A Prospective, Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of VGX-3100 Delivered Intramuscularly Followed by Electroporation With CELLECTRA™-5PSP for the Treatment of HPV-16 and/or HPV-18 Related High Grade Squamous Intraepithelial Lesion (HSIL) of the Cervix
Phase: PHASE3
Conditions: Cervical Dysplasia, Cervical High Grade Squamous Intraepithelial Lesion, HSIL
Sponsor: Inovio Pharmaceuticals

Official Title: 
NCT Number: 
NCT03185013
Document Dates:
Protocol Version 5.0: 20 November 2019 
Protocol Version 4.0: 29 March 2018 
Protocol Version 3.0: 28 September 2016 
Protocol Version 2.1: 10 June 2016 
Protocol Version 2.0: 06 June 2016
A Prospective, Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of 
VGX-3100 Delivered Intramuscularly Followed by Electroporation With 
CELLECTRA™-5PSP for the Treatment of HPV-16 and/or HPV-18 Related High 
Grade Squamous Intraepithelial Lesion (HSIL) of the Cervix

16.1.1 
Protocol and Protocol Amendments 
This section includes the following: 
Protocol version 2.0, dated 06Jun2016  
Protocol version 2.1, dated 10Jun2016  
Protocol version 3.0, dated 23Sept2016  
Protocol version 4.0, dated 29Mar2018  
Protocol version 5.0, dated 20Nov2019  
Protocol Administrative Memo 1, dated 10Sept2018 
Protocol Administrative Memo 2, dated 29Apr2019 
Protocol Administrative Memo 3, dated 26Mar2021 
1

 
 
 
 
HPV-301 
REVEAL I Trial  
(Randomized Evaluation of VGX-3100X and Electroporation for the Treatment of 
Cervical HSIL) 
 
A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
PHASE 3 STUDY OF VGX-3100X DELIVERED INTRAMUSCULARLY FOLLOWED 
BY ELECTROPORATION WITH CELLECTRA™ 5PSP FOR THE TREATMENT OF 
HPV-16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS INTRAEPITHELIAL 
LESION (HSIL) OF THE CERVIX   
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
U.S. BB-IND #13683 
 
Version 2.0 
06 June 2016 
 
 
 
 
 
 
 
• 
• 
VIO 
PHARMACEUTICALS 
2

 
A P R O S P E C TI V E, R A N D O MI Z E D, D O U B L E -B LI N D, P L A C E B O -C O N T R O L L E D P H A S E 3  
S T U D Y O F V G X -3 1 0 0 X D E LI V E R E D I N T R A M U S C U L A R L Y F O L L O W E D B Y 
E L E C T R O P O R A TI O N WI T H C E L L E C T R A ™ 5 P S P F O R T H E T R E A T M E N T O F H P V - 1 6 
A N D/ O R H P V - 1 8 R E L A T E D HI G H G R A D E S Q U A M O U S I N T R A E PI T H E LI A L L E SI O N 
(H SI L ) O F T H E C E R VI X   
S h ort Title:   
Ra n d o mize d  E val uati o n  of  V G X -3 1 0 0 X  a n d  Electr o p orati o n  f or  t he                  
treat me nt of Cer vical H SI L ( R E V E A L I) 
 
Bi ol o gic al P r o d uct:    
 V G X - 3 1 0 0 X 
 
P r ot oc ol N u m ber:    
 H P V - 3 0 1 
 
S p o ns or:  
 I n o vi o P har mace uticals, I nc. 
 
 6 6 0 W. Ger ma nt o w n Pi ke, S uite 1 1 0 
 
 Pl y m o ut h Meeti n g, P A 1 9 4 6 2 
 
P ri nci p al I n vesti g at or:   
 
, M. D., M. S. 
 
 
 
 
 R ut gers Ne w Jerse y Me dical Sc h o ol  
 
 1 8 5 S. Ora n ge A ve., M S B E- 5 0 6 
 
 Ne war k, NJ 0 7 1 0 3 
 
Me dic al M o nit or:  
 
, M. D., P h. D. 
 
 
 
 
 I n o vi o P har mace uticals, I nc. 
 
 
 
C O N FI D E N TI A L  
T he i nf or m ati o n i n t his d oc u me nt is c o nsi dere d pri vile ge d a n d c o nfi de nti al b y I n o vi o P h ar m ace utic als a n d m a y n ot be 
discl ose d t o ot hers e xce pt t o t he e xte nt necess ar y t o o bt ai n I nstit uti o n al Re vie w B o ar d/ Et hics c o m mittee a p pr o v al a n d 
i nf or me d c o nse nt, or as re q uire d b y l oc al re g ul at or y a ut h orities. Pers o ns t o w h o m t his i nf or m ati o n is discl ose d m ust 
be i nf or me d t h at t his i nf or m ati o n is pri vile ge d a n d c o nfi de nti al a n d t h at it s h o ul d n ot be f urt her discl ose d wit h o ut t he 
w ritte n  per missi o n  of  I n o vi o  P h ar m ace utic als.  A n y  s u p ple me nt al  i nf or m ati o n  a d de d  t o  t hi s  d oc u me nt  is  als o 
c o nfi de nti al  a n d  pr o priet ar y  i nf or m ati o n  of  I n o vi o  P h ar m ace utic als  a n d  m ust  be  ke pt  i n  c o nfi de nce  i n  t he  s a me 
m a n ner as t he c o nte nts of t his d oc u me nt.  
 
3
P P D
P P D
P P D
P P D

 
SUMMARY OF CHANGES  
 
The following is a list of significant protocol changes from HPV-301 protocol version 1.0 dated 26 Apr 
2016 to HPV-301 protocol version 2.0 dated 06 June 2016. All other changes are administrative and do 
not significantly affect the safety of subjects, study scope, or scientific quality of the protocol.  
1. Added rationale for selection of non-frozen formulation for phase 3 study 
2. Added additional background information to Section 2 Study Design 
3. Clarified inclusion and exclusion criteria  
4. Administrative changes made throughout the protocol for clarification  
 
 
 
4

 
PROTOCOL ACKNOWLEDGEMENT  
 
 
I have read this Protocol and agree that it contains all necessary details for carrying out the study 
described. I understand that it must be reviewed by the Institutional Review Board or Independent Ethics 
Committee overseeing the conduct of the study and approved or given favorable opinion before 
implementation. 
 
The signature of the Investigator below constitute his/her approval of this protocol and provide the 
necessary assurances that this study will be conducted according to the Declaration of Helsinki, ICH-
GCP guidelines, local legal and regulatory requirements as well as to all stipulations of the protocol in 
both the clinical and administrative sections, including statements regarding confidentiality. 
 
 
 
__________________________________________________________ 
Investigator – Signature                      Date (DD/MMM/YYYY)       
 
 
________________________________________ 
Investigator – Printed Name        
 
 
 
 
 
Site Number: ___________________________________   
 
Site Name: _____________________________________ 
 
 
5

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

4.2 
Exclusion Criteria ........................................................................................................................ 39 
4.3 
Discontinuation/Withdrawal of Study Subjects .......................................................................... 40 
4.3.1 Criteria for Discontinuation of Investigational Product .................................................... 40 
4.3.2 Criteria for WithdrawAl from the Study ........................................................................... 41 
4.3.3 Sponsor Notification of Discontinuation/ Withdrawal ..................................................... 41 
4.3.4 Reason for Discontinuation/Withdrawal........................................................................... 41 
5 Study Treatment .................................................................................................................................. 42 
5.1 
Investigational Products .............................................................................................................. 42 
5.2 
Blinding ....................................................................................................................................... 42 
5.3 
Packaging and Labeling of investigational product .................................................................... 43 
5.4 
Handling of investigational product ............................................................................................ 43 
5.5 
Dispensing of Investigational Product ........................................................................................ 43 
5.6 
Investigational product Accountability ....................................................................................... 44 
5.7 
Return and Destruction of  Investigational Product .................................................................... 44 
5.8 
Investigational Device ................................................................................................................. 44 
5.9 
Use of investigational device ...................................................................................................... 46 
5.10 Packaging and Labeling of Investigational Device ..................................................................... 47 
5.11 Handling of investigational device .............................................................................................. 47 
5.12 Investigational Device Accountability ........................................................................................ 47 
5.13 Return of Investigational Devices ............................................................................................... 48 
6 Study Procedures and Treatments ..................................................................................................... 48 
6.1 
Before Treatment Procedures ...................................................................................................... 48 
6.1.1 Screening Evaluations....................................................................................................... 48 
6.2 
During Treatment Procedures by Visit ........................................................................................ 49 
6.2.1 Day 0 ................................................................................................................................. 49 
6.2.2 8-14 Days Post Dose 1 Phone call .................................................................................... 50 
6.2.3 Week 4 .............................................................................................................................. 50 
6.2.4 8-14 Days Post Dose 2 ...................................................................................................... 51 
6.2.5 Week 12 ............................................................................................................................ 51 
6.2.6 8-14 Days Post Dose 3 ...................................................................................................... 51 
6.2.7 Week 15 ............................................................................................................................ 51 
6.2.8 Week 28 ............................................................................................................................ 52 
6.2.9 Week 36 ............................................................................................................................ 52 
6.2.10 Week 40 Phone call .......................................................................................................... 53 
6.2.11 Week 62 ............................................................................................................................ 53 
6.2.12 Week 88 ............................................................................................................................ 53 
6.3 
Evaluations and Procedures ........................................................................................................ 53 
7

6.3.1 Informed Consent ............................................................................................................. 53 
6.3.2 Assignment of Subject Identification Numbers ................................................................ 54 
6.3.3 Safety Evaluations ............................................................................................................ 54 
6.4 
Injection and Electroporation (EP) .............................................................................................. 56 
6.4.1 Risks of Treatment Procedures ......................................................................................... 56 
6.4.2 Management of Anxiety and Pain due to Treatment ........................................................ 57 
6.5 
Assessment of Laboratory Abnormalities ................................................................................... 57 
6.6 
Assessment of Clinical Study Adverse Events............................................................................ 57 
6.7 
Assessment of Injection Site Reactions ...................................................................................... 58 
6.8 
Assessment of Patient Reported Outcomes ................................................................................. 58 
6.9 
Peripheral Blood Immunogenicity Assessments ......................................................................... 59 
6.10 Tissue Immunogenicity Assessment ........................................................................................... 59 
6.11 HLA Typing ................................................................................................................................ 59 
6.12 Pap Smears and HPV Testing ..................................................................................................... 60 
6.13 Colposcopy and Cervical Biopsies .............................................................................................. 60 
6.13.1 Ectocervical Biopsies ........................................................................................................ 60 
6.13.2 Unscheduled Biopsies ....................................................................................................... 61 
6.14 Concomitant Medications/Treatments ........................................................................................ 61 
6.15 Restrictions .................................................................................................................................. 61 
6.15.1 Prohibited Concomitant Medications and Treatments ...................................................... 61 
6.15.2 Other Restrictions ............................................................................................................. 61 
7 Evaluation of Safety and Management of Toxicity ........................................................................... 62 
7.1 
Safety Parameters ........................................................................................................................ 62 
7.1.1 Adverse Events: ................................................................................................................ 62 
7.1.2 Serious Adverse Events: ................................................................................................... 62 
7.1.3 Unexpected Adverse Drug Reactions and Expedited Reporting ...................................... 63 
7.1.4 Unanticipated (Serious) Adverse Device Effect (UADE) ................................................ 64 
7.1.5 Assessing Severity (Intensity) .......................................................................................... 64 
7.1.6 Causal Relationship of Clinical Material to Adverse Events ............................................ 65 
7.1.7 Abnormal Laboratory Value ............................................................................................. 65 
7.1.8 Post-Study Reporting Requirements ................................................................................. 66 
7.1.9 Procedures for Documenting Pregnancy During Study .................................................... 66 
7.2 
Methods and Timing of the Collection and Recording of Safety Data ....................................... 66 
7.3 
Safety and Toxicity Management ............................................................................................... 67 
7.3.1 Events Requiring Expedited Reporting ............................................................................ 67 
7.3.2 Stopping Rules (Criteria for Pausing of Study) ................................................................ 67 
8

8 Statistical Analysis Plan ...................................................................................................................... 68 
8.1 
General Considerations ............................................................................................................... 68 
8.2 
Randomization and Blinding ....................................................................................................... 68 
8.3 
Sample Size/Power ...................................................................................................................... 69 
8.4 
Analyses Populations .................................................................................................................. 69 
8.5 
Subject Disposition ..................................................................................................................... 69 
8.6 
Demographic and Other Baseline Characteristics ....................................................................... 69 
8.7 
Medical History ........................................................................................................................... 69 
8.8 
Prior and Concomitant Medications ............................................................................................ 69 
8.9 
Efficacy Analyses ........................................................................................................................ 70 
8.10 Immunogenicity Analyses ........................................................................................................... 71 
8.11 Safety Analyses ........................................................................................................................... 71 
8.11.1 Adverse Events ................................................................................................................. 71 
8.11.2 Laboratory Data ................................................................................................................ 71 
8.12 Vital Signs ................................................................................................................................... 71 
8.13 Physical Examination .................................................................................................................. 72 
8.14 Patient Reported Outcomes ......................................................................................................... 72 
8.15 Missing Values ............................................................................................................................ 72 
8.16 Interim Analysis .......................................................................................................................... 72 
9 Data Collection, Monitoring and Reporting ..................................................................................... 72 
9.1 
Confidentiality and Privacy ......................................................................................................... 72 
9.2 
Source Documents ...................................................................................................................... 73 
9.3 
Records Retention ....................................................................................................................... 73 
9.4 
Safety and Quality Monitoring .................................................................................................... 73 
9.4.1 Data & Safety Monitoring Board ...................................................................................... 73 
9.4.2 Pathology Adjucation Committee ..................................................................................... 74 
9.4.3 Clinical Monitoring .......................................................................................................... 74 
9.5 
Adverse Experience (AE) Reporting ........................................................................................... 75 
9.5.1 Study Reporting Period of Adverse Events ...................................................................... 75 
9.5.2 Study Reporting Period of Serious Adverse Events ......................................................... 75 
9.5.3 Notification of SerioUs Adverse Events ........................................................................... 76 
9.5.4 Reporting of Device Related Complaints ......................................................................... 76 
9.6 
Study Discontinuation ................................................................................................................. 77 
10 Ethics 77 
10.1 Investigator and Sponsor Responsibilities .................................................................................. 77 
10.2 Institutional Review Board or Institutional Ethics committee (IRB/IEC) .................................. 77 
10.3 Office of Biotechnology Activities (OBA) ................................................................................. 77 
11 Protection of Human Subjects ............................................................................................................ 78 
9

11.1 Compliance with Informed Consent Regulations ....................................................................... 78 
11.2 Compliance with IRB/IEC Requirements ................................................................................... 78 
11.3 Compliance with Good Clinical Practice .................................................................................... 78 
11.4 Compliance with Electronic Records/Signatures Regulations (21CFR Part 11) ........................ 78 
11.5 Compliance with Protocol ........................................................................................................... 78 
11.6 Changes to the Protocol............................................................................................................... 78 
12 Financing and Insurance ..................................................................................................................... 78 
13 Publication Policy ................................................................................................................................ 79 
14 References............................................................................................................................................. 80 
15 Appendices ........................................................................................................................................... 82 
15.1 APPENDIX A:   Subject Diary Card .......................................................................................... 83 
15.2 APPENDIX B:  Error Reporting Form ....................................................................................... 98 
15.3 APPENDIX C:  Guidelines for Colposcopy, Biopsy, and Surgical Excision ............................. 99 
15.4 Appendix D: EQ-5D-5L Health Questionnaire ......................................................................... 101 
15.5 Appendix E:  SF-36 v2 Questionnaire ...................................................................................... 104 
 
 
 
 
 
10

I 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AIS 
Adenocarcinoma-in-situ 
AGC 
Atypical Glandular Cell 
ASC-H  
Atypical Squamous Cells, cannot exclude High grade 
squamous intraepithelial lesion 
ASC-US  
Atypical squamous cells of undetermined significance 
BMI 
Body Mass Index 
CEF 
Cytomegalovirus, Epstein Barr Virus and Influenza 
CFR 
Code of Federal Regulations 
CIB 
Clinical Investigator’s Brochure 
CIN 
Cervical Intraepithelial Neoplasia 
CKC 
CMI 
Cold knife conization 
Cell-mediated immunity 
CMR 
Complete Metabolic Response 
CMV 
Cytomegalovirus 
CRF 
Case Report Forms 
CPK 
Creatine Phosphokinase 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTL 
Cytotoxic T-cells 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of Acquired Immunodeficiency Syndrome  
DNA 
Deoxyribonucleic Acid 
ECC 
Endocervical Curettage 
EP 
DLT 
Electroporation with CELLECTRA™ 5PSP 
Dose Limiting Toxicity 
DSMB 
Data & Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EP 
Electroporation 
ERER 
Events Requiring Expedited Reporting 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISpot 
Enzyme Linked Immunosorbent Spot-forming Assay 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HCG 
Human Chorionic Gonadotropin 
HSIL 
High grade squamous intraepithelial lesion 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPV 
HPV 16/18 
Human Papillomavirus 
HPV-16 and/or HPV-18 
IC 
Intracavitary 
11

ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IFN-γ 
Interferon Gamma 
IL-12 
Interleukin 12 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IXRS 
Interactive Response System 
LAST 
Lower Anogenital Squamous Terminology 
LEEP 
Loop Electrosurgical Excision Procedure 
LLETZ 
LSIL 
Large Loop Excision of Transformation Zone 
Low Grade Squamous Intraepithelial Lesion 
MedDRA® 
Medical Dictionary for Drug Regulatory Affairs 
mITT 
Modified Intent to Treat 
NILM 
Negative for intraepithelial lesion or malignancy 
NIH 
National Institutes of Health 
OP 
Principal Investigator 
Investigator 
Oropharyngeal  
Lead Investigator for overall study activities 
Lead Investigator for individual site(s) 
PAC  
Pathology Adjudication Committee 
PBMC 
Peripheral Blood Mononuclear Cells 
PRO 
Patient Reported Outcomes 
PE 
Physical exam 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SARS 
SDC 
Severe Acute Respiratory Syndrome 
Subject Diary Card 
SID 
Subject Identification   
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
sWFI 
Sterile Water for Injection 
TNF 
Tumor Necrosis Factor 
ULN 
Upper Limit of Normal 
WOCBP 
Women of Childbearing Potential 
 
 
12

II CLINICAL PROTOCOL SYNOPSIS 
 
Title of Study:  A Prospective, Randomized, Double-blind, Placebo-Controlled Phase 3 Study of 
VGX-3100X Delivered Intramuscularly followed by Electroporation with CELLECTRA™ 5PSP 
for the Treatment of HPV-16 and/or HPV-18 related High Grade Squamous Intraepithelial Lesion 
(HSIL)0F1 of the Cervix 
Estimated Number of Study Centers and Countries/Regions:  Approximately 100 Sites  in 
up to 25 Countries 
Study Phase: 3 
Primary Hypothesis:  Three 6 mg doses of VGX-3100X (DNA Plasmids encoding E6 and E7 
proteins of HPV-16 and HPV-18) delivered intramuscularly (IM) followed by electroporation 
(EP) with CELLECTRA™ 5PSP to adult women with histologically confirmed HSIL[Cervical 
Intraepithelial Neoplasia (CIN) 2, CIN 3] of the cervix, associated with HPV-16 and/or HPV-18 
will result in a higher percentage of women with histopathological regression of cervical HSIL 
lesions to no evidence of cervical HSIL and virologic clearance of HPV-16 and/or HPV-18 
compared to placebo delivered IM followed by EP with CELLECTRA™ 5PSP at the Week 36 
visit  
Study Drug Dose 
6 mg (1 ml) 
Administration 
Intramuscular injection followed by EP with the CELLECTRA™ 5PSP 
device 
Schedule 
Day 0, Week 4, and Week 12 study visits 
No. of Subjects 
Approximately 165 subjects will be randomized in a 2:1 ratio to receive 
VGX-3100X or placebo 
Study Duration 
88 weeks 
Primary Objective 
Determine the efficacy of VGX-3100X compared with placebo with 
respect to combined histopathologic regression of cervical HSIL and 
virologic clearance of HPV-16 and/or HPV-18 
Primary Endpoint 
Proportion of subjects with no evidence of  cervical HSIL on histology 
(i.e. biopsy or excisional treatment) and no evidence of HPV-16 and/or 
HPV-18 in ThinPrepTM cervical samples by type specific HPV testing 
at Week 36 visit 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of 
VGX-3100X delivered IM followed by EP 
with CELLECTRA™ 5PSP 
1a. Incidence and severity of local and 
systemic events for 7 and 28 days 
following each investigational treatment  
and for the duration of the study (through 
Week 88 visit) 
 
 
 
1 Terminology based on 2012 consensus recommendation on Lower Anogenital Squamous Terminology (LAST) from the 
American Society of Colposcopy and Cervical Pathology (ASCCP) and the College of American Pathologists (CAP) 
13

Secondary Objectives 
Associated Secondary Endpoints 
 
1b. Incidence and severity of serious adverse 
events (SAE) and Unanticipated [Serious] 
Adverse Device Effects (UADE) for 7 and 
28 days following each investigational 
treatment and for the duration of the study 
(through Week 88 visit) 
2. Determine the efficacy of VGX-3100X 
compared with placebo as measured by 
histopathologic regression of cervical 
HSIL  
2. Proportion of subjects with no evidence of  
cervical HSIL  on histology (i.e. biopsies or 
excisional treatment) at Week 36 visit 
3. Determine the efficacy of VGX-3100X 
compared with placebo as measured by 
virologic clearance of HPV-16 and/or 
HPV-18 
3. Proportion of subjects with no evidence of 
HPV-16 and/or HPV-18 in ThinPrepTM 
cervical samples  by type specific HPV 
testing at Week 36 visit 
4. Determine the efficacy of VGX-3100X 
compared with placebo as measured by 
complete histopathologic regression of  
cervical HSIL to normal 
4. Proportion of subjects with no evidence of 
Low grade squamous intraepithelial 
lesion (LSIL) or HSIL (i.e.  no evidence of 
CIN1, CIN2 or CIN3) on histology (i.e. 
biopsies or excisional treatment) at Week 36 
visit 
5. Determine the efficacy of VGX-3100X 
compared with placebo as measured by both 
complete histopathologic regression of  
cervical HSIL to normal and virologic 
clearance of HPV-16 and/or HPV-18 
5. Proportion of subjects with no evidence of 
LSIL or HSIL (i.e. no evidence of CIN1, 
CIN2 or CIN3 on biopsies or excisional 
treatment) on histology (i.e. biopsies or 
excisional treatment) and no evidence of 
HPV-16 and/or HPV-18  by type specific 
HPV testing at Week 36 visit 
6. Determine the efficacy of VGX-3100X 
compared with placebo as measured by 
histopathologic non-progression 
6. Proportion of subjects with no progression 
of cervical HSIL from baseline on 
histology (i.e. biopsies or excisional 
treatment) at Week 36 visit 
7. Determine the humoral and cellular immune 
response following administration of VGX-
3100X compared with placebo at post dose 
3, Week 36 and Week 88 visits compared to 
baseline  
 
 
7a. Levels of serum anti-HPV-16 and anti-
HPV-18 antibody concentrations at 
baseline, Week 15, 36, and 88 visits 
7b. Interferon-γ ELISpot response magnitudes 
at baseline, Weeks 15, 36, and 88 visits 
7c. Flow Cytometry response magnitudes at 
baseline and Week 15 visits 
 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Evaluate tissue immune responses to VGX-
3100X in cervical samples 
1. Assessment of markers including but not 
limited to CD8+ and FoxP3+ infiltrating 
cells. Additional assessments may include 
visualization of Granulysin, Perforin, 
14

Exploratory Objectives 
Associated Exploratory Endpoints 
CD137, CD103 and PD-L1 in cervical 
tissue as sample allows.  Markers listed 
here may change as new relevant 
information becomes available 
2. Describe the clearance of HPV-16 and/or 
HPV-18 infection from anatomic locations  
outside the cervix 
2. Proportion of subjects who have cleared 
HPV-16 and/or HPV-18 on specimens from 
outside the cervix (inclusive of oropharynx, 
vagina and peri-anus) at Week 36 Visit 
3. Evaluate effect of HLA type on efficacy 
 
3. HLA (per-locus and per-allele basis) in 
conjunction with histologic regression of  
cervical HSIL at Week 36 visit 
4. Describe 
association 
of 
previous 
colposcopy, cytology and HPV testing 
results with histologic regression at Week 
36   
4. Colposcopy, cytology, and HPV test results 
at Weeks 15 and 28 visits in conjunction 
with histologic regression of cervical HSIL 
at Week 36 visit 
5. Describe 
the 
durability 
of 
virologic 
clearance of HPV-16 and/or HPV-18 for 
subjects 
treated 
with 
VGX-3100X 
compared with those treated with placebo 
5. Proportion of subjects with no evidence of 
HPV-16 and/or HPV-18 by type specific 
HPV testing at Weeks 62 and 88 visits 
6. Describe the patient-reported outcomes for 
subjects treated with VGX-3100X 
6. The following two questionnaires: Short 
Form Health Survey, version 2 (SF-36v2TM) 
and EQ-5D-5LTM will be self-administered 
prior to first dose (i.e. Day 0), following 
each dose, and at Weeks 28, 40 and 88 to 
measure score(s). 
 
Study Design:   
This Phase 3 study design is based upon the Phase 2b study design and results.  HPV-301 is a 
prospective, randomized, double-blind, placebo controlled Phase 3 study to determine the 
efficacy, safety, and tolerability of VGX-3100X administered by IM injection followed by EP 
delivered with CELLECTRA™ 5PSP in adult women with histologically confirmed cervical HSIL 
(CIN2, CIN3) associated with HPV-16 and/or HPV-18 (HPV 16/18). The composite primary 
endpoint is histologic regression of cervical HSIL, and clearance of the underlying HPV 16/18 
infection. A sample of approximately 165 subjects will be randomized to receive either 6 mg (in 
1 ml) VGX-3100X or placebo, each IM followed by EP, in a 2:1 ratio. This sample size provides 
90% power to declare VGX-3100X superior to placebo, assuming, based upon Phase 2b study 
results, that the true proportion of subjects whose lesion(s) regress and whose HPV 16/18 clears 
is 40% and 15% for VGX-3100X and placebo, respectively, and assuming 90% evaluability from 
randomization.  
To be eligible for the study, women age 18 years and above must consent to participate and have 
biopsy/biopsies of the cervical lesion(s) at the time of screening. The biopsy slides are sent to a 
Pathology Adjudication Committee (PAC) in a blinded manner to establish the presence of 
15

cervical HSIL (CIN2, CIN3) prior to enrollment. Subjects must also have a cervical specimen test 
positive for HPV 16/18 by Cobas® HPV test to be eligible for participation in the study.  
All eligible subjects will receive three doses of VGX-3100X or placebo administered IM followed 
immediately by EP with the CELLECTRA™ 5PSP device. The first study treatment is 
administered on Day 0, the second at Week 4, and the third (final) study treatment is administered 
at Week 12. The first dose is administered as soon as possible following confirmation of the 
cervical HSIL diagnosis and cervical sample positive for HPV 16/18 but no more than 10 weeks 
following collection of the subject’s biopsy specimen used for diagnosis by the PAC during 
screening.  
Subjects are randomized in a stratified manner according to (a) the CIN severity observed in the 
biopsy specimens at screening (i.e. CIN2 vs. CIN3), (b) BMI category (≤25 vs. >25 kg/m2), and 
(c) age category (<25 years vs. ≥25 years). To ensure CIN2 disease is not over-represented in the 
study, the percentage of subjects enrolled with CIN2 will not exceed 50% of the total enrolled.  
The long term follow up plan following the Week 36 efficacy assessment will include safety, 
cytology and HPV testing for a period of approximately 1 year (Week 88). 
Efficacy: Visualization of a normal appearing cervix by colposcopy and cytology are insufficient 
evidence to confirm disease regression. Therefore, disease regression will be based on 
histopathological assessment, which is considered the definitive method for diagnosis. Subjects 
will also be assessed by colposcopy, cytology, HPV testing at screening, Day 0, and Weeks 15, 
28, 36, 62 and 88.  Digital photographs of the cervix will be also used to document colposcopic 
exam findings. 
Tissue to be analyzed for evidence of histopathologic regression will be obtained at Week 36 
either by excision (i.e. loop electrosurgical excision procedure (LEEP), large loop excision of 
transformation zone (LLETZ), cold knife conization (CKC)) or by biopsy (4 Quadrant Biopsy or 
4 Quadrant Biopsy with Endocervical Curettage (ECC)) based upon the assessment at Week 28 
of cytology, High Risk (HR) HPV status, and colposcopic findings (see Tables 4 and 5, for 
Minimally Required Procedures).   
 
Safety: All subjects will be followed for 88 weeks. 
Subjects will be monitored for: 
1) Local and systemic events for 7 days following each investigational treatment as noted on a 
Subject Diary Card (SDC); 
2) All adverse events including SAEs, UADEs, and other unexpected AEs for the duration of 
the study; 
Data Safety & Monitoring Board (DSMB): The DSMB will meet quarterly to review unblinded 
safety data and histopathologic regression results. The DSMB will be charged with advising the 
Sponsor if there appears to be a safety issue and with advising the Sponsor if it appears that the 
proportion of the subjects with histopathologic regression in the VGX-3100X group is 
unacceptably low compared to the placebo group. No formal interim analysis will be performed.   
Immunogenicity: Humoral and cell mediated immune responses in response to VGX-3100X 
treatment may be evaluated in blood samples taken at baseline (both Screening as well as Day 
0 prior to dosing) and at Weeks 15, 36, and 88. Cervical tissue samples may also be analyzed 
16

for evidence of elevated immune responses at Week 36 as compared to baseline (screening). 
Virology: Cervical cytology samples will be obtained to characterize HPV infection at Day 0 
(prior to dosing) and at Weeks 15, 28, 36, 62, and 88 by Cobas® HPV test.  Additionally, if there 
is residual tissue in the paraffin block after histologic diagnoses have been rendered, then 
unstained slides and/or the relevant paraffin blocks may be collected to test for the presence of 
HPV 16/18. Vaginal, oropharyngeal and peri-anal samples will be obtained to characterize HPV 
infection at Day 0 (prior to dosing) and at Weeks 15, 36, and 88. 
HLA typing: The relationship between subject HLA types and efficacy responses will be explored 
using available PBMC sample collected for immunogenicity analysis. 
Study Population: 
Inclusion Criteria: 
1. Women aged 18 years and above; 
2. Confirmed cervical infection with HPV types 16 and/or 18 at screening;  
3. Cervical tissue specimen/slides provided to Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study 
drug; 
4. Histologic evidence of cervical HSIL as confirmed by PAC at screening; 
5. Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form 
prior to study-related activities; 
6. Must be judged by Investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision, 4-quadrant biopsy with ECC, or 4-quadrant biopsy) required at Week 
36; 
7. Has satisfactory colposcopy, defined as full visualization of the squamo-columnar junction 
(Type I or II transformation zone) and complete visualization of the upper limit of aceto-white 
epithelium or suspected CIN disease; 
8. Must have a cervical lesion that is accessible for sampling by biopsy instrument (e.g. Mini-
Tischler device); 
9. Must have a cervical lesion of adequate size to ensure that a visible lesion remains after 
screening biopsy; 
10. Must meet one of the following criteria with respect to their reproductive capacity: 
a) Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months or 
spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL 
b) Is surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 12 months prior to screening 
c) Women of Child Bearing Potential (WOCBP) is willing to use a contraceptive method 
with failure rate of less than 1% per year when used consistently and correctly from 
screening until 6 months following the last dose of investigational product. Acceptable 
methods are the following: 
o Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. Hormonal 
contraceptives must not be used in subjects with a history of hypercoagulability (e.g., 
deep vein thrombosis, pulmonary embolism). 
17

o Abstinence from penile-vaginal intercourse when this is the subject’s preferred and 
usual lifestyle 
o Intrauterine device or intrauterine system 
o Male partner sterilization at least 6 months prior to the female subject’s entry into the 
study, and this male is the sole partner for that subject 
11. Has normal screening ECG or screening ECG with no clinically significant findings, as judged 
by the investigator. 
Exclusion Criteria: 
1. Has microscopic or gross evidence of adenocarcinoma-in-situ (AIS), high grade vulvar, 
vaginal (inclusive of cervical HPV-related lesions that extend into the vaginal vault), or anal 
intraepithelial neoplasia or invasive cancer in any histopathologic specimen at screening; 
2. More than 10 weeks have elapsed between date of initial tissue biopsy for screening and day 
of first dose(i.e. Day 0); 
3. Has cervical lesion(s) that cannot be fully visualized on colposcopy due to extension high into 
cervical canal at screening; 
4. Has history of ECC which showed cervical HSIL indeterminate, or insufficient for diagnosis 
(ECC is not performed as part of study screening); 
5. Has treatment for cervical HSIL or genital warts within 4 weeks prior to screening; 
6. Is pregnant, breastfeeding or considering becoming pregnant during the study; 
7. Has history of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are 
allowed, e.g. GardasilTM, CervarixTM); 
8. Has presence of any abnormal clinical screening laboratory values greater than Grade 1 per 
Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 within 30 days prior to Day 
0 or less than Grade 1 but deemed clinically significant by the investigator; 
9. Has immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening 
b) Primary immunodeficiencies 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day 
of prednisone equivalent; (use of inhaled, otic, and ophthalmic corticosteroids are 
allowed) 
d) 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) 
e) History of solid organ or bone marrow transplantation 
f) Any prior history of other clinically significant immunosuppressive or clinically 
diagnosed 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; 
10. Has received any non-study, non-live vaccine within 2 weeks of Day 0; 
11. Has received any non-study, live vaccine (e.g. measles vaccine) within 4 weeks of Day 0; 
12. Has current or history of clinically significant, medically unstable disease which, in the 
judgment of the investigator, would jeopardize the safety of the subject, interfere with study 
assessments or endpoint evaluation, or otherwise impact the validity of the study results (e.g. 
chronic renal failure; angina, myocardial ischemia or infarction, class 3 or higher congestive 
heart failure, cardiomyopathy, or clinically significant arrhythmias); 
18

13. Has malignancy or treatment for malignancy within 2 years of screening, with the exception 
of superficial skin cancers that only require local excision;  
14. Presence of acute or chronic bleeding or clotting disorder that would contraindicate IM 
injections, or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks 
of Day 0; 
15. Has history of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic 
agents; 
16. Has sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm 
Hg or a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
17. Has resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at 
screening or Day 0; 
18. Has prior major surgery within 4 weeks of Day 0; 
19. Has participated in an interventional study with an investigational compound or device within 
30 days of signing informed consent; participation in an observational study is permitted; 
20. Has less than two acceptable sites available for IM injection considering the deltoid and 
anterolateral quadriceps muscles; 
21. Has tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
22. Has cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is 
located in ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 
23. Has metal implants or implantable medical device within the electroporation area; 
24. Has active drug or alcohol use or dependence that, in the opinion of the investigator, would 
interfere with adherence to study requirements; 
25. Is a prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment 
of either a psychiatric or physical (i.e. infectious disease) illness; 
26. Is an active military service personnel; 
27. Is a study-related staff or family member of study-related staff; 
28. Has 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. 
 
 
19

Table 1: Schedule of Events 
Tests  
Screening 
(-10 wks to -1 Day) 
Weeks 
Day 0 
8-14 days post Day 0 
Phone Call 
4 (± 4 days) 
8-14 days post Wk 4 
Phone Call 
12 (± 4 days) 
8-14 days post Wk 12 
Phone Call 
15 (± 1 week) 
28 (± 1 week) 
36 (± 1 week) 
40 (± 2 weeks) 
Phone call  
62 (± 2 weeks) 
88 (± 2 weeks) 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Medical History  
X 
  
  
  
  
  
  
  
  
  
  
  
       
Demographics  
X 
  
  
  
  
  
  
  
  
  
  
  
  
Socio-behaviorala 
X 
  
  
  
  
  
  
  
  
X 
  
  
X 
Inclusion / Exclusion 
X 
 X 
  
  
  
  
  
  
  
  
  
  
  
Randomization 
  
X 
  
  
  
  
  
  
  
  
  
  
  
Physical examinationb 
X 
X 
  
X 
  
X 
  
X 
X 
X 
  
X 
X 
Vital signs 
Xc 
X 
  
X 
  
X 
  
X 
X 
X 
  
X 
X 
Screening safetyd 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy Teste 
X 
X 
  
X 
  
X 
  
X 
X 
X 
  
X  
 X 
HIV Testing  by ELISA 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Blood immunologic samplesf 
X 
X 
  
  
  
  
  
Xg 
  
X 
  
  
X 
ThinPrepTM h,i 
X 
X 
  
  
  
  
  
X 
X 
X 
  
X 
X 
Cervical Digene swabsi,j 
X 
X 
  
  
  
  
  
X 
 X 
X 
  
  
X 
Colposcopy, lesion photographyk 
Xl 
X 
  
  
  
  
  
X 
X 
X 
  
X 
X 
Ectocervical biopsym 
X 
  
  
  
  
  
  
  
  
Xn 
  
  
  
Surgical excisionm 
  
  
  
  
  
  
  
  
  
Xn 
  
  
  
OPo, vaginal, anal swabs 
  
X 
  
  
  
  
  
X 
  
X 
  
  
X 
Inject VGX-3100X/Placebo 
  
X 
  
X 
  
X 
  
  
  
  
  
  
  
Post treatment assessment 
  
 X 
X 
 X 
X 
 X 
Xp 
  
  
  
 
  
  
Distribute SDC 
  
X 
  
X 
  
X 
  
  
  
  
  
  
  
Review SDC  
  
  
X 
  
X 
  
Xp 
  
  
  
  
  
  
PROs 
  
X 
 X 
  
 X 
  
Xp 
  
 Xq 
  
X q 
 
 X 
 
a Socio-Behavioral assessments, e.g. self-reported smoking and alcohol history 
b Full physical examination (PE) mandatory at screening and study discharge (Wk 88), otherwise targeted PE as determined 
by the Investigator or per subject complaints unless signs or symptoms dictate the need for a full PE; 
c Screening vital signs must include a measured height and weight and calculated BMI; 
d Screening 12-Lead ECG, complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), serum creatinine 
(Cr), serum glucose, serum ALT, serum CPK and urinalysis performed within 30 days prior to  dose administration on Day 
0; 
e Negative spot urine pregnancy test is required at screening and prior to each study treatment, colposcopy and surgical 
excision; 
20

f At least 34 mL [4 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum per time point (a total of at least 68 mL of 
whole blood and 8 ml serum should be collected prior to dosing on Day 0). HLA testing will performed once from an existing 
PBMC sample; 
g At least 51 mL [6 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum should be collected at Week 15; 
h HPV genotyping and Pap smears are performed on the same ThinPrepTM cervical specimen; 
i Request that the subject abstain from sexual activity and refrain from use of douching or vaginal lubricants/medication for 
a period of 24 hours prior to cervical specimen collection; 
j Collected prior to the ThinPrepTM sample; 
k Photographs of the cervix and the associated lesion must be collected prior to and after biopsies and at all colposcopic 
examinations.; 
l Screening colposcopy is optional if adequate colposcopy was performed upon collection of initial biopsy and corresponding 
lesion photography is available; 
m Screening biopsy of the lesion should be collected as Paraffin-embedded cervical tissue, fresh cervical tissue, or H&E 
slides. Tissue to be analyzed for evidence of histopathologic regression will be obtained at Week 36 visit either by excision 
(i.e. LEEP, CKC) or by 4 Quadrant Biopsy or 4 Quadrant Biopsy with ECC based upon the assessment at Week 28 of 
cytology, HR HPV status, and colposcopic findings (See Tables 5 and 6); 
n Slides from biopsy and/or excised tissue must be reviewed by the PAC and residual cervical tissue from entry and/or Week 
36 specimen(s) (paraffin blocks or unstained slides) should be sent to the central pathology laboratory for 
immunohistochemistry (IHC) and HPV testing; 
o Oropharynx (OP) by oral rinse; 
p Activities at 8 to 14 days Post-Dose 3 phone call may be done at Week 15 if timing overlaps. 
q PROs to be completed by subject 8-14 days after Week 28 visit and Week 40 phone call 
 
 
 
 
 
 
 
21

1 INTRODUCTION 
1.1 
BACKGROUND  
1.1.1 
HPV INFECTION, CERVICAL INTRAEPITHELIAL NEOPLASIA AND CERVICAL 
CANCER  
Infection with human papillomavirus (HPV) can lead to malignant neoplasia, localized primarily in 
the anogenital area and aerodigestive tract, in both men and women.  HPV types tropic to mucosal 
tissues are classified into high-risk (HR), based on their potential to cause cancer, and low-risk (LR) 
(causing generally benign lesions). HPV-16 and HPV-18 are the most significant amongst high-risk 
types since they are responsible for most HPV-caused cancers [1].  In the US alone, approximately 
14 million new genital HPV infections occur annually, and approximately half of these infections are 
with a HR HPV type [2, 3].  Up to 13000 women in the US alone are diagnosed with cervical cancer 
each year, which leads to an estimated 4120 deaths [4].  HPV-16 is the most common high-risk 
genotype and combined with HPV-18 these two genotypes are estimated to cause about 70% of all 
cervical cancers [5, 6]. 
Incident infection by HPV is characterized by ongoing viral replication and shedding and is 
associated with early histologic changes (grade 1 cervical intraepithelial neoplasia) when the female 
cervix is infected with HPV.  Most cases of genital HPV infection clear spontaneously, but persistent 
infection with one or more oncogenic (high-risk) HPV genotypes can lead to the development of 
precancerous, histologic high grade squamous intraepithelial lesions of the cervix, HSIL which is 
inclusive of grade 2 and 3 cervical intraepithelial neoplasia (CIN2/3) [7].   Over time, typically years, 
cervical HSIL can progress to invasive cancer of the cervix [8, 9].  The basis for these changes are 
attributed to the viral proteins E6 and E7.  Infected cells produce E6 and E7 constitutively which 
increases the degradation of cell cycle regulation proteins p53 and pRb, respectively, resulting in 
unrestricted cell growth and neoplasia.   
While the currently available prophylactic HPV vaccines (Cervarix™, Gardasil™, and Gardasil™-9) 
are highly effective in preventing persistent infection and the subsequent development of high-grade 
CIN caused by HPV-16, HPV-18 and other HPV types, the prophylactic vaccines have no therapeutic 
effect upon existing HPV infection or existing HPV-related intraepithelial neoplasia [10].  This 
means that the large number of women who already have high grade cervical dysplasia, either 
because they were too old to have received the prophylactic vaccine or they didn’t respond to 
vaccination, must currently only rely upon surgery and the chance of spontaneous regression to treat 
their condition and avoid progression to cancer.  Furthermore, the number of US-eligible teenagers 
who complete the prophylactic vaccination series remains low; 39.7% of US girls ages 13-17 
completed their prophylactic HPV immunization series in 2014, which leaves a potentially 
vulnerable, under-protected population [11]. The current approaches to the management of cervical 
HSIL typically require surgery (i.e. LEEP/LEETZ, laser ablation, or conization); however, surgical 
excision does not necessarily address the underlying HPV-infection, and can adversely impact the 
reproductive health of women of childbearing age.  Therefore, VGX-3100X is being developed as a 
non-surgical therapeutic option for the precancerous precursor to cervical cancer, cervical HSIL, and 
the underlying, pathogenic HPV infection.  
22

1.1.2 
VGX-3100X 
VGX-3100X contains the identical plasmids to target HPV-16 E6/E7 and HPV-18 E6/E7 antigens 
that were included in VGX-3100. The plasmids were designed and constructed using proprietary 
synthetic vaccine (SynCon™) technology. This process involves synthetically deriving consensus 
genes across multiple strains and optimizing DNA inserts at the genetic level to allow high expression 
in human cells. Together, VGX-3100X and the CELLECTRA™ device represent an integrated 
investigational product designed as a non-surgical treatment of HPV 16/18-related cervical HSIL 
(CIN2, CIN3) via an immune response directed against HPV 16/18. 
The initial formulation was designated as VGX-3100 (water-for-injection w/1% w/w poly-L-
glutamate (WFI/LGS); frozen storage) and has been administered to more than 250 subjects in Phase 
1 and Phase 2 clinical trials.VGX-3100X was developed to be a non-frozen formulation using saline 
sodium citrate (SSC) buffer. VGX-3100X was administered to 116 subjects in a Phase 1 clinical trial, 
HPV-101. In study HPV-101, three 6 mg doses of VGX-3100X, non-frozen formulation were 
delivered intramuscularly followed by electroporation with CELLECTRA™ 5P to healthy adults.  
Based upon interim analysis data at study Week 14, the non-frozen formulation was considered non-
inferior to the frozen formulation based upon a 2-fold rise in overall Spot Forming Units (SPU) to 
the antigens encoded by the plasmids per 106 Peripheral Blood Mononuclear Cells (PBMC) as 
measured from baseline to Week 14 using the interferon-γ ELISpot assay. 
Proof of concept was demonstrated in the prospective, randomized, double blind, placebo-controlled 
Phase 2b study of VGX-3100 followed by EP in the treatment of high grade cervical dysplasia, 
cervical HSIL associated with HPV-16 and/or 18.  The Phase 2b study, HPV-003, enrolled 167 
subjects with high grade cervical dysplasia from seven countries and one United States Territory 
(Australia, Canada, Estonia, Republic of Georgia, India, South Africa, United States and Puerto 
Rico). Subjects were randomized in a 3:1 ratio to the treatment arm (VGX-3100) or the placebo arm, 
respectively. All subjects were to receive treatment on Day 0, Week 4 and Week 12. All subjects 
were to repeat cervical biopsy or LEEP of the cervix at Week 36 to assess efficacy defined as 
regression of high grade CIN by histopathology.   The primary endpoint was histopathologic 
regression of cervical lesions to CIN1 or less at the Week 36 visit.   A secondary endpoint was 
clearance of HPV 16/18 in combination with histopathologic regression of cervical lesions to CIN1 
or less. The proportions of subjects who met the primary and secondary endpoints were significantly 
higher in the VGX-3100 group vs. placebo in both per protocol and modified intent to treat analyses.  
Robust T-cell activity was detected in VGX-3100 recipients compared to placebo recipients. VGX-
3100 was generally safe and well tolerated when administered intramuscularly with electroporation.  
1.1.3 
ELECTROPORATION 
VGX-3100X is delivered using the CELLECTRA™ in vivo electroporation (EP) device. EP is a 
physical method of tissue transfection whereby the generation of short, controlled electrical pulses 
creates a localized electric field at the injection site of the DNA vaccine which increases cell 
membrane permeability and improves the transfection of DNA and subsequent immunogenicity [12, 
13]. EP is believed to increase the uptake and processing of plasmid DNA, thereby enabling increased 
expression and enhanced vaccine immunogenicity by 10 to 100 fold [14, 15]. This technology has 
been used for more than three decades by molecular biologists for cell transfection and has 
demonstrated versatility in use, as shown by its functionality in combination with a range of 
molecules, tissue types, disease indications, and across species [16]. 
23

The CELLECTRA™ device developed by Inovio is used for investigational purposes to administer 
plasmid-based DNA, in both prophylactic and therapeutic settings. Following successful proof-of-
concept studies in animals, Inovio has optimized both pulse pattern and voltage to increase 
transfection efficiency, and has demonstrated that the device helps to elicit favorable immunogenicity 
in several species (e.g., mice, pigs, and rhesus macaques) [17, 18].  
VGX-3100 has been administered throughout Phase 1 and Phase 2 investigations with the 
CELLECTRA™ 2000 device. A next generation device, CELLECTRA™ 5PSP, will be used in 
Phase 3. Both designs of the CELLECTRA™ device enhance the intracellular uptake of VGX-3100X 
by the delivery of electrical current, and the electrical current delivery and pulse pattern 
(electroporation) is identical in both designs. CELLECTRA™ 2000 involves a manual injection of 
VGX-3100X while the CELLECTRA™ 5PSP device will automate the intramuscular delivery of 
VGX-3100X and delivery of the EP pulses triggered by a single button press. Neither the dosage nor 
volume of VGX-3100X administered differs between the two devices. Administration of VGX-
3100X with the CELLECTRA™ 5PSP also allows selection of the needle array length from 13 to 19 
to 25 mm depending on the estimate of the recipient’s subcutaneous fat and muscle tissue.  
The technology differences between the CELLECTRATM 2000 and CELLECTRATM 5PSP design 
(Table 2) are not significant and do not present any new risks. The device design change does not 
affect the indications for use, operating principle, energy type, environmental specifications, and 
sterilization or performance specifications. The material changes are to the outer housing of the 
device and not to patient-contacting materials.  
24

Table 2. Comparative Device Overview 
 
CELLECTRATM 5PSP 
CELLECTRATM 2000 
Array Specifications 
Electrode Number and Material 
(no bore) 
5 Stainless steel, 304 electrodes 
pentagonal arrangement 
5 Stainless steel, 304 electrodes 
pentagonal arrangement 
Electrode Length 
1.555 ± .020” (39.5mm) 
1.555 ± .020” (39.5mm) 
Electrode Gauge 
22 Gauge (0.0278-0.0280 inch diameter) 
21 Gauge (0.028±0.001 inch diameter) 
Electrode Trocar Tip 
15 ± 2° 
15 ± 2° 
Array Housing 
Bayer Makrolon 2458C and Loctite 3921 
GE Plastics (Sabic) Lexan HPS2 
Sterilization Method and Sterility 
Assurance Level (SAL) 
Gamma Irradiation- kGy To Be 
Determined SAL 10-6 
Gamma Irradiation 25-40kGy 
SAL 10-6 
VGX-3100(X) IM Injection Method 
Automated (Handset mediated) 
Manual (needle and syringe) 
Injection Needle Material (full bore) 
Stainless steel, 304 
Stainless steel, 304 
Injection Needle Length 
2.102 ± .020” (54.4mm) 
2.0” hypodermic needle recommended 
Injection Needle Gauge 
21 Gauge (.03250-0.03200 inch 
diameter) 
21 Gauge 
Injection Needle Trocar Tip 
15° (double ended) 
15° (single ended) 
VGX-3100(X) IM Injection Depth 
13, 19 and 25mm 
13 and 19 mm 
VGX-3100(X) IM Injection Volume 
1.0±0.1mL 
1.0±0.1mL 
Electroporation Parameters 
Voltage 
40-200 V maximum (varies with subject 
tissue impedance; 12V for device 
operation) 
40-200 V maximum (varies with subject 
tissue impedance; 7.2V for device 
operation) 
Pulse Width 
52 milliseconds (ms) 
52 milliseconds (ms) 
Pulse Current 
0.5 A; 1.0 A max 
0.5 A ; 1.0 A max 
Maximum Phase Charge 
Maximum Delivered Charge  = 
78mC (max) = 0.5A x 0.052 seconds x 3 
pulses 
Maximum Delivered Charge  = 
78mC (max) = 0.5A x 0.052 seconds x 3 
pulses 
Frequency 
Up to 4 Hz between pulses 
Up to 4 Hz between pulses 
Benchtop design verification testing and a non-significant risk device functionality study will be 
completed prior to Phase 3 to support that the dimensional changes, change to the ergonomics of the 
patient user interface and injection method result in the CELLECTRA™5PSP device design meeting 
its safety and performance specifications, and no change to the administration of VGX-3100(X) by 
electroporation. Inovio’s device experience demonstrates that delivery of electroporation pulses into 
muscle immediately following injection of DNA plasmids is well-tolerated in humans and no 
significant safety issues have been identified [19-21].  
1.1.4 
SELECTION OF STUDY DESIGN  
This Phase 3 study employs a prospective, randomized, double-blind, placebo controlled study 
design to further demonstrate the safety and efficacy of VGX-3100X followed by EP in women with 
25

cervical HSIL associated with HPV 16/18.  The primary clinical hypothesis is that VGX-3100X is a 
surgery-sparing, therapeutic option for the treatment of cervical HSIL and the underlying, pathogenic 
HPV 16/18 infection, which is supported by the findings of the Phase 2b trial. A placebo-controlled 
study is selected for this trial because it provides scientific rigor to distinguish an effective treatment, 
particularly in cervical HSIL for which spontaneous regression does occur. 
1.2 
DOSE AND REGIMEN RATIONALE   
A total dose of 6 mg VGX-3100X DNA has been selected for this study based on previous human 
experience with both VGX-3100 and VGX-3100X, preclinical data with VGX-3100X and other DNA 
vaccines, and the safety and immunogenicity data generated in the HPV-001, HPV-003, and HPV-101 
studies. In HPV-001 trial, the 6 mg dose was delivered IM followed by EP, which showed trends toward 
higher response rates and magnitudes of IFN-γ ELISpot responses compared to the low (0.6 mg) and mid-
dose (2 mg) cohorts (Table 2) without significant safety issues [19].  
This dose-trend was consistent with prior expectation, a feature of the finding that suggests it is a true 
effect rather than random variation. Adverse events from previous human studies with VGX-3100 and 
closely related DNA plasmid products have been limited to injection site pain from the injection and 
electroporation procedure, which were not clinically meaningful. 
Based on the information above, the 6 mg dose was selected for study in the Phase 2b study. The results 
obtained in the phase 2 study suggest that the 6 mg dose was efficacious with an acceptable safety profile, 
therefore the 6 mg dose will also be evaluated in this Phase 3 trial. 
 
 
 
Table 3. Percent of Protocol HPV-001 subjects responding and average SFU/106 PBMC in 
responders for each antigen by cohort in Interferon-γ ELISpot  
Cohort 
Low 
Mid 
High 
Antigen %Response 
AVG 
%Response 
AVG 
%Response 
AVG 
HPV-16E6 
33% 
107 
50% 
243 
50% 
1341 
HPV-16E7 
17% 
198 
50% 
104 
67% 
143 
HPV-18E6 
50% 
359 
50% 
338 
83% 
664 
HPV-18E7 
33% 
159 
17% 
179 
50% 
834 
Any 
67% 
221 
67% 
210 
83% 
556 
1.3 
RISKS/BENEFIT ASSESSMENT 
1.3.1 
RISKS ASSOCIATED WITH CURRENT THERAPEUTIC OPTIONS 
Currently, treatment of women with cervical HSIL usually consists of either surgical removal of the 
affected tissue by CKC, LEEP, ablative therapy via laser, or cryotherapy.  All treatments for cervical 
26

HSIL are associated with a variety of short and long term general and reproductive health risks as 
listed in Table 4. 
Table 4. Risks Associated with Surgical Treatments for Cervical HSIL 
Surgical Treatments 
for cervical HSIL 
Risks 
CKC 
LEEP 
Ablative therapy (Laser 
or Cryotherapy)  
Pain 
Exposure to anesthesia 
Heavy bleeding 
Infection 
Menstruation problems 
Cervical stenosis (can lead to alteration of squamo-columnar junction) 
Shortening of the cervix 
Decreased fertility/difficulty getting pregnant 
Cervical incompetence 
Pre-term birth and related low birth weight 
Incomplete treatment of cervical dysplasia 
Inadequate treatment of an occult early invasive cancer 
Adapted from FAQs Loop Electrosurgical Excision Procedure (LEEP) American College of Obstetricians and 
Gynecologists (2014) [11]. 
More importantly, none of the currently available surgical treatments for cervical HSIL eradicate the 
underlying cause of the high grade cervical dysplasia, persistent infection with one or more of the 
high-risk HPV types, and therefore, leaves patients at risk for recurrent cervical HSIL as well as high 
grade dysplasia of the vulva and vagina due to the potentially broader infection of the genitourinary 
area. 
Although professional guidelines typically advocate immediate excisional therapy for adults with 
cervical HSIL, scientific data indicates that the rate of progression from pre-invasive to invasive 
cervical disease is slow, typically thought to take several years [8].  The risk of a “missed diagnosis” 
of an occult early invasive cervical cancer exists for all current treatment modalities including 
surgical and ablative therapies.  Furthermore, approximately 17-18% of patients with high grade CIN 
will experience recurrence of dysplasia following surgical intervention [8], which illustrates that 
current standard of care for cervical dysplasia requires improvement.  The study design includes 
numerous safeguards to detect disease progression or the presence of an undiagnosed occult early 
invasive cervical cancer.  These include, careful selection of immunocompetent patients, thorough 
screening and baseline evaluation, frequent cervical colposcopy, cytology and high-risk HPV testing 
throughout the trial.  Investigators will be comprised of experienced gynecologists, who will have 
the discretion to obtain biopsies at any point if disease progression is suspected. 
1.3.2 
POTENTIAL RISKS OF STUDY PARTICIPATION 
A risk associated with VGX-3100X for the treatment of high grade cervical dysplasia are the 
injection site reactions related to the IM injection and/or electroporation.  Based on the phase 1 and 
2 clinical experience, the injection site reactions associated with the IM injection and electroporation 
are generally mild (e.g. erythema) and limited to a few days in duration at most.   
27

A second risk is the “delay” in “definitive treatment” of the high grade cervical dysplasia and the 
“missed diagnosis” of an occult early invasive cervical cancer for the VGX-3100X non-responders 
or placebo recipients, who do not spontaneously regress.  This risk is mitigated by careful serial 
cytology, HPV testing, and colposcopic exams, throughout the course of the study, and the well 
accepted understanding that cervical dysplasia progresses slowly, typically over years, which makes 
close, active follow-up possible.  Also, only investigators who are experienced in the management 
of cervical cancer will be chosen, and they will have the option of performing additional, ad hoc 
colposcopic exams and cervical biopsies if they suspect potential disease progression.  
A DSMB will also advise the Sponsor if it appears that the frequency of regression in the VGX-
3100X group is unacceptably low compared to the placebo group.  These measures should minimize 
the risk - even perhaps below that of standard care - of progression of the cervical HSIL and the risk 
of harboring an undiagnosed occult early invasive cervical cancer. All subjects with suggestion of 
residual disease will undergo excisional therapy by CKC or LEEP at Week 36 as part of the efficacy 
assessment.  Subjects whose cytology, HPV testing, ECC results (if applicable) and colposcopic 
exam suggest disease regression will undergo 4 quadrant biopsy or 4 quadrant biopsy with ECC 
(based upon Tables 4 & 5) to provide histopathologic confirmation of regression. In the Phase 2b 
study, the rate at which microinvasive cancer was found in larger surgical excision samples in 
subjects who had no evidence of invasive cancer by initial biopsy was 1.8%, (2/114 with specimens), 
which is consistent with and even lower than the rate of 6.7% that has been reported under standard 
of care settings [22]. 
1.3.3 
POTENTIAL BENEFITS OF STUDY PARTICIPATION 
All currently accepted treatments for high grade cervical dysplasia are surgical procedures (LEEP, 
CKC, Laser ablation) which are all associated with risks inherent with any surgical procedure 
including anesthesia, post-operative bleeding and/or infection, damage to other organs, shortening 
and/or deformation of the cervix, pain, etc.  Due to the risk of shortening and/or deformation of the 
cervix there are additional well accepted risks including cervical stenosis, infertility, cervical 
incompetence, preterm birth, and inability to visualize the transformation zone.  Additionally, none 
of the surgical treatments systemically address the underlying oncogenic root cause, the high risk 
HPV infection in the lower genital tract, which leaves an underlying risk for further disease 
manifestations and transmission of HPV. VGX-3100X+ EP is not associated with any of the risks 
associated with the surgical procedures outlined above (except for pain, which is transient, very 
quickly-resolving, and restricted to the deltoid/quadriceps treatment site) and has demonstrated the 
ability to not only eradicate the high grade dysplasia but also the ability to eradicate the underlying 
HPV infection.  Subjects receiving placebo, who represent women of child-bearing potential, may 
benefit from the opportunity to be closely managed under careful surveillance over the course of this 
study and those who regress spontaneously will be able to avoid excisional therapy. 
2 STUDY DESIGN 
This Phase 3 1 study design is based upon the Phase 2b study design and results. HPV-301 is a 
prospective, randomized, double-blind, placebo controlled study to determine the efficacy, safety, and 
tolerability of VGX-3100X administered by IM injection followed by EP delivered with CELLECTRA™ 
5PSP in adult women with histologically confirmed cervical HSIL (CIN2, CIN3) associated with HPV 
16/18. 
28

A sample of approximately 165 subjects will be randomized to receive either 6 mg (in 1 ml) VGX-3100X 
or placebo, each IM followed by EP, in a 2:1 ratio. This sample size provides 90% power to declare VGX-
3100X superior to placebo, assuming, based upon Phase 2b study results, that the true proportion of 
subjects whose lesion(s) regress and whose HPV 16/18 clears is 40% and 15% for VGX-3100X and 
placebo, respectively, and assuming 90% evaluability from randomization.  
Subjects will be randomized in a stratified manner according to (a) the CIN severity observed in the 
biopsy specimens at screening (i.e. CIN2 vs. CIN3), (b) BMI category (≤25 vs. >25 kg/m2), and (c) age 
category (<25 years vs. ≥25 years). To ensure CIN2 disease is not over-represented in the study, the 
percentage of subjects enrolled with CIN2 will not exceed 50% of the total enrolled. 
To be eligible for the study, subjects age 18 years and above must consent to participate and have cervical 
biopsy/biopsies of the cervical lesion(s) at the time of screening. Slides of the biopsy will be sent to a 
PAC in a blinded manner to establish the presence of cervical HSIL within screening. In order to be 
eligible for continued enrollment, the PAC must assign the histologic diagnosis of cervical HSIL.  
Subjects must also have a cervical specimen test positive for HPV 16/18 by Cobas® HPV test to be eligible 
for participation in the study. 
2.1 
ENDPOINT ASSESSMENT 
In the Phase 2b study, subjects were randomized 3:1 to the VGX-3100 arm or the Placebo arm. All 
subjects were scheduled to receive treatment on Day 0, Week 4 and Week 12 and undergo repeat cervical 
biopsy or surgical excision (i.e. LEEP, LLETZ, CKC) of the cervix at Week 36 to assess efficacy. The 
primary endpoint was histopathologic regression of cervical lesions to CIN1 or less at the Week 36 visit, 
and the secondary endpoint was clearance of HPV 16/18 in combination with histopathologic regression 
of cervical lesions to CIN1 or less.     
The primary endpoint for the Phase 3 study is based upon the results of the Phase 2b study.  Given that 
HPV persistence is an important factor in the clinical progression of dysplasia and also based upon the 
findings of the secondary objective of the Phase 2b study, the responder definition for the Phase 3 primary 
endpoint determination will take into consideration both histological regression of cervical HSIL and 
clearance of high-risk HPV 16/18.  
The proportion of subjects who achieved this endpoint in the Phase 2b study was 39.5% of VGX-3100 
subjects versus 15.4% for placebo, in the modified-intention-to-treat analysis.  The composite endpoint 
of histologic regression and virologic clearance will be primary in the Phase 3 study, and histologic 
regression endpoint will be a secondary endpoint. 
2.1.1 
HISTOLOGY ASSESSMENT 
Regression of cervical HSIL will be determined by histopathological assessment of cervical tissue, which 
is considered the definitive method for diagnosis of cervical dysplasia. Digital photographs are also used 
to document colposcopic exam findings. Tissue to be analyzed for evidence of histopathologic regression 
will be is obtained at Week 36 either by excision (i.e. LEEP, LLETZ, CKC) or by 4 Quadrant Biopsy or 
by 4 Quadrant Biopsy with ECC based upon the assessment at Week 28 of cytology, HR HPV status, and 
colposcopic findings as outlined in Tables 5 and 6 for subjects 25 years and above and below 25 years, 
respectively. 
 
 
29

Table 5.  Minimally Required Procedure at Week 36 for subjects age 25 years and above  
Age 
Clinical and laboratory information at Week 28 
Minimally required 
procedure at Week 36a 
Colposcopy 
Cytology 
HPV 16/18 
testing 
Quality 
Finding 
25 
and 
above 
NA 
NA 
HSIL, ASC-H, AGC, 
Carcinoma, AIS 
NA 
Tissue Excision 
unsatisfactory 
lesion 
NA 
NA 
Tissue Excision 
unsatisfactory 
no lesion 
LSIL, ASC-US 
positive 
Tissue Excision 
unsatisfactory 
no lesion 
LSIL, ASC-US 
negative 
4Q biopsy and ECC 
unsatisfactory 
no lesion 
NILM 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
LSIL, ASC-US 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
positive 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
negative 
4Q biopsy 
Abbreviations: NA; not applicable because there is no impact to the decision at Week 36 due to a superseding finding; 4Q; 
four quadrant; NILM Negative for intraepithelial lesion and malignancy; ASC-US Atypical squamous cells of undetermined 
significance; AGC Atypical glandular cells; ASC-H Atypical squamous cells, cannot rule out high-grade lesion; AIS 
Adenocarcinoma-in-situ 
a any subject with prior ECC requires a negative ECC at Week 28 to allow 4Q biopsy and ECC, at minimum, at Week 36    
 
Table 6.  Minimally Required Procedure at Week 36 for subjects under 25 years  
Age 
Clinical and laboratory information at Week 28 
Minimally required 
procedure at Week 36a 
Colposcopy 
Cytology 
HPV 16/18 
testing 
Quality 
Finding 
18-24 
NA 
NA 
Carcinoma, AIS 
NA 
Tissue Excision 
unsatisfactory 
lesion 
NA 
NA 
Tissue Excision 
unsatisfactory 
no lesion 
HSIL, ASC-H, AGC 
NA 
Tissue Excision 
unsatisfactory 
no lesion 
NILM, ASC-US, LSIL 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
LSIL, ASC-US, HSIL, 
ASC-H, AGCb 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
positive 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
negative 
4Q biopsy 
Abbreviations: NA; not applicable because there is no impact to the decision at Week 36 due to a superseding finding; 4Q; 
four quadrant; NILM Negative for intraepithelial lesion and malignancy; ASC-US Atypical squamous cells of undetermined 
significance; AGC Atypical glandular cells; ASC-H Atypical squamous cells, cannot rule out high-grade lesion; AIS 
Adenocarcinoma-in-situ 
a any subject with prior ECC requires a negative ECC at Week 28 to allow 4Q biopsy and ECC, at minimum, at Week 36   
b if cytology result is AGC “favor neoplasia”, tissue excision is recommended 
 
2.1.2 
VIROLOGIC (HPV) ASSESSMENT 
Cervical cytology samples will be obtained to characterize HPV infection at screening, Day 0 (prior to 
dosing) and Weeks 15, 28, 36, 62, and 88.  Also, if there is residual tissue in the paraffin block after 
histologic diagnoses have been rendered, then unstained slides and/or the relevant paraffin blocks may 
be collected for testing of HPV 16/18. Vaginal, oropharyngeal and peri-anal samples will be obtained to 
30

 
 

Whenever possible, these studies may be performed on tissue sections from the diagnostic screening 
biopsy (pre-dose) and from tissue obtained post-dose(s) (Week 36). 
2.2 
TREATMENT PLAN 
The three dose regimen of VGX-3100 appeared to be safe and well tolerated in the Phase 2b study, 
therefore all eligible subjects who consent to participate in the Phase 3 study will receive the same three 
6 mg doses of VGX-3100X or placebo administered in 1 mL IM (deltoid, preferred site, or anterolateral 
quadriceps, alternate site), each followed immediately by EP with the CELLECTRA™ 5PSP device. The 
first study treatment will be administered on Day 0, the second at Week 4, and the third (final) study 
treatment will be administered at Week 12 which is consistent with the Phase 2b study. The first study 
treatment will be given as soon as possible following confirmation of the cervical HSIL diagnosis and 
HPV-16/18 status but no more than 10 weeks following collection of the subject’s biopsy specimen used 
for diagnosis by the PAC during screening, contemporaneous with the positive testing for HPV-16/18. 
2.3 
SAFETY MONITORING PLAN 
Although cervical HSIL is thought to require years to progress to cervical cancer, subjects in the Phase 
2b study were followed closely throughout. HPV testing (Weeks 14 and 24), cytology (Week 14) and 
colposcopy (Week 24) were all mandatory during the observation period prior to obtaining tissue for 
determination of the primary histologic endpoint at Week 36. Investigators were also instructed to 
perform additional testing (including biopsy) if disease progression was suspected. These instances were 
infrequent as only 11 unscheduled biopsies were deemed necessary over the course of the Phase 2b study. 
In addition, the rate at which occult microinvasive cancer was discovered after 36 weeks was less frequent 
than what is reported in the literature [22]. Both observations would imply that the mandatory monitoring 
employed in the Phase 2b study was sufficient; however cervical disease will be monitored even more 
closely in this Phase 3 study. Colposcopy, cytology and HPV testing will be required at 8 to 14 week 
intervals throughout the observation period leading up to the primary endpoint 36 weeks after the first 
dose. Although less frequent monitoring may be adequate, the more frequent monitoring is designed to 
afford an even wider margin of safety and an opportunity to explore predictors of efficacy.     
Safety monitoring will include: 
• Local and systemic events for 7 days following each treatment as noted on a Subject Diary Card 
(SDC). 
• All adverse events including SAEs, UADEs, and other unexpected AEs for the duration of the 
study; 
In the Phase 2b study, the safety profile was carefully evaluated and treatment with VGX-3100 was well-
tolerated based on observations through Week 88 in all subjects. The most common adverse events were 
administration-site reactions, which included pain, tenderness, erythema and swelling, and were generally 
mild and limited to a few days in duration.  Only erythema showed a statistically higher incidence in 
VGX-3100 (78%) vs placebo (57%) in the 7- and 28-day periods after a dose. One additional AE, 
sinusitis, was also statistically significantly increased over the course of the entire study period but 
resolved without sequelae in the VGX-3100 arm compared to the Placebo arm (10% vs. 0%).      
As outlined above, safety monitoring and visit frequency has been designed to take into account the 
potential risk of delay in the usual treatment of the high grade cervical dysplasia and also the potential 
for a missed diagnosis of an occult early invasive cervical cancer for the VGX-3100X non-responders or 
placebo recipients, who do not regress.  Serial cytology, HPV testing, and colposcopic exams are applied 
32

throughout the course of the study with the well accepted understanding that cervical dysplasia progresses 
slowly, typically over years, which makes close, active follow-up possible.  All subjects with suggestion 
of residual disease will undergo excisional therapy by LEEP or CKC at Week 36 as part of the efficacy 
assessment.  Subjects whose cytology, HPV testing, ECC results (if applicable) and colposcopic exam 
suggest disease regression will undergo 4 quadrant biopsy or 4 quadrant biopsy with ECC (based upon 
Table 5 and 6) to provide histopathologic confirmation of regression. The use of a 4 quadrant biopsy in 
Phase 3 is a change from the approach used in Phase 2b to optimize the evaluation of histopathologic 
regression taking into consideration the inherent limitations of colposcopy and tissue biopsy samples in 
the absence of visible lesions [23].  
In the Phase 2b study, the cervical tissue sample was initially read by a local pathologist and/or central 
pathology laboratory for rapid local medical management.  The definitive histopathologic assessment was 
determined by an independent blinded Pathology Adjudication Panel, comprised of experienced 
cytopathologists from independent medical centers in the US.  Seven reports included the terms 
‘(adeno)squamous cell carcinoma’ or the premalignant condition of ‘adenocarcinoma in situ’ (AIS) in the 
final Phase 2b study results which included all 88 weeks of follow up. Three of the cases were reported 
as AIS, (2 VGX-3100, 1 placebo), out of which two cases (1 VGX-3100, 1 placebo) were confirmed as 
AIS by the PAC. AIS is a pre-invasive glandular lesion which can be difficult to capture on standard of 
care screening with initial punch biopsy and is more commonly identified by full excision (e.g. LEEP, 
conization).  There were four reports that included the term squamous cell carcinoma, of which two were 
confirmed by the PAC, both in the VGX-3100 group.  The other two cases (1 VGX-3100, 1 placebo) 
were diagnosed as CIN3 by the PAC.  The rate at which microinvasive cancer was found in larger surgical 
excision samples in subjects who had no evidence of invasive cancer by initial biopsy was 1.8%, (2/114 
with specimens), which is consistent with and even lower than the rate of 6.7% that has been reported 
under standard of care settings [22].   
Importantly, investigators in the Phase 3 study will be chosen only if they are experienced in the 
management of cervical cancer as was the case in the Phase 2b study. Phase 3 investigators are instructed 
to perform additional, ad hoc colposcopic exams and cervical biopsies if they suspect potential disease 
progression. Subjects that undergo an unscheduled biopsy will be classified as a non-responder in the 
efficacy analysis as outlined in Table 6. These measures should minimize the risk of progression of 
cervical HSIL and the risk of harboring an undiagnosed occult early invasive cervical cancer. The 
frequency of close monitoring by experienced investigators should minimize the risk of cancer 
progression on the study what is expected with standard of care. 
2.3.1 
DATA SAFETY & MONITORING BOARD (DSMB) 
An independent Data Safety & Monitoring Board (DSMB) will provide safety oversight.  The DSMB 
will be scheduled to meet quarterly. If there are no new safety data or regression/clearance results to 
review for a quarterly scheduled meeting the DSMB will be notified and the meeting may be cancelled; 
ad hoc meetings may be scheduled to review new data as applicable. The DSMB will be charged with 
advising the Sponsor if there appears to be a safety issue and with advising the Sponsor if it appears that 
the proportion of the subjects with regression in the VGX-3100X group is unacceptably low compared to 
the placebo group. However, no formal interim analysis will be performed. 
2.4 
LONG TERM FOLLOW UP PLAN 
In the Phase 2b study, all subjects were scheduled to be followed for 1 year after the histopathologic 
assessment for the primary endpoint (to study Week 88). The establishment of efficacy based on 
33

histopathologic evidence dictated the removal of tissue at week 36 by either punch biopsy (ies) or more 
extensive surgical resection (i.e. LEEP, CKC). Subjects with colposcopic evidence of residual disease 
were to undergo LEEP/CKC. A higher proportion of patients who received placebo had a LEEP 
performed than those who received VGX-3100 (Table 8). 
Cytology and HPV 16/18 clearance from the cervix was to be assessed at study Weeks 62 and 88 to 
evaluate for recurrence of dysplasia and HPV infection after removal of tissue at Week 36.  Overall, in 
the phase 2b study, the majority of subjects had improved cytology and had cleared their underlying HPV 
16/18 cervical infection by the Week 62 and 88 visits. For Weeks 62 and 88, there were no clinically 
meaningful differences noted between the subjects who received an excisional treatment (e.g. LEEP, 
CKC) and those that showed histopathologic regression and therefore only underwent a biopsy, as shown 
in Table 8 which summarizes the HPV and cytology results following Week 36.  
Table 8.  HPV-003 HPV and Cytology results at Weeks 36, 62 and 88, mITT population  
Week Testa 
VGX-3100 
Placebo 
LEEP/CKCb 
%(n/N) 
Biopsyc 
%(n/N) 
LEEP/CKC 
%(n/N) 
Biopsy 
%(n/N) 
36 
HPV 
41% (19/46) 
63% (36/57) 
29% (6/21) 
29% (5/17) 
36 
Pap 
NA 
NA 
NA 
NA 
62 
HPV 
89% (50/56) 
82% (42/51) 
96% (27/28) 
82% (9/11) 
62 
Pap 
93% (52/56) 
100% (51/51) 93% (26/28) 
82% (9/11) 
88 
HPV 
89% (48/54) 
89% (42/47) 
89% (24/27) 
100% (10/10) 
88 
Pap 
96% (52/54) 
91% (43/47) 
85% (23/26) 
100% (11/11) 
Abbreviations: NA, not applicable, Pap smear was not done at Week 36 
a  HPV =  HPV 16/18 testing; Pap = cytology testing  
b LEEP or CKC done, at or before the study week as specified  
c Only biopsy done, at or before the study week as specified 
Clearance of HPV 16/18 from the cervix was observed in both treatment groups (Figure 1a) at similar 
rates until after the second dose when clearance in the VGX-3100 recipients continued to rise while the 
rate appeared to plateau in the placebo group. 
34

Figure 1.  HPV 16/18 Clearance and Pap Smear Findings in Phase 2b mITT Population by
Treatment Group
At Week 36, clearance was significantly higher among VGX-3100 subjects that had biopsy (63%) versus 
LEEP/CKC (41%), which likely reflects the association between clearance of the underlying HPV 
infection and the likelihood of having signs indicative of regression by colposcopic exam. HPV 16/18 
clearance data (mITT population) post-Week 36 are described as follows: HPV 16/18 clearance at Week 
62 was 89% (50/56) for VGX-3100 post-LEEP/CKC, 82% (42/51) for VGX-3100 post Biopsy only, 96% 
(27/28) for Placebo post-LEEP/CKC, and 82% (9/11) for Placebo post Biopsy only.  HPV 16/18 clearance 
at Week 88 was 89% (48/54) for VGX-3100 post-LEEP/CKC, 89% (42/47) for VGX-3100 post Biopsy 
only, 89% (24/27) for Placebo post-LEEP/CKC, and 100% (10/10) for Placebo post Biopsy only. 
The majority of subjects had cleared their underlying cervical HPV 16/18 infection by Week 62 without 
meaningful changes through Week 88, and without meaningful differences between groups. Forty-seven 
of 53 (89%) and 46 of 49 (94%) subjects at Weeks 62 and 88, respectively (mITT population) with 
histopathologic evidence of CIN2/3 regression (regressors) in the VGX-3100 treatment group 
experienced HPV 16/18 clearance. Despite the use of therapeutic resection for many VGX-3100 
recipients whose CIN2/3 did not regress by Week 36 (non-regressors), HPV 16/18 clearance rates were 
notably lower (85% at Week 88) compared to regressors.  
In the subjects who initially cleared HPV 16/18 by Week 36, only one HPV 16/18 recurrence was 
identified at the Week 62 and 88 evaluations. Specifically, one subject who had HPV types 16 and 82 and 
CIN2 at screening, was HPV negative at Week 36, but tested HPV type 16 positive at Week 62, and then 
cleared HPV 16 at Week 88. The subject showed histopathologic regression at Week 36. No recurrences 
were identified in the eleven subjects in the placebo group with valid HPV data at Weeks 62 or 88. There 
were no (0/51) recurrences identified in the VGX-3100 treated group at Week 88. Overall, these virologic 
clearance findings support that study subjects had no increased risk as compared to standard of care.  
Cytology (mITT population) post-Week 36 are described as follows: Improvement compared to study 
entry for Pap smear cytology results at Week 62 were 93% (52/56) for VGX-3100 post-LEEP/CKC, 
100% (51/51) for VGX-3100 post-Biopsy only, 93% (26/28) for Placebo post-LEEP/CKC, and 82% 
(9/11) for Placebo post-Biopsy only. At Week 62, cytopathologic improvement was reported for 104 of 
Week 14
Week 62
Week 88
a.
b.
35

125 (83%) subjects in the VGX-3100 treatment group and 34 of 42 (83%) subjects in the placebo 
treatment group (mITT population).  
There were no instances of possible progression, and all cases that did not meet the definition of 
improvement were due to either no change from baseline, sample considered not evaluable, or no data 
available.  Improvement compared to study entry for Pap smear cytology results at Week 88 were 96% 
(52/54) for VGX-3100 post-LEEP/CKC, 91% (43/47) for VGX-3100 post-Biopsy only, 85% (23/26) for 
Placebo post-LEEP/CKC, and 100% (11/11) for Placebo post-Biopsy only.  At Week 88, possible 
progression (atypical glandular cells) was reported in a single Placebo subject in the post-LEEP/CKC 
group (3%) and no subjects treated with VGX-3100. All other cases that did not meet the definition of 
improvement were due to either no change from baseline, sample considered not evaluable, or no data 
available. The majority of subjects showed improvement, and there was no meaningful difference 
between the Week 62 and Week 88 evaluations.   These findings support that study subjects had no 
increased risk of progression based upon cytology as compared to standard of care. 
The protocol-specified removal of dysplastic cervical tissue at Week 36 by either method substantially 
affected the clearance of HPV 16/18 and normalization of cytologic findings as expected, regardless of 
treatment group (Figure 1a, b). HPV 16/18 clearance rises at a sharp rate after tissue is removed at Week 
36 whether the excision is wide (LEEP/CKC) or more limited (biopsy). Notably, the method of tissue 
collection at the Week 36 endpoint did not appreciably affect the HPV 16/18 clearance rates beyond 
Week 36 (Table 8).   Based upon the Phase 2b results, the risk of progression or recurrence of cervical 
dysplasia is low and comparable to the rates observed post-LEEP/CKC in clinical practice.  The long 
term follow up planned for this Phase 3 study will include safety, cytology and HPV 16/18 testing at 6 
months and also 1 year following the Week 36 histopathologic assessment, which is highly conservative 
given the expectation that few subjects will have persistent evidence of disease after the removal of tissue 
at Week 36 which is supported by the findings in the Phase 2b study. 
3 HYPOTHESIS AND STUDY OBJECTIVES 
3.1 
HYPOTHESIS 
Three 6 mg doses of VGX-3100X (DNA Plasmids encoding E6 and E7 proteins of HPV-16 and HPV-
18) delivered IM followed by EP with CELLECTRA™ 5PSP to adult women with histologically 
confirmed HSIL of the cervix, associated with HPV-16 and/or HPV-18 will result in a higher percentage 
of women with histopathological regression of cervical HSIL lesions to no evidence of cervical HSIL and 
virologic clearance of HPV 16/18 compared to placebo delivered IM followed by EP with 
CELLECTRA™ 5PSP at the Week 36 visit. 
3.2 
PRIMARY OBJECTIVE AND ENDPOINT 
Objective 
Endpoint 
Determine 
the 
efficacy 
of 
VGX-3100X 
compared with placebo with respect to 
combined histopathologic regression of cervical 
HSIL and virologic clearance of HPV-16 and/or 
HPV-18 
Proportion of subjects with no evidence of  
cervical HSIL on histology (i.e. biopsy or 
excisional treatment) and no evidence of HPV-
16 and/or HPV-18 in ThinPrep® cervical 
samples by type specific HPV testing at Week 
36 visit 
36

3.3 
SECONDARY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Objectives 
Associated Endpoints 
1. Evaluate the safety and tolerability of VGX-
3100X delivered IM followed by EP with 
CELLECTRA™ 5PSP 
1a. Incidence and severity of local and systemic 
events for 7 and 28 days following each 
investigational treatment  and for the duration 
of the study (through Week 88 visit) 
1b. Incidence and severity of serious adverse 
events (SAE) and Unanticipated [Serious] 
Adverse Device Effects (UADE) for 7 and 28 
days following each investigational treatment 
and for the duration of the study (through 
Week 88 visit) 
2. Determine 
the 
efficacy 
of 
VGX-3100X 
compared with placebo as measured by 
histopathologic regression of  cervical HSIL  
2. Proportion of subjects with no evidence of  
cervical HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 36 visit 
3. Determine the efficacy of VGX-3100X 
compared with placebo as measured by 
virologic clearance of HPV-16 and/or HPV-18 
3. Proportion of subjects with no evidence of 
HPV-16 and/or HPV-18 in ThinPrep® cervical 
samples  by type specific HPV testing at Week 
36 visit 
4. Determine 
the 
efficacy 
of 
VGX-3100X 
compared with placebo as measured by 
complete 
histopathologic 
regression 
of   
cervical HSIL to normal 
4. Proportion of subjects with no evidence of LSIL 
or HSIL (i.e.  no evidence of CIN1, CIN2 or 
CIN3) on histology (i.e. biopsies or excisional 
treatment) at Week 36 visit 
5. Determine 
the 
efficacy 
of 
VGX-3100X 
compared with placebo as measured by both 
complete histopathologic regression of  cervical 
HSIL to normal and virologic clearance of 
HPV-16 and/or HPV-18 
5. Proportion of subjects with no evidence of LSIL 
or HSIL (i.e. no evidence of CIN1, CIN2 or 
CIN3 on biopsies or excisional treatment) on 
histology (i.e. biopsies or excisional treatment) 
and no evidence of HPV-16 and/or HPV-18  by 
type specific HPV testing at Week 36 visit 
6. Determine the efficacy of VGX-3100X 
compared with placebo as measured by 
histopathologic non-progression 
6. Proportion of subjects with no progression of 
cervical HSIL from baseline on histology (i.e. 
biopsies or excisional treatment) at Week 36 
visit 
7. Determine the humoral and cellular immune 
response following administration of VGX-
3100X compared with placebo at post dose 3, 
Week 36 and Week 88 visits compared to 
baseline  
 
 
7a. Levels of serum anti-HPV-16 and anti-HPV-18 
antibody concentrations at baseline, Week 15, 
36, and 88 visits 
7b. Interferon-γ ELISpot response magnitudes at 
baseline, Weeks 15, 36, and 88 visits 
7c. Flow Cytometry response magnitudes at 
baseline and Week 15 visits 
37

3.4 
EXPLORATORY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Objectives 
Associated Endpoints 
1. Evaluate tissue immune responses to VGX-
3100X in cervical samples 
Assessment of markers including but not 
limited to CD8+ and FoxP3+ infiltrating cells. 
Additional assessments may include 
visualization of Granulysin, Perforin, CD137, 
CD103 and PD-L1 in cervical tissue as sample 
allows.  Markers listed here may change as new 
relevant information becomes available 
2. Describe the clearance of HPV-16 and/or HPV-
18 infection from anatomic locations  outside 
the cervix 
2. Proportion of subjects who have cleared HPV-16 
and/or HPV-18 on specimens from outside the 
cervix (inclusive of oropharynx, vagina and peri-
anus) at Week 36 Visit 
3. Evaluate effect of HLA type on efficacy 
 
3. HLA (per-locus and per-allele basis) in 
conjunction with histologic regression of  
cervical HSIL at Week 36 visit 
4. Describe association of previous colposcopy, 
cytology and HPV testing results with 
histologic regression at Week 36   
4. Colposcopy, cytology, and HPV test results at 
Weeks 15 and 28 visits in conjunction with 
histologic regression of cervical HSIL at Week 
36 visit 
5. Describe the durability of virologic clearance of 
HPV-16 and/or HPV-18 for subjects treated 
with VGX-3100X compared with those treated 
with placebo 
5. Proportion of subjects with no evidence of HPV-
16 and/or HPV-18 by type specific HPV testing 
at Weeks 62 and 88 visits 
6. Describe the patient-reported outcomes for 
subjects treated with VGX-3100X 
6. The following two questionnaires; Short Form 
Health Survey, version 2 (SF-36v2TM) and EQ-
5D-5LTM will be self-administered prior to first 
dose (i.e. Day 0), following each dose, and at 
Weeks 28, 40 and 88 to measure score(s). 
 
 
38

4 SELECTION OF SUBJECTS 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in the study: 
1. Women aged 18 years and above; 
2. Confirmed cervical infection with HPV types 16 and/or 18 at screening;  
3. Cervical tissue specimen/slides provided to Study Pathology Adjudication Committee for diagnosis 
must be collected within 10 weeks prior to anticipated date of first dose of study drug; 
4. Histologic evidence of cervical HSIL as confirmed by PAC at screening; 
5. Must understand, agree and be able to comply with the requirements of the protocol. Subjects must 
be willing and able to provide voluntary consent to participate and sign a Consent Form prior to study-
related activities; 
6. Must be judged by Investigator to be an appropriate candidate for the protocol-specified procedure 
(i.e. excision, 4-quadrant biopsy with ECC, or 4-quadrant biopsy) required at Week 36 
7. Has satisfactory colposcopy, defined as full visualization of the squamo-columnar junction (Type I 
or II transformation zone) and complete visualization of the upper limit of aceto-white epithelium or 
suspected CIN disease; 
8. Must have a cervical lesion that is accessible for sampling by biopsy instrument (e.g. Mini-Tischler 
device); 
9. Must have a cervical lesion of adequate size to ensure that a visible lesion remains after screening 
biopsy; 
10. Must meet one of the following criteria with respect to their reproductive capacity: 
a) Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months or 
spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL 
b) Is surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 12 months prior to screening 
c) WOCBP is willing to use a contraceptive method with failure rate of less than 1% per year when 
used consistently and correctly from screening until 6 months following the last dose of 
investigational product. Acceptable methods are the following: 
o Hormonal contraception: either combined or progestin-alone including oral contraceptives, 
injectable, implants, vaginal ring, or percutaneous patches. Hormonal contraceptives must not 
be used in subjects with a history of hypercoagulability (e.g., deep vein thrombosis, pulmonary 
embolism). 
o Abstinence from penile-vaginal intercourse when this is the subject’s preferred and usual 
lifestyle 
o Intrauterine device or intrauterine system 
o Male partner sterilization at least 6 months prior to the female subject’s entry into the study, 
and this male is the sole partner for that subject 
39

11. Has normal screening ECG or screening ECG with no clinically significant findings, as judged by the 
investigator. 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from enrollment in the study: 
1. Has microscopic or gross evidence of adenocarcinoma-in-situ (AIS), high grade vulvar, vaginal 
(inclusive of cervical HPV-related lesions that extend into the vaginal vault), or anal intraepithelial 
neoplasia or invasive cancer in any histopathologic specimen at screening; 
2. More than 10 weeks have elapsed between date of initial tissue biopsy for screening and day of first 
dose(i.e. Day 0); 
3. Has cervical lesion(s) that cannot be fully visualized on colposcopy due to extension high into cervical 
canal at screening; 
4. Has history of ECC which showed cervical HSIL indeterminate, or insufficient for diagnosis (ECC is 
not performed as part of study screening); 
5. Has treatment for cervical HSIL or genital warts within 4 weeks prior to screening; 
6. Is pregnant, breastfeeding or considering becoming pregnant during the study; 
7. Has history of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are 
allowed, e.g. GardasilTM, CervarixTM); 
8. Has presence of any abnormal clinical screening laboratory values greater than Grade 1 per Common 
Toxicity Criteria for Adverse Events (CTCAE) v 4.03 within 30 days prior to Day 0 or less than Grade 
1 but deemed clinically significant by the investigator; 
9. Has immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening 
b) Primary immunodeficiencies 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent; (use of inhaled, otic, and ophthalmic corticosteroids are allowed) 
d) 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) 
e) History of solid organ or bone marrow transplantation 
f) Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
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. 
10. Has received any non-study, non-live vaccine within 2 weeks of Day 0; 
11. Has received any non-study, live vaccine (e.g. measles vaccine) within 4 weeks of Day 0; 
12. Has current or history of clinically significant, medically unstable disease which, in the judgment of 
the investigator, would jeopardize the safety of the subject, interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results (e.g. chronic renal failure; 
40

angina, myocardial ischemia or infarction, class 3 or higher congestive heart failure, cardiomyopathy, 
or clinically significant arrhythmias); 
13. Has malignancy or treatment for malignancy within 2 years of screening, with the exception of 
superficial skin cancers that only require local excision;  
14. Presence of acute or chronic bleeding or clotting disorder that would contraindicate IM injections, or 
use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of Day 0; 
15. Has history of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic agents; 
16. Has sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or a 
diastolic blood pressure >95 mm Hg at Screening or Day 0; 
17. Has resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at screening 
or Day 0; 
18. Has prior major surgery within 4 weeks of Day 0; 
19. Has participated in an interventional study with an investigational compound or device within 30 days 
of signing informed consent; participation in an observational study is permitted; 
20. Has less than two acceptable sites available for IM injection considering the deltoid and anterolateral 
quadriceps muscles; 
21. Has tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
22. Has cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located 
in ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 
23. Has metal implants or implantable medical device within the electroporation area; 
24. Has active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere 
with adherence to study requirements; 
25. Is a prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of 
either a psychiatric or physical (i.e. infectious disease) illness; 
26. Is an active military service personnel; 
27. Is a study-related staff or family member of study-related staff; 
28. Has 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 STUDY SUBJECTS 
4.3.1 
CRITERIA FOR DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
Subjects who manifest Grade 4 toxicity attributable to the study treatment will be discontinued from 
the study treatment.  Subjects will not receive further study treatment but will be encouraged to 
continue follow-up safety assessment through study discharge and not discontinue from the study.  
If a subject manifests Grade 3 toxicity attributable to the study treatment, the medical monitor and 
Investigator will discuss whether further treatment should be continued for that subject.  
 
41

4.3.2 
CRITERIA FOR WITHDRAWAL FROM THE STUDY 
All randomized subjects should be encouraged to complete all study treatments and follow-up visits. 
A subject will be considered to have completed the study when she completes all scheduled study 
treatments and follow-up visits. However, a subject may voluntarily withdraw from study 
participation at any time or be withdrawn at any time at the discretion of the investigator for any 
maternal obstetrical or medical complications after consultation with the medical monitor. 
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. The site should also counsel the 
subject on the importance of maintaining the assigned visit schedule for follow-up and treatment of 
HSIL (CIN2, CIN3), and ascertain whether or not the subject wishes to and/or should continue in the 
study based on previous noncompliance. 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 they can appropriately be withdrawn from the study. 
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. 
If a subject elects to withdraw from the study (during or after study treatments), she should be 
encouraged to stay in the study and complete all follow-up visits and procedures. Subjects who are 
withdrawn from study participation after starting randomized treatment will not be replaced. Reasons 
for study withdrawal will be recorded in the eCRF and the subject’s source document. 
4.3.3 
SPONSOR NOTIFICATION OF DISCONTINUATION/ WITHDRAWAL  
The investigator or study coordinator must notify the Sponsor immediately when a subject has been 
discontinued/withdrawn due to an AE. If a subject discontinues from the study or is withdrawn from 
the study prior to study completion, all applicable activities scheduled for the final study visit should 
be performed at the time of discontinuation. The investigator will make every effort to have all 
scheduled immune assessment blood samples collected as indicated in the Schedule of Events in the 
synopsis, Table 1. Any AEs and/or SAEs present at the time of discontinuation/withdrawal should 
be followed in accordance with the safety requirements outlined in section 7.1 – Safety Parameters. 
4.3.4 
REASON FOR DISCONTINUATION/WITHDRAWAL 
The primary reason for a subject discontinuing further dosing or withdrawal from the study itself is 
to be selected from the following standard categories and recorded on the CRF: 
• Adverse Event (Adverse Reaction): Clinical or laboratory events occurred that, in the medical 
judgment of the investigator for the best interest of the subject, are grounds for discontinuation. 
This includes serious and non-serious adverse events regardless of relation to study drug. 
• Death of subject  
• Subject voluntarily withdrew consent:  The subject desired to withdraw from further participation 
in the study in the absence of an investigator-determined medical need to withdraw. If the subject 
gave a reason for withdrawal, it must be recorded on the CRF. This reason does not allow for 
42

further data collection and should not be selected if follow-up data collection of this subject is 
anticipated by the subject. 
•
Investigator decision to withdraw the subject from participation:  Investigator determined a
medical need to withdraw the subject.  Investigator must consult the Sponsor’s Medical Monitor
before withdrawing a subject from participation in the study
•
Protocol Violation: The subject’s findings or conduct failed to meet the protocol entry criteria or
failed to adhere to the protocol requirements (e.g., treatment noncompliance, failure to return for
defined number of visits). The violation should be discussed with the Sponsor’s Medical Monitor
prior to discontinuation of study treatments or study withdrawal.
•
Lost to Follow-up: The subject fails to attend study visits and study personnel are unable to
contact the subject after repeated attempts including telephone calls, letter sent by certified mail
or equivalent.
•
Other: The subject was terminated for a reason other than those listed above, such as the
termination of the study by the Sponsor
5 
STUDY TREATMENT 
5.1 
INVESTIGATIONAL PRODUCTS 
Investigational product (IP) 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.  The active and placebo 
formulations to be used in this study are described in Table 9.  Both IPs will presented in clear glass 
cartridges and will be injected intramuscularly. 
VGX-3100X and placebo will be provided by Inovio Pharmaceuticals, Inc. or its designee. 
Table 9. Investigational Products 
Product 
Formulation 
Dose 
VGX-3100X 
6 mg (1:1 mix of SynCon™ HPV-16 E6/E7 and HPV-18 E6/E7 plasmids) in 150 
mM sodium chloride and 15 mM sodium citrate 
1 mL 
Placebo 
150 mM sodium chloride and 15 mM sodium citrate 
1 mL 
5.2 
BLINDING 
This study is double-blinded with blinding maintained throughout the study by use of identical packaging 
for both the active product and the placebo. There is no difference in appearance for both the active 
product and the placebo.  
The investigator may request to unblind a subject’s treatment assignment in case of an emergency or 
serious medical condition when knowledge of the study treatment is essential for proper clinical 
management of the subject, as judged by the investigator.  It is preferred, but not required, that the 
investigator first contact the Medical Monitor to discuss options before unblinding the subject’s treatment 
assignment.  In case of non-emergency, investigator must contact Medical Monitor to discuss the options 
before unblinding the subject’s treatment assignment.  
43

The Sponsor’s or designee’s pharmacovigilance staff may unblind the treatment assignment for any 
subject with an SAE, UADE, or AE of interest. No personnel directly involved with the study will be 
unblinded.  If expedited regulatory reporting is required for an event, the report may be submitted to 
regulatory authorities with the subject’s treatment assignment, in accordance with local regulations. 
5.3 
PACKAGING AND LABELING OF INVESTIGATIONAL PRODUCT 
Each cartridge will be labeled with a single-panel label and then individually packaged within a pouch 
that will contain an additional, double-panel label with tear-off. Both VGX-3100X and placebo labels 
will include, at minimum, the following information in Table 10:   
Table 10. Example Labels for Investigational Product 
Cartridges 
(primary container) 
Pouches 
(secondary package) 
VGX-3100X or Placebo 
Insert cap end 
IM administration 
Inovio Pharmaceuticals, Inc. 
Study ID/Material ID 
VGX-3100X or Placebo 
Single-use, 1 mL 
Storage temperature, expiration date 
CAUTION: New Drug – Limited by United States Law 
to  
Investigation Use 
Inovio Pharmaceuticals, Inc. 
5.4 
HANDLING OF INVESTIGATIONAL PRODUCT 
Inovio Pharmaceuticals, Inc. will be responsible for assuring the quality of the IP is adequate for the 
duration of the trial. Unless otherwise specified, IP will be shipped in a refrigerated condition with a 
temperature monitoring device. If the temperature monitoring device denotes temperatures outside the 
pre-specified range for any product, the Sponsor, or its designee should be contacted immediately. 
Immediately upon arrival, IPs should be transferred from the shipping container into 2–8 °C (36-46 °F) 
storage, in a secure area, according to local regulations. The Sponsor should be notified of any deviations 
from this recommended storage condition.  
Refrigerator temperature logs must be maintained at the clinical site and temperatures must be recorded 
and monitored regularly. 
5.5 
DISPENSING OF INVESTIGATIONAL PRODUCT 
It is the responsibility of the Investigator to ensure that the IP is only dispensed to study subjects. It must 
be dispensed only from official study sites by authorized personnel according to local regulations. 
When a subject is eligible for randomization, remove the pouch from the refrigerator and allow to reach 
room temperature. The product cartridge must not be removed from the pouch until immediately prior to 
administration. The pouch must not be discarded until 1) administration is completed and 2) all pertinent 
information from the pouch label has been documented in source.  
The product must be used within 4 hours of removal from the refrigerator. 
44

The device user manual and instructions for use will inform clinical personnel about placement of the IP 
cartridge into the device, as well as the steps for injection and electroporation. 
5.6 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of investigational product is 
maintained at the study site. Records or logs must comply with applicable regulations and guidelines, and 
should include: 
• Amount received and placed in storage area; 
• Amount currently in storage area; 
• Label ID number and use date or expiry date; 
• Dates and initials of person responsible for each investigational product inventory 
entry/movement; 
• Amount dispensed to each subject, including unique subject identifiers; 
• Amount transferred to another area/site for dispensing or storage; 
• Amount returned to Sponsor; 
• Amount destroyed at study site, if applicable. 
5.7 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused and/or partially used IP must be returned to 
Inovio Pharmaceuticals, Inc., or its designee, if not authorized by Inovio Pharmaceuticals, Inc. to be 
destroyed at the site. 
The IP cartridge will be discarded along with the disposable array within a sharp’s container at site. 
All IP returned to Inovio Pharmaceuticals, Inc., or its designee, must be accompanied by the appropriate 
documentation. Returned supplies should be in the original containers. Empty containers should not be 
returned to Inovio Pharmaceuticals, Inc. It is the Investigator’s responsibility to arrange for disposal of 
all empty containers, provided that procedures for proper disposal have been established according to 
applicable federal, state, local and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. The return of unused IP(s) should be arranged by the responsible Study 
Monitor. 
If IP(s) are to be 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 according to applicable regulation and 
guidelines and institutional procedures, and appropriate records of the disposal have been documented. 
The unused IP can only be destroyed after being inspected and reconciled by the responsible Inovio 
Pharmaceuticals, Inc. or designated Study Monitor 
5.8 
INVESTIGATIONAL DEVICE 
The needle array component of CELLECTRA™ 5PSP device is provided sterile and is intended for single-
use. CELLECTRA™ 5PSP device is intended to be used by qualified and trained healthcare professionals 
in clinical settings. The Investigator for this study will be trained in the use of the device. 
CELLECTRA™ 5PSP has 3 main components that are used in conjunction with the drug cartridge (see 
Figure 2): 
45

1. Base – Acts as a docking station for the Handset and as the primary display for entering subject 
information; must be used with the provided Power Supply 
2. Handset – Controls delivery of the drug and electrical pulses 
3. Array (single-use sterile) – Attaches to the Handset and contains the injection needle, electrodes 
and sensors used for drug delivery and electroporation.   
4. Drug Cartridge (single-use) – a separate container-closure containing the IP solution. The 
Cartridge is inserted into the array for administration of the IP.  
 
Figure 2. Components of the CELLECTRA™ 5PSP device and drug cartridge 
 
 
 
The CELLECTRA™ 5PSP device has unique features that make using it different from using 
other injection systems: 
1. 
Each Handset is uniquely paired to a Base. The serial numbers on the bottom of the Base 
and Handset must match. 
2. 
There is no communication between the Base and Handset when separated; the Handset 
must be placed onto the Base to share power or data. 
3. 
The Handset has an internal battery that must be charged on the Base before use. 
4. 
Needle depth is selectable on the Handset at the following lengths: 13 mm, 19 mm, or 
25 mm. Even though the system provides a needle depth recommendation based on a 
3 
4 
2 
1 
Assembled View 
Stored View 
46

Subject’s height and weight, the user will be asked to manually enter the needle depth 
based on the protocol requirements (refer section 5.9), described  
5. 
Injecting the placebo and delivering electrical pulses takes time (usually 10 seconds). 
The Handset will let you know when treatment is complete. 
6. 
The Subject should be maintained in a safe and secure, braced position due to 
involuntary muscle spasms that may occur during delivery of the electrical pulses. 
Before using the CELLECTRA™ 5PSP device, the Investigator and research staff must be trained 
by the Inovio Pharmaceuticals Inc. device trainer(s) and be requested to read the entire user 
manual and complete the Self-Assessment. 
5.9 
USE OF INVESTIGATIONAL DEVICE 
The instructions for use of the device are located in the CELLECTRATM5PSP User Manual. Users of the 
CELLECTRATM 5PSP device must successfully complete training. Training will include review of the 
entire device user manual and instruction video and hands-on training. After training on the proper use of 
the CELLECTRATM5PSP device, intended users at each site will be required to demonstrate their 
competence in its use to Inovio or its designee. 
Briefly, the Handset and Array should be prepared according to the instructions in the user manual. 
Remove the array from its packaging while avoiding contact with the end of the array that attaches to the 
handset, and insert the drug cartridge into the array with the arrow on the cartridge pointing away from 
the handset.  
Attach the Array to the Handset and set the needle depth on the handset to the longest needle length 
judged to allow safe injection into the muscle per the investigator’s assessment.   
The subject must be in a safe and secure, braced position.  The subject’s body should touch the bed or be 
braced against the bed or have the study staff performing electroporation or assistant in the position to 
brace the subject’s arm or leg (as appropriate) as the EP is administered.  The user will then insert the 
CELLECTRA™ 5PSP needle array into the deltoid (or anterolateral quadriceps muscle as an alternate 
option, if deltoid muscle is not possible or appropriate) of the participant in accordance with the 
CELLECTRA™ 5PSP user’s manual instructions. Once triggered by the user, the device will 
automatically deliver the blinded treatment followed by the EP pulses. The entire treatment period lasts 
for about 10 seconds. 
The treatment 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. Individuals whose credentials do not meet the relevant local requirements may perform the 
treatment procedure under both of the conditions below: 
1. The procedure must be performed under the direct supervision of the Investigator or an approved 
Sub-Investigator who has already been trained by the sponsor’s personnel. 
2. The CV and any relevant qualifications of the individual must be reviewed and approved by the 
sponsor or its designee to perform the procedure. 
Any deviation from the above procedures must be approved by the sponsor or its designee. 
47

5.10  PACKAGING AND LABELING OF INVESTIGATIONAL DEVICE 
See below Figure 3 for example CELLECTRA™ 5PSP device component labels. 
 
Figure 3. Device Labels (Base, Handset, Array) 
 
           
                        
 
                                  BASE                                                                      HANDSET 
 
 
                                                                              ARRAY 
5.11  HANDLING OF INVESTIGATIONAL DEVICE 
The CELLECTRA™ 5PSP device and its components must be stored in a secure location according to the 
instructions in the User Manual. 
5.12  INVESTIGATIONAL DEVICE ACCOUNTABILITY 
The investigative site is responsible for maintaining investigational device and accountability logs. The 
device must have full traceability from the receipt of the products through the subject use, disposal or 
return of the products. The Site must document acknowledgement of receipt and notify Inovio upon 
receipt of investigational product. This includes the content shipped and condition upon receipt.  
For each subject treatment, there must be a record of each product used for that subject, i.e. 
CELLECTRA™ 5PSP serial number, array lot number and the study drug lot number. The used sterile 
disposable array attachment must be discarded after use in accordance with institutional policy regarding 
disposal of sharp needles/instruments. 
. 
. 
In O VI O 
lnput: USB-B 5V =-= 3A 
, M.-. t M.., C t
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CELLECTRA®5PSP 
IREFI M01-004420-02 Rev: 03 
BXXXXXX (I [g] ! 
... I lnovio Pharmaceuticals Inc., YYYY-MM 
-
San Diego, CA 92121 USA 
Made in USA. 
M12--004640--02 Rev. 03 
CELLECTRA® SPSP' 
I REif I M01-00'4371..02 Rev: 05 
-
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. . . ·o p;i,11rmaei!11JIICal!!l Inc_, YYYY-lillM, 
an Dlil'.{jD; GA ~1211 USA 
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I 
I 
48

5.13  RETURN OF INVESTIGATIONAL DEVICES 
Upon completion or termination of the study, all investigational devices and unused components must be 
returned to Inovio Pharmaceuticals, Inc. 
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 responsible Study Monitor. 
If product is to be 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 according to applicable regulation and 
guidelines and institutional procedures, and appropriate records of the disposal have been documented. 
6 STUDY PROCEDURES AND TREATMENTS 
This section lists the procedures and parameters for each planned study evaluation.  The timing of each 
assessment is listed in the Schedule of Events Table (see Table 1). 
A subject will be required to provide informed consent for use of any information collected prior to 
consenting and before any additional study specific procedures are performed.   
Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. 
Therefore, adherence to the study design requirements, including those specified in the Schedule of 
Events Table are essential and required for study conduct 
6.1 
BEFORE TREATMENT PROCEDURES 
6.1.1 
SCREENING EVALUATIONS 
After providing informed consent, subject’s cervical biopsy tissue samples (e.g., formalin fixed 
tissue, paraffin-embedded tissue) and/or biopsy slides will be sent to the PAC for review by two 
study pathologists. Discordant results will be reviewed by a third pathologist to achieve a consensus 
diagnosis. Subjects must have a diagnosis of histologic HSIL (CIN2 or CIN3) confirmed by the PAC 
and a screening cervical specimen (i.e. ThinPrepTM) test positive for HPV-16 and/or HPV-18 by 
Cobas® HPV test to be eligible for randomization into the study (provided the subject also meets 
other eligibility criteria). Subjects whose specimens also test positive for other HPV genotypes are 
not excluded as long as they have a positive result for HPV-16 and/or HPV-18. There will be a 
maximum allowable window of 10 weeks from the date of collection of the qualifying biopsy 
sample(s) (i.e. slides/samples(s) reviewed by PAC with HSIL consensus diagnosis), until the date of 
first study treatment (i.e. Day 0).  
• Biopsy specimens and colposcopic photographs obtained within 10 weeks prior to Day 0 as 
part of standard of care before the informed consent may be used as part of the screening and 
evaluation process.   
• If the pathology results of the initial biopsy obtained as part of standard of care are available 
confirming the presence of HSIL (CIN 2 or CIN 3), those biopsy slides or sample(s) may be 
sent directly to the PAC for concurrence after the subject has signed the informed consent.   
• For those individuals diagnosed with cervical HSIL by a local pathologist, where the initial 
biopsy slides or tissue obtained as part of standard of care are not available or cannot be 
obtained within a reasonable timeframe, colposcopy with cervical photography may be 
49

performed and an additional biopsy sample may be collected during screening at the 
discretion of the investigator and consent of the subject. The additional biopsy sample may 
be sent directly to the PAC for review, if allowable per local or institutional guidelines. 
The assessments during the screening period will determine the subjects’ continued eligibility for 
the study and also their ability to comply with protocol requirements by completing all assessments.  
The following evaluations/actions, unless noted, will be performed within 10 weeks and up to 1 day 
prior to dosing on Day 0 – except for the safety laboratory collections/assessments, which must be 
performed within 30 days prior to Day 0. All screening assessment values must be reviewed prior to 
study treatment. 
• Signed informed consent 
• ThinPrepTM sample for HPV typing and pap smear (subject should be requested to abstain 
from sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to sample collection) 
• Colposcopy with lesion photography and cervical biopsy 
• Demographics; including age, and race/ethnicity 
• Medical history; including concomitant medications review, history of prior cervical 
dysplasia, and pregnancy history 
• Socio-Behavioral Assessment; including self-reported smoking history, self-reported 
exposure to second-hand smoke, self-reported alcohol intake history, contraceptive 
history 
• Determination of eligibility per inclusion / exclusion criteria 
• Full Physical Examination (including height, weight and BMI measurements) 
• Vital signs (including oral temperature, respiratory rate, blood pressure and heart rate) 
• 12-lead ECG (within 30 days prior to Day 0) 
• Baseline laboratory evaluations (includes CPK, hematology and serum chemistry, 
urinalysis)  to be performed (within 30 days prior to Day 0); 
• Urine pregnancy test 
• Serology (HIV Antibody) (within 30 days prior to Day 0) 
• Whole blood (at least 34 mL) and serum (at least 4 mL)  for baseline immunologic assay 
• 2 Digene cervical brush samples  
6.2 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will be randomized to receive study treatment.  Visit 
dates and windows must be calculated from Day 0. 
6.2.1 
DAY 0 
The following evaluation will be performed on Day 0 prior to study treatment: 
• Determination of eligibility per inclusion / exclusion criteria 
• Randomization 
• Targeted Physical Exam 
• Vital signs 
• Urine pregnancy test 
50

• Whole blood (at least 34 mL) and serum (at least 4 mL)  for baseline immunologic assay 
(a total of at least 68 mL of whole blood and 8 ml serum should be collected prior to 
dosing on Day 0) 
• Colposcopy with lesion photography 
• ThinPrepTM sample for HPV typing and pap smear (subject should be requested to 
abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to sample collection) 
• 2 Digene cervical brush samples 
• Oropharynx (OP) sample by oral rinse and vaginal and anal swabs 
• Patient-Reported Outcomes (PROs) completion 
Study treatment will be administered and the following evaluations will be performed on Day 
0 post-treatment: 
• Post treatment adverse event and injection site reaction assessment within a minimum of 
30 minutes after study treatment  
• Distribute Subject Diary Card (SDC)  
• Download EP data from device  
 
6.2.2 
8-14 DAYS POST DOSE 1 PHONE CALL 
The following information will be evaluated during phone call: 
• Post treatment adverse event and injection site reaction evaluation 
• Review Day 0 SDC  
o The subject should submit their SDC (via email, fax, mail) to site personnel 
prior to the phone visit. If the SDC is not received in advance, site personnel 
should review all diary elements verbally. The hard copy of the SDC should 
be collected and reviewed at the next in-person study visit. After completing 
a review of SDC and post treatment injection assessment with the subject on 
the phone, the Investigator or study personnel will determine whether an office 
visit is needed for further evaluation. 
• PRO completion 
6.2.3 
WEEK 4  
The following study evaluation will be performed on Week 4 prior to study treatment (± 4 
days): 
• Targeted Physical Exam 
• Vital signs 
• Urine pregnancy test 
• Collect SDC for dose 1 
The following study evaluations will be performed on Week 4 post treatment: 
• Post treatment adverse event and injection site reaction assessment within a minimal of 
30 minutes after study treatment;  
• Distribute SDC  
• Download EP data from device  
51

6.2.4 
8-14 DAYS POST DOSE 2  
The following information will be evaluated during phonecall:   
• Post treatment adverse event and injection site reaction evaluation 
• Review SDC for dose 2 
o The subject should submit their SDC (via email, fax, mail) to site personnel prior 
to the phone visit. If the SDC is not received in advance, site personnel should 
review all diary elements verbally. The hard copy of the SDC should be collected 
and reviewed at the next in-person study visit. After completing a review of SDC 
and post treatment injection assessment with the subject on the phone, the 
Investigator or study personnel will determine whether an office visit is needed for 
further evaluation. 
• PRO completion 
6.2.5 
WEEK 12 
The following study evaluation will be performed on Week 12 prior to study treatment (± 
4 days): 
• Targeted Physical Exam  
• Vital signs 
• Urine pregnancy test 
• Collect SDC regarding Dose 2 
The following study evaluations will be performed Week 12 post treatment: 
• Post treatment adverse event and injection site reaction assessment within a minimal of 
30 minutes after study treatment;  
• Distribute SDC  
• Download EP data from device  
6.2.6 
8-14 DAYS POST DOSE 3  
The following information will be evaluated during phonecall:   
• Post treatment adverse event and injection site reaction evaluation 
• Review SDC for dose 3 
o The subject should submit their SDC (via email, fax, mail) to site personnel prior 
to the phone visit. If the SDC is not received in advance, site personnel should 
review all diary elements verbally. The hard copy of the SDC should be collected 
and reviewed at the next in-person study visit. After completing a review of SDC 
and post treatment injection assessment with the subject on the phone, the 
Investigator or study personnel will determine whether an office visit is needed for 
further evaluation. 
• PRO completion 
6.2.7 
WEEK 15 
The following study evaluations will be performed on Week 15 ± 1 week: 
• Targeted physical assessment 
52

• Vital signs 
• Urine pregnancy test 
• Whole blood (at least 51 mL) and serum (at least 4 mL) for immunologic assays 
• Post-treatment injection site reaction assessment 
• ThinPrepTM sample for HPV typing and pap smear (subject should be requested to abstain 
from sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to sample collection)  
• 2 Digene cervical brush samples 
• Oropharynx (OP) by oral rinse and vaginal and anal swabs 
• Collect SDC  
• Colposcopy and lesion photography 
6.2.8 
WEEK 28 
The following study evaluations/actions will be performed on Week 28 ± 1 weeks: 
• Targeted physical Assessment 
• Vital signs 
• Urine pregnancy testing 
• 
ThinPrepTM sample for HPV typing and pap smear (subject should be requested to abstain 
from sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to sample collection)  
• 
2 Digene cervical brush samples 
• Colposcopy and lesion photography to assess for possible disease progression 
• PRO to be completed by subject 8-14 days after Week 28 visit 
6.2.9 
WEEK 36 
The following study evaluations will be performed on Week 36 ± 1 week: 
• Socio-Behavioral Assessment; including self-reported smoking history, self-reported 
exposure to second-hand smoke, self-reported alcohol intake history, contraceptive 
history 
• Targeted physical assessment 
• Vital signs 
• Whole blood (at least 34 mL) and serum (at least 4 mL) for immunologic assays 
• Urine pregnancy test 
• ThinPrepTM sample for HPV typing and pap smear (subject should be requested to 
abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to sample collection) 
• 2 Digene cervical brush samples 
• Oropharynx (OP) by oral rinse and vaginal and anal swabs 
• Colposcopy and lesion photography  
• Biopsy or surgical excision  
The investigator will utilize information collected at Week 28 to determine the appropriate method for 
obtaining tissue for histopathologic assessment as described in Tables 4 & 5 for minimally required 
procedure (4 quadrant biopsies, 4 quadrant biopsies and ECC, or excision).  
53

6.2.10 
WEEK 40 PHONE CALL 
The following study evaluations will be performed on Week 40 ± 2 weeks via a phone call:   
• Review of histology results as read by PAC from Week 36  
• PRO to be completed by subject 8-14 days after Week 40  
6.2.11 
WEEK 62 
The following study evaluations will be performed on Week 62 ± 2 weeks: 
• Targeted physical assessment 
• Vital Signs 
• ThinPrepTM sample for HPV typing and pap smear (subject should be requested to abstain 
from sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to sample collection) 
• 2 Digene cervical brush samples 
• Colposcopy and lesion photography 
6.2.12 
WEEK 88 
The following study evaluations will be performed on Week 88 ± 2 weeks: 
• Socio-Behavioral Assessment; including self-reported smoking history, self-reported 
exposure to second-hand smoke, self-reported alcohol intake history, contraceptive 
history 
• Full Physical Exam 
• Vital Signs 
• ThinPrep® sample for HPV PCR and pap smear (subject should be requested to abstain 
from sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to sample collection) 
• 2 Digene cervical brush samples 
• Colposcopy and lesion photography 
• Whole blood (at least 34 mL) and serum (at least 4 mL) for immunologic assays 
• Oropharynx (OP) by oral rinse and vaginal and anal swabs 
• PRO completion 
6.3 
EVALUATIONS AND PROCEDURES 
6.3.1 
INFORMED CONSENT 
All subjects must sign the informed consent prior to any study related procedures being performed 
(i.e., prior to any screening activities). The informed consent documentation must be in accordance 
with applicable regulations and GCP. Qualified study personnel will meet with prospective study 
subjects, explain the study, and provide them with an informed consent form (ICF) that describes the 
screening tests, eligibility criteria for entering the study, study treatments and follow-up procedures, 
in a language understandable to the subject. Explanation of the study includes, but is not limited to, 
study objectives, potential benefits and risks, discomforts/inconveniences, and the 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 study personnel will 
54

d oc u me nt  t he  pr ocess  of  o btai ni n g  i nf or me d  c o nse nt  wit hi n  t he  s o urce  rec or d.  Si g n e d  I C Fs  are 
mai ntai ne d i n t he s u bject’s s o urce rec or ds a n d m ust be accessi ble f or verifi cati o n at a n y ti me.  
6. 3. 2  
A S SI G N M E N T O F S U B J E C T I D E N TI FI C A TI O N N U M B E R S  
Eac h  s u bject  w h o  c o nse nts  will  be  assi g ne d  a  u ni q ue s u bject i de ntificati o n  n u m ber  ( SI D),  w hic h 
i de ntifies t he s u bject f or all st u d y-rel ate d pr oce d ures. SI Ds are a c o m bi nati o n of a u pt o t w o al p ha 
letters st u d y c o d e, t w o al p ha letter  C o u ntr y c o d e, t w o di git site n u m ber, pl us 3-di git s u bject n u m ber 
starti n g  wit h 
 ( e. g., 
).  O n ce  assi g ne d,  SI Ds  ca n n ot  be  re use d  f or  a n y  reas o n. 
I nf or mati o n re gar din g t h e SI D a n d scree n date m ust be d oc u me nte d o n a Scree ni n g l o g/s yste m an d 
i n t he I nteracti ve Res po nse Tec h n ol o g y ( I X R S). 
S u bjects meeti n g  eli gi bilit y criteri a will be ra n d o mize d b y a c o m p uter ge nerate d all ocati o n sc he d ule.  
6. 3. 3  
S A F E T Y E V A L U A TI O N S  
6. 3. 3. 1  
P h ysic al E x a m 
A f ull p h ysical e x a mi nati o n  ( P E) will be c o n d u cte d d uri n g s cree ni n g a n d st u d y disc h ar ge.  It  
will i ncl u de a n assess me nt of t he f oll o wi n g: ge neral  a p peara n ce, s ki n, hea d, e yes, ears, n ose, 
a n d t hr oat, a n d l y m p h n o des, a n d res pirat or y, car di o vasc ular, gastr oi ntesti n al,  ge nit o uri n ar y, 
m usc ul os keletal, a n d ne ur ol o gical s yste ms.   
A  tar gete d  p h ysi cal  a ss ess me nt  will  be  perf or me d  at  ot her  visits  as deter mi ne d  b y  t he 
in vesti gat or  or  directe d  per  s u bject  c o m plai nts.  T he  i njecti o n  site  is  t o  be  assesse d  b y  t he 
st u d y pers o n n el at 3 0 mi n utes after eac h st u d y treat me nt . 
6. 3. 3. 2  
 Vit al Si g ns  
Vital si g ns will be meas ure d at s pecifie d visits a n d  will i ncl u de:  
•  Sitti n g s yst olic  a n d diast olic bl o o d press ures wit h s u bject sitti n g at rest f or at least 5 
mi n utes bef ore meas ure m e nt 
•  Res pirati o n rate  
•  H eart r ate  
•  Oral te m per at ure meas ur e d wit h a n a ut o mate d t her m o meter   
 
 
6. 3. 3. 3  
Wei g ht a n d Hei g ht 
Wei g ht ( k g) a n d hei g ht (c m) will be c ollecte d at scree ni n g i n or der t o calc ulate t he B MI ( B MI 
= k g/ m 2). 
6. 3. 3. 4  
Me dic al Hist or y  
All rele va nt  (as j u d ge d b y t he i n vesti gat or) past a n d prese nt c o n diti o ns  at scree ni n g, as w ell 
as pri or s ur gical pr oce d ur es will be rec or d e d f or t h e mai n b o d y s yste ms.  T h e me dica l hist or y 
will i ncl u de a) a n y pri or hist or y of CI N dia g n ose d – wit h dia g n osis date(s) a n d res p ecti ve 
CI N le v el(s), a n d b ) if treate d pre vi o usl y f or CI N, t he res pecti ve treat me nt t y pe(s) a n d date(s).  
6. 3. 3. 5  
S oci o -Be h a vi or al Assess me nt  
S oci o -Be h a vi oral Assess me nt, i ncl u di n g self-re p orte d s m o ki n g hist or y, self-re p orte d hist or y 
of  e x p os ure  t o  sec o n d -ha n d  s m o ke,  self -re p ort e d  alc o h ol  i nta ke  hist or y,  self-re p orte d 
5 5
P P
D
P P D

recreational drug use history, self-reported history of contraceptive use and type of 
contraceptive if known, reproductive history, history of prior cervical dysplasia, and 
pregnancy history will be obtained. 
6.3.3.6 
Laboratory Evaluations 
At screening, blood samples will be taken to be tested for serum chemistry and hematology.  
Complete blood count (CBC): 
• White blood cell (WBC) count w/ differential 
• Red blood cell (RBC) count 
• Hemoglobin, Hematocrit 
• Platelet count 
Serum Chemistry: 
• Glucose 
• SGPT (serum glutamic-pyruvic transaminase)/ALT 
• BUN (blood urea nitrogen) 
• Creatinine 
• Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
• CPK (creatine phosphokinase) 
Urinalysis (UA):  
Urine samples will be tested at screening by dipstick for glucose, protein, and hematuria. If 
abnormal (presence of protein, hematuria, or glucose ≥ 1+) a microscopic examination should 
be performed. 
6.3.3.7 
Demographics 
Demographic information will be collected via self-report (unless noted otherwise), including 
the following: 
• Age (via date of birth) 
• Race/ethnicity 
6.3.3.8 
Urine Pregnancy Testing 
For subjects of reproductive potential, a negative spot urine pregnancy test is required prior 
to each study treatment, colposcopy and surgical excision. 
6.3.3.9 
ECG 
A single 12-lead ECG will be obtained during Screening after the subject has been in a supine 
position for 10 to 15 minutes. The ECG should include measurements of ventricular rate, PR, 
QRS, QRS axis, QT, QTcb or QTcf, ST segment, Twave as well as an investigator assessment 
of whether the ECG is normal or abnormal (automated interpretations of ECG should not be 
used). Abnormal ECGs should be interpreted as “clinically significant (CS)” or “not clinically 
significant (NCS)” by the investigator 
 
56

6.3.3.10 
Subject Post Treatment Assessments 
SDC will capture subject reported local and systemic events for 7 days after the study 
treatment as shown in Appendix A.  
The subject will be provided a SDC and will be asked to record the following the evening of 
study treatment through Day 6: 
• Oral temperature and time taken (before 11:59 pm) 
• General symptoms of feeling unwell 
• Pain and itching at injection site 
• Measure redness, swelling, bruising at injection site 
• Medications taken 
The completed SDC will be reviewed with the subject and research staff at 8 -14 Days post-
dose. 
The study staff will review the SDC for general symptoms (e.g. malaise, fatigue, headache, 
nausea, and myalgia/arthralgia), injection site reaction symptoms (e.g. pain, erythema and 
edema), medical events and medications. All reported events will be assessed for clinical 
significance (CS) and reported as adverse event accordingly. 
6.4 
INJECTION AND ELECTROPORATION (EP)  
Subjects will receive a 3-dose series of either 1 ml VGX-3100X or Placebo by IM injection in the deltoid 
(or anterolateral quadriceps muscle as an alternate option, if deltoid muscle is not possible or appropriate) 
followed immediately by EP with the CELLECTRA™ 5PSP. Study treatment must not be given within 2 
cm of a tattoo, keloid or hypertrophic scar.  If there is implanted metal, implanted device, within the same 
limb then use of the deltoid muscle on the same side of the body is excluded.  
6.4.1 
RISKS OF TREATMENT PROCEDURES 
Table 11 summarizes reported AEs and potential risk to study treatment.  
Table 11. Summary of Reported Adverse Events and Potential Risks or VGX-3100X delivered IM 
EP with CELLECTRA™ 5PSP 
Very Common  
• 
Mild to moderate injection site pain or tenderness 
• 
Malaise/fatigue, myalgia, or headache in the first few days following injection 
• 
Upper respiratory tract infection 
• 
Brief muscle contractions which may be uncomfortable 
• 
Nausea 
Common  
• 
Arthralgia 
• 
Injection site reactions such as erythema, pruritus, swelling, hematoma 
• 
Anxiety related to the administration procedure 
Less Common  
• 
Severe injection site pain or tenderness 
• 
Vasovagal reaction/lightheadedness/dizziness related to the administration procedure 
• 
Temporary bleeding at the injection site 
• 
Rash following administration  
57

Uncommon or rare  
• 
Injection site reactions such as laceration, induration, bruising/ecchymosis, or scab  
• 
Infection at the injection site  
• 
Muscle damage resulting in transient changes in creatine phosphokinase  
• 
Transient changes in clinical laboratory values 
Unknown frequency or 
theoretical potential risks 
• 
Severe localized administration site reaction, such as sterile abscess or secondary 
bacterial infection  
• 
Allergic reaction, including urticaria, angioedema, bronchospasm, or anaphylaxis  
• 
Chills, flu-like syndrome 
• 
Autoimmune disease 
• 
Electrical injury  
• 
Disruption of function of implanted electronic medical devices (if CELLECTRA TM 
5PSP device is not used per User Manual) 
• 
Exacerbation of unstable cardiac disease 
• 
Effects on the fetus and on pregnancy 
 
6.4.2 
MANAGEMENT OF ANXIETY AND PAIN DUE TO TREATMENT 
Subjects may be offered topical anesthetic (i.e. EMLA or equivalent), to prevent significant 
discomfort from the treatment procedure. If a topical anesthetic is used, an approximately 1.5 cm 
diameter amount will be applied with occlusion to the site of injection ~30 minutes prior to treatment.  
Subjects may be offered a mild sedative (e.g. 0.5-1 mg lorazepam), or equivalent, for anxiety related 
to the treatment procedure. Mild sedatives may be administered approximately 1 hour prior to 
treatment at day 0, Weeks 4 and/or 12. Subjects who receive a mild sedative should not be allowed 
to operate a motor vehicle for 3-4 hours after receiving medication and should have arranged 
transportation to depart the study site. 
Subjects may be offered an analgesic (e.g. ibuprofen, ketorolac) after injection/EP.  
Subjects who are allergic to or have contraindications to EMLA, ibuprofen, ketorolac or a mild 
sedative may be offered a suitable alternative.  
EMLA cream or sedatives should be added to the concomitant medications. 
6.5 
ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well as urine 
pregnancy testing at Screening will be performed for inclusion into the study as listed in section 6.1.1. 
6.6 
ASSESSMENT OF CLINICAL STUDY ADVERSE EVENTS 
The injection site will be assessed by study personnel prior to and within minimum of 30 minutes after 
each study treatment and at 2 to 4 weeks post study treatment visits.  They will also be advised to record 
local and systemic AEs for 7 days on a SDC as shown in Appendix A. 
A Medical/Clinical Assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any adverse events, concomitant medications new onset illness or disease, as 
well as contraceptive compliance. Subjects will be reminded to contact study personnel and immediately 
report any event that happens for the duration of the study. Unsolicited adverse events will be captured 
58

from the time of the informed consent to study discharge. These events will be recorded on the subject’s 
CRF. 
6.7 
ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the investigator will be instructed to use 
the following grading scale: 
Table 12. 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 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/Redness* 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling** 
2.5-5 cm and does 
not interfere with 
activity 
5.1-10 cm or interferes 
with activity 
>10 cm or 
prevents daily 
activity 
Necrosis 
- September 2007 “FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials” 
*In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a 
continuous variable 
**Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement 
6.8 
ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, previously-validated patient-reported outcomes 
(PRO) instruments will be provided to the subjects.  PRO questionnaires will include the following, along 
with the license holder, respective numbers of items and domains, and listed domains: 
• Short Form Health Survey, version 2 (SF-36v2TM) (Optum, Inc.):  generically measures 
functional health and well-being, for physical and mental health; consists of thirty-six items 
covering eight domains (Physical functioning, Role limitations due to physical problems, Bodily 
pain, General health, Vitality, Social functioning, Role limitations due to emotional problems, and 
Mental health) [24] ( See Appendix D for sample questionnaire).  
• EQ-5D-5L (EuroQol Research Foundation): generically measures activities & general health 
status; consists of six items covering six domains (Mobility, Self-care, Usual activity, 
Pain/discomfort, Anxiety/depression, and Global health status via VAS) [25, 26] (see Appendix 
E for sample questionnaire).  
59

 
The PRO instruments will be provided to subject and will be instructed to complete the questionnaire at 
the following time points:  
• Day 0 (before the first study treatment) 
• 8-14 days post dose 1 
• 8-14 days post dose 2 
• 8-14 days post dose 3 
• 8 -14 days post Week 28 
• 8-14 days post Week 40 
• Week 88  
Administration of PRO instruments will be performed according to the validated procedure and 
guidelines of each respective instrument, except for some assessments for exploratory analyses.   
6.9 
PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at baseline (screening and Day 0 prior to dosing) and 
at Weeks 15, 36, 88. Details of the immunology sample collection and shipment information will be 
provided in the Laboratory Manual. 
A standardized binding ELISA may be performed to measure the anti–HPV-16/18 antibody response 
induced by VGX-3100X. 
PBMCs will be isolated from whole blood samples. Assessment of cellular immune activity may occur 
via the application of the Interferon-γ enzyme-linked immunosorbent spot (IFN-γ ELISpot) assay as well 
as flow cytometry.  
Additional assessment of cellular immune activity may occur via the application Flow Cytometry for the 
purposes of performing a Lytic Granule Loading Assay. The Lytic Granule Loading assay may examine 
the following external cellular markers: CD3, CD4, CD8 (T cell identification), CD137, CD38 and CD69 
(T cell activation markers) as well as PD-1 (exhaustion/activation marker). The Lytic Granule Loading 
assay may additionally analyze the following intracellular markers: Granzyme A, Granzyme B, 
Granulysin and Perforin (proteins involved in lytic degranulation and cytotoxic potential). Markers 
examined in this assay may change as new relevant data become available. 
6.10 TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue or additional slides in the paraffin block after histologic diagnoses have been 
rendered, then unstained slides and/or the relevant paraffin blocks may be collected for 
immunohistochemistry (IHC).  Assessment of markers may include, but are not limited to, CD8+ and 
FoxP3+ infiltrating cells as well as assessment of cell death via Cleaved Caspase 3 assessment. Additional 
assessments may include visualization of Granulysin, Perforin, CD137, CD103 and PD-L1 in cervical 
tissue as sample allows.  Markers listed here may change as new relevant information becomes available 
6.11 HLA TYPING 
HLA testing will be performed on PBMC from any single blood sample collected for immunogenicity 
analysis. If the subject has a record of previous high resolution HLA testing and access to the results, then 
HLA testing is not required. 
60

The DNA extracted from the blood sample will be used to determine if alleles at the MHC locus affect 
the immune response to study treatment. Data arising from this study will be subject to same 
confidentiality as the rest of the study. This specimen will be destroyed immediately after the analysis 
and the results checked. 
6.12  PAP SMEARS AND HPV TESTING 
Pap smears will be obtained using ThinPrepTM test kits at the screening, Day 0, Weeks 15, 28, 36, 62, 88 
and read in a central laboratory. HPV PCR by Cobas® HPV test will be performed on the ThinPrepTM 
specimen. At each of these visits, menstrual cycle status & recent history will be collected via self-report.  
If the Pap smear result suggests progression to cancer at Day 0, Weeks 15, 28 or 36, the investigator may 
schedule an ad hoc visit to perform a colposcopy and possible biopsy if clinically indicated. 
The subject will be requested to abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to collection of ThinPrepTM samples to eliminate 
potential interference with the results of HPV testing.   
 At visits where multiple cervical samples are collected, the two Digene cervical brushes will be collected 
prior to the ThinPrepTM sample. Details of sample collection and shipment information will be provided 
in laboratory manual. 
6.13  COLPOSCOPY AND CERVICAL BIOPSIES 
Colposcopy at screening must be adequate, defined as full visualization of the squamo-columnar junction 
(Type I or II transformation zone) and complete visualization of the upper limit of aceto-white epithelium 
or suspected dysplasia. An ECC is not required for study entry. However, if an ECC was done as part of 
routine care during the screening period, and found to have evidence of cervical HSIL such subject should 
not be enrolled in the study. Colposcopy is not required to be performed at screening if adequate 
colposcopy was previously obtained upon collection of initial biopsy.  All colposcopies performed after 
informed consent must be conducted according to the procedures outlined in Appendix C. 
Interval colposcopies will be performed at Day 0, Weeks 15, 28, 36, 62, and 88.  An unscheduled 
colposcopy may be performed at the discretion of the investigator if there is suspicion of disease 
worsening or progression. 
Digital photographs of the cervix will be captured during each colposcopic examination to document the 
clinical findings. If a biopsy or surgical excision is performed, images of the cervix should be collected 
before and after the procedure. Each site will be instructed on 1) the technique for capturing the proper 
images using a standard approach and 2) the process for uploading the images to a secure server. 
Additionally, after subject is enrolled if vaginal or vulvar lesion should develop, photograph should be 
taken to document the clinical exam finding.  
6.13.1 
ECTOCERVICAL BIOPSIES 
Ectocervical biopsies are required at screening to confirm eligibility.  If the criteria outlined in Table 
5 or 6 are met, ectocervical biopsies may also be performed at Week 36 to provide tissue for 
histopathologic assessment of disease regression.   
Biopsies should not be performed at any other visit unless there is suspicion of disease progression.  
Removal of additional tissue by biopsy before Week 36 will bias results toward improvement 
regardless of whether the subject is in the active or placebo group. The bias introduced will obviously 
61

be more significant for smaller lesions.  For this reason, if biopsies are obtained prior to Week 36, 
the subject will be treated as a non-regressor. Subject safety is paramount in this study. Therefore, if 
at any time the investigator may suspect disease progression and the standard of medical care would 
be to perform an unscheduled biopsy prior to Week 36, then his or her medical judgment should 
prevail over the default “Schedule of Events”, Table 1. 
6.13.2 
UNSCHEDULED BIOPSIES 
In the event unscheduled biopsy is performed prior to Week 36, subject will be considered as non-
responder. The subject will discontinue further study treatment and continue in the study for safety 
follow-up visits. The subject will be managed according to standard of care and Investigator’s 
judgement based on results of histological diagnosis from unscheduled biopsy Additional 
instructions for collecting ectocervical biopsies are detailed in Appendix C. All biopsy 
samples/excised tissue will be sent to the PAC for review.   
6.14  CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to screening biopsy date 
of eligible subjects must be recorded on the CRF. Actual or estimated start and stop dates must be 
provided. Medical procedures performed within 8 weeks prior to screening biopsy date of eligible 
subjects that do not affect subject’s eligibility for participation and during the study (including over the 
counter or herbal), will be recorded on the CRFs. 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. Medication that is considered necessary for the subject’s safety and well-being may 
be given at the discretion of the investigator and recorded in the appropriate sections of the CRF.   
6.15  RESTRICTIONS 
6.15.1 
PROHIBITED CONCOMITANT MEDICATIONS AND TREATMENTS 
The following medications and treatments are prohibited: 
• Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent; use of inhaled otic and ophthalmic corticosteroids are allowed 
• 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) at screening and throughout the study 
• Administration of any non-study related, non-live vaccine within 2 weeks of any study treatment 
or within 4 weeks of any study treatment for any non-study, live vaccine 
• Blood thinners/Anticoagulants within 2 weeks of any study treatment 
 
6.15.2 
OTHER RESTRICTIONS 
Subjects should not use alcohol or drugs that would interfere with study requirements during the 
course of the study and should report ALL medications/drugs taken to the investigator and/or other 
study personnel. 
Subjects should refrain from becoming pregnant until 6 months following the last dose of 
investigational product by using appropriate contraceptive measures as (See Inclusion Criteria, 
Section 4.1).  Lapses in contraceptive use should be reported to investigator and/or other study 
personnel. 
62

Subject should abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to collection of ThinPrepTM samples. 
7 EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
7.1.1 
ADVERSE EVENTS: 
An adverse event (AE) is defined as any unfavorable and unintended change in the structure, 
function, or chemistry of the body, or worsening of a pre-existing condition, temporally associated 
with the use of a product whether or not considered related to the use of the product. In this study, 
such changes will be monitored, classified, and summarized, as Clinical or Laboratory AEs. Medical 
condition/diseases present before starting the investigational drug will be considered adverse events 
only if they worsen after starting study treatment. Throughout the course of the study, all solicited 
and unsolicited AEs will be monitored and reported on an AE CRF, including the event’s seriousness, 
severity, action taken, and relationship to investigational product(s). AEs should be followed until 
resolution or stable and the outcome will be documented on the appropriate CRF. All AEs should be 
recorded in standard medical terminology rather than the subject’s own words. 
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 study drug). 
• Any pre-existing condition that increases in severity, or changes in nature during or as a 
consequence of the study drug phase of a human clinical trial, will also be considered an AE. 
• Complications of pregnancy; see Section 7.1.9 for additional information. 
• AEs that occur from the study screening visit onwards and throughout the duration of the study, 
including the follow-up off study drug period will be recorded as an AE. 
• Conditions that lead to a medical or surgical procedure. 
AEs do not include the following: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed as a result of 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 informed consent form 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. 
 
7.1.2 
SERIOUS ADVERSE EVENTS: 
A serious adverse event (SAE) is any AE that meets one of the following conditions: 
63

• Death during the period of surveillance defined by the protocol; 
• Is immediately life-threatening (e.g., subject was, in the view of the Investigator, at immediate 
risk of death from the event as it occurred). This does not include an AE that, had it occurred in 
a more serious form, might have caused death; 
• An event requiring inpatient hospitalization or prolongation of existing hospitalization during the 
period of protocol defined surveillance (including any overnight stay in the hospital, regardless 
of 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 congenital anomaly or birth defect; 
• An important medical event that may not result in death, be life threatening, or require 
hospitalization, but based upon appropriate medical judgment, may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include 1) allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, 2) blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, 3) the development of drug dependency or drug abuse or 4) the 
development of a malignancy; 
• Is medically significant or requires intervention to prevent one or other of the outcomes listed 
above. 
7.1.2.1 
Clarification of Serious Adverse Events 
• Death is an outcome of an AE, and not an adverse event in itself. 
• The subject may not have been on investigational medicinal product at the occurrence of the 
event.  
• Dosing may have been given as treatment cycles or interrupted temporarily before the onset 
of the SAE, but may have contributed to the event.  
• “Life-threatening” means that the subject was at immediate risk of death from the event as 
it occurred. This does not include an event that might have led to death if it had occurred 
with greater severity. 
• Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is an SAE. 
• Inpatient hospitalization means that the subject has been formally admitted to a hospital for 
medical reasons, for any length of time. This may or may not be overnight. It does not include 
presentation and care within an emergency department nor does it include full day or 
overnight stays in observation status. 
 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis will be documented as the AE and/or 
SAE and not the individual signs/symptoms. 
Serious adverse events that are ongoing should be followed until resolution or are clinically stable. 
The reporting period for SAEs is described in Section 9.5. 
7.1.3 
UNEXPECTED ADVERSE DRUG REACTIONS AND EXPEDITED REPORTING 
An adverse drug reaction (ADR) is any noxious and unintended responses to a medicinal product 
related to any dose, for which a causal relationship between a medicinal product and an adverse event 
64

is at least a reasonable possibility; i.e., there is evidence to suggest a causal relationship between the 
product and the adverse event. An unexpected ADR is one, the nature or severity of which is not 
consistent with the applicable product information (investigator’s brochure, protocol, and user 
manual). Reports that add significant information on specificity or severity of a known, already 
documented SAE constitute unexpected events. For example, an event more specific or more severe 
than described in the Investigator's Brochure or protocol would be considered "unexpected.” Specific 
examples would be (a) acute renal failure as a labeled ADR with a subsequent new report of 
interstitial nephritis and (b) hepatitis with a first report of fulminant hepatitis.  
The Sponsor will assess each serious ADR report for expectedness, to determine if it is a serious 
unexpected suspected adverse reaction (SUSAR) which requires prompt reporting to regulatory 
authorities and participating investigators as an expedited report, according to the applicable 
regulatory requirements. Additional occurrences of the SUSAR will be required to be reported on an 
expedited basis until the applicable product information is amended. 
In addition to single-case reports of SUSARs, the Sponsor shall notify regulatory authorities and 
participating investigators of information that might materially influence the benefit-risk assessment 
of a medicinal product, sufficient to consider changes in product administration or overall conduct 
of a clinical investigation. Examples of such information include a clinically important increase in 
the rate of occurrence of a serious expected adverse event, the identification of a significant hazard 
to the subject population, or a major safety finding from a study conducted in animals. 
7.1.4 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
Unanticipated adverse device effect means 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.  
Per the definition above, a UADE is a type of serious adverse event (SAE) that requires expedited 
reporting on the part of the sponsor. As a reminder, all SAEs regardless of relationship to device, 
drug or procedure are to be reported to Sponsor by the study investigator within 24 hours. Sponsor 
will assess each device related SAE to determine if anticipated based on prior identification within 
the investigational plan.  
7.1.5 
ASSESSING SEVERITY (INTENSITY) 
Adverse events should be captured once on the CRF at the maximum severity reported.  
The investigator will grade laboratory AEs and clinical AEs with respect to the following levels of 
severity as per Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 for applicable subject 
populations: 
• Mild (Grade 1) 
• Moderate (Grade 2) 
• Severe (Grade 3) 
• Potentially Life Threatening (Grade 4)  
65

The investigator will grade injection site reactions in accordance with September 2007 FDA 
Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials. 
7.1.6 
CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS 
 A causally related AE is one judged to have a reasonable possibility of a relationship to the 
administration of the IP and/or the investigational device. An AE may also be assessed as not related 
to the IP and/or the investigational 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 adverse events and judging 
the relationship between the administration of the IP and device and a subsequent AE. The 
investigator is aware of the subject’s clinical state and thus may be sensitive to distinctions between 
events due to the underlying disease process versus events that may be product related and may have 
observed the event. The Sponsor will assess the overall safety of the IP delivered by EP and determine 
whether to report expeditiously to the regulatory agencies. 
Investigators should use their knowledge of the subject, the circumstances surrounding the event, 
available site and non-site laboratory and clinical records, and an evaluation of any potential 
alternative causes to determine whether or not an adverse event is considered to be related to the IP 
and/or the investigational device indicating "yes" or "no" accordingly. Causality should be assessed 
by the investigator as “yes, related” or “no, unrelated” by the following criteria: 
• Yes – there is a reasonable possibility that administration of the Study Treatment contributed to 
the event; 
• No – there is no reasonable possibility that administration of the Study 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 the investigational device; 
• 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 study; 
• Presence of risk factors in the Study Subject or use of concomitant medications known to increase 
the occurrence of the event. 
 
 
7.1.7 
ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK, urinalysis) independent of the underlying medical 
condition that require medical or surgical intervention or lead to IP interruption or discontinuation 
must be recorded as an AE, or SAE, if applicable. In addition, laboratory or other abnormal 
assessments (e.g., electrocardiogram, x-rays, vital signs) that are associated with signs and/or 
symptoms must be recorded as an AE or SAE if they meet the definition of an AE (or SAE) as 
described in Section 7.1. If the laboratory abnormality is part of a syndrome, record the syndrome or 
diagnosis (e.g., anemia) not the laboratory result (e.g., decreased hemoglobin). 
66

Any laboratory abnormality 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 study treatment 
• Has accompanying or inducing symptoms or signs 
• Is judged by the investigator as clinically significant 
7.1.8 
POST-STUDY REPORTING REQUIREMENTS 
All AEs and SAEs including deaths, regardless of cause or relationship, must be reported for subjects 
on study (including any protocol-required post-treatment follow-up). 
Investigators are not obligated to actively seek AEs or SAEs beyond the follow up period for subjects. 
However, if the investigator learns of an AE or SAE that occurs after the completion or termination 
visit and the event is deemed by the investigator to be related to the study treatment, he/she should 
promptly document and report the event to the study team and medical monitor. 
7.1.9 
PROCEDURES FOR DOCUMENTING PREGNANCY DURING STUDY 
Subjects who are pregnant or expect to become pregnant during the course of the study up to 6 months 
following the last study treatment of investigational product will be excluded from participation in 
the study. Should a subject become pregnant after enrolling in the study, she will not be given any 
further study treatments. A Pregnancy Form will be completed by the site personnel and submitted 
to the sponsor study team and medical monitor within 24 hours after learning of the pregnancy.  The 
investigator will also report this event to the IRB within 24 hours of becoming aware of the 
pregnancy. Sites must request the subject’s permission to query pregnancy outcome and follow each 
subject to determine the outcome of the pregnancy. Results will be summarized in the clinical study 
report (CSR).  
Subjects who become pregnant at any point during the study will continue to be followed for safety 
assessments without receiving further study treatment. Procedures that are contraindicated during 
pregnancy, including additional treatments, must not be performed. Investigators should use clinical 
judgment regarding subsequent study-related blood collection based on the presence or absence of 
anemia in each subject. Subjects who are not withdrawn will continue to be followed for safety 
assessments to study discharge per protocol.  
All pregnancies that occur from the time of first study treatment through the follow up visits must be 
reported. The investigator will monitor the subject and follow the outcome of the pregnancy. If the 
end of the pregnancy occurs after the study has been completed, the outcome will be reported directly 
to the study team and the medical monitor. 
7.2 
METHODS AND TIMING OF THE COLLECTION AND RECORDING OF SAFETY DATA 
Non-serious AEs and SAEs (and UADEs) will be collected for each subject from the time when informed 
consent is obtained through Week 88. 
The sources of AEs cover: 
1. The subject’s response to questions about her health (a standard non-leading question such as 
‘How have you been feeling since your last visit?’ is asked at each visit). 
2. Symptoms spontaneously reported by the subject. 
67

3.  E val uati o ns  a n d  e x a mi nati o ns  w here  t h e  fi n di n gs  are  assesse d  b y  t h e  i n vesti gat or  t o  b e 
cli nicall y si gnifica nt c ha n ges or a b n or m alities.  
4.  Ot her i nf or mati o n relati n g t o t he s u bject’s healt h bec o mi n g k n o w n t o t he i n vesti gat or (e. g. 
h os pitalizati o n).  
All A Es will be r e p orte d o n t he a p pr o priate C R F. A n y S A E ( or U A D E) o cc urri n g d uri n g t he c o urse of 
t he st u d y m ust be re p orte d t o t he s p o ns or wit hi n 2 4 h o urs of a w are n ess. 
7. 3  
S A F E T Y A N D T O XI CI T Y M A N A G E M E N T  
T he Me dical M o nit or will be res p o nsi ble f or t he o verall safet y m o nit ori n g of t he st u d y.  
Safet y assess me nts i ncl u de t he f oll o wi n g:  
•  I n ci de nce of all a d verse e ve nts classifie d b y s yste m or ga n class ( S O C), preferre d ter m, se v erit y, 
a n d relati o ns hi p t o st u d y treat me nt 
•  C ha n ges i n s afet y la b or at or y p ara m eters (e. g., he m at ol o g y, ser u m c he mistr y, a n d uri nal ysis) 
•  L ocal a n d s yste mic i njecti o n site re vie w; s pecial atte nti o n will  be pai d t o t he e x a mi nati o n of t he 
i njecti o n site. A d mi nistrati o n site reacti o ns a n d t he s u bject's c o m plai nts will be d oc u me nte d. 
7. 3. 1  
E V E N T S R E Q UI RI N G E X P E DI T E D R E P O R TI N G  
E ve nts re q uiri n g e x pe dite d re p orti n g ( E R E R) will be defi ne d as relate d a d v erse e ve nts d u e t o V G X-
3 1 0 0 X / place b o deli vere d wit h C E L L E C T R A ™ 5 P S P  t hat meets a n y of t he f oll o wi n g criteria:  
•  Gra de 3 or greater a d mi nistrati o n site er yt he ma, a n d/ or i n d urati o n rec or de d ≥ 2 h o urs after St u d y 
Treat me nt  
•  Gra de 4 or greater a d mi nistrati o n site pai n, te n der ness rec or de d ≥ 2 h o urs after St u d y Treat me nt 
•  Gra de 3 or greater f e ver  
•  Gra de 3 or greater s yste mic s y m pt o ms, i ncl u di n g ge n eralize d pr urit us 
As per t he T o xicit y Gr a de  f or H ealt h y A d ults a n d per C T C A E v 4. 0 3 .  T he m ost se vere gra de f or 
t hat partic ular e v e nt is t o be d oc u me nte d i n t he C R Fs. 
Sites will i nf or m t he S p o ns or vial e mail a n d t o desi g nee vial p h o ne or fa x of a n y E R E R wit hi n 2 4 
h o urs t o disc uss w het her f urt her d osi n g s h o ul d c o nti n ue b y c o nt acti n g I n o vi o as f oll o ws. 
      E M AI L:     Safet y @i n o vi o.c o m    
S A F E T Y F A X: 
 or 
 
S A F E T Y P H O N E: 
 
 
7. 3. 2  
S T O P PI N G R U L E S ( C RI T E RI A F O R P A U SI N G O F S T U D Y)  
•  If at a n y ti me d uri n g a st u d y o n e-t hir d ( 1/ 3) or m ore of t he s u bjects e x perie n ce a n E R E R , f urt her 
e nr oll me nt a n d st u d y tr eat me nt will be halte d i m me diatel y u ntil a t h or o u g h i n vesti gati o n has 
bee n  c o n d ucte d b y  t he  Me dical M o nit or, Pri nci pal  I n vesti gat or  f or  t h e  trial, a n d t he D S M B. 
O nl y t he D S M B ma y r e vie w u n bli n de d data i n ma ki n g t heir  rec o m me n d ati o n t o t he S p o ns or 
re gar di n g c o nti n uati o n of a trial.  
6 8
P P D
P P D
P P D

• If any SAE (or potentially life-threatening AE), or death assessed as related to study treatment 
occurs, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, 
IRB (if applicable) and the DSMB. 
• If three or more subjects in this study, experience the same Grade 3 or 4 adverse event, assessed 
as related to study treatment, further enrollment and study treatment will be halted immediately 
until a thorough investigation has been conducted by the Medical Monitor, Principal 
Investigator for the trial, and the DSMB. 
• In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to study 
treatment, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, 
IRB (if applicable) and the DSMB.  
The sponsor or designee will notify all investigators and IRBs/EC (if required) regarding the outcome 
of any investigation stemming from a Study Pause.  
Guidelines for assessing relatedness are detailed in Section 7.1.6. 
8 STATISTICAL ANALYSIS PLAN 
8.1 
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 with 
a histologic diagnosis of cervical HSIL. The study’s primary endpoint is binary: regression to 
CIN1/normal and clearance of HPV-16 and/or 18 infection from cervical tissue based on tissue collected 
at Week 36. The primary hypothesis is that VGX-3100X will be superior to placebo regarding the 
proportion who achieve the primary endpoint.  Secondary efficacy analyses involve regression to 
CIN1/normal, clearance of HPV-16 and/or 18 infection from cervical tissue and non-progression of 
cervical lesions. Other secondary analyses concern safety and humoral and cellular immunological 
measures.  Exploratory analyses concern tissue immunological measures, durability of clearance of HPV-
16 and/or 18 infection from cervical tissue, clearance of HPV-16 and/or 18 infection from non-cervical 
tissue, effect of HLA type on efficacy, association of colposcopy, cytology, and virology and efficacy, 
and patient-reported outcomes. 
8.2 
RANDOMIZATION AND BLINDING 
Subjects will be randomized (2 VGX-3100X:1 Placebo) in a stratified manner according to a) the degree 
of CIN observed in the biopsy specimens at screening (CIN2 vs. CIN3), b) BMI category (≤25 vs. >25 
kg/m2), and c) age category (<25 years vs. ≥25 years).  There will be no pre-determined number of 
subjects required to be randomized within each stratum.  To ensure that milder CIN2 disease is not over-
represented in the study, the percentage of subjects enrolled with CIN2 will not exceed 50% of the total 
enrolled. 
The study is double-blinded. 
69

8.3 
SAMPLE SIZE/POWER 
A sample of 165 subjects will be randomized to receive either 6 mg VGX-3100X or placebo IM followed 
by EP in a 2:1 ratio. This sample size provides 90% power to declare VGX-3100X superior to placebo, 
assuming the true proportion of subjects who achieve the primary endpoints is 40% and 15% for VGX-
3100X and placebo, respectively, and assuming 90% evaluability from randomization.  These 
assumptions are based on the mITT result from the Phase 2 study.     
8.4 
ANALYSES POPULATIONS 
Analysis populations will include: 
• The modified intention to treat (mITT) population includes all subjects who receive at least one 
dose of Study Treatment. Subjects in this sample will be grouped to treatment arms as randomized.  
Analysis of the mITT population will be primary for the analysis of efficacy in this study. 
• The per-protocol (PP) population comprises subjects who receive all doses of Study Treatments 
and have no protocol violations. Subjects in this sample will be grouped to treatment arms as 
randomized.  Analyses on the PP population will be considered supportive of the corresponding 
mITT population for the analysis of efficacy.  Subjects excluded from the PP population will be 
identified and documented prior to unblinding of the study database. 
• The safety analysis set includes all subjects who receive at least one does of Study Treatment. 
Subjects will be analyzed as to the treatment they received.  
Subjects who do not complete the study will not be replaced. 
8.5 
SUBJECT DISPOSITION 
Disposition will be summarized by treatment arm for all randomized subjects 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. 
8.6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline 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 mITT population.  Prior and concomitant medications will also be 
summarized with percentages in this fashion.  
8.7 
MEDICAL HISTORY 
The percentage of subjects with abnormal medical history findings will be summarized by body system, 
by treatment arm, for the mITT population. 
8.8 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior medications are those that were used before the start of the trial (prior to Day 0).  Concomitant 
medications are those used during the course of the trial (on or after Day 0).  Partial start dates of prior 
and concomitant medications will be assumed to be the earliest possible date consistent with the partial 
date.  Partial stop dates of prior and concomitant medications will be assumed to be the latest possible 
70

date consistent with the partial date.  Data for all prior and concomitant medications will be summarized 
with percentages by treatment arm, for the mITT population. 
8.9 
EFFICACY ANALYSES 
The true treatment effect on the primary endpoint is δ = pV – pP, where pV and pP denote the true population 
probabilities of the primary endpoint for VGX-3100X and Placebo, respectively.  The primary hypothesis 
of superiority is:  
H0: δ ≤ 0 vs. H1: δ > 0. 
A p-value for this hypothesis test and corresponding 95% confidence interval will be computed based on 
the method of Miettinen and Nurminen [27].  Superiority will be concluded if the one-sided p-value is 
<0.025 and the corresponding lower bound of the 95% CI exceeds zero. 
The secondary efficacy endpoints will be analyzed in the same manner as the primary hypothesis, but 
without the hypothesis test p-values. 
The histopathologic efficacy time frame is defined by those who have undergone a biopsy or surgical 
excision at any time starting from 14 days prior to the protocol-specified target date of Week 36.  It also 
includes subjects who underwent early intervention prior to this time frame; these subjects are considered 
as failures for the efficacy endpoints.  Table 13 provides details for the definition of the primary endpoint 
response. 
Table 13.  Definition of Primary Endpoint Responder  and Non-Responder 
Responder 
Non-Responder 
Subject with no histologic evidence of 
cervical HSILa at Week 36 evaluation and 
no evidence of HPV-16 or HPV-18 at 
Week 36  
AND 
Subject in which a cervical tissue sample 
was NOT obtained between collection of 
tissue to determine entry eligibility up to 
Week 36 primary endpoint visit 
Subject with histologic evidence of cervical HSIL, 
AIS, cervical carcinoma at Week 36 evaluation  
OR 
Subject with evidence of HPV-16 or HPV-18 at Week 
36 
OR 
Subject in which an additional cervical tissue sample 
was obtained between collection of tissue to determine 
entry eligibility up to Week 36 primary endpoint visit 
a no evidence of HSIL is defined by histology as negative, squamous atypia, or LSIL 
Exploratory analyses will examine the relationship between the primary efficacy endpoint and a) HLA 
results, b) colposcopy results, c) cytology results, and d) HPV results.  As each of these results are 
categorical, relationships will be examined with contingency tables and logistic regression models which 
model the primary endpoint versus these results and treatment group as regressor variables. 
Other exploratory analyses will examine durability of clearance of HPV-16 and/or 18 infection from 
cervical tissue at Weeks 62 and 88, and clearance of HPV-16 and/or 18 infection from non-cervical tissue.  
71

Descriptive statistics will be utilized; percentages of subjects who cleared will be presented by time point 
or anatomic location and treatment group. 
8.10     IMMUNOGENICITY ANALYSES 
Post-baseline cellular and humoral response magnitude may be compared between treatment groups using 
a difference in medians and associated non-parametric 95% CI.  Post-baseline tissue response magnitude 
will be compared between treatment groups using a difference in means and associated t-distribution 
based 95% CIs. 
Valid samples for statistical analysis purposes will be those collected within 7 or 14 days of the specified 
time points (see Table 1).  Baseline is defined as the last measurement prior to the first treatment 
administration. 
8.11  SAFETY ANALYSES 
8.11.1 
ADVERSE EVENTS 
All AEs 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 14 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 [27].  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. 
Any AEs with a missing or partial onset date will be included in the overall AEs, but not be included 
within specified day-range summaries. AE duration will be calculated as (Stop Date – Start Date) + 
1. 
8.11.2 
LABORATORY DATA 
Continuous response variables per time point and changes from baseline will be summarized with 
mean, median, minimum, and maximum values, and categorical response variables will be 
summarized per time point with percentages, by treatment arm.  Baseline is defined as the last 
measurement prior to the first treatment administration. 
8.12 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 mITT population.  Baseline is defined as the last measurement prior to the first treatment 
administration. 
72

8.13 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 mITT population. 
8.14 PATIENT REPORTED OUTCOMES 
As an exploratory endpoint, patient reported outcomes among subjects who receive VGX-3100X will be 
compared between those with excision versus those without excision, based on PRO endpoints.  This 
comparison will utilize the median difference in endpoints or the difference in proportions of subjects 
with endpoints and associated non-parametric or Miettinen and Nurminen [27] 95% CIs, for continuous 
responses and binary responses, respectively. 
8.15 MISSING VALUES 
Missing data will not be imputed or replaced, and calculations will be done on reported values. 
A subject’s regression outcome is missing if her CIN grade and HPV clearance at Week 36 cannot be 
determined.  Any subject who had suspected disease progression before Week 36 will be considered a 
non-regressor regardless of the Week 36 result, even if missing. 
8.16  INTERIM ANALYSIS 
No formal interim analyses will be performed for this study.  For reasons of futility (early evidence of 
poor efficacy of VGX-3100X) or safety issues, the DSMB could recommend stopping enrollment at any 
time.  The type I error of 0.05 will not be adjusted for possible early stopping due to futility. 
9 DATA COLLECTION, MONITORING AND REPORTING 
9.1 
CONFIDENTIALITY AND PRIVACY 
A report of the results of this study may be published or sent to the appropriate health authorities in any 
country in which the study products are legally marketed or may ultimately be marketed, but the subject’s 
name will not be disclosed in these documents. The subject’s name may be disclosed to the study sponsor, 
Sponsor, the governing health authorities or the Food and Drug Administration (FDA), if they inspect the 
study records. Appropriate precautions will be taken to maintain confidentiality of medical records and 
personal information. 
Written Authorization and other documentation in accordance with the relevant country and local privacy 
requirements (where applicable) are to be obtained from each subject prior to enrollment into the study, 
and/or from the subject’s legally authorized representative in accordance with the applicable privacy 
requirements (e.g., the Health Insurance Portability and Accountability Act Standards for Privacy of 
Individually Identifiable Health Information (HIPAA). 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a 
signed subject authorization informing the subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
73

• The rights of the research subject to revoke their authorization for use of their PHI 
The rights of the research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the sponsor retains the ability to 
use all information collected prior to the revocation of subject authorization. For subjects that have 
revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at 
least vital status (i.e., that the subject is alive) at the end of their scheduled study period. 
9.2 
SOURCE DOCUMENTS 
Source data is all information, original records or clinical findings, laboratory results, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data 
are contained in original source documents. Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subject’s diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories, and at medical records and within information technology systems that are involved in the 
clinical trial. 
A medical history must be present in the source documents. A medication history must be present in the 
source documents. All prescription and nonprescription medications taken within l week prior to entry 
must be recorded on the CRF. Actual or estimated start and stop dates must be provided. 
9.3 
RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution should 
make available for direct access all requested 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 study essential documents for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation 
of clinical development of the investigational product. This retention period may be superseded by 
applicable regulatory requirements (e.g. minimum of 25 years for Health Canada). The sponsor will 
inform the investigator/institution as to when these documents are no longer needed to be retained. 
9.4 
SAFETY AND QUALITY MONITORING  
9.4.1 
DATA & SAFETY MONITORING BOARD 
A Data & Safety Monitoring Board (DSMB) will be established to protect the research subjects 
through independent analysis of emerging data from the trial.  The DSMB will meet quarterly or as 
data are available to review unblinded safety data and regression/clearance results.  If there are no 
new safety data or regression/clearance results to review for a quarterly scheduled meeting the DSMB 
will be notified and the meeting may be cancelled; Ad hoc meetings may be scheduled to review new 
data as applicable. The DSMB will be charged with advising the Sponsor if there appears to be a 
safety issue and with advising the Sponsor if it appears that regression in the VGX-3100X group is 
unacceptably low compared to the placebo group. No formal interim analysis will be performed. The 
74

DSMB Chair, upon consultation with the other voting members of the DSMB, has the authority to 
recommend suspension or stopping the study and to request a full DSMB review and ad hoc statistical 
analyses.   
The standard operating procedures of the DSMB will be documented in the DSMB charter, including 
the board’s accountability to Inovio. 
 
9.4.2 
PATHOLOGY ADJUCATION COMMITTEE 
All cervical biopsies will be read by a central expert Pathology Adjudication Committee (PAC) to 
ensure consistent assignment of disease status for both study eligibility and the efficacy analysis. The 
PAC will consist of a total of three pathologists. Each specimen will be read by two pathologists 
independently in a blinded fashion.  If the two pathologists agree the reading will be considered the 
clinical disease status for the subject.  If the readings of the first two pathologists are discordant, the 
third pathologist will review and if there is agreement among any of the three readings, it will stand 
as the clinical disease status for that subject.  If there is no agreement after the third review, the three 
reviewers will perform a simultaneous review and come to consensus or a majority rule of 2 of 3 if 
consensus cannot be reached.  A fourth pathologist will be identified to support the PAC in the event 
that one of the other pathologists is absent. 
9.4.3 
CLINICAL MONITORING 
Clinical Monitoring of the clinical trial will be performed by experienced monitors, who will report 
to the Sponsor or the Sponsor designee. Records for all clinical subjects in this trial will be monitored. 
The following clinical site monitoring tasks will be performed at all sites: 
• Prior to trial initiation, a site visit will be conducted to review all relevant forms and 
documentation, to ensure the site is qualified and compliant with all applicable requirements. 
• All clinical site monitoring visits will be documented. 
• Periodic site visits will be performed throughout the study. 
• The site monitor will be responsible for addressing and documenting the following study conduct 
activities and obligations and will: 
o Assure that the study is being conducted in accordance with the protocol, applicable regulatory 
agency regulations, and IRB policies 
o Discuss study conduct issues and incidents of noncompliance with the Investigator and/or 
study 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 serious 
adverse events (SAE) and provide subsequent follow-up report of the final outcome to the 
IRB 
o Throughout the study, inspect all source documents to ensure they are complete, logical, 
consistent, attributable, legible, contemporaneous, original, and accurate (ALCOA).  
o Assure that the study facilities continue to be acceptable 
o Compare the study 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 per 
laboratory manual requirements 
75

9. 5  
A D V E R S E E X P E RI E N C E ( A E) R E P O R TI N G  
T o ass ure t he safet y of t h e s u bject s, i nf or mati o n a b o ut all A Es (see Secti o n 7. 1), w het her v ol u nteere d b y 
t he  s u bject,  disc o ver e d  b y  i n vesti gat or  or  st u d y  staff  q uesti o ni n g,  or  detect e d  t hr o u g h  p h ysical 
e x a mi nati o n,  la b orat or y  test  or  ot her  mea ns,  w ill  be  c ollecte d  a n d  rec or de d  i n  t he  s u bject’s  s o urce 
d oc u me nts a n d f oll o we d as a p pr o priat e. 
9. 5. 1  
S T U D Y R E P O R TI N G P E RI O D O F A D V E R S E E V E N T S  
All s olicite d a n d u ns olicite d a d verse e v e nts will be c ollecte d t hr o u g h o ut t he st u d y a n d rec or de d o n 
t he A E C R F. Safet y e ve nts will be a nal yze d a n d s u m marize d t hr o u g h o ut t h e st u d y. E m p h asis will be 
place d o n t he f oll o wi n g :  
•  C ertai n A Es  of i nterest  will be s olicite d d uri n g t he 7 da ys f oll o wi n g eac h a d mi nistrati o n of St u d y 
Treat me nt a n d s u m marize d se paratel y  
•  U ns olicite d A Es , S A Es or U A D Es  will be c ollecte d a n d s u m marize d f or t he e ntire st u d y p eri o d  
9. 5. 2  
S T U D Y R E P O R TI N G P E RI O D O F S E RI O U S A D V E R S E E V E N T S  
T he re p orti n g peri o d f or S A Es ( wit h o ut re gar d t o ca usalit y  or relati o ns hi p ) is c o m prise d of t he peri o d 
f oll o wi n g  t h e  si g ni n g  of  t he  i nf or me d  c o nse nt  f or m  u ntil  t he  e n d  of  t he  st u d y.  Eac h  A E  will  be 
assesse d  t o  d eter mi ne  w het her  it  meets  seri o us ness  criteria.  If  t he  A E  is  c o nsi dere d  seri o us,  t he 
i n vesti gat or s h o ul d rec or d t his e ve nt t o t he S p o ns or wit hi n 2 4 h o urs of b ec o mi n g a w are of t h e e ve nt. 
T he i n vesti gat or ma y als o directl y re p ort t his e ve nt t o t he Et hics C o m mittee acc or di n g t o its sta n dar d 
o perati n g  pr o ce d ur es.  E x pecte d ness  of  S A Es  will  be  deter mi ne d  b y t he  S p o ns or usi n g  refere n ce 
safet y i nf or m ati o n s pecifie d i n t he I n v esti gat or’s Br oc h ure  a n d pr ot o c ol. A n e ve nt ma y q ualit y f or 
e x pe dite d  re p orti n g  t o  re g ul at or y  a ut h orities  if  it  is  a n  S A E,  u ne x pecte d  per  refere n ce  safet y 
i nf or mati o n a n d c o nsi der e d rel ate d f oll o wi n g t h e g ui deli nes i n Secti o n 7. 1. 3 ( S us pecte d U ne x pecte d 
Seri o us A d vers e Reacti o n, S U S A R) a n d 7. 1. 4 ( U na ntici pate d [seri o us] a d verse de vice effect) i n li ne 
wit h  rele va nt  le gislati o n.  All  i n vesti gat ors  will  recei ve  a  s afet y  letter  n otif yi n g  t he m  of  rel e va nt 
S U S A R re p orts. T he i n vesti gat or s h o ul d n otif y t h e I nstit uti o nal Re vie w B oar d (I R B)/ I nstit uti o nal 
Et hics C o m mittee  (I E C) as s o o n as is practical, of seri o us e ve nts i n writi n g w here t his is re q uire d b y 
l ocal re g ulat or y a ut h orities, a n d i n acc or da nce wit h t he l ocal i nstit uti o nal p olic y. At a n y ti me aft er 
c o m pleti o n of t he S A E re p orti n g peri o d, if a n i n vesti gat or bec o mes a ware of a n S A E t hat is s us pecte d 
b y t he i n vesti gat or t o be relate d t o t he st u d y dr u g, t he e v e nt will be re p orte d t o t he S p o ns or or its 
desi g nee. If t he i n vesti gat or bec o mes a w are of a n S A E i n a st u d y s u bject af ter t he last sc he d ule d 
f oll o w-u p visit, a n d c o nsi ders t he e ve nt relate d t o pri or St u d y Treat me nt, t he i n vesti gat or will re p ort 
it t o t he S p o ns or or t he a p pr o priate desi g nee. 
S P O N S O R  C O N T A C T I N F O R M A TI O N : 
      E M AI L:     Safet y @i n o vi o.c o m    
S A F E T Y F A X: 
 or 
 
S A F E T Y P H O N E: 
 
T h e pref err e d m et h o d f or pr o vi di n g S A E f or m s a n d a n y s u p p orti n g d o c u me nts t o t he S p o ns or is as 
a n  att ac h m e nt  t o  a n e-m ail  m ess a ge,  t o t h e e mail a d dresses  as  i n di cat e d  a b o v e  a n d b y  facsi mil e 
( Fa x), t o i n cl u d e a fa x c o vers h eet t h at i d e ntifi es t h e re p ort er a n d c o nt act i nf or m ati o n t o t h e desi g n ee.  
7 6
P P D
P P D
P P D

All supporting documents for SAE reports, including medical records and diagnostic test results, 
will include reference to the study subject number. The study site will redact all other subject 
identifying information present on SAE supporting documents prior to sending the report to the 
Sponsor.  
The report should contain as much clinical safety information as possible, but at minimum, the 
initial report must include the following information: 
• 
Event 
• 
Study number 
• 
Subject number (SID) and initials  
• 
Investigational Device serial number 
• 
Lot numbers  
• 
Reporter name and contact information 
In the case of a “minimum report” (one that is solely comprised of the information bulleted above), 
a more detailed follow-up report will be sent as soon as more information becomes available but no 
later than 5 calendar days after the date of the initial report. The investigator will supply the Sponsor 
and the IRB with any additional requested information. The original SAE form must be kept at the 
study site. The Sponsor or its representative will be responsible for determining and in turn, 
reporting SAEs to regulatory authorities according to the applicable regulatory requirements. SAEs 
must be followed by the investigator until resolution, even if this extends beyond the study-reporting 
period. Resolution of an SAE is defined as the return to baseline status or stabilization of the 
condition with the expectation that it will remain chronic. 
In the event of death, if an autopsy is performed, a copy of the report will be sent to the Sponsor. 
9.5.3 
NOTIFICATION OF SERIOUS ADVERSE EVENTS 
In accordance with local regulations, the Sponsor shall notify the appropriate regulatory authorities, 
and all participating investigators in a written safety report of any adverse experience associated with 
the use of the product that is both serious and unexpected and any significant new safety information 
that might materially influence the benefit-risk assessment of a medicinal product, sufficient to 
consider changes in product administration or overall conduct of a clinical investigation.. The 
Sponsor will notify regulatory agencies within the time frame specified by local requirements but no 
later than 10 working days for UADE, 7 days for a fatal or life-threatening SUSAR and 15 days for 
all other SUSARS (see Section 7.1.3 and 7.1.4).  
9.5.4 
REPORTING OF DEVICE RELATED COMPLAINTS 
A product complaint is defined as “any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a device after it is released for distribution.” All product complaints that meet this 
definition must be reported to the sponsor with 10 days of discovery 
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.  
Any problems experienced during the treatment procedure including potential malfunctions of the 
device, error messages displayed on the device screen following treatment or errors that occur during 
the treatment procedure must be reported to the Sponsor or designee immediately for evaluation. The 
77

error reporting form must be completed and emailed to the Sponsor at 
 as 
shown in Appendix B. 
9.6 
STUDY DISCONTINUATION 
Inovio Pharmaceuticals reserves the right to discontinue the study at this site or at multiple sites for safety 
or administrative reasons at any time. In particular, a site that does not recruit at a reasonable rate may be 
discontinued. Should the study be terminated and/or the site closed for whatever reason, all non-source 
documentation and study product pertaining to the study must be returned to Inovio Pharmaceuticals or 
its representative. 
The study may be discontinued at any time by an IRB, Inovio Pharmaceuticals Inc., the FDA or other 
government agencies as part of their duties to ensure that research subjects are protected. 
10 ETHICS 
10.1  INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The investigator and Sponsor are responsible for ensuring that the clinical study is performed in 
accordance with the protocol, the Declaration of Helsinki, principles of Good Clinical Practice 
(GCP), and applicable regulatory requirements.  
10.2 INSTITUTIONAL REVIEW BOARD OR INSTITUTIONAL ETHICS COMMITTEE (IRB/IEC) 
The investigator will undertake the study after full approval of the protocol and adjunctive 
materials (e.g., informed consent form, advertising) has been obtained from the applicable 
IRB/IEC and a copy of this approval has been received by the sponsor. 
Investigator responsibilities relevant to the IRB include the following: 
• During the conduct of the study, submit progress reports to the IRB/IEC as required.  
• Notify the Sponsor immediately of any SAEs or serious unanticipated adverse device 
effects. 
• If Sponsor notifies you about any reportable safety events notify the IRB immediately. 
• As required, obtain approval from the IRB/IEC for protocol amendments and for 
revisions to the consent form or subject recruitment advertisements; 
• Reports on, and reviews of, the trial and its progress will be submitted to the IRB by the 
investigator at intervals stipulated in their guidelines and in accordance with pertinent 
regulations and guidelines. 
• Maintain a file of study-related information that includes all correspondence with the 
IRB; 
• Notify IRB when study is completed (i.e. after the last study visit of the final study 
subject); 
• After study completion provide the IRB with a final report on the study. 
10.3 OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA) 
The investigator and Sponsor are responsible for ensuring that the clinical study is reviewed and approved 
according to local and applicable global regulations (e.g., NIH Office of Biotechnology Activities) 
governing research that involves recombinant or synthetic nucleic acid molecules.   
78

11 PROTECTION OF HUMAN SUBJECTS 
11.1  COMPLIANCE WITH INFORMED CONSENT REGULATIONS  
Written informed consent is to be obtained from each subject prior to Screening into the study, and/or 
from the subject’s legally authorized representative.  The process for obtaining informed consent must 
also be documented in the subject’s medical record.  
11.2  COMPLIANCE WITH IRB/IEC REQUIREMENTS 
This study is to be conducted in accordance with applicable IRB/IEC regulations.  The Investigator must 
obtain approval from a properly constituted IRB/IEC prior to initiating the study and re-approval or 
review at least annually.  Sponsor is to be notified immediately if the responsible IRB/IEC has been 
disqualified or if proceedings leading to disqualification have begun.  Copies of all IRB/IEC 
correspondence with the investigator must be provided to Sponsor. 
11.3  COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and guidelines.  
11.4  COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS (21CFR 
PART 11) 
When applicable, this study is to be conducted in compliance with the regulations on electronic records 
and electronic signature. 
11.5  COMPLIANCE WITH PROTOCOL 
Subjects are not required to follow special instructions specific to the Investigational Device used in this 
study however will be asked to complete a subject diary card during their study participation.  Subjects 
will be provided with Investigator emergency contact information and advised to report all adverse events. 
While every effort should be made to avoid protocol deviations, should a deviation be discovered, 
Sponsor must be informed immediately. Any protocol deviation impacting Subject safety must be 
reported to the Medical Monitor immediately. 
11.6  CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol without approval 
by Sponsor and prior review and documented approval/favorable opinion from the IRB of a protocol 
amendment, except where necessary to eliminate immediate hazards to study subjects, or when the 
changes involve only logistical or administrative aspects of the study (e.g., change in monitors, change 
of telephone numbers).  
12 FINANCING AND INSURANCE 
Inovio Pharmaceuticals is the sponsor in all participating countries and is fully supporting the study.  
Clinical trial insurance has been taken out according to the laws of the countries where the study will be 
conducted. 
79

13 PUBLICATION POLICY 
Publication of the results of this trial in its entirety will be allowed. The proposed presentation, abstract 
and/or manuscript must be made available to The Sponsor 60 days prior to submission for publication. 
The Sponsor shall have thirty (30) days after receipt of the copies to object to the proposed presentation 
or publication because there is patentable subject matter that needs protection. In the event that The 
Sponsor makes such objection, the researcher(s) shall refrain from making such publication or 
presentation for a maximum of three (3) months from the date of receipt of such objection in order for 
patent application(s) (directed to the patentable subject matter contained in the proposed publication or 
presentation) to be filed with the United States Patent and Trademark Office and/or foreign patent 
office(s). 
 
 
80

14  REFERENCES 
1. 
Centers for Disease C, Prevention. Human papillomavirus-associated cancers - United States, 
2004-2008. MMWR Morb Mortal Wkly Rep 2012,61:258-261. 
2. 
Satterwhite CL, Torrone E, Meites E, Dunne EF, Mahajan R, Ocfemia MC, et al. Sexually 
transmitted infections among US women and men: prevalence and incidence estimates, 2008. Sex 
Transm Dis 2013,40:187-193. 
3. 
Hariri S, Unger ER, Sternberg M, Dunne EF, Swan D, Patel S, et al. Prevalence of genital human 
papillomavirus among females in the United States, the National Health And Nutrition 
Examination Survey, 2003-2006. J Infect Dis 2011,204:566-573. 
4. 
American Cancer Society. Cancer Facts & Figures. In. Atlanta; 2016. 
5. 
Bruni L, Alberto G, Aldea M, Serrano B, Valencia S, Brotons M, et al. Human Papillomavirus 
and Related Diseases in theWorld. Summary Report 2015-12-23. ICO Information Centre on HPV 
and Cancer (HPV Information Centre). In; 2015. 
6. 
Guan P, Howell-Jones R, Li N, Bruni L, de Sanjose S, Franceschi S, et al. Human papillomavirus 
types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. Int J 
Cancer 2012,131:2349-2359. 
7. 
Apgar BS, Zoschnick L, Wright TC, Jr. The 2001 Bethesda System terminology. Am Fam 
Physician 2003,68:1992-1998. 
8. 
McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW, et al. Natural history of 
cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: 
a retrospective cohort study. Lancet Oncol 2008,9:425-434. 
9. 
McIndoe WA, McLean MR, Jones RW, Mullins PR. The invasive potential of carcinoma in situ 
of the cervix. Obstet Gynecol 1984,64:451-458. 
10. 
Future Ii Study Group. Supplementary Material: Quadrivalent vaccine against human 
papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007,356:1915-1927. 
11. 
The American College of Obstetricians and Gynecologists. FAQs Loop Electrosurgical Excision 
Procedure (LEEP). In; 2014. 
12. 
Aihara H, Miyazaki J. Gene transfer into muscle by electroporation in vivo. Nat.Biotechnol. 
1998,16:867-870. 
13. 
Gehl J, Mir LM. Determination of optimal parameters for in vivo gene transfer by electroporation, 
using a rapid in vivo test for cell permeabilization. Biochemical and Biophysical Research 
Communications 1999,261:377-380. 
14. 
Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospects for success. 
Curr.Opin.Immunol. 2011,23:421-429. 
15. 
van Drunen Littel-van den H, Hannaman D. Electroporation for DNA immunization: clinical 
application. Expert.Rev.Vaccines. 2010,9:503-517. 
16. 
Bodles-Brakhop AM, Heller R, Draghia-Akli R. Electroporation for the Delivery of DNA-based 
Vaccines and Immunotherapeutics: Current Clinical Developments. Mol Ther. 2009. 
81

17. 
Hirao LA, Wu L, Khan AS, Satishchandran A, Draghia-Akli R, Weiner DB. 
Intradermal/subcutaneous immunization by electroporation improves plasmid vaccine delivery 
and potency in pigs and rhesus macaques. Vaccine 2008,26:440-448. 
18. 
Khan AS, Pope MA, Draghia-Akli R. Highly efficient constant-current electroporation increases 
in vivo plasmid expression. DNA & Cell Biology 2005,24:810-818. 
19. 
Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, et al. Immunotherapy against 
HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci.Transl.Med. 
2012,4:155ra138. 
20. 
Diehl MC, Lee JC, Daniels SE, Tebas P, Khan AS, Giffear M, et al. Tolerability of intramuscular 
and intradermal delivery by CELLECTRA((R)) adaptive constant current electroporation device 
in healthy volunteers. Hum Vaccin Immunother 2013,9:2246-2252. 
21. 
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. 
22. 
Xiang L, Li J, Yang W, Xu X, Wu X, Wang H, et al. Conization Using an Electrosurgical Knife 
for 
Cervical 
Intraepithelial 
Neoplasia 
and 
Microinvasive 
Carcinoma. 
PLoS 
One 
2015,10:e0131790. 
23. 
Stoler MH, Vichnin MD, Ferenczy A, Ferris DG, Perez G, Paavonen J, et al. The accuracy of 
colposcopic biopsy: analyses from the placebo arm of the Gardasil clinical trials. Int J Cancer 
2011,128:1354-1362. 
24. 
EuroQol G. EuroQol--a new facility for the measurement of health-related quality of life. Health 
Policy 1990,16:199-208. 
25. 
Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Measurement 
properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-
country study. Qual Life Res 2013,22:1717-1727. 
26. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. Pharmacoeconomics 1993,4:353-365. 
27. 
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985,4:213-226. 
 
 
 
82

15 APPENDICES 
 
 
 
 
83

15.1 APPENDIX A:  SUBJECT DIARY CARD 
 
Subject Diary 
HPV-301 
Subject#: _____ _ 
Injection Date: ___ _ 
Note to Participant: 
For questions or problems, please contact your Site Coordinator. 
Participant Diary HPV-30 I 
Version I.0 -10May2016 
Name: -------------
Telephone: (~ _ __,) --------
Email (optional): ________ _ 
Page I 
84

 
General Instructions 
Temperature 
Take your temperature orally around the same time each evening, using the thermometer provided and 
record it in the space provided. Also record the time at which you took your temperature. If you recently 
drank very hot or cold liquids, wait 15 minute before taking your temperature. 
Injection Site Sym1>toms 
Pain and itching 
Some people experience pain in the ar a where they were injected. Some people may also experience 
itching in the area where they were injected. 
• 
By pain we mean that the place, here you were injected hurts even when it isn't touched. 
If you experience pain or itching at the injection site, use the following categories to describe how severe 
these symptoms were. If you don 't experience one or more of these symptoms, mark the O E box. 
• 
Mild 
I only had a little discomfort. I could still use my arm like always. 
• 
Mode1·ate 
•• I noticed the discomfort and didn 't use my arm as much as usual. 
• 
Severe • • 
I really noticed the discomfort. It kept me from doing something I wanted or had to do. 
"'. 
Redness, swelling, and bmising 
Some people experience redness, swelling, or brnising in the area where they were injected. If you 
experience redness, swelling, or brnising, measure the area using the measuring tool you were provided, and 
record the measurement in the space provided. 
To measure the area of redness, swelling, or bruising, do the following: 
• 
Place the measuring tool over the area where you were 
injected, with the dot over the center of the area. 
• 
Select the circle, here the longest part of the area touches 
the line. 
• 
If the area is in behveen two circles, select the larger 
circle. 
For example, the area shown to the right measures 3 
centimeters (cm) because it is touching the 3cm line. 
General and Other Symptoms or Medications 
If you have additional symptoms that are not listed, or if you sought medical care for any reason from a 
health care provider (e.g. doctor's office, emergency room), or if you took any medications, the. e should be 
listed in the spaces provided. Please designate any symptoms as Mild, Moderate, or Severe. 
• 
Mild (::) 
• 
Moderate 
• 
Severe ~• • 
I only had minor discomfort. I went about my usual activities. 
I noticed the symptom. It bothered me enough that I didn 't do a much as I u ·ually do. 
I really noticed the ymptom. It kept me from doing something I wanted or had to do. 
Participant Diary HPV-301 
Version 1.0 - 10 May 2016 
Page2 
85

 
Day 0: Evening oflnjection 
Subject#: ____ _ 
Date: __ / __ / __ 
Sometime during U1e evening on the day you were injected, fill out the information below. The items on this page 
refer to the time from your injection to 11:59 p.m. on the day of injection (Day 0). Jf any of the information changes 
after you fill out Uus page but before 11:59 p.m. tonight, make any necessary changes below. 
Tern erature 
Evening Temp.: 
•c or °F (circle one) 
Time Taken: 
AM or PM ( circle one) 
General Symptoms 
If you experience any of these symptoms, mark the box that describes your worst the symptom until 1 t:59 p.m. 
tonight (Day 0). See General Instructions on page 2 for more information. 
Symptom 
None 
Mild 
Moderate 
Severe 
Unusually tin:cVfeeling unwell 
Muscle aches 
Headache 
Nausea 
Joint pain 
Injection Site ymptoms 
If you experience an injection site symptom, mark the box U1at describes your worst symptom until 11:59 p.m. tonight 
(Day 0). See General Instructions on page 2 for more information. 
Symptom 
None 
Mild 
Moderate 
Severe 
Pain 
Itching 
Redness, Swelling, or Bruising 
None 
Provide Maxim um Measurement 
Redness 
cm at the longest part 
Swelling 
cm at the longest pa1t 
Bruising 
cm at the longest part 
Other Sym ptoms 
If you experience symptoms other than the ones above, write them in tl1e space below according to the General 
Instructions on page 2. 
Did you expel'ience any other symptoms? D Yes D o 
Svmot.om or Medical Event 
Did you take any medications'? D Yes D No 
Ifycs, please list out the namc(s) and dosagc(s) below: 
Participant Diary HPV-301 
Version 1.0 - 10 May 2016 
Mild 
Moder-ate Severe 
Page 3 
86

 
General Instructions 
Temperature 
Take your temperature orally around the same time each evening. using the thermometer provided and 
record it in the space provided. Also record the time at 
hich you took your temperature. If you recentl y 
drank very hot or cold liquids. i ail 15 minutes before taking your temperature. 
Injection Site Symptoms 
Pain and itchin g 
Some p ople experience pain in the area where they were injected. 
ome people ma also experience 
itching in the area where they were injected. 
• 
By pain we mean that the place where you were injected hurts even when it isn't touched. 
If you experience pain or itching at the injection site, us the following categories to describe ho" 
evere 
these symptoms were. If you don't experience one or more of these symptom ·. mark the 
O 'E box. 
• 
Mild 
•• 
I only had a little discomfort. I could still use my arm like always. 
• 
Modente 
•• I noticed the discomfort and didn 't use my arm as much as usual. 
• 
Seve1·e 
e,_• 
I really noticed the discomfort. It kept me from doing something I wanted or had to do . 
• 
Redness, s, elling, and bruising 
Some people experience redness, swelling, or bruising in the area where they were injected. If you 
experience redness, swelling, or bruising, measure the area using the measuring tool you were provided, and 
record the measurem ent in the space provided. 
To measure the area of redness, swelling, or bruising, do the following: 
• 
Place the measuring tool over the area where you were 
injected, with the dot over the center of the area. 
• 
Select the circle where the longest part of the area touches 
the line. 
• 
If the area is in between~ o circles, select the larger 
circle. 
For example, the area shown to the right measures 3 
centimeters (cm) because it is touching the 3cm line. 
General and Other Sym1>toms or Medications 
If you have additional symptoms that are not listed, or if you ought medical care for any rea on from a 
health care provider (e.g. doctor's office, emergency room), or if you took any medications, these should be 
listed in the spaces provided. Please designate any symptoms as Mild, Moderate, or Severe. 
• 
Mild 
I nly had minor discomfort. I went about my usual activities. 
• 
Moderate •• 
I noticed the symptom. It bothered me enough that I didn ' t do a much a I u ually do. 
• 
Severe 
e,_• • 
I really noticed the symptom. It kept me from doing ·omething I wanted or had to do. 
Participant Diary HPV-301 
Version 1.0 - 10 May 2016 
Page4 
87

 
Day 1: 1 Day After Injection Subject#: ____ _ 
Date: 
/ 
/ 
---------
The items on this page refer to the time between midnight of last night and 11:59 p.m. today (Day 1). If any of the 
information changes afi:er you fill out this page but before 11:59 p.m. tonight make any necessary changes below. 
Tcm cl'atm·c 
Evening Temp.: 
°C or °F (circle one) 
Tin1e Taken: 
AM or PM ( circle one) 
General Symptoms 
If you experience any of these symptoms, mark the box that describes your worst symptom between midnight and 
11 :59 p.m. tonight (Day 1). See General Instructions on page 4 for more information. 
Sym ptom 
None 
Mild 
Moderate 
Severe 
Unusually tired/feeling unwell 
Muscle aches 
Headache 
Nausea 
Joint pain 
Injection Site Symptoms 
lf you experience an injection site symptom, mark the box that describes your worst symptom between midnight and 
11:59 p.m. tonight (Day I). See General lnstrudions on page 4 for more information. 
Symptom 
None 
Mild 
Modemte 
Sevel'e 
Pain 
Itching 
Redness, Swelling, or Bruisin g 
None 
Provide Maximum Measurement 
Redness 
cm at the longest part 
Swelling-
cm at the long-est part 
Bmising 
cm at the longest part 
Other Sym ptoms 
lf you experience symptoms other than the ones above, write them in the space below according to the General 
Instructions on page 4. 
Did you experience any other symptoms'? D Yes D o 
Sympt.om or Medical Event 
Did you take any mcdicat.ions? D Yes D No 
If yes, please list out the name(s) and dosage(s) below: 
Participant Diary HPV-301 
Version 1.0 - 10 May 2016 
Mild Modernte Severe 
Page5 
88

 
General Instructions 
Tem1>erature 
Take your temperature orally around the same time each evening, using the thermometer provided and 
record it in the space provided. Also record the time at which you took your temperature. If you recently 
drank very hot or cold liquids, wait 15 minutes before taking your temperature. 
Injection Site Symptoms 
Pain and itching 
ome people experience pain in the area where they were injected. 
ome people may also experience 
itching in the area where they were injected. 
• 
By pain we mean that the place where you were injected hurts even when it isn't touched. 
If you experience pain or itching at the injection si te, use the following categories to describe how severe 
these symptoms were. If you don ' t experience one or more of these symptoms, mark the O 1E box. 
• 
Mild 
•• 
l only had a little discomfort. I could still use my an11 like always. 
• 
Moderate 
• • I noticed the discomfort and didn t use my arm as much as usual. 
• 
Severe •• 
I really noticed the discomfort. It kept me from doing something I wanted or had to do. 
,... . 
Redness, s, elling, and bruising 
Some people experience redness swelling, or bmising in the area where they were injected. If you 
experience redness, sv elling, or bmising, measure the area using the measuring tool you were provided, and 
record the measurement in the space provided. 
To measure the area of redness, swelling, or bruising, do the following: 
• 
Place the measuring tool over the area where you were 
injected, with the dot over the center of the area. 
• 
Select the circle where the longest part of the area touches 
the line. 
• 
If the area is in between two circles, select the larger 
circle. 
For example, the area shown to the right measures 3 
centimeters (cm) because it is touching the 3cm line. 
General and Other Symptoms or Medications 
If you have additional ymptoms that are not listed, or if you sought medical care for any reason from a 
health care provider (e.g. doctor's office, emergency room), or if you took any medications these should be 
listed in the space provided. Please de ignate any symptoms as Mild, Moderate, or evere. 
• 
Mild 
• 
Mode1·ate 
• 
Severe ~• • 
I only had minor discomfort. I went about my usual activities. 
I noticed the symptom. It bothered me enough that I didn 't do as much as I usually do. 
I really noticed the symptom. It kept me from doing something I wanted or had to do. 
Participant Diary HPV-301 
Version 1.0 - 10 May 2016 
Page6 
89

 
Day 2: 2 Days After Injection 
Subject#: ___ _ 
Date: __ / __ / __ 
The items on this page refer to the time between midnight of last night and 11:59 p.m. today (Day 2). If any of the 
information changes afi:er you fill out this page but before 11:59 p.m. tonight, make any necessary changes below. 
Tem el'atm·e 
Evening Temp.: 
°C or °F (circle one) 
Tin1e Taken: 
AM or PM ( circle one) 
General Symptoms 
If you experience any of these symptoms, mark the box that describes your worst symptom until t 1:59 p.m. tonight 
(Day 2). See General Instructions on page 6 for more information. 
Symptom 
None 
Mild 
Moderate 
Severe 
Unusually tired/feeling unwell 
Muscle aches 
Headache 
Nausea 
Joint pain 
Injection Site Symptoms 
If you experience an injection site symptom, mark the box that describes your worst symptom until 11:59 p.m. tonight 
(Day 2). See General Instructions on page 6 for more information. 
Symptom 
None 
Mild 
Moderate 
Severe 
Pain 
ltchin~ 
Redness, Swelling, or Bruising 
None 
Provide Maximum Measurement 
Redness 
cm at the longest part 
Swelling 
cm at the longest pa1t 
Bruising 
cm at the longest part 
Other Sym ptoms 
Tfyou experience symptoms other than the ones above, write them in the space below according to the General 
Instructions on page 6. 
Did you experience any otJ1er symptoms? D Yes D o 
Symptom or Medical Event 
Did you take any medications? D Y cs D No 
Ifycs, please list out t.he nrune(s) and dosage(s) below: 
Participant Diary HPV-301 
Version 1.0 - 10 May 2016 
Mild Moderate Severe 
Page 7 
90

 
General Instructions 
Tem1>erature 
Take your temperature orally around the same time each evening, using the thermometer provided and 
record it in the space provided. Also record the time at which you took your temperature. If you recentl y 
drank very hot or cold liquids, wait 15 minutes before taking your temperature. 
Injection Site Symptoms 
Pain and itchin g 
ome people experience pain in the area where they were injected. 
ome people may also experience 
itching in the area where they were injected. 
• 
By pain we mean that the place where you were injected hurts even when it isn't touched. 
If you experience pain or itching at the injection site, use the following categories to describe how severe 
these symptoms were. If you don't experience one or more of these symptoms, mark the 
O 1E box. 
• 
Mild 
•• 
l only had a little discomfort. I could still use my an11 like always. 
• 
Moderate •• 
I noticed the discomfort and didn t use my arm as much as usual. 
• 
Severe • • 
I really noticed the discomfort. It kept me from doing something I wanted or had to do. 
,... . 
Redness, s, elling, and bruising 
Some people experience redness swelling, or bmising in the area where they were injected. If you 
experience redness, sv elling, or bmising, measure the area using the measuring tool you were provided, and 
record the measurement in the space provided. 
To measure the area of redness, swelling, or bruising, do the following: 
• 
Place the measuring tool over the area where you were 
injected, with the dot over the center of the area. 
• 
Select the circle where the longest part of the area touches 
the line. 
• 
If the area is in between two circles, select the larger 
circle. 
For example, the area shown to the right measures 3 
centimeters (cm) because it is touching the 3cm line. 
General and Other Symptoms or Medications 
If you have additional ymptoms that are not li ted, or if you sought medical care for any rea on from a 
health care provider (e.g. doctor's office, emergency room), or if you took any medications these should be 
listed in the space provided. Please de ignate any symptoms a. Mild, Moderate, or Severe. 
• 
Mild 
• 
Mode1·ate 
• 
Severe ~• • 
I only had minor discomfort. I went about my usual activities. 
I noticed the symptom. It bothered me enough that I didn 't do as much as I usually do. 
I really noticed the symptom. It kept me from doing something I wanted or had to do. 
Participant Diary HPV-301 
Version 1.0 - 10 May 2016 
Page 
91

 
Day 3: 3 Days After Injection Subject#: ____ _ 
Date: __ / __ / __ 
The ilems on this page refer to the time between midnight of last night and 11:59 p.m. loday (Day 3). lf any of the 
information changes afi:er you fill out this page but before 11:59 p.m. tonight, make any necessary changes below. 
Tem el'atm·e 
Evening Temp.: 
°C or °F (circle one) 
Tin1e Taken: 
AM or PM ( circle one) 
General Symptoms 
If you experience any of these symptoms, mark the box that describes your worst symptom until t 1:59 p.m. tonight 
(Day 3). See General Instructions on page 8 for more information. 
Sym ptom 
None 
Mild 
Moderate 
Severe 
Unusually tired/feeling unwell 
Muscle aches 
Headache 
Nausea 
Joint pain 
Injection Site Symptoms 
lf you experience an injection site symptom, mark !he box that describes your worst symptom until 11:59 p.m.tonight 
(Day 3). See General Instructions on page 8 for more information. 
Symptom 
None 
Mild 
Moderate 
Severe 
Pain 
Itchin~ 
Redness, Swelling, or Bruisin g 
None 
Provide Maximum Measurement 
Redness 
cm at the longest part 
Swelling 
cm at the longest pa1t 
Bruising 
cm at the longest part 
Other Sym ptoms 
Tf you experience symptoms other than the ones above, write them in the space below according to the General 
Instructions on page 8. 
Did you experience any otJ1er symptoms? D Yes D o 
Symptom or Medical Event 
Did you take any medications? D Yes D No 
Ifycs, please list out t.hc namc(s) and dosagc(s) below: 
Participant Diary HPV-301 
Version 1.0 - 10 May 2016 
Mild Moderate Severe 
Page9 
92

 
General Instructions 
Tem1>erature 
Take your temperature orally around the same time each evening, using the thermometer provided and 
record it in the space provided. Also record the time at which you took your temperature. If you recently 
drank very hot or cold liquids, wait 15 minutes before taking your temperature. 
Injection Site Symptoms 
Pain and itching 
Some people experience pain in the ar a where they were injected. 
ome people may also experience 
itching in the area where they were injected. 
• 
By pain we mean that the place where you, ere injected hurts even when it isn't touched. 
If you experience pain or itching at the injection site use the following categories to describe ho\ severe 
these symptoms, ere. If you don 't experience one or more of these symptoms, mark the O 'E box. 
• 
Mild •• 
I only had a little discomfort. I could still use my arm like always. 
• 
Modernte 
I noticed the discomfort and didn 't use my arm as much as usual. 
• 
Severe ~• • 
I really noticed the discomfort. It kept me from doing something I wanted or had to do. 
Redness, swelling, and bruising 
Some people experience redness, swelling, or bruising in the area where they were injected. If you 
experience redness, swelling or bruising, measure the area using the measuring tool you were provided, and 
record the measurement in the space provided. 
To measure the area of redness swelling, or brnising, do the following: 
• 
Place the measuring tool over the area where you were 
injected, with the dot over the center of the area. 
• 
Select the circle where the longest part of the area touches 
the line. 
• 
If the area is in between two circles, select the larger 
circle. 
For example, the area shown to the right measures 3 
centimeters (cm) because it is touching the 3cm line. 
General and Other Sym1>toms or Medications 
If you have additional s mptoms that are not listed, or if ou sought medical care for any reason from a 
health care provider (e.g. doctor's office, emergency room), or if you took any medications, these should be 
Ii ted in the paces provided. Please de ignate any symptom as Mild, Moderate, or Severe. 
• 
Mild 
• 
Moderate •• 
• 
Severe ~• • 
I only had minor discomfort. I went about my usual activities. 
I noticed the symptom. It bothered me enough that I didn 't do as much a I usually do. 
I really noticed the symptom. It kept me from doing. omething I wanted or had to do. 
Participant Diary HPV-301 
Version 1.0 - 10 May 2016 
Page 10 
93

 
Day 4: 4 Days After Injection 
Subject#: ____ _ 
Date: 
/ 
/ 
---------
The items on this page refer to the time between midnight of last night and 11:59 p.m. today (Day 4). If any of the 
information changes afi:er you fill out this page but before 11:59 p.m. tonight, make any necessary changes below. 
Tem el'atm·e 
Evening Temp.: 
°C or °F (circle one) 
Tin1e Taken: 
AM or PM ( circle one) 
General Symptoms 
If you experience any of these symptoms, mark the box that describes your worst symptom until t 1:59 p.m. tonight 
(Day 4). See General Instructions on page 10 for more information. 
Symptom 
None 
Mild 
Moderate 
Severe 
Unusually tired/feeling unwell 
Muscle aches 
Headache 
Nausea 
Joint pain 
Injection Site Symptoms 
If you experience an injection site symptom, mark the box that describes your worst symptom until 11:59 p.m. tonight 
(Day 4). See General Instructions on page IO for more information. 
Symptom 
None 
Mild 
Moderate 
Severe 
Pain 
Itching 
Redness, Swellin!!, or Bruisin!! 
None 
Provide Maximum Measurement 
Redness 
cm at the longest oa1t 
Swelling 
cm at the lon,gest part 
Bruising 
cm al the longest oar! 
Other Symptoms 
If you experience symptoms other than the ones above, write them in the space below according to the General 
Instructions on page 10. 
Did you expel'ience any other sympt.oms? 0 Yes O o 
Symptom or Medical Event 
Did you take any medications? D Yes D No 
If yes, please list out the name(s) and dosage(s) below: 
Participant Diary HPV-301 
Version 1.0 - 10 May 2016 
Mild 
D 
D 
D 
D 
Moderate Severe 
D 
D 
D 
D 
D 
D 
D 
Page 11 
94

 
General Instructions 
Tem1>erature 
Take your temperature orally around the same time each evening, using the thermometer provided and 
record it in the space provided. Also record the time at which you took your temperature. If you recentl y 
drank very hot or cold liquids, wait 15 minutes before taking your temperature. 
Injection Site Symptoms 
Pain and itchin g 
ome people experience pain in the area where they were injected. 
ome people may also experience 
itching in the area where they were injected. 
• 
By pain we mean that the place where you were injected hurts even when it isn't touched. 
If you experience pain or itching at the injection site, use the following categories to describe how severe 
these symptoms were. If you don't experience one or more of these symptoms, mark the 
O 1E box. 
• 
Mild •• 
l only had a little discomfort. I could still use my an11 like always. 
• 
Moderate •• 
I noticed the discomfort and didn t use my arm as much as usual. 
• 
Severe • • 
I really noticed the discomfort. It kept me from doing something I wanted or had to do. 
,... . 
Redness, s, elling, and bruising 
Some people experience redness swelling, or bmising in the area where they were injected. If you 
experience redness, sv elling, or bmising, measure the area using the measuring tool you were provided, and 
record the measurement in the space provided. 
To measure the area of redness, swelling, or bruising, do the following: 
• 
Place the measuring tool over the area where you were 
injected, with the dot over the center of the area. 
• 
Select the circle where the longest part of the area touches 
the line. 
• 
If the area is in between two circles, select the larger 
circle. 
For example, the area shown to the right measures 3 
centimeters (cm) becau e it is touching the 3cm line. 
General and Other Symptoms or Medications 
If you have additional ymptoms that are not li ted, or if you sought medical care for any reason from a 
health care provider (e.g. doctor's office, emergency room), or if you took any medications these should be 
listed in the space provided. Please de ignate any symptoms a. Mild, Moderate, or Severe. 
• 
Mild 
• 
Mode1·ate 
• 
Severe ~• • 
I only had minor discomfort. I went about my usual activities. 
I noticed the symptom. It bothered me enough that I didn 't do as much as I usually do. 
I really noticed the symptom. It kept me from doing something I wanted or had to do. 
Participant Diary HPV-301 
Version 1.0 - 10 May 2016 
Page 12 
95

 
Day 5: 5 Days After Injection Subject#: ____ _ 
Date: __ / __ / __ 
The items on this page refer to the time between midnight of last night and 11:59 p.m. today (Day 5). If any of the 
information changes afi:er you fill out this page but before 11:59 p.m. tonight, make any necessary changes below. 
Tem el'atm·e 
Evening Temp.: 
°C or °F (circle one) 
Tin1e Taken: 
AM or PM ( circle one) 
General Symptoms 
If you experience any of these symptoms, mark the box that describes your worst symptom until t 1:59 p.m. tonight 
(Day 5). See General Instructions on page 12 for more information. 
Symptom 
None 
Mild 
Moderate 
Severe 
Unusually tired/feeling unwell 
Muscle aches 
Headache 
Nausea 
Joint pain 
Injection Site Symptoms 
If you experience an injection site symptom, mark the box that describes your worst symptom until 11:59 p.m. tonight 
(Day 5). See General Instructions on page 12 for more information. 
Symptom 
None 
Mild 
Moderate 
Severe 
Pain 
ltchin~ 
Redness, Swelling, or Bruising 
None 
Provide Maximum Measurement 
Redness 
cm at the longest part 
Swelling 
cm at the longest pa1t 
Bruising 
cm at the longest part 
Other Sym ptoms 
Tf you experience symptoms other than the ones above, write them in the space below according to the General 
Instructions on page 12. 
Did you experience any otJ1cr symptoms? D Y cs D o 
Symptom or Medical Event 
Did you take any medications? D Yes D No 
Ifycs, please list out the namc(s) and dosagc(s) below: 
Participant Diary HPV-301 
Version 1.0 - 10 May 2016 
Mild Moderate Severe 
Page 13 
96

 
General Instructions 
Temperature 
Take your temperature orally around the same time each evening, using the thermometer provided and 
record it in the space provided. Also record the time at which you took your temperature. If you recently 
drank very hot or cold liquids, wait 15 minute before taking your temperature. 
Injection Site Sym1>toms 
Pain and itching 
Some people experience pain in the ar a where they were injected. Some people may also experience 
itching in the area where they were injected. 
• 
By pain we mean that the place, here you were injected hurts even when it isn't touched. 
If you experience pain or itching at the injection site, use the following categories to describe how severe 
these symptoms were. If you don 't experience one or more of these symptoms, mark the 
O E box. 
• 
Mild 
I only had a little discomfort. I could still use my arm like always. 
• 
Mode1·ate •• I noticed the discomfort and didn 't use my arm as much as usual. 
• 
Severe • • 
I really noticed the discomfort. It kept me from doing something I wanted or had to do. 
"'. 
Redness, swelling, and brnising 
Some people experience redness, swelling, or brnising in the area where they were injected. If you 
experience redness, swelling, or brnising, measure the area using the measuring tool you, ere provided, and 
record the measurement in the space provided. 
To measure the area of redness, s, elling, or bruising, do the following: 
• 
Place the measuring tool over the area, here you ,. ere 
injected, with the dot over the center of the area. 
• 
Select the ci rel e 
here the Ion gest part of the area touches 
the line. 
• 
If the area is in bet\veen two circles, select the larger 
circle. 
For example, the area shown to the right measures 3 
centimeters (cm) because it is touching the 3cm line. 
General and Other Symptoms or Medications 
If you have additional symptoms that are not listed, or if you sought medical care for any reason from a 
health care provider (e.g. doctor's office, emergency room), or if you took any medications, the. e should be 
listed in the spaces provided. Please designate any symptoms as Mild, Moderate, or Severe. 
• 
Mild (::) 
• 
Moderate 
• 
Severe ~• • 
I only had minor discomfort. I went about my usual activities. 
I noticed the ·ymptom. It bothered me enough that I didn 't do as much a I u ·ually do. 
I really noticed the symptom. It kept me from doing something I wanted or had to do. 
Participant Diary HPV-301 
Version 1.0 - 10 May 2016 
Page 14 
97

 
Day 6: 6 Days After Injection Subject#: ____ _ 
Date: 
/ 
/ 
---------
The items on this page refer to the time between midnight of last night and 11: 59 p.m. today (Day 6). lf any of the 
symptoms you reported on previous pages have not gone away ("resolved"), you will need to let the Site Coordinator 
or Doctor know. 
T em erat.ure 
Evening Temp.: 
•c or °F ( circle one) 
Time Taken: 
AM or PM (circle one) 
General Symptoms 
If you experience any of these symptoms, mark the box that describes your worst symptom until 11 :59 p.m. tonight 
(Day 6). See General Instructions on page 14 for more information. 
Svm otom 
None 
Mild 
Moderate 
Severe 
Unusually tired/feelin_g unwell 
Muscle aches 
Headache 
D 
Nausea 
D 
Joint pain 
D 
Injection Site Symptoms 
If you experience an injection site symptom, mark the box that describes your worst symptom until J l :59 p.m. tonight 
(Day 6). See General Instructions on page 14 for more information. 
Svmotom 
None 
Mild 
Moderate 
Severe 
Pain 
Itching 
Redness, Swelling, or Bruisin !! 
None 
Provide Maximum Measurement 
Redness 
cm at the lon~est part 
Swelling 
cm at the longest oatt 
Bruising 
cm at the longest part 
Other Symptoms 
lf you experi(.."IJCe symptoms other than the ones above, write them in the space below according to the General 
Instructions on page 14. 
Did you experience any other symptoms'! D Yes D o 
Symptom or Medical Event 
Did you take any medications? D Yes D No 
If yes, please list out the name(s) and dosage(s) below: 
Participant Diary HPV-301 
Version LO - 10 May 2016 
Mild 
D 
D 
D 
D 
Modemte Severe 
D 
D 
D 
D 
D 
D 
D 
D 
Page 15 
98

15.2 APPENDIX B:  ERROR REPORTING FORM 
 
• 
• 
1no v10 
PHA.RMACEUTICAlS 
CELLECTRA® 5PSP Device Error Form 
Please complete the form and fax to (267) 440-4242 or scan the form to 
 
Protocol# 
Site# ---
Subject ID 
Week# ___ Visit Date ___ 
DEVICE INFORMATION 
CELLECTRA® 5PSP Base Serial No: 
I I I I I I I I I I I I I I I I I I I I I 
Located on label on the front cover 
CELLECTRA®5PSP Handset Serial No I I I I I I I I I I I I I I I I I I I I I 
Located on label on the handle 
CELLECTRA® 5PSP Array Lot No: 
I I I I I I I I I I I I I I I I I I I I I 
Located on label on the oackaoe 
Time of Treatment: 
Type and Location of Treatment: D IM 
D ID 
Arm 
Arm 
Quadriceps 
Quadriceps 
D Other Location, specify: 
IM-6P ONLY, was the EP Guide used? 0 YES O NO 
If EP Guide was used, please provide reason and include subject's BMI. 
Was injection successful? 
D YES 
D NO 
If NO, please provide reason and include needle gauge and syringe volume used. 
Did the display on the device read EP successful? D YES 
O NO 
If NO, please check all complications that led to failure and describe complication below 
D Impedance Test Error message displayed, fill out Impedance Test Error section below 
D Electroporation Error message displayed, fill out Electroporation Error section below 
D EP aborted by trigger or keypad error message displayed 
D Battery level too low for electroporation message displayed 
D Difficulty inserting array into muscle or skin 
D Other, please specify below 
Describe device complication below(continue on back if necessary): 
Total# of arrays used: 
Total # of attempts: 
lmeedance Test Error (IM-5P Onll£l 
Was the array fully inserted in subject's arm? 
D YES 
O NO 
(or thigh as applicable) 
Were all attempts performed on the same day? 
D YES 
O NO 
Was a different location used for each attempt? 
D YES 
O NO 
Was a new array used for each attempt? 
D YES 
O NO 
Please provide any additional information below (continue on back if necessary): 
Electroeoration Error 
Were there 3 (IM) or 4 (ID) involuntary muscle contractions? 
D NO (how many 
Was the array fully inserted in the subject's arm? 
D YES 
O NO 
Was the array inserted perpendicular to the subject's skin? 
D YES 
O NO 
Did the needles of the array appear damaged in any way? 
D YES 
O NO 
If you were provided a sharps shuttle, please eject the array into a shuttle and ship to lnovio. 
Please provide any additional information below (continue on back if necessary): 
99

15.3 APPENDIX C:  GUIDELINES FOR COLPOSCOPY, BIOPSY, AND SURGICAL EXCISION 
Colposcopy Procedure 
It is recommended that all study colposcopies performed after informed consent be according the procedures 
recommended by the American Society of Colposcopy and Cervical Pathology (ASCCP): 
1. Use warm, clean water to lubricate the vaginal speculum.  Avoid other lubricant substances which could 
obscure results. 
2. If the vaginal walls are lax, a lateral vaginal sidewall retractor aligned perpendicular to the speculum may 
facilitate visualization. 
3. Examine the cervico-vaginal secretions and remove any excess mucus from the cervix with saline-soaked 
cotton swabs. 
4. Obtain any required specimens required for cytology and HPV testing. 
5. Using low-power magnification (5x to 10 x) inspect the cervix for obvious areas of abnormalities. 
6. Swab or spray the cervix with 3-5% acetic acid.  Reapply every 2-3 minutes during the examination. 
7. Use the green or blue filter to examine blood vessels.  Increase magnification (15x) 
8. Identify the distal and proximal boarders of the transformation zone. 
a. The inner border is the entire 360-degree circumference of the squamocolumnar junction 
i. If the junction is proximal to the external os, in the canal, use a cotton-tipped applicator to 
pry either the anterior lip up or the posterior lip down or use an endocervical speculum 
ii. If the junction is not visualized in its entire circumference, the colposcopy is deemed  
inadequate  
b. The distal limit of the transformation zone may be identified by finding the most distal crypt 
openings or nabothian follicles in the lips of the cervix and drawing an imaginary line connecting 
these landmarks 
9. Inspect the entire new squamocolumnar junction and detect and evaluate any abnormal areas.   
10. Evaluate the upper third portion of the vagina. 
11. Lugol or Schiller’s solution may be applied to further define previously identified lesions.   
Cervical Biopsies  
 Endocervical Curettage 
ECC is to be performed using a kervorkian curette or equivalent instrument.  Rotate and scrape the curette 360○ in 
the endocervical canal and use a cytobrush to remove the specimen.  Deposit the specimen onto a Telfa pad before 
depositing in the specimen vial containing 10% neutral buffered formalin solution and labeled with the subject 
identification (SID) number. 
 Ectocervical Biopsies 
Ectocervical biopsies should only be performed prior to Week 36 if disease progression is suspected.  Only the 
suspect lesion should be biopsied in that circumstance.   
If the subject is eligible for 4 quadrant biopsy at the Week 36 visit, the following procedure should be followed: 
1. Label each specimen vial containing 10% neutral buffered formalin solution with the subject’s ID number and 
the quadrant number according to the figure below. 
2. Perform and record colposcopy findings from each quadrant according to the following categories 
a. Negative (no lesion present) 
b. Low Grade  (e.g. pale acetowhite lesion on or off the squamocolumnar junction 
c. High Grade  (e.g. dense acetowhite lesion often with mosaic pattern or punctation) 
d. Suspicion of invasive cancer 
e. Invasive cancer 
100

3. Perform colposcopic directed biopsies from all quadrants with lesions. 
4. Multiple biopsies can be obtained of a lesion at the discretion of the investigator but must be uniquely labeled  
5. If a quadrant is free of lesions, obtain a random biopsy at the squamocolumnar junction in that quadrant at 2, 
4, 8, or 10 o’clock. 
6. Prepare the biopsy specimen vials for shipment according to the Laboratory Manual. 
 
Figure 1 – Biopsy Quadrant Numbers 
 
 
 
 
Surgical Excision 
For subjects undergoing surgical excision at the Week 36 visit, the following procedure should be followed: 
1. Label each specimen vial containing 10% neutral buffered formalin solution with the SID number and the 
specimen type. 
2. Record colposcopy findings from each quadrant according to the following categories 
a. Negative (no lesion present) 
b. Low Grade  (e.g. pale acetowhite lesion on or off the squamocolumnar junction 
c. High Grade  (e.g. dense acetowhite lesion often with mosaic pattern or punctation) 
d. Suspicion of invasive cancer 
e. Invasive cancer 
3. Perform the LEEP or CKC per usual practice. 
4. Specimen should be marked at 12 o’clock with suture or gentian violet ink for purposes of orientation 
5. Prepare the biopsy specimen vials for shipment according to the Laboratory Manual. 
 
 
 
I 
Ou er 
II 
IV 
III 
101

15.4  APPENDIX D: EQ-5D-5L HEALTH QUESTIONNAIRE 
 
UK (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
Health Questionnaire 
English version for the UK 
EQ-SD-SL 
102

 
2 
UK (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
Under each heading, please tick the ONE box that best describes your health TODAY. 
MOBILITY 
I have no problems in walking about 
 
I have slight problems in walking about 
 
I have moderate problems in walking about 
 
I have severe problems in walking about 
 
I am unable to walk about 
 
SELF-CARE 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities) 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 
103

 
 
 
 
• We would like to know how good or bad your health is TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• Mark an X on the scale to indicate how your health is TODAY. 
• Now, please write the number you marked on the scale in the box 
below. 
The best health 
you can imagine 
100 
 
95 
 
90 
 
85 
 
80 
 
75 
 
70 
65 
60 
55 
50 
45 
40 
35 
30 
25 
20 
15 
10 
5 
0 
The worst health 
you can imagine 
YOUR HEALTH TODAY = D 
104

15.5 APPENDIX E:  SF-36 V2 QUESTIONNAIRE 
 
 
 
 
Your Health and Well-Being 
This survey asks for your views about your health. This information will help 
keep track of how you feel and how well you are able to do your usual activities. 
Thank you/or completing this survey! 
For each of the following questions, please mark an IZJ in the one box tha best 
describes your answer. 
1. In general, would you say your health is: 
Excellent 
Very good 
Good 
Fair 
Poor 
T 
T 
T 
T 
T 
2. Compared to one vear ago, how would you rate your health in general 
!!.!ill'.? 
Somewhat 
About the 
Somewhat 
Much worse 
now than one 
better 
same as 
worse 
now than one 
year ago 
now than one 
one year ago 
now than one 
year ago 
year ago 
year ago 
T 
T 
T 
T 
T 
SF-3 6v2~ Health Survey © 1992, 1996, 2000 Medical Outcomes Tmst and QualityMetric Incorporated All rights reserved. 
SF-36e is a registered trademark of Medical Outcomes Trust. 
(SF-36v241 Health Survey Standard, United States (English)) 
105

 
3. The following questions are about activities you might do during a typical 
day. Does yom· health now limit you in these activities? If so, how much? 
Yes. 
Yes, 
o, not 
limited 
limited 
limited 
a lot 
a little 
at all 
... 
y 
... 
• Vieorous activities. such as running, lifting 
heavy objects, pa1t icipating in strem1otis spo1t s .................. .... D ........... D 2 ... .. . .... . . . D 3 
b 
Moderate activities. such as moving a table, pushing 
a vacuum cleaner, bowling, or playing golf.. ........................... D 1 .. .. . . .... .. . D 2 . .... . . . ... , . D 3 
, Lifting or can)'ing groceries .................................................... D 1 .. . .. .. . .. .. . D 2 . .... ... .. . .. D 3 
h 
Walking several hundred yards .................... .... ....................... D 1 .. . .. .... . ... D 1 . .. .. .. . .. .. . D , 
SF-36v2 Heallh Smvey © 1992, 1996, 2000 Medical Outcomes Trust and QualityMelric Incorporated. All rights reserved 
SF-36"' is a registered trademark of Medical Outcomes Trust 
(SF-36v2 Health SlllVey Standard, United Slates (English)) 
106

 
4. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities~ 
result of vour phvsical health? 
, Cut down on the amount of 
time you spent on work or 
All of 
the time 
Most of 
the time 
Some of 
the time 
A little of 
None of 
the time 
the time 
other activities ................................. 
1. .. .... .. . .. .. 0 2. .. . . . . . .. . .. . 0 i .. .. . .. .. . . .. . D ............. D , 
b 
Accomplished less than you 
,voukl like ........... ............................. 
1. .. .... ... .. .. 0 2. .. .. . . . .. . .. . 0 i .... .. .. . .... . D 4 .... . .... . . . . D , 
, Were limited in the kind of 
work or other acti·vities ............... ..... D 1 ... .... ... .. .,0 2. .. .. ... ..... O i .... .. .. . .. ... D 4 .... ... .. .. .. D , 
d Had difficultv performing the 
work or other activities (for 
example. it took extra effo1t) ........... 
1. .. .... .... . .. 0 ............. 0 J. ... .. ... .... . D 4 .... ... .. . . . . D , 
5. During the past 4 weeks, how much of the time have you had any of the 
following problems with your work or other regular daily activities~ 
result of am emotional problems (such as feeling depressed or anxious)? 
, Cut down on the amount of 
time you spent on work or 
All of 
the time 
Most of 
the ti.me 
Some of 
the time 
A little of 
None of 
the time 
the ti.me 
other activities ........... .... ...... .. ........... 
1 ..... . .... . .. . 0 2. .. .... . .. ... . 0 J. . .... .. .. .... D 4 . .. .. .. .. .. . . D , 
b Accomplished le s than you 
would like ..................... ........ ........... 
1. .. .. . ... . .. .. 0 2. .. .. .. . .. . .. . 0 J. . . . .. ... . . .. . D ............. D , 
, Did work or other activities 
less carefully than usual.. .... .. ........... 
1. .. .... .. . .. .. 0 2. .. . ... . .. . .. . 0 i . . .. .. . .. .... . D 4 .... . .. .. . . . . D , 
SF-36v2 Health Survey © 1992, 1996, 2000 Medical Outcomes Trust and QuatityMetric Inc.orpornted. All rights resen•ed. 
SF-36 is a registered trademark of Medical Outcomes Trust. 
(SF-36v210 Health Survey Standard, United Slates (English)) 
107

 
 
6. During the past 4 weeks, to what extent bas your physical health or 
emotional problems interfered with your normal social acth ities with 
family, friends, neighbors, or groups? 
Not at all 
Slightly 
Moderately 
Quite a bit 
Extremely 
• • • • 
D2 
D , 
7. How much bodilv pain have you had during the past 4 week,s? 
one 
Ve1ymild 
Mild 
Moderate 
Severe 
Very severe 
• • • • • • 
D 1 
D J 
D i 
D 4 
8. During the past 4 weeks, how much did pain interfere with your normal 
work (including both work outside the home and housework)? 
A little bit 
Moderately 
Quite a bit 
Extremely 
• • • 
D , 
SF-36v2 Health Survey© 1992, 1996, 2000 Medical Outcomes Trust and QualityMenic Incorporated. All rights reserved 
SF-36~ is a registered trademruk of Medical Outcomes Trust 
(SF-36v2 Health Survey Standard, United Stat"~ (English)) 
108

 
 
9. These questions are about how you feel and how things have been with you 
during the past 4 weeks. For each question, please give the one answer that 
comes closest to the way you have been feeling. How much of the time 
during the past 4 weeks ... 
All of 
the time 
Most of 
the time 
Some of A little of the 
-one of 
the time 
time 
the time 
• Did you feel full of life? ............. ..... 
1. . . . .. . . . . .. . . D 2. .. . . . .... . . . . 0 L .. .. . ...... . 0 4 .. . , . .. .. . . . .. D i 
b Have you been ve1y ne1vous? .......... 
1 . . . . . .. . ..... . 0 2 . .. . . . .... . . . . 0 L . .. .. ... .. ... O 4 . .. . • .• .
•. . D i 
, Have you felt so down in the 
dumps that notl1ing could 
cheer you up? ................................... 
1 •. •••. ••.••••. D 2 . .. . . . .... . . . . 0 , .............. 0 4 .. . . . .. . . . .. . . D i 
d Have you felt calm and 
peaceful. .......................................... 
1. . . . . . . . . . . . . . 0 2 .. . . . .... . . . . 0 , .............. 0 4 .... . . . . . . . . .. D i 
• Did you have a lot of energy? .......... 
1. . . •. . . . ... . . . D i. .. . . . .... . . . . O L . .. .. ... .. . . . O 4 . . . . . .. . . . . . . . 
i 
r Have you felt downhea1t ed 
and depressed'> ............. .. ................. 
1. . . . .. . . . . .. . . 0 2 . .. . . . .... . . . . 0 l. . .. .. . . . .... . O 4... . . .. . . . .. .. D i 
i Did you feel wom out? .................... 
1. . . . . . . . ..... . 0 2 . .. . . . .... . . . . 0 l. . .. .. ... .. . . . O 4 . .. . •.••. •. •. . D i 
h Have you been happy? ..................... 
1. . . . .. . . . . . . . . 0 2 . .. . . . .... . . . . 0 l. . .. .. ... .... . O 4.. . . . .. . . . .. .. D i 
; Did you feel tired? ........................... 
1. . . •. . •. . . . . . . D 2 . .. . . . .... . . . . 0 L . .. .. . . . .. . . . O 4.. . . . .. . . . .. .. D i 
10. During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting with 
friends, relatives, etc.)? 
All of 
the time 
Most of 
the time 
Some of 
the time 
T 
0 , 
A little of 
None of 
the time 
the time 
T 
T 
0 4 
o ; 
SF-36v2 Health Swvey © 1992, 1996, 2000 Medical Outcomes Trust and QualityMetric Incorporated. All rights m eiveci 
SF-36"' is a registered trademark of Medical Outcomes Trust. 
(SF-36v2 Health Survey Standard, United States (English)) 
109

 
11. 
How TRUE or FALSE is each of the following statements for you? 
, I seem to 12:et sick a little 
Definitely 
tnie 
T 
Mostly 
tme 
T 
Don't 
know 
T 
Mostly 
false 
T 
Definitely 
false 
T 
easier thar~ other people .................. D , ............ D 1 . .. . . . . .. .. .. D 3 .. . ...... . . .. ~.D 4 .... . .. . . . . . .. D _; 
b 
I am a.s healthy as 
anybody J know .......................... .... 
I . .. .. . .. . . .. . . 
2. .. . .. . .. .. .. 
3.- . .. . . . . . .... . o 4 . . . . .. .. . . . .. 
_; 
, I expect my health to 
get '1,VOl'Se . . . . . .. .. .. . .. . . . .. . . .. . .... . .. .. .. . ... . . 
. .. . .. .. . . . . . . 
2. . .... . .. .. .. 
3 . .. .. .. . . . . . ... . 
4 . .. . . .. .. ... . . 
d My health is excellent.. ............... .... 
I . .. .... . . . .. . . 
l. .. .... ... . . . 
3 .. . ...... . . .... . o ............ 
_; 
Thank you/or completing these questions! 
110

" l n L, VI O 
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, 
• t 
J'I 
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1. 1 
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H P V- 3 0 1 P R O T O C O L 
A Pr os p e cti v e, R a n d o mi z e d. D o u hl e- bli n d, Pl a c e b o -C o ntr oll e d P h as e 3 St u d y of V G X- 3 I O O X 
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Bi ost atisti ci a n/ 
 
 
M e di c al M o nit or 
V e rsi o n 2. 0 
0 3 J u n e 2 0 1 6 
 
 
Date C D D- M M M- Y Y Y Y) 
D at e ( D D- M M M- Y Y Y Y) 
D at e ( D D- M M M- Y Y Y Y) 
D at e ( D D- M M M- Y Y Y Y) 
D at e ( D D- M M M- Y Y Y Y) 
D at e ( D D- M M M- Y Y Y Y) 
D at e ( D D- M M M- Y Y Y Y) 
1 1 1
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
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P P D

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t n _( _, VI _ O 
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H P V- 3 0 1 P R O T O C O L 
A Pr os p e cti v e, R a n d o mi z e d. D o u bl e- bli n d. Pl a c e b o- C o ntr oll e d P h as e 3 St u d y of V G X- 3 l O O X 
D eli v er e d I ntr a m us c ul arl y f oll o w e d b y El e ctr o p or ati o n wit h C E L L E C T R A 1 '1 5 P S P f or t h e 
Tr e at m e nt of H P V- 1 6 a n d/ or H P V - 1 8 r el at e d Hi g h Gr a d e S q u a m o us I ntr a e pit h eli al L esi o n 
( H Sil..) of t he C er vi x 
Writte n 
b y: 
 
Bi ost atisti ci a n/ 
 
M e di c al M o nit or 
 
 
 
V e rsi o n 2. 0 
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D at e ( D D- M M M- Y Y Y Y) 
D at e ( D D- M M M- Y Y Y Y) 
D at e ( D D- M M M-Y Y Y Y) 
 
D at e ( D D- M M M- Y Y Y Y) 
D at e ( D D- M M M- Y Y Y Y) 
D at e ( D D- M M M- Y Y Y Y) 
D a te (D D -M M M -Y Y Y Y) 
1 1 2
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

 
 
 
HPV-301 
REVEAL I Trial  
(Randomized Evaluation of VGX-3100X and Electroporation for the Treatment of 
Cervical HSIL) 
 
A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
PHASE 3 STUDY OF VGX-3100X DELIVERED INTRAMUSCULARLY FOLLOWED 
BY ELECTROPORATION WITH CELLECTRA™ 5PSP FOR THE TREATMENT OF 
HPV-16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS INTRAEPITHELIAL 
LESION (HSIL) OF THE CERVIX   
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
U.S. BB-IND #13683 
 
Version 2.1 
10 June 2016 
 
 
 
 
 
 
 
113

 
A P R O S P E C TI V E, R A N D O MI Z E D, D O U B L E- B LI N D, P L A C E B O- C O N T R O L L E D 
P H A S E 3 S T U D Y O F V G X- 3 1 0 0 X D E LI V E R E D I N T R A M U S C U L A R L Y F O L L O W E D B Y 
E L E C T R O P O R A TI O N WI T H C E L L E C T R A ™ 5 P S P F O R T H E T R E A T M E N T O F H P V-
1 6 A N D/ O R H P V- 1 8 R E L A T E D HI G H G R A D E S Q U A M O U S I N T R A E PI T H E LI A L 
L E SI O N ( H SI L) O F T H E C E R VI X   
S h ort Title:   
R E V E A L I 
Trial ( Ra n d o mize d 
E val uati o n 
of 
V G X- 3 1 0 0 X a n d 
Electr o p orati o n f or t he treat me nt of Cer vical H SI L) 
 
Bi ol o gic al P r o d uct:    
 V G X- 3 1 0 0 X 
 
P r ot oc ol N u m ber:    
 H P V- 3 0 1 
 
S p o ns or:  
 I n o vi o P har mace uticals, I nc. 
 
 6 6 0 W. Ger ma nt o w n Pi ke, S uite 1 1 0 
 
 Pl y m o ut h Meeti n g, P A 1 9 4 6 2 
 
P ri nci p al I n vesti g at or:   
 
, M. D., M. S. 
 
 
 
 
 R ut gers Ne w Jerse y Me dical Sc h o ol 
 
 1 8 5 S. Ora n ge A ve., M S B E- 5 0 6 
 
 Ne war k, NJ 0 7 1 0 3 
 
Me dic al M o nit or:  
 
, M. D., P h. D. 
 
 
 
 
 I n o vi o P har mace uticals, I nc. 
 
 
 
C O N FI D E N TI A L 
T he i nf o r m ati o n i n t his d oc u me nt is c o nsi dere d pri vile ge d a n d c o nfi de nti al b y I n o vi o P h ar m ace utic als a n d m a y 
n ot be discl ose d t o ot hers e xce pt t o t he e xte nt necess ar y t o o bt ai n I nstit uti o n al Re vie w B o ar d/ Et hics c o m mittee 
a p pr o v al a n d i nf o r me d c o nse nt, or as re q uire d b y l oc al re g ul at or y a ut h orities. Pers o ns t o w h o m t his i nf or m ati o n 
is discl ose d m ust be i nf o r me d t h at t his i nf or m ati o n is pri vile ge d a n d c o nfi de nti al a n d t h at it s h o ul d n ot be f urt her 
discl ose d wit h o ut t he w ritte n per missi o n of I n o vi o P h ar m ace utic als. A n y s u p ple me nt al i nf or m ati o n a d de d t o t his 
d oc u me nt is als o c o nfi de nti al a n d pr o priet ar y i nf or m ati o n of I n o vi o P h ar m ac e uti c als a n d m ust be ke pt i n 
c o nfi de nce i n t he s a me m a n ner as t he c o nte nts of t his d oc u me nt.  
 
1 1 4
P P D
P P D
P P D
P P D

 
SUMMARY OF CHANGES  
 
The following is a list of significant protocol changes from HPV-301 protocol version 1.0 dated 26 Apr 
2016 to HPV-301 protocol version 2.0 dated 06 June 2016. All other changes are administrative and do 
not significantly affect the safety of subjects, study scope, or scientific quality of the protocol.  
1. 
Added rationale for selection of non-frozen formulation for phase 3 study 
2. 
Added additional background information to Section 2 Study Design 
3. 
Clarified inclusion and exclusion criteria  
4. 
Administrative changes made throughout the protocol for clarification  
 
Additional administrative and formatting changes were made to protocol version 2.0 dated 06June2016 
resulting in protocol version 2.1 dated 10June 2016. 
 
 
 
115

 
PROTOCOL ACKNOWLEDGEMENT  
 
 
I have read this Protocol and agree that it contains all necessary details for carrying out the study 
described. I understand that it must be reviewed by the Institutional Review Board or Independent 
Ethics Committee overseeing the conduct of the study and approved or given favorable opinion 
before implementation. 
 
The signature of the Investigator below constitute his/her approval of this protocol and provide the 
necessary assurances that this study will be conducted according to the Declaration of Helsinki, 
ICH-GCP guidelines, local legal and regulatory requirements as well as to all stipulations of the 
protocol in both the clinical and administrative sections, including statements regarding 
confidentiality. 
 
 
 
__________________________________________________________ 
Investigator – Signature                      Date (DD/MMM/YYYY)       
 
 
________________________________________ 
Investigator – Printed Name        
 
 
 
 
 
Site Number: ___________________________________   
 
Site Name: _____________________________________ 
 
 
116

 
 
 
 
 
 
 
 
 
 
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I 
LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
AIS 
Adenocarcinoma-in-situ 
AGC 
Atypical Glandular Cell 
ASC-H  
Atypical Squamous Cells, cannot exclude High grade 
squamous intraepithelial lesion 
ASC-US  
Atypical squamous cells of undetermined significance 
BMI 
Body Mass Index 
CEF 
Cytomegalovirus, Epstein Barr Virus and Influenza 
CFR 
Code of Federal Regulations 
CIB 
Clinical Investigator’s Brochure 
CIN 
Cervical Intraepithelial Neoplasia 
CKC 
CMI 
Cold knife conization 
Cell-mediated immunity 
CMR 
Complete Metabolic Response 
CMV 
Cytomegalovirus 
CRF 
Case Report Forms 
CPK 
Creatine Phosphokinase 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTL 
Cytotoxic T-cells 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of Acquired Immunodeficiency Syndrome  
DNA 
Deoxyribonucleic Acid 
ECC 
Endocervical Curettage 
EP 
DLT 
Electroporation with CELLECTRA™ 5PSP 
Dose Limiting Toxicity 
DSMB 
Data & Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EP 
Electroporation 
ERER 
Events Requiring Expedited Reporting 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISpot 
Enzyme Linked Immunosorbent Spot-forming Assay 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HCG 
Human Chorionic Gonadotropin 
HSIL 
High grade squamous intraepithelial lesion 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
122

HPV 
HPV-16/18 
Human Papillomavirus 
HPV-16 and/or HPV-18 
IC 
Intracavitary 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IFN-γ 
Interferon Gamma 
IL-12 
Interleukin 12 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IXRS 
Interactive Response System 
LAST 
Lower Anogenital Squamous Terminology 
LEEP 
Loop Electrosurgical Excision Procedure 
LLETZ 
LSIL 
Large Loop Excision of Transformation Zone 
Low Grade Squamous Intraepithelial Lesion 
MedDRA® 
Medical Dictionary for Drug Regulatory Affairs 
mITT 
Modified Intent to Treat 
NILM 
Negative for intraepithelial lesion or malignancy 
NIH 
National Institutes of Health 
OP 
Principal Investigator 
Investigator 
Oropharyngeal  
Lead Investigator for overall study activities 
Lead Investigator for individual site(s) 
PAC  
Pathology Adjudication Committee 
PBMC 
Peripheral Blood Mononuclear Cells 
PDC 
Participant Diary Card 
PRO 
Patient Reported Outcomes 
PE 
Physical exam 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SID 
Subject Identification   
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
sWFI 
Sterile Water for Injection 
TNF 
Tumor Necrosis Factor 
ULN 
Upper Limit of Normal 
WOCBP 
Women of Childbearing Potential 
 
 
 
 
123

II CLINICAL PROTOCOL SYNOPSIS 
 
Title of Study:  A Prospective, Randomized, Double-blind, Placebo-Controlled Phase 3 Study of 
VGX-3100X Delivered Intramuscularly followed by Electroporation with CELLECTRA™ 5PSP 
for the Treatment of HPV-16 and/or HPV-18 related High Grade Squamous Intraepithelial Lesion 
(HSIL)0F1 of the Cervix 
Estimated Number of Study Centers and Countries/Regions:  Approximately 100 Sites  in up 
to 25 Countries 
Study Phase: 3 
Primary Hypothesis:  Three 6 mg doses of VGX-3100X (DNA Plasmids encoding E6 and E7 
proteins of HPV-16 and HPV-18) delivered intramuscularly (IM) followed by electroporation 
(EP) with CELLECTRA™ 5PSP to adult women with histologically confirmed HSIL[Cervical 
Intraepithelial Neoplasia (CIN)2, CIN3] of the cervix, associated with HPV-16 and/or HPV-18 
will result in a higher percentage of women with histopathological regression of cervical HSIL 
lesions to no evidence of cervical HSIL and virologic clearance of HPV-16 and/or HPV-18 
compared to placebo delivered IM followed by EP with CELLECTRA™ 5PSP at the Week 36 
visit  
Study Drug Dose 
6 mg (1 ml) 
Administration 
Intramuscular injection followed by EP with the CELLECTRA™ 5PSP 
device 
Schedule 
Day 0, Week 4, and Week 12 study visits 
No. of Subjects 
Approximately 165 subjects will be randomized in a 2:1 ratio to receive 
VGX-3100X or placebo 
Study Duration 
88 weeks 
Primary Objective 
Determine the efficacy of VGX-3100X compared with placebo with respect 
to combined histopathologic regression of cervical HSIL and virologic 
clearance of HPV-16 and/or HPV-18 
Primary Endpoint 
Proportion of subjects with no evidence of  cervical HSIL on histology 
(i.e. biopsy or excisional treatment) and no evidence of HPV-16 and/or 
HPV-18 in ThinPrep™ cervical samples by type specific HPV testing at 
Week 36 visit 
 
 
 
 
 
1 Terminology based on 2012 consensus recommendation on Lower Anogenital Squamous Terminology (LAST) from 
the American Society of Colposcopy and Cervical Pathology (ASCCP) and the College of American Pathologists (CAP) 
124

 
 

 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Evaluate tissue immune responses to 
VGX-3100X in cervical samples 
1. Assessment of markers including but not 
limited to CD8+ and FoxP3+ infiltrating cells. 
Additional assessments may include 
visualization of Granulysin, Perforin, CD137, 
CD103 and PD-L1 in cervical tissue as sample 
allows.  Markers listed here may change as 
new relevant information becomes available 
2. Describe the clearance of HPV-16 
and/or 
HPV-18 
infection 
from 
anatomic locations  outside the cervix 
2. Proportion of subjects who have cleared HPV-
16 and/or HPV-18 on specimens from outside 
the cervix (inclusive of oropharynx, vagina and 
peri-anus) at Week 36 Visit 
3. Evaluate effect of HLA type on 
efficacy 
 
3. HLA (per-locus and per-allele basis) in 
conjunction with histologic regression of  
cervical HSIL at Week 36 visit 
4. Describe 
association 
of 
previous 
colposcopy, cytology and HPV testing 
results with histologic regression at 
Week 36   
4. Colposcopy, cytology, and HPV test results at 
Weeks 15 and 28 visits in conjunction with 
histologic regression of cervical HSIL at Week 
36 visit 
5. Describe the durability of virologic 
clearance of HPV-16 and/or HPV-18 
for subjects treated with VGX-3100X 
compared with those treated with 
placebo 
5. Proportion of subjects with no evidence of 
HPV-16 and/or HPV-18 by type specific HPV 
testing at Weeks 62 and 88 visits 
6. Describe the patient-reported outcomes 
for subjects treated with VGX-3100X 
6. The following two questionnaires: Short Form 
Health Survey, version 2 (SF-36v2™) and EQ-
5D-5L™ will be self-administered prior to first 
dose (i.e. Day 0), following each dose, and at 
Weeks 28, 40 and 88 to measure score(s). 
Study Design: 
This Phase 3 study design is based upon the Phase 2b study design and results.  HPV-301 is a 
prospective, randomized, double-blind, placebo controlled Phase 3 study to determine the efficacy, 
safety, and tolerability of VGX-3100X administered by IM injection followed by EP delivered with 
CELLECTRA™ 5PSP in adult women with histologically confirmed cervical HSIL (CIN2, CIN3) 
associated with HPV-16 and/or HPV-18 (HPV-16/18). The composite primary endpoint is histologic 
regression of cervical HSIL, and clearance of the underlying HPV-16/18 infection. A sample of 
approximately 165 subjects will be randomized to receive either 6 mg (in 1 ml) VGX-3100X or 
placebo, each IM followed by EP, in a 2:1 ratio. This sample size provides 90% power to declare 
VGX-3100X superior to placebo, assuming, based upon Phase 2b study results, that the true 
proportion of subjects whose lesion(s) regress and whose HPV-16/18 clears is 40% and 15% for 
VGX-3100X and placebo, respectively, and assuming 90% evaluability from randomization. 
126

To be eligible for the study, women age 18 years and above must consent to participate and have 
biopsy/biopsies of the cervical lesion(s) at the time of screening. The biopsy slides are sent to a 
Pathology Adjudication Committee (PAC) in a blinded manner to establish the presence of cervical 
HSIL (CIN2, CIN3) prior to enrollment. Subjects must also have a cervical specimen test positive 
for HPV-16/18 by Cobas™ HPV test to be eligible for participation in the study.  
All eligible subjects will receive three doses of VGX-3100X or placebo administered IM followed 
immediately by EP with the CELLECTRA™ 5PSP device. The first study treatment is administered 
on Day 0, the second at Week 4, and the third (final) study treatment is administered at Week 12. 
The first dose is administered as soon as possible following confirmation of the cervical HSIL 
diagnosis and cervical sample positive for HPV-16/18 but no more than 10 weeks following 
collection of the subject’s biopsy specimen used for diagnosis by the PAC during screening.  
Subjects are randomized in a stratified manner according to (a) the CIN severity observed in the 
biopsy specimens at screening (i.e. CIN2 vs. CIN3), (b) BMI category (≤25 vs. >25 kg/m2), and (c) 
age category (<25 years vs. ≥25 years). To ensure CIN2 disease is not over-represented in the study, 
the percentage of subjects enrolled with CIN2 will not exceed 50% of the total enrolled.  
The long term follow up plan following the Week 36 efficacy assessment will include safety, 
cytology and HPV testing for a period of approximately 1 year (Week 88). 
Efficacy: Visualization of a normal appearing cervix by colposcopy and cytology are insufficient 
evidence to confirm disease regression. Therefore, disease regression will be based on 
histopathological assessment, which is considered the definitive method for diagnosis. Subjects will 
also be assessed by colposcopy, cytology, HPV testing at screening, Day 0, and Weeks 15, 28, 36, 
62 and 88.  Digital photographs of the cervix will be also used to document colposcopic exam 
findings. 
Tissue to be analyzed for evidence of histopathologic regression will be obtained at Week 36 either 
by excision (i.e. loop electrosurgical excision procedure (LEEP), large loop excision of 
transformation zone (LLETZ), cold knife conization (CKC)) or by biopsy (4 Quadrant Biopsy or 4 
Quadrant Biopsy with Endocervical Curettage (ECC)) based upon the assessment at Week 28 of   
cytology, High Risk (HR) HPV status, and colposcopic findings (see Tables 4 and 5, for Minimally 
Required Procedures).   
Safety: All subjects will be followed for 88 weeks. 
 
Subjects will be monitored for: 
1) Local and systemic events for 7 days following each investigational treatment as noted on a 
Participant Diary Card (PDC); 
2) All adverse events including SAEs, UADEs, and other unexpected AEs for the duration of the 
study; 
 
 
 
127

Data Safety & Monitoring Board (DSMB): The DSMB will meet quarterly to review unblinded 
safety data and histopathologic regression results. The DSMB will be charged with advising the 
Sponsor if there appears to be a safety issue and with advising the Sponsor if it appears that the 
proportion of the subjects with histopathologic regression in the VGX-3100X group is unacceptably 
low compared to the placebo group. No formal interim analysis will be performed.   
Immunogenicity: Humoral and cell mediated immune responses in response to VGX-3100X 
treatment may be evaluated in blood samples taken at baseline (both Screening as well as Day 0 prior 
to dosing) and at Weeks 15, 36, and 88. Cervical tissue samples may also be analyzed for evidence 
of elevated immune responses at Week 36 as compared to baseline (screening). 
Virology: Cervical cytology samples will be obtained to characterize HPV infection at Day 0 (prior 
to dosing) and at Weeks 15, 28, 36, 62, and 88 by Cobas™ HPV test.  Additionally, if there is residual 
tissue in the paraffin block after histologic diagnoses have been rendered, then unstained slides 
and/or the relevant paraffin blocks may be collected to test for the presence of HPV-16/18. Vaginal, 
oropharyngeal and peri-anal samples will be obtained to characterize HPV infection at Day 0 (prior 
to dosing) and at Weeks 15, 36, and 88. 
HLA typing: The relationship between subject HLA types and efficacy responses will be explored 
using available PBMC sample collected for immunogenicity analysis. 
Study Population 
Inclusion Criteria: 
1. Women aged 18 years and above; 
2. Confirmed cervical infection with HPV types 16 and/or 18 at screening;  
3. Cervical tissue specimen/slides provided to Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study drug; 
4. Histologic evidence of cervical HSIL as confirmed by PAC at screening; 
5. Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form 
prior to study-related activities; 
6. Must be judged by Investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision, 4-quadrant biopsy with ECC, or 4-quadrant biopsy) required at Week 
36; 
7. Has satisfactory colposcopy, defined as full visualization of the squamo-columnar junction 
(Type I or II transformation zone) and complete visualization of the upper limit of aceto-white 
epithelium or suspected CIN disease; 
8. Must have a cervical lesion that is accessible for sampling by biopsy instrument (e.g. Mini-
Tischler device); 
9. Must have a cervical lesion of adequate size to ensure that a visible lesion remains after screening 
biopsy; 
10. Must meet one of the following criteria with respect to their reproductive capacity: 
a) Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months or 
spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL 
128

b) Is surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 12 months prior to screening 
c) Women of Child Bearing Potential (WOCBP) is willing to use a contraceptive method with 
failure rate of less than 1% per year when used consistently and correctly from screening 
until 6 months following the last dose of investigational product. Acceptable methods are 
the following: 
o Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. Hormonal 
contraceptives must not be used in subjects with a history of hypercoagulability (e.g., 
deep vein thrombosis, pulmonary embolism). 
o Abstinence from penile-vaginal intercourse when this is the subject’s preferred and usual 
lifestyle 
o Intrauterine device or intrauterine system 
o Male partner sterilization at least 6 months prior to the female subject’s entry into the 
study, and this male is the sole partner for that subject 
11. Has normal screening ECG or screening ECG with no clinically significant findings, as judged 
by the investigator. 
Exclusion Criteria: 
1. Has microscopic or gross evidence of adenocarcinoma-in-situ (AIS), high grade vulvar, vaginal 
(inclusive of cervical HPV-related lesions that extend into the vaginal vault), or anal 
intraepithelial neoplasia or invasive cancer in any histopathologic specimen at screening; 
2. More than 10 weeks have elapsed between date of initial tissue biopsy for screening and day of 
first dose(i.e. Day 0); 
3. Has cervical lesion(s) that cannot be fully visualized on colposcopy due to extension high into 
cervical canal at screening; 
4. Has history of ECC which showed cervical HSIL indeterminate, or insufficient for diagnosis 
(ECC is not performed as part of study screening); 
5. Has treatment for cervical HSIL or genital warts within 4 weeks prior to screening; 
6. Is pregnant, breastfeeding or considering becoming pregnant during the study; 
7. Has history of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are 
allowed, e.g. Gardasil™, Cervarix™); 
8. Has presence of any abnormal clinical screening laboratory values greater than Grade 1 per 
Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 within 30 days prior to Day 0 
or less than Grade 1 but deemed clinically significant by the investigator; 
9. Has immunosuppression as a result of underlying illness or treatment including: 
a)  History of or positive serologic test for HIV at screening 
b)  Primary immunodeficiencies 
c)  Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent; (use of inhaled, otic, and ophthalmic corticosteroids are allowed) 
d)  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) 
129

e)  History of solid organ or bone marrow transplantation 
f) Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
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; 
10. Has received any non-study, non-live vaccine within 2 weeks of Day 0; 
11. Has received any non-study, live vaccine (e.g. measles vaccine) within 4 weeks of Day 0; 
12. Has current or history of clinically significant, medically unstable disease which, in the judgment 
of the investigator, would jeopardize the safety of the subject, interfere with study assessments 
or endpoint evaluation, or otherwise impact the validity of the study results (e.g. chronic renal 
failure; angina, myocardial ischemia or infarction, class 3 or higher congestive heart failure, 
cardiomyopathy, or clinically significant arrhythmias); 
13. Has malignancy or treatment for malignancy within 2 years of screening, with the exception of 
superficial skin cancers that only require local excision;  
14. Presence of acute or chronic bleeding or clotting disorder that would contraindicate IM 
injections, or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of 
Day 0; 
15. Has history of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic 
agents; 
16. Has sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg 
or a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
17. Has resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at 
screening or Day 0; 
18. Has prior major surgery within 4 weeks of Day 0; 
19. Has participated in an interventional study with an investigational compound or device within 
30 days of signing informed consent; participation in an observational study is permitted; 
20. Has less than two acceptable sites available for IM injection considering the deltoid and 
anterolateral quadriceps muscles; 
21. Has tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
22. Has cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is 
located in ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 
23. Has metal implants or implantable medical device within the electroporation area; 
24. Has active drug or alcohol use or dependence that, in the opinion of the investigator, would 
interfere with adherence to study requirements; 
25. Is a prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment 
of either a psychiatric or physical (i.e. infectious disease) illness; 
26. Is an active military service personnel; 
27. Is a study-related staff or family member of study-related staff; 
28. Has 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. 
 
 
130

Table 1. Schedule of Events 
Tests 
Screening 
(-10 wks to -1 Day) 
Weeks 
Day 0 
8-14 days post Day 0 
Phone Call 
4 (± 4 days) 
8-14 days post Wk 4 
Phone Call 
12 (± 4 days) 
8-14 days post Wk 12 
Phone Call 
15 (± 1 week) 
28 (± 1 week) 
36 (± 1 week) 
40 (± 2 weeks) 
Phone call 
62 (± 2 weeks) 
88 (± 2 weeks) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behaviorala 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
Vital signs 
Xc 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
Screening safetyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Teste 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
HIV Testing  by ELISA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood immunologic samplesf 
X 
X 
 
 
 
 
 
Xg 
 
X 
 
 
X 
ThinPrep™ h,i 
X 
X 
 
 
 
 
 
X 
X 
X 
 
X 
X 
Cervical Digene swabsi,j 
X 
X 
 
 
 
 
 
X 
X 
X 
 
 
X 
Colposcopy, lesion photographyk 
Xl 
X 
 
 
 
 
 
X 
X 
X 
 
X 
X 
Ectocervical biopsym 
X 
 
 
 
 
 
 
 
 
Xn 
 
 
 
Surgical excisionm 
 
 
 
 
 
 
 
 
 
Xn 
 
 
 
OPo, vaginal, anal swabs 
 
X 
 
 
 
 
 
X 
 
X 
 
 
X 
Inject VGX-3100X/Placebo 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Post treatment assessment 
 
X 
X 
X 
X 
X 
Xp 
 
 
 
 
 
 
Distribute PDC 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Review PDC 
 
 
X 
 
X 
 
Xp 
 
 
 
 
 
 
PROs 
 
X 
X 
 
X 
 
Xp 
 
Xq 
 
X q 
 
X 
 
a Socio-Behavioral assessments, e.g. self-reported smoking and alcohol history 
b Full physical examination (PE) mandatory at screening and study discharge (Wk 88), otherwise targeted PE as 
determined by the Investigator or per subject complaints unless signs or symptoms dictate the need for a full PE; 
c Screening vital signs must include a measured height and weight and calculated BMI; 
d Screening 12-Lead ECG, complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), serum 
creatinine (Cr), serum glucose, serum ALT, serum CPK and urinalysis performed within 30 days prior to  dose 
administration on Day 0; 
131

e Negative spot urine pregnancy test is required at screening and prior to each study treatment, colposcopy and surgical 
excision; 
f At least 34 mL [4 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum per time point (a total of at least 68 
mL of whole blood and 8 ml serum should be collected prior to dosing on Day 0). HLA testing will performed once 
from an existing PBMC sample; 
g At least 51 mL [6 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum should be collected at Week 15; 
h HPV genotyping and Pap smears are performed on the same ThinPrep™ cervical specimen; 
i Request that the subject abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to cervical specimen collection; 
j Collected prior to the ThinPrep™ sample; 
k Photographs of the cervix and the associated lesion must be collected prior to and after biopsies and at all 
colposcopic examinations; 
l Screening colposcopy is optional if adequate colposcopy was performed upon collection of initial biopsy and 
corresponding lesion photography is available; 
m Screening biopsy of the lesion should be collected as Paraffin-embedded cervical tissue, fresh cervical tissue, or 
H&E slides. Tissue to be analyzed for evidence of histopathologic regression will be obtained at Week 36 visit 
either by excision (i.e. LEEP, CKC) or by 4 Quadrant Biopsy or 4 Quadrant Biopsy with ECC based upon the 
assessment at Week 28 of cytology, HR HPV status, and colposcopic findings (See Tables 5 and 6); 
n Slides from biopsy and/or excised tissue must be reviewed by the PAC and residual cervical tissue from entry 
and/or Week 36 specimen(s) (paraffin blocks or unstained slides) should be sent to the central pathology laboratory 
for immunohistochemistry (IHC) and HPV testing; 
o Oropharynx (OP) by oral rinse; 
p Activities at 8 to 14 days Post-Dose 3 phone call may be done at Week 15 if timing overlaps. 
q PROs to be completed by subject 8-14 days after Week 28 visit and Week 40 phone call 
 
 
 
 
 
 
 
132

1 INTRODUCTION 
1.1 
BACKGROUND  
1.1.1 
HPV INFECTION, CERVICAL INTRAEPITHELIAL NEOPLASIA AND 
CERVICAL CANCER  
Infection with human papillomavirus (HPV) can lead to malignant neoplasia, localized primarily 
in the anogenital area and aerodigestive tract, in both men and women.  HPV types tropic to 
mucosal tissues are classified into high-risk (HR), based on their potential to cause cancer, and 
low-risk (LR) (causing generally benign lesions). HPV-16 and HPV-18 are the most significant 
amongst high-risk types since they are responsible for most HPV-caused cancers [1].  In the US 
alone, approximately 14 million new genital HPV infections occur annually, and approximately 
half of these infections are with a HR HPV type [2, 3].  Up to 13000 women in the US alone are 
diagnosed with cervical cancer each year, which leads to an estimated 4120 deaths [4].  HPV-16 
is the most common high-risk genotype and combined with HPV-18 these two genotypes are 
estimated to cause about 70% of all cervical cancers [5, 6]. 
Incident infection by HPV is characterized by ongoing viral replication and shedding and is 
associated with early histologic changes (grade 1 cervical intraepithelial neoplasia) when the 
female cervix is infected with HPV.  Most cases of genital HPV infection clear spontaneously, but 
persistent infection with one or more oncogenic (high-risk) HPV genotypes can lead to the 
development of precancerous, histologic high grade squamous intraepithelial lesions of the cervix, 
HSIL which is inclusive of grade 2 and 3 cervical intraepithelial neoplasia (CIN2/3) [7].   Over 
time, typically years, cervical HSIL can progress to invasive cancer of the cervix [8, 9].  The basis 
for these changes are attributed to the viral proteins E6 and E7.  Infected cells produce E6 and E7 
constitutively which increases the degradation of cell cycle regulation proteins p53 and pRb, 
respectively, resulting in unrestricted cell growth and neoplasia.   
While the currently available prophylactic HPV vaccines (Cervarix™, Gardasil™, and Gardasil™-
9) are highly effective in preventing persistent infection and the subsequent development of high-
grade CIN caused by HPV-16, HPV-18 and other HPV types, the prophylactic vaccines have no 
therapeutic effect upon existing HPV infection or existing HPV-related intraepithelial neoplasia 
[10].  This means that the large number of women who already have high grade cervical dysplasia, 
either because they were too old to have received the prophylactic vaccine or they didn’t respond 
to vaccination, must currently only rely upon surgery and the chance of spontaneous regression to 
treat their condition and avoid progression to cancer.  Furthermore, the number of US-eligible 
teenagers who complete the prophylactic vaccination series remains low; 39.7% of US girls ages 
13-17 completed their prophylactic HPV immunization series in 2014, which leaves a potentially 
vulnerable, under-protected population [11]. The current approaches to the management of 
cervical HSIL typically require surgery (i.e. LEEP/LEETZ, laser ablation, or conization); 
however, surgical excision does not necessarily address the underlying HPV-infection, and can 
adversely impact the reproductive health of women of childbearing age.  Therefore, VGX-3100X 
is being developed as a non-surgical therapeutic option for the precancerous precursor to cervical 
cancer, cervical HSIL, and the underlying, pathogenic HPV infection.  
133

1.1.2 
VGX-3100X 
VGX-3100X contains the identical plasmids to target HPV-16 E6/E7 and HPV-18 E6/E7 antigens 
that were included in VGX-3100. The plasmids were designed and constructed using proprietary 
synthetic vaccine (SynCon™) technology. This process involves synthetically deriving consensus 
genes across multiple strains and optimizing DNA inserts at the genetic level to allow high 
expression in human cells. Together, VGX-3100X and the CELLECTRA™ device represent an 
integrated investigational product designed as a non-surgical treatment of HPV-16/18-related 
cervical HSIL (CIN2, CIN3) via an immune response directed against HPV-16/18. 
The initial formulation was designated as VGX-3100 (water-for-injection w/1% w/w poly-L-
glutamate (WFI/LGS); frozen storage) and has been administered to more than 250 subjects in 
Phase 1 and Phase 2 clinical trials.VGX-3100X was developed to be a non-frozen formulation 
using saline sodium citrate (SSC) buffer. VGX-3100X was administered to 116 subjects in a Phase 
1 clinical trial, HPV-101. In study HPV-101, three 6 mg doses of VGX-3100X, non-frozen 
formulation were delivered intramuscularly followed by electroporation with CELLECTRA™ 5P 
to healthy adults.  Based upon interim analysis data at study Week 14, the non-frozen formulation 
was considered non-inferior to the frozen formulation based upon a 2-fold rise in overall Spot 
Forming Units (SPU) to the antigens encoded by the plasmids per 106 Peripheral Blood 
Mononuclear Cells (PBMC) as measured from baseline to Week 14 using the interferon-γ ELISpot 
assay. 
Proof of concept was demonstrated in the prospective, randomized, double blind, placebo-
controlled Phase 2b study of VGX-3100 followed by EP in the treatment of high grade cervical 
dysplasia, cervical HSIL associated with HPV-16 and/or HPV-18.  The Phase 2b study, HPV-003, 
enrolled 167 subjects with high grade cervical dysplasia from seven countries and one United 
States Territory (Australia, Canada, Estonia, Republic of Georgia, India, South Africa, United 
States and Puerto Rico). Subjects were randomized in a 3:1 ratio to the treatment arm (VGX-3100) 
or the placebo arm, respectively. All subjects were to receive treatment on Day 0, Week 4 and 
Week 12. All subjects were to repeat cervical biopsy or LEEP of the cervix at Week 36 to assess 
efficacy defined as regression of high grade CIN by histopathology.   The primary endpoint was 
histopathologic regression of cervical lesions to CIN1 or less at the Week 36 visit.   A secondary 
endpoint was clearance of HPV-16/18 in combination with histopathologic regression of cervical 
lesions to CIN1 or less. The proportions of subjects who met the primary and secondary endpoints 
were significantly higher in the VGX-3100 group vs. placebo in both per protocol and modified 
intent to treat analyses.  Robust T-cell activity was detected in VGX-3100 recipients compared to 
placebo recipients. VGX-3100 was generally safe and well tolerated when administered 
intramuscularly with electroporation.  
1.1.3 
ELECTROPORATION 
VGX-3100X is delivered using the CELLECTRA™ in vivo electroporation (EP) device. EP is a 
physical method of tissue transfection whereby the generation of short, controlled electrical pulses 
creates a localized electric field at the injection site of the DNA vaccine which increases cell 
membrane permeability and improves the transfection of DNA and subsequent immunogenicity  
134

[12, 13]. EP is believed to increase the uptake and processing of plasmid DNA, thereby enabling 
increased expression and enhanced vaccine immunogenicity by 10 to 100 fold [14, 15]. This 
technology has been used for more than three decades by molecular biologists for cell transfection 
and has demonstrated versatility in use, as shown by its functionality in combination with a range 
of molecules, tissue types, disease indications, and across species [16]. 
The CELLECTRA™ device developed by Inovio is used for investigational purposes to administer 
plasmid-based DNA, in both prophylactic and therapeutic settings. Following successful proof-
of-concept studies in animals, Inovio has optimized both pulse pattern and voltage to increase 
transfection efficiency, and has demonstrated that the device helps to elicit favorable 
immunogenicity in several species (e.g., mice, pigs, and rhesus macaques) [17, 18].  
VGX-3100 has been administered throughout Phase 1 and Phase 2 investigations with the 
CELLECTRA™ 2000 device. A next generation device, CELLECTRA™ 5PSP, will be used in 
Phase 3. Both designs of the CELLECTRA™ device enhance the intracellular uptake of VGX-
3100X by the delivery of electrical current, and the electrical current delivery and pulse pattern 
(electroporation) is identical in both designs. CELLECTRA™ 2000 involves a manual injection 
of VGX-3100X while the CELLECTRA™ 5PSP device will automate the intramuscular delivery 
of VGX-3100X and delivery of the EP pulses triggered by a single button press. Neither the dosage 
nor volume of VGX-3100X administered differs between the two devices. Administration of 
VGX-3100X with the CELLECTRA™ 5PSP also allows selection of the needle array length from 
13 to 19 to 25 mm depending on the estimate of the recipient’s subcutaneous fat and muscle tissue.  
The technology differences between the CELLECTRA™ 2000 and CELLECTRA™ 5PSP design 
(Table 2) are not significant and do not present any new risks. The device design change does not 
affect the indications for use, operating principle, energy type, environmental specifications, and 
sterilization or performance specifications. The material changes are to the outer housing of the 
device and not to patient-contacting materials.  
135

Table 2. Comparative Device Overview 
 
CELLECTRA™ 5PSP 
CELLECTRA™ 2000 
Array Specifications 
Electrode Number and Material 
(no bore) 
5 Stainless steel, 304 electrodes 
pentagonal arrangement 
5 Stainless steel, 304 electrodes 
pentagonal arrangement 
Electrode Length 
1.555 ± .020” (39.5mm) 
1.555 ± .020” (39.5mm) 
Electrode Gauge 
22 Gauge (0.0278-0.0280 inch diameter) 21 Gauge (0.028±0.001 inch diameter) 
Electrode Trocar Tip 
15 ± 2° 
15 ± 2° 
Array Housing 
Bayer Makrolon 2458C and Loctite 
3921 
GE Plastics (Sabic) Lexan HPS2 
Sterilization Method and Sterility 
Assurance Level (SAL) 
Gamma Irradiation- kGy To Be 
Determined SAL 10-6 
Gamma Irradiation 25-40kGy 
SAL 10-6 
VGX-3100X IM Injection Method 
Automated (Handset mediated) 
Manual (needle and syringe) 
Injection Needle Material (full bore) 
Stainless steel, 304 
Stainless steel, 304 
Injection Needle Length 
2.102 ± .020” (54.4mm) 
2.0” hypodermic needle recommended 
Injection Needle Gauge 
21 Gauge (.03250-0.03200 inch 
diameter) 
21 Gauge 
Injection Needle Trocar Tip 
15° (double ended) 
15° (single ended) 
VGX-3100X IM Injection Depth 
13, 19 and 25mm 
13 and 19 mm 
VGX-3100X IM Injection Volume 
1.0±0.1mL 
1.0±0.1mL 
Electroporation Parameters 
Voltage 
40-200 V maximum (varies with subject 
tissue impedance; 12V for device 
operation) 
40-200 V maximum (varies with subject 
tissue impedance; 7.2V for device 
operation) 
Pulse Width 
52 milliseconds (ms) 
52 milliseconds (ms) 
Pulse Current 
0.5 A; 1.0 A max 
0.5 A ; 1.0 A max 
Maximum Phase Charge 
Maximum Delivered Charge  = 
78mC (max) = 0.5A x 0.052 seconds x 3 
pulses 
Maximum Delivered Charge  = 
78mC (max) = 0.5A x 0.052 seconds x 3 
pulses 
Frequency 
Up to 4 Hz between pulses 
Up to 4 Hz between pulses 
Benchtop design verification testing and a non-significant risk device functionality study will be 
completed prior to Phase 3 to support that the dimensional changes, change to the ergonomics of the 
patient user interface and injection method result in the CELLECTRA™ 5PSP device design meeting 
its safety and performance specifications, and no change to the administration of VGX-3100X by 
electroporation. Inovio’s device experience demonstrates that delivery of electroporation pulses into 
muscle immediately following injection of DNA plasmids is well-tolerated in humans and no 
significant safety issues have been identified [19-21].  
136

1.1.4 
SELECTION OF STUDY DESIGN  
This Phase 3 study employs a prospective, randomized, double-blind, placebo controlled study 
design to further demonstrate the safety and efficacy of VGX-3100X followed by EP in women 
with cervical HSIL associated with HPV-16/18.  The primary clinical hypothesis is that VGX-
3100X is a surgery-sparing, therapeutic option for the treatment of cervical HSIL and the 
underlying, pathogenic HPV-16/18 infection, which is supported by the findings of the Phase 2b 
trial. A placebo-controlled study is selected for this trial because it provides scientific rigor to 
distinguish an effective treatment, particularly in cervical HSIL for which spontaneous regression 
does occur. 
1.2 
 DOSE AND REGIMEN RATIONALE   
A total dose of 6 mg VGX-3100X DNA has been selected for this study based on previous human 
experience with both VGX-3100 and VGX-3100X, preclinical data with VGX-3100X and other 
DNA vaccines, and the safety and immunogenicity data generated in the HPV-001, HPV-003, and 
HPV-101 studies. In HPV-001 trial, the 6 mg dose was delivered IM followed by EP, which showed 
trends toward higher response rates and magnitudes of IFN-γ ELISpot responses compared to the 
low (0.6 mg) and mid-dose (2 mg) cohorts (Table 3) without significant safety issues [19].  
This dose-trend was consistent with prior expectation, a feature of the finding that suggests it is a 
true effect rather than random variation. Adverse events from previous human studies with VGX-
3100 and closely related DNA plasmid products have been limited to injection site pain from the 
injection and electroporation procedure, which were not clinically meaningful. 
Based on the information above, the 6 mg dose was selected for study in the Phase 2b study. The 
results obtained in the phase 2 study suggest that the 6 mg dose was efficacious with an acceptable 
safety profile, therefore the 6 mg dose will also be evaluated in this Phase 3 trial. 
137

Table 3. Percent of Protocol HPV-001 Subjects Responding and Average SFU/106 PBMC in 
Responders for each Antigen by Cohort in Interferon-γ ELISpot  
Cohort 
Low 
Mid 
High 
Antigen 
%Response 
AVG 
%Response 
AVG 
%Response 
AVG 
HPV-16E6 
33% 
107 
50% 
243 
50% 
1341 
HPV-16E7 
17% 
198 
50% 
104 
67% 
143 
HPV-18E6 
50% 
359 
50% 
338 
83% 
664 
HPV-18E7 
33% 
159 
17% 
179 
50% 
834 
Any 
67% 
221 
67% 
210 
83% 
556 
1.3 
RISKS/BENEFIT ASSESSMENT 
1.3.1 
RISKS ASSOCIATED WITH CURRENT THERAPEUTIC OPTIONS 
Currently, treatment of women with cervical HSIL usually consists of either surgical removal of 
the affected tissue by CKC, LEEP, ablative therapy via laser, or cryotherapy.  All treatments for 
cervical HSIL are associated with a variety of short and long term general and reproductive health 
risks as listed in Table 4. 
Table 4. Risks Associated with Surgical Treatments for Cervical HSIL 
Surgical Treatments for 
Cervical HSIL 
Risks 
CKC 
LEEP 
Ablative therapy (Laser or 
Cryotherapy)  
Pain 
Exposure to anesthesia 
Heavy bleeding 
Infection 
Menstruation problems 
Cervical stenosis (can lead to alteration of squamo-columnar junction) 
Shortening of the cervix 
Decreased fertility/difficulty getting pregnant 
Cervical incompetence 
Pre-term birth and related low birth weight 
Incomplete treatment of cervical dysplasia 
Inadequate treatment of an occult early invasive cancer 
Adapted from FAQs Loop Electrosurgical Excision Procedure (LEEP) American College of Obstetricians and 
Gynecologists (2014) [11]. 
138

More importantly, none of the currently available surgical treatments for cervical HSIL eradicate 
the underlying cause of the high grade cervical dysplasia, persistent infection with one or more of 
the high-risk HPV types, and therefore, leaves patients at risk for recurrent cervical HSIL as well 
as high grade dysplasia of the vulva and vagina due to the potentially broader infection of the 
genitourinary area. 
Although professional guidelines typically advocate immediate excisional therapy for adults with 
cervical HSIL, scientific data indicates that the rate of progression from pre-invasive to invasive 
cervical disease is slow, typically thought to take several years [8].  The risk of a “missed 
diagnosis” of an occult early invasive cervical cancer exists for all current treatment modalities 
including surgical and ablative therapies.  Furthermore, approximately 17-18% of patients with 
high grade CIN will experience recurrence of dysplasia following surgical intervention [8], which 
illustrates that current standard of care for cervical dysplasia requires improvement.  The study 
design includes numerous safeguards to detect disease progression or the presence of an 
undiagnosed occult early invasive cervical cancer.  These include, careful selection of 
immunocompetent patients, thorough screening and baseline evaluation, frequent cervical 
colposcopy, cytology and high-risk HPV testing throughout the trial.  Investigators will be 
comprised of experienced gynecologists, who will have the discretion to obtain biopsies at any 
point if disease progression is suspected. 
1.3.2 
POTENTIAL RISKS OF STUDY PARTICIPATION 
A risk associated with VGX-3100X for the treatment of high grade cervical dysplasia are the 
injection site reactions related to the IM injection and/or electroporation.  Based on the phase 1 
and 2 clinical experience, the injection site reactions associated with the IM injection and 
electroporation are generally mild (e.g. erythema) and limited to a few days in duration at most.   
A second risk is the “delay” in “definitive treatment” of the high grade cervical dysplasia and the 
“missed diagnosis” of an occult early invasive cervical cancer for the VGX-3100X non-
responders or placebo recipients, who do not spontaneously regress.  This risk is mitigated by 
careful serial cytology, HPV testing, and colposcopic exams, throughout the course of the study, 
and the well accepted understanding that cervical dysplasia progresses slowly, typically over 
years, which makes close, active follow-up possible.  Also, only investigators who are 
experienced in the management of cervical cancer will be chosen, and they will have the option 
of performing additional, ad hoc colposcopic exams and cervical biopsies if they suspect potential 
disease progression.  
A DSMB will also advise the Sponsor if it appears that the frequency of regression in the VGX-
3100X group is unacceptably low compared to the placebo group.  These measures should 
minimize the risk - even perhaps below that of standard care - of progression of the cervical HSIL 
and the risk of harboring an undiagnosed occult early invasive cervical cancer. All subjects with 
suggestion of residual disease will undergo excisional therapy by CKC or LEEP at Week 36 as 
part of the efficacy assessment.  Subjects whose cytology, HPV testing, ECC results (if 
applicable) and colposcopic exam suggest disease regression will undergo 4 quadrant biopsy or 
4 quadrant biopsy with ECC (based upon Tables 4 & 5) to provide histopathologic confirmation 
of regression. In the Phase 2b study, the rate at which microinvasive cancer was found in larger 
139

surgical excision samples in subjects who had no evidence of invasive cancer by initial biopsy 
was 1.8%, (2/114 with specimens), which is consistent with and even lower than the rate of 6.7% 
that has been reported under standard of care settings [22]. 
1.3.3 
POTENTIAL BENEFITS OF STUDY PARTICIPATION 
All currently accepted treatments for high grade cervical dysplasia are surgical procedures (LEEP, 
CKC, Laser ablation) which are all associated with risks inherent with any surgical procedure 
including anesthesia, post-operative bleeding and/or infection, damage to other organs, shortening 
and/or deformation of the cervix, pain, etc.  Due to the risk of shortening and/or deformation of 
the cervix there are additional well accepted risks including cervical stenosis, infertility, cervical 
incompetence, preterm birth, and inability to visualize the transformation zone.  Additionally, none 
of the surgical treatments systemically address the underlying oncogenic root cause, the high risk 
HPV infection in the lower genital tract, which leaves an underlying risk for further disease 
manifestations and transmission of HPV. VGX-3100X+ EP is not associated with any of the risks 
associated with the surgical procedures outlined above (except for pain, which is transient, very 
quickly-resolving, and restricted to the deltoid/quadriceps treatment site) and has demonstrated 
the ability to not only eradicate the high grade dysplasia but also the ability to eradicate the 
underlying HPV infection.  Subjects receiving placebo, who represent women of child-bearing 
potential, may benefit from the opportunity to be closely managed under careful surveillance over 
the course of this study and those who regress spontaneously will be able to avoid excisional 
therapy. 
2 STUDY DESIGN 
This Phase 3 study design is based upon the Phase 2b study design and results. HPV-301 is a 
prospective, randomized, double-blind, placebo controlled study to determine the efficacy, safety, 
and tolerability of VGX-3100X administered by IM injection followed by EP delivered with 
CELLECTRA™ 5PSP in adult women with histologically confirmed cervical HSIL (CIN2, CIN3) 
associated with HPV-16/18. 
A sample of approximately 165 subjects will be randomized to receive either 6 mg (in 1 ml) VGX-
3100X or placebo, each IM followed by EP, in a 2:1 ratio. This sample size provides 90% power to 
declare VGX-3100X superior to placebo, assuming, based upon Phase 2b study results, that the true 
proportion of subjects whose lesion(s) regress and whose HPV-16/18 clears is 40% and 15% for 
VGX-3100X and placebo, respectively, and assuming 90% evaluability from randomization.  
Subjects will be randomized in a stratified manner according to (a) the CIN severity observed in the 
biopsy specimens at screening (i.e. CIN2 vs. CIN3), (b) BMI category (≤25 vs. >25 kg/m2), and (c) 
age category (<25 years vs. ≥25 years). To ensure CIN2 disease is not over-represented in the study, 
the percentage of subjects enrolled with CIN2 will not exceed 50% of the total enrolled. 
To be eligible for the study, subjects age 18 years and above must consent to participate and have 
cervical biopsy/biopsies of the cervical lesion(s) at the time of screening. Slides of the biopsy will 
be sent to a PAC in a blinded manner to establish the presence of cervical HSIL within screening. 
In order to be eligible for continued enrollment, the PAC must assign the histologic diagnosis of 
140

cervical HSIL. Subjects must also have a cervical specimen test positive for HPV-16/18 by Cobas™ 
HPV test to be eligible for participation in the study. 
2.1 
ENDPOINT ASSESSMENT 
In the Phase 2b study, subjects were randomized 3:1 to the VGX-3100 arm or the Placebo arm. All 
subjects were scheduled to receive treatment on Day 0, Week 4 and Week 12 and undergo repeat 
cervical biopsy or surgical excision (i.e. LEEP, LLETZ, CKC) of the cervix at Week 36 to assess 
efficacy. The primary endpoint was histopathologic regression of cervical lesions to CIN1 or less at 
the Week 36 visit, and the secondary endpoint was clearance of HPV-16/18 in combination with 
histopathologic regression of cervical lesions to CIN1 or less.     
The primary endpoint for the Phase 3 study is based upon the results of the Phase 2b study.  Given 
that HPV persistence is an important factor in the clinical progression of dysplasia and also based 
upon the findings of the secondary objective of the Phase 2b study, the responder definition for the 
Phase 3 primary endpoint determination will take into consideration both histological regression of 
cervical HSIL and clearance of high-risk HPV-16/18.  
The proportion of subjects who achieved this endpoint in the Phase 2b study was 39.5% of VGX-
3100 subjects versus 15.4% for placebo, in the modified-intention-to-treat analysis.  The composite 
endpoint of histologic regression and virologic clearance will be primary in the Phase 3 study, and 
histologic regression endpoint will be a secondary endpoint. 
2.1.1 
HISTOLOGY ASSESSMENT 
Regression of cervical HSIL will be determined by histopathological assessment of cervical tissue, 
which is considered the definitive method for diagnosis of cervical dysplasia. Digital photographs 
are also used to document colposcopic exam findings. Tissue to be analyzed for evidence of 
histopathologic regression will be is obtained at Week 36 either by excision (i.e. LEEP, LLETZ, 
CKC) or by 4 Quadrant Biopsy or by 4 Quadrant Biopsy with ECC based upon the assessment at 
Week 28 of cytology, HR HPV status, and colposcopic findings as outlined in Tables 5 and 6 for 
subjects 25 years and above and below 25 years, respectively. 
 
141

Table 5.  Minimally Required Procedure at Week 36 for Subjects Age 25 Years and Above  
Age 
Clinical and Laboratory Information at Week 28 
Minimally Required 
Procedure at Week 36a 
Colposcopy 
Cytology 
HPV-16/18 
Testing 
Quality 
Finding 
25 and 
above 
NA 
NA 
HSIL, ASC-H, AGC, 
Carcinoma, AIS 
NA 
Tissue Excision 
unsatisfactory 
lesion 
NA 
NA 
Tissue Excision 
unsatisfactory 
no lesion 
LSIL, ASC-US 
positive 
Tissue Excision 
unsatisfactory 
no lesion 
LSIL, ASC-US 
negative 
4Q biopsy and ECC 
unsatisfactory 
no lesion 
NILM 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
LSIL, ASC-US 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
positive 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
negative 
4Q biopsy 
 
Table 6.  Minimally Required Procedure at Week 36 for Subjects Under 25 Years  
Age 
Clinical and Laboratory Information at Week 28 
Minimally Required 
Procedure at Week 36a 
Colposcopy 
Cytology 
HPV-16/18 
Testing 
Quality 
Finding 
18-24 
NA 
NA 
Carcinoma, AIS 
NA 
Tissue Excision 
unsatisfactory 
lesion 
NA 
NA 
Tissue Excision 
unsatisfactory 
no lesion 
HSIL, ASC-H, AGC 
NA 
Tissue Excision 
unsatisfactory 
no lesion 
NILM, ASC-US, LSIL 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
LSIL, ASC-US, HSIL, 
ASC-H, AGCb 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
positive 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
negative 
4Q biopsy 
Abbreviations: NA; not applicable because there is no impact to the decision at Week 36 due to a superseding finding; 4Q; four 
quadrant; NILM Negative for intraepithelial lesion and malignancy; ASC-US Atypical squamous cells of undetermined 
significance; AGC Atypical glandular cells; ASC-H Atypical squamous cells, cannot rule out high-grade lesion; AIS 
Adenocarcinoma-in-situ 
a any subject with prior ECC requires a negative ECC at Week 28 to allow 4Q biopsy and ECC, at minimum, at Week 36   
b if cytology result is AGC “favor neoplasia”, tissue excision is recommended 
2.1.2 
VIROLOGIC (HPV) ASSESSMENT 
Cervical cytology samples will be obtained to characterize HPV infection at screening, Day 0 
(prior to dosing) and Weeks 15, 28, 36, 62, and 88.  Also, if there is residual tissue in the paraffin 
block after histologic diagnoses have been rendered, then unstained slides and/or the relevant 
paraffin blocks may be collected for testing of HPV-16/18. Vaginal, oropharyngeal and peri-anal 
142

2. 1. 3
2. 1. 4

If there is residual tissue in the paraffin block after histologic diagnoses have been rendered, then 
unstained slides and/or the relevant paraffin blocks will be collected for immunohistochemistry 
(IHC). Whenever possible, these studies may be performed on tissue sections from the diagnostic 
screening biopsy (pre-dose) and from tissue obtained post-dose(s) (Week 36). 
2.2 
TREATMENT PLAN 
The three dose regimen of VGX-3100 appeared to be safe and well tolerated in the Phase 2b study, 
therefore all eligible subjects who consent to participate in the Phase 3 study will receive the same 
three 6 mg doses of VGX-3100X or placebo administered in 1 mL IM (deltoid, preferred site, or 
anterolateral quadriceps, alternate site), each followed immediately by EP with the CELLECTRA™ 
5PSP device. The first study treatment will be administered on Day 0, the second at Week 4, and 
the third (final) study treatment will be administered at Week 12 which is consistent with the Phase 
2b study. The first study treatment will be given as soon as possible following confirmation of the 
cervical HSIL diagnosis and HPV-16/18 status but no more than 10 weeks following collection of 
the subject’s biopsy specimen used for diagnosis by the PAC during screening, contemporaneous 
with the positive testing for HPV-16/18. 
2.3 
SAFETY MONITORING PLAN 
Although cervical HSIL is thought to require years to progress to cervical cancer, subjects in the 
Phase 2b study were followed closely throughout. HPV testing (Weeks 14 and 24), cytology (Week 
14) and colposcopy (Week 24) were all mandatory during the observation period prior to obtaining 
tissue for determination of the primary histologic endpoint at Week 36. Investigators were also 
instructed to perform additional testing (including biopsy) if disease progression was suspected. 
These instances were infrequent as only 11 unscheduled biopsies were deemed necessary over the 
course of the Phase 2b study. In addition, the rate at which occult microinvasive cancer was 
discovered after 36 weeks was less frequent than what is reported in the literature [22]. Both 
observations would imply that the mandatory monitoring employed in the Phase 2b study was 
sufficient; however cervical disease will be monitored even more closely in this Phase 3 study. 
Colposcopy, cytology and HPV testing will be required at 8 to 14 week intervals throughout the 
observation period leading up to the primary endpoint 36 weeks after the first dose. Although less 
frequent monitoring may be adequate, the more frequent monitoring is designed to afford an even 
wider margin of safety and an opportunity to explore predictors of efficacy.     
Safety monitoring will include: 
 Local and systemic events for 7 days following each treatment as noted on a Participant Diary 
Card (PDC). 
 All adverse events including SAEs, UADEs, and other unexpected AEs for the duration of the 
study; 
In the Phase 2b study, the safety profile was carefully evaluated and treatment with VGX-3100 was 
well-tolerated based on observations through Week 88 in all subjects. The most common adverse 
events were administration-site reactions, which included pain, tenderness, erythema and swelling, 
and were generally mild and limited to a few days in duration.  Only erythema showed a statistically 
144

higher incidence in VGX-3100 (78%) vs. placebo (57%) in the 7- and 28-day periods after a dose. 
One additional AE, sinusitis, was also statistically significantly increased over the course of the 
entire study period but resolved without sequelae in the VGX-3100 arm compared to the Placebo 
arm (10% vs. 0%).      
As outlined above, safety monitoring and visit frequency has been designed to take into account the 
potential risk of delay in the usual treatment of the high grade cervical dysplasia and also the 
potential for a missed diagnosis of an occult early invasive cervical cancer for the VGX-3100X non-
responders or placebo recipients, who do not regress.  Serial cytology, HPV testing, and colposcopic 
exams are applied throughout the course of the study with the well accepted understanding that 
cervical dysplasia progresses slowly, typically over years, which makes close, active follow-up 
possible.  All subjects with suggestion of residual disease will undergo excisional therapy by LEEP 
or CKC at Week 36 as part of the efficacy assessment.  Subjects whose cytology, HPV testing, ECC 
results (if applicable) and colposcopic exam suggest disease regression will undergo 4 quadrant 
biopsy or 4 quadrant biopsy with ECC (based upon Table 5 and 6) to provide histopathologic 
confirmation of regression. The use of a 4 quadrant biopsy in Phase 3 is a change from the approach 
used in Phase 2b to optimize the evaluation of histopathologic regression taking into consideration 
the inherent limitations of colposcopy and tissue biopsy samples in the absence of visible lesions 
[23].  
In the Phase 2b study, the cervical tissue sample was initially read by a local pathologist and/or 
central pathology laboratory for rapid local medical management.  The definitive histopathologic 
assessment was determined by an independent blinded Pathology Adjudication Panel, comprised of 
experienced cytopathologists from independent medical centers in the US.  Seven reports included 
the terms ‘(adeno)squamous cell carcinoma’ or the premalignant condition of ‘adenocarcinoma in 
situ’ (AIS) in the final Phase 2b study results which included all 88 weeks of follow up. Three of 
the cases were reported as AIS, (2 VGX-3100, 1 placebo), out of which two cases (1 VGX-3100, 1 
placebo) were confirmed as AIS by the PAC. AIS is a pre-invasive glandular lesion which can be 
difficult to capture on standard of care screening with initial punch biopsy and is more commonly 
identified by full excision (e.g. LEEP, conization).  There were four reports that included the term 
squamous cell carcinoma, of which two were confirmed by the PAC, both in the VGX-3100 group.  
The other two cases (1 VGX-3100, 1 placebo) were diagnosed as CIN3 by the PAC.  The rate at 
which microinvasive cancer was found in larger surgical excision samples in subjects who had no 
evidence of invasive cancer by initial biopsy was 1.8%, (2/114 with specimens), which is consistent 
with and even lower than the rate of 6.7% that has been reported under standard of care settings 
[22].  
Importantly, investigators in the Phase 3 study will be chosen only if they are experienced in the 
management of cervical cancer as was the case in the Phase 2b study. Phase 3 investigators are 
instructed to perform additional, ad hoc colposcopic exams and cervical biopsies if they suspect 
potential disease progression. Subjects that undergo an unscheduled biopsy will be classified as a 
non-responder in the efficacy analysis as outlined in Table 6. These measures should minimize the 
risk of progression of cervical HSIL and the risk of harboring an undiagnosed occult early invasive 
cervical cancer. The frequency of close monitoring by experienced investigators should minimize 
the risk of cancer progression on the study what is expected with standard of care.   
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2.3.1 
DATA SAFETY & MONITORING BOARD (DSMB) 
An independent Data Safety & Monitoring Board (DSMB) will provide safety oversight.  The 
DSMB will be scheduled to meet quarterly. If there are no new safety data or regression/clearance 
results to review for a quarterly scheduled meeting the DSMB will be notified and the meeting 
may be cancelled; ad hoc meetings may be scheduled to review new data as applicable. The DSMB 
will be charged with advising the Sponsor if there appears to be a safety issue and with advising 
the Sponsor if it appears that the proportion of the subjects with regression in the VGX-3100X 
group is unacceptably low compared to the placebo group. However, no formal interim analysis 
will be performed. 
2.4 
LONG TERM FOLLOW UP PLAN 
In the Phase 2b study, all subjects were scheduled to be followed for 1 year after the histopathologic 
assessment for the primary endpoint (to study Week 88). The establishment of efficacy based on 
histopathologic evidence dictated the removal of tissue at week 36 by either punch biopsy (ies) or 
more extensive surgical resection (i.e. LEEP, CKC). Subjects with colposcopic evidence of residual 
disease were to undergo LEEP/CKC. A higher proportion of patients who received placebo had a 
LEEP performed than those who received VGX-3100 (Table 8). 
Cytology and HPV-16/18 clearance from the cervix was to be assessed at study Weeks 62 and 88 to 
evaluate for recurrence of dysplasia and HPV infection after removal of tissue at Week 36.  Overall, 
in the phase 2b study, the majority of subjects had improved cytology and had cleared their 
underlying HPV-16/18 cervical infection by the Week 62 and 88 visits. For Weeks 62 and 88, there 
were no clinically meaningful differences noted between the subjects who received an excisional 
treatment (e.g. LEEP, CKC) and those that showed histopathologic regression and therefore only 
underwent a biopsy, as shown in Table 8 which summarizes the HPV and cytology results following 
Week 36.  
Table 8.  HPV-003 HPV and Cytology Results at Weeks 36, 62 and 88, mITT Population  
Week 
Testa 
VGX-3100 
Placebo 
LEEP/CKCb 
%(n/N) 
Biopsyc 
%(n/N) 
LEEP/CKC 
%(n/N) 
Biopsy 
%(n/N) 
36 
HPV 
41% (19/46) 
63% (36/57) 
29% (6/21) 
29% (5/17) 
36 
Pap 
NA 
NA 
NA 
NA 
62 
HPV 
89% (50/56) 
82% (42/51) 
96% (27/28) 
82% (9/11) 
62 
Pap 
93% (52/56) 
100% (51/51) 
93% (26/28) 
82% (9/11) 
88 
HPV 
89% (48/54) 
89% (42/47) 
89% (24/27) 
100% (10/10) 
88 
Pap 
96% (52/54) 
91% (43/47) 
85% (23/26) 
100% (11/11) 
Abbreviations: NA, not applicable, Pap smear was not done at Week 36 
a  HPV =  HPV-16/18 testing; Pap = cytology testing  
146

b LEEP or CKC done, at or before the study week as specified  
c Only biopsy done, at or before the study week as specified 
Clearance of HPV-16/18 from the cervix was observed in both treatment groups (Figure 1a) at 
similar rates until after the second dose when clearance in the VGX-3100 recipients continued to 
rise while the rate appeared to plateau in the placebo group. 
Figure 1.  HPV-16/18 Clearance and Pap Smear Findings in Phase 2b mITT Population by 
Treatment Group
At Week 36, clearance was significantly higher among VGX-3100 subjects that had biopsy (63%) 
versus LEEP/CKC (41%), which likely reflects the association between clearance of the underlying 
HPV infection and the likelihood of having signs indicative of regression by colposcopic 
exam. HPV-16/18 clearance data (mITT population) post-Week 36 are described as follows: HPV-
16/18 clearance at Week 62 was 89% (50/56) for VGX-3100 post-LEEP/CKC, 82% (42/51) for 
VGX-3100 post Biopsy only, 96% (27/28) for Placebo post-LEEP/CKC, and 82% (9/11) for Placebo 
post Biopsy only.  HPV-16/18 clearance at Week 88 was 89% (48/54) for VGX-3100 post-
LEEP/CKC, 89% (42/47) for VGX-3100 post Biopsy only, 89% (24/27) for Placebo post-
LEEP/CKC, and 100% (10/10) for Placebo post Biopsy only. 
The majority of subjects had cleared their underlying cervical HPV-16/18 infection by Week 62 
without meaningful changes through Week 88, and without meaningful differences between groups. 
Forty-seven of 53 (89%) and 46 of 49 (94%) subjects at Weeks 62 and 88, respectively (mITT 
population) with histopathologic evidence of CIN2/3 regression (regressors) in the VGX-3100 
treatment group experienced HPV-16/18 clearance. Despite the use of therapeutic resection for 
many VGX-3100 recipients whose CIN2/3 did not regress by Week 36 (non-regressors), HPV-16/18 
clearance rates were notably lower (85% at Week 88) compared to regressors. 
In the subjects who initially cleared HPV-16/18 by Week 36, only one HPV-16/18 recurrence was 
identified at the Week 62 and 88 evaluations. Specifically, one subject who had HPV types 16 and 
82 and CIN2 at screening, was HPV negative at Week 36, but tested HPV type 16 positive at Week 
Week 14
Week 62
Week 88
a.
b.
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62, and then cleared HPV-16 at Week 88. The subject showed histopathologic regression at Week 
36. No recurrences were identified in the eleven subjects in the placebo group with valid HPV data 
at Weeks 62 or 88. There were no (0/51) recurrences identified in the VGX-3100 treated group at 
Week 88. Overall, these virologic clearance findings support that study subjects had no increased 
risk as compared to standard of care.  
Cytology (mITT population) post-Week 36 are described as follows: Improvement compared to 
study entry for Pap smear cytology results at Week 62 were 93% (52/56) for VGX-3100 post-
LEEP/CKC, 100% (51/51) for VGX-3100 post-Biopsy only, 93% (26/28) for Placebo post-
LEEP/CKC, and 82%  
(9/11) for Placebo post-Biopsy only. At Week 62, cytopathologic improvement was reported for 
104 of 125 (83%) subjects in the VGX-3100 treatment group and 34 of 42 (83%) subjects in the 
placebo treatment group (mITT population).  
There were no instances of possible progression, and all cases that did not meet the definition of 
improvement were due to either no change from baseline, sample considered not evaluable, or no 
data available.  Improvement compared to study entry for Pap smear cytology results at Week 88 
were 96% (52/54) for VGX-3100 post-LEEP/CKC, 91% (43/47) for VGX-3100 post-Biopsy only, 
85% (23/26) for Placebo post-LEEP/CKC, and 100% (11/11) for Placebo post-Biopsy only.  At 
Week 88, possible progression (atypical glandular cells) was reported in a single Placebo subject in 
the post-LEEP/CKC group (3%) and no subjects treated with VGX-3100. All other cases that did 
not meet the definition of improvement were due to either no change from baseline, sample 
considered not evaluable, or no data available. The majority of subjects showed improvement, and 
there was no meaningful difference between the Week 62 and Week 88 evaluations.   These findings 
support that study subjects had no increased risk of progression based upon cytology as compared 
to standard of care. 
The protocol-specified removal of dysplastic cervical tissue at Week 36 by either method 
substantially affected the clearance of HPV-16/18 and normalization of cytologic findings as 
expected, regardless of treatment group (Figure 1a, b). HPV-16/18 clearance rises at a sharp rate 
after tissue is removed at Week 36 whether the excision is wide (LEEP/CKC) or more limited 
(biopsy). Notably, the method of tissue collection at the Week 36 endpoint did not appreciably affect 
the HPV-16/18 clearance rates beyond Week 36 (Table 8).   Based upon the Phase 2b results, the 
risk of progression or recurrence of cervical dysplasia is low and comparable to the rates observed 
post-LEEP/CKC in clinical practice.  The long term follow up planned for this Phase 3 study will 
include safety, cytology and HPV-16/18 testing at 6 months and also 1 year following the Week 36 
histopathologic assessment, which is highly conservative given the expectation that few subjects 
will have persistent evidence of disease after the removal of tissue at Week 36 which is supported 
by the findings in the Phase 2b study. 
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3 HYPOTHESIS AND STUDY OBJECTIVES 
3.1 
HYPOTHESIS 
Three 6 mg doses of VGX-3100X (DNA Plasmids encoding E6 and E7 proteins of HPV-16 and 
HPV-18) delivered IM followed by EP with CELLECTRA™ 5PSP to adult women with 
histologically confirmed HSIL of the cervix, associated with HPV-16 and/or HPV-18 will result in 
a higher percentage of women with histopathological regression of cervical HSIL lesions to no 
evidence of cervical HSIL and virologic clearance of HPV-16/18 compared to placebo delivered IM 
followed by EP with CELLECTRA™ 5PSP at the Week 36 visit. 
3.2 
PRIMARY OBJECTIVE AND ENDPOINT 
Objective 
Endpoint 
Determine 
the 
efficacy 
of 
VGX-3100X 
compared with placebo with respect to 
combined histopathologic regression of cervical 
HSIL and virologic clearance of HPV-16 and/or 
HPV-18 
Proportion of subjects with no evidence of  
cervical HSIL on histology (i.e. biopsy or 
excisional treatment) and no evidence of 
HPV-16 and/or HPV-18 in ThinPrep™ 
cervical samples by type specific HPV testing 
at Week 36 visit 
3.3 
SECONDARY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Secondary Objectives 
Associated Endpoints 
1. Evaluate the safety and tolerability of VGX-
3100X delivered IM followed by EP with 
CELLECTRA™ 5PSP 
1a. Incidence and severity of local and systemic 
events for 7 and 28 days following each 
investigational treatment  and for the duration 
of the study (through Week 88 visit) 
1b. Incidence and severity of serious adverse 
events (SAE) and Unanticipated [Serious] 
Adverse Device Effects (UADE) for 7 and 28 
days following each investigational treatment 
and for the duration of the study (through 
Week 88 visit) 
2. Determine the efficacy of VGX-3100X 
compared with placebo as measured by 
histopathologic regression of  cervical HSIL  
2. Proportion of subjects with no evidence of  
cervical HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 36 visit 
3. Determine the efficacy of VGX-3100X 
compared with placebo as measured by 
virologic clearance of HPV-16 and/or HPV-
18 
3. Proportion of subjects with no evidence of 
HPV-16 and/or HPV-18 in ThinPrep™ cervical 
samples  by type specific HPV testing at Week 
36 visit 
149

 
 
3. 4
 
 

Exploratory Objectives 
Associated Endpoints 
3. Evaluate effect of HLA type on efficacy 
 
3. HLA (per-locus and per-allele basis) in 
conjunction with histologic regression of  
cervical HSIL at Week 36 visit 
4. Describe association of previous colposcopy, 
cytology and HPV testing results with 
histologic regression at Week 36   
4. Colposcopy, cytology, and HPV test results at 
Weeks 15 and 28 visits in conjunction with 
histologic regression of cervical HSIL at Week 
36 visit 
5. Describe the durability of virologic clearance 
of HPV-16 and/or HPV-18 for subjects treated 
with VGX-3100X compared with those treated 
with placebo 
5. Proportion of subjects with no evidence of 
HPV-16 and/or HPV-18 by type specific HPV 
testing at Weeks 62 and 88 visits 
6. Describe the patient-reported outcomes for 
subjects treated with VGX-3100X 
6. The following two questionnaires; Short Form 
Health Survey, version 2 (SF-36v2™) and EQ-
5D-5L™ will be self-administered prior to first 
dose (i.e. Day 0), following each dose, and at 
Weeks 28, 40 and 88 to measure score(s). 
4 SELECTION OF SUBJECTS 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in the study: 
1. Women aged 18 years and above; 
2. Confirmed cervical infection with HPV types 16 and/or 18 at screening;  
3. Cervical tissue specimen/slides provided to Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study 
drug; 
4. Histologic evidence of cervical HSIL as confirmed by PAC at screening; 
5. Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form 
prior to study-related activities; 
6. Must be judged by Investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision, 4-quadrant biopsy with ECC, or 4-quadrant biopsy) required at 
Week 36 
7. Has satisfactory colposcopy, defined as full visualization of the squamo-columnar junction 
(Type I or II transformation zone) and complete visualization of the upper limit of aceto-
white epithelium or suspected CIN disease; 
151

8. Must have a cervical lesion that is accessible for sampling by biopsy instrument (e.g. Mini-
Tischler device); 
9. Must have a cervical lesion of adequate size to ensure that a visible lesion remains after 
screening biopsy; 
10. Must meet one of the following criteria with respect to their reproductive capacity: 
a) Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months or 
spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL 
b) Is surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 12 months prior to screening 
c) WOCBP is willing to use a contraceptive method with failure rate of less than 1% per 
year when used consistently and correctly from screening until 6 months following the 
last dose of investigational product. Acceptable methods are the following: 
o Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. Hormonal 
contraceptives must not be used in subjects with a history of hypercoagulability (e.g., 
deep vein thrombosis, pulmonary embolism). 
o Abstinence from penile-vaginal intercourse when this is the subject’s preferred and 
usual lifestyle 
o Intrauterine device or intrauterine system 
o Male partner sterilization at least 6 months prior to the female subject’s entry into the 
study, and this male is the sole partner for that subject 
11. Has normal screening ECG or screening ECG with no clinically significant findings, as 
judged by the investigator. 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from enrollment in the study: 
1. Has microscopic or gross evidence of adenocarcinoma-in-situ (AIS), high grade vulvar, 
vaginal (inclusive of cervical HPV-related lesions that extend into the vaginal vault), or anal 
intraepithelial neoplasia or invasive cancer in any histopathologic specimen at screening; 
2. More than 10 weeks have elapsed between date of initial tissue biopsy for screening and day 
of first dose(i.e. Day 0); 
3. Has cervical lesion(s) that cannot be fully visualized on colposcopy due to extension high 
into cervical canal at screening; 
4. Has history of ECC which showed cervical HSIL indeterminate, or insufficient for diagnosis 
(ECC is not performed as part of study screening); 
5. Has treatment for cervical HSIL or genital warts within 4 weeks prior to screening; 
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6. Is pregnant, breastfeeding or considering becoming pregnant during the study; 
7. Has history of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines 
are allowed, e.g. Gardasil™, Cervarix™); 
8. Has presence of any abnormal clinical screening laboratory values greater than Grade 1 per 
Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 within 30 days prior to Day 0 
or less than Grade 1 but deemed clinically significant by the investigator; 
9. Has immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening 
b) Primary immunodeficiencies 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent; (use of inhaled, otic, and ophthalmic corticosteroids are allowed) 
d) 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) 
e) History of solid organ or bone marrow transplantation 
f) Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
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. 
10. Has received any non-study, non-live vaccine within 2 weeks of Day 0; 
11. Has received any non-study, live vaccine (e.g. measles vaccine) within 4 weeks of Day 0; 
12. Has current or history of clinically significant, medically unstable disease which, in the 
judgment of the investigator, would jeopardize the safety of the subject, interfere with study 
assessments or endpoint evaluation, or otherwise impact the validity of the study results (e.g. 
chronic renal failure; angina, myocardial ischemia or infarction, class 3 or higher congestive 
heart failure, cardiomyopathy, or clinically significant arrhythmias); 
13. Has malignancy or treatment for malignancy within 2 years of screening, with the exception of 
superficial skin cancers that only require local excision;  
14. Presence of acute or chronic bleeding or clotting disorder that would contraindicate IM 
injections, or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of 
Day 0; 
15. Has history of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic 
agents; 
16. Has sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm 
Hg or a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
17. Has resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at 
screening or Day 0; 
18. Has prior major surgery within 4 weeks of Day 0; 
153

19. Has participated in an interventional study with an investigational compound or device within 
30 days of signing informed consent; participation in an observational study is permitted; 
20. Has less than two acceptable sites available for IM injection considering the deltoid and 
anterolateral quadriceps muscles; 
21. Has tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
22. Has cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is 
located in ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 
23. Has metal implants or implantable medical device within the electroporation area; 
24. Has active drug or alcohol use or dependence that, in the opinion of the investigator, would 
interfere with adherence to study requirements; 
25. Is a prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment 
of either a psychiatric or physical (i.e. infectious disease) illness; 
26. Is an active military service personnel; 
27. Is a study-related staff or family member of study-related staff; 
28. Has 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 STUDY SUBJECTS 
4.3.1 
CRITERIA FOR DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
Subjects who manifest Grade 4 toxicity attributable to the study treatment will be discontinued 
from the study treatment.  Subjects will not receive further study treatment but will be encouraged 
to continue follow-up safety assessment through study discharge and not discontinue from the 
study.  
If a subject manifests Grade 3 toxicity attributable to the study treatment, the medical monitor and 
Investigator will discuss whether further treatment should be continued for that subject.  
4.3.2 
CRITERIA FOR WITHDRAWAL FROM THE STUDY 
All randomized subjects should be encouraged to complete all study treatments and follow-up 
visits. A subject will be considered to have completed the study when she completes all scheduled 
study treatments and follow-up visits. However, a subject may voluntarily withdraw from study 
participation at any time or be withdrawn at any time at the discretion of the investigator for any 
maternal obstetrical or medical complications after consultation with the medical monitor. 
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. The site should also counsel the 
subject on the importance of maintaining the assigned visit schedule for follow-up and treatment 
of HSIL (CIN2, CIN3), and ascertain whether or not the subject wishes to and/or should continue 
in the study based on previous noncompliance. In cases where the subject does not return for the 
154

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 they can appropriately be withdrawn from the 
study. 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. 
4.3.3 
SPONSOR NOTIFICATION OF DISCONTINUATION/ WITHDRAWAL  
The investigator or study coordinator must notify the Sponsor immediately when a subject has 
been discontinued/withdrawn due to an AE. If a subject discontinues from the study or is 
withdrawn from the study prior to study completion, all applicable activities scheduled for the 
final study visit should be performed at the time of discontinuation. The investigator will make 
every effort to have all scheduled immune assessment blood samples collected as indicated in the 
Schedule of Events in the synopsis, Table 1. Any AEs and/or SAEs present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in section 7.1 – Safety Parameters. 
4.3.4 
REASON FOR DISCONTINUATION/WITHDRAWAL 
The primary reason for a subject discontinuing further dosing or withdrawal from the study itself 
is to be selected from the following standard categories and recorded on the CRF: 
 Adverse Event (Adverse Reaction): Clinical or laboratory events occurred that, in the medical 
judgment of the investigator for the best interest of the subject, are grounds for discontinuation. 
This includes serious and non-serious adverse events regardless of relation to study drug. 
 Death of subject  
 Subject voluntarily withdrew consent:  The subject desired to withdraw from further 
participation in the study in the absence of an investigator-determined medical need to 
withdraw. If the subject gave a reason for withdrawal, it must be recorded on the CRF. This 
reason does not allow for further data collection and should not be selected if follow-up data 
collection of this subject is anticipated by the subject. 
 Investigator decision to withdraw the subject from participation:  Investigator determined a 
medical need to withdraw the subject.  Investigator must consult the Sponsor’s Medical 
Monitor before withdrawing a subject from participation in the study 
 Protocol Violation: The subject’s findings or conduct failed to meet the protocol entry criteria 
or failed to adhere to the protocol requirements (e.g., treatment noncompliance, failure to 
return for defined number of visits). The violation should be discussed with the Sponsor’s 
Medical Monitor prior to discontinuation of study treatments or study withdrawal. 
155

 Lost to Follow-up: The subject fails to attend study visits and study personnel are unable to 
contact the subject after repeated attempts including telephone calls, letter sent by certified 
mail or equivalent. 
 Other: The subject was terminated for a reason other than those listed above, such as the 
termination of the study by the Sponsor 
5 STUDY TREATMENT 
5.1 
INVESTIGATIONAL PRODUCTS 
Investigational product (IP) 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.  The active and 
placebo formulations to be used in this study are described in Table 9.  Both IPs will presented in 
clear glass cartridges and will be injected intramuscularly. 
VGX-3100X and placebo will be provided by Inovio Pharmaceuticals, Inc. or its designee. 
Table 9. Investigational Products 
Product 
Formulation 
Dose 
VGX-3100X 
6 mg (1:1 mix of SynCon™ HPV-16 E6/E7 and HPV-18 E6/E7 plasmids) in 150 
mM sodium chloride and 15 mM sodium citrate 
1 mL 
Placebo 
150 mM sodium chloride and 15 mM sodium citrate 
1 mL 
5.2 
BLINDING 
This study is double-blinded with blinding maintained throughout the study by use of identical 
packaging for both the active product and the placebo. There is no difference in appearance for both 
the active product and the placebo.  
The investigator may request to unblind a subject’s treatment assignment in case of an emergency 
or serious medical condition when knowledge of the study treatment is essential for proper clinical 
management of the subject, as judged by the investigator.  It is preferred, but not required, that the 
investigator first contact the Medical Monitor to discuss options before unblinding the subject’s 
treatment assignment.  In case of non-emergency, investigator must contact Medical Monitor to 
discuss the options before unblinding the subject’s treatment assignment.  
The Sponsor’s or designee’s pharmacovigilance staff may unblind the treatment assignment for any 
subject with an SAE, UADE, or AE of interest. No personnel directly involved with the study will 
be unblinded.  If expedited regulatory reporting is required for an event, the report may be submitted 
to regulatory authorities with the subject’s treatment assignment, in accordance with local 
regulations. 
156

5.3 
PACKAGING AND LABELING OF INVESTIGATIONAL PRODUCT 
Each cartridge will be labeled with a single-panel label and then individually packaged within a 
pouch that will contain an additional, double-panel label with tear-off. Both VGX-3100X and 
placebo labels will include, at minimum, the following information in Table 10:   
Table 10. Example Labels for Investigational Product 
 
5.4 
HANDLING OF INVESTIGATIONAL PRODUCT 
Inovio Pharmaceuticals, Inc. will be responsible for assuring the quality of the IP is adequate for 
the duration of the trial. Unless otherwise specified, IP will be shipped in a refrigerated condition 
with a temperature monitoring device. If the temperature monitoring device denotes temperatures 
outside the pre-specified range for any product, the Sponsor, or its designee should be contacted 
immediately. 
Immediately upon arrival, IPs should be transferred from the shipping container into 2–8 °C (36-46 
°F) storage, in a secure area, according to local regulations. The Sponsor should be notified of any 
deviations from this recommended storage condition.  
Refrigerator temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. 
5.5 
DISPENSING OF INVESTIGATIONAL PRODUCT 
It is the responsibility of the Investigator to ensure that the IP is only dispensed to study subjects. It 
must be dispensed only from official study sites by authorized personnel according to local 
regulations. 
When a subject is eligible for randomization, remove the pouch from the refrigerator and allow to 
reach room temperature. The product cartridge must not be removed from the pouch until 
immediately prior to administration. The pouch must not be discarded until 1) administration is 
completed and 2) all pertinent information from the pouch label has been documented in source.  
The product must be used within 4 hours of removal from the refrigerator. 
Cartridges 
(primary container) 
Pouches 
(secondary package) 
VGX-3100X or Placebo 
Insert cap end 
IM administration 
Inovio Pharmaceuticals, Inc. 
Study ID/Material ID 
VGX-3100X or Placebo 
Single-use, 1 mL 
Storage temperature, expiration date 
CAUTION: New Drug – Limited by United States 
Law to  Investigation Use 
Inovio Pharmaceuticals, Inc. 
157

The device user manual and instructions for use will inform clinical personnel about placement of 
the IP cartridge into the device, as well as the steps for injection and electroporation. 
5.6 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of investigational product 
is maintained at the study site. Records or logs must comply with applicable regulations and 
guidelines, and should include: 
• 
Amount received and placed in storage area; 
• 
Amount currently in storage area; 
• 
Label ID number and use date or expiry date; 
• 
Dates and initials of person responsible for each investigational product inventory 
entry/movement; 
• 
Amount dispensed to each subject, including unique subject identifiers; 
• 
Amount transferred to another area/site for dispensing or storage; 
• 
Amount returned to Sponsor; 
• 
Amount destroyed at study site, if applicable. 
5.7 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused and/or partially used IP must be returned 
to Inovio Pharmaceuticals, Inc., or its designee, if not authorized by Inovio Pharmaceuticals, Inc. to 
be destroyed at the site. 
The IP cartridge will be discarded along with the disposable array within a sharp’s container at site. 
All IP returned to Inovio Pharmaceuticals, Inc., or its designee, must be accompanied by the 
appropriate documentation. Returned supplies should be in the original containers. Empty 
containers should not be returned to Inovio Pharmaceuticals, Inc. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for proper 
disposal have been established according to applicable federal, state, local and institutional 
guidelines and procedures, and provided that appropriate records of disposal are kept. The return of 
unused IP(s) should be arranged by the responsible Study Monitor. 
If IP(s) are to be 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 according to applicable 
regulation and guidelines and institutional procedures, and appropriate records of the disposal have 
been documented. The unused IP can only be destroyed after being inspected and reconciled by the 
responsible Inovio Pharmaceuticals, Inc. or designated Study Monitor 
 
158

5.8 
INVESTIGATIONAL DEVICE 
The needle array component of CELLECTRA™ 5PSP device is provided sterile and is intended for 
single-use. CELLECTRA™ 5PSP device is intended to be used by qualified and trained healthcare 
professionals in clinical settings. The Investigator for this study will be trained in the use of the 
device. 
CELLECTRA™ 5PSP has 3 main components that are used in conjunction with the drug cartridge 
(see Figure 2): 
1. 
Base – Acts as a docking station for the Handset and as the primary display for entering 
subject information; must be used with the provided Power Supply 
2. 
Handset – Controls delivery of the drug and electrical pulses 
3. 
Array (single-use sterile) – Attaches to the Handset and contains the injection needle, 
electrodes and sensors used for drug delivery and electroporation.   
4. 
Drug Cartridge (single-use) – a separate container-closure containing the IP solution. The 
Cartridge is inserted into the array for administration of the IP.  
 
Figure 2. Components of the CELLECTRA™ 5PSP Device and Drug Cartridge 
 
3 
4 
2 
1 
Assembled View 
Stored View 
159

The CELLECTRA™ 5PSP device has unique features that make using it different from using 
other injection systems: 
1. Each Handset is uniquely paired to a Base. The serial numbers on the bottom of the Base and 
Handset must match. 
2. There is no communication between the Base and Handset when separated; the Handset must 
be placed onto the Base to share power or data. 
3. The Handset has an internal battery that must be charged on the Base before use. 
4. Needle depth is selectable on the Handset at the following lengths: 13 mm, 19 mm, or 25 mm. 
Even though the system provides a needle depth recommendation based on a Subject’s height 
and weight, the user will be asked to manually enter the needle depth based on the protocol 
requirements (refer section 5.9), described  
5. Injecting the placebo and delivering electrical pulses takes time (usually 10 seconds). The 
Handset will let you know when treatment is complete. 
6. The Subject should be maintained in a safe and secure, braced position due to involuntary 
muscle spasms that may occur during delivery of the electrical pulses. 
Before using the CELLECTRA™ 5PSP device, the Investigator and research staff must be trained 
by the Inovio Pharmaceuticals Inc. device trainer(s) and be requested to read the entire user manual 
and complete the Self-Assessment. 
5.9 
USE OF INVESTIGATIONAL DEVICE 
The instructions for use of the device are located in the CELLECTRA™ 5PSP User Manual. Users 
of the CELLECTRA™ 5PSP device must successfully complete training. Training will include 
review of the entire device user manual and instruction video and hands-on training. After training 
on the proper use of the CELLECTRA™ 5PSP device, intended users at each site will be required to 
demonstrate their competence in its use to Inovio or its designee. 
Briefly, the Handset and Array should be prepared according to the instructions in the user manual. 
Remove the array from its packaging while avoiding contact with the end of the array that attaches 
to the handset, and insert the drug cartridge into the array with the arrow on the cartridge pointing 
away from the handset.  
Attach the Array to the Handset and set the needle depth on the handset to the longest needle length 
judged to allow safe injection into the muscle per the investigator’s assessment.   
The subject must be in a safe and secure, braced position.  The subject’s body should touch the bed 
or be braced against the bed or have the study staff performing electroporation or assistant in the 
position to brace the subject’s arm or leg (as appropriate) as the EP is administered.  The user will 
then insert the CELLECTRA™ 5PSP needle array into the deltoid (or anterolateral quadriceps 
muscle as an alternate option, if deltoid muscle is not possible or appropriate) of the participant in 
accordance with the CELLECTRA™ 5PSP user’s manual instructions. Once triggered by the user, 
the device will automatically deliver the blinded treatment followed by the EP pulses. The entire 
treatment period lasts for about 10 seconds. 
160

The treatment 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. Individuals whose credentials do not meet the relevant local requirements may 
perform the treatment procedure under both of the conditions below: 
1. The procedure must be performed under the direct supervision of the Investigator or an 
approved Sub-Investigator who has already been trained by the sponsor’s personnel. 
2. The CV and any relevant qualifications of the individual must be reviewed and approved 
by the sponsor or its designee to perform the procedure. 
Any deviation from the above procedures must be approved by the sponsor or its designee. 
5.10  PACKAGING AND LABELING OF INVESTIGATIONAL DEVICE 
See below Figure 3 for example CELLECTRA™ 5PSP device component labels. 
Figure 3. Device Labels (Base, Handset, Array) 
           
                        
 
                                  BASE                                                                      HANDSET 
 
                                                                              ARRAY 
 
161

5.11  HANDLING OF INVESTIGATIONAL DEVICE 
The CELLECTRA™ 5PSP device and its components must be stored in a secure location according 
to the instructions in the User Manual. 
5.12  INVESTIGATIONAL DEVICE ACCOUNTABILITY 
The investigative site is responsible for maintaining investigational device and accountability logs. 
The device must have full traceability from the receipt of the products through the subject use, 
disposal or return of the products. The Site must document acknowledgement of receipt and notify 
Inovio upon receipt of investigational product. This includes the content shipped and condition upon 
receipt.  
For each subject treatment, there must be a record of each product used for that subject, i.e. 
CELLECTRA™ 5PSP serial number, array lot number and the study drug lot number. The used 
sterile disposable array attachment must be discarded after use in accordance with institutional 
policy regarding disposal of sharp needles/instruments. 
5.13  RETURN OF INVESTIGATIONAL DEVICES 
Upon completion or termination of the study, all investigational devices and unused components 
must be returned to Inovio Pharmaceuticals, Inc. 
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 responsible Study Monitor. 
If product is to be 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 according to applicable 
regulation and guidelines and institutional procedures, and appropriate records of the disposal have 
been documented. 
6 STUDY PROCEDURES AND TREATMENTS 
This section lists the procedures and parameters for each planned study evaluation.  The timing of 
each assessment is listed in the Schedule of Events Table (see Table 1). 
A subject will be required to provide informed consent for use of any information collected prior to 
consenting and before any additional study specific procedures are performed.   
Protocol waivers or exemptions are not allowed with the exception of immediate safety concerns. 
Therefore, adherence to the study design requirements, including those specified in the Schedule of 
Events Table are essential and required for study conduct 
 
162

6.1 
BEFORE TREATMENT PROCEDURES 
6.1.1 
SCREENING EVALUATIONS 
After providing informed consent, subject’s cervical biopsy tissue samples (e.g., formalin fixed 
tissue, paraffin-embedded tissue) and/or biopsy slides will be sent to the PAC for review by two 
study pathologists. Discordant results will be reviewed by a third pathologist to achieve a 
consensus diagnosis. Subjects must have a diagnosis of histologic HSIL (CIN2 or CIN3) 
confirmed by the PAC and a screening cervical specimen (i.e. ThinPrep™) test positive for HPV-
16 and/or HPV-18 by Cobas™ HPV test to be eligible for randomization into the study (provided 
the subject also meets other eligibility criteria). Subjects whose specimens also test positive for 
other HPV genotypes are not excluded as long as they have a positive result for HPV-16 and/or 
HPV-18. There will be a maximum allowable window of 10 weeks from the date of collection of 
the qualifying biopsy sample(s) (i.e. slides/samples(s) reviewed by PAC with HSIL consensus 
diagnosis), until the date of first study treatment (i.e. Day 0).  
 Biopsy specimens and colposcopic photographs obtained within 10 weeks prior to Day 0 as 
part of standard of care before the informed consent may be used as part of the screening and 
evaluation process.   
 If the pathology results of the initial biopsy obtained as part of standard of care are available 
confirming the presence of HSIL (CIN2 or CIN3), those biopsy slides or sample(s) may be 
sent directly to the PAC for concurrence after the subject has signed the informed consent.   
 For those individuals diagnosed with cervical HSIL by a local pathologist, where the initial 
biopsy slides or tissue obtained as part of standard of care are not available or cannot be 
obtained within a reasonable timeframe, colposcopy with cervical photography may be 
performed and an additional biopsy sample may be collected during screening at the discretion 
of the investigator and consent of the subject. The additional biopsy sample may be sent 
directly to the PAC for review, if allowable per local or institutional guidelines. 
The assessments during the screening period will determine the subjects’ continued eligibility for 
the study and also their ability to comply with protocol requirements by completing all 
assessments.  
The following evaluations/actions, unless noted, will be performed within 10 weeks and up to 1 
day prior to dosing on Day 0 – except for the safety laboratory collections/assessments, which 
must be performed within 30 days prior to Day 0. All screening assessment values must be 
reviewed prior to study treatment. 
 Signed informed consent 
 ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain from 
sexual activity and refrain from use of douching or vaginal lubricants/medication for a period 
of 24 hours prior to sample collection) 
 Colposcopy with lesion photography and cervical biopsy 
 Demographics; including age, and race/ethnicity 
 Medical history; including concomitant medications review, history of prior cervical 
dysplasia, and pregnancy history 
163

 Socio-Behavioral Assessment; including self-reported smoking history, self-reported exposure 
to second-hand smoke, self-reported alcohol intake history, contraceptive history 
 Determination of eligibility per inclusion / exclusion criteria 
 Full Physical Examination (including height, weight and BMI measurements) 
 Vital signs (including oral temperature, respiratory rate, blood pressure and heart rate) 
 12-lead ECG (within 30 days prior to Day 0) 
 Baseline laboratory evaluations (includes CPK, hematology and serum chemistry, urinalysis)  
to be performed (within 30 days prior to Day 0); 
 Urine pregnancy test 
 Serology (HIV Antibody) (within 30 days prior to Day 0) 
 Whole blood (at least 34 mL) and serum (at least 4 mL)  for baseline immunologic assay 
 2 Digene cervical brush samples  
6.2 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will be randomized to receive study treatment.  Visit 
dates and windows must be calculated from Day 0. 
6.2.1 
DAY 0 
The following evaluation will be performed on Day 0 prior to study treatment: 
 Determination of eligibility per inclusion / exclusion criteria 
 Randomization 
 Targeted Physical Exam 
 Vital signs 
 Urine pregnancy test 
 Whole blood (at least 34 mL) and serum (at least 4 mL)  for baseline immunologic assay (a 
total of at least 68 mL of whole blood and 8 ml serum should be collected prior to dosing on 
Day 0) 
 Colposcopy with lesion photography 
 ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain from 
sexual activity and refrain from use of douching or vaginal lubricants/medication for a period 
of 24 hours prior to sample collection) 
 2 Digene cervical brush samples 
 Oropharynx (OP) sample by oral rinse and vaginal and anal swabs 
 Patient-Reported Outcomes (PROs) completion 
Study treatment will be administered and the following evaluations will be performed on Day 0 
post-treatment: 
 Post treatment adverse event and injection site reaction assessment within a minimum of 30 
minutes after study treatment  
 Distribute Participant Diary Card (PDC)  
164

 Download EP data from device  
6.2.2 
8-14 DAYS POST DOSE 1 PHONE CALL 
The following information will be evaluated during phone call: 
 Post treatment adverse event and injection site reaction evaluation 
 Review Day 0 PDC  
o The subject should submit their PDC (via email, fax, mail) to site personnel prior to the 
phone visit. If the PDC is not received in advance, site personnel should review all diary 
elements verbally. The hard copy of the PDC should be collected and reviewed at the next 
in-person study visit. After completing a review of PDC and post treatment injection 
assessment with the subject on the phone, the Investigator or study personnel will 
determine whether an office visit is needed for further evaluation. 
 PRO completion 
6.2.3 
WEEK 4  
The following study evaluation will be performed on Week 4 prior to study treatment (± 4 
days): 
 Targeted Physical Exam 
 Vital signs 
 Urine pregnancy test 
 Collect PDC for dose 1 
The following study evaluations will be performed on Week 4 post treatment: 
 Post treatment adverse event and injection site reaction assessment within a minimal of 30 
minutes after study treatment;  
 Distribute PDC  
 Download EP data from device  
6.2.4 
8-14 DAYS POST DOSE 2 PHONE CALL 
The following information will be evaluated during phonecall:   
 Post treatment adverse event and injection site reaction evaluation 
 Review PDC for dose 2 
o The subject should submit their PDC (via email, fax, mail) to site personnel prior to the 
phone visit. If the PDC is not received in advance, site personnel should review all diary 
elements verbally. The hard copy of the PDC should be collected and reviewed at the next 
in-person study visit. After completing a review of PDC and post treatment injection 
assessment with the subject on the phone, the Investigator or study personnel will 
determine whether an office visit is needed for further evaluation. 
 PRO completion 
165

6.2.5 
WEEK 12 
The following study evaluation will be performed on Week 12 prior to study treatment (± 4 
days): 
 
Targeted Physical Exam  
 
Vital signs 
 
Urine pregnancy test 
 
Collect PDC regarding Dose 2 
The following study evaluations will be performed Week 12 post treatment: 
 
 
Post treatment adverse event and injection site reaction assessment within a minimal of 30 
minutes after study treatment;  
 
Distribute PDC  
 
Download EP data from device  
6.2.6 
8-14 DAYS POST DOSE 3 PHONE CALL 
The following information will be evaluated during phonecall:   
 
Post treatment adverse event and injection site reaction evaluation 
 
Review PDC for dose 3 
o The subject should submit their PDC (via email, fax, mail) to site personnel prior to the 
phone visit. If the PDC is not received in advance, site personnel should review all diary 
elements verbally. The hard copy of the PDC should be collected and reviewed at the next 
in-person study visit. After completing a review of PDC and post treatment injection 
assessment with the subject on the phone, the Investigator or study personnel will 
determine whether an office visit is needed for further evaluation. 
 
PRO completion 
6.2.7 
WEEK 15 
The following study evaluations will be performed on Week 15 ± 1 week: 
 Targeted physical assessment 
 Vital signs 
 Urine pregnancy test 
 Whole blood (at least 51 mL) and serum (at least 4 mL) for immunologic assays 
 Post-treatment injection site reaction assessment 
 ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain from 
sexual activity and refrain from use of douching or vaginal lubricants/medication for a period 
of 24 hours prior to sample collection)  
 2 Digene cervical brush samples 
 Oropharynx (OP) by oral rinse and vaginal and anal swabs 
166

 Collect PDC  
 Colposcopy and lesion photography 
6.2.8 
WEEK 28 
The following study evaluations/actions will be performed on Week 28 ± 1 weeks: 
 
Targeted physical Assessment 
 
Vital signs 
 
Urine pregnancy testing 
 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from sexual activity and refrain from use of douching or vaginal lubricants/medication for a 
period of 24 hours prior to sample collection)  
 
2 Digene cervical brush samples 
 
Colposcopy and lesion photography to assess for possible disease progression 
 
PRO to be completed by subject 8-14 days after Week 28 visit 
6.2.9 
WEEK 36 
The following study evaluations will be performed on Week 36 ± 1 week: 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-reported 
exposure to second-hand smoke, self-reported alcohol intake history, contraceptive history 
 
Targeted physical assessment 
 
Vital signs 
 
Whole blood (at least 34 mL) and serum (at least 4 mL) for immunologic assays 
 
Urine pregnancy test 
 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from sexual activity and refrain from use of douching or vaginal lubricants/medication for a 
period of 24 hours prior to sample collection) 
 
2 Digene cervical brush samples 
 
Oropharynx (OP) by oral rinse and vaginal and anal swabs 
 
Colposcopy and lesion photography  
 
Biopsy or surgical excision  
The investigator will utilize information collected at Week 28 to determine the appropriate method 
for obtaining tissue for histopathologic assessment as described in Tables 4 & 5 for minimally 
required procedure (4 quadrant biopsies, 4 quadrant biopsies and ECC, or excision).  
6.2.10 
     WEEK 40 PHONE CALL 
The following study evaluations will be performed on Week 40 ± 2 weeks via a phone call:   
 
Review of histology results as read by PAC from Week 36  
 
PRO to be completed by subject 8-14 days after Week 40  
167

6.2.11 
WEEK 62 
The following study evaluations will be performed on Week 62 ± 2 weeks: 
 
Targeted physical assessment 
 
Vital Signs 
 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from sexual activity and refrain from use of douching or vaginal lubricants/medication for a 
period of 24 hours prior to sample collection) 
 
2 Digene cervical brush samples 
 
Colposcopy and lesion photography 
6.2.12 
WEEK 88 
The following study evaluations will be performed on Week 88 ± 2 weeks: 
 
Socio-Behavioral Assessment; including self-reported smoking history, self-reported 
exposure to second-hand smoke, self-reported alcohol intake history, contraceptive history 
 
Full Physical Exam 
 
Vital Signs 
 
ThinPrep™ sample for HPV PCR and pap smear (subject should be requested to abstain from 
sexual activity and refrain from use of douching or vaginal lubricants/medication for a period 
of 24 hours prior to sample collection) 
 
2 Digene cervical brush samples 
 
Colposcopy and lesion photography 
 
Whole blood (at least 34 mL) and serum (at least 4 mL) for immunologic assays 
 
Oropharynx (OP) by oral rinse and vaginal and anal swabs 
 
PRO completion 
6.3 
EVALUATIONS AND PROCEDURES 
6.3.1 
INFORMED CONSENT 
All subjects must sign the informed consent prior to any study related procedures being performed 
(i.e., prior to any screening activities). The informed consent documentation must be in accordance 
with applicable regulations and GCP. Qualified study personnel will meet with prospective study 
subjects, explain the study, and provide them with an informed consent form (ICF) that describes 
the screening tests, eligibility criteria for entering the study, study treatments and follow-up 
procedures, in a language understandable to the subject. Explanation of the study includes, but is 
not limited to, study objectives, potential benefits and risks, discomforts/inconveniences, and the 
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 study 
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. 
168

6. 3. 2  
A S SI G N M E N T O F S U B J E C T I D E N TI FI C A TI O N N U M B E R S 
Eac h s u bject w h o c o nse nts will be assi g ne d a u ni q ue s u bject i de ntificati o n n u m ber ( SI D), w hic h 
i de ntifies t he s u bject f or all st u d y-relate d pr oce d ures. SI Ds are a c o m bi nati o n of a u p t o t w o al p ha 
letters st u d y c o de, t w o al p ha letter C o u ntr y c o d e, t w o di git site n u m ber, pl us 3- di git s u bject 
n u m ber  starti n g wit h  
 (e. g., 
). O nce assi g ne d, SI Ds ca n n ot be re use d f or a n y reas o n. 
I nf or mati o n re gar di n g t he SI D a n d scree n d ate m ust be d oc u me nte d o n a Scree ni n g l o g/s yste m 
a n d i n t he I nteracti ve Res p o nse Tec h n ol o g y (I X R S). 
S u bjects meeti n g eli gi bilit y criteria will be ra n d o mize d b y a c o m p uter ge nerate d all ocati o n 
sc he d ule.  
6. 3. 3  
S A F E T Y E V A L U A TI O N S 
6. 3. 3. 1  
P h ysic al E x a m  
A f ull p h ysi cal e x a mi nati o n ( P E) will be c o n d ucte d d uri n g scree ni n g a n d st u d y disc har ge.  
It will i ncl u de a n assess me nt of t he f oll o wi n g: ge neral a p peara n ce, s ki n, hea d, e yes, ears, 
n ose, a n d t hr oat, a n d l y m p h n o des, a n d res pirat or y, car di o vasc ul ar, gastr oi ntesti nal, 
ge nit o uri nar y, m usc ul os k eletal, a n d ne ur ol o gi cal s yste ms.   
A tar gete d p h ysic al assess me nt will be perf or me d at ot her visits as deter mi ne d b y t he 
i n vesti gat or or dir ecte d p er s u bject c o m plai nts. T he i njecti o n site is t o be assesse d b y t he 
st u d y pers o n n el at 3 0 mi n utes after eac h st u d y tr eat me nt.   
6. 3. 3. 2  
 Vit al Si g ns 
Vital si g ns will be meas ure d at s pe cifie d visits a n d will i ncl u de: 
 S itti n g s yst olic a n d diast olic bl o o d press ures wit h s u bject sitti n g at rest f or at least 5 
mi n utes bef ore me as ure m e nt 
 Res pirati o n rate 
 H eart rate  
 Or al te m perat ure me as ur e d wit h a n a ut o mate d t her m o meter  
6. 3. 3. 3  
We i g ht a n d Hei g ht 
Wei g ht ( k g) a n d h ei g ht (c m) will be c ollecte d at scree ni n g i n or der t o cal c ulate t he B MI 
( B MI = k g/ m2). 
6. 3. 3. 4  
M e dic al Hist or y 
All rele va nt (as j u d ge d b y t h e i n vesti gat or) past a n d prese nt c o n diti o ns at scree ni n g, as well 
as pri or s ur gical pr oce d ures will be rec or de d f or t he mai n b o d y s yste ms.  T he me dica l 
hist or y will i ncl u d e a) a n y pri or hist or y of CI N dia g n ose d – wit h dia g n osis date(s) a n d 
res pecti ve CI N l e vel(s), a n d b) if treate d pre vi o usl y f or CI N, t he res pecti ve tr eat me nt t y p e(s) 
a n d date(s). 
 
 
1 6 9
P P
D
P P D

6.3.3.5 
Socio-Behavioral Assessment 
Socio-Behavioral Assessment, including self-reported smoking history, self-reported 
history of exposure to second-hand smoke, self-reported alcohol intake history, self-
reported recreational drug use history, self-reported history of contraceptive use and type 
of contraceptive if known, reproductive history, history of prior cervical dysplasia, and 
pregnancy history will be obtained. 
6.3.3.6 
Laboratory Evaluations 
At screening, blood samples will be taken to be tested for serum chemistry and hematology.  
Complete blood count (CBC): 
 White blood cell (WBC) count w/ differential 
 Red blood cell (RBC) count 
 Hemoglobin, Hematocrit 
 Platelet count 
Serum Chemistry: 
 Glucose 
 SGPT (serum glutamic-pyruvic transaminase)/ALT 
 BUN (blood urea nitrogen) 
 Creatinine 
 Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
 CPK (creatine phosphokinase) 
Urinalysis (UA):  
Urine samples will be tested at screening by dipstick for glucose, protein, and hematuria. 
If abnormal (presence of protein, hematuria, or glucose ≥ 1+) a microscopic examination 
should be performed. 
6.3.3.7 
Demographics 
Demographic information will be collected via self-report (unless noted otherwise), 
including the following: 
 
Age (via date of birth) 
 
Race/ethnicity 
6.3.3.8 
Urine Pregnancy Testing 
For subjects of reproductive potential, a negative spot urine pregnancy test is required prior 
to each study treatment, colposcopy and surgical excision. 
6.3.3.9 
ECG 
A single 12-lead ECG will be obtained during Screening after the subject has been in a 
supine position for 10 to 15 minutes. The ECG should include measurements of ventricular 
rate, PR, QRS, QRS axis, QT, QTcb or QTcf, ST segment, Twave as well as an investigator 
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assessment of whether the ECG is normal or abnormal (automated interpretations of ECG 
should not be used). Abnormal ECGs should be interpreted as “clinically significant (CS)” 
or “not clinically significant (NCS)” by the investigator 
6.3.3.10 
Subject Post Treatment Assessments 
PDC will capture subject reported local and systemic events for 7 days after the study 
treatment as shown in Appendix A.  
The subject will be provided a PDC and will be asked to record the following the evening of 
study treatment through Day 6: 
 
Oral temperature and time taken (before 11:59 pm) 
 
General symptoms of feeling unwell 
 
Pain and itching at injection site 
 
Measure redness, swelling, bruising at injection site 
 
Medications taken 
The completed PDC will be reviewed with the subject and research staff at 8 -14 Days post-
dose. 
The study staff will review the PDC for general symptoms (e.g. malaise, fatigue, headache, 
nausea, and myalgia/arthralgia), injection site reaction symptoms (e.g. pain, erythema and 
edema), medical events and medications. All reported events will be assessed for clinical 
significance (CS) and reported as adverse event accordingly. 
6.4 
INJECTION AND ELECTROPORATION (EP)  
Subjects will receive a 3-dose series of either 1 ml VGX-3100X or Placebo by IM injection in the 
deltoid (or anterolateral quadriceps muscle as an alternate option, if deltoid muscle is not possible 
or appropriate) followed immediately by EP with the CELLECTRA™ 5PSP. Study treatment must 
not be given within 2 cm of a tattoo, keloid or hypertrophic scar.  If there is implanted metal, 
implanted device, within the same limb then use of the deltoid muscle on the same side of the body 
is excluded.  
 
 
 
 
 
 
 
 
 
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6.4.1 
RISKS OF TREATMENT PROCEDURES 
Table 11 summarizes reported AEs and potential risk to study treatment.  
Table 11. Summary of Reported Adverse Events and Potential Risks or VGX-3100X 
Delivered IM EP with CELLECTRA™ 5PSP 
 
Very Common  
 
Mild to moderate injection site pain or tenderness 
 
Malaise/fatigue, myalgia, or headache in the first few days following injection 
 
Upper respiratory tract infection 
 
Brief muscle contractions which may be uncomfortable 
 
Nausea 
Common  
 
Arthralgia 
 
Injection site reactions such as erythema, pruritus, swelling, hematoma 
 
Anxiety related to the administration procedure 
Less Common  
 
Severe injection site pain or tenderness 
 
Vasovagal reaction/lightheadedness/dizziness related to the administration 
procedure 
 
Temporary bleeding at the injection site 
 
Rash following administration  
Uncommon or rare  
 
Injection site reactions such as laceration, induration, bruising/ecchymosis, or scab  
 
Infection at the injection site  
 
Muscle damage resulting in transient changes in creatine phosphokinase  
 
Transient changes in clinical laboratory values 
Unknown frequency or 
theoretical potential risks 
 
Severe localized administration site reaction, such as sterile abscess or secondary 
bacterial infection  
 
Allergic reaction, including urticaria, angioedema, bronchospasm, or anaphylaxis  
 
Chills, flu-like syndrome 
 
Autoimmune disease 
 
Electrical injury  
 
Disruption of function of implanted electronic medical devices (if CELLECTRA™  
5PSP device is not used per User Manual) 
 
Exacerbation of unstable cardiac disease 
 
Effects on the fetus and on pregnancy 
6.4.2 
MANAGEMENT OF ANXIETY AND PAIN DUE TO TREATMENT 
Subjects may be offered topical anesthetic (i.e. EMLA or equivalent), to prevent significant 
discomfort from the treatment procedure. If a topical anesthetic is used, an approximately 1.5 cm 
diameter amount will be applied with occlusion to the site of injection ~30 minutes prior to 
treatment.  
Subjects may be offered a mild sedative (e.g. 0.5-1 mg lorazepam), or equivalent, for anxiety 
related to the treatment procedure. Mild sedatives may be administered approximately 1 hour prior 
to treatment at day 0, Weeks 4 and/or 12. Subjects who receive a mild sedative should not be 
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allowed to operate a motor vehicle for 3-4 hours after receiving medication and should have 
arranged transportation to depart the study site. 
Subjects may be offered an analgesic (e.g. ibuprofen, ketorolac) after injection/EP.  
Subjects who are allergic to or have contraindications to EMLA, ibuprofen, ketorolac or a mild 
sedative may be offered a suitable alternative.  
EMLA cream or sedatives should be added to the concomitant medications. 
6.5 
ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well as urine 
pregnancy testing at Screening will be performed for inclusion into the study as listed in section 
6.1.1. 
6.6 
ASSESSMENT OF CLINICAL STUDY ADVERSE EVENTS 
The injection site will be assessed by study personnel prior to and within minimum of 30 minutes 
after each study treatment and at 2 to 4 weeks post study treatment visits.  They will also be advised 
to record local and systemic AEs for 7 days on a PDC as shown in Appendix A. 
A Medical/Clinical Assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any adverse events, concomitant medications new onset illness or 
disease, as well as contraceptive compliance. Subjects will be reminded to contact study personnel 
and immediately report any event that happens for the duration of the study. Unsolicited adverse 
events will be captured from the time of the informed consent to study discharge. These events will 
be recorded on the subject’s CRF.   
6.7 
ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the investigator will be instructed to 
use the following grading scale: 
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Table 12. 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 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort to 
touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/Redness* 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling** 
2.5-5 cm and does 
not interfere with 
activity 
5.1-10 cm or interferes 
with activity 
>10 cm or 
prevents daily 
activity 
Necrosis 
- September 2007 “FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials” 
*In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded 
as a continuous variable 
**Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement 
6.8 
ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, previously-validated patient-reported 
outcomes (PRO) instruments will be provided to the subjects.  PRO questionnaires will include the 
following, along with the license holder, respective numbers of items and domains, and listed 
domains: 
 
 Short Form Health Survey, version 2 (SF-36v2™) (Optum, Inc.):  generically measures 
functional health and well-being, for physical and mental health; consists of thirty-six items 
covering eight domains (Physical functioning, Role limitations due to physical problems, Bodily  
 pain, General health, Vitality, Social functioning, Role limitations due to emotional problems, 
and Mental health) [24] ( See Appendix D for sample questionnaire).  
 EQ-5D-5L (EuroQol Research Foundation): generically measures activities & general health 
status; consists of six items covering six domains (Mobility, Self-care, Usual activity, 
Pain/discomfort, Anxiety/depression, and Global health status via VAS) [25, 26] (see Appendix 
E for sample questionnaire).  
 
174

The PRO instruments will be provided to subject and will be instructed to complete the questionnaire 
at the following time points:  
 
 Day 0 (before the first study treatment) 
 8-14 days post dose 1 
 8-14 days post dose 2 
 8-14 days post dose 3 
 8 -14 days post Week 28 
 8-14 days post Week 40 
 Week 88  
 
Administration of PRO instruments will be performed according to the validated procedure and 
guidelines of each respective instrument, except for some assessments for exploratory analyses.   
6.9 
PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at baseline (screening and Day 0 prior to dosing) 
and at Weeks 15, 36, 88. Details of the immunology sample collection and shipment information 
will be provided in the Laboratory Manual. 
A standardized binding ELISA may be performed to measure the anti–HPV-16/18 antibody 
response induced by VGX-3100X. 
PBMCs will be isolated from whole blood samples. Assessment of cellular immune activity may 
occur via the application of the Interferon-γ enzyme-linked immunosorbent spot (IFN-γ ELISpot) 
assay as well as flow cytometry.  
Additional assessment of cellular immune activity may occur via the application Flow Cytometry 
for the purposes of performing a Lytic Granule Loading Assay. The Lytic Granule Loading assay 
may examine the following external cellular markers: CD3, CD4, CD8 (T cell identification), 
CD137, CD38 and CD69 (T cell activation markers) as well as PD-1 (exhaustion/activation marker). 
The Lytic Granule Loading assay may additionally analyze the following intracellular markers: 
Granzyme A, Granzyme B, Granulysin and Perforin (proteins involved in lytic degranulation and 
cytotoxic potential). Markers examined in this assay may change as new relevant data become 
available. 
6.10 TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue or additional slides in the paraffin block after histologic diagnoses have 
been rendered, then unstained slides and/or the relevant paraffin blocks may be collected for 
immunohistochemistry (IHC).  Assessment of markers may include, but are not limited to, CD8+ 
and FoxP3+ infiltrating cells as well as assessment of cell death via Cleaved Caspase 3 assessment. 
Additional assessments may include visualization of Granulysin, Perforin, CD137, CD103 and PD-
L1 in cervical tissue as sample allows.  Markers listed here may change as new relevant information 
becomes available. 
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6.11 HLA TYPING 
HLA testing will be performed on PBMC from any single blood sample collected for 
immunogenicity analysis. If the subject has a record of previous high resolution HLA testing and 
access to the results, then HLA testing is not required. 
The DNA extracted from the blood sample will be used to determine if alleles at the MHC locus 
affect the immune response to study treatment. Data arising from this study will be subject to same 
confidentiality as the rest of the study. This specimen will be destroyed immediately after the 
analysis and the results checked. 
6.12  PAP SMEARS AND HPV TESTING 
Pap smears will be obtained using ThinPrep™ test kits at the screening, Day 0, Weeks 15, 28, 36, 
62, 88 and read in a central laboratory. HPV PCR by Cobas™ HPV test will be performed on the 
ThinPrep™ specimen. At each of these visits, menstrual cycle status & recent history will be 
collected via self-report.  If the Pap smear result suggests progression to cancer at Day 0, Weeks 15, 
28 or 36, the investigator may schedule an ad hoc visit to perform a colposcopy and possible biopsy 
if clinically indicated. 
The subject will be requested to abstain from sexual activity and refrain from use of douching or 
vaginal lubricants/medication for a period of 24 hours prior to collection of ThinPrep™ samples to 
eliminate potential interference with the results of HPV testing.   
 At visits where multiple cervical samples are collected, the two Digene cervical brushes will be 
collected prior to the ThinPrep™ sample. Details of sample collection and shipment information will 
be provided in laboratory manual. 
6.13  COLPOSCOPY AND CERVICAL BIOPSIES 
Colposcopy at screening must be adequate, defined as full visualization of the squamo-columnar 
junction (Type I or II transformation zone) and complete visualization of the upper limit of aceto-
white epithelium or suspected dysplasia. An ECC is not required for study entry. However, if an 
ECC was done as part of routine care during the screening period, and found to have evidence of 
cervical HSIL such subject should not be enrolled in the study. Colposcopy is not required to be 
performed at screening if adequate colposcopy was previously obtained upon collection of initial 
biopsy.  All colposcopies performed after informed consent must be conducted according to the 
procedures outlined in Appendix C. 
Interval colposcopies will be performed at Day 0, Weeks 15, 28, 36, 62, and 88.  An unscheduled 
colposcopy may be performed at the discretion of the investigator if there is suspicion of disease 
worsening or progression. 
Digital photographs of the cervix will be captured during each colposcopic examination to document 
the clinical findings. If a biopsy or surgical excision is performed, images of the cervix should be 
collected before and after the procedure. Each site will be instructed on 1) the technique for capturing 
the proper images using a standard approach and 2) the process for uploading the images to a secure 
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server. Additionally, after subject is enrolled if vaginal or vulvar lesion should develop, photograph 
should be taken to document the clinical exam finding.    
6.13.1 
ECTOCERVICAL BIOPSIES 
Ectocervical biopsies are required at screening to confirm eligibility.  If the criteria outlined in 
Table 5 or 6 are met, ectocervical biopsies may also be performed at Week 36 to provide tissue 
for histopathologic assessment of disease regression.   
Biopsies should not be performed at any other visit unless there is suspicion of disease 
progression.  Removal of additional tissue by biopsy before Week 36 will bias results toward 
improvement regardless of whether the subject is in the active or placebo group. The bias 
introduced will obviously be more significant for smaller lesions.  For this reason, if biopsies are 
obtained prior to Week 36, the subject will be treated as a non-regressor. Subject safety is 
paramount in this study. Therefore, if at any time the investigator may suspect disease progression 
and the standard of medical care would be to perform an unscheduled biopsy prior to Week 36, 
then his or her medical judgment should prevail over the default “Schedule of Events”, Table 1. 
6.13.2 
UNSCHEDULED BIOPSIES 
In the event unscheduled biopsy is performed prior to Week 36, subject will be considered as 
non-responder. The subject will discontinue further study treatment and continue in the study for 
safety follow-up visits. The subject will be managed according to standard of care and 
Investigator’s judgement based on results of histological diagnosis from unscheduled biopsy 
Additional instructions for collecting ectocervical biopsies are detailed in Appendix C. All biopsy 
samples/excised tissue will be sent to the PAC for review.   
6.14  CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to screening biopsy 
date of eligible subjects must be recorded on the CRF. Actual or estimated start and stop dates must 
be provided. Medical procedures performed within 8 weeks prior to screening biopsy date of eligible 
subjects that do not affect subject’s eligibility for participation and during the study (including over 
the counter or herbal), will be recorded on the CRFs. 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. Medication that is considered necessary for the subject’s 
safety and well-being may be given at the discretion of the investigator and recorded in the 
appropriate sections of the CRF.   
6.15  RESTRICTIONS 
6.15.1 
PROHIBITED CONCOMITANT MEDICATIONS AND TREATMENTS 
The following medications and treatments are prohibited:  
 
177

 Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent; use of inhaled otic and ophthalmic corticosteroids are allowed 
 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) at screening and throughout the study 
 Administration of any non-study related, non-live vaccine within 2 weeks of any study 
treatment or within 4 weeks of any study treatment for any non-study, live vaccine 
 Blood thinners/Anticoagulants within 2 weeks of any study treatment 
 
6.15.2 
OTHER RESTRICTIONS 
Subjects should not use alcohol or drugs that would interfere with study requirements during 
the course of the study and should report ALL medications/drugs taken to the investigator 
and/or other study personnel. 
Subjects should refrain from becoming pregnant until 6 months following the last dose of 
investigational product by using appropriate contraceptive measures as (See Inclusion Criteria, 
Section 4.1).  Lapses in contraceptive use should be reported to investigator and/or other study 
personnel. 
Subject should abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to collection of ThinPrep™ samples. 
7 EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
7.1.1 
ADVERSE EVENTS 
An adverse event (AE) is defined as any unfavorable and unintended change in the structure, 
function, or chemistry of the body, or worsening of a pre-existing condition, temporally 
associated with the use of a product whether or not considered related to the use of the product. 
In this study, such changes will be monitored, classified, and summarized, as Clinical or 
Laboratory AEs. Medical condition/diseases present before starting the investigational drug will 
be considered adverse events only if they worsen after starting study treatment. Throughout the 
course of the study, all solicited and unsolicited AEs will be monitored and reported on an AE 
CRF, including the event’s seriousness, severity, action taken, and relationship to investigational 
product(s). AEs should be followed until resolution or stable and the outcome will be documented 
on the appropriate CRF. All AEs should be recorded in standard medical terminology rather than 
the subject’s own words. 
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 study drug). 
178

 Any pre-existing condition that increases in severity, or changes in nature during or as a 
consequence of the study drug phase of a human clinical trial, will also be considered an AE. 
 Complications of pregnancy; see Section 7.1.9 for additional information. 
 AEs that occur from the study screening visit onwards and throughout the duration of the study, 
including the follow-up off study drug period will be recorded as an AE. 
 Conditions that lead to a medical or surgical procedure. 
AEs do not include the following: 
 Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed as a result of 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 informed consent form 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. 
7.1.2 
SERIOUS ADVERSE EVENTS 
A serious adverse event (SAE) is any AE that meets one of the following conditions: 
 Death during the period of surveillance defined by the protocol; 
 Is immediately life-threatening (e.g., subject was, in the view of the Investigator, at immediate 
risk of death from the event as it occurred). This does not include an AE that, had it occurred 
in a more serious form, might have caused death; 
 An event requiring inpatient hospitalization or prolongation of existing hospitalization during 
the period of protocol defined surveillance (including any overnight stay in the hospital, 
regardless of 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 or substantial disruption of the ability 
to conduct normal life functions; 
 Results in congenital anomaly or birth defect; 
 An important medical event that may not result in death, be life threatening, or require 
hospitalization, but based upon appropriate medical judgment, may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include 1) allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, 2) blood dyscrasias or convulsions that do not 
179

result in inpatient hospitalization, 3) the development of drug dependency or drug abuse or 4) 
the development of a malignancy; 
 Is medically significant or requires intervention to prevent one or other of the outcomes listed 
above. 
7.1.2.1 
Clarification of Serious Adverse Events 
 Death is an outcome of an AE, and not an adverse event in itself. 
 The subject may not have been on investigational medicinal product at the occurrence 
of the event.  
 Dosing may have been given as treatment cycles or interrupted temporarily before the 
onset of the SAE, but may have contributed to the event.  
 “Life-threatening” means that the subject was at immediate risk of death from the event 
as it occurred. This does not include an event that might have led to death if it had 
occurred with greater severity. 
 Complications that occur during hospitalizations are AEs. If a complication prolongs 
the hospitalization, it is an SAE. 
 Inpatient hospitalization means that the subject has been formally admitted to a hospital 
for medical reasons, for any length of time. This may or may not be overnight. It does 
not include presentation and care within an emergency department nor does it include 
full day or overnight stays in observation status. 
 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE and/or SAE and not the individual signs/symptoms. 
Serious adverse events that are ongoing should be followed until resolution or are clinically 
stable. The reporting period for SAEs is described in Section 9.5. 
7.1.3 
UNEXPECTED ADVERSE DRUG REACTIONS AND EXPEDITED REPORTING 
An adverse drug reaction (ADR) is any noxious and unintended responses to a medicinal product 
related to any dose, for which a causal relationship between a medicinal product and an adverse 
event is at least a reasonable possibility; i.e., there is evidence to suggest a causal relationship 
between the product and the adverse event. An unexpected ADR is one, the nature or severity of 
which is not consistent with the applicable product information (investigator’s brochure, protocol, 
and user manual). Reports that add significant information on specificity or severity of a known, 
already documented SAE constitute unexpected events. For example, an event more specific or 
more severe than described in the Investigator's Brochure or protocol would be considered 
"unexpected.” Specific examples would be (a) acute renal failure as a labeled ADR with a 
subsequent new report of interstitial nephritis and (b) hepatitis with a first report of fulminant 
hepatitis.  
The Sponsor will assess each serious ADR report for expectedness, to determine if it is a serious 
unexpected suspected adverse reaction (SUSAR) which requires prompt reporting to regulatory 
authorities and participating investigators as an expedited report, according to the applicable 
180

regulatory requirements. Additional occurrences of the SUSAR will be required to be reported on 
an expedited basis until the applicable product information is amended. 
In addition to single-case reports of SUSARs, the Sponsor shall notify regulatory authorities and 
participating investigators of information that might materially influence the benefit-risk 
assessment of a medicinal product, sufficient to consider changes in product administration or 
overall conduct of a clinical investigation. Examples of such information include a clinically 
important increase in the rate of occurrence of a serious expected adverse event, the identification 
of a significant hazard to the subject population, or a major safety finding from a study conducted 
in animals. 
7.1.4 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
Unanticipated adverse device effect means 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.  
Per the definition above, a UADE is a type of serious adverse event (SAE) that requires expedited 
reporting on the part of the sponsor. As a reminder, all SAEs regardless of relationship to device, 
drug or procedure are to be reported to Sponsor by the study investigator within 24 hours. Sponsor 
will assess each device related SAE to determine if anticipated based on prior identification within 
the investigational plan.  
7.1.5 
ASSESSING SEVERITY (INTENSITY) 
Adverse events should be captured once on the CRF at the maximum severity reported.  
The investigator will grade laboratory AEs and clinical AEs with respect to the following levels 
of severity as per Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 for applicable 
subject populations: 
 Mild (Grade 1) 
 Moderate (Grade 2) 
 Severe (Grade 3) 
 Potentially Life Threatening (Grade 4)  
The investigator will grade injection site reactions in accordance with September 2007 FDA 
Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials. 
7.1.6 
CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS 
 A causally related AE is one judged to have a reasonable possibility of a relationship to the 
administration of the IP and/or the investigational device. An AE may also be assessed as not 
181

related to the IP and/or the investigational 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 adverse events and 
judging the relationship between the administration of the IP and device and a subsequent AE. 
The investigator is aware of the subject’s clinical state and thus may be sensitive to distinctions 
between events due to the underlying disease process versus events that may be product related 
and may have observed the event. The Sponsor will assess the overall safety of the IP delivered 
by EP and determine whether to report expeditiously to the regulatory agencies. 
Investigators should use their knowledge of the subject, the circumstances surrounding the event, 
available site and non-site laboratory and clinical records, and an evaluation of any potential 
alternative causes to determine whether or not an adverse event is considered to be related to the 
IP and/or the investigational device indicating "yes" or "no" accordingly. Causality should be 
assessed by the investigator as “yes, related” or “no, unrelated” by the following criteria: 
 
Yes – there is a reasonable possibility that administration of the Study Treatment contributed 
to the event; 
 
No – there is no reasonable possibility that administration of the Study 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 the investigational device; 
 
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 study; 
 
Presence of risk factors in the Study Subject or use of concomitant medications known to 
increase the occurrence of the event. 
7.1.7 
ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK, urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to IP interruption or 
discontinuation must be recorded as an AE, or SAE, if applicable. In addition, laboratory or other 
abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are associated with signs 
and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE (or SAE) 
as described in Section 7.1. If the laboratory abnormality is part of a syndrome, record the 
syndrome or diagnosis (e.g., anemia) not the laboratory result (e.g., decreased hemoglobin). 
Any laboratory abnormality 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 study treatment 
 Has accompanying or inducing symptoms or signs 
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 Is judged by the investigator as clinically significant 
7.1.8 
POST-STUDY REPORTING REQUIREMENTS 
All AEs and SAEs including deaths, regardless of cause or relationship, must be reported for 
subjects on study (including any protocol-required post-treatment follow-up). 
Investigators are not obligated to actively seek AEs or SAEs beyond the follow up period for 
subjects. However, if the investigator learns of an AE or SAE that occurs after the completion or 
termination visit and the event is deemed by the investigator to be related to the study treatment, 
he/she should promptly document and report the event to the study team and medical monitor. 
7.1.9 
PROCEDURES FOR DOCUMENTING PREGNANCY DURING STUDY 
Subjects who are pregnant or expect to become pregnant during the course of the study up to 6 
months following the last study treatment of investigational product will be excluded from 
participation in the study. Should a subject become pregnant after enrolling in the study, she will 
not be given any further study treatments. A Pregnancy Form will be completed by the site 
personnel and submitted to the sponsor study team and medical monitor within 24 hours after 
learning of the pregnancy.  The investigator will also report this event to the IRB within 24 hours 
of becoming aware of the pregnancy. Sites must request the subject’s permission to query 
pregnancy outcome and follow each subject to determine the outcome of the pregnancy. Results 
will be summarized in the clinical study report (CSR).  
Subjects who become pregnant at any point during the study will continue to be followed for safety 
assessments without receiving further study treatment. Procedures that are contraindicated during 
pregnancy, including additional treatments, must not be performed. Investigators should use 
clinical judgment regarding subsequent study-related blood collection based on the presence or 
absence of anemia in each subject. Subjects who are not withdrawn will continue to be followed 
for safety assessments to study discharge per protocol.  
All pregnancies that occur from the time of first study treatment through the follow up visits must 
be reported. The investigator will monitor the subject and follow the outcome of the pregnancy. If 
the end of the pregnancy occurs after the study has been completed, the outcome will be reported 
directly to the study team and the medical monitor. 
7.2 
METHODS AND TIMING OF THE COLLECTION AND RECORDING OF SAFETY 
DATA 
Non-serious AEs and SAEs (and UADEs) will be collected for each subject from the time when 
informed consent is obtained through Week 88. 
The sources of AEs cover: 
1. 
The subject’s response to questions about her health (a standard non-leading question such as 
‘How have you been feeling since your last visit?’ is asked at each visit). 
2. 
Symptoms spontaneously reported by the subject. 
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3.  
E val uati o ns a n d e x a mi nati o ns w here t he fi n di n gs are assesse d b y t he i n vesti gat or t o be 
cli nicall y si g nifica nt c ha n ges or a b n or m alities. 
4.  
Ot her i nf or mati o n relati n g t o t he s u bject’s healt h bec o mi n g k n o w n t o t he i n vesti gat or (e. g. 
h os pitaliz ati o n).  
All A Es will be re p orte d o n t he a p pr o priate C R F. A n y S A E ( or U A D E) occ urri n g d uri n g t h e c o urse 
of t he st u d y m ust be re p orte d t o t he s p o ns or wit hi n 2 4 h o urs of a ware n ess. 
7. 3  
S A F E T Y A N D T O XI CI T Y M A N A G E M E N T 
T he Me dical M o nit or will be res p o nsi ble f or t he o verall safet y m o nit ori n g of t he st u d y.  
Safet y assess me nts i ncl u de t he f oll o wi n g: 
 
In ci de nce of all a d vers e e ve nts classifie d b y s yste m or ga n class ( S O C), preferre d ter m, se v erit y, 
a n d relati o ns hi p t o st u d y treat me nt 
 
C ha n ges i n s afet y la b orat or y p ara m eters (e. g., he m at ol o g y, ser u m c he mistr y, a n d uri nal ysis) 
 
L ocal a n d s yste mic i njecti o n site re vie w; s peci al atte nti o n will be p ai d t o t he e x a mi nati o n of 
t he i njecti o n site. A d mi nistrati o n site reacti o ns a n d t he s u bject's c o m plai nts will be d oc u me nte d. 
7. 3. 1  
E V E N T S R E Q UI RI N G E X P E DI T E D R E P O R TI N G  
E ve nts re q uiri n g e x pe dite d re p orti n g ( E R E R) will be defi ne d as relate d a d verse e ve nts d u e t o 
V G X - 3 1 0 0 X/ place b o deli vere d wit h C E L L E C T R A™ 5 P S P t hat meets a n y of t he f oll o wi n g 
criteria: 
 Gr a de 3 or greater a d mi nistrati o n site er yt he ma, a n d/ or i n d urati o n rec or de d ≥ 2 h o urs after 
St u d y Treat me nt  
 Gra de 4 or greater a d mi nistrati o n site pai n, te n der ness rec or de d ≥ 2 h o urs after St u d y 
Treat me nt 
 Gra de 3 or greater fe ver 
 Gr a de 3 or greater s yste mic s y m pt o ms, i ncl u di n g ge n eralize d pr urit us 
As pe r t he T o xicit y Gra d e f or Healt h y A d ults a n d per C T C A E v 4. 0 3.  T h e m ost se vere gra de f or 
t hat partic ular e v e nt is t o be d oc u me nte d i n t he C R Fs. 
Sites will i nf or m t he S p o ns or vial e mail a n d t o desi g nee vial p h o ne or fa x of a n y E R E R wit hi n 2 4 
h o urs t o disc uss w het her f urt her d osi n g s h o ul d c o nti n ue b y c o nt acti n g I n o vi o as f oll o ws. 
E M AI L:     Safet y @i n o vi o.c o m    
S A F E T Y F A X: 
 or 
 
S A F E T Y P H O N E: 
 
 
 
1 8 4
P P D
P P D
P P D

7.3.2 
STOPPING RULES (CRITERIA FOR PAUSING OF STUDY) 
 If at any time during a study one-third (1/3) or more of the subjects experience an ERER, 
further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, 
and the DSMB. Only the DSMB may review unblinded data in making their recommendation 
to the Sponsor regarding continuation of a trial.  
 If any SAE (or potentially life-threatening AE), or death assessed as related to study treatment 
occurs, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, 
IRB (if applicable) and the DSMB. 
 If three or more subjects in this study, experience the same Grade 3 or 4 adverse event, 
assessed as related to study treatment, further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, 
Principal Investigator for the trial, and the DSMB. 
 In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to study 
treatment, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, 
IRB (if applicable) and the DSMB.  
The sponsor or designee will notify all investigators and IRBs/EC (if required) regarding the 
outcome of any investigation stemming from a Study Pause.  
Guidelines for assessing relatedness are detailed in Section 7.1.6. 
8 STATISTICAL ANALYSIS PLAN 
8.1 
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 
with a histologic diagnosis of cervical HSIL. The study’s primary endpoint is binary: regression to 
CIN1/normal and clearance of HPV-16 and/or HPV-18 infection from cervical tissue based on tissue 
collected at Week 36. The primary hypothesis is that VGX-3100X will be superior to placebo 
regarding the proportion who achieve the primary endpoint.  Secondary efficacy analyses involve 
regression to CIN1/normal, clearance of HPV-16 and/or HPV-18 infection from cervical tissue and 
non-progression of cervical lesions. Other secondary analyses concern safety and humoral and 
cellular immunological measures.  Exploratory analyses concern tissue immunological measures, 
durability of clearance of HPV-16 and/or HPV-18 infection from cervical tissue, clearance of HPV-
16 and/or HPV-18 infection from non-cervical tissue, effect of HLA type on efficacy, association 
of colposcopy, cytology, and virology and efficacy, and patient-reported outcomes. 
185

8.2 
RANDOMIZATION AND BLINDING 
Subjects will be randomized (2 VGX-3100X:1 Placebo) in a stratified manner according to a) the 
degree of CIN observed in the biopsy specimens at screening (CIN2 vs. CIN3), b) BMI category 
(≤25 vs. >25 kg/m2), and c) age category (<25 years vs. ≥25 years).  There will be no pre-determined 
number of subjects required to be randomized within each stratum.  To ensure that milder CIN2 
disease is not over-represented in the study, the percentage of subjects enrolled with CIN2 will not 
exceed 50% of the total enrolled. 
The study is double-blinded. 
8.3 
SAMPLE SIZE/POWER 
A sample of 165 subjects will be randomized to receive either 6 mg VGX-3100X or placebo IM 
followed by EP in a 2:1 ratio. This sample size provides 90% power to declare VGX-3100X superior 
to placebo, assuming the true proportion of subjects who achieve the primary endpoints is 40% and 
15% for VGX-3100X and placebo, respectively, and assuming 90% evaluability from 
randomization. These assumptions are based on the mITT result from the Phase 2 study. 
8.4 
ANALYSES POPULATIONS 
Analysis populations will include: 
 The modified intention to treat (mITT) population includes all subjects who receive at least one 
dose of Study Treatment. Subjects in this sample will be grouped to treatment arms as 
randomized.  Analysis of the mITT population will be primary for the analysis of efficacy in this 
study. 
 The per-protocol (PP) population comprises subjects who receive all doses of Study Treatments 
and have no protocol violations. Subjects in this sample will be grouped to treatment arms as 
randomized.  Analyses on the PP population will be considered supportive of the corresponding 
mITT population for the analysis of efficacy.  Subjects excluded from the PP population will be 
identified and documented prior to unblinding of the study database. 
 The safety analysis set includes all subjects who receive at least one does of Study Treatment. 
Subjects will be analyzed as to the treatment they received.  
Subjects who do not complete the study will not be replaced. 
8.5 
SUBJECT DISPOSITION 
Disposition will be summarized by treatment arm for all randomized subjects 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. 
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8.6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline 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 mITT population.  Prior and concomitant 
medications will also be summarized with percentages in this fashion.  
8.7 
MEDICAL HISTORY 
The percentage of subjects with abnormal medical history findings will be summarized by body 
system, by treatment arm, for the mITT population. 
8.8 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior medications are those that were used before the start of the trial (prior to Day 0).  Concomitant 
medications are those used during the course of the trial (on or after Day 0).  Partial start dates of 
prior and concomitant medications will be assumed to be the earliest possible date consistent with 
the partial date.  Partial stop dates of prior and concomitant medications will be assumed to be the 
latest possible date consistent with the partial date.  Data for all prior and concomitant medications 
will be summarized with percentages by treatment arm, for the mITT population.   
8.9 
EFFICACY ANALYSES 
The true treatment effect on the primary endpoint is  = pV – pP, where pV and pP denote the true 
population probabilities of the primary endpoint for VGX-3100X and Placebo, respectively.  The 
primary hypothesis of superiority is:  
H0:   0 vs. H1:  > 0. 
A p-value for this hypothesis test and corresponding 95% confidence interval will be computed 
based on the method of Miettinen and Nurminen [27].  Superiority will be concluded if the one-
sided p-value is <0.025 and the corresponding lower bound of the 95% CI exceeds zero. 
The secondary efficacy endpoints will be analyzed in the same manner as the primary hypothesis, 
but without the hypothesis test p-values. 
The histopathologic efficacy time frame is defined by those who have undergone a biopsy or surgical 
excision at any time starting from 14 days prior to the protocol-specified target date of Week 36.  It 
also includes subjects who underwent early intervention prior to this time frame; these subjects are 
considered as failures for the efficacy endpoints.  Table 13 provides details for the definition of the 
primary endpoint response.   
 
 
 
187

8. 1 0
8. 1 1
8. 1 1. 1

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 14 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 
[27].  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. 
Any AEs with a missing or partial onset date will be included in the overall AEs, but not be 
included within specified day-range summaries. AE duration will be calculated as (Stop Date – 
Start Date) + 1. 
8.11.2 
LABORATORY DATA 
Continuous response variables per time point and changes from baseline will be summarized with 
mean, median, minimum, and maximum values, and categorical response variables will be 
summarized per time point with percentages, by treatment arm.  Baseline is defined as the last 
measurement prior to the first treatment administration. 
8.12 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 mITT population.  Baseline is defined as the last measurement prior to the 
first treatment administration. 
8.13 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 mITT population. 
8.14 PATIENT REPORTED OUTCOMES 
As an exploratory endpoint, patient reported outcomes among subjects who receive VGX-3100X 
will be compared between those with excision versus those without excision, based on PRO 
endpoints.  This comparison will utilize the median difference in endpoints or the difference in 
proportions of subjects with endpoints and associated non-parametric or Miettinen and Nurminen 
[27] 95% CIs, for continuous responses and binary responses, respectively. 
 
 
189

8.15 MISSING VALUES 
Missing data will not be imputed or replaced, and calculations will be done on reported values. 
A subject’s regression outcome is missing if her CIN grade and HPV clearance at Week 36 cannot 
be determined.  Any subject who had suspected disease progression before Week 36 will be 
considered a non-regressor regardless of the Week 36 result, even if missing. 
8.16  INTERIM ANALYSIS 
No formal interim analyses will be performed for this study.  For reasons of futility (early evidence 
of poor efficacy of VGX-3100X) or safety issues, the DSMB could recommend stopping enrollment 
at any time.  The type I error of 0.05 will not be adjusted for possible early stopping due to futility. 
9 DATA COLLECTION, MONITORING AND REPORTING 
9.1 
CONFIDENTIALITY AND PRIVACY 
A report of the results of this study may be published or sent to the appropriate health authorities in 
any country in which the study products are legally marketed or may ultimately be marketed, but 
the subject’s name will not be disclosed in these documents. The subject’s name may be disclosed 
to the study sponsor, Sponsor, the governing health authorities or the Food and Drug Administration 
(FDA), if they inspect the study records. Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information. 
Written Authorization and other documentation in accordance with the relevant country and local 
privacy requirements (where applicable) are to be obtained from each subject prior to enrollment 
into the study, and/or from the subject’s legally authorized representative in accordance with the 
applicable privacy requirements (e.g., the Health Insurance Portability and Accountability Act 
Standards for Privacy of Individually Identifiable Health Information (HIPAA). 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following: 
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of the research subject to revoke their authorization for use of their PHI 
The rights of the research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the sponsor retains the ability 
to use all information collected prior to the revocation of subject authorization. For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to 
collect at least vital status (i.e., that the subject is alive) at the end of their scheduled study period. 
190

9.2 
SOURCE DOCUMENTS 
Source data is all information, original records or clinical findings, laboratory results, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in original source documents. Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, subject’s 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records 
kept at the pharmacy, at the laboratories, and at medical records and within information technology 
systems that are involved in the clinical trial. 
A medical history must be present in the source documents. A medication history must be present 
in the source documents. All prescription and nonprescription medications taken within l week prior 
to entry must be recorded on the CRF. Actual or estimated start and stop dates must be provided. 
9.3 
RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution 
should make available for direct access all requested 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 study essential documents for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. This retention period 
may be superseded by applicable regulatory requirements (e.g. minimum of 25 years for Health 
Canada). The sponsor will inform the investigator/institution as to when these documents are no 
longer needed to be retained. 
9.4 
SAFETY AND QUALITY MONITORING  
9.4.1 
DATA & SAFETY MONITORING BOARD 
A Data & Safety Monitoring Board (DSMB) will be established to protect the research subjects 
through independent analysis of emerging data from the trial.  The DSMB will meet quarterly or 
as data are available to review unblinded safety data and regression/clearance results.  If there are 
no new safety data or regression/clearance results to review for a quarterly scheduled meeting the 
DSMB will be notified and the meeting may be cancelled; Ad hoc meetings may be scheduled to 
review new data as applicable. The DSMB will be charged with advising the Sponsor if there 
appears to be a safety issue and with advising the Sponsor if it appears that regression in the VGX-
3100X group is unacceptably low compared to the placebo group. No formal interim analysis will 
be performed. The DSMB Chair, upon consultation with the other voting members of the DSMB, 
has the authority to recommend suspension or stopping the study and to request a full DSMB 
191

review and ad hoc statistical analyses.  The standard operating procedures of the DSMB will be 
documented in the DSMB charter, including the board’s accountability to Inovio. 
9.4.2 
PATHOLOGY ADJUCATION COMMITTEE 
All cervical biopsies will be read by a central expert Pathology Adjudication Committee (PAC) to 
ensure consistent assignment of disease status for both study eligibility and the efficacy analysis. 
The PAC will consist of a total of three pathologists. Each specimen will be read by two 
pathologists independently in a blinded fashion.  If the two pathologists agree the reading will be 
considered the clinical disease status for the subject.  If the readings of the first two pathologists 
are discordant, the third pathologist will review and if there is agreement among any of the three 
readings, it will stand as the clinical disease status for that subject.  If there is no agreement after 
the third review, the three reviewers will perform a simultaneous review and come to consensus 
or a majority rule of 2 of 3 if consensus cannot be reached.  A fourth pathologist will be identified 
to support the PAC in the event that one of the other pathologists is absent. 
9.4.3 
CLINICAL MONITORING 
Clinical Monitoring of the clinical trial will be performed by experienced monitors, who will 
report to the Sponsor or the Sponsor designee. Records for all clinical subjects in this trial will be 
monitored. The following clinical site monitoring tasks will be performed at all sites: 
 Prior to trial initiation, a site visit will be conducted to review all relevant forms and 
documentation, to ensure the site is qualified and compliant with all applicable requirements. 
 All clinical site monitoring visits will be documented. 
 Periodic site visits will be performed throughout the study. 
 The site monitor will be responsible for addressing and documenting the following study 
conduct activities and obligations and will: 
o Assure that the study is being conducted in accordance with the protocol, applicable 
regulatory agency regulations, and IRB policies 
o Discuss study conduct issues and incidents of noncompliance with the Investigator and/or 
study 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 serious 
adverse events (SAE) and provide subsequent follow-up report of the final outcome to the 
IRB 
o Throughout the study, inspect all source documents to ensure they are complete, logical, 
consistent, attributable, legible, contemporaneous, original, and accurate (ALCOA).  
o 
Assure that the study facilities continue to be acceptable 
o Compare the study 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 per 
laboratory manual requirements 
192

9. 5  
A D V E R S E E X P E RI E N C E ( A E) R E P O R TI N G 
T o ass ure t he s afet y of t he s u bjects, i nf or mati o n a b o ut all A Es (see Secti o n 7. 1 ), w het her v ol u nteere d 
b y t he s u bject, disc o vere d b y i n vesti gat or or st u d y staff q u esti o ni n g, or detecte d t hr o u g h p h ysi cal 
e x a mi nati o n, la b orat or y t est or ot her mea ns, will be c ollecte d a n d rec or de d i n t he s u bject’s s o urce 
d oc u me nts a n d f oll o we d as a p pr o priat e. 
9. 5. 1  
S T U D Y R E P O R TI N G P E RI O D O F A D V E R S E E V E N T S 
All s olicite d a n d u ns olicite d a d verse e v e nts will be c ollecte d t hr o u g h o ut t he st u d y a n d rec or de d 
o n t he A E C R F. Safet y e ve nts will be a nal yze d a n d s u m marize d t hr o u g h o ut t he st u d y. E m p hasis 
will be place d o n t he f oll o wi n g :  
 C ertai n A Es of i nterest will be s olicite d d uri n g t he 7 da ys f oll o wi n g eac h a d mi nistrati o n of 
St u d y Treat me nt a n d s u m marize d se paratel y 
 U ns olicite d A Es, S A Es or U A D Es will be c ollect e d a n d s u m marize d f or t he e ntire st u d y p eri o d  
9. 5. 2  
S T U D Y R E P O R TI N G P E RI O D O F S E RI O U S A D V E R S E E V E N T S 
T he re p orti n g p eri o d f or S A Es ( wit h o ut re gar d t o ca usalit y or relati o ns hi p) is c o m prise d of t h e 
peri o d f oll o wi n g t he si g ni n g of t he i nf or m e d c o nse nt f or m u ntil t he e n d of t he st u d y. Eac h A E will 
be assesse d t o deter mi ne w het her it meets seri o us ness criteria. If t he A E is c o nsi dere d seri o us, t he 
i n vesti gat or s h o ul d rec or d t his e ve nt t o t he S p o ns or wit hi n 2 4 h o urs of bec o mi n g a ware of t he 
e ve nt. T he i n vesti gat or ma y als o directl y re p ort t his e ve nt t o t he Et hics C o m mittee acc or di n g t o 
its sta n dar d o perati n g pr oce d ures. E x pecte d ness of S A Es will be deter mi ne d b y t he S p o ns or usi n g 
refere nce safet y i nf or mati o n s pecifie d i n t he I n vesti gat or’s Br oc h ure a n d pr ot oc ol. A n e ve nt ma y 
q ualit y f or e x pe dite d re p orti n g t o re g ulat or y a ut h orities if it is a n S A E, u n e x pecte d per refere nce 
safet y i nf or mati o n a n d c o nsi dere d relate d f oll o wi n g t he g ui d eli nes i n Secti o n 7. 1.3  ( S us pecte d 
U ne x pecte d Seri o us A d v erse Reacti o n, S U S A R) a n d 7. 1. 4 ( U na ntici pate d [seri o us] a d verse de vi ce 
effect) i n li ne wit h rele v a nt le gislati o n. All i n vesti gat ors will recei ve a s afet y letter n otif yi n g t he m 
of rele va nt S U S A R re p orts. T he i n vesti gat or s h o ul d n otif y t he I nstit uti o nal Re vie w B oar d (I R B)/ 
I nstit uti o nal Et hics C o m mittee (I E C) as s o o n as is practical, of seri o us e ve nts i n writi n g w here t his 
is re q uire d b y l o cal re g ul at ory a ut h orities, a n d i n acc or da n ce wit h t he l ocal i nstit uti o nal p olic y. At 
a n y ti me after c o m pleti o n of t he S A E re p orti n g peri o d, if a n i n vesti gat or bec o mes a ware of a n 
S A E t hat is s us pecte d b y t he i n vesti gat or t o be relate d t o t he st u d y dr u g, t he e ve nt will be re p orte d 
t o t he S p o ns or or its desi g nee. If t he i n vesti gat or bec o mes a ware of a n S A E i n a st u d y s u bject aft er 
t he last sc he d ule d f oll o w- u p visit, a n d c o nsi ders t he e ve nt relate d t o pri or St u d y Treat me nt, t he 
i n vesti gat or will re p ort it t o t he S p o ns or or t he a p pr o priate desi g nee. 
S P O N S O R C O N T A C T I N F O R M A TI O N  
E M AI L:     Safet y @i n o vi o.c o m    
S A F E T Y F A X: 
 or 
 
S A F E T Y P H O N E: 
 
1 9 3
P P D
P P D
P P D

The preferred method for providing SAE forms and any supporting documents to the Sponsor is 
as an attachment to an e-mail message, to the email addresses as indicated above and by facsimile 
(Fax), to include a fax coversheet that identifies the reporter and contact information to the 
designee.  
All supporting documents for SAE reports, including medical records and diagnostic test results, 
will include reference to the study subject number. The study site will redact all other subject 
identifying information present on SAE supporting documents prior to sending the report to the 
Sponsor.  
The report should contain as much clinical safety information as possible, but at minimum, the 
initial report must include the following information: 
 
Event 
 
Study number 
 
Subject number (SID) and initials  
 
Investigational Device serial number 
 
Lot numbers  
 
Reporter name and contact information 
 
In the case of a “minimum report” (one that is solely comprised of the information bulleted 
above), a more detailed follow-up report will be sent as soon as more information becomes 
available but no later than 5 calendar days after the date of the initial report. The investigator will 
supply the Sponsor and the IRB with any additional requested information. The original SAE 
form must be kept at the study site. The Sponsor or its representative will be responsible for 
determining and in turn, reporting SAEs to regulatory authorities according to the applicable 
regulatory requirements. SAEs must be followed by the investigator until resolution, even if this 
extends beyond the study-reporting period. Resolution of an SAE is defined as the return to 
baseline status or stabilization of the condition with the expectation that it will remain chronic. 
In the event of death, if an autopsy is performed, a copy of the report will be sent to the Sponsor. 
9.5.3 
NOTIFICATION OF SERIOUS ADVERSE EVENTS 
In accordance with local regulations, the Sponsor shall notify the appropriate regulatory 
authorities, and all participating investigators in a written safety report of any adverse experience 
associated with the use of the product that is both serious and unexpected and any significant new 
safety information that might materially influence the benefit-risk assessment of a medicinal 
product, sufficient to consider changes in product administration or overall conduct of a clinical 
investigation. The Sponsor will notify regulatory agencies within the time frame specified by local 
requirements but no later than 10 working days for UADE, 7 days for a fatal or life-threatening 
SUSAR and 15 days for all other SUSARS (see Section 7.1.3 and 7.1.4).  
 
 
194

9.5.4 
REPORTING OF DEVICE RELATED COMPLAINTS 
A product complaint is defined as “any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a device after it is released for distribution.” All product complaints that meet this 
definition must be reported to the sponsor with 10 days of discovery 
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.  
Any problems experienced during the treatment procedure including potential malfunctions of the 
device, error messages displayed on the device screen following treatment or errors that occur 
during the treatment procedure must be reported to the Sponsor or designee immediately for 
evaluation. The error reporting form must be completed and emailed to the Sponsor at 
 as shown in Appendix B. 
9.6 
STUDY DISCONTINUATION 
Inovio Pharmaceuticals reserves the right to discontinue the study at this site or at multiple sites for 
safety or administrative reasons at any time. In particular, a site that does not recruit at a reasonable 
rate may be discontinued. Should the study be terminated and/or the site closed for whatever reason, 
all non-source documentation and study product pertaining to the study must be returned to Inovio 
Pharmaceuticals or its representative. 
The study may be discontinued at any time by an IRB, Inovio Pharmaceuticals Inc., the FDA or 
other government agencies as part of their duties to ensure that research subjects are protected. 
10 ETHICS 
10.1  INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The investigator and Sponsor are responsible for ensuring that the clinical study is performed in 
accordance with the protocol, the Declaration of Helsinki, principles of Good Clinical Practice 
(GCP), and applicable regulatory requirements.  
 
10.2 INSTITUTIONAL REVIEW BOARD OR INSTITUTIONAL ETHICS COMMITTEE 
(IRB/IEC) 
The investigator will undertake the study after full approval of the protocol and adjunctive materials 
(e.g., informed consent form, advertising) has been obtained from the applicable IRB/IEC and a 
copy of this approval has been received by the sponsor. 
Investigator responsibilities relevant to the IRB include the following: 
 During the conduct of the study, submit progress reports to the IRB/IEC as required.  
195

 Notify the Sponsor immediately of any SAEs or serious unanticipated adverse device effects. 
 If Sponsor notifies you about any reportable safety events notify the IRB immediately. 
 As required, obtain approval from the IRB/IEC for protocol amendments and for revisions to 
the consent form or subject recruitment advertisements; 
 Reports on, and reviews of, the trial and its progress will be submitted to the IRB by the 
investigator at intervals stipulated in their guidelines and in accordance with pertinent 
regulations and guidelines. 
 Maintain a file of study-related information that includes all correspondence with the IRB; 
 Notify IRB when study is completed (i.e. after the last study visit of the final study subject); 
 After study completion provide the IRB with a final report on the study. 
10.3 OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA) 
The investigator and Sponsor are responsible for ensuring that the clinical study is reviewed and 
approved according to local and applicable global regulations (e.g., NIH Office of Biotechnology 
Activities) governing research that involves recombinant or synthetic nucleic acid molecules.   
11 PROTECTION OF HUMAN SUBJECTS 
11.1  COMPLIANCE WITH INFORMED CONSENT REGULATIONS  
Written informed consent is to be obtained from each subject prior to Screening into the study, 
and/or from the subject’s legally authorized representative.  The process for obtaining informed 
consent must also be documented in the subject’s medical record.  
11.2  COMPLIANCE WITH IRB/IEC REQUIREMENTS 
This study is to be conducted in accordance with applicable IRB/IEC regulations.  The Investigator 
must obtain approval from a properly constituted IRB/IEC prior to initiating the study and re-
approval or review at least annually.  Sponsor is to be notified immediately if the responsible 
IRB/IEC has been disqualified or if proceedings leading to disqualification have begun.  Copies of 
all IRB/IEC correspondence with the investigator must be provided to Sponsor. 
11.3  COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and guidelines.  
11.4  COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES REGULATIONS 
(21CFR PART 11) 
When applicable, this study is to be conducted in compliance with the regulations on electronic 
records and electronic signature. 
196

11.5  COMPLIANCE WITH PROTOCOL 
Subjects are not required to follow special instructions specific to the Investigational Device used 
in this study however will be asked to complete a participant diary card during their study 
participation.  Subjects will be provided with Investigator emergency contact information and 
advised to report all adverse events. While every effort should be made to avoid protocol deviations, 
should a deviation be discovered, Sponsor must be informed immediately. Any protocol deviation 
impacting Subject safety must be reported to the Medical Monitor immediately. 
11.6  CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol without 
approval by Sponsor and prior review and documented approval/favorable opinion from the IRB of 
a protocol amendment, except where necessary to eliminate immediate hazards to study subjects, or 
when the changes involve only logistical or administrative aspects of the study (e.g., change in 
monitors, change of telephone numbers).  
12 FINANCING AND INSURANCE 
Inovio Pharmaceuticals is the sponsor in all participating countries and is fully supporting the study.  
Clinical trial insurance has been taken out according to the laws of the countries where the study 
will be conducted. 
13 PUBLICATION POLICY 
Publication of the results of this trial in its entirety will be allowed. The proposed presentation, 
abstract and/or manuscript must be made available to The Sponsor 60 days prior to submission for 
publication. The Sponsor shall have thirty (30) days after receipt of the copies to object to the 
proposed presentation or publication because there is patentable subject matter that needs protection. 
In the event that The Sponsor makes such objection, the researcher(s) shall refrain from making such 
publication or presentation for a maximum of three (3) months from the date of receipt of such 
objection in order for patent application(s) (directed to the patentable subject matter contained in the 
proposed publication or presentation) to be filed with the United States Patent and Trademark Office 
and/or foreign patent office(s). 
 
 
197

14  REFERENCES 
1. 
Centers for Disease C, Prevention. Human papillomavirus-associated cancers - United 
States, 2004-2008. MMWR Morb Mortal Wkly Rep 2012,61:258-261. 
2. 
Satterwhite CL, Torrone E, Meites E, Dunne EF, Mahajan R, Ocfemia MC, et al. Sexually 
transmitted infections among US women and men: prevalence and incidence estimates, 
2008. Sex Transm Dis 2013,40:187-193. 
3. 
Hariri S, Unger ER, Sternberg M, Dunne EF, Swan D, Patel S, et al. Prevalence of genital 
human papillomavirus among females in the United States, the National Health And 
Nutrition Examination Survey, 2003-2006. J Infect Dis 2011,204:566-573. 
4. 
American Cancer Society. Cancer Facts & Figures. In. Atlanta; 2016. 
5. 
Bruni L, Alberto G, Aldea M, Serrano B, Valencia S, Brotons M, et al. Human 
Papillomavirus and Related Diseases in theWorld. Summary Report 2015-12-23. ICO 
Information Centre on HPV and Cancer (HPV Information Centre). In; 2015. 
6. 
Guan P, Howell-Jones R, Li N, Bruni L, de Sanjose S, Franceschi S, et al. Human 
papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical 
infection to cancer. Int J Cancer 2012,131:2349-2359. 
7. 
Apgar BS, Zoschnick L, Wright TC, Jr. The 2001 Bethesda System terminology. Am Fam 
Physician 2003,68:1992-1998. 
8. 
McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW, et al. Natural history 
of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial 
neoplasia 3: a retrospective cohort study. Lancet Oncol 2008,9:425-434. 
9. 
McIndoe WA, McLean MR, Jones RW, Mullins PR. The invasive potential of carcinoma in 
situ of the cervix. Obstet Gynecol 1984,64:451-458. 
10. 
Future Ii Study Group. Supplementary Material: Quadrivalent vaccine against human 
papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007,356:1915-1927. 
11. 
The American College of Obstetricians and Gynecologists. FAQs Loop Electrosurgical 
Excision Procedure (LEEP). In; 2014. 
12. 
Aihara H, Miyazaki J. Gene transfer into muscle by electroporation in vivo. Nat.Biotechnol. 
1998,16:867-870. 
13. 
Gehl J, Mir LM. Determination of optimal parameters for in vivo gene transfer by 
electroporation, using a rapid in vivo test for cell permeabilization. Biochemical and 
Biophysical Research Communications 1999,261:377-380. 
14. 
Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospects for success. 
Curr.Opin.Immunol. 2011,23:421-429. 
15. 
van Drunen Littel-van den H, Hannaman D. Electroporation for DNA immunization: clinical 
application. Expert.Rev.Vaccines. 2010,9:503-517. 
198

16. 
Bodles-Brakhop AM, Heller R, Draghia-Akli R. Electroporation for the Delivery of DNA-
based Vaccines and Immunotherapeutics: Current Clinical Developments. Mol Ther. 2009. 
17. 
Hirao LA, Wu L, Khan AS, Satishchandran A, Draghia-Akli R, Weiner DB. 
Intradermal/subcutaneous immunization by electroporation improves plasmid vaccine 
delivery and potency in pigs and rhesus macaques. Vaccine 2008,26:440-448. 
18. 
Khan AS, Pope MA, Draghia-Akli R. Highly efficient constant-current electroporation 
increases in vivo plasmid expression. DNA & Cell Biology 2005,24:810-818. 
19. 
Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, et al. Immunotherapy 
against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. 
Sci.Transl.Med. 2012,4:155ra138. 
20. 
Diehl MC, Lee JC, Daniels SE, Tebas P, Khan AS, Giffear M, et al. Tolerability of 
intramuscular and intradermal delivery by CELLECTRA™ adaptive constant current 
electroporation device in healthy volunteers. Hum Vaccin Immunother 2013,9:2246-2252. 
21. 
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. 
22. 
Xiang L, Li J, Yang W, Xu X, Wu X, Wang H, et al. Conization Using an Electrosurgical 
Knife for Cervical Intraepithelial Neoplasia and Microinvasive Carcinoma. PLoS One 
2015,10:e0131790. 
23. 
Stoler MH, Vichnin MD, Ferenczy A, Ferris DG, Perez G, Paavonen J, et al. The accuracy 
of colposcopic biopsy: analyses from the placebo arm of the cerva clinical trials. Int J Cancer 
2011,128:1354-1362. 
24. 
EuroQol G. EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy 1990,16:199-208. 
25. 
Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Measurement 
properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-
country study. Qual Life Res 2013,22:1717-1727. 
26. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity 
and activity impairment instrument. Pharmacoeconomics 1993,4:353-365. 
27. 
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985,4:213-226. 
 
 
 
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15 APPENDICES 
 
 
 
 
200

15.1 APPENDIX A:  PARTICIPANT DIARY CARD 
 
201

 
202

 
203

 
204

 
205

 
206

 
207

 
208

 
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214

 
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15.2 APPENDIX B:  ERROR REPORTING FORM 
216

 
217

15.3 APPENDIX C:  GUIDELINES FOR COLPOSCOPY, BIOPSY, AND SURGICAL 
EXCISION 
Colposcopy Procedure 
It is recommended that all study colposcopies performed after informed consent be according the procedures 
recommended by the American Society of Colposcopy and Cervical Pathology (ASCCP): 
1. Use warm, clean water to lubricate the vaginal speculum.  Avoid other lubricant substances which could 
obscure results. 
2. If the vaginal walls are lax, a lateral vaginal sidewall retractor aligned perpendicular to the speculum may 
facilitate visualization. 
3. Examine the cervico-vaginal secretions and remove any excess mucus from the cervix with saline-soaked 
cotton swabs. 
4. Obtain any required specimens required for cytology and HPV testing. 
5. Using low-power magnification (5x to 10 x) inspect the cervix for obvious areas of abnormalities. 
6. Swab or spray the cervix with 3-5% acetic acid.  Reapply every 2-3 minutes during the examination. 
7. Use the green or blue filter to examine blood vessels.  Increase magnification (15x) 
8. Identify the distal and proximal boarders of the transformation zone. 
a. The inner border is the entire 360-degree circumference of the squamocolumnar junction 
i. If the junction is proximal to the external os, in the canal, use a cotton-tipped 
applicator to pry either the anterior lip up or the posterior lip down or use an 
endocervical speculum 
ii. If the junction is not visualized in its entire circumference, the colposcopy is deemed  
inadequate  
b. The distal limit of the transformation zone may be identified by finding the most distal crypt 
openings or nabothian follicles in the lips of the cervix and drawing an imaginary line 
connecting these landmarks 
9. Inspect the entire new squamocolumnar junction and detect and evaluate any abnormal areas.   
10. Evaluate the upper third portion of the vagina. 
11. Lugol or Schiller’s solution may be applied to further define previously identified lesions.   
Cervical Biopsies  
 Endocervical Curettage 
ECC is to be performed using a kervorkian curette or equivalent instrument.  Rotate and scrape the curette 
360○ in the endocervical canal and use a cytobrush to remove the specimen.  Deposit the specimen onto a 
Telfa pad before depositing in the specimen vial containing 10% neutral buffered formalin solution and 
labeled with the subject identification (SID) number. 
 Ectocervical Biopsies 
Ectocervical biopsies should only be performed prior to Week 36 if disease progression is suspected.  Only 
the suspect lesion should be biopsied in that circumstance.   
If the subject is eligible for 4 quadrant biopsy at the Week 36 visit, the following procedure should be 
followed: 
1. Label each specimen vial containing 10% neutral buffered formalin solution with the subject’s ID number 
and the quadrant number according to the figure below. 
2. Perform and record colposcopy findings from each quadrant according to the following categories 
218

a. Negative (no lesion present) 
b. Low Grade  (e.g. pale acetowhite lesion on or off the squamocolumnar junction 
c. High Grade  (e.g. dense acetowhite lesion often with mosaic pattern or punctation) 
d. Suspicion of invasive cancer 
e. Invasive cancer 
3. Perform colposcopic directed biopsies from all quadrants with lesions. 
4. Multiple biopsies can be obtained of a lesion at the discretion of the investigator but must be uniquely 
labeled  
5. If a quadrant is free of lesions, obtain a random biopsy at the squamocolumnar junction in that quadrant 
at 2, 4, 8, or 10 o’clock. 
6. Prepare the biopsy specimen vials for shipment according to the Laboratory Manual. 
 
Figure 1 – Biopsy Quadrant Numbers 
 
 
 
 
Surgical Excision 
For subjects undergoing surgical excision at the Week 36 visit, the following procedure should be followed: 
1. Label each specimen vial containing 10% neutral buffered formalin solution with the SID number and 
the specimen type. 
2. Record colposcopy findings from each quadrant according to the following categories 
a. Negative (no lesion present) 
b. Low Grade  (e.g. pale acetowhite lesion on or off the squamocolumnar junction 
c. High Grade  (e.g. dense acetowhite lesion often with mosaic pattern or punctation) 
d. Suspicion of invasive cancer 
e. Invasive cancer 
3. Perform the LEEP or CKC per usual practice. 
4. Specimen should be marked at 12 o’clock with suture or gentian violet ink for purposes of orientation 
5. Prepare the biopsy specimen vials for shipment according to the Laboratory Manual. 
 
219

 
 
220

1 5. 4
 

 
 

 
 
 
 
 We would like to know how good or bad your health is TODAY. 
 
 This scale is numbered from 0 to 100. 
 
 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
 
 Mark an X on the scale to indicate how your health is TODAY. 
 
 Now, please write the number you marked on the scale in the box 
below. 
The best health 
you can imagine 
100 
 
95 
 
90 
 
85 
 
80 
 
75 
 
70 
 
65 
 
60 
 
55 
 
50 
 
45 
 
40 
 
35 
 
30 
 
25 
 
20 
 
15 
 
10 
 
5 
 
0 
The worst health 
you can imagine 
YOUR HEALTH TODAY = 
223

15.5 APPENDIX E:  SF-36 V2 QUESTIONNAIRE 
 
 
224

 
 
225

 
226

 
227

 
228

 
229

 
230

 
 
231

H P V- 3 0 1
R E V E A L
I Trial ( Ra n d o mize d E val uati o n of V G X- 3 1 0 0 X a n d Etectr o p orati o n f or t he
treat me nt of Cer vical H SI L)
A Pr os p e cti v e, R a n d o mi z e d, D o u ble- bli n d,
Pl a c e b o- C o ntr oll e d P h as e 3 St u d y of
V G X- 3 1 0 0 X Deli vere d I ntr a m us c ul arl y f oll o we d b y El e ctr o p or ati o n wit h
C E L L E C T R A T M 5 P S P f or t h e Tr e at m e nt of H P V- 1 6 a n dl or H P V- 1 8 r el at e d Hi g h
Gr a d e S q u a m o us l ntr a e pit h eti al Lesi o n f H SI L) O F 1 of t h e Cer vi x
Pr ot oc ol VersI o n 2. 1
1 O-J U N- 2 0 1 6
Writte n
b y:
Date
f D D M M M
Y Y Y Y)
Bi ostatisticia W
Date f O D- M M M- Y Y Y Y)
Me dical
M o nit or
Date
( D D- M M M- Y Y Y Y)
Date
( D D- M M M- Y Y Y Y)
Date
( D D- M M M- Y Y Y Y)
2 3 2
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

H P V- 3 0 1
R E V E A L
I Trial ( Ra n d o mize d E val uati o n of V G X- 3 1 0 0 X a n d Electr o p orati o n f or t h e
tr e at m e nt of Cer vical
H SI L)
A Pr os p e cti v e, R a n d o mi z e d, D o u bl e- bli n d,
Pl a c e b o- C o ntr oll e d P h as e 3 St u d y of
V G X- 3 1 0 0 X D eli v er e d I ntr a m us c ul arl y f oll o w e d b y El e ctr o p or ati o n wit h
C E L L E C T R A T M 5 P S P f or t h e Tr e at m e nt of H P V- 7 6 a n d/ or H P V- 1 8 r el at e d Hi g h
Gr a d e S q u a m o us l ntr a e pit h eli al L esi o n f H SI L) O FJ of t h e C er vi x
Pr ot oc ol Versi o n
2. 7
7 O-J U N- 2 0 1 6
Writte n
b y:
we d a n d A p pr o v e d b y:
Date
( D D- M M M- Y Y Y Y)
Bi ostatisticia n!
_
_
_
_
_
_
_
_
_
_
_
_
_
_
Date
( D D- M M M- Y Y Y Y)
Me dical
M o nit or
Date
( D D- M M M- Y Y Y Y)
Date
( D D- M M M- Y Y Y Y)
Date
( D D- M M M- Y Y Y Y)
2 3 3
P P D
P P D
P P D
P P D
P P D
P P D
P P D

 
 
 
HPV-301 
REVEAL 1 Trial  
(Randomized Evaluation of VGX-3100 and Electroporation for the Treatment of Cervical 
HSIL) 
 
A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
PHASE 3 STUDY OF VGX-3100 DELIVERED INTRAMUSCULARLY FOLLOWED BY 
ELECTROPORATION WITH CELLECTRA™ 5PSP FOR THE TREATMENT OF HPV-
16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS INTRAEPITHELIAL 
LESION (HSIL) OF THE CERVIX   
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
U.S. BB-IND #13683 
EudraCT #2016-002761-63 
 
Version 3.0 
23 September 2016 
 
 
 
 
 
 
 
234

 
A P R O S P E C TI V E, R A N D O MI Z E D, D O U B L E -B LI N D, P L A C E B O -C O N T R O L L E D 
P H A S E 3  S T U D Y O F V G X -3 1 0 0 D E LI V E R E D I N T R A M U S C U L A R L Y F O L L O W E D B Y 
E L E C T R O P O R A TI O N WI T H C E L L E C T R A ™ 5 P S P F O R T H E T R E A T M E N T O F H P V -
1 6 A N D/ O R H P V - 1 8 R E L A T E D HI G H G R A D E S Q U A M O U S I N T R A E PI T H E LI A L 
L E SI O N ( H SI L ) O F T H E C E R VI X   
S h ort Title:   
R E V E A L 1 Trial  ( Ra n d o mize d  E val uati o n  of  V G X - 3 10 0  a n d 
Electr o p orati o n f or t he treat me nt of Cer vical H SI L) 
 
Bi ol o gic al Pr o d uct:    
 V G X - 3 1 0 0 
 
Pr ot oc ol N u m ber:    
 H P V - 3 0 1 
 
S p o ns or:  
 I n o vi o P har m ace uticals, I n c. 
 
 6 6 0 W. Ger ma nt o w n Pi ke, S uite 1 1 0 
 
 Pl y m o ut h Meeti n g, P A 1 9 4 6 2 
 
Pri nci p al I n vesti g at or:   
 
, M. D., M. S. 
 
 
 
 
 R ut gers N e w J erse y Me dical Sc h o ol  
 
 1 8 5 S. Ora n ge A v e., M S B E- 5 0 6 
 
 Ne war k, NJ 0 7 1 0 3 
 
Me dic al M o nit or:   
 
, M. D., P h. D. 
 
 
 
 
 I n o vi o P har m ace uticals, I n c. 
 
C O N FI D E N TI A L  
T he i nf or m ati o n i n t his d oc u me nt is c o nsi dere d pri vile ge d a n d c o nfi de nti al b y I n o vi o P h ar m ace utic als a n d m a y 
n ot be discl ose d t o ot hers e xce pt t o t he e xte nt necess ar y t o o bt ai n I nstit uti o n al Re vie w B o ar d/ Et hics c o m mittee 
a p pr o v al a n d i nf or me d c o ns e nt, or as re q uire d b y l oc al re g ul at or y a ut h orities. Pers o ns t o w h o m t his i nf or m ati o n 
is discl ose d m ust be i nf or me d t h at t his i nf or m ati o n is pri vile ge d a n d c o nfi de nti al a n d t h at it s h o ul d n ot be f urt her 
discl ose d wit h o ut t he w ritte n per missi o n of I n o vi o P h ar m ace utic als. A n y s u p ple me nt al i nf or m ati o n a d de d t o t his 
d oc u me nt  is  als o  c o nfi de nti al  a n d  pr o priet ar y  i nf or m ati o n  of  I n o vi o  P h ar m ace uti c als  a n d  m ust  be  ke pt  i n 
c o nfi de nce i n t he s a me m a n ner as t he c o nte nts of t his d oc u me nt.  
 
2 3 5
P P D
P P D
P P D
P P D

SUMMARY OF CHANGES  
The following is a list of significant protocol changes from HPV-301 protocol version 2.1 dated 
10 June 2016 to HPV-301 protocol version 3.0 dated 23 September 2016. All other changes are 
administrative and do not significantly affect the safety of subjects, study scope, or scientific 
quality of the protocol.  
1. 
Name of the investigational product has been changed from VGX-3100X to VGX-3100. The 
term VGX-3100 as used in this document denotes 3.0 ± 0.2 mg/mL pGX3001 bulk plasmid 
and 3.0 ± 0.2 mg/mL pGX3002 bulk plasmid in saline sodium citrate (SSC) buffer, 
refrigerated formulation 
2. 
The primary analysis for the study has been changed from modified-intention-to-treat 
(mITT) based on complete data to intention-to-treat (ITT) analysis. Based on this change, 
the number of subjects to be enrolled in the study is now 198 instead of 165 
3. 
The following modification have been made to the objectives and endpoints: 
a. Changed the exploratory objective of “clearance of HPV-16 and/or HPV-18 infection 
from anatomic location outside the cervix” to secondary objective 
b. Added association of microRNA profile to the exploratory objective 
c. Specified the countries where patient reported outcome will be collected in the 
exploratory endpoint 
4. 
The following modification have been made to inclusion and exclusion criteria: 
a. Inclusion criteria 10c) clarified the duration of use of contraceptive method from 
screening until week 36 
b. Exclusion criteria 4 has been modified to remove the treatment of genital warts within 
4 weeks of screening 
5. 
The following modification have been made to the study evaluation: 
a. Added an additional in-person visit to allow collection of samples for HPV typing by 
cobasTM HPV test and mircoRNA profile test 
b. Changed the method of collection from peri-anal to intra-anal swab 
c. Removed the collection of non-cervical samples (i.e. oropharyngeal rinse, vaginal 
and intra-anal samples) at Week 15 visit 
d. Additional time-points for patient reported outcome questionnaire completion at 
Weeks 4, 12 and 36 visits 
e. Removed collection of digene swabs at Week 62 visit 
f. Specified collection of weight at Day 0, Weeks 4 and 12 to align with collection of 
BMI data for study treatment purposes 
g. Clarified socio-behavioral assessment at Weeks 36 and 88 will include data 
collection of any change from screening 
6. 
Section 2.1.3 Definition of responder and non-responder has been modified to include 
additional category in definition of non-responder 
7. 
Added information on supplementation of subjects in case more than 10% of subjects from 
randomization of the study treatment discontinue prior to the Week 36 primary endpoint 
procedure 
8. 
Section 5.7 Return and destruction of investigational product has been updated to clarify 
process for destruction and return of unused investigational product 
236

9. 
Section 6.1.1 Screening evaluation has been updated to include the information on subjects 
that can be qualified for screening into the study  
10. 
Section 6.15.1 Prohibited concomitant medication and treatment has been updated to add the 
restriction of use of any Blood thinners/anticoagulants, aspirin or other medication that affect 
blood clotting should not be taken X days prior to undergoing biopsy or surgical excision 
11. 
Added reporting of progression of HSIL to microinvasive or invasive squamous cell 
carcinoma as an SAE  
12. 
Section 7.3.1 has been modified to replace the term “Events requiring expedited reporting” 
to “Adverse events of special interest”. Added clarification on reporting requirements to 
sponsor 
13. 
Section 7.4.2 has been updated to reflect change in reporting contact details in event of SAE 
14. 
Section 8 Statistical analysis section has been modified to reflect that missing data will be 
considered as a failure for ITT efficacy analysis. A subgroup analysis for primary and 
secondary efficacy endpoints will be performed by history of exposure to prophylactic HPV 
vaccine. 
15. 
Section 9.4.2 Pathology adjudication committee section has been updated to clarify in case 
of disagreement between first two pathologists, the third pathologist will review the 
histology slides independently. Also, if there is disagreement across all three pathologist, 
worst diagnosis will be reported as clinical disease status for the subject. 
 
 
 
237

PROTOCOL ACKNOWLEDGEMENT 
I have read this Protocol and agree that it contains all necessary details for carrying out the study 
described. I understand that it must be reviewed by the Institutional Review Board or Independent 
Ethics Committee overseeing the conduct of the study and approved or given favorable opinion 
before implementation. 
The signature of the Investigator below constitute his/her approval of this protocol and provide the 
necessary assurances that this study will be conducted according to the Declaration of Helsinki, 
ICH-GCP guidelines, local legal and regulatory requirements as well as to all stipulations of the 
protocol in both the clinical and administrative sections, including statements regarding 
confidentiality. 
__________________________________________________________ 
Investigator – Signature                      Date (DD/MMM/YYYY)       
________________________________________ 
Investigator – Printed Name        
Site Number: ___________________________________  
Site Name: _____________________________________ 
238

TABLE OF CONTENTS 
 
SUMMARY OF CHANGES ...................................................................................................................... 3 
Protocol Acknowledgement ....................................................................................................................... 5 
Table of Contents ........................................................................................................................................ 6 
i 
List Of Abbreviations and definitions................................................................................................ 11 
ii Clinical Protocol Synopsis ................................................................................................................... 14 
1 Introduction ......................................................................................................................................... 23 
1.1 
Background ................................................................................................................................. 23 
1.1.1 HPV Infection, Cervical Intraepithelial Neoplasia and Cervical Cancer .......................... 23 
1.1.2 VGX-3100 ........................................................................................................................ 24 
1.1.3 Electroporation ................................................................................................................. 24 
1.1.4 Selection of study design .................................................................................................. 27 
1.2 
Dose and Regimen Rationale ...................................................................................................... 27 
1.3 
Risks/Benefit Assessment ........................................................................................................... 28 
1.3.1 Risks associated with Current Therapeutic Options ......................................................... 28 
1.3.2 Potential Risks of Study Participation .............................................................................. 29 
1.3.3 Potential Benefits of Study Participation .......................................................................... 29 
2 Study Design ......................................................................................................................................... 30 
2.1 
Endpoint Assessment .................................................................................................................. 30 
2.1.1 Histology Assessment ....................................................................................................... 31 
2.1.2 Virologic (HPV) Assessment............................................................................................ 32 
2.1.3 Definition of Responder and Non-Responder .................................................................. 33 
2.1.4 Immunogenicity AssessmenT ........................................................................................... 34 
2.2 
Treatment Plan ............................................................................................................................ 34 
2.3 
Safety Monitoring Plan ............................................................................................................... 34 
2.3.1 Data and safety Monitoring Board (DSMB) ..................................................................... 36 
2.4 
Long Term Follow up Plan ......................................................................................................... 36 
3 Hypothesis and Study Objectives ....................................................................................................... 39 
3.1 
Hypothesis ................................................................................................................................... 39 
3.2 
Primary Objective and Endpoint ................................................................................................. 39 
3.3 
Secondary Objectives and Associated Endpoints ....................................................................... 40 
3.4 
Exploratory Objectives and Associated Endpoints ..................................................................... 41 
4 Selection of Subjects ............................................................................................................................ 41 
239

4.1 
Inclusion Criteria ......................................................................................................................... 41 
4.2 
Exclusion Criteria........................................................................................................................ 42 
4.3 
Discontinuation/Withdrawal of Study Subjects .......................................................................... 45 
4.3.1 Criteria for Discontinuation of Investigational Product .................................................... 45 
4.3.2 Criteria for WithdrawAl from the Study ........................................................................... 45 
4.3.3 Sponsor Notification of Discontinuation/ Withdrawal ..................................................... 45 
4.3.4 Reason for Discontinuation/Withdrawal .......................................................................... 46 
4.3.5 Supplementation of study subjects ................................................................................... 46 
5 Study Treatment .................................................................................................................................. 46 
5.1 
Investigational Products .............................................................................................................. 46 
5.2 
Blinding ....................................................................................................................................... 47 
5.3 
Packaging and Labeling of investigational product .................................................................... 47 
5.4 
Handling of investigational product ............................................................................................ 47 
5.5 
Dispensing of Investigational Product ........................................................................................ 48 
5.6 
Investigational product Accountability ....................................................................................... 48 
5.7 
Return and Destruction of  Investigational Product .................................................................... 48 
5.8 
Investigational Device ................................................................................................................. 49 
5.9 
Use of investigational device ...................................................................................................... 51 
5.10 Packaging and Labeling of Investigational Device ..................................................................... 51 
5.11 Handling of investigational device .............................................................................................. 52 
5.12 Investigational Device Accountability ........................................................................................ 52 
5.13 Return of Investigational Devices ............................................................................................... 52 
6 Study Procedures and Treatments ..................................................................................................... 53 
6.1 
Before Treatment Procedures ...................................................................................................... 53 
6.1.1 Screening Evaluations ...................................................................................................... 53 
6.2 
During Treatment Procedures by Visit ........................................................................................ 55 
6.2.1 Day 0 ................................................................................................................................. 55 
6.2.2 8-14 Days Post Dose 1 Phone call .................................................................................... 56 
6.2.3 Week 4 .............................................................................................................................. 56 
6.2.4 8-14 Days Post Dose 2 Phone Call ................................................................................... 56 
6.2.5 Week 8 .............................................................................................................................. 56 
6.2.6 Week 12 ............................................................................................................................ 57 
6.2.7 8-14 Days Post Dose 3 Phone Call ................................................................................... 57 
6.2.8 Week 15 ............................................................................................................................ 57 
6.2.9 Week 28 ............................................................................................................................ 58 
240

6.2.10 Week 36 ............................................................................................................................ 58 
6.2.11 Week 40 Phone call .......................................................................................................... 59 
6.2.12 Week 62 ............................................................................................................................ 59 
6.2.13 Week 88 ............................................................................................................................ 59 
6.3 
Evaluations and Procedures ........................................................................................................ 60 
6.3.1 Informed Consent ............................................................................................................. 60 
6.3.2 Assignment of Subject Identification Numbers ................................................................ 60 
6.3.3 Safety Evaluations ............................................................................................................ 60 
6.4 
Injection and Electroporation (EP) .............................................................................................. 62 
6.4.1 Risks of Treatment Procedures ......................................................................................... 63 
6.4.2 Management of Anxiety and Pain due to Treatment ........................................................ 63 
6.5 
Assessment of Laboratory Abnormalities ................................................................................... 64 
6.6 
Assessment of Clinical Study Adverse Events ........................................................................... 64 
6.7 
Assessment of Injection Site Reactions ...................................................................................... 64 
6.8 
Assessment of Patient Reported Outcomes ................................................................................. 65 
6.9 
Peripheral Blood Immunogenicity Assessments ......................................................................... 65 
6.10 Tissue Immunogenicity Assessment ........................................................................................... 66 
6.11 HLA Typing ................................................................................................................................ 66 
6.12 Pap Smears and HPV Testing ..................................................................................................... 66 
6.13 Colposcopy and Cervical Biopsies .............................................................................................. 67 
6.13.1 Ectocervical Biopsies ........................................................................................................ 67 
6.13.2 Unscheduled Biopsies ....................................................................................................... 68 
6.14 Concomitant Medications/Treatments ........................................................................................ 68 
6.15 Restrictions .................................................................................................................................. 68 
6.15.1 Prohibited Concomitant Medications and Treatments ...................................................... 68 
6.15.2 Other Restrictions ............................................................................................................. 68 
7 Evaluation of Safety and Management of Toxicity........................................................................... 69 
7.1 
Safety Parameters ........................................................................................................................ 69 
7.1.1 Adverse Events ................................................................................................................. 69 
7.1.2 Serious Adverse Events .................................................................................................... 70 
7.1.3 Unexpected Adverse Drug Reactions and Expedited Reporting ...................................... 71 
7.1.4 Unanticipated (Serious) Adverse Device Effect (UADE) ................................................ 72 
7.1.5 Assessing Severity (Intensity) .......................................................................................... 72 
7.1.6 Causal Relationship of Clinical Material to Adverse Events ............................................ 72 
241

7.1.7 Abnormal Laboratory Value ............................................................................................. 73 
7.1.8 Post-Study Reporting Requirements ................................................................................. 73 
7.1.9 Procedures for Documenting Pregnancy During Study .................................................... 74 
7.2 
Methods and Timing of the Collection and Recording of Safety Data ....................................... 74 
7.3 
Safety and Toxicity Management ............................................................................................... 75 
7.3.1 Adverse events of special interest ..................................................................................... 75 
7.3.2 Stopping Rules (Criteria for Pausing of Study) ................................................................ 75 
7.4 
Study Reporting Period of Adverse Events ................................................................................. 76 
7.4.1 Study reporting period of Adverse Events of special interest ........................................... 76 
7.4.2 Study Reporting Period of Serious Adverse Events ......................................................... 76 
7.4.3 Notification of SerioUs Adverse Events ........................................................................... 77 
7.4.4 Reporting of Device Related Complaints ......................................................................... 77 
7.5 
Study Discontinuation ................................................................................................................. 78 
8 Statistical Analysis Plan ...................................................................................................................... 78 
8.1 
General Considerations ............................................................................................................... 78 
8.2 
Randomization and Blinding ....................................................................................................... 78 
8.3 
Sample Size/Power ...................................................................................................................... 79 
8.4 
Analyses Populations .................................................................................................................. 79 
8.5 
Subject Disposition ..................................................................................................................... 79 
8.6 
Demographic and Other Baseline Characteristics ....................................................................... 79 
8.7 
Medical History ........................................................................................................................... 79 
8.8 
Prior and Concomitant Medications ............................................................................................ 80 
8.9 
Efficacy Analyses ........................................................................................................................ 80 
8.10 Immunogenicity Analyses ........................................................................................................... 81 
8.11 Safety Analyses ........................................................................................................................... 81 
8.11.1 Adverse Events ................................................................................................................. 81 
8.11.2 Laboratory Data ................................................................................................................ 82 
8.12 Vital Signs ................................................................................................................................... 82 
8.13 Physical Examination .................................................................................................................. 82 
8.14 Patient Reported Outcomes ......................................................................................................... 82 
8.15 Missing Values ............................................................................................................................ 82 
8.16 subgroup analyses ....................................................................................................................... 83 
8.17 Interim Analysis .......................................................................................................................... 83 
9 Data Collection, Monitoring and Reporting ..................................................................................... 83 
9.1 
Confidentiality and Privacy ......................................................................................................... 83 
9.2 
Source Documents ...................................................................................................................... 84 
242

9.3 
Records Retention ....................................................................................................................... 84 
9.4 
Safety and Quality Monitoring .................................................................................................... 84 
9.4.1 Data & Safety Monitoring Board...................................................................................... 84 
9.4.2 Pathology Adjucation Committee ..................................................................................... 85 
9.4.3 Clinical Monitoring .......................................................................................................... 85 
10 Ethics 86 
10.1 Investigator and Sponsor Responsibilities .................................................................................. 86 
10.2 Institutional Review Board or Institutional Ethics committee (IRB/IEC) .................................. 86 
10.3 Office of Biotechnology Activities (OBA) ................................................................................. 86 
11 Protection of Human Subjects ............................................................................................................ 86 
11.1 Compliance with Informed Consent Regulations ....................................................................... 86 
11.2 Compliance with IRB/IEC Requirements ................................................................................... 86 
11.3 Compliance with Good Clinical Practice .................................................................................... 87 
11.4 Compliance with Electronic Records/Signatures Regulations (21CFR Part 11) ........................ 87 
11.5 Compliance with Protocol ........................................................................................................... 87 
11.6 Changes to the Protocol .............................................................................................................. 87 
12 Financing and Insurance ..................................................................................................................... 87 
13 Publication Policy ................................................................................................................................ 87 
14 References ............................................................................................................................................ 88 
15 Appendices ........................................................................................................................................... 90 
15.1 Appendix A:   Participant Diary Card ......................................................................................... 91 
15.2 Appendix B:  Guidelines for Colposcopy, Biopsy, and Surgical Excision ............................... 106 
 
 
 
 
243

I 
LIST OF ABBREVIATIONS AND DEFINITIONS 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AIS 
Adenocarcinoma-in-situ 
AGC 
Atypical Glandular Cell 
ASC-H  
Atypical Squamous Cells, cannot exclude High grade squamous 
intraepithelial lesion 
ASC-US  
Atypical squamous cells of undetermined significance 
BMI 
Body Mass Index 
Baseline 
Prior to first dose 
CEF 
Cytomegalovirus, Epstein Barr Virus and Influenza 
CFR 
Code of Federal Regulations 
CIB 
Clinical Investigator’s Brochure 
CIN 
Cervical Intraepithelial Neoplasia 
CKC 
Cold knife conization 
CMI 
Cell mediated immunity 
CMR 
Complete Metabolic Response 
CMV 
Cytomegalovirus 
CRF 
Case Report Forms 
CPK 
Creatine Phosphokinase 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTL 
Cytotoxic T-cells 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of Acquired Immunodeficiency Syndrome  
DNA 
Deoxyribonucleic Acid 
ECC 
Endocervical Curettage 
EP 
Electroporation with CELLECTRA™ 5PSP 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EP 
Electroporation 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISpot 
Enzyme Linked Immunosorbent Spot-forming Assay 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HCG 
Human Chorionic Gonadotropin 
HSIL 
High grade squamous intraepithelial lesion 
244

HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPV 
Human Papillomavirus 
HPV-16/18 
HPV-16 and/or HPV-18 
IC 
Intracavitary 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
IFN-γ 
Interferon Gamma 
IL-12 
Interleukin 12 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IXRS 
Interactive Response System 
LAST 
Lower Anogenital Squamous Terminology 
LEEP 
Loop Electrosurgical Excision Procedure 
LLETZ 
Large Loop Excision of Transformation Zone 
LSIL 
Low grade squamous intraepithelial lesion 
MedDRA® 
Medical Dictionary for Drug Regulatory Affairs 
mITT 
Modified Intent to Treat 
NILM 
Negative for intraepithelial lesion or malignancy 
NIH 
National Institutes of Health 
OP 
Oropharyngeal  
Principal Investigator 
Lead Investigator for overall study activities 
Investigator 
Lead Investigator for individual site(s) 
PAC  
Pathology Adjudication Committee 
PBMC 
Peripheral Blood Mononuclear Cells 
PDC 
Participant Diary Card 
PRO 
Patient Reported Outcomes 
PE 
Physical exam 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SID 
Subject Identification   
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
sWFI 
Sterile Water for Injection 
245

TNF 
Tumor Necrosis Factor 
ULN 
Upper Limit of Normal 
WOCBP 
Women of Childbearing Potential 
 
 
 
 
 
246

II CLINICAL PROTOCOL SYNOPSIS 
 
Title of Study:  A Prospective, Randomized, Double-blind, Placebo-Controlled Phase 3 Study of 
VGX-3100 Delivered Intramuscularly followed by Electroporation with CELLECTRA™ 5PSP for 
the Treatment of HPV-16 and/or HPV-18 related High Grade Squamous Intraepithelial Lesion 
(HSIL)0F1 of the Cervix 
Estimated Number of Study Centers and Countries/Regions:  Approximately 125 Sites  in up 
to 25 Countries 
Study Phase: 3 
Primary Hypothesis:  Three 6 mg doses of VGX-3100 (DNA Plasmids encoding E6 and E7 
proteins of HPV-16 and HPV-18) delivered intramuscularly (IM) followed by electroporation 
(EP) with CELLECTRA™ 5PSP to adult women with histologically confirmed HSIL[Cervical 
Intraepithelial Neoplasia (CIN)2, CIN3] of the cervix, associated with HPV-16 and/or HPV-18 
will result in a higher percentage of women with histopathological regression of cervical HSIL 
lesions to no evidence of cervical HSIL and virologic clearance of HPV-16 and/or HPV-18 
compared to placebo delivered IM followed by EP with CELLECTRA™ 5PSP at the Week 36 
visit  
Study Drug Dose 
6 mg (1 ml) 
Administration 
Intramuscular injection followed by EP with the CELLECTRA™ 5PSP 
device 
Schedule 
Day 0, Week 4, and Week 12 study visits 
No. of Subjects 
Approximately 198 subjects will be randomized in a 2:1 ratio to receive 
VGX-3100 or placebo 
Study Duration 
88 weeks 
Primary Objective 
Determine the efficacy of VGX-3100 compared with placebo with respect 
to combined histopathologic regression of cervical HSIL and virologic 
clearance of HPV-16 and/or HPV-18 
Primary Endpoint 
Proportion of subjects with no evidence of  cervical HSIL on histology 
(i.e. biopsy or excisional treatment) and no evidence of HPV-16 and/or 
HPV-18 in cervical samples by type specific HPV testing at Week 36 visit 
 
 
 
 
 
1 Terminology based on 2012 consensus recommendation on Lower Anogenital Squamous Terminology (LAST) from 
the American Society of Colposcopy and Cervical Pathology (ASCCP) and the College of American Pathologists (CAP) 
247

Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of 
VGX-3100 delivered IM followed by EP 
with CELLECTRA™ 5PSP 
1a. Incidence and severity of local and systemic 
events for 7 and 28 days following each 
investigational treatment  and for the duration of 
the study (through Week 88 visit) 
1b. Incidence and severity of serious adverse events 
and Unanticipated [Serious] Adverse Device 
Effects for 7 and 28 days following each 
investigational treatment and for the duration of 
the study (through Week 88 visit) 
2. Determine VGX-3100 efficacy compared 
to 
placebo 
as 
measured 
by 
histopathologic regression of cervical 
HSIL 
2. Proportion of subjects with no evidence of  
cervical HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 36 visit 
3. Determine VGX-3100 efficacy compared 
to placebo as measured by virologic 
clearance of HPV-16 and/or HPV-18 
3. Proportion of subjects with no evidence of 
HPV-16 and/or HPV-18 in cervical samples by 
type specific HPV testing at Week 36 visit 
4. Determine VGX-3100 efficacy compared 
to placebo as measured by complete 
histopathologic regression of cervical 
HSIL to normal 
4. Proportion of subjects with no evidence of Low 
grade squamous intraepithelial lesion (LSIL) 
or HSIL (i.e.  no evidence of CIN1, CIN2 or 
CIN3) on histology (i.e. biopsies or excisional 
treatment) at Week 36 visit 
5. Determine VGX-3100 efficacy compared 
to placebo as measured by both complete 
histopathologic regression of cervical 
HSIL to normal and virologic clearance 
of HPV-16 and/or HPV-18 
5. Proportion of subjects with no evidence of LSIL 
or HSIL (i.e. no evidence of CIN1, CIN2 or 
CIN3 on biopsies or excisional treatment) on 
histology (i.e. biopsies or excisional treatment) 
and no evidence of HPV-16 and/or HPV-18 by 
type specific HPV testing at Week 36 visit 
6. Determine VGX-3100 efficacy compared 
to 
placebo 
as 
measured 
by 
histopathologic non-progression 
6. Proportion of subjects with no progression of 
cervical HSIL to cervical carcinoma from 
baseline on histology (i.e. biopsies or excisional 
treatment) at Week 36 visit 
7. Describe the clearance of HPV-16 and/or 
HPV-18 infection from non-cervical 
anatomic locations 
7. Proportion of subjects who have cleared HPV-16 
and/or HPV-18 on specimens from non-cervical 
anatomic locations (oropharynx, vagina and 
intra-anal) at Week 36 Visit 
8. Determine the humoral and cellular 
immune 
response 
following 
administration of VGX-3100 compared 
with placebo at post dose 3, Week 36 and 
Week 88 visits compared to baseline  
8a. Levels of serum anti-HPV-16 and anti-HPV-18 
antibody concentrations at baseline, Week 15, 
36, and 88 visits 
8b. Interferon-γ ELISpot response magnitudes at 
baseline, Weeks 15, 36, and 88 visits 
8c. Flow Cytometry response magnitudes at 
baseline and Week 15 visits 
248

 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Evaluate tissue immune responses to 
VGX-3100 in cervical samples 
1. Assessment of markers including but not 
limited to CD8+ and FoxP3+ infiltrating cells. 
Additional assessments may include 
visualization of Granulysin, Perforin, CD137, 
CD103 and PD-L1 in cervical tissue as sample 
allows.  Markers listed here may change as 
new relevant information becomes available 
2. Evaluate effect of Human Leukocyte 
Antigen (HLA) type on efficacy 
2. HLA (per-locus and per-allele basis) in 
conjunction with histologic regression of 
cervical HSIL at Week 36 visit 
3. Describe association of microRNA 
(miRNA) profile, previous colposcopy, 
cytology and HPV testing results with 
Week 36 histologic regression 
3. Colposcopy, cytology, and HPV test results 
(Weeks 8, 15 and 28 visits) and miRNA profile 
(baseline, Week 8) in conjunction with 
histologic regression of cervical HSIL at Week 
36 visit 
4. Describe the durability of virologic 
clearance of HPV-16 and/or HPV-18 
for subjects treated with VGX-3100 
compared with those treated with 
placebo 
4. Proportion of subjects with no evidence of 
HPV-16 and/or HPV-18 by type specific HPV 
testing at Weeks 62 and 88 visits 
5. Describe the patient-reported outcomes 
for subjects treated with VGX-3100  
5. Patient-reported outcome questionnaires self-
administered at baseline, after each dose at 
Weeks 4, 12, 8-14 days following each dose, 
and at Weeks 28, 36, 40 and 88 by subjects 
enrolled in US, Canada, Mexico, Germany and 
UK 
Study Design: 
This Phase 3 study design is based upon the Phase 2b study design and results.  HPV-301 is a 
prospective, randomized, double-blind, placebo controlled Phase 3 study to determine the efficacy 
safety, and tolerability of VGX-3100 administered by IM injection followed by EP delivered with 
CELLECTRA™ 5PSP in adult women with histologically confirmed cervical HSIL (CIN2, CIN3) 
associated with HPV-16 and/or HPV-18 (HPV-16/18). The composite primary endpoint is histologic 
regression of cervical HSIL, and clearance of the underlying HPV-16/18 infection. A sample of 
approximately 198 subjects will be randomized to receive either 6 mg (in 1 ml) VGX-3100 or 
placebo, each IM followed by EP, in a 2:1 ratio. This sample size provides 90% power to declare 
VGX-3100 superior to placebo, assuming, based upon Phase 2b study results, that the true 
proportion of subjects whose lesion(s) regress and whose HPV-16/18 clears is 35% and 14% for 
VGX-3100 and placebo, respectively. 
To be eligible for the study, women age 18 years and above must consent to participate and have 
biopsy/biopsies of the cervical lesion(s) at the time of screening. The biopsy slides are sent to central 
249

pathology lab for Pathology Adjudication Committee (PAC) review in a blinded manner to establish 
the presence of cervical HSIL (CIN2, CIN3) prior to enrollment. Subjects must also have a cervical 
ThinPrep™ specimen test positive for HPV-16/18 by cobas™ HPV test to be eligible for participation 
in the study.  
All eligible subjects will receive three doses of VGX-3100 or placebo administered IM followed 
immediately by EP with the CELLECTRA™ 5PSP device. The first study treatment is administered 
on Day 0, the second at Week 4, and the third (final) study treatment is administered at Week 12. 
The first dose is administered as soon as possible following confirmation of the cervical HSIL 
diagnosis and cervical sample positive for HPV-16/18 but no more than 10 weeks following 
collection of the subject’s biopsy specimen used for diagnosis by the PAC during screening.  
Subjects are randomized in a stratified manner according to (a) the CIN severity observed in the 
biopsy specimens at screening (i.e. CIN2 vs. CIN3), (b) Body Mass Index (BMI) category (≤25 vs. 
>25 kg/m2), and (c) age category (<25 years vs. ≥25 years). To ensure CIN2 disease is not over-
represented in the study, the percentage of subjects enrolled with CIN2 will not exceed 50% of the 
total enrolled.  
The long term follow up plan following the Week 36 efficacy assessment will include safety, 
cytology and HPV testing for a period of approximately 1 year (Week 88). 
Efficacy: Visualization of a normal appearing cervix by colposcopy and cytology are insufficient 
evidence to confirm disease regression. Therefore, disease regression will be based on 
histopathological assessment, which is considered the definitive method for diagnosis. Subjects will 
also be assessed by colposcopy, cytology, and HPV testing at screening, and at specified visits on 
and after Day 0. Digital photographs of the cervix following application of acetic acid will also be 
used to document colposcopic exam findings. 
Tissue to be analyzed for evidence of histopathologic regression will be obtained at Week 36 either 
by excision (e.g. loop electrosurgical excision procedure (LEEP), large loop excision of 
transformation zone (LLETZ), cold knife conization (CKC)) or by biopsy (4 Quadrant Biopsy or 4 
Quadrant Biopsy with Endocervical Curettage (ECC)) based upon the assessment at Week 28 of 
cytology, High Risk (HR) HPV status, and colposcopic findings (see Tables 5 and 6, for Minimally 
Required Procedures).   
Safety: All subjects will be followed for 88 weeks. 
 
Subjects will be monitored for: 
1) Local and systemic events for 7 days following each investigational treatment as noted on a 
Participant Diary Card (PDC); 
2) All adverse events including SAEs, UADEs, and other unexpected AEs for the duration of the 
study; 
Data and Safety Monitoring Board (DSMB): The DSMB will meet quarterly to review unblinded 
safety data and histopathologic regression results. The DSMB will be charged with advising the 
Sponsor if there appears to be a safety issue and with advising the Sponsor if it appears that the 
proportion of the subjects with histopathologic regression in the VGX-3100 group is unacceptably 
low compared to the placebo group. No formal interim analysis will be performed.   
250

Immunogenicity: Humoral and cell mediated immune responses in response to VGX-3100 treatment 
may be evaluated in blood samples taken at baseline (both Screening as well as Day 0 prior to dosing) 
and at Weeks 15, 36, and 88. Cervical tissue samples may also be analyzed for evidence of elevated 
immune responses at Week 36 as compared to baseline (screening). 
Virology: Cervical cytology samples will be obtained to characterize HPV infection at Day 0 (prior 
to dosing) and at Weeks 8, 15, 28, 36, 62, and 88 by cobas™ HPV test. Additionally, if there is 
residual tissue in the paraffin block from cervical tissue after histologic diagnoses have been 
rendered at screening and Week 36, then unstained slides and/or the relevant paraffin blocks may 
be tested for the presence of HPV-16/18. Vaginal brush and oropharyngeal rinse samples will be 
obtained at Day 0 (prior to dosing), Weeks 36 and 88 while intra-anal samples will be obtained on 
Day 0 (prior to dosing) and Week 36 to characterize HPV infection.  
HLA typing: The relationship between subject HLA types and efficacy responses will be explored 
using available PBMC sample collected for immunogenicity analysis. 
Study Population 
Inclusion Criteria: 
1. Women aged 18 years and above; 
2. Confirmed cervical infection with HPV types 16 and/or 18 at screening by cobas™ HPV test;  
3. Cervical tissue specimen/slides provided to Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study drug; 
4. Histologic evidence of cervical HSIL as confirmed by PAC at screening; 
5. Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form 
prior to study-related activities; 
6. Must be judged by Investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision, 4-quadrant biopsy with ECC, or 4-quadrant biopsy) required at Week 
36; 
7. Satisfactory colposcopy at screening, defined as full visualization of the squamo-columnar 
junction (Type I or II transformation zone) and complete visualization of the upper limit of aceto-
white epithelium or suspected CIN disease; 
8. Cervical lesion that is accessible for sampling by biopsy instrument (e.g. Mini-Tischler device); 
9. Cervical lesion of adequate size to ensure that a visible lesion remains after screening biopsy; 
10. Must meet one of the following criteria with respect to their reproductive capacity: 
a) Post-menopausal as defined by spontaneous amenorrhea for more than 12 months or 
spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL; 
b) Surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 12 months prior to screening; 
c) Women of Child Bearing Potential (WOCBP) is willing to use a contraceptive method with 
failure rate of less than 1% per year when used consistently and correctly from screening 
until Week 36. The following methods are acceptable : 
o Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. Hormonal 
251

contraceptives must not be used in subjects with a history of hypercoagulability (e.g., 
deep vein thrombosis, pulmonary embolism); 
o Abstinence from penile-vaginal intercourse when this is the subject’s preferred and usual 
lifestyle; 
o Intrauterine device or intrauterine system; 
o Male partner sterilization at least 6 months prior to the female subject’s entry into the 
study, and this male is the sole partner for that subject 
11. Normal screening ECG or screening ECG with no clinically significant findings, as judged by 
the investigator. 
Exclusion Criteria: 
1. Microscopic or gross evidence of adenocarcinoma-in-situ (AIS), high grade vulvar, vaginal 
(inclusive of cervical HPV-related lesions that extend into the vaginal vault), or anal 
intraepithelial neoplasia or invasive cancer in any histopathologic specimen at screening; 
2. Cervical lesion(s) that cannot be fully visualized on colposcopy due to extension high into 
cervical canal at screening; 
3. History of ECC which showed cervical HSIL indeterminate, or insufficient for diagnosis (ECC 
is not performed as part of study screening); 
4. Treatment for cervical HSIL within 4 weeks prior to screening; 
5. Pregnant, breastfeeding or considering becoming pregnant during the study; 
6. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are 
allowed, e.g. Gardasil™, Cervarix™); 
7. Presence of any abnormal clinical screening laboratory values greater than Grade 1 per Common 
Toxicity Criteria for Adverse Events (CTCAE) v 4.03 or less than Grade 1 but deemed clinically 
significant by the investigator within 30 days prior to Day 0; 
8. Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening (performed within 30 days prior 
to Day 0) 
b) Primary immunodeficiencies 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent; (use of inhaled, otic, and ophthalmic corticosteroids are allowed); 
d) 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); 
e) History of solid organ or bone marrow transplantation; 
f) Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
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; 
9. Receipt of any non-study, non-live vaccine within 2 weeks of Day 0; 
10. Receipt of any non-study, live vaccine (e.g. measles vaccine) within 4 weeks of Day 0; 
11. Current or history of clinically significant, medically unstable disease which, in the judgment of 
the investigator, would jeopardize the safety of the subject, interfere with study assessments or 
252

endpoint evaluation, or otherwise impact the validity of the study results (e.g. chronic renal 
failure; angina, myocardial ischemia or infarction, class 3 or higher congestive heart failure, 
cardiomyopathy, or clinically significant arrhythmias); 
12. Malignancy or treatment for malignancy within 2 years of screening, with the exception of 
superficial skin cancers that only require local excision;  
13. Presence of acute or chronic bleeding or clotting disorder that would contraindicate IM 
injections, or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of 
Day 0; 
14. History of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic 
agents; 
15. Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or 
a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
16. Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at 
screening or Day 0; 
17. Prior major surgery within 4 weeks of Day 0; 
18. Participation in an interventional study with an investigational compound or device within 30 
days of signing informed consent; participation in an observational study is permitted; 
19. Less than two acceptable sites available for IM injection considering the deltoid and anterolateral 
quadriceps muscles; 
20. Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
21. Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located 
in ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 
22. Metal implants or implantable medical device within the electroporation area; 
23. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere 
with adherence to study requirements; 
24. Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of 
either a psychiatric or physical (i.e. infectious disease) illness; 
25. Active military service personnel; 
26. Study-related staff or family member of study-related staff; 
27. 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. 
 
 
253

Table 1. Schedule of Events 
Tests 
Screening 
(-10 wks to -1 Day) 
 
Weeks 
Day 0 
8-14 days post Day 0 
Phone Call 
4 (± 4 days) 
8-14 days post Wk 4 
Phone Call 
8 (± 4 days) 
12 (± 4 days) 
8-14 days post Wk 12 
Phone Call 
15 (± 1 week) 
28 (± 1 week) 
36 (± 1 week) 
40 (± 2 weeks) 
Phone call 
62 (± 2 weeks) 
88 (± 2 weeks) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behaviorala 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
Vital signs 
Xc 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
Screening safetyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Teste 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
X 
HIV Antibody Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood immunologic samplesf 
X 
X 
 
 
 
X 
 
 
Xg 
 
X 
 
 
X 
ThinPrep™ h,i 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
 
X 
X 
Cervical Digene swabsi,j 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
X 
Colposcopy, lesion 
photographyk 
Xl 
X 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
Ectocervical biopsym 
X 
 
 
 
 
 
 
 
 
 
Xn 
 
 
 
Surgical excisionm 
 
 
 
 
 
 
 
 
 
 
Xn 
 
 
 
OP rinse, vaginal swabs 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Intra-anal swabso 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Inject VGX-3100/Placebo 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Post treatment assessment 
 
X 
X 
X 
X 
X 
X 
Xq 
X 
 
 
 
 
 
Distribute PDC 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Review PDC 
 
 
X 
 
X 
X 
 
Xq 
 
 
 
 
 
 
PROsp 
 
X 
X 
X 
X 
 
X 
Xq 
 
X 
X 
X 
 
X 
 
a Socio-Behavioral assessments, e.g. self-reported smoking and alcohol history 
b Full physical examination (PE) mandatory at screening and study discharge (Week 88), otherwise targeted physical 
assessment as determined by the Investigator or per subject complaints unless signs or symptoms dictate the need for 
a full PE; 
c Screening vital signs must include a measured height and weight. Weight will be collected on Day 0, Weeks 4 and 12; 
254

d Screening safety includes 12-Lead ECG, complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), 
serum creatinine (Cr), serum glucose, serum ALT, serum CPK and urinalysis performed within 30 days prior to  Day 
0; 
e Negative spot urine pregnancy test is required at screening and prior to each study treatment, colposcopy and surgical 
excision; 
f At least 34 mL [4 x 8.5 mL yellow (ACD) tubes] whole blood and 8 mL serum per time point (a total of at least 68 mL 
of whole blood and 16 ml serum should be collected prior to dosing on Day 0). HLA testing will performed once from 
an existing PBMC sample; 
g At least 51 mL [6 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum should be collected at Week 15; 
h HPV genotyping and Pap smears are performed on the same ThinPrep™ cervical specimen; 
i Request that the subject abstain from sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to cervical specimen collection; 
j Collected prior to the ThinPrep™ sample; 
k Acetic acid should be applied to the cervix then photographs of the cervix and the associated lesion should be collected 
prior to and after biopsies and at all colposcopic examinations; 
l Screening colposcopy is optional if adequate colposcopy was performed upon collection of initial biopsy ; 
m Screening biopsy of the lesion should be collected as Paraffin-embedded cervical tissue, fresh cervical tissue, or H&E 
slides. Tissue to be analyzed for evidence of histopathologic regression will be obtained at Week 36 visit either by 
excision (e.g. LEEP,  LLETZ, CKC) or by 4 Quadrant Biopsy or 4 Quadrant Biopsy with ECC based upon the 
assessment at Week 28 of cytology, HR HPV status, and colposcopic findings (See Tables 5 and 6); 
n Slides from biopsy and/or excised tissue must be reviewed by the PAC and residual cervical tissue from screening 
and/or Week 36 specimen(s) (paraffin blocks or unstained slides) may be used for immunohistochemistry (IHC) and 
HPV testing; 
o To be collected only if subject consents for intra-anal sample collection  
p One or both PRO questionnaires (i.e. SF-36 and EQ-5D-5L) will be completed by subjects enrolled in US, Canada, 
Mexico, Germany and UK at multiple visits during the study. Refer to Section 6.8 for details 
q Activities at 8 to 14 days Post-Dose 3 phone call may be done at Week 15 if timing overlaps. 
 
 
 
 
 
 
255

1 INTRODUCTION 
1.1 
BACKGROUND  
1.1.1 
HPV INFECTION, CERVICAL INTRAEPITHELIAL NEOPLASIA AND 
CERVICAL CANCER  
Infection with human papillomavirus (HPV) can lead to malignant neoplasia, localized primarily 
in the anogenital area and aerodigestive tract, in both men and women.  HPV types tropic to 
mucosal tissues are classified into high-risk (HR), based on their potential to cause cancer, and 
low-risk (LR) (causing generally benign lesions). HPV-16 and HPV-18 are the most significant 
amongst high-risk types since they are responsible for most HPV-caused cancers [1].  In the US 
alone, approximately 14 million new genital HPV infections occur annually, and approximately 
half of these infections are with a HR HPV type [2, 3].  Up to 13000 women in the US alone are 
diagnosed with cervical cancer each year, which leads to an estimated 4120 deaths [4].  HPV-16 
is the most common high-risk genotype and combined with HPV-18 these two genotypes are 
estimated to cause about 70% of all cervical cancers [5, 6]. 
Incident infection by HPV is characterized by ongoing viral replication and shedding and is 
associated with early histologic changes (grade 1 cervical intraepithelial neoplasia) when the 
female cervix is infected with HPV.  Most cases of genital HPV infection clear spontaneously, but 
persistent infection with one or more oncogenic (high-risk) HPV genotypes can lead to the 
development of precancerous, histologic high grade squamous intraepithelial lesions of the cervix, 
HSIL which is inclusive of grade 2 and 3 cervical intraepithelial neoplasia (CIN2/3) [7].   Over 
time, typically years, cervical HSIL can progress to invasive cancer of the cervix [8, 9].  The basis 
for these changes are attributed to the viral proteins E6 and E7.  Infected cells produce E6 and E7 
constitutively which increases the degradation of cell cycle regulation proteins p53 and pRb, 
respectively, resulting in unrestricted cell growth and neoplasia.   
While the currently available prophylactic HPV vaccines (Cervarix™, Gardasil™, and Gardasil™-
9) are highly effective in preventing persistent infection and the subsequent development of high-
grade CIN caused by HPV-16, HPV-18 and other HPV types, the prophylactic vaccines have no 
therapeutic effect upon existing HPV infection or existing HPV-related intraepithelial neoplasia 
[10].  This means that the large number of women who already have high grade cervical dysplasia, 
either because they were too old to have received the prophylactic vaccine or they didn’t respond 
to vaccination, must currently only rely upon surgery and the chance of spontaneous regression to 
treat their condition and avoid progression to cancer.  Furthermore, the number of US-eligible 
teenagers who complete the prophylactic vaccination series remains low; 39.7% of US girls ages 
13-17 completed their prophylactic HPV immunization series in 2014, which leaves a potentially 
vulnerable, under-protected population [11]. The current approaches to the management of 
cervical HSIL typically require surgery (i.e. LEEP/LEETZ, laser ablation, or conization); 
however, surgical excision does not necessarily address the underlying HPV-infection, and can 
adversely impact the reproductive health of women of childbearing age.  Therefore, VGX-3100 is 
being developed as a non-surgical therapeutic option for the precancerous precursor to cervical 
cancer, cervical HSIL, and the underlying, pathogenic HPV infection.  
 
256

1.1.2 
VGX-3100 
VGX-3100 contains plasmids that target HPV-16 E6/E7 and HPV-18 E6/E7 antigens. The 
plasmids were designed and constructed using proprietary synthetic vaccine (SynCon™) 
technology. This process involves synthetically deriving consensus genes across multiple strains 
and optimizing DNA inserts at the genetic level to allow high expression in human cells. Together, 
VGX-3100 and the CELLECTRA™ device represent an integrated investigational product 
designed as a non-surgical treatment of HPV-16/18-related cervical HSIL (CIN2, CIN3) via an 
immune response directed against HPV-16/18. 
The initial formulation of VGX-3100 was water for injection with 1% w/w poly-L-glutamate 
(WFI/LGS) that required frozen storage.  This WFI/LGS formulation has been administered to 
more than 250 subjects in Phase 1 and 2 clinical trials. A buffered formulation of VGX-31002 was 
developed using a saline sodium citrate (SSC) solution, which is stored non-frozen (5°C). This 
SSC formulation of VGX-3100 was administered to 116 subjects in a Phase 1 clinical trial, HPV-
101. In study HPV-101, three 6 mg doses of VGX-3100 as the SSC formulation were delivered 
IM followed by EP with CELLECTRA™ 5P to healthy adults.  Based upon interim analysis data 
at study Week 14, the SSC formulation is considered non-inferior to the WFI/LGS formulation 
based upon a 2-fold rise in overall Spot Forming Units (SPU) to the antigens encoded by the 
plasmids per 106 Peripheral Blood Mononuclear Cells (PBMC) as measured from baseline to 
Week 14 using the interferon-γ ELISpot assay.
Proof of concept was demonstrated in the prospective, randomized, double blind, placebo-
controlled Phase 2b study of VGX-3100 (WFI/LGS formulation) followed by EP in the treatment 
of high grade cervical dysplasia, cervical HSIL associated with HPV-16 and/or HPV-18.  The 
Phase 2b study, HPV-003, enrolled 167 subjects with high grade cervical dysplasia from seven 
countries and one United States Territory (Australia, Canada, Estonia, Republic of Georgia, India, 
South Africa, United States and Puerto Rico). Subjects were randomized in a 3:1 ratio to the 
treatment arm (VGX-3100, WFI/LGS formulation) or the placebo arm, respectively. All subjects 
were to receive treatment on Day 0, Week 4 and Week 12. All subjects were to repeat cervical 
biopsy or LEEP of the cervix at Week 36 to assess efficacy defined as regression of high grade 
CIN by histopathology.   The primary endpoint was histopathologic regression of cervical lesions 
(CIN2 or CIN3) to CIN1 or less at the Week 36 visit.   A secondary endpoint was clearance of 
HPV-16/18 in combination with histopathologic regression of cervical lesions to CIN1 or less. 
The proportions of subjects who met the primary and secondary endpoints were significantly 
higher in the VGX-3100 group vs. placebo in both per protocol and modified intent to treat 
analyses.  Robust T-cell activity was detected in VGX-3100 recipients compared to placebo 
recipients. VGX-3100 was generally safe and well tolerated when administered intramuscularly 
with electroporation.  
1.1.3 
ELECTROPORATION 
VGX-3100 is delivered using the CELLECTRA™ in vivo electroporation (EP) device. EP is a 
physical method of tissue transfection whereby the generation of short, controlled electrical pulses 
2 Designated in earlier version of the HPV-301 protocol as VGX-3100X 
257

creates a localized electric field at the injection site of the DNA vaccine which increases cell 
membrane permeability and improves the transfection of DNA and subsequent immunogenicity  
[12, 13]. EP is believed to increase the uptake and processing of plasmid DNA, thereby enabling 
increased expression and enhanced vaccine immunogenicity by 10 to 100 fold [14, 15]. This 
technology has been used for more than three decades by molecular biologists for cell transfection 
and has demonstrated versatility in use, as shown by its functionality in combination with a range 
of molecules, tissue types, disease indications, and across species [16]. 
The CELLECTRA™ device developed by Inovio is used for investigational purposes to administer 
plasmid-based DNA, in both prophylactic and therapeutic settings. Following successful proof-
of-concept studies in animals, Inovio has optimized both pulse pattern and voltage to increase 
transfection efficiency, and has demonstrated that the device helps to elicit favorable 
immunogenicity in several species (e.g., mice, pigs, and rhesus macaques) [17, 18].  
VGX-3100, WFI/LGS formulation, has been administered throughout Phase 1 and Phase 2 
investigations with the CELLECTRA™ 2000 device. A next generation device, CELLECTRA™ 
5PSP, will be used in Phase 3. Both designs of the CELLECTRA™ device enhance the 
intracellular uptake of VGX-3100 by the delivery of electrical current, and the electrical current 
delivery and pulse pattern (electroporation) is identical in both designs. CELLECTRA™ 2000 
involves a manual injection of VGX-3100 while the CELLECTRA™ 5PSP device will automate 
the intramuscular delivery of VGX-3100 and delivery of the EP pulses triggered by a single button 
press. Neither the dosage nor volume of VGX-3100 administered differs between the two devices. 
Administration of VGX-3100 with the CELLECTRA™ 5PSP also allows selection of the array 
needle length (13, 19 or 25 mm) depending on the estimate of the recipient’s subcutaneous fat and 
muscle tissue.  
The technology differences between the CELLECTRA™ 2000 and CELLECTRA™ 5PSP design 
(Table 2) are not significant and do not present any new risks. The device design change does not 
affect the indications for use, operating principle, energy type, environmental specifications, and 
sterilization or performance specifications. The material changes are to the outer housing of the 
device and not to patient-contacting materials.  
258

Table 2. Comparative Device Overview 
 
CELLECTRA™ 5PSP 
CELLECTRA™ 2000 
Array Specifications 
Electrode Number and Material 
(no bore) 
5 Stainless steel, 304 electrodes 
pentagonal arrangement 
5 Stainless steel, 304 electrodes 
pentagonal arrangement 
Electrode Length 
1.555 ± 0.020” (39.5mm) 
1.555 ± 0.020” (39.5mm) 
Electrode Gauge 
22 Gauge (0.0278-0.0280 inch diameter) 22 Gauge (0.028±0.001 inch diameter) 
Electrode Trocar Tip 
15 ± 2° 
15 ± 2° 
Array Housing 
Bayer Makrolon 2458C and Loctite 
3921 
GE Plastics (Sabic) Lexan HPS2 
Sterilization Method and Sterility 
Assurance Level (SAL) 
Gamma Irradiation 25-40kGy SAL 10-6 
Gamma Irradiation 25-40kGy 
SAL 10-6 
VGX-3100 IM Injection Method 
Automated (Handset mediated) 
Manual (needle and syringe) 
Injection Needle Material (full bore) 
Stainless steel, 304 
Stainless steel, 304 
Injection Needle Length 
2.102 ± 0.020” (54.4mm) 
2.0” hypodermic needle recommended 
Injection Needle Gauge 
21 Gauge (0.03250-0.03200 inch 
diameter) 
21 Gauge 
Injection Needle Trocar Tip 
15° (double ended) 
15° (single ended) 
VGX-3100 IM Injection Depth 
13, 19 and 25 mm 
13,19 and 25 mm 
VGX-3100 IM Injection Volume 
1.0±0.1mL 
1.0±0.1mL 
Electroporation Parameters 
Voltage delivered to subject tissue 
40-200 V maximum (varies with subject 
tissue impedance) 
40-200 V maximum (varies with subject 
tissue impedance) 
Pulse Width 
52 milliseconds (ms) 
52 milliseconds (ms) 
Pulse Current 
0.5 A; 1.0 A max 
0.5 A ; 1.0 A max 
Maximum Phase Charge 
Maximum Delivered Charge  = 
78mC (max) = 0.5A x 0.052 seconds x 3 
pulses 
Maximum Delivered Charge  = 
78mC (max) = 0.5A x 0.052 seconds x 3 
pulses 
Frequency 
Pulses initiated at 1.0 second intervals 
Pulses initiated at 1.0 second intervals 
Benchtop design verification testing and a non-significant risk device functionality study will be 
completed prior to Phase 3 to support that the dimensional changes, change to the ergonomics of the 
patient user interface and injection method result in the CELLECTRA™ 5PSP device design meeting 
its safety and performance specifications, and no change to the administration of VGX-3100 by 
electroporation. Inovio’s device experience demonstrates that delivery of electroporation pulses into 
muscle immediately following injection of DNA plasmids is well-tolerated in humans and no 
significant safety issues have been identified [19-21].  
 
259

1.1.4 
SELECTION OF STUDY DESIGN 
This Phase 3 study employs a prospective, randomized, double-blind, placebo controlled study 
design to further demonstrate the safety and efficacy of VGX-3100 followed by EP in women with 
cervical HSIL associated with HPV-16/18.  The primary clinical hypothesis is that VGX-3100 is 
a surgery-sparing, therapeutic option for the treatment of cervical HSIL and the underlying, 
pathogenic HPV-16/18 infection, which is supported by the findings of the Phase 2b trial. A 
placebo-controlled study is selected for this trial because it provides scientific rigor to distinguish 
an effective treatment, particularly in cervical HSIL for which spontaneous regression does occur. 
1.2 
 DOSE AND REGIMEN RATIONALE  
A total dose of 6 mg VGX-3100 DNA has been selected for this study based on previous human 
experience with both the WFI/LGS and SSC formulations of VGX-3100, preclinical data with VGX-
3100 and other DNA vaccines, and the safety and immunogenicity data generated in the HPV-001, 
HPV-003, and HPV-101 studies. In HPV-001 trial, the 6 mg dose was delivered IM followed by EP, 
which showed trends toward higher response rates and magnitudes of IFN-γ ELISpot responses 
compared to the low (0.6 mg) and mid-dose (2 mg) cohorts (Table 3) without significant safety 
issues [19].  
This dose-trend was consistent with prior expectation, a feature of the finding that suggests it is a 
true effect rather than random variation. Adverse events from previous human studies with VGX-
3100 (frozen formulation) and closely related DNA plasmid products have been limited to injection 
site pain from the injection and electroporation procedure, which were not clinically meaningful. 
Based on the information above, the 6 mg dose was selected for study in the Phase 2b study. The 
results obtained in the phase 2 study suggest that the 6 mg dose was efficacious with an acceptable 
safety profile, therefore the 6 mg dose will also be evaluated in this Phase 3 trial. 
Table 3. Percent of Protocol HPV-001 Subjects Responding and Average SFU/106 PBMC in 
Responders for each Antigen by Cohort in Interferon-γ ELISpot  
Cohort 
Low 
Mid 
High 
Antigen 
%Response 
AVG 
%Response 
AVG 
%Response 
AVG 
HPV-16E6 
33% 
107 
50% 
243 
50% 
1341 
HPV-16E7 
17% 
198 
50% 
104 
67% 
143 
HPV-18E6 
50% 
359 
50% 
338 
83% 
664 
HPV-18E7 
33% 
159 
17% 
179 
50% 
834 
Any 
67% 
221 
67% 
210 
83% 
556 
260

1.3 
RISKS/BENEFIT ASSESSMENT 
1.3.1 
RISKS ASSOCIATED WITH CURRENT THERAPEUTIC OPTIONS 
Currently, treatment of women with cervical HSIL usually consists of either surgical removal of 
the affected tissue by CKC, LEEP, ablative therapy via laser, or cryotherapy.  All treatments for 
cervical HSIL are associated with a variety of short and long term general and reproductive health 
risks as listed in Table 4. 
Table 4. Risks Associated with Surgical Treatments for Cervical HSIL 
Surgical Treatments for 
Cervical HSIL 
Risks 
CKC 
LEEP 
Ablative therapy (Laser or 
Cryotherapy)  
Pain 
Exposure to anesthesia 
Heavy bleeding 
Infection 
Menstruation problems 
Cervical stenosis (can lead to alteration of squamo-columnar junction) 
Shortening of the cervix 
Decreased fertility/difficulty getting pregnant 
Cervical incompetence 
Pre-term birth and related low birth weight 
Incomplete treatment of cervical dysplasia 
Inadequate treatment of an occult early invasive cancer 
Adapted from FAQs Loop Electrosurgical Excision Procedure (LEEP) American College of Obstetricians and 
Gynecologists (2014) [11]. 
More importantly, none of the currently available surgical treatments for cervical HSIL eradicate 
the underlying cause of the high grade cervical dysplasia, persistent infection with one or more of 
the high-risk HPV types, and therefore, leaves patients at risk for recurrent cervical HSIL as well 
as high grade dysplasia of the vulva and vagina due to the potentially broader infection of the 
genitourinary area. 
Although professional guidelines typically advocate immediate excisional therapy for adults with 
cervical HSIL, scientific data indicates that the rate of progression from pre-invasive to invasive 
cervical disease is slow, typically thought to take several years [8].  The risk of a “missed 
diagnosis” of an occult early invasive cervical cancer exists for all current treatment modalities 
including surgical and ablative therapies.  Furthermore, approximately 17-18% of patients with 
high grade CIN will experience recurrence of dysplasia following surgical intervention [8], which 
illustrates that current standard of care for cervical dysplasia requires improvement.  The study 
design includes numerous safeguards to detect disease progression or the presence of an 
undiagnosed occult early invasive cervical cancer.  These include, careful selection of 
immunocompetent patients, thorough screening and baseline evaluation, frequent cervical 
colposcopy, cytology and high-risk HPV testing throughout the trial.  Investigators will be 
261

comprised of experienced gynecologists, who will have the discretion to obtain biopsies at any 
point if disease progression is suspected. 
1.3.2 
POTENTIAL RISKS OF STUDY PARTICIPATION 
A risk associated with VGX-3100 for the treatment of high grade cervical dysplasia are the 
injection site reactions related to the IM injection and/or electroporation.  Based on the phase 1 
and 2 clinical experience, the injection site reactions associated with the IM injection and 
electroporation are generally mild (e.g. erythema) and limited to a few days in duration at most.   
A second risk is the “delay” in “definitive treatment” of the high grade cervical dysplasia and the 
“missed diagnosis” of an occult early invasive cervical cancer for the VGX-3100 non-responders 
or placebo recipients, who do not spontaneously regress.  This risk is mitigated by careful serial 
cytology, HPV testing, and colposcopic exams, throughout the course of the study, and the well 
accepted understanding that cervical dysplasia progresses slowly, typically over years, which 
makes close, active follow-up possible.  Also, only investigators who are experienced in the 
management of cervical cancer will be chosen, and they will have the option of performing 
additional, ad hoc colposcopic exams and cervical biopsies if they suspect potential disease 
progression.  
A DSMB will also advise the Sponsor if it appears that the frequency of regression in the VGX-
3100 group is unacceptably low compared to the placebo group.  These measures should 
minimize the risk - even perhaps below that of standard care - of progression of the cervical HSIL 
and the risk of harboring an undiagnosed occult early invasive cervical cancer. All subjects with 
suggestion of residual disease will undergo excisional therapy (e.g. CKC, LLETZ, LEEP) at 
Week 36 as part of the efficacy assessment.  Subjects whose cytology, HPV testing, ECC results 
(if applicable) and colposcopic exam suggest disease regression will undergo 4 quadrant biopsy 
or 4 quadrant biopsy with ECC (based upon Tables 5 & 6) to provide histopathologic 
confirmation of regression. In the Phase 2b study, the rate at which microinvasive cancer was 
found in larger surgical excision samples in subjects who had no evidence of invasive cancer by 
initial biopsy was 1.8%, (2/114 with specimens), which is consistent with and even lower than 
the rate of 6.7% that has been reported under standard of care settings [22]. 
1.3.3 
POTENTIAL BENEFITS OF STUDY PARTICIPATION 
All currently accepted treatments for high grade cervical dysplasia are surgical procedures (LEEP, 
CKC, Laser ablation) which are all associated with risks inherent with any surgical procedure 
including anesthesia, post-operative bleeding and/or infection, damage to other organs, shortening 
and/or deformation of the cervix, pain, etc.  Due to the risk of shortening and/or deformation of 
the cervix there are additional well accepted risks including cervical stenosis, infertility, cervical 
incompetence, preterm birth, and inability to visualize the transformation zone.  Additionally, none 
of the surgical treatments systemically address the underlying oncogenic root cause, the high risk 
HPV infection in the lower genital tract, which leaves an underlying risk for further disease 
manifestations and transmission of HPV. VGX-3100+ EP is not associated with any of the risks 
associated with the surgical procedures outlined above (except for pain, which is transient and 
restricted to the deltoid/quadriceps treatment site) and has demonstrated the ability to not only 
eradicate the high grade dysplasia but also the ability to eradicate the underlying HPV infection.  
262

Subjects receiving placebo, who represent women of child-bearing potential, may benefit from the 
opportunity to be closely managed under careful surveillance over the course of this study and 
those who regress spontaneously will be able to avoid excisional therapy. 
2 STUDY DESIGN 
This Phase 3 study design is based upon the Phase 2b study design and results. HPV-301 is a 
prospective, randomized, double-blind, placebo controlled study to determine the efficacy, safety, 
and tolerability of VGX-3100 administered by IM injection followed by EP delivered with 
CELLECTRA™ 5PSP in adult women with histologically confirmed cervical HSIL (CIN2, CIN3) 
associated with HPV-16/18. 
A sample of approximately 198 subjects will be randomized to receive either 6 mg (in 1 ml) VGX-
3100 or placebo, each IM followed by EP, in a 2:1 ratio. This sample size provides 90% power to 
declare VGX-3100 superior to placebo, assuming, based upon Phase 2b study results, that the true 
proportion of subjects whose lesion(s) regress and whose HPV-16/18 clears is 35% and 14% for 
VGX-3100 and placebo, respectively.  
Subjects will be randomized in a stratified manner according to (a) the CIN severity observed in the 
biopsy specimens at screening (i.e. CIN2 vs. CIN3), (b) BMI category (≤25 vs. >25 kg/m2), and (c) 
age category (<25 years vs. ≥25 years). To ensure CIN2 disease is not over-represented in the study, 
the percentage of subjects enrolled with CIN2 will not exceed 50% of the total enrolled. 
To be eligible for the study, subjects age 18 years and above must consent to participate and have 
cervical biopsy/biopsies of the cervical lesion(s) at the time of screening. Slides of the biopsy will 
be sent to a PAC in a blinded manner to establish the presence of cervical HSIL within screening. 
In order to be eligible for continued enrollment, the PAC must assign the histologic diagnosis of 
cervical HSIL. Subjects must also have a cervical specimen test positive for HPV-16/18 by cobas™ 
HPV test to be eligible for participation in the study. 
2.1 
ENDPOINT ASSESSMENT 
In the Phase 2b study, subjects were randomized 3:1 to the VGX-3100 frozen formulation arm or 
the Placebo arm. All subjects were scheduled to receive treatment on Day 0, Week 4 and Week 12 
and undergo repeat cervical biopsy or surgical excision (i.e. LEEP, LLETZ, CKC) of the cervix at 
Week 36 to assess efficacy. The primary endpoint was histopathologic regression of cervical lesions 
to CIN1 or less at the Week 36 visit, and the secondary endpoint was clearance of HPV-16/18 in 
combination with histopathologic regression of cervical lesions to CIN1 or less.     
The primary endpoint for the Phase 3 study is based upon the results of the Phase 2b study.  Given 
that HPV persistence is an important factor in the clinical progression of dysplasia and also based 
upon the findings of the secondary objective of the Phase 2b study, the responder definition for the 
Phase 3 primary endpoint determination will take into consideration both histological regression of 
cervical HSIL and clearance of high-risk HPV-16/18.  
The proportion of subjects who achieved this endpoint in the Phase 2b study was 35% (40%) of 
VGX-3100 subjects versus 14% (15%) for placebo, in an intention-to-treat analysis and modified 
intention-to-treat analysis, respectively.  The composite endpoint of histologic regression and 
263

virologic clearance will be primary in the Phase 3 study, and histologic regression endpoint will be 
a secondary endpoint. 
2.1.1 
HISTOLOGY ASSESSMENT 
Regression of cervical HSIL will be determined by histopathological assessment of cervical tissue, 
which is considered the definitive method for diagnosis of cervical dysplasia. Digital photographs 
of acetowhite lesions are also used to document colposcopic exam findings. Tissue to be analyzed 
for evidence of histopathologic regression will be is obtained at Week 36 either by excision (e.g. 
LEEP, LLETZ, CKC) or by 4 Quadrant Biopsy or by 4 Quadrant Biopsy with ECC based upon 
the assessment at Week 28 of cytology, HR HPV status, and colposcopic findings as outlined in 
Tables 5 and 6 for subjects 25 years and above and below 25 years, respectively. 
264

Table 5.  Minimally Required Procedure at Week 36 for Subjects Age 25 Years and Above  
Age 
Clinical and Laboratory Information at Week 28 
Minimally Required 
Procedure at Week 36a 
Colposcopy 
Cytology 
HPV-16/18 
Testing 
Quality 
Finding 
25 
and 
above 
NA 
NA 
HSIL, ASC-H, AGC, 
Carcinoma, AIS 
NA 
Tissue Excision 
unsatisfactory 
lesion 
NA 
NA 
Tissue Excision 
unsatisfactory 
no lesion 
LSIL, ASC-US 
positive 
Tissue Excision 
unsatisfactory 
no lesion 
LSIL, ASC-US 
negative 
4Q biopsy and ECC 
unsatisfactory 
no lesion 
NILM 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
LSIL, ASC-US 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
positive 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
negative 
4Q biopsy 
Table 6.  Minimally Required Procedure at Week 36 for Subjects Under 25 Years  
Age 
Clinical and Laboratory Information at Week 28 
Minimally Required 
Procedure at Week 36a 
Colposcopy 
Cytology 
HPV-16/18 
Testing 
Quality 
Finding 
18-24 
NA 
NA 
Carcinoma, AIS 
NA 
Tissue Excision 
unsatisfactory 
lesion 
NA 
NA 
Tissue Excision 
unsatisfactory 
no lesion 
HSIL, ASC-H, AGC 
NA 
Tissue Excision 
unsatisfactory 
no lesion 
NILM, ASC-US, LSIL 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
LSIL, ASC-US, HSIL, 
ASC-H, AGCb 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
positive 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
negative 
4Q biopsy 
Abbreviations: NA; not applicable because there is no impact to the decision at Week 36 due to a superseding finding; 4Q; 
four quadrant; NILM Negative for intraepithelial lesion and malignancy; ASC-US Atypical squamous cells of undetermined 
significance; AGC Atypical glandular cells; ASC-H Atypical squamous cells, cannot rule out high-grade lesion; AIS 
Adenocarcinoma-in-situ 
a any subject with prior ECC requires a negative ECC at Week 28 to allow 4Q biopsy and ECC, at minimum, at Week 36   
b if cytology result is AGC “favor neoplasia”, tissue excision is recommended 
2.1.2 
VIROLOGIC (HPV) ASSESSMENT 
Cervical cytology samples will be obtained to characterize HPV infection at screening, Day 0 
(prior to dosing) and Weeks 8, 15, 28, 36, 62, and 88.  Also, if there is residual tissue in the paraffin 
block after histologic diagnoses have been rendered, then unstained slides and/or the relevant 
paraffin blocks may be collected for testing of HPV-16/18. Vaginal and oropharyngeal samples 
will be obtained to characterize HPV infection at Day 0 (prior to dosing) and at Weeks 36, and 88 
to assess virologic response to treatment at sites other than the cervix. Intra-anal samples will be 
265

obtained (if subject consents to intra-anal sampling) to characterize HPV infection at Day 0 (prior 
to dosing) and at Week 36 to assess virologic response to treatment at sites other than the cervix. 
2.1.3 
DEFINITION OF RESPONDER AND NON-RESPONDER 
Responder and non-responder definitions (Table 7) for the primary endpoint takes into account 
both histopathologic regression of cervical HSIL and virologic (HPV-16 and/or HPV-18) 
clearance from cervical samples since HPV persistence is an important factor in the clinical 
progression of HSIL. The responder definition also excludes subjects whose cervix is biopsied at 
any time after their initial biopsy to determine eligibility and the Week 36 endpoint tissue 
collection. This exclusion is included to reduce the potential for artefactual increases in the 
treatment effect caused by removal of HSIL tissue and potentially HPV-16/-18 by unplanned 
interval biopsies.  To qualify as a responder, the subject must have: 1) an acceptable histology 
specimen at Week 36, which is interpretable by the independent PAC, and 2) an acceptable HPV 
ThinPrep™ sample at Week 36, with an associated valid HPV-testing result.  A responder is 
defined as a subject with: 1) no histologic evidence of cervical HSIL and 2) no evidence of HPV-
16 or HPV-18 at the Week 36 evaluation.  Also, to be considered a responder, the subject must 
not have had an unscheduled cervical tissue sample obtained after study entry and the Week 36 
visit.  Conversely, any subject with: 1) histologic evidence of cervical HSIL at the Week 36 
evaluation, OR 2) evidence of HPV-16 or HPV-18 at the Week 36 visit, OR 3) a cervical tissue 
sample obtained after study entry and the Week 36 visit OR 4) no Week 36 visit sample will be 
designated as a non-responder.   
Table 7.  Definition of Primary Endpoint Responder  and Non-Responder 
Responder 
Non-Responder 
Subject with no histologic evidence of cervical 
HSILa at Week 36 evaluation and no evidence of 
HPV-16 and/or HPV-18 at Week 36b  
AND 
Subject in which a cervical tissue sample was NOT 
obtained between collection of tissue to determine 
entry eligibility up to Week 36 primary endpoint visit 
Subject with histologic evidence of cervical HSIL, AIS, 
cervical carcinoma at Week 36 evaluation  
OR 
Subject with evidence of HPV-16 or HPV-18 at Week 36 
OR 
Subject in which an additional cervical tissue sample was 
obtained between collection of tissue to determine entry 
eligibility up to Week 36 primary endpoint visit 
OR 
Subject with no Week 36 primary endpoint sample result 
a no evidence of HSIL is defined by histology as negative, squamous atypia, or LSIL 
b the histopathologic efficacy time frame is defined by those who have undergone a biopsy or surgical excision at 
any time starting from 14 days prior to the protocol-specified target date of Week 36 
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2.1.4 
 IMMUNOGENICITY ASSESSMENT 
Humoral and cell mediated immune responses in response to VGX-3100 treatment may be 
evaluated in blood samples taken at baseline (both screening as well as Day 0 prior to dosing) and 
at Weeks 15, 36, and 88. Cervical tissue samples may also be analyzed for evidence of elevated 
immune responses at Week 36 as compared to baseline (screening).   
If there is residual tissue in the paraffin block after histologic diagnoses have been rendered, then 
unstained slides and/or the relevant paraffin blocks may be collected for immunohistochemistry 
(IHC). Whenever possible, these studies may be performed on tissue sections from the diagnostic 
screening biopsy (pre-dose) and from tissue obtained post-dose(s) (Week 36). 
2.2 
TREATMENT PLAN 
The three dose regimen of VGX-3100 appeared to be safe and well tolerated in the Phase 2b study, 
therefore all eligible subjects who consent to participate in the Phase 3 study will receive the same 
three 6 mg doses of VGX-3100 refrigerated formulation or placebo administered in 1 mL IM 
(deltoid, preferred site, or anterolateral quadriceps, alternate site), each followed immediately by EP 
with the CELLECTRA™ 5PSP device. The first study treatment will be administered on Day 0, the 
second at Week 4, and the third (final) study treatment will be administered at Week 12 which is 
consistent with the Phase 2b study. The first study treatment will be given as soon as possible 
following confirmation of the cervical HSIL diagnosis and HPV-16/18 status but no more than 10 
weeks following collection of the subject’s biopsy specimen used for diagnosis by the PAC during 
screening, contemporaneous with the positive testing for HPV-16/18. 
2.3 
SAFETY MONITORING PLAN 
Although cervical HSIL is thought to require years to progress to cervical cancer, subjects in the 
Phase 2b study were followed closely throughout. HPV testing (Weeks 14 and 24), cytology (Week 
14) and colposcopy (Week 24) were all mandatory during the observation period prior to obtaining 
tissue for determination of the primary histologic endpoint at Week 36. Investigators were also 
instructed to perform additional testing (including biopsy) if disease progression was suspected. 
These instances were infrequent as only 11 unscheduled biopsies were deemed necessary over the 
course of the Phase 2b study. In addition, the rate at which occult microinvasive cancer was 
discovered after 36 weeks was less frequent than what is reported in the literature [22]. Both 
observations would imply that the mandatory monitoring employed in the Phase 2b study was 
sufficient; however cervical disease will be monitored even more closely in this Phase 3 study. 
Colposcopy, cytology and HPV testing will be required at 8 to 14 week intervals throughout the 
observation period leading up to the primary endpoint 36 weeks after the first dose. Although less 
frequent monitoring may be adequate, the more frequent monitoring is designed to afford an even 
wider margin of safety and an opportunity to explore predictors of efficacy.     
Safety monitoring will include: 
• Local and systemic events for 7 days following each treatment as noted on a Participant Diary 
Card (PDC). 
• All adverse events including SAEs, UADEs, and other unexpected AEs for the duration of the 
study; 
267

In the Phase 2b study, the safety profile was carefully evaluated and treatment with VGX-3100 was 
well-tolerated based on observations through Week 88 in all subjects. The most common adverse 
events were administration-site reactions, which included pain, tenderness, erythema and swelling, 
and were generally mild and limited to a few days in duration.  Only erythema showed a statistically 
higher incidence in VGX-3100 (78%) vs. placebo (57%) in the 7- and 28-day periods after a dose. 
One additional AE, sinusitis, was also statistically significantly increased over the course of the 
entire study period but resolved without sequelae in the VGX-3100 arm compared to the Placebo 
arm (10% vs. 0%).      
As outlined above, safety monitoring and visit frequency has been designed to take into account the 
potential risk of delay in the usual treatment of the high grade cervical dysplasia and also the 
potential for a missed diagnosis of an occult early invasive cervical cancer for the VGX-3100 non-
responders or placebo recipients, who do not regress.  Serial cytology, HPV testing, and colposcopic 
exams are applied throughout the course of the study with the well accepted understanding that 
cervical dysplasia progresses slowly, typically over years, which makes close, active follow-up 
possible.  All subjects with suggestion of residual disease will undergo excisional therapy by LEEP 
or CKC at Week 36 as part of the efficacy assessment.  Subjects whose cytology, HPV testing, ECC 
results (if applicable) and colposcopic exam suggest disease regression will undergo 4 quadrant 
biopsy or 4 quadrant biopsy with ECC (based upon Table 5 and 6) to provide histopathologic 
confirmation of regression. The use of a 4 quadrant biopsy in Phase 3 is a change from the approach 
used in Phase 2b to optimize the evaluation of histopathologic regression taking into consideration 
the inherent limitations of colposcopy and tissue biopsy samples in the absence of visible lesions 
[23].  
In the Phase 2b study, the cervical tissue sample was initially read by a local pathologist and/or 
central pathology laboratory for rapid local medical management.  The definitive histopathologic 
assessment was determined by an independent blinded Pathology Adjudication Panel, comprised of 
experienced cytopathologists from independent medical centers in the US.  Seven reports included 
the terms ‘(adeno)squamous cell carcinoma’ or the premalignant condition of ‘adenocarcinoma in 
situ’ (AIS) in the final Phase 2b study results which included all 88 weeks of follow up. Three of 
the cases were reported as AIS, (2 VGX-3100, 1 placebo), out of which two cases (1 VGX-3100, 1 
placebo) were confirmed as AIS by the Pathology Adjudication Panel. AIS is a pre-invasive 
glandular lesion which can be difficult to capture on standard of care screening with initial punch 
biopsy and is more commonly identified by full excision (e.g. LEEP, conization).  There were four 
reports that included the term squamous cell carcinoma, of which two were confirmed by the 
Pathology Adjudication Panel, both in the VGX-3100 group.  The other two cases (1 VGX-3100, 1 
placebo) were diagnosed as CIN3 by the Pathology Adjudication Panel.  The rate at which 
microinvasive cancer was found in larger surgical excision samples in subjects who had no evidence 
of invasive cancer by initial biopsy was 1.8%, (2/114 with specimens), which is consistent with and 
even lower than the rate of 6.7% that has been reported under standard of care settings [22].  
Importantly, investigators in the Phase 3 study will be chosen only if they are experienced in the 
management of cervical cancer as was the case in the Phase 2b study. Phase 3 investigators are 
instructed to perform additional, ad hoc colposcopic exams and cervical biopsies if they suspect 
potential disease progression. Subjects that undergo an unscheduled biopsy will be classified as a 
268

non-responder in the efficacy analysis as outlined in Table 6. These measures should minimize the 
risk of progression of cervical HSIL and the risk of harboring an undiagnosed occult early invasive 
cervical cancer. The frequency of close monitoring by experienced investigators should minimize 
the risk of cancer progression on the study what is expected with standard of care.   
2.3.1 
DATA AND SAFETY MONITORING BOARD (DSMB) 
An independent Data and Safety Monitoring Board (DSMB) will provide safety oversight.  The 
DSMB will be scheduled to meet quarterly. If there are no new safety data or regression/clearance 
results to review for a quarterly scheduled meeting the DSMB will be notified and the meeting 
may be cancelled; ad hoc meetings may be scheduled to review new data as applicable. The DSMB 
will be charged with advising the Sponsor if there appears to be a safety issue and with advising 
the Sponsor if it appears that the proportion of the subjects with regression in the VGX-3100 group 
is unacceptably low compared to the placebo group. However, no formal interim analysis will be 
performed. 
2.4 
LONG TERM FOLLOW UP PLAN 
In the Phase 2b study, all subjects were scheduled to be followed for 1 year after the histopathologic 
assessment for the primary endpoint (to study Week 88). The establishment of efficacy based on 
histopathologic evidence dictated the removal of tissue at week 36 by either punch biopsy (ies) or 
more extensive surgical resection (i.e. LEEP, CKC). Subjects with colposcopic evidence of residual 
disease were to undergo LEEP/CKC. A higher proportion of patients who received placebo had a 
LEEP performed than those who received VGX-3100 (Table 8). 
Cytology and HPV-16/18 clearance from the cervix was to be assessed at study Weeks 62 and 88 to 
evaluate for recurrence of dysplasia and HPV infection after removal of tissue at Week 36.  Overall, 
in the phase 2b study, the majority of subjects had improved cytology and had cleared their 
underlying HPV-16/18 cervical infection by the Week 62 and 88 visits. For Weeks 62 and 88, there 
were no clinically meaningful differences noted between the subjects who received an excisional 
treatment (e.g. LEEP, CKC) and those that showed histopathologic regression and therefore only 
underwent a biopsy, as shown in Table 8 which summarizes the HPV and cytology results following 
Week 36.  
269

Table 8.  HPV-003 HPV and Cytology Results at Weeks 36, 62 and 88, mITT Population 
Week
Testa
VGX-3100
Placebo
LEEP/CKCb
%(n/N)
Biopsyc
%(n/N)
LEEP/CKC
%(n/N)
Biopsy
%(n/N)
36
HPV
41% (19/46)
63% (36/57)
29% (6/21)
29% (5/17)
36
Pap
NA
NA
NA
NA
62
HPV
89% (50/56)
82% (42/51)
96% (27/28)
82% (9/11)
62
Pap
93% (52/56)
100% (51/51)
93% (26/28)
82% (9/11)
88
HPV
89% (48/54)
89% (42/47)
89% (24/27)
100% (10/10)
88
Pap
96% (52/54)
91% (43/47)
85% (23/26)
100% (11/11)
Abbreviations: NA, not applicable, Pap smear was not done at Week 36
a  HPV =  HPV-16/18 testing; Pap = cytology testing 
b LEEP or CKC done, at or before the study week as specified 
c Only biopsy done, at or before the study week as specified
Clearance of HPV-16/18 from the cervix was observed in both treatment groups (Figure 1a) at 
similar rates until after the second dose when clearance in the VGX-3100 recipients continued to 
rise while the rate appeared to plateau in the placebo group. 
Figure 1.  HPV-16/18 Clearance and Pap Smear Findings in Phase 2b mITT Population by 
Treatment Group
At Week 36, clearance was significantly higher among VGX-3100 subjects that had biopsy (63%) 
versus LEEP/CKC (41%), which likely reflects the association between clearance of the underlying 
HPV infection and the likelihood of having signs indicative of regression by colposcopic 
exam. HPV-16/18 clearance data (mITT population) post-Week 36 are described as follows: HPV-
Week 14
Week 62
Week 88
a.
b.
270

16/18 clearance at Week 62 was 89% (50/56) for VGX-3100 post-LEEP/CKC, 82% (42/51) for 
VGX-3100 post Biopsy only, 96% (27/28) for Placebo post-LEEP/CKC, and 82% (9/11) for Placebo 
post Biopsy only.  HPV-16/18 clearance at Week 88 was 89% (48/54) for VGX-3100 post-
LEEP/CKC, 89% (42/47) for VGX-3100 post Biopsy only, 89% (24/27) for Placebo post-
LEEP/CKC, and 100% (10/10) for Placebo post Biopsy only. 
The majority of subjects had cleared their underlying cervical HPV-16/18 infection by Week 62 
without meaningful changes through Week 88, and without meaningful differences between groups. 
Forty-seven of 53 (89%) and 46 of 49 (94%) subjects at Weeks 62 and 88, respectively (mITT 
population) with histopathologic evidence of CIN2/3 regression (regressors) in the VGX-3100 
treatment group experienced HPV-16/18 clearance. Despite the use of therapeutic resection for 
many VGX-3100 recipients whose CIN2/3 did not regress by Week 36 (non-regressors), HPV-16/18 
clearance rates were notably lower (85% at Week 88) compared to regressors.  
In the subjects who initially cleared HPV-16/18 by Week 36, only one HPV-16/18 recurrence was 
identified at the Week 62 and 88 evaluations. Specifically, one subject in the VGX-3100 group 
whose lesion was biopsied at Week 36 had HPV types 16 and 82 and CIN2 at screening, was HPV 
negative at Week 36, but tested HPV type 16 positive at Week 62, and then cleared HPV-16 at Week 
88. The subject showed histopathologic regression at Week 36. No recurrences were identified in 
the eleven subjects in the placebo group whose lesions were biopsied at Week 36 with valid HPV 
data at Weeks 62 or 88. There were no (0/51) recurrences identified in the VGX-3100 treated group 
at Week 88. Overall, these virologic clearance findings support that study subjects had no increased 
risk as compared to standard of care.  
Cytology (mITT population) post-Week 36 are described as follows: Improvement compared to 
study entry for Pap smear cytology results at Week 62 were 93% (52/56) for VGX-3100 post-
LEEP/CKC, 100% (51/51) for VGX-3100 post-Biopsy only, 93% (26/28) for Placebo post-
LEEP/CKC, and 82% (9/11) for Placebo post-Biopsy only. At Week 62, cytopathologic 
improvement was reported for 104 of 125 (83%) subjects in the VGX-3100 treatment group and 34 
of 42 (83%) subjects in the placebo treatment group (mITT population).  
There were no instances of possible progression, and all cases that did not meet the definition of 
improvement were due to either no change from baseline, sample considered not evaluable, or no 
data available.  Improvement compared to study entry for Pap smear cytology results at Week 88 
were 96% (52/54) for VGX-3100 post-LEEP/CKC, 91% (43/47) for VGX-3100 post-Biopsy only, 
85% (23/26) for Placebo post-LEEP/CKC, and 100% (11/11) for Placebo post-Biopsy only.  At 
Week 88, possible progression (atypical glandular cells) was reported in a single Placebo subject in 
the post-LEEP/CKC group (3%) and no subjects treated with VGX-3100. All other cases that did 
not meet the definition of improvement were due to either no change from baseline, sample 
considered not evaluable, or no data available. The majority of subjects showed improvement, and 
there was no meaningful difference between the Week 62 and Week 88 evaluations.   These findings 
support that study subjects had no increased risk of progression based upon cytology as compared 
to standard of care. 
The protocol-specified removal of dysplastic cervical tissue at Week 36 by either method 
substantially affected the clearance of HPV-16/18 and normalization of cytologic findings as 
expected, regardless of treatment group (Figure 1a, b). HPV-16/18 clearance rises at a sharp rate 
271

after tissue is removed at Week 36 whether the excision is wide (e.g. LEEP, LLETZ, CKC) or more 
limited (biopsy). Notably, the method of tissue collection at the Week 36 endpoint did not 
appreciably affect the HPV-16/18 clearance rates beyond Week 36 (Table 8).   Based upon the Phase 
2b results, the risk of progression or recurrence of cervical dysplasia is low and comparable to the 
rates observed post-LEEP/CKC in clinical practice.  The long term follow up planned for this Phase 
3 study will include safety, cytology and HPV-16/18 testing at 6 months and also 1 year following 
the Week 36 histopathologic assessment, which is highly conservative given the expectation that 
few subjects will have persistent evidence of disease after the removal of tissue at Week 36 which 
is supported by the findings in the Phase 2b study. 
3 HYPOTHESIS AND STUDY OBJECTIVES 
3.1 
HYPOTHESIS 
Three 6 mg doses of VGX-3100 (DNA Plasmids encoding E6 and E7 proteins of HPV-16 and HPV-
18) delivered IM followed by EP with CELLECTRA™ 5PSP to adult women with histologically 
confirmed HSIL of the cervix, associated with HPV-16 and/or HPV-18 will result in a higher 
percentage of women with histopathological regression of cervical HSIL lesions to no evidence of 
cervical HSIL and virologic clearance of HPV-16/18 compared to placebo delivered IM followed 
by EP with CELLECTRA™ 5PSP at the Week 36 visit. 
3.2 
PRIMARY OBJECTIVE AND ENDPOINT 
Objective 
Endpoint 
Determine 
the 
efficacy 
of 
VGX-3100 
compared with placebo with respect to 
combined 
histopathologic 
regression 
of 
cervical HSIL and virologic clearance of 
HPV-16 and/or HPV-18 
Proportion of subjects with no evidence of  
cervical HSIL on histology (i.e. biopsy or 
excisional treatment) and no evidence of HPV-16 
and/or HPV-18 in cervical samples by type 
specific HPV testing at Week 36 visit 
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3.3 
SECONDARY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of 
VGX-3100 delivered IM followed by EP 
with CELLECTRA™ 5PSP 
1a. Incidence and severity of local and systemic 
events for 7 and 28 days following each 
investigational treatment  and for the duration 
of the study (through Week 88 visit) 
1b. Incidence and severity of SAE and UADE for 7 
and 28 days following each investigational 
treatment and for the duration of the study 
(through Week 88 visit) 
2.Determine VGX-3100 efficacy compared 
to placebo as measured by histopathologic 
regression of cervical HSIL  
2. Proportion of subjects with no evidence of  
cervical HSIL  on histology (i.e. biopsies or 
excisional treatment) at Week 36 visit 
3. Determine VGX-3100 efficacy compared 
to placebo as measured by virologic 
clearance of HPV-16 and/or HPV-18 
3. Proportion of subjects with no evidence of HPV-
16 and/or HPV-18 in cervical samples  by type 
specific HPV testing at Week 36 visit 
4. Determine VGX-3100 efficacy compared 
to placebo as measured by complete 
histopathologic regression of   cervical 
HSIL to normal 
4. Proportion of subjects with no evidence of Low 
grade squamous intraepithelial lesion (LSIL) or 
HSIL (i.e.  no evidence of CIN1, CIN2 or CIN3) 
on histology (i.e. biopsies or excisional 
treatment) at Week 36 visit 
5. Determine VGX-3100 efficacy compared 
to placebo as measured by both complete 
histopathologic regression of  cervical 
HSIL to normal and virologic clearance of 
HPV-16 and/or HPV-18 
5. Proportion of subjects with no evidence of LSIL 
or HSIL (i.e. no evidence of CIN1, CIN2 or 
CIN3 on biopsies or excisional treatment) on 
histology (i.e. biopsies or excisional treatment) 
and no evidence of HPV-16 and/or HPV-18  by 
type specific HPV testing at Week 36 visit 
6. Determine the efficacy of VGX-3100 
compared with placebo as measured by 
histopathologic non-progression 
6. Proportion of subjects with no progression of 
cervical HSIL to cervical carcinoma from 
baseline on histology (i.e. biopsies or excisional 
treatment) at Week 36 visit 
7. Describe the clearance of HPV-16 and/or 
HPV-18 
infection 
from 
non-cervical 
anatomic locations 
7. Proportion of subjects who have cleared HPV-16 
and/or HPV-18 on specimens from non-cervical 
anatomic locations (i oropharynx, vagina and 
intra-anal) at Week 36 Visit 
8. Determine the humoral and cellular 
immune response following administration 
of VGX-3100 compared with placebo at 
post dose 3, Week 36 and Week 88 visits 
compared to baseline  
8a. Levels of serum anti-HPV-16 and anti-HPV-18 
antibody concentrations at baseline, Week 15, 
36, and 88 visits 
8b. Interferon-γ ELISpot response magnitudes at 
baseline, Weeks 15, 36, and 88 visits 
8c. Flow Cytometry response magnitudes at 
baseline and Week 15 visits 
273

3.4 
EXPLORATORY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Exploratory Objectives 
Associated Endpoints 
1. Evaluate tissue immune responses to VGX-
3100 in cervical samples 
1. Assessment of markers including but not 
limited to CD8+ and FoxP3+ infiltrating 
cells. Additional assessments may include 
visualization of Granulysin, Perforin, CD137, 
CD103 and PD-L1 in cervical tissue as 
sample allows.  Markers listed here may 
change as new relevant information becomes 
available 
2. Evaluate effect of HLA type on efficacy 
 
2. HLA (per-locus and per-allele basis) in 
conjunction with histologic regression of  
cervical HSIL at Week 36 visit 
3. Describe 
association 
of 
microRNA 
(miRNA) profile, previous colposcopy, 
cytology and HPV testing results with 
Week 36 histologic regression  
3. Colposcopy, cytology, and HPV test results 
(Weeks 8, 15 and 28 visits) and miRNA 
profile (baseline, Week 8) in conjunction 
with histologic regression of cervical HSIL at 
Week 36 visit 
4. Describe the durability of virologic 
clearance of HPV-16 and/or HPV-18 for 
subjects treated with VGX-3100 compared 
with those treated with placebo 
4. Proportion of subjects with no evidence of 
HPV-16 and/or HPV-18 by type specific 
HPV testing at Weeks 62 and 88 visits 
5. Describe the patient-reported outcomes for 
subjects treated with VGX-3100 
5. Patient-reported outcome questionnaires will 
be self-administered at baseline, Weeks 4, 
and 12, 8-14 days following each dose, and at 
Weeks 28, 36, 40 and 88 by subjects enrolled 
in US, Canada, Mexico, Germany and UK. 
4 SELECTION OF SUBJECTS 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in the study: 
1. Women aged 18 years and above; 
2. Confirmed cervical infection with HPV types 16 and/or 18 at screening by cobasTM HPV test;  
3. Cervical tissue specimen/slides provided to Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study 
drug; 
4. Histologic evidence of cervical HSIL as confirmed by PAC at screening; 
274

5. Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form 
prior to study-related activities; 
6. Must be judged by Investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision, 4-quadrant biopsy with ECC, or 4-quadrant biopsy) required at Week 
36; 
7. Satisfactory colposcopy at screening, defined as full visualization of the squamo-columnar 
junction (Type I or II transformation zone) and complete visualization of the upper limit of 
aceto-white epithelium or suspected CIN disease; 
8. Cervical lesion that is accessible for sampling by biopsy instrument (e.g. Mini-Tischler device); 
9. Cervical lesion of adequate size to ensure that a visible lesion remains after screening biopsy; 
10. Must meet one of the following criteria with respect to their reproductive capacity: 
a) Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months or 
spontaneous amenorrhea for 6-12 months with FSH level >40 mIU/mL 
b) Is surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 12 months prior to screening 
c) WOCBP is willing to use a contraceptive method with failure rate of less than 1% per year 
when used consistently and correctly from screening until Week 36. The following methods 
are acceptable: 
o Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. Hormonal 
contraceptives must not be used in subjects with a history of hypercoagulability (e.g., 
deep vein thrombosis, pulmonary embolism). 
o Abstinence from penile-vaginal intercourse when this is the subject’s preferred and 
usual lifestyle 
o Intrauterine device or intrauterine system 
o Male partner sterilization at least 6 months prior to the female subject’s entry into the 
study, and this male is the sole partner for that subject 
11. Normal screening ECG or screening ECG with no clinically significant findings, as judged by 
the investigator. 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from enrollment in the study: 
1. Microscopic or gross evidence of adenocarcinoma-in-situ (AIS), high grade vulvar, vaginal 
(inclusive of cervical HPV-related lesions that extend into the vaginal vault), or anal 
intraepithelial neoplasia or invasive cancer in any histopathologic specimen at screening; 
275

2. Cervical lesion(s) that cannot be fully visualized on colposcopy due to extension high into 
cervical canal at screening; 
3. History of ECC which showed cervical HSIL indeterminate, or insufficient for diagnosis (ECC 
is not performed as part of study screening); 
4. Treatment for cervical HSIL within 4 weeks prior to screening; 
5. Pregnant, breastfeeding or considering becoming pregnant during the study; 
6. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are 
allowed, e.g. Gardasil™, Cervarix™); 
7. Presence of any abnormal clinical screening laboratory values greater than Grade 1 per 
Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 or less than Grade 1 but 
deemed clinically significant by the investigator within 30 days prior to Day 0; 
8. Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening (performed within 30 days prior to 
Day 0) 
b) Primary immunodeficiencies 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent; (use of inhaled, otic, and ophthalmic corticosteroids are allowed) 
d) 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) 
e) History of solid organ or bone marrow transplantation 
f) Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
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. 
9. Receipt of any non-study, non-live vaccine within 2 weeks of Day 0; 
10. Receipt of any non-study, live vaccine (e.g. measles vaccine) within 4 weeks of Day 0; 
11. Current or history of clinically significant, medically unstable disease which, in the judgment 
of the investigator, would jeopardize the safety of the subject, interfere with study assessments 
or endpoint evaluation, or otherwise impact the validity of the study results (e.g. chronic renal 
failure; angina, myocardial ischemia or infarction, class 3 or higher congestive heart failure, 
cardiomyopathy, or clinically significant arrhythmias); 
12. Malignancy or treatment for malignancy within 2 years of screening, with the exception of 
superficial skin cancers that only require local excision;  
13. Presence of acute or chronic bleeding or clotting disorder that would contraindicate IM 
injections, or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of 
Day 0; 
276

14. History of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic 
agents; 
15. Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or 
a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
16. Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at 
screening or Day 0; 
17. Prior major surgery within 4 weeks of Day 0; 
18. Participation in an interventional study with an investigational compound or device within 30 
days of signing informed consent; participation in an observational study is permitted; 
19. Less than two acceptable sites available for IM injection considering the deltoid and 
anterolateral quadriceps muscles; 
20. Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
21. Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located 
in ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 
22. Metal implants or implantable medical device within the electroporation area; 
23. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere 
with adherence to study requirements; 
24. Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of 
either a psychiatric or physical (i.e. infectious disease) illness; 
25. Active military service personnel; 
26. Study-related staff or family member of study-related staff; 
27. 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.  
 
 
277

4.3 
DISCONTINUATION/WITHDRAWAL OF STUDY SUBJECTS 
4.3.1 
CRITERIA FOR DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
Subjects who manifest Grade 4 toxicity attributable to the study treatment will be discontinued 
from the study treatment.  Subjects will not receive further study treatment but will be encouraged 
to continue follow-up safety assessment through study discharge and not discontinue from the 
study.  
If a subject manifests Grade 3 toxicity attributable to the study treatment, the medical monitor and 
Investigator will discuss whether further treatment should be continued for that subject.  
4.3.2 
CRITERIA FOR WITHDRAWAL FROM THE STUDY 
All randomized subjects should be encouraged to complete all study treatments and follow-up 
visits. A subject will be considered to have completed the study when she completes all scheduled 
study treatments and follow-up visits. However, a subject may voluntarily withdraw from study 
participation at any time or be withdrawn at any time at the discretion of the investigator for any 
maternal obstetrical or medical complications after consultation with the medical monitor. 
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. The site should also counsel the 
subject on the importance of maintaining the assigned visit schedule for follow-up and treatment 
of HSIL (CIN2, CIN3), and ascertain whether or not the subject wishes to and/or should continue 
in the study based on previous noncompliance. 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. 
4.3.3 
SPONSOR NOTIFICATION OF DISCONTINUATION/ WITHDRAWAL  
The investigator or study coordinator must notify the Sponsor within 24 hours if a subject has been 
discontinued/withdrawn due to an AE. If a subject discontinues from the study or is withdrawn 
from the study prior to study completion, all applicable activities scheduled for the final study visit 
should be performed at the time of discontinuation. The investigator will make every effort to have 
all scheduled immune assessment blood samples collected as indicated in the Schedule of Events 
in the synopsis, Table 1. Any AEs and/or SAEs present at the time of discontinuation/withdrawal 
should be followed in accordance with the safety requirements outlined in section 7.1 – Safety 
Parameters. 
 
 
 
278

 
4.3.4 
REASON FOR DISCONTINUATION/WITHDRAWAL 
The primary reason for a subject discontinuing further dosing or withdrawal from the study itself 
is to be selected from the following standard categories and recorded on the CRF: 
• Adverse Event (Adverse Reaction): Clinical or laboratory events occurred that, in the medical 
judgment of the investigator for the best interest of the subject, are grounds for discontinuation. 
This includes serious and non-serious adverse events regardless of relation to study drug. 
• Death of subject  
• Subject voluntarily withdrew consent: The subject desired to withdraw from further 
participation in the study in the absence of an investigator-determined medical need to 
withdraw. If the subject gave a reason for withdrawal, it must be recorded on the CRF. This 
reason does not allow for further data collection and should not be selected if follow-up data 
collection of this subject is anticipated by the subject. 
• Investigator decision to withdraw the subject from participation: Investigator determined a 
medical need to withdraw the subject. Investigator must consult the Sponsor’s Medical 
Monitor before withdrawing a subject from participation in the study 
• Protocol Violation: The subject’s findings or conduct failed to meet the protocol entry criteria 
or failed to adhere to the protocol requirements (e.g., treatment noncompliance, failure to 
return for defined number of visits). The violation should be discussed with the Sponsor’s 
Medical Monitor prior to discontinuation of study treatments or study withdrawal. 
• Lost to Follow-up: The subject fails to attend study visits and study personnel are unable to 
contact the subject after repeated attempts including telephone calls, letter sent by certified 
mail or equivalent. 
• Other: The subject was terminated for a reason other than those listed above, such as the 
termination of the study by the Sponsor. 
4.3.5 
SUPPLEMENTATION OF STUDY SUBJECTS 
If more than 10% of subjects from randomization of study treatment discontinue prior to the Week 
36 primary endpoint procedures, then supplementation of study subjects will be considered. 
5 STUDY TREATMENT 
5.1 
INVESTIGATIONAL PRODUCTS 
Investigational product (IP) 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. The active and placebo 
formulations to be used in this study are described in Table 9. Both IPs will presented in clear glass 
cartridges and will be injected intramuscularly. 
VGX-3100 and placebo will be provided by Inovio Pharmaceuticals, Inc. or its designee. 
279

Table 9. Investigational Products 
Product 
Formulation 
Dose 
VGX-3100 
6 mg (1:1 mix of SynCon™ HPV-16 E6/E7 and HPV-18 E6/E7 plasmids) in 150 mM 
sodium chloride and 15 mM sodium citrate 
1 mL 
Placebo 
150 mM sodium chloride and 15 mM sodium citrate 
1 mL 
5.2 
BLINDING 
This study is double-blinded with blinding maintained throughout the study by use of identical 
packaging for both the active product and the placebo. There is no difference in appearance for both 
the active product and the placebo.  
The investigator may request to unblind a subject’s treatment assignment in case of an emergency 
or serious medical condition when knowledge of the study treatment is essential for proper clinical 
management of the subject, as judged by the investigator. It is preferred, but not required, that the 
investigator first contact the Medical Monitor to discuss options before unblinding the subject’s 
treatment assignment.  In case of non-emergency, investigator must contact Medical Monitor to 
discuss the options before unblinding the subject’s treatment assignment.  
The Sponsor’s or designee’s pharmacovigilance staff may unblind the treatment assignment for any 
subject with an SAE, UADE, or AE of interest. No personnel directly involved with the study will 
be unblinded.  If expedited regulatory reporting is required for an event, the report may be submitted 
to regulatory authorities with the subject’s treatment assignment, in accordance with local 
regulations. 
5.3 
PACKAGING AND LABELING OF INVESTIGATIONAL PRODUCT 
Each cartridge will be labeled with a single-panel label and then individually packaged within a 
pouch that will contain an additional, double-panel label with tear-off. Both VGX-3100 and placebo 
labels will include, at minimum, the following information in Table 10:   
Table 10. Example Labels for Investigational Product 
 
5.4 
HANDLING OF INVESTIGATIONAL PRODUCT 
Inovio Pharmaceuticals, Inc. will be responsible for assuring the quality of the IP is adequate for 
the duration of the trial. Unless otherwise specified, IP will be shipped in a refrigerated condition 
Cartridges (primary container) 
Pouches (secondary package) 
VGX-3100 or Placebo 
Insert cap end 
IM administration 
Inovio Pharmaceuticals, Inc. 
Study ID/Material ID 
VGX-3100 or Placebo 
Single-use, 1 mL 
Storage temperature, expiration date 
CAUTION: New Drug – Limited by United States Law to Investigational Use 
Inovio Pharmaceuticals, Inc. 
280

with a temperature monitoring device. If the temperature monitoring device denotes temperatures 
outside the pre-specified range for any product, the Sponsor, or its designee should be contacted 
immediately. 
Immediately upon arrival, IPs should be transferred from the shipping container into 2–8 °C (36-46 
°F) storage, in a secure area, according to local regulations. The Sponsor should be notified of any 
deviations from this recommended storage condition.  
Refrigerator temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. 
5.5 
DISPENSING OF INVESTIGATIONAL PRODUCT 
It is the responsibility of the Investigator to ensure that the IP is only dispensed to study subjects. It 
must be dispensed only from official study sites by authorized personnel according to local 
regulations. 
When a subject is eligible for randomization, remove the pouch from the refrigerator and allow to 
reach room temperature. The product cartridge must not be removed from the pouch until 
immediately prior to administration. The pouch must not be discarded until 1) administration is 
completed and 2) all pertinent information from the pouch label has been documented in source.  
The product must be used within 4 hours of removal from the refrigerator. 
The device user manual and instructions for use will inform clinical personnel about placement of 
the IP cartridge into the device, as well as the steps for injection and electroporation. 
5.6 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of investigational product 
is maintained at the study site. Records or logs must comply with applicable regulations and 
guidelines, and should include: 
• 
Amount received and placed in storage area; 
• 
Amount currently in storage area; 
• 
Label ID number and use date or expiry date; 
• 
Dates and initials of person responsible for each investigational product inventory 
entry/movement; 
• 
Amount dispensed to each subject, including unique subject identifiers; 
• 
Amount transferred to another area/site for dispensing or storage; 
• 
Amount returned to Sponsor; 
• 
Amount destroyed at study site, if applicable. 
5.7 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused IP must be destroyed at site per institution 
policy or returned to Inovio Pharmaceuticals, Inc. or its designee, if site cannot destroy IP.  
The used IP cartridge will be discarded along with the disposable array within a sharps container at 
site. 
281

It is the Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. The return of unused IP(s) should be arranged by the responsible Study Monitor. 
The unused IP can only be destroyed after being inspected and reconciled by the responsible Inovio 
Pharmaceuticals, Inc. or designated Study Monitor. 
If IP is returned to Inovio Pharmaceuticals, Inc., or its designee, must be accompanied by the 
appropriate documentation. Returned supplies should be in the original containers. Empty 
containers should not be returned to Inovio Pharmaceuticals, Inc. The return of unused IP(s) should 
be arranged with the responsible Inovio personnel and/or Clinical Monitor. 
5.8 
INVESTIGATIONAL DEVICE 
The needle array component of CELLECTRA™ 5PSP device is provided sterile and is intended for 
single-use. CELLECTRA™ 5PSP device is intended to be used by qualified and trained healthcare 
professionals in clinical settings. The Investigator for this study will be trained in the use of the 
device. 
CELLECTRA™ 5PSP has 3 main components that are used in conjunction with the drug cartridge 
(see Figure 2): 
1. 
Base – Acts as a docking station for the Handset and as the primary display for entering 
subject information; must be used with the provided Power Supply 
2. 
Handset – Controls delivery of the drug and electrical pulses 
3. 
Array (single-use sterile) – Attaches to the Handset and contains the injection needle, 
electrodes and sensors used for drug delivery and electroporation.   
4. 
Drug Cartridge (single-use) – a separate container-closure containing the IP solution. The 
Cartridge is inserted into the array for administration of the IP.  
282

Figure 2. Components of the CELLECTRA™ 5PSP Device and Drug Cartridge 
 
 
 
The CELLECTRA™ 5PSP device has unique features that make using it different from using 
other injection systems: 
1. Each Handset is uniquely paired to a Base. The serial numbers on the bottom of the Base and 
Handset must match. 
2. There is no communication between the Base and Handset when separated; the Handset must 
be placed onto the Base to share power or data. 
3. The Handset has an internal battery that must be charged on the Base before use. 
4. Needle depth is selectable on the Handset at the following lengths: 13 mm, 19 mm, or 25 mm. 
Even though the system provides a needle depth recommendation based on a Subject’s height 
and weight, the user will be asked to manually enter the needle depth based on the protocol 
requirements (refer section 5.9), described  
5. Injecting the placebo and delivering electrical pulses takes time (usually 10 seconds). The 
Handset will let you know when treatment is complete. 
6. The Subject should be maintained in a safe and secure, braced position due to involuntary 
muscle spasms that may occur during delivery of the electrical pulses. 
3 
4 
2 
1 
Assembled View 
Stored View 
283

Before using the CELLECTRA™ 5PSP device, the Investigator and research staff must be trained 
by the Inovio Pharmaceuticals Inc. device trainer(s) and be requested to read the entire user manual 
and complete the Self-Assessment. 
5.9 
USE OF INVESTIGATIONAL DEVICE 
The instructions for use of the device are located in the CELLECTRA™ 5PSP User Manual. Users 
of the CELLECTRA™ 5PSP device must successfully complete training. Training will include 
review of the entire device user manual and instruction video and hands-on training. After training 
on the proper use of the CELLECTRA™ 5PSP device, intended users at each site will be required to 
demonstrate their competence in its use to Inovio or its designee. 
Briefly, the Handset and Array should be prepared according to the instructions in the user manual. 
Remove the array from its packaging while avoiding contact with the end of the array that attaches 
to the handset, and insert the drug cartridge into the array with the arrow on the cartridge pointing 
away from the handset.  
Attach the Array to the Handset and set the needle depth on the handset to the longest needle length 
judged to allow safe injection into the muscle per the investigator’s assessment.   
The subject must be in a safe and secure, braced position.  The subject’s body should touch the bed 
or be braced against the bed or have the study staff performing electroporation or assistant in position 
to brace the subject’s arm or leg (as appropriate) as the EP is administered.  The user will then insert 
the CELLECTRA™ 5PSP needle array into the deltoid (or anterolateral quadriceps muscle as an 
alternate option, if deltoid muscle is not possible or appropriate) of the subject in accordance with 
the CELLECTRA™ 5PSP user’s manual instructions. Once triggered by the user, the device will 
automatically deliver the blinded treatment followed by the EP pulses. The entire treatment period 
lasts for about 10 seconds. 
The treatment 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. Individuals whose credentials do not meet the relevant local requirements may 
perform the treatment procedure under both of the conditions below: 
1. The procedure must be performed under the direct supervision of the Investigator or an 
approved Sub-Investigator who has already been trained by the sponsor’s personnel. 
2. The CV and any relevant qualifications of the individual must be reviewed and approved 
by the sponsor or its designee to perform the procedure. 
Any deviation from the above procedures must be approved by the sponsor or its designee. 
5.10 PACKAGING AND LABELING OF INVESTIGATIONAL DEVICE 
See below Figure 3 for example CELLECTRA™ 5PSP device component labels. 
 
 
 
284

Figure 3. Device Labels (Base, Handset, Array) 
         
            
 
                                  BASE                                                                      HANDSET 
 
 
                                                                              ARRAY 
5.11  HANDLING OF INVESTIGATIONAL DEVICE 
The CELLECTRA™ 5PSP device and its components must be stored in a secure location according 
to the instructions in the User Manual. 
5.12  INVESTIGATIONAL DEVICE ACCOUNTABILITY 
The investigative site is responsible for maintaining investigational device and accountability logs. 
The device must have full traceability from the receipt of the products through the subject use, 
disposal or return of the products. The Site must document acknowledgement of receipt and notify 
Inovio upon receipt of investigational product. This includes the content shipped and condition upon 
receipt.  
For each subject treatment, there must be a record of each product used for that subject, i.e. 
CELLECTRA™ 5PSP serial number, array lot number and the study drug lot number. The used 
sterile disposable array attachment must be discarded after use in accordance with institutional 
policy regarding disposal of sharp needles/instruments. 
5.13  RETURN OF INVESTIGATIONAL DEVICES 
Upon completion or termination of the study, all investigational devices and unused components 
must be returned to Inovio Pharmaceuticals, Inc. 
285

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 responsible Study Monitor. 
If product is to be 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 according to applicable 
regulation and guidelines and institutional procedures, and appropriate records of the disposal have 
been documented. 
6 STUDY PROCEDURES AND TREATMENTS 
This section lists the procedures and parameters for each planned study evaluation.  The timing of 
each assessment is listed in the Schedule of Events Table (see Table 1). 
A subject will be required to provide informed consent for use of any information collected prior to 
consenting and before any additional study specific procedures are performed.   
Protocol waivers or exemptions will not be granted with the exception of immediate safety concerns. 
Therefore, adherence to the study design requirements, including those specified in the Schedule of 
Events Table are essential and required for study conduct. 
6.1 
BEFORE TREATMENT PROCEDURES 
6.1.1 
SCREENING EVALUATIONS 
Subjects who have been identified with standard of care biopsy results of CIN 1/2, CIN 2, CIN 
2/3 or CIN 3 and who consent to participate in the study will be eligible for screening and will 
have biopsy slides or tissue sent to the central pathology lab for review by PAC for evaluation 
prior to enrollment.  
Additionally, Investigators may discuss with the Sponsor on a case-by-case basis the screening of 
subjects with abnormal cytology findings (e.g. HSIL or ASCUS with or without local HPV-16 or 
18 genotype results) obtained as part of standard of care. The specific circumstances MUST be 
submitted in writing (e.g. email or fax) and the medical monitor MUST be consulted prior to 
screening a volunteer with these cytology findings (e.g. ASCUS or HSIL with or without HPV-16 
or 18) for this study. The initial biopsy results may have been obtained at a referring institution by 
someone other than the site investigator. 
• In the case where the subject has an ASCUS or HSIL cytology result without HPV-16 or 
18 genotyping results available locally and if approved by Inovio, the site may proceed 
with initial study screening by sending ThinPrep™ samples to the central laboratory to 
screen for HPV 16/18 by cobas™ assay. A non-specific result from local testing of 
“Positive for high risk HPV” is not sufficient and will require the collection of the 
ThinPrep™ sample for HPV-16 and/or HPV-18 testing by cobas™ assay.  If the central 
lab ThinPrep™ sample result is positive for HPV-16 and/or HPV-18, the site may continue 
screening including performing the initial colposcopy and biopsy. Biopsy tissue must be 
sent to the central pathology laboratory directly and not tested locally. 
286

• In the case where the subject has an ASCUS or HSIL cytology result with HPV-16 or 18 
positive genotype results available locally and if approved by Inovio, the site may proceed 
with initial study screening including performing the initial colposcopy and biopsy. Biopsy 
tissue must be sent to the central pathology laboratory directly and not tested locally. 
Subjects who consent to participate will have biopsy slides or paraffin-embedded tissue block(s) 
from a previous biopsy and/or newly collected cervical biopsy tissue samples (formalin fixed 
tissue) sent to the central pathology lab for review by PAC. There will be a maximum allowable 
window of 10 weeks from the date of collection of the qualifying biopsy sample(s) (i.e. 
slides/samples(s) reviewed by PAC with HSIL consensus diagnosis), until the date of first study 
treatment (i.e. Day 0).  
• Biopsy specimens and colposcopic photographs obtained within 10 weeks prior to Day 0 
as part of standard of care before the informed consent may be used as part of the screening 
and evaluation process.  If the pathology results of the initial biopsy obtained as part of 
standard of care are available confirming the presence of cervical HSIL (CIN2 or CIN3), 
those biopsy slides or sample(s) may be sent directly to the central pathology lab after the 
subject has signed the informed consent.   
• For those individuals diagnosed with cervical HSIL by a local pathologist, where the initial 
biopsy slides or tissue obtained as part of standard of care are not available or cannot be 
obtained within a reasonable timeframe, colposcopy with cervical photography may be 
performed and an additional biopsy sample may be collected during screening at the 
discretion of the investigator and consent of the subject. The 10 week screening window 
begins upon collection of the biopsy sample that will be evaluated by the PAC.  
Subjects must have a histologic diagnosis of cervical HSIL (CIN2 or CIN3) confirmed by the PAC 
and a screening ThinPrep™ cervical specimen test positive for HPV-16 and/or HPV-18 by 
cobas™ HPV test to be eligible for randomization into the study (provided the subject also meets 
other eligibility criteria). Subjects whose specimens also test positive for other HPV genotypes are 
not excluded as long as they have a positive result for HPV-16 and/or HPV-18. The assessments 
during the screening period will determine the subjects’ continued eligibility for the study and also 
their ability to comply with protocol requirements by completing all assessments.  
The following evaluations/actions, unless noted, will be performed within 10 weeks and up to Day 
0 – except for the safety laboratory collections/assessments, which must be performed within 30 
days prior to Day 0. All screening assessment values must be reviewed prior to study treatment. 
• Signed informed consent 
• Demographics; including age, and race/ethnicity 
• Medical history; including concomitant medications review, history of prior cervical 
dysplasia, and pregnancy history 
• Socio-Behavioral Assessment; including self-reported smoking history, self-reported exposure 
to second-hand smoke, self-reported alcohol intake history, contraceptive history 
• Vital signs (including oral temperature, respiratory rate, blood pressure and heart rate) 
• Full Physical Examination (including height, weight and BMI measurements) 
287

• ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain from 
any sexual activity and refrain from use of douching or vaginal lubricants/medication for a 
period of 24 hours prior to sample collection) 
• 2 Digene cervical swab samples  
• Urine pregnancy test 
• Colposcopy with lesion photography and/or cervical biopsy 
• 12-lead ECG (within 30 days prior to Day 0) 
• Baseline laboratory evaluations (includes CPK, hematology and serum chemistry, urinalysis)  
to be performed (within 30 days prior to Day 0); 
• Serology (HIV Antibody, within 30 days of Day 0) 
• Determination of eligibility per inclusion / exclusion criteria 
• Whole blood (at least 34 mL) and serum (at least 8 mL) for baseline immunology including 
miRNA profile 
6.2 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will be randomized to receive study treatment.  Visit 
dates and windows must be calculated from Day 0. 
6.2.1 
DAY 0 
The following evaluations will be performed on Day 0 prior to study treatment: 
• Determination of eligibility per inclusion / exclusion criteria 
• Randomization 
• Targeted Physical assessment 
• Vital signs 
• Urine pregnancy test 
• Whole blood (at least 34 mL) and serum (at least 8 mL) for baseline immunology including 
miRNA profile (a total of at least 68 mL of whole blood and 16 ml serum should be collected 
prior to dosing on Day 0) 
• ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain from 
any sexual activity and refrain from use of douching or vaginal lubricants/medication for a 
period of 24 hours prior to sample collection) 
• 2 Digene cervical swab samples 
• Oropharynx (OP) sample by oral rinse and vaginal swabs for HPV testing 
• Intra-anal swabs (if subject has consented for intra-anal sampling) for HPV testing 
• Colposcopy with lesion photography 
• Patient-Reported Outcome (PRO) questionnaires (SF-36 and EQ-5D-5L) completion by a 
subject (if enrolled in US, Canada, Mexico, Germany and UK only) 
Study treatment will be administered and the following evaluations will be performed on Day 0 
post-treatment: 
• Post treatment adverse event and injection site reaction assessment at least 30 minutes after 
study treatment  
288

• Distribute Participant Diary Card (PDC)  
• Download EP data from device within 24-48 hours of study treatment  
 
6.2.2 
8-14 DAYS POST DOSE 1 PHONE CALL 
The following information will be evaluated during phone call: 
• Post treatment adverse event and injection site reaction evaluation 
• Review Day 0 PDC (after reviewing the PDC and post treatment injection assessment with the 
subject on the phone, the Investigator or study personnel will determine whether an office visit 
is needed for further evaluation) 
• PRO questionnaires (SF-36 and EQ-5D-5L) completion by a subject (if enrolled in US, 
Canada, Mexico, Germany and UK only) 
 
6.2.3 
WEEK 4  
The following study evaluation will be performed on Week 4 prior to study treatment (±4 days): 
• Targeted Physical assessment 
• Vital signs including weight 
• Urine pregnancy test 
• Collect PDC for dose 1 
The following study evaluations will be performed on Week 4 post treatment: 
• Post treatment adverse event and injection site reaction assessment at least 30 minutes after 
study treatment;  
• Distribute PDC  
• Download EP data from device within 24-48 hours of study treatment  
• PRO questionnaire (EQ-5D-5L only) completion by a subject (if enrolled in US, Canada, 
Mexico, Germany and UK only) 
 
6.2.4 
8-14 DAYS POST DOSE 2 PHONE CALL 
The following information will be evaluated during phonecall:   
• Post treatment adverse event and injection site reaction evaluation 
• Review PDC for dose 2 (after reviewing the PDC and post treatment injection assessment with 
the subject on the phone, the Investigator or study personnel will determine whether an office 
visit is needed for further evaluation) 
• PRO questionnaires (SF-36 and EQ-5D-5L) completion by a subject (if enrolled in US, 
Canada, Mexico, Germany and UK only) 
 
6.2.5 
WEEK 8 
The following study evaluation will be performed during the visit 
289

• Vital sign 
• Targeted Physical assessment 
• Collect and review PDC for dose 2 
• Post treatment adverse event and injection site reaction evaluation 
• 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from any sexual activity and refrain from use of douching or vaginal lubricants/medication for 
a period of 24 hours prior to sample collection) 
• 
Whole blood and serum for immunology including miRNA profile 
 
6.2.6 
WEEK 12 
The following study evaluation will be performed on Week 12 prior to study treatment (±4 
days): 
• 
Targeted Physical assessment 
• 
Vital signs including weight 
• 
Urine pregnancy test 
The following study evaluations will be performed Week 12 post treatment: 
• 
Post treatment adverse event and injection site reaction assessment within a minimal of 30 
minutes after study treatment;  
• 
Distribute PDC  
• 
Download EP data from device within 24-48 hours of study treatment  
• 
PRO questionnaire (EQ-5D-5L only) completion by a subject (if enrolled in US, Canada, 
Mexico, Germany and UK only) 
 
6.2.7 
8-14 DAYS POST DOSE 3 PHONE CALL 
The following information will be evaluated during phonecall:   
• 
Post treatment adverse event and injection site reaction evaluation 
• 
Review PDC for dose 3 (after reviewing the PDC and post treatment injection assessment 
with the subject on the phone, the Investigator or study personnel will determine whether an 
office visit is needed for further evaluation) 
• 
PRO questionnaires (SF-36 and EQ-5D-5L) completion by a subject (if enrolled in US, 
Canada, Mexico, Germany and UK only) 
 
6.2.8 
WEEK 15 
The following study evaluations will be performed on Week 15 ± 1 week: 
• Targeted physical assessment 
• Vital signs 
• Post-treatment injection site reaction assessment 
• Urine pregnancy test 
290

• Whole blood (at least 51 mL) and serum (at least 4 mL) for immunology 
• ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain from 
any sexual activity and refrain from use of douching or vaginal lubricants/medication for a 
period of 24 hours prior to sample collection)  
• 2 Digene cervical swab samples 
• Collect PDC  
• Colposcopy and lesion photography 
 
6.2.9 
WEEK 28 
The following study evaluations/actions will be performed on Week 28 ± 1 week: 
• 
Targeted physical assessment 
• 
Vital signs 
• 
Urine pregnancy test 
• 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from any sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to sample collection)  
• 
2 Digene cervical swab samples 
• 
Colposcopy and lesion photography to assess for possible disease progression 
• 
PRO questionnaires (SF-36 and EQ-5D-5L) completion 8-14 days post Week 28 visit by a 
subject enrolled in US, Canada, Mexico, Germany and UK only 
 
6.2.10 
WEEK 36 
The following study evaluations will be performed on Week 36 ± 1 week: 
• 
Targeted physical assessment 
• 
Vital signs 
• 
Socio-Behavioral assessment (change in smoking alcohol intake or recreational drug use from 
baseline) 
• 
Whole blood and serum for immunology 
• 
Urine pregnancy test 
• 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from any sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to sample collection) 
• 
2 Digene cervical swab samples 
• 
Oropharynx (OP) by oral rinse and vaginal swab for HPV testing 
• 
Intra-anal swab (if subject has consented to intra-anal sampling) for HPV testing 
• 
Colposcopy and lesion photography  
• 
Biopsy or surgical excision based on information collected at Week 28 to determine the 
minimally required tissue collection procedure (e.g. 4 quadrant biopsies, 4 quadrant biopsies 
and ECC, or surgical excision) to be used for histopathologic assessment at Week 36 as 
described in Tables 5 & 6 
291

• 
PRO questionnaire (EQ-5D-5L only) completion by a subjects enrolled in US, Canada, 
Mexico, Germany and UK only 
 
6.2.11 
WEEK 40 PHONE CALL 
The following study evaluations will be performed on Week 40 ± 2 weeks via a phone call:   
• 
Review of histology results as read by PAC from Week 36  
• 
PRO questionnaires (SF-36 and EQ-5D-5L) completion 8-14 days post Week 40 by a subject 
by subjects enrolled in US, Canada, Mexico, Germany and UK only 
 
6.2.12 
WEEK 62 
The following study evaluations will be performed on Week 62 ± 2 weeks: 
• 
Targeted physical assessment 
• 
Vital Signs 
• 
Urine pregnancy test 
• 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from any sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to sample collection) 
• 
Colposcopy and lesion photography 
 
6.2.13 
WEEK 88 
The following study evaluations will be performed on Week 88 ± 2 weeks: 
• 
Full Physical Exam 
• 
Vital Signs 
• 
Socio-Behavioral Assessment (change in smoking alcohol intake or recreational drug use 
from baseline) 
• 
Urine pregnancy test 
• 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from sexual activity and refrain from use of douching or vaginal lubricants/medication for a 
period of 24 hours prior to sample collection) 
• 
2 Digene cervical swab samples 
• 
Oropharynx (OP) by oral rinse and vaginal swabs for HPV testing 
• 
Colposcopy and lesion photography 
• 
Whole blood and serum  for immunology 
• 
PRO questionnaires (SF-36 and EQ-5D-5L) completion by a subject (if enrolled in US, 
Canada, Mexico, Germany and UK only) 
 
 
292

6. 3  
E V A L U A TI O N S  A N D P R O C E D U R E S  
6. 3. 1  
I N F O R M E D C O N S E N T 
A ll s u bjects m ust si g n t he i nf or me d c o nse nt pri or t o a n y st u d y relate d pr oce d ures bei n g perf or m e d 
(i.e., pri or t o a n y scree ni n g acti vities). T h e i nf or me d c o nse nt d o c u me ntati o n m ust be i n acc or da nce 
wit h a p plica ble re g ul ati o ns a n d G C P. Q u alifie d st u d y p ers o n nel will meet wit h pr os pec ti ve st u d y 
s u bjects, e x plai n t he st u d y, a n d pr o vi de t he m wit h a n i nf or me d c o nse nt f or m (I C F) t h at descri bes 
t he  scree ni n g  tests,  eli gi bilit y  criteri a  f or  e nteri n g  t he  st u d y,  st u d y  treat me nts  a n d  f oll o w- u p 
pr oce d ur es, i n a la n g ua ge u n dersta n da ble t o t he s u bject. E x pla nati o n of t he st u d y i ncl u d es, b ut is 
n ot li mite d t o, st u d y o bjecti ves, p ote ntial be nefits a n d ris ks, disc o mf orts/i nc o n ve nie nces, a n d t he 
s u bject’s ri g hts a n d res p o nsi bilities. T he s u bject is t he n re q ueste d t o si g n a n d date t he I C F. A c o p y 
of t he  si g ne d i nf or me d c o nse nt d oc u me ntati o n m ust be pr o vi de d t o t he s u bject. T he q ualifie d st u d y 
pers o n nel  will  d oc u me nt  t he  pr ocess  of  o btai ni n g  i nf or me d  c o nse nt  wit hi n  t he  s o urce  rec or d. 
Si g ne d I C Fs are mai ntai n e d i n t he s u bject’s s o urce rec or ds a n d m ust b e a ccessi ble f or verificati o n 
at a n y ti me. 
6. 3. 2  
A S SI G N M E N T O F S U B J E C T I D E N TI FI C A TI O N N U M B E R S  
E ac h s u bject  w h o c o nse nts will be assi g ne d a u ni q ue s u bject i de ntificati o n n u m ber ( SI D), w hic h 
i de ntifies t he s u bject f or all st u d y-relate d pr oce d ures. SI Ds are a c o m bi nati o n of a  u p t o t w o al p ha 
letters  st u d y  c o de,  t w o al p ha  letter  C o u ntr y c o d e,  t w o  di git  site  n u m ber,  pl us 3- di git s u bject 
n u m ber  starti n g  wit h 
  (e. g., 
).  O nce  assi g ne d,  SI Ds  ca n n ot  be  re use d  f or  a n y 
reas o n.  I nf or mati o n  re gar di n g  t he  SI D  a n d  s cree n  date  m ust  be  d oc u m e nte d  o n  a  Scree ni n g 
l o g/s yst e m an d i n t he I nt eracti ve R es p o nse Tec h n ol o g y ( I X R S). 
S u bjects  meeti n g  eli gi bilit y  criteria will  be  ra n d o mize d  b y  a  c o m p uter ge nerate d  all ocati o n 
sc he d ule.  
6. 3. 3  
S A F E T Y E V A L U A TI O N S  
6. 3. 3. 1  
P h ysic al E x a m 
A f ull p h ysi cal  e x a mi nati o n  ( P E) will be c o n d ucte d d uri n g scree ni n g a n d st u d y disc har ge.  
It will i ncl u de a n assess me nt of t he f oll o wi n g: ge neral  a p peara n ce, s ki n, hea d, e yes, ears, 
n ose,  a n d  t hr oat,  a n d  l y m p h  n o des,  a n d  res pirat or y,  car di o vasc ul ar,  gastr oi ntesti nal,  
ge nit o uri nar y, m usc ul os k eletal, a n d ne ur ol o gi cal s yste ms.   
A  tar gete d  p h ysical  assess me nt  will  be  perf or me d  at  ot her  visits  as deter mi ne d  b y  t he 
i n vesti gat or or direct e d p er s u bject c o m plai nts.  
6. 3. 3. 2  
Vit al Si g ns  
Vital si g ns will be meas ure d at s pecifie d v isits a n d will i ncl u de:  
•  Sitti n g s yst olic  a n d diast olic bl o o d press ures wit h s u bject sitti n g at rest f or at least 
5 mi n utes bef ore meas ure m e nt 
•  Res pirati o n rate  
•  H eart r ate  
•  Oral te m per at ure meas ur e d wit h a n a ut o mate d t her m o meter   
2 9 3
P P
D
P P D

6.3.3.3 
Weight and Height 
Weight and height will be collected at screening in order to calculate the BMI. Weight will 
be collected on Day 0, Weeks 4 and 12. 
6.3.3.4 
Medical History 
All relevant (as judged by the investigator) past and present conditions at screening, as well 
as prior surgical procedures will be recorded for the main body systems.  The medical 
history will include a) any prior history of CIN diagnosed – with diagnosis date(s) and 
respective CIN level(s), and b) if treated previously for CIN, the respective treatment type(s) 
and date(s). 
6.3.3.5 
Socio-Behavioral Assessment 
Socio-Behavioral Assessment, including self-reported smoking history, self-reported 
history of exposure to second-hand smoke, self-reported alcohol intake history, self-
reported recreational drug use history, self-reported history of contraceptive use and type 
of contraceptive if known, reproductive history, history of prior cervical dysplasia, and 
pregnancy history will be obtained at Screening.  
At Weeks 36 and 88, socio-behavioral assessment will be performed to document any 
change from screening. 
6.3.3.6 
Laboratory Evaluations 
At screening, blood samples will be taken to be tested for serum chemistry and hematology.  
Complete blood count (CBC): 
• White blood cell (WBC) count with differential 
• Red blood cell (RBC) count 
• Hemoglobin, Hematocrit 
• Platelet count 
Serum Chemistry: 
• Glucose 
• Serum glutamic-pyruvic transaminase (SGPT)/Alanine aminotransferase (ALT) 
• Blood urea nitrogen (BUN ) 
• Creatinine 
• Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
• Creatine Phosphokinase (CPK) 
Urinalysis (UA):  
Urine samples will be tested at screening by dipstick for glucose, protein, and hematuria. If 
abnormal (presence of protein, hematuria, or glucose ≥ 1+) a microscopic examination 
should be performed. 
294

6.3.3.7 
Demographics 
Demographic information will be collected via self-report (unless noted otherwise), 
including the following: 
• Age 
• Race/ethnicity 
6.3.3.8 
Urine Pregnancy Testing 
For subjects of reproductive potential, a negative spot urine pregnancy test is required prior 
to each study treatment, colposcopy and surgical excision. 
6.3.3.9 
ECG 
A single 12-lead ECG will be obtained during Screening after the subject has been in a 
supine position for 10 to 15 minutes. The ECG should include measurements of ventricular 
rate, PR, QRS, QRS axis, QT, QTcb or QTcf, ST segment, T wave as well as an investigator 
assessment of whether the ECG is normal or abnormal (automated interpretations of ECG 
should not be used). Abnormal ECGs should be interpreted as “clinically significant (CS)” 
or “not clinically significant (NCS)” by the investigator. 
6.3.3.10 
Subject Self Evaluation 
Subjects will be provided a PDC (as shown in Appendix A) and will be asked to record the 
following the evening of study treatment through Day 6: 
• 
Oral temperature and time taken (before 11:59 pm) 
• 
General symptoms of feeling unwell 
• 
Pain and itching at injection site 
• 
Measure redness, swelling, bruising at injection site 
• 
Medications taken 
The completed PDC will be reviewed with the subject by the study staff at 8 -14 dDays post-
dose phone call and next in-person visit. 
The study staff will review the PDC for general symptoms (e.g. malaise, fatigue, headache, 
nausea, and myalgia/arthralgia), injection site reaction symptoms (e.g. pain, erythema and 
edema), medical events and medications. All reported events will be assessed for clinical 
significance (CS) and reported as adverse event accordingly in CRF. 
6.4 
INJECTION AND ELECTROPORATION (EP)  
Subjects will receive a 3-dose series of either 1 ml VGX-3100 or Placebo by IM injection in the 
deltoid (or anterolateral quadriceps muscle as an alternate option, if deltoid muscle is not possible 
or appropriate) followed immediately by EP with the CELLECTRA™ 5PSP. Study treatment must 
not be given within 2 cm of a tattoo, keloid or hypertrophic scar.  If there is implanted metal, 
implanted device, within the same limb then use of the deltoid muscle on the same side of the body 
is excluded.  
 
295

6.4.1 
RISKS OF TREATMENT PROCEDURES 
Table 11 summarizes reported AEs and potential risk to study treatment.  
Table 11. Summary of Reported Adverse Events and Potential Risks or VGX-3100 Delivered 
IM EP with CELLECTRA™ 5PSP 
Very Common  
• 
Mild to moderate injection site pain or tenderness 
• 
Malaise/fatigue, myalgia, or headache in the first few days following injection 
• 
Upper respiratory tract infection 
• 
Brief muscle contractions which may be uncomfortable 
• 
Nausea 
Common  
• 
Arthralgia 
• 
Injection site reactions such as erythema, pruritus, swelling, hematoma 
• 
Anxiety related to the administration procedure 
Less Common  
• 
Severe injection site pain or tenderness 
• 
Vasovagal reaction/lightheadedness/dizziness related to the administration 
procedure 
• 
Temporary bleeding at the injection site 
• 
Rash following administration  
Uncommon or rare  
• 
Injection site reactions such as laceration, induration, bruising/ecchymosis, or scab  
• 
Infection at the injection site  
• 
Muscle damage resulting in transient changes in creatine phosphokinase  
• 
Transient changes in clinical laboratory values 
Unknown frequency or 
theoretical potential risks 
• 
Severe localized administration site reaction, such as sterile abscess or secondary 
bacterial infection  
• 
Allergic reaction, including urticaria, angioedema, bronchospasm, or anaphylaxis  
• 
Chills, flu-like syndrome 
• 
Autoimmune disease 
• 
Electrical injury1 
• 
Disruption of function of implanted electronic medical devices (if CELLECTRA™  
5PSP device is not used per User Manual)1 
• 
Exacerbation of unstable cardiac disease1 
• 
Effects on the fetus and on pregnancy 
1device only 
6.4.2 
MANAGEMENT OF ANXIETY AND PAIN DUE TO TREATMENT 
Subjects may be offered topical anesthetic (e.g. EMLA or equivalent), to prevent significant 
discomfort from the treatment procedure. If a topical anesthetic is used, an approximately 1.5 cm 
diameter amount will be applied with occlusion to the site of injection ~30 minutes prior to 
treatment.  
Subjects may be offered a mild sedative (e.g. 0.5-1 mg lorazepam), or equivalent, for anxiety 
related to the treatment procedure. Mild sedatives may be administered approximately 1 hour prior 
to treatment at day 0, Weeks 4 and/or 12. Subjects who receive a mild sedative should not be 
allowed to operate a motor vehicle for 3-4 hours after receiving medication and should have 
arranged transportation to depart the study site. 
Subjects may be offered an analgesic (e.g. ibuprofen, ketorolac) after injection/EP.  
296

Subjects who are allergic to or have contraindications to EMLA, ibuprofen, ketorolac or a mild 
sedative may be offered a suitable alternative.  
Medication taken for anxiety or pain management should be added to the concomitant 
medications. 
6.5 
ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well as urine 
pregnancy testing at Screening will be performed for inclusion into the study as listed in section 
6.1.1. 
6.6 
ASSESSMENT OF CLINICAL STUDY ADVERSE EVENTS 
The injection site will be assessed by study personnel prior to and within minimum of 30 minutes 
after each study treatment and at 2 to 4 weeks post study treatment visits.  They will also be advised 
to record local and systemic AEs for 7 days on a PDC as shown in Appendix A. 
A Medical/Clinical Assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any adverse events, concomitant medications new onset illness or 
disease, as well as contraceptive compliance. Subjects will be reminded to contact study personnel 
and immediately report any event that happens for the duration of the study. Unsolicited adverse 
events will be captured from the time of the informed consent to study discharge. These events will 
be recorded on the subject’s CRF.   
6.7 
ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the investigator will be instructed to 
use the following grading scale: 
Table 12. 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 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/Redness* 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling** 
2.5-5 cm and 
does not interfere 
with activity 
5.1-10 cm or interferes 
with activity 
>10 cm or prevents 
daily activity 
Necrosis 
- September 2007 “FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials” 
*In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded 
as a continuous variable 
**Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement 
297

6.8 
ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, two previously-validated patient-reported 
outcomes (PRO) instruments will be provided to the subjects enrolled in US, Canada, Mexico, UK 
and Germany. The following two PRO questionnaires will be used: 
1. Short Form Health Survey, version 2 (SF-36v2™) (Optum, Inc.):  generically measures 
functional health and well-being, for physical and mental health; consists of thirty-six items 
covering eight domains (Physical functioning, Role limitations due to physical problems, 
Bodily pain, General health, Vitality, Social functioning, Role limitations due to emotional 
problems, and Mental health) [24] 
2. EQ-5D-5L (EuroQol Research Foundation): generically measures activities & general 
health status; consists of six items covering six domains (Mobility, Self-care, Usual activity, 
Pain/discomfort, Anxiety/depression, and Global health status) [25, 26] 
Either one or both PRO instruments (refer to Section 6.2) will be provided to the subject who will 
be instructed to complete the questionnaire at the following time points:  
• Day 0 (before the first study treatment) 
• 8-14 days post dose 1 
• Week 4 (after study treatment) 
• 8-14 days post dose 2 
• Week 12 (after study treatment) 
• 8-14 days post dose 3 
• 8 -14 days post Week 28 
• Week 36 (after biopsy or surgical excision) 
• 8-14 days post Week 40 
• Week 88  
Administration of PRO instruments will be performed according to the validated procedure and 
guidelines of each respective instrument, except for some assessments for exploratory analyses. 
Additional instructions will be provided separately  
6.9 
PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at baseline (screening and Day 0 prior to dosing) 
and at Weeks 8, 15, 36, 88. Details of the immunology sample collection and shipment information 
will be provided in the Laboratory Manual. 
A standardized binding ELISA may be performed to measure the anti–HPV-16/18 antibody 
response induced by VGX-3100. 
PBMCs will be isolated from whole blood samples. Assessment of cellular immune activity may 
occur via the application of the Interferon-γ enzyme-linked immunosorbent spot (IFN-γ ELISpot) 
assay as well as flow cytometry.  
Additional assessment of cellular immune activity may occur via the application Flow Cytometry 
for the purposes of performing a Lytic Granule Loading Assay. The Lytic Granule Loading assay 
may examine the following external cellular markers: CD3, CD4, CD8 (T cell identification), 
298

CD137, CD38 and CD69 (T cell activation markers) as well as PD-1 (exhaustion/activation marker). 
The Lytic Granule Loading assay may additionally analyze the following intracellular markers: 
Granzyme A, Granzyme B, Granulysin and Perforin (proteins involved in lytic degranulation and 
cytotoxic potential). Markers examined in this assay may change as new relevant data become 
available. 
Profiling of miRNA may occur via the use of either sera or plasma obtained at Screening, Day 0 as 
well as Week 8.  Assessment of Day 0 samples alone will explore predictive algorithms for response 
to treatment with VGX-3100 prior to dosing.  Assessment of Week 8 samples may be done as a 
comparison against Day 0 in order to look for changes in miRNA profiles that occur once dosing 
with VGX-3100 has begun to explore construction of an algorithm to predict treatment success with 
VGX-3100. 
6.10 TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue or additional slides in the paraffin block after histologic diagnoses have 
been rendered, then unstained slides and/or the relevant paraffin blocks may be collected for 
immunohistochemistry (IHC).  Assessment of markers may include, but are not limited to, CD8+ 
and FoxP3+ infiltrating cells as well as assessment of cell death via Cleaved Caspase 3 assessment. 
Additional assessments may include visualization of Granulysin, Perforin, CD137, CD103 and PD-
L1 in cervical tissue as sample allows.  Markers listed here may change as new relevant information 
becomes available. 
6.11 HLA TYPING 
HLA testing will be performed on PBMC from any single blood sample collected for 
immunogenicity analysis. If the subject has a record of previous high resolution HLA testing and 
access to the results, then HLA testing is not required. 
The DNA extracted from the blood sample will be used to determine if alleles at the MHC locus 
affect the immune response to study treatment. Data arising from this analysis will be subject to the 
same confidentiality restrictions as the rest of the study. This specimens will be destroyed after the 
analysis is completed. 
6.12  PAP SMEARS AND HPV TESTING 
Pap smears will be obtained using ThinPrep™ test kits at the screening, Day 0, Weeks 8, 15, 28, 36, 
62, 88 and read in a central laboratory. HPV PCR by cobas™ HPV test will be performed on the 
ThinPrep™ specimen. At each of these visits, menstrual cycle status & recent history will be 
collected via self-report.  If the Pap smear result suggests progression to cancer at Day 0, Weeks 15, 
28 or 36, the investigator may schedule an ad hoc visit to perform a colposcopy and possible biopsy 
if clinically indicated. 
The subject will be requested to abstain from any sexual activity and refrain from use of douching 
or vaginal lubricants/medication for a period of 24 hours prior to collection of ThinPrep™ samples 
to eliminate potential interference with the results of HPV testing.   
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 At visits (i.e. Screening, Day 0, and Weeks 15, 28, 36 and 88) where multiple cervical samples are 
collected, the two Digene cervical swab will be collected prior to the ThinPrep™ sample. 
Immunology testing may be performed from digene swab. 
Details of sample collection and shipment information will be provided in laboratory manual. 
Additionally, if there is residual tissue available from cervical tissue from screening and Week 36 
after the histologic diagnosis have been rendered, then unstained slides and/or paraffin blocks may 
be collected to test for HPV typing. 
Also, non-cervical swabs (i.e. oropharyngeal rinse, vaginal brush and intra-anal swabs) will be 
collected at specified visits for HPV typing. 
6.13  COLPOSCOPY AND CERVICAL BIOPSIES 
Colposcopy at screening must be adequate, defined as full visualization of the squamo-columnar 
junction (Type I or II transformation zone) and complete visualization of the upper limit of aceto-
white epithelium or suspected dysplasia. An ECC is not required for study entry. However, if an 
ECC was done as part of routine care during the screening period, and found to have evidence of 
cervical HSIL such subject should not be enrolled in the study. Colposcopy is not required to be 
performed at screening if adequate colposcopy was previously obtained upon collection of initial 
biopsy.  All colposcopies performed after informed consent should be conducted according to the 
guidelines outlined in Appendix B. 
Interval colposcopies will be performed at Day 0, Weeks 15, 28, 36, 62, and 88.  An unscheduled 
colposcopy may be performed at the discretion of the investigator if there is suspicion of disease 
worsening or progression. 
Digital photographs of the cervix will be captured after application of acetic acid at each colposcopic 
examination to document the clinical findings. If a biopsy or surgical excision is performed, images 
of the cervix should be collected before and after the procedure. Each site will be instructed on 1) 
the technique for capturing the proper images using a standard approach and 2) the process for 
uploading the images to a secure server. Additionally, if a vaginal or vulvar lesion should develop 
after a subject is enrolled, photographs should also be taken to document the clinical exam finding.    
6.13.1 
ECTOCERVICAL BIOPSIES 
Ectocervical biopsies are required at screening to confirm eligibility.  If the criteria outlined in 
Table 5 or 6 are met, ectocervical biopsies may also be performed at Week 36 to provide tissue 
for histopathologic assessment of disease regression.   
Visualization of a normal appearing cervix by colposcopy is insufficient evidence to confirm 
disease regression at Week 36. Biopsy must be performed at the location of the screening biopsy 
if no disease is visible at Week 36. 
Biopsies should not be performed at any other visit unless there is suspicion of disease 
progression.  Removal of additional tissue by biopsy before Week 36 will bias results toward 
improvement regardless of whether the subject is in the active or placebo group. The bias 
introduced will obviously be more significant for smaller lesions.  For this reason, if biopsies are 
obtained prior to Week 36, the subject will be classified as a non-regressor in the efficacy 
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analyses. Subject safety is paramount in this study. Therefore, if at any time the investigator may 
suspect disease progression and the standard of medical care would be to perform an unscheduled 
biopsy prior to Week 36, then his or her medical judgment should prevail over the default 
“Schedule of Events”, Table 1. 
6.13.2 
UNSCHEDULED BIOPSIES 
In the event an unscheduled biopsy is performed prior to Week 36, the subject will be classified 
as a non-responder. The subject will discontinue further study treatment and continue in the study 
for safety follow-up visits. The subject will be managed according to standard of care and the 
Investigator’s judgement based on the results of the histological diagnosis from the unscheduled 
biopsy Additional instructions for collecting ectocervical biopsies are detailed in Appendix B. 
All biopsy samples/excised tissue will be sent to the central pathology lab for review by PAC.   
6.14  CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to the screening 
biopsy date of eligible subjects must be recorded on the CRF. Actual or estimated start and stop 
dates must be provided. Medical procedures performed within 8 weeks prior to screening biopsy 
date of eligible subjects that do not affect subject’s eligibility for participation and during the study 
(including over the counter or herbal), will be recorded on the CRFs. 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. Medication that is considered necessary 
for the subject’s safety and well-being may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the CRF.   
6.15  RESTRICTIONS 
6.15.1 
PROHIBITED CONCOMITANT MEDICATIONS AND TREATMENTS 
The following medications and treatments are prohibited:  
• Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent; use of inhaled otic and ophthalmic corticosteroids are allowed 
• 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) at screening and throughout the study 
• Administration of any non-study related, non-live vaccine within 2 weeks of any study 
treatment or within 4 weeks of any study treatment for any non-study, live vaccine 
• Blood thinners (e.g. anticoagulants, antiplatelet drugs) or other medication that affects blood 
clotting within 2 to 14 days (e.g., 4-5 drug half-lives) of any study treatment, biopsy or 
excisional procedure (e.g. LEEP) 
 
6.15.2 
OTHER RESTRICTIONS 
Subjects should not use alcohol or drugs that would interfere with study requirements during 
the course of the study and should report ALL medications/drugs taken to the investigator 
and/or other study personnel. 
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Subjects should refrain from becoming pregnant until 6 months following the last dose of 
investigational product by using appropriate contraceptive measures as (See Inclusion Criteria, 
Section 4.1).  Lapses in contraceptive use should be reported to investigator and/or other study 
personnel. 
Subject should abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to collection of ThinPrep™ samples. 
7 EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
7.1.1 
ADVERSE EVENTS 
An adverse event (AE) is defined as any unfavorable and unintended change in the structure, 
function, or chemistry of the body, or worsening of a pre-existing condition, temporally 
associated with the use of a product whether or not considered related to the use of the product. 
In this study, such changes will be monitored, classified, and summarized, as Clinical or 
Laboratory AEs. Medical condition/diseases present before starting the investigational drug will 
be considered adverse events only if they worsen after starting study treatment. Throughout the 
course of the study, all solicited and unsolicited AEs will be monitored and reported on an AE 
CRF, including the event’s seriousness, severity, action taken, and relationship to investigational 
product(s). AEs should be followed until resolution or stable and the outcome will be documented 
on the appropriate CRF. All AEs should be recorded in standard medical terminology rather than 
the subject’s own words. 
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 study drug). 
• Any pre-existing condition that increases in severity, or changes in nature during or as a 
consequence of the study drug phase of a human clinical trial, will also be considered an AE. 
• Complications of pregnancy (e.g., spontaneous abortion, miscarriage, ectopic pregnancy, fetal 
death, still birth, congenital anomaly of the fetus/newborn); see Section 7.1.9 for additional 
information on pregnancy reporting. 
• AEs that occur from the study screening visit onwards and throughout the duration of the study, 
including the follow-up off study drug period will be recorded as an AE. 
• Conditions that lead to a medical or surgical procedure. 
AEs do not include the following: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed as a result of 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. 
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• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the informed consent form 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. 
7.1.2 
SERIOUS ADVERSE EVENTS 
A serious adverse event (SAE) is any AE that meets one of the following conditions: 
• Death during the period of surveillance defined by the protocol; 
• Is immediately life-threatening (e.g., subject was, in the view of the Investigator, at immediate 
risk of death from the event as it occurred). This does not include an AE that, had it occurred 
in a more serious form, might have caused death; 
• An event requiring inpatient hospitalization or prolongation of existing hospitalization during 
the period of protocol defined surveillance (including any overnight stay in the hospital, 
regardless of 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 or substantial disruption of the ability 
to conduct normal life functions; 
• Results in congenital anomaly or birth defect; 
• An important medical event that may not result in death, be life threatening, or require 
hospitalization, but based upon appropriate medical judgment, may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include 1) allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, 2) blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, 3) the development of drug dependency or drug abuse or 4) 
the development of a malignancy; 
• Is medically significant or requires intervention to prevent one or other of the outcomes listed 
above. 
7.1.2.1 
Clarification of Serious Adverse Events 
• Death is an outcome of an AE, and not an adverse event in itself. 
• The subject may not have been on investigational medicinal product at the occurrence 
of the event.  
• Dosing may have been given as treatment cycles or interrupted temporarily before the 
onset of the SAE, but may have contributed to the event.  
• “Life-threatening” means that the subject was at immediate risk of death from the event 
as it occurred. This does not include an event that might have led to death if it had 
occurred with greater severity. 
• Complications that occur during hospitalizations are AEs. If a complication prolongs 
the hospitalization, it is an SAE. 
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• Inpatient hospitalization means that the subject has been formally admitted to a hospital 
for medical reasons, for any length of time. This may or may not be overnight. It does 
not include presentation and care within an emergency department nor does it include 
full day or overnight stays in observation status. 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE and/or SAE and not the individual signs/symptoms. 
Serious adverse events that are ongoing should be followed until resolution or are clinically 
stable. The reporting period for SAEs is described in Section 9.5. 
7.1.2.2 
Event Reporting for Disease Progression or Exclusionary Histologic Findings 
Post-study Treatment 
After starting study treatment, if there is histologic confirmation of progression of cervical 
HSIL to micro invasive or invasive squamous cell carcinoma, the event must be reported as 
an SAE. Post-study treatment histologic diagnosis of adenocarcinoma-in-situ or 
adenocarcinoma should also be reported as an SAE. In both instances, the condition for 
SAE reporting should be categorized as a medically important event unless another criterion 
is met. 
7.1.3 
UNEXPECTED ADVERSE DRUG REACTIONS AND EXPEDITED 
REPORTING 
An adverse drug reaction (ADR) is any noxious and unintended responses to a medicinal product 
related to any dose, for which a causal relationship between a medicinal product and an adverse 
event is at least a reasonable possibility; i.e., there is evidence to suggest a causal relationship 
between the product and the adverse event. An unexpected ADR is one, the nature or severity of 
which is not consistent with the applicable product information (investigator’s brochure, protocol, 
and user manual). Reports that add significant information on specificity or severity of a known, 
already documented SAE constitute unexpected events. For example, an event more specific or 
more severe than described in the Investigator's Brochure or protocol would be considered 
"unexpected.” Specific examples would be (a) acute renal failure as a labeled ADR with a 
subsequent new report of interstitial nephritis and (b) hepatitis with a first report of fulminant 
hepatitis.  
The Sponsor will assess each serious ADR report for expectedness, to determine if it is a serious 
unexpected suspected adverse reaction (SUSAR) which requires prompt reporting to regulatory 
authorities and participating investigators as an expedited report, according to the applicable 
regulatory requirements. Additional occurrences of the SUSAR will be required to be reported on 
an expedited basis until the applicable product information is amended. 
In addition to single-case reports of SUSARs, the Sponsor shall notify regulatory authorities and 
participating investigators of information that might materially influence the benefit-risk 
assessment of a medicinal product, sufficient to consider changes in product administration or 
overall conduct of a clinical investigation. Examples of such information include a clinically 
important increase in the rate of occurrence of a serious expected adverse event, the identification 
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of a significant hazard to the subject population, or a major safety finding from a study conducted 
in animals. 
7.1.4 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
Unanticipated adverse device effect means 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.  
Per the definition above, a UADE is a type of serious adverse event (SAE) that requires expedited 
reporting on the part of the sponsor. As a reminder, all SAEs regardless of relationship to device, 
drug or procedure are to be reported to Sponsor by the study investigator within 24 hours. Sponsor 
will assess each device related SAE to determine if anticipated based on prior identification within 
the investigational plan.  
For countries recognizing and regulating CE Mark devices, SAEs related only to the device which 
meet the medical device vigilance (MDV) reporting criteria will be handled by the Sponsor under 
the post-market surveillance/vigilance reporting requirements per MEDDEV 2.12-1. In such 
cases, the Sponsor will report as per the regulations to the relevant health authorities that require 
MDV reporting.  
7.1.5 
ASSESSING SEVERITY (INTENSITY) 
Adverse events should be captured once on the CRF at the maximum severity reported.  
The investigator will grade laboratory AEs and clinical AEs with respect to the following levels 
of severity as per Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 for applicable 
subject populations: 
• Mild (Grade 1) 
• Moderate (Grade 2) 
• Severe (Grade 3) 
• Potentially Life Threatening (Grade 4)  
The investigator will grade injection site reactions in accordance with September 2007 FDA 
Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials. 
7.1.6 
CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE 
EVENTS 
 A causally related AE is one judged to have a reasonable possibility of a relationship to the 
administration of the IP and/or the investigational device. An AE may also be assessed as not 
related to the IP and/or the investigational 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 adverse events and 
judging the relationship between the administration of the IP and device and a subsequent AE. 
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The investigator is aware of the subject’s clinical state and thus may be sensitive to distinctions 
between events due to the underlying disease process versus events that may be product related 
and may have observed the event. The Sponsor will assess the overall safety of the IP delivered 
by EP and determine whether to report expeditiously to the regulatory agencies. 
Investigators should use their knowledge of the subject, the circumstances surrounding the event, 
available site and non-site laboratory and clinical records, and an evaluation of any potential 
alternative causes to determine whether or not an adverse event is considered to be related to the 
IP and/or the investigational device indicating "yes" or "no" accordingly. Causality should be 
assessed by the investigator as “yes, related” or “no, unrelated” by the following criteria: 
• 
Yes – there is a reasonable possibility that administration of the Study Treatment contributed 
to the event; 
• 
No – there is no reasonable possibility that administration of the Study 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 the investigational device; 
• 
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 study; 
• 
Presence of risk factors in the Study Subject or use of concomitant medications known to 
increase the occurrence of the event. 
7.1.7 
ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK, urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to IP interruption or 
discontinuation must be recorded as an AE, or SAE, if applicable. In addition, laboratory or other 
abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are associated with signs 
and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE (or SAE) 
as described in Section 7.1. If the laboratory abnormality is part of a syndrome, record the 
syndrome or diagnosis (e.g., anemia) not the laboratory result (e.g., decreased hemoglobin). 
Any laboratory abnormality 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 study treatment 
• Has accompanying or inducing symptoms or signs 
• Is judged by the investigator as clinically significant 
7.1.8 
POST-STUDY REPORTING REQUIREMENTS 
All AEs and SAEs including deaths, regardless of cause or relationship, must be reported for 
subjects on study (including any protocol required post-treatment follow-up). 
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Investigators are not obligated to actively seek AEs or SAEs beyond the follow up period for 
subjects. However, if the investigator learns of an AE or SAE that occurs after the completion or 
termination visit and the event is deemed by the investigator to be related to the study treatment, 
he/she should promptly document and report the event to the study team and medical monitor. 
7.1.9 
PROCEDURES FOR DOCUMENTING PREGNANCY DURING STUDY 
Subjects who are pregnant or expect to become pregnant during the course of the study up to Week 
36 will be excluded from participation in the study. Should a subject become pregnant after 
enrolling in the study, she will not be given any further study treatments. A Pregnancy Form will 
be completed by the site personnel and submitted to the sponsor or its designee within 24 hours 
after learning of the pregnancy.  Site personnel will submit the Pregnancy Form to the Sponsor or 
its designee by fax, as described in Section 7.4.2. 
The investigator will also report this event to the IRB within 24 hours of becoming aware of the 
pregnancy. Sites must request the subject’s permission to query pregnancy outcome and follow 
each subject to determine the outcome of the pregnancy. Results will be summarized in the clinical 
study report (CSR).  
Subjects who become pregnant at any point during the study will continue to be followed for safety 
assessments without receiving further study treatment. Procedures that are contraindicated during 
pregnancy, including additional treatments, must not be performed. Investigators should use 
clinical judgment regarding subsequent study-related blood collection based on the presence or 
absence of anemia in each subject.  
All pregnancies that occur from the time of first study treatment through the follow up visits must 
be reported. The investigator will monitor the subject and follow the outcome of the pregnancy. If 
the end of the pregnancy occurs after the study has been completed, the outcome will be reported 
directly to the study team and the medical monitor. 
7.2 
METHODS AND TIMING OF THE COLLECTION AND RECORDING OF 
SAFETY DATA 
Non-serious AEs and SAEs (and UADEs) will be collected for each subject from the time when 
informed consent is obtained through Week 88. 
The sources of AEs cover: 
1. 
The subject’s response to questions about her health (a standard non-leading question such as 
‘How have you been feeling since your last visit?’ is asked at each visit). 
2. 
Symptoms spontaneously reported by the subject. 
3. 
Evaluations and examinations where the findings are assessed by the investigator to be 
clinically significant changes or abnormalities. 
4. 
Other information relating to the subject’s health becoming known to the investigator (e.g. 
hospitalization).  
All AEs will be reported on the appropriate CRF. Any SAE (or UADE) occurring during the course 
of the study must be reported to the sponsor within 24 hours of awareness. 
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7.3 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor will be responsible for the overall safety monitoring of the study.  
Safety assessments include the following: 
• 
Incidence of all adverse events classified by system organ class (SOC), preferred term, severity, 
and relationship to study treatment 
• 
Changes in safety laboratory parameters (e.g., hematology, serum chemistry, and urinalysis) 
• 
Local and systemic injection site review; special attention will be paid to the examination of 
the injection site. Administration site reactions and the subject's complaints will be documented. 
7.3.1 
ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest (AESI) are the adverse events deemed related to VGX-
3100/placebo delivered with CELLECTRA™ 5PSP that require expedited communication from 
the Site to the Sponsor and meet any of the following criteria: 
• Grade 3 or greater persistent administration site erythema, and/or induration recorded ≥ 2 
hours immediately after Study Treatment  
• Grade 4 or greater persistent administration site pain, tenderness recorded ≥ 2 hours 
immediately after Study Treatment 
• Grade 3 or greater fever 
• Grade 3 or greater systemic symptoms, including generalized pruritus 
Sites will inform the Sponsor via method described in section 7.4.1 within 24 hours to discuss 
whether further dosing for the particular subject should continue.   
7.3.2 
STOPPING RULES (CRITERIA FOR PAUSING OF STUDY) 
• If at any time during a study one-third (1/3) or more of the subjects experience an AESI, 
further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, 
and the DSMB. Only the DSMB may review unblinded data in making their recommendation 
to the Sponsor regarding continuation of a trial.  
• If any SAE (or potentially life-threatening AE), or death assessed as related to study treatment 
occurs, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, 
IRB (if applicable) and the DSMB. 
• If three or more subjects in this study, experience the same Grade 3 or 4 adverse event, 
assessed as related to study treatment, further enrollment and study treatment will be halted 
immediately until a thorough investigation has been conducted by the Medical Monitor, 
Principal Investigator for the trial, and the DSMB. 
• In the event of two identical, unexpected, Grade 4 toxicities, assessed as related to study 
treatment, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, 
IRB (if applicable) and the DSMB.  
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T he  s p o ns or  or  desi g nee  will  n otif y  all  i n vesti gat ors  a n d  I R Bs/ E C  (if  re q uire d)  re gar di n g  t he 
o utc o me of a n y i n vesti gati o n ste m mi n g fr o m a St u d y Pa use.  
G ui deli nes f or ass essi n g relate d ness are d etaile d i n Secti o n 7. 1. 6 . 
7. 4  
S T U D Y R E P O R TI N G P E RI O D O F A D V E R S E E V E N T S  
A ll s olicite d a n d u ns olicite d a d verse e v e nts will be c ollecte d t hr o u g h o ut t he st u d y a n d rec or de d 
o n t he A E C R F.  
7. 4. 1  
S T U D Y R E P O R TI N G P E RI O D O F A D V E R S E E V E N T S  O F S P E CI A L 
I N T E R E S T 
A d verse e v e nts of s pecial i nterest ( A E SI) (see Secti o n 7. 3. 1 ) re q uire e x pe dite d c o m m u nicati o n 
fr o m t he Site t o t he S p o ns or. Wit hi n 2 4 h o urs of t he site's a ware ness of t he e ve nt, A E SI  m ust be 
re p orte d b y t h e I n v esti gat or t hr o u g h data e ntr y i n t he A d vers e E ve nt electr o nic case re p ort f or m 
(e C R F)  via  t he  M e di dat a  R A V E  electr o nic  data  ca pt ure  ( E D C)  s yste m.  I n  t he  e ve nt  t hat  t he 
Me di data R A V E E D C s yste m is u na vaila ble,  t he i n vesti gat or m ust n otif y t he S p o ns or via e mail 
or p h o ne.  
A E SI re p orti n g if E D C s yste m is u n a v ail a ble  
E M AI L:   
  
S A F E T Y P H O N E: 
 
7. 4. 2  
S T U D Y R E P O R TI N G P E RI O D O F S E RI O U S A D V E R S E E V E N T S  
T he re p orti n g peri o d f or S A Es ( wit h o ut re gar d t o ca usalit y or relati o ns hi p) is c o m prise d of t he 
peri o d f oll o wi n g t he si g ni n g of t he i nf or me d c o nse nt f or m u ntil t he e n d of t he st u d y. Eac h A E will 
be assess e d t o det er mi ne w het her it m eets seri o us ness criteria. If t he A E is c o nsi dere d seri o us, t he 
i n vesti gat or s h o ul d rec or d t his e ve nt t o t he S p o ns or wit hi n 2 4 h o urs of bec o mi n g a ware of t he 
e ve nt. T he i n vesti gat or ma y als o directl y re p ort t his e ve nt t o t he Et hics C o m mittee acc or di n g t o 
its sta n dar d o p erati n g pr o ce d ures. E x pecte d ness of S A Es will be deter mi ne d b y t he S p o ns or usi n g 
refere nce saf et y i nf or mati o n s pecifie d i n t he I n vesti gat or’s Br oc h ure a n d pr ot oc ol. A n e ve nt ma y 
q ualif y f or e x pe dite d re p orti n g t o re g ulat or y a ut h orities if it is a n S A E, u ne x pecte d per refere nce 
safet y i nf or mati o n a n d  c o nsi dere d r elate d f oll o wi n g t h e  g ui deli nes  i n Secti o n 7. 1. 3  ( S us pecte d 
U ne x pecte d  Seri o us  A d verse  R eacti o n,  S U S A R)  a n d 7. 1. 4 ( U na ntici pate d  [seri o us]  a d verse 
de vice  effect)  i n  li ne  wit h  rele va nt  le gislati o n.  All  i n vesti gat ors  will  recei ve  a  safet y  l etter 
n otif yi n g t he m of rele va nt S U S A R re p orts. T he i n vesti gat or s h o ul d n o tif y t he I nstit uti o nal Re vie w 
B oar d (I R B)/  I nstit uti o nal Et hics C o m mittee  (I E C) as s o o n as is practical, of seri o us e ve nts  i n 
writi n g w h ere t his is r e q uire d b y l ocal  re g ulat or y a ut h orities, a n d i n acc or da nce wit h t he l ocal 
i nstit uti o nal p olic y. At a n y ti me after c o m pleti o n of t he S A E re p orti n g peri o d, if a n i n vesti gat or 
bec o mes a ware of a n S A E t hat is s us pecte d b y t he i n vesti gat or t o be relate d t o t he st u d y dr u g, t he 
e ve nt will be re p orte d t o t he S p o ns or or its desi g n ee. If t he i n v esti gat or bec o mes a ware of  a n S A E 
i n a st u d y s u bject after t he last sc he d ule d f oll o w-u p visit, a n d c o nsi ders t he e ve nt relate d t o pri or 
St u d y Treat me nt, t he i n vesti gat or will re p ort it t o t he S p o ns or  or t he a p pr o priate desi g nee. 
3 0 9
P P D

Wit hi n  2 4  h o urs  of  t he  site's  a w are n ess  of  t he  e ve nt,  all  S A Es  (re gar dl ess  of  relati o ns hi p  t o 
i n vesti gati o nal pr o d uct) m ust be r e p orte d b y t he I n v esti gat or t hr o u g h data e ntr y i n t he A d vers e 
E ve nt electr o ni c cas e r e p ort f or m (e C R F) via t he Me di data R A V E electr o nic data ca pt ure ( E D C) 
s yste m.  I n t he e ve nt t hat t he Me di dat a R A V E E D C s yste m is u n a vaila ble, t he pa per S A E Re p ort 
f or m s h o ul d be use d a n d fa x e d t o t he P P D P har mac o vi gila n ce ( P V G) Safet y H otli ne Fa x N u m ber 
s h o w n bel o w: 
F acsi mile ( F A X) re p orti n g if re q uire d a: 
A mericas F A X #: 
 
E ur o pe F A X # : 
 
a: Re p orti n g b y F A X is re q uire d f or pa per S A E Re p ort F or ms if electr o nic data ca pt ure 
( E D C) is n ot a vaila ble, re dacte d s u p p orti n g me dical rec or ds, a n d Pre g na nc y Re p ort F or ms.  
All s u p p orti n g d o c u m e nts f or S A E r e p orts, i n cl u di n g m e dical rec or ds a n d dia g n osti c t est res ults, 
will i n cl u d e r ef er e nce t o t h e st u d y s u bj ect n u m b er. T h e st u d y sit e will re dact all ot h er s u bj ect 
i de ntif yi n g i nf or m ati o n pr es e nt o n S A E s u p p orti n g d o c u m e nts pri or t o s e n di n g t h e re p ort t o t h e 
S p o ns or . T h e s u p p orti n g d o cu m e nts f or S A E re p orts s h o ul d b e s e nt b y fa x t o t h e P P D P V G S afet y 
H otli n e Fa x N u m ber, s h o w n a b o v e.  
In v esti gat or will s u p pl y t he S p o ns or a n d t h e I R B wit h m ore i nf or m ati o n as it b ec o m es a v ail a ble 
a n d a n y a d diti o n al r e q u este d i nf or m ati o n. T h e S p o ns or or its re pres e nt ati v e will b e res p o nsi ble 
f or d et er mi ni n g a n d i n t ur n, r e p orti n g S A Es t o re g ulat or y a ut h oriti es acc or di n g t o t he a p pli ca ble 
r e g ulat or y r e q uir e m e nts. S A Es m ust be f oll o w e d b y t h e i n v esti gat or u ntil res ol uti o n, e v e n if t his 
e xte n ds  b e y o n d  t he  st u d y -r e p orti n g  p eri o d.  R es ol uti o n  of  a n  S A E  is  d efi ne d  as  t h e  ret ur n  t o 
baseli n e st at us or st a biliz ati o n of t he c o n diti o n wit h t h e e x p ect ati o n t h at it will re m ai n c hr o ni c.  
I n t h e e v e nt of deat h, if a n a ut o ps y is p erf or m e d, a c o p y of t h e re p ort will b e se nt t o t h e S p o ns or. 
7. 4. 3  
N O TI FI C A TI O N O F S E RI O U S A D V E R S E E V E N T S  
In  acc or da n ce  wit h  l ocal  re g ulati o ns,  t he  S p o ns or  s hall  n otif y  t h e  a p pr o priate  re g ulat or y 
a ut h orities, a n d all partici pati n g i n vesti gat ors i n a writte n safet y re p ort of a n y a d verse e x perie nce 
ass ociate d w it h t he use of t he pr o d uct t hat is b ot h seri o us a n d u ne x pecte d a n d a n y si g nifica nt ne w 
safet y  i nf or mati o n  t hat  mi g ht  materiall y  i nfl ue n ce  t he  be nefit-ris k  assess me nt  of  a  me dici nal 
pr o d uct, s ufficie nt t o c o nsi der c ha n ges i n pr o d uct a d mi nistrati o n or o veral l c o n d uct of a cli nical 
i n vesti gati o n. T he S p o ns or will n otif y re g ul at or y a ge n cies wit hi n t he ti me fra me s pecifie d b y l o cal 
re q uire me nts b ut n o later t ha n 1 0 w or ki n g d a ys f or U A D E, 7 da ys f or a fat al or life-t hreat e ni n g 
S U S A R a n d 1 5 da ys f or all ot her S U S A R S (see Secti o n 7. 1. 3  a n d 7. 1. 4 ).  
7. 4. 4  
R E P O R TI N G O F D E VI C E R E L A T E D C O M P L AI N T S  
A 
pr o d uct  c o m plai nt  ( or  de vice  defi cie nc y)  i n v ol ves  a n y  writte n,  electr o nic,  or  oral 
c o m m u nicati o n  t hat  alle ges  d eficie n cies  relate d  t o  t he  i de ntit y,  q ualit y,  d ura bilit y,  relia bilit y , 
safet y,  eff ecti ve ness, or  perf or ma n ce of  a de vi ce s uc h  as malf u ncti o n, mis use or us e err or a n d 
i na de q uate la beli n g. A m alf u ncti o n is defi ne d as t he fail ure of a d e vice t o meet its perf or ma nce 
s pecificati o ns or ot her wise perf or m as i nte n de d. T he i nte n de d perf or ma n ce of a d e vice refers t o 
3 1 0
P P D
P P D

the intended use for which the device is labeled. All product complaints that meet this definition 
must be reported to the sponsor with 10 days of discovery. Any product complaint that involves 
an AE or SAE must be also reported per Section 7.4. 
Any problems experienced including potential malfunctions of the device, error messages 
displayed on the device screen following treatment or errors that occur during the treatment 
procedure must be reported to the Sponsor or designee immediately for evaluation.  
Additional instructions on reporting to be provided separately. 
7.5 
STUDY DISCONTINUATION 
Inovio Pharmaceuticals reserves the right to discontinue the study at this site or at multiple sites for 
safety or administrative reasons at any time. In particular, a site that does not recruit at a reasonable 
rate may be discontinued. Should the study be terminated and/or the site closed for whatever reason, 
all non-source documentation and study product pertaining to the study must be returned to Inovio 
Pharmaceuticals or its representative. 
The study may be discontinued at any time by an IRB, Inovio Pharmaceuticals Inc., the FDA or 
other government agencies as part of their duties to ensure that research subjects are protected. 
8 STATISTICAL ANALYSIS PLAN 
8.1 
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 
with a histologic diagnosis of cervical HSIL. The study’s primary endpoint is binary: regression to 
CIN1/normal and clearance of HPV-16 and/or HPV-18 infection, based on tissue collected at Week 
36. The primary hypothesis is that VGX-3100 will be superior to placebo regarding the proportion 
who achieve the primary endpoint.  Secondary efficacy analyses involve regression to CIN1/normal, 
clearance of HPV-16 and/or HPV-18 infection from cervical tissue and non-progression of cervical 
lesions. Other secondary analyses concern safety and humoral and cellular immunological measures.  
Exploratory analyses concern tissue immunological measures, durability of clearance of HPV-16 
and/or HPV-18 infection from cervical tissue, effect of HLA type on efficacy, association of 
colposcopy, cytology, and virology and efficacy, and patient-reported outcomes. 
8.2 
RANDOMIZATION AND BLINDING 
Subjects will be randomized (2 VGX-3100:1 Placebo) in a stratified manner according to a) the 
degree of CIN observed in the biopsy specimens at screening (CIN2 vs. CIN3), b) BMI category 
(≤25 vs. >25 kg/m2), and c) age category (<25 years vs. ≥25 years). There will be no pre-determined 
number of subjects required to be randomized within each stratum. To ensure that milder CIN2 
disease is not over-represented in the study, the percentage of subjects enrolled with CIN2 will not 
exceed 50% of the total enrolled. 
The study is double-blinded. 
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8.3 
SAMPLE SIZE/POWER 
A sample of 198 subjects will be randomized to receive either 6 mg VGX-3100 or placebo IM 
followed by EP in a 2:1 ratio. This sample size provides 90% power to declare VGX-3100 superior 
to placebo, assuming the true proportion of subjects who achieve the primary endpoints is 35% and 
14% for VGX-3100 and placebo, respectively. These proportions also incorporate missing data 
(~10%) classified as non-regressors (failures). The assumptions are based on the Phase 2 study 
results. 
8.4 
ANALYSES POPULATIONS 
Analysis populations will include: 
• 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 primary for the analysis of efficacy in this study. 
• The modified intention to treat (mITT) population includes all subjects who receive at least one 
dose of Study Treatment and who have the analysis endpoint of interest. Subjects in this sample 
will be grouped to treatment arms as randomized.  Analysis of the mITT population will be 
considered supportive for the corresponding ITT population for the analysis of efficacy. 
• The per-protocol (PP) population comprises subjects who receive all doses of Study Treatments 
and have no protocol violations and who have the analysis endpoint of interest. Subjects in this 
sample will be grouped to treatment arms as randomized.  Analyses on the PP population will 
be considered supportive of the corresponding ITT population for the analysis of efficacy.  
Subjects excluded from the PP population will be identified and documented prior to unblinding 
of the study database. 
• The safety analysis set includes all subjects who receive at least one does of Study Treatment. 
Subjects will be analyzed as to the treatment they received.  
8.5 
SUBJECT 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. 
8.6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline 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 population.  Prior and concomitant medications 
will also be summarized with percentages in this fashion.  
8.7 
MEDICAL HISTORY 
The percentage of subjects with abnormal medical history findings will be summarized by body 
system, by treatment arm, for the ITT population. 
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8.8 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior medications are those that were used before the start of the trial (prior to Day 0).  Concomitant 
medications are those used during the course of the trial (on or after Day 0).  Partial start dates of 
prior and concomitant medications will be assumed to be the earliest possible date consistent with 
the partial date.  Partial stop dates of prior and concomitant medications will be assumed to be the 
latest possible date consistent with the partial date.  Data for all prior and concomitant medications 
will be summarized with percentages by treatment arm, for the mITT population.   
8.9 
EFFICACY ANALYSES 
The true treatment effect on the primary endpoint is δ = pV – pP, where pV and pP denote the true 
population probabilities of the primary endpoint for VGX-3100 and Placebo, respectively.  The 
primary hypothesis of superiority is:  
H0: δ ≤ 0 vs. H1: δ > 0. 
A p-value for this hypothesis test and corresponding 95% confidence interval will be computed 
based on the method of Miettinen and Nurminen [27].  Superiority will be concluded if the one-
sided p-value is <0.025 and the corresponding lower bound of the 95% CI exceeds zero. 
The secondary efficacy endpoints will be analyzed in the same manner as the primary hypothesis, 
but without the hypothesis test p-values. 
The histopathologic efficacy time frame is defined by those who have undergone a biopsy or surgical 
excision at any time starting from 14 days prior to the protocol-specified target date of Week 36.  It 
also includes subjects who undergo early intervention prior to this time frame or subjects who have 
no endpoint data for this time frame; these subjects are considered as failures for the efficacy 
endpoints.  Table 13 provides details for the definition of the primary endpoint response.   
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Table 13.  Definition of Primary Endpoint Responder and Non-Responder 
Responder 
Non-Responder 
Subject with no histologic evidence of cervical 
HSILa at Week 36 evaluation and no evidence of 
HPV-16 and/or HPV-18 at Week 36b  
AND 
Subject in which a cervical tissue sample was NOT 
obtained between collection of tissue to determine 
entry eligibility up to Week 36 primary endpoint visit 
Subject with histologic evidence of cervical HSIL, AIS, cervical 
carcinoma at Week 36 evaluation  
OR 
Subject with evidence of HPV-16 or HPV-18 at Week 36 
OR 
Subject in which an additional cervical tissue sample was 
obtained between collection of tissue to determine entry 
eligibility up to Week 36 primary endpoint visit 
OR 
Subjects with no Week 36 primary endpoint visit sample result 
a no evidence of HSIL is defined by histology as negative, squamous atypia, or LSIL 
b the histopathologic efficacy time frame is defined by those who have undergone a biopsy or surgical excision at any 
time starting from 14 days prior to the protocol-specified target date of Week 36 
Exploratory analyses will examine the relationship between the primary efficacy endpoint and a) 
HLA results, b) miRNA results, c) colposcopy results, d) cytology results, and e) HPV results.  As 
each of these results are categorical, relationships will be examined with contingency tables and 
logistic regression models which model the primary endpoint versus these results and treatment 
group as regressor variables. 
Other exploratory analyses will examine durability of clearance of HPV-16 and/or HPV-18 infection 
from cervical tissue at Weeks 62 and 88.  Descriptive statistics will be utilized; percentages of 
subjects who cleared will be presented by time point or anatomic location and treatment group. 
8.10     IMMUNOGENICITY ANALYSES 
Post-baseline cellular and humoral response magnitude may be compared between treatment groups 
using a difference in medians and associated non-parametric 95% CI.  Post-baseline tissue response 
magnitude will be compared between treatment groups using a difference in means and associated 
t-distribution based 95% CIs. 
Valid samples for statistical analysis purposes will be those collected within 7 or 14 days of the 
specified time points (see Table 1).  Baseline is defined as the last measurement prior to the first 
treatment administration. 
The mITT population will be used for immunogenicity analyses. 
8.11  SAFETY ANALYSES 
8.11.1 
ADVERSE EVENTS 
All AEs 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 
314

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 14 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 
[27].  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. 
Any AEs with a missing or partial onset date will be included in the overall AEs, but not be 
included within specified day-range summaries. AE duration will be calculated as (Stop Date – 
Start Date) + 1. 
8.11.2 
LABORATORY DATA 
Continuous response variables per time point and changes from baseline will be summarized with 
mean, median, minimum, and maximum values, and categorical response variables will be 
summarized per time point with percentages, by treatment arm.  Baseline is defined as the last 
measurement prior to the first treatment administration. 
8.12 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 mITT population.  Baseline is defined as the last measurement prior to the 
first treatment administration. 
8.13 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 ITT population. 
8.14 PATIENT REPORTED OUTCOMES 
As an exploratory endpoint, patient reported outcomes among subjects who receive VGX-3100 will 
be compared between those with excision versus those without excision, based on PRO endpoints.  
This comparison will utilize the median difference in endpoints or the difference in proportions of 
subjects with endpoints and associated non-parametric or Miettinen and Nurminen [27] 95% CIs, 
for continuous responses and binary responses, respectively. 
The mITT population will be used for PRO analyses. 
8.15 MISSING VALUES 
Missing data will be considered as non-regressors (failures) for the ITT efficacy analysis.  A 
subject’s regression outcome is missing if her CIN grade and HPV clearance at Week 36 cannot be 
determined. Also, any subject who undergoes an unscheduled procedure in which cervical tissue 
315

sample was obtained before Week 36 will be considered a non-regressor regardless of the Week 36 
result.  
Efficacy analyses using the mITT population will be conducted and will serve as sensitivity analyses 
regarding missing data. 
8.16 SUBGROUP ANALYSES 
Primary and secondary efficacy endpoints will be analyzed by history of exposure to prophylactic 
HPV vaccines. 
8.17 INTERIM ANALYSIS 
No formal interim analyses will be performed for this study.  For reasons of futility (early evidence 
of poor efficacy of VGX-3100) or safety issues, the DSMB could recommend stopping enrollment 
at any time.  The type I error of 0.05 will not be adjusted for possible early stopping due to futility. 
9 DATA COLLECTION, MONITORING AND REPORTING 
9.1 
CONFIDENTIALITY AND PRIVACY 
A report of the results of this study may be published or sent to the appropriate health authorities in 
any country in which the study products are legally marketed or may ultimately be marketed, but 
the subject’s name will not be disclosed in these documents. The subject’s name may be disclosed 
to the study sponsor, Sponsor, the governing health authorities or the Food and Drug Administration 
(FDA), if they inspect the study records. Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information. 
Written Authorization and other documentation in accordance with the relevant country and local 
privacy requirements (where applicable) are to be obtained from each subject prior to enrollment 
into the study, and/or from the subject’s legally authorized representative in accordance with the 
applicable privacy requirements (e.g., the Health Insurance Portability and Accountability Act 
Standards for Privacy of Individually Identifiable Health Information (HIPAA). 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of the research subject to revoke their authorization for use of their PHI 
The rights of the research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the sponsor retains the ability 
to use all information collected prior to the revocation of subject authorization. For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to 
collect at least vital status (i.e., that the subject is alive) at the end of their scheduled study period. 
316

9.2 
SOURCE DOCUMENTS 
Source data is all information, original records or clinical findings, laboratory results, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in original source documents. Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, subject’s 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records 
kept at the pharmacy, at the laboratories, and at medical records and within information technology 
systems that are involved in the clinical trial. 
A medical history must be present in the source documents. A medication history must be present 
in the source documents. All prescription and nonprescription medications taken within l week prior 
to entry must be recorded on the CRF. Actual or estimated start and stop dates must be provided. 
9.3 
RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution 
should make available for direct access all requested 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 study essential documents for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. This retention period 
may be superseded by applicable regulatory requirements (e.g. minimum of 25 years for Health 
Canada). The sponsor will inform the investigator/institution as to when these documents are no 
longer needed to be retained. 
9.4 
SAFETY AND QUALITY MONITORING  
9.4.1 
DATA & SAFETY MONITORING BOARD 
A Data & Safety Monitoring Board (DSMB) will be established to protect the research subjects 
through independent analysis of emerging data from the trial.  The DSMB will meet quarterly to 
review unblinded safety data and regression/clearance results.  If there are no new safety data or 
regression/clearance results to review for a quarterly scheduled meeting the DSMB will be notified 
and the meeting may be cancelled; Ad hoc meetings may be scheduled to review new data as 
applicable. The DSMB will be charged with advising the Sponsor if there appears to be a safety 
issue and with advising the Sponsor if it appears that regression in the VGX-3100 group is 
unacceptably low compared to the placebo group. No formal interim analysis will be performed. 
The DSMB Chair, upon consultation with the other voting members of the DSMB, has the 
authority to recommend suspension or stopping the study and to request a full DSMB review and 
ad hoc statistical analyses. The DSMB charter will define the membership, responsibilities and 
procedures for the meeting.  
317

9.4.2 
PATHOLOGY ADJUCATION COMMITTEE 
All histology slides (i.e. cervical biopsies or surgical excision tissue) will be read by a Pathology 
Adjudication Committee (PAC) to ensure consistent assignment of disease status for both study 
eligibility and the efficacy analysis. The PAC will consist of a total of four pathologists in separate 
locations. Each specimen will be read by two pathologists independently in a blinded fashion.  If 
the two pathologists agree the reading will be considered the clinical disease status for the subject.  
If the readings of the first two pathologists are discordant, the third pathologist will review the 
discordant slide(s) independently and if there is agreement among any of the three readings, it will 
stand as the clinical disease status for that subject.  If there is no agreement after the third review, 
the most severe diagnosis would be deemed the final diagnosis.  
9.4.3 
CLINICAL MONITORING 
Clinical Monitoring of the clinical trial will be performed by experienced monitors, who will 
report to the Sponsor or the Sponsor designee. Records for all clinical subjects in this trial will be 
monitored. The following clinical site monitoring tasks will be performed at all sites: 
• Prior to trial initiation, a site visit will be conducted to review all relevant forms and 
documentation, to ensure the site is qualified and compliant with all applicable requirements. 
• All clinical site monitoring visits will be documented. 
• Periodic site visits will be performed throughout the study. 
• The site monitor will be responsible for addressing and documenting the following study 
conduct activities and obligations and will: 
o Assure that the study is being conducted in accordance with the protocol, applicable 
regulatory agency regulations, and IRB policies 
o Discuss study conduct issues and incidents of noncompliance with the Investigator and/or 
study 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 serious 
adverse events (SAE) and provide subsequent follow-up report of the final outcome to the 
IRB 
o Throughout the study, inspect all source documents to ensure they are complete, logical, 
consistent, attributable, legible, contemporaneous, original, and accurate (ALCOA).  
o Assure that the study facilities continue to be acceptable 
o Compare the study 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 per 
laboratory manual requirements 
318

10 ETHICS 
10.1  INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The investigator and Sponsor are responsible for ensuring that the clinical study is performed in 
accordance with the protocol, the Declaration of Helsinki, principles of Good Clinical Practice 
(GCP), and applicable regulatory requirements.  
10.2 INSTITUTIONAL REVIEW BOARD OR INSTITUTIONAL ETHICS 
COMMITTEE (IRB/IEC) 
The investigator will undertake the study after full approval of the protocol and adjunctive materials 
(e.g., informed consent form, advertising) has been obtained from the applicable IRB/IEC and a 
copy of this approval has been received by the sponsor. 
Investigator responsibilities relevant to the IRB include the following: 
• During the conduct of the study, submit progress reports to the IRB/IEC as required.  
• Notify the Sponsor immediately of any SAEs or serious unanticipated adverse device effects. 
• If Sponsor notifies you about any reportable safety events notify the IRB immediately. 
• As required, obtain approval from the IRB/IEC for protocol amendments and for revisions to 
the consent form or subject recruitment advertisements; 
• Reports on, and reviews of, the trial and its progress will be submitted to the IRB by the 
investigator at intervals stipulated in their guidelines and in accordance with pertinent 
regulations and guidelines. 
• Maintain a file of study-related information that includes all correspondence with the IRB; 
• Notify IRB when study is completed (i.e. after the last study visit of the final study subject); 
• After study completion provide the IRB with a final report on the study. 
10.3 OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA) 
The investigator and Sponsor are responsible for ensuring that the clinical study is reviewed and 
approved according to local and applicable global regulations (e.g., NIH Office of Biotechnology 
Activities) governing research that involves recombinant or synthetic nucleic acid molecules.   
11 PROTECTION OF HUMAN SUBJECTS 
11.1  COMPLIANCE WITH INFORMED CONSENT REGULATIONS  
Written informed consent is to be obtained from each subject prior to Screening into the study, 
and/or from the subject’s legally authorized representative.  The process for obtaining informed 
consent must also be documented in the subject’s medical record.  
11.2  COMPLIANCE WITH IRB/IEC REQUIREMENTS 
This study is to be conducted in accordance with applicable IRB/IEC regulations.  The Investigator 
must obtain approval from a properly constituted IRB/IEC prior to initiating the study and re-
approval or review at least annually.  Sponsor is to be notified immediately if the responsible 
IRB/IEC has been disqualified or if proceedings leading to disqualification have begun.  Copies of 
all IRB/IEC correspondence with the investigator must be provided to Sponsor. 
319

11.3  COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and guidelines.  
11.4  COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES 
REGULATIONS (21CFR PART 11) 
When applicable, this study is to be conducted in compliance with the regulations on electronic 
records and electronic signature. 
11.5  COMPLIANCE WITH PROTOCOL 
Subjects are not required to follow special instructions specific to the Investigational Product used 
in this study however will be asked to complete a participant diary card during their study 
participation.  Subjects will be provided with Investigator emergency contact information and 
advised to report all adverse events. While every effort should be made to avoid protocol deviations, 
should a deviation be discovered, Sponsor must be informed immediately. Any protocol deviation 
impacting Subject safety must be reported to the Medical Monitor immediately. 
11.6  CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol without 
approval by Sponsor and prior review and documented approval/favorable opinion from the IRB of 
a protocol amendment, except where necessary to eliminate immediate hazards to study subjects, or 
when the changes involve only logistical or administrative aspects of the study (e.g., change in 
monitors, change of telephone numbers).  
12 FINANCING AND INSURANCE 
Inovio Pharmaceuticals is the sponsor in all participating countries and is fully supporting the study.  
Clinical trial insurance has been taken out according to the laws of the countries where the study 
will be conducted. 
13 PUBLICATION POLICY 
Publication of the results of this trial in its entirety will be allowed. The proposed presentation, 
abstract and/or manuscript must be made available to The Sponsor 60 days prior to submission for 
publication. The Sponsor shall have thirty (30) days after receipt of the copies to object to the 
proposed presentation or publication because there is patentable subject matter that needs protection. 
In the event that The Sponsor makes such objection, the researcher(s) shall refrain from making such 
publication or presentation for a maximum of three (3) months from the date of receipt of such 
objection in order for patent application(s) (directed to the patentable subject matter contained in the 
proposed publication or presentation) to be filed with the United States Patent and Trademark Office 
and/or foreign patent office(s). 
 
 
320

14  REFERENCES 
1. 
Centers for Disease C, Prevention. Human papillomavirus-associated cancers - United 
States, 2004-2008. MMWR Morb Mortal Wkly Rep 2012,61:258-261. 
2. 
Satterwhite CL, Torrone E, Meites E, Dunne EF, Mahajan R, Ocfemia MC, et al. Sexually 
transmitted infections among US women and men: prevalence and incidence estimates, 
2008. Sex Transm Dis 2013,40:187-193. 
3. 
Hariri S, Unger ER, Sternberg M, Dunne EF, Swan D, Patel S, et al. Prevalence of genital 
human papillomavirus among females in the United States, the National Health And 
Nutrition Examination Survey, 2003-2006. J Infect Dis 2011,204:566-573. 
4. 
American Cancer Society. Cancer Facts & Figures. In. Atlanta; 2016. 
5. 
Bruni L, Alberto G, Aldea M, Serrano B, Valencia S, Brotons M, et al. Human 
Papillomavirus and Related Diseases in theWorld. Summary Report 2015-12-23. ICO 
Information Centre on HPV and Cancer (HPV Information Centre). In; 2015. 
6. 
Guan P, Howell-Jones R, Li N, Bruni L, de Sanjose S, Franceschi S, et al. Human 
papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical 
infection to cancer. Int J Cancer 2012,131:2349-2359. 
7. 
Apgar BS, Zoschnick L, Wright TC, Jr. The 2001 Bethesda System terminology. Am Fam 
Physician 2003,68:1992-1998. 
8. 
McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW, et al. Natural history 
of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial 
neoplasia 3: a retrospective cohort study. Lancet Oncol 2008,9:425-434. 
9. 
McIndoe WA, McLean MR, Jones RW, Mullins PR. The invasive potential of carcinoma in 
situ of the cervix. Obstet Gynecol 1984,64:451-458. 
10. 
Future Ii Study Group. Supplementary Material: Quadrivalent vaccine against human 
papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007,356:1915-1927. 
11. 
The American College of Obstetricians and Gynecologists. FAQs Loop Electrosurgical 
Excision Procedure (LEEP). In; 2014. 
12. 
Aihara H, Miyazaki J. Gene transfer into muscle by electroporation in vivo. Nat.Biotechnol. 
1998,16:867-870. 
13. 
Gehl J, Mir LM. Determination of optimal parameters for in vivo gene transfer by 
electroporation, using a rapid in vivo test for cell permeabilization. Biochemical and 
Biophysical Research Communications 1999,261:377-380. 
14. 
Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospects for success. 
Curr.Opin.Immunol. 2011,23:421-429. 
15. 
van Drunen Littel-van den H, Hannaman D. Electroporation for DNA immunization: clinical 
application. Expert.Rev.Vaccines. 2010,9:503-517. 
321

16. 
Bodles-Brakhop AM, Heller R, Draghia-Akli R. Electroporation for the Delivery of DNA-
based Vaccines and Immunotherapeutics: Current Clinical Developments. Mol Ther. 2009. 
17. 
Hirao LA, Wu L, Khan AS, Satishchandran A, Draghia-Akli R, Weiner DB. 
Intradermal/subcutaneous immunization by electroporation improves plasmid vaccine 
delivery and potency in pigs and rhesus macaques. Vaccine 2008,26:440-448. 
18. 
Khan AS, Pope MA, Draghia-Akli R. Highly efficient constant-current electroporation 
increases in vivo plasmid expression. DNA & Cell Biology 2005,24:810-818. 
19. 
Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, et al. Immunotherapy 
against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. 
Sci.Transl.Med. 2012,4:155ra138. 
20. 
Diehl MC, Lee JC, Daniels SE, Tebas P, Khan AS, Giffear M, et al. Tolerability of 
intramuscular and intradermal delivery by CELLECTRA™ adaptive constant current 
electroporation device in healthy volunteers. Hum Vaccin Immunother 2013,9:2246-2252. 
21. 
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. 
22. 
Xiang L, Li J, Yang W, Xu X, Wu X, Wang H, et al. Conization Using an Electrosurgical 
Knife for Cervical Intraepithelial Neoplasia and Microinvasive Carcinoma. PLoS One 
2015,10:e0131790. 
23. 
Stoler MH, Vichnin MD, Ferenczy A, Ferris DG, Perez G, Paavonen J, et al. The accuracy 
of colposcopic biopsy: analyses from the placebo arm of the cerva clinical trials. Int J Cancer 
2011,128:1354-1362. 
24. 
EuroQol G. EuroQol--a new facility for the measurement of health-related quality of life. 
Health Policy 1990,16:199-208. 
25. 
Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Measurement 
properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-
country study. Qual Life Res 2013,22:1717-1727. 
26. 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity 
and activity impairment instrument. Pharmacoeconomics 1993,4:353-365. 
27. 
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985,4:213-226. 
 
 
 
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15 APPENDICES 
 
 
 
 
323

 
 
15.1 APPENDIX A:  PARTICIPANT DIARY CARD 
 
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15.2 APPENDIX B:  GUIDELINES FOR COLPOSCOPY, BIOPSY, AND 
SURGICAL EXCISION 
Colposcopy Procedure 
It is recommended that all study colposcopies performed after informed consent be according the procedures 
recommended by the American Society of Colposcopy and Cervical Pathology (ASCCP): 
1. Use warm, clean water to lubricate the vaginal speculum.  Avoid other lubricant substances which could 
obscure results. 
2. If the vaginal walls are lax, a lateral vaginal sidewall retractor aligned perpendicular to the speculum may 
facilitate visualization. 
3. Examine the cervico-vaginal secretions and remove any excess mucus from the cervix with saline-soaked 
cotton swabs. 
4. Obtain any required specimens required for cytology and HPV testing. 
5. Using low-power magnification (5x to 10 x) inspect the cervix for obvious areas of abnormalities. 
6. Swab or spray the cervix with 3-5% acetic acid.  Reapply every 2-3 minutes during the examination. 
7. Use the green or blue filter to examine blood vessels.  Increase magnification (15x) 
8. Identify the distal and proximal boarders of the transformation zone. 
a. The inner border is the entire 360-degree circumference of the squamocolumnar junction 
i. If the junction is proximal to the external os, in the canal, use a cotton-tipped 
applicator to pry either the anterior lip up or the posterior lip down or use an 
endocervical speculum 
ii. If the junction is not visualized in its entire circumference, the colposcopy is deemed  
inadequate  
b. The distal limit of the transformation zone may be identified by finding the most distal crypt 
openings or nabothian follicles in the lips of the cervix and drawing an imaginary line 
connecting these landmarks 
9. Inspect the entire new squamocolumnar junction and detect and evaluate any abnormal areas.   
10. Evaluate the upper third portion of the vagina. 
11. Lugol or Schiller’s solution may be applied to further define previously identified lesions.   
Cervical Biopsies  
 Endocervical Curettage 
ECC is to be performed using a kervorkian curette or equivalent instrument.  Rotate and scrape the curette 
360○ in the endocervical canal and use a cytobrush to remove the specimen.  Deposit the specimen onto a 
Telfa pad before depositing in the specimen vial containing 10% neutral buffered formalin solution and 
labeled with the subject identification (SID) number. 
 Ectocervical Biopsies 
Ectocervical biopsies should only be performed prior to Week 36 if disease progression is suspected.  Only 
the suspect lesion should be biopsied in that circumstance.   
If the subject is eligible for 4 quadrant biopsy at the Week 36 visit, the following procedure should be 
followed: 
1. Label each specimen vial containing 10% neutral buffered formalin solution with the subject’s ID number 
and the quadrant number according to the figure below. 
2. Perform and record colposcopy findings from each quadrant according to the following categories 
339

a. Negative (no lesion present) 
b. Low Grade  (e.g. pale acetowhite lesion on or off the squamocolumnar junction 
c. High Grade  (e.g. dense acetowhite lesion often with mosaic pattern or punctation) 
d. Suspicion of invasive cancer 
e. Invasive cancer 
3. Perform colposcopic directed biopsies from all quadrants with lesions. 
4. Multiple biopsies can be obtained of a lesion at the discretion of the investigator but must be uniquely 
labeled  
5. If a quadrant is free of lesions, obtain a random biopsy at the squamocolumnar junction in that quadrant 
at 2, 4, 8, or 10 o’clock. 
6. Prepare the biopsy specimen vials for shipment according to the Laboratory Manual. 
 
Figure 1 – Biopsy Quadrant Numbers 
 
 
 
 
Surgical Excision 
For subjects undergoing surgical excision at the Week 36 visit, the following procedure should be followed: 
1. Label each specimen vial containing 10% neutral buffered formalin solution with the SID number and 
the specimen type. 
2. Record colposcopy findings from each quadrant according to the following categories 
a. Negative (no lesion present) 
b. Low Grade  (e.g. pale acetowhite lesion on or off the squamocolumnar junction 
c. High Grade  (e.g. dense acetowhite lesion often with mosaic pattern or punctation) 
d. Suspicion of invasive cancer 
e. Invasive cancer 
3. Perform the LEEP or CKC per usual practice. 
4. Specimen should be marked at 12 o’clock with suture or gentian violet ink for purposes of orientation 
5. Prepare the biopsy specimen vials for shipment according to the Laboratory Manual. 
 
340

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Date ( D D- M M M- Y Y Y Y)
C O N FI D E N TI A L
Pa ge 1 of 2
3 4 8
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

 
 
 
 
HPV-301 
REVEAL 1 Trial  
(Randomized Evaluation of VGX-3100 and Electroporation for the Treatment of Cervical 
HSIL) 
 
A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
PHASE 3 STUDY OF VGX-3100 DELIVERED INTRAMUSCULARLY FOLLOWED BY 
ELECTROPORATION WITH CELLECTRA™ 5PSP FOR THE TREATMENT OF HPV-
16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS INTRAEPITHELIAL 
LESION (HSIL) OF THE CERVIX   
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
U.S. BB-IND #13683 
EudraCT #2016-002761-63 
 
Version 4.0 
29 March 2018 
 
 
349

 
A P R O S P E C TI V E, R A N D O MI Z E D, D O U B L E- B LI N D, P L A C E B O- C O N T R O L L E D 
P H A S E 3 S T U D Y O F V G X- 3 1 0 0 D E LI V E R E D I N T R A M U S C U L A R L Y F O L L O W E D B Y 
E L E C T R O P O R A TI O N WI T H C E L L E C T R A ™ 5 P S P F O R T H E T R E A T M E N T O F H P V-
1 6 A N D/ O R H P V- 1 8 R E L A T E D HI G H G R A D E S Q U A M O U S I N T R A E PI T H E LI A L 
L E SI O N ( H SI L) O F T H E C E R VI X   
S h ort Title:   
R E V E A L 1 Trial ( Ra n d o mize d E val uati o n of V G X- 3 1 0 0 a n d 
Electr o p orati o n f or t he tr eat me nt of Cer vical H SI L) 
 
Bi ol o gic al Pr o d uct:    
 V G X - 3 1 0 0 
 
Pr ot oc ol N u m ber:    
 H P V - 3 0 1 
 
S p o ns or:  
 I n o vi o P har m ace uticals, I n c. 
 
 6 6 0 W. Ger ma nt o w n Pi ke, S uite 1 1 0 
 
 Pl y m o ut h Meeti n g, P A 1 9 4 6 2 
 
P ri nci p al I n vesti g at or:   
 
, M. D., M. S. 
 
 
 
 
 R ut gers Ne w J erse y Me dical Sc h o ol 
 
 1 8 5 S. Ora n ge A ve., M S B E- 5 0 6 
 
 Ne war k, NJ 0 7 1 0 3 
 
M e dic al M o nit or:   
 
, M. D., P h. D. 
 
 
 
 
 I n o vi o P har m ace uticals, I n c. 
 
C O N FI D E N TI A L 
T he i nf o r m ati o n i n t his d oc u me nt is c o nsi dere d pri vile ge d a n d c o nfi de nti al b y I n o vi o P h ar m ace utic als a n d m a y 
n ot be discl ose d t o ot hers e xce pt t o t he e xte nt necess ar y t o o bt ai n I nstit uti o n al Re vie w B o ar d/ Et hics c o m mittee 
a p pr o v al a n d i nf o r me d c o nse nt, or as re q uire d b y l oc al re g ul at or y a ut h orities. Pers o ns t o w h o m t his i nf or m ati o n 
is discl ose d m ust be i nf o r me d t h at t his i nf or m ati o n is pri vile ge d a n d c o nfi de nti al a n d t h at it s h o ul d n ot be f urt her 
discl ose d wit h o ut t he w ritte n per missi o n of I n o vi o P h ar m ace utic als. A n y s u p ple me nt al i nf or m ati o n a d de d t o t his 
d oc u me nt is als o c o nfi de nti al a n d pr o priet ar y i nf or m ati o n of I n o vi o P h ar m ace uti c als a n d m ust be ke pt i n 
c o nfi de nce i n t he s a me m a n ner as t he c o nte nts of t his d oc u me nt. 
3 5 0
P P D
P P D
P P D
P P D

SUMMARY OF CHANGES 
The following is a list of protocol changes organized categorically and secondarily in order of 
appearance from HPV-301 protocol version 3.0 dated 23 September 2016 to HPV-301 protocol 
version 4.0 dated 29 March 2018.   
1. The modifications and updates to the Hypothesis, Objectives and Endpoints are as follows: 
a. A footnote was added to the primary hypothesis for the purpose of clarification and 
alignment with the time frame for analysis. 
b. The wording of Secondary Endpoint 1b has been modified to more accurately state 
that all Adverse Events, not just SAEs will be reported through the entire duration 
that a subject is in the study. 
c. The wording of Secondary Objective 8 has been revised to more clearly reflect that 
immunology results are assessed relative to baseline levels. 
d. The Week 88 blood sample to test immune responses has been eliminated and the 
corresponding text has been removed from Secondary Objective 8. 
e. For Exploratory Objective 3, DNA methylation has been added to investigate as an 
additional potential biomarker. 
f. An Exploratory Endpoint 6 has been added to describe the association of a baseline 
tissue-based score derived using immunologic markers (Immunoscore) to the      
Week 36 efficacy endpoint. 
2. The revisions to the Inclusion and Exclusion criteria are as follows:  
a. Inclusion criteria 1 has been revised to clarify that to be eligible, women must meet 
the minimum age of consent per local regulations, given that the age of consent can 
be older than 18 years in certain countries.  
b. Inclusion criteria 10(a) has been modified to align the definition of ‘post-
menopausal’ with the medical literature,  which defines postmenopausal as having 
amenorrhea for 12 months [1, 2]. 
c. Exclusion criteria 3 has been clarified to reflect that patients who have a prior ECC 
that shows potentially untreated carcinoma (therefore, requiring more immediate 
treatment), or untreated HSIL, (i.e. a lesion that cannot be fully visualized) would be 
excluded.  
d. Exclusion criteria 7 has been revised to clarify that potential subjects with abnormal 
clinical screening laboratory values that resolve could qualify for screening.  The 
window for use of clinical laboratory results at screening has been extended from 
30 days to 45 days, which is still considered an acceptable acute time period but 
allows for screening activities to be completed with less risk of having to repeat blood 
draws during the screening period. 
e. For Exclusion criteria 8, malnutrition has been added to the list of potentially 
immunocompromising conditions.  
351

f. For Exclusions 9 and 10, ‘Day 0’ has been changed to ‘dosing’ to more accurately 
reflect the applicability for all doses. 
g. Exclusion criteria 12 has been modified to add the example of local anogenital 
malignancy that has been curatively treated.  
3. Updates to the Schedule of Events Table have been made as follows: 
a. The screening window for dosing has been clarified as 10 weeks from the date of 
collection of biopsy. 
b. The assessment of AEs and SAEs has been added as a separate line item to the table 
to align with Section 6, Study Procedures and Treatments. 
c. Footnote (e) has been revised to reflect that the requirement of pregnancy testing is 
only for women of child bearing potential. 
d. Footnote (f) has been revised to clarify that 8 ml of serum should be collected only 
at Screening, Day 0 and Week 8.  
e. Footnote (k) has been revised to add clarifying details for the lesion photography 
process, (also as described in Sections 6.1.1, 6.2 and 6.13). 
f. Footnote (p) has been revised to reflect the addition of quality of life questions at the 
Week 40 phone call visit for subjects enrolled in United States of America (USA), 
Canada, Germany, Mexico and United Kingdom (UK) (also as described in Sections 
6.2 and 6.8). 
4. General updates and clarifications: 
a. For the Study Design Section in Clinical Protocol Synopsis, the term ‘enrollment’ 
has been replaced with the more specific term ‘randomization’ regarding the process 
of biopsy slide review by the Pathology Adjudication Committee (PAC). 
b. For the Section 2 (Study Design) and Section 8.2 (Randomization and Blinding), a 
statement has been added indicating that a group of sequential allocation numbers 
will be designated for use by each participating country.  
c. For Section 1.1.3 (Electroporation), the Table of Comparative Device Overview has 
been removed and a statement has been added referring to the VGX-3100 
Investigator Brochure, where the most current information can be found. 
d. For Section 2.1.3 (Definition of Responder and Non-Responder), text describing the 
definitions of responder and non-responder for the primary endpoint has been added 
to correspond with the section table. Also, additional tables describing the definitions 
of responder and non-responder for the secondary efficacy endpoints have been 
added. 
e. In Section 5 (Sample Label for Investigational Product and Device), the device 
description has been updated to align with other study related documents (i.e. 
pharmacy manual, Investigator brochure).   
352

f. In Sections 5.8 (CELLECTRA™ 5PSP Device) and 5.9 (Use of CELLECTRA™ 5PSP 
Device), the content has been updated to align with the VGX-3100 Investigator 
Brochure and Device User Manual. 
g. For Section 6.1.1 (Screening Evaluations), ASCUS with or without a positive HPV 
test result has been substituted with ASC-H with or without a positive HPV test result 
to represent a higher probability condition that may qualify for screening. 
h. Additional language to clarify the approach to lesion photography has been added to 
the study procedures and treatments sections, 6.1.1, 6.2 and 6.13, (in addition to the 
Schedule of Events Table footnotes) 
i. Sections 6.1 (Before Treatment Procedures) and 6.2 (During Treatment Procedures 
by Visit) have been revised to align with the Schedule of Events Table. 
j. For Section 6.3.3.10 (Subject Self Evaluation), additional guidance has been added 
regarding the assessment and reporting of events from Participant Diary Card (PDC). 
k. For Section 6.4.1 (Risks of Treatment Procedures) has been revised to refer to the 
VGX- 3100 Investigator Brochure, which has the most current information. 
l. Section 6.9 (Peripheral Blood Immunogenicity Assessments) has been revised to add 
information regarding the DNA methylation biomarker. 
m. Section 6.10 (Tissue Immunogenicity Assessment) has been revised to add details 
regarding the Immunoscore analysis, which corresponds with Exploratory 
Objective 6.  
n. Section 7.1. (Safety Parameters) has been revised as follows: 
i. For Section 7.1.3 (Unexpected Adverse Drug Reactions and Expedited 
Reporting), the guidance for assessing severity has been updated adding 
Grade 5 to align with the Common Toxicity Criteria for Adverse Events 
(CTCAE) grading scale. 
ii. For Section 7.1.9 (Procedures for Documenting Pregnancy during Study), has 
been modified to clarify the timing of reporting of pregnancy in the study (i.e. 
all pregnancies that occur from the time of first screening procedure must be 
reported) and correct a potential discrepancy in the prior version.  
o. Section 7.3 (Safety and Toxicity Management) has been modified to align with safety 
assessments as stated in the section describing study design of clinical protocol 
synopsis. 
p. Section 8 (Statistical Analysis Plan) has been revised to align with the changes made 
to Objectives and Endpoints as follows: 
i. Section 8.1 (General Considerations): details of microRNA and DNA 
methylation testing have been added. 
ii. Section 8.8 (Prior and Concomitant Medications) has been revised to clarify 
that the start dates for prior and concomitant medications will not be imputed. 
353

iii. Section 8.9 (Efficacy Analysis) has been revised to add a description 
regarding the Immunoscore analysis per Exploratory Objective 6.  
iv. Section 8.10 (Immunogenicity Analyses) has additional clarifying 
information regarding the evaluation of immune assays. 
v. Section 8.11.1 (Adverse Events) has been revised to clarify the use of start 
and stop dates of adverse events for analysis purposes.  
vi. Section 8.14 (Patient Reported Outcomes) has been revised to change the 
testing method from non-parametric or Miettinen and Nurminen to Wilcoxon 
rank-sum test or Pearson chi-square test/Fisher’s exact test, which is 
appropriate for scales with multiple categories rather than only two 
categories. 
q. Section 9.4.2 (Pathology Adjudication Committee) now refers to the PAC charter, 
which has the most current information regarding the PAC review process. 
r. The Participant Diary Card is unchanged but has been removed from the Appendix 
since the Participant Diary Card is a separate document. 
5. Additional minor grammatical and administrative changes have been made throughout the 
document for improvement of general readability. 
 
 
354

 
INVESTIGATOR ACKNOWLEDGEMENT 
 
I have read this Protocol and agree that it contains all necessary details for carrying out the study 
described. I understand that it must be reviewed by the Institutional Review Board or Independent 
Ethics Committee overseeing the conduct of the study and approved or given favorable opinion 
before implementation. 
 
The signature of the Investigator below constitute his/her approval of this protocol and provide the 
necessary assurances that this study will be conducted according to the Declaration of Helsinki, 
ICH-GCP guidelines, local legal and regulatory requirements as well as to all stipulations of the 
protocol in both the clinical and administrative sections, including statements regarding 
confidentiality. 
 
 
 
__________________________________________________________ 
Investigator – Signature                      Date (DD/MMM/YYYY)       
 
 
________________________________________ 
Investigator – Printed Name        
 
 
 
 
 
Site Number: ___________________________________   
 
Site Name: _____________________________________ 
 
 
355

TABLE OF CONTENTS 
Summary of Changes .................................................................................................................................. 3 
Investigator Acknowledgement ................................................................................................................. 7 
Table of Contents ........................................................................................................................................ 8 
i 
List Of Abbreviations and definitions................................................................................................ 13 
ii Clinical Protocol Synopsis ................................................................................................................... 15 
1 Introduction ......................................................................................................................................... 24 
1.1 
Background ................................................................................................................................. 24 
1.1.1 HPV Infection, Cervical Intraepithelial Neoplasia and Cervical Cancer .......................... 24 
1.1.2 VGX-3100 ........................................................................................................................ 25 
1.1.3 Electroporation ................................................................................................................. 25 
1.1.4 Selection of study design .................................................................................................. 26 
1.2 
Dose and Regimen Rationale ...................................................................................................... 27 
1.3 
Risks/Benefit Assessment ........................................................................................................... 27 
1.3.1 Risks associated with Current Therapeutic Options ......................................................... 27 
1.3.2 Potential Risks of Study Participation .............................................................................. 28 
1.3.3 Potential Benefits of Study Participation .......................................................................... 29 
2 Study Design ......................................................................................................................................... 30 
2.1 
Endpoint Assessment .................................................................................................................. 30 
2.1.1 Histology Assessment ....................................................................................................... 31 
2.1.2 Virologic (HPV) Assessment............................................................................................ 32 
2.1.3 Definition of Responder and Non-Responder .................................................................. 32 
2.1.4 Immunogenicity AssessmenT ........................................................................................... 36 
2.2 
Treatment Plan ............................................................................................................................ 36 
2.3 
Safety Monitoring Plan ............................................................................................................... 36 
2.3.1 Data and safety Monitoring Board (DSMB) ..................................................................... 38 
2.4 
Long Term Follow up Plan ......................................................................................................... 38 
3 Hypothesis and Study Objectives ....................................................................................................... 41 
3.1 
Hypothesis ................................................................................................................................... 41 
3.2 
Primary Objective and Endpoint ................................................................................................. 41 
3.3 
Secondary Objectives and Associated Endpoints ....................................................................... 42 
3.4 
Exploratory Objectives and Associated Endpoints ..................................................................... 43 
4 Selection of Subjects ............................................................................................................................ 43 
4.1 
Inclusion Criteria ......................................................................................................................... 43 
4.2 
Exclusion Criteria........................................................................................................................ 44 
4.3 
Discontinuation/Withdrawal of Study Subjects .......................................................................... 46 
356

4.3.1 Criteria for Discontinuation of Investigational Product .................................................... 46 
4.3.2 Criteria for WithdrawAl from the Study ........................................................................... 46 
4.3.3 Sponsor Notification of Discontinuation/ Withdrawal ..................................................... 47 
4.3.4 Reason for Discontinuation/Withdrawal .......................................................................... 47 
4.3.5 Supplementation of study subjects ................................................................................... 47 
5 Study Treatment .................................................................................................................................. 48 
5.1 
Investigational Products .............................................................................................................. 48 
5.2 
Blinding ....................................................................................................................................... 48 
5.3 
Packaging and Labeling of investigational product .................................................................... 48 
5.4 
Handling of investigational product ............................................................................................ 49 
5.5 
Dispensing of Investigational Product ........................................................................................ 49 
5.6 
Investigational product Accountability ....................................................................................... 50 
5.7 
Return and Destruction of  Investigational Product .................................................................... 50 
5.8 
CELLECTRATM 5PSP Device .................................................................................................... 50 
5.9 
Use of CELLECTRA™ 5PSP device ........................................................................................... 53 
5.10 Packaging and Labeling of CELLECTRA™ 5PSP Device .......................................................... 53 
5.11 Handling of CELLECTRA™ 5PSP device .................................................................................. 54 
5.12 CELLECTRA™ 5PSP Device Accountability ............................................................................. 54 
5.13 Return of CELLECTRA™ 5PSP Devices .................................................................................... 54 
6 Study Procedures and Treatments ..................................................................................................... 55 
6.1 
Before Treatment Procedures ...................................................................................................... 55 
6.1.1 Screening Evaluations ...................................................................................................... 55 
6.2 
During Treatment Procedures by Visit ........................................................................................ 57 
6.2.1 Day 0 ................................................................................................................................. 57 
6.2.2 8-14 Days Post Dose 1 Phone call .................................................................................... 58 
6.2.3 Week 4 .............................................................................................................................. 58 
6.2.4 8-14 Days Post Dose 2 Phone Call ................................................................................... 58 
6.2.5 Week 8 .............................................................................................................................. 58 
6.2.6 Week 12 ............................................................................................................................ 59 
6.2.7 8-14 Days Post Dose 3 Phone Call ................................................................................... 59 
6.2.8 Week 15 ............................................................................................................................ 59 
6.2.9 Week 28 ............................................................................................................................ 60 
6.2.10 Week 36 ............................................................................................................................ 60 
6.2.11 Week 40 Phone call .......................................................................................................... 60 
6.2.12 Week 62 ............................................................................................................................ 61 
357

6.2.13 Week 88 ............................................................................................................................ 61 
6.3 
Evaluations and Procedures ........................................................................................................ 61 
6.3.1 Informed Consent ............................................................................................................. 61 
6.3.2 Assignment of Subject Identification Numbers ................................................................ 62 
6.3.3 Safety Evaluations ............................................................................................................ 62 
6.4 
Injection and Electroporation (EP) .............................................................................................. 64 
6.4.1 Risks of Treatment Procedures ......................................................................................... 64 
6.4.2 Management of Anxiety and Pain due to Treatment ........................................................ 65 
6.5 
Assessment of Laboratory Abnormalities ................................................................................... 65 
6.6 
Assessment of Clinical Study Adverse Events ........................................................................... 65 
6.7 
Assessment of Injection Site Reactions ...................................................................................... 66 
6.8 
Assessment of Patient Reported Outcomes ................................................................................. 66 
6.9 
Peripheral Blood Immunogenicity Assessments ......................................................................... 67 
6.10 Tissue Immunogenicity Assessment ........................................................................................... 68 
6.11 HLA Typing ................................................................................................................................ 68 
6.12 Pap Smears and HPV Testing ..................................................................................................... 68 
6.13 Colposcopy and Cervical Biopsies .............................................................................................. 69 
6.13.1 Ectocervical Biopsies ........................................................................................................ 69 
6.13.2 Unscheduled Biopsies ....................................................................................................... 70 
6.14 Concomitant Medications/Treatments ........................................................................................ 70 
6.15 Restrictions .................................................................................................................................. 70 
6.15.1 Prohibited Concomitant Medications and Treatments ...................................................... 70 
6.15.2 Other Restrictions ............................................................................................................. 71 
7 Evaluation of Safety and Management of Toxicity........................................................................... 71 
7.1 
Safety Parameters ........................................................................................................................ 71 
7.1.1 Adverse Events ................................................................................................................. 71 
7.1.2 Serious Adverse Events .................................................................................................... 72 
7.1.3 Unexpected Adverse Drug Reactions and Expedited Reporting ...................................... 73 
7.1.4 Unanticipated (Serious) Adverse Device Effect (UADE) ................................................ 74 
7.1.5 Assessing Severity (Intensity) .......................................................................................... 74 
7.1.6 Causal Relationship of Clinical Material to Adverse Events ............................................ 75 
7.1.7 Abnormal Laboratory Value ............................................................................................. 75 
7.1.8 Post-Study Reporting Requirements ................................................................................. 76 
7.1.9 Procedures for Documenting Pregnancy During Study .................................................... 76 
358

7.2 
Methods and Timing of the Collection and Recording of Safety Data ....................................... 76 
7.3 
Safety and Toxicity Management ............................................................................................... 77 
7.3.1 Adverse events of special interest ..................................................................................... 77 
7.3.2 Stopping Rules (Criteria for Pausing of Study) ................................................................ 77 
7.4 
Study Reporting Period of Adverse Events ................................................................................. 78 
7.4.1 Study reporting period of Adverse Events of special interest ........................................... 78 
7.4.2 Study Reporting Period of Serious Adverse Events ......................................................... 78 
7.4.3 Notification of SerioUs Adverse Events ........................................................................... 79 
7.4.4 Reporting of Device Related Complaints ......................................................................... 80 
7.5 
Study Discontinuation ................................................................................................................. 80 
8 Statistical Analysis Plan ...................................................................................................................... 80 
8.1 
General Considerations ............................................................................................................... 80 
8.2 
Randomization and Blinding ....................................................................................................... 81 
8.3 
Sample Size/Power ...................................................................................................................... 81 
8.4 
Analyses Populations .................................................................................................................. 81 
8.5 
Subject Disposition ..................................................................................................................... 81 
8.6 
Demographic and Other Baseline Characteristics ....................................................................... 82 
8.7 
Medical History ........................................................................................................................... 82 
8.8 
Prior and Concomitant Medications ............................................................................................ 82 
8.9 
Efficacy Analyses ........................................................................................................................ 82 
8.10 Immunogenicity Analyses ........................................................................................................... 83 
8.11 Safety Analyses ........................................................................................................................... 83 
8.11.1 Adverse Events ................................................................................................................. 83 
8.11.2 Laboratory Data ................................................................................................................ 83 
8.12 Vital Signs ................................................................................................................................... 84 
8.13 Physical Examination .................................................................................................................. 84 
8.14 Patient Reported Outcomes ......................................................................................................... 84 
8.15 Missing Values ............................................................................................................................ 84 
8.16 subgroup analyses ....................................................................................................................... 84 
8.17 Interim Analysis .......................................................................................................................... 84 
9 Data Collection, Monitoring and Reporting ..................................................................................... 84 
9.1 
Confidentiality and Privacy ......................................................................................................... 84 
9.2 
Source Documents ...................................................................................................................... 85 
9.3 
Records Retention ....................................................................................................................... 85 
9.4 
Safety and Quality Monitoring .................................................................................................... 86 
9.4.1 Data & Safety Monitoring Board...................................................................................... 86 
359

9.4.2 Pathology Adjucation Committee ..................................................................................... 86 
9.4.3 Clinical Monitoring .......................................................................................................... 86 
10 Ethics 87 
10.1 Investigator and Sponsor Responsibilities .................................................................................. 87 
10.2 Institutional Review Board or Institutional Ethics committee (IRB/IEC) .................................. 87 
10.3 Office of Biotechnology Activities (OBA) ................................................................................. 88 
11 Protection of Human Subjects ............................................................................................................ 88 
11.1 Compliance with Informed Consent Regulations ....................................................................... 88 
11.2 Compliance with IRB/IEC Requirements ................................................................................... 88 
11.3 Compliance with Good Clinical Practice .................................................................................... 88 
11.4 Compliance with Electronic Records/Signatures Regulations (21CFR Part 11) ........................ 88 
11.5 Compliance with Protocol ........................................................................................................... 88 
11.6 Changes to the Protocol .............................................................................................................. 88 
12 Financing and Insurance ..................................................................................................................... 89 
13 Publication Policy ................................................................................................................................ 89 
14 References ............................................................................................................................................ 90 
15 Appendix .............................................................................................................................................. 92 
15.1 Appendix A:  Guidelines for Colposcopy, Biopsy, and Surgical Excision ................................. 92 
 
 
 
 
360

I 
LIST OF ABBREVIATIONS AND DEFINITIONS 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AIS 
Adenocarcinoma-in-situ 
AGC 
Atypical Glandular Cell 
ASC-H  
Atypical Squamous Cells, cannot exclude High grade squamous intraepithelial lesion 
ASC-US  
Atypical squamous cells of undetermined significance 
BMI 
Body Mass Index 
Baseline 
Prior to first dose 
CEF 
Cytomegalovirus, Epstein Barr Virus and Influenza 
CFR 
Code of Federal Regulations 
CIN 
Cervical Intraepithelial Neoplasia 
CKC 
Cold knife conization 
CMI 
Cell mediated immunity 
CMR 
Complete Metabolic Response 
CMV 
Cytomegalovirus 
CRF 
Case Report Forms 
CPK 
Creatine Phosphokinase 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTL 
Cytotoxic T-cells 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of Acquired Immunodeficiency Syndrome  
DNA 
Deoxyribonucleic Acid 
DNAme 
Methylated Deoxyribonucleic Acid 
ECC 
Endocervical Curettage 
EP 
Electroporation with CELLECTRA™ 5PSP 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISpot 
Enzyme Linked Immunosorbent Spot-forming Assay 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCG 
Human Chorionic Gonadotropin 
HSIL 
High grade squamous intraepithelial lesion 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPV 
Human Papillomavirus 
HPV-16/18 
HPV-16 and/or HPV-18 
361

ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IHC 
Immunohistochemistry 
IFN-γ 
Interferon Gamma 
IL-12 
Interleukin 12 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IUD 
Intrauterine Device 
IXRS 
Interactive Response System 
LAST 
Lower Anogenital Squamous Terminology 
LEEP 
Loop Electrosurgical Excision Procedure 
LLETZ 
Large Loop Excision of Transformation Zone 
LSIL 
Low grade squamous intraepithelial lesion 
MedDRA® 
Medical Dictionary for Drug Regulatory Affairs 
miRNA 
Micro Ribonucleic Acid 
mITT 
Modified Intent to Treat 
NILM 
Negative for intraepithelial lesion or malignancy 
NIH 
National Institutes of Health 
OP 
Oropharyngeal  
Principal Investigator 
Lead Investigator for overall study activities 
Investigator 
Lead Investigator for individual site(s) 
PAC  
Pathology Adjudication Committee 
PBMC 
Peripheral Blood Mononuclear Cells 
PDC 
Participant Diary Card 
PRO 
Patient Reported Outcomes 
PE 
Physical exam 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SID 
Subject Identification   
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
sWFI 
Sterile Water for Injection 
TNF 
Tumor Necrosis Factor 
ULN 
Upper Limit of Normal 
WOCBP 
Women of Childbearing Potential 
362

II CLINICAL PROTOCOL SYNOPSIS 
 
Title of Study:  A Prospective, Randomized, Double-blind, Placebo-Controlled Phase 3 Study of 
VGX-3100 Delivered Intramuscularly followed by Electroporation with CELLECTRA™ 5PSP for 
the Treatment of HPV-16 and/or HPV-18 related High Grade Squamous Intraepithelial Lesion 
(HSIL)0F1 of the Cervix 
Estimated Number of Study Centers and Countries/Regions:  Approximately 125 Sites  in up 
to 25 Countries 
Study Phase: 3 
Primary Hypothesis:  Three 6 mg doses of VGX-3100 (DNA Plasmids encoding E6 and E7 
proteins of HPV-16 and HPV-18) delivered intramuscularly (IM) followed by electroporation 
(EP) with CELLECTRA™ 5PSP to adult women with histologically confirmed HSIL[Cervical 
Intraepithelial Neoplasia (CIN)2, CIN3] of the cervix, associated with HPV-16 and/or HPV-18 
will result in a higher percentage of women with histopathological regression of cervical HSIL 
lesions to no evidence of cervical HSIL and virologic clearance of HPV-16 and/or HPV-18 
compared to placebo delivered IM followed by EP with CELLECTRA™ 5PSP at the Week 36 
visit2  
Study Drug Dose 
6 mg (1 ml) 
Administration 
Intramuscular injection followed by EP with the CELLECTRA™ 5PSP 
device 
Schedule 
Day 0, Week 4, and Week 12 study visits 
No. of Subjects 
Approximately 198 subjects will be randomized in a 2:1 ratio to receive 
VGX-3100 or placebo 
Study Duration 
88 weeks 
Primary Objective 
Determine the efficacy of VGX-3100 compared with placebo with respect 
to combined histopathologic regression of cervical HSIL and virologic 
clearance of HPV-16 and/or HPV-18 
Primary Endpoint 
Proportion of subjects with no evidence of  cervical HSIL on histology 
(i.e. biopsy or excisional treatment) and no evidence of HPV-16 and/or 
HPV-18 in cervical samples by type specific HPV testing at Week 36 visit 
 
 
 
 
1 Terminology based on 2012 consensus recommendation on Lower Anogenital Squamous Terminology (LAST) from 
the American Society of Colposcopy and Cervical Pathology (ASCCP) and the College of American Pathologists (CAP) 
2 The time frame is defined as any time starting from 14 days prior to the protocol-specified target date of Week 36 
363

 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of 
VGX-3100 delivered IM followed by EP 
with CELLECTRA™ 5PSP 
1a. Incidence and severity of local and systemic 
events for 7 and 28 days following each 
investigational treatment  and for the duration of 
the study (through Week 88 visit) 
1b. Incidence and severity of all adverse events 
including Serious adverse events (SAEs) (e.g. 
Suspected unexpected serious adverse reaction 
(SUSAR), Unexpected adverse device effect 
(UADE) and other unexpected AEs) for the 
duration of the study (through Week 88 visit) 
2. Determine VGX-3100 efficacy compared 
to placebo as measured by histopathologic 
regression of cervical HSIL 
2. Proportion of subjects with no evidence of  
cervical HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 36 visit 
3. Determine VGX-3100 efficacy compared 
to placebo as measured by virologic 
clearance of HPV-16 and/or HPV-18 
3. Proportion of subjects with no evidence of 
HPV-16 and/or HPV-18 in cervical samples 
by type specific HPV testing at Week 36 visit 
4. Determine VGX-3100 efficacy compared 
to placebo as measured by complete 
histopathologic regression of cervical 
HSIL to normal 
4. Proportion of subjects with no evidence of Low 
grade squamous intraepithelial lesion (LSIL) 
or HSIL (i.e.  no evidence of CIN1, CIN2 or 
CIN3) on histology (i.e. biopsies or excisional 
treatment) at Week 36 visit 
5. Determine VGX-3100 efficacy compared 
to placebo as measured by both complete 
histopathologic regression of cervical 
HSIL to normal and virologic clearance 
of HPV-16 and/or HPV-18 
5. Proportion of subjects with no evidence of 
LSIL or HSIL (i.e. no evidence of CIN1, CIN2 
or CIN3 on biopsies or excisional treatment) on 
histology (i.e. biopsies or excisional treatment) 
and no evidence of HPV-16 and/or HPV-18 
by type specific HPV testing at Week 36 visit 
6. Determine VGX-3100 efficacy compared 
to placebo as measured by histopathologic 
non-progression 
6. Proportion of subjects with no progression of 
cervical HSIL to cervical carcinoma from 
baseline on histology (i.e. biopsies or excisional 
treatment) at Week 36 visit 
7. Describe the clearance of HPV-16 and/or 
HPV-18 
infection 
from 
non-cervical 
anatomic locations 
7. Proportion of subjects who have cleared HPV-
16 and/or HPV-18 on specimens from non-
cervical 
anatomic 
locations 
(oropharynx, 
vagina and intra-anal) at Week 36 Visit 
8.Determine the humoral and cellular 
immune response to VGX-3100 compared 
with placebo at post dose 3 and Week 36 
visits as assessed relative to baseline  
8a. Levels of serum anti-HPV-16 and anti-HPV-18 
antibody concentrations at Weeks 15 and 36 
visits 
8b. Interferon-γ ELISpot response magnitudes at 
baseline, Weeks 15 and 36 visits 
364

8c. Flow Cytometry response magnitudes at 
baseline and Week 15 visits 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Evaluate tissue immune responses to 
VGX-3100 in cervical samples 
1. Assessment of markers including but not 
limited to CD8+ and FoxP3+ infiltrating 
cells. Additional assessments may include 
visualization of Granulysin, Perforin, 
CD137, CD103 and PD-L1 in cervical tissue 
as sample allows.  Markers listed here may 
change as new relevant information 
becomes available 
2. Evaluate effect of Human Leukocyte 
Antigen (HLA) type on efficacy 
2. HLA (per-locus and per-allele basis) in 
conjunction with histologic regression of 
cervical HSIL at Week 36 visit 
3. Describe 
association 
of 
microRNA 
(miRNA) profiles, DNA methylation 
profile, previous colposcopy, cytology 
and HPV testing results with Week 36 
histologic regression 
3. Colposcopy, cytology, and HPV test results 
(Weeks 8, 15 and 28 visits), miRNA profile 
(baseline, Week 8) and DNA methylation 
profile (baseline, Week 15) in conjunction 
with histologic regression of cervical HSIL at 
Week 36 visit 
4. Describe the durability of virologic 
clearance of HPV-16 and/or HPV-18 for 
subjects 
treated 
with 
VGX-3100 
compared with those treated with placebo 
4. Proportion of subjects with no evidence of 
HPV-16 and/or HPV-18 by type specific 
HPV testing at Weeks 62 and 88 visits 
5. Describe the patient-reported outcomes 
for subjects treated with VGX-3100  
5. Patient-reported 
outcome 
questionnaires 
self-administered at baseline, after each dose 
at Weeks 4, 12, 8-14 days following each 
dose, and at Weeks 28, 36, 40 and 88 by 
subjects enrolled in US, Canada, Mexico, 
Germany and UK 
6. Describe the association of a tissue-based 
score derived using immunologic markers 
(Immunoscore) at baseline to histological 
and virological response to VGX-3100  at 
Week 36 
6. Immunoscore results for VGX-3100 treated 
subjects in conjunction with histological and 
virological outcomes at Week 36 
Study Design: 
This Phase 3 study design is based upon the Phase 2b study design and results.  HPV-301 is a 
prospective, randomized, double-blind, placebo controlled Phase 3 study to determine the efficacy 
safety, and tolerability of VGX-3100 administered by IM injection followed by EP delivered with 
CELLECTRA™ 5PSP in adult women with histologically confirmed cervical HSIL (CIN2, CIN3) 
associated with HPV-16 and/or HPV-18 (HPV-16/18). The composite primary endpoint is histologic 
regression of cervical HSIL, and clearance of the underlying HPV-16/18 infection. A sample of 
365

approximately 198 subjects will be randomized to receive either 6 mg (in 1 ml) VGX-3100 or 
placebo, each IM followed by EP, in a 2:1 ratio. This sample size provides 90% power to declare 
VGX-3100 superior to placebo, assuming, based upon Phase 2b study results, that the true 
proportion of subjects whose lesion(s) regress and whose HPV-16/18 clears is 35% and 14% for 
VGX-3100 and placebo, respectively. 
To be eligible for the study, women age 18 years and above must consent to participate and have 
biopsy/biopsies of the cervical lesion(s) at the time of screening. The biopsy slides are sent to a 
central pathology lab for Pathology Adjudication Committee (PAC) review in a blinded manner to 
establish the presence of cervical HSIL (CIN2, CIN3) prior to randomization. Subjects must also 
have a cervical ThinPrep™ specimen test positive for HPV-16/18 by cobas™ HPV test to be eligible 
for participation in the study.  
All eligible subjects will receive three doses of VGX-3100 or placebo administered IM followed 
immediately by EP with the CELLECTRA™ 5PSP device. The first study treatment is administered 
on Day 0, the second at Week 4, and the third (final) study treatment is administered at Week 12. 
The first dose is administered as soon as possible following confirmation of the cervical HSIL 
diagnosis and cervical sample positive for HPV-16/18 but no more than 10 weeks following 
collection of the subject’s biopsy specimen used for diagnosis by the PAC during screening.  
Subjects are randomized in a stratified manner according to (a) the CIN severity observed in the 
biopsy specimens at screening (i.e. CIN2 vs. CIN3), (b) Body Mass Index (BMI) category (≤25 vs. 
>25 kg/m2), and (c) age category (<25 years vs. ≥25 years). To ensure CIN2 disease is not over-
represented in the study, the percentage of subjects enrolled with CIN2 will not exceed 50% of the 
total enrolled. A group of sequential allocation numbers will be designated for use by each 
participating country. 
The long term follow up plan following the Week 36 efficacy assessment will include safety, 
cytology and HPV testing for a period of approximately 1 year (Week 88). 
Efficacy: Visualization of a normal appearing cervix by colposcopy and cytology are insufficient 
evidence to confirm disease regression. Therefore, disease regression will be based on 
histopathological assessment, which is considered the definitive method for diagnosis. Subjects will 
also be assessed by colposcopy, cytology, and HPV testing at screening, and at specified visits on 
and after Day 0. Digital photographs of the cervix following application of acetic acid will also be 
used to document colposcopic exam findings. 
Tissue to be analyzed for evidence of histopathologic regression will be obtained at Week 36 either 
by excision (e.g. loop electrosurgical excision procedure (LEEP), large loop excision of 
transformation zone (LLETZ), cold knife conization (CKC)) or by biopsy (4 Quadrant Biopsy or 4 
Quadrant Biopsy with Endocervical Curettage (ECC)) based upon the assessment at Week 28 of 
cytology, High Risk (HR) HPV status, and colposcopic findings (see Tables 5 and 6, for Minimally 
Required Procedures).   
Safety: All subjects will be followed for 88 weeks. 
 
Subjects will be monitored for: 
366

1) Local and systemic events for 7 days following each investigational treatment as noted on a 
Participant Diary Card (PDC); 
2) All adverse events including SAEs, UADEs, and other unexpected AEs for the duration of the 
study; 
Data and Safety Monitoring Board (DSMB): The DSMB will meet quarterly to review unblinded 
safety data and histopathologic regression results. The DSMB will be charged with advising the 
Sponsor if there appears to be a safety issue and with advising the Sponsor if it appears that the 
proportion of the subjects with histopathologic regression in the VGX-3100 group is unacceptably 
low compared to the placebo group. No formal interim analysis will be performed.   
Immunogenicity: Humoral and cell mediated immune responses in response to VGX-3100 treatment 
will be evaluated in blood samples taken at baseline (both Screening as well as Day 0 prior to dosing) 
and at Weeks15, and 36. Cervical tissue samples will also be analyzed for evidence of elevated 
immune responses at Week 36 as compared to baseline (screening). 
Virology: Cervical cytology samples will be obtained to characterize HPV infection at Day 0 (prior 
to dosing) and at Weeks 8, 15, 28, 36, 62, and 88 by cobas™ HPV test. Additionally, if there is 
residual tissue in the paraffin block from cervical tissue after histologic diagnoses have been 
rendered at screening and Week 36, then unstained slides and/or the relevant paraffin blocks may 
be tested for the presence of HPV-16/18. Vaginal brush and oropharyngeal rinse samples will be 
obtained at Day 0 (prior to dosing), Weeks 36 and 88 while intra-anal samples will be obtained on 
Day 0 (prior to dosing) and Week 36 to characterize HPV infection.  
HLA typing: The relationship between subject HLA types and efficacy responses will be explored 
using available PBMC sample collected for immunogenicity analysis. 
Study Population 
Inclusion Criteria: 
1. Women aged 18 years and above and meets the minimum age of consent per local regulations; 
2. Confirmed cervical infection with HPV types 16 and/or 18 at screening by cobas™ HPV test;  
3. Cervical tissue specimen/slides provided to Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study drug; 
4. Histologic evidence of cervical HSIL as confirmed by PAC at screening; 
5. Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form 
prior to study-related activities; 
6. Must be judged by Investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision, 4-quadrant biopsy with ECC, or 4-quadrant biopsy) required at Week 
36; 
7. Satisfactory colposcopy at screening, defined as full visualization of the squamo-columnar 
junction (Type I or II transformation zone) and complete visualization of the upper limit of aceto-
white epithelium or suspected CIN disease; 
8. Cervical lesion that is accessible for sampling by biopsy instrument (e.g. Mini-Tischler device); 
9. Cervical lesion of adequate size to ensure that a visible lesion remains after screening biopsy; 
10. Must meet one of the following criteria with respect to their reproductive capacity: 
367

a) Post-menopausal as defined by spontaneous amenorrhea for more than 12 months; 
b) Surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 12 months prior to screening; 
c) Women of Child Bearing Potential (WOCBP) is willing to use a contraceptive method with 
failure rate of less than 1% per year when used consistently and correctly from screening 
until Week 36. The following methods are acceptable : 
i. Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. Hormonal 
contraceptives must not be used in subjects with a history of hypercoagulability (e.g., 
deep vein thrombosis, pulmonary embolism); 
ii. Abstinence from penile-vaginal intercourse when this is the subject’s preferred and usual 
lifestyle; 
iii. Intrauterine device or intrauterine system; 
iv. Male partner sterilization at least 6 months prior to the female subject’s entry into the 
study, and this male is the sole partner for that subject; 
11. Normal screening ECG or screening ECG with no clinically significant findings, as judged by 
the investigator. 
Exclusion Criteria: 
1. Microscopic or gross evidence of adenocarcinoma-in-situ (AIS), high grade vulvar, vaginal 
(inclusive of cervical HPV-related lesions that extend into the vaginal vault), or anal 
intraepithelial neoplasia or invasive cancer in any histopathologic specimen at screening; 
2. Cervical lesion(s) that cannot be fully visualized on colposcopy due to extension high into 
cervical canal at screening; 
3. ECC that shows a potentially untreated carcinoma, untreated HSIL, indeterminate, or 
insufficient for diagnosis (ECC is not required to be performed as part of study screening); 
4. Treatment for cervical HSIL within 4 weeks prior to screening; 
5. Pregnant, breastfeeding or considering becoming pregnant through Week 36 visit; 
6. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are 
allowed, e.g. Gardasil™, Silgard™, Cervarix™); 
7. Presence of any unresolved abnormal clinical screening laboratory values of Grade 1 or greater 
per Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 and deemed clinically 
significant by the investigator within  45 days prior to Day 0; 
8. Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening (performed within 30 days prior 
to Day 0) 
b) Primary immunodeficiencies 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent; (use of inhaled, otic, and ophthalmic corticosteroids are allowed); 
d) 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); 
e) History of solid organ or bone marrow transplantation; 
368

f) Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
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 
g) Subjects who are malnourished (i.e. medically significant unintentional weight loss, 
kwashiorkor, or marasmus) based on screening labs, medical history and physical exam per 
the investigator’s clinical judgment.  
9. Receipt of any non-study, non-live vaccine within 2 weeks of  dosing; 
10. Receipt of any non-study, live vaccine (e.g. measles vaccine) within 4 weeks of dosing; 
11. Current or history of clinically significant, medically unstable disease which, in the judgment of 
the investigator, would jeopardize the safety of the subject, interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results (e.g. chronic renal 
failure; angina, myocardial ischemia or infarction, class 3 or higher congestive heart failure, 
cardiomyopathy, or clinically significant arrhythmias); 
12. Malignancy or systemic treatment for malignancy within 2 years of screening (with the 
exception of curatively treated, localized anogenital cancers and superficial skin cancers which 
are permitted)   
13. Presence of acute or chronic bleeding or clotting disorder that would contraindicate IM 
injections, or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of 
Day 0; 
14. History of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic 
agents; 
15. Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or 
a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
16. Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at 
screening or Day 0; 
17. Prior major surgery within 4 weeks of Day 0; 
18. Participation in an interventional study with an investigational compound or device within 30 
days of signing informed consent; participation in an observational study is permitted; 
19. Less than two acceptable sites available for IM injection considering the deltoid and anterolateral 
quadriceps muscles; 
20. Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
21. Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located 
in ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 
22. Metal implants or implantable medical device within the electroporation area; 
23. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere 
with adherence to study requirements; 
24. Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of 
either a psychiatric or physical (i.e. infectious disease) illness; 
25. Active military service personnel; 
26. Study-related staff or family member of study-related staff; 
27. 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. 
 
 
369

Table 1. Schedule of Events 
Tests 
Screening 
(-10 weeks to -1 Day  
from Date of Biopsy) 
 
Weeks 
Day 0 
8-14 days post Day 0 
Phone Call 
4 (± 4 days) 
8-14 days post Week 4 
Phone Call 
8 (± 4 days) 
12 (± 4 days) 
8-14 days  
post Week 12 
15 (± 1 week) 
28 (± 1 week) 
36 (± 1 week) 
40 (± 2 weeks) 
Phone call 
62 (± 2 weeks) 
88 (± 2 weeks) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behaviorala 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam/assessmentb 
X 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
Vital signs 
Xc 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
Screening safetyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Teste 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
X 
HIV Antibody Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood immunologic 
samplesf 
X 
X 
 
 
 
X 
 
 
Xg 
 
X 
 
 
 
Cervical Digene swabsi,j 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
X 
ThinPrep™ h,i 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
 
X 
X 
Colposcopy, lesion 
photographk 
Xl 
X 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
Ectocervical biopsym 
X 
 
 
 
 
 
 
 
 
 
Xn 
 
 
 
Surgical excisionm 
 
 
 
 
 
 
 
 
 
 
Xn 
 
 
 
OP rinse, vaginal swabs 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Intra-anal swabso 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Inject VGX-3100/Placebo 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Post treatment assessment 
 
X 
X 
X 
X 
X 
X 
Xq 
X 
 
 
 
 
 
AE/SAE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Distribute PDC 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Review PDC 
 
 
X 
 
X 
X 
 
Xq 
 
 
 
 
 
 
PROsp 
 
X 
X 
X 
X 
 
X 
Xq 
 
X 
X 
X 
 
X 
 
a Socio-Behavioral assessments, e.g. self-reported smoking and alcohol history 
b Full physical examination (PE) mandatory at screening and study discharge (Week 88), otherwise targeted physical 
assessment as determined by the Investigator or per subject complaints unless signs or symptoms dictate the need for 
a full PE; 
c Screening vital signs must include a measured height and weight. Weight will be collected on Day 0, Weeks 4 and 12; 
370

d Screening safety includes 12-Lead ECG, complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), 
serum creatinine (Cr), serum glucose, serum ALT, serum CPK and urinalysis performed within 45 days prior to  Day 
0; 
e For WOCBP, a negative spot urine pregnancy test is required at screening and prior to each study treatment, colposcopy 
and surgical excision;   
f At least 34 mL [4 x 8.5 mL yellow (ACD) tubes] whole blood per time point and 8 mL serum per time point at 
Screening, Day 0 and Week 8 (4 ml serum per time point at Week 15 and 36).   A total of at least 68 mL of whole blood 
and 16 ml serum should be collected prior to dosing on Day 0. HLA testing will performed once from an existing 
PBMC sample; 
g At least 51 mL [6 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum should be collected at Week 15; 
h HPV genotyping and Pap smears are performed on the same ThinPrep™ cervical specimen; 
i Request that the subject abstain from sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to cervical specimen collection; 
j Collected prior to the ThinPrep™ sample; 
k A photograph of the lesion with at least one attempt should done as follows: Acetic acid should first be applied to the 
cervix then photographs of the cervix and the associated lesion should be photographed prior to and after biopsies (if 
applicable) and at all colposcopic examinations; if repeat photographs are sought, they should be done at the next 
protocol-specified colposcopy visit.   
l Screening colposcopy is optional if adequate colposcopy was performed upon collection of initial biopsy; 
m Screening biopsy of the lesion should be collected as Paraffin-embedded cervical tissue, fresh cervical tissue, or H&E 
slides. Tissue to be analyzed for evidence of histopathologic regression will be obtained at Week 36 visit either by 
excision (e.g. LEEP,  LLETZ, CKC) or by 4 Quadrant Biopsy or 4 Quadrant Biopsy with ECC based upon the 
assessment at Week 28 of cytology, HR HPV status, and colposcopic findings (See Tables 5 and 6); 
n Slides from biopsy and/or excised tissue must be reviewed by the PAC and residual cervical tissue from screening 
and/or Week 36 specimen(s) (paraffin blocks or unstained slides) may be used for immunohistochemistry (IHC) and 
HPV testing; 
o To be collected only if subject consents for intra-anal sample collection  
p One or both PRO questionnaires (i.e. SF-36 and EQ-5D-5L) will be completed by subjects enrolled in USA, Canada, 
Mexico, Germany and UK at multiple visits during the study. Additional quality of life questions will be asked at the 
Week 40 phone call.  Refer to Section 6.8 for details 
q Activities at 8 to 14 days Post-Dose 3 phone call may be done at Week 15 if timing overlaps. 
 
 
 
 
 
 
371

1 INTRODUCTION 
1.1 
BACKGROUND  
1.1.1 
HPV INFECTION, CERVICAL INTRAEPITHELIAL NEOPLASIA AND 
CERVICAL CANCER  
Infection with human papillomavirus (HPV) can lead to malignant neoplasia, localized primarily 
in the anogenital area and aerodigestive tract, in both men and women.  HPV types tropic to 
mucosal tissues are classified into high-risk (HR), based on their potential to cause cancer, and 
low-risk (LR) (causing generally benign lesions). HPV-16 and HPV-18 are the most significant 
amongst high-risk types since they are responsible for most HPV-caused cancers [3].  In the US 
alone, approximately 14 million new genital HPV infections occur annually, and approximately 
half of these infections are with a HR HPV type [4, 5].  Up to 13000 women in the US alone are 
diagnosed with cervical cancer each year, which leads to an estimated 4120 deaths [6].  HPV-16 
is the most common high-risk genotype and combined with HPV-18 these two genotypes are 
estimated to cause about 70% of all cervical cancers [7, 8]. 
Incident infection by HPV is characterized by ongoing viral replication and shedding and is 
associated with early histologic changes (grade 1 cervical intraepithelial neoplasia) when the 
female cervix is infected with HPV.  Most cases of genital HPV infection clear spontaneously, but 
persistent infection with one or more oncogenic (high-risk) HPV genotypes can lead to the 
development of precancerous, histologic high grade squamous intraepithelial lesions of the cervix, 
HSIL which is inclusive of grade 2 and 3 cervical intraepithelial neoplasia (CIN2/3) [9].   Over 
time, typically years, cervical HSIL can progress to invasive cancer of the cervix [10, 11].  The 
basis for these changes are attributed to the viral proteins E6 and E7.  Infected cells produce E6 
and E7 constitutively which increases the degradation of cell cycle regulation proteins p53 and 
pRb, respectively, resulting in unrestricted cell growth and neoplasia.   
While the currently available prophylactic HPV vaccines (Cervarix™, Gardasil™, and Gardasil™-
9) are highly effective in preventing persistent infection and the subsequent development of high-
grade CIN caused by HPV-16, HPV-18 and other HPV types, the prophylactic vaccines have no 
therapeutic effect upon existing HPV infection or existing HPV-related intraepithelial neoplasia 
[12].  This means that the large number of women who already have high grade cervical dysplasia, 
either because they were too old to have received the prophylactic vaccine or they didn’t respond 
to vaccination, must currently only rely upon surgery and the chance of spontaneous regression to 
treat their condition and avoid progression to cancer.  Furthermore, the number of US-eligible 
teenagers who complete the prophylactic vaccination series remains low; 39.7% of US girls ages 
13-17 completed their prophylactic HPV immunization series in 2014, which leaves a potentially 
vulnerable, under-protected population [13]. The current approaches to the management of 
cervical HSIL typically require surgery (i.e. LEEP/LEETZ, laser ablation, or conization); 
however, surgical excision does not necessarily address the underlying HPV-infection, and can 
adversely impact the reproductive health of women of childbearing age.  Therefore, VGX-3100 is 
being developed as a non-surgical therapeutic option for the precancerous precursor to cervical 
cancer, cervical HSIL, and the underlying, pathogenic HPV infection.  
 
372

1.1.2 
VGX-3100 
VGX-3100 contains plasmids that encode HPV-16 E6/E7 and HPV-18 E6/E7 antigens. The 
plasmids were designed and constructed using proprietary synthetic vaccine (SynCon™) 
technology. This process involves synthetically deriving consensus genes across multiple strains 
and optimizing DNA inserts at the genetic level to allow high expression in human cells. Together, 
VGX-3100 and the CELLECTRA™ device represent an integrated investigational product 
designed as a non-surgical treatment of HPV-16/18-related cervical HSIL (CIN2, CIN3) via an 
immune response directed against HPV-16/18. 
The initial formulation of VGX-3100 was water for injection with 1% w/w poly-L-glutamate 
(WFI/LGS) that required frozen storage.  This WFI/LGS formulation has been administered to 
more than 250 subjects in Phase 1 and 2 clinical trials. A buffered formulation of VGX-31003 was 
developed using a saline sodium citrate (SSC) solution, which is stored non-frozen (5°C). This 
SSC formulation of VGX-3100 was administered to 116 subjects in a Phase 1 clinical trial, HPV-
101. In study HPV-101, three 6 mg doses of VGX-3100 as the SSC formulation were delivered 
IM followed by EP with CELLECTRA™ 5P to healthy adults.  Based upon interim analysis data 
at study Week 14, the SSC formulation is considered non-inferior to the WFI/LGS formulation 
based upon a 2-fold rise in overall Spot Forming Units (SPU) to the antigens encoded by the 
plasmids per 106 Peripheral Blood Mononuclear Cells (PBMC) as measured from baseline to 
Week 14 using the interferon-γ ELISpot assay. 
Proof of concept was demonstrated in the prospective, randomized, double blind, placebo-
controlled Phase 2b study of VGX-3100 (WFI/LGS formulation) followed by EP in the treatment 
of high grade cervical dysplasia, cervical HSIL associated with HPV-16 and/or HPV-18.  The 
Phase 2b study, HPV-003, enrolled and dosed 167 subjects with high grade cervical dysplasia 
from seven countries and one United States Territory (Australia, Canada, Estonia, Republic of 
Georgia, India, South Africa, United States and Puerto Rico). Subjects were randomized in a 3:1 
ratio to the treatment arm (VGX-3100, WFI/LGS formulation) or the placebo arm, respectively. 
All subjects were to receive treatment on Day 0, Week 4 and Week 12. All subjects were to repeat 
cervical biopsy or LEEP of the cervix at Week 36 to assess efficacy defined as regression of high 
grade CIN by histopathology.   The primary endpoint was histopathologic regression of cervical 
lesions (CIN2 or CIN3) to CIN1 or less at the Week 36 visit.   A secondary endpoint was clearance 
of HPV-16/18 in combination with histopathologic regression of cervical lesions to CIN1 or less. 
The proportions of subjects who met the primary and secondary endpoints were significantly 
higher in the VGX-3100 group vs. placebo in both per protocol and modified intent to treat 
analyses.  Robust T-cell activity was detected in VGX-3100 recipients compared to placebo 
recipients. VGX-3100 was generally safe and well tolerated when administered intramuscularly 
with electroporation.  
1.1.3 
ELECTROPORATION 
VGX-3100 is delivered using the CELLECTRA™ in vivo electroporation (EP) device. EP is a 
physical method of tissue transfection whereby the generation of short, controlled electrical pulses 
3 Designated in earlier version of the HPV-301 protocol as VGX-3100X 
373

creates a localized electric field at the injection site of the DNA vaccine which increases cell 
membrane permeability and improves the transfection of DNA and subsequent immunogenicity  
[14, 15]. EP is believed to increase the uptake and processing of plasmid DNA, thereby enabling 
increased expression and enhanced vaccine immunogenicity by 10 to 100 fold [16, 17]. This 
technology has been used for more than three decades by molecular biologists for cell transfection 
and has demonstrated versatility in use, as shown by its functionality in combination with a range 
of molecules, tissue types, disease indications, and across species [18]. 
The CELLECTRA™ device developed by Inovio is used for investigational purposes to administer 
plasmid-based DNA, in both prophylactic and therapeutic settings. Following successful proof-
of-concept studies in animals, Inovio has optimized both pulse pattern and voltage to increase 
transfection efficiency, and has demonstrated that the device helps to elicit favorable 
immunogenicity in several species (e.g., mice, pigs, and rhesus macaques) [19, 20].  
VGX-3100, WFI/LGS formulation, has been administered throughout Phase 1 and Phase 2 
investigations with the CELLECTRA™ 2000 device. A next generation device, CELLECTRA™ 
5PSP, will be used in Phase 3. Both designs of the CELLECTRA™ device enhance the 
intracellular uptake of VGX-3100 by the delivery of electrical current, and the electrical current 
delivery and pulse pattern (electroporation) is identical in both designs. CELLECTRA™ 2000 
involves a manual injection of VGX-3100 while the CELLECTRA™ 5PSP device will automate 
the intramuscular delivery of VGX-3100 and delivery of the EP pulses triggered by a single button 
press. Neither the dosage nor volume of VGX-3100 administered differs between the two devices. 
Administration of VGX-3100 with the CELLECTRA™ 5PSP also allows selection of the array 
needle length (13, 19 or 25 mm) depending on the estimate of the recipient’s subcutaneous fat and 
muscle tissue.  
The technology differences between the CELLECTRA™ 2000 and CELLECTRA™ 5PSP design 
are not significant and do not present any new risks. The device design change does not affect the 
indications for use, operating principle, energy type, environmental specifications, and 
sterilization or performance specifications. The material changes are to the outer housing of the 
device and not to patient-contacting materials.  
Benchtop design verification testing and a non-significant risk device functionality study will be 
completed prior to Phase 3 to support that the dimensional changes, change to the ergonomics of 
the patient user interface and injection method result in the CELLECTRA™ 5PSP device design 
meeting its safety and performance specifications, and no change to the administration of VGX-
3100 by electroporation. Inovio’s device experience demonstrates that delivery of electroporation 
pulses into muscle immediately following injection of DNA plasmids is well-tolerated in humans 
and no significant safety issues have been identified [21-23]. For further information concerning 
the 5PSP device please refer to the User Manual and the Investigator’s Brochure.  
1.1.4 
SELECTION OF STUDY DESIGN  
This Phase 3 study employs a prospective, randomized, double-blind, placebo controlled study 
design to further demonstrate the safety and efficacy of VGX-3100 followed by EP in women with 
cervical HSIL associated with HPV-16/18.  The primary clinical hypothesis is that VGX-3100 is 
a surgery-sparing, therapeutic option for the treatment of cervical HSIL and the underlying, 
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pathogenic HPV-16/18 infection, which is supported by the findings of the Phase 2b trial. A 
placebo-controlled study is selected for this trial because it provides scientific rigor to distinguish 
an effective treatment, particularly in cervical HSIL for which spontaneous regression does occur. 
1.2 
 DOSE AND REGIMEN RATIONALE   
A total dose of 6 mg VGX-3100 DNA has been selected for this study based on previous human 
experience with both the WFI/LGS and SSC formulations of VGX-3100, preclinical data with 
VGX-3100 and other DNA vaccines, and the safety and immunogenicity data generated in the 
HPV-001, HPV-003, and HPV-101 studies. In HPV-001 trial, the 6 mg dose was delivered IM 
followed by EP, which showed trends toward higher response rates and magnitudes of IFN-γ 
ELISpot responses compared to the low (0.6 mg) and mid-dose (2 mg) cohorts (Table 2) without 
significant safety issues [21].  
This dose-trend was consistent with prior expectation, a feature of the finding that suggests it is a 
true effect rather than random variation. Adverse events from previous human studies with 
VGX- 3100 (frozen formulation) and closely related DNA plasmid products have been limited to 
injection site pain from the injection and electroporation procedure, which were not clinically 
meaningful. 
Based on the information above, the 6 mg dose was selected for study in the Phase 2b study. The 
results obtained in the phase 2 study suggest that the 6 mg dose was efficacious with an acceptable 
safety profile, therefore the 6 mg dose will also be evaluated in this Phase 3 trial. 
Table 2. Percent of Protocol HPV-001 Subjects Responding and Average SFU/106 PBMC 
in Responders for each Antigen by Cohort in Interferon-γ ELISpot  
Cohort 
Low 
Mid 
High 
Antigen 
%Response 
AVG 
%Response 
AVG 
%Response 
AVG 
HPV-16E6 
33% 
107 
50% 
243 
50% 
1341 
HPV-16E7 
17% 
198 
50% 
104 
67% 
143 
HPV-18E6 
50% 
359 
50% 
338 
83% 
664 
HPV-18E7 
33% 
159 
17% 
179 
50% 
834 
Any 
67% 
221 
67% 
210 
83% 
556 
 
1.3 
RISKS/BENEFIT ASSESSMENT 
1.3.1 
RISKS ASSOCIATED WITH CURRENT THERAPEUTIC OPTIONS 
Currently, treatment of women with cervical HSIL usually consists of either surgical removal of 
the affected tissue by CKC, LEEP, ablative therapy via laser, or cryotherapy.  All treatments for 
375

cervical HSIL are associated with a variety of short and long term general and reproductive health 
risks as listed in Table 3. 
Table 3. Risks Associated with Surgical Treatments for Cervical HSIL 
Surgical Treatments for 
Cervical HSIL 
Risks 
CKC 
LEEP 
Ablative therapy (Laser or 
Cryotherapy)  
Pain 
Exposure to anesthesia 
Heavy bleeding 
Infection 
Menstruation problems 
Cervical stenosis (can lead to alteration of squamo-columnar junction) 
Shortening of the cervix 
Decreased fertility/difficulty getting pregnant 
Cervical incompetence 
Pre-term birth and related low birth weight 
Incomplete treatment of cervical dysplasia 
Inadequate treatment of an occult early invasive cancer 
Adapted from FAQs Loop Electrosurgical Excision Procedure (LEEP) American College of Obstetricians and 
Gynecologists (2014) [13]. 
More importantly, none of the currently available surgical treatments for cervical HSIL eradicate 
the underlying cause of the high grade cervical dysplasia, persistent infection with one or more of 
the high-risk HPV types, and therefore, leaves patients at risk for recurrent cervical HSIL as well 
as high grade dysplasia of the vulva and vagina due to the potentially broader infection of the 
genitourinary area. 
Although professional guidelines typically advocate immediate excisional therapy for adults with 
cervical HSIL, scientific data indicates that the rate of progression from pre-invasive to invasive 
cervical disease is slow, typically thought to take several years [10].  The risk of a “missed 
diagnosis” of an occult early invasive cervical cancer exists for all current treatment modalities 
including surgical and ablative therapies.  Furthermore, approximately 17-18% of patients with 
high grade CIN will experience recurrence of dysplasia following surgical intervention [10], which 
illustrates that current standard of care for cervical dysplasia requires improvement.  The study 
design includes numerous safeguards to detect disease progression or the presence of an 
undiagnosed occult early invasive cervical cancer.  These include, careful selection of 
immunocompetent patients, thorough screening and baseline evaluation, frequent cervical 
colposcopy, cytology and high-risk HPV testing throughout the trial.  Investigators will be 
comprised of experienced gynecologists, who will have the discretion to obtain biopsies at any 
point if disease progression is suspected. 
1.3.2 
POTENTIAL RISKS OF STUDY PARTICIPATION 
A risk associated with VGX-3100 for the treatment of high grade cervical dysplasia are the 
injection site reactions related to the IM injection and/or electroporation.  Based on the phase 1 
376

and 2 clinical experience, the injection site reactions associated with the IM injection and 
electroporation are generally mild (e.g. erythema) and limited to a few days in duration at most.   
A second risk is the “delay” in “definitive treatment” of the high grade cervical dysplasia and the 
“missed diagnosis” of an occult early invasive cervical cancer for the VGX-3100 non-responders 
or placebo recipients, who do not spontaneously regress.  This risk is mitigated by careful serial 
cytology, HPV testing, and colposcopic exams, throughout the course of the study, and the well 
accepted understanding that cervical dysplasia progresses slowly, typically over years, which 
makes close, active follow-up possible.  Also, only investigators who are experienced in the 
management of cervical cancer will be chosen, and they will have the option of performing 
additional, ad hoc colposcopic exams and cervical biopsies if they suspect potential disease 
progression.  
A DSMB will also advise the Sponsor if it appears that the frequency of regression in the VGX-
3100 group is unacceptably low compared to the placebo group.  These measures should minimize 
the risk - even perhaps below that of standard care - of progression of the cervical HSIL and the 
risk of harboring an undiagnosed occult early invasive cervical cancer. All subjects with 
suggestion of residual disease will undergo excisional therapy (e.g. CKC, LLETZ, LEEP) at Week 
36 as part of the efficacy assessment.  Subjects whose cytology, HPV testing, ECC results (if 
applicable) and colposcopic exam suggest disease regression will undergo 4 quadrant biopsy or 4 
quadrant biopsy with ECC (based upon Tables 5 & 6) to provide histopathologic confirmation of 
regression. In the Phase 2b study, the rate at which microinvasive cancer was found in larger 
surgical excision samples in subjects who had no evidence of invasive cancer by initial biopsy was 
1.8%, (2/114 with specimens), which is consistent with and even lower than the rate of 6.7% that 
has been reported under standard of care settings [24]. 
1.3.3 
POTENTIAL BENEFITS OF STUDY PARTICIPATION 
All currently accepted treatments for high grade cervical dysplasia are surgical procedures (LEEP, 
CKC, Laser ablation) which are all associated with risks inherent with any surgical procedure 
including anesthesia, post-operative bleeding and/or infection, damage to other organs, shortening 
and/or deformation of the cervix, pain, etc.  Due to the risk of shortening and/or deformation of 
the cervix there are additional well accepted risks including cervical stenosis, infertility, cervical 
incompetence, preterm birth, and inability to visualize the transformation zone.  Additionally, none 
of the surgical treatments systemically address the underlying oncogenic root cause, the high risk 
HPV infection in the lower genital tract, which leaves an underlying risk for further disease 
manifestations and transmission of HPV. VGX-3100+ EP is not associated with any of the risks 
associated with the surgical procedures outlined above (except for pain, which is transient and 
restricted to the deltoid/quadriceps treatment site) and has demonstrated the ability to not only 
eradicate the high grade dysplasia but also the ability to eradicate the underlying HPV infection.  
Subjects receiving placebo, who represent women of child-bearing potential, may benefit from the 
opportunity to be closely managed under careful surveillance over the course of this study and 
those who regress spontaneously will be able to avoid excisional therapy. 
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2 STUDY DESIGN 
This Phase 3 study design is based upon the Phase 2b study design and results. HPV-301 is a 
prospective, randomized, double-blind, placebo controlled study to determine the efficacy, safety, 
and tolerability of VGX-3100 administered by IM injection followed by EP delivered with 
CELLECTRA™ 5PSP in adult women with histologically confirmed cervical HSIL (CIN2, CIN3) 
associated with HPV-16/18. 
A sample of approximately 198 subjects will be randomized to receive either 6 mg (in 1 ml) VGX-
3100 or placebo, each IM followed by EP, in a 2:1 ratio. This sample size provides 90% power to 
declare VGX-3100 superior to placebo, assuming, based upon Phase 2b study results, that the true 
proportion of subjects whose lesion(s) regress and whose HPV-16/18 clears is 35% and 14% for 
VGX-3100 and placebo, respectively.  
Subjects will be randomized in a stratified manner according to (a) the CIN severity observed in the 
biopsy specimens at screening (i.e. CIN2 vs. CIN3), (b) BMI category (≤25 vs. >25 kg/m2), and (c) 
age category (<25 years vs. ≥25 years). To ensure CIN2 disease is not over-represented in the study, 
the percentage of subjects enrolled with CIN2 will not exceed 50% of the total enrolled. A group of 
sequential allocation numbers will be designated for use by each participating country. 
To be eligible for the study, subjects age 18 years and above must consent to participate and have 
cervical biopsy/biopsies of the cervical lesion(s) at the time of screening. Slides of the biopsy will 
be sent to a PAC in a blinded manner to establish the presence of cervical HSIL within screening. 
In order to be eligible for continued enrollment, the PAC must assign the histologic diagnosis of 
cervical HSIL. Subjects must also have a cervical specimen test positive for HPV-16/18 by cobas™ 
HPV test to be eligible for participation in the study. 
2.1 
ENDPOINT ASSESSMENT 
In the Phase 2b study, subjects were randomized 3:1 to the VGX-3100 frozen formulation arm or 
the Placebo arm. All subjects were scheduled to receive treatment on Day 0, Week 4 and Week 12 
and undergo repeat cervical biopsy or surgical excision (i.e. LEEP, LLETZ, CKC) of the cervix at 
Week 36 to assess efficacy. The primary endpoint was histopathologic regression of cervical lesions 
to CIN1 or less at the Week 36 visit, and the secondary endpoint was clearance of HPV-16/18 in 
combination with histopathologic regression of cervical lesions to CIN1 or less.     
The primary endpoint for the Phase 3 study is based upon the results of the Phase 2b study.  Given 
that HPV persistence is an important factor in the clinical progression of dysplasia and also based 
upon the findings of the secondary objective of the Phase 2b study, the responder definition for the 
Phase 3 primary endpoint determination will take into consideration both histological regression of 
cervical HSIL and clearance of high-risk HPV-16/18.  
The proportion of subjects who achieved this endpoint in the Phase 2b study was 35% (40%) of 
VGX-3100 subjects versus 14% (15%) for placebo, in an intention-to-treat analysis and modified 
intention-to-treat analysis, respectively.  The composite endpoint of histologic regression and 
virologic clearance will be primary in the Phase 3 study, and histologic regression endpoint will be 
a secondary endpoint. 
378

2.1.1 
HISTOLOGY ASSESSMENT 
Regression of cervical HSIL will be determined by histopathological assessment of cervical tissue, 
which is considered the definitive method for diagnosis of cervical dysplasia. Digital photographs 
of acetowhite lesions are also used to document colposcopic exam findings. Tissue to be analyzed 
for evidence of histopathologic regression will be obtained at Week 36 either by excision (e.g. 
LEEP, LLETZ, CKC) or by 4 Quadrant Biopsy or by 4 Quadrant Biopsy with ECC based upon 
the assessment at Week 28 of cytology, HR HPV status, and colposcopic findings as outlined in 
Tables 4 and 5 for subjects 25 years and above and below 25 years, respectively. 
Table 4.  Minimally Required Procedure at Week 36 for Subjects Age 25 Years and Above  
Age 
Clinical and Laboratory Information at Week 28 
Minimally Required 
Procedure at Week 36a 
Colposcopy 
Cytology 
HPV-16/18 
Testing 
Quality 
Finding 
25 
and 
above 
NA 
NA 
HSIL, ASC-H, AGC, 
Carcinoma, AIS 
NA 
Tissue Excision 
unsatisfactory 
lesion 
NA 
NA 
Tissue Excision 
unsatisfactory 
no lesion 
LSIL, ASC-US 
positive 
Tissue Excision 
unsatisfactory 
no lesion 
LSIL, ASC-US 
negative 
4Q biopsy and ECC 
unsatisfactory 
no lesion 
NILM 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
LSIL, ASC-US 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
positive 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
negative 
4Q biopsy 
Table 5.  Minimally Required Procedure at Week 36 for Subjects Under 25 Years  
Age 
Clinical and Laboratory Information at Week 28 
Minimally Required 
Procedure at Week 36a 
Colposcopy 
Cytology 
HPV-16/18 
Testing 
Quality 
Finding 
18-24 
NA 
NA 
Carcinoma, AIS 
NA 
Tissue Excision 
unsatisfactory 
lesion 
NA 
NA 
Tissue Excision 
unsatisfactory 
no lesion 
HSIL, ASC-H, AGC 
NA 
Tissue Excision 
unsatisfactory 
no lesion 
NILM, ASC-US, LSIL 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
LSIL, ASC-US, HSIL, 
ASC-H, AGCb 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
positive 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
negative 
4Q biopsy 
Abbreviations: NA; not applicable because there is no impact to the decision at Week 36 due to a superseding finding; 4Q; 
four quadrant; NILM Negative for intraepithelial lesion and malignancy; ASC-US Atypical squamous cells of undetermined 
significance; AGC Atypical glandular cells; ASC-H Atypical squamous cells, cannot rule out high-grade lesion; AIS 
Adenocarcinoma-in-situ 
a Any subject with prior ECC requires a negative ECC at Week 28 to allow 4Q biopsy and ECC, at minimum, at Week 36   
b If cytology result is AGC “favor neoplasia”, tissue excision is recommended 
379

2.1.2 
VIROLOGIC (HPV) ASSESSMENT 
Cervical cytology samples will be obtained to characterize HPV infection at screening, Day 0 
(prior to dosing) and Weeks 8, 15, 28, 36, 62, and 88.  Also, if there is residual tissue in the paraffin 
block after histologic diagnoses have been rendered, then unstained slides and/or the relevant 
paraffin blocks may be collected for testing of HPV-16/18. Vaginal and oropharyngeal samples 
will be obtained to characterize HPV infection at Day 0 (prior to dosing) and at Weeks 36, and 88 
to assess virologic response to treatment at sites other than the cervix. Intra-anal samples will be 
obtained (if subject consents to intra-anal sampling) to characterize HPV infection at Day 0 (prior 
to dosing) and at Week 36 to assess virologic response to treatment at sites other than the cervix. 
2.1.3 
DEFINITION OF RESPONDER AND NON-RESPONDER 
Responder and non-responder definitions (Table 6) for the primary endpoint takes into account 
both histopathologic regression of cervical HSIL and virologic (HPV-16 and/or HPV-18) 
clearance from cervical samples since HPV persistence is an important factor in the clinical 
progression of HSIL. The responder definition also excludes subjects whose cervix is biopsied at 
any time between their initial biopsy to determine eligibility and the Week 36 endpoint tissue 
collection. This exclusion is included to reduce the potential for artefactual increases in the 
treatment effect caused by removal of HSIL tissue and potentially HPV-16/18 by unplanned 
interval biopsies.  
To qualify as a responder, the subject must have:  
1. An acceptable histology specimen at Week 36, which is interpretable by the independent 
PAC, and  
2. An acceptable HPV ThinPrep™ sample at Week 36, with an associated valid HPV-testing 
result.   
A responder is defined as a subject with:  
1) No histologic evidence of cervical HSIL   
2) No evidence of HPV-16 and/or HPV-18 at the Week 36 evaluation  
3) The subject must not have had an unscheduled cervical tissue sample obtained between 
Screening and the Week 36 evaluation. 
Conversely, the following will designate the subject as a non-responder:  
1)  Histologic evidence of cervical HSIL at the Week 36 evaluation, OR  
2)  Evidence of HPV-16 or HPV-18 at the Week 36 evaluation, OR  
3)  A cervical tissue sample obtained between Screening and the Week 36 evaluation OR  
4)  Lack of either an acceptable Week 36 histology specimen or HPV ThinPrep™ sample.    
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Table 6.  Definition of Primary Endpoint Responder  and Non-Responder 
Responder 
Non-Responder 
Subject with no histologic evidence of cervical 
HSILa at Week 36 evaluation and no evidence of 
HPV-16 and/or HPV-18 at Week 36b 
AND 
Subject in which a cervical tissue sample was NOT 
obtained between collection of tissue to determine 
entry eligibility up to Week 36 primary endpoint 
visit 
Subject with histologic evidence of cervical HSIL, AIS, or 
cervical carcinoma at Week 36 evaluation 
OR 
Subject with evidence of HPV-16 or HPV-18 at Week 36 
OR 
Subject in which an additional cervical tissue sample was 
obtained between collection of tissue to determine entry 
eligibility up to Week 36 primary endpoint visit 
OR 
Subject with no Week 36 primary endpoint sample result 
a No evidence of HSIL is defined by histology as negative, squamous atypia, or LSIL 
b The histopathologic efficacy time frame is defined by those who have undergone a biopsy or surgical excision at 
any time starting from 14 days prior to the protocol-specified target date of Week 36.  The first tissue removal sample 
within the time frame determines the histology endpoint.  The most recent HPV clearance result prior to tissue removal within 
the time frame determines the HPV clearance endpoint. 
Responder and non-responder definitions for the secondary efficacy endpoints are detailed in Table 
7 – Table 11. 
Table 7:  Definition of Secondary Regression Endpoint Responder and Non-Responder 
Responder 
Non-Responder 
Subject with no histologic evidence of cervical 
HSILa at Week 36 visitb 
AND 
Subject in which a cervical tissue sample was 
NOT obtained between collection of tissue to 
determine entry eligibility up to Week 36 visit 
Subject with histologic evidence of cervical HSIL, AIS, 
cervical carcinoma at Week 36 visit 
OR 
Subject in which an additional cervical tissue sample was 
obtained between collection of tissue to determine entry 
eligibility up to Week 36 visit 
OR 
Subjects with no Week 36 visit sample result 
 
a No evidence of HSIL is defined by histology as negative, squamous atypia, or LSIL 
b The efficacy time frame is defined by those who have undergone a biopsy or surgical excision at any time starting from 14 days 
prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology 
endpoint. 
381

Table 8:  Definition of Secondary Complete Regression Endpoint Responder and Non-Responder 
Responder 
Non-Responder 
Subject with no histologic evidence of cervical 
HSIL squamous atypia, or LSIL at Week 36 visita 
AND 
Subject in which a cervical tissue sample was 
NOT obtained between collection of tissue to 
determine entry eligibility up to Week 36 visit 
Subject with histologic evidence of cervical HSIL, squamous 
atypia, LSIL, AIS, cervical carcinoma at Week 36 visit 
OR 
Subject in which an additional cervical tissue sample was 
obtained between collection of tissue to determine entry 
eligibility up to Week 36 visit 
OR 
Subjects with no Week 36 visit sample result 
 
a The efficacy time frame is defined by those who have undergone a biopsy or surgical excision at any time starting from 14 days 
prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology 
endpoint. 
Table 9: Definition of Secondary Non-progression Endpoint Responder and Non-Responder 
Responder 
Non-Responder 
Subject with no histologic evidence of a worsening 
of cervical condition at Week 36 visita relative to 
baseline 
AND 
Subject in which a cervical tissue sample was 
NOT obtained between collection of tissue to 
determine entry eligibility up to Week 36 visit 
Subject with histologic evidence of worsening of cervical 
condition at Week 36 visit relative to baseline 
OR 
Subject in which an additional cervical tissue sample was 
obtained between collection of tissue to determine entry 
eligibility up to Week 36 visit 
OR 
Subjects with no Week 36 visit sample result 
 
a The efficacy time frame is defined by those who have undergone a biopsy or surgical excision at any time starting from 14 days 
prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology 
endpoint. 
 
382

Table 10:  Definition of Secondary Complete Regression and Clearance Endpoint Responder and Non-
Responder 
Responder 
Non-Responder 
Subject with no histologic evidence of cervical 
HSIL, squamous atypia, or LSILa at Week 36 visit 
and no evidence of HPV-16 and/or HPV-18 at 
Week 36 visitb 
AND 
Subject in which a cervical tissue sample was 
NOT obtained between collection of tissue to 
determine entry eligibility up to Week 36 visit 
Subject with histologic evidence of cervical HSIL, squamous 
atypia, or LSIL AIS, cervical carcinoma at Week 36 visit 
OR 
Subject with evidence of HPV-16 or HPV-18 at Week 36 visit 
OR 
Subject in which an additional cervical tissue sample was 
obtained between collection of tissue to determine entry 
eligibility up to Week 36 visit 
OR 
Subjects with no Week 36 visit sample result 
a No evidence of HSIL is defined by histology as negative, squamous atypia, or LSIL 
b The efficacy time frame is defined by those who have undergone a biopsy or surgical excision at any time starting from 14 days 
prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the 
histology endpoint.  The most recent HPV clearance result prior to tissue removal within the time frame determines the HPV 
clearance endpoint. 
Table 11:  Definition of Secondary Clearance Endpoint Responder and Non-Responder 
Responder 
Non-Responder 
Subject with no histologic evidence of HPV-16 
and/or HPV-18 at Week 36 visita 
AND 
Subject in which a cervical tissue sample was 
NOT obtained between collection of tissue to 
determine entry eligibility up to Week 36 visit 
Subject with evidence of HPV-16 or HPV-18 at Week 36 visit 
OR 
Subject in which an additional cervical tissue sample was 
obtained between collection of tissue to determine entry 
eligibility up to Week 36 visit 
OR 
Subjects with no Week 36 visit sample result 
 
 
a The efficacy time frame is defined by those who have undergone HPV testing at any time starting from 14 days prior to the 
protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology endpoint.  
The most recent HPV clearance result prior to tissue removal within the time frame determines the HPV clearance endpoint. 
 
383

2.1.4 
IMMUNOGENICITY ASSESSMENT 
Humoral and cell mediated immune responses in response to VGX-3100 treatment will be 
evaluated in blood samples taken at baseline (both screening as well as Day 0 prior to dosing) and 
at Weeks 15, and 36. Cervical tissue samples will also be analyzed for evidence of elevated 
immune responses at Week 36 as compared to baseline (screening).   
If there is residual tissue in the paraffin block after histologic diagnoses have been rendered, then 
unstained slides and/or the relevant paraffin blocks may be collected for immunohistochemistry 
(IHC). Whenever possible, these studies may be performed on tissue sections from the diagnostic 
screening biopsy (pre-dose) and from tissue obtained post-dose(s) (Week 36). 
2.2 
TREATMENT PLAN 
The three dose regimen of VGX-3100 appeared to be safe and well tolerated in the Phase 2b study, 
therefore all eligible subjects who consent to participate in the Phase 3 study will receive the same 
three 6 mg doses of VGX-3100 refrigerated formulation or placebo administered in 1 mL IM 
(deltoid, preferred site, or anterolateral quadriceps, alternate site), each followed immediately by EP 
with the CELLECTRA™ 5PSP device. The first study treatment will be administered on Day 0, the 
second at Week 4, and the third (final) study treatment will be administered at Week 12 which is 
consistent with the Phase 2b study. The first study treatment will be given as soon as possible 
following confirmation of the cervical HSIL diagnosis and HPV-16/18 status but no more than 10 
weeks following collection of the subject’s biopsy specimen used for diagnosis by the PAC during 
screening, contemporaneous with the positive testing for HPV-16/18. 
2.3 
SAFETY MONITORING PLAN 
Although cervical HSIL is thought to require years to progress to cervical cancer, subjects in the 
Phase 2b study were followed closely throughout. HPV testing (Weeks 14 and 24), cytology (Week 
14) and colposcopy (Week 24) were all mandatory during the observation period prior to obtaining 
tissue for determination of the primary histologic endpoint at Week 36. Investigators were also 
instructed to perform additional testing (including biopsy) if disease progression was suspected. 
These instances were infrequent as only 11 unscheduled biopsies were deemed necessary over the 
course of the Phase 2b study. In addition, the rate at which occult microinvasive cancer was 
discovered after 36 weeks was less frequent than what is reported in the literature [24]. Both 
observations would imply that the mandatory monitoring employed in the Phase 2b study was 
sufficient; however cervical disease will be monitored even more closely in this Phase 3 study. 
Colposcopy, cytology and HPV testing will be required at 8 to 14 week intervals throughout the 
observation period leading up to the primary endpoint 36 weeks after the first dose. Although less 
frequent monitoring may be adequate, the more frequent monitoring is designed to afford an even 
wider margin of safety and an opportunity to explore predictors of efficacy.     
Safety monitoring will include: 
 Local and systemic events for 7 days following each treatment as noted on a Participant Diary 
Card (PDC). 
 All adverse events including SAEs, UADEs, and other unexpected AEs for the duration of the 
study; 
384

In the Phase 2b study, the safety profile was carefully evaluated and treatment with VGX-3100 was 
well-tolerated based on observations through Week 88 in all subjects. The most common adverse 
events were administration-site reactions, which included pain, tenderness, erythema and swelling, 
and were generally mild and limited to a few days in duration.  Only erythema showed a statistically 
higher incidence in VGX-3100 (78%) vs. placebo (57%) in the 7- and 28-day periods after a dose. 
One additional AE, sinusitis, was also statistically significantly increased over the course of the 
entire study period but resolved without sequelae in the VGX-3100 arm compared to the Placebo 
arm (10% vs. 0%).      
As outlined above, safety monitoring and visit frequency has been designed to take into account the 
potential risk of delay in the usual treatment of the high grade cervical dysplasia and also the 
potential for a missed diagnosis of an occult early invasive cervical cancer for the VGX-3100 non-
responders or placebo recipients, who do not regress.  Serial cytology, HPV testing, and colposcopic 
exams are applied throughout the course of the study with the well accepted understanding that 
cervical dysplasia progresses slowly, typically over years, which makes close, active follow-up 
possible.  All subjects with suggestion of residual disease will undergo excisional therapy by LEEP 
or CKC at Week 36 as part of the efficacy assessment.  Subjects whose cytology, HPV testing, ECC 
results (if applicable) and colposcopic exam suggest disease regression will undergo 4 quadrant 
biopsy or 4 quadrant biopsy with ECC (based upon Table 5 and 6) to provide histopathologic 
confirmation of regression. The use of a 4 quadrant biopsy in Phase 3 is a change from the approach 
used in Phase 2b to optimize the evaluation of histopathologic regression taking into consideration 
the inherent limitations of colposcopy and tissue biopsy samples in the absence of visible lesions 
[25].  
In the Phase 2b study, the cervical tissue sample was initially read by a local pathologist and/or 
central pathology laboratory for rapid local medical management.  The definitive histopathologic 
assessment was determined by an independent blinded Pathology Adjudication Panel, comprised of 
experienced cytopathologists from independent medical centers in the US.  Seven reports included 
the terms ‘(adeno)squamous cell carcinoma’ or the premalignant condition of ‘adenocarcinoma in 
situ’ (AIS) in the final Phase 2b study results which included all 88 weeks of follow up. Three of 
the cases were reported as AIS, (2 VGX-3100, 1 placebo), out of which two cases (1 VGX-3100, 1 
placebo) were confirmed as AIS by the Pathology Adjudication Panel. AIS is a pre-invasive 
glandular lesion which can be difficult to capture on standard of care screening with initial punch 
biopsy and is more commonly identified by full excision (e.g. LEEP, conization).  There were four 
reports that included the term squamous cell carcinoma, of which two were confirmed by the 
Pathology Adjudication Panel, both in the VGX-3100 group.  The other two cases (1 VGX-3100, 1 
placebo) were diagnosed as CIN3 by the Pathology Adjudication Panel.  The rate at which 
microinvasive cancer was found in larger surgical excision samples in subjects who had no evidence 
of invasive cancer by initial biopsy was 1.8%, (2/114 with specimens), which is consistent with and 
even lower than the rate of 6.7% that has been reported under standard of care settings [24].  
Importantly, investigators in the Phase 3 study will be chosen only if they are experienced in the 
management of cervical cancer as was the case in the Phase 2b study. Phase 3 investigators are 
instructed to perform additional, ad hoc colposcopic exams and cervical biopsies if they suspect 
potential disease progression. Subjects that undergo an unscheduled biopsy will be classified as a 
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non-responder in the efficacy analysis as outlined in Table 6. These measures should minimize the 
risk of progression of cervical HSIL and the risk of harboring an undiagnosed occult early invasive 
cervical cancer. The frequency of close monitoring by experienced investigators should minimize 
the risk of cancer progression on the study what is expected with standard of care.   
2.3.1 
DATA AND SAFETY MONITORING BOARD (DSMB) 
An independent Data and Safety Monitoring Board (DSMB) will provide safety oversight.  The 
DSMB will be scheduled to meet quarterly. If there are no new safety data or regression/clearance 
results to review for a quarterly scheduled meeting the DSMB will be notified and the meeting 
may be cancelled; ad hoc meetings may be scheduled to review new data as applicable. The DSMB 
will be charged with advising the Sponsor if there appears to be a safety issue and with advising 
the Sponsor if it appears that the proportion of the subjects with regression in the VGX-3100 group 
is unacceptably low compared to the placebo group. However, no formal interim analysis will be 
performed. 
2.4 
LONG TERM FOLLOW UP PLAN 
In the Phase 2b study, all subjects were scheduled to be followed for 1 year after the histopathologic 
assessment for the primary endpoint (to study Week 88). The establishment of efficacy based on 
histopathologic evidence dictated the removal of tissue at week 36 by either punch biopsy (ies) or 
more extensive surgical resection (i.e. LEEP, CKC). Subjects with colposcopic evidence of residual 
disease were to undergo LEEP/CKC. A higher proportion of patients who received placebo had a 
LEEP performed than those who received VGX-3100 (Table 12). 
Cytology and HPV-16/18 clearance from the cervix was to be assessed at study Weeks 62 and 88 to 
evaluate for recurrence of dysplasia and HPV infection after removal of tissue at Week 36.  Overall, 
in the phase 2b study, the majority of subjects had improved cytology and had cleared their 
underlying HPV-16/18 cervical infection by the Week 62 and 88 visits. For Weeks 62 and 88, there 
were no clinically meaningful differences noted between the subjects who received an excisional 
treatment (e.g. LEEP, CKC) and those that showed histopathologic regression and therefore only 
underwent a biopsy, as shown in Table 8 which summarizes the HPV and cytology results following 
Week 36.  
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Table 12.  HPV-003 HPV and Cytology Results at Weeks 36, 62 and 88, mITT Population 
Week
Testa
VGX-3100
Placebo
LEEP/CKCb
%(n/N)
Biopsyc
%(n/N)
LEEP/CKC
%(n/N)
Biopsy
%(n/N)
36
HPV
41% (19/46)
63% (36/57)
29% (6/21)
29% (5/17)
36
Pap
NA
NA
NA
NA
62
HPV
89% (50/56)
82% (42/51)
96% (27/28)
82% (9/11)
62
Pap
93% (52/56)
100% (51/51)
93% (26/28)
82% (9/11)
88
HPV
89% (48/54)
89% (42/47)
89% (24/27)
100% (10/10)
88
Pap
96% (52/54)
91% (43/47)
85% (23/26)
100% (11/11)
Abbreviations: NA, not applicable, Pap smear was not done at Week 36 
a  HPV =  HPV-16/18 testing; Pap = cytology testing  
b LEEP or CKC done, at or before the study week as specified  
c Only biopsy done, at or before the study week as specified 
Clearance of HPV-16/18 from the cervix was observed in both treatment groups (Figure 1a) at 
similar rates until after the second dose when clearance in the VGX-3100 recipients continued to 
rise while the rate appeared to plateau in the placebo group. 
Figure 1.  HPV-16/18 Clearance and Pap Smear Findings in Phase 2b mITT Population by 
Treatment Group
At Week 36, clearance was significantly higher among VGX-3100 subjects that had biopsy (63%) 
versus LEEP/CKC (41%), which likely reflects the association between clearance of the underlying 
HPV infection and the likelihood of having signs indicative of regression by colposcopic 
exam. HPV-16/18 clearance data (mITT population) post-Week 36 are described as follows: HPV-
Week 14
Week 62
Week 88
a.
b.
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16/18 clearance at Week 62 was 89% (50/56) for VGX-3100 post-LEEP/CKC, 82% (42/51) for 
VGX-3100 post Biopsy only, 96% (27/28) for Placebo post-LEEP/CKC, and 82% (9/11) for Placebo 
post Biopsy only.  HPV-16/18 clearance at Week 88 was 89% (48/54) for VGX-3100 post-
LEEP/CKC, 89% (42/47) for VGX-3100 post Biopsy only, 89% (24/27) for Placebo post-
LEEP/CKC, and 100% (10/10) for Placebo post Biopsy only. 
The majority of subjects had cleared their underlying cervical HPV-16/18 infection by Week 62 
without meaningful changes through Week 88, and without meaningful differences between groups. 
Forty-seven of 53 (89%) and 46 of 49 (94%) subjects at Weeks 62 and 88, respectively (mITT 
population) with histopathologic evidence of CIN2/3 regression (regressors) in the VGX-3100 
treatment group experienced HPV-16/18 clearance. Despite the use of therapeutic resection for 
many VGX-3100 recipients whose CIN2/3 did not regress by Week 36 (non-regressors), HPV-16/18 
clearance rates were notably lower (85% at Week 88) compared to regressors.  
In the subjects who initially cleared HPV-16/18 by Week 36, only one HPV-16/18 recurrence was 
identified at the Week 62 and 88 evaluations. Specifically, one subject in the VGX-3100 group 
whose lesion was biopsied at Week 36 had HPV types 16 and 82 and CIN2 at screening, was HPV 
negative at Week 36, but tested HPV type 16 positive at Week 62, and then cleared HPV-16 at Week 
88. The subject showed histopathologic regression at Week 36. No recurrences were identified in 
the eleven subjects in the placebo group whose lesions were biopsied at Week 36 with valid HPV 
data at Weeks 62 or 88. There were no (0/51) recurrences identified in the VGX-3100 treated group 
at Week 88. Overall, these virologic clearance findings support that study subjects had no increased 
risk as compared to standard of care.  
Cytology (mITT population) post-Week 36 are described as follows: Improvement compared to 
study entry for Pap smear cytology results at Week 62 were 93% (52/56) for VGX-3100 post-
LEEP/CKC, 100% (51/51) for VGX-3100 post-Biopsy only, 93% (26/28) for Placebo post-
LEEP/CKC, and 82% (9/11) for Placebo post-Biopsy only. At Week 62, cytopathologic 
improvement was reported for 104 of 125 (83%) subjects in the VGX-3100 treatment group and 34 
of 42 (83%) subjects in the placebo treatment group (mITT population).  
There were no instances of possible progression, and all cases that did not meet the definition of 
improvement were due to either no change from baseline, sample considered not evaluable, or no 
data available.  Improvement compared to study entry for Pap smear cytology results at Week 88 
were 96% (52/54) for VGX-3100 post-LEEP/CKC, 91% (43/47) for VGX-3100 post-Biopsy only, 
85% (23/26) for Placebo post-LEEP/CKC, and 100% (11/11) for Placebo post-Biopsy only.  At 
Week 88, possible progression (atypical glandular cells) was reported in a single Placebo subject in 
the post-LEEP/CKC group (3%) and no subjects treated with VGX-3100. All other cases that did 
not meet the definition of improvement were due to either no change from baseline, sample 
considered not evaluable, or no data available. The majority of subjects showed improvement, and 
there was no meaningful difference between the Week 62 and Week 88 evaluations.   These findings 
support that study subjects had no increased risk of progression based upon cytology as compared 
to standard of care. 
The protocol-specified removal of dysplastic cervical tissue at Week 36 by either method 
substantially affected the clearance of HPV-16/18 and normalization of cytologic findings as 
expected, regardless of treatment group (Figure 1a, b). HPV-16/18 clearance rises at a sharp rate 
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after tissue is removed at Week 36 whether the excision is wide (e.g. LEEP, LLETZ, CKC) or more 
limited (biopsy). Notably, the method of tissue collection at the Week 36 endpoint did not 
appreciably affect the HPV-16/18 clearance rates beyond Week 36 (Table 8).   Based upon the Phase 
2b results, the risk of progression or recurrence of cervical dysplasia is low and comparable to the 
rates observed post-LEEP/CKC in clinical practice.  The long term follow up planned for this Phase 
3 study will include safety, cytology and HPV-16/18 testing at 6 months and also 1 year following 
the Week 36 histopathologic assessment, which is highly conservative given the expectation that 
few subjects will have persistent evidence of disease after the removal of tissue at Week 36 which 
is supported by the findings in the Phase 2b study. 
3 HYPOTHESIS AND STUDY OBJECTIVES 
3.1 
HYPOTHESIS 
Three 6 mg doses of VGX-3100 (DNA Plasmids encoding E6 and E7 proteins of HPV-16 and HPV-
18) delivered IM followed by EP with CELLECTRA™ 5PSP to adult women with histologically 
confirmed HSIL of the cervix, associated with HPV-16 and/or HPV-18 will result in a higher 
percentage of women with histopathological regression of cervical HSIL lesions to no evidence of 
cervical HSIL and virologic clearance of HPV-16/18 compared to placebo delivered IM followed 
by EP with CELLECTRA™ 5PSP at the Week 36 visit.4 
3.2 
PRIMARY OBJECTIVE AND ENDPOINT 
Objective 
Endpoint 
Determine 
the 
efficacy 
of 
VGX-3100 
compared with placebo with respect to 
combined 
histopathologic 
regression 
of 
cervical HSIL and virologic clearance of 
HPV-16 and/or HPV-18 
Proportion of subjects with no evidence of  
cervical HSIL on histology (i.e. biopsy or 
excisional treatment) and no evidence of HPV-16 
and/or HPV-18 in cervical samples by type 
specific HPV testing at Week 36 visit 
4 The time frame is defined as any time starting from 14 days prior to the protocol-specified target date of Week 36. 
389

3.3 
SECONDARY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of 
VGX-3100 delivered IM followed by EP 
with CELLECTRA™ 5PSP 
1a. Incidence and severity of local and systemic 
events for 7 and 28 days following each 
investigational treatment  and for the duration of 
the study (through Week 88 visit) 
1b. Incidence and severity of all adverse events 
including SAEs (e.g. SUSAR, UADE and other 
unexpected AEs) for the duration of the study 
(through Week 88 visit) 
2.Determine VGX-3100 efficacy compared 
to placebo as measured by histopathologic 
regression of cervical HSIL  
2. Proportion of subjects with no evidence of  
cervical HSIL  on histology (i.e. biopsies or 
excisional treatment) at Week 36 visit 
3. Determine VGX-3100 efficacy compared 
to placebo as measured by virologic 
clearance of HPV-16 and/or HPV-18 
3. Proportion of subjects with no evidence of HPV-
16 and/or HPV-18 in cervical samples  by type 
specific HPV testing at Week 36 visit 
4. Determine VGX-3100 efficacy compared 
to placebo as measured by complete 
histopathologic regression of   cervical 
HSIL to normal 
4. Proportion of subjects with no evidence of Low 
grade squamous intraepithelial lesion (LSIL) or 
HSIL (i.e.  no evidence of CIN1, CIN2 or CIN3) 
on histology (i.e. biopsies or excisional 
treatment) at Week 36 visit 
5. Determine VGX-3100 efficacy compared 
to placebo as measured by both complete 
histopathologic regression of  cervical 
HSIL to normal and virologic clearance of 
HPV-16 and/or HPV-18 
5. Proportion of subjects with no evidence of LSIL 
or HSIL (i.e. no evidence of CIN1, CIN2 or CIN3 
on biopsies or excisional treatment) on histology 
(i.e. biopsies or excisional treatment) and no 
evidence of HPV-16 and/or HPV-18  by type 
specific HPV testing at Week 36 visit 
6. Determine the efficacy of VGX-3100 
compared with placebo as measured by 
histopathologic non-progression 
6. Proportion of subjects with no progression of 
cervical HSIL to cervical carcinoma from 
baseline on histology (i.e. biopsies or excisional 
treatment) at Week 36 visit 
7. Describe the clearance of HPV-16 and/or 
HPV-18 
infection 
from 
non-cervical 
anatomic locations 
7. Proportion of subjects who have cleared HPV-16 
and/or HPV-18 on specimens from non-cervical 
anatomic locations (i oropharynx, vagina and 
intra-anal) at Week 36 Visit 
8. Determine the humoral and cellular 
immune response to VGX-3100 compared 
with placebo  at post dose 3, and Week 36 
visits as assessed relative to baseline 
8a. Levels of serum anti-HPV-16 and anti-HPV-18 
antibody concentrations at Weeks 15, and 36 
visits 
8b. Interferon-γ ELISpot response magnitudes at 
baseline, Weeks 15, and 36 visits 
8c. Flow Cytometry response magnitudes at 
baseline and Week 15 visits 
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3.4 
EXPLORATORY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Exploratory Objectives 
Associated Endpoints 
1. Evaluate tissue immune responses to 
VGX-3100 in cervical samples 
1. Assessment of markers including but not limited 
to CD8+ and FoxP3+ infiltrating cells. 
Additional assessments may include 
visualization of Granulysin, Perforin, CD137, 
CD103 and PD-L1 in cervical tissue as sample 
allows.  Markers listed here may change as new 
relevant information becomes available 
2. Evaluate effect of HLA type on efficacy 
 
2. HLA (per-locus and per-allele basis) in 
conjunction with histologic regression of  
cervical HSIL at Week 36 visit 
3. Describe 
association 
of 
microRNA 
(miRNA) profiles, DNA methylation 
profile, previous colposcopy, cytology 
and HPV testing results with Week 36 
histologic regression  
3. Colposcopy, cytology, and HPV test results 
(Weeks 8, 15 and 28 visits), miRNA profile 
(baseline, Week 8) and DNA methylation profile 
(baseline, Week 15) in conjunction with 
histologic regression of cervical HSIL at Week 
36 visit 
4. Describe the durability of virologic 
clearance of HPV-16 and/or HPV-18 for 
subjects 
treated 
with 
VGX-3100 
compared with those treated with placebo 
4. Proportion of subjects with no evidence of HPV-
16 and/or HPV-18 by type specific HPV testing 
at Weeks 62 and 88 visits 
5. Describe the patient-reported outcomes 
for subjects treated with VGX-3100 
5. Patient-reported outcome questionnaires will be 
self-administered at baseline, Weeks 4, and 12, 
8-14 days following each dose, and at Weeks 28, 
36, 40 and 88 by subjects enrolled in US, 
Canada, Mexico, Germany and UK. 
6.  Determine whether a tissue-based score 
derived using an immunologic markers 
(Immunoscore) at baseline is predictive 
for histological and virological response 
to VGX-3100  at Week 36 
 6    Immunoscore results for VGX-3100 treated    
subjects and in conjunction with histological and 
virological outcomes at Week 36 
 
4 SELECTION OF SUBJECTS 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in the study: 
1. Women aged 18 years and above and meets minimum age of consent per local regulations); 
2. Confirmed cervical infection with HPV types 16 and/or 18 at screening by cobasTM  HPV test;  
3. Cervical tissue specimen/slides provided to Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study drug; 
4. Histologic evidence of cervical HSIL as confirmed by PAC at screening; 
391

5. Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form 
prior to study-related activities; 
6. Must be judged by Investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision, 4-quadrant biopsy with ECC, or 4-quadrant biopsy) required at Week 
36; 
7. Satisfactory colposcopy at screening, defined as full visualization of the squamo-columnar 
junction (Type I or II transformation zone) and complete visualization of the upper limit of 
aceto-white epithelium or suspected CIN disease; 
8. Cervical lesion that is accessible for sampling by biopsy instrument (e.g. Mini-Tischler device); 
9. Cervical lesion of adequate size to ensure that a visible lesion remains after screening biopsy; 
10. Must meet one of the following criteria with respect to their reproductive capacity: 
a) Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months 
b) Is surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 12 months prior to screening 
c) WOCBP is willing to use a contraceptive method with failure rate of less than 1% per year 
when used consistently and correctly from screening until Week 36. The following methods 
are acceptable: 
i. Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. Hormonal 
contraceptives must not be used in subjects with a history of hypercoagulability (e.g., 
deep vein thrombosis, pulmonary embolism). 
ii. Abstinence from penile-vaginal intercourse when this is the subject’s preferred and 
usual lifestyle 
iii. Intrauterine device or intrauterine system 
iv. Male partner sterilization at least 6 months prior to the female subject’s entry into the 
study, and this male is the sole partner for that subject 
11. Normal screening ECG or screening ECG with no clinically significant findings, as judged by 
the investigator. 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from enrollment in the study: 
1. Microscopic or gross evidence of adenocarcinoma-in-situ (AIS), high grade vulvar, vaginal 
(inclusive of cervical HPV-related lesions that extend into the vaginal vault), or anal 
intraepithelial neoplasia or invasive cancer in any histopathologic specimen at screening; 
2. Cervical lesion(s) that cannot be fully visualized on colposcopy due to extension high into 
cervical canal at screening; 
3. ECC shows a potentially untreated carcinoma, untreated HSIL, indeterminate, or insufficient 
for diagnosis (ECC is not required to be performed as part of study screening); 
4. Treatment for cervical HSIL within 4 weeks prior to screening; 
5. Pregnant, breastfeeding or considering becoming pregnant through Week 36 visit; 
6. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are 
allowed, e.g. Gardasil™, Silgard™, Cervarix™); 
392

7. Presence of any unresolved abnormal clinical screening laboratory values of Grade 1 or greater 
per CTCAE v 4.03 and deemed clinically significant by the investigator within 45 days prior 
to Day 0; 
8. Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening (performed within 30 days prior to 
Day 0) 
b) Primary immunodeficiencies 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent; (use of inhaled, otic, and ophthalmic corticosteroids are allowed) 
d) 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) 
e) History of solid organ or bone marrow transplantation 
f) Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
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. 
g) Subjects who are malnourished (i.e. medically significant unintentional weight loss, 
kwashiorkor, or marasmus) based on screening labs, medical history and physical exam per 
investigator’s clinical judgment. 
9. Receipt of any non-study, non-live vaccine within 2 weeks of dosing; 
10. Receipt of any non-study, live vaccine (e.g. measles vaccine) within 4 weeks of dosing; 
11. Current or history of clinically significant, medically unstable disease which, in the judgment 
of the investigator, would jeopardize the safety of the subject, interfere with study assessments 
or endpoint evaluation, or otherwise impact the validity of the study results (e.g. chronic renal 
failure; angina, myocardial ischemia or infarction, class 3 or higher congestive heart failure, 
cardiomyopathy, or clinically significant arrhythmias); 
12. Malignancy or systemic treatment for malignancy within 2 years of screening (with the 
exception of curatively treated, localized anogenital cancers and superficial skin cancers which 
are allowed);  
13. Presence of acute or chronic bleeding or clotting disorder that would contraindicate IM 
injections, or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of 
Day 0; 
14. History of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic 
agents; 
15. Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or 
a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
16. Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at 
screening or Day 0; 
17. Prior major surgery within 4 weeks of Day 0; 
18. Participation in an interventional study with an investigational compound or device within 30 
days of signing informed consent; participation in an observational study is permitted; 
19. Less than two acceptable sites available for IM injection considering the deltoid and 
anterolateral quadriceps muscles; 
393

20. Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
21. Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located 
in ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 
22. Metal implants or implantable medical device within the electroporation area; 
23. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere 
with adherence to study requirements; 
24. Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of 
either a psychiatric or physical (i.e. infectious disease) illness; 
25. Active military service personnel; 
26. Study-related staff or family member of study-related staff; 
27. 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 STUDY SUBJECTS 
4.3.1 
CRITERIA FOR DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
Subjects who manifest Grade 4 toxicity attributable to the study treatment will be discontinued 
from the study treatment.  Subjects will not receive further study treatment but will be encouraged 
to continue follow-up safety assessment through study discharge and not discontinue from the 
study.  
If a subject manifests Grade 3 toxicity attributable to the study treatment, the medical monitor and 
Investigator will discuss whether further treatment should be continued for that subject.  
4.3.2 
CRITERIA FOR WITHDRAWAL FROM THE STUDY 
All randomized subjects should be encouraged to complete all study treatments and follow-up 
visits. A subject will be considered to have completed the study when she completes all scheduled 
study treatments and follow-up visits. However, a subject may voluntarily withdraw from study 
participation at any time or be withdrawn at any time at the discretion of the investigator for any 
maternal obstetrical or medical complications after consultation with the medical monitor. 
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. The site should also counsel the 
subject on the importance of maintaining the assigned visit schedule for follow-up and treatment 
of HSIL (CIN2, CIN3), and ascertain whether or not the subject wishes to and/or should continue 
in the study based on previous noncompliance. 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. 
394

4.3.3 
SPONSOR NOTIFICATION OF DISCONTINUATION/ WITHDRAWAL  
The investigator or study coordinator must notify the Sponsor within 24 hours if a subject has been 
discontinued/withdrawn due to an AE. If a subject discontinues from the study or is withdrawn 
from the study prior to study completion, all applicable activities scheduled for the final study visit 
should be performed at the time of discontinuation. The investigator will make every effort to have 
all scheduled immune assessment blood samples collected as indicated in the Schedule of Events 
in the synopsis, Table 1. Any AEs and/or SAEs present at the time of discontinuation/withdrawal 
should be followed in accordance with the safety requirements outlined in section 7.1 – Safety 
Parameters. 
4.3.4 
REASON FOR DISCONTINUATION/WITHDRAWAL 
The primary reason for a subject discontinuing further dosing or withdrawal from the study itself 
is to be selected from the following standard categories and recorded on the CRF: 
 Adverse Event (Adverse Reaction): Clinical or laboratory events occurred that, in the medical 
judgment of the investigator for the best interest of the subject, are grounds for discontinuation. 
This includes serious and non-serious adverse events regardless of relation to study drug. 
 Death of subject  
 Subject voluntarily withdrew consent: The subject desired to withdraw from further 
participation in the study in the absence of an investigator-determined medical need to 
withdraw. If the subject gave a reason for withdrawal, it must be recorded on the CRF. This 
reason does not allow for further data collection and should not be selected if follow-up data 
collection of this subject is anticipated by the subject. 
 Investigator decision to withdraw the subject from participation: Investigator determined a 
medical need to withdraw the subject. Investigator must consult the Sponsor’s Medical 
Monitor before withdrawing a subject from participation in the study 
 Protocol Violation: The subject’s findings or conduct failed to meet the protocol entry criteria 
or failed to adhere to the protocol requirements (e.g., treatment noncompliance, failure to 
return for defined number of visits). The violation should be discussed with the Sponsor’s 
Medical Monitor prior to discontinuation of study treatments or study withdrawal. 
 Lost to Follow-up: The subject fails to attend study visits and study personnel are unable to 
contact the subject after repeated attempts including telephone calls, letter sent by certified 
mail or equivalent. 
 Other: The subject was terminated for a reason other than those listed above, such as the 
termination of the study by the Sponsor. 
4.3.5 
SUPPLEMENTATION OF STUDY SUBJECTS 
If more than 10% of subjects from randomization of study treatment discontinue prior to the Week 
36 primary endpoint procedures, then supplementation of study subjects will be considered. 
395

5 STUDY TREATMENT 
5.1 
INVESTIGATIONAL PRODUCTS 
Investigational product (IP) 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. The active and placebo 
formulations to be used in this study are described in Table 13. Both IPs will presented in clear glass 
cartridges and will be injected intramuscularly. 
VGX-3100 and placebo will be provided by Inovio Pharmaceuticals, Inc. or its designee. 
Table 13. Investigational Products 
Product 
Formulation 
Dose 
VGX-3100 
6 mg (1:1 mix of SynCon™ HPV-16 E6/E7 and HPV-18 E6/E7 plasmids) in 150 mM 
sodium chloride and 15 mM sodium citrate 
1 mL 
Placebo 
150 mM sodium chloride and 15 mM sodium citrate 
1 mL 
5.2 
BLINDING 
This study is double-blinded with blinding maintained throughout the study by use of identical 
packaging for both the active product and the placebo. There is no difference in appearance for both 
the active product and the placebo.  
The investigator may request to unblind a subject’s treatment assignment in case of an emergency 
or serious medical condition when knowledge of the study treatment is essential for proper clinical 
management of the subject, as judged by the investigator. It is preferred, but not required, that the 
investigator first contact the Medical Monitor to discuss options before unblinding the subject’s 
treatment assignment.  In case of non-emergency, investigator must contact Medical Monitor to 
discuss the options before unblinding the subject’s treatment assignment.  
The Sponsor’s or designee’s pharmacovigilance staff may unblind the treatment assignment for any 
subject with an SAE, UADE, or AE of interest. No personnel directly involved with the study will 
be unblinded.  If expedited regulatory reporting is required for an event, the report may be submitted 
to regulatory authorities with the subject’s treatment assignment, in accordance with local 
regulations. 
5.3 
PACKAGING AND LABELING OF INVESTIGATIONAL PRODUCT 
Each cartridge will be labeled with a single-panel label and then individually packaged within a 
pouch that will contain an additional, double-panel label with tear-off. Both VGX-3100 and placebo 
labels will include, at minimum, the following information in Table 14:   
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Table 14. Example Labels for Investigational Product 
Cartridges 
(primary container) 
Pouches 
(secondary packaging) 
VGX-3100 or Placebo 
Insert cap end 
IM administration 
Sponsor name 
LABEL BODY 
Material ID/Study ID 
VGX-3100 or Placebo 
Single-use cartridge containing 1ml 
IM administration via CELLECTRA® 5PSP 
Store at 5°C, expiration date 
Caution Statement  
Sponsor name and address 
LABEL TEAR OFF 
Material ID/Study ID 
VGX-3100 or Placebo 
Patient ID: _______________ 
Date (DD/MMM/YYYY): _______________ 
Must be used by (time): _______________ 
5.4 
HANDLING OF INVESTIGATIONAL PRODUCT 
Inovio Pharmaceuticals, Inc. will be responsible for assuring the quality of the IP is adequate for 
the duration of the trial. Unless otherwise specified, IP will be shipped in a refrigerated condition 
with a temperature monitoring device. If the temperature monitoring device denotes temperatures 
outside the pre-specified range for any product, the Sponsor, or its designee should be contacted 
immediately. 
Immediately upon arrival, IPs should be transferred from the shipping container into 2–8 °C (36-46 
°F) storage, in a secure area, according to local regulations. The Sponsor should be notified of any 
deviations from this recommended storage condition.  
Refrigerator temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. 
5.5 
DISPENSING OF INVESTIGATIONAL PRODUCT 
It is the responsibility of the Investigator to ensure that the IP is only dispensed to study subjects. It 
must be dispensed only from official study sites by authorized personnel according to local 
regulations. 
When a subject is eligible for randomization, remove the pouch from the refrigerator and allow to 
reach room temperature. The product cartridge must not be removed from the pouch until 
immediately prior to administration. The pouch must not be discarded until 1) administration is 
completed and 2) all pertinent information from the pouch label has been documented in source.  
The product must be used within 4 hours of removal from the refrigerator. 
The device user manual and instructions for use will inform clinical personnel about placement of 
the IP cartridge into the device, as well as the steps for injection and electroporation. 
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5.6 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of investigational product 
is maintained at the study site. Records or logs must comply with applicable regulations and 
guidelines, and should include: 
• 
Amount received and placed in storage area; 
• 
Amount currently in storage area; 
• 
Label ID number and use date or expiry date; 
• 
Dates and initials of person responsible for each investigational product inventory 
entry/movement; 
• 
Amount dispensed to each subject, including unique subject identifiers; 
• 
Amount transferred to another area/site for dispensing or storage; 
• 
Amount returned to Sponsor; 
• 
Amount destroyed at study site, if applicable. 
5.7 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused IP must be destroyed at site per institution 
policy or returned to Inovio Pharmaceuticals, Inc. or its designee, if site cannot destroy IP.  
The used IP cartridge will be discarded along with the disposable array within a sharps container at 
site. 
It is the Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. The return of unused IP(s) should be arranged by the responsible Study Monitor. 
The unused IP can only be destroyed after being inspected and reconciled by the responsible Inovio 
Pharmaceuticals, Inc. or designated Study Monitor. 
If IP is returned to Inovio Pharmaceuticals, Inc., or its designee, it must be accompanied by the 
appropriate documentation. Returned supplies should be in the original containers. Empty 
containers should not be returned to Inovio Pharmaceuticals, Inc. The return of unused IP(s) should 
be arranged with the responsible Inovio personnel and/or Clinical Monitor. 
5.8 
CELLECTRATM 5PSP DEVICE 
The Investigational product\placebo will be delivered using the CELLECTRA™ 5PSP device. The 
device consists of five (5) main components (see Figure 2): 
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Figure 2: CELLECTRA 5PSP Base Station with Handset  
1) The 5PSP Base Station serves as a charging dock 
for the Handset and can accept limited data inputs as 
well as store records. 
2) The reusable 5PSP Handset is battery powered and 
delivers the electroporation pulses. The Handset 
accepts the disposable array. 
3) The 5PSP Sterile Single Use Array consists of five 
(5) needle-electrodes bonded into a plastic housing 
that also accepts the (shipped separately) Drug 
Cartridge. The array accepts a standard, commercially 
available glass cartridge. 
4) USB International Power Supply 
5) Flash Drive used to transfer device logging data to 
the manufacturer. 
Base Station 
The base station communicates instructions, alerts, and error messages to the user through a touch 
screen graphical user interface (GUI).  It also accepts data inputs from the user, e.g., patient 
identification code, height, and weight; it communicates with the handset; provides energy access 
for the system through connection with standard wall electrical power supply sources (100-220V, 
~0.5Amp, 50-60Hz); and serves as a docking and recharging station for the handset.  The base 
station is illustrated in Figure 3. 
Figure 3: CELLECTRA™5PSP Base Station 
Handset 
The handset facilitates delivery of the needles for injection and the electroporation pulses into the 
muscle tissue and executes the treatment sequence (drug injection, impedance check, and 
electroporation pulses).  It has a display screen and speakers for user feedback and an embedded 
processor for running the system software that controls and measures all of the elements of the 
399

handset. The handset is powered by a custom, rechargeable battery pack that has its own safety 
circuit. The handset is designed with three independent fail-safes to minimize the risk of electrical 
shock, short, or fire. The handset is illustrated in Figure 4. 
Figure 4: CELLECTRA™5PSP Handset 
Array  
The array is a single-use, sterile, disposable component constructed of commonly-used medical 
plastics and metals, with 5 fixed, stainless-steel electrodes (needles) and 1 intramuscular injection 
needle. The needles are covered by a plastic shroud that retracts as the needles are inserted into the 
patient, then returns to the starting position as the needles are removed and locks out to prevent 
accidental needle sticks.  The opposite end of the array accepts the drug cartridge, which is inserted 
cap-end-first until the bottom of the cartridge is flush with the opening of the array (indicated by an 
audible 'click').  When properly inserted, the septum is punctured and the cartridge cannot be 
removed.  The array is illustrated in Figure 5. The array features no software. 
Figure 5: CELLECTRA™ 5PSP Array 
Handset without array attached
Handset with array attached
Array, shroud closed (top)  
Array, shroud retracted (right)
Insertion of cartridge into array 
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5.9 
USE OF CELLECTRA™ 5PSP DEVICE 
The instructions for use of the device are located in the CELLECTRA™ 5PSP User Manual. Users 
of the CELLECTRA™ 5PSP device must successfully complete training. Training will include 
review of the device user manual as well as hands-on training. After training on the proper use of 
the CELLECTRA™ 5PSP device, intended users at each site will be required to demonstrate their 
competence in its use to Inovio or its designee. An instructional video has been prepared for review 
by site personnel on an as needed basis. 
The treatment 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.  
Any deviation from the above procedures must be approved by the sponsor or its designee. 
5.10 PACKAGING AND LABELING OF CELLECTRA™ 5PSP DEVICE 
See below Figure 6 for example CELLECTRA™ 5PSP device component labels. 
Figure 6. Device Labels (Base, Handset, Array) 
BASE STATION   
 
HANDSET  
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ARRAY  
 
 
 
 
 
 
 
 
 
5.11  HANDLING OF CELLECTRA™ 5PSP DEVICE 
The CELLECTRA™ 5PSP device and its components must be stored in a secure location according 
to the instructions in the User Manual. 
5.12  CELLECTRA™ 5PSP DEVICE ACCOUNTABILITY 
The investigative site is responsible for maintaining device and accountability logs. The device must 
have full traceability from the receipt of the products through the subject use, disposal or return of 
the products. The Site must document acknowledgement of receipt and notify Inovio upon receipt 
of investigational product. This includes the content shipped and condition upon receipt.  
For each subject treatment, there must be a record of each product used for that subject, i.e. 
CELLECTRA™ 5PSP serial number, array lot number and the study drug lot number. The used 
sterile disposable array attachment must be discarded after use in accordance with institutional 
policy regarding disposal of sharp needles/instruments. 
5.13  RETURN OF CELLECTRA™ 5PSP DEVICES 
Upon completion or termination of the study, all devices and unused components must be returned 
to Inovio Pharmaceuticals, Inc. 
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 Inovio Pharmaceuticals, Inc. or the responsible Study 
Monitor. 
If product is to be 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 according to applicable 
regulation and guidelines and institutional procedures, and appropriate records of the disposal have 
been documented. 
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6 STUDY PROCEDURES AND TREATMENTS 
This section lists the procedures and parameters for each planned study evaluation.  The timing of 
each assessment is listed in the Schedule of Events Table (see Table 1). 
A subject will be required to provide informed consent for use of any information collected prior to 
consenting and before any additional study specific procedures are performed.   
Protocol waivers or exemptions will not be granted with the exception of immediate safety concerns. 
Therefore, adherence to the study design requirements, including those specified in the Schedule of 
Events Table are essential and required for study conduct. 
6.1 
BEFORE TREATMENT PROCEDURES 
6.1.1 
SCREENING EVALUATIONS 
Subjects who have been identified with standard of care biopsy results of CIN 1/2, CIN 2, CIN 
2/3 or CIN 3 and who consent to participate in the study will be eligible for screening and will 
have biopsy slides or tissue sent to the central pathology lab for review by PAC for evaluation 
prior to enrollment.  
Additionally, Investigators may discuss with the Sponsor on a case-by-case basis the screening of 
subjects with abnormal cytology findings (i.e. HSIL or ASC-H with or without local HPV-16 or 
18 genotype results) obtained as part of standard of care. The specific circumstances MUST be 
submitted in writing (e.g. email or fax) and the medical monitor MUST be consulted prior to 
screening a volunteer with these cytology findings (i.e. ASC-H or HSIL with or without HPV-16 
or 18) for this study. The initial biopsy results may have been obtained at a referring institution by 
someone other than the site investigator. 
 In the case where the subject has an ASC-H or HSIL cytology result without HPV-16 or 
18 genotyping results available locally and if approved by Inovio, the site may proceed 
with initial study screening by sending ThinPrep™ samples to the central laboratory to 
screen for HPV 16/18 by cobas™ assay. A non-specific result from local testing of 
“Positive for high risk HPV” is not sufficient and will require the collection of the 
ThinPrep™ sample for HPV-16 and/or HPV-18 testing by cobas™ assay.  If the central 
lab ThinPrep™ sample result is positive for HPV-16 and/or HPV-18, the site may continue 
screening including performing the initial colposcopy and biopsy. Biopsy tissue must be 
sent to the central pathology laboratory directly and not tested locally. 
 In the case where the subject has an ASC-H or HSIL cytology result with HPV-16 or 18 
positive genotype results available locally and if approved by Inovio, the site may proceed 
with initial study screening including performing the initial colposcopy and biopsy. Biopsy 
tissue must be sent to the central pathology laboratory directly and not tested locally. 
Subjects who consent to participate will have biopsy slides or paraffin-embedded tissue block(s) 
from a previous biopsy and/or newly collected cervical biopsy tissue samples (formalin fixed 
tissue) sent to the central pathology lab for review by PAC. There will be a maximum allowable 
window of 10 weeks from the date of collection of the qualifying biopsy sample(s) (i.e. 
403

slides/samples(s) reviewed by PAC with HSIL consensus diagnosis), until the date of first study 
treatment (i.e. Day 0).  
 Biopsy specimens and colposcopic photographs obtained within 10 weeks prior to Day 0 
as part of standard of care before the informed consent may be used as part of the screening 
and evaluation process.  If the pathology results of the initial biopsy obtained as part of 
standard of care are available confirming the presence of cervical HSIL (CIN2 or CIN3), 
those biopsy slides or sample(s) may be sent directly to the central pathology lab after the 
subject has signed the informed consent.   
For those individuals diagnosed with cervical HSIL by a local pathologist, where the initial biopsy 
slides or tissue obtained as part of standard of care are not available or cannot be obtained within 
a reasonable time frame, colposcopy should be performed and an additional biopsy sample 
collected during screening. A photograph of the lesion with at least one attempt should done as 
follows: Acetic acid should first be applied to the cervix then photographs of the cervix and the 
associated lesion should be photographed prior to and after biopsies (if applicable) and at all 
colposcopic examinations; if repeat photographs are sought, they should be done at the next 
protocol-specified colposcopy visit.   
The 10 week screening window begins upon collection of the biopsy sample that will be evaluated 
by the PAC.  
Subjects must have a histologic diagnosis of cervical HSIL (CIN2 or CIN3) confirmed by the PAC 
and a screening ThinPrep™ cervical specimen test positive for HPV-16 and/or HPV-18 by 
cobas™ HPV test to be eligible for randomization into the study (provided the subject also meets 
other eligibility criteria). Subjects whose specimens also test positive for other HPV genotypes are 
not excluded as long as they have a positive result for HPV-16 and/or HPV-18. Subjects’ post-
menopausal status must meet requirements as specified in the inclusion criteria [1, 2]. The 
assessments during the screening period will determine the subjects’ continued eligibility for the 
study and also their ability to comply with protocol requirements by completing all assessments.  
The following evaluations/actions, unless noted, will be performed within 10 weeks and up to Day 
0 – except for the safety laboratory collections/assessments, which must be performed within 45 
days prior to Day 0. All screening assessment values must be reviewed prior to study treatment. 
 Signed informed consent 
 Demographics; including age, and race/ethnicity 
 Medical history; including concomitant medications review, history of prior cervical 
dysplasia, and pregnancy history 
 Socio-Behavioral Assessment; including self-reported smoking history, self-reported exposure 
to second-hand smoke, self-reported alcohol intake history, contraceptive history 
 Vital signs (including oral temperature, respiratory rate, blood pressure and heart rate) 
 Full Physical Examination (including height, weight and BMI measurements) 
 2 Digene cervical swab samples  
 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain from 
any sexual activity and refrain from use of douching or vaginal lubricants/medication for a 
period of 24 hours prior to sample collection) 
404

 Urine pregnancy test 
 Colposcopy with lesion photography and/or cervical biopsy (Screening colposcopy and 
photography is optional if adequate colposcopy was performed upon collection of initial 
biopsy) 
 12-lead ECG (within 45 days prior to Day 0) 
 Baseline laboratory evaluations (includes CPK, hematology and serum chemistry, urinalysis)  
to be performed (within 45 days prior to Day 0); 
 Serology (HIV Antibody, within 45 days of Day 0) 
 Determination of eligibility per inclusion / exclusion criteria 
 Whole blood (at least 34 mL) and serum (at least 8 mL) for baseline immunology including 
miRNA profile 
6.2 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will be randomized to receive study treatment.  Visit 
dates and windows must be calculated from Day 0. 
6.2.1 
DAY 0 
The following evaluations will be performed on Day 0 prior to study treatment: 
 Determination of eligibility per inclusion / exclusion criteria 
 Randomization 
 Targeted Physical assessment 
 Vital signs 
 Urine pregnancy test 
 Whole blood (at least 34 mL) and serum (at least 8 mL) for baseline immunology including 
miRNA profile (a total of at least 68 mL of whole blood and 16 ml serum should be collected 
prior to dosing on Day 0) 
 2 Digene cervical swab samples 
 ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain from 
any sexual activity and refrain from use of douching or vaginal lubricants/medication for a 
period of 24 hours prior to sample collection) 
 Oropharynx (OP) sample by oral rinse and vaginal swabs for HPV testing 
 Intra-anal swabs (if subject has consented for intra-anal sampling) for HPV testing 
 
Colposcopy (accompanying lesion photography should be attempted at least once) 
 Patient-Reported Outcome (PRO) questionnaires (SF-36 and EQ-5D-5L) completion by a 
subject (if enrolled in US, Canada, Mexico, Germany and UK only) 
Study treatment will be administered and the following evaluations will be performed on Day 0 
post-treatment: 
 Post treatment adverse event and injection site reaction assessment at least 30 minutes after 
study treatment  
 Distribute Participant Diary Card (PDC)  
 Download EP data from device within 48 hours of study treatment  
405

6.2.2 
8-14 DAYS POST DOSE 1 PHONE CALL 
The following information will be evaluated during phone call: 
 Post treatment adverse event and injection site reaction evaluation 
 Review Day 0 PDC (after reviewing the PDC and post treatment injection assessment with the 
subject on the phone, the Investigator or study personnel will determine whether an office visit 
is needed for further evaluation) 
 PRO questionnaires (SF-36 and EQ-5D-5L) completion by a subject (if enrolled in US, 
Canada, Mexico, Germany and UK only) 
6.2.3 
WEEK 4  
The following study evaluation will be performed on Week 4 prior to study treatment (±4 days): 
 Targeted Physical assessment 
 Vital signs including weight 
 Urine pregnancy test 
 Collect PDC for dose 1 
The following study evaluations will be performed on Week 4 post treatment: 
 Post treatment adverse event and injection site reaction assessment at least 30 minutes after 
study treatment;  
 Distribute PDC  
 Download EP data from device within 48 hours of study treatment  
 PRO questionnaire (EQ-5D-5L only) completion by a subject (if enrolled in US, Canada, 
Mexico, Germany and UK only) 
6.2.4 
8-14 DAYS POST DOSE 2 PHONE CALL 
The following information will be evaluated during phone call:   
 Post treatment adverse event and injection site reaction evaluation 
 Review PDC for dose 2 (after reviewing the PDC and post treatment injection assessment with 
the subject on the phone, the Investigator or study personnel will determine whether an office 
visit is needed for further evaluation) 
 PRO questionnaires (SF-36 and EQ-5D-5L) completion by a subject (if enrolled in US, 
Canada, Mexico, Germany and UK only) 
6.2.5 
WEEK 8 
The following study evaluation will be performed during the visit 
 Vital signs 
 Targeted Physical assessment 
 Collect and review PDC for dose 2 
 Post treatment adverse event and injection site reaction evaluation 
406

 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from any sexual activity and refrain from use of douching or vaginal lubricants/medication for 
a period of 24 hours prior to sample collection) 
 
Whole blood (at least 34 ml) and serum (at least 8 ml serum) for immunology including 
miRNA profile 
6.2.6 
WEEK 12 
The following study evaluation will be performed on Week 12 prior to study treatment (±4 
days): 
 
Targeted Physical assessment 
 
Vital signs including weight 
 
Urine pregnancy test 
The following study evaluations will be performed Week 12 post treatment: 
 
Post treatment adverse event and injection site reaction assessment at least 30 minutes after 
study treatment;  
 
Distribute PDC  
 
Download EP data from device within 48 hours of study treatment  
 
PRO questionnaire (EQ-5D-5L only) completion by a subject (if enrolled in US, Canada, 
Mexico, Germany and UK only) 
6.2.7 
8-14 DAYS POST DOSE 3 PHONE CALL 
The following information will be evaluated during phone call:   
 
Post treatment adverse event and injection site reaction evaluation 
 
Review PDC for dose 3 (after reviewing the PDC and post treatment injection assessment 
with the subject on the phone, the Investigator or study personnel will determine whether an 
office visit is needed for further evaluation) 
 
PRO questionnaires (SF-36 and EQ-5D-5L) completion by a subject (if enrolled in US, 
Canada, Mexico, Germany and UK only) 
6.2.8 
WEEK 15 
The following study evaluations will be performed on Week 15 ± 1 week: 
 Targeted physical assessment 
 Vital signs 
 Post-treatment injection site reaction assessment 
 Urine pregnancy test 
 Whole blood (at least 51 mL) and serum (at least 4 mL) for immunology 
 2 Digene cervical swab samples 
 ThinPrep™ sample for HPV typing and pap smear (subject should be instructed to abstain from 
any sexual activity and refrain from use of douching or vaginal lubricants/medication for a 
period of 24 hours prior to sample collection)  
 Collect PDC  
407

 Colposcopy (lesion photography should be attempted at least once) 
6.2.9 
WEEK 28 
The following study evaluations/actions will be performed on Week 28 ± 1 week: 
 
Targeted physical assessment 
 
Vital signs 
 
Urine pregnancy test 
 
2 Digene cervical swab samples 
 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from any sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to sample collection)  
 
Colposcopy (lesion photography should be attempted at least once) to assess for possible disease 
progression. 
 
ECC (only to be collected if ECC was done as part of Screening) 
 
PRO questionnaires (SF-36 and EQ-5D-5L) completion 8-14 days post Week 28 visit by a 
subject enrolled in US, Canada, Mexico, Germany and UK only 
6.2.10 
WEEK 36 
The following study evaluations will be performed on Week 36 ± 1 week: 
 
Targeted physical assessment 
 
Vital signs 
 
Socio-Behavioral assessment (change in smoking alcohol intake or recreational drug use from 
baseline) 
 
Whole blood (at least 34 ml) and serum (at least 4 ml) for immunology 
 
Urine pregnancy test 
 
2 Digene cervical swab samples  
 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from any sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to sample collection) 
 
Oropharynx (OP) by oral rinse and vaginal swab for HPV testing 
 
Intra-anal swab (if subject has consented to intra-anal sampling) for HPV testing 
 
Colposcopy (lesion photography should be attempted at least once)  
 
Biopsy or surgical excision based on information collected at Week 28 to determine the 
minimally required tissue collection procedure (e.g. 4 quadrant biopsies, 4 quadrant biopsies 
and ECC, or surgical excision) to be used for histopathologic assessment at Week 36 as 
described in Tables 5 & 6 
 
PRO questionnaire (EQ-5D-5L only) completion by a subjects enrolled in US, Canada, 
Mexico, Germany and UK only 
6.2.11 
WEEK 40 PHONE CALL 
The following study evaluations will be performed on Week 40 ± 2 weeks via a phone call:   
 
AE/SAE assessment 
408

 
Review of histology results as read by PAC from Week 36  
 
Completion of quality of life questions will asked to subjects enrolled in US, Canada, Mexico, 
Germany and UK only 
 
PRO questionnaires (SF-36 and EQ-5D-5L) completion 8-14 days post Week 40 by a subject 
by subjects enrolled in US, Canada, Mexico, Germany and UK only 
6.2.12 
WEEK 62 
The following study evaluations will be performed on Week 62 ± 2 weeks: 
 
Targeted physical assessment 
 
Vital Signs 
 
Urine pregnancy test 
 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from any sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to sample collection) 
 
Colposcopy (lesion photography should be attempted at least once) 
6.2.13 
WEEK 88 
The following study evaluations will be performed on Week 88 ± 2 weeks: 
 
Full Physical Exam 
 
Vital Signs 
 
Socio-Behavioral Assessment (change in smoking alcohol intake or recreational drug use 
from baseline) 
 
Urine pregnancy test 
 
2 Digene cervical swab samples 
 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from sexual activity and refrain from use of douching or vaginal lubricants/medication for a 
period of 24 hours prior to sample collection) 
 
Oropharynx (OP) by oral rinse and vaginal swabs for HPV testing 
 
Colposcopy (lesion photography should be attempted at least once) 
 
PRO questionnaires (SF-36 and EQ-5D-5L) completion by a subject (if enrolled in US, 
Canada, Mexico, Germany and UK only) 
 
6.3 
EVALUATIONS AND PROCEDURES 
6.3.1 
INFORMED CONSENT 
All subjects must sign the informed consent prior to any study related procedures being performed 
(i.e., prior to any screening activities). The informed consent documentation must be in accordance 
with applicable regulations and GCP. Qualified study personnel will meet with prospective study 
subjects, explain the study, and provide them with an informed consent form (ICF) that describes 
the screening tests, eligibility criteria for entering the study, study treatments and follow-up 
procedures, in a language understandable to the subject. Explanation of the study includes, but is 
not limited to, study objectives, potential benefits and risks, discomforts/inconveniences, and the 
409

s u bject’s ri g hts a n d res p o nsi bilities. T he s u bject is t he n re q ueste d t o si g n a n d date t he I C F. A c o p y 
of t he si g ne d i nf or me d c o nse nt d oc u me ntati o n m ust be pr o vi de d t o t he s u bject. T he q ualifie d st u d y 
pers o n nel will d oc u me nt t he pr ocess of o btai ni n g i nf or me d c o nse nt wit hi n t he s o urce rec or d. 
Si g ne d I C Fs are mai ntai n e d i n t he s u bject’s s o urce rec or ds a n d m ust b e accessi ble f or verificati o n 
at a n y ti me. 
6. 3. 2  
A S S I G N M E N T O F S U B J E C T I D E N TI FI C A TI O N N U M B E R S 
Eac h s u bject w h o c o nse nts will be assi g ne d a u ni q ue s u bject i de ntificati o n n u m ber ( SI D), w hic h 
i de ntifies t he s u bject f or all st u d y-relate d pr oce d ures. SI Ds are a c o m bi nati o n of a u p t o t w o al p ha 
letters st u d y c o de, t w o al p ha letter C o u ntr y c o d e, t w o di git site n u m ber, pl us 3- di git s u bject 
n u m ber  starti n g wit h  
 (e. g., 
). O nce assi g ne d, SI Ds ca n n ot be re use d f or a n y 
reas o n. I nf or mati o n re gar di n g t he SI D a n d s cree n date m ust be d oc u m e nte d o n a Scree ni n g 
l o g/s yst e m a n d i n t he I nt eracti ve R es p o nse Tec h n ol o g y (I X R S). 
S u bjects meeti n g eli gi bilit y criteria will be ra n d o mize d b y a c o m p uter ge nerate d all ocati o n 
sc he d ule.  
6. 3. 3  
S A F E T Y E V A L U A TI O N S 
6. 3. 3. 1  
P h ysic al E x a m  
A f ull p h ysi cal e x a mi nati o n ( P E) will be c o n d ucte d d uri n g scree ni n g a n d st u d y disc har ge.  
It will i ncl u de a n assess me nt of t he f oll o wi n g: ge neral a p peara n ce, s ki n, hea d, e yes, ears, 
n ose, a n d t hr oat, a n d l y m p h n o des, a n d res pirat or y, car di o vasc ul ar, gastr oi ntesti nal, 
ge nit o uri nar y, m usc ul os k eletal, a n d ne ur ol o gi cal s yste ms.   
A tar gete d p h ysic al assess me nt will be perf or me d at ot her visits as deter mi ne d b y t he 
i n vesti gat or or direct e d p er s u bject c o m plai nts.  
6. 3. 3. 2  
Vit al Si g ns  
Vital si g ns will be meas ure d at s pe cifie d visits a n d will i ncl u de: 
 S itti n g s yst olic a n d diast olic bl o o d press ures wit h s u bject sitti n g at rest f or at least 
5 mi n utes bef ore me as ure m e nt 
 Res pirati o n rate 
 H eart rate  
 Oral te m perat ure me as ur e d wit h a n a ut o mate d t her m o meter  
6. 3. 3. 3  
Wei g ht a n d Hei g ht 
Wei g ht a n d hei g ht will b e c ollecte d at scree ni n g i n or der t o calc ulate t he B MI. Wei g ht will 
be c ollecte d o n Da y 0, Wee ks 4 a n d 1 2. 
6. 3. 3. 4  
M e dic al Hist or y 
All rele va nt (as j u d ge d b y t h e i n vesti gat or) past a n d prese nt c o n diti o ns at scree ni n g, as well 
as pri or s ur gical pr oce d ures will be rec or de d f or t he mai n b o d y s yste ms.  T he me dica l 
hist or y will i ncl u d e a) a n y pri or hist or y of CI N dia g n ose d – wit h dia g n osis date(s) a n d 
res pecti ve CI N l e vel(s), a n d b) if treate d pre vi o usl y f or CI N, t he res pecti ve tr eat me nt t y p e(s) 
a n d date(s). 
4 1 0
P P D
P P
D

6.3.3.5 
Socio-Behavioral Assessment 
Socio-Behavioral Assessment, including self-reported smoking history, self-reported 
history of exposure to second-hand smoke, self-reported alcohol intake history, self-
reported recreational drug use history, self-reported history of contraceptive use and type 
of contraceptive if known, reproductive history, history of prior cervical dysplasia, and 
pregnancy history will be obtained at Screening.  
At Weeks 36 and 88, socio-behavioral assessment will be performed to document any 
change from screening. 
6.3.3.6 
Laboratory Evaluations 
At screening, blood samples will be taken to be tested for serum chemistry and hematology.  
Complete blood count (CBC): 
 White blood cell (WBC) count with differential 
 Red blood cell (RBC) count 
 Hemoglobin, Hematocrit 
 Platelet count 
Serum Chemistry: 
 Glucose 
 Serum glutamic-pyruvic transaminase (SGPT)/Alanine aminotransferase (ALT) 
 Blood urea nitrogen (BUN ) 
 Creatinine 
 Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
 Creatine Phosphokinase (CPK) 
Urinalysis (UA):  
Urine samples will be tested at screening by dipstick for glucose, protein, and hematuria. If 
abnormal (presence of protein, hematuria, or glucose ≥ 1+) a microscopic examination 
should be performed. 
6.3.3.7 
Demographics 
Demographic information will be collected via self-report (unless noted otherwise), 
including the following: 
 Age 
 Race/ethnicity 
6.3.3.8 
Urine Pregnancy Testing 
For subjects of reproductive potential, a negative spot urine pregnancy test is required prior 
to each study treatment, colposcopy and surgical excision. 
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6.3.3.9 
ECG 
A single 12-lead ECG will be obtained during Screening after the subject has been in a 
supine position for 10 to 15 minutes. The ECG should include measurements of ventricular 
rate, PR, QRS, QRS axis, QT, QTcb or QTcf, ST segment, T wave as well as an investigator 
assessment of whether the ECG is normal or abnormal (automated interpretations of ECG 
should not be used). Abnormal ECGs should be interpreted as “clinically significant (CS)” 
or “not clinically significant (NCS)” by the investigator. 
6.3.3.10 
Subject Self Evaluation 
Subjects will be provided a PDC and will be asked to record the following the evening of 
study treatment through Day 6: 
 
Oral temperature and time taken (before 11:59 pm) 
 
General symptoms of feeling unwell 
 
Pain and itching at injection site 
 
Measure redness, swelling, bruising at injection site 
 
Medications taken 
The completed PDC will be reviewed with the subject by the study staff at 8 -14 days post-
dose phone call and next in-person visit. 
The study staff will review the PDC for general symptoms (e.g. malaise, fatigue, headache, 
nausea, and myalgia/arthralgia), injection site reaction symptoms (e.g. pain, erythema and 
edema), medical events and medications.  
Any PDC 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 PDC entry does not meet the criteria of a Grade 1 or higher AE as per 
the CTCAE guidelines, 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 
PDC entry and final AE reporting (i.e. grading) do not agree, the reasoning should be 
recorded in the source documents. 
6.4 
INJECTION AND ELECTROPORATION (EP)  
Subjects will receive a 3-dose series of either 1 ml VGX-3100 or Placebo by IM injection in the 
deltoid (or anterolateral quadriceps muscle as an alternate option, if deltoid muscle is not possible 
or appropriate) followed immediately by EP with the CELLECTRA™ 5PSP. Study treatment must 
not be given within 2 cm of a tattoo, keloid or hypertrophic scar.  If there is implanted metal, 
implanted device, within the same limb then use of the deltoid muscle on the same side of the body 
is excluded.  
6.4.1 
RISKS OF TREATMENT PROCEDURES 
A summary of the potential risks of IM administration followed by EP with the CELLECTRA™ 
5PSP can be found in the VGX-3100 Investigator’s Brochure. 
 
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6.4.2 
MANAGEMENT OF ANXIETY AND PAIN DUE TO TREATMENT 
Subjects may be offered topical anesthetic (e.g. EMLA or equivalent), to prevent significant 
discomfort from the treatment procedure. If a topical anesthetic is used, an approximately 1.5 cm 
diameter amount will be applied with occlusion to the site of injection ~30 minutes prior to 
treatment.  
Subjects may be offered a mild sedative (e.g. 0.5-1 mg lorazepam), or equivalent, for anxiety 
related to the treatment procedure. Mild sedatives may be administered approximately 1 hour prior 
to treatment at Day 0, Weeks 4 and/or 12. Subjects who receive a mild sedative should not be 
allowed to operate a motor vehicle for 3-4 hours after receiving medication and should have 
arranged transportation to depart the study site. 
Subjects may be offered an analgesic (e.g. ibuprofen, ketorolac) after injection/EP.  
Subjects who are allergic to or have contraindications to EMLA, ibuprofen, ketorolac or a mild 
sedative may be offered a suitable alternative.  
Medication taken for anxiety or pain management should be added to the concomitant 
medications. 
6.5 
ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well as urine 
pregnancy testing at Screening will be performed for inclusion into the study as listed in section 
6.1.1. 
6.6 
ASSESSMENT OF CLINICAL STUDY ADVERSE EVENTS 
The injection site will be assessed by study personnel prior to and at least 30 minutes after each 
study treatment and at 2 to 4 weeks post study treatment visits.  They will also be advised to record 
local and systemic AEs for 7 days on a PDC. 
An adverse event assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any adverse events, concomitant medications new onset illness or 
disease, as well as contraceptive compliance. Subjects will be reminded to contact study personnel 
and immediately report any event that happens for the duration of the study. Unsolicited adverse 
events will be captured from the time of the informed consent to study discharge. These events will 
be recorded on the subject’s CRF.   
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6.7 
ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the investigator will be instructed to 
use the following grading scale:  
Table 15. 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 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/Redness* 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling** 
2.5-5 cm and 
does not interfere 
with activity 
5.1-10 cm or interferes 
with activity 
>10 cm or prevents 
daily activity 
Necrosis 
- September 2007 “FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials” 
*In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded 
as a continuous variable 
**Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement 
6.8 
ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, two previously-validated patient-reported 
outcomes (PRO) instruments will be provided to the subjects enrolled in US, Canada, Mexico, UK 
and Germany. The following two PRO questionnaires will be used: 
1. Short Form Health Survey, version 2 (SF-36v2™) (Optum, Inc.):  generically measures 
functional health and well-being, for physical and mental health; consists of thirty-six items 
covering eight domains (Physical functioning, Role limitations due to physical problems, 
Bodily pain, General health, Vitality, Social functioning, Role limitations due to emotional 
problems, and Mental health) [26] 
2. EQ-5D-5L (EuroQol Research Foundation): generically measures activities & general 
health status; consists of six items covering six domains (Mobility, Self-care, Usual activity, 
Pain/discomfort, Anxiety/depression, and Global health status) [27, 28] 
Either one or both PRO instruments (refer to Section 6.2) will be provided to the subject who will 
be instructed to complete the questionnaire at the following time points:  
 Day 0 (before the first study treatment) 
 8-14 days post dose 1 
 Week 4 (after study treatment) 
 8-14 days post dose 2 
 Week 12 (after study treatment) 
414

 8-14 days post dose 3 
 8 -14 days post Week 28 
 Week 36 (after biopsy or surgical excision) 
 8-14 days post Week 40 
 Week 88  
Administration of PRO instruments will be performed according to the validated procedure and 
guidelines of each respective instrument, except for some assessments for exploratory analyses. 
Additional instructions will be provided separately. 
Additional questions related to the subject’s quality of life following surgery or biopsy will be 
completed at the Week 40 phone call for subjects enrolled in USA, Canada, Mexico, UK and 
Germany. 
6.9 
PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at baseline (screening and Day 0 prior to dosing) 
and at Weeks 8, 15, and 36.  
Details of the immunology sample collection and shipment information will be provided in the 
Laboratory Manual. 
A standardized binding ELISA may be performed to measure the anti–HPV-16/18 antibody 
response induced by VGX-3100. 
PBMCs will be isolated from whole blood samples. Assessment of cellular immune activity may 
occur via the application of the Interferon-γ enzyme-linked immunosorbent spot (IFN-γ ELISpot) 
assay as well as flow cytometry.  
Additional assessment of cellular immune activity may occur via the application Flow Cytometry 
for the purposes of performing a Lytic Granule Loading Assay. The Lytic Granule Loading assay 
may examine the following external cellular markers: CD3, CD4, CD8 (T cell identification), 
CD137, CD38 and CD69 (T cell activation markers) as well as PD-1 (exhaustion/activation marker). 
The Lytic Granule Loading assay may additionally analyze the following intracellular markers: 
Granzyme A, Granzyme B, Granulysin and Perforin (proteins involved in lytic degranulation and 
cytotoxic potential). Markers examined in this assay may change as new relevant data become 
available. 
Profiling of miRNA may occur via the use of either sera or plasma obtained at Screening, Day 0 as 
well as Week 8.  Assessment of Day 0 samples alone will explore predictive algorithms for response 
to treatment with VGX-3100 prior to dosing.  Assessment of Week 8 samples may be done as a 
comparison against Day 0 in order to look for changes in miRNA profiles that occur once dosing 
with VGX-3100 has begun to explore construction of an algorithm to predict treatment success with 
VGX-3100. 
Profiling of DNA methylation status will occur via the use of nucleic acid isolated from Digene 
brushes used at Screening, Day 0 and Week 15.  Assessment of Day 0 samples alone will explore 
predictive algorithms for response to treatment with VGX-3100 prior to dosing.  Assessment of 
Week 15 samples may be done as a comparison against Day 0 in order to look for changes in DNA 
415

methylation profiles that occur once dosing with VGX-3100 has finished to explore construction of 
an algorithm to predict treatment success with VGX-3100.       
6.10 TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue or additional slides in the paraffin block after histologic diagnoses have 
been rendered, then unstained slides and/or the relevant paraffin blocks may be collected for immune 
assessment.  Available tissue collected from pre- and post- treatment may be assessed for the 
presence of immune cells using immunohistochemistry or immunofluorescence. The presence of 
immune signatures may also be analyzed through the assessment of various transcripts suggestive 
of an inflammatory or an immunosuppressive tissue microenvironment. 
An Immunoscore algorithm will be applied to cervical tissue obtained at baseline.  The algorithm is 
composed of scoring patients based on infiltration of immune cells stained with CD8, FoxP3, CD103 
and Perforin.  Scoring will occur in epithelium designated as HSIL.   
For HSIL epithelium, 1 point will be assigned for patients who show at least two of the following 
three parameters:  
 CD8 count per mm2 >375,  
 perforin count per per mm2 >0 and  
 CD103 count per per mm2 >150   
Additionally, 1 point will be assigned for each for the following parameters:  
 FoxP3/CD8 ratio <1:3,  
 CD103/CD8 ratio >2:1,  
 CD103/ perforin ratio >10:1 and  
 CD103/FoxP3 ration > 1.5:1    
6.11 HLA TYPING 
HLA testing will be performed on PBMC from any single blood sample collected for 
immunogenicity analysis. If the subject has a record of previous high resolution HLA testing and 
access to the results, then HLA testing is not required. 
The DNA extracted from the blood sample will be used to determine if alleles at the MHC locus 
affect the immune response to study treatment. Data arising from this analysis will be subject to the 
same confidentiality restrictions as the rest of the study. This specimens will be destroyed after the 
analysis is completed. 
6.12  PAP SMEARS AND HPV TESTING 
Pap smears will be obtained using ThinPrep™ test kits at the screening, Day 0, Weeks 8, 15, 28, 36, 
62, 88 and read in a central laboratory. HPV PCR by cobas™ HPV test will be performed on the 
ThinPrep™ specimen. At each of these visits, menstrual cycle status & recent history will be 
collected via self-report.  If the Pap smear result suggests progression to cancer at Day 0, Weeks 15, 
28 or 36, the investigator may schedule an ad hoc visit to perform a colposcopy and possible biopsy 
if clinically indicated. 
416

The subject will be requested to abstain from any sexual activity and refrain from use of douching 
or vaginal lubricants/medication for a period of 24 hours prior to collection of ThinPrep™ samples 
to eliminate potential interference with the results of HPV testing.   
 At visits (i.e. Screening, Day 0, and Weeks 15, 28, 36 and 88) where multiple cervical samples are 
collected, the two Digene cervical swab will be collected prior to the ThinPrep™ sample. 
Immunology testing may be performed from Digene swab. 
Details of sample collection and shipment information will be provided in the laboratory manual. 
Additionally, if there is residual tissue available from cervical tissue from screening and Week 36 
after the histologic diagnosis have been rendered, then unstained slides and/or paraffin blocks may 
be collected to test for HPV typing. 
Also, non-cervical swabs (i.e. oropharyngeal rinse, vaginal brush and intra-anal swabs) will be 
collected at specified visits for HPV typing. 
6.13  COLPOSCOPY AND CERVICAL BIOPSIES 
Colposcopy at screening must be adequate, defined as full visualization of the squamo-columnar 
junction (Type I or II transformation zone) and complete visualization of the upper limit of aceto-
white epithelium or suspected dysplasia. An ECC is not required for study entry. However, if an 
ECC was done as part of routine care during the screening period, and found to have evidence of 
cervical HSIL such subject should not be enrolled in the study. Colposcopy is not required to be 
performed at screening if adequate colposcopy was previously obtained upon collection of initial 
biopsy.  All colposcopies performed after informed consent should be conducted according to the 
guidelines outlined in Appendix A. 
Interval colposcopies will be performed at Day 0, Weeks 15, 28, 36, 62, and 88.  An unscheduled 
colposcopy may be performed at the discretion of the investigator if there is suspicion of disease 
worsening or progression. 
At least one attempt to photograph the lesion should done as follows: Acetic acid should first be 
applied to the cervix then photograph(s) of the cervix and the associated lesion should be taken prior 
to and after biopsies (if applicable) and at all colposcopic examinations; if repeat photographs are 
sought, they should be done at the next protocol-specified colposcopy visit.  Pictures should be taken 
to obtain a quality image to the extent feasible according to investigator judgment.   
If a biopsy or surgical excision is performed, images of the cervix should be collected before and 
after the procedure. Each site will be instructed on 1) the technique for capturing the proper images 
using a standard approach and 2) the process for uploading the images to a secure server. 
Additionally, if a vaginal or vulvar lesion should develop after a subject is enrolled, photographs 
should also be taken to document the clinical exam finding.    
6.13.1 
ECTOCERVICAL BIOPSIES 
Ectocervical biopsies are required at screening to confirm eligibility.  If the criteria outlined in 
Table 5 or 6 are met, ectocervical biopsies may also be performed at Week 36 to provide tissue 
for histopathologic assessment of disease regression.   
417

Visualization of a normal appearing cervix by colposcopy is insufficient evidence to confirm 
disease regression at Week 36. Biopsy must be performed at the location of the screening biopsy 
if no disease is visible at Week 36. 
Biopsies should not be performed at any other visit unless there is suspicion of disease 
progression.  Removal of additional tissue by biopsy before Week 36 will bias results toward 
improvement regardless of whether the subject is in the active or placebo group. The bias 
introduced will obviously be more significant for smaller lesions.  For this reason, if biopsies are 
obtained prior to Week 36, the subject will be classified as a non-regressor in the efficacy 
analyses. Subject safety is paramount in this study. Therefore, if at any time the investigator may 
suspect disease progression and the standard of medical care would be to perform an unscheduled 
biopsy prior to Week 36, then his or her medical judgment should prevail over the default 
“Schedule of Events”, Table 1. 
6.13.2 
UNSCHEDULED BIOPSIES 
In the event an unscheduled biopsy is performed prior to Week 36, the subject will be classified 
as a non-responder. The subject will discontinue further study treatment and continue in the study 
for safety follow-up visits. The subject will be managed according to standard of care and the 
Investigator’s judgment based on the results of the histological diagnosis from the unscheduled 
biopsy Additional instructions for collecting ectocervical biopsies are detailed in Appendix A. 
All biopsy samples/excised tissue will be sent to the central pathology lab for review by PAC.   
6.14  CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to the screening 
biopsy date of eligible subjects must be recorded on the CRF. Actual or estimated start and stop 
dates must be provided. Medical procedures performed within 8 weeks prior to screening biopsy 
date of eligible subjects that do not affect subject’s eligibility for participation and during the study 
(including over the counter or herbal), will be recorded on the CRFs. 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. Medication that is considered necessary 
for the subject’s safety and well-being may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the CRF.   
6.15  RESTRICTIONS 
6.15.1 
PROHIBITED CONCOMITANT MEDICATIONS AND TREATMENTS 
The following medications and treatments are prohibited:  
 Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent; use of inhaled otic and ophthalmic corticosteroids are allowed 
 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) at screening and throughout the study 
 Administration of any non-study related, non-live vaccine within 2 weeks of any study 
treatment or within 4 weeks of any study treatment for any non-study, live vaccine 
418

 Blood thinners (e.g. anticoagulants, antiplatelet drugs) or other medication that affects blood 
clotting within 2 to 14 days (e.g., 4-5 drug half-lives) of any study treatment, biopsy or 
excisional procedure (e.g. LEEP) 
6.15.2 
OTHER RESTRICTIONS 
Subjects should not use alcohol or drugs that would interfere with study requirements during 
the course of the study and should report ALL medications/drugs taken to the investigator 
and/or other study personnel. 
Subjects should refrain from becoming pregnant until 6 months following the last dose of 
investigational product by using appropriate contraceptive measures as (See Inclusion Criteria, 
Section 4.1).  Lapses in contraceptive use should be reported to investigator and/or other study 
personnel. 
Subject should abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to collection of ThinPrep™ samples. 
7 EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
7.1.1 
ADVERSE EVENTS 
An adverse event (AE) is defined as any unfavorable and unintended change in the structure, 
function, or chemistry of the body, or worsening of a pre-existing condition, temporally 
associated with the use of a product whether or not considered related to the use of the product. 
In this study, such changes will be monitored, classified, and summarized, as Clinical or 
Laboratory AEs. Medical condition/diseases present before starting the investigational drug will 
be considered adverse events only if they worsen after starting study treatment. Throughout the 
course of the study, all solicited and unsolicited AEs will be monitored and reported on an AE 
CRF, including the event’s seriousness, severity, action taken, and relationship to investigational 
product(s). AEs should be followed until resolution or stable and the outcome will be documented 
on the appropriate CRF. All AEs should be recorded in standard medical terminology rather than 
the subject’s own words. 
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 study drug). 
 Any pre-existing condition that increases in severity, or changes in nature during or as a 
consequence of the study drug phase of a human clinical trial, will also be considered an AE. 
 Complications of pregnancy (e.g., spontaneous abortion, miscarriage, ectopic pregnancy, fetal 
death, still birth, congenital anomaly of the fetus/newborn); see Section 7.1.9 for additional 
information on pregnancy reporting. 
 AEs that occur from the study screening visit onwards and throughout the duration of the study, 
including the follow-up off study drug period will be recorded as an AE. 
 Conditions that lead to a medical or surgical procedure. 
419

AEs do not include the following: 
 Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed as a result of 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 informed consent form 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. 
7.1.2 
SERIOUS ADVERSE EVENTS 
A serious adverse event (SAE) is any AE that meets one of the following conditions: 
 Death during the period of surveillance defined by the protocol; 
 Is immediately life-threatening (e.g., subject was, in the view of the Investigator, at immediate 
risk of death from the event as it occurred). This does not include an AE that, had it occurred 
in a more serious form, might have caused death; 
 An event requiring inpatient hospitalization or prolongation of existing hospitalization during 
the period of protocol defined surveillance (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 or substantial disruption of the ability 
to conduct normal life functions; 
 Results in congenital anomaly or birth defect; 
 An important medical event that may not result in death, be life threatening, or require 
hospitalization, but based upon appropriate medical judgment, may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include 1) allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, 2) blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, 3) the development of drug dependency or drug abuse or 4) 
the development of a malignancy; 
 Is medically significant or requires intervention to prevent one or other of the outcomes listed 
above. 
7.1.2.1 
Clarification of Serious Adverse Events 
 Death is an outcome of an AE, and not an adverse event in itself. 
 The subject may not have been on investigational medicinal product at the occurrence 
of the event.  
420

 Dosing may have been given as treatment cycles or interrupted temporarily before the 
onset of the SAE, but may have contributed to the event.  
 “Life-threatening” means that the subject was at immediate risk of death from the event 
as it occurred. This does not include an event that might have led to death if it had 
occurred with greater severity. 
 Complications that occur during hospitalizations are AEs. If a complication prolongs 
the hospitalization, it is an SAE. 
 Inpatient hospitalization means that the subject has been formally admitted to a hospital 
for medical reasons, for any length of time. This may or may not be overnight. It does 
not include presentation and care within an emergency department nor does it include 
full day or overnight stays in observation status. 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE and/or SAE and not the individual signs/symptoms. 
Serious adverse events that are ongoing should be followed until resolution or are clinically 
stable. The reporting period for SAEs is described in Section 7.4. 
7.1.2.2 
Event Reporting for Disease Progression or Exclusionary Histologic Findings 
Post-study Treatment 
After starting study treatment, if there is histologic confirmation of progression of cervical 
HSIL to micro invasive or invasive squamous cell carcinoma, the event must be reported as 
an SAE. Post-study treatment histologic diagnosis of adenocarcinoma-in-situ or 
adenocarcinoma should also be reported as an SAE. In both instances, the condition for 
SAE reporting should be categorized as a medically important event unless another criterion 
is met. 
7.1.3 
UNEXPECTED ADVERSE DRUG REACTIONS AND EXPEDITED 
REPORTING 
An adverse drug reaction (ADR) is any noxious and unintended responses to a medicinal product 
related to any dose, for which a causal relationship between a medicinal product and an adverse 
event is at least a reasonable possibility; i.e., there is evidence to suggest a causal relationship 
between the product and the adverse event. An unexpected ADR is one, the nature or severity of 
which is not consistent with the applicable product information (investigator’s brochure, protocol, 
and user manual). Reports that add significant information on specificity or severity of a known, 
already documented SAE constitute unexpected events. For example, an event more specific or 
more severe than described in the Investigator's Brochure or protocol would be considered 
"unexpected.” Specific examples would be (a) acute renal failure as a labeled ADR with a 
subsequent new report of interstitial nephritis and (b) hepatitis with a first report of fulminant 
hepatitis.  
The Sponsor will assess each serious ADR report for expectedness, to determine if it is a serious 
unexpected suspected adverse reaction (SUSAR) which requires prompt reporting to regulatory 
authorities and participating investigators as an expedited report, according to the applicable 
421

regulatory requirements. Additional occurrences of the SUSAR will be required to be reported on 
an expedited basis until the applicable product information is amended. 
In addition to single-case reports of SUSARs, the Sponsor shall notify regulatory authorities and 
participating investigators of information that might materially influence the benefit-risk 
assessment of a medicinal product, sufficient to consider changes in product administration or 
overall conduct of a clinical investigation. Examples of such information include a clinically 
important increase in the rate of occurrence of a serious expected adverse event, the identification 
of a significant hazard to the subject population, or a major safety finding from a study conducted 
in animals. 
7.1.4 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
Unanticipated adverse device effect means 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.  
Per the definition above, a UADE is a type of serious adverse event (SAE) that requires expedited 
reporting on the part of the sponsor. As a reminder, all SAEs regardless of relationship to device, 
drug or procedure are to be reported to Sponsor by the study investigator within 24 hours. Sponsor 
will assess each device related SAE to determine if anticipated based on prior identification within 
the investigational plan.  
For countries recognizing and regulating CE Mark devices, SAEs related only to the device which 
meet the medical device vigilance (MDV) reporting criteria will be handled by the Sponsor under 
the post-market surveillance/vigilance reporting requirements per MEDDEV 2.12-1. In such 
cases, the Sponsor will report as per the regulations to the relevant health authorities that require 
MDV reporting.  
7.1.5 
ASSESSING SEVERITY (INTENSITY) 
Adverse events should be captured once on the CRF at the maximum severity reported.  
The investigator will grade laboratory AEs and clinical AEs with respect to the following levels 
of severity as per Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 for applicable 
subject populations: 
 Grade 1 (Mild) 
 Grade 2 (Moderate) 
 Grade 3 (Severe) 
 Grade 4 (Potentially Life Threatening)  
 Grade 5 (e.g. Death) 
The investigator will grade injection site reactions in accordance with 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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7.1.6 
CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE 
EVENTS 
 A causally related AE is one judged to have a reasonable possibility of a relationship to the 
administration of the IP and/or the CELLECTRA™ 5PSP device. An AE may also be assessed as 
not related to the IP and/or the 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 adverse events and judging the 
relationship between the administration of the IP and device and a subsequent AE. The investigator 
is aware of the subject’s clinical state and thus may be sensitive to distinctions between events due 
to the underlying disease process versus events that may be product related and may have observed 
the event. The Sponsor will assess the overall safety of the IP delivered by EP and determine 
whether to report expeditiously to the regulatory agencies. 
Investigators should use their knowledge of the subject, the circumstances surrounding the event, 
available site and non-site laboratory and clinical records, and an evaluation of any potential 
alternative causes to determine whether or not an adverse event is considered to be related to the 
IP and/or the device indicating "yes" or "no" accordingly. Causality should be assessed by the 
investigator as “yes, related” or “no, unrelated” by the following criteria: 
 
Yes – there is a reasonable possibility that administration of the Study Treatment contributed 
to the event; 
 
No – there is no reasonable possibility that administration of the Study 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 the device; 
 
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 study; 
 
Presence of risk factors in the Study Subject or use of concomitant medications known to 
increase the occurrence of the event. 
7.1.7 
ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK, urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to IP interruption or 
discontinuation must be recorded as an AE, or SAE, if applicable. In addition, laboratory or other 
abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are associated with signs 
and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE (or SAE) 
as described in Section 7.1. If the laboratory abnormality is part of a syndrome, record the 
syndrome or diagnosis (e.g., anemia) not the laboratory result (e.g., decreased hemoglobin). 
Any laboratory abnormality 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: 
423

 Requires therapeutic intervention or diagnostic tests 
 Leads to discontinuation of study treatment 
 Has accompanying or inducing symptoms or signs 
 Is judged by the investigator as clinically significant 
7.1.8 
POST-STUDY REPORTING REQUIREMENTS 
All AEs and SAEs including deaths, regardless of cause or relationship, must be reported for 
subjects on study (including any protocol required post-treatment follow-up). 
Investigators are not obligated to actively seek AEs or SAEs beyond the follow up period for 
subjects. However, if the investigator learns of an AE or SAE that occurs after the completion or 
termination visit and the event is deemed by the investigator to be related to the study treatment, 
he/she should promptly document and report the event to the study team and medical monitor. 
7.1.9 
PROCEDURES FOR DOCUMENTING PREGNANCY DURING STUDY 
Subjects who are pregnant or expect to become pregnant during the course of the study up to Week 
36 will be excluded from participation in the study. Should a subject become pregnant after 
enrolling in the study, she will not be given any further study treatments. A Pregnancy Form will 
be completed by the site personnel and submitted to the sponsor or its designee within 24 hours 
after learning of the pregnancy.  Site personnel will submit the Pregnancy Form to the Sponsor or 
its designee by fax, as described in Section 7.4.2. 
The investigator will also report this event to the IRB within 24 hours of becoming aware of the 
pregnancy. Sites must request the subject’s permission to query pregnancy outcome and follow 
each subject to determine the outcome of the pregnancy. Results will be summarized in the clinical 
study report (CSR).  
Subjects who become pregnant at any point during the study will continue to be followed for safety 
assessments without receiving further study treatment. Procedures that are contraindicated during 
pregnancy, including additional treatments, must not be performed. Investigators should use 
clinical judgment regarding subsequent study-related blood collection based on the presence or 
absence of anemia in each subject.  
All pregnancies that occur from the time of first screening procedure through the follow up visits 
must be reported. The investigator will monitor the subject and follow the outcome of the 
pregnancy. If the end of the pregnancy occurs after the study has been completed, the outcome 
will be reported directly to the study team and the medical monitor. 
7.2 
METHODS AND TIMING OF THE COLLECTION AND RECORDING OF 
SAFETY DATA 
Non-serious AEs and SAEs (and UADEs) will be collected for each subject from the time when 
informed consent is obtained through Week 88. 
The sources of AEs cover: 
1. 
The subject’s response to questions about her health (a standard non-leading question such as 
‘How have you been feeling since your last visit?’ is asked at each visit). 
424

2. 
Symptoms spontaneously reported by the subject. 
3. 
Evaluations and examinations where the findings are assessed by the investigator to be 
clinically significant changes or abnormalities. 
4. 
Other information relating to the subject’s health becoming known to the investigator (e.g. 
hospitalization).  
All AEs will be reported on the appropriate CRF. Any SAE (or UADE) occurring during the course 
of the study must be reported to the sponsor within 24 hours of awareness. 
7.3 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor will be responsible for the overall safety monitoring of the study.  
Safety assessments include the following: 
 
Incidence of all adverse events classified by system organ class (SOC), preferred term, severity, 
and relationship to study treatment  
 
 
 
Local and systemic injection site review; special attention will be paid to the examination of 
the injection site. Administration site reactions and the subject's complaints will be documented. 
7.3.1 
ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest (AESI) are the adverse events deemed related to VGX-
3100/placebo delivered with CELLECTRA™ 5PSP that require expedited communication from 
the Site to the Sponsor and meet any of the following criteria: 
 Grade 3 or greater persistent administration site erythema, and/or induration recorded ≥ 2 
hours immediately after Study Treatment  
 Grade 4 or greater persistent administration site pain, tenderness recorded ≥ 2 hours 
immediately after Study Treatment 
 Grade 3 or greater fever 
 Grade 3 or greater systemic symptoms, including generalized pruritus 
Sites will inform the Sponsor via method described in section 7.4.1 within 24 hours to discuss 
whether further dosing for the particular subject should continue.   
7.3.2 
STOPPING RULES (CRITERIA FOR PAUSING OF STUDY) 
 If at any time during a study one-third (1/3) or more of the subjects experience an AESI, 
further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, 
and the DSMB. Only the DSMB may review unblinded data in making their recommendation 
to the Sponsor regarding continuation of a trial.  
 If any SAE (or potentially life-threatening AE), or death assessed as related to study treatment 
occurs, further enrollment and study treatment will be halted immediately until a thorough 
investigation has been conducted by the Medical Monitor, Principal Investigator for the trial, 
IRB (if applicable) and the DSMB. 
425

 If t hree or m or e s u bjects i n t his st u d y, e x perie n ce t he s a me Gra de 3 or 4 a d verse e v e nt, 
assesse d as rel ate d t o st u d y treat me nt, f urt her e nr oll me nt a n d st u d y treat me nt will be halte d 
i m me diatel y u ntil a t h or o u g h i n vesti gati o n has bee n c o n d u cte d b y t he Me dical M o nit or, 
Pri nci pal I n v esti gat or f or t he trial, a n d t he D S M B. 
 In t he e ve nt of t w o i d e ntical, u ne x pecte d, Gra d e 4 t o xicities, assesse d as relate d t o st u d y 
treat me nt, f urt her e nr oll me nt a n d st u d y treat me nt will be halte d i m me diatel y u ntil a t h or o u g h 
i n vesti gati o n has bee n c o n d ucte d b y t he Me dical M o nit or, Pri nci pal I n v esti gat or f or t he trial, 
IR B (if a p plica ble) a n d t he D S M B.  
T he s p o ns or or desi g nee will n otif y all i n vesti gat ors a n d I R Bs/ E C (if re q uire d) re gar di n g t he 
o utc o me of a n y i n vesti gati o n ste m mi n g fr o m a St u d y Pa use.  
G ui deli nes f or ass essi n g relate d ness are d etaile d i n Secti o n 7. 1. 6 . 
7. 4  
S T U D Y R E P O R TI N G P E RI O D O F A D V E R S E E V E N T S 
All s olicite d a n d u ns olicite d a d verse e ve nts will b e c ollect e d t hr o u g h o ut t h e st u d y a n d rec or de d o n 
t he A E C R F.  
7. 4. 1  
S T U D Y R E P O R TI N G P E RI O D O F A D V E R S E E V E N T S O F S P E CI A L 
I N T ER E S T 
A d verse e v e nts of s pecial i nterest ( A E SI) (see Secti o n 7. 3. 1 ) re q uire e x pe dite d c om m u nicati o n 
fr o m t he Site t o t he S p o ns or. Wit hi n 2 4 h o urs of t he site's a ware ness of t he e ve nt, A E SI m ust be 
re p orte d b y t h e I n v esti gat or t hr o u g h data e ntr y i n t he A d verse E ve nt electr o nic case re p ort f or m 
(e C R F) via t he M e di dat a R A V E electr o nic data ca pt ure ( E D C) s yste m. I n t he e ve nt t hat t he 
Me di data R A V E E D C s yste m is u na vaila ble, t he i n vesti gat or m ust n otif y t he S p o ns or via e mail 
or p h o ne.  
A E SI re p orti n g if E D C s yste m is u n a v ail a ble  
E M AI L:   
  
S A F E T Y P H O N E: 
 
7. 4. 2  
S T U D Y R E P O R TI N G P E RI O D O F S E RI O U S A D V E R S E E V E N T S 
T he re p orti n g peri o d f or S A Es ( wit h o ut re gar d t o ca usalit y or relati o ns hi p) is c o m prise d of t he 
peri o d f oll o wi n g t he si g ni n g of t he i nf or me d c o nse nt f or m u ntil t he e n d of t he st u d y. Eac h A E will 
be assess e d t o det er mi ne w het her it m eets seri o us ness criteri a. If t he A E is c o nsi dere d seri o us, t he 
i n vesti gat or s h o ul d rec or d t his e ve nt t o t he S p o ns or wit hi n 2 4 h o urs of bec o mi n g a ware of t he 
e ve nt. T he i n vesti gat or ma y als o directl y re p ort t his e ve nt t o t he Et hics C o m mittee acc or di n g t o 
its sta n dar d o p erati n g pr oce d ures. E x pecte d ness of S A Es will be deter mi ne d b y t he S p o ns or usi n g 
refere nce safet y i nf or mati o n s pecifie d i n t he I n vesti gat or’s Br oc h ure.  
A n e ve nt m a y q ualif y f or e x pe dite d re p orti n g t o re g ulat or y a ut h orities if it is a n S A E, u ne x pecte d 
per refere n ce s afet y i nf or mati o n a n d c o nsi dere d relate d f oll o wi n g t he g ui d eli nes i n Secti o n 7. 1. 3  
( S us pecte d U ne x pecte d Seri o us A d verse Reacti o n, S U S A R) a n d 7. 1. 4 ( U na ntici pate d [seri o us] 
a d verse d e vice effect) i n li ne wit h rele va nt le gislati o n. All i n vesti gat ors will recei v e a safet y letter 
4 2 6
P P D

n otif yi n g t he m of rele va nt S U S A R re p orts. T he i n vesti gat or s h o ul d n otif y t he I nstit uti o nal Re vie w 
B oar d (I R B)/ I nstit uti o nal Et hics C o m mittee (I E C) as s o o n as is practical, of seri o us e ve nts i n 
wr iti n g w h ere t his is re q uire d b y l ocal re g ulat or y a ut h orities, a n d i n acc or da nce wit h t he l ocal 
i nstit uti o nal p olic y.  
At a n y ti me aft er c o m pleti o n of t he S A E re p orti n g peri o d, if a n i n vesti gat or bec o mes a ware of a n 
S A E t hat is s us pecte d b y t he i n vesti gat or t o be relate d t o t he st u d y dr u g, t he e ve nt will be re p orte d 
t o t he S p o ns or or its desi g nee. If t he i n v esti gat or b ec o mes a ware of a n S A E i n a st u d y s u bject after 
t he last sc he d ul e d f oll o w- u p visit, a n d c o nsi d ers t he e v e nt rel ate d t o pri or St u d y Treat me nt, t he 
i n vesti gat or will re p ort it t o t he S p o ns or or t he a p pr o priate desi g nee. 
W it hi n 2 4 h o urs of t he site's a w are n ess of t he e ve nt, all S A Es (re gar dl ess of relati o ns hi p t o 
i n vesti gati o nal pr o d uct) m ust be re p orte d b y t he I n v esti gat or t hr o u g h data e ntr y i n t he A d verse 
E ve nt electr o ni c cas e re p ort f or m (e C R F) via t he Me di data R A V E electr o nic data ca pt ure ( E D C) 
s yste m.  I n t he e ve nt t hat t he Me di dat a R A V E E D C s yste m is u n a vaila ble, t he pa per S A E Re p ort 
f or m s h o ul d be use d a n d fa x e d t o t he P P D P har mac o vi gila n ce ( P V G) Safet y H otli ne Fa x N u m ber 
s h o w n bel o w: 
F acsi mile ( F A X) re p orti n g if re q uire d a: 
A mericas F A X #: 
 
E ur o pe F A X # : 
 
a: Re p orti n g b y F A X is re q uire d f or pa p er S A E Re p ort F or ms if electr o nic data ca pt ure 
( E D C) is n ot a vaila ble, re d acte d s u p p orti n g me dical rec or ds, a n d Pre g na nc y Re p ort F or ms.  
All s u p p orti n g d o c u m e nts f or S A E re p orts, i n cl u di n g m e dical rec or ds a n d dia g n osti c t est res ults, 
will i n cl u d e refere nce t o t h e st u d y s u bj ect n u m b er. T h e st u d y sit e will re dact all ot h er s u bj ect 
i de ntif yi n g i nf or m ati o n pres e nt o n S A E s u p p orti n g d o c u m e nts pri or t o s e n di n g t h e re p ort t o t h e 
S p o ns or. T h e s u p p orti n g d o c u m e nts f or S A E re p orts s h o ul d b e s e nt b y fa x t o t h e P P D P V G S afet y 
H otli n e Fa x N u m ber, s h o w n a b o v e. 
I n v esti gat or will s u p pl y t he S p o ns or a n d t h e I R B wit h m ore i nf or m ati o n as it b ec o m es a v ail a ble 
a n d a n y a d diti o n al re q u este d i nf or m ati o n. T h e S p o ns or or its re pres e nt ati v e will b e res p o nsi ble 
f or d et er mi ni n g a n d i n t ur n, re p orti n g S A Es t o re g ulat or y a ut h oriti es acc or di n g t o t he a p pli ca ble 
re g ulat or y re q uire m e nts. S A Es m ust be f oll o we d b y t h e i n v esti gat or u ntil res ol uti o n, e v e n if t his 
e xte n ds b e y o n d t he st u d y-re p orti n g p eri o d. R es ol uti o n of a n S A E is d efi ne d as t h e ret ur n t o 
baseli n e st at us or st a biliz ati o n of t he c o n diti o n wit h t h e e x p ect ati o n t h at it will re m ai n c hr o ni c. 
I n t h e e v e nt of deat h, if a n a ut o ps y is p erf or m e d, a c o p y of t h e re p ort will b e se nt t o t h e S p o ns or. 
7. 4. 3  
N O TI FI C A TI O N O F S E RI O U S A D V E R S E E V E N T S 
I n acc or da n ce wit h l oc al re g ulati o ns, t he S p o ns or s hall n otif y t h e a p pr o priate re g ulat or y 
a ut h orities, a n d all partici pati n g i n vesti gat ors i n a writte n safet y re p ort of a n y a d verse e x perie nce 
ass ociate d wit h t he use of t he pr o d uct t hat is b ot h seri o us a n d u ne x pecte d a n d a n y si g nifica nt ne w 
safet y i nf or mati o n t hat mi g ht materiall y i nfl ue n ce t he be nefit-ris k assess me nt of a me dici nal 
pr o d uct, s ufficie nt t o c o nsi der c ha n ges i n pr o d uct a d mi nistrati o n or o verall c o n d uct of a cli nical 
4 2 7
P P D
P P D

investigation. The Sponsor will notify regulatory agencies within the time frame specified by local 
requirements but no later than 10 working days for UADE, 7 days for a fatal or life-threatening 
SUSAR and 15 days for all other SUSARS (see Section 7.1.3 and 7.1.4).  
7.4.4 
REPORTING OF DEVICE RELATED COMPLAINTS 
A product complaint (or device deficiency) involves any written, electronic, or oral 
communication that alleges deficiencies related to the identity, quality, durability, reliability, 
safety, effectiveness, or performance of a device such as malfunction, misuse or use error 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. All product complaints that meet this definition 
must be reported to the sponsor with 10 days of discovery. Any product complaint that involves 
an AE or SAE must be also reported per Section 7.4. 
Any problems experienced including potential malfunctions of the device, error messages 
displayed on the device screen following treatment or errors that occur during the treatment 
procedure must be reported to the Sponsor or designee immediately for evaluation.  
Additional instructions on reporting to be provided separately. 
7.5 
STUDY DISCONTINUATION 
Inovio Pharmaceuticals reserves the right to discontinue the study at this site or at multiple sites for 
safety or administrative reasons at any time. In particular, a site that does not recruit at a reasonable 
rate may be discontinued. Should the study be terminated and/or the site closed for whatever reason, 
all non-source documentation and study product pertaining to the study must be returned to Inovio 
Pharmaceuticals or its representative. 
The study may be discontinued at any time by an IRB, Inovio Pharmaceuticals Inc., the FDA or 
other government agencies as part of their duties to ensure that research subjects are protected. 
8 STATISTICAL ANALYSIS PLAN 
8.1 
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 
with a histologic diagnosis of cervical HSIL. The study’s primary endpoint is binary: regression to 
CIN1/normal and clearance of HPV-16 and/or HPV-18 infection, based on tissue collected at Week 
36. The primary hypothesis is that VGX-3100 will be superior to placebo regarding the proportion 
who achieve the primary endpoint.  Secondary efficacy analyses involve regression to CIN1/normal, 
clearance of HPV-16 and/or HPV-18 infection from cervical tissue and non-progression of cervical 
lesions. Other secondary analyses concern safety and humoral and cellular immunological measures, 
and association of Immunoscores and efficacy.  Exploratory analyses concern tissue immunological 
measures, durability of clearance of HPV-16 and/or HPV-18 infection from cervical tissue, effect 
of HLA type on efficacy, association of colposcopy, cytology, virology, other microRNA (miRNA) 
profiles, and DNA methylation profile and efficacy, and patient-reported outcomes. 
428

8.2 
RANDOMIZATION AND BLINDING 
Subjects will be randomized (2 VGX-3100:1 Placebo) in a stratified manner according to a) the 
degree of CIN observed in the biopsy specimens at screening (CIN2 vs. CIN3), b) BMI category 
(≤25 vs. >25 kg/m2), and c) age category (<25 years vs. ≥25 years). There will be no pre-determined 
number of subjects required to be randomized within each stratum. To ensure that milder CIN2 
disease is not over-represented in the study, the percentage of subjects enrolled with CIN2 will not 
exceed 50% of the total enrolled. A group of sequential allocation numbers will be designated for 
use by each participating country. 
The study is double-blinded. 
8.3 
SAMPLE SIZE/POWER 
A sample of 198 subjects will be randomized to receive either 6 mg VGX-3100 or placebo IM 
followed by EP in a 2:1 ratio. This sample size provides 90% power to declare VGX-3100 superior 
to placebo, assuming the true proportion of subjects who achieve the primary endpoints is 35% and 
14% for VGX-3100 and placebo, respectively. These proportions also incorporate missing data 
(~10%) classified as non-regressors (failures). The assumptions are based on the Phase 2 study 
results. 
8.4 
ANALYSES POPULATIONS 
Analysis populations will include: 
 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 primary for the analysis of efficacy in this study. 
 The modified intention to treat (mITT) population includes all subjects who receive at least one 
dose of Study Treatment and who have the analysis endpoint of interest. Subjects in this sample 
will be grouped to treatment arms as randomized.  Analysis of the mITT population will be 
considered supportive for the corresponding ITT population for the analysis of efficacy. 
 The per-protocol (PP) population comprises subjects who receive all doses of Study Treatments 
and have no protocol violations and who have the analysis endpoint of interest. Subjects in this 
sample will be grouped to treatment arms as randomized.  Analyses on the PP population will 
be considered supportive of the corresponding ITT population for the analysis of efficacy.  
Subjects excluded from the PP population will be identified and documented prior to unblinding 
of the study database. 
 The safety analysis set includes all subjects who receive at least one does of Study Treatment. 
Subjects will be analyzed as to the treatment they received.  
8.5 
SUBJECT 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. 
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8.6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline 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 population.  Prior and concomitant medications 
will also be summarized with percentages in this fashion.  
8.7 
MEDICAL HISTORY 
The percentage of subjects with abnormal medical history findings will be summarized by body 
system, by treatment arm, for the ITT population. 
8.8 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior medications are those that were used before the start of the trial (prior to Day 0).  Concomitant 
medications are those used during the course of the trial (on or after Day 0).  Partial stop dates of 
prior and 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 prior and concomitant medications will be 
summarized with percentages by treatment arm, for the mITT population. 
8.9 
EFFICACY ANALYSES 
The true treatment effect on the primary endpoint is  = pV – pP, where pV and pP denote the true 
population probabilities of the primary endpoint for VGX-3100 and Placebo, respectively.  The 
primary hypothesis of superiority is:  
H0:   0 vs. H1:  > 0. 
A p-value for this hypothesis test and corresponding 95% confidence interval will be computed 
based on the method of Miettinen and Nurminen [29].  Superiority will be concluded if the one-
sided p-value is <0.025 and the corresponding lower bound of the 95% CI exceeds zero. 
The secondary efficacy endpoints will be analyzed in the same manner as the primary hypothesis, 
but without the hypothesis test p-values. 
The histopathologic efficacy time frame is defined by those who have undergone a biopsy or surgical 
excision at any time starting from 14 days prior to the protocol-specified target date of Week 36.  It 
also includes subjects who undergo early intervention prior to this time frame or subjects who have 
no endpoint data for this time frame; these subjects are considered as failures for the efficacy 
endpoints.  Table 7 through Table 11 provide details for the definition of the endpoint responses.   
An exploratory analysis will examine the relationship between the primary efficacy endpoint and 
also the secondary efficacy endpoints of regression and clearance individually and the Immunoscore 
results.  Relationships will be examined by using logistic regression models which model the 
efficacy outcomes versus the Immunoscore results and treatment group as regressor variables. 
An exploratory analyses will examine the relationship between the primary efficacy endpoint and a) 
HLA results, b) miRNA results, c) DNA methylation results, d) colposcopy results, e) cytology 
results, and f) HPV results.  Relationships will be examined by using logistic regression models 
which model the primary endpoint outcome versus these results and treatment group as regressor 
variables. 
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Other exploratory analyses will examine durability of clearance of HPV-16 and/or HPV-18 infection 
from cervical tissue at Weeks 62 and 88.  Descriptive statistics will be utilized; percentages of 
subjects who cleared will be presented by time point or anatomic location and treatment group. 
8.10     IMMUNOGENICITY ANALYSES 
Post-baseline cellular and humoral responses will be compared between treatment groups using a 
difference in medians and associated exact non-parametric 95% CI.  Increases from baseline in 
interferon-γ ELISpot response magnitudes and in CD8+ / CD137+ PBMCs Perforin+ results and 
HPV E6 and E7 titers from ELISA at Weeks 8, 15 and 36 visits will be evaluated. 
Post-baseline tissue response magnitude will be compared between treatment groups using a 
difference in means and associated t-distribution based 95% CIs. 
Valid samples for statistical analysis purposes will be those collected within 7 or 14 days of the 
specified time points (see Table 1).  Baseline is defined as the last measurement prior to the first 
treatment administration. 
The mITT population will be used for immunogenicity analyses. 
8.11  SAFETY ANALYSES 
8.11.1 
ADVERSE EVENTS 
All AEs 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 28 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 
[29].  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. 
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. 
8.11.2 
LABORATORY DATA 
Continuous response variables per time point and changes from baseline will be summarized with 
mean, median, minimum, and maximum values, and categorical response variables will be 
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summarized per time point with percentages, by treatment arm.  Baseline is defined as the last 
measurement prior to the first treatment administration. 
8.12 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 mITT population.  Baseline is defined as the last measurement prior to the 
first treatment administration. 
8.13 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 ITT population. 
8.14 PATIENT REPORTED OUTCOMES 
As an exploratory endpoint, patient reported outcomes among subjects who receive VGX-3100 will 
be compared between those with excision versus those without excision, based on PRO endpoints.  
This comparison will utilize the median endpoint or the proportion of subjects with endpoints and 
associated Wilcoxon rank-sum test or Pearson chi-square test/Fisher’s exact test, for continuous 
responses and categorical responses, respectively. 
The mITT population will be used for PRO analyses. 
8.15 MISSING VALUES 
Missing data will be considered as non-regressors (failures) for the ITT efficacy analysis.  A 
subject’s regression outcome is missing if her CIN grade and HPV clearance at Week 36 cannot be 
determined. Also, any subject who undergoes an unscheduled procedure in which cervical tissue 
sample was obtained before Week 36 will be considered a non-regressor regardless of the Week 36 
result. Efficacy analyses using the mITT population will be conducted and will serve as sensitivity 
analyses regarding missing data. 
8.16 SUBGROUP ANALYSES 
Primary and secondary efficacy endpoints will be analyzed by history of exposure to prophylactic 
HPV vaccines. 
8.17 INTERIM ANALYSIS 
No formal interim analyses will be performed for this study.  For reasons of futility (early evidence 
of poor efficacy of VGX-3100) or safety issues, the DSMB could recommend stopping enrollment 
at any time.  The type I error of 0.05 will not be adjusted for possible early stopping due to futility. 
9 DATA COLLECTION, MONITORING AND REPORTING 
9.1 
CONFIDENTIALITY AND PRIVACY 
A report of the results of this study may be published or sent to the appropriate health authorities in 
any country in which the study products are legally marketed or may ultimately be marketed, but 
the subject’s name will not be disclosed in these documents. The subject’s name may be disclosed 
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to the study sponsor, Sponsor, the governing health authorities or the Food and Drug Administration 
(FDA), if they inspect the study records. Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information. 
Written Authorization and other documentation in accordance with the relevant country and local 
privacy requirements (where applicable) are to be obtained from each subject prior to enrollment 
into the study, and/or from the subject’s legally authorized representative in accordance with the 
applicable privacy requirements (e.g., the Health Insurance Portability and Accountability Act 
Standards for Privacy of Individually Identifiable Health Information (HIPAA). 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following: 
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of the research subject to revoke their authorization for use of their PHI 
The rights of the research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the sponsor retains the ability 
to use all information collected prior to the revocation of subject authorization. For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to 
collect at least vital status (i.e., that the subject is alive) at the end of their scheduled study period. 
9.2 
SOURCE DOCUMENTS 
Source data is all information, original records or clinical findings, laboratory results, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in original source documents. Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, subject’s 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records 
kept at the pharmacy, at the laboratories, and at medical records and within information technology 
systems that are involved in the clinical trial. 
A medical history must be present in the source documents. A medication history must be present 
in the source documents. All prescription and nonprescription medications taken within l week prior 
to entry must be recorded on the CRF. Actual or estimated start and stop dates must be provided. 
9.3 
RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution 
should make available for direct access all requested 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). 
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It is the investigator’s responsibility to retain study essential documents for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. This retention period 
may be superseded by applicable regulatory requirements (e.g. minimum of 25 years for Health 
Canada). The sponsor will inform the investigator/institution as to when these documents are no 
longer needed to be retained. 
9.4 
SAFETY AND QUALITY MONITORING  
9.4.1 
DATA & SAFETY MONITORING BOARD 
A Data & Safety Monitoring Board (DSMB) will be established to protect the research subjects 
through independent analysis of emerging data from the trial.  The DSMB will meet quarterly to 
review unblinded safety data and regression/clearance results.  If there are no new safety data or 
regression/clearance results to review for a quarterly scheduled meeting the DSMB will be notified 
and the meeting may be cancelled; Ad hoc meetings may be scheduled to review new data as 
applicable. The DSMB will be charged with advising the Sponsor if there appears to be a safety 
issue and with advising the Sponsor if it appears that regression in the VGX-3100 group is 
unacceptably low compared to the placebo group. No formal interim analysis will be performed. 
The DSMB Chair, upon consultation with the other voting members of the DSMB, has the 
authority to recommend suspension or stopping the study and to request a full DSMB review and 
ad hoc statistical analyses. The DSMB charter will define the membership, responsibilities and 
procedures for the meeting.  
9.4.2 
PATHOLOGY ADJUCATION COMMITTEE 
All histology slides (i.e. cervical biopsies or surgical excision tissue) will be read by a Pathology 
Adjudication Committee (PAC) to ensure consistent assignment of disease status for both study 
eligibility and the efficacy analysis. The PAC will consist of a total of four pathologists in separate 
locations. Each specimen will be read by two pathologists independently in a blinded fashion.    
9.4.3 
CLINICAL MONITORING 
Clinical Monitoring of the clinical trial will be performed by experienced monitors, who will 
report to the Sponsor or the Sponsor designee. Records for all clinical subjects in this trial will be 
monitored. The following clinical site monitoring tasks will be performed at all sites: 
 Prior to trial initiation, a site visit will be conducted to review all relevant forms and 
documentation, to ensure the site is qualified and compliant with all applicable requirements. 
 All clinical site monitoring visits will be documented. 
 Periodic site visits will be performed throughout the study. 
 The site monitor will be responsible for addressing and documenting the following study 
conduct activities and obligations and will: 
o Assure that the study is being conducted in accordance with the protocol, applicable 
regulatory agency regulations, and IRB policies 
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o Discuss study conduct issues and incidents of noncompliance with the Investigator and/or 
study 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 serious 
adverse events (SAE) and provide subsequent follow-up report of the final outcome to the 
IRB 
o Throughout the study, inspect all source documents to ensure they are complete, logical, 
consistent, attributable, legible, contemporaneous, original, and accurate (ALCOA).  
o Assure that the study facilities continue to be acceptable 
o Compare the study 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 per 
laboratory manual requirements 
10 ETHICS 
10.1  INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The investigator and Sponsor are responsible for ensuring that the clinical study is performed in 
accordance with the protocol, the Declaration of Helsinki, principles of Good Clinical Practice 
(GCP), and applicable regulatory requirements.  
10.2 INSTITUTIONAL REVIEW BOARD OR INSTITUTIONAL ETHICS 
COMMITTEE (IRB/IEC) 
The investigator will undertake the study after full approval of the protocol and adjunctive materials 
(e.g., informed consent form, advertising) has been obtained from the applicable IRB/IEC and a 
copy of this approval has been received by the sponsor. 
Investigator responsibilities relevant to the IRB include the following: 
 During the conduct of the study, submit progress reports to the IRB/IEC as required.  
 Notify the Sponsor immediately of any SAEs or serious unanticipated adverse device effects. 
 If Sponsor notifies you about any reportable safety events notify the IRB immediately. 
 As required, obtain approval from the IRB/IEC for protocol amendments and for revisions to 
the consent form or subject recruitment advertisements; 
 Reports on, and reviews of, the trial and its progress will be submitted to the IRB by the 
investigator at intervals stipulated in their guidelines and in accordance with pertinent 
regulations and guidelines. 
 Maintain a file of study-related information that includes all correspondence with the IRB; 
 Notify IRB when study is completed (i.e. after the last study visit of the final study subject); 
 After study completion provide the IRB with a final report on the study. 
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10.3 OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA) 
The investigator and Sponsor are responsible for ensuring that the clinical study is reviewed and 
approved according to local and applicable global regulations (e.g., NIH Office of Biotechnology 
Activities) governing research that involves recombinant or synthetic nucleic acid molecules.   
11 PROTECTION OF HUMAN SUBJECTS 
11.1  COMPLIANCE WITH INFORMED CONSENT REGULATIONS  
Written informed consent is to be obtained from each subject prior to Screening into the study, 
and/or from the subject’s legally authorized representative.  The process for obtaining informed 
consent must also be documented in the subject’s medical record.  
11.2  COMPLIANCE WITH IRB/IEC REQUIREMENTS 
This study is to be conducted in accordance with applicable IRB/IEC regulations.  The Investigator 
must obtain approval from a properly constituted IRB/IEC prior to initiating the study and re-
approval or review at least annually.  Sponsor is to be notified immediately if the responsible 
IRB/IEC has been disqualified or if proceedings leading to disqualification have begun.  Copies of 
all IRB/IEC correspondence with the investigator must be provided to Sponsor. 
11.3  COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and guidelines.  
11.4  COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES 
REGULATIONS (21CFR PART 11) 
When applicable, this study is to be conducted in compliance with the regulations on electronic 
records and electronic signature. 
11.5  COMPLIANCE WITH PROTOCOL 
Subjects are not required to follow special instructions specific to the Investigational Product used 
in this study however will be asked to complete a participant diary card during their study 
participation.  Subjects will be provided with Investigator emergency contact information and 
advised to report all adverse events. While every effort should be made to avoid protocol deviations, 
should a deviation be discovered, Sponsor must be informed immediately. Any protocol deviation 
impacting Subject safety must be reported to the Medical Monitor immediately. 
11.6  CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol without 
approval by Sponsor and prior review and documented approval/favorable opinion from the IRB of 
a protocol amendment, except where necessary to eliminate immediate hazards to study subjects, or 
when the changes involve only logistical or administrative aspects of the study (e.g., change in 
monitors, change of telephone numbers).  
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12 FINANCING AND INSURANCE 
Inovio Pharmaceuticals is the sponsor in all participating countries and is fully supporting the study.  
Clinical trial insurance has been taken out according to the laws of the countries where the study 
will be conducted. 
13 PUBLICATION POLICY 
Publication of the results of this trial in its entirety will be allowed. The proposed presentation, 
abstract and/or manuscript must be made available to The Sponsor 60 days prior to submission for 
publication. The Sponsor shall have thirty (30) days after receipt of the copies to object to the 
proposed presentation or publication because there is patentable subject matter that needs protection. 
In the event that The Sponsor makes such objection, the researcher(s) shall refrain from making such 
publication or presentation for a maximum of three (3) months from the date of receipt of such 
objection in order for patent application(s) (directed to the patentable subject matter contained in the 
proposed publication or presentation) to be filed with the United States Patent and Trademark Office 
and/or foreign patent office(s). 
 
 
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14  REFERENCES 
1. 
Kahwati LC, Haigler L, Rideout S, Markova T. What is the best way to diagnose menopause? J Fam 
Pract 2005,54:1000-1002. 
2. 
Sarri G, Davies M, Lumsden MA, Guideline Development G. Diagnosis and management of 
menopause: summary of NICE guidance. BMJ 2015,351:h5746. 
3. 
Centers for Disease C, Prevention. Human papillomavirus-associated cancers - United States, 2004-
2008. MMWR Morb Mortal Wkly Rep 2012,61:258-261. 
4. 
Satterwhite CL, Torrone E, Meites E, Dunne EF, Mahajan R, Ocfemia MC, et al. Sexually 
transmitted infections among US women and men: prevalence and incidence estimates, 2008. Sex 
Transm Dis 2013,40:187-193. 
5. 
Hariri S, Unger ER, Sternberg M, Dunne EF, Swan D, Patel S, et al. Prevalence of genital human 
papillomavirus among females in the United States, the National Health And Nutrition Examination 
Survey, 2003-2006. J Infect Dis 2011,204:566-573. 
6. 
American Cancer Society. Cancer Facts & Figures. In. Atlanta; 2016. 
7. 
Bruni L, Alberto G, Aldea M, Serrano B, Valencia S, Brotons M, et al. Human Papillomavirus and 
Related Diseases in theWorld. Summary Report 2015-12-23. ICO Information Centre on HPV and 
Cancer (HPV Information Centre). In; 2015. 
8. 
Guan P, Howell-Jones R, Li N, Bruni L, de Sanjose S, Franceschi S, et al. Human papillomavirus 
types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. Int J 
Cancer 2012,131:2349-2359. 
9. 
Apgar BS, Zoschnick L, Wright TC, Jr. The 2001 Bethesda System terminology. Am Fam Physician 
2003,68:1992-1998. 
10. 
McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW, et al. Natural history of 
cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a 
retrospective cohort study. Lancet Oncol 2008,9:425-434. 
11. 
McIndoe WA, McLean MR, Jones RW, Mullins PR. The invasive potential of carcinoma in situ of 
the cervix. Obstet Gynecol 1984,64:451-458. 
12. 
Future Ii Study Group. Supplementary Material: Quadrivalent vaccine against human papillomavirus 
to prevent high-grade cervical lesions. N Engl J Med 2007,356:1915-1927. 
13. 
The American College of Obstetricians and Gynecologists. FAQs Loop Electrosurgical Excision 
Procedure (LEEP). In; 2014. 
14. 
Aihara H, Miyazaki J. Gene transfer into muscle by electroporation in vivo. Nat.Biotechnol. 
1998,16:867-870. 
15. 
Gehl J, Mir LM. Determination of optimal parameters for in vivo gene transfer by electroporation, 
using a rapid in vivo test for cell permeabilization. Biochemical and Biophysical Research 
Communications 1999,261:377-380. 
16. 
Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospects for success. 
Curr.Opin.Immunol. 2011,23:421-429. 
438

17. 
van Drunen Littel-van den H, Hannaman D. Electroporation for DNA immunization: clinical 
application. Expert.Rev.Vaccines. 2010,9:503-517. 
18. 
Bodles-Brakhop AM, Heller R, Draghia-Akli R. Electroporation for the Delivery of DNA-based 
Vaccines and Immunotherapeutics: Current Clinical Developments. Mol Ther. 2009. 
19. 
Hirao 
LA, 
Wu 
L, 
Khan 
AS, 
Satishchandran 
A, 
Draghia-Akli 
R, 
Weiner 
DB. 
Intradermal/subcutaneous immunization by electroporation improves plasmid vaccine delivery and 
potency in pigs and rhesus macaques. Vaccine 2008,26:440-448. 
20. 
Khan AS, Pope MA, Draghia-Akli R. Highly efficient constant-current electroporation increases in 
vivo plasmid expression. DNA & Cell Biology 2005,24:810-818. 
21. 
Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, et al. Immunotherapy against 
HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci.Transl.Med. 
2012,4:155ra138. 
22. 
Diehl MC, Lee JC, Daniels SE, Tebas P, Khan AS, Giffear M, et al. Tolerability of intramuscular 
and intradermal delivery by CELLECTRA((R)) adaptive constant current electroporation device in 
healthy volunteers. Hum Vaccin Immunother 2013,9:2246-2252. 
23. 
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. 
24. 
Xiang L, Li J, Yang W, Xu X, Wu X, Wang H, et al. Conization Using an Electrosurgical Knife for 
Cervical Intraepithelial Neoplasia and Microinvasive Carcinoma. PLoS One 2015,10:e0131790. 
25. 
Stoler MH, Vichnin MD, Ferenczy A, Ferris DG, Perez G, Paavonen J, et al. The accuracy of 
colposcopic biopsy: analyses from the placebo arm of the Gardasil clinical trials. Int J Cancer 
2011,128:1354-1362. 
26. 
Maruish ME. User’s manual for the SF-36v2 Health Survey. 3rd ed. Lincoln, RI: Quality Metric 
Incorporated; 2011. 
27. 
EuroQol G. EuroQol--a new facility for the measurement of health-related quality of life. Health 
Policy 1990,16:199-208. 
28. 
Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Measurement properties 
of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual 
Life Res 2013,22:1717-1727. 
29. 
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985,4:213-226. 
 
 
 
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15 APPENDIX 
15.1 APPENDIX A:  GUIDELINES FOR COLPOSCOPY, BIOPSY, AND 
SURGICAL EXCISION 
Colposcopy Procedure 
It is recommended that all study colposcopies performed after informed consent be according the procedures 
recommended by the American Society of Colposcopy and Cervical Pathology (ASCCP): 
1. Use warm, clean water to lubricate the vaginal speculum.  Avoid other lubricant substances which could 
obscure results. 
2. If the vaginal walls are lax, a lateral vaginal sidewall retractor aligned perpendicular to the speculum may 
facilitate visualization. 
3. Examine the cervico-vaginal secretions and remove any excess mucus from the cervix with saline-soaked 
cotton swabs. 
4. Obtain any required specimens required for cytology and HPV testing. 
5. Using low-power magnification (5x to 10 x) inspect the cervix for obvious areas of abnormalities. 
6. Swab or spray the cervix with 3-5% acetic acid.  Reapply every 2-3 minutes during the examination. 
7. Use the green or blue filter to examine blood vessels.  Increase magnification (15x) 
8. Identify the distal and proximal boarders of the transformation zone. 
a. The inner border is the entire 360-degree circumference of the squamocolumnar junction 
i. If the junction is proximal to the external os, in the canal, use a cotton-tipped 
applicator to pry either the anterior lip up or the posterior lip down or use an 
endocervical speculum 
ii. If the junction is not visualized in its entire circumference, the colposcopy is deemed  
inadequate  
b. The distal limit of the transformation zone may be identified by finding the most distal crypt 
openings or nabothian follicles in the lips of the cervix and drawing an imaginary line 
connecting these landmarks 
9. Inspect the entire new squamocolumnar junction and detect and evaluate any abnormal areas.   
10. Evaluate the upper third portion of the vagina. 
11. Lugol or Schiller’s solution may be applied to further define previously identified lesions.   
Cervical Biopsies  
 Endocervical Curettage 
ECC is to be performed using a kervorkian curette or equivalent instrument.  Rotate and scrape the curette 
360○ in the endocervical canal and use a cytobrush to remove the specimen.  Deposit the specimen onto a 
Telfa pad before depositing in the specimen vial containing 10% neutral buffered formalin solution and 
labeled with the subject identification (SID) number. 
 Ectocervical Biopsies 
Ectocervical biopsies should only be performed prior to Week 36 if disease progression is suspected.  Only 
the suspect lesion should be biopsied in that circumstance.   
If the subject is eligible for 4 quadrant biopsy at the Week 36 visit, the following procedure should be 
followed: 
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1. Label each specimen vial containing 10% neutral buffered formalin solution with the subject’s ID number 
and the quadrant number according to the figure below. 
2. Perform and record colposcopy findings from each quadrant according to the following categories 
a. Negative (no lesion present) 
b. Low Grade  (e.g. pale acetowhite lesion on or off the squamocolumnar junction 
c. High Grade  (e.g. dense acetowhite lesion often with mosaic pattern or punctation) 
d. Suspicion of invasive cancer 
e. Invasive cancer 
3. Perform colposcopic directed biopsies from all quadrants with lesions. 
4. Multiple biopsies can be obtained of a lesion at the discretion of the investigator but must be uniquely 
labeled  
5. If a quadrant is free of lesions, obtain a random biopsy at the squamocolumnar junction in that quadrant 
at 2, 4, 8, or 10 o’clock. 
6. Prepare the biopsy specimen vials for shipment according to the Laboratory Manual. 
 
Figure 1 – Biopsy Quadrant Numbers 
 
 
Surgical Excision 
For subjects undergoing surgical excision at the Week 36 visit, the following procedure should be followed: 
1. Label each specimen vial containing 10% neutral buffered formalin solution with the SID number and 
the specimen type. 
2. Record colposcopy findings from each quadrant according to the following categories 
a. Negative (no lesion present) 
b. Low Grade  (e.g. pale acetowhite lesion on or off the squamocolumnar junction 
c. High Grade  (e.g. dense acetowhite lesion often with mosaic pattern or punctation) 
d. Suspicion of invasive cancer 
e. Invasive cancer 
3. Perform the LEEP or CKC per usual practice. 
4. Specimen should be marked at 12 o’clock with suture or gentian violet ink for purposes of orientation 
5. Prepare the biopsy specimen vials for shipment according to the Laboratory Manual. 
 
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4 4 2
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P P D
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Pr ot o c ol A p pr o v al P a g e
H P V- 3 0 1
A P R O S P E C TI V E, R A N D O M I Z E D, D O U B L E. B LI N D, P L A C E B O- C O N T R O L L E D
P H A S E 3 S T U D Y O F V G X- 3 1 0 0 D E LI V E R E D I N T R A M U S C U L A R L Y F O L L O W E D B Y
E L E C T R O P O R A TI O N 
WI T H C E L L E C T R A" S P S P F O R T H E T R E A T M E N T O F H P V.
1 6 A N D/ O R H P V.I 8 R E L A T E D HI G H G R A D E S Q U A M O U S I N T R A E PI T H E LI A L
L E SI O N ( H SI L) O F T H E C E R VI X
, -*" 1 l" u' 3, x ?l X' J:[ I', f nl a 1 2 o 1 8
Writt e n b y:
D at e ( d d M m m y y y y)
R e vi e w e d a n d A p pr o v e d b y ( Dir e ct or or a b o v e):
, M D, P h D 
D at e ( d d M m m y y y y)
M e di c al M o nit or
D at e ( d d M m m y y y y)
D at e ( d d M m m y y y y)
D at e ( d d M m m y y y y)
C O N FI D E N TI A L
D at e ( d d M m m y y y y)
P a g e 1 of 1
4 4 3
P P D
P P D
P P D
P P D
P P D

4 4 4
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

 
 
 
 
HPV-301 
REVEAL 1 Trial  
(Randomized Evaluation of VGX-3100 and Electroporation for the Treatment of Cervical 
HSIL) 
 
A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
PHASE 3 STUDY OF VGX-3100 DELIVERED INTRAMUSCULARLY FOLLOWED BY 
ELECTROPORATION WITH CELLECTRA™ 5PSP FOR THE TREATMENT OF HPV-
16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS INTRAEPITHELIAL 
LESION (HSIL) OF THE CERVIX   
 
 
Sponsored by: 
Inovio Pharmaceuticals, Inc. 
 
U.S. BB-IND #13683 
EudraCT #2016-002761-63 
 
Version 5.0 
20 November 2019 
 
 
445

 
A P R O S P E C TI V E, R A N D O MI Z E D, D O U B L E -B LI N D, P L A C E B O -C O N T R O L L E D 
P H A S E 3  S T U D Y O F V G X -3 1 0 0 D E LI V E R E D I N T R A M U S C U L A R L Y F O L L O W E D B Y 
E L E C T R O P O R A TI O N WI T H C E L L E C T R A ™ 5 P S P F O R T H E T R E A T M E N T O F H P V -
1 6 A N D/ O R H P V - 1 8 R E L A T E D HI G H G R A D E S Q U A M O U S I N T R A E PI T H E LI A L 
L E SI O N ( H SI L ) O F T H E C E R VI X   
S h ort Title:   
R E V E A L 1 Trial  ( Ra n d o mize d  E val uati o n  of  V G X - 3 10 0  a n d 
Electr o p orati o n f or t he treat me nt of Cer vical H SI L) 
 
Bi ol o gic al Pr o d uct:    
 V G X - 3 1 0 0 
 
Pr ot oc ol N u m ber:    
 H P V - 3 0 1 
 
S p o ns or:  
 I n o vi o P har m ace uticals, I n c. 
 
 6 6 0 W. Ger ma nt o w n Pi ke, S uite 1 1 0 
 
 Pl y m o ut h Meeti n g, P A 1 9 4 6 2 
 
Pri nci p al I n vesti g at or:   
 
, M. D., M. S. 
 
 
 
 
 R ut gers N e w J erse y Me dical Sc h o ol  
 
 1 8 5 S. Ora n ge A v e., M S B E- 5 0 6 
 
 Ne war k, NJ 0 7 1 0 3 
 
Me dic al M o nit or:   
 
, M. D., P h. D. 
 
 
 
 
 I n o vi o P har m ace uticals, I n c. 
 
C O N FI D E N TI A L  
T he i nf or m ati o n i n t his d oc u me nt is c o nsi dere d pri vile ge d a n d c o nfi de nti al b y In o vi o P h ar m ace utic als a n d m a y 
n ot be discl ose d t o ot hers e xce pt t o t he e xte nt necess ar y t o o bt a i n Instit uti o n al R e vie w B o ar d/ E t hics co m mittee 
a p pr o v al a n d i nf or me d c o ns e nt, or as re q uire d b y l oc al re g ul at or y a ut h orities. Pers o ns t o w h o m t his i nf or m ati o n 
is discl ose d m ust be i nf or me d t h at t his i nf or m ati o n is pri vile ge d a n d c o nfi de nti al a n d t h at it s h o ul d n ot be f urt her 
discl ose d wit h o ut t he w ritte n per missi o n of In o vi o P h ar m ace utic als. A n y s u p ple me nt al i nf or m ati o n a d de d t o t his 
d oc u me nt  is  als o  c o nfi de nti al  a n d  pr o priet ar y  i nf or m ati o n  of In o vi o P h ar m ace uti c als  a n d  m ust  be  ke pt  i n 
c o nfi de nce i n t he s a me m a n ner as t he c o nte nts of t his d oc u m e nt. 
4 4 6
P P D
P P D
P P D
P P D

SUMMARY OF CHANGES 
The following is a list of protocol changes in order of appearance from HPV-301 protocol version 
4.0 dated 29 March 2018 to HPV-301 protocol version 5.0 dated 13-Jun-2019, after which 
administrative clarifications are listed.  
1. HLA testing and associated exploratory endpoint #2 has been removed from the protocol in 
consideration of the HPV-003 results which showed no clear association of HLA 
background as a predictor of response. 
2. Group-level unblinded (VGX-3100, Placebo) summaries and analyses of efficacy will be 
produced once the primary endpoint Week 36 visit 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 88 visit.  The 
summaries and analyses will allow the Sponsor to have results with respect to the primary 
endpoint and all other efficacy endpoints corresponding to the cervix and the Week 36 visit 
on which to make decisions regarding the VGX-3100 program, while still gathering 
secondary and exploratory endpoint and safety data through the final Week 88 visit.  The 
planned set of summaries and analyses is comprised of a) the primary composite endpoint 
of histopathologic regression and virologic clearance, b) the secondary endpoint of 
histopathologic regression, c) the secondary endpoint of virologic clearance, d) the 
secondary composite endpoint of histopathologic regression to normal and virologic 
clearance, e) the secondary endpoint of histopathologic regression to normal, and f) the 
secondary endpoint of histopathologic non-progression. None of these summaries or 
analyses will be provided if the total count of subjects who experience the event of interest 
is greater than 0 and the count for any treatment group relative to this total count is less 
than 3% for a given summary/analysis.  Also, items a) through f) are planned to be 
produced in the order in which they are listed, but as there are intersecting endpoints among 
these items, items among b) through f) will not be produced if the difference in total count 
of subjects who experience the event of interest is greater than 0 and the count for any 
treatment group is 0, relative to any preceding item in the set.  The group-level unblinded 
(VGX-3100, Placebo) production of the summaries and analyses will not include anyone 
directly involved with the trial or any additional unblinded personnel; only the external 
Contract Research Organization (CRO), PPD, which has already been 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.  
3. The stopping rules outlined in Section 7.3.2, Stopping Rules (Criteria for Pausing of 
Study), have been clarified to focus on unexpected verified events and not include events 
that are already described as known adverse drug reactions.   
Administrative Changes: 
1. Text was included to clarify that the calculation of Body Mass Index (BMI) used to 
determine the stratification group at randomization should be performed using the Day 0 
measurements. 
447

2. Text was included to clarify that the designation of age category (<25 years vs. ≥25 years) 
used to determine the stratification group at randomization should be performed using the 
age at Day 0. 
3. An inconsistency in the text in Exclusion Criteria #8a was corrected to clarify that HIV 
testing should be performed within 45 days prior to Day 0. This change will make the text 
in the exclusion criteria consistent with the text in Section 6.1.1, Screening Evaluations, of 
the protocol.  
4. A statement was added to Section 1.1.3, Electroporation, for informational purposes 
indicating that CELLECTRA™ 5PSP device is CE Marked in the European Union. 
5. References to table numbers for Tables 4 and 5: Minimally Required Procedures at Week 
36 were corrected throughout the document. 
6. In Section 2.1.3, the definition of non-responder has been clarified to indicate that subjects 
who undergo excision or whose cervix are biopsied at any time between their initial dose 
of study drug and the Week 36 endpoint tissue collection would be considered non-
responders, because the point of initial dose represents the start of therapy, in contrast to the 
screening period. Also confirming ECC alone is not included under these circumstances. 
7. The timing of the virology clearance sample has been clarified to include samples taken on 
the same date as tissue removal, as time of tissue removal is not captured. 
8. Text regarding return of devices has been updated in Section 5.13, CELLECTRA™ 5PSP 
Device, to clarify that devices and device components may be returned to Inovio, which 
allows the possibility of destruction of device components on site or carry over of supplies 
for another study, where appropriate. 
9. Digene sample collection has been removed from Week 88 Visit as there is no endpoint 
associated to this sample at this time point.   
10. Table 15 was updated to clarify prevents daily activity.  The timeframe for daily activity 
refers to an impact lasting > 24 hours. 
11. The pregnancy reporting timeframe for those participants that become pregnant while 
participating in the trial that is outlined in Section 7.1.9, Procedures for Documenting 
Pregnancy During Study, was corrected to reflect that pregnancies will begin being 
collected starting from first study treatment instead of first screening procedure. Beginning 
collection of pregnancies during screening would require the Investigator to follow 
pregnancies even for subjects that are not eligible for the study and are considered screen 
failures.  It is not the Sponsor’s intent to collect information regarding pregnancy outcome 
for subjects that are not exposed to Investigational Product. 
12. Administrative clarifications were made to Section 8, Statistical Analysis Plan, as follows: 
a. Section 8.1: correction that the association of Immunoscores and efficacy is an 
exploratory and not a secondary objective. 
448

b. Section 8.10: correction that immunogenicity assessments will be conducted post-
baseline at Weeks 15 and 36.  Week 8 was removed for consistency with other 
protocol sections. 
c. Section 8.11.2: because there are no safety laboratory post-baseline measurements, 
this section that pertained to changes from baseline is not applicable and was 
removed. 
d. Section 8.14: further clarity and specification was included regarding the planned 
PRO analyses. 
13. Clarification was made to Section 15, Appendix A: Guidelines for Colposcopy, Biopsy, 
and Surgical Excision.  Study participants qualifying for 4 quadrant biopsies should have 
biopsies collected from all four quadrants regardless of visible lesion being present. 
14. Additional minor grammatical changes have been made for improvement of general 
readability. 
 
 
 
449

 
INVESTIGATOR ACKNOWLEDGEMENT 
 
I have read this Protocol and agree that it contains all necessary details for carrying out the study 
described. I understand that it must be reviewed by the Institutional Review Board or Independent 
Ethics Committee overseeing the conduct of the study and approved or given favorable opinion 
before implementation. 
 
The signature of the Investigator below constitute his/her approval of this protocol and provide the 
necessary assurances that this study will be conducted according to the Declaration of Helsinki, 
ICH-GCP guidelines, local legal and regulatory requirements as well as to all stipulations of the 
protocol in both the clinical and administrative sections, including statements regarding 
confidentiality. 
 
 
 
__________________________________________________________ 
Investigator – Signature                      Date (DD/MMM/YYYY)       
 
 
________________________________________ 
Investigator – Printed Name        
 
 
 
 
 
Site Number: ___________________________________   
 
Site Name: _____________________________________ 
 
 
450

TABLE OF CONTENTS 
Summary of Changes .................................................................................................................................. 3 
Investigator Acknowledgement ................................................................................................................. 6 
Table of Contents ........................................................................................................................................ 7 
i 
List Of Abbreviations and definitions................................................................................................ 12 
ii Clinical Protocol Synopsis ................................................................................................................... 14 
1 Introduction ......................................................................................................................................... 24 
1.1 
Background ................................................................................................................................. 24 
1.1.1 HPV Infection, Cervical Intraepithelial Neoplasia and Cervical Cancer .......................... 24 
1.1.2 VGX-3100 ........................................................................................................................ 25 
1.1.3 Electroporation ................................................................................................................. 25 
1.1.4 Selection of study design .................................................................................................. 26 
1.2 
Dose and Regimen Rationale ...................................................................................................... 27 
1.3 
Risks/Benefit Assessment ........................................................................................................... 27 
1.3.1 Risks associated with Current Therapeutic Options ......................................................... 27 
1.3.2 Potential Risks of Study Participation .............................................................................. 28 
1.3.3 Potential Benefits of Study Participation .......................................................................... 29 
2 Study Design ......................................................................................................................................... 30 
2.1 
Endpoint Assessment .................................................................................................................. 30 
2.1.1 Histology Assessment ....................................................................................................... 31 
2.1.2 Virologic (HPV) Assessment............................................................................................ 32 
2.1.3 Definition of Responder and Non-Responder .................................................................. 32 
2.1.4 Immunogenicity Assessment ............................................................................................ 36 
2.2 
Treatment Plan ............................................................................................................................ 36 
2.3 
Safety Monitoring Plan ............................................................................................................... 36 
2.3.1 Data and safety Monitoring Board (DSMB) ..................................................................... 38 
2.4 
Long Term Follow up Plan ......................................................................................................... 38 
2.5 
Group-level Unblinding .............................................................................................................. 41 
3 Hypothesis and Study Objectives ....................................................................................................... 41 
3.1 
Hypothesis ................................................................................................................................... 41 
3.2 
Primary Objective and Endpoint ................................................................................................. 42 
3.3 
Secondary Objectives and Associated Endpoints ....................................................................... 43 
3.4 
Exploratory Objectives and Associated Endpoints ..................................................................... 44 
4 Selection of Subjects ............................................................................................................................ 44 
4.1 
Inclusion Criteria ......................................................................................................................... 44 
4.2 
Exclusion Criteria........................................................................................................................ 45 
451

4.3 
Discontinuation/Withdrawal of Study Subjects .......................................................................... 47 
4.3.1 Criteria for Discontinuation of Investigational Product .................................................... 47 
4.3.2 Criteria for WithdrawAl from the Study ........................................................................... 47 
4.3.3 Sponsor Notification of Discontinuation/ Withdrawal ..................................................... 47 
4.3.4 Reason for Discontinuation/Withdrawal .......................................................................... 48 
4.3.5 Supplementation of study subjects ................................................................................... 48 
5 Study Treatment .................................................................................................................................. 48 
5.1 
Investigational Products .............................................................................................................. 48 
5.2 
Blinding ....................................................................................................................................... 49 
5.3 
Packaging and Labeling of investigational product .................................................................... 49 
5.4 
Handling of investigational product ............................................................................................ 50 
5.5 
Dispensing of Investigational Product ........................................................................................ 50 
5.6 
Investigational product Accountability ....................................................................................... 51 
5.7 
Return and Destruction of  Investigational Product .................................................................... 51 
5.8 
CELLECTRATM 5PSP Device .................................................................................................... 51 
5.9 
Use of CELLECTRA™ 5PSP device ........................................................................................... 54 
5.10 Packaging and Labeling of CELLECTRA™ 5PSP Device .......................................................... 54 
5.11 Handling of CELLECTRA™ 5PSP device .................................................................................. 55 
5.12 CELLECTRA™ 5PSP Device Accountability ............................................................................. 55 
5.13 Return of CELLECTRA™ 5PSP Devices .................................................................................... 55 
6 Study Procedures and Treatments ..................................................................................................... 56 
6.1 
Before Treatment Procedures ...................................................................................................... 56 
6.1.1 Screening Evaluations ...................................................................................................... 56 
6.2 
During Treatment Procedures by Visit ........................................................................................ 58 
6.2.1 Day 0 ................................................................................................................................. 58 
6.2.2 8-14 Days Post Dose 1 Phone call .................................................................................... 59 
6.2.3 Week 4 .............................................................................................................................. 59 
6.2.4 8-14 Days Post Dose 2 Phone Call ................................................................................... 59 
6.2.5 Week 8 .............................................................................................................................. 59 
6.2.6 Week 12 ............................................................................................................................ 60 
6.2.7 8-14 Days Post Dose 3 Phone Call ................................................................................... 60 
6.2.8 Week 15 ............................................................................................................................ 60 
6.2.9 Week 28 ............................................................................................................................ 61 
6.2.10 Week 36 ............................................................................................................................ 61 
6.2.11 Week 40 Phone call .......................................................................................................... 61 
452

6.2.12 Week 62 ............................................................................................................................ 62 
6.2.13 Week 88 ............................................................................................................................ 62 
6.3 
Evaluations and Procedures ........................................................................................................ 62 
6.3.1 Informed Consent ............................................................................................................. 62 
6.3.2 Assignment of Subject Identification Numbers ................................................................ 63 
6.3.3 Safety Evaluations ............................................................................................................ 63 
6.4 
Injection and Electroporation (EP) .............................................................................................. 65 
6.4.1 Risks of Treatment Procedures ......................................................................................... 65 
6.4.2 Management of Anxiety and Pain due to Treatment ........................................................ 66 
6.5 
Assessment of Laboratory Abnormalities ................................................................................... 66 
6.6 
Assessment of Clinical Study Adverse Events ........................................................................... 66 
6.7 
Assessment of Injection Site Reactions ...................................................................................... 67 
6.8 
Assessment of Patient Reported Outcomes ................................................................................. 67 
6.9 
Peripheral Blood Immunogenicity Assessments ......................................................................... 68 
6.10 Tissue Immunogenicity Assessment ........................................................................................... 69 
6.11 Pap Smears and HPV Testing ..................................................................................................... 69 
6.12 Colposcopy and Cervical Biopsies .............................................................................................. 70 
6.12.1 Ectocervical Biopsies ........................................................................................................ 70 
6.12.2 Unscheduled Biopsies ....................................................................................................... 71 
6.13 Concomitant Medications/Treatments ........................................................................................ 71 
6.14 Restrictions .................................................................................................................................. 71 
6.14.1 Prohibited Concomitant Medications and Treatments ...................................................... 71 
6.14.2 Other Restrictions ............................................................................................................. 71 
7 Evaluation of Safety and Management of Toxicity........................................................................... 72 
7.1 
Safety Parameters ........................................................................................................................ 72 
7.1.1 Adverse Events ................................................................................................................. 72 
7.1.2 Serious Adverse Events .................................................................................................... 73 
7.1.3 Unexpected Adverse Drug Reactions and Expedited Reporting ...................................... 74 
7.1.4 Unanticipated (Serious) Adverse Device Effect (UADE) ................................................ 75 
7.1.5 Assessing Severity (Intensity) .......................................................................................... 75 
7.1.6 Causal Relationship of Clinical Material to Adverse Events ............................................ 75 
7.1.7 Abnormal Laboratory Value ............................................................................................. 76 
7.1.8 Post-Study Reporting Requirements ................................................................................. 77 
7.1.9 Procedures for Documenting Pregnancy During Study .................................................... 77 
453

7.2 
Methods and Timing of the Collection and Recording of Safety Data ....................................... 77 
7.3 
Safety and Toxicity Management ............................................................................................... 78 
7.3.1 Adverse events of special interest ..................................................................................... 78 
7.3.2 Stopping Rules (Criteria for Pausing of Study) ................................................................ 78 
7.4 
Study Reporting Period of Adverse Events ................................................................................. 79 
7.4.1 Study reporting period of Adverse Events of special interest ........................................... 79 
7.4.2 Study Reporting Period of Serious Adverse Events ......................................................... 79 
7.4.3 Notification of SerioUs Adverse Events ........................................................................... 80 
7.4.4 Reporting of Device Related Complaints ......................................................................... 81 
7.5 
Study Discontinuation ................................................................................................................. 81 
8 Statistical Analysis Plan ...................................................................................................................... 81 
8.1 
General Considerations ............................................................................................................... 81 
8.2 
Randomization and Blinding ....................................................................................................... 81 
8.3 
Sample Size/Power ...................................................................................................................... 82 
8.4 
Analyses Populations .................................................................................................................. 82 
8.5 
Subject Disposition ..................................................................................................................... 82 
8.6 
Demographic and Other Baseline Characteristics ....................................................................... 82 
8.7 
Medical History ........................................................................................................................... 83 
8.8 
Prior and Concomitant Medications ............................................................................................ 83 
8.9 
Efficacy Analyses ........................................................................................................................ 83 
8.10 Immunogenicity Analyses ........................................................................................................... 84 
8.11 Safety Analyses ........................................................................................................................... 84 
8.11.1 Adverse Events ................................................................................................................. 84 
8.12 Vital Signs ................................................................................................................................... 84 
8.13 Physical Examination .................................................................................................................. 85 
8.14 Patient Reported Outcomes ......................................................................................................... 85 
8.15 Missing Values ............................................................................................................................ 85 
8.16 subgroup analyses ....................................................................................................................... 85 
8.17 Interim Analysis .......................................................................................................................... 85 
9 Data Collection, Monitoring and Reporting ..................................................................................... 86 
9.1 
Confidentiality and Privacy ......................................................................................................... 86 
9.2 
Source Documents ...................................................................................................................... 87 
9.3 
Records Retention ....................................................................................................................... 87 
9.4 
Safety and Quality Monitoring .................................................................................................... 87 
9.4.1 Data & Safety Monitoring Board...................................................................................... 87 
9.4.2 Pathology Adjucation Committee ..................................................................................... 88 
454

9.4.3 Clinical Monitoring .......................................................................................................... 88 
10 Ethics  .................................................................................................................................................. 89 
10.1 Investigator and Sponsor Responsibilities .................................................................................. 89 
10.2 Institutional Review Board or Institutional Ethics committee (IRB/IEC) .................................. 89 
10.3 Office of Biotechnology Activities (OBA) ................................................................................. 89 
11 Protection of Human Subjects ............................................................................................................ 89 
11.1 Compliance with Informed Consent Regulations ....................................................................... 89 
11.2 Compliance with IRB/IEC Requirements ................................................................................... 89 
11.3 Compliance with Good Clinical Practice .................................................................................... 90 
11.4 Compliance with Electronic Records/Signatures Regulations (21CFR Part 11) ........................ 90 
11.5 Compliance with Protocol ........................................................................................................... 90 
11.6 Changes to the Protocol .............................................................................................................. 90 
12 Financing and Insurance ..................................................................................................................... 90 
13 Publication Policy ................................................................................................................................ 90 
14 References ............................................................................................................................................ 91 
15 Appendix .............................................................................................................................................. 93 
15.1 Appendix A:  Guidelines for Colposcopy, Biopsy, and Surgical Excision ................................. 93 
 
 
 
 
455

I 
LIST OF ABBREVIATIONS AND DEFINITIONS 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AIS 
Adenocarcinoma-in-situ 
AGC 
Atypical Glandular Cell 
ASC-H  
Atypical Squamous Cells, cannot exclude High grade squamous intraepithelial lesion 
ASC-US  
Atypical squamous cells of undetermined significance 
BMI 
Body Mass Index 
Baseline 
Prior to first dose 
CEF 
Cytomegalovirus, Epstein Barr Virus and Influenza 
CFR 
Code of Federal Regulations 
CIN 
Cervical Intraepithelial Neoplasia 
CKC 
Cold knife conization 
CMI 
Cell mediated immunity 
CMR 
Complete Metabolic Response 
CMV 
Cytomegalovirus 
CRF 
Case Report Forms 
CPK 
Creatine Phosphokinase 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTL 
Cytotoxic T-cells 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIDS 
Division of Acquired Immunodeficiency Syndrome  
DNA 
Deoxyribonucleic Acid 
DNAme 
Methylated Deoxyribonucleic Acid 
ECC 
Endocervical Curettage 
EP 
Electroporation with CELLECTRA™ 5PSP 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISpot 
Enzyme Linked Immunosorbent Spot-forming Assay 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HCG 
Human Chorionic Gonadotropin 
HSIL 
High grade squamous intraepithelial lesion 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPV 
Human Papillomavirus 
HPV-16/18 
HPV-16 and/or HPV-18 
456

ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IHC 
Immunohistochemistry 
IFN-γ 
Interferon Gamma 
IL-12 
Interleukin 12 
IM 
Intramuscular 
IND 
Investigational New Drug Application 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
IUD 
Intrauterine Device 
IXRS 
Interactive Response System 
LAST 
Lower Anogenital Squamous Terminology 
LEEP 
Loop Electrosurgical Excision Procedure 
LLETZ 
Large Loop Excision of Transformation Zone 
LSIL 
Low grade squamous intraepithelial lesion 
MedDRA® 
Medical Dictionary for Drug Regulatory Affairs 
miRNA 
Micro Ribonucleic Acid 
mITT 
Modified Intent to Treat 
NILM 
Negative for intraepithelial lesion or malignancy 
NIH 
National Institutes of Health 
OP 
Oropharyngeal  
Principal Investigator 
Lead Investigator for overall study activities 
Investigator 
Lead Investigator for individual site(s) 
PAC  
Pathology Adjudication Committee 
PBMC 
Peripheral Blood Mononuclear Cells 
PDC 
Participant Diary Card 
PRO 
Patient Reported Outcomes 
PE 
Physical exam 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PP 
Per Protocol 
SAE 
Serious Adverse Event 
SID 
Subject Identification   
SOC 
System Organ Class 
SSC 
Saline Sodium Citrate 
sWFI 
Sterile Water for Injection 
TNF 
Tumor Necrosis Factor 
ULN 
Upper Limit of Normal 
WOCBP 
Women of Childbearing Potential 
457

 
 
II CLINICAL PROTOCOL SYNOPSIS 
 
Title of Study:  A Prospective, Randomized, Double-blind, Placebo-Controlled Phase 3 Study of 
VGX-3100 Delivered Intramuscularly followed by Electroporation with CELLECTRA™ 5PSP for 
the Treatment of HPV-16 and/or HPV-18 related High Grade Squamous Intraepithelial Lesion 
(HSIL)0F1 of the Cervix 
Estimated Number of Study Centers and Countries/Regions:  Approximately 125 Sites  in up 
to 25 Countries 
Study Phase: 3 
Primary Hypothesis:  Three 6 mg doses of VGX-3100 (DNA Plasmids encoding E6 and E7 
proteins of HPV-16 and HPV-18) delivered intramuscularly (IM) followed by electroporation 
(EP) with CELLECTRA™ 5PSP to adult women with histologically confirmed HSIL[Cervical 
Intraepithelial Neoplasia (CIN)2, CIN3] of the cervix, associated with HPV-16 and/or HPV-18 
will result in a higher percentage of women with histopathological regression of cervical HSIL 
lesions to no evidence of cervical HSIL and virologic clearance of HPV-16 and/or HPV-18 
compared to placebo delivered IM followed by EP with CELLECTRA™ 5PSP at the Week 36 
visit2  
Study Drug Dose 
6 mg (1 ml) 
Administration 
Intramuscular injection followed by EP with the CELLECTRA™ 5PSP 
device 
Schedule 
Day 0, Week 4, and Week 12 study visits 
No. of Subjects 
Approximately 198 subjects will be randomized in a 2:1 ratio to receive 
VGX-3100 or placebo 
Study Duration 
88 weeks 
Primary Objective 
Determine the efficacy of VGX-3100 compared with placebo with respect 
to combined histopathologic regression of cervical HSIL and virologic 
clearance of HPV-16 and/or HPV-18 
Primary Endpoint 
Proportion of subjects with no evidence of  cervical HSIL on histology 
(i.e. biopsy or excisional treatment) and no evidence of HPV-16 and/or 
HPV-18 in cervical samples by type specific HPV testing at Week 36 visit 
 
 
 
 
1 Terminology based on 2012 consensus recommendation on Lower Anogenital Squamous Terminology (LAST) from 
the American Society of Colposcopy and Cervical Pathology (ASCCP) and the College of American Pathologists (CAP) 
2 The time frame is defined as any time starting from 14 days prior to the protocol-specified target date of Week 36 
458

 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of 
VGX-3100 delivered IM followed by EP 
with CELLECTRA™ 5PSP 
1a. Incidence and severity of local and systemic 
events for 7 and 28 days following each 
investigational treatment  and for the duration of 
the study (through Week 88 visit) 
1b. Incidence and severity of all adverse events 
including Serious adverse events (SAEs) (e.g. 
Suspected unexpected serious adverse reaction 
(SUSAR), Unexpected adverse device effect 
(UADE) and other unexpected AEs) for the 
duration of the study (through Week 88 visit) 
2. Determine VGX-3100 efficacy compared 
to placebo as measured by histopathologic 
regression of cervical HSIL 
2. Proportion of subjects with no evidence of  
cervical HSIL on histology (i.e. biopsies or 
excisional treatment) at Week 36 visit 
3. Determine VGX-3100 efficacy compared 
to placebo as measured by virologic 
clearance of HPV-16 and/or HPV-18 
3. Proportion of subjects with no evidence of 
HPV-16 and/or HPV-18 in cervical samples 
by type specific HPV testing at Week 36 visit 
4. Determine VGX-3100 efficacy compared 
to placebo as measured by complete 
histopathologic regression of cervical 
HSIL to normal 
4. Proportion of subjects with no evidence of Low 
grade squamous intraepithelial lesion (LSIL) 
or HSIL (i.e.  no evidence of CIN1, CIN2 or 
CIN3) on histology (i.e. biopsies or excisional 
treatment) at Week 36 visit 
5. Determine VGX-3100 efficacy compared 
to placebo as measured by both complete 
histopathologic regression of cervical 
HSIL to normal and virologic clearance 
of HPV-16 and/or HPV-18 
5. Proportion of subjects with no evidence of 
LSIL or HSIL (i.e. no evidence of CIN1, CIN2 
or CIN3 on biopsies or excisional treatment) on 
histology (i.e. biopsies or excisional treatment) 
and no evidence of HPV-16 and/or HPV-18 
by type specific HPV testing at Week 36 visit 
6. Determine VGX-3100 efficacy compared 
to placebo as measured by histopathologic 
non-progression 
6. Proportion of subjects with no progression of 
cervical HSIL to cervical carcinoma from 
baseline on histology (i.e. biopsies or excisional 
treatment) at Week 36 visit 
7. Describe the clearance of HPV-16 and/or 
HPV-18 
infection 
from 
non-cervical 
anatomic locations 
7. Proportion of subjects who have cleared HPV-
16 and/or HPV-18 on specimens from non-
cervical 
anatomic 
locations 
(oropharynx, 
vagina and intra-anal) at Week 36 Visit 
8.Determine the humoral and cellular 
immune response to VGX-3100 compared 
with placebo at post dose 3 and Week 36 
visits as assessed relative to baseline  
8a. Levels of serum anti-HPV-16 and anti-HPV-18 
antibody concentrations at Weeks 15 and 36 
visits 
8b. Interferon-γ ELISpot response magnitudes at 
baseline, Weeks 15 and 36 visits 
459

8c. Flow Cytometry response magnitudes at 
baseline and Week 15 visits 
Exploratory Objectives 
Associated Exploratory Endpoints 
1. Evaluate tissue immune responses to 
VGX-3100 in cervical samples 
1. Assessment of markers including but not 
limited to CD8+ and FoxP3+ infiltrating 
cells. Additional assessments may include 
visualization of Granulysin, Perforin, CD137, 
CD103 and PD-L1 in cervical tissue as 
sample allows.  Markers listed here may 
change as new relevant information becomes 
available 
2. Describe 
association 
of 
microRNA 
(miRNA) profiles, DNA methylation 
profile, previous colposcopy, cytology 
and HPV testing results with Week 36 
histologic regression 
2. Colposcopy, cytology, and HPV test results 
(Weeks 8, 15 and 28 visits), miRNA profile 
(baseline, Week 8) and DNA methylation 
profile (baseline, Week 15) in conjunction 
with histologic regression of cervical HSIL at 
Week 36 visit 
3. Describe the durability of virologic 
clearance of HPV-16 and/or HPV-18 for 
subjects 
treated 
with 
VGX-3100 
compared with those treated with placebo 
3. Proportion of subjects with no evidence of 
HPV-16 and/or HPV-18 by type specific 
HPV testing at Weeks 62 and 88 visits 
4. Describe the patient-reported outcomes 
for subjects treated with VGX-3100  
4. Patient-reported outcome questionnaires self-
administered at baseline, after each dose at 
Weeks 4, 12, 8-14 days following each dose, 
and at Weeks 28, 36, 40 and 88 by subjects 
enrolled in US, Canada, Mexico, Germany 
and UK 
5. Describe the association of a tissue-based 
score derived using immunologic markers 
(Immunoscore) at baseline to histological 
and virological response to VGX-3100  at 
Week 36 
5. Immunoscore results for VGX-3100 treated 
subjects in conjunction with histological and 
virological outcomes at Week 36 
Study Design: 
This Phase 3 study design is based upon the Phase 2b study design and results.  HPV-301 is a 
prospective, randomized, double-blind, placebo controlled Phase 3 study to determine the efficacy 
safety, and tolerability of VGX-3100 administered by IM injection followed by EP delivered with 
CELLECTRA™ 5PSP in adult women with histologically confirmed cervical HSIL (CIN2, CIN3) 
associated with HPV-16 and/or HPV-18 (HPV-16/18). The composite primary endpoint is histologic 
regression of cervical HSIL, and clearance of the underlying HPV-16/18 infection. A sample of 
approximately 198 subjects will be randomized to receive either 6 mg (in 1 ml) VGX-3100 or 
placebo, each IM followed by EP, in a 2:1 ratio. This sample size provides 90% power to declare 
VGX-3100 superior to placebo, assuming, based upon Phase 2b study results, that the true 
460

proportion of subjects whose lesion(s) regress and whose HPV-16/18 clears is 35% and 14% for 
VGX-3100 and placebo, respectively. 
To be eligible for the study, women age 18 years and above must consent to participate and have 
biopsy/biopsies of the cervical lesion(s) at the time of screening. The biopsy slides are sent to a 
central pathology lab for Pathology Adjudication Committee (PAC) review in a blinded manner to 
establish the presence of cervical HSIL (CIN2, CIN3) prior to randomization. Subjects must also 
have a cervical ThinPrep™ specimen test positive for HPV-16/18 by cobas™ HPV test to be eligible 
for participation in the study.  
All eligible subjects will receive three doses of VGX-3100 or placebo administered IM followed 
immediately by EP with the CELLECTRA™ 5PSP device. The first study treatment is administered 
on Day 0, the second at Week 4, and the third (final) study treatment is administered at Week 12. 
The first dose is administered as soon as possible following confirmation of the cervical HSIL 
diagnosis and cervical sample positive for HPV-16/18 but no more than 10 weeks following 
collection of the subject’s biopsy specimen used for diagnosis by the PAC during screening.  
Subjects are randomized in a stratified manner according to (a) the CIN severity observed in the 
biopsy specimens at screening (i.e. CIN2 vs. CIN3), (b) Body Mass Index (BMI) category (≤25 vs. 
>25 kg/m2) on Day 0, and (c) age category (<25 years vs. ≥25 years) on Day 0. To ensure CIN2 
disease is not over-represented in the study, the percentage of subjects enrolled with CIN2 will not 
exceed 50% of the total enrolled. A group of sequential allocation numbers will be designated for 
use by each participating country. 
The long term follow up plan following the Week 36 efficacy assessment will include safety, 
cytology and HPV testing for a period of approximately 1 year (Week 88). 
Efficacy: Visualization of a normal appearing cervix by colposcopy and cytology are insufficient 
evidence to confirm disease regression. Therefore, disease regression will be based on 
histopathological assessment, which is considered the definitive method for diagnosis. Subjects will 
also be assessed by colposcopy, cytology, and HPV testing at screening, and at specified visits on 
and after Day 0. Digital photographs of the cervix following application of acetic acid will also be 
used to document colposcopic exam findings. 
Tissue to be analyzed for evidence of histopathologic regression will be obtained at Week 36 either 
by excision (e.g. loop electrosurgical excision procedure (LEEP), large loop excision of 
transformation zone (LLETZ), cold knife conization (CKC)) or by biopsy (4 Quadrant Biopsy or 4 
Quadrant Biopsy with Endocervical Curettage (ECC)) based upon the assessment at Week 28 of 
cytology, High Risk (HR) HPV status, and colposcopic findings (see Tables 4 and 5, for Minimally 
Required Procedures).   
Safety: All subjects will be followed for 88 weeks. 
 
Subjects will be monitored for: 
1) Local and systemic events for 7 days following each investigational treatment as noted on a 
Participant Diary Card (PDC); 
2) All adverse events including SAEs, UADEs, and other unexpected AEs for the duration of the 
study; 
461

Data and Safety Monitoring Board (DSMB): The DSMB will meet quarterly to review unblinded 
safety data and histopathologic regression results. The DSMB will be charged with advising the 
Sponsor if there appears to be a safety issue and with advising the Sponsor if it appears that the 
proportion of the subjects with histopathologic regression in the VGX-3100 group is unacceptably 
low compared to the placebo group; no formal interim analysis will be performed for this purpose.   
Immunogenicity: Humoral and cell mediated immune responses in response to VGX-3100 treatment 
will be evaluated in blood samples taken at baseline (both Screening as well as Day 0 prior to dosing) 
and at Weeks 15 and 36. Cervical tissue samples will also be analyzed for evidence of elevated 
immune responses at Week 36 as compared to baseline (screening). 
Virology: Cervical cytology samples will be obtained to characterize HPV infection at Day 0 (prior 
to dosing) and at Weeks 8, 15, 28, 36, 62, and 88 by cobas™ HPV test. Additionally, if there is 
residual tissue in the paraffin block from cervical tissue after histologic diagnoses have been 
rendered at screening and Week 36, then unstained slides and/or the relevant paraffin blocks may 
be tested for the presence of HPV-16/18. Vaginal brush and oropharyngeal rinse samples will be 
obtained at Day 0 (prior to dosing), Weeks 36 and 88 while intra-anal samples will be obtained on 
Day 0 (prior to dosing) and Week 36 to characterize HPV infection.  
Group-level Unblinding: Group-level unblinded (VGX-3100, Placebo) summaries and analyses of 
efficacy will be produced once the primary endpoint Week 36 visit 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 88 visit.  The summaries and 
analyses will allow the Sponsor to have results with respect to the primary endpoint and all other 
efficacy endpoints corresponding to the cervix and the Week 36 visit on which to make decisions 
regarding the VGX-3100 program, while still gathering secondary and exploratory endpoint and 
safety data through the final Week 88 visit.  The planned set of summaries and analyses is 
comprised of a) the primary composite endpoint of histopathologic regression and virologic 
clearance, b) the secondary endpoint of histopathologic regression, c) the secondary endpoint of 
virologic clearance, d) the secondary composite endpoint of histopathologic regression to normal 
and virologic clearance, e) the secondary endpoint of histopathologic regression to normal, and f) 
the secondary endpoint of histopathologic non-progression.  None of these summaries or analyses 
will be provided if the total count of subjects who experience the event of interest is greater than 0 
and the count any treatment group relative to this total count is less than 3% for a given 
summary/analysis.  Also, items a) through f) are planned to be produced in the order in which they 
are listed, but as there are intersecting endpoints among these items, items among b) through f) will 
not be produced if the difference in total count of subjects who experience the event of interest is 
greater than 0 and the count for any treatment group is 0, relative to any preceding item in the set.  
The group-level unblinded (VGX-3100, Placebo) production of the summaries and analyses will 
not include anyone directly involved with the trial or any additional unblinded personnel; only the 
external Contract Research Organization (CRO), PPD, which has already been 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. 
 
 
462

Study Population 
Inclusion Criteria: 
1. Women aged 18 years and above and meets the minimum age of consent per local regulations; 
2. Confirmed cervical infection with HPV types 16 and/or 18 at screening by cobas™ HPV test;  
3. Cervical tissue specimen/slides provided to Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study drug; 
4. Histologic evidence of cervical HSIL as confirmed by PAC at screening; 
5. Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form 
prior to study-related activities; 
6. Must be judged by Investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision, 4-quadrant biopsy with ECC, or 4-quadrant biopsy) required at Week 
36; 
7. Satisfactory colposcopy at screening, defined as full visualization of the squamo-columnar 
junction (Type I or II transformation zone) and complete visualization of the upper limit of aceto-
white epithelium or suspected CIN disease; 
8. Cervical lesion that is accessible for sampling by biopsy instrument (e.g. Mini-Tischler device); 
9. Cervical lesion of adequate size to ensure that a visible lesion remains after screening biopsy; 
10. Must meet one of the following criteria with respect to their reproductive capacity: 
a) Post-menopausal as defined by spontaneous amenorrhea for more than 12 months; 
b) Surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 12 months prior to screening; 
c) Women of Child Bearing Potential (WOCBP) is willing to use a contraceptive method with 
failure rate of less than 1% per year when used consistently and correctly from screening 
until Week 36. The following methods are acceptable : 
i. Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. Hormonal 
contraceptives must not be used in subjects with a history of hypercoagulability (e.g., 
deep vein thrombosis, pulmonary embolism); 
ii. Abstinence from penile-vaginal intercourse when this is the subject’s preferred and usual 
lifestyle; 
iii. Intrauterine device or intrauterine system; 
iv. Male partner sterilization at least 6 months prior to the female subject’s entry into the 
study, and this male is the sole partner for that subject; 
11. Normal screening ECG or screening ECG with no clinically significant findings, as judged by 
the investigator. 
Exclusion Criteria: 
1. Microscopic or gross evidence of adenocarcinoma-in-situ (AIS), high grade vulvar, vaginal 
(inclusive of cervical HPV-related lesions that extend into the vaginal vault), or anal 
intraepithelial neoplasia or invasive cancer in any histopathologic specimen at screening; 
2. Cervical lesion(s) that cannot be fully visualized on colposcopy due to extension high into 
cervical canal at screening; 
463

3. ECC that shows a potentially untreated carcinoma, untreated HSIL, indeterminate, or 
insufficient for diagnosis (ECC is not required to be performed as part of study screening); 
4. Treatment for cervical HSIL within 4 weeks prior to screening; 
5. Pregnant, breastfeeding or considering becoming pregnant through Week 36 visit; 
6. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are 
allowed, e.g. Gardasil™, Silgard™, Cervarix™); 
7. Presence of any unresolved abnormal clinical screening laboratory values of Grade 1 or greater 
per Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 and deemed clinically 
significant by the investigator within  45 days prior to Day 0; 
8. Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening (performed within 45 days prior 
to Day 0) 
b) Primary immunodeficiencies 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent; (use of inhaled, otic, and ophthalmic corticosteroids are allowed); 
d) 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); 
e) History of solid organ or bone marrow transplantation; 
f) Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
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 
g) Subjects who are malnourished (i.e. medically significant unintentional weight loss, 
kwashiorkor, or marasmus) based on screening labs, medical history and physical exam per 
the investigator’s clinical judgment.  
9. Receipt of any non-study, non-live vaccine within 2 weeks of  dosing; 
10. Receipt of any non-study, live vaccine (e.g. measles vaccine) within 4 weeks of dosing; 
11. Current or history of clinically significant, medically unstable disease which, in the judgment of 
the investigator, would jeopardize the safety of the subject, interfere with study assessments or 
endpoint evaluation, or otherwise impact the validity of the study results (e.g. chronic renal 
failure; angina, myocardial ischemia or infarction, class 3 or higher congestive heart failure, 
cardiomyopathy, or clinically significant arrhythmias); 
12. Malignancy or systemic treatment for malignancy within 2 years of screening (with the 
exception of curatively treated, localized anogenital cancers and superficial skin cancers which 
are permitted)   
13. Presence of acute or chronic bleeding or clotting disorder that would contraindicate IM 
injections, or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of 
Day 0; 
14. History of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic 
agents; 
15. Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or 
a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
464

16. Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at 
screening or Day 0; 
17. Prior major surgery within 4 weeks of Day 0; 
18. Participation in an interventional study with an investigational compound or device within 30 
days of signing informed consent; participation in an observational study is permitted; 
19. Less than two acceptable sites available for IM injection considering the deltoid and anterolateral 
quadriceps muscles; 
20. Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
21. Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located 
in ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 
22. Metal implants or implantable medical device within the electroporation area; 
23. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere 
with adherence to study requirements; 
24. Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of 
either a psychiatric or physical (i.e. infectious disease) illness; 
25. Active military service personnel; 
26. Study-related staff or family member of study-related staff; 
27. 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. 
 
 
465

Table 1. Schedule of Events 
Tests 
Screening 
(-10 weeks to -1 Day  
from Date of Biopsy) 
 
Weeks 
Day 0 
8-14 days post Day 0 
Phone Call 
4 (± 4 days) 
8-14 days post Week 4 
Phone Call 
8 (± 4 days) 
12 (± 4 days) 
8-14 days  
post Week 12 
15 (± 1 week) 
28 (± 1 week) 
36 (± 1 week) 
40 (± 2 weeks) 
Phone call 
62 (± 2 weeks) 
88 (± 2 weeks) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Socio-behaviorala 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Inclusion / Exclusion 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam/assessmentb 
X 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
Vital signs 
Xc 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X 
X 
Screening safetyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Teste 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
X 
HIV Antibody Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood immunologic 
samplesf 
X 
X 
 
 
 
X 
 
 
Xg 
 
X 
 
 
 
Cervical Digene swabsi,j 
X 
X 
 
 
 
 
 
 
X 
X 
X 
 
 
 
ThinPrep™ h,i 
X 
X 
 
 
 
X 
 
 
X 
X 
X 
 
X 
X 
Colposcopy, lesion 
photographk 
Xl 
X 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
Ectocervical biopsym 
X 
 
 
 
 
 
 
 
 
 
Xn 
 
 
 
Surgical excisionm 
 
 
 
 
 
 
 
 
 
 
Xn 
 
 
 
OP rinse, vaginal swabs 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
Intra-anal swabso 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Inject VGX-3100/Placebo 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Post treatment assessment 
 
X 
X 
X 
X 
X 
X 
Xq 
X 
 
 
 
 
 
AE/SAE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Distribute PDC 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Review PDC 
 
 
X 
 
X 
X 
 
Xq 
 
 
 
 
 
 
PROsp 
 
X 
X 
X 
X 
 
X 
Xq 
 
X 
X 
X 
 
X 
 
a Socio-Behavioral assessments, e.g. self-reported smoking and alcohol history 
b Full physical examination (PE) mandatory at screening and study discharge (Week 88), otherwise targeted physical 
assessment as determined by the Investigator or per subject complaints unless signs or symptoms dictate the need for 
a full PE; 
c Screening vital signs must include a measured height and weight. Weight will be collected on Day 0, Weeks 4 and 12; 
466

d Screening safety includes 12-Lead ECG, complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), 
serum creatinine (Cr), serum glucose, serum ALT, serum CPK and urinalysis performed within 45 days prior to  Day 
0; 
e For WOCBP, a negative spot urine pregnancy test is required at screening and prior to each study treatment, colposcopy 
and surgical excision;   
f At least 34 mL [4 x 8.5 mL yellow (ACD) tubes] whole blood per time point and 8 mL serum per time point at 
Screening, Day 0 and Week 8 (4 ml serum per time point at Week 15 and 36).   A total of at least 68 mL of whole blood 
and 16 ml serum should be collected prior to dosing on Day 0.  
g At least 51 mL [6 x 8.5 mL yellow (ACD) tubes] whole blood and 4 mL serum should be collected at Week 15; 
h HPV genotyping and Pap smears are performed on the same ThinPrep™ cervical specimen; 
i Request that the subject abstain from sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to cervical specimen collection; 
j Collected prior to the ThinPrep™ sample; 
k A photograph of the lesion with at least one attempt should done as follows: Acetic acid should first be applied to the 
cervix then photographs of the cervix and the associated lesion should be photographed prior to and after biopsies (if 
applicable) and at all colposcopic examinations; if repeat photographs are sought, they should be done at the next 
protocol-specified colposcopy visit.   
l Screening colposcopy is optional if adequate colposcopy was performed upon collection of initial biopsy; 
m Screening biopsy of the lesion should be collected as Paraffin-embedded cervical tissue, fresh cervical tissue, or H&E 
slides. Tissue to be analyzed for evidence of histopathologic regression will be obtained at Week 36 visit either by 
excision (e.g. LEEP,  LLETZ, CKC) or by 4 Quadrant Biopsy or 4 Quadrant Biopsy with ECC based upon the 
assessment at Week 28 of cytology, HR HPV status, and colposcopic findings (See Tables 4 and 5); 
n Slides from biopsy and/or excised tissue must be reviewed by the PAC and residual cervical tissue from screening 
and/or Week 36 specimen(s) (paraffin blocks or unstained slides) may be used for immunohistochemistry (IHC) and 
HPV testing; 
o To be collected only if subject consents for intra-anal sample collection  
p One or both PRO questionnaires (i.e. SF-36 and EQ-5D-5L) will be completed by subjects enrolled in USA, Canada, 
Mexico, Germany and UK at multiple visits during the study. Additional quality of life questions will be asked at the 
Week 40 phone call.  Refer to Section 6.8 for details 
q Activities at 8 to 14 days Post-Dose 3 phone call may be done at Week 15 if timing overlaps. 
 
 
 
 
 
 
467

1 INTRODUCTION 
1.1 
BACKGROUND  
1.1.1 
HPV INFECTION, CERVICAL INTRAEPITHELIAL NEOPLASIA AND 
CERVICAL CANCER  
Infection with human papillomavirus (HPV) can lead to malignant neoplasia, localized primarily 
in the anogenital area and aerodigestive tract, in both men and women.  HPV types tropic to 
mucosal tissues are classified into high-risk (HR), based on their potential to cause cancer, and 
low-risk (LR) (causing generally benign lesions). HPV-16 and HPV-18 are the most significant 
amongst high-risk types since they are responsible for most HPV-caused cancers [1].  In the US 
alone, approximately 14 million new genital HPV infections occur annually, and approximately 
half of these infections are with a HR HPV type [2, 3].  Up to 13000 women in the US alone are 
diagnosed with cervical cancer each year, which leads to an estimated 4120 deaths [4].  HPV-16 
is the most common high-risk genotype and combined with HPV-18 these two genotypes are 
estimated to cause about 70% of all cervical cancers [5, 6]. 
Incident infection by HPV is characterized by ongoing viral replication and shedding and is 
associated with early histologic changes (grade 1 cervical intraepithelial neoplasia) when the 
female cervix is infected with HPV.  Most cases of genital HPV infection clear spontaneously, but 
persistent infection with one or more oncogenic (high-risk) HPV genotypes can lead to the 
development of precancerous, histologic high grade squamous intraepithelial lesions of the cervix, 
HSIL which is inclusive of grade 2 and 3 cervical intraepithelial neoplasia (CIN2/3) [7].   Over 
time, typically years, cervical HSIL can progress to invasive cancer of the cervix [8, 9].  The basis 
for these changes are attributed to the viral proteins E6 and E7.  Infected cells produce E6 and E7 
constitutively which increases the degradation of cell cycle regulation proteins p53 and pRb, 
respectively, resulting in unrestricted cell growth and neoplasia.   
While the currently available prophylactic HPV vaccines (Cervarix™, Gardasil™, and Gardasil™-
9) are highly effective in preventing persistent infection and the subsequent development of high-
grade CIN caused by HPV-16, HPV-18 and other HPV types, the prophylactic vaccines have no 
therapeutic effect upon existing HPV infection or existing HPV-related intraepithelial neoplasia 
[10].  This means that the large number of women who already have high grade cervical dysplasia, 
either because they were too old to have received the prophylactic vaccine or they didn’t respond 
to vaccination, must currently only rely upon surgery and the chance of spontaneous regression to 
treat their condition and avoid progression to cancer.  Furthermore, the number of US-eligible 
teenagers who complete the prophylactic vaccination series remains low; 39.7% of US girls ages 
13-17 completed their prophylactic HPV immunization series in 2014, which leaves a potentially 
vulnerable, under-protected population [11]. The current approaches to the management of 
cervical HSIL typically require surgery (i.e. LEEP/LEETZ, laser ablation, or conization); 
however, surgical excision does not necessarily address the underlying HPV-infection, and can 
adversely impact the reproductive health of women of childbearing age.  Therefore, VGX-3100 is 
being developed as a non-surgical therapeutic option for the precancerous precursor to cervical 
cancer, cervical HSIL, and the underlying, pathogenic HPV infection.  
 
468

1.1.2 
VGX-3100 
VGX-3100 contains plasmids that encode HPV-16 E6/E7 and HPV-18 E6/E7 antigens. The 
plasmids were designed and constructed using proprietary synthetic vaccine (SynCon™) 
technology. This process involves synthetically deriving consensus genes across multiple strains 
and optimizing DNA inserts at the genetic level to allow high expression in human cells. Together, 
VGX-3100 and the CELLECTRA™ device represent an integrated investigational product 
designed as a non-surgical treatment of HPV-16/18-related cervical HSIL (CIN2, CIN3) via an 
immune response directed against HPV-16/18. 
The initial formulation of VGX-3100 was water for injection with 1% w/w poly-L-glutamate 
(WFI/LGS) that required frozen storage.  This WFI/LGS formulation has been administered to 
more than 250 subjects in Phase 1 and 2 clinical trials. A buffered formulation of VGX-31003 was 
developed using a saline sodium citrate (SSC) solution, which is stored non-frozen (5°C). This 
SSC formulation of VGX-3100 was administered to 116 subjects in a Phase 1 clinical trial, HPV-
101. In study HPV-101, three 6 mg doses of VGX-3100 as the SSC formulation were delivered 
IM followed by EP with CELLECTRA™ 5P to healthy adults.  Based upon interim analysis data 
at study Week 14, the SSC formulation is considered non-inferior to the WFI/LGS formulation 
based upon a 2-fold rise in overall Spot Forming Units (SPU) to the antigens encoded by the 
plasmids per 106 Peripheral Blood Mononuclear Cells (PBMC) as measured from baseline to 
Week 14 using the interferon-γ ELISpot assay. 
Proof of concept was demonstrated in the prospective, randomized, double blind, placebo-
controlled Phase 2b study of VGX-3100 (WFI/LGS formulation) followed by EP in the treatment 
of high grade cervical dysplasia, cervical HSIL associated with HPV-16 and/or HPV-18.  The 
Phase 2b study, HPV-003, enrolled and dosed 167 subjects with high grade cervical dysplasia 
from seven countries and one United States Territory (Australia, Canada, Estonia, Republic of 
Georgia, India, South Africa, United States and Puerto Rico). Subjects were randomized in a 3:1 
ratio to the treatment arm (VGX-3100, WFI/LGS formulation) or the placebo arm, respectively. 
All subjects were to receive treatment on Day 0, Week 4 and Week 12. All subjects were to repeat 
cervical biopsy or LEEP of the cervix at Week 36 to assess efficacy defined as regression of high 
grade CIN by histopathology.   The primary endpoint was histopathologic regression of cervical 
lesions (CIN2 or CIN3) to CIN1 or less at the Week 36 visit.   A secondary endpoint was clearance 
of HPV-16/18 in combination with histopathologic regression of cervical lesions to CIN1 or less. 
The proportions of subjects who met the primary and secondary endpoints were significantly 
higher in the VGX-3100 group vs. placebo in both per protocol and modified intent to treat 
analyses.  Robust T-cell activity was detected in VGX-3100 recipients compared to placebo 
recipients. VGX-3100 was generally safe and well tolerated when administered intramuscularly 
with electroporation.  
1.1.3 
ELECTROPORATION 
VGX-3100 is delivered using the CELLECTRA™ in vivo electroporation (EP) device. EP is a 
physical method of tissue transfection whereby the generation of short, controlled electrical pulses 
3 Designated in earlier version of the HPV-301 protocol as VGX-3100X 
469

creates a localized electric field at the injection site of the DNA vaccine which increases cell 
membrane permeability and improves the transfection of DNA and subsequent immunogenicity 
[12, 13]. EP is believed to increase the uptake and processing of plasmid DNA, thereby enabling 
increased expression and enhanced vaccine immunogenicity by 10 to 100 fold [14, 15]. This 
technology has been used for more than three decades by molecular biologists for cell transfection 
and has demonstrated versatility in use, as shown by its functionality in combination with a range 
of molecules, tissue types, disease indications, and across species [16]. 
The CELLECTRA™ device developed by Inovio is used for investigational purposes to administer 
plasmid-based DNA, in both prophylactic and therapeutic settings. Following successful proof-
of-concept studies in animals, Inovio has optimized both pulse pattern and voltage to increase 
transfection efficiency, and has demonstrated that the device helps to elicit favorable 
immunogenicity in several species (e.g., mice, pigs, and rhesus macaques) [17, 18].  
VGX-3100, WFI/LGS formulation, has been administered throughout Phase 1 and Phase 2 
investigations with the CELLECTRA™ 2000 device. A next generation device, CELLECTRA™ 
5PSP, will be used in Phase 3. Both designs of the CELLECTRA™ device enhance the 
intracellular uptake of VGX-3100 by the delivery of electrical current, and the electrical current 
delivery and pulse pattern (electroporation) is identical in both designs. CELLECTRA™ 2000 
involves a manual injection of VGX-3100 while the CELLECTRA™ 5PSP device will automate 
the intramuscular delivery of VGX-3100 and delivery of the EP pulses triggered by a single button 
press. Neither the dosage nor volume of VGX-3100 administered differs between the two devices. 
Administration of VGX-3100 with the CELLECTRA™ 5PSP also allows selection of the array 
needle length (13, 19 or 25 mm) depending on the estimate of the recipient’s subcutaneous fat and 
muscle tissue.  
The technology differences between the CELLECTRA™ 2000 and CELLECTRA™ 5PSP design 
are not significant and do not present any new risks. The device design change does not affect the 
indications for use, operating principle, energy type, environmental specifications, and 
sterilization or performance specifications. The material changes are to the outer housing of the 
device and not to patient-contacting materials.  
Benchtop design verification testing and a non-significant risk device functionality study was 
completed prior to Phase 3 to support that the dimensional changes, change to the ergonomics of 
the patient user interface and injection method result in the CELLECTRA™ 5PSP device design 
meeting its safety and performance specifications, and no change to the administration of VGX-
3100 by electroporation. Inovio’s device experience demonstrates that delivery of electroporation 
pulses into muscle immediately following injection of DNA plasmids is well-tolerated in humans 
and no significant safety issues have been identified [19-21]. The CELLECTRA™ 5PSP device is 
CE Marked in the European Union. For further information concerning the 5PSP device please 
refer to the User Manual and the Investigator’s Brochure.  
1.1.4 
SELECTION OF STUDY DESIGN  
This Phase 3 study employs a prospective, randomized, double-blind, placebo controlled study 
design to further demonstrate the safety and efficacy of VGX-3100 followed by EP in women with 
cervical HSIL associated with HPV-16/18.  The primary clinical hypothesis is that VGX-3100 is 
470

a surgery-sparing, therapeutic option for the treatment of cervical HSIL and the underlying, 
pathogenic HPV-16/18 infection, which is supported by the findings of the Phase 2b trial. A 
placebo-controlled study is selected for this trial because it provides scientific rigor to distinguish 
an effective treatment, particularly in cervical HSIL for which spontaneous regression does occur. 
1.2 
 DOSE AND REGIMEN RATIONALE   
A total dose of 6 mg VGX-3100 DNA has been selected for this study based on previous human 
experience with both the WFI/LGS and SSC formulations of VGX-3100, preclinical data with 
VGX-3100 and other DNA vaccines, and the safety and immunogenicity data generated in the 
HPV-001, HPV-003, and HPV-101 studies. In HPV-001 trial, the 6 mg dose was delivered IM 
followed by EP, which showed trends toward higher response rates and magnitudes of IFN-γ 
ELISpot responses compared to the low (0.6 mg) and mid-dose (2 mg) cohorts (Table 2) without 
significant safety issues [19].  
This dose-trend was consistent with prior expectation, a feature of the finding that suggests it is a 
true effect rather than random variation. Adverse events from previous human studies with 
VGX- 3100 (frozen formulation) and closely related DNA plasmid products have been limited to 
injection site pain from the injection and electroporation procedure, which were not clinically 
meaningful. 
Based on the information above, the 6 mg dose was selected for study in the Phase 2b study. The 
results obtained in the phase 2 study suggest that the 6 mg dose was efficacious with an acceptable 
safety profile, therefore the 6 mg dose will also be evaluated in this Phase 3 trial. 
Table 2. Percent of Protocol HPV-001 Subjects Responding and Average SFU/106 PBMC 
in Responders for each Antigen by Cohort in Interferon-γ ELISpot  
Cohort 
Low 
Mid 
High 
Antigen 
%Response 
AVG 
%Response 
AVG 
%Response 
AVG 
HPV-16E6 
33% 
107 
50% 
243 
50% 
1341 
HPV-16E7 
17% 
198 
50% 
104 
67% 
143 
HPV-18E6 
50% 
359 
50% 
338 
83% 
664 
HPV-18E7 
33% 
159 
17% 
179 
50% 
834 
Any 
67% 
221 
67% 
210 
83% 
556 
 
1.3 
RISKS/BENEFIT ASSESSMENT 
1.3.1 
RISKS ASSOCIATED WITH CURRENT THERAPEUTIC OPTIONS 
Currently, treatment of women with cervical HSIL usually consists of either surgical removal of 
the affected tissue by CKC, LEEP, ablative therapy via laser, or cryotherapy.  All treatments for 
471

cervical HSIL are associated with a variety of short and long term general and reproductive health 
risks as listed in Table 3. 
Table 3. Risks Associated with Surgical Treatments for Cervical HSIL 
Surgical Treatments for 
Cervical HSIL 
Risks 
CKC 
LEEP 
Ablative therapy (Laser or 
Cryotherapy)  
Pain 
Exposure to anesthesia 
Heavy bleeding 
Infection 
Menstruation problems 
Cervical stenosis (can lead to alteration of squamo-columnar junction) 
Shortening of the cervix 
Decreased fertility/difficulty getting pregnant 
Cervical incompetence 
Pre-term birth and related low birth weight 
Incomplete treatment of cervical dysplasia 
Inadequate treatment of an occult early invasive cancer 
Adapted from FAQs Loop Electrosurgical Excision Procedure (LEEP) American College of Obstetricians and 
Gynecologists (2014) [11]. 
More importantly, none of the currently available surgical treatments for cervical HSIL eradicate 
the underlying cause of the high grade cervical dysplasia, persistent infection with one or more of 
the high-risk HPV types, and therefore, leaves patients at risk for recurrent cervical HSIL as well 
as high grade dysplasia of the vulva and vagina due to the potentially broader infection of the 
genitourinary area. 
Although professional guidelines typically advocate immediate excisional therapy for adults with 
cervical HSIL, scientific data indicates that the rate of progression from pre-invasive to invasive 
cervical disease is slow, typically thought to take several years [8].  The risk of a “missed 
diagnosis” of an occult early invasive cervical cancer exists for all current treatment modalities 
including surgical and ablative therapies.  Furthermore, approximately 17-18% of patients with 
high grade CIN will experience recurrence of dysplasia following surgical intervention [8], which 
illustrates that current standard of care for cervical dysplasia requires improvement.  The study 
design includes numerous safeguards to detect disease progression or the presence of an 
undiagnosed occult early invasive cervical cancer.  These include, careful selection of 
immunocompetent patients, thorough screening and baseline evaluation, frequent cervical 
colposcopy, cytology and high-risk HPV testing throughout the trial.  Investigators will be 
comprised of experienced gynecologists, who will have the discretion to obtain biopsies at any 
point if disease progression is suspected. 
1.3.2 
POTENTIAL RISKS OF STUDY PARTICIPATION 
A risk associated with VGX-3100 for the treatment of high grade cervical dysplasia are the 
injection site reactions related to the IM injection and/or electroporation.  Based on the phase 1 
472

and 2 clinical experience, the injection site reactions associated with the IM injection and 
electroporation are generally mild (e.g. erythema) and limited to a few days in duration at most.   
A second risk is the “delay” in “definitive treatment” of the high grade cervical dysplasia and the 
“missed diagnosis” of an occult early invasive cervical cancer for the VGX-3100 non-responders 
or placebo recipients, who do not spontaneously regress.  This risk is mitigated by careful serial 
cytology, HPV testing, and colposcopic exams, throughout the course of the study, and the well 
accepted understanding that cervical dysplasia progresses slowly, typically over years, which 
makes close, active follow-up possible.  Also, only investigators who are experienced in the 
management of cervical cancer will be chosen, and they will have the option of performing 
additional, ad hoc colposcopic exams and cervical biopsies if they suspect potential disease 
progression.  
A DSMB will also advise the Sponsor if it appears that the frequency of regression in the VGX-
3100 group is unacceptably low compared to the placebo group.  These measures should minimize 
the risk - even perhaps below that of standard care - of progression of the cervical HSIL and the 
risk of harboring an undiagnosed occult early invasive cervical cancer. All subjects with 
suggestion of residual disease will undergo excisional therapy (e.g. CKC, LLETZ, LEEP) at Week 
36 as part of the efficacy assessment.  Subjects whose cytology, HPV testing, ECC results (if 
applicable) and colposcopic exam suggest disease regression will undergo 4 quadrant biopsy or 4 
quadrant biopsy with ECC (based upon Tables 4 & 5) to provide histopathologic confirmation of 
regression. In the Phase 2b study, the rate at which microinvasive cancer was found in larger 
surgical excision samples in subjects who had no evidence of invasive cancer by initial biopsy was 
1.8%, (2/114 with specimens), which is consistent with and even lower than the rate of 6.7% that 
has been reported under standard of care settings [22]. 
1.3.3 
POTENTIAL BENEFITS OF STUDY PARTICIPATION 
All currently accepted treatments for high grade cervical dysplasia are surgical procedures (LEEP, 
CKC, Laser ablation) which are all associated with risks inherent with any surgical procedure 
including anesthesia, post-operative bleeding and/or infection, damage to other organs, shortening 
and/or deformation of the cervix, pain, etc.  Due to the risk of shortening and/or deformation of 
the cervix there are additional well accepted risks including cervical stenosis, infertility, cervical 
incompetence, preterm birth, and inability to visualize the transformation zone.  Additionally, none 
of the surgical treatments systemically address the underlying oncogenic root cause, the high risk 
HPV infection in the lower genital tract, which leaves an underlying risk for further disease 
manifestations and transmission of HPV. VGX-3100+ EP is not associated with any of the risks 
associated with the surgical procedures outlined above (except for pain, which is transient and 
restricted to the deltoid/quadriceps treatment site) and has demonstrated the ability to not only 
eradicate the high grade dysplasia but also the ability to eradicate the underlying HPV infection.  
Subjects receiving placebo, who represent women of child-bearing potential, may benefit from the 
opportunity to be closely managed under careful surveillance over the course of this study and 
those who regress spontaneously will be able to avoid excisional therapy. 
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2 STUDY DESIGN 
This Phase 3 study design is based upon the Phase 2b study design and results. HPV-301 is a 
prospective, randomized, double-blind, placebo controlled study to determine the efficacy, safety, 
and tolerability of VGX-3100 administered by IM injection followed by EP delivered with 
CELLECTRA™ 5PSP in adult women with histologically confirmed cervical HSIL (CIN2, CIN3) 
associated with HPV-16/18. 
A sample of approximately 198 subjects will be randomized to receive either 6 mg (in 1 ml) VGX-
3100 or placebo, each IM followed by EP, in a 2:1 ratio. This sample size provides 90% power to 
declare VGX-3100 superior to placebo, assuming, based upon Phase 2b study results, that the true 
proportion of subjects whose lesion(s) regress and whose HPV-16/18 clears is 35% and 14% for 
VGX-3100 and placebo, respectively.  
Subjects will be randomized in a stratified manner according to (a) the CIN severity observed in the 
biopsy specimens at screening (i.e. CIN2 vs. CIN3), (b) BMI category (≤25 vs. >25 kg/m2) on Day 
0, and (c) age category (<25 years vs. ≥25 years) on Day 0. To ensure CIN2 disease is not over-
represented in the study, the percentage of subjects enrolled with CIN2 will not exceed 50% of the 
total enrolled. A group of sequential allocation numbers will be designated for use by each 
participating country. 
To be eligible for the study, subjects age 18 years and above must consent to participate and have 
cervical biopsy/biopsies of the cervical lesion(s) at the time of screening. Slides of the biopsy will 
be sent to a PAC in a blinded manner to establish the presence of cervical HSIL within screening. 
In order to be eligible for continued enrollment, the PAC must assign the histologic diagnosis of 
cervical HSIL. Subjects must also have a cervical specimen test positive for HPV-16/18 by cobas™ 
HPV test to be eligible for participation in the study. 
2.1 
ENDPOINT ASSESSMENT 
In the Phase 2b study, subjects were randomized 3:1 to the VGX-3100 frozen formulation arm or 
the Placebo arm. All subjects were scheduled to receive treatment on Day 0, Week 4 and Week 12 
and undergo repeat cervical biopsy or surgical excision (i.e. LEEP, LLETZ, CKC) of the cervix at 
Week 36 to assess efficacy. The primary endpoint was histopathologic regression of cervical lesions 
to CIN1 or less at the Week 36 visit, and the secondary endpoint was clearance of HPV-16/18 in 
combination with histopathologic regression of cervical lesions to CIN1 or less.     
The primary endpoint for the Phase 3 study is based upon the results of the Phase 2b study.  Given 
that HPV persistence is an important factor in the clinical progression of dysplasia and also based 
upon the findings of the secondary objective of the Phase 2b study, the responder definition for the 
Phase 3 primary endpoint determination will take into consideration both histological regression of 
cervical HSIL and clearance of high-risk HPV-16/18.  
The proportion of subjects who achieved this endpoint in the Phase 2b study was 35% (40%) of 
VGX-3100 subjects versus 14% (15%) for placebo, in an intention-to-treat analysis and modified 
intention-to-treat analysis, respectively.  The composite endpoint of histologic regression and 
virologic clearance will be primary in the Phase 3 study, and histologic regression endpoint will be 
a secondary endpoint. 
474

2.1.1 
HISTOLOGY ASSESSMENT 
Regression of cervical HSIL will be determined by histopathological assessment of cervical tissue, 
which is considered the definitive method for diagnosis of cervical dysplasia. Digital photographs 
of acetowhite lesions are also used to document colposcopic exam findings. Tissue to be analyzed 
for evidence of histopathologic regression will be obtained at Week 36 either by excision (e.g. 
LEEP, LLETZ, CKC) or by 4 Quadrant Biopsy or by 4 Quadrant Biopsy with ECC based upon 
the assessment at Week 28 of cytology, HR HPV status, and colposcopic findings as outlined in 
Tables 4 and 5 for subjects 25 years and above and below 25 years, respectively. 
Table 4.  Minimally Required Procedure at Week 36 for Subjects Age 25 Years and Above  
Age 
Clinical and Laboratory Information at Week 28 
Minimally Required 
Procedure at Week 36a 
Colposcopy 
Cytology 
HPV-16/18 
Testing 
Quality 
Finding 
25 
and 
above 
NA 
NA 
HSIL, ASC-H, AGC, 
Carcinoma, AIS 
NA 
Tissue Excision 
unsatisfactory 
lesion 
NA 
NA 
Tissue Excision 
unsatisfactory 
no lesion 
LSIL, ASC-US 
positive 
Tissue Excision 
unsatisfactory 
no lesion 
LSIL, ASC-US 
negative 
4Q biopsy and ECC 
unsatisfactory 
no lesion 
NILM 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
LSIL, ASC-US 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
positive 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
negative 
4Q biopsy 
Table 5.  Minimally Required Procedure at Week 36 for Subjects Under 25 Years  
Age 
Clinical and Laboratory Information at Week 28 
Minimally Required 
Procedure at Week 36a 
Colposcopy 
Cytology 
HPV-16/18 
Testing 
Quality 
Finding 
18-24 
NA 
NA 
Carcinoma, AIS 
NA 
Tissue Excision 
unsatisfactory 
lesion 
NA 
NA 
Tissue Excision 
unsatisfactory 
no lesion 
HSIL, ASC-H, AGC 
NA 
Tissue Excision 
unsatisfactory 
no lesion 
NILM, ASC-US, LSIL 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
LSIL, ASC-US, HSIL, 
ASC-H, AGCb 
NA 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
positive 
4Q biopsy and ECC 
satisfactory 
NA 
NILM 
negative 
4Q biopsy 
Abbreviations: NA; not applicable because there is no impact to the decision at Week 36 due to a superseding finding; 4Q; 
four quadrant; NILM Negative for intraepithelial lesion and malignancy; ASC-US Atypical squamous cells of undetermined 
significance; AGC Atypical glandular cells; ASC-H Atypical squamous cells, cannot rule out high-grade lesion; AIS 
Adenocarcinoma-in-situ 
a Any subject with prior ECC requires a negative ECC at Week 28 to allow 4Q biopsy and ECC, at minimum, at Week 36   
b If cytology result is AGC “favor neoplasia”, tissue excision is recommended 
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2.1.2 
VIROLOGIC (HPV) ASSESSMENT 
Cervical cytology samples will be obtained to characterize HPV infection at screening, Day 0 
(prior to dosing) and Weeks 8, 15, 28, 36, 62, and 88.  Also, if there is residual tissue in the paraffin 
block after histologic diagnoses have been rendered, then unstained slides and/or the relevant 
paraffin blocks may be collected for testing of HPV-16/18. Vaginal and oropharyngeal samples 
will be obtained to characterize HPV infection at Day 0 (prior to dosing) and at Weeks 36, and 88 
to assess virologic response to treatment at sites other than the cervix. Intra-anal samples will be 
obtained (if subject consents to intra-anal sampling) to characterize HPV infection at Day 0 (prior 
to dosing) and at Week 36 to assess virologic response to treatment at sites other than the cervix. 
2.1.3 
DEFINITION OF RESPONDER AND NON-RESPONDER 
Responder and non-responder definitions (Table 6) for the primary endpoint takes into account 
both histopathologic regression of cervical HSIL and virologic (HPV-16 and/or HPV-18) 
clearance from cervical samples since HPV persistence is an important factor in the clinical 
progression of HSIL. The responder definition also excludes subjects who undergo excision or 
whose cervix is biopsied at any time between their initial dose and the Week 36 endpoint tissue 
collection. This exclusion is included to reduce the potential for artefactual increases in the 
treatment effect caused by removal of HSIL tissue and potentially HPV-16/18 by unplanned 
interval biopsies.  
To qualify as a responder, the subject must have:  
1. An acceptable histology specimen at Week 36, which is interpretable by the independent 
PAC, and  
2. An acceptable HPV ThinPrep™ sample at Week 36, with an associated valid HPV-testing 
result.   
A responder is defined as a subject with:  
1) No histologic evidence of cervical HSIL   
2) No evidence of HPV-16 and/or HPV-18 at the Week 36 evaluation  
3) The subject must not have had an unscheduled excision or biopsy sample obtained between 
initial dose and the Week 36 evaluation. 
Conversely, the following will designate the subject as a non-responder:  
1)  Histologic evidence of cervical HSIL at the Week 36 evaluation, OR  
2)  Evidence of HPV-16 or HPV-18 at the Week 36 evaluation, OR  
3)  An excision or biopsy sample obtained between initial dose and the Week 36 evaluation OR  
4)  Lack of either an acceptable Week 36 histology specimen or HPV ThinPrep™ sample.    
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Table 6.  Definition of Primary Endpoint Responder  and Non-Responder 
Responder 
Non-Responder 
Subject with no histologic evidence of cervical 
HSILa at Week 36 evaluation and no evidence of 
HPV-16 and/or HPV-18 at Week 36b 
AND 
Subject in which an excision or biopsy samplec was 
NOT obtained between initial dose up to Week 36 
primary endpoint visit 
Subject with histologic evidence of cervical HSIL, AIS, or 
cervical carcinoma at Week 36 evaluation 
OR 
Subject with evidence of HPV-16 or HPV-18 at Week 36 
OR 
Subject in which an excision or biopsy sample was 
obtained between initial dose up to Week 36 primary 
endpoint visit 
OR 
Subject with no Week 36 primary endpoint sample result 
a No evidence of HSIL is defined by histology as negative, squamous atypia, or LSIL 
b The histopathologic efficacy time frame is defined by those who have undergone a biopsy or surgical excision at any time 
starting from 14 days prior to the protocol-specified target date of Week 36.  The first tissue removal sample within the time 
frame determines the histology endpoint.  The most recent HPV clearance result prior to tissue removal, which includes results 
from the same date, within the time frame determines the HPV clearance endpoint. 
c Excludes ECC-only samples 
Responder and non-responder definitions for the secondary efficacy endpoints are detailed in Table 
7 – Table 11. 
Table 7:  Definition of Secondary Regression Endpoint Responder and Non-Responder 
Responder 
Non-Responder 
Subject with no histologic evidence of cervical 
HSILa at Week 36 visitb 
AND 
Subject in which an excision or biopsy samplec 
was NOT obtained between initial dose up to 
Week 36 visit 
Subject with histologic evidence of cervical HSIL, AIS, 
cervical carcinoma at Week 36 visit 
OR 
Subject in which an excision or biopsy samplec was obtained 
between initial dose up to Week 36 visit 
OR 
Subjects with no Week 36 visit sample result 
 
a No evidence of HSIL is defined by histology as negative, squamous atypia, or LSIL 
b The efficacy time frame is defined by those who have undergone a biopsy or surgical excision at any time starting from 14 days  
prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology 
endpoint. 
c Excludes ECC-only samples 
477

Table 8:  Definition of Secondary Complete Regression Endpoint Responder and Non-Responder 
Responder 
Non-Responder 
Subject with no histologic evidence of cervical 
HSIL squamous atypia, or LSIL at Week 36 visita 
AND 
Subject in which an excision or biopsy sampleb 
was NOT obtained between initial dose up to 
Week 36 visit 
Subject with histologic evidence of cervical HSIL, squamous 
atypia, LSIL, AIS, cervical carcinoma at Week 36 visit 
OR 
Subject in which an excision or biopsy sampleb was obtained 
between initial dose up to Week 36 visit 
OR 
Subjects with no Week 36 visit sample result 
 
a The efficacy time frame is defined by those who have undergone a biopsy or surgical excision at any time starting from 14 days 
prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology 
endpoint. 
b Excludes ECC-only samples 
 
Table 9: Definition of Secondary Non-progression Endpoint Responder and Non-Responder 
Responder 
Non-Responder 
Subject with no histologic evidence of a worsening 
of cervical condition at Week 36 visita relative to 
baseline 
AND 
Subject in which an excision or biopsy sampleb 
was NOT obtained between initial dose up to 
Week 36 visit 
Subject with histologic evidence of worsening of cervical 
condition at Week 36 visit relative to baseline 
OR 
Subject in which an excision or biopsy sampleb was obtained 
between initial dose up to Week 36 visit 
OR 
Subjects with no Week 36 visit sample result 
 
a The efficacy time frame is defined by those who have undergone a biopsy or surgical excision at any time starting from 14 days 
prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology 
endpoint. 
b Excludes ECC-only samples 
 
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Table 10:  Definition of Secondary Complete Regression and Clearance Endpoint Responder and Non-
Responder 
Responder 
Non-Responder 
Subject with no histologic evidence of cervical 
HSIL, squamous atypia, or LSILa at Week 36 visit 
and no evidence of HPV-16 and/or HPV-18 at 
Week 36 visitb 
AND 
Subject in which an excision or biopsy samplec 
was NOT obtained between initial dose up to 
Week 36 visit 
Subject with histologic evidence of cervical HSIL, squamous 
atypia, or LSIL AIS, cervical carcinoma at Week 36 visit 
OR 
Subject with evidence of HPV-16 or HPV-18 at Week 36 visit 
OR 
Subject in which an excision or biopsy samplec was obtained 
between initial dose up to Week 36 visit 
OR 
Subjects with no Week 36 visit sample result 
a No evidence of HSIL is defined by histology as negative, squamous atypia, or LSIL 
b The efficacy time frame is defined by those who have undergone a biopsy or surgical excision at any time starting from 14 days 
prior to the protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the 
histology endpoint.  The most recent HPV clearance result prior to tissue removal, which includes results from the same date, within 
the time frame determines the HPV clearance endpoint. 
c Excludes ECC-only samples 
 
Table 11:  Definition of Secondary Clearance Endpoint Responder and Non-Responder 
Responder 
Non-Responder 
Subject with no histologic evidence of HPV-16 
and/or HPV-18 at Week 36 visita 
AND 
Subject in which an excision or biopsy sampleb 
was NOT obtained between initial dose up to 
Week 36 visit 
Subject with evidence of HPV-16 or HPV-18 at Week 36 visit 
OR 
Subject in which an excision or biopsy sampleb was obtained 
between initial dose up to Week 36 visit 
OR 
Subjects with no Week 36 visit sample result 
 
 
a The efficacy time frame is defined by those who have undergone HPV testing at any time starting from 14 days prior to the 
protocol-specified target date of Week 36. The first tissue removal sample within the time frame determines the histology endpoint.  
The most recent HPV clearance result prior to tissue removal, which includes results from the same date, within the time frame 
determines the HPV clearance endpoint. 
b Excludes ECC-only samples 
 
 
479

 
 
2.1.4 
IMMUNOGENICITY ASSESSMENT 
Humoral and cell mediated immune responses in response to VGX-3100 treatment will be 
evaluated in blood samples taken at baseline (both screening as well as Day 0 prior to dosing) and 
at Weeks 15 and 36. Cervical tissue samples will also be analyzed for evidence of elevated immune 
responses at Week 36 as compared to baseline (screening).   
If there is residual tissue in the paraffin block after histologic diagnoses have been rendered, then 
unstained slides and/or the relevant paraffin blocks may be collected for immunohistochemistry 
(IHC). Whenever possible, these studies may be performed on tissue sections from the diagnostic 
screening biopsy (pre-dose) and from tissue obtained post-dose(s) (Week 36). 
2.2 
TREATMENT PLAN 
The three dose regimen of VGX-3100 appeared to be safe and well tolerated in the Phase 2b study, 
therefore all eligible subjects who consent to participate in the Phase 3 study will receive the same 
three 6 mg doses of VGX-3100 refrigerated formulation or placebo administered in 1 mL IM 
(deltoid, preferred site, or anterolateral quadriceps, alternate site), each followed immediately by EP 
with the CELLECTRA™ 5PSP device. The first study treatment will be administered on Day 0, the 
second at Week 4, and the third (final) study treatment will be administered at Week 12 which is 
consistent with the Phase 2b study. The first study treatment will be given as soon as possible 
following confirmation of the cervical HSIL diagnosis and HPV-16/18 status but no more than 10 
weeks following collection of the subject’s biopsy specimen used for diagnosis by the PAC during 
screening, contemporaneous with the positive testing for HPV-16/18. 
2.3 
SAFETY MONITORING PLAN 
Although cervical HSIL is thought to require years to progress to cervical cancer, subjects in the 
Phase 2b study were followed closely throughout. HPV testing (Weeks 14 and 24), cytology (Week 
14) and colposcopy (Week 24) were all mandatory during the observation period prior to obtaining 
tissue for determination of the primary histologic endpoint at Week 36. Investigators were also 
instructed to perform additional testing (including biopsy) if disease progression was suspected. 
These instances were infrequent as only 11 unscheduled biopsies were deemed necessary over the 
course of the Phase 2b study. In addition, the rate at which occult microinvasive cancer was 
discovered after 36 weeks was less frequent than what is reported in the literature [22]. Both 
observations would imply that the mandatory monitoring employed in the Phase 2b study was 
sufficient; however cervical disease will be monitored even more closely in this Phase 3 study. 
Colposcopy, cytology and HPV testing will be required at 8 to 14 week intervals throughout the 
observation period leading up to the primary endpoint 36 weeks after the first dose. Although less 
frequent monitoring may be adequate, the more frequent monitoring is designed to afford an even 
wider margin of safety and an opportunity to explore predictors of efficacy.     
Safety monitoring will include: 
• Local and systemic events for 7 days following each treatment as noted on a Participant Diary 
Card (PDC). 
480

• All adverse events including SAEs, UADEs, and other unexpected AEs for the duration of the 
study; 
In the Phase 2b study, the safety profile was carefully evaluated and treatment with VGX-3100 was 
well-tolerated based on observations through Week 88 in all subjects. The most common adverse 
events were administration-site reactions, which included pain, tenderness, erythema and swelling, 
and were generally mild and limited to a few days in duration.  Only erythema showed a statistically 
higher incidence in VGX-3100 (78%) vs. placebo (57%) in the 7- and 28-day periods after a dose. 
One additional AE, sinusitis, was also statistically significantly increased over the course of the 
entire study period but resolved without sequelae in the VGX-3100 arm compared to the Placebo 
arm (10% vs. 0%).      
As outlined above, safety monitoring and visit frequency has been designed to take into account the 
potential risk of delay in the usual treatment of the high grade cervical dysplasia and also the 
potential for a missed diagnosis of an occult early invasive cervical cancer for the VGX-3100 non-
responders or placebo recipients, who do not regress.  Serial cytology, HPV testing, and colposcopic 
exams are applied throughout the course of the study with the well accepted understanding that 
cervical dysplasia progresses slowly, typically over years, which makes close, active follow-up 
possible.  All subjects with suggestion of residual disease will undergo excisional therapy by LEEP 
or CKC at Week 36 as part of the efficacy assessment.  Subjects whose cytology, HPV testing, ECC 
results (if applicable) and colposcopic exam suggest disease regression will undergo 4 quadrant 
biopsy or 4 quadrant biopsy with ECC (based upon Table 4 and 5) to provide histopathologic 
confirmation of regression. The use of a 4 quadrant biopsy in Phase 3 is a change from the approach 
used in Phase 2b to optimize the evaluation of histopathologic regression taking into consideration 
the inherent limitations of colposcopy and tissue biopsy samples in the absence of visible lesions 
[23].  
In the Phase 2b study, the cervical tissue sample was initially read by a local pathologist and/or 
central pathology laboratory for rapid local medical management.  The definitive histopathologic 
assessment was determined by an independent blinded Pathology Adjudication Panel, comprised of 
experienced cytopathologists from independent medical centers in the US.  Seven reports included 
the terms ‘(adeno)squamous cell carcinoma’ or the premalignant condition of ‘adenocarcinoma in 
situ’ (AIS) in the final Phase 2b study results which included all 88 weeks of follow up. Three of 
the cases were reported as AIS, (2 VGX-3100, 1 placebo), out of which two cases (1 VGX-3100, 1 
placebo) were confirmed as AIS by the Pathology Adjudication Panel. AIS is a pre-invasive 
glandular lesion which can be difficult to capture on standard of care screening with initial punch 
biopsy and is more commonly identified by full excision (e.g. LEEP, conization).  There were four 
reports that included the term squamous cell carcinoma, of which two were confirmed by the 
Pathology Adjudication Panel, both in the VGX-3100 group.  The other two cases (1 VGX-3100, 1 
placebo) were diagnosed as CIN3 by the Pathology Adjudication Panel.  The rate at which 
microinvasive cancer was found in larger surgical excision samples in subjects who had no evidence 
of invasive cancer by initial biopsy was 1.8%, (2/114 with specimens), which is consistent with and 
even lower than the rate of 6.7% that has been reported under standard of care settings [22].  
481

Importantly, investigators in the Phase 3 study will be chosen only if they are experienced in the 
management of cervical cancer as was the case in the Phase 2b study. Phase 3 investigators are 
instructed to perform additional, ad hoc colposcopic exams and cervical biopsies if they suspect 
potential disease progression. Subjects that undergo an unscheduled biopsy will be classified as a 
non-responder in the efficacy analysis as outlined in Table 6. These measures should minimize the 
risk of progression of cervical HSIL and the risk of harboring an undiagnosed occult early invasive 
cervical cancer. The frequency of close monitoring by experienced investigators should minimize 
the risk of cancer progression on the study what is expected with standard of care.   
2.3.1 
DATA AND SAFETY MONITORING BOARD (DSMB) 
An independent Data and Safety Monitoring Board (DSMB) will provide safety oversight.  The 
DSMB will be scheduled to meet quarterly. If there are no new safety data or regression/clearance 
results to review for a quarterly scheduled meeting the DSMB will be notified and the meeting 
may be cancelled; ad hoc meetings may be scheduled to review new data as applicable. The DSMB 
will be charged with advising the Sponsor if there appears to be a safety issue and with advising 
the Sponsor if it appears that the proportion of the subjects with regression in the VGX-3100 group 
is unacceptably low compared to the placebo group; no formal interim analysis will be performed 
for this purpose. 
2.4 
LONG TERM FOLLOW UP PLAN 
In the Phase 2b study, all subjects were scheduled to be followed for 1 year after the histopathologic 
assessment for the primary endpoint (to study Week 88). The establishment of efficacy based on 
histopathologic evidence dictated the removal of tissue at week 36 by either punch biopsy (ies) or 
more extensive surgical resection (i.e. LEEP, CKC). Subjects with colposcopic evidence of residual 
disease were to undergo LEEP/CKC. A higher proportion of patients who received placebo had a 
LEEP performed than those who received VGX-3100 (Table 12). 
Cytology and HPV-16/18 clearance from the cervix was to be assessed at study Weeks 62 and 88 to 
evaluate for recurrence of dysplasia and HPV infection after removal of tissue at Week 36.  Overall, 
in the phase 2b study, the majority of subjects had improved cytology and had cleared their 
underlying HPV-16/18 cervical infection by the Week 62 and 88 visits. For Weeks 62 and 88, there 
were no clinically meaningful differences noted between the subjects who received an excisional 
treatment (e.g. LEEP, CKC) and those that showed histopathologic regression and therefore only 
underwent a biopsy, as shown in Table 8 which summarizes the HPV and cytology results following 
Week 36.  
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Table 12.  HPV-003 HPV and Cytology Results at Weeks 36, 62 and 88, mITT Population 
Week
Testa
VGX-3100
Placebo
LEEP/CKCb
%(n/N)
Biopsyc
%(n/N)
LEEP/CKC
%(n/N)
Biopsy
%(n/N)
36
HPV
41% (19/46)
63% (36/57)
29% (6/21)
29% (5/17)
36
Pap
NA
NA
NA
NA
62
HPV
89% (50/56)
82% (42/51)
96% (27/28)
82% (9/11)
62
Pap
93% (52/56)
100% (51/51)
93% (26/28)
82% (9/11)
88
HPV
89% (48/54)
89% (42/47)
89% (24/27)
100% (10/10)
88
Pap
96% (52/54)
91% (43/47)
85% (23/26)
100% (11/11)
Abbreviations: NA, not applicable, Pap smear was not done at Week 36
a  HPV =  HPV-16/18 testing; Pap = cytology testing 
b LEEP or CKC done, at or before the study week as specified 
c Only biopsy done, at or before the study week as specified
Clearance of HPV-16/18 from the cervix was observed in both treatment groups (Figure 1a) at 
similar rates until after the second dose when clearance in the VGX-3100 recipients continued to 
rise while the rate appeared to plateau in the placebo group. 
Figure 1.  HPV-16/18 Clearance and Pap Smear Findings in Phase 2b mITT Population by 
Treatment Group
At Week 36, clearance was significantly higher among VGX-3100 subjects that had biopsy (63%) 
versus LEEP/CKC (41%), which likely reflects the association between clearance of the underlying 
HPV infection and the likelihood of having signs indicative of regression by colposcopic 
exam. HPV-16/18 clearance data (mITT population) post-Week 36 are described as follows: HPV-
Week 14
Week 62
Week 88
a.
b.
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16/18 clearance at Week 62 was 89% (50/56) for VGX-3100 post-LEEP/CKC, 82% (42/51) for 
VGX-3100 post Biopsy only, 96% (27/28) for Placebo post-LEEP/CKC, and 82% (9/11) for Placebo 
post Biopsy only.  HPV-16/18 clearance at Week 88 was 89% (48/54) for VGX-3100 post-
LEEP/CKC, 89% (42/47) for VGX-3100 post Biopsy only, 89% (24/27) for Placebo post-
LEEP/CKC, and 100% (10/10) for Placebo post Biopsy only. 
The majority of subjects had cleared their underlying cervical HPV-16/18 infection by Week 62 
without meaningful changes through Week 88, and without meaningful differences between groups. 
Forty-seven of 53 (89%) and 46 of 49 (94%) subjects at Weeks 62 and 88, respectively (mITT 
population) with histopathologic evidence of CIN2/3 regression (regressors) in the VGX-3100 
treatment group experienced HPV-16/18 clearance. Despite the use of therapeutic resection for 
many VGX-3100 recipients whose CIN2/3 did not regress by Week 36 (non-regressors), HPV-16/18 
clearance rates were notably lower (85% at Week 88) compared to regressors.  
In the subjects who initially cleared HPV-16/18 by Week 36, only one HPV-16/18 recurrence was 
identified at the Week 62 and 88 evaluations. Specifically, one subject in the VGX-3100 group 
whose lesion was biopsied at Week 36 had HPV types 16 and 82 and CIN2 at screening, was HPV 
negative at Week 36, but tested HPV type 16 positive at Week 62, and then cleared HPV-16 at Week 
88. The subject showed histopathologic regression at Week 36. No recurrences were identified in 
the eleven subjects in the placebo group whose lesions were biopsied at Week 36 with valid HPV 
data at Weeks 62 or 88. There were no (0/51) recurrences identified in the VGX-3100 treated group 
at Week 88. Overall, these virologic clearance findings support that study subjects had no increased 
risk as compared to standard of care.  
Cytology (mITT population) post-Week 36 are described as follows: Improvement compared to 
study entry for Pap smear cytology results at Week 62 were 93% (52/56) for VGX-3100 post-
LEEP/CKC, 100% (51/51) for VGX-3100 post-Biopsy only, 93% (26/28) for Placebo post-
LEEP/CKC, and 82% (9/11) for Placebo post-Biopsy only. At Week 62, cytopathologic 
improvement was reported for 104 of 125 (83%) subjects in the VGX-3100 treatment group and 34 
of 42 (83%) subjects in the placebo treatment group (mITT population).  
There were no instances of possible progression, and all cases that did not meet the definition of 
improvement were due to either no change from baseline, sample considered not evaluable, or no 
data available.  Improvement compared to study entry for Pap smear cytology results at Week 88 
were 96% (52/54) for VGX-3100 post-LEEP/CKC, 91% (43/47) for VGX-3100 post-Biopsy only, 
85% (23/26) for Placebo post-LEEP/CKC, and 100% (11/11) for Placebo post-Biopsy only.  At 
Week 88, possible progression (atypical glandular cells) was reported in a single Placebo subject in 
the post-LEEP/CKC group (3%) and no subjects treated with VGX-3100. All other cases that did 
not meet the definition of improvement were due to either no change from baseline, sample 
considered not evaluable, or no data available. The majority of subjects showed improvement, and 
there was no meaningful difference between the Week 62 and Week 88 evaluations.   These findings 
support that study subjects had no increased risk of progression based upon cytology as compared 
to standard of care. 
The protocol-specified removal of dysplastic cervical tissue at Week 36 by either method 
substantially affected the clearance of HPV-16/18 and normalization of cytologic findings as 
expected, regardless of treatment group (Figure 1a, b). HPV-16/18 clearance rises at a sharp rate 
484

after tissue is removed at Week 36 whether the excision is wide (e.g. LEEP, LLETZ, CKC) or more 
limited (biopsy). Notably, the method of tissue collection at the Week 36 endpoint did not 
appreciably affect the HPV-16/18 clearance rates beyond Week 36 (Table 8).   Based upon the Phase 
2b results, the risk of progression or recurrence of cervical dysplasia is low and comparable to the 
rates observed post-LEEP/CKC in clinical practice.  The long term follow up planned for this Phase 
3 study will include safety, cytology and HPV-16/18 testing at 6 months and also 1 year following 
the Week 36 histopathologic assessment, which is highly conservative given the expectation that 
few subjects will have persistent evidence of disease after the removal of tissue at Week 36 which 
is supported by the findings in the Phase 2b study. 
 
2.5 
GROUP-LEVEL UNBLINDING 
Group-level unblinded (VGX-3100, Placebo) summaries and analyses of efficacy will be produced 
once the primary endpoint Week 36 visit 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 88 visit.  The summaries and analyses will allow the 
Sponsor to have results with respect to the primary endpoint and all other efficacy endpoints 
corresponding to the cervix and the Week 36 visit on which to make decisions regarding the VGX-
3100 program, while still gathering secondary and exploratory endpoint and safety data through 
the final Week 88 visit.  The planned set of summaries and analyses is comprised of a) the primary 
composite endpoint of histopathologic regression and virologic clearance, b) the secondary 
endpoint of histopathologic regression, c) the secondary endpoint of virologic clearance, d) the 
secondary composite endpoint of histopathologic regression to normal and virologic clearance, e) 
the secondary endpoint of histopathologic regression to normal, and f) the secondary endpoint of 
histopathologic non-progression. None of these summaries or analyses will be provided if the total 
count of subjects who experience the event of interest is greater than 0 and the count for any 
treatment group relative to this total count is less than 3% for a given summary/analysis.  Also, 
items a) through f) are planned to be produced in the order in which they are listed, but as there are 
intersecting endpoints among these items, items among b) through f) will not be produced if the 
difference in total count of subjects who experience the event of interest is greater than 0 and the 
count for any treatment group is 0, relative to any preceding item in the set.  The group-level 
unblinded (VGX-3100, Placebo) production of the summaries and analyses will not include anyone 
directly involved with the trial or any additional unblinded personnel; only the external Contract 
Research Organization (CRO), PPD, which has already been 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. 
 
3 HYPOTHESIS AND STUDY OBJECTIVES 
3.1 
HYPOTHESIS 
Three 6 mg doses of VGX-3100 (DNA Plasmids encoding E6 and E7 proteins of HPV-16 and HPV-
18) delivered IM followed by EP with CELLECTRA™ 5PSP to adult women with histologically 
485

confirmed HSIL of the cervix, associated with HPV-16 and/or HPV-18 will result in a higher 
percentage of women with histopathological regression of cervical HSIL lesions to no evidence of 
cervical HSIL and virologic clearance of HPV-16/18 compared to placebo delivered IM followed 
by EP with CELLECTRA™ 5PSP at the Week 36 visit.4 
3.2 
PRIMARY OBJECTIVE AND ENDPOINT 
Objective 
Endpoint 
Determine 
the 
efficacy 
of 
VGX-3100 
compared with placebo with respect to 
combined 
histopathologic 
regression 
of 
cervical HSIL and virologic clearance of 
HPV-16 and/or HPV-18 
Proportion of subjects with no evidence of  
cervical HSIL on histology (i.e. biopsy or 
excisional treatment) and no evidence of HPV-16 
and/or HPV-18 in cervical samples by type 
specific HPV testing at Week 36 visit 
4 The time frame is defined as any time starting from 14 days prior to the protocol-specified target date of Week 36. 
486

3.3 
SECONDARY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Secondary Objectives 
Associated Secondary Endpoints 
1. Evaluate the safety and tolerability of 
VGX-3100 delivered IM followed by EP 
with CELLECTRA™ 5PSP 
1a. Incidence and severity of local and systemic 
events for 7 and 28 days following each 
investigational treatment  and for the duration of 
the study (through Week 88 visit) 
1b. Incidence and severity of all adverse events 
including SAEs (e.g. SUSAR, UADE and other 
unexpected AEs) for the duration of the study 
(through Week 88 visit) 
2.Determine VGX-3100 efficacy compared 
to placebo as measured by histopathologic 
regression of cervical HSIL  
2. Proportion of subjects with no evidence of  
cervical HSIL  on histology (i.e. biopsies or 
excisional treatment) at Week 36 visit 
3. Determine VGX-3100 efficacy compared 
to placebo as measured by virologic 
clearance of HPV-16 and/or HPV-18 
3. Proportion of subjects with no evidence of HPV-
16 and/or HPV-18 in cervical samples  by type 
specific HPV testing at Week 36 visit 
4. Determine VGX-3100 efficacy compared 
to placebo as measured by complete 
histopathologic regression of   cervical 
HSIL to normal 
4. Proportion of subjects with no evidence of Low 
grade squamous intraepithelial lesion (LSIL) or 
HSIL (i.e.  no evidence of CIN1, CIN2 or CIN3) 
on histology (i.e. biopsies or excisional 
treatment) at Week 36 visit 
5. Determine VGX-3100 efficacy compared 
to placebo as measured by both complete 
histopathologic regression of  cervical 
HSIL to normal and virologic clearance of 
HPV-16 and/or HPV-18 
5. Proportion of subjects with no evidence of LSIL 
or HSIL (i.e. no evidence of CIN1, CIN2 or CIN3 
on biopsies or excisional treatment) on histology 
(i.e. biopsies or excisional treatment) and no 
evidence of HPV-16 and/or HPV-18  by type 
specific HPV testing at Week 36 visit 
6. Determine the efficacy of VGX-3100 
compared with placebo as measured by 
histopathologic non-progression 
6. Proportion of subjects with no progression of 
cervical HSIL to cervical carcinoma from 
baseline on histology (i.e. biopsies or excisional 
treatment) at Week 36 visit 
7. Describe the clearance of HPV-16 and/or 
HPV-18 
infection 
from 
non-cervical 
anatomic locations 
7. Proportion of subjects who have cleared HPV-16 
and/or HPV-18 on specimens from non-cervical 
anatomic locations (i oropharynx, vagina and 
intra-anal) at Week 36 Visit 
8. Determine the humoral and cellular 
immune response to VGX-3100 compared 
with placebo  at post dose 3, and Week 36 
visits as assessed relative to baseline 
8a. Levels of serum anti-HPV-16 and anti-HPV-18 
antibody concentrations at Weeks 15, and 36 
visits 
8b. Interferon-γ ELISpot response magnitudes at 
baseline, Weeks 15, and 36 visits 
8c. Flow Cytometry response magnitudes at 
baseline and Week 15 visits 
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3.4 
EXPLORATORY OBJECTIVES AND ASSOCIATED ENDPOINTS 
Exploratory Objectives 
Associated Endpoints 
1. Evaluate tissue immune responses to 
VGX-3100 in cervical samples 
1. Assessment of markers including but not limited 
to CD8+ and FoxP3+ infiltrating cells. 
Additional assessments may include 
visualization of Granulysin, Perforin, CD137, 
CD103 and PD-L1 in cervical tissue as sample 
allows.  Markers listed here may change as new 
relevant information becomes available 
2. Describe 
association 
of 
microRNA 
(miRNA) profiles, DNA methylation 
profile, previous colposcopy, cytology 
and HPV testing results with Week 36 
histologic regression  
2. Colposcopy, cytology, and HPV test results 
(Weeks 8, 15 and 28 visits), miRNA profile 
(baseline, Week 8) and DNA methylation profile 
(baseline, Week 15) in conjunction with 
histologic regression of cervical HSIL at Week 
36 visit 
3. Describe the durability of virologic 
clearance of HPV-16 and/or HPV-18 for 
subjects 
treated 
with 
VGX-3100 
compared with those treated with placebo 
3. Proportion of subjects with no evidence of HPV-
16 and/or HPV-18 by type specific HPV testing 
at Weeks 62 and 88 visits 
4. Describe the patient-reported outcomes 
for subjects treated with VGX-3100 
4. Patient-reported outcome questionnaires will be 
self-administered at baseline, Weeks 4, and 12, 
8-14 days following each dose, and at Weeks 28, 
36, 40 and 88 by subjects enrolled in US, 
Canada, Mexico, Germany and UK. 
5.  Determine whether a tissue-based score 
derived using an immunologic markers 
(Immunoscore) at baseline is predictive 
for histological and virological response 
to VGX-3100  at Week 36 
 6    Immunoscore results for VGX-3100 treated    
subjects and in conjunction with histological and 
virological outcomes at Week 36 
 
4 SELECTION OF SUBJECTS 
4.1 
INCLUSION CRITERIA 
Each subject must meet all of the following criteria to be enrolled in the study: 
1. Women aged 18 years and above and meets minimum age of consent per local regulations); 
2. Confirmed cervical infection with HPV types 16 and/or 18 at screening by cobasTM  HPV test;  
3. Cervical tissue specimen/slides provided to Study Pathology Adjudication Committee for 
diagnosis must be collected within 10 weeks prior to anticipated date of first dose of study drug; 
4. Histologic evidence of cervical HSIL as confirmed by PAC at screening; 
5. Must understand, agree and be able to comply with the requirements of the protocol. Subjects 
must be willing and able to provide voluntary consent to participate and sign a Consent Form 
prior to study-related activities; 
488

6. Must be judged by Investigator to be an appropriate candidate for the protocol-specified 
procedure (i.e. excision, 4-quadrant biopsy with ECC, or 4-quadrant biopsy) required at Week 
36; 
7. Satisfactory colposcopy at screening, defined as full visualization of the squamo-columnar 
junction (Type I or II transformation zone) and complete visualization of the upper limit of 
aceto-white epithelium or suspected CIN disease; 
8. Cervical lesion that is accessible for sampling by biopsy instrument (e.g. Mini-Tischler device); 
9. Cervical lesion of adequate size to ensure that a visible lesion remains after screening biopsy; 
10. Must meet one of the following criteria with respect to their reproductive capacity: 
a) Is post-menopausal as defined by spontaneous amenorrhea for more than 12 months 
b) Is surgically sterile due to absence of ovaries or due to a bilateral tubal ligation/occlusion 
performed more than 12 months prior to screening 
c) WOCBP is willing to use a contraceptive method with failure rate of less than 1% per year 
when used consistently and correctly from screening until Week 36. The following methods 
are acceptable: 
i. Hormonal contraception: either combined or progestin-alone including oral 
contraceptives, injectable, implants, vaginal ring, or percutaneous patches. Hormonal 
contraceptives must not be used in subjects with a history of hypercoagulability (e.g., 
deep vein thrombosis, pulmonary embolism). 
ii. Abstinence from penile-vaginal intercourse when this is the subject’s preferred and 
usual lifestyle 
iii. Intrauterine device or intrauterine system 
iv. Male partner sterilization at least 6 months prior to the female subject’s entry into the 
study, and this male is the sole partner for that subject 
11. Normal screening ECG or screening ECG with no clinically significant findings, as judged by 
the investigator. 
4.2 
EXCLUSION CRITERIA 
Subjects meeting any of the following criteria will be excluded from enrollment in the study: 
1. Microscopic or gross evidence of adenocarcinoma-in-situ (AIS), high grade vulvar, vaginal 
(inclusive of cervical HPV-related lesions that extend into the vaginal vault), or anal 
intraepithelial neoplasia or invasive cancer in any histopathologic specimen at screening; 
2. Cervical lesion(s) that cannot be fully visualized on colposcopy due to extension high into 
cervical canal at screening; 
3. ECC shows a potentially untreated carcinoma, untreated HSIL, indeterminate, or insufficient 
for diagnosis (ECC is not required to be performed as part of study screening); 
4. Treatment for cervical HSIL within 4 weeks prior to screening; 
5. Pregnant, breastfeeding or considering becoming pregnant through Week 36 visit; 
6. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are 
allowed, e.g. Gardasil™, Silgard™, Cervarix™); 
7. Presence of any unresolved abnormal clinical screening laboratory values of Grade 1 or greater 
per CTCAE v 4.03 and deemed clinically significant by the investigator within 45 days prior 
to Day 0; 
489

8. Immunosuppression as a result of underlying illness or treatment including: 
a) History of or positive serologic test for HIV at screening (performed within 45 days prior to 
Day 0) 
b) Primary immunodeficiencies 
c) Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent; (use of inhaled, otic, and ophthalmic corticosteroids are allowed) 
d) 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) 
e) History of solid organ or bone marrow transplantation 
f) Any prior history of other clinically significant immunosuppressive or clinically diagnosed 
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. 
g) Subjects who are malnourished (i.e. medically significant unintentional weight loss, 
kwashiorkor, or marasmus) based on screening labs, medical history and physical exam per 
investigator’s clinical judgment. 
9. Receipt of any non-study, non-live vaccine within 2 weeks of dosing; 
10. Receipt of any non-study, live vaccine (e.g. measles vaccine) within 4 weeks of dosing; 
11. Current or history of clinically significant, medically unstable disease which, in the judgment 
of the investigator, would jeopardize the safety of the subject, interfere with study assessments 
or endpoint evaluation, or otherwise impact the validity of the study results (e.g. chronic renal 
failure; angina, myocardial ischemia or infarction, class 3 or higher congestive heart failure, 
cardiomyopathy, or clinically significant arrhythmias); 
12. Malignancy or systemic treatment for malignancy within 2 years of screening (with the 
exception of curatively treated, localized anogenital cancers and superficial skin cancers which 
are allowed);  
13. Presence of acute or chronic bleeding or clotting disorder that would contraindicate IM 
injections, or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of 
Day 0; 
14. History of seizures unless seizure free for 5 years with the use of one or fewer antiepileptic 
agents; 
15. Sustained, manually confirmed, sitting systolic blood pressure >150 mm Hg or <90 mm Hg or 
a diastolic blood pressure >95 mm Hg at Screening or Day 0; 
16. Resting heart rate <50 bpm (unless attributable to athletic conditioning) or >100 bpm at 
screening or Day 0; 
17. Prior major surgery within 4 weeks of Day 0; 
18. Participation in an interventional study with an investigational compound or device within 30 
days of signing informed consent; participation in an observational study is permitted; 
19. Less than two acceptable sites available for IM injection considering the deltoid and 
anterolateral quadriceps muscles; 
20. Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 
21. Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located 
in ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 
490

22. Metal implants or implantable medical device within the electroporation area; 
23. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere 
with adherence to study requirements; 
24. Prisoner or subject who is compulsorily detained (involuntarily incarcerated) for treatment of 
either a psychiatric or physical (i.e. infectious disease) illness; 
25. Active military service personnel; 
26. Study-related staff or family member of study-related staff; 
27. 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 STUDY SUBJECTS 
4.3.1 
CRITERIA FOR DISCONTINUATION OF INVESTIGATIONAL PRODUCT 
Subjects who manifest Grade 4 toxicity attributable to the study treatment will be discontinued 
from the study treatment.  Subjects will not receive further study treatment but will be encouraged 
to continue follow-up safety assessment through study discharge and not discontinue from the 
study.  
If a subject manifests Grade 3 toxicity attributable to the study treatment, the medical monitor and 
Investigator will discuss whether further treatment should be continued for that subject.  
4.3.2 
CRITERIA FOR WITHDRAWAL FROM THE STUDY 
All randomized subjects should be encouraged to complete all study treatments and follow-up 
visits. A subject will be considered to have completed the study when she completes all scheduled 
study treatments and follow-up visits. However, a subject may voluntarily withdraw from study 
participation at any time or be withdrawn at any time at the discretion of the investigator for any 
maternal obstetrical or medical complications after consultation with the medical monitor. 
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. The site should also counsel the 
subject on the importance of maintaining the assigned visit schedule for follow-up and treatment 
of HSIL (CIN2, CIN3), and ascertain whether or not the subject wishes to and/or should continue 
in the study based on previous noncompliance. 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. 
4.3.3 
SPONSOR NOTIFICATION OF DISCONTINUATION/ WITHDRAWAL  
The investigator or study coordinator must notify the Sponsor within 24 hours if a subject has been 
discontinued/withdrawn due to an AE. If a subject discontinues from the study or is withdrawn 
from the study prior to study completion, all applicable activities scheduled for the final study visit 
should be performed at the time of discontinuation. The investigator will make every effort to have 
491

all scheduled immune assessment blood samples collected as indicated in the Schedule of Events 
in the synopsis, Table 1. Any AEs and/or SAEs present at the time of discontinuation/withdrawal 
should be followed in accordance with the safety requirements outlined in section 7.1 – Safety 
Parameters. 
4.3.4 
REASON FOR DISCONTINUATION/WITHDRAWAL 
The primary reason for a subject discontinuing further dosing or withdrawal from the study itself 
is to be selected from the following standard categories and recorded on the CRF: 
• Adverse Event (Adverse Reaction): Clinical or laboratory events occurred that, in the medical 
judgment of the investigator for the best interest of the subject, are grounds for discontinuation. 
This includes serious and non-serious adverse events regardless of relation to study drug. 
• Death of subject  
• Subject voluntarily withdrew consent: The subject desired to withdraw from further 
participation in the study in the absence of an investigator-determined medical need to 
withdraw. If the subject gave a reason for withdrawal, it must be recorded on the CRF. This 
reason does not allow for further data collection and should not be selected if follow-up data 
collection of this subject is anticipated by the subject. 
• Investigator decision to withdraw the subject from participation: Investigator determined a 
medical need to withdraw the subject. Investigator must consult the Sponsor’s Medical 
Monitor before withdrawing a subject from participation in the study 
• Protocol Violation: The subject’s findings or conduct failed to meet the protocol entry criteria 
or failed to adhere to the protocol requirements (e.g., treatment noncompliance, failure to 
return for defined number of visits). The violation should be discussed with the Sponsor’s 
Medical Monitor prior to discontinuation of study treatments or study withdrawal. 
• Lost to Follow-up: The subject fails to attend study visits and study personnel are unable to 
contact the subject after repeated attempts including telephone calls, letter sent by certified 
mail or equivalent. 
• Other: The subject was terminated for a reason other than those listed above, such as the 
termination of the study by the Sponsor. 
4.3.5 
SUPPLEMENTATION OF STUDY SUBJECTS 
If more than 10% of subjects from randomization of study treatment discontinue prior to the Week 
36 primary endpoint procedures, then supplementation of study subjects will be considered. 
5 STUDY TREATMENT 
5.1 
INVESTIGATIONAL PRODUCTS 
Investigational product (IP) 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. The active and placebo 
formulations to be used in this study are described in Table 13. Both IPs will presented in clear glass 
cartridges and will be injected intramuscularly. 
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VGX-3100 and placebo will be provided by Inovio Pharmaceuticals, Inc. or its designee. 
Table 13. Investigational Products 
Product 
Formulation 
Dose 
VGX-3100 
6 mg (1:1 mix of SynCon™ HPV-16 E6/E7 and HPV-18 E6/E7 plasmids) in 150 mM 
sodium chloride and 15 mM sodium citrate 
1 mL 
Placebo 
150 mM sodium chloride and 15 mM sodium citrate 
1 mL 
5.2 
BLINDING 
This study is double-blinded with blinding maintained throughout the study by use of identical 
packaging for both the active product and the placebo. There is no difference in appearance for both 
the active product and the placebo.  
The investigator may request to unblind a subject’s treatment assignment in case of an emergency 
or serious medical condition when knowledge of the study treatment is essential for proper clinical 
management of the subject, as judged by the investigator. It is preferred, but not required, that the 
investigator first contact the Medical Monitor to discuss options before unblinding the subject’s 
treatment assignment.  In case of non-emergency, investigator must contact Medical Monitor to 
discuss the options before unblinding the subject’s treatment assignment.  
The Sponsor’s or designee’s pharmacovigilance staff may unblind the treatment assignment for any 
subject with an SAE, UADE, or AE of interest. No personnel directly involved with the study will 
be unblinded.  If expedited regulatory reporting is required for an event, the report may be submitted 
to regulatory authorities with the subject’s treatment assignment, in accordance with local 
regulations. 
5.3 
PACKAGING AND LABELING OF INVESTIGATIONAL PRODUCT 
Each cartridge will be labeled with a single-panel label and then individually packaged within a 
pouch that will contain an additional, double-panel label with tear-off. Both VGX-3100 and placebo 
labels will include, at minimum, the following information in Table 14:   
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Table 14. Example Labels for Investigational Product 
Cartridges 
(primary container) 
Pouches 
(secondary packaging) 
VGX-3100 or Placebo 
Insert cap end 
IM administration 
Sponsor name 
LABEL BODY 
Material ID/Study ID 
VGX-3100 or Placebo 
Single-use cartridge containing 1ml 
IM administration via CELLECTRA® 5PSP 
Store at 5°C, expiration date 
Caution Statement  
Sponsor name and address 
LABEL TEAR OFF 
Material ID/Study ID 
VGX-3100 or Placebo 
Patient ID: _______________ 
Date (DD/MMM/YYYY): _______________ 
Must be used by (time): _______________ 
5.4 
HANDLING OF INVESTIGATIONAL PRODUCT 
Inovio Pharmaceuticals, Inc. will be responsible for assuring the quality of the IP is adequate for 
the duration of the trial. Unless otherwise specified, IP will be shipped in a refrigerated condition 
with a temperature monitoring device. If the temperature monitoring device denotes temperatures 
outside the pre-specified range for any product, the Sponsor, or its designee should be contacted 
immediately. 
Immediately upon arrival, IPs should be transferred from the shipping container into 2–8 °C (36-46 
°F) storage, in a secure area, according to local regulations. The Sponsor should be notified of any 
deviations from this recommended storage condition.  
Refrigerator temperature logs must be maintained at the clinical site and temperatures must be 
recorded and monitored regularly. 
5.5 
DISPENSING OF INVESTIGATIONAL PRODUCT 
It is the responsibility of the Investigator to ensure that the IP is only dispensed to study subjects. It 
must be dispensed only from official study sites by authorized personnel according to local 
regulations. 
When a subject is eligible for randomization, remove the pouch from the refrigerator and allow to 
reach room temperature. The product cartridge must not be removed from the pouch until 
immediately prior to administration. The pouch must not be discarded until 1) administration is 
completed and 2) all pertinent information from the pouch label has been documented in source.  
The product must be used within 4 hours of removal from the refrigerator. 
The device user manual and instructions for use will inform clinical personnel about placement of 
the IP cartridge into the device, as well as the steps for injection and electroporation. 
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5.6 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
It is the responsibility of the Investigator to ensure that a current record of investigational product 
is maintained at the study site. Records or logs must comply with applicable regulations and 
guidelines, and should include: 
• 
Amount received and placed in storage area; 
• 
Amount currently in storage area; 
• 
Label ID number and use date or expiry date; 
• 
Dates and initials of person responsible for each investigational product inventory 
entry/movement; 
• 
Amount dispensed to each subject, including unique subject identifiers; 
• 
Amount transferred to another area/site for dispensing or storage; 
• 
Amount returned to Sponsor; 
• 
Amount destroyed at study site, if applicable. 
5.7 
RETURN AND DESTRUCTION OF INVESTIGATIONAL PRODUCT 
Upon completion or termination of the study, all unused IP must be destroyed at site per institution 
policy or returned to Inovio Pharmaceuticals, Inc. or its designee, if site cannot destroy IP.  
The used IP cartridge will be discarded along with the disposable array within a sharps container at 
site. 
It is the Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. The return of unused IP(s) should be arranged by the responsible Study Monitor. 
The unused IP can only be destroyed after being inspected and reconciled by the responsible Inovio 
Pharmaceuticals, Inc. or designated Study Monitor. 
If IP is returned to Inovio Pharmaceuticals, Inc., or its designee, it must be accompanied by the 
appropriate documentation. Returned supplies should be in the original containers. Empty 
containers should not be returned to Inovio Pharmaceuticals, Inc. The return of unused IP(s) should 
be arranged with the responsible Inovio personnel and/or Clinical Monitor. 
5.8 
CELLECTRATM 5PSP DEVICE 
The Investigational product\placebo will be delivered using the CELLECTRA™ 5PSP device. The 
device consists of five (5) main components (see Figure 2): 
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Figure 2: CELLECTRA 5PSP Base Station with Handset  
1) The 5PSP Base Station serves as a charging dock 
for the Handset and can accept limited data inputs as 
well as store records. 
2) The reusable 5PSP Handset is battery powered and 
delivers the electroporation pulses. The Handset 
accepts the disposable array.
3) The 5PSP Sterile Single Use Array consists of five 
(5) needle-electrodes bonded into a plastic housing 
that also accepts the (shipped separately) Drug 
Cartridge. The array accepts a standard, commercially 
available glass cartridge.
4) USB International Power Supply 
5) Flash Drive used to transfer device logging data to 
the manufacturer.
Base Station 
The base station communicates instructions, alerts, and error messages to the user through a touch 
screen graphical user interface (GUI).  It also accepts data inputs from the user, e.g., patient 
identification code, height, and weight; it communicates with the handset; provides energy access 
for the system through connection with standard wall electrical power supply sources (100-220V, 
~0.5Amp, 50-60Hz); and serves as a docking and recharging station for the handset.  The base 
station is illustrated in Figure 3. 
Figure 3: CELLECTRA™5PSP Base Station 
Handset
The handset facilitates delivery of the needles for injection and the electroporation pulses into the 
muscle tissue and executes the treatment sequence (drug injection, impedance check, and 
electroporation pulses).  It has a display screen and speakers for user feedback and an embedded 
processor for running the system software that controls and measures all of the elements of the 
496

handset. The handset is powered by a custom, rechargeable battery pack that has its own safety 
circuit. The handset is designed with three independent fail-safes to minimize the risk of electrical 
shock, short, or fire. The handset is illustrated in Figure 4. 
Figure 4: CELLECTRA™5PSP Handset
Array  
The array is a single-use, sterile, disposable component constructed of commonly-used medical 
plastics and metals, with 5 fixed, stainless-steel electrodes (needles) and 1 intramuscular injection 
needle. The needles are covered by a plastic shroud that retracts as the needles are inserted into the 
patient, then returns to the starting position as the needles are removed and locks out to prevent 
accidental needle sticks.  The opposite end of the array accepts the drug cartridge, which is inserted 
cap-end-first until the bottom of the cartridge is flush with the opening of the array (indicated by an 
audible 'click').  When properly inserted, the septum is punctured and the cartridge cannot be 
removed.  The array is illustrated in Figure 5. The array features no software.
Figure 5: CELLECTRA™ 5PSP Array
Handset without array attached
Handset with array attached
Array, shroud closed (top) 
Array, shroud retracted (right)
Insertion of cartridge into array
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5.9 
USE OF CELLECTRA™ 5PSP DEVICE 
The instructions for use of the device are located in the CELLECTRA™ 5PSP User Manual. Users 
of the CELLECTRA™ 5PSP device must successfully complete training. Training will include 
review of the device user manual as well as hands-on training. After training on the proper use of 
the CELLECTRA™ 5PSP device, intended users at each site will be required to demonstrate their 
competence in its use to Inovio or its designee. An instructional video has been prepared for review 
by site personnel on an as needed basis. 
The treatment 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.  
Any deviation from the above procedures must be approved by the sponsor or its designee. 
5.10 PACKAGING AND LABELING OF CELLECTRA™ 5PSP DEVICE 
See below Figure 6 for example CELLECTRA™ 5PSP device component labels. 
Figure 6. Device Labels (Base, Handset, Array) 
BASE STATION   
 
HANDSET  
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ARRAY  
 
 
 
 
 
 
 
 
 
5.11  HANDLING OF CELLECTRA™ 5PSP DEVICE 
The CELLECTRA™ 5PSP device and its components must be stored in a secure location according 
to the instructions in the User Manual. 
5.12  CELLECTRA™ 5PSP DEVICE ACCOUNTABILITY 
The investigative site is responsible for maintaining device and accountability logs. The device must 
have full traceability from the receipt of the products through the subject use, disposal or return of 
the products. The Site must document acknowledgement of receipt and notify Inovio upon receipt 
of the device. This includes the content shipped and condition upon receipt.  
For each subject treatment, there must be a record of each product used for that subject, i.e. 
CELLECTRA™ 5PSP serial number and array lot number. The used sterile disposable array 
attachment must be discarded after use in accordance with institutional policy regarding disposal of 
sharp needles/instruments. 
5.13  RETURN OF CELLECTRA™ 5PSP DEVICES 
Upon completion or termination of Inovio studies, the Base Station and Handset must be returned 
to Inovio Pharmaceuticals, Inc. 
Device components 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 device components identified above should be arranged by Inovio Pharmaceuticals, Inc. or the 
responsible Study Monitor. 
Unused 5PSP Arrays may be either returned to Inovio or destroyed on site. If 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 according to applicable regulation and guidelines and 
institutional procedures, and appropriate records of the disposal have been documented. 
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6 STUDY PROCEDURES AND TREATMENTS 
This section lists the procedures and parameters for each planned study evaluation.  The timing of 
each assessment is listed in the Schedule of Events Table (see Table 1). 
A subject will be required to provide informed consent for use of any information collected prior to 
consenting and before any additional study specific procedures are performed.   
Protocol waivers or exemptions will not be granted with the exception of immediate safety concerns. 
Therefore, adherence to the study design requirements, including those specified in the Schedule of 
Events Table are essential and required for study conduct. 
6.1 
BEFORE TREATMENT PROCEDURES 
6.1.1 
SCREENING EVALUATIONS 
Subjects who have been identified with standard of care biopsy results of CIN 1/2, CIN 2, CIN 
2/3 or CIN 3 and who consent to participate in the study will be eligible for screening and will 
have biopsy slides or tissue sent to the central pathology lab for review by PAC for evaluation 
prior to enrollment.  
Additionally, Investigators may discuss with the Sponsor on a case-by-case basis the screening of 
subjects with abnormal cytology findings (i.e. HSIL or ASC-H with or without local HPV-16 or 
18 genotype results) obtained as part of standard of care. The specific circumstances MUST be 
submitted in writing (e.g. email or fax) and the medical monitor MUST be consulted prior to 
screening a volunteer with these cytology findings (i.e. ASC-H or HSIL with or without HPV-16 
or 18) for this study. The initial biopsy results may have been obtained at a referring institution by 
someone other than the site investigator. 
• In the case where the subject has an ASC-H or HSIL cytology result without HPV-16 or 
18 genotyping results available locally and if approved by Inovio, the site may proceed 
with initial study screening by sending ThinPrep™ samples to the central laboratory to 
screen for HPV 16/18 by cobas™ assay. A non-specific result from local testing of 
“Positive for high risk HPV” is not sufficient and will require the collection of the 
ThinPrep™ sample for HPV-16 and/or HPV-18 testing by cobas™ assay.  If the central 
lab ThinPrep™ sample result is positive for HPV-16 and/or HPV-18, the site may continue 
screening including performing the initial colposcopy and biopsy. Biopsy tissue must be 
sent to the central pathology laboratory directly and not tested locally. 
• In the case where the subject has an ASC-H or HSIL cytology result with HPV-16 or 18 
positive genotype results available locally and if approved by Inovio, the site may proceed 
with initial study screening including performing the initial colposcopy and biopsy. Biopsy 
tissue must be sent to the central pathology laboratory directly and not tested locally. 
Subjects who consent to participate will have biopsy slides or paraffin-embedded tissue block(s) 
from a previous biopsy and/or newly collected cervical biopsy tissue samples (formalin fixed 
tissue) sent to the central pathology lab for review by PAC. There will be a maximum allowable 
window of 10 weeks from the date of collection of the qualifying biopsy sample(s) (i.e. 
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slides/samples(s) reviewed by PAC with HSIL consensus diagnosis), until the date of first study 
treatment (i.e. Day 0).  
• Biopsy specimens and colposcopic photographs obtained within 10 weeks prior to Day 0 
as part of standard of care before the informed consent may be used as part of the screening 
and evaluation process.  If the pathology results of the initial biopsy obtained as part of 
standard of care are available confirming the presence of cervical HSIL (CIN2 or CIN3), 
those biopsy slides or sample(s) may be sent directly to the central pathology lab after the 
subject has signed the informed consent.   
For those individuals diagnosed with cervical HSIL by a local pathologist, where the initial biopsy 
slides or tissue obtained as part of standard of care are not available or cannot be obtained within 
a reasonable time frame, colposcopy should be performed and an additional biopsy sample 
collected during screening. A photograph of the lesion with at least one attempt should done as 
follows: Acetic acid should first be applied to the cervix then photographs of the cervix and the 
associated lesion should be photographed prior to and after biopsies (if applicable) and at all 
colposcopic examinations; if repeat photographs are sought, they should be done at the next 
protocol-specified colposcopy visit.   
The 10 week screening window begins upon collection of the biopsy sample that will be evaluated 
by the PAC.  
Subjects must have a histologic diagnosis of cervical HSIL (CIN2 or CIN3) confirmed by the PAC 
and a screening ThinPrep™ cervical specimen test positive for HPV-16 and/or HPV-18 by 
cobas™ HPV test to be eligible for randomization into the study (provided the subject also meets 
other eligibility criteria). Subjects whose specimens also test positive for other HPV genotypes are 
not excluded as long as they have a positive result for HPV-16 and/or HPV-18. Subjects’ post-
menopausal status must meet requirements as specified in the inclusion criteria [24, 25]. The 
assessments during the screening period will determine the subjects’ continued eligibility for the 
study and also their ability to comply with protocol requirements by completing all assessments.  
The following evaluations/actions, unless noted, will be performed within 10 weeks and up to Day 
0 – except for the safety laboratory collections/assessments, which must be performed within 45 
days prior to Day 0. All screening assessment values must be reviewed prior to study treatment. 
• Signed informed consent 
• Demographics; including age, and race/ethnicity 
• Medical history; including concomitant medications review, history of prior cervical 
dysplasia, and pregnancy history 
• Socio-Behavioral Assessment; including self-reported smoking history, self-reported exposure 
to second-hand smoke, self-reported alcohol intake history, contraceptive history 
• Vital signs (including oral temperature, respiratory rate, blood pressure and heart rate) 
• Full Physical Examination (including height, weight and BMI measurements) 
• 2 Digene cervical swab samples  
• 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain from 
any sexual activity and refrain from use of douching or vaginal lubricants/medication for a 
period of 24 hours prior to sample collection) 
501

• Urine pregnancy test 
• Colposcopy with lesion photography and/or cervical biopsy (Screening colposcopy and 
photography is optional if adequate colposcopy was performed upon collection of initial 
biopsy) 
• 12-lead ECG (within 45 days prior to Day 0) 
• Baseline laboratory evaluations (includes CPK, hematology and serum chemistry, urinalysis)  
to be performed (within 45 days prior to Day 0); 
• Serology (HIV Antibody, within 45 days of Day 0) 
• Determination of eligibility per inclusion / exclusion criteria 
• Whole blood (at least 34 mL) and serum (at least 8 mL) for baseline immunology including 
miRNA profile 
6.2 
DURING TREATMENT PROCEDURES BY VISIT 
Once eligibility has been confirmed, the subject will be randomized to receive study treatment.  Visit 
dates and windows must be calculated from Day 0. 
6.2.1 
DAY 0 
The following evaluations will be performed on Day 0 prior to study treatment: 
• Determination of eligibility per inclusion / exclusion criteria 
• Randomization 
• Targeted Physical assessment 
• Vital signs 
• Urine pregnancy test 
• Whole blood (at least 34 mL) and serum (at least 8 mL) for baseline immunology including 
miRNA profile (a total of at least 68 mL of whole blood and 16 ml serum should be collected 
prior to dosing on Day 0) 
• 2 Digene cervical swab samples 
• ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain from 
any sexual activity and refrain from use of douching or vaginal lubricants/medication for a 
period of 24 hours prior to sample collection) 
• Oropharynx (OP) sample by oral rinse and vaginal swabs for HPV testing 
• Intra-anal swabs (if subject has consented for intra-anal sampling) for HPV testing 
• 
Colposcopy (accompanying lesion photography should be attempted at least once) 
• Patient-Reported Outcome (PRO) questionnaires (SF-36 and EQ-5D-5L) completion by a 
subject (if enrolled in US, Canada, Mexico, Germany and UK only) 
Study treatment will be administered and the following evaluations will be performed on Day 0 
post-treatment: 
• Post treatment adverse event and injection site reaction assessment at least 30 minutes after 
study treatment  
• Distribute Participant Diary Card (PDC)  
• Download EP data from device within 48 hours of study treatment  
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6.2.2 
8-14 DAYS POST DOSE 1 PHONE CALL 
The following information will be evaluated during phone call: 
• Post treatment adverse event and injection site reaction evaluation 
• Review Day 0 PDC (after reviewing the PDC and post treatment injection assessment with the 
subject on the phone, the Investigator or study personnel will determine whether an office visit 
is needed for further evaluation) 
• PRO questionnaires (SF-36 and EQ-5D-5L) completion by a subject (if enrolled in US, 
Canada, Mexico, Germany and UK only) 
6.2.3 
WEEK 4  
The following study evaluation will be performed on Week 4 prior to study treatment (±4 days): 
• Targeted Physical assessment 
• Vital signs including weight 
• Urine pregnancy test 
• Collect PDC for dose 1 
The following study evaluations will be performed on Week 4 post treatment: 
• Post treatment adverse event and injection site reaction assessment at least 30 minutes after 
study treatment;  
• Distribute PDC  
• Download EP data from device within 48 hours of study treatment  
• PRO questionnaire (EQ-5D-5L only) completion by a subject (if enrolled in US, Canada, 
Mexico, Germany and UK only) 
6.2.4 
8-14 DAYS POST DOSE 2 PHONE CALL 
The following information will be evaluated during phone call:   
• Post treatment adverse event and injection site reaction evaluation 
• Review PDC for dose 2 (after reviewing the PDC and post treatment injection assessment with 
the subject on the phone, the Investigator or study personnel will determine whether an office 
visit is needed for further evaluation) 
• PRO questionnaires (SF-36 and EQ-5D-5L) completion by a subject (if enrolled in US, 
Canada, Mexico, Germany and UK only) 
6.2.5 
WEEK 8 
The following study evaluation will be performed during the visit 
• Vital signs 
• Targeted Physical assessment 
• Collect and review PDC for dose 2 
• Post treatment adverse event and injection site reaction evaluation 
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• 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from any sexual activity and refrain from use of douching or vaginal lubricants/medication for 
a period of 24 hours prior to sample collection) 
• 
Whole blood (at least 34 ml) and serum (at least 8 ml serum) for immunology including 
miRNA profile 
6.2.6 
WEEK 12 
The following study evaluation will be performed on Week 12 prior to study treatment (±4 
days): 
• 
Targeted Physical assessment 
• 
Vital signs including weight 
• 
Urine pregnancy test 
The following study evaluations will be performed Week 12 post treatment: 
• 
Post treatment adverse event and injection site reaction assessment at least 30 minutes after 
study treatment;  
• 
Distribute PDC  
• 
Download EP data from device within 48 hours of study treatment  
• 
PRO questionnaire (EQ-5D-5L only) completion by a subject (if enrolled in US, Canada, 
Mexico, Germany and UK only) 
6.2.7 
8-14 DAYS POST DOSE 3 PHONE CALL 
The following information will be evaluated during phone call:   
• 
Post treatment adverse event and injection site reaction evaluation 
• 
Review PDC for dose 3 (after reviewing the PDC and post treatment injection assessment 
with the subject on the phone, the Investigator or study personnel will determine whether an 
office visit is needed for further evaluation) 
• 
PRO questionnaires (SF-36 and EQ-5D-5L) completion by a subject (if enrolled in US, 
Canada, Mexico, Germany and UK only) 
6.2.8 
WEEK 15 
The following study evaluations will be performed on Week 15 ± 1 week: 
• Targeted physical assessment 
• Vital signs 
• Post-treatment injection site reaction assessment 
• Urine pregnancy test 
• Whole blood (at least 51 mL) and serum (at least 4 mL) for immunology 
• 2 Digene cervical swab samples 
• ThinPrep™ sample for HPV typing and pap smear (subject should be instructed to abstain from 
any sexual activity and refrain from use of douching or vaginal lubricants/medication for a 
period of 24 hours prior to sample collection)  
• Collect PDC  
504

• Colposcopy (lesion photography should be attempted at least once) 
6.2.9 
WEEK 28 
The following study evaluations/actions will be performed on Week 28 ± 1 week: 
• 
Targeted physical assessment 
• 
Vital signs 
• 
Urine pregnancy test 
• 
2 Digene cervical swab samples 
• 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from any sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to sample collection)  
• 
Colposcopy (lesion photography should be attempted at least once) to assess for possible disease 
progression. 
• 
ECC (only to be collected if ECC was done as part of Screening) 
• 
PRO questionnaires (SF-36 and EQ-5D-5L) completion 8-14 days post Week 28 visit by a 
subject enrolled in US, Canada, Mexico, Germany and UK only 
6.2.10 
WEEK 36 
The following study evaluations will be performed on Week 36 ± 1 week: 
• 
Targeted physical assessment 
• 
Vital signs 
• 
Socio-Behavioral assessment (change in smoking alcohol intake or recreational drug use from 
baseline) 
• 
Whole blood (at least 34 ml) and serum (at least 4 ml) for immunology 
• 
Urine pregnancy test 
• 
2 Digene cervical swab samples  
• 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from any sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to sample collection) 
• 
Oropharynx (OP) by oral rinse and vaginal swab for HPV testing 
• 
Intra-anal swab (if subject has consented to intra-anal sampling) for HPV testing 
• 
Colposcopy (lesion photography should be attempted at least once)  
• 
Biopsy or surgical excision based on information collected at Week 28 to determine the 
minimally required tissue collection procedure (e.g. 4 quadrant biopsies, 4 quadrant biopsies 
and ECC, or surgical excision) to be used for histopathologic assessment at Week 36 as 
described in Tables 4 & 5 
• 
PRO questionnaire (EQ-5D-5L only) completion by a subjects enrolled in US, Canada, 
Mexico, Germany and UK only 
6.2.11 
WEEK 40 PHONE CALL 
The following study evaluations will be performed on Week 40 ± 2 weeks via a phone call:   
• 
AE/SAE assessment 
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• 
Review of histology results as read by PAC from Week 36  
• 
Completion of quality of life questions will asked to subjects enrolled in US, Canada, Mexico, 
Germany and UK only 
• 
PRO questionnaires (SF-36 and EQ-5D-5L) completion 8-14 days post Week 40 by a subject 
by subjects enrolled in US, Canada, Mexico, Germany and UK only 
6.2.12 
WEEK 62 
The following study evaluations will be performed on Week 62 ± 2 weeks: 
• 
Targeted physical assessment 
• 
Vital Signs 
• 
Urine pregnancy test 
• 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from any sexual activity and refrain from use of douching or vaginal lubricants/medication 
for a period of 24 hours prior to sample collection) 
• 
Colposcopy (lesion photography should be attempted at least once) 
6.2.13 
WEEK 88 
The following study evaluations will be performed on Week 88 ± 2 weeks: 
• 
Full Physical Exam 
• 
Vital Signs 
• 
Socio-Behavioral Assessment (change in smoking alcohol intake or recreational drug use 
from baseline) 
• 
Urine pregnancy test 
• 
ThinPrep™ sample for HPV typing and pap smear (subject should be requested to abstain 
from sexual activity and refrain from use of douching or vaginal lubricants/medication for a 
period of 24 hours prior to sample collection) 
• 
Oropharynx (OP) by oral rinse and vaginal swabs for HPV testing 
• 
Colposcopy (lesion photography should be attempted at least once) 
• 
PRO questionnaires (SF-36 and EQ-5D-5L) completion by a subject (if enrolled in US, 
Canada, Mexico, Germany and UK only) 
 
6.3 
EVALUATIONS AND PROCEDURES 
6.3.1 
INFORMED CONSENT 
All subjects must sign the informed consent prior to any study related procedures being performed 
(i.e., prior to any screening activities). The informed consent documentation must be in accordance 
with applicable regulations and GCP. Qualified study personnel will meet with prospective study 
subjects, explain the study, and provide them with an informed consent form (ICF) that describes 
the screening tests, eligibility criteria for entering the study, study treatments and follow-up 
procedures, in a language understandable to the subject. Explanation of the study includes, but is 
not limited to, study objectives, potential benefits and risks, discomforts/inconveniences, and the 
subject’s rights and responsibilities. The subject is then requested to sign and date the ICF. A copy 
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of t he si g ne d i nf or me d c o nse nt d oc u me ntati o n m ust be pr o vi de d t o t he s u bject. T he q ualifie d st u d y 
pers o n nel  will  d oc u me nt  t he  pr ocess  of  o btai ni n g  i nf or me d  c o nse nt  wit hi n  t he  s o urce  rec or d. 
Si g ne d I C Fs are mai ntai n e d i n t he s u bject’s s o urce rec or ds a n d m ust b e accessi bl e f or verificati o n 
at a n y ti me. 
6. 3. 2  
A S SI G N M E N T O F S U B J E C T I D E N TI FI C A TI O N N U M B E R S  
Eac h s u bject  w h o c o nse nts will be assi g ne d a u ni q ue s u bject i de ntificati o n n u m ber ( SI D), w hic h 
i de ntifies t he s u bject f or all st u d y-relate d pr oce d ures. SI Ds are a c o m bi nati o n of a u p t o t w o al p ha 
letters  st u d y  c o de,  t w o al p ha  letter  C o u ntr y c o d e,  t w o  di git  site  n u m ber,  pl us 3- di git s u bject 
n u m ber  starti n g  wit h 
  (e. g., 
).  O nce  assi g ne d,  SI Ds  ca n n ot  be  re use d  f or  a n y 
reas o n.  I nf or mati o n  re gar di n g  t he  SI D  a n d  s cree n  date  m ust  be  d oc u m e nte d  o n  a  Scree ni n g 
l o g/s yst e m an d i n t he I nt eracti ve R es p o nse Tec h n ol o g y ( I X R S). 
S u bjects  meeti n g  eli gi bilit y  criteria will  be  ra n d o mize d  b y  a  c o m p uter ge nerate d  all ocati o n 
sc he d ule.  
6. 3. 3  
S A F E T Y E V A L U A TI O N S  
6. 3. 3. 1  
P h ysic al E x a m 
A f ull p h ysi cal e x a mi nati o n  ( P E) will be c o n d ucte d d uri n g scree ni n g a n d st u d y disc har ge.  
It will i ncl u de a n assess me nt of t he f oll o wi n g: ge neral  a p peara n ce, s ki n, hea d, e yes, ears, 
n ose,  a n d  t hr oat,  a n d  l y m p h  n o des,  a n d  res pirat or y,  car di o vasc ul ar,  gastr oi ntesti nal,  
ge n it o uri nar y, m usc ul os k eletal, a n d ne ur ol o gi cal s yste ms.   
A  tar gete d  p h ysical  assess me nt  will  be  perf or me d  at  ot her  visits  as deter mi ne d  b y  t he 
i n vesti gat or or direct e d p er s u bject c o m plai nts.  
6. 3. 3. 2  
Vit al Si g ns  
Vital si g ns will be meas ure d at s pecifie d visits a n d will i ncl u de:  
•  Sitti n g s yst olic  a n d diast olic bl o o d press ures wit h s u bject sitti n g at rest f or at least 
5 mi n utes bef ore meas ure m e nt 
•  Res pirati o n rate  
•  H eart r ate  
•  Oral te m per at ure meas ur e d wit h a n a ut o mate d t her m o meter   
6. 3. 3. 3  
Wei g ht a n d Hei g ht 
Wei g ht a n d  hei g ht will  b e c ollecte d at scree ni n g i n or der t o calc ulate t he B MI. Wei g ht will 
be c ollecte d o n Da y 0, Wee k s 4 a n d 1 2. 
6. 3. 3. 4  
Me dic al Hist or y  
All rele va nt  (as j u d ge d b y t h e i n vesti gat or) past a n d prese nt c o n diti o ns  at scree ni n g, as well 
as  pri or  s ur gical  pr oce d ures  will  be  rec or d e d  f or  t he  mai n  b o d y  s yste ms.  T he  me dica l 
hist or y  will  i ncl u d e  a)  a n y  pri or hist or y  of CI N  dia g n ose d – wit h  dia g n osis  date(s)  a n d 
res pecti ve CI N l e vel(s), a n d b) if treate d pre vi o usl y f or CI N, t he res pecti ve treat me nt t y p e(s) 
a n d date(s).  
5 0 7
P P
D
P P D

6.3.3.5 
Socio-Behavioral Assessment 
Socio-Behavioral Assessment, including self-reported smoking history, self-reported 
history of exposure to second-hand smoke, self-reported alcohol intake history, self-
reported recreational drug use history, self-reported history of contraceptive use and type 
of contraceptive if known, reproductive history, history of prior cervical dysplasia, and 
pregnancy history will be obtained at Screening.  
At Weeks 36 and 88, socio-behavioral assessment will be performed to document any 
change from screening. 
6.3.3.6 
Laboratory Evaluations 
At screening, blood samples will be taken to be tested for serum chemistry and hematology.  
Complete blood count (CBC): 
• White blood cell (WBC) count with differential 
• Red blood cell (RBC) count 
• Hemoglobin, Hematocrit 
• Platelet count 
Serum Chemistry: 
• Glucose 
• Serum glutamic-pyruvic transaminase (SGPT)/Alanine aminotransferase (ALT) 
• Blood urea nitrogen (BUN ) 
• Creatinine 
• Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate) 
• Creatine Phosphokinase (CPK) 
Urinalysis (UA):  
Urine samples will be tested at screening by dipstick for glucose, protein, and hematuria. If 
abnormal (presence of protein, hematuria, or glucose ≥ 1+) a microscopic examination 
should be performed. 
6.3.3.7 
Demographics 
Demographic information will be collected via self-report (unless noted otherwise), 
including the following: 
• Age 
• Race/ethnicity 
6.3.3.8 
Urine Pregnancy Testing 
For subjects of reproductive potential, a negative spot urine pregnancy test is required prior 
to each study treatment, colposcopy and surgical excision. 
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6.3.3.9 
ECG 
A single 12-lead ECG will be obtained during Screening after the subject has been in a 
supine position for 10 to 15 minutes. The ECG should include measurements of ventricular 
rate, PR, QRS, QRS axis, QT, QTcb or QTcf, ST segment, T wave as well as an investigator 
assessment of whether the ECG is normal or abnormal (automated interpretations of ECG 
should not be used). Abnormal ECGs should be interpreted as “clinically significant (CS)” 
or “not clinically significant (NCS)” by the investigator. 
6.3.3.10 
Subject Self Evaluation 
Subjects will be provided a PDC and will be asked to record the following the evening of 
study treatment through Day 6: 
• 
Oral temperature and time taken (before 11:59 pm) 
• 
General symptoms of feeling unwell 
• 
Pain and itching at injection site 
• 
Measure redness, swelling, bruising at injection site 
• 
Medications taken 
The completed PDC will be reviewed with the subject by the study staff at 8 -14 days post-
dose phone call and next in-person visit. 
The study staff will review the PDC for general symptoms (e.g. malaise, fatigue, headache, 
nausea, and myalgia/arthralgia), injection site reaction symptoms (e.g. pain, erythema and 
edema), medical events and medications.  
Any PDC 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 PDC entry does not meet the criteria of a Grade 1 or higher AE as per 
the CTCAE guidelines, 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 
PDC entry and final AE reporting (i.e. grading) do not agree, the reasoning should be 
recorded in the source documents. 
6.4 
INJECTION AND ELECTROPORATION (EP)  
Subjects will receive a 3-dose series of either 1 ml VGX-3100 or Placebo by IM injection in the 
deltoid (or anterolateral quadriceps muscle as an alternate option, if deltoid muscle is not possible 
or appropriate) followed immediately by EP with the CELLECTRA™ 5PSP. Study treatment must 
not be given within 2 cm of a tattoo, keloid or hypertrophic scar.  If there is implanted metal, 
implanted device, within the same limb then use of the deltoid muscle on the same side of the body 
is excluded.  
6.4.1 
RISKS OF TREATMENT PROCEDURES 
A summary of the potential risks of IM administration followed by EP with the CELLECTRA™ 
5PSP can be found in the VGX-3100 Investigator’s Brochure. 
 
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6.4.2 
MANAGEMENT OF ANXIETY AND PAIN DUE TO TREATMENT 
Subjects may be offered topical anesthetic (e.g. EMLA or equivalent), to prevent significant 
discomfort from the treatment procedure. If a topical anesthetic is used, an approximately 1.5 cm 
diameter amount will be applied with occlusion to the site of injection ~30 minutes prior to 
treatment.  
Subjects may be offered a mild sedative (e.g. 0.5-1 mg lorazepam), or equivalent, for anxiety 
related to the treatment procedure. Mild sedatives may be administered approximately 1 hour prior 
to treatment at Day 0, Weeks 4 and/or 12. Subjects who receive a mild sedative should not be 
allowed to operate a motor vehicle for 3-4 hours after receiving medication and should have 
arranged transportation to depart the study site. 
Subjects may be offered an analgesic (e.g. ibuprofen, ketorolac) after injection/EP.  
Subjects who are allergic to or have contraindications to EMLA, ibuprofen, ketorolac or a mild 
sedative may be offered a suitable alternative.  
Medication taken for anxiety or pain management should be added to the concomitant 
medications. 
6.5 
ASSESSMENT OF LABORATORY ABNORMALITIES 
Blood will be drawn for serum chemistry, hematology and serology assessments as well as urine 
pregnancy testing at Screening will be performed for inclusion into the study as listed in section 
6.1.1. 
6.6 
ASSESSMENT OF CLINICAL STUDY ADVERSE EVENTS 
The injection site will be assessed by study personnel prior to and at least 30 minutes after each 
study treatment and at 2 to 4 weeks post study treatment visits.  They will also be advised to record 
local and systemic AEs for 7 days on a PDC. 
An adverse event assessment will be conducted at each visit during which subjects will be queried 
regarding the occurrence of any adverse events, concomitant medications new onset illness or 
disease, as well as contraceptive compliance. Subjects will be reminded to contact study personnel 
and immediately report any event that happens for the duration of the study. Unsolicited adverse 
events will be captured from the time of the informed consent to study discharge. These events will 
be recorded on the subject’s CRF.   
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6.7 
ASSESSMENT OF INJECTION SITE REACTIONS 
When evaluating injection site reactions throughout the study, the investigator will be instructed to 
use the following grading scale:  
Table 15. 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 
(ER) visit or 
hospitalization 
Tenderness 
Mild discomfort 
to touch 
Discomfort with 
movement 
Significant 
discomfort at rest 
ER visit or 
hospitalization 
Erythema/Redness* 
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
dermatitis 
Induration/Swelling** 
2.5-5 cm and 
does not interfere 
with activity 
5.1-10 cm or interferes 
with activity 
>10 cm or prevents 
daily activity 
Necrosis 
- September 2007 “FDA Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials” 
*In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded 
as a continuous variable 
**Induration/Swelling should be evaluated and graded using the functional scale as well as the actual measurement 
*** Sponsor defines daily as impact lasting > 24 hours  
6.8 
ASSESSMENT OF PATIENT REPORTED OUTCOMES 
To assess quality of life and related impacts on subjects, two previously-validated patient-reported 
outcomes (PRO) instruments will be provided to the subjects enrolled in US, Canada, Mexico, UK 
and Germany. The following two PRO questionnaires will be used: 
1. Short Form Health Survey, version 2 (SF-36v2™) (Optum, Inc.):  generically measures 
functional health and well-being, for physical and mental health; consists of thirty-six items 
covering eight domains (Physical functioning, Role limitations due to physical problems, 
Bodily pain, General health, Vitality, Social functioning, Role limitations due to emotional 
problems, and Mental health) [26] 
2. EQ-5D-5L (EuroQol Research Foundation): generically measures activities & general 
health status; consists of six items covering six domains (Mobility, Self-care, Usual activity, 
Pain/discomfort, Anxiety/depression, and Global health status) [27, 28] 
Either one or both PRO instruments (refer to Section 6.2) will be provided to the subject who will 
be instructed to complete the questionnaire at the following time points:  
• Day 0 (before the first study treatment) 
• 8-14 days post dose 1 
• Week 4 (after study treatment) 
• 8-14 days post dose 2 
• Week 12 (after study treatment) 
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• 8-14 days post dose 3 
• 8 -14 days post Week 28 
• Week 36 (after biopsy or surgical excision) 
• 8-14 days post Week 40 
• Week 88  
Administration of PRO instruments will be performed according to the validated procedure and 
guidelines of each respective instrument, except for some assessments for exploratory analyses. 
Additional instructions will be provided separately. 
Additional questions related to the subject’s quality of life following surgery or biopsy will be 
completed at the Week 40 phone call for subjects enrolled in USA, Canada, Mexico, UK and 
Germany. 
6.9 
PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENTS 
Whole blood and serum samples will be obtained at baseline (screening and Day 0 prior to dosing) 
and at Weeks 8, 15, and 36.  
Details of the immunology sample collection and shipment information will be provided in the 
Laboratory Manual. 
A standardized binding ELISA may be performed to measure the anti–HPV-16/18 antibody 
response induced by VGX-3100. 
PBMCs will be isolated from whole blood samples. Assessment of cellular immune activity may 
occur via the application of the Interferon-γ enzyme-linked immunosorbent spot (IFN-γ ELISpot) 
assay as well as flow cytometry.  
Additional assessment of cellular immune activity may occur via the application Flow Cytometry 
for the purposes of performing a Lytic Granule Loading Assay. The Lytic Granule Loading assay 
may examine the following external cellular markers: CD3, CD4, CD8 (T cell identification), 
CD137, CD38 and CD69 (T cell activation markers) as well as PD-1 (exhaustion/activation marker). 
The Lytic Granule Loading assay may additionally analyze the following intracellular markers: 
Granzyme A, Granzyme B, Granulysin and Perforin (proteins involved in lytic degranulation and 
cytotoxic potential). Markers examined in this assay may change as new relevant data become 
available. 
Profiling of miRNA may occur via the use of either sera or plasma obtained at Screening, Day 0 as 
well as Week 8.  Assessment of Day 0 samples alone will explore predictive algorithms for response 
to treatment with VGX-3100 prior to dosing.  Assessment of Week 8 samples may be done as a 
comparison against Day 0 in order to look for changes in miRNA profiles that occur once dosing 
with VGX-3100 has begun to explore construction of an algorithm to predict treatment success with 
VGX-3100. 
Profiling of DNA methylation status will occur via the use of nucleic acid isolated from Digene 
brushes used at Screening, Day 0 and Week 15.  Assessment of Day 0 samples alone will explore 
predictive algorithms for response to treatment with VGX-3100 prior to dosing.  Assessment of 
Week 15 samples may be done as a comparison against Day 0 in order to look for changes in DNA 
512

methylation profiles that occur once dosing with VGX-3100 has finished to explore construction of 
an algorithm to predict treatment success with VGX-3100.       
6.10 TISSUE IMMUNOGENICITY ASSESSMENT 
If there is residual tissue or additional slides in the paraffin block after histologic diagnoses have 
been rendered, then unstained slides and/or the relevant paraffin blocks may be collected for immune 
assessment.  Available tissue collected from pre- and post- treatment may be assessed for the 
presence of immune cells using immunohistochemistry or immunofluorescence. The presence of 
immune signatures may also be analyzed through the assessment of various transcripts suggestive 
of an inflammatory or an immunosuppressive tissue microenvironment. 
An Immunoscore algorithm will be applied to cervical tissue obtained at baseline.  The algorithm is 
composed of scoring patients based on infiltration of immune cells stained with CD8, FoxP3, CD103 
and Perforin.  Scoring will occur in epithelium designated as HSIL.   
For HSIL epithelium, 1 point will be assigned for patients who show at least two of the following 
three parameters:  
• CD8 count per mm2 >375,  
• perforin count per per mm2 >0 and  
• CD103 count per per mm2 >150   
Additionally, 1 point will be assigned for each for the following parameters:  
• FoxP3/CD8 ratio <1:3,  
• CD103/CD8 ratio >2:1,  
• CD103/ perforin ratio >10:1 and  
• CD103/FoxP3 ration > 1.5:1    
6.11 PAP SMEARS AND HPV TESTING 
Pap smears will be obtained using ThinPrep™ test kits at the screening, Day 0, Weeks 8, 15, 28, 36, 
62, 88 and read in a central laboratory. HPV typing including PCR by cobas™ HPV test will be 
performed on the ThinPrep™ specimen. At each of these visits, menstrual cycle status & recent 
history will be collected via self-report.  If the Pap smear result suggests progression to cancer at 
Day 0, Weeks 15, 28 or 36, the investigator may schedule an ad hoc visit to perform a colposcopy 
and possible biopsy if clinically indicated. 
The subject will be requested to abstain from any sexual activity and refrain from use of douching 
or vaginal lubricants/medication for a period of 24 hours prior to collection of ThinPrep™ samples 
to eliminate potential interference with the results of HPV testing.   
 At visits (i.e. Screening, Day 0, and Weeks 15, 28, and 36) where multiple cervical samples are 
collected, the two Digene cervical swab will be collected prior to the ThinPrep™ sample. 
Immunology testing may be performed from Digene swab. 
Details of sample collection and shipment information will be provided in the laboratory manual. 
513

Additionally, if there is residual tissue available from cervical tissue from screening and Week 36 
after the histologic diagnosis have been rendered, then unstained slides and/or paraffin blocks may 
be collected to test for HPV typing. 
Also, non-cervical swabs (i.e. oropharyngeal rinse, vaginal brush and intra-anal swabs) will be 
collected at specified visits for HPV typing. 
6.12  COLPOSCOPY AND CERVICAL BIOPSIES 
Colposcopy at screening must be adequate, defined as full visualization of the squamo-columnar 
junction (Type I or II transformation zone) and complete visualization of the upper limit of aceto-
white epithelium or suspected dysplasia. An ECC is not required for study entry. However, if an 
ECC was done as part of routine care during the screening period, and found to have evidence of 
cervical HSIL such subject should not be enrolled in the study. Colposcopy is not required to be 
performed at screening if adequate colposcopy was previously obtained upon collection of initial 
biopsy.  All colposcopies performed after informed consent should be conducted according to the 
guidelines outlined in Appendix A. 
Interval colposcopies will be performed at Day 0, Weeks 15, 28, 36, 62, and 88.  An unscheduled 
colposcopy may be performed at the discretion of the investigator if there is suspicion of disease 
worsening or progression. 
At least one attempt to photograph the lesion should done as follows: Acetic acid should first be 
applied to the cervix then photograph(s) of the cervix and the associated lesion should be taken prior 
to and after biopsies (if applicable) and at all colposcopic examinations; if repeat photographs are 
sought, they should be done at the next protocol-specified colposcopy visit.  Pictures should be taken 
to obtain a quality image to the extent feasible according to investigator judgment.   
If a biopsy or surgical excision is performed, images of the cervix should be collected before and 
after the procedure. Each site will be instructed on 1) the technique for capturing the proper images 
using a standard approach and 2) the process for uploading the images to a secure server. 
Additionally, if a vaginal or vulvar lesion should develop after a subject is enrolled, photographs 
should also be taken to document the clinical exam finding.    
6.12.1 
ECTOCERVICAL BIOPSIES 
Ectocervical biopsies are required at screening to confirm eligibility.  If the criteria outlined in 
Table 4 or 5 are met, ectocervical biopsies may also be performed at Week 36 to provide tissue 
for histopathologic assessment of disease regression.   
Visualization of a normal appearing cervix by colposcopy is insufficient evidence to confirm 
disease regression at Week 36. Biopsy must be performed at the location of the screening biopsy 
if no disease is visible at Week 36. 
Biopsies should not be performed at any other visit unless there is suspicion of disease 
progression.  Removal of additional tissue by biopsy before Week 36 will bias results toward 
improvement regardless of whether the subject is in the active or placebo group. The bias 
introduced will obviously be more significant for smaller lesions.  For this reason, if biopsies are 
obtained prior to Week 36, the subject will be classified as a non-regressor in the efficacy 
514

analyses. Subject safety is paramount in this study. Therefore, if at any time the investigator may 
suspect disease progression and the standard of medical care would be to perform an unscheduled 
biopsy prior to Week 36, then his or her medical judgment should prevail over the default 
“Schedule of Events”, Table 1. 
6.12.2 
UNSCHEDULED BIOPSIES 
In the event an unscheduled biopsy is performed after the initial dose and prior to Week 36, the 
subject will be classified as a non-responder. The subject will discontinue further study treatment 
and continue in the study for safety follow-up visits. The subject will be managed according to 
standard of care and the Investigator’s judgment based on the results of the histological diagnosis 
from the unscheduled biopsy. Additional instructions for collecting ectocervical biopsies are 
detailed in Appendix A. All biopsy samples/excised tissue will be sent to the central pathology 
lab for review by PAC.   
6.13  CONCOMITANT MEDICATIONS/TREATMENTS 
All medications (prescription and nonprescription) taken within 8 weeks prior to the screening 
biopsy date of eligible subjects must be recorded on the CRF. Actual or estimated start and stop 
dates must be provided. Medical procedures performed within 8 weeks prior to screening biopsy 
date of eligible subjects that do not affect subject’s eligibility for participation and during the study 
(including over the counter or herbal), will be recorded on the CRFs. 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. Medication that is considered necessary 
for the subject’s safety and well-being may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the CRF.   
6.14  RESTRICTIONS 
6.14.1 
PROHIBITED CONCOMITANT MEDICATIONS AND TREATMENTS 
The following medications and treatments are prohibited:  
• Long term use (≥ 7 days) of oral or parenteral glucocorticoids at a dose of ≥20 mg/day of 
prednisone equivalent; use of inhaled otic and ophthalmic corticosteroids are allowed 
• 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) at screening and throughout the study 
• Administration of any non-study related, non-live vaccine within 2 weeks of any study 
treatment or within 4 weeks of any study treatment for any non-study, live vaccine 
• Blood thinners (e.g. anticoagulants, antiplatelet drugs) or other medication that affects blood 
clotting within 2 to 14 days (e.g., 4-5 drug half-lives) of any study treatment, biopsy or 
excisional procedure (e.g. LEEP) 
6.14.2 
OTHER RESTRICTIONS 
Subjects should not use alcohol or drugs that would interfere with study requirements during 
the course of the study and should report ALL medications/drugs taken to the investigator 
and/or other study personnel. 
515

Subjects should refrain from becoming pregnant until 6 months following the last dose of 
investigational product by using appropriate contraceptive measures as (See Inclusion Criteria, 
Section 4.1).  Lapses in contraceptive use should be reported to investigator and/or other study 
personnel. 
Subject should abstain from sexual activity and refrain from use of douching or vaginal 
lubricants/medication for a period of 24 hours prior to collection of ThinPrep™ samples. 
7 EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY 
7.1 
SAFETY PARAMETERS 
7.1.1 
ADVERSE EVENTS 
An adverse event (AE) is defined as any unfavorable and unintended change in the structure, 
function, or chemistry of the body, or worsening of a pre-existing condition, temporally 
associated with the use of a product whether or not considered related to the use of the product. 
In this study, such changes will be monitored, classified, and summarized, as Clinical or 
Laboratory AEs. Medical condition/diseases present before starting the investigational drug will 
be considered adverse events only if they worsen after starting study treatment. Throughout the 
course of the study, all solicited and unsolicited AEs will be monitored and reported on an AE 
CRF, including the event’s seriousness, severity, action taken, and relationship to investigational 
product(s). AEs should be followed until resolution or stable and the outcome will be documented 
on the appropriate CRF. All AEs should be recorded in standard medical terminology rather than 
the subject’s own words. 
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 study drug). 
• Any pre-existing condition that increases in severity, or changes in nature during or as a 
consequence of the study drug phase of a human clinical trial, will also be considered an AE. 
• Complications of pregnancy (e.g., spontaneous abortion, miscarriage, ectopic pregnancy, fetal 
death, still birth, congenital anomaly of the fetus/newborn); see Section 7.1.9 for additional 
information on pregnancy reporting. 
• AEs that occur from the study screening visit onwards and throughout the duration of the study, 
including the follow-up off study drug period will be recorded as an AE. 
• Conditions that lead to a medical or surgical procedure. 
AEs do not include the following: 
• Medical or surgical procedures (e.g., surgery, endoscopy, tooth extraction, transfusion) 
performed as a result of 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. 
516

• Any medical condition or clinically significant laboratory abnormality with an onset date 
before the informed consent form 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. 
7.1.2 
SERIOUS ADVERSE EVENTS 
A serious adverse event (SAE) is any AE that meets one of the following conditions: 
• Death during the period of surveillance defined by the protocol; 
• Is immediately life-threatening (e.g., subject was, in the view of the Investigator, at immediate 
risk of death from the event as it occurred). This does not include an AE that, had it occurred 
in a more serious form, might have caused death; 
• An event requiring inpatient hospitalization or prolongation of existing hospitalization during 
the period of protocol defined surveillance (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 or substantial disruption of the ability 
to conduct normal life functions; 
• Results in congenital anomaly or birth defect; 
• An important medical event that may not result in death, be life threatening, or require 
hospitalization, but based upon appropriate medical judgment, may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include 1) allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, 2) blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, 3) the development of drug dependency or drug abuse or 4) 
the development of a malignancy; 
• Is medically significant or requires intervention to prevent one or other of the outcomes listed 
above. 
7.1.2.1 
Clarification of Serious Adverse Events 
• Death is an outcome of an AE, and not an adverse event in itself. 
• The subject may not have been on investigational medicinal product at the occurrence 
of the event.  
• Dosing may have been given as treatment cycles or interrupted temporarily before the 
onset of the SAE, but may have contributed to the event.  
• “Life-threatening” means that the subject was at immediate risk of death from the event 
as it occurred. This does not include an event that might have led to death if it had 
occurred with greater severity. 
• Complications that occur during hospitalizations are AEs. If a complication prolongs 
the hospitalization, it is an SAE. 
• Inpatient hospitalization means that the subject has been formally admitted to a hospital 
for medical reasons, for any length of time. This may or may not be overnight. It does 
517

not include presentation and care within an emergency department nor does it include 
full day or overnight stays in observation status. 
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis will be 
documented as the AE and/or SAE and not the individual signs/symptoms. 
Serious adverse events that are ongoing should be followed until resolution or are clinically 
stable. The reporting period for SAEs is described in Section 7.4. 
7.1.2.2 
Event Reporting for Disease Progression or Exclusionary Histologic Findings 
Post-study Treatment 
After starting study treatment, if there is histologic confirmation of progression of cervical 
HSIL to micro invasive or invasive squamous cell carcinoma, the event must be reported as 
an SAE. Post-study treatment histologic diagnosis of adenocarcinoma-in-situ or 
adenocarcinoma should also be reported as an SAE. In both instances, the condition for 
SAE reporting should be categorized as a medically important event unless another criterion 
is met. 
7.1.3 
UNEXPECTED ADVERSE DRUG REACTIONS AND EXPEDITED 
REPORTING 
An adverse drug reaction (ADR) is any noxious and unintended responses to a medicinal product 
related to any dose, for which a causal relationship between a medicinal product and an adverse 
event is at least a reasonable possibility; i.e., there is evidence to suggest a causal relationship 
between the product and the adverse event. An unexpected ADR is one, the nature or severity of 
which is not consistent with the applicable product information (investigator’s brochure, protocol, 
and user manual). Reports that add significant information on specificity or severity of a known, 
already documented SAE constitute unexpected events. For example, an event more specific or 
more severe than described in the Investigator's Brochure or protocol would be considered 
"unexpected.” Specific examples would be (a) acute renal failure as a labeled ADR with a 
subsequent new report of interstitial nephritis and (b) hepatitis with a first report of fulminant 
hepatitis.  
The Sponsor will assess each serious ADR report for expectedness, to determine if it is a serious 
unexpected suspected adverse reaction (SUSAR) which requires prompt reporting to regulatory 
authorities and participating investigators as an expedited report, according to the applicable 
regulatory requirements. Additional occurrences of the SUSAR will be required to be reported on 
an expedited basis until the applicable product information is amended. 
In addition to single-case reports of SUSARs, the Sponsor shall notify regulatory authorities and 
participating investigators of information that might materially influence the benefit-risk 
assessment of a medicinal product, sufficient to consider changes in product administration or 
overall conduct of a clinical investigation. Examples of such information include a clinically 
important increase in the rate of occurrence of a serious expected adverse event, the identification 
of a significant hazard to the subject population, or a major safety finding from a study conducted 
in animals. 
 
518

7.1.4 
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) 
Unanticipated adverse device effect means 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.  
Per the definition above, a UADE is a type of serious adverse event (SAE) that requires expedited 
reporting on the part of the sponsor. As a reminder, all SAEs regardless of relationship to device, 
drug or procedure are to be reported to Sponsor by the study investigator within 24 hours. Sponsor 
will assess each device related SAE to determine if anticipated based on prior identification within 
the investigational plan.  
For countries recognizing and regulating CE Mark devices, SAEs related only to the device which 
meet the medical device vigilance (MDV) reporting criteria will be handled by the Sponsor under 
the post-market surveillance/vigilance reporting requirements per MEDDEV 2.12-1. In such 
cases, the Sponsor will report as per the regulations to the relevant health authorities that require 
MDV reporting.  
 
7.1.5 
ASSESSING SEVERITY (INTENSITY) 
Adverse events should be captured once on the CRF at the maximum severity reported.  
The investigator will grade laboratory AEs and clinical AEs with respect to the following levels 
of severity as per Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 for applicable 
subject populations: 
• Grade 1 (Mild) 
• Grade 2 (Moderate) 
• Grade 3 (Severe) 
• Grade 4 (Potentially Life Threatening)  
• Grade 5 (e.g. Death) 
The investigator will grade injection site reactions in accordance with September 2007 FDA 
Guidance for Industry—Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials.  Please refer to Table 15 Grading Scale for Injection 
Site Reactions in Section titled “Assessment of Injection Site Reactions” above. 
 
7.1.6 
CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE 
EVENTS 
 A causally related AE is one judged to have a reasonable possibility of a relationship to the 
administration of the IP and/or the CELLECTRA™ 5PSP device. An AE may also be assessed as 
not related to the IP and/or the device. Because the investigator is knowledgeable about the subject 
519

(e.g., medical history, concomitant medications), administers the IP, and monitors the subject’s 
response to the IP, the investigator is responsible for reporting adverse events and judging the 
relationship between the administration of the IP and device and a subsequent AE. The investigator 
is aware of the subject’s clinical state and thus may be sensitive to distinctions between events due 
to the underlying disease process versus events that may be product related and may have observed 
the event. The Sponsor will assess the overall safety of the IP delivered by EP and determine 
whether to report expeditiously to the regulatory agencies. 
Investigators should use their knowledge of the subject, the circumstances surrounding the event, 
available site and non-site laboratory and clinical records, and an evaluation of any potential 
alternative causes to determine whether or not an adverse event is considered to be related to the 
IP and/or the device indicating "yes" or "no" accordingly. Causality should be assessed by the 
investigator as “yes, related” or “no, unrelated” by the following criteria: 
• 
Yes – there is a reasonable possibility that administration of the Study Treatment contributed 
to the event; 
• 
No – there is no reasonable possibility that administration of the Study 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 the device; 
• 
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 study; 
• 
Presence of risk factors in the Study Subject or use of concomitant medications known to 
increase the occurrence of the event. 
7.1.7 
ABNORMAL LABORATORY VALUE 
Laboratory abnormalities are usually not recorded as AEs or SAEs. However, laboratory 
abnormalities (e.g., serum chemistry, CBC, CPK, urinalysis) independent of the underlying 
medical condition that require medical or surgical intervention or lead to IP interruption or 
discontinuation must be recorded as an AE, or SAE, if applicable. In addition, laboratory or other 
abnormal assessments (e.g., electrocardiogram, x-rays, vital signs) that are associated with signs 
and/or symptoms must be recorded as an AE or SAE if they meet the definition of an AE (or SAE) 
as described in Section 7.1. If the laboratory abnormality is part of a syndrome, record the 
syndrome or diagnosis (e.g., anemia) not the laboratory result (e.g., decreased hemoglobin). 
Any laboratory abnormality 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 study treatment 
• Has accompanying or inducing symptoms or signs 
• Is judged by the investigator as clinically significant 
520

7.1.8 
POST-STUDY REPORTING REQUIREMENTS 
All AEs and SAEs including deaths, regardless of cause or relationship, must be reported for 
subjects on study (including any protocol required post-treatment follow-up). 
Investigators are not obligated to actively seek AEs or SAEs beyond the follow up period for 
subjects. However, if the investigator learns of an AE or SAE that occurs after the completion or 
termination visit and the event is deemed by the investigator to be related to the study treatment, 
he/she should promptly document and report the event to the study team and medical monitor. 
7.1.9 
PROCEDURES FOR DOCUMENTING PREGNANCY DURING STUDY 
Subjects who are pregnant or expect to become pregnant during the course of the study up to Week 
36 will be excluded from participation in the study. Should a subject become pregnant after 
receiving the first study treatment in the study, she will not be given any further study treatments. 
A Pregnancy Form will be completed by the site personnel and submitted to the sponsor or its 
designee within 24 hours after learning of the pregnancy.  Site personnel will submit the Pregnancy 
Form to the Sponsor or its designee by fax, as described in Section 7.4.2. 
The investigator will also report this event to the IRB within 24 hours of becoming aware of the 
pregnancy. Sites must request the subject’s permission to query pregnancy outcome and follow 
each subject to determine the outcome of the pregnancy. Results will be summarized in the clinical 
study report (CSR).  
Subjects who become pregnant at any point during the study will continue to be followed for safety 
assessments without receiving further study treatment. Procedures that are contraindicated during 
pregnancy, including additional treatments, must not be performed. Investigators should use 
clinical judgment regarding subsequent study-related blood collection based on the presence or 
absence of anemia in each subject.  
All pregnancies that occur from the time of first study treatment through the follow up visits must 
be reported. The investigator will monitor the subject and follow the outcome of the pregnancy. If 
the end of the pregnancy occurs after the study has been completed, the outcome will be reported 
directly to the study team and the medical monitor. 
7.2 
METHODS AND TIMING OF THE COLLECTION AND RECORDING OF 
SAFETY DATA 
Non-serious AEs and SAEs (and UADEs) will be collected for each subject from the time when 
informed consent is obtained through Week 88. 
The sources of AEs cover: 
1. 
The subject’s response to questions about her health (a standard non-leading question such as 
‘How have you been feeling since your last visit?’ is asked at each visit). 
2. 
Symptoms spontaneously reported by the subject. 
3. 
Evaluations and examinations where the findings are assessed by the investigator to be 
clinically significant changes or abnormalities. 
4. 
Other information relating to the subject’s health becoming known to the investigator (e.g. 
hospitalization).  
521

All AEs will be reported on the appropriate CRF. Any SAE (or UADE) occurring during the course 
of the study must be reported to the sponsor within 24 hours of awareness. 
7.3 
SAFETY AND TOXICITY MANAGEMENT 
The Medical Monitor will be responsible for the overall safety monitoring of the study.  
Safety assessments include the following: 
• 
Incidence of all adverse events classified by system organ class (SOC), preferred term, severity, 
and relationship to study treatment  
• 
Local and systemic injection site review; special attention will be paid to the examination of 
the injection site. Administration site reactions and the subject's complaints will be documented. 
7.3.1 
ADVERSE EVENTS OF SPECIAL INTEREST 
Adverse events of special interest (AESI) are the adverse events deemed related to VGX-
3100/placebo delivered with CELLECTRA™ 5PSP that require expedited communication from 
the Site to the Sponsor and meet any of the following criteria: 
• Grade 3 or greater persistent administration site erythema, and/or induration recorded ≥ 2 
hours immediately after Study Treatment  
• Grade 4 or greater persistent administration site pain, tenderness recorded ≥ 2 hours 
immediately after Study Treatment 
• Grade 3 or greater fever 
• Grade 3 or greater systemic symptoms, including generalized pruritus 
Sites will inform the Sponsor via method described in section 7.4.1 within 24 hours to discuss 
whether further dosing for the particular subject should continue.   
7.3.2 
STOPPING RULES (CRITERIA FOR PAUSING OF STUDY) 
• If at any time during a study one-third (1/3) or more of the subjects experience an AESI, 
verified per protocol definition, further enrollment and study treatment will be halted until a 
thorough review has been conducted by the Medical Monitor, Principal Investigator for the 
trial, and the DSMB. Only the DSMB may review unblinded data in making their 
recommendation to the Sponsor regarding continuation of a trial.  
• If any SAE (or potentially life-threatening AE), or death verified as related to study treatment 
occurs, further enrollment and study treatment will be halted until a thorough review has been 
conducted by the Medical Monitor, Principal Investigator for the trial, IRB (if applicable) and 
the DSMB. 
• If three or more subjects in this study, experience the same Grade 3 or 4 unexpected adverse 
event, verified per protocol definition and assessed as related to study treatment, further 
enrollment and study treatment will be halted until a thorough review has been conducted by 
the Medical Monitor, Principal Investigator for the trial, and the DSMB. 
• In the event of two identical, unexpected, Grade 4 toxicities, verified per protocol definition 
and assessed as related to study treatment, further enrollment and study treatment will be 
522

halte d  u ntil  a  t h or o u g h re vie w h as  bee n  c o n d ucte d  b y  t he  Me di cal  M o nit or,  Pri nci pal 
I n v esti gat or f or t he trial, I R B (if a p plica ble) a n d t he D S M B.  
T he  s p o ns or  or  desi g nee  will  n otif y  all  i n vesti gat ors  a n d  I R Bs/ E C  (if  re q uire d)  re gar di n g  t he 
o utc o me of a n y i n vesti gati o n ste m mi n g fr o m a St u d y Pa use.  
G ui deli nes  f or assessi n g cli nical  a b n or malities  are  i n Secti o n  7. 1  i n  ge n eral  a n d  i n  t he  Ta bl e 
pr o vi de d i n Secti o n 7. 1. 5 . 
G ui deli nes f or ass essi n g relate d ness are d etaile d i n Secti o n 7. 1. 6 . 
7. 4  
S T U D Y R E P O R TI N G P E RI O D O F A D V E R S E E V E N T S  
All s olicite d a n d u ns olic ite d a d verse e ve nts will b e c ollect e d t hr o u g h o ut t h e st u d y a n d rec or de d o n 
t he A E C R F.  
7. 4. 1  
S T U D Y R E P O R TI N G P E RI O D O F A D V E R S E E V E N T S  O F S P E CI A L 
I N T E R E S T 
A d verse e v e nts of s pecial i nterest ( A E SI) (see Secti o n 7. 3. 1 ) re q uire e x pe dite d c o m m u nicati o n 
fr o m t he Site t o t he Sp o ns or. Wit hi n 2 4 h o urs of t he site's a ware ness of t he e ve nt, A E SI  m ust be 
re p orte d b y t h e I n v esti gat or t hr o u g h data e ntr y i n t he A d vers e E ve nt electr o nic case re p ort f or m 
(e C R F)  via  t he  M e di dat a  R A V E  electr o nic  data  ca pt ure  ( E D C)  s yste m.  I n  t he  eve nt  t hat  t he 
Me di data R A V E E D C s yste m is u na vaila ble,  t he i n vesti gat or m ust n otif y t he S p o ns or via e mail 
or p h o ne.  
A E SI re p orti n g if E D C s yste m is u n a v ail a ble  
E M AI L:   
 
S A F E T Y P H O N E: 
 
7. 4. 2  
S T U D Y R E P O R TI N G P E RI O D O F S E RI O U S A D V E R S E E V E N T S  
T he re p orti n g peri o d f or S A Es ( wit h o ut re gar d t o ca usalit y or relati o ns hi p) is c o m prise d of t he 
peri o d f oll o wi n g t he si g ni n g of t he i nf or me d c o nse nt f or m u ntil t he e n d of t he st u d y. Eac h A E will 
be assess e d t o det er mi ne w het her it m eets seri o us ness criteri a. If t he A E is c o nsi dere d seri o us, t he 
i n vesti gat or s h o ul d recor d  t his e ve nt t o t he S p o ns or wit hi n 2 4 h o urs of bec o mi n g a ware of t he 
e ve nt. T he i n vesti gat or ma y als o directl y re p ort t his e ve nt t o t he Et hics C o m mittee acc or di n g t o 
its sta n dar d o p erati n g pro ce d ures. E x pecte d ness of S A Es will be deter mi ne d b y t he S p o ns or usi n g 
refere nce saf et y i nf or mati o n s pecifie d i n t he I n vesti gat or’s Br o c h ure .  
A n e ve nt m a y q uali fy f or e x pe dite d re p orti n g t o re g ulat or y  a ut h orities if it is a n S A E, u ne x pecte d 
per r efere n ce s afet y i nf or mati o n a n d c o nsi dere d relate d f oll o wi n g t he g ui d eli nes i n Secti o n 7. 1. 3  
( S us pecte d U ne x pecte d  Seri o us A d verse Reacti o n, S U S A R) a n d 7. 1. 4 ( U na ntici pate d [seri o us] 
a d verse d e vice effect) i n li ne wit h rele va nt le gislati o n. All i n vesti gat ors will r ecei v e a safet y letter 
n otif yi n g t he m of rele va nt S U S A R re p orts. T he i n vesti gat or s h o ul d n otif y t he I nstit uti o nal Re vie w 
B oar d (I R B)/  I nstit uti o nal Et hics C o m mittee  (I E C) as s o o n as is practical, of seri o us e ve nts  i n 
writi n g w h ere t his is r e q uire d b y l ocal  re g ulat or y a ut h orities, a n d i n acc or da nce wit h t he l ocal 
i nstit uti o nal p olic y.  
5 2 3
P P D

At a n y ti me aft er c o m pleti o n of t he S A E re p orti n g peri o d, if a n i n vesti gat or bec o mes a w are of a n 
S A E t hat is s us pecte d b y t he i n vesti gat or t o be relate d t o t he st u d y dr u g, t he  e ve nt will be re p orte d 
t o t he S p o ns or or its desi g nee. If t he i n vesti gat or b ec o mes a ware of a n S A E i n a st u d y s u bject after 
t he last sc he d ul e d f oll o w-u p visit, a n d c o nsi d ers t he e v e nt rel ate d t o pri or St u d y Treat me nt, t he 
i n vesti gat or will re p ort it t o t he S p o ns or or t he a p pr o priate desi g nee. 
Wit hi n  2 4  h o urs  of  t he  site's  a w are n ess  of  t he  e ve nt,  all  S A Es  (re gar dl ess  of  relati o ns hi p  t o 
i n vesti gati o nal pr o d uct) m ust be r e p orte d b y t he I n v esti gat or t hr o u g h data e ntr y i n t he A d vers e 
E ve nt electr o ni c cas e r e p ort f or m (e C R F) via t he Me di data R A V E electr o nic data ca pt ure ( E D C) 
s yste m.  I n t he e ve nt t hat t he Me di dat a R A V E E D C s yste m is u n a vaila ble, t he pa per S A E Re p ort 
f or m s h o ul d be use d a n d fa x e d t o t he P P D P har mac o vi gila n ce ( P V G) Safet y H otli ne Fa x N u m ber 
s h o w n bel o w: 
F acsi mile ( F A X) re p orti n g if re q uire d a: 
A mericas F A X #: 
 
E ur o pe F A X # : 
 
a: Re p orti n g b y F A X is re q uire d f or pa per S A E Re p ort F or ms if electr o nic data ca pt ure 
( E D C) is n ot a vaila ble, re dacte d s u p p orti n g me dical rec or ds, a n d Pre g na nc y Re p ort F or ms.  
All s u p p orti n g d o c u m e nts f or S A E r e p orts, i n cl u di n g m e dical rec or ds a n d dia g n o sti c t est res ults, 
will i n cl u d e r ef er e nce t o t h e st u d y s u bj ect n u m b er. T h e st u d y sit e will re dact all ot h er s u bj ect 
i de ntif yi n g i nf or m ati o n pr es e nt o n S A E s u p p orti n g d o c u m e nts pri or t o s e n di n g t h e re p ort t o t h e 
S p o ns or . T h e s u p p orti n g d o c u m e nts f or S A E re p orts s h o ul d b e s e nt b y fa x t o t h e P P D P V G S afet y 
H otli n e Fa x N u m ber, s h o w n a b o v e.  
In v esti gat or will s u p pl y t he S p o ns or a n d t h e I R B wit h m ore i nf or m ati o n as it b ec o m es a v ail a ble 
a n d a n y a d diti o n al r e q u este d i nf or m ati o n. T h e S p o ns or or its re pres e nt ati v e wil l b e res p o nsi ble 
f or d et er mi ni n g a n d i n t ur n, r e p orti n g S A Es t o re g ulat or y a ut h oriti es acc or di n g t o t he a p pli ca ble 
r e g ulat or y r e q uir e m e nts. S A Es m ust be f oll o w e d b y t h e i n v esti gat or u ntil res ol uti o n, e v e n if t his 
e xte n ds  b e y o n d  t he  st u d y -r e p orti n g  p eri o d. R es ol uti o n  of  a n  S A E  is  d efi ne d  as  t h e  ret ur n  t o 
baseli n e st at us or st a biliz ati o n of t he c o n diti o n wit h t h e e x p ect ati o n t h at it will re m ai n c hr o ni c.  
I n t h e e v e nt of deat h, if a n a ut o ps y is p erf or m e d, a c o p y of t h e re p ort will b e se nt t o t h e S p o ns or. 
7. 4. 3  
N O TI FI C A TI O N O F S E RI O U S A D V E R S E E V E N T S  
I n  acc or da n ce  wit h  l ocal  re g ulati o ns,  t he  S p o ns or  s hall  n otif y  t h e  a p pr o priate  re g ulat or y 
a ut h orities, a n d all partici pati n g i n vesti gat ors i n a writte n safet y re p ort of a n y a d verse e x perie nce 
ass ociate d wit h t he use of t he pr o d uct t hat is b ot h seri o us a n d u ne x pecte d a n d a n y si g nifica nt ne w 
safet y  i nf or mati o n  t hat  mi g ht  materiall y  i nfl ue n ce  t he  be nefit-ris k  assess me nt  of  a  me dici nal 
pr o d uct, s ufficie nt t o c o nsi der c ha n ges i n pr o d uct a d mi nistrati o n or o verall c o n d uct of a cli n ical 
i n vesti gati o n. T he S p o ns or will n otif y re g ul at or y a ge n cies wit hi n t he ti me fra me s pecifie d b y l o cal 
re q uire me nts b ut n o later t ha n 1 0 w or ki n g d a ys f or U A D E, 7 da ys f or a fat al or life-t hreat e ni n g 
S U S A R a n d 1 5 da ys f or all ot her S U S A R S (see Secti o n 7. 1. 3  a n d 7. 1. 4) .  
 
5 2 4
P P D
P P D

7.4.4 
REPORTING OF DEVICE RELATED COMPