one when 75% of the cases 
accrue. If the prespecified criteria for efficacy are met at either interim analysis, then enrollment 
will continue until 4500 subjects have been enrolled, and blinded follow-up will continue until 
at least those 4500 subjects have a minimum of 6 months of safety follow-up. At that point, the 
trial would be unblinded and placebo-recipients will be offered the active product.    
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12 months 
post-dose 2. All Phase 3 segment subjects will be followed for 56 weeks from the Day 0 dosing 
[i.e., Week 56 will be the planned End of Study (EOS) visit for this segment of the trial]. 
 
Figure 1: Enrollment and Dose Group Design 
 
 
 
External Committee Reviews 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will convene 
regularly to review all available unblinded safety data. For the Phase 3 segment, the DSMB 
will also review efficacy in an unblinded fashion. Additionally, for the Phase 3 segment, an 
independent, blinded Endpoint Adjudication Committee (EAC) will review and confirm COVID-
19 cases.  
 
Details of each committee’s scope will be provided in the respective charters. 
Page 686 of 768


INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 13 of 94 
 
  
Criteria for Evaluation:  
 
Research Hypothesis:  
INO-4800 delivered ID followed immediately by EP will be well-tolerated, exhibit an acceptable 
safety profile, result in generation of cellular and humoral immune responses to SARS-CoV-2 
Spike glycoprotein and provide protection against virologically-confirmed COVID-19 disease in 
subjects at high risk of SARS-CoV-2 exposure.  
 
Phase 2 Segment Objectives and Endpoints: 
 
Primary Objective 
Primary Endpoint 
1.  Evaluate the cellular and humoral 
immune response to INO-4800 
administered by ID injection followed 
immediately by EP  
  
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot 
1b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
Secondary Objective 
Secondary Endpoints 
1.  Evaluate the safety and tolerability of 
INO-4800 administered by ID injection 
followed immediately by EP    
  
1a. Incidence of solicited and unsolicited injection site 
reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)   
Exploratory Objective 
Exploratory Endpoint 
1.  Evaluate the expanded immunological 
profile of antibody response and T cell 
immune response 
  
1a.  Antigen-specific cellular immune response 
measured by flow cytometry 
1b. Expanded immunological profile which may 
include additional assessments of T and B cell 
numbers and molecular changes by measuring 
immunologic proteins and mRNA levels of genes 
of interest as determined by sample availability 
 
Phase 3 Segment Objectives and Endpoints: 
 
Primary Objective 
Primary Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease in 
subjects who are SARS-CoV-2 
negative at baseline  
 
1.   Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 (End 
of Study (EOS)) in subjects who are SARS-CoV-2 
seronegative at baseline 
Secondary Objectives 
Secondary Endpoints 
1. Evaluate the safety and tolerability of 
INO-4800    
 
1a. Incidence of solicited and unsolicited injection site 
reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 14 of 94 
 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality 
 
2.  Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of severity in 
subjects who are SARS-CoV-2 
seronegative at baseline       
2a.  Incidence of non-severe COVID-19 disease in 
SARS-CoV-2 seronegative subjects starting 14 
days after completion of the 2-dose regimen until 
EOS  
2b. Incidence of severe COVID-19 disease in SARS-
CoV-2 seronegative subjects starting 14 days after 
completion of the 2-dose regimen until EOS 
2c. Incidence of deaths due to COVID-19 in SARS-
CoV-2 seronegative subjects starting 14 days after 
completion of the 2-dose regimen until EOS 
3.  Evaluate the cellular and humoral 
immune response to INO-4800  
3a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot  
3b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
 
4. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease in 
subjects who are SARS-CoV-2 
seropositive at baseline  
 
4.  Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 (End 
of Study (EOS)) in subjects who are SARS-CoV-
2 seropositive at baseline 
Exploratory Objective 
Exploratory Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease 
from SARS-CoV-2 variants in subjects 
who are SARS-CoV-2 seronegative at 
baseline 
1. Incidence of virologically-confirmed COVID-19 
disease from a SARS-CoV-2 variant starting 14 
days after completion of the 2-dose regimen until 
12 months post-dose 2 (End of Study (EOS)) in 
subjects who are SARS-CoV-2 seronegative at 
baseline 
2. Evaluate the efficacy of INO-4800 in 
the prevention of SARS-CoV-2 
asymptomatic infection in subjects 
who are SARS-CoV-2 seronegative at 
baseline     
2. Incidence of SARS-CoV-2 asymptomatic 
infections in SARS-CoV-2 seronegative subjects 
starting 14 days after completion of the 2-dose 
regimen until EOS 
3.  Evaluate the immunological profile by 
assessing both antibody response and 
T cell immune response  
3a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels  
3b. Antigen-specific cellular immune response such as 
measured by flow cytometry  
4. Evaluate antibody persistence  
4a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels at Week 30 or later.  
4b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay at Week 
30 or later 
 
 
Immunogenicity Assessment:  
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 15 of 94 
 
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 3 and Table 4).  Assays such as binding enzyme-linked immunosorbent assay (ELISA), 
pseudovirus-based neutralization assay, and enzyme-linked immunosorbent spot-forming 
assay (ELISpot) will be evaluated at serial timepoints. 
Safety Assessment:  
Subjects will be followed for safety during the trial through scheduled clinic visits and phone 
calls. Adverse events (AEs), regardless of relationship to study drug, will be collected from 
the time of consent until 28 days post-dose 2 (i.e., Day 56). SAEs, Medically Attended Adverse 
Events (MAAEs) and AESIs will be collected from time of consent until EOS. SAEs, AESIs 
and treatment-related AEs will be followed to resolution or stabilization. For the Phase 2 
segment and at selected sites in the Phase 3 segment, solicited local and systemic AEs will 
be collected for 7 days following each dose using a participant diary. 
Subjects will also be monitored for COVID-19.  
Please refer to the Schedule of Events (Table 3 and Table 4) for safety assessments to be 
performed.  
Efficacy Assessment (Phase 3 segment only):  
Subjects will receive either active investigational product (INO-4800) or placebo (placebo for 
INO-4800) in a 2-dose regimen administered on Days 0 and 28 intradermally followed 
immediately by EP. Subjects will be monitored through regularly scheduled clinic visits and 
phone calls throughout the trial. Subjects will be regularly tested for SARS-CoV-2 infection 
using serologic testing. If COVID-19 disease is suspected based on symptoms per the case 
definition or laboratory testing, site personnel will arrange for a clinic visit. Subjects with 
symptom(s) or a positive SARS-CoV-2 test result will be reviewed by the EAC. 
Clinical Trial Population: 
Phase 2 segment: Healthy subjects at high risk for SARS-CoV-2 exposure who are 18 years 
and older. 
Phase 3 segment: Subjects at high risk for SARS-CoV-2 exposure including subjects at high 
risk for severe COVID-19 who are 18 years and older. 
Inclusion Criteria: Phase 2 segment 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, vital signs and 
physical examination performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar 
workers, store cashiers, hairdressers and barbers, veterinary staff, daycare 
workers, Transportation Security Administration screening staff, school 
teachers and college professors teaching in-person classes) 
2. Factory workers (when working in confined settings with large numbers of 
employees) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) 
4. User of public transportation (e.g., bus, train, subway) at least 3 times weekly 
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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 16 of 94 
 
5. Nursing home staff or correctional facility staff  
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists.) Physicians should not be enrolled unless they 
are assigned to dedicated COVID-19 treatment wards or other settings with 
prolonged exposure 
10. Others, if approved by the medical monitor.   
f. Screening laboratory results within normal limits for testing laboratory or are deemed 
not clinically significant by the Investigator; 
g. Must meet one of the following criteria with respect to reproductive capacity: 
1. Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
2. Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or 
tubal ligation, absence of ovaries and/or uterus in females). In the case of 
vasectomy, subjects should wait six (6) months post-vasectomy prior to 
enrolling;  
3. Use of medically effective contraception with a failure rate of < 1% per year 
when used consistently and correctly from screening until 3 months following 
last dose. Acceptable methods include:  
i. hormonal contraception including implants, injections or oral; 
ii. two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
iii. intrauterine device or intrauterine system; 
iv. abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Inclusion Criteria: Phase 3 segment 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Per investigator judgment, healthy or stable with pre-existing medical conditions that 
do not require significant change in medication or have led to a hospitalization in the 3 
months prior to enrollment or who, in the judgment of the investigator, are unlikely to 
require a significant change in therapy or hospitalization for worsening disease through 
Day 56; 
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings. Examples 
include:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar 
workers, street vendors, store cashiers, hairdressers and barbers, veterinary 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 17 of 94 
 
staff, daycare workers, airport screening staff, school teachers and college 
professors teaching in-person classes, college students attending in-person 
classes, office workers and volunteers who have multiple brief exposures to 
people regularly) 
2. Factory workers (when working in confined settings with large numbers of 
employees, meat-packing facilities) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) and delivery 
services  
4. User of public transportation (e.g., bus, train, subway) or public facilities (e.g. 
gyms) at least 3 times weekly 
5. Nursing home staff or correctional facility staff 
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, medical assistants and technicians, respiratory therapists, 
physical therapists, social workers, dentists and dental hygienists)  
10. Others, if in the opinion of the PI, the risk of COVID-19 exposure is comparable 
to the examples above.   
f. Must meet one of the following criteria with respect to reproductive capacity: 
1. Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
2. Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or 
tubal ligation, absence of ovaries and/or uterus in females). In the case of 
vasectomy, subjects should wait six (6) months post-vasectomy prior to 
enrolling;  
3. Use of medically effective contraception with a failure rate of < 1% per year 
when used consistently and correctly from screening until last dose. Acceptable 
methods include:  
i. hormonal contraception including implants, injections or oral; 
ii. two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
iii. intrauterine device or intrauterine system; 
iv. abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 
Exclusion Criteria: Phase 2 segment 
a. Acute febrile illness with temperature >100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat); 
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the Screening visit until 3 
months following the last dose; 
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INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 18 of 94 
 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or a 
detectable viral load within the past 3 months; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous receipt of an investigational vaccine for prevention or treatment of COVID-19, 
MERS or SARS (documented receipt of placebo in previous trial would be permissible 
for trial eligibility); 
h. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg prior to first dose; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin 
cancers that only required local excision and non-metastatic prostate cancer 
not requiring treatment; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in 
therapy or hospitalization for worsening disease during the 6 weeks prior to 
enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a 
single antiepileptic agent; 
i. 
Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed); 
• 
Current or anticipated use of disease modifying doses of systemic anti-
rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, 
cyclosporine, 
methotrexate) and biologic disease modifying drugs such as TNF-α inhibitors 
(e.g., infliximab, adalimumab or etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the 
subject or require therapy that would interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results. 
j. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
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Clinical Protocol 
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Protocol Version: 2.0USA 
 
Page 19 of 94 
 
• 
Any metal implants or implantable medical device within the electroporation 
site; 
k. Blood donation or transfusion within 1 month prior to Day 0; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the past 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
 
Exclusion Criteria: Phase 3 segment 
a. Acute febrile illness with temperature ≥100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat) on Day 
0 prior to dosing; 
b. Positive serologic test for SARS-CoV-2 at Screening (this criterion only applies after 
approximately 402 subjects positive for SARS-CoV-2 serologic test are randomized, 
after which this criterion will apply to all remaining subjects); 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children starting from the Screening visit until the last dose; 
d. Positive urine pregnancy test during screening or immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or a 
detectable viral load within 3 months prior to screening; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days prior to Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous or planned receipt of an investigational (including Emergency Use 
Authorization (EUA) or local equivalent authorization) or licensed vaccine for 
prevention or treatment of COVID-19, MERS or SARS (documented receipt of placebo 
in previous trial would be permissible for trial eligibility); 
h. Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed) in the past 6 months; 
• 
Current or anticipated use of disease modifying doses of systemic anti-
rheumatic 
drugs 
(e.g., 
azathioprine, 
cyclophosphamide, 
cyclosporine, 
methotrexate) and biologic disease modifying drugs such as TNF-α inhibitors 
(e.g., infliximab, adalimumab or etanercept) or others; 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the 
subject or require therapy that would interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results. 
i. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 20 of 94 
 
• 
Any metal implants or implantable medical device within the electroporation 
site; 
j. 
Blood donation or transfusion within 1 month prior to Day 0; 
k. People who work remotely or in a socially distanced setting with minimal risk of 
exposure to SARS-CoV-2; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the prior 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
Clinical Trial Treatment: 
Phase 2 Segment 
Active Investigational Product: One or two 1.0mg ID injection(s) of INO-4800 (~0.1mL dose 
volume) followed immediately by EP administered on Day 0 and Day 28 (±3 days)  
Placebo: One or two ID injection(s) of saline sodium citrate buffer (SSC-0001) (~0.1mL) 
followed immediately by EP administered on Day 0 and Day 28 (±3 days) 
Phase 3 Segment 
Active Investigational Product: Two 1.0mg ID injections of INO-4800 followed immediately by 
EP administered in separate limbs at Day 0 and Day 28 (±3 days) 
Placebo: Two ID injections of placebo for INO-4800 followed immediately by EP administered 
in separate limbs at Day 0 and Day 28 (±3 days) 
Formulation: 
INO-4800 is formulated in sodium chloride and sodium citrate buffer, refrigerated. Placebo 
[sterile saline sodium citrate buffer (placebo for INO-4800)], refrigerated. 
 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
 
 
 
Protocol Version: 2.0USA 
 
Page 21 of 94 
 
TABLE 3 – PHASE 2 SEGMENT SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Tel 
#1 
Wk 
4 
Tel 
#2 
Wk
6 
Tel 
#3 
Wk 
30 
Wk 
56 
Illness 
Illness  
Screena 
Day 0 
Phone call - Day 7 (±3d) 
Day 28 
(±3d) 
Phone call - Day 35 (±3d) 
Day 42 (±5d) 
Phone Call - Day 56 (±5d) 
Day 210 (±5d) 
Day 393 (± 5d) 
COVID-19 assessment visitm  
COVID-19 convalescent visitn 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behavioral Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
Vital Signs 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
Xp 
Xp 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differentialc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Chemistryc 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
HIV Serology  
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis Routined 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Pregnancy Teste 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
 
INO-4800 or Placebo + EPf 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Download EP Datag 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Adverse Eventsh  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Samplesi 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
Humoral Samplesj 
 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
SARS-CoV-2 Serologyk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
SARS-CoV-2 RT-PCR (Saliva and Swabs) 
Xl 
 
 
 
 
 
 
 
 
 
 
Xl 
Xl 
Distribute Diary 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Review/Collect Diaryo 
 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
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Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
 
 
 
Protocol Version: 2.0USA 
 
Page 22 of 94 
 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0.   
b. 
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits.  
c. 
Hemoglobin A1c collected at screening only. Chemistry includes Na, K, Cl, HCO3, Ca, PO4, glucose, BUN, Cr, alkaline phosphatase, AST, ALT, LDH, total bilirubin.  
d. 
Dipstick for glucose, protein, and hematuria. Microscopic examination should be performed if dipstick is abnormal.  
e. 
Serum pregnancy test at Screening. Urine pregnancy test at other visits.  
f. 
Intradermal injection(s) in skin preferably over deltoid muscle, or alternately over anterolateral quadriceps muscle, followed by EP at Day 0 and Day 28. 
g. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
h. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
i. 
On Day 0, cellular sampling requires 64 mL of whole blood (8 Cell Preparation Tubes (CPT), each 8 mL of whole blood) prior to 1st dose. At all other time points, collect 32 mL of 
whole blood (4 CPT tubes, each 8 mL of whole blood).   
j. 
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce eight serum aliquots of 1 
mL each). At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce four serum aliquots of 1 mL each.  
k. 
SARS-CoV-2 antibody.   
l. 
Saliva specimen at Screening; Nasal swabs and saliva specimens at COVID-19 assessment and convalescent visits. Genotyping may also be performed on sample(s) collected at 
the COVID-19 assessment visit. 
m. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The assessment visit may be performed in the clinic, in the subject’s vehicle 
or at the subject’s home and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test.  
n. 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of 
symptoms, the date of positive SARS-CoV-2 test. If acute symptoms are ongoing, the site should follow up with the subject via phone call or an unscheduled visit after symptom 
resolution or stabilization.   
o. 
Diary should be reviewed at the 7-day post-dose phone call and collected at the next in-office visit. 
p. 
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation. 
 
 
 
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Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
CONFIDENTIAL 
 
 
 
Protocol Version: 2.0USA 
 
Page 23 of 94 
 
TABLE 4 – PHASE 3 SEGMENT SCHEDULE OF EVENTS 
Tests and assessments 
Sc 
D0 
Tel 
#1 
Wk 
4 
Wk
6 
Tel 
#2-6 
Wk 
18 
Tel 
#7-11 
Wk 
30 
Tel 
#12-13 
Wk
42 
Tel 
#14-16 
Wk 
56 
Illness 
Illness 
Screena 
Day 0 
Phone call - Day 14 (±3d) 
Day 28 
(±3d) 
Day 42 (±5d)k 
Phone call - Days 56, 70, 84, 
98, 112 (±5d) 
Day 126 (±5d) 
Phone calls - Days 140, 154 
168, 182, 196 (±5d) 
Day 210 (±5d) 
Phone calls - Days 238, 266 
(±5d) 
Day 294 (±5d) 
Phone calls 
Days 322, 350, 378 (±5d) 
Day 393 (± 5d) 
COVID-19 assessment visitl  
COVID-19 convalescent visitm 
Pre 
Post 
Pre 
Post 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behavioral Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examb 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Vital Signs 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Xn 
Xn 
Height and Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV Serology 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testc 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
INO-4800 or Placebo + EPd 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Download EP Datae 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Eventsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cellular Samplesg 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
X 
Humoral Samplesh 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Xr 
X 
SARS-CoV-2 Serologyi 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
SARS-CoV-2 RT-PCR 
(Nasopharyngeal swabs) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
 
Distribute Diaryp 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Review/Collect Diaryq 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
a. 
Screening assessment occurs from -30 days to -1 day of Day 0. Screening and Day 0 visits may be combined if eligibility is able to be confirmed prior to dosing. If so, all assessments 
for Screening and Day 0 must be performed at the combined visit.  
b. 
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits.  
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Clinical Protocol 
Protocol Version Date: 08-Oct-2021 
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Protocol Version: 2.0USA 
 
Page 24 of 94 
 
c. 
In women of childbearing potential. Urine pregnancy test at all indicated visits.  
d. 
Intradermal injection(s) in skin preferably over deltoid region, or alternately over anterolateral quadriceps region, followed by EP at Day 0 and Day 28. 
e. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
f. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
g. 
On Day 0, cellular sampling requires 64 mL of whole blood prior to 1st dose. At all other time points, collect 32 mL of whole blood. Cellular samples will be collected at selected clinical sites 
(estimated to include 711 subjects) 
h. 
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce four serum aliquots of 2 mL 
each). At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce two serum aliquots of 2 mL each.  
i. 
SARS-CoV-2 antibody. 
j. 
The Day 0 RT-PCR results will not be required prior to dosing on that day. 
k. 
Day 42 visit must occur at least 10 days after Day 28 visit. 
l. 
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The assessment visit may be performed in the clinic, subject’s vehicle, or at a 
home visit and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test.  
m. 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of 
symptoms, the date of positive SARS-CoV-2 test. If acute symptoms are ongoing the site should follow up with the subject via phone call or unscheduled visit after symptom resolution 
or stabilization 
n. 
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation.   
o. 
Genotyping may also be performed on sample(s) collected at the COVID-19 assessment visit.  
p. 
Diaries to be used at selected sites only (estimated to include 711 subjects). 
q. 
Diary should be reviewed at the 14-day post-dose phone call or visit and collected at the next in-office visit. 
r. 
When possible, cellular and humoral immunology samples will be collected. Cellular samples will be collected at selected sites only. 
 
 
 
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Clinical Protocol 
Protocol Version Date:08-Oct-2021 
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Protocol Version: 2.0USA 
 
Page 25 of 94 
 
 
INTRODUCTION 
This document is a protocol for a human research trial to be conducted according to U.S. 
and international standards of Good Clinical Practice (GCP) (FDA Title 21 part 312, 812 
and International Conference on Harmonization (ICH) guidelines), applicable government 
regulations and Institutional research policies and procedures. 
 
BACKGROUND AND SCIENTIFIC RATIONALE 
Given the continued number of cases globally, SARS-CoV-2 infections remain a serious 
unmet medical concern. Appropriate measures to prevent SARS-CoV-2 infections, 
including its variants, are not yet widely available. 
 
BACKGROUND INFORMATION 
In late 2019, a cluster of cases of pneumonia of unknown etiology was reported in Wuhan, 
Hubei province, China [2-4]. These cases were announced on January 6, 2020 as testing 
negative for influenza, severe acute respiratory syndrome (SARS), and Middle East 
respiratory syndrome (MERS). On January 7, 2020 a novel virus was isolated by the 
Chinese Center for Disease Control and Prevention (CDC) from the throat swab sample 
of a patient, and the isolate was named “Wuhan-Hu-1.” The gene sequence of that isolate 
was then generated and determined to be of a novel coronavirus [5, 6]. That gene 
sequence was publicly posted on January 10, and the novel coronavirus was preliminarily 
named 2019-nCoV. Subsequently, on February 11, 2020, the virus was named SARS-
CoV-2 by the International Committee on Taxonomy of Viruses (ICTV) [7, 8], due to its 
similarity with the original SARS virus. That same day, the World Health Organization 
(WHO) announced a specific name of the disease, “COVID-19,” associated with infection 
by this novel coronavirus, as based on the novel coronavirus origin and year of first 
reported cases. The first cluster of human cases identified comprised people who worked, 
visited, or lived around the local Huanan seafood wholesale market in Wuhan, where live 
animals and fresh meat and fish were on sale, suggesting that an animal was the source 
of the novel respiratory virus being transmitted to humans.  
Epidemiologic data suggest that droplets expelled during face-to-face exposure during 
talking, coughing, or sneezing is the most common mode of transmission while contact 
surface spread remains yet another possible mode of transmission [9].  
SARS-CoV-2 infection rapidly emerged as a global threat to public health, joining other 
coronavirus-related diseases, such as SARS and MERS. COVID-19 was declared a 
Public Health Emergency of International Concern (PHEIC) by the WHO on January 20, 
2020, and was declared a pandemic on March 11, 2020 [10], associated with substantial 
morbidity and mortality [11]. As of July 25, 2020, a total of nearly 16 million laboratory-
confirmed COVID-19 cases have been reported internationally, including over 643,000 
deaths [12]. However, given the lack of widespread testing, the true number of cases of 
COVID-19 is likely far higher than reported. Preliminary results from large U.S.-based 
seroepidemiological surveys indicate an estimated incidence rate of SARS-CoV-2 
infections to be 6 to 24 times that of the number of reported cases of COVID-19 [13].  
An article in JAMA by Wu and McGoogan [14] provided a summary of a major report by 
the Chinese Center for Disease Control and Prevention (China CDC) [15]. Of a total of 
72,314 case records, 44,672 (62%) were confirmed as SARS-CoV-2 infections based on 
positive viral nucleic acid test results on throat swabs, 16,186 (22%) as suspected cases 
based on symptoms and exposures only, 10,567 (15%) as clinically diagnosed based on 
symptoms, exposures, and presence of lung imaging features consistent with coronavirus 
pneumonia, and 889 (1%) as asymptomatic cases based on a positive viral nucleic acid 
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Clinical Protocol 
Protocol Version Date:08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 26 of 94 
 
test result but lacking typical symptoms including fever, dry cough, and fatigue [16]. The 
overall case-fatality ratio (CFR) was 2.3% (1023 deaths among 44,672 confirmed cases). 
No deaths occurred in the group aged 9 years and younger, but cases in those aged 70 
to 79 years had an 8.0% CFR and cases in those aged 80 years and older had a 14.8% 
CFR. The CFR was 49.0% among critical cases. CFR was elevated among those with 
preexisting comorbid conditions - 10.5% for cardiovascular disease, 7.3% for diabetes, 
6.3% for chronic respiratory disease, 6.0% for hypertension, and 5.6% for cancer [16]. 
These initial reports of the CFR documented the level of seriousness of COVID-19.  
Given the novelty of SARS-CoV-2, its rapid spread among humans and its associated 
morbidity and mortality, there has been an explosion of epidemiological, clinical, virologic, 
and other scientific data regarding the propagation of effects of this virus emerging from 
China, the United States, and many other countries. These data have established that 1) 
SARS-CoV-2 is transmitted person-to-person [17], even from those who are asymptomatic 
or presymptomatic [18-20], 2) the virus is very infectious, with estimates of the R0 
(Reproductive number) ranging from 1.50 to 6.49, with a mean average of 3.28 and a 
median average of 2.79 [21], 3) the constellation of symptoms, signs, and an incubation 
period ranging between  2 and 14 days [22], and 4)  the asymptomatic proportion of those 
infected being substantial, perhaps as high as  80% [17, 23-25]. Further, research has 
found that the risk of death from COVID-19 increases with age and with serious, comorbid 
conditions including hypertension, diabetes, cardiovascular disease, obesity, etc.   
Finally, although much has been learned very quickly about SARS-CoV-2 and COVID-19, 
much more is still to be determined. The aforementioned CFR and similar estimates are 
from crude analyses that have only accounted for moderate to serious cases. Therefore, 
the true CFR is likely significantly lower. Further, the infection-fatality ratio (IFR), which is 
the proportion who die among all those infected regardless of any symptomology, is likely 
still even lower than the CFR, but both the CFR and IFR will not be known with certainty 
until well-designed and controlled seroepidemiology surveys have been conducted using 
well-validated antibody assays and thorough questionnaires to obtain symptom history. 
Also, the presence of natural immunity of those infected who survive and the durability of 
such natural immunity is to be determined. Thus, the existence and possibility of 
reinfection and recurrent infection is unknown. 
 CLINICAL PRESENTATION, TRANSMISSION AND IMMUNE RESPONSE 
A study in The Lancet by Huang and colleagues [4] reported the epidemiological, clinical, 
laboratory, and radiological characteristics, as well as treatment and clinical outcomes, of 
patients with laboratory-confirmed COVID-19 pneumonia. Common symptoms at onset of 
illness were fever (n=40, 98% of 41 patients), cough (n=31, 76%), and myalgia or fatigue 
(n=18, 44%);  less  common  symptoms  were  sputum  production  (n=11, 28%  of  39 
patients),  headache  (n=3, 8%  of  38 patients), hemoptysis (n=2, 5% of 39 patients), and 
diarrhea (n=1, 3% of 38 patients). Dyspnea developed in 22 (55%) of 40 patients (median 
time from illness onset to dyspnea was 8 days [Interquartile range 5 - 13 days]). Twenty-
six (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal 
findings on chest CT scan. Complications included acute respiratory distress syndrome 
(n=12, 29%), RNAaemia (n=6, 15%), acute cardiac injury (n=5, 12%) and secondary 
infection (n=4, 10%).  
Wiersinga et al. summarized the common symptoms of COVID-19 in hospitalized patients 
as fever (70-90%), dry cough (60-86%), shortness of breath (53-80%), fatigue (38%), 
myalgias (15-44%), nausea/vomiting or diarrhea (15-39%), headache, weakness (25%) 
and rhinorrhea (7%). Anosmia and ageusia may be the sole presenting symptom in 
approximately 3% of individuals with COVID-19. Common laboratory abnormalities 
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Clinical Protocol 
Protocol Version Date:08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 27 of 94 
 
include lymphopenia (83%), elevated inflammatory markers (e.g., erythrocyte 
sedimentation rate, C-reactive protein, ferritin, tumor necrosis factor-alpha, IL-1, IL-6) and 
abnormal coagulation parameters (e.g., prolonged prothrombin time, thrombocytopenia, 
elevated D-dimer and low fibrinogen). Common radiographic findings include bilateral, 
lower lobe infiltrates on chest radiographic imaging and bilateral, peripheral, lower-lobe 
ground-glass opacities and/or consolidation on chest computed tomographic imaging [9].  
Transmission of SARS-CoV-2 occurred mainly after days of illness [26] and was 
associated with modest viral loads in the respiratory tract early in the illness, with viral 
loads peaking approximately 10 days after symptom onset [27]. Higher viral loads were 
detected soon after symptom onset, with higher viral loads detected in the nose than in 
the throat. Analysis of these samples suggested that the viral nucleic acid shedding 
pattern of patients infected with SARS-CoV-2 resembles that of patients with influenza 
[28] and appears different from that seen in patients infected with SARS-CoV [27]. The 
viral load that was detected in the asymptomatic patient was similar to that in the 
symptomatic patients, which suggests the transmission potential of asymptomatic or 
minimally symptomatic patients [11]. The SARS-CoV-2 transmission time window from 
COVID-19 patients is perhaps 2 days before symptom onset up to 37 days after symptom 
onset [20]. It is estimated that 48% to 62% of transmission may occur via presymptomatic 
carriers [9].  
Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10-15 
days following the onset of COVID-19 symptoms. Seow et al. observed seroconversion in 
>95% with neutralizing antibody responses when sampled beyond 8 days after onset of 
symptoms [29]. However, declining neutralizing antibody titers were observed during the 
follow-up period. Long, et al, when following 37 asymptomatic individuals and 37 
symptomatic patients into the early convalescent phase, observed that the IgG levels in 
93.3% of the asymptomatic group and 96.8% of the symptomatic group declined during 
the early convalescent phase [30]. T cells play a critical role in antiviral immunity but their 
numbers and functional state in SARS-CoV-2 infected patients remain largely unclear. 
Diao and colleagues performed a retrospective review of total T cell counts, and CD4+ and 
CD8+ T cell subsets based on inpatient data from 522 patients with laboratory-confirmed 
SARS-CoV-2 infection and 40 healthy controls in Wuhan from December 2019 to January 
2020. T cell numbers including total T cells, CD4+ and CD8+ T cells in the severe and 
critical disease groups as well as those who died were significantly lower than in the 
mild/moderate disease group. Most importantly, the numbers of total T cells, CD8+ T cells 
and CD4+ T cells in severe COVID-19 cases, including those who died, were lower 
suggesting that there is a profound T cell loss in COVID-19 disease. Counts of total T 
cells, CD8+ T cells or CD4+ T cells were negatively correlated with patient survival [31]. 
It is quite likely that CD4+ T cell, CD8+ T cell, and neutralizing antibody all contribute to 
clearance of the acute infection. There is an ongoing need to understand the magnitude 
and composition of the human CD4+ and CD8+ T cell responses to SARS-CoV-2. If 
natural infection with SARS-CoV-2 elicits potent CD4+ and CD8+ T cell responses 
commonly associated with protective antiviral immunity, COVID-19 is a strong candidate 
for rapid vaccine development [32].  
 CURRENT TREATMENT AND UNMET NEED 
Currently, there is no licensed prophylactic vaccine against COVID-19, however there are 
several vaccines that are available under Emergency Use Authorization (EUA) in the 
United States and other countries. Numerous vaccine efforts are underway. Given the 
growing concerns regarding the emergence of new strains of SARS-CoV-2, an effective 
prophylactic vaccine ideally induces immunity against not only SARS-CoV-2 Wuhan-Hu-
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1 but also its variants. Due to rapid spread of SARS-CoV-2 infections even from 
asymptomatic and mildly infected patients, there is an urgent need for additional vaccines 
for prevention of SARS-CoV-2 infections. 
 
RATIONALE FOR PROPHYLACTIC VACCINE DEVELOPMENT 
SARS-CoV-2 has become a pandemic resulting in substantial morbidity and mortality. Due 
to rapid spread of SARS-CoV-2 infections even from asymptomatic and mildly infected 
patients, there is an urgent need for appropriate measures to prevent, control and treat 
SARS-CoV-2 infections.  
To address this critical need for a medical countermeasure for prevention of COVID-19 
disease, we at Inovio Pharmaceuticals have employed our synthetic DNA-based vaccine 
technology. This technology is highly amenable to accelerated developmental timelines, 
due to the ability to rapidly design multiple test constructs, manufacture large quantities of 
the drug product, and leverage established regulatory pathways to the clinic. Furthermore, 
this technology platform has demonstrated proof of concept efficacy and safety in humans 
in a Phase 3 (REVEAL1) randomized, double-blind, placebo-controlled study for human 
papillomavirus (HPV) associated cervical pre-cancer (NCT03185013) and several Phase 
2 trials for related and other indications and several Phase 2 trials for related and other 
indications. We have additionally built upon our prior experience in developing a MERS 
coronavirus (MERS-CoV) vaccine to accelerate the development of a SARS-CoV-2 
vaccine candidate. In a Phase 1 clinical study, the MERS-CoV vaccine candidate was safe 
and well tolerated, eliciting immune responses in more than 85% of participants after two 
vaccinations that were durable through 1 year of follow-up [33].   
 DNA VACCINES 
Since the 1990s, a novel approach to vaccination against a broad array of target antigens 
and diseases has been in development. This involves the direct introduction of plasmid 
deoxyribonucleic acid (DNA) containing the gene encoding the immunogen against which 
an immune response is sought into appropriate host tissues and the in situ production of 
the target immunogen(s). This approach offers a combination of potential advantages, 
including the stimulation of both B- and T-cell responses, stability of the vaccine across a 
broad temperature range, absence of infectivity of the immunogen itself, the speed with 
which the vaccine can be constructed (for example in the face of an epidemic or pandemic 
as it is the case here with SARS-CoV-2), and the relative ease and generic nature of large-
scale manufacture. Many scientific publications have addressed the potential of DNA 
vaccination [34-43]. Immune responses in animal models have been obtained using genes 
from a variety of infectious agents including influenza viruses, hepatitis B virus, human 
immunodeficiency virus, human papillomaviruses, Marburg virus, MERS coronavirus, 
rabies virus, SARS coronavirus, West Nile virus (WNV), Zika virus, and other infectious 
agents as plasmodium, mycoplasma, and many more [42, 44]. In many cases, protection 
from disease in animal models has also been demonstrated.  
DNA vaccines are able to generate both CD4+ and CD8+ T cell responses. The ability to 
generate MHC-Class I restricted CD8+ T cells (cytolytic T lymphocytes), which generally 
are not made following administration of inactivated viruses, proteins or peptides, may be 
important for key responses against certain pathogens, as well as enabling cross-strain 
specific responses when many antibody responses are strain-specific. Because the 
encoded protein is synthesized in vivo by the host following administration, DNA vaccines 
can encode membrane-bound proteins instead of solely the soluble versions [45]. This 
can be important because key neutralizing epitopes are located in regions that would be 
excluded, or not formed in a monomeric truncated soluble version. Some early research 
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in COVID-19 control has already suggested that neutralizing antibodies may not be 
sufficient and that cell-mediated immunity may be necessary [46]. 
Unlike certain other vectors (such as heterologous viral vectors), DNA vaccines do not 
stimulate adaptive immune responses against themselves, although the DNA itself does 
stimulate certain innate immune responses [47]. In other words, they do not generate anti-
vector immunity that could stunt antigen-specific responses following multiple exposures. 
 USE OF ELECTROPORATION WITH DNA VACCINES 
Electroporation (EP) enhances gene expression of plasmid DNA delivered by the 
intramuscular (IM) or intradermal (ID) routes of administration (Figure 2). Following IM or 
ID delivery of a DNA vaccine or therapeutic product, EP facilitates entry of the DNA into 
the target site: muscle or dermal cells. Following cellular uptake, there is efficient 
production of the proteins encoded by the DNA expression plasmid system. The different 
EP devices, each with varying electrical parameters and protocols, have been reviewed 
[48]. EP has been extensively tested in animal species such as dogs, pigs, cattle, and 
NHPs to deliver therapeutic genes that encode for a variety of hormones, cytokines, 
enzymes or antigens  for the activation of both cellular and humoral responses [49, 50]. 
Importantly, immune responses generated by DNA vaccines delivered with EP are far 
superior to responses to the same vaccines delivered without EP [50]. IM and ID delivery 
of DNA vaccines with EP has been studied extensively, and optimum conditions for 
plasmid uptake and expression have been described for therapeutic indications, vaccines 
and tumor animal model systems [51, 52].  
 INOVIO’S PROPRIETARY TECHNOLOGY AGAINST COVID-19  
Inovio Pharmaceuticals has developed INO-4800 as a DNA vaccine that contains 10 
mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM sodium chloride and 15 
mM sodium citrate). pGX9501 is a DNA plasmid expressing a synthetic consensus 
(SynCon®) sequence of the SARS-CoV-2 Wuhan-Hu-1 full length Spike glycoprotein. The 
ID route of delivery has been selected for INO-4800 based on recent findings from multiple 
DNA vaccine development programs where ID delivery has driven equivalent if not 
superior humoral and cellular responses to IM delivery while improving tolerability 
(clinicaltrials.gov NCT02464670, clinicaltrials.gov NCT02431767) [53-55]. 
Following ID injection, the Inovio Pharmaceuticals’ EP device [48] referred to as the 
CELLECTRA® 2000 for ID administration (3P-ID) device is used to facilitate DNA entry 
into the cells.  
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Figure 2: The Potential Mechanism of Action Underlying Electroporation 
 
 NONHUMAN PRIMATE (NHP) CHALLENGE STUDIES FOLLOWING VACCINATION WITH 
INO-4800 
NHPs are a valuable model in the development of COVID-19 vaccines and therapeutics 
as they can be infected with wild-type SARS-CoV-2, and present with early infection that 
mimics aspects of human disease [56].  Rhesus macaques (n=5) received two 
immunizations of INO-4800 (1.0 mg), at Week 0 and Week 4.  Naïve control animals (n=5) 
did not receive vaccine.  Humoral and cellular immune responses were monitored for 15 
weeks (~4 months) following prime immunization for memory responses. All animals 
seroconverted following a single INO-4800 immunization, with serum IgG titers detected 
against the full-length S1+S2 extracellular domain (ECD), S1, S2, and receptor binding 
domain (RBD) regions of the SARS-CoV-2 S protein.  
INO-4800 immunized macaques and unvaccinated controls were challenged with SARS-
CoV-2 13 weeks (~3 months) post-final immunization. NHPs received a challenge dose of 
1.1x104 PFU of SARS-CoV-2 by intranasal and intratracheal inoculation. Peak viral RNA 
loads in the BAL were significantly lower in the INO-4800 vaccinated group, along with 
significantly lower viral RNA loads at day 7 post-challenge, indicating protection from lower 
respiratory disease. While RNA was detected in the nasal swabs of both the control and 
INO-4800 vaccinated animals, viral mRNA levels trended downwards in INO-4800 
vaccinated animals by more than 2 logs and were achieved sooner on average. Overall, 
the reduced viral loads following exposure to SARS-CoV-2 infection at 17 weeks after 
immunization show an important durable impact mediated by the vaccine [57].  
 FIRST-IN-HUMAN PHASE 1 TRIAL OF INO-4800 
In the open-label, Phase 1 clinical trial, we initially evaluated the safety and 
immunogenicity of INO-4800 in 40 healthy participants, 18-50 years of age.  There were 
two groups of 20 participants each who received either 1.0 mg or 2.0 mg of INO-4800 
intradermally followed by EP at 0 and 4 weeks. In the first 40 subjects, by Week 8, 11 
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adverse events were reported of which all were Grade 1 in severity of which 6 were related 
to study drug. The frequency of AEs did not increase with the second administration.  
From the immunogenicity analysis of the initial 40 subjects enrolled, two subjects were 
excluded from the analysis, one due to early discontinuation prior to the Week 4 dose for 
non-study reasons and the other due to suspected exposure to SARS-CoV-2 before the 
first dose of INO-4800 was administered based on a baseline positive SARS-CoV-2 
serology. Thirty-eight (38) evaluable subjects had cellular and/or humoral immune 
responses following the second dose of INO-4800. Assessment of data from both Week 
6 and Week 8 ELISpot revealed that 74% and 100% of the subjects generated T cell 
responses in the 1.0 mg and 2.0 mg groups, respectively. By Week 6, 95% (36 of 38) of 
the participants seroconverted by generating binding and/or neutralizing antibodies. 
Overall, INO-4800 elicited antigen-specific humoral and cellular immune responses 
against the SARS-CoV-2 Spike protein while demonstrating favorable safety and 
tolerability. 
The protocol was amended to include an additional 80 healthy participants to evaluate 
safety and immunogenicity of INO-4800 in older and elderly age populations. A lower dose 
level (0.5 mg) was also added for evaluation of dose-sparing potential. A total of 40 
participants were enrolled into three dose levels (0.5 mg, 1.0 mg and 2.0 mg), such that 
each Group included 20 participants 18-50 years of age, 10 participants 51-64 years of 
age, and 10 participants 65 years of age and older. Doses were delivered intradermally 
followed by EP at 0 and 4 weeks. As of March 10, 2021, 35 related adverse events were 
reported cumulatively, of which all but three (Grade 2 injection site pruritus, lethargy and 
abdominal pain) were Grade 1 in severity. 
Additional analyses showed that INO-4800 provides broad cross-reactive immune 
responses against variants of concern (VOC). Clinical samples, collected at varying 
timepoints post-immunization from subjects enrolled during Phase 1 INO-4800 clinical 
trial, were analyzed against the spike protein of different VOC (including UK variant 
B.1.1.7, South African variant B.1.351, and Brazilian variant P.1. strains) [58]. The results 
revealed neutralization activity against the P.1 variant (neutralizing antibodies levels 
comparable to those against wild-type) and reduced, but still measurable neutralization 
activity against the B.1.1.7 and B.1.351 variants. Additionally, it has been demonstrated 
that INO-4800 induces cross-reactive T cell responses against B.1.1.7, B.1.351, and P.1 
variants that are comparable to the wild-type strain. Taken together, these data 
demonstrate that INO-4800 maintains cellular and/or humoral immune responses against 
the major SARS-CoV-2 variants that are currently in circulation, which will likely be critical 
factors necessary to impact the ongoing COVID-19 pandemic. 
Please refer to the Investigator’s Brochure, which will include future updates through the 
duration of the study. 
 PROPOSED PHASE 2/3 TRIAL OF INO-4800 
This Phase 2/3 trial is designed to begin with a Phase 2 segment to evaluate both the 1.0 
mg and 2.0 mg doses in approximately 400 subjects, including in the older (51 to 64 years 
of age) and elderly subjects (65 years of age and older), to enable selection of a dose or 
age-related doses for an efficacy evaluation in a subsequent Phase 3 segment involving 
>7000 subjects.  
The current safety and immunogenicity data from the Phase 2 segment strongly support 
the selection and advancement of the 2.0 mg dose of INO-4800 into the Phase 3 segment 
(see Section 1.3.7 for immunogenicity details). INO-4800’s competitive safety/tolerability 
profile, nonclinical data supporting its potential to confer durable protection against severe 
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disease, ability to serve as a safe and tolerable homologous booster, and thermostability 
profile collectively support its potential as an additional tool for COVID-19 prevention with 
distinct advantages to facilitate global distribution and uptake. 
1.3.6.1 
Safety and tolerability of INO-4800  
Safety and tolerability data collected on INO-4800 to date mirror the favorable safety 
profile of Inovio’s plasmid DNA vaccines against multiple targets and indications.  
Nonclinical studies have revealed no safety concerns. Clinical studies (Phase 1 and Phase 
2) have also not revealed any safety concerns as per reviews by independent Data Safety 
Monitoring Boards.   
1.3.6.2 
Nonclinical INO-4800 Data in Support of Potential Efficacy 
The efficacy of INO-4800 in protecting against SARS-CoV-2 disease has been 
demonstrated in multiple nonclinical models. In the AAV6 human ACE2-transduced 
mouse model challenged with SARS-CoV-2, complete protection against lung virus load 
was observed [59]. Applying clinically relevant dosing and CELLECTRA-ID delivery 
parameters, INO-4800 has been tested in multiple nonhuman primate models, the gold 
standard large animal model for COVID-19 vaccine testing. We demonstrated protection 
against lung disease and viral load in the lower and upper respiratory tract in the rhesus 
macaque model after one or two doses of INO-4800 [60][61]. Furthermore, the durability 
of the impact of INO-4800 in reducing lung viral load was demonstrated in a rhesus 
macaque challenged with SARS-CoV-2 several months after immunization [57]. In 
conclusion, multiple nonclinical models have demonstrated the efficacy of INO-4800.  
1.3.6.3 
Potential Role of INO-4800 as a Booster 
INO-4800 offers a potential role in serving as a booster to maintain protection against 
COVID-19 over time in the context of a potential endemic disease scenario. Unlike viral 
vectors, DNA elicits no anti-vector response and, therefore, can be repeatedly 
administered without a reduction in the generated immune responses. When subjects in 
the INO-4800 Phase 1 were provided a booster dose 6 to 10.5 months following the 2-
dose regimen, there was no appreciable change in reactogenicity when compared to the 
first two doses, indicating that repeat dosing with INO-4800, as with other vaccines in 
Inovio’s DNA platform, does not lead to an increase in reactogenicity. Inovio’s DNA 
platform experience with Oncology DNA-vaccine targets have established that more than 
10 sequential administrations of vaccine is capable of consistent re-boosting from an 
immunological perspective with no associated changes in safety and reactogenicity. 
1.3.6.4 
Thermostability of INO-4800  
INO-4800 offers thermostability that could facilitate vaccine distribution globally. The 
current shelf life applied to INO-4800 clinical supplies is 24 months when stored at its 
recommended refrigerated storage condition of 5 ± 3°C. A 24-month real-time study for 
INO-4800 under refrigerated conditions (5°C) is ongoing; current Month 9 results are all 
within specification. Percent supercoiled forms, which is the strongest indication of DNA 
plasmid stability, decreased by only 2% (T0 97%, M9 95%) over the duration of the study 
to date, while percent total circular forms remained at 99%.  
Inovio has a platform stability program with 12 different DNA plasmid products, all 
constructed with the same plasmid backbone and formulated in the same SSC buffer, at 
various DNA concentrations, and the stability data to date are all consistent with the 
excellent stability profile seen with INO-4800. 
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 DOSE AND REGIMEN RATIONALE 
The intent is to evaluate INO-4800 as a prophylactic vaccine against COVID-19 disease. 
Based on Inovio’s extensive experience developing vaccine candidates against infectious 
diseases via the ID route ([54], [33]), a 2-dose regimen was considered to be optimal, 
based on the balanced humoral and cellular responses obtained 2 weeks post-dose 2, 
which supports evaluation of a 2-dose regimen (Days 0 and 28). 
In the Phase 2 segment of this trial, 1.0 mg and 2.0 mg of vaccine were administered by 
ID injection and followed immediately by EP at Day 0 and Day 28. The selection of the 
doses to test in Phase 2 is supported by the safety profile in the Phase 1 trial of INO-4800 
(COVID19-001, NCT04336410) in addition to our prior experience in developing a MERS 
coronavirus (MERS-CoV) vaccine (INO-4700) [16, 17]. The safety data for INO-4800 is 
provided in the Investigator’s Brochure (IB). 
The objective of the Phase 2 segment of the Phase 2/3 trial was to further evaluate the 
1.0 mg and 2.0 mg doses of INO-4800 for each age group in order to select the optimal 
vaccination regimen in the Phase 3 efficacy segment. The final decision between the two 
doses by age group relies on safety and immunogenicity. The 1.0 mg and 2.0 mg doses 
in the Phase 1 study had a similar safety profile. The review of the Phase 2 data by the 
independent DSMB has not revealed any safety signals of concern to date. Furthermore, 
there have not been substantial differences in the safety profile between the 1.0 mg and 
2.0 mg dosing groups to impact Phase 3 dose selection. However, the interim immunology 
data from the Phase 2 study revealed favorable immunogenicity with the 2.0 mg dose over 
the 1.0 mg dose. Data were analyzed for two age groups:  ≥18 to ≤50 years of age and 
≥51 years of age. The results illustrate that the 2.0 mg dose induced higher levels of 
SARS-CoV-2 spike specific antibodies as well as higher levels of IFN-gamma producing 
cells.    
   
1.3.7.1 
Binding Antibody Response 
The binding antibody response was measured for all Phase 2 subjects at Day 0 and Week 
6.  Across all ages, the geometric mean titer (GMT) for the 1.0 mg dose group was 123.3 
at Day 0 compared to 938.8 at Week 6. The geometric mean fold rise was 7.8. The GMT 
for the 2.0 mg dose group was 93.5 at baseline compared to 2210.0 at Week 6. The 
geometric mean fold rise was 23.5. 
Subjects 18-50 years old in the 1.0 mg dose group had a GMT that was 148.5 at Day 0 
compared to 1182.1 at Week 6.  The geometric mean fold rise in binding antibody titers 
was 7.9. The GMT for the 2.0 mg dose group was 99.5 at baseline compared to 2671.2 at 
Week 6. The geometric mean fold rise was 26.5. 
Subjects ≥51 years old in the 1.0 mg dose group had a GMT that was 87.5 at Day 0 
compared to 623.3 at Week 6. The geometric mean fold rise in titers was 7.6. The GMT 
for the 2.0 mg dose group was 84.0 at baseline compared to 1613.7 at Week 6. The 
geometric mean fold rise in binding antibodies was 19.2.  
1.3.7.2 
Neutralizing Antibody Response 
The neutralizing antibody response was measured for all Phase 2 subjects at Days 0 and 
Week 6.  Across all ages the geometric mean titer (GMT) for the 1.0 mg dose group was 
32.2 at Day 0 compared to 93.6 at Week 6.  The geometric mean fold rise in neutralizing 
titers was 2.9. The GMT for the 2.0 mg dose group was 35.8 at baseline compared to 
150.6 at Week 6.  The geometric mean fold rise was 4.3. 
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Subjects 18-50 years old in the 1.0 mg dose group had a GMT that was 34.5 at Day 0 
compared to 112.6 at Week 6.  The geometric mean fold rise in neutralizing titers was 3.3. 
The GMT for the 2.0 mg dose group was 32.2 at baseline compared to 159.9 at week 6. 
The geometric mean fold rise was 5.0. 
Subjects ≥51 years old in the 1.0 mg dose group had a GMT that was 28.4 at Day 0 
compared to 67.4 at Week 6. The geometric mean fold rise in neutralizing titers was 2.3. 
The GMT for the 2.0 mg dose group was 43.3 at baseline compared to 135.7 at Week 6. 
The geometric mean fold rise was 3.2. 
1.3.7.3 
ELISPOT analysis 
ELISPOT analysis was performed for all Phase 2 subjects at Day 0 and Week 6. Across 
all ages, the median for the 1.0 mg dose group was 0 at Day 0 compared to 6.7 at Week 
6. The median for the 2.0 mg dose group was 2.2 at baseline compared to 18.9 at Week 
6. Subjects 18-50 years old in the 1.0 mg dose group had a median of that was 1.1 at Day 
0 compared to 7.6 at Week 6. The median for the 2.0 mg dose group was 0.6 at baseline 
compared to 18.9 at Week 6.  Subjects ≥51 years old in the 1.0 mg dose group had a median that 
was 0 at Day 0 compared to 10 at Week 6. The median for the 2.0 mg dose group was 3.3 at 
baseline compared to 18.4 at Week 6.   
 
RISKS AND POTENTIAL BENEFITS  
As of Dec 31, 2020, no treatment related serious adverse events have been reported for 
INO-4800. There may be side effects and discomforts that are not yet known.  
Please refer to the Investigator’s Brochure and User Manual, which will include future 
updates of the risk profile delineated in this section through the duration of the study. 
 POTENTIAL BENEFITS 
As part of the trial, subjects will have access to COVID-19 diagnostic and antibody testing 
to which they might not otherwise have access. Additionally, subjects will have the benefit 
of contributing to research to help others in a time of a global pandemic.  Benefits related 
to receipt of INO-4800 and protection from COVID-19 disease are unknown because the 
efficacy of INO-4800 remains unknown.      
 PRODUCT RISKS 
1.4.2.1. 
Expected Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Device 
In accordance with the International Council for Harmonisation (ICH), Inovio-sponsored 
studies have been designed to minimize risk to study participants. Expected risks of INO-
4800 delivered ID followed by EP with the CELLECTRA® 2000 device are listed below in 
Table5. 
Table 5: Expected Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Devicea  
Frequency among subjectsb 
Event 
Very Common 
(≥10%) 
• 
Injection site pruritus 
• 
Injection site erythema or redness 
• 
Injection site painc or tenderness  
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Common 
(≥1% to <10%) 
• 
Injection site bruising 
• 
Injection site swelling or induration 
Uncommon or Rare (<1%) 
• 
Administration site lesions or bleeding  
• 
Temporary severe injection site pain or 
tenderness 
a Investigator’s Brochure v4.0, dated 16-Nov-2020 
b EU commission guideline on the SmPC September 2009 [62] 
c Brief muscle contractions may occur and could be uncomfortable 
1.4.2.2  
Theoretical Risks of INO-4800 Delivered ID followed by EP using the 
CELLECTRA® 2000 Device 
The following adverse events have been observed at least once, as of Dec. 31, 2020, 
across all clinical trials with Inovio DNA products delivered intradermally followed by EP 
using the CELLECTRA® 2000 device: 
• 
Allergic reaction 
• 
Anxiety 
• 
Creatine phosphokinase (CPK) elevations that are transient 
• 
Injection site infection, paresthesia, hypoesthesia, hematoma, or scab 
• 
Vasovagal reaction, lightheadedness or dizziness. 
The following events have not been observed, as of Dec. 31, 2020, in any subject or any 
clinical trials with Inovio DNA products delivered intradermally followed by EP using the 
CELLECTRA® 2000 device. While considered theoretical and unlikely to occur, any 
occurrence of these events should be reported to the Sponsor during this trial: 
• 
Antibody-dependent enhancement of disease (i.e., potential for greater respiratory 
disease upon exposure to SARS-CoV-2 due to priming of immune cells from prior 
vaccination. Although observed in nonclinical models for vaccines against other 
viruses such as SARS, the occurrence or observation of antibody-dependent 
enhancement of the disease with COVID-19 vaccines in humans remains 
unknown) 
• 
Cardiac arrhythmias (product-related); Please note that “ICD or pacemaker (to 
prevent a life-threatening arrhythmia) that is located ipsilateral to the deltoid 
injection site (unless deemed acceptable by a cardiologist)” is an exclusion 
criterion (‘j’) in this protocol; 
• 
Death (product-related); 
• 
Disruption of function of implanted electronic medical device(s); Please note that 
“ICD or pacemaker (to prevent a life-threatening arrhythmia) that is located 
ipsilateral to the deltoid injection site (unless deemed acceptable by a cardiologist)” 
is an exclusion criterion (‘j’) in this protocol; 
• 
Effects on fetus and/or pregnancy; Please note inclusion criterion in this protocol 
which requires use of medically effective contraception in women of childbearing 
potential; 
• 
Electrical injury (e.g., electrocution); Please note warning within the device User 
Manual (Section 7). Since the device is not connected to any power supply during 
the EP procedure of a subject, this theoretical event is unlikely but has the potential 
to occur to the user of the device (e.g., study site staff). This will be mitigated 
through device training and user qualification prior to use; 
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• 
Fire hazard to the facility; This theoretical event is unlikely but has the potential to 
occur to the clinical trial site. The possibility of this event has been mitigated 
through device design; 
• 
Hearing damage (product-related); The possibility of this event has been mitigated 
through the device design. The audio is limited in volume and is of very short 
duration. 
• 
Inaccurate energy delivery, the result of which is covered in other events listed 
here (e.g., tissue damage); 
• 
Injection site laceration; This has not been observed but would be theoretically 
possible with any needle; 
• 
Major injury to deeper tissue and/or bone; This event is not foreseeable given the 
array needle length is limited to 3.2 mm;  
• 
Muscle damage; This event is not foreseeable given the array needle length is 
limited to 3.2 mm; 
• 
Paresis or paralysis with possible loss of nerve function; There are minor nerves 
innervating the skin and subcutaneous tissues that may be disrupted, but are 
extremely unlikely to result in serious injury; 
• 
Radiation hazard to eyes and skin; This theoretical event is unlikely but has the 
potential to occur to the user of the device (e.g., study site staff). The possibility of 
this event has been mitigated through the device design; 
• 
Tissue injury/burn;  
• 
User/subject unaware that treatment was incomplete; 
• 
Worsening of unstable cardiac disease; Please note that “Cardiovascular diseases 
(e.g., myocardial infarction, congestive heart failure, cardiomyopathy or clinically 
significant arrhythmias) requiring changes in therapy or hospitalization for 
worsening disease during the 6 weeks prior to enrollment” is an exclusion criterion 
(‘h’) in this protocol. 
There have been no AEs associated with EP errors or failures. 
 OVERALL BENEFIT/RISK CONCLUSION 
While EUA vaccines are currently becoming available in many countries, the global 
availability to the general population remains limited. In the context of the ongoing COVID-
19 pandemic resulting in substantial morbidity and mortality, the overall cumulative safety 
profile of Inovio’s DNA platform across all of its products, and INO-4800’s Phase 1 adverse 
events being generally limited to local injection site reactions, the benefit risk profile 
justifies the conduct of the Phase 2/3 trial. 
 
OBJECTIVES AND PURPOSE 
The overall purpose of this clinical trial is to evaluate the safety, immunogenicity and 
efficacy of INO-4800. 
 
HYPOTHESIS 
INO-4800 delivered ID followed immediately by EP will be well-tolerated, exhibit an 
acceptable safety profile, result in generation of cellular and humoral immune responses 
to SARS-CoV-2 Spike glycoprotein and provide protection against virologically-confirmed 
COVID-19 disease in subjects at high risk of SARS-CoV-2 exposure.  
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CLINICAL TRIAL DESIGN AND ENDPOINTS 
This is an operationally seamless Phase 2/3, randomized, placebo-controlled, multi-
center trial to evaluate the safety, immunogenicity, and efficacy of INO-4800, 
administered by ID injection followed immediately by EP using the CELLECTRA® 2000 
device, in a 2-dose regimen (Days 0 and 28) in adults who are at high risk of SARS-CoV-
2 exposure. Subjects 18 years of age and older are expected to be enrolled across two 
(2) segments of this study. In the Phase 2 segment, approximately 400 seronegative 
subjects will be enrolled. In the Phase 3 segment, approximately 6714 seronegative 
subjects are expected to be enrolled, and 402 seropositive subjects will be enrolled. The 
subjects and data from Phase 2 are independent from that of Phase 3.  The primary 
objectives of this trial are to identify in seronegative subjects an optimal age-related dose 
(Phase 2 segment) for subsequent evaluation for efficacy (Phase 3 segment).  
 
Phase 2 Segment – Dose Selection 
 
In the Phase 2 segment, approximately 400 subjects 18 years of age and older will be 
evaluated across four (4) dose groups (Table 1, Figure 1). Subjects will be randomized 
at a 3:3:1:1 ratio to receive either 1.0 mg or 2.0 mg of active investigational product (INO-
4800) or 1 or 2 injections of placebo (placebo for INO-4800). Dose groups receiving INO-
4800 will enroll approximately 150 subjects per group. Dose groups receiving placebo will 
enroll approximately 50 subjects per group. Randomization will be such that 
approximately 240 subjects aged 18-50 years, 120 subjects aged 51-64 years and 40 
subjects aged ≥ 65 years will be enrolled. Initial enrollment will include subjects aged 18-
50 years. Initiation of enrollment of older subjects 51-64 years of age and elderly subjects 
65 years and older will depend on review of safety and immunogenicity data from those 
age groups generated in the Phase 1 study (COVID19-001). 
 
Dose selection for evaluation of efficacy in the Phase 3 segment will be based on Week 6 
immunogenicity data and Week 8 safety data from the Phase 2 segment. Group-level 
unblinded summaries and analyses of safety will be produced once the Week 8 phone call 
visit data are completed for all subjects in the Phase 2 segment. Group-level unblinded 
summaries and analyses of immunogenicity will be produced once the Week 6 visit data 
are completed for all subjects in the Phase 2 segment. Subject treatment assignments will 
be unblinded after Phase 2 subjects have reached the Week 30 visit. 
 
 
Phase 3 Segment – Efficacy 
In the Phase 3 segment, approximately 6714 seronegative and 402 seropositive subjects 
18 years of age and older will be randomized at a 2:1 ratio to receive either active 
investigational product (INO-4800, 2.0mg) or placebo (placebo for INO-4800).  
Approximately half of seronegative subjects and approximately half of seropositive 
subjects will be 18-50 years of age, and the other half will be ≥ 51 years of age as is 
operationally feasible. Also, approximately 711 subjects will be ≥65 years of age, if 
operationally feasible. 
Subjects will be randomized in a stratified manner according to (a) age category (18-50 
years vs. ≥51 years) on Day 0, and (b) presence of or absence on Day 0 of any of the 
following underlying medical conditions that increase risk of severe COVID-19 disease, 
per CDC criteria [1], as listed below: 
• 
Cancer 
• 
Chronic kidney disease 
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• 
Chronic lung diseases, including Chronic obstructive pulmonary disease (COPD), 
asthma (moderate-to-severe), interstitial lung disease, cystic fibrosis, pulmonary 
hypertension 
• 
Neurologic conditions including stroke or cerebrovascular disease, that do not impact 
cognition 
• 
Diabetes (type 1 or type 2) 
• 
Hypertension 
• 
Heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies 
• 
HIV infection (CD4 count >200 cells/mm3 or undetectable viral load) 
• 
Liver disease 
• 
Obesity (BMI ≥ 30 kg/m2) 
• 
Sickle cell disease or thalassemia, or 
• 
Smoking (current or former smoker). 
This segment of the trial is case-driven. Among seronegative subjects, a total of 149 
observed cases will be required for 90% power to declare the vaccine efficacious (>30%), 
assuming a true efficacy of 60%. A sample size of 6714 seronegative subjects is expected 
to be required to achieve the 149 cases assuming an underlying attack rate of 3.7%. The 
actual sample size may differ if the observed attack rate is different than projected.  There 
are two formal interim analyses of efficacy; one when 50% of the cases accrue and one 
when 75% of the cases accrue. If the prespecified criteria for efficacy are met at either 
interim analysis, then enrollment will continue until 4500 subjects have been enrolled, 
and blinded follow-up will continue until at least those 4500 subjects have a minimum of 
6 months of safety follow-up. At that point, the trial would be unblinded and placebo-
recipients will be offered the active product.    
 
The primary efficacy endpoint window will begin 14 days post-dose 2 and will end at 12 
months post-dose 2. All Phase 3 segment subjects will be followed for 56 weeks from the 
Day 0 dosing [i.e., Week 56 will be the planned End of Study (EOS) visit for this segment 
of the trial]. 
 
External Committee Reviews 
 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will 
convene regularly to review all available unblinded safety data, and additionally upon 
completion of the Week 8 phone call visit for all subjects enrolled during the Phase 2 
segment. For the Phase 3 segment, the DSMB will also review efficacy in an unblinded 
fashion. Additionally, for Phase 3, an independent, blinded Endpoint Adjudication 
Committee (EAC) will review and confirm COVID-19 cases. 
 
Details of each committee’s scope will be provided in the respective charters. 
 
PRIMARY OBJECTIVES 
See Table 6. 
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PRIMARY ENDPOINTS 
Table 6: Primary Objectives and Associated Endpoints 
Phase 2 Primary Objective 
Phase 2 Primary Endpoints 
1.  Evaluate the cellular and humoral 
immune response to INO-4800 
administered by ID injection followed 
immediately by EP  
1a. Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot assay 
1b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay 
Phase 3 Primary Objective 
Phase 3 Associated Primary Endpoint 
1. Evaluate the efficacy of INO-4800 in 
the prevention of COVID-19 disease 
in subjects who are SARS-CoV-2 
negative at baseline  
1.   Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 
(End of Study (EOS)) in subjects who are SARS-
CoV-2 seronegative at baseline  
 
SECONDARY OBJECTIVES 
See Table 7. 
 
SECONDARY ENDPOINTS 
Table 7: Secondary Objectives and Associated Endpoints 
Phase 2 Secondary Objectives 
Phase 2 Secondary Endpoints 
1.  Evaluate the safety and tolerability of 
INO-4800 administered by ID 
injection followed immediately by EP  
 
1a. Incidence of solicited and unsolicited injection 
site reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
 1d. Incidence of adverse events of special interest 
(AESIs)   
Phase 3 Secondary Objectives 
Phase 3 Secondary Endpoints 
1. Evaluate the safety and tolerability 
of INO-4800    
 
1a. Incidence of solicited and unsolicited injection 
site reactions 
1b. Incidence of solicited and unsolicited systemic 
adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity and 
relationship to investigational product  
1c. Incidence of serious adverse events (SAEs) 
1d. Incidence of adverse events of special interest 
(AESIs)  
1e. Incidence of all-cause mortality  
2. Evaluate efficacy of INO-4800 in the 
prevention of COVID-19 disease 
according to degrees of disease 
severity in subjects who are SARS-
CoV-2 seronegative at baseline    
2a.  Incidence of non-severe COVID-19 disease in 
SARS-CoV-2 seronegative subjects starting 14 
days after completion of the 2-dose regimen until 
EOS  
2b. Incidence of severe COVID-19 disease in SARS-
CoV-2 seronegative subjects starting 14 days 
after completion of the 2-dose regimen until EOS 
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2c. Incidence of deaths due to COVID-19 in SARS-
CoV-2 seronegative subjects starting 14 days 
after completion of the 2-dose regimen until EOS 
3.   Evaluate the cellular and humoral 
immune response to INO-4800  
3a.  Antigen-specific cellular immune response 
measured by IFN-gamma ELISpot  
3b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay  
4. Evaluate the efficacy of INO-4800 
in the prevention of COVID-19 
disease in subjects who are SARS-
CoV-2 seropositive at baseline  
 
4.  Incidence of virologically-confirmed COVID-19 
disease starting 14 days after completion of the 
2-dose regimen until 12 months post-dose 2 
(End of Study (EOS)) in subjects who are SARS-
CoV-2 seropositive at baseline 
 
EXPLORATORY OBJECTIVE 
See Table 8. 
 
EXPLORATORY ENDPOINTS 
Table 8: Exploratory Objectives and Associated Endpoints 
Phase 2 Exploratory Objective 
Phase 2 Exploratory Endpoints 
1.  Evaluate the expanded 
immunological profile of antibody 
response and T cell immune 
response 
1a.  Antigen-specific cellular immune response 
measured by flow cytometry. 
1b. Expanded immunological profile which may 
include additional assessments of T and B cell 
numbers and molecular changes by measuring 
immunologic proteins and mRNA levels of genes 
of interest as determined by sample availability 
Phase 3 Exploratory Objective 
Phase 3 Exploratory Endpoints 
1. Evaluate the efficacy of INO-4800 
in the prevention of COVID-19 
disease from SARS-CoV-2 variants 
in subjects who are SARS-CoV-2 
seronegative at baseline 
1. Incidence of virologically-confirmed COVID-19 
disease from a SARS-CoV-2 variant starting 14 
days after completion of the 2-dose regimen until 
12 months post-dose 2 (End of Study (EOS)) in 
subjects who are SARS-CoV-2 seronegative at 
baseline 
2. Evaluate the efficacy of INO-4800 
in the prevention of SARS-CoV-2 
asymptomatic infection in subjects 
who are SARS-CoV-2 seronegative 
at baseline     
2. Incidence of SARS-CoV-2 asymptomatic 
infections in SARS-CoV-2 seronegative subjects 
starting 14 days after completion of the 2-dose 
regimen until EOS 
3. Evaluate the immunological profile 
by assessing both antibody 
response and T cell immune 
response  
3a.  SARS-CoV-2 Spike glycoprotein antigen-
specific binding antibody levels  
3b.  Antigen-specific cellular immune response 
measured by flow cytometry  
4. Evaluate antibody persistence  
4a. SARS-CoV-2 Spike glycoprotein antigen specific 
binding antibody levels at Week 30 or later.  
4b. Neutralizing antibody response measured by a 
pseudovirus-based neutralization assay at Week 
30 or later 
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EFFICACY ASSESSMENT (PHASE 3 SEGMENT ONLY) 
Subjects will receive either active investigational product (INO-4800, dose selected from 
the Phase 2 segment) or placebo (placebo for INO-4800) in a 2-dose regimen 
administered intradermally followed immediately by EP on Days 0 and 28. Subjects will 
be monitored through regularly scheduled clinic visits and phone calls throughout the trial. 
Subjects will be regularly tested for SARS-CoV-2 infection using serologic testing. If 
COVID-19 disease is suspected based on symptoms or laboratory testing, site personnel 
will arrange for a clinic visit. Subjects with symptom(s) or a positive SARS-CoV-2 test 
result will be reviewed by the independent blinded EAC.  
The mechanism for review and confirmation of cases will be outlined in an EAC Charter.  
 CASE DEFINITION FOR VIROLOGICALLY-CONFIRMED COVID-19 DISEASE: 
•  Positive testing by SARS-CoV-2 RT-PCR assay (performed at central lab*) 
with fever (temperature of 100.4ºF/38.0ºC or higher), or  
• 
Positive testing by SARS-CoV-2 RT-PCR assay (performed at central lab*) 
with any of the following COVID-19 related symptoms: 
• 
Feeling feverish or chills  
• 
Cough  
• 
Shortness of breath or difficulty breathing  
• 
Fatigue  
• 
Muscle or body aches  
• 
Headache  
• 
New loss of taste or smell  
• 
Sore throat  
• 
Congestion or runny nose  
• 
Nausea or vomiting  
• 
Diarrhea  
*Local lab results will be accepted if the subject is hospitalized and a sample is 
not able to be obtained for analysis at central lab. 
3.7.1.1 Case Definition for Severe COVID-19 
• Confirmed COVID-19 disease (per Section 3.7.1) with any of the following:  
a. Clinical signs at rest indicative of severe systemic illness (respiratory 
rate ≥ 30 per minute, heart rate ≥ 125 per minute, SpO2 ≤ 93% on room 
air at sea level or PaO2/FiO2 < 300 mm Hg),  
b. Respiratory failure (defined as needing high-flow oxygen, noninvasive 
ventilation, mechanical ventilation or ECMO),  
c. Evidence of shock (SBP < 90 mm Hg, DBP < 60 mm Hg, or requiring 
vasopressors),  
d. Significant acute renal, hepatic, or neurologic dysfunction,  
e. Admission to an ICU, or  
f. Death.  
3.7.1.2 Case Definition for Non-Severe COVID-19  
• Confirmed COVID-19 disease (per Section 3.7.1);   
• Does not meet the case definition of Severe COVID-19 disease (Section 
3.7.1.1) 
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 CASE DEFINITION FOR SARS-COV-2 ASYMPTOMATIC INFECTION  
Positive testing by SARS-CoV-2 serologic assay (performed at central lab);  
• Without clinical signs or symptoms of COVID-19 disease since the previous 
negative serologic test.  
 
SAFETY ASSESSMENT 
Subjects will be followed for safety during the trial through scheduled clinic visits and 
phone calls. AEs, regardless of relationship to study drug, will be collected from the time 
of consent until 28 days post-dose 2 (i.e., Day 56). SAEs, MAAEs and AESIs will be 
collected from time of consent until EOS. SAEs, AESIs, and treatment-related AEs will be 
followed to resolution or stabilization. For the Phase 2 segment and at selected sites in 
the Phase 3 segment, solicited local and systemic AEs will be collected for 7 days following 
each dose using a participant diary. 
Subjects will also be monitored for COVID-19 disease. 
Please refer to the Schedule of Events (Table 3 and Table 4) for safety assessments to 
be performed.   
 
IMMUNOGENICITY ASSESSMENT 
Immunology blood samples will be collected at serial timepoints (see Schedule of Events, 
Table 3 and Table 4). Assays such as binding ELISA, pseudovirus-based neutralization 
assay, and ELISpot will be evaluated at serial timepoints. 
 
CLINICAL TRIAL POPULATION 
 
INCLUSION CRITERIA 
 PHASE 2 SEGMENT 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Assessed by the Investigator to be healthy based on medical history, vital signs and 
physical examination performed at Screening;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar workers, 
store cashiers, hairdressers and barbers, veterinary staff, daycare workers, 
Transportation Security Administration screening staff, school teachers and 
college professors teaching in-person classes) 
2. Factory workers (when working in confined settings with large numbers of 
employees) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) 
4. User of public transportation (e.g., bus, train, subway) at least 3 times weekly 
5. Nursing home staff or correctional facility staff  
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
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7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol. Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field) 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, respiratory therapists, physical therapists, social workers, 
dentists and dental hygienists.) Physicians should not be enrolled unless they are 
assigned to dedicated COVID-19 treatment wards or other settings with prolonged 
exposure) 
10. Others, if approved by the medical monitor;   
f. Screening laboratory results within normal limits for testing laboratory or are deemed 
not clinically significant by the Investigator; 
g. Must meet one of the following criteria with respect to reproductive capacity: 
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or tubal 
ligation, absence of ovaries and/or uterus in females). In the case of vasectomy, 
subjects should wait six (6) months post-vasectomy prior to enrolling;  
• 
Use of medically effective contraception with a failure rate of < 1% per year when 
used consistently and correctly from screening until 3 months following last dose. 
Acceptable methods include:  
o hormonal contraception including implants, injections or oral; 
o two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
o intrauterine device or intrauterine system; 
o abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 PHASE 3 SEGMENT 
a. Able to provide informed consent and have signed Informed Consent Form (ICF) prior 
to screening procedures; 
b. Men and non-pregnant women 18 years of age or older;  
c. Per investigator judgment, healthy or stable with pre-existing medical conditions that 
do not require significant change in medication or have led to a hospitalization in the 
3 months prior to enrollment or who, in the judgment of the investigator, are unlikely 
to require a significant change in therapy or hospitalization for worsening disease 
through Day 56;  
d. Able and willing to comply with all study procedures; 
e. Working or residing in an environment with high risk of exposure to SARS-CoV-2 for 
whom exposure may be relatively prolonged or for whom personal protective 
equipment (PPE) may be inconsistently used, especially in confined settings. 
Examples include:  
1. Retail/service workers/educators (restaurant waitresses/waiters and bar workers, 
street vendors, store cashiers, hairdressers and barbers, veterinary staff, daycare 
workers, airport screening staff, school teachers and college professors teaching 
in-person classes, college students attending in-person classes, office workers 
and volunteers who have multiple brief exposures to people regularly) 
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2. Factory workers (when working in confined settings with large numbers of 
employees, meat-packing facilities) 
3. Drivers providing bus, taxi or shared ride services (e.g., Uber, Lyft) and delivery 
services  
4. User of public transportation (e.g., bus, train, subway) or public facilities (e.g. 
gyms) at least 3 times weekly 
5. Nursing home staff or correctional facility staff 
6. Retirement community residents or adult day program attendees who are 
regularly eating, socializing and/or exercising in common areas 
7. Person 51 years or older living in a multigenerational (at least 3 generations) 
household 
8. First responders (emergency medical technicians, police who are regularly 
assigned on patrol) Note: Firefighters typically use face shields and other 
protective gear but may be considered if they regularly assist with medical 
emergencies in the field 
9. Health care workers with prolonged patient interaction (includes nurses and 
nursing assistants, medical assistants and technicians, respiratory therapists, 
physical therapists, social workers, dentists and dental hygienists)  
10. Others, if in the opinion of the PI, the risk of COVID-19 exposure is comparable 
to the examples above. 
f. Must meet one of the following criteria with respect to reproductive capacity: 
1. Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
2. Surgically sterile or has a partner who is sterile (i.e., vasectomy in males or tubal 
ligation, absence of ovaries and/or uterus in females). In the case of vasectomy, 
subjects should wait six (6) months post-vasectomy prior to enrolling;  
3. Use of medically effective contraception with a failure rate of < 1% per year when 
used consistently and correctly from screening until last dose. Acceptable 
methods include:  
i. hormonal contraception including implants, injections or oral; 
ii. two barrier methods, e.g., condom and cervical cap (with spermicide) or 
diaphragm (with spermicide); 
iii. intrauterine device or intrauterine system; 
iv. abstinence when this is the subject’s preferred and usual lifestyle. Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception. 
 
EXCLUSION CRITERIA 
 PHASE 2 SEGMENT 
a. Acute febrile illness with temperature > 100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat);  
b. Positive serologic or molecular (RT-PCR) test for SARS-CoV-2 at Screening; 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children within the projected duration of the trial starting from the Screening visit until 
3 months following the last dose; 
d. Positive serum pregnancy test during screening or positive urine pregnancy test 
immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or 
a detectable viral load within the past 3 months; 
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f. Is currently participating or has participated in a study with an investigational product 
within 30 days preceding Day 0 (documented receipt of placebo in a previous trial 
would be permissible for trial eligibility); 
g. Previous receipt of an investigational vaccine for prevention or treatment of COVID-
19, MERS or SARS (documented receipt of placebo in previous trial would be 
permissible for trial eligibility). 
h. Medical conditions as follows:  
• 
Respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) 
requiring significant changes in therapy or hospitalization for worsening disease 
during the 6 weeks prior to enrollment; 
• 
History of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, 
generalized urticarial or angioedema) 
• 
Uncontrolled hypertension, defined as resting systolic blood pressure >160 mm 
Hg or a resting diastolic blood pressure >100 mm Hg prior to first dose; 
• 
Uncontrolled diabetes mellitus (Hemoglobin A1c > 8.0%); 
• 
Malignancy within the past 2 years, with the exception of superficial skin cancers 
that only required local excision and non-metastatic prostate cancer not requiring 
treatment; 
• 
Cardiovascular diseases (e.g., myocardial infarction, congestive heart failure, 
cardiomyopathy or clinically significant arrhythmias) requiring changes in therapy 
or hospitalization for worsening disease during the 6 weeks prior to enrollment; 
• 
History of seizures within the past 2 years with the use of no more than a single 
antiepileptic agent; 
i. 
Immunosuppression as a result of underlying illness or treatment including: 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed) in the prior 6 months; 
• 
Current or anticipated use of disease modifying doses of systemic anti-rheumatic 
drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and 
biologic disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, 
adalimumab or etanercept); 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the subject 
or require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
j. 
Lack of acceptable sites for ID injection and EP considering the skin above the 
deltoid and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
ICD or pacemaker (to prevent a life-threatening arrhythmia) that is located 
ipsilateral to the deltoid injection site (unless deemed acceptable by a 
cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation site; 
k. Blood donation or transfusion within 1 month prior to Day 0; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the prior 2 years; 
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n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
 PHASE 3 SEGMENT 
a. Acute febrile illness with temperature ≥100.4°F (38.0°C) or acute onset of upper or 
lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat) on 
Day 0 prior to dosing; 
b. Positive serologic test for SARS-CoV-2 at Screening (after approximately 402 
subjects positive for SARS-CoV-2 serologic test are randomized, this criterion will 
apply to all remaining subjects); 
c. Pregnant or breastfeeding, or intending to become pregnant or intending to father 
children starting from the Screening visit until the last dose; 
d. Positive urine pregnancy test during screening or  immediately prior to dosing; 
e. Known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or 
a detectable viral load within 3 months prior to screening; 
f. Is currently participating or has participated in a study with an investigational product 
within 30 days prior to Day 0 (documented receipt of placebo in a previous trial would 
be permissible for trial eligibility); 
g. Previous or planned receipt of an investigational (including Emergency Use 
Authorization (EUA) or local equivalent authorization) or licensed vaccine for 
prevention or treatment of COVID-19, MERS or SARS (documented receipt of 
placebo in previous trial would be permissible for trial eligibility); 
h. Immunosuppression as a result of underlying illness or treatment including: 
 
• 
Primary immunodeficiencies (conditions including hypothyroidism, Hashimoto’s 
thyroiditis and vitiligo are allowed); 
• 
Long term use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 
mg/day of prednisone equivalent (use of inhaled, topical, nasal, otic, and 
ophthalmic corticosteroids are allowed) in the past 6 months; 
• 
Current or anticipated use of disease modifying doses of systemic anti-rheumatic 
drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, methotrexate) and 
biologic disease modifying drugs such as TNF-α inhibitors (e.g., infliximab, 
adalimumab or etanercept) or others; 
• 
History of solid organ or bone marrow transplantation; 
• 
History of or current receipt of any other clinically significant immunosuppressive 
drugs 
• 
Diagnosis of an autoimmune disease that may jeopardize the safety of the subject 
or require therapy that would interfere with study assessments or endpoint 
evaluation, or otherwise impact the validity of the study results. 
i. 
Lack of acceptable sites for ID injection and EP considering the skin above the deltoid 
and anterolateral quadriceps muscles. The following are unacceptable sites: 
• 
Tattoos, keloids or hypertrophic scars located within 2 cm of intended 
administration site; 
• 
Implantable-Cardioverter-Defibrillator (ICD) or pacemaker (to prevent a life-
threatening arrhythmia) that is located ipsilateral to the deltoid injection site 
(unless deemed acceptable by a cardiologist); 
• 
Any metal implants or implantable medical device within the electroporation site; 
j. 
Blood donation or transfusion within 1 month prior to Day 0; 
k. People who work remotely or in a socially distanced setting with minimal risk of 
exposure to SARS-CoV-2; 
l. 
Prisoners or subjects who are compulsorily detained (involuntary incarceration); 
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m. Reported alcohol or substance abuse/dependence or illicit drug use (excluding 
marijuana use) within the prior 2 years; 
n. Any illness or condition that in the opinion of the investigator may affect the safety of 
the subject or the evaluation of any study endpoint. 
 
DISCONTINUATION/WITHDRAWAL OF CLINICAL TRIAL SUBJECTS 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at 
the discretion of the Investigator should any untoward effect occur. In addition, the 
Investigator or the Sponsor has the right to discontinue a subject from the trial at any time. 
The Investigator must notify the Sponsor immediately when a subject has been 
discontinued/withdrawn due to an Adverse Event (AE). If a subject withdraws from the trial 
or is discontinued from the trial prior to trial completion, all applicable activities scheduled 
for the final trial visit (i.e., Day 393) should be performed at the time of 
discontinuation/withdrawal if the subject agrees. Any related AEs, AESIs, and/or Serious 
Adverse Events (SAEs) present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.9. 
Unless a subject refuses to continue participation, all follow-up visits and procedures 
should be completed as indicated in the Schedule of Events (Table 3 and Table 4) 
following the second dose whether or not the subject has completed both doses. 
If a subject decides to be vaccinated  with a non-study prophylactic COVID-19 vaccine, 
either authorized under emergency use or licensed,during the trial, subjects should 
provide details of the non-study COVID-19 vaccine received to study staff  and subjects 
should be requested to remain in the trial until the last visit. Additionally, subjects should 
also be advised that we do not have adequate information about the safety and 
effectiveness of another prophylactic COVID-19 vaccine when received following the 
receipt of INO-4800. As is already the case, if a subject is enrolled and receives a non-
study prophylactic COVID-19 vaccine, either authorized under emergency use or licensed, 
while on study, the Investigator should enter the details as a concomitant medication. The 
subject should be followed (according to the Schedule of Events outlined in Table 3 of the 
Protocol). 
Should a subject fail to attend the clinic for a required study visit, the site should attempt 
to contact the subject and reschedule the missed visit as soon as possible. In cases where 
the subject does not return for the rescheduled visit or cannot be reached to reschedule 
the missed visit, the site should make every effort to regain contact with the subject (3 
telephone calls and if that fails, then a certified letter to the subject’s last known mailing 
address) so that the subject’s disposition can be considered as withdrawn from the study 
(i.e. lost to follow-up). If the contact with subject is re-established, site should contact 
medical monitor to discuss whether subject can continue study treatment or follow-up 
visits for the study. For all other subjects withdrawing from the study, an alternative reason 
for discontinuation should be recorded in the eCRF. 
Reasons for discontinuation/withdrawal from the trial may include but are not limited to the 
following: 
• 
Subject withdrawal of consent at any time; 
• 
Any medical condition that the Investigator or Sponsor determines may jeopardize the 
subject’s safety if he or she continues in the trial; 
• 
Investigator, DSMB or Sponsor determines it is in the best interest of the subject; 
• 
Subject non-compliance. 
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Every effort should be made to obtain information on subjects who withdraw from the trial. 
The primary reason for withdrawal from the trial should be documented on the appropriate 
CRF. However, subjects will not be followed for any reason after consent has been 
withdrawn. Data and/or samples collected prior to withdrawal of consent will be analyzed.  
Reasons for discontinuing subject dosing may include but are not limited to the following: 
• 
Adverse Event (Adverse Reaction); 
• 
The Investigator or trial coordinator must notify the Sponsor immediately when a 
subject has been discontinued/withdrawn due to an Adverse Event (AE). 
• 
Any medical condition that may jeopardize the subject’s safety if he or she continues 
on trial; 
• 
Pregnancy. 
 
CLINICAL TRIAL INVESTIGATIONAL PRODUCT INFORMATION 
 
INVESTIGATIONAL PRODUCT (IP) AND STUDY DEVICE 
 INO-4800 AND PLACEBO 
Investigational product is defined as a pharmaceutical form of an active ingredient or 
placebo being tested or used as a reference in the study, whether blinded or unblinded. 
INO-4800 is the active investigational product to be used in this study. The INO-4800 drug 
product contains 10 mg/mL of the DNA plasmid pGX9501 in 1X SSC buffer (150 mM 
sodium chloride and 15 mM sodium citrate). pGX9501 is a DNA plasmid expressing a 
synthetic consensus (SynCon®) sequence of the SARS-CoV-2 full length Spike 
glycoprotein. 
Phase 2 segment: 
Active Investigational Product (INO-4800): A volume of 0.4 mL will be filled into 2-mL glass 
vials that are fitted with rubber stoppers and sealed aluminum caps. 
Placebo (placebo for INO-4800): Sterile saline sodium citrate (SSC) buffer, which contains 
sterile 150 mM sodium chloride and 15 mM sodium citrate in 10-mL glass vials, stoppered, 
and sealed with aluminum caps. 
Phase 3 segment: 
Active Investigational Product (INO-4800): A volume of 0.4 mL or 0.8 mL will be filled into 
2-mL glass vials that are fitted with rubber stoppers and sealed aluminum caps. 
Placebo (placebo for INO-4800): Sterile saline sodium citrate (SSC) buffer, which contains 
sterile 150 mM sodium chloride and 15 mM sodium citrate at a volume of 0.8 mL in 2-mL 
glass vials, stoppered, and sealed with aluminum caps. 
 CELLECTRA® 2000 
Electroporation is a procedure used to enhance cellular DNA uptake within host cells 
following DNA vaccine ID delivery. This study will use the CELLECTRA® 2000, a portable, 
battery-powered medical device designed to generate a controlled, electric field that 
temporarily and reversibly increases cellular membrane permeability without clinically 
damaging the tissue. During the period of increased permeability, injected plasmid DNA 
can be introduced into the cells. 
As mentioned above, the CELLECTRA® 2000 device is intended to enhance the uptake 
and expression of DNA plasmid-based biologics in order to enhance vaccine efficacy. The 
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Clinical Protocol 
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Protocol Version: 2.0USA 
 
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DNA plasmid is delivered separately via needle and syringe ID injection immediately prior 
to the electroporation. The electroporation is accomplished through a sterile, disposable 
needle Array attached to an Applicator delivering controlled electrical pulses as follows: 
• 
An EP administration consists of four pulses. 
• 
An array of three stainless steel electrode needles is used to deliver the electrical 
pulses into the tissue. The Array needle length that penetrates into the skin and 
tissue is approximately 3.2 mm. To date, we have not had any safety concerns 
associated with the depth of the array electrode needles. Within the Array needle 
depth of 3.2 mm, there are no major blood vessels (arteries, veins) or nerve 
structures at the authorized sites of administration overlying the deltoid or the 
anterolateral quadricep muscle. There are superficial capillaries and minor nerves 
innervating the skin, including subcutaneous tissues that may be disrupted by 
needle insertion, but are extremely unlikely to result in serious injury; intradermal 
injection followed by EP of these structures poses no significant risk to the subject 
except for possibly injection site reactions. 
• 
The CELLECTRA® 2000 generates four 52ms ±1ms electrical current controlled 
DC pulses. The nominal current is set to 0.2A ±10% by modulating voltage, or 
capped at 200V ±5%, determined by patient tissue impedance. 
• 
The total energy delivered by the device is determined by the combination of four 
device parameters: Pulse Current, Pulse Voltage, Number of Pulses, and Pulse 
Width. The parameters are pre-set by Inovio to be a pulse current of 0.2A, a pulse 
voltage of 200V, and 4 pulses at 52ms pulse width. The parameters are verified 
prior to shipment and cannot be changed by the user.  
• 
In eight clinical trials administering ID injection followed by EP using the 
CELLECTRA® 2000, total energy delivered ranged from 0.9J to 7.8J, which have 
been generally safe and well-tolerated. In addition, Inovio has calculated the total 
maximum energy delivered ID as 8.32J for normal use conditions. Higher energy 
pulses ranging from 10.7J to 11.7J were evaluated in a guinea pig model which 
induced erythema localized to the electrode insertion site. Taken together, these 
nonclinical data and Inovio’s clinical experience provide evidence that the total 
energy delivered by the CELLECTRA® 2000 device will not result in 
unacceptable risks when delivered to patients. Further, a published study 
evaluated the Visual Analog Scale (VAS) pain scores of normal use conditions 
(0.2A), and found ID injection followed by EP using the CELLECTRA® 2000 
device to be safe and well tolerated [63]. 
• 
The specified current is constantly maintained through voltage modulation using 
an analog feedback loop. Measurements of voltage and current are processed for 
error reporting and collected for data logging. 
The CELLECTRA® 2000 device is comprised of three components: (1) A battery-powered 
Pulse Generator, (2) an ID Applicator that is connected to the pulse generator, and (3) a 
three-point sterile disposable ID Array of stainless steel needles. The Pulse Generator 
and ID Applicator are reusable components. These components should be cleaned and 
disinfected prior to each subject’s use according to the Cleaning and Maintenance 
procedure in the User Manual. The Pulse Generator and ID Applicator have been 
validated for up to 30 cleaning and disinfection cycles based on a maximum of 30 subjects 
being treated in a day. Therefore, the Pulse Generator and ID Applicator’s use should be 
limited to 30 subjects in a day. Any potential risk of damage to the device due to cleaning 
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Clinical Protocol 
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Protocol Version: 2.0USA 
 
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and disinfection for more than 30 cycles has not been validated. Always inspect the device 
before use according to the instructions in the Maintenance section of the User Manual. 
 
DOSING REGIMENS 
Phase 2 Segment 
• 
Active Investigational Product: One or two 1.0mg ID injection(s) of INO-4800 (~0.1mL 
dose volume each) followed immediately by EP administered on Day 0 and Day 28 
(±3 days) 
• 
Placebo: One or two ID injection(s) of placebo for INO-4800 (~0.1mL) followed 
immediately by EP administered on Day 0 and Day 28 (±3 days) 
Phase 3 Segment 
• 
Active Investigational Product: Two 1.0mg ID injections of INO-4800 (~0.1mL dose 
volume) followed immediately by EP administered in separate limbs on Day 0 and Day 
28 (±3 days) 
• 
Placebo: Two ID injections of  placebo for INO-4800 (~0.1mL) followed immediately 
by EP administered in separate limbs on Day 0 and Day 28 (±3 days) 
 BLINDING 
This study is blinded. The Sponsor, subjects and clinical site staff, with the exception of 
the site’s pharmacy personnel, will be blinded. There is no difference in appearance 
between INO-4800 and the placebo; however, they are distinguishable based on the vial 
size and/or labelling on the vials. In the Phase 2 segment, the vials will be of different sizes 
and have unblinded labelling. In the Phase 3 segment, the vials will be the same size but 
will have unblinded labelling. To maintain the blind, vials will only be handled by 
designated unblinded personnel (site pharmacist) at the site. 
Under exceptional circumstances, the PI may desire to unblind a subject’s dose 
assignment in case of an emergency or serious medical condition when knowledge of the 
study product or dose is deemed by the PI to be absolutely essential for proper clinical 
management of the subject. Under such emergency circumstances, the Sponsor urges 
the PI to first contact the Medical Monitor (MM) to review options before unblinding the 
subject’s dose assignment. In case of non-emergency, PI must contact MM to discuss the 
options before unblinding the subject’s dose assignment.  
The Phase 2 segment of the trial will be unblinded following subjects reaching the Week 
30 visit. For the Phase 3 segment, it is not deemed appropriate to unblind a subject’s 
treatment assignment for the purpose of assisting the subject in making a decision 
regarding receipt a different COVID-19 vaccine (emergency use or licensed vaccine).  
Subjects may be advised that without efficacy data, INO-4800 has not been proven to be 
more protective than placebo in the prevention of COVID-19 and SARS-CoV-2 infection.  
The Sponsor’s pharmacovigilance staff may unblind a subject’s dose assignment for an 
SAE, unanticipated adverse device effect (UADE), or adverse event of special interest 
(AESI) when the event is assessed as related and unexpected. If expedited regulatory 
reporting is required for such an event, the report may be submitted to regulatory 
authorities with the subject’s dose assignment, in accordance with local regulations. 
 
 
PACKAGING AND LABELING 
 INO-4800 OR PLACEBO 
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Each vial of INO-4800 or placebo will be labeled consistent with the example product label 
provided in the IB.  
 CELLECTRA® 2000 
Please see shipping box for shipping documents and contents. 
The CELLECTRA® 2000 device and its components bear labels that identify the device 
name and place of business of the manufacturer. The CELLECTRA® 2000 User Manual 
describes all relevant contraindications, hazards, potential risks and adverse effects, 
interfering substances or devices, warnings, and precautions. Each Pulse Generator has 
a unique serial number, and each ID Applicator has a unique serial number. Each ID Array 
has a Lot Number and Expiration Date. Examples of device labels are provided in the IB. 
The CELLECTRA® 2000 device, and its components, will be shipped directly from the 
manufacturer to the study site. 
 
HANDLING AND STORAGE 
 INO-4800 AND PLACEBO 
INO-4800 and Placebo will be shipped at 2–8°C. If the temperature monitoring devices in 
the shipping container(s) denote temperatures outside this 2–8°C (36-46°F) range, the 
Sponsor, or its designee, should be contacted immediately. 
Upon arrival, the INO-4800 and placebo must be transferred from the shipping container 
into 2–8°C (36-46°F) storage, in a secure area, in accordance with local regulations by 
designated personnel (e.g., pharmacy personnel). The Sponsor must be notified of any 
deviations from this storage condition. Refrigerator temperature logs must be maintained 
at the clinical site and temperatures must be recorded and monitored regularly. For further 
details see Pharmacy Manual and IB. 
 CELLECTRA® 2000 
See User Manual for operating and storage conditions. 
 
PREPARATION AND DISPENSING 
In the Phase 2 segment, INO-4800 is supplied in 2-mL vials at a concentration of 10 
mg/mL at a minimum volume of 0.4 mL.  placebo for INO-4800 is supplied in 10-mL vials 
at a minimum volume of 2 mL.  
In the Phase 3 segment, INO-4800 is supplied in 2-mL vials at a concentration of 10 
mg/mL at a minimum volume of 0.4 or 0.8 mL.  placebo for INO-4800 is supplied in 2-mL 
vials at a minimum volume of 0.8 mL. 
Blinded staff involved in the clinical execution of the study should not come in contact with 
vials of INO-4800 or placebo for INO-4800. Vials will only be handled by designated 
unblinded personnel (e.g., pharmacy) at the site. When a subject is eligible for enrollment, 
unblinded personnel will draw INO-4800 or placebo for INO-4800 into a blinded syringe in 
accordance with the subject’s randomized treatment assignment according to a 
randomization schedule. The syringe will be transferred to blinded site personnel for 
administration.  
Each INO-4800 and placebo vial will contain a volume of product sufficient to dose multiple 
subjects. The preparation and dispensing information will be provided in the Pharmacy 
Manual. 
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Protocol Version: 2.0USA 
 
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USE OF STUDY DEVICE 
The instructions for use of the CELLECTRA® 2000 device are provided in the User 
Manual. Each clinical site will receive training for use of the CELLECTRA® 2000 device 
prior to first dose. The EP procedure must be performed by qualified personnel. Any 
individual designated to perform the procedure should be permitted by the relevant local 
authorities to administer parenteral injections to patients (e.g., MD, DO, RN) in addition to 
successfully completing device training provided by Sponsor personnel.  
 
INVESTIGATIONAL DRUG AND STUDY DEVICE ACCOUNTABILITY 
 INVESTIGATIONAL PRODUCT (IP) ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current accountability record of 
investigational products (INO-4800 or placebo) is maintained at the study site. The 
investigational products must have full traceability from the receipt of the products through 
subject use, disposal or return of the products. Records or logs must comply with 
applicable regulations and guidelines. The accountability information is provided in the 
Pharmacy Manual. 
 CELLECTRA® 2000 ACCOUNTABILITY 
The investigational site is responsible for maintaining device accountability logs. The 
device must have full traceability from the receipt of the products through subject use, 
disposal or return of the products. The site must document acknowledgement of receipt 
and notify Inovio upon receipt of study devices. This includes the content shipped and 
condition upon receipt. 
For each subject administration, there must be a record of each product used for that 
subject, i.e., Pulse Generator serial number, ID Applicator serial number, and ID Array lot 
number. The ID Applicator is reusable with a new ID Array and sheath for each procedure. 
The sterile ID Array and sheath are single use only and must be discarded after use in 
accordance with institutional policy regarding disposal of sharp needles/instruments. 
 
RETURN AND DESTRUCTION OF INVESTIGATIONAL DRUG AND STUDY DEVICE 
 INO-4800 AND PLACEBO 
Upon completion or termination of the study, all unused vials of INO-4800 or placebo must 
be destroyed at the study site in accordance with institution policy or returned to Inovio 
Pharmaceuticals, Inc., or its designee if the site cannot destroy IP. 
The used vials of INO-4800 and placebo will be discarded in accordance with the site’s 
used IP disposal procedure. It is the Investigator’s responsibility to arrange for disposal of 
all empty vials, provided that procedures for proper disposal have been established in 
accordance with applicable national, local and institutional guidelines and procedures, and 
provided that appropriate records of disposal are kept. If requested by the Sponsor, the 
return of unused IP vials should be arranged by the responsible Inovio Representative. 
The unused IP vials should only be destroyed after being inspected and reconciled by the 
responsible Inovio Pharmaceuticals, Inc., personnel or designated Clinical Monitor. If IP 
vials are returned to Inovio Pharmaceuticals, Inc., or its designee, the IP must be 
accompanied by the appropriate documentation. The return of unused IP(s) should be 
arranged with the responsible Inovio personnel and/or Clinical Monitor. 
 RETURN OF CELLECTRA® 2000 
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Upon completion or termination of the study, an Inovio Representative will provide 
instructions regarding the component(s) to be returned to Inovio Pharmaceuticals, Inc., 
destroyed onsite or shipped to a destruction vendor. 
All products returned to Inovio Pharmaceuticals, Inc. must be accompanied by the 
appropriate return documentation. Returned supplies should be in the original containers. 
The return of all products identified above should be arranged by the Inovio 
Representative. The ID Arrays should be discarded in the sharps container immediately 
after use. The used ID Applicators can either be destroyed at the site, shipped to a 
destruction vendor, or returned to Inovio. If the used ID Applicators are destroyed on site, 
it is the Investigator’s responsibility to ensure that arrangements have been made for the 
disposal, written authorization has been granted by Inovio Pharmaceuticals, Inc., or its 
designee, procedures for proper disposal have been established in accordance with 
applicable regulation and guidelines and institutional procedures, and appropriate records 
of the disposal have been documented. 
 
CLINICAL TRIAL PROCEDURES AND SCHEDULE 
The Schedule of Events (36TTables 3 and 436T) in the Clinical Protocol Synopsis summarizes 
the procedures to be performed at each visit. Individual procedures are described in detail 
below. It may be necessary to perform these procedures at unscheduled time points if 
deemed clinically necessary by the Investigator. A subject will be required to provide 
informed consent (Section 6.2) prior to any study procedure being performed. Protocol 
waivers or exemptions will not be granted. Therefore, adherence to the study design and 
assessments are essential and required for study conduct. 
 
PROCEDURE BY VISIT 
Refer to Sections 6.1.1 and 6.1.2 for trial procedures and the times at which they are to 
be performed. 
 CLINICAL TRIAL SCREENING EVALUATIONS 
The assessments performed during Screening will determine the subject’s eligibility for 
the study and also their ability to comply with protocol requirements by completing all 
screening assessments. The following screening evaluations will be performed for both 
Phase 2 and Phase 3 segments within 30 days prior to dosing on Day 0. All screening 
assessment values must be reviewed prior to the first Study IP administration. Screening 
and Day 0 visits may be on the same day if eligibility is able to be confirmed prior to 
randomization. If so, all assessments for Screening and Day 0 must be performed at the 
combined visit. 
If a subject does not meet an inclusion or exclusion criterion due to a transient and non-
clinically significant event at Screening, relevant Screening evaluations may be repeated 
within the same 30-day Screening period. If the subject fails twice, they will be considered 
a screen failure. 
• 
Signed and dated informed consent (Section 6.2); 
• 
Review and confirm all inclusion/exclusion criteria (Section 4.1 and 4.2); 
• 
Obtain and document complete medical history, surgical history (including all 
clinically significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Section 6.1.1.1); 
• 
Collect demographics; 
• 
Collect socio-behavioral assessment information (Section 6.4); 
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• 
Collect AEs (Section 6.4.4); 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Record height and weight (Section 6.4); 
• 
Collect urine for pregnancy test (Section 6.4); 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8).  
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect saliva for SARS-CoV-2 RT-PCR (Section 6.4.8). 
 
6.1.1.1 
Medical History 
A medical history will be obtained by the Investigator or qualified designee at the time of 
Screening. Medical history will include all active conditions, and any other past conditions, 
as well as surgical procedures, that are considered to be clinically significant by the 
Investigator and/or having occurred within 3 months prior to Screening. Subjects should 
be queried about any history of Hepatitis B, Hepatitis C and HIV.   
In the Phase 3 segment, subjects with a self-reported history of Hepatitis B or C must 
provide documentation of liver enzymes that are not significantly elevated within the past 
3 months. If such a report of liver enzyme testing is not available, this testing should be 
performed at Screening. Subjects with a history of Hepatitis C without cirrhosis who have 
completed treatment and have proof of an undetectable viral load at least 12 weeks 
following treatment may be enrolled and do not require liver enzymes within the past  
months. 
Subjects with self-reported HIV must provide documentation of controlled HIV infection 
based on a CD4 count greater than 200 cells/mm3 or an undetectable viral load within the 
past 3 months. If a recent CD4 count and/or viral load is not available, this testing should 
be performed at Screening. 
Illnesses first occurring or detected after the signing of the informed consent, or during the 
study and/or worsening of an existing illness in severity, frequency or nature after signing 
of the informed consent are to be documented as AEs on the Case Report Forms (CRF). 
Prior treatments, defined as administered up to 12 weeks prior to the time of informed 
consent and stopped prior to dosing on Day 0, should be recorded in the CRF as prior 
medications. Concomitant treatments, defined as continuing on Day 0 or new treatments 
taken at or after Day 0, should be recorded in the CRF as concomitant medications. 
 CLINICAL TRIAL EVALUATIONS AND PROCEDURES 
Once eligibility has been confirmed, the subject will be randomized to receive a treatment 
assignment (INO-4800 or placebo). Visit dates and windows must be calculated from Day 
0, unless otherwise noted. All subjects will be followed until the Day 393 Visit. All subjects 
will be followed in accordance with assessments outlined below. 
6.1.2.1 
Day 0 and Day 28 (Dosing Visits) 
The following evaluations will be performed on Day 0 and Day 28 prior to dose 
administration: 
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Both Phase 2 and Phase 3 segments: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Obtain any updates to medical history, surgical history (including all clinically 
significant procedures within the past 12 weeks), present conditions and 
concomitant illnesses (Day 0 visit only) (Section 6.1.1.1); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect urine for urine pregnancy test (Section 6.4); 
• 
Collect blood for HIV serology (Day 0 visit only) (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Day 0 visit only) (Phase 3 cellular immunology collection at selected sites only) 
(Section 6.5); 
• 
Review restrictions for injection and EP (Section 6.4.7); 
• 
Randomize subject (instructions to be provided under separate cover) (Day 0 visit 
only). 
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect diary from Day 0 dose (Day 28 visit only). 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8); 
• 
Collect nasopharyngeal swabs for SARS-CoV-2 RT-PCR (Day 0 only) (Section 
6.4.8); 
• 
Collect diary from Day 0 dose during Day 28 visit only(for selected sites only). 
 
The following evaluations will be performed on Day 0 and Day 28 after IP plus EP 
administration: 
• 
Collect any new AEs (Section 6.4.4); 
• 
Download EP Data; 
• 
Provide supplies for subject to use at home, as required (e.g. thermometer, wound 
guide); 
• 
Phase 2 segment: Distribute diary; 
• 
Phase 3 segment, for selected sites: Distribute diary. 
6.1.2.2 
Post-dose phone calls 
Phase 2 segment: Day 7 and Day 35 
Phase 3 segment: Day 14  
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
 
Phase 2 segment only: 
• 
Review diary (Section 6.4). 
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Phase 3 segment only: 
• 
Review diary (for selected sites)(Section 6.4); 
6.1.2.3 
Day 42 Visit 
Both Phase 2 and Phase 3 segments: The following evaluations will be performed at this 
visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4);  
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 cellular immunology collection at selected sites only)(Section 6.5);  
 
Phase 2 segment only: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect diary from Day 28 visit. 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8); 
• 
Collect diary from Day 28 visit (for selected sites only); 
• 
Ensure subject has necessary supplies at home (e.g. thermometer). 
6.1.2.4 
Phone calls  
Phase 2 segment: Day 56 
Phase 3 segment: Days 56, 70, 84, 98, 112, 140, 154, 168, 182, 196, 238, 266, 322, 
350, and 378 
In the Phase 3 segment, phone calls to subjects have been spaced bi-weekly 
between study visits through Day 210, and approximately monthly between visits 
from Day 210 to Day 393.   
 
Guidelines for information to be collected during the phone call can be found in the 
Phone Script. The following evaluations will be performed during the phone call: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Ask about any symptoms of COVID-19 disease; Arrange on-site visit if any signs 
and symptoms of COVID-19 disease are present (Section 6.4.9); 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
6.1.2.5 
Follow up clinic visits 
Phase 2 segment: Day 210 
Phase 3 segment: Days 126, 210 and 294 Visits 
Both Phase 2 and Phase 3 segments: The following evaluations will be performed at these 
visits: 
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• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); SAEs, AESIs, and 
MAAEs will be reported after the Day 56 Visit. 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 Day 201 visit only; Phase 3 cellular immunology collection at selected 
sites only) (Section 6.5); 
 
Phase 3 segment: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8);  
• 
Ensure subject has necessary supplies at home (e.g. thermometer). 
6.1.2.6 
Day 393 Visit or EOS 
Phase 2 and Phase 3 segments: The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); SAEs, AESIs, and 
MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Ask about any symptoms of COVID-19 disease; 
• 
Full physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
 
Phase 2 segment: 
• 
Collect blood for CBC with differential and serum chemistry (Section 6.4); 
• 
Collect urine for routine urinalysis (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Section 6.4.6); 
• 
Collect urine pregnancy test (Section 6.4). 
 
Phase 3 segment: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 cellular immunology collection at selected sites only) (Section 6.5). 
6.1.2.7 
COVID-19 Assessment Visit 
For both the Phase 2 and Phase 3 segments of the study, subjects will be evaluated 
during a COVID-19 assessment visit when acute COVID-19 is suspected based on 
symptoms or positive SARS-CoV-2 testing. The assessment visit may be performed in 
the clinic, subject’s vehicle, or at a home visit and should be performed within 3 days of 
a positive SARS-CoV-2 test or site knowledge of COVID-19 symptom onset. The 
virologic-confirmation of a case will be based on SARS-CoV-2 RT-PCR testing from the 
central lab. A local RT-PCR result will be considered acceptable in the case where a 
subject is hospitalized and a sample for central lab analysis is not able to be obtained, if 
it was obtained using. an assay performed by a laboratory accredited according to 
standards set by a national or regional accreditation body.  
If a local lab is used to confirm the case, the report from the laboratory must be provided.  
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Phase 2 and Phase 3 segments: The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); Only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Optional targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
 
Phase 2 only: 
• 
Collect nasal swabs and saliva for SARS-CoV-2 RT-PCR detection (Section 6.4.8). 
Phase 3 only: 
• 
Collect whole blood and serum for cellular and humoral immunology assessment, 
where possible (Phase 3 cellular immunology collection at selected sites only) 
(Section 6.5) 
• 
Collect nasopharyngeal swabs for SARS-CoV-2 RT-PCR testing (Section 6.4.8). 
6.1.2.8 
COVID-19 Convalescent Visit 
Phase 2 and Phase 3 segments: For subjects with confirmed SARS-CoV-2 infection 
during the trial, a convalescent visit should be scheduled approximately 28 days after 
symptom onset, or in the absence of symptoms, after the collection date of a positive 
SARS-CoV-2 test. If symptoms are ongoing at 28 days after symptom onset, the site 
should follow up with the subject via phone call or unscheduled visit after symptom 
resolution or stabilization.  
The following evaluations will be performed at this visit: 
• 
Collect all present and/or new or ongoing AEs (Section 6.4.4); Only SAEs, AESIs 
and MAAEs will be reported after the Day 56 Visit; 
• 
Document any present conditions and concomitant illnesses; 
• 
Record current concomitant medications/treatments (Section 6.4.6); 
• 
Targeted physical examination (Section 6.4); 
• 
Record vital signs (Section 6.4); 
• 
Collect whole blood and serum for cellular and humoral immunology assessment 
(Phase 3 cellular immunology collection at selected sites only) (Section 6.5); 
 
Phase 2 segment only: 
• 
Collect nasal swabs and saliva for SARS-CoV-2 RT-PCR detection (Section 6.4.8). 
 
Phase 3 segment only: 
• 
Collect serum for SARS-CoV-2 antibody testing (Section 6.4.8). 
 
INFORMED CONSENT 
All subjects must sign the informed consent prior to participating in any clinical trial-related 
procedures. The informed consent documentation must be in compliance with applicable 
regulations and GCP. Qualified clinical trial personnel will: 
• 
Meet with prospective clinical trial subjects; 
• 
Explain the clinical trial; 
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• 
Provide clinical trial subjects with an Informed Consent Form (ICF) that includes the 
following in a language that is understandable to the subject: 
• 
Screening test(s) description; 
• 
Eligibility criteria for entering the clinical trial; 
• 
Clinical trial treatments and follow-up procedures description; 
• 
Explanation of the clinical trial, including but is not limited to: 
• 
Clinical trial objectives; 
• 
Potential benefits and risks; 
• 
Discomforts/inconveniences; 
• 
Subject’s rights and responsibilities. 
The subject is then requested to sign and date the ICF. A copy of the signed informed 
consent documentation must be provided to the subject. The qualified clinical trial 
personnel will document the process of obtaining informed consent within the source 
record. Signed ICFs are maintained in the subject’s source records and must be 
accessible for verification at any time. Signing of the ICF begins the 30-day screening 
period. 
 
ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS 
Each subject who consents will be assigned a unique subject identification number (SID), 
which identifies the subject for all clinical trial-related procedures. SIDs are a combination 
of a site code and a subject number. After SIDs are assigned, they cannot be reused or 
reassigned for any reason. Information regarding the SID and screen date will be 
documented on a screening and enrollment log/system and in the CRF.   
Previously screen failed subjects may be rescreened provided there is a valid documented 
reason for rescreening (i.e. changes to the person’s health or situation that would make 
them possibly eligible at this later time). If rescreening occurs, the subject will keep their 
original Subject ID.  
 
SAFETY EVALUATIONS 
PHYSICAL AND TARGETED PHYSICAL EXAM  
A full physical examination will be conducted during Screening and at study 
discharge/EOS (e.g. Day 393). A targeted physical assessment will be performed at other 
visits as determined by the Investigator based on subject symptoms.  
VITAL SIGNS 
Vital signs including temperature, respiration rate, blood pressure and heart rate will be 
measured at Screening and at visits specified in the Schedule of Events (36TTables 3 and 
436T).  
At the COVID-19 assessment and convalescent visits, temperature, respiration rate, 
heart rate and oxygen saturation should be performed.   
HEIGHT AND WEIGHT 
Weight and height will be collected at Screening. 
SOCIO-BEHAVIORAL ASSESSMENT  
A Socio-behavioral Assessment, including self-reported smoking and vaping history, and 
self-reported history of exposure to second-hand smoke will be obtained at Screening. 
LABORATORY EVALUATIONS 
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Blood samples will be collected at visits specified in the Schedule of Events (36TTables 3 and 
436T). A total of approximately mL 245-330mL of blood will be drawn from each subject over 
the course of the study (inclusive of relevant safety and immunology samples at regular 
study visits per Tables 3 and 4). If the subject is evaluated at COVID-19 visits, an 
additional volume of approximately 85-120mL will be collected. Subjects may be asked to 
return for additional blood draws if collected blood sample is lost or unevaluable for any 
reason. 
Hematology [Complete blood count (CBC) with automated differential]: 
White blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, hematocrit and 
platelet count will be measured at Screening (Phase 2 segment only) and at visits specified 
in the Schedule of Events (36TTables 3 and 436T). Hemoglobin A1c will additionally be performed 
at Screening (Phase 2 segment only). 
Serum chemistry: 
Electrolytes [Sodium (Na), Potassium (K), Chloride (Cl), Bicarbonate (HCO3), Calcium 
(Ca), Phosphate (PO4)], glucose, Blood Urea Nitrogen (BUN), Creatinine (Cr),  alkaline 
phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), LDH,  
and total bilirubin (TBili) at Screening (Phase 2 segment only) and at visits specified in the 
Schedule of Events (36TTables 3 and 436T).  
Urinalysis:  
Urine samples will be tested by dipstick for glucose, protein, and hematuria at Screening 
(Phase 2 segment only) and at visits specified in the Schedule of Events (36TTables 3 and 
436T). If abnormal (presence of protein, hematuria, or glucose ≥ 1+), a microscopic 
examination should be performed.  
Serology: 
HIV antibody or rapid test will be measured at Day 0 only.  
Antibodies to SARS-CoV-2 will be measured at Screening and at visits specified in the 
Schedule of Events (Tables 3 and 4). 
Pregnancy Testing:  
Pregnancy testing will be performed on women of childbearing potential (WOCBP). All 
women will be assumed to be of childbearing potential unless they are:  
• 
Women who are post-menopausal as defined by reported spontaneous 
amenorrhea for ≥ 12 months; 
• 
Women who are surgically sterile or have a partner who is sterile (i.e., vasectomy 
in males or tubal ligation, absence of ovaries and/or uterus in females). In the 
case of a vasectomy, subjects should wait six (6) months post-vasectomy to be 
considered sterile. 
Phase 2: For WOCBP, a serum pregnancy test will be obtained at Screening and a urine 
pregnancy test will be performed immediately prior to any dosing and at the subject’s last 
visit.  
Phase 3: For WOCBP, a urine pregnancy test will be obtained at Screening and will be 
performed immediately prior to any dosing. 
A negative result for urine β-HCG (test must have a sensitivity of at least 25 mIU/mL) must 
be available prior to each administration of IP. If the β-HCG test is positive, indicating that 
the subject is pregnant prior to completing the specified dose regimen, then no further IP 
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will be administered. Every attempt should be made to follow pregnant subjects for the 
remainder of the study and to determine the outcome of the pregnancy (see Section 7.12). 
DIARY 
Diaries will be implemented in the Phase 2 segment of the protocol and at selected sites 
(estimated to include 711 subjects) in the Phase 3 segment.  Subjects will be provided a 
diary to record the following solicited local and systemic AEs: 
• 
Oral temperature and time taken (each daily entry before 11:59 pm) 
• 
Solicited systemic symptoms 
• 
Solicited local injection site symptoms 
• 
Concomitant medications 
The diary should be completed once daily starting the evening of each study dose through 
6 days post-dose. The completed diary post-dose 1 and post-dose 2 will be reviewed with 
the subject by the study staff during the next study phone call or visit and collected at the 
next in-person study visit. The study staff will review the diary with the subject to assess 
for temperature, solicited systemic symptoms (unusually tired/feeling unwell, muscle 
aches, headache, nausea, joint pain) and solicited injection site symptoms (pain, itching, 
redness, swelling, bruising). In addition, unsolicited symptoms and concomitant 
medications will be assessed.  
Any diary entry determined to meet the Common Terminology Criteria for Adverse Events 
version 5.0 (CTCAE) criteria for a Grade 1 or higher adverse event should be documented 
as an adverse event unless deemed part of the subject’s ongoing medical history. Injection 
site reactions should be graded per the Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials, issued September 
2007 (See Section 6.4.5). If the diary entry does not meet the criteria of a Grade 1 or 
higher AE as per the relevant guidelines, Investigator clinical judgment can be used to 
determine whether the entry should be recorded as an AE and documented accordingly 
in the site’s source. For cases where the diary entry and final AE reporting (i.e. grading) 
do not agree, the reasoning should be recorded in the source documents. 
 INTRADERMAL INJECTION AND EP  
Phase 2 and Phase 3 segments: 
A complete administration procedure is defined as an ID injection (formation of a wheal) 
of IP followed by insertion of the ID Array needles (electrodes) through the skin and into 
the wheal followed by delivery of four electroporation pulses. This procedure is broadly 
described as administration because it involves more than the injection of a drug. 
Only if the deltoid area is not a suitable location for administration (see exclusion criterion 
‘j’), the ID injection can then be administered above the lateral quadriceps followed 
immediately by EP. IP must not be given within 2 cm of a tattoo, scar, keloid, or active 
lesion/rash. Also, ID injection followed immediately by EP must not be performed on the 
skin of an extremity which has any metal implants or implantable medical device (e.g., 
surgical rods, pins or joint replacements). If a subject has an implanted cardiac defibrillator 
or pacemaker, ID injection/EP must not be performed above the deltoid muscle on the 
same side of the body where the device is located. 
There are three steps that must be performed as part of the administration procedure: 
1. Injection of IP (INO-4800 or placebo) 
2. Insertion of the array into the subject’s skin 
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3. Pressing the trigger button on the EP applicator  
Table 9 below is provided as guidance on how to appropriately complete the procedure 
when injection of IP has occurred, but the subject did not receive EP. 
Table 9: Guidance for how to manage an incomplete administration after IP has 
been injected 
Was IP 
injected? 
Was the array 
inserted into skin? 
Was trigger button 
pressed? 
Action 
Yes 
Yes (if array gets 
dislodged before 
the trigger button 
is pressed, the 
same array may 
be re-inserted) 
No 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
Yes 
No 
Yes 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
Yes 
No 
No 
If the drug injection wheal is 
discernable, EP should be 
attempted at the site of drug 
injection to complete the 
procedure 
 
 
Reinjection of IP (i.e. protocol-specified IP has already been delivered) is not permitted. 
Delivery of a second electroporation in tissue is not permitted. 
Training will be provided by the Sponsor on use of the device. 
Phase 2 segment: 
Subjects will receive a two-dose regimen of one or two 1.0 mg ID injections of INO-4800 
or placebo in a volume of ~0.1 mL in an acceptable skin location for injection and 
subsequently followed immediately by EP of each injection site with CELLECTRA® 2000 
at Day 0 and Day 28. For subjects assigned to receive two injections + EP at each dosing 
visit, the two injections must be performed in acceptable locations on two different limbs. 
Phase 3 segment: 
Subjects will receive a two-dose regimen of two 1.0 mg ID injections of INO-4800 or 
placebo in a volume of ~0.1 mL in an acceptable skin location for injection on different 
limbs and subsequently followed immediately by EP of the injection site with 
CELLECTRA® 2000 at Day 0 and Day 28. 
 MANAGEMENT OF PAIN DUE TO ELECTROPORATION (EP) PROCEDURES 
In case of pain, subjects may be treated with a non-narcotic analgesic (e.g., 
acetaminophen) after injection/EP.  
Medication taken for pain management will be documented as concomitant medications. 
 ASSESSMENT OF LABORATORY ABNORMALITIES 
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In Phase 2, samples will be collected for serum chemistry, hematology, and urinalysis at 
the visits listed in the Schedule of Events (36TTables 3 and 436T) and as listed in Section 6.4.  
Laboratory AEs will be assessed and graded in accordance with the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. Laboratory values that are 
not clinically significant (NCS) in the Investigator’s opinion will not be reported as AEs. 
 ASSESSMENT OF CLINICAL TRIAL ADVERSE EVENTS (AES) 
Subjects will be queried regarding the occurrence of any AEs including AEs related to 
injection site reactions, concomitant medications and new onset illness or disease during 
their study visits and phone calls. Subjects will be reminded to contact study personnel 
and immediately report any event for the duration of the study. All AEs will be captured 
from the time of the informed consent until 28 days post-dose 2 (Day 56). Following the 
Day 56 visit, only SAEs, AESIs and MAAEs will be collected. All related AEs, AESIs and 
SAEs will be followed to resolution or stabilization. These events will be recorded on the 
subject’s CRF. 
 ASSESSMENT OF INJECTION SITE REACTIONS  
Reactions arising from the IP administration procedure may be reported as administration 
site or injection site reactions. When evaluating administration (injection) site reactions 
throughout the study, it is most important to be as specific as possible by selecting the 
most appropriate term (see Table 10 below) and using the grading scale as listed in the 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, issued September 2007. All subjects will be observed for 30 
minutes following the IP administration procedure for immediate AEs.  In addition, other 
events associated with administration (injection) site reactions (e.g., hematoma, infection 
or necrosis) should also be reported with preferred terms specific for administration 
(injection) site reactions.  
Table 10: Grading Scale for Injection Site Reactions 
Local Reaction to 
Injectable Product 
(Grade) 
Mild (1) 
Moderate (2) 
Severe (3) 
Potentially 
Life 
Threatening 
(4) 
Pain 
Does not 
interfere with 
activity 
Repeated use 
of non-
narcotic pain 
reliever >24 
hours or 
interferes with 
activity 
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity 
Emergency 
room visit or 
hospitalization 
Tenderness 
Mild 
discomfort to 
touch 
Discomfort 
with 
movement 
Significant 
discomfort at 
rest 
ER visit or 
hospitalization 
Erythema/Rednessa 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swellingb 
2.5-5 cm and 
no 
5.1-10 cm or 
interferes with 
activity 
>10 cm or 
prevents daily 
activity 
Necrosis 
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interference 
w/ activity 
September 2007 “FDA Guidance for Industry-Toxicity Grading Scale for Healthy Adult and Adolescent 
Volunteers Enrolled in Preventive Vaccine Clinical Trials” 
a In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable 
b Should be evaluated and graded using the functional scale as well as the actual measurement. 
 
 CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription, including receipt of any non-study 
COVID-19 vaccine (authorized under emergency use or licensed)) taken between 
informed consent and study discharge (see Section 4.2) must be recorded on the CRFs. 
Actual or estimated start and stop dates must be provided. This information will be 
obtained from the subject and/or any available medical records. The indication for the 
medication, dose, and dose regimen will be documented.  
Therapy considered necessary for the subject’s welfare may be given at the discretion of 
the Investigator or medical provider. If the permissibility of a specific medication/treatment 
is in question, please contact the Medical Monitor. 
The decision to administer a prohibited medication/treatment (Section 6.4.7) is made with 
the safety of the clinical trial subject as the primary consideration. When possible, the 
Sponsor should be notified before the prohibited medication/treatment is administered. 
 RESTRICTIONS  
In the Phase 2 segment of the trial, subjects should refrain from becoming pregnant until 
3 months following the last dose of investigational product by using appropriate 
contraceptive measures (see Section 4.1.1). In the Phase 3 segment of the trial, subjects 
should refrain from becoming pregnant until receipt of the last dose of investigation 
product by using appropriate contraceptive measures (See Section 4.1). 
Subjects must not receive any non-study related vaccine (e.g., influenza vaccine) within 2 
weeks prior to the first dose of IP, or within 2 weeks of (before or after) any subsequent 
dose of IP.  
Subjects must not have fever (oral temperature ≥38.0 degrees Celsius or 100.4o 
Fahrenheit) within 72 hours prior to each dosing. 
Subjects should not receive hydroxychloroquine during the trial. In the Phase 3 segment, 
subjects should not receive any other drug/vaccine intended as COVID-19 prophylaxis 
during the trial. Subjects should be reminded that if and when appropriate, the Sponsor 
would offer INO-4800 to those who received placebo in the trial if INO-4800 is 
demonstrated to be efficacious.  
 
For subjects in the Phase 2 segment of the trial, the receipt of any non-study prophylactic 
COVID-19 vaccine (authorized under emergency use or licensed) is not restricted, based 
upon increasing availability of EUA vaccine in the US and completion of the Phase 3 dose 
selection from the Phase 2 data.  
If a subject informs the site of their intent to receive a non-study prophylactic COVID-19 
vaccine available either authorized under emergency use or when licensed, the subject 
should be informed that the safety and effectiveness of receiving INO-4800 followed by 
another COVID-19 vaccine has not been studied. 
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Subjects should not participate in any other interventional trials for the duration of this trial. 
Subjects must not receive disease modifying doses of anti-rheumatic drugs (e.g., 
azathioprine, cyclophosphamide, cyclosporine, methotrexate), biologic disease modifying 
drugs such as TNF-α inhibitors (e.g., infliximab, adalimumab or etanercept) and long term 
use (≥7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of prednisone 
equivalent (use of inhaled, topical, nasal, otic, and ophthalmic corticosteroids are allowed).  
 SARS-COV-2 TESTING 
Phase 2 segment: 
SARS-CoV-2 antibody and RT-PCR testing will be used during screening to test for 
previous or current SARS-CoV-2 infection. During the trial, subjects who report symptoms 
suggestive of COVID-19 will be assessed at a COVID-19 assessment visit in the clinic or 
subject’s vehicle or at the subject’s home. During this visit, nasal swabs and saliva will be 
collected to detect SARS-CoV-2 using the RT-PCR assay. Genotyping may also be 
performed. If the subject is confirmed to be COVID-19 positive, a follow-up nasal swab 
and saliva will be collected to detect SARS-CoV-2 using the RT-PCR assay at the COVID-
19 convalescent visit. 
Phase 3 segment: 
SARS-CoV-2 antibody testing will be used during screening to test for previous SARS-
CoV-2 infection and during each subsequent visit (see Table 4: Schedule of Events) to 
identify SARS-CoV-2 infections that may occur regardless of symptoms between study 
visits. 
SARS-CoV-2 RT-PCR testing will be conducted on nasopharyngeal specimens collected 
at Day 0. The Day 0 SARS-CoV-2 RT-PCR results will not be required prior to dosing on 
that day. 
For subjects who are seronegative at baseline, if at any time during the trial, either the 
SARS-CoV-2 antibody or an RT-PCR test result is positive, the subject will be notified of 
the result and will be evaluated at a COVID-19 assessment visit. During that visit, which 
may be conducted in the clinic, from the subject’s vehicle, or in the subject’s home, 
nasopharyngeal swabs will be collected to detect SARS-CoV-2 using the RT-PCR assay. 
Genotyping may also be performed on the sample(s) collected at the COVID-19 
assessment visit.  
 COVID-19 DISEASE MONITORING 
During both the Phase 2 and Phase 3 segments of the trial, all subjects will be monitored 
for the development of symptoms suggestive of COVID-19 disease. For the Phase 3 
segment, frequent (approximately bi-weekly) scheduled clinic visits or phone calls will 
occur.  
All subjects in the trial should be instructed to do the following: 
• 
Take their temperature daily at home starting on the Day 0 visit for the duration of 
the trial.     
• 
Monitor for symptoms suggestive of COVID-19 (e.g., feeling feverish or chills, 
cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, 
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headache, new loss of taste or smell, sore throat, congestion or runny nose, 
nausea or vomiting, diarrhea) starting on the Day 0 visit for the duration of the trial.  
If at any time during the study, the subject experiences a fever of ≥ 100.4°F/38°C or 
symptoms suggestive of COVID-19, the subject should contact the site. The site staff 
should arrange for a clinic visit (COVID-19 assessment visit) within 3 days of the site being 
aware of either a positive SARS-CoV-2 test or COVID-19 symptom onset. The COVID-19 
assessment visit may be performed either at the clinic, in the subject’s vehicle or in the 
subject’s home. 
Subjects with a confirmed COVID-19 diagnosis, per the case definition outlined in Section 
3.7, prior to dose 2 or who have a positive SARS-CoV-2 PCR test at Day 0 will be 
discontinued from further dosing and will be followed until EOS for safety and resolution 
of COVID-19. Subjects with confirmed SARS-CoV-2 infection will return for a convalescent 
visit approximately 28 days after symptom onset, or in the absence of symptoms, after the 
collection date of the positive SARS-CoV-2 sample. If symptoms are ongoing at 28 days 
after symptom onset, the site should follow up with the subject via phone call or 
unscheduled visit after symptom resolution or stabilization. Recovery from COVID-19 
disease requires either resolution of clinical symptoms except for loss of taste/smell, or 
with sequelae that appear to be permanent.     
Subjects who require medical care for COVID-19 (or any other suspected condition) will 
be referred to their primary health care provider or a medical treatment facility if the 
Investigator believes that the subject should be managed beyond routine care that can be 
provided by the study site. Subjects referred for treatment will continue study follow-up 
according to the protocol schedule. If subjects are treated or hospitalized due to their 
illness, the study team will request COVID-19 specific test results, treatments, treatment 
outcomes and diagnostics from medical treatment facilities with the subject’s written 
permission. These results and diagnostics will be recorded in the study and/or safety 
database consistent with protocol reporting requirements. 
 
IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at visits specified in the Schedule of 
Events (36TTables 3 and 436T) for cellular and humoral immunology assessments. Binding 
ELISA will be evaluated at serial timepoints. Cellular sampling requires 32 mL of whole 
blood be collected at each visit. Humoral sampling requires collection of 8.5 mL of whole 
blood in a single 10-mL red top serum collection tube to produce two serum aliquots of 2 
mL each. However, baseline (Day 0) immunology samples are required to serve as a 
baseline for all subsequent immunology testing. Therefore, a total of 68 mL whole blood 
for cellular sampling and 8 mL serum for humoral sampling is required on Day 0 prior to 
1st dose. Subjects may be asked to return for additional blood draws if collected blood 
sample is lost or unevaluable for any reason. Details of the immunology sample collection 
and shipment information will be provided in the Laboratory Manual.  
Humoral samples will be collected on all subjects and cellular samples will be collected at 
selected sites (from approximately 711 subjects). Both humoral and cellular analysis will 
be conducted in the first 102 subjects age 18-50 and in the first 102 subjects age 51 and 
older enrolled at the sites that are selected for cellular sample collection. In addition, 
cellular and humoral samples will be analyzed on all subjects with COVID-19 when 
samples are available. 
The immune responses to INO-4800 will be measured using assays that include a 
pseudovirus-based neutralization assay and ELISpot. Determination of additional 
analyses using assays not specified, such as assessment of immunological gene 
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expression or flow cytometry, assessment of immunological protein expression on 
collected samples for immunological endpoints will be made on an ongoing basis 
throughout the trial. 
 
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
 
SAFETY PARAMETERS 
The safety of INO-4800 will be measured and graded in accordance with the Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. 
 
ADVERSE EVENTS (AES) 
Any untoward medical occurrence in a patient or clinical investigation subject administered 
a pharmaceutical product and which does not necessarily have a causal relationship with 
this treatment.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of a medicinal product, whether or not considered related to the medicinal product.  
Adverse Events (AEs) include the following: 
• Pre- or post-treatment complications that occur as a result of protocol mandated 
procedure during or after screening (before the administration of clinical trial drug); 
• Any pre-existing condition that increases in severity, or changes in nature during or as 
a consequence of the clinical trial drug administration phase; 
• Complications of pregnancy (refer to Section 7.11). 
Adverse Events (AEs) do not include the following: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed; however, the condition that leads to the procedure is an AE; 
• Pre-existing diseases or conditions or laboratory abnormalities present or detected 
before the Screening Visit that do not worsen; 
• Situations where an untoward medical occurrence has not occurred (e.g., 
hospitalization for elective surgery, social and/or convenience admissions); 
• Overdose without clinical sequelae; 
• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the ICF is signed, is not an AE; it is considered to be pre-existing and will be 
documented on the medical history CRF; 
• Uncomplicated pregnancy; 
• An induced elective abortion to terminate a pregnancy without medical reason; 
• Confirmed COVID-19 disease.  
 
ADVERSE DRUG REACTION (ADR) 
All noxious and unintended responses to a medicinal product related to any dose. This 
means that a causal relationship between the medicinal product and an adverse event is 
at least a reasonable possibility (i.e., the relationship cannot be ruled out). 
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SERIOUS ADVERSE EVENTS (SAES) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death;  
• Is life-threatening; 
o Refers to an event in which the subject was at risk of death at the time of the event. 
It does not refer to an event which hypothetically might have caused death if it 
were more severe 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
o Includes any hospitalization in which the subject has been admitted to the hospital 
regardless the length of stay, even if the hospitalization is only a precautionary 
measure to allow continued observation. However, hospitalization (including 
hospitalization for an elective procedure) for a pre-existing condition that has not 
worsened, does not constitute an SAE 
• Results in persistent or significant disability/incapacity; 
o A substantial disruption of a person's ability to conduct normal life functions (i.e., 
the adverse event resulted in a significant, persistent or permanent change, 
impairment, damage or disruption in the subject’s body function/structure, physical 
activities and/or quality of life) 
• Results in congenital anomaly or birth defect and/or; 
• An important medical event.  
o An event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the subject or may require intervention to 
prevent one of the other outcomes listed above. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse 
Clarification of Serious Adverse Events (SAEs) 
• Death itself is not an AE. Death is an outcome of an AE, but when the cause of death 
has not been provided, use the event term: death of unknown cause; 
• Confirmed COVID-19 disease that requires hospitalization is recorded on the 
Suspected COVID-19 Clinical Event CRF, and not recorded as an SAE; 
• COVID-19 disease with an outcome of death is recorded on the Suspected COVID-19 
Clinical Event CRF, and not recorded as an SAE; 
• The subject may not have been receiving an investigational medicinal product at the 
occurrence of the event; 
• Complications associated with COVID-19 disease that occur or prolong 
hospitalization are recorded on the Suspected COVID-19 Clinical Event CRF; 
• The Pregnancy outcomes of spontaneous abortion (miscarriage), ectopic pregnancy, 
fetal demise/stillbirth in a subject or subject partner following exposure to study 
treatment is considered to be an SAE. 
 
UNEXPECTED ADVERSE DRUG REACTION 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g., Investigator’s Brochure [IB] for an unapproved investigational 
product, package insert/summary of product characteristics for an approved product). 
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UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application (including a supplementary plan or application), or any other unanticipated 
serious problem associated with a device that relates to the rights, safety, or welfare of 
subjects.  
A UADE is a type of SAE that requires reporting to the Sponsor in accordance with Section 
7.9. 
 
DEVICE DEFICIENCY 
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety or performance. 
Note: Device deficiencies include malfunctions, use errors and inadequate labelling. 
 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor is responsible for the overall safety monitoring of the clinical trial. 
Safety monitoring assessments include but are not limited to:  
• Incidence of all AEs classified by system organ class, preferred term, severity and 
causal relationship to clinical trial treatment; 
• Changes in laboratory parameters; 
• Local and systemic injection site review; special attention will be paid to the examination 
of the injection site. 
 ADVERSE EVENT OF SPECIAL INTEREST (AESI)  
An adverse event of special interest (serious or non-serious) is one of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor can be 
appropriate.  
For the purpose of this clinical trial, the AESIs listed in Appendix A are to be reported to 
the Sponsor in accordance with Section 7.9. 
 MEDICALLY ATTENDED ADVERSE EVENT (MAAE) 
A medically attended adverse event (serious or non-serious) is defined as an adverse 
event that leads to an unplanned contact with a health care provider. 
 ABNORMAL LABORATORY VALUE 
The Investigator will annotate each abnormal lab value as clinically significant (CS) or not 
clinically significant (NCS). 
Laboratory values that are NCS in the Investigator’s opinion should not be reported as an 
adverse event. 
Any abnormal laboratory value that is new in onset or worsened in severity or frequency 
from the baseline condition and meets one of the following criteria will be recorded as an 
AE: 
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• 
Requires therapeutic intervention or diagnostic tests; 
• 
Leads to discontinuation of further administration of the investigational product in 
the clinical trial; 
• 
Has accompanying or inducing symptoms or signs; 
• 
Is judged by the Investigator as clinically significant (CS). 
Abnormal laboratory values that meet the criteria of an AE or SAE should be reported in 
accordance with Section 7.9. 
 CLINICAL TRIAL STOPPING RULES 
The Investigator is to immediately notify the Medical Monitor if the following are observed: 
• 
Any SAE related to study treatment (i.e., IP and/or the study device); 
• 
Any Grade 4 AEs related to study treatment (i.e., IP and/or the study device); 
• 
Any report of anaphylaxis related to study treatment (i.e., IP and/or the study 
device); 
• 
Any suspected Severe COVID-19 disease case (per Sections 3.7.1.1 and Section 
3.7.1.2). 
The Medical Monitor will notify the Chair of the Safety Review Committee, who will make 
a determination as to whether to temporarily halt dosing until a more formal review of the 
case(s) is made. Such a formal review may include an ad hoc meeting of the DSMB, after 
consultation with the DSMB Chair. Following such a meeting, the DSMB chair will render 
a recommendation to the Medical Monitor regarding continuation of trial dosing. The 
Sponsor will independently investigate the case(s) and, after review of the DSMB 
recommendations, will communicate a final decision as to whether to lift the dosing 
suspension or whether to continue dosing. These deliberations will be documented and 
will be provided to the IRBs and FDA, where required.   
In the case of suspected Severe COVID-19 cases, the trial will be paused if a vaccine-to-
placebo case split yields a relative risk with a 90% confidence interval lower bound >1.  
The minimum case split corresponding to this criterion is 8:0. In this scenario, the trial will 
pause until at least one additional case is accrued and the DSMB can review the data and 
make a recommendation regarding continued enrollment in the trial. 
 
SAFETY DATA REPORTING PERIOD, METHOD OF COLLECTION AND SUBMISSION 
All AEs will be collected from the time informed consent is obtained through Day 56. 
MAAEs, AESIs and SAEs only will continue to be collected after the Day 56 visit and will 
be followed to resolution or stabilization. This information will be captured in the CRF. 
If the Investigator determines that the AE meets serious criteria, then the AE will be 
recorded as an SAE. 
SAEs and AESIs will be reported to the Sponsor from the time the subject signs the 
informed consent until the last visit. 
All SAEs (regardless of causal relationship) and AESIs will be reported on the SAE Report 
Form and submitted to the Sponsor within 24 hours of becoming aware of the event. The 
SAE Report Form will be either emailed to safety.inovio@apcerls.com or faxed to
The original SAE Report Form must be kept at the clinical trial site. 
The event will be data entered into the CRF. 
 
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For the events that are considered an AESI, the Investigator will contact the Sponsor within 
24 hours of becoming aware of the event to discuss whether dosing should continue. 
Table 11: SAE Contact Information 
Sponsor Safety Email: safety.inovio@apcerls.com  
Sponsor Safety Fax: 
Sponsor Safety Phone: 
 
Table 12: Medical Monitor Direct Contact Information 
Primary point of contact, ICON Medical Monitor: 
M.D.  
Email: 
 
Phone: 
 
Inovio Medical Monitor:  
, Jr., M.D., FACP, FIDSA 
Email: 
 
Cell Phone: 
 
 
All SAEs, treatment-related AEs, MAAEs and AESIs must be followed by the Investigator 
until resolution or return to baseline status, stabilization of the event (i.e., the expectation 
that it will remain chronic), even if it extends beyond the clinical trial reporting period or 
until it is determined that the subject is lost to follow up. 
Follow-up information is to be submitted to the Sponsor on an SAE Report Form and within 
24 hours of becoming aware of the information. 
If medical records are submitted to the Sponsor with the SAE Report Form, the clinical 
trial site must: 
• Redact the medical records of all personal data (e.g., confidential subject data, 
Personal Identifying Information [PII]) 
• Provide the subject’s assigned identification number (SID) on the records 
 ADVERSE EVENT REPORTING 
This section provides details on reporting the safety information. 
 SUBMITTING THE INITIAL SERIOUS ADVERSE EVENT (SAE) REPORT FORM 
The Investigator should include as much safety information as possible when submitting 
the initial report, but the report must include the following at a minimum:  
• 
The adverse event; 
• 
The subject’s assigned identification number (SID); 
• 
Investigational product(s) (IP) and/or study device; 
• 
Investigator causal relationship to the IP(s) and/or study device; 
• 
Serious criteria; 
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• 
Reporter name and contact information. 
If a case is submitted to the Sponsor with only the “minimum” information, a more detailed 
or updated follow-up report will be sent to the Sponsor as soon as possible but no later 
than three (3) calendar days after the date of the initial report. 
 RECORDING THE EVENT 
Investigators should use correct medical terminology/concepts when recording AEs on the 
EDC and SAE Report Form. The use of colloquialisms and abbreviations should be 
avoided. 
A medical diagnosis, if known, should be recorded rather than individual signs and 
symptoms. However, if the signs and/or symptoms cannot be medically characterized as 
a single diagnosis or syndrome, each individual sign and/or symptom should be recorded. 
If a diagnosis is subsequently established, all previous signs and/or symptoms will be 
subsumed and replaced with a single medical diagnosis. 
 ASSESSING SEVERITY (INTENSITY) 
Severity is used to describe the intensity of a specific event (e.g., mild, moderate, severe). 
The Investigator will assess and grade clinical AEs or SAEs (based on discussions with 
clinical trial subjects) in accordance with CTCAE. 
 CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS (AES) 
A causally related AE is one judged to have a possible, probable or definite relationship 
to the administration of the IP and/or the study device. An AE may also be assessed as 
not related to the IP and/or the study device. Because the Investigator is knowledgeable 
about the subject (e.g., medical history, concomitant medications), administers the IP, and 
monitors the subject’s response to the IP, the Investigator is responsible for reporting AEs 
and judging the relationship between the administration of the IP and EP and a 
subsequent AE. The Investigator is aware of the subject’s clinical state and may have 
observed the event, and thus may be sensitive to distinctions between events due to the 
underlying disease process versus events that may be product-related.  
Investigators should use their knowledge of the clinical trial subject, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to determine 
whether an AE is considered to be related to the IP and/or the study device and the causal 
relationship reported as "Yes" or "No" accordingly. Causality should be assessed by the 
Investigator as related to drug, related to device, or related to both drug and device (i.e., 
related to both or indiscernible) by the following criteria: 
• 
Yes – there is a reasonable possibility that administration of the clinical trial 
treatment (drug or device or both drug and device) contributed to the event 
• 
No – there is no reasonable possibility that administration of the clinical trial 
treatment contributed to the event and there are more likely causes 
The following guidance should also be taken into consideration: 
• 
Temporal relationship of event to administration of IP and/or EP; 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of IP, or reintroduction of IP (where applicable); 
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• 
Known association of the event with the IP, EP or with similar treatments; 
• 
Known association of the event with the disease under trial; 
• 
Presence of risk factors in the clinical trial subject or use of concomitant 
medications known to increase the occurrence of the event. 
The rationale for the Investigator’s causal assessment is to be recorded on the SAE Report 
Form. 
The Sponsor will assess the overall safety of the IP delivered by EP and determine 
whether to report expeditiously to the regulatory authority(ies). 
 REPORTING SUSPECTED COVID-19 DISEASE CASES DURING THE TRIAL 
For both Phase 2 and Phase 3 segments of the trial, all suspected COVID-19 disease 
cases based on reported COVID-19 symptoms and/or SARS-CoV-2 test results should be 
entered into the Suspected COVID-19 Clinical Event CRF within 24 hours of awareness. 
Cases will be tracked until final determination of whether the case meets criteria of a 
confirmed COVID-19 disease case, per the case definition. For the Phase 2 segment of 
the trial, this determination will be made by the Investigator. For the Phase 3 segment, this 
determination will be made by the EAC. 
If the reported COVID-19 disease case is later determined not to be a confirmed COVID-
19 case, the event (e.g. symptoms or other diagnosis), if serious, would be reported as an 
SAE within 24 hours following determination by the Investigator (Phase 2 segment) or 
notification by EAC (Phase 3 segment).  
If the reported COVID-19 disease case is later determined not to be a confirmed COVID-
19 case, the event (e.g. symptoms or other diagnosis), if non-serious and if occurring from 
the time of consent until 28 days post-dose 2, would be reported as an AE following 
determination by the Investigator (Phase 2 segment) or notification by EAC (Phase 3 
segment). 
 REPORTING PREGNANCY DURING THE CLINICAL TRIAL 
Subjects in Phase 2 who are pregnant or expect to become pregnant prior to 3 months 
following the last dose will be excluded from participation in the clinical trial.  
Subjects in Phase 3 who are pregnant or expect to become pregnant prior to the last dose 
will be excluded from participation in the clinical trial.  
All pregnancies that occur from the time of first administration of clinical trial treatment 
through study completion (i.e., Day 393) will be reported to the Sponsor. If clinical trial site 
staff become aware that a subject becomes pregnant after the first dose in the clinical trial, 
she will not be given any additional treatments with the IP. A Pregnancy Form will be 
completed by the site and submitted to the Sponsor within 24 hours after becoming aware 
of the pregnancy. 
The Investigator will report this event to their IRB/REB/EC in accordance with their policies 
and procedures.  
The clinical trial site must request the subject’s permission to query pregnancy outcome 
and follow the subject for outcome of the pregnancy. The subject will continue to be 
followed for safety assessments without receiving additional IP until clinical trial discharge 
in accordance with this protocol. Procedures that are contraindicated during pregnancy, 
including additional dose administrations, must not be performed. The Investigator should 
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use clinical judgment regarding subsequent clinical trial-related blood collection based on 
the presence or absence of anemia in each subject.  
Male subjects will be instructed through the ICF to immediately inform the Investigator if 
their partner becomes pregnant until study completion. A Pregnancy Form will be 
completed by the site and submitted to the Sponsor within 24 hours after becoming aware 
of the pregnancy. The pregnant partner will be asked to sign a Pregnancy Information 
Collection Consent Form to allow for follow-up on her pregnancy. If the authorization has 
been signed, the Investigator will collect and report details of the course and outcome of 
the pregnancy in the partner of a male subject exposed to IP. The site will update the 
Pregnancy Form with additional information on the course and outcome of the pregnancy 
and submit the form to the Sponsor.  
If an Investigator is contacted by the male subject or his pregnant partner, the Investigator 
may provide information on the risks of the pregnancy and the possible effects on the fetus 
to support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
If the end of the pregnancy occurs after the clinical trial has been completed, the outcome 
will be reported directly to the Sponsor. 
 REPORTING DEVICE-RELATED COMPLAINTS OR DEFICIENCIES 
All product complaints that meet the definition of device deficiency must be reported to the 
Sponsor within 10 days of discovery, with the exception of SAEs which require 24-hour 
reporting. The error reporting or complaint form must be completed and emailed to the 
Sponsor at clinicalcomplaint@inovio.com. 
Device deficiencies include malfunctions, misuse or use errors and inadequate labeling. 
A malfunction is defined as the failure of a device to meet its performance specifications 
or otherwise perform as intended. The intended performance of a device refers to the 
intended use for which the device is labeled or marketed. 
Any problems experienced during the treatment procedure including malfunctions of the 
device (e.g. significant device malfunction causing injury or resulting in a hazard which 
could cause injury to the subject or user), error messages displayed on the device screen 
following treatment, or errors that occur during the treatment procedure must immediately 
be reported to the Sponsor or its designee for evaluation. The Sponsor will review these 
reports for potential hazards that could cause an SAE. If Inovio determines that the 
malfunction could cause an SAE, the Inovio Medical Monitor will decide whether the Chair 
of the Safety Review Committee should be notified in accordance with Section 7.8.4.  
 NOTIFYING REGULATORY AUTHORITIES AND INSTITUTIONAL REVIEW BOARDS 
(IRBS)/RESEARCH ETHICS BOARDS (REBS)/ETHICS COMMITTEES (ECS) OF SAFETY 
INFORMATION 
 SPONSOR RESPONSIBILITIES 
• 
Determine whether the safety information meets the requirements for expedited 
reporting to the applicable regulatory authorities; 
• 
Prepare and submit the safety report to the applicable regulatory authorities; 
• 
Send all participating PIs a safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) that will include a statement if there is or is not any significant new 
safety information that might influence the risk-benefit assessment of the IP and/or 
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study device, sufficient to consider changes in product administration or overall 
conduct of the clinical investigation. 
 PRINCIPAL INVESTIGATOR (PI) RESPONSIBILITIES 
• 
Forward a copy of the safety report and Investigator Safety Letter (i.e., Dear 
Investigator Letter) to their IRB/REB/EC as soon as practical in accordance with the 
governing policy and/or procedures; 
• 
Notify their IRB/REB/EC of safety information (i.e., SAEs, pregnancies, and AESIs) 
that occur at their clinical trial site in accordance with their local institutional policy. 
 POST-TRIAL REPORTING REQUIREMENTS 
PIs are not obligated to actively seek AEs or SAEs beyond the clinical trial reporting period. 
However, if the PI becomes aware of an AE or SAE that occurs after the Completion or 
Termination Visit and the event is deemed by the PI to be related to the clinical trial 
treatment, the PI should promptly document and report the event to the Sponsor. 
 CLINICAL TRIAL DISCONTINUATION  
INOVIO reserves the right to discontinue the clinical trial at a site or at multiple sites for 
safety or administrative reasons at any time. In particular, a clinical trial site that does not 
recruit at a reasonable rate may be discontinued. Additionally, the clinical trial may be 
discontinued at any time by an IRB/REB/EC, INOVIO, or a regulatory authority as part of 
their duties to ensure that clinical trial subjects are protected.  
If the clinical trial is discontinued and/or the clinical trial site closed for any 
reason, all IP and devices must be returned to INOVIO or its 
representative. The PI should ensure that their site file documents are complete 
prior to archiving, and provide copies of any requested documents to INOVIO 
for its Trial Master File (TMF). 
 
STATISTICAL CONSIDERATIONS 
 
STATISTICAL AND ANALYTICAL PLAN 
The formal Statistical Analysis Plan is contained in the sections that follow. 
 
GENERAL CONSIDERATIONS 
The statistical analysis of the data will be performed by Inovio Pharmaceuticals or its 
representative.  
This is an operationally seamless Phase 2/3 trial.  The subjects and data from Phase 2 
are independent from that of Phase 3.   
Phase 2 Segment:  This is a four-arm, multi-center, placebo-controlled, blinded, and 
randomized clinical trial in subjects at high risk of SARS-CoV-2 exposure. The trial’s 
primary endpoints are antigen-specific cellular immune response measured by IFN-
gamma ELISpot and neutralizing antibody responses. Secondary efficacy endpoints are 
safety measures.  Exploratory endpoints are antigen-specific cellular immune response 
measured by flow cytometry and other T and B cell measures.  
Phase 3 Segment: This is a two-arm, multi-center, placebo-controlled, double-blinded, and 
randomized clinical trial in subjects at high risk of SARS-CoV-2 exposure. The study’s 
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primary endpoint is the incidence of virologically-confirmed COVID-19 disease in subjects 
who are SARS-CoV-2 seronegative at baseline starting 14 days after completion of the 2-
dose regimen until 12 months post-dose 2.  The primary hypothesis is that INO-4800 will 
be efficacious relative to placebo (relative efficacy > 30%). Secondary efficacy analyses 
involve non-severe cases, severe cases, cases resulting in death, and cases among 
baseline SARS-CoV-2 seropositive subjects. Other secondary analyses concern safety 
and cellular and neutralizing antibody response. Exploratory analyses concern efficacy 
against variants, efficacy against asymptomatic infection, and binding antibody and 
cellular immunological measures. 
 
STATISTICAL HYPOTHESES 
Phase 2 Segment: This is an estimation segment pertaining to immunogenicity and safety.  
There are no hypotheses. 
Phase 3 Segment: The primary hypothesis of relative efficacy greater than 30% among 
baseline SARS-CoV-2 seronegative subjects will be tested with H0: p ≥ .70/(.70+k) vs. H1: 
p < .70/(.70+k), where p is the true proportion of subjects with disease who receive INO-
4800 relative to the total number of subjects with disease, and k is the total amount of 
follow-up time in the placebo group divided by the total amount of follow-up time in the 
INO-4800 group. There are no other formal hypotheses. 
 
ANALYTICAL POPULATIONS 
Analysis populations will be: 
The per-protocol (PP) population includes all subjects who receive all doses of Study 
Treatments and have no protocol violations. Subjects in the PP population will be grouped 
to treatment arms as randomized.  Subjects excluded from the PP population will be 
identified and documented prior to unblinding of the trial database.  Analyses on the PP 
population among those who are baseline SARS-CoV-2 seronegative will be primary for 
the analyses of efficacy in the Phase 3 segment of this trial. 
The modified intention to treat (mITT) population includes all subjects who receive at least 
one dose of Study Treatment. Subjects in this population will be grouped to treatment 
arms as randomized.  Analysis of the mITT population will be considered supportive for 
the corresponding PP population for the analyses of efficacy in the Phase 3 segment of 
this trial. 
The intention to treat (ITT) population includes all subjects who are randomized. Subjects 
in this sample will be grouped to treatment arms as randomized.  Analysis of the ITT 
population will be considered supportive for the corresponding PP population for the 
analyses of efficacy in the Phase 3 segment of this trial. 
The safety analysis population includes all subjects who receive at least one dose of Study 
Treatment. Subjects will be analyzed according to the treatments received. 
 
DESCRIPTION OF STATISTICAL METHODS 
 PRIMARY ANALYSIS 
Phase 2 Segment 
Post-baseline increases from baseline in interferon-γ ELISpot response magnitudes will 
be compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
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Post-baseline increases from baseline in neutralizing antibody response titers will be 
compared between treatment groups using ratios of geometric mean fold-rises and 
associated t-distribution based 95% CIs. 
The summaries listed above will be stratified according to NP positive/negative status and 
according to prior receipt of any non-study prophylactic COVID-19 vaccine of the subjects. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more than 
198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more than 380 
days after Dose 2 for the Week 56 timepoint. Baseline is defined as the last measurement 
prior to the first treatment administration. 
The PP population will be used for these immunogenicity analyses. 
Phase 3 Segment 
Among subjects who are SARS-CoV-2 seronegative at baseline, the primary hypothesis 
of relative efficacy greater than 30% will be tested with H0: p ≥ 0.70/(0.70+k) vs. H1: p < 
0.70/(0.70+k), where p is the true proportion of subjects with disease who receive INO-
4800 relative to the total number of subjects with disease, and k is the total amount of 
follow-up time in the placebo group divided by the total amount of follow-up time in the 
INO-4800 group. 
A p-value for this hypothesis test and corresponding confidence interval will be computed 
based on the exact binomial method of Clopper-Pearson. Success will be concluded if the 
one-sided p-value is <0.022 and the corresponding lower bound of the two-sided 95.6% 
CI for efficacy exceeds 30% (alpha-level adjusted for interim analyses, see Section 8.5.6), 
and the point estimate for efficacy exceeds 50%. 
For calculating k, an individual subject’s follow-up time is either: 
o the date of first disease diagnosis – date of the start of surveillance period +1 (for 
subjects who are cases), or 
o the date of last follow-up – date of the start of surveillance period +1 (for subjects who 
are non-cases). 
This methodology is based on the following. Assuming that the number of subjects who 
are cases in the INO-4800 group follows a Poisson distribution with parameter λv and the 
number of subjects who are cases in the placebo group follows a Poisson distribution with 
parameter λc, then conditional on total number of subjects with cases, t, the number of 
subjects who are cases in the INO-4800 group follows a binomial distribution with 
parameters (t, p=λv/(λv+λc)).  The relationship between p and efficacy is: efficacy = (1-
(1+k)p)/(1-p).  Therefore, testing efficacy > 30% corresponds to testing p < 0.70/(0.70+k).  
Similarly, the confidence interval for efficacy is (1-(1+k)UBp)/(1-UBp), (1-(1+k)LBp)/(1-LBp), 
where UB and LB are the Clopper-Pearson upper and lower limits for the proportion. 
The efficacy time frame is defined by symptoms beginning at any time starting from 14 
days after Dose 2 and ending 12 months after Dose 2.  Subjects identified as cases that 
started prior to this time point will be excluded.  Subjects with multiple instances meeting 
the case definition will be counted only once, using the first such instance.    
The PP population will be primary for the analysis of efficacy in this trial. Efficacy analysis 
using the mITT population will also be conducted counting cases from 14 days postdose 
1 as a supportive analysis.  The ITT population will also be used for a supportive analysis 
counting cases starting from randomization. 
 SECONDARY ANALYSES 
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8.5.2.1 Efficacy 
Phase 3 Segment 
The secondary efficacy incidence endpoints will be analyzed in the same manner as the 
primary hypothesis, but with 95% CIs and without the hypothesis test p-value.  
8.5.2.2 Immunogenicity 
 
   Phase 3 Segment 
Post-baseline increases from baseline in interferon-γ ELISpot response magnitudes will 
be compared between treatment groups using differences in medians and associated 
non-parametric 95% CIs. 
Post-baseline increases from baseline in neutralizing antibody response titers will be 
compared between treatment groups using ratios of geometric mean fold-rises and 
associated t-distribution based 95% CIs. 
The summaries listed above will be stratified according to disease status of the subjects 
and by baseline SARS-CoV-2 serostatus. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more than 
198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more than 
380 days after Dose 2 for the Week 56 timepoint.. Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for these immunogenicity analyses. 
 SAFETY ANALYSES 
8.5.3.1 Adverse Events 
All AEs including injection-site reactions will be summarized among the Safety 
Population by frequency per treatment arm. These frequencies will be presented overall 
and separately by dose, and will depict overall, by system organ class and by preferred 
term, the percentage of subjects affected. Additional frequencies will be presented with 
respect to maximum severity and to strongest relationship to Study Treatment. Multiple 
occurrences of the same AE will be counted only once following a worst-case approach 
with respect to severity and relationship to Study Treatment. All serious AEs will also be 
summarized as above. 
The main summary of safety data will be based on events occurring within 30 days of 
any dose. For this summary, the frequency of preferred term events will be compared 
between study arms with risk differences and 95% confidence intervals, using the 
method of Miettinen and Nurminen. As this analysis will use many event categories, and 
produce many confidence intervals, caution should be exercised when interpreting these 
confidence intervals.  Separate summaries will be based on events occurring within 7 
days of any dose and regardless of when they occurred. 
The analyses listed above will be performed according to the Phase of the trial. For the 
Phase 2 segment, the analyses listed above will also be performed according to prior 
receipt of any non-study prophylactic COVID-19 vaccine.  For the Phase 3 segment, the 
analyses listed above will also be performed according to SARS-CoV-2 serostatus at 
baseline. 
For AE data, partial start dates will be imputed to the date of treatment to conservatively 
report the event as treatment-emergent, whenever the portion of the date is consistent 
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with that of the study treatment. Otherwise, it will be imputed to the earliest date 
consistent with the partial date. A completely missing onset date will be imputed as the 
day of treatment. Partial stop dates will be assumed to be the latest possible day 
consistent with the partial date. AE duration will be calculated as (Stop Date – Start 
Date) + 1. 
8.5.3.2 Vital Signs 
Measurements for vital signs as well as changes from baseline will be summarized with 
descriptive statistics: mean, standard deviation, minimum, median, and maximum 
values by time point and treatment arm, for the Safety population. Baseline is defined 
as the last measurement prior to the first treatment administration. These summaries 
will be performed according to Phase. For the Phase 2 segment, the analyses listed 
above will also be performed according to prior receipt of any non-study prophylactic 
COVID-19 vaccine.  For the Phase 3 segment, the analyses listed above will also be 
performed according to SARS-CoV-2 serostatus at baseline. 
 DISPOSITION 
Disposition will be summarized by treatment arm for the ITT population and will include 
the number and percentage randomized, the number and percentage who received each 
dose and the number who completed the trial.  The number and percentage of subjects 
who discontinued will be summarized overall and by reason.  The number in each analysis 
population will also be presented. These summaries will be performed according to Phase. 
For the Phase 3 segment, the analyses listed above will also be performed according to 
SARS-CoV-2 serostatus at baseline. 
 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
8.5.5.1 Demographics 
Demographic data will be summarized with descriptive statistics: mean standard 
deviation, minimum, median, and maximum values for continuous variables, and 
percentages for categorical variables, by treatment arm, for the ITT and PP populations. 
These summaries will be performed according to Phase. For the Phase 3 segment, the 
analyses listed above will also be performed according to SARS-CoV-2 serostatus at 
baseline. 
8.5.5.2 Prior Medications 
Prior medications are those that were used before the start of the trial (prior to Day 0). 
Partial stop dates of prior medications will be assumed to be the latest possible date 
consistent with the partial date; start dates will not be imputed. Data for all prior 
medications will be summarized with percentages by treatment arm, for the ITT and PP 
populations. These summaries will be performed according to Phase. For the Phase 3 
segment, the analyses listed above will also be performed according to SARS-CoV-2 
serostatus at baseline. 
 INTERIM ANALYSES  
For safety issues, the DSMB could recommend stopping enrollment at any time; no 
formal interim analysis will be performed for this purpose. The two-sided type I error of 
0.05 will not be adjusted for possible early stopping due to this aspect. 
 
For the Phase 2 segment, group-level unblinded summaries of the immunogenicity and 
safety data will be produced once Week 6 visit immunology data and Week 8 visit safety 
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data are complete for all subjects who have not discontinued, while maintaining subject-
level blinding.  Long-term follow-up data will continue to be collected for all subjects who 
have not discontinued with remaining visits through the final visit.  These summaries will 
allow the Sponsor to have results for the purposes of dose selection for the Phase 3 
portion.  No subject-level immunogenicity data will be produced, and subject-level 
immunogenicity data will not be available in the clinical trial database until all other clinical 
trial data are finalized at the end of the trial.  No safety summary will be provided if the 
total number of subjects who experience the event of interest is greater than 0 and the 
count of the number of subjects with the event in a given treatment group relative to the 
total produces a percentage less than 3%, for a given summary.  The group-level 
unblinded production of the summaries will not include anyone directly involved with the 
trial or any additional unblinded personnel; only the external Contract Research 
Organization (CRO), ICON, which will already be providing unblinded summaries for the 
Data Safety Monitoring Board, will be utilized.  Thus, the trial will remain blinded to the 
Sponsor with respect to subject treatment assignment.  
 
For the Phase 3 segment, there are two planned formal interim efficacy analyses: one at 
50% (75 cases) and one at 75% (112 cases) of the total required for the primary endpoint 
(149 cases).  The Lan-DeMets O’Brien-Fleming approximate alpha-spending function will 
be used for the efficacy and futility boundaries.  As such, the first interim analysis will utilize 
a one-sided nominal alpha of 0.0016, and the second interim analysis will utilize a one-
sided nominal alpha of 0.0092.  The final analysis will utilize a one-sided nominal alpha of 
0.022.  The DSMB will be responsible for the interim evaluations. The unblinded interim 
analyses will not include anyone directly involved with the trial or any additional unblinded 
personnel; only the external Contract Research Organization (CRO), ICON, which will 
already be providing unblinded summaries for the Data Safety Monitoring Board, will be 
utilized.  Thus, the trial will remain blinded to the Sponsor with respect to subject treatment 
assignment.  
 
If the prespecified criteria for efficacy above are met at either interim analysis, then 
enrollment will continue until 4500 subjects have been enrolled, and blinded follow-up will 
continue until 4500 subjects have 6 months of safety follow-up.  At that point, the trial 
would be unblinded, and subjects who received placebo will be offered the active product. 
 MULTIPLICITY 
There is one primary hypothesis that will be tested.  As there are two interim analyses of 
the primary endpoint, the type I error rate will be controlled at two-sided 0.05 by using the 
Lan-DeMets O’Brien-Fleming approximate alpha-spending function (see Section 8.5.6).  
 MISSING VALUES 
Missing data will not be imputed. 
For the ITT analyses of efficacy in the Phase 3 segment, subjects with missing or 
unevaluable data regarding case definition will be considered cases (failures). 
 EXPLORATORY ANALYSES  
8.5.9.1 Efficacy 
Phase 3 segment 
The exploratory efficacy endpoints will be analyzed in the same manner as the primary 
hypothesis, but with a 95% CI and without the hypothesis test p-value.   
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8.5.9.2 Immunogenicity 
Phase 2 segment 
Post-baseline increases from baseline in cellular response magnitudes will be 
compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
The summaries listed above will be stratified according to NP positive/negative status 
and according to prior receipt of any non-study prophylactic COVID-19 vaccine of the 
subjects. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more 
than 198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more 
than 380 days after Dose 2 for the Week 56 timepoint. . Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
Phase 3 Segment 
Post-baseline increases in antibody titers from ELISA will be compared between 
treatment groups using ratios of geometric mean fold-rises and associated 95% t-
distribution based CIs. 
Post-baseline increases from baseline in cellular response magnitudes will be 
compared between treatment groups using differences in medians and associated non-
parametric 95% CIs. 
Post-baseline increases from baseline in neutralizing antibody response titers will be 
compared between treatment groups using ratios of geometric mean fold-rises and 
associated t-distribution based 95% CIs. 
The summaries listed above will be stratified according to disease status of the 
subjects. 
Valid samples for statistical analysis purposes will be those collected: at least 6 and no 
more than 30 days after Dose 2 for the Week 6 timepoint; at least 174 and no more 
than 198 days after Dose 2 for the Week 30 timepoint; and at least 356 and no more 
than 380 days after Dose 2 for the Week 56 timepoint. . Baseline is defined as the last 
measurement prior to the first treatment administration. 
The PP population will be used for immunogenicity analyses. 
8.5.9.3 Concomitant Medications 
Concomitant medications are those used during the course of the trial (on or after Day 
0). Partial stop dates of concomitant medications will be assumed to be the latest 
possible date consistent with the partial date; start dates will not be imputed. Data for 
all concomitant medications will be summarized with percentages by treatment arm, for 
the ITT and PP populations. These summaries will be performed according to Phase. 
For the Phase 3 segment, the analyses listed above will also be performed according 
to SARS-CoV-2 serostatus at baseline. 
 
SAMPLE SIZE/POWER 
Phase 3 segment: The trial is case-driven. A total of 149 observed cases among baseline 
SARS-CoV-2 seronegative subjects will be required to provide 90% power to declare the 
vaccine efficacious (>30%), assuming a true efficacy of 60% and utilizing the methodology 
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described in Section 8.5.1 and Section 8.5.6.  A sample size of 6714 baseline SARS-CoV-
2 seronegative subjects will be required to achieve this number of cases assuming an 
underlying attack rate of 3.7%.   
 
RANDOMIZATION AND BLINDING  
Phase 2 Segment 
Subjects will be randomized (3 INO-4800 1.0 mg, one injection: 3 INO-4800 2.0 mg, two 
injections:1 Placebo, one injection: 1 Placebo, two injections). 
The study is blinded. It is double-blinded within dose group.  Randomization and blinding 
will avoid bias in the assignment of subjects to treatment, increase the likelihood that 
known and unknown subject attributes (e.g., demographics and other baseline 
characteristics) are evenly balanced between treatment groups, and enable valid 
statistical comparisons between treatment groups. Subject treatment assignments will be 
unblinded after Phase 2 subjects have reached the Week 30 visit. 
Phase 3 Segment 
Subjects will be randomized (2 INO-4800:1 Placebo).  Randomization will be stratified 
according to two factors, each with two levels: a) age-group age category (18-50 years vs. 
≥51 years) on Day 0, and b) presence or absence on Day 0 of underlying medical 
conditions that increase risk of severe COVID-19 disease, per US CDC criteria. 
The study is double-blinded. Randomization and blinding will avoid bias in the assignment 
of subjects to treatment, increase the likelihood that known and unknown subject attributes 
(e.g., demographics and other baseline characteristics) are evenly balanced between 
treatment groups, and enable valid statistical comparisons between treatment groups. 
 
ETHICS 
 
INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The Investigator and Sponsor are responsible for ensuring that the clinical trial is 
performed in accordance with the protocol, the principles of the Declaration of Helsinki, 
Good Clinical Practice (GCP) and applicable regulatory requirements. 
 
INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD (REB)/ETHICS 
COMMITTEE (EC) 
The Investigator will commence the clinical trial after full approval of the protocol and 
adjunctive materials (e.g., ICF, advertising) has been obtained from the applicable 
IRB/REB/EC and a copy of IRB/REB/EC approval documentation has been received by 
the Sponsor. 
Investigator responsibilities relevant to the IRB/REB/EC include the following: 
• Submit continuing review reports to the IRB/REB/EC as required, and request re-
review and approval of the clinical trial at least once a year during the conduct of 
the clinical trial; 
• Notify the Sponsor immediately of any suspected unexpected adverse drug or 
device events/effects; 
• Notify the IRB/REB/EC immediately if the Sponsor notifies the Investigator about 
any reportable safety events; 
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• Obtain approval from the IRB/REB/EC for protocol amendments and for revisions 
to the consent form or subject recruitment advertisements, as required; 
• Submit reports on, and reviews of, the clinical trial and its progress to the 
IRB/REB/EC at intervals stipulated in their guidelines and in accordance with 
pertinent regulations and guidelines; 
• Maintain a file of clinical trial-related information (refer to clinical trial files) that 
includes all correspondence with the IRB/REB/EC; 
• Notify the IRB/REB/EC when the clinical trial is completed (i.e., after the last clinical 
trial visit of the final clinical trial subject); 
• After clinical trial completion (within three [3] months is recommended), provide the 
IRB/REB/EC with a final report on the clinical trial. 
Institutional Biosafety Committee (IBC) 
The Investigator will undertake the trial after full approval of the protocol and adjunctive 
materials (e.g., pharmacy manual) has been obtained from the applicable IBC and a copy 
of this approval has been received by the Sponsor. 
Investigator responsibilities relevant to the IBC include the following: 
• 
Notify the Sponsor, IBC and NIH OSP within 30 days of any: 
o Substantial problems or violation of the NIH Guidelines 
o Significant research related accidents or illnesses 
• 
Notify the IBC to any changes to the research (dosage, procedure, etc.) or facility 
(new space, remodeling, etc.).   
 
PROTECTION OF HUMAN SUBJECTS 
 COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent must be obtained from each subject prior to the subject’s 
enrollment in the clinical trial. The process for obtaining informed consent must be 
documented in the subject’s medical record (also refer to Section 6.2). 
 COMPLIANCE WITH INSTITUTIONAL REVIEW BOARD (IRB)/RESEARCH ETHICS BOARD 
(REB)/ETHICS COMMITTEE (EC) REQUIREMENTS 
This clinical trial is to be conducted in accordance with applicable IRB/REB/EC 
regulations. The Investigator must obtain approval from a properly constituted 
IRB/REB/EC prior to initiating the clinical trial and obtain re-approval or review at least 
annually. The Sponsor is to be notified immediately if the responsible IRB/REB/EC has 
been disqualified or if proceedings leading to disqualification have begun. Copies of all 
IRB/REB/EC correspondence with the Investigator should be provided to the Sponsor. 
 COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
 COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS (21CFR 
PART 11) 
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When applicable, this clinical trial is to be conducted in compliance with the regulations on 
electronic records and electronic signature. 
 COMPLIANCE WITH PROTOCOL 
Subjects are not required to follow special instructions specific to the IP used in this clinical 
trial. Subjects will be provided with Investigator emergency contact information and 
advised to report all AEs. While every effort should be made to avoid protocol deviations, 
should an important deviation be discovered, the Sponsor must be informed immediately. 
Any protocol deviation impacting subject safety must be reported to the Medical Monitor 
immediately. 
 CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from, or changes to, the protocol 
without Sponsor approval and prior review and documented approval/favorable opinion of 
the protocol amendment from the IRB/REB/EC, except where necessary to eliminate 
immediate hazards to clinical trial subjects, or when the changes involve only logistical or 
administrative aspects of the clinical trial (e.g., change in monitors, change of telephone 
numbers).  
 DATA COLLECTION, MONITORING AND REPORTING 
 CONFIDENTIALITY AND PRIVACY 
A report of the results of this clinical trial may be published or sent to the appropriate 
regulatory authorities in any country in which the clinical trial products are legally marketed 
or may ultimately be marketed, but the subject’s name/identity will not be disclosed in 
these documents. The clinical trial Sponsor, its agents, the IRB/REB/EC and regulatory 
authorities will have direct access to the subjects’ medical records for the purposes of trial-
related monitoring, auditing and inspection. Appropriate precautions will be taken to 
maintain confidentiality of medical records and personal information. 
Written Authorization and other documentation are to be obtained from each subject, 
and/or from the subject’s legally authorized representative, prior to enrollment in the 
clinical trial, in accordance with all applicable laws, regulations and/or directives relating 
to privacy and data protection. 
 SOURCE DOCUMENTS 
Source data is all information, electronic or hardcopy original records or clinical findings, 
laboratory results, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the clinical trial. 
Examples of original source data records may include:  
• Hospital records 
• Clinical and office charts 
• Laboratory notes 
• Memoranda 
• Pharmacy dispensing records 
• Recorded data from automated instruments 
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• Copies of electronic medical records (EMR) certified after verification as being 
accurate and complete 
• X-rays 
• Subject files and records kept at the pharmacy, at the laboratories, at the medical 
records facility and within information technology (IT) systems that are involved in 
the clinical trial  
The Investigator/institution will permit clinical trial-related monitoring, audits, IRB/REB/EC 
review and regulatory inspections by providing direct access to source data/documents 
related to this clinical trial. 
 RECORDS RETENTION 
Upon request of the Clinical Monitor, Sponsor or its agent(s), auditor, IRB/REB/EC or 
regulatory authority, the Investigator/institution should make available for direct access all 
requested clinical trial-related records. 
CRFs will be provided for each subject. Subjects must not be identified by name on any 
CRFs. Subjects will be identified by their subject identification number (SID). 
It is the Investigator’s responsibility to retain clinical trial essential documents for at least 
two (2) years after the last approval of a marketing application in their country and until 
there are no pending or contemplated marketing applications in their country or at least 
two (2) years have elapsed since the formal discontinuation of clinical development of 
INO-4800. This retention period may be superseded by local requirements. The Sponsor 
will inform the Investigator/institution when these documents are no longer needed to be 
retained. 
If the Records Retention requirements are addressed in a governing clinical trial 
agreement, it is the Investigator’s responsibility to retain clinical trial essential documents 
in accordance with the governing clinical trial agreement and applicable local 
requirements. 
 SAFETY AND QUALITY MONITORING 
 SAFETY REVIEW 
The Sponsor’s Safety Review Committee (SRC), composed of the Sponsor’s Medical 
Monitor, the ICON Medical Monitor and 1 additional physician, will review blinded safety 
and tolerability data on a regular basis throughout the trial. The SRC will refer any of the 
events listed in Section 7.8.4 or any other safety concerns to the DSMB Chair. 
For both the Phase 2 and 3 segments, the Data Safety Monitoring Board (DSMB) will 
convene regularly to review all available unblinded safety data, and additionally upon 
completion of the Week 8 phone call visit for all subjects enrolled during the Phase 2 
segment. The DSMB will review unblinded safety and tolerability data, including AEs of 
clinical significance, AESIs and SAEs, as well as safety laboratory data for all enrolled 
subjects. The DSMB will also evaluate the data for signals of vaccine-enhanced disease 
and in the event of a signal, advise whether to halt the trial. The DSMB will advise 
regarding any safety concerns and will make recommendations regarding continued 
enrollment, safety pause and trial suspension. For the Phase 3 segment, the DSMB will 
also review efficacy in an unblinded fashion. 
If the safety data is considered unfavorable during any safety review, the DSMB may 
recommend a trial pause or trial termination at which time further enrollment and 
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administration of IP to subjects will be paused. The Sponsor will perform an investigation 
and consult with the DSMB and other experts, if needed, to determine whether to resume 
dosing of the remainder of the subjects. For further details, see the DSMB Charter.  
 CLINICAL MONITORING 
Clinical Monitoring will be performed by qualified Clinical Monitors who will report to the 
Sponsor or the Sponsor’s designee. The following clinical trial site monitoring tasks will be 
performed at all clinical trial sites: 
• 
Prior to subject screening at the site, a Site Initiation Visit will be conducted to 
review all relevant forms and documentation, and ensure that the clinical trial site 
staff are qualified and compliant with all applicable requirements 
• 
All clinical trial site monitoring visits will be documented 
• 
Periodic clinical trial site visits will be performed throughout the clinical trial 
• 
The Clinical Monitor will address and document the following trial conduct activities 
and obligations: 
o Assure that the trial is being conducted in accordance with the protocol, 
applicable regulatory agency regulations, and IRB/REB/EC policies. 
o Discuss trial conduct issues and incidents of noncompliance with the 
Investigator and/or trial personnel and document them on the resolution trip 
report. Report any significant unresolved problems immediately to the 
Sponsor. 
o Remind the Investigator as necessary of the obligation to immediately report 
all SAEs and provide subsequent follow-up report of the final outcome to the 
IRB. 
o Throughout the trial, inspect source documents to ensure they are complete, 
logical, consistent, attributable, legible, contemporaneous, original, accurate 
and complete (ALCOA-C). 
o Assure that the trial facilities, including the pharmacy, continue to be 
acceptable. 
o Compare the trial CRFs with source documents to assure that the data are 
accurate and complete and that the protocol is being followed. 
o Assure that investigational drug and device accountability and reconciliation of 
records are complete and accurate. 
o Assure that all subject specimens are being stored and forwarded properly for 
testing in accordance with laboratory manual requirements. 
 FINANCING AND INSURANCE 
Inovio Pharmaceuticals is the Sponsor of this study.  The Department of Defense, Joint 
Program Executive Office is providing funding for the Phase 2 segment of the study and 
Inovio is providing funding for the Phase 3 segment. Clinical trial insurance has been taken 
out according to the laws of the countries where the study will be conducted. The 
investigative site is being compensated for the conduct of this study and will follow the 
terms described in the clinical trial agreement. This agreement was executed separately 
from this clinical trial protocol. The Investigators will be required to provide full financial 
disclosure information per ICH E6 R1. 
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 PUBLICATION POLICY 
Publication of the results of this clinical trial in its entirety will be allowed. The proposed 
presentation, abstract and/or manuscript must be made available to the Sponsor for 
review and approval in accordance with the governing clinical trial agreement. 
 
 
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 LIST OF ABBREVIATIONS 
ADE 
Adverse Device Effect 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALCOA-C 
Attributable, Legible, Contemporaneous, Original, Accurate and Complete 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CBC 
Complete Blood Count 
Cl 
Chloride 
COVID-19 
Coronavirus Disease 2019 
Cr 
Creatinine 
CRF 
Case Report Form 
CS 
Clinically Significant 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
ELISpot 
Enzyme-linked immunosorbent spot-forming assay 
EP 
Electroporation 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCO3 
Biocarbonate 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICD 
Implantable-Cardioverter-defibrillator 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonization 
ID 
Intradermal 
IM 
Intramuscular 
Inovio 
Inovio Pharmaceuticals Inc. 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
K 
Potassium 
MAAE 
Medically Attended Adverse Event 
mITT 
modified Intent to Treat 
MM 
Medical Monitor 
MERS 
Middle East Respiratory Syndrome  
MERS-CoV 
Middle East Respiratory Syndrome Coronavirus 
mRNA 
Messenger RNA 
Na 
Sodium 
NCS 
Not Clinically Significant 
NHP 
Non-human Primates 
NP 
Nucleocapsid Protein 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PII 
Personal Identifying Information 
PO4 
Potassium 
Page 762 of 768


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COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 89 of 94 
 
PT 
Preferred Term 
RBC 
Red blood cell 
REB 
Research Ethics Board 
RR 
Respiratory Rate 
RT-PCR 
Reverse Transcription Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SARS 
Severe Acute Respiratory Syndrome  
SARS-CoV 
Severe Acute Respiratory Syndrome Coronavirus 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus - 2 
SID 
Subject Identification Number 
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
SynCon 
Synthetic consensus 
TBili 
Total Bilirubin 
TMF 
Trial Master File 
UADE 
Unanticipated Adverse Device Effect 
WBC 
White blood cell 
WHO 
World Health Organization 
WOCBP 
Women of Child-bearing Potential 
 
 
 
Page 763 of 768


INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 90 of 94 
 
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1. 
Centers for Disease Control and Prevention. People with Certain Medical Conditions. 
March 29, 2021; Available from: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-
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Lu, H., C.W. Stratton, and Y.W. Tang, Outbreak of pneumonia of unknown etiology in 
Wuhan, China: The mystery and the miracle. J Med Virol, 2020. 92(4): p. 401-402. 
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Hui, D.S., et al., The continuing 2019-nCoV epidemic threat of novel coronaviruses to 
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4. 
Huang, C., et al., Clinical features of patients infected with 2019 novel coronavirus in 
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GenBank. Severe acute respiratory syndrome coronavirus 2 isolate Wuhan-Hu-1, 
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Smith, T.R.F., et al., Immunogenicity of a DNA vaccine candidate for COVID-19. Nat 
Commun, 2020. 11(1): p. 2601. 
7. 
World Health Organization, Clinical Management of Sever Acute Respiratory Infection 
When Novel Coronavirus (2016-nCoV) Infection is Suspected. Interim Guidance. 2020. 
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World Health Organization, Novel Coronavirus (2019-nCoV) Situation Report. 2020. 
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Wiersinga, W.J., et al., Pathophysiology, Transmission, Diagnosis, and Treatment of 
Coronavirus Disease 2019 (COVID-19): A Review. JAMA, 2020. 
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World Health Organization, WHO Director-General's opening remarks at the media 
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Zou, L., et al., SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected 
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Center for Systems Science and Engineering at Johns Hopkins University, COVID-19 
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Havers, F.P., et al., Seroprevalence of Antibodies to SARS-CoV-2 in 10 Sites in the 
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Wu, Z. and J.M. McGoogan, Characteristics of and Important Lessons From the 
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2020. 
15. 
The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, The 
epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases 
(COVID-19) in China. Chin J Epidemiol, 2020. 41(Epub ahead of print). 
16. 
The Novel Coronavirus Pneumonia Emergency Response Epidemiology Team, Vital 
Surveillances: The Epidemiological Characteristics of an Outbreak of 2019 Novel 
Coronavirus Diseases (COVID-19) — China, 2020. China CDC Weekly, 2020. 2(8): p. 
113-122. 
17. 
Chan, J.F., et al., A familial cluster of pneumonia associated with the 2019 novel 
coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet, 
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Rothe, C., et al., Transmission of 2019-nCoV Infection from an Asymptomatic Contact in 
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Ganyani, T., et al., Estimating the generation interval for coronavirus disease (COVID-
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He, X., et al., Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat 
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Page 764 of 768


INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 91 of 94 
 
21. 
Liu, Y., et al., The reproductive number of COVID-19 is higher compared to SARS 
coronavirus. J Travel Med, 2020. 27(2). 
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testing/symptoms.html. 
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Gudbjartsson, D.F., et al., Spread of SARS-CoV-2 in the Icelandic Population. N Engl J 
Med, 2020. 
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Day, M., Covid-19: four fifths of cases are asymptomatic, China figures indicate. BMJ, 
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Long, Q.X., et al., Clinical and immunological assessment of asymptomatic SARS-CoV-2 
infections. Nat Med, 2020. 
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Diao, B., et al., Reduction and Functional Exhaustion of T Cells in Patients With 
Coronavirus Disease 2019 (COVID-19). Front Immunol, 2020. 11: p. 827. 
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Grifoni, A., et al., Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans 
with COVID-19 Disease and Unexposed Individuals. Cell, 2020. 181(7): p. 1489-1501 
e15. 
33. 
Modjarrad, K., et al., Safety and immunogenicity of an anti-Middle East respiratory 
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trial. Lancet Infect Dis, 2019. 19(9): p. 1013-1022. 
34. 
Suschak, J.J., J.A. Williams, and C.S. Schmaljohn, Advancements in DNA vaccine 
vectors, non-mechanical delivery methods, and molecular adjuvants to increase 
immunogenicity. Hum Vaccin Immunother, 2017. 13(12): p. 2837-2848. 
35. 
Manickan, E., K.L. Karem, and B.T. Rouse, DNA Vaccines - A Modern Gimmick or a 
Boon to Vaccinology? Crit Rev Immunol, 2017. 37(2-6): p. 483-498. 
36. 
Porter, K.R. and K. Raviprakash, DNA Vaccine Delivery and Improved Immunogenicity. 
Curr Issues Mol Biol, 2017. 22: p. 129-138. 
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Li, L. and N. Petrovsky, Molecular mechanisms for enhanced DNA vaccine 
immunogenicity. Expert Rev Vaccines, 2016. 15(3): p. 313-29. 
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Marc, M.A., E. Dominguez-Alvarez, and C. Gamazo, Nucleic acid vaccination strategies 
against infectious diseases. Expert Opin Drug Deliv, 2015. 12(12): p. 1851-65. 
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Grunwald, T. and S. Ulbert, Improvement of DNA vaccination by adjuvants and 
sophisticated delivery devices: vaccine-platforms for the battle against infectious 
diseases. Clin Exp Vaccine Res, 2015. 4(1): p. 1-10. 
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Tregoning, J.S. and E. Kinnear, Using Plasmids as DNA Vaccines for Infectious 
Diseases. Microbiol Spectr, 2014. 2(6). 
41. 
Williams, J.A., Improving DNA vaccine performance through vector design. Curr Gene 
Ther, 2014. 14(3): p. 170-89. 
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Liu, M.A., DNA vaccines: an historical perspective and view to the future. Immunol Rev, 
2011. 239(1): p. 62-84. 
Page 765 of 768


INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 92 of 94 
 
43. 
Wahren, B. and M.A. Liu, DNA Vaccines: Recent Developments and the Future. 
Vaccines (Basel), 2014. 2(4): p. 785-796wahren. 
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Ledgerwood, J.E. and B.S. Graham, DNA vaccines: a safe and efficient platform 
technology for responding to emerging infectious diseases. Hum Vaccin, 2009. 5(9): p. 
623-6. 
45. 
Keefer, M.C., et al., Studies of high doses of a human immunodeficiency virus type 1 
recombinant glycoprotein 160 candidate vaccine in HIV type 1-seronegative humans. 
The AIDS Vaccine Clinical Trials Network. AIDS Res Hum Retroviruses, 1994. 10(12): p. 
1713-23. 
46. 
Wu, F., et al., Neutralizing antibody responses to SARS-CoV-2 in a COVID-19 recovered 
patient cohort and their implications. Medrxiv Preprint, 2020. 
47. 
Martin, J.E., et al., A DNA vaccine for Ebola virus is safe and immunogenic in a phase I 
clinical trial. Clin Vaccine Immunol, 2006. 13(11): p. 1267-77. 
48. 
Prud'homme, G.J., et al., Electroporation-enhanced nonviral gene transfer for the 
prevention or treatment of immunological, endocrine and neoplastic diseases. Curr Gene 
Ther, 2006. 6(2): p. 243-73. 
49. 
Hirao, L.A., et al., Combined effects of IL-12 and electroporation enhances the potency 
of DNA vaccination in macaques. Vaccine, 2008. 26(25): p. 3112-20. 
50. 
Rosati, M., et al., Increased immune responses in rhesus macaques by DNA vaccination 
combined with electroporation. Vaccine, 2008. 26(40): p. 5223-9. 
51. 
Curcio, C., et al., DNA immunization using constant-current electroporation affords long-
term protection from autochthonous mammary carcinomas in cancer-prone transgenic 
mice. Cancer Gene Ther., 2008. 15(2): p. 108-114. 
52. 
Ugen, K.E., et al., Regression of subcutaneous B16 melanoma tumors after intratumoral 
delivery of an IL-15-expressing plasmid followed by in vivo electroporation. Cancer Gene 
Ther., 2006. 13(10): p. 969-974. 
53. 
Tebas, P., et al., Safety and Immunogenicity of an Anti-Zika Virus DNA Vaccine - 
Preliminary Report. N Engl J Med, 2017. 
54. 
Tebas, P., et al., Intradermal SynCon(R) Ebola GP DNA Vaccine is Temperature Stable 
and Safely Demonstrates Cellular and Humoral Immunogenicity Advantages in Healthy 
Volunteers. J Infect Dis, 2019. 
55. 
De Rosa, S.C., et al., Robust antibody and cellular responses induced by DNA-only 
vaccination for HIV. JCI Insight, 2020. 5(13). 
56. 
Chandrashekar, A., et al., SARS-CoV-2 infection protects against rechallenge in rhesus 
macaques. Science, 2020. 
57. 
Patel, A., et al., Intradermal-delivered DNA vaccine provides anamnestic protection in a 
rhesus macaque SARS-CoV-2 challenge model. bioRxiv, 2020: p. 2020.07.28.225649. 
58. 
Andrade, V.M., et al., INO-4800 DNA Vaccine Induces Neutralizing Antibodies and T cell 
Activity Against Global SARS-CoV-2 Variants. bioRxiv, 2021: p. 2021.04.14.439719. 
59. 
Gary E., W.B.M., Parzych E.M., Griffin B.D., Zhu X., Tailor N., Tursi N.J., Chan M., 
Purwar M., Vendramelli R., Choi J., Frost K.L, Reeder S., Liaw K., Tello E., Ali A.R., Yun 
K., Pei Y.,Thomas S.,Rghei A.D.,  Guilleman M.M., Muthumani K., Smith T., Wootton 
S.K., Patel A., Weiner D.B., Kobasa D., A novel mouse AAV6 hACE2 transduction 
model of wild-type SARS-CoV-2 infection studied using synDNA immunogens. iScience, 
2021. 
60. 
Gooch, K., et al., One or two dose regimen of the SARS-CoV-2 synthetic DNA vaccine 
INO-4800 protects against respiratory tract disease burden in nonhuman primate 
challenge model. Research Square 2021. 
61. 
Trevor, S. Development of INO-4800, a DNA-vaccine for COVID-19. in Keystone 
Symposia Antibodies and Vaccines as Drugs for COVID-19. 2021. 
62. 
European Commission, Directorate-General: A Guideline on Summary of Product 
Characteristics (SmPC). 2009, EMA. 
Page 766 of 768


INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 93 of 94 
 
63. 
Diehl, M.C., et al., Tolerability of intramuscular and intradermal delivery by 
CELLECTRA((R)) adaptive constant current electroporation device in healthy volunteers. 
Hum Vaccin Immunother, 2013. 9(10): p. 2246-52. 
 
 
Page 767 of 768


INO-4800 
  
COVID19-311 
Inovio Pharmaceuticals, Inc. 
 
Clinical Protocol 
Protocol Version Date:08-Oct-2021 
CONFIDENTIAL 
Protocol Version: 2.0USA 
 
Page 94 of 94 
 
 APPENDICES 
 APPENDIX A: ADVERSE EVENTS OF SPECIAL INTEREST  
For the purpose of standardization across multiple vaccine platforms, including those substantially 
different from Inovio’s platform, the below table lists AEs of special interest (AESIs) relevant to 
COVID-19 vaccine development.  
Body System 
AESI 
Respiratory 
Acute respiratory distress syndrome (ARDS) 
Pneumonitis/Pneumonia 
Neurologic 
Generalized convulsion 
Aseptic meningitis 
Guillain-Barré Syndrome (GBS) 
Encephalitis/Myelitis 
Acute disseminated encephalomyelitis (ADEM) 
CNS vasculopathy (stroke) 
Bell’s Palsy 
Transverse myelitis  
Narcolepsy 
Hematologic 
Thrombocytopenia 
Immune thrombocytopenia (ITP) 
Disseminated intravascular coagulation (DIC) 
Hemorrhagic stroke 
Non-hemorrhagic stroke 
Deep Vein Thrombosis (DVT) 
Pulmonary Embolism (PE) 
Immunologic 
Anaphylaxis 
Vasculitides 
Cardiac  
Acute cardiac failure 
Myocarditis/pericarditis 
Acute myocardial infarction 
Other 
Septic shock-like syndrome 
Appendicitis 
Multisystem Inflammatory Syndrome 
Acute kidney failure 
 
Page 768 of 768

SAP_001.pdf: 
Official Title: 
NCT Number: 
NCT04642638
Document Dates:
Statistical Analysis Plan Final Version 2.0 (Phase 2 segment): 20 January 2022 
Statistical Analysis Plan Final Version 1.0 (Phase 3 segment): 29 July 2022 
Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the Safety,
Immunogenicity, and Efficacy of INO-4800, a Prophylactic Vaccine Against
COVID-19 Disease, Administered Intradermally Followed by Electroporation in
Adults at High Risk of SARS-CoV-2 Exposure


Inovio Pharmaceuticals, Inc. 
Clinical Study Report for Protocol COVID19-311 
 
 
CONFIDENTIAL 
 
 
 
16.1.9 Documentation of Statistical Methods 
Phase 2 SAP Version 2.0, dated 20 Jan 2022 
Phase 3 SAP Version 1.0, dated 27 July 2022 
 
 
Page 1 of 47


Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
BST1302-SOP-T01/v1.0/2020
Page 1 of 22
  
Protocol Title:
Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate 
the Safety, Immunogenicity, and Efficacy of INO-4800, a Prophylactic 
Vaccine against COVID-19 Disease, Administered Intradermally 
Followed by Electroporation in Healthy Seronegative Adults at High 
Risk of SARS-CoV-2 Exposure
Protocol Number:
COVID19-311
Protocol Version, Date:
Final v2.0 USA; 08-OCT-2021
ICON GPHS ID:
5309-0001 
Document Version, Date:
Final v2.0; 20-JAN-2022
Prepared by:
, Ph.D
ICON GPHS 
On behalf of:
Inovio Pharmaceuticals, Inc.
660 W. Germantown Pike, Suite 110
Plymouth Meeting, PA 19462 
Confidentiality statement:

The information provided in this document is strictly confidential.

The recipients of the SAP must not disclose the confidential information contained within 
this document or any related information to other persons without the permission of the 
sponsor.

In addition, the recipient of the SAP must keep this confidential document in a controlled 
environment which prevents unauthorized access to the document.
Page 2 of 47


Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
BST1302-SOP-T01/v1.0/2020
Page 2 of 22
Signature Page
Prepared at ICON GPHS by:
, PhD, 
pp 
, 
, Biostatistics
Signature
Date
Approved at ICON GPHS by:
, PhD
 Principal Investigator
Signature
Date
Approved at SPONSOR by:
 Biostatistics
Signature
Date
Page 3 of 47


Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
BST1302-SOP-T01/v1.0/2020
Page 3 of 22
Revision History
Version
Date
Revisions
0.1
16 November 2020
Initial draft
0.2
12 January 2021
Internal Review
0.3
15 March 2021
Sponsor request to split out Phase 2 from 
Phase 3 for clarity
1.0
9 April 2021
Final v1.0
1.1
06-DEC-2021
Revised draft to incorporate changes in 
protocol USA v2.0
1.2
05-JAN-2022
Revised draft to incorporate comments from 
Inovio: unblinding at Week 30 
2.0
20-JAN-2022
Final v2.0
Page 4 of 47


Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
BST1302-SOP-T01/v1.0/2020
Page 4 of 22
Table of Contents
List of Abbreviations .........................................................................................................6
1
Introduction................................................................................................................7
2
Study Objectives........................................................................................................7
2.1
Primary objective ..................................................................................................................................... 7
2.2
Secondary objectives............................................................................................................................... 7
2.3
Exploratory objective................................................................................................................................ 7
2.4
Safety objective(s) ................................................................................................................................... 7
2.5
General study design............................................................................................................................... 7
2.6
Randomization and blinding..................................................................................................................... 8
2.7
Study treatments and assessments......................................................................................................... 9
3
Study Endpoints ......................................................................................................12
3.1
Primary endpoints .................................................................................................................................. 12
3.2
Secondary endpoints ............................................................................................................................. 12
3.3
Exploratory endpoints ............................................................................................................................ 12
4
Sample Size and Power...........................................................................................12
5
Analysis Populations...............................................................................................12
5.1
Analysis Population................................................................................................................................ 12
5.1.1
Intention-To-Treat population (ITT) .................................................................................................... 12
5.1.2
Modified Intention-To-Treat population (mITT)................................................................................... 12
5.1.3
Safety population (Safety) .................................................................................................................. 12
5.1.4
Per-Protocol population (PP).............................................................................................................. 13
5.2
Protocol deviations/violations and exclusions from analysis sets ......................................................... 13
6
Statistical Considerations and Analysis................................................................13
6.1
Derived Variables................................................................................................................................... 13
6.2
Handling of missing data and outliers.................................................................................................... 14
6.2.1
Missing data analysis methods........................................................................................................... 14
7
Statistical Methods ..................................................................................................15
7.1
General statistical conventions .............................................................................................................. 15
7.2
Subject disposition................................................................................................................................. 16
7.3
Protocol deviations................................................................................................................................. 17
7.4
Demographics and baseline characteristics .......................................................................................... 17
7.4.1
Demographics..................................................................................................................................... 17
7.4.2
Medical history.................................................................................................................................... 17
7.4.3
Prior and concomitant medications .................................................................................................... 17
Page 5 of 47


Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
BST1302-SOP-T01/v1.0/2020
Page 5 of 22
7.5
Extent of exposure................................................................................................................................. 17
7.5.1
Treatment duration ............................................................................................................................. 17
7.5.2
Treatment compliance ........................................................................................................................ 17
7.6
Immunogenicity analysis........................................................................................................................ 17
7.7
Safety analysis....................................................................................................................................... 19
7.7.1
Adverse events................................................................................................................................... 19
7.7.2
Clinical laboratory evaluations............................................................................................................ 21
7.7.3
Vital signs ........................................................................................................................................... 21
7.8
Interim analysis ...................................................................................................................................... 21
8
Changes to Planned Analysis from Study Protocol .............................................22
Page 6 of 47


Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2
Version: Final v2.0; Date: 20-JAN-2022
BST1302-SOP-T01/v1.0/2020
Page 6 of 22
List of Abbreviations
Abbreviation
Explanation
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
alanine transaminase
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass Index
BP
Blood Pressure
BUN
blood urea nitrogen
CBC
Complete Blood Count
CI
Confidence Interval
CONSORT
Consolidated Standards of Reporting Trials
COVID19
Corona Virus Disease
CPT
cell preparation tubes
CRF
Case Report Form
CSR
Clinical Study Report
DSMB
Data Safety and Monitoring Board
ECG
electrocardiogram
ELISpot
enzyme-linked immune absorbent spot
EOS
End of Study
EP
electroporation
GCP
Good Clinical Practice
GMFR
Geometric Mean Fold Rise
H0
null hypothesis
H1
alternative hypothesis
HCO3
bicarbonate
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation
IFN
interferon
IP
Investigational Product
IRT
Interactive Response Technology
ITT
Intent-to-treat
K
Potassium
LDH
Lactate Dehydrogenase
MAAE
Medically Attended Adverse Events
MedDRA
Medical Dictionary for Regulatory Activities
mRNA
messenger Ribonucleic Acid
O2
Oxygen
PCR
Polymerase chain reaction
PO4
Phosphate
PP
Per Protocol
PT
Preferred Term
RT
reverse transcriptase
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SARS
Severe Acute Respiratory Syndrome 
SD
standard deviation
SI
International system of units
SOC
system organ class
TEAE
Treatment Emergent Adverse Event
TLF
Table Listing and Figure
WHO
World Health Organization
Page 7 of 47


Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
BST1302-SOP-T01/v1.0/2020
Page 7 of 22
1
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the statistical 
methods, data derivations, and data displays for the study protocol COVID 19-311 version 2.0 USA “Phase 
2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate the Safety, Immunogenicity, and Efficacy of 
INO-4800, a Prophylactic Vaccine against COVID-19 Disease, Administered Intradermally Followed by 
Electroporation in Healthy Seronegative Adults at High Risk of SARS-CoV-2 Exposure” dated 08-OCT-2021
for the analysis of the Phase 2 portion of the trial. A subsequent SAP will be developed specific for the 
Phase 3 portion of the trial. The table of contents and templates for the Tables, Listings, and Figures (TLFs)
will be produced in a separate document.
Any deviations from this SAP will be described and justified in the Clinical Study Report (CSR). 
The preparation of this SAP has been based on International Conference on Harmonisation (ICH) E9 and 
Good Clinical Practice (GCP) guidelines.
All data analyses and generation of TLFs will be performed using SAS 9.4® or higher.
2
Study Objectives
2.1
Primary objective

Evaluate the cellular and humoral immune response to INO-4800 administered by ID injection 
followed immediately by EP.
2.2
Secondary objectives

Evaluate the safety and tolerability of INO-4800 administered by ID injection followed immediately by 
EP
2.3
Exploratory objective

Evaluate the expanded immunological profile of antibody response and T cell immune response
2.4
Safety objective(s)
The safety objectives are included within the secondary objectives and include the following:

Evaluate the safety and tolerability of INO-4800 administered by ID injection followed immediately by 
EP
2.5
General study design
This is an operationally seamless Phase 2/3, randomized, placebo-controlled, multicenter trial to evaluate the 
safety, immunogenicity, and efficacy of INO-4800, administered by ID injection followed immediately by EP 
using the CELLECTRA® 2000 device, in a 2-dose regimen (Days 0 and 28) in adults who are at high risk of 
SARS-CoV-2 exposure. 
Page 8 of 47


Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
BST1302-SOP-T01/v1.0/2020
Page 8 of 22
In the Phase 2 segment, approximately 400 subjects 18 years of age and older will be randomized at a 
3:3:1:1 ratio across four dose groups (Table 1).
Table 1: Phase 2 Segment Dose Groups
Study 
Group
Expected Number 
of Subjects
Dosing 
Days
Number of 
Injections + EP per 
Dosing Visit
INO-4800 
(mg) per 
injection
INO-4800 (mg) 
per Dosing 
Visit
Total Dose 
(mg)
INO-4800
150
0, 28
1
1.0
1.0
2.0
INO-4800
150
0, 28
2a
1.0
2.0
4.0
Placebo
50
0, 28
1
0
0
0
Placebo
50
0, 28
2a
0
0
0
Total
400
aINO-4800 or placebo will be injected ID followed immediately by EP in an acceptable location on two different limbs at each 
dosing visit.
Dose selection for evaluation of efficacy in the Phase 3 segment will be based on Week 6 immunogenicity 
data and Week 8 safety data from the Phase 2 segment. Group-level unblinded summaries and analyses of 
immunogenicity and safety will be produced once the Week 6 immunogenicity data and Week 8 phone call 
visit data are completed for all subjects in the Phase 2 segment.
The total study duration is 393 days from Screening to end of study.  
For safety issues or evidence of poor efficacy, the DSMB could recommend stopping enrollment at any time; 
no formal interim analysis will be performed for this purpose. 
2.6
Randomization and blinding
At each clinical site, subjects who are eligible to enter phase 2 segment will be randomized to one of four 
treatment arms (INO-4800 1.0 mg, one injection; INO-4800 2.0 mg, two injections; Placebo, one injection;
Placebo, two injections) in a 3:3:1:1 ratio, respectively, via the Y’Prime interactive response technology (IRT) 
randomization system. Randomization in this study will follow a permuted block randomization method. No 
stratification will be conducted.
This segment of the trial is double-blinded within dose-level, and group level unblinded summaries and 
analyses of immunogenicity and safety will be produced once the Week 6 immunogenicity data and Week 8 
phone call visit data are completed for all subjects in the Phase 2 segment, which will be presented to the 
sponsor for dose selection for the Phase 3 portion. Per study protocol USA v2.0, all subjects will be 
unblinded when all subjects have completed the Week 30 study visit after identification and approval of the 
study populations.
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Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
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Emergency unblinding procedures during the trial may be taken if the knowledge of the product administered 
is essential for the medical management of the subject by the principal investigator. Unblinding will be 
conducted through the IRT system. Notification to sponsor and medical monitor will be made for each 
unblinding and a record will be kept at each study site for all unbroken treatment codes and the reason for 
the need to break the treatment assignment. 
2.7
Study treatments and assessments
The maximum duration of study participation from initial dosing to end of follow-up period is 393 days. The 
screening period can precede this active participation period by 1 to 30 days, for a total maximum duration of 
up to 423 days.
The investigational products (IPs) are: INO-4800, formulated in sodium chloride and sodium citrate buffer, 
refrigerated, and Placebo [sterile saline sodium citrate buffer (SSC-0001)], refrigerated.
Dosing regimens in Phase 2 Segment

Active Investigational Product: One or two 1.0mg ID injection(s) of INO-4800 (~0.1mL dose volume 
each) followed immediately by EP administered on Day 0 and Day 28 (±3 days)

Placebo: One or two ID injection(s) of SSC-0001 (~0.1mL) followed immediately by EP administered 
on Day 0 and Day 28 (±3 days)
Once eligibility has been confirmed, the subject will be randomized to receive a treatment assignment (INO-
4800 or placebo). Visit dates and windows must be calculated from Day 0, unless otherwise noted. All 
subjects will be followed until the Day 393 Visit. All subjects will be followed in accordance with assessments 
outlined in the protocol.
The sponsor will continuously monitor emerging results from ongoing trials. Any evidence will be assessed 
by the Data and Safety Monitoring Board (DSMB) who will advise regarding any safety concerns and will 
make recommendations regarding continued enrollment, safety pause and trial suspension. If the safety data 
is considered unfavorable during any safety review, the DSMB may recommend a trial pause or trial 
termination at which time further enrollment and administration of IP to subjects will be paused. The Sponsor 
will perform an investigation and consult with the DSMB and other experts, if needed, to determine whether 
to resume dosing of the remainder of the subjects. For further details, see the DSMB Charter.
The detailed descriptions of procedures and assessments to be conducted during the Phase 2 segment in 
this trial are summarized in Phase 2 Segment Schedule of Events in Table 2 below.
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Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2
                                                                                                   Version: Final v2.0; Date: 20-JAN-2022
BST1302-SOP-T01/v1.0/2020
Page 10 of 22
Table 2: Phase 2 Segment Schedule of Events
Tests and assessments
Sc
D0
Tel #1
Wk
4
Tel #2
Wk6
Tel #3
Wk 30
Wk
56
Illness
Illness 
Screena
Day 0
Phone call - Day 7 (±3d)
Day 28
(±3d)
Phone call - Day 35 (±3d)
Day 42 (±5d)
Phone Call - Day 56 (±5d)
Day 210 (±5d)
Day 393 (± 5d)
COVID-19 assessment visitm
COVID-19 convalescent visitn
Pre
Post
Pre
Post
Informed Consent
X
Inclusion/Exclusion Criteria
X
Medical history
X
X
Demographics
X
Socio-behavioral Assessment
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
Physical Examb
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
Xp
Xp
Height and Weight
X
CBC with differentialc
X
X
X
X
X
Chemistryc
X
X
X
X
X
HIV Serology 
X
Urinalysis Routined
X
X
X
X
X
Pregnancy Teste
X
X
X
X
INO-4800 or Placebo + EPf
X
X
Download EP Datag
X
X
Adverse Eventsh
X
X
X
X
X
X
X
X
X
X
X
X
X
Cellular Samplesi
X
X
X
X
X
Humoral Samplesj
X
X
X
X
X
SARS-CoV-2 Serologyk
X
SARS-CoV-2 RT-PCR (Saliva and Swab)
Xl
Xl
Xl
Distribute Diary
X
X
Review/Collect Diaryo
X
X
X
X
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Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2
                                                                                                   Version: Final v2.0; Date: 20-JAN-2022
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a.
Screening assessment occurs from -30 days to -1 day of Day 0.  
b.
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits.
c.
Hemoglobin A1c collected at screening only. Chemistry includes Na, K, Cl, HCO3, Ca, PO4, glucose, BUN, Cr, alkaline phosphatase, AST, ALT, LDH, total bilirubin. 
d.
Dipstick for glucose, protein, and hematuria. Microscopic examination should be performed if dipstick is abnormal. 
e.
Serum pregnancy test at Screening. Urine pregnancy test at other visits.
f.
Intradermal injection(s) in skin preferably over deltiod muscle, or alternately over anterolateral quadriceps muscle, followed by EP at Day 0 and Day 28.
g.
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio.
h.
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS.
i.
On Day 0, cellular sampling requires 64 mL of whole blood (8 Cell Preparation Tubes (CPT), each 8 mL of whole blood) prior to 1st dose. At all other time points, collect 32 mL of whole 
blood (4 CPT tubes, each 8 mL of whole blood).
j.
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce eight serum aliquots of 1 mL 
each). At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce four serum aliquots of 1 mL each. 
k.
SARS-CoV-2 antibody.
l.
Saliva specimen at Screening; Nasal swab and saliva specimens at COVID-19 assessment and convalescent visits. Genotyping may also be performed on sample(s) collected at the 
COVID-19 assessment visit.
m.
Subjects will be evaluated during a “COVID-19 assessment visit” when acute COVID-19 is suspected. The assessment visit may be performed in the clinic, in the subject’s vehicle or at the 
subject’s home and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test. 
n.
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of symptoms, 
the date of positive SARS-CoV-2 test. If acute symptoms are ongoing, the site should follow up with the subject via phone call or an unscheduled visit after symptom resolution or stabilization.
o.
Diary should be reviewed at the 7-day post-dose phone call and collected at the next in-office visit.
p.
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation.
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Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
BST1302-SOP-T01/v1.0/2020
Page 12 of 22
3
Study Endpoints
3.1
Primary endpoints

Antigen-specific cellular immune response measured by IFN-gamma ELISpot

Neutralizing antibody response measured by a pseudovirus-based neutralization assay
3.2
Secondary endpoints

Incidence of solicited and unsolicited injection site reactions

Incidence of solicited and unsolicited systemic adverse events (AEs) by system organ class (SOC), 
preferred term (PT), severity and relationship to investigational product 

Incidence of serious adverse events (SAEs)

Incidence of adverse events of special interest (AESIs)  
3.3
Exploratory endpoints

Antigen-specific cellular immune response measured by flow cytometry.

Expanded immunological profile which may include additional assessments of T and B cell numbers 
and molecular changes by measuring immunologic proteins and mRNA levels of genes of interest 
as determined by sample availability
4
Sample Size and Power
The phase 2 segment of this trial was not powered to conduct any formal hypothesis testing.
5
Analysis Populations
5.1
Analysis Population
5.1.1
Intention-To-Treat population (ITT)
The ITT population includes all subjects who are randomized. Subjects in this sample will be grouped to 
treatment arms as randomized. 
5.1.2
Modified Intention-To-Treat population (mITT)
The mITT population includes all subjects who receive at least one dose of Study Treatment. Subjects in this 
population will be grouped to treatment arms as randomized.  
5.1.3
Safety population (Safety)
The safety analysis population includes all subjects who receive at least one dose of Study Treatment. 
Subjects will be analyzed according to the treatment received. If a subject receives one dose of one 
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Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
BST1302-SOP-T01/v1.0/2020
Page 13 of 22
treatment and one dose of another treatment accidently, the subject will be analyzed according to the 
treatments received.
5.1.4
Per-Protocol population (PP)
The per-protocol (PP) population includes all subjects who receive all doses of Study Treatments and have 
no protocol violations. Subjects in the PP population will be grouped to treatment arms as randomized.  
Subjects excluded from the PP population will be identified and documented prior to unblinding of the trial 
database.  Analyses on the PP population will be primary for the analysis of immunogenicity in the Phase 2
segment of this trial.
5.2
Protocol deviations/violations and exclusions from analysis sets
Protocol deviation data will be captured in the clinical trial management system. Extracts of all protocol 
deviations will be reviewed periodically and prior to final analysis. All protocol deviations and the exclusion of 
participants from analysis sets will be identified prior to unblinding, through clinical review input provided by 
the sponsor, using the following sources of information:

Supportive participant listings, provided by the ICON statistician based upon data recorded in the clinical 
trial management system
Further, deviations from the protocol will be classified as major or minor. Classification of major and minor
protocol deviations is determined prior to participant enrollment and is outlined in detail in the protocol 
deviation criteria documentation managed by the clinical trial management team.
6
Statistical Considerations and Analysis
6.1
Derived Variables
The below table provides the list of derived variables for demographic and baseline characteristics, various 
duration derivations, baseline derivation and other important derivations applicable for this segment of the 
trial.
Table 3: Derived Variables
Variables
Formula
Demographic and Baseline Characteristics
Body Mass Index
Weight (kg) / [height (m)] ^2
Age
Calculated at the time of informed consent. Sample SAS code to calculate age 
is: age = floor ((intck(‘month’, date of birth, informed consent date) –
(day(informed consent date) < day(date of birth)) ) / 12)
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Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
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Variables
Formula
Baseline
Baseline is defined as the last measurement prior to the first treatment 
administration
Derivation of Durations
Study day at any visit
Date of interest – date of first dose. One day is added if the difference is ≥ 0.
Duration of any events
End Date of Event – Start date of event + 1
Other Derivations
Incidence in a group
The proportion of the participants experiencing the outcome of interest 
compared to the total number of participants at risk of experiencing the outcome 
of interest. (e.g. the incident rate of SAEs after vaccination are the number of 
participants with an SAE reported after vaccination divided by the number of 
participants that received the vaccination).
Geometric Mean Fold 
Rise (GMFR)
The ratio of the geometric mean post-baseline result to the geometric mean 
baseline result of a particular lab/assay result.
6.2
Handling of missing data and outliers
6.2.1
Missing data analysis methods
No imputations will be conducted for missing data.
6.2.1.1
Handling of missing or incomplete dates
Imputation rules for missing or partial adverse event start/stop dates

If the AE start date day is missing (month and year provided) then set the date to the first of the 
month, unless the month and year are the same as the first dose. In this case, set the date to the 
date of first dose.

If the AE start month is missing (day and year provided) then set the month to January, unless the 
day and year are the same as the year of the first dose. In this case, set the date to the date of first 
dose.

If the AE start date day and month are missing (year is provided) then set the month and day to 
January 1, unless the year is the same as the year of the first dose. In this case, set the date to the 
date of first dose.

If the AE end date day is missing (month and year provided) then set the date to the last day of the 
month.
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Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
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Page 15 of 22

If the AE end date month is missing (day and year provided) then set the date to the latest calendar 
month consistent with the day.

If the AE end date day and month is missing (year is provided) then set the date to December 31.

If the year of the AE start date or AE end date are missing, then a query to the site must be made to 
gather additional information.
o
If the start date is completely missing, then set the start date to the date of first dose.  If the 
end date is completely missing, then set the end date to the date of latest follow-up.
o
If the start date day is missing (month provided), then set the date to the first of the month, 
unless the month is the same as the first dose. In this case, set the date to the date of first 
dose.  If the end date day is missing (month provided), then set the date to the last day of 
the month.
o
If the start date month is missing (day provided), then set the month date to January, unless 
the day is the same as the first dose. In this case, set the date to the date of first dose.  If the 
end date month is missing (day provided), then set the date to the latest calendar month 
consistent with the day.
o
If the start date year is missing (day and month provided), then set the year to the year in 
which the patient was first screened, unless the day and month are the same as the first 
dose. In this case, set the date to the date of first dose.  If the end date year is missing (day 
and month provided), then set the date to the latest calendar year in which the patient is 
followed.
Imputation rules for missing or partial prior/concomitant medication start/stop dates

Start dates will not be imputed.

Partial stop dates of prior/concomitant medications will be assumed to be the latest possible date 
consistent with the partial date.  If day, month, and year are missing assign ‘continuing’ status to the 
stop date.
7
Statistical Methods
7.1
General statistical conventions
All statistical procedures will be completed using SAS version 9.4 or higher.
Unless otherwise stated, all statistical testing will be two-sided and will be performed using a significance 
(alpha) of 0.05. Two-sided 95% confidence intervals (CI) will be provided when relevant.
Continuous variables will be summarized using descriptive statistics, including number of subjects (n), mean, 
median, standard deviation (SD), minimum, and maximum. Means and medians will be rounded to one more 
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Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
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Page 16 of 22
decimal place than what is reported in the data. Standard deviations will be rounded to two more decimal 
places than what is reported in the data.
For categorical variables, summaries will include counts of subjects and percentages. Percentages will be 
rounded to one decimal place.
For summary purposes, baseline is defined as the last measurement prior to the first treatment 
administration. All summaries will be presented by treatment group, unless otherwise specified.
All subject data, including those derived, will be presented in individual subject data listings. Unless 
otherwise stated, unscheduled visit results will be included in date/time chronological order, within patient 
listings. All listings will be sorted by investigational site, subject ID, date/time and visit. The treatment group
as well as the patient’s sex and age will be stated on each listing. Unless otherwise stated, data listings will 
be based on all subjects randomized (ITT Population).
7.2
Subject disposition
Subject disposition information will be summarized by treatment group, age stratum, race, ethnicity, sex at 
birth, country, and overall. A CONSORT diagram will be constructed that details the number of subjects 
screened, the number enrolled and eligible for vaccination, the number randomized to each trial arm, the 
number receiving the first and second vaccination, the number of early terminations, the number completing 
the study, and the number eligible for analysis.
The primary reason for early withdrawal will also be tabulated.
The number of subjects randomized will be used as the denominator for the proportion calculation. Subject
disposition will be listed along with inclusion or exclusion criteria that were not met for randomization.
The number and percent of subjects in each analysis set will also be tabulated. A listing of each subject
excluded from an analysis population will be listed as well as the reason why they were excluded from the 
population.
Treatment misallocations occur when a subject received a different treatment than they were randomized to. 
In these cases:

If a subject was randomized but not treated, then the subject will be included with their randomized 
treatment group the subject disposition summaries. These subjects will be included in the ITT 
population only.

If a subject was treated but not randomized, then by definition the subject will be excluded from the 
immunogenicity analyses since randomized treatment is missing but will be included in the ITT 
population and in the Safety population according to the treatment actually received for all safety 
analyses.
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Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
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Page 17 of 22

If a subject was randomized but received a different treatment regimen, then the subject will be 
included according to their randomized treatment group for all immunogenicity analyses in the 
ITT/mITT population but will be excluded from immunogenicity analyses in the PP population.  These 
subjects will be included according to the treatment regimen actually received for all safety analyses.
7.3
Protocol deviations/violations
The number of patients excluded from ITT, mITT, Safety, and Per-protocol analysis sets and reasons for 
exclusion will be summarized by treatment group and overall. Population membership details will be listed, 
including reason for exclusion from each population (on randomized subjects).
Protocol deviations will also be listed.
7.4
Demographics and baseline characteristics
7.4.1
Demographics
Age at consent, height, weight, and other continuous demographic variables at baseline will be summarized 
descriptively. Sex, primary race, ethnicity, and other categorical variables will be summarized using the ITT 
and PP populations.
7.4.2
Medical history
Medical history will be listed.
7.4.3
Prior and concomitant medications
Data for all prior and concomitant medications will be summarized with percentages by treatment arm, for the 
ITT and PP populations. 
Prior and concomitant medications will also be listed.
7.5
Extent of exposure
7.5.1
Treatment duration
Study treatment exposure will be summarized as the number of subjects receiving a total of 1 and 2 doses of 
product and will be presented by treatment group on the ITT, mITT, PP, and safety populations.
7.5.2
Treatment compliance
A full course of study product administration consists of two doses of vaccine. A summary table detailing the 
total number of doses received will be presented along with the reason a dose was not administered or 
missed. A summary of subjects receiving the dose outside the dosing window, 25 to 31 days post first dose, 
will be presented.
7.6
Immunogenicity analysis
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Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
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Page 18 of 22
The immunogenicity analyses will be performed using the PP population. Valid samples for statistical 
analysis purposes will include those collected at least 6 and no more than 30 days after Dose 2 for the Week 
6 timepoint; at least 174 and no more than 198 days after Dose 2 for the Week 30 timepoint; and at least 356 
and no more than 380 days after Dose 2 for the Week 56 timepoint. Baseline is defined as the last
measurement prior to the first treatment administration.
The analyses will be stratified according to NP positive/negative status of the subjects, prior receipt of any 
non-study prophylactic COVID-19 vaccine of the subjects, and age group. Strata for age group are 18 – 50, 
51+ and 65+ years at Dose 1. Strata for NP status are positive and negative at each time point (week 6, 
week 30, and week 56). Strata for prior receipt of any non-study prophylactic COVID-19 vaccine are yes and 
no at each time point. Additionally, a composite stratification of NP positive or non-study vaccinated and NP 
negative and not non-study vaccinated will be utilized.
At each post baseline time point, post-baseline increase from baseline in interferon-γ ELISpot magnitude
and post baseline increase from baseline in cellular immune magnitude measured by flow cytometry will be 
summarized using the median by treatment group. Differences in medians and associated nonparametric 
95% CIs between treatment groups will be calculated.
The following sample of SAS code will be used to construct these confidence intervals.
proc npar1way hl alpha=.05 data=<DATASET>;
   class armcd;
   var <OUTCOME>;
   exact hl;
   ods select HodgesLehmann;
run;
In above SAS codes:

Armcd represents active treatment and placebo, i.e., 1.0 mg INO-4800, 1injection placebo, or 2.0 mg
INO-4800, and 2 injections placebo.

OUTCOME represents interferon-γ ELISpot or flow cytometry increases from baseline.

hl adds Hodges-Lehmann confidence interval for location differences between treatment groups.
At each post baseline time point, post-baseline changes in neutralizing antibody (PRNT50) titers from ELISA
will be summarized with GMFRs by treatment group.  The GMFRs will be compared between treatment 
groups using ratios and associated 95% t-distribution based CIs.
The following sample of SAS code will be used to construct these confidence intervals.
proc mixed data=<DATASET>;
   class armcd(ref=’xx’);
   model LR = armcd;
   lsmeans armcd / cl diff alpha=0.05;
   ods output diffs=diff;
run;
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Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
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data diff1; set diff;
   GMFR=10**(Estimate);
   Lclm=10**(lower);
   Uclm=10**(upper);
run;
In above SAS codes:

Armcd represents active treatment and placebo, i.e., 1.0 mg INO-4800, 1 injection placebo, or 2.0 
mg INO-4800, and 2 injections placebo.

LR represents log10 Yi/ Bi, where Yi is the post dose assay result for subject i; and Bi is the baseline 
assay result for subject i.  

xx represents reference arm (i.e., 1 injection placebo or 2 injection placebo or 1.0 mg INO-4800 or 
2.0 mg INO-4800)
7.7
Safety analysis
This section describes the safety analyses that will be conducted including all data collected in subjects who 
drop out.
All definitions relative to safety endpoints are detailed in Section 3.
Safety analyses will be conducted on the safety population and will be performed for all safety variables 
specified below. All safety data will be summarized by treatment group. The summaries/analyses will be 
stratified according to NP positive/negative status of the subjects, prior receipt of any non-study prophylactic 
COVID-19 vaccine of the subjects, and age group. Strata for age group are 18 – 50, 51+ and 65+ years at 
Dose 1.  Strata for NP status are positive and negative at each time point.  Strata for prior receipt of any non-
study prophylactic COVID-19 vaccine are yes and no at each time point. Additionally, a composite 
stratification of NP positive or non-study vaccinated and NP negative and not non-study vaccinated will be 
utilized.
The safety analyses of changes from baseline to a specific time point in safety variables (e.g., laboratory 
parameters, vital signs, ECG) will include subjects from the safety population who have data available for 
both the baseline and the time point under considerations unless otherwise specified.
7.7.1
Adverse events
All adverse events (AE) will be classified by Primary System Organ Class (SOC) and Preferred Term (PT) 
according to the Medical Dictionary for Regulatory Activities (MedDRA) Version 23.0 or higher.
In summaries by SOC and PT, adverse events will be sorted by descending frequency within each SOC and 
PT according to the total number of events. In summaries by PT, AEs will be sorted by decreasing frequency 
according to the total number of events.
All AEs will be captured from the time of the informed consent until 28 days post-dose 2 (Day 56). Following 
the Day 56 visit, only SAEs, AESIs and MAAEs will be collected.
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Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
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Page 20 of 22
AEs will be classified as pre-treatment or treatment emergent (TEAE) defined as follows:

Pre-treatment: any AE that started before the first dose date of the study treatment

TEAE: any AE that was newly developed at or after the first dose date of study treatment
Details for imputing missing or partial start dates of adverse events are described in section 6.2.
AE summary tables will include the following:

All TEAEs

Related TEAEs (AE will be defined as related if causality is either probable, possible, or definite)

TEAEs by maximum severity

TEAEs leading to treatment discontinuation

Serious TEAEs

TEAEs leading to death
All AEs including injection-site reactions will be summarized among the Safety Population by frequency per 
treatment arm. These frequencies will be presented overall and separately by dose, and will depict overall, 
by system organ class and by preferred term, the percentage of subjects affected.
Where a subject has the same adverse event, based on preferred terminology, reported multiple times in the 
treatment period, the subject will only be counted once at the preferred terminology level in adverse event 
frequency tables.
Where a subject has multiple adverse events within the same system organ class in the treatment period, the 
subject will only be counted once at the system organ class level in adverse event frequency tables.
Adverse events by severity and separately by relationship will be summarized based on the most intense 
event during the treatment period and strongest relationship to study treatment, respectively.
The main summary of safety data will be based on events occurring within 30 days of any dose. For this 
summary, the frequency of preferred term events will be compared between study arms with risk differences 
and 95% confidence intervals, using the method of Miettinen and Nurminen. As this analysis will use many 
event categories, and produce many confidence intervals, caution should be exercised when interpreting 
these confidence intervals. Separate summaries will be based on events occurring within 7 days of any dose 
and regardless of when they occurred.
The following sample of SAS code will be used to construct confidence intervals of the risk difference with 
the method of Miettinen and Nurminen:
proc freq data = <DATASET>; 
  tables armcd * <OUTCOME> / riskdiff(CL= MN);
Page 21 of 47


Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
BST1302-SOP-T01/v1.0/2020
Page 21 of 22
  weight <COUNT>;
run;
7.7.2
Clinical laboratory evaluations
For the purposes of summarization in both the tables and listings, all laboratory values will be presented in
the International System of Units (SI). If a lab value is reported using a nonnumeric qualifier (e.g., less than 
(<) a certain value, or greater than (>) a certain value), the given numeric value will be used in the summary 
statistics, ignoring the nonnumeric qualifier.
All laboratory data obtained after the start of study medication dosing up to and including the final visit will be 
used for the laboratory safety analysis. Laboratory summaries will be provided including values measured 
during the follow-up period, where appropriate.
Visit value and change and/or percent change from baseline (where applicable) will be summarized by 
treatment group using descriptive statistics for all laboratory parameters which are listed in the protocol.
Shift tables among the safety population will be summarized by treatment group using the baseline values 
and highest/lowest values obtained post baseline. Lab results will be classified as Normal or Abnormal based 
upon local laboratory normal ranges.
7.7.3
Vital signs
Visit values and changes from baseline for vital sign measurements (pulse, blood pressure, SpO2, 
temperature, respiratory rate) will be summarized by treatment group at each visit using descriptive statistics. 
Visit values will be calculated as the mean of all available measurements per parameter.
7.8
Interim analysis
For safety issues or evidence of poor efficacy, the DSMB could recommend stopping enrollment at any time; 
no formal interim analysis for this segment of the trial will be performed. 
Group-level unblinded summaries of the immunogenicity and safety data will be produced once Week 6 visit 
immunology data and Week 8 visit safety data are complete for all subjects who have not discontinued, while 
maintaining subject-level blinding. Long-term follow-up data will continue to be collected for all subjects who 
have not discontinued with remaining visits through the final visit. These summaries will allow the Sponsor to 
have results for the purposes of dose selection for the Phase 3 portion. No subject-level immunogenicity 
data will be produced, and subject-level immunogenicity data will not be available in the clinical trial database 
until all other clinical trial data are finalized at the end of the trial. No safety summary will be provided if the 
total number of subjects who experience the event of interest is greater than 0 and the count of the number 
of subjects with the event in a given treatment group relative to the total produces a percentage less than 
3%, for a given summary. The group-level unblinded production of the summaries will not include anyone 
directly involved with the trial or any additional unblinded personnel; only the external Contract Research 
Organization (CRO), ICON, which will already be providing unblinded summaries for the Data Safety 
Page 22 of 47


Statistical Analysis Plan (SAP) - Phase 2 Segment
Inovio COVID19-311 SAP – Ph 2                                                                                                    Version: Final v2.0; Date: 20-JAN-2022
BST1302-SOP-T01/v1.0/2020
Page 22 of 22
Monitoring Board, will be utilized. Thus, the trial will remain blinded to the Sponsor with respect to subject 
treatment assignment.
Based upon the wide availability of EUA and licensed vaccines in the US and completion of the data 
collection towards the Phase 3 dose selection, the Sponsor recognizes that subjects may want to know 
whether they received INO-4800 or placebo in order to make fully informed choices about receiving a non-
study prophylactic COVID-19 vaccine (either authorized under emergency use or when licensed). Therefore, 
once all subjects have reached the Week 30 Visit timepoint, all subjects will be unblinded (as specified in 
study protocol USA v2.0).  
8
Changes to Planned Analysis from Study Protocol
Not applicable.
Page 23 of 47


 Statistical Analysis Plan (SAP)  Phase 3 Segment 
Inovio, INO-4800 
 
Version: Final v1.0, Date: 27 July 2022 
BST1302-SOP-T01/v1.0/2020 
 
 
Page 1 of 24 
 
 
Protocol Title: 
Phase 2/3 Randomized, Blinded, Placebo-Controlled Trial to Evaluate 
the Safety, Immunogenicity, and Efficacy of INO-4800, a Prophylactic 
Vaccine against COVID-19 Disease, Administered Intradermally 
Followed by Electroporation in Adults at High Risk of SARS-CoV-2 
Exposure  
Protocol Number: 
COVID19-311 
Protocol Version, Date: 
Version 6.0, 30 April 2021 
ICON GPHS ID: 
0131-0017 
Document Version, Date: 
Final version 1.0; 27 July 2022 
 
Prepared by: 
 PhD CStat. 
ICON GPHS  
On behalf of: 
Inovio Pharmaceuticals, Inc. 
660 W. Germantown Pike, Suite 110 
Plymouth Meeting, PA 19462 
 
 
Confidentiality statement: 
 
The information provided in this document is strictly confidential. 
 
The recipients of the SAP must not disclose the confidential information contained within 
this document or any related information to other persons without the permission of the 
sponsor. 
 
In addition, the recipient of the SAP must keep this confidential document in a controlled 
environment which prevents unauthorized access to the document. 
 
 
Page 24 of 47


Statistical Analysis Plan (SAP)
Phase 3 Segment
Inovio, INO-4800
Version: Final v1.0, Date: 27 July 2022
BST1302-SOP-T01/v1.0/2020
Page 2 of 24
Signature Page
Prepared at ICON GPHS by:
, PhD CStat.
 Biostatistics
Signature
Date
Reviewed at ICON GPHS by:
, PhD
Principal Investigator
Signature
Date
Approved at Inovio Pharmaceuticals, Inc. by:
, PhD
Biostatistics
Signature
Date
Page 25 of 47


 Statistical Analysis Plan (SAP)  Phase 3 Segment 
Inovio, INO-4800 
 
Version: Final v1.0, Date: 27 July 2022 
BST1302-SOP-T01/v1.0/2020 
 
 
Page 3 of 24 
Revision History 
Version 
Date 
Revisions 
0.1 
29-September-2021 
Initial draft 
0.2 
29-September-2021 
Revised draft after internal review. 
0.3 
17-November-2021 
Revised draft addressing comments from 
sponsor. 
0.4 
22-June-22 
The study has been terminated, analysis will 
be restricted to primary efficacy and safety. 
0.5 
04-July-2022 
Revised following sponsor comments. 
1.0 
27-Jul-22 
Update schedule of assessments from protocol 
version 6 and removed lab analyses 
Final version 
 
 
Page 26 of 47


 Statistical Analysis Plan (SAP)  Phase 3 Segment 
Inovio, INO-4800 
 
Version: Final v1.0, Date: 27 July 2022 
BST1302-SOP-T01/v1.0/2020 
 
 
Page 4 of 24 
List of Abbreviations 
Abbreviation 
Explanation 
AE 
adverse event 
AESIs 
adverse events of special interest 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
BP 
blood pressure 
CI 
Confidence Interval 
COVID-19 
coronavirus disease 2019 
CPT 
Cell Preparation Tubes 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
computed tomography (scan) 
CYP3A 
cytochrome P450 3A4 
DRC 
Democratic Republic of the Congo 
DSMB 
Data and Safety Monitoring Board 
EAC 
Endpoint Adjudication Committee  
EC 
Ethic Committee 
ECG 
electrocardiogram 
EOS 
end of study 
EP 
electroporation 
FACTS 
fixed and adaptive clinical trial simulator 
GCP 
Good Clinical Practice 
GMFR 
Geometric mean fold rise   
GMT 
Geometric mean titer 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ID 
intradermal 
IP 
investigational product 
IRT 
Interactive Response Technology 
ITT 
intention-to-treat (population) 
mITT 
modified intention-to-treat (population) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mMRC 
modified Medical Research Council 
PAR 
paracetamol 
PP 
per protocol 
PT 
Preferred Term 
QTc 
corrected QT interval 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acquired respiratory syndrome - coronavirus 2 
SD 
standard deviation 
SI 
International System of Units 
SOC 
system-organ class 
SpO2 
blood oxygen saturation level 
SSC 
saline sodium citrate 
SSG 
Statistical Support Group 
TBD 
to be determined 
TEAE 
treatment emergent adverse event 
TLF(s) 
Table(s), Listing(s), and Figure(s) 
WHO 
World Health Organization 
 
 
Page 27 of 47


Statistical Analysis Plan (SAP)
Phase 3 Segment
Inovio, INO-4800
Version: Final v1.0, Date: 27 July 2022
BST1302-SOP-T01/v1.0/2020
Page 5 of 24
Introduction .......................................................................................................................7
1.1 Study Objectives........................................................................................................................................... 7
1.1.1 Primary objective....................................................................................................................................... 7
1.1.2 Secondary objectives ................................................................................................................................ 7
1.1.3 Exploratory objectives ............................................................................................................................... 7
1.2 Study Design ................................................................................................................................................ 8
1.2.1 Design Configuration................................................................................................................................. 8
1.2.2 Randomization and Blinding...................................................................................................................... 8
1.2.3 Study Duration......................................................................................................................................... 10
1.2.4 Study Treatments and Assessments ...................................................................................................... 10
1.2.5 Sample Size and Power.......................................................................................................................... 11
Types of Planned Analyses ...........................................................................................11
2.1 Data Safety Monitoring Board Analyses .................................................................................................... 11
2.2 Interim Analyses ......................................................................................................................................... 11
General Considerations for Data Analysis ..................................................................12
3.1 Analysis Populations .................................................................................................................................. 12
3.1.1 Intention-To-Treat population (ITT)......................................................................................................... 12
3.1.2 Modified Intention-To-Treat population (mITT) ....................................................................................... 12
3.1.3 Safety population (Safety)....................................................................................................................... 12
3.1.4 Per-Protocol population (PP)................................................................................................................... 12
3.2 Strata and Covariates................................................................................................................................. 12
3.3 Multiplicity ................................................................................................................................................... 12
3.4 Derived Variables ....................................................................................................................................... 12
3.5 Handling of Missing Data and Outliers....................................................................................................... 13
3.5.1 Missing data analysis methods ............................................................................................................... 14
3.5.2 Missing or incomplete dates.................................................................................................................... 14
3.6 General Statistical Conventions ................................................................................................................. 15
3.7 Disposition of Subjects ............................................................................................................................... 15
3.8 Extent of Exposure and Compliance.......................................................................................................... 16
3.8.1 Treatment Duration ................................................................................................................................. 16
3.8.2 Treatment Compliance ............................................................................................................................ 16
3.9 Protocol Deviations/violations and exclusions from analysis sets ............................................................. 16
Baseline Characteristics and Demographics..............................................................17
4.1 Baseline Characteristics............................................................................................................................. 17
4.2 Medical History ........................................................................................................................................... 17
4.3 Demographics ............................................................................................................................................ 17
4.4 Prior and Concomitant Medications ........................................................................................................... 17
Efficacy, Immunogenicity, and Safety Analyses ........................................................18
5.1 Primary Analysis......................................................................................................................................... 18
5.1.1 Primary Endpoint..................................................................................................................................... 18
5.1.2 Statistical Hypothesis for the Primary Efficacy Endpoint ........................................................................ 18
5.1.3 Analysis of Primary Efficacy.................................................................................................................... 19
5.1.4 Sensitivity Analysis.................................................................................................................................. 19
5.1.5 Changes from Protocol-Specified Primary Efficacy Analysis.................................................................. 19
5.2 Secondary Efficacy and Immunogenicity Analyses ................................................................................... 20
5.3 Exploratory Efficacy and Immunogenicity Analyses .................................................................................. 20
5.4 Safety Analysis ........................................................................................................................................... 20
5.4.1 Adverse Events and Deaths.................................................................................................................... 20
5.4.2 Vital signs ................................................................................................................................................ 21
5.4.3 Changes from Protocol-Specified Safety Analysis.................................................................................. 22
Appendices ......................................................................................................................23
Page 28 of 47


 Statistical Analysis Plan (SAP)  Phase 3 Segment 
Inovio, INO-4800 
 
Version: Final v1.0, Date: 27 July 2022 
BST1302-SOP-T01/v1.0/2020 
 
 
Page 6 of 24 
6.1 Appendix A  Phase 3 Schedule of Events................................................................................................ 23 
 
 
Page 29 of 47


Statistical Analysis Plan (SAP)
Phase 3 Segment
Inovio, INO-4800
Version: Final v1.0, Date: 27 July 2022
BST1302-SOP-T01/v1.0/2020
Page 7 of 24
Introduction
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the statistical 
methods, data derivations, and data displays for study protocol COVID19-311 version 6
Phase 2/3 
Randomized, Blinded, Placebo-Controlled Trial to Evaluate the Safety, Immunogenicity, and Efficacy of INO-
4800, a Prophylactic Vaccine against COVID-19 Disease, Administered Intradermally Followed by 
Electroporation in Healthy Seronegative Adults at High Risk of SARS-CoV-2 Exposure
30 April 2021
for the analysis of the Phase 3 segment of the trial. The table of contents and templates for the Tables, 
Listings, and Figures (TLFs) will be produced in a separate document.
Any deviations from this SAP will be described and justified in the Clinical Study Report (CSR). 
The preparation of this SAP has been based on International Council for Harmonization (ICH) E9 and Good 
Clinical Practice (GCP) guidelines.
1.1 Study Objectives
The overall purpose of this clinical trial is to evaluate the safety, immunogenicity, and efficacy of INO-4800 to 
prevent COVID-19 in subjects at high risk of exposure to SARS-CoV-2.
1.1.1 Primary objective
The primary objective of this clinical trial is to evaluate the efficacy of INO-4800 in the prevention of COVID-
19 disease in subjects who are SARS-CoV-2 negative at baseline.
1.1.2 Secondary objectives
The secondary objectives of this clinical trial are:
1.
To evaluate the safety and tolerability of INO-4800.
2.
To evaluate efficacy of INO-4800 in the prevention of COVID-19 disease according to degrees of 
disease severity in subjects who are SARS-CoV-2 seronegative at baseline.
3.
To evaluate the cellular and humoral immune response to INO-4800.
4.
To evaluate the efficacy of INO-4800 in the prevention of COVID-19 disease in subjects who are 
SARS-CoV-2 seropositive at baseline.
1.1.3 Exploratory objectives
The exploratory objectives of this clinical trial are:
1.
To evaluate the efficacy of INO-4800 in the prevention of COVID-19 disease from SARS-CoV-2 
variants in subjects who are SARS-CoV-2 seronegative at baseline.
2.
To evaluate the efficacy of INO-4800 in the prevention of SARS-CoV-2 asymptomatic infection in 
subjects who are SARS-CoV-2 seronegative at baseline.
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 Statistical Analysis Plan (SAP)  Phase 3 Segment 
Inovio, INO-4800 
 
Version: Final v1.0, Date: 27 July 2022 
BST1302-SOP-T01/v1.0/2020 
 
 
Page 8 of 24 
3. To evaluate the immunological profile by assessing both antibody response and T cell immune 
response. 
4. To evaluate antibody persistence.  
1.2 Study Design 
1.2.1 Design Configuration 
This SAP pertains to the Phase 3 segment of an operationally seamless Phase 2/3, randomized, placebo-
controlled, multi-center trial to evaluate the efficacy, safety, and immunogenicity of INO-4800, administered 
by ID injection followed immediately by EP using the CELLECTRA® 2000 device, in a 2-dose regimen (Days 
0 and 28) in adults who are at high risk of SARS-CoV-2 exposure. The subjects and data from Phase 3 are 
independent from that of Phase 2. Approximately 6714 seronegative and 402 seropositive subjects 18 years 
of age and older will be randomized at a 2:1 ratio to receive either active investigational product (INO-4800, 
2.0 mg) or placebo (SSC-0001). Approximately half of seronegative subjects and approximately half of 
seropositive subjects will be 18-50 years of age, a
 
The Phase 3 segment of the trial is case-driven. Among seronegative subjects, a total of 149 observed cases 
will be required for 90% power to declare the vaccine efficacious (>30%), assuming a true efficacy of 60%. A 
sample size of 6714 seronegative subjects is expected to be required to achieve the 149 cases assuming an 
underlying attack rate of 3.7%. The actual sample size may differ if the observed attack rate is different than 
projected. There are two formal interim analyses of efficacy; one when 50% of the cases accrue and one 
when 75% of the cases accrue. If the prespecified criteria for efficacy are met at either interim analysis, then 
enrollment will continue until 4500 subjects have been enrolled, and blinded follow-up will continue until at 
least those 4500 subjects have a minimum of 6 months of safety follow-up. At that point, the trial would be 
unblinded and placebo-recipients will be offered the active product.  
-confirmed COVID-19 disease in 
subjects who are SARS-CoV-2 seronegative at baseline starting 14 days after completion of the 2-dose 
regimen until 12 months post-dose 2. All subjects will be followed for 56 weeks from the Day 0 dosing (i.e., 
Week 56 will be the planned End of Study [EOS] visit for this segment of the trial).  
The total study duration is 393 days from screening to study discharge/EOS.  
The Data Safety Monitoring Board (DSMB) will convene regularly to review all available unblinded efficacy 
and safety data. Additionally, an independent, blinded Endpoint Adjudication Committee (EAC) will review 
and confirm COVID-19 cases. 
1.2.2 Randomization and Blinding 
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 Statistical Analysis Plan (SAP)  Phase 3 Segment 
Inovio, INO-4800 
 
Version: Final v1.0, Date: 27 July 2022 
BST1302-SOP-T01/v1.0/2020 
 
 
Page 9 of 24 
This study is double blinded. Approximately 6714 seronegative and 402 seropositive subjects 18 years of age 
and older will be randomized at a 2:1 ratio to receive either active investigational product (INO-4800, 2.0 mg) 
or placebo (SSC-0001). See Table 1. Approximately half of seronegative subjects and approximately half of 
seropositive subjects will be 18-50 years of age, and the other half will be 51 years of age as is operationally 
feasible. Also, approximately 711 subjects will be 65 years of age, if operationally feasible.  
Randomization in this trial will be conducted by YPrime. Subjects will be randomized in a stratified manner 
according to (a) age category (18-
0 of any of the following underlying medical conditions that increase risk of severe COVID-19 disease, per 
CDC criteria, as listed below: 
 
Cancer  
 
Chronic kidney disease 
 
Chronic lung diseases, including Chronic obstructive pulmonary disease (COPD), asthma 
(moderate-to-severe), interstitial lung disease, cystic fibrosis, pulmonary hypertension 
 
Neurologic conditions including stroke or cerebrovascular disease, that do not impact cognition 
 
Diabetes (type 1 or type 2) 
 
Hypertension 
 
Heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies 
 
HIV infection (CD4 count >200 cells/mm3 or undetectable viral load) 
 
Liver disease 
 
2) 
 
Sickle cell disease or thalassemia, or 
 
Smoking (current or former smoker). 
 
Table 1: Sample Size for Randomization   
Treatment 
Arm 
Sero 
status 
Expected 
Number of 
Subjects 
Approx. 
Expected 
Number of 
Subjects by 
Age Group 
Dosing 
Days 
Number of 
Injections + EP 
per Dosing 
Visit 
INO-4800 
(mg) per 
injection 
INO-4800 
(mg) per 
Dosing Visit 
Total Dose of 
INO-4800 
(mg) 
18-50 
51+a 
INO-4800 
Seroneg 
4476 
2238 
2238 
0, 28 
2 
1.0 
2.0 
4.0 
Seropos 
268 
134 
134 
Placebo 
Seroneg 
2238 
1119 
1119 
0, 28 
2 
0 
0 
0 
Seropos 
134 
67 
67 
Total 
Seroneg 
6714 
3357 
3357 
 
 
 
 
 
Seropos 
402 
201 
201 
 
 
 
 
 
Total 
7116 
 
 
 
 
 
aat 
 
 
This Phase 3 segment of the clinical trial is case-driven. Among seronegative subjects, a total of 149 
observed cases will be required for 90% power to declare the vaccine efficacious (>30%), assuming a true 
Page 32 of 47


 Statistical Analysis Plan (SAP)  Phase 3 Segment 
Inovio, INO-4800 
 
Version: Final v1.0, Date: 27 July 2022 
BST1302-SOP-T01/v1.0/2020 
 
 
Page 10 of 24 
efficacy of 60%. A sample size of 6714 seronegative subjects is expected to be required to achieve the 149 
cases assuming an underlying attack rate of 3.7%. The actual sample size may differ if the observed attack 
rate is different than projected. There are two formal interim analyses of efficacy; one when 50% of the cases 
accrue and one when 75% of the cases accrue. If the prespecified criteria for efficacy are met at either 
interim analysis, then enrollment will continue until 4500 subjects have been enrolled, and blinded follow-up 
will continue until at least those 4500 subjects have a minimum of 6 months of safety follow-up. At that point, 
the trial would be unblinded and placebo recipients will be offered the active product. 
Study staff at each site (coordinators and PI) along with the participants, and sponsor representatives will be 
blinded throughout the course of the trial.  At ICON, unblinded personnel will consist of a biostatistician and 
statistical programmer. The DSMB members will also be unblinded. Emergency unblinding procedures may 
be taken if the knowledge of the product administered is essential for the medical management of the 
participant by the principal investigator. Individual, emergency participant unblinding will be conducted 
through the IRT system. Notification to sponsor and medical monitor and associated documentation will be 
made for each unblinding. 
Formal unblinding of the trial will be done after database lock and after identification and approval of the per-
protocol analysis set. 
1.2.3 Study Duration 
The maximum duration for study participation from screening to end of follow-up period is 393 days. 
1.2.4 Study Treatments and Assessments 
The investigational product (IP) INO-4800 is formulated in sodium chloride and sodium citrate buffer, 
refrigerated. Placebo (sterile saline sodium citrate buffer [SSC-0001]), refrigerated. 
Dosing regimens in Phase 3 Segment: 
 
Active Investigational Product: Two 1.0 mg ID injections of INO-4800 (~0.1mL dose volume) followed 
immediately by EP administered in separate limbs on Day 0 and Day 28 (±3 days). 
 
Placebo: Two ID injections of SSC-0001 (~0.1mL) followed immediately by EP administered in 
separate limbs on Day 0 and Day 28 (±3 days).  
Once eligibility has been confirmed, the subject will be randomized to receive a treatment assignment (INO-
4800 or placebo). Visit dates and windows must be calculated from Day 0, unless otherwise noted. All 
subjects will be followed until the Day 393 Visit. All subjects will be followed in accordance with assessments 
outlined in the Protocol 6.1.2. 
The Data and Safety Monitoring Board (DSMB) will advise regarding any safety concerns and will make 
recommendations regarding continued enrollment, safety pause, and trial suspension. If the safety data are 
considered unfavorable during any safety review, the DSMB may recommend a trial pause or trial 
termination. The Sponsor will perform an investigation and consult with the DSMB and other experts, if 
Page 33 of 47


Statistical Analysis Plan (SAP)
Phase 3 Segment
Inovio, INO-4800
Version: Final v1.0, Date: 27 July 2022
BST1302-SOP-T01/v1.0/2020
Page 11 of 24
needed, to determine whether to resume dosing of the remainder of the subjects. For further details, see the 
DSMB Charter.
The detailed descriptions of procedures and assessments to be conducted during this study are summarized 
in the Phase 3 Schedule of Events in Appendix A. 
1.2.5 Sample Size and Power
The Phase 3 segment of this trial is case-driven. A total of 149 observed cases among baseline SARS-CoV-
2 seronegative subjects will be required to provide 90% power to declare the vaccine efficacious (>30%), 
assuming a true efficacy of 60%, with a one-sided type 1 error of 0.022. A sample size of 6714 baseline 
SARS-CoV-2 seronegative subjects will be required to achieve 149 cases assuming an underlying attack 
rate of 3.7%. The actual sample size may differ if the observed attack rate is different than projected.
Types of Planned Analyses
2.1 Data Safety Monitoring Board Analyses
The DSMB will meet approximately monthly until all subjects are enrolled in the trial, then bimonthly once all 
subjects are enrolled for the duration of the trial. The DSMB may also meet ad hoc as needed outside of the 
scheduled meetings and shall be disbanded upon completion of the trial. 
The following data/documents will be generated for DSMB review:
Baseline characteristics, demographics, participant disposition.
Adverse events (AEs), adverse event of special interest (AESI), medically attended adverse events 
(MAAEs), and serious adverse events (SAEs).
o
Tabulated for each trial group by system organ class (SOC) and preferred term (PT), 
severity, seriousness, duration, treatment given, and the relationship to the trial drug and 
device.
o
Clinical test results and laboratory values (including raw values, changes from baseline, and 
clinical abnormalities).
Listing of administration (injection) site reactions, including grading, duration, and treatment 
provided.
Listing of deaths.
COVID-19 disease.
Any other supporting data requested by the DSMB.
2.2 Interim Analyses
Two formal interim analyses of efficacy are planned for review by the independent DSMB, as described in 
the clinical protocol and in the DSMB Charter: one at 50% (75 cases) and one at 75% (112 cases) of the 
total required cases for the primary endpoint (149 cases). However, the trial has been terminated prior to 
Page 34 of 47


Statistical Analysis Plan (SAP)
Phase 3 Segment
Inovio, INO-4800
Version: Final v1.0, Date: 27 July 2022
BST1302-SOP-T01/v1.0/2020
Page 12 of 24
observing 75 cases, and therefore, these analyses will not be conducted. For safety issues, the DSMB could 
recommend stopping enrollment at any time; no formal interim analysis will be performed for this purpose.
Therefore, the two-sided type I error of 0.05 will not be adjusted for interim analyses.
General Considerations for Data Analysis
3.1 Analysis Populations
3.1.1 Intention-To-Treat population (ITT)
The ITT population includes all subjects who are randomized, regardless of protocol violations or missing 
data. Subjects in this sample will be grouped to treatment arms as randomized. Analysis of the ITT 
population will be considered supportive for the corresponding Per-Protocol population for the analysis of 
efficacy. 
3.1.2 Modified Intention-To-Treat population (mITT)
The mITT population includes all subjects who receive at least one dose of study treatment. Subjects in this 
population will be grouped to treatment arms as randomized. Analysis of the mITT population will be 
considered supportive for the corresponding Per-Protocol population for the analysis of efficacy.
3.1.3 Safety population (Safety)
The safety analysis population includes all subjects who receive at least one dose of study treatment. 
Subjects will be analyzed according to the treatments received. 
3.1.4 Per-Protocol population (PP)
The PP population includes all subjects who receive all doses of study treatments and have no protocol 
violations. Subjects in the PP population will be grouped to treatment arms as randomized. Subjects 
excluded from the PP population will be identified and documented prior to unblinding of the trial database. 
Analyses of the PP population among those who are baseline SARS-CoV-2 seronegative will be primary for 
the analysis of efficacy. 
3.2 Strata and Covariates
SARS-CoV-2 serostatus at baseline will be used as a stratification factor for several analyses. No covariates
will be included in the analyses.
3.3 Multiplicity
Not applicable.
3.4 Derived Variables
Derived variables for demographic and baseline characteristics, various duration derivations, and other 
derivations are listed in Table 2. 
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 Statistical Analysis Plan (SAP)  Phase 3 Segment 
Inovio, INO-4800 
 
Version: Final v1.0, Date: 27 July 2022 
BST1302-SOP-T01/v1.0/2020 
 
 
Page 13 of 24 
Table 2: Derived Variables 
Variables 
Formula 
Demographic and Baseline Characteristics 
Body Mass Index 
Weight (kg) / [height (m)] ^2 
Derivation of Durations 
Study day at any visit 
Date of interest  date of first dose of trial vaccine
0. 
Duration of any events 
End Date of Event  Start date of event + 1 
Baseline Derivations 
  
Baseline 
The baseline value is defined as the last observation prior to or on the date of the first 
dose of study drug; missing data will not be imputed. 
Change from baseline 
Post baseline value  Baseline; missing data will not be imputed. 
Other Derivations 
Incidence 
The number of subjects with a specific event divided by the total follow up time (in days) 
among the subjects in the treatment or control group and at risk of an initial occurrence of 
the event. 
p 
The true proportion of subjects with disease who receive INO-4800 relative to the total 
number of subjects with disease.   
k 
 
The total amount of follow-up time (in days) in the placebo group divided by the total 
amount of follow-up time (in days) in the INO-4800 group                          
-up time is either: 
 
the date of first disease diagnosis  date of the start of surveillance period + 1 
(for subjects who are cases), or 
 
the date of last follow-up  date of the start of surveillance period + 1 (for subjects 
who are non-cases). 
The primary hypothesis of relative efficacy greater than 30% will be tested with H0: p 
1: p < .70/(.70+k). 
Vaccine Efficacy   
 1  Risk in the vaccinated group / Risk in the unvaccinated group* 100, where risk is 
defined as the number of subjects with disease divided by the number of subjects in risk.  
Also equal to (1-(1+k)p)/(1-p), where k and p are defined above. 
Confidence interval for 
efficacy 
[(1-(1+k)UBp)/(1-UBp), (1-(1+k)LBp)/(1-LBp)],where UB and LB are the Clopper-Pearson 
upper and lower limits for the proportion, p; and p and k are defined above. 
Geometric mean titer 
(GMT) 
GMT is calculated as anti-log10 (mean [log10 Ti]) where Ti is the assay result for subject i. 
Geometric mean fold rise 
(GMFR) 
GMFR is calculated as anti-log10 (mean [log10 (Yi/ Bi)]) where Yi is the post dose assay 
result for subject i; and Bi is the baseline assay result for subject i. 
3.5 Handling of Missing Data and Outliers  
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No imputations will be conducted for missing data. No data will be excluded for being an outlier.  
3.5.1 Missing data analysis methods 
For the ITT analyses of efficacy, subjects with missing or unevaluable data regarding case definition will be 
considered cases (failures).   
3.5.2 Missing or incomplete dates 
3.5.2.1 Imputation rules for missing or partial AE start/stop dates 
 
If the AE start date day is missing (month and year provided) then set the date to the first of the 
month, unless the month and year are the same as the first dose. In this case, set the date to the 
date of first dose. 
 
If the AE start month is missing (day and year provided) then set the month to January, unless the 
day and year are the same as the year of the first dose. In this case, set the date to the date of first 
dose. 
 
If the AE start date day and month are missing (year is provided) then set the month and day to 
January 1, unless the year is the same as the year of the first dose. In this case, set the date to the 
date of first dose. 
 
If the AE end date day is missing (month and year provided) then set the date to the last day of the 
month. 
 
If the AE end date month is missing (day and year provided) then set the date to the latest calendar 
month consistent with the day. 
 
If the AE end date month is missing (year is provided) then set the date to December 31. 
 
If the year of the AE start date or AE end date are missing, then a query to the site must be made to 
gather additional information. 
o 
If the start date is completely missing, then set the start date to the date of first dose.  If the 
end date is completely missing, then set the end date to the date of latest follow-up. 
o 
If the start date day is missing (month provided), then set the date to the first of the month, 
unless the month is the same as the first dose. In this case, set the date to the date of first 
dose.  If the end date day is missing (month provided), then set the date to the last day of 
the month. 
o 
If the start date month is missing (day provided), then set the month date to January, unless 
the day is the same as the first dose. In this case, set the date to the date of first dose.  If the 
end date month is missing (day provided), then set the date to the latest calendar month 
consistent with the day. 
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o 
If the start date year is missing (day and month provided), then set the year to the year in 
which the patient was first screened, unless the day and month are the same as the first 
dose. In this case, set the date to the date of first dose.  If the end date year is missing (day 
and month provided), then set the date to the latest calendar year in which the patient is 
followed. 
3.5.2.2 Imputation rules for missing or partial medication start/stop dates 
 
 Start dates will not be imputed. 
 
Partial stop dates will be assumed to be the latest possible date consistent with the partial date.  If 
day, month, and year 
 
3.6 General Statistical Conventions 
All statistical procedures will be completed using SAS version 9.4 or higher.  
Unless otherwise stated, all statistical testing will be two-sided and will be performed using a significance 
(alpha) of 0.05. Two-sided 95% confidence intervals (CI) will be provided when relevant.  
Continuous variables will be summarized using descriptive statistics, including number of subjects (n), mean, 
median, standard deviation (SD), minimum, and maximum. Means and medians will be rounded to one more 
decimal place than what is reported in the data. Standard deviations will be rounded to two more decimal 
places than what is reported in the data.  
For categorical variables, summaries will include counts of subjects and percentages. Percentages will be 
rounded to one decimal place.  
For summary purposes, baseline will be defined as the last available pre-dose value. All summaries will be 
presented by treatment group and SARS-CoV-2 serostatus at baseline, unless otherwise specified.  
For any subject who receives an approved COVID19 vaccine after being dosed with INO-4800/placebo, the 
follow-up time will be divided to account for pre- and post- receipt of approved vaccine.  For the main 
analyses and summaries of efficacy, data from the pre- receipt of an approved vaccine period will be used. 
Subject data, including those derived, will be presented in individual subject data listings. Unless otherwise 
stated, unscheduled visit results will be included in date/time chronological order, within patient listings only. 
All listings will be sorted by treatment, subject ID, date/time, and visit. The treatment group, as well as the 
subjects randomized (ITT population).  
3.7 Disposition of Subjects 
Subject disposition will be summarized by treatment arm and overall, as well as SARS-CoV-2 serostatus at 
baseline. The number and percent of subjects screened, screened failure, randomized to each trial arm, 
receiving the first and second dose, early terminations, and completing the study will be summarized. The 
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number of subjects randomized will be used as the denominator for the proportion calculation. The number in 
each analysis population will also be tabulated. Subject disposition will be listed along with inclusion or 
exclusion criteria that were not met for randomization, and the primary reason for early withdrawal will also 
be tabulated. Subject enrollment by site will also be tabulated by treatment arm and overall.   
Treatment misallocations occur when a subject received a different treatment than they were randomized. In 
these cases: 
 
If a subject was randomized but not treated, then they will be reported under their randomized 
treatment group in the subject disposition summaries.  These subjects will be included in the ITT 
population only. 
 
If a subject was treated but not randomized, then by definition they will be excluded from the efficacy 
analyses because randomized treatment is missing but will be included in the ITT population and in the 
Safety population according to the treatment actually received for all safety analyses. 
 
If a subject was randomized but received a different treatment, then the subject will be included 
according to their randomized treatment group for all efficacy analyses in the ITT/mITT population but 
will be excluded from the efficacy analyses in the PP population. These subjects will be included 
according to  treatment they actually received for all safety analyses. 
3.8 Extent of Exposure and Compliance 
3.8.1 Treatment Duration 
Study treatment exposure will be summarized as the number of subjects receiving a total of 1 or 2 doses of 
product and will be presented by treatment group, as well as SARS-CoV-2 serostatus at baseline on the ITT 
mITT, PP, and safety populations.  
3.8.2 Treatment Compliance 
A full course of study product administration consists of 2 doses of vaccine. A summary by treatment group, 
as well as SARS-CoV-2 serostatus at baseline detailing the total number of doses received will be presented 
along with the reason a second dose was not administered or missed. A summary of subjects receiving the 
second dose outside the dosing window, 25 to 31 days post first dose, will be presented. 
3.9 Protocol Deviations/violations and exclusions from analysis sets 
Protocol deviation data will be captured in the clinical trial management system. Extracts of all protocol 
deviations will be reviewed periodically and prior to interim and final analyses. All protocol deviations and the 
exclusion of participants from analysis sets will be identified prior to unblinding through clinical review input 
provided by the sponsor using supportive participant listings provided by the ICON GPHS statistician based 
upon data recorded in the clinical trial management system.  
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Further, deviations from the protocol will be classified as major or minor. Classification of major and minor 
protocol deviations is determined prior to participant enrollment and is outlined in detail in the protocol 
deviation criteria documentation managed by the clinical trial management team. A summary table 
presenting protocol deviations will be generated by treatment arm and SARS-CoV-2 serostatus at baseline 
for the ITT population. Protocol deviations will also be listed.
The number of subjects excluded from mITT, Safety, and Per-Protocol analysis sets and reasons for 
exclusions will be summarized by treatment group and overall, as well as SARS-CoV-2 serostatus at 
baseline. 
Population membership details will be listed, including reason for exclusion from each population (on 
randomized subjects). 
Baseline Characteristics and Demographics
4.1 Baseline Characteristics
Age group (18-50, 
51 years), baseline SARS-CoV-2 serostatus, and the presence of any increased risk 
factor (listed in SAP section 1.2.2) in subjects will be summarized using frequency counts and proportions for 
qualitative results for the ITT and PP populations. 
4.2 Medical History
A summary of prior and concomitant medical conditions and surgical procedures will be presented by system 
organ class (SOC) and preferred term (PT) using the Medical Dictionary for Regulatory Affairs (MedDRA) 
version 23.0, by treatment arm and SARS-CoV-2 serostatus at baseline.
4.3 Demographics
Demographic data will be summarized with descriptive statistics, including mean, standard deviation, 
minimum, median, and maximum values for continuous variables and frequency counts and percentages for 
categorical variables, by treatment arm and SARS-CoV-2 serostatus at baseline.
Age, height, weight, body mass index (BMI) and other continuous demographic variables at baseline will be 
summarized descriptively. Sex, primary race, ethnicity, and other categorical variables will be summarized 
using the ITT and PP populations.
4.4 Prior and Concomitant Medications
Medications used in this study will be coded by using the World Health Organization Drug Dictionary 
Enhanced (WHODrug version Mar2020 B3).
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Prohibited prior and concomitant medications are described in the protocol. This list includes medications for 
the prevention of COVID-19 and influenza vaccinations received within 2 weeks prior to the first dose of IP, 
or within 2 weeks of (before or after) any subsequent dose of IP. 
4.4.1.1 Prior Medications
Prior medications are those that were stopped before the start of the trial. Data for all prior medications will 
be summarized descriptively by ATC class and preferred name using percentages by treatment arm and 
SARS-CoV-2 serostatus at baseline, for the ITT and PP populations. 
4.4.1.2 Concomitant Medications
Concomitant medications include all medications, including vaccines, used by subjects during the course of 
the trial stopped on or after the start of the trial. Data for all concomitant medications will be summarized 
descriptively by ATC class and preferred name using percentages by treatment arm and SARS-CoV-2 
serostatus at baseline, for the ITT and PP populations. 
Efficacy, Immunogenicity, and Safety Analyses
5.1 Primary Analysis
The primary objective of this clinical trial is to evaluate the efficacy of INO-4800 in the prevention of COVID-
19 disease in subjects who are SARS-CoV-2 negative at baseline. 
5.1.1 Primary Endpoint
The primary endpoint is the first occurrence of virologically-confirmed COVID-19 disease with onset during a 
surveillance period from 14 days after completion of the 2-dose regimen up to 12 months post-dose 2 (EOS) 
in subjects who are SARS-CoV-2 seronegative at baseline.
An independent, blinded Endpoint Adjudication Committee (EAC) will review and confirm COVID-19 cases.
5.1.2 Statistical Hypothesis for the Primary Efficacy Endpoint
The primary hypothesis is that INO-4800 will be efficacious relative to placebo (vaccine efficacy > 30%)
among baseline SARS-CoV-2 seronegative subjects. The null hypothesis given below will be tested against 
the alternative hypothesis:
H0: p 
70/(.70+k) 
                                                                H1: p < .70/(.70+k)
where p is the true proportion of subjects with disease who receive INO-4800 relative to the total number of 
subjects with disease, and k is the total amount of follow-up time in the placebo group divided by the total 
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amount of follow-up time in the INO-4800 group. 
-up time is 
either: 
 
the date of first disease diagnosis  date of the start of surveillance period +1 (for subjects who are 
cases), or 
 
the date of last follow-up  date of the start of surveillance period +1 (for subjects who are non-cases). 
However, the trial has been terminated, and therefore, this hypothesis test will not be conducted.  A 
confidence interval (detailed in the following section) will be used for analysis. 
5.1.3 Analysis of Primary Efficacy 
The Clopper-Pearson method will be used to compute the 95% confidence interval for the primary efficacy 
analysis. The outcome variable will be incidence of virologically-confirmed COVID-19 disease starting 14 
days after completion of the 2-dose regimen until 12 months post-dose 2 (EOS). 
This methodology is based on the assumption that the number of subjects who are cases in the INO-4800 
and placebo group foll
v 
c, respectively, and conditional on 
total number of subjects with cases, t, the number of subjects who are cases in the INO-4800 group follows a 
v
v
c)).  The relationship between p and efficacy is: efficacy = 
(1-(1+k)p)/(1-p).   The confidence interval for efficacy is (1-(1+k)UBp)/(1-UBp), (1-(1+k)LBp)/(1-LBp), where 
UB and LB are the Clopper-Pearson upper and lower limits for the proportion, respectively. 
The efficacy time frame is defined by symptoms beginning at any time starting from 14 days after Dose 2 and 
ending 12 months after Dose 2. Subjects identified as cases that started prior to this time point will be 
excluded. Subjects with multiple instances meeting the case definition will be counted only once, using the 
first such instance.  
The PP population among those who are baseline SARS-CoV-2 seronegative will be primary for the analysis 
of efficacy in this trial.  
The following sample SAS code will be used to construct the exact binomial method of Clopper-Pearson: 
proc freq data = <DATASET>;  
tables <OUTCOME> /binomial(CL= CLOPPERPEARSON); 
exact binomial; 
run; 
5.1.4 Sensitivity Analysis 
Efficacy analysis using the mITT population will also be conducted counting cases from 14 days post dose 1 
as a supportive analysis. The ITT population will also be used for a supportive analysis counting cases 
starting from randomization. 
5.1.5 Changes from Protocol-Specified Primary Efficacy Analysis 
  Because the trial has been terminated, neither the interim nor the final hypothesis testing will be conducted. 
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5.2 Secondary Efficacy and Immunogenicity Analyses 
No secondary efficacy or immunogenicity endpoints will be analyzed. 
5.3 Exploratory Efficacy and Immunogenicity Analyses 
No exploratory efficacy or immunogenicity endpoints will be analyzed. 
5.4 Safety Analysis 
The safety endpoints include: 
 
The incidence of solicited and unsolicited injection site reactions.  
 
The incidence of solicited and unsolicited systemic adverse events (AEs) by system organ class 
(SOC), preferred term (PT), severity, and relationship to investigational product.  
 
The incidence of serious adverse events (SAEs).  
 
The incidence of adverse events of special interest (AESIs). 
 
The incidence of all-cause mortality. 
Safety analyses will be conducted on the safety population and will be performed for all safety variables 
specified below. All safety data will be summarized and analyzed by treatment group and SARS-CoV-2 
serostatus at baseline.  
The safety analyses of changes from baseline to a specific time point in safety variables (e.g., laboratory 
parameters, vital signs, ECG) will only include subjects from the safety population who have data available 
from both the baseline and the time point under consideration unless otherwise specified.  
5.4.1 Adverse Events and Deaths 
All AEs will be classified by Primary System Organ Class (SOC) and Preferred Term (PT) according to the 
Medical Dictionary for Regulatory Activities (MedDRA) Version 23.0 or higher.  
In summaries by SOC and PT, AEs will be sorted by descending frequency within each SOC and PT 
according to the total number of events. In summaries by PT, AEs will be sorted by descending frequency 
according to the total number of events.  
AEs will be classified as pre-treatment or treatment emergent (TEAE) defined as follows: 
 
Pre-treatment: any AE that started before the first dose date of the study treatment 
 
TEAE: Any AE that was newly developed at or after the first dose date of study treatment. 
Details for imputing missing or partial start dates of AEs are described in SAP section 3.5.2.1. 
AE summaries will include the following: 
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All TEAEs 
 
Related TEAEs (AE will be defined as related if causality is either probably, possible, or definite) 
 
TEAEs by maximum severity, including 
 
 
Medically Attended AEs 
 
TEAEs leading to treatment discontinuation 
 
Serious TEAEs 
 
TEAEs leading to death 
All AEs, including injection-site reactions, will be summarized among the Safety Population by frequency per 
treatment arm. These frequencies will be presented overall and separately by dose, and will depict overall, 
by system organ class and by preferred term, the percentage of subjects affected. In addition, an overall 
summary for categories above will be prepared by treatment arm.  
Where a subject has the same AE, based on preferred terminology, reported multiple times in the treatment 
period, the subject will only be counted once at the preferred terminology level in AE frequency.  
Where a subject has multiple AEs within the same system organ class in the treatment period, the subject 
will only be counted once at the system organ class level in AE frequency.  
 Adverse events by severity and separately by relationship will be summarized based on the most intense 
event during the treatment period and strongest relationship to study treatment, respectively. 
The main summary of safety data will be based on events occurring within 30 days of any dose. For this 
summary, the frequency of preferred term events will be compared between study arms with risk differences 
and 95% confidence intervals, using the method of Miettinen and Nurminen. As this analysis will use many 
event categories, and produce many confidence intervals, caution should be exercised when interpreting 
these confidence intervals. Separate summaries will be based on events occurring within 7 days of any dose 
and regardless of when they occurred. 
The following sample SAS code will be used to construct confidence intervals of the risk difference with the 
method of Miettinen and Nurminen: 
proc freq data = <DATASET>;  
tables armcd * <OUTCOME> / riskdiff(CL=(MN)); 
run;  
5.4.2 Vital signs 
Measurements for vital signs (pulse, blood pressure, SpO2, temperature, respiratory rate) as well as 
changes from baseline will be summarized with descriptive statistics. Visit values will be calculated as the 
mean of all available measurements per parameter.  
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5.4.3 Changes from Protocol-Specified Safety Analysis 
Not applicable.
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Appendices
6.1 Appendix A
Phase 3 Schedule of Events
Tests and assessments
Sc
D0
Tel 
#1
Wk
4
Wk6
Tel
#2-6
Wk 
18
Tel
#7-11
Wk 
30
Tel
#12-13
Wk4
2
Tel
#14-16
Wk
56
Illness
Illness
Informed Consent
X
Inclusion/Exclusion Criteria
X
Medical history
X
X
Demographics
X
Socio-behavioral Assessment
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examb
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
Xn
Xn
Height and Weight
X
HIV Serology
X
Pregnancy Testc
X
X
X
INO-4800 or Placebo + EPd
X
X
Download EP Datae
X
X
Adverse Eventsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cellular Samplesg
X
X
X
X
Xr
X
Humoral Samplesh
X
X
X
X
Xr
X
SARS-CoV-2 Serologyi
X
X
X
X
X
X
X
X
X
SARS-CoV-2 RT-PCR 
(Nasopharyngeal swabs)
X
Xo
Distribute Diaryp
X
X
Review/Collect Diaryq
X
X
X
a.
Screening assessment occurs from -30 days to -1 day of Day 0. Screening and Day 0 visits may be combined if eligibility is able to be confirmed prior to dosing. If so, all assessments for
Screening and Day 0 must be performed at the combined visit.
b.
Full physical examination only at Screening and Day 393 (or EOS). Targeted physical exam at other indicated visits.
c.
In women of childbearing potential. Urine pregnancy test at all indicated visits.
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d. 
Intradermal injection(s) in skin preferably over deltoid region, or alternately over anterolateral quadriceps region, followed by EP at Day 0 and Day 28. 
e. 
Following administration of INO-4800 or placebo, EP data will be downloaded from the CELLECTRA® 2000 device and provided to Inovio. 
f. 
AEs to be collected from time of consent to Day 56; SAEs, MAAEs, and AESIs to be collected from time of consent to EOS. 
g. 
On Day 0, cellular sampling requires 64 mL of whole blood prior to 1st dose. At all other time points, collect 32 mL of whole blood. Cellular samples will be collected at selected clinical sites 
(estimated to include 711 subjects) 
h. 
On Day 0, humoral sampling requires a total of 17 mL of whole blood (two 10-mL red top serum collection tubes, each 8.5 mL of whole blood, to produce four serum aliquots of 2 mL each). 
At all other time points, collect 8.5 mL of whole blood in a single 10-mL red top serum collection tube to produce two serum aliquots of 2 mL each.  
i. 
SARS-CoV-2 antibody. 
j. 
The Day 0 RT-PCR results will not be required prior to dosing on that day. 
k. 
Day 42 visit must occur at least 10 days after Day 28 visit. 
l. 
-
-19 is 
at a home 
visit and should be completed within 3 days of symptom onset or within 3 days of a positive result of a SARS-CoV-2 test.  
m. 
For subjects with confirmed SARS-CoV-2 infection during the trial, a convalescent visit should be scheduled approximately 28 days after symptom onset, or in the absence of symptoms, 
the date of positive SARS-CoV-2 test. If acute symptoms are ongoing the site should follow up with the subject via phone call or unscheduled visit after symptom resolution or stabilization 
n. 
Vital signs to be performed at COVID-19 assessment and convalescent visits include temperature, respiration rate, heart rate and oxygen saturation.   
o. 
Genotyping may also be performed on sample(s) collected at the COVID-19 assessment visit.  
p. 
Diaries to be used at selected sites only (estimated to include 711 subjects). 
q. 
Diary should be reviewed at the 14-day post-dose phone call or visit and collected at the next in-office visit. 
r. 
When possible, cellular and humoral immunology samples will be collected. Cellular samples will be collected at selected sites only. 
 
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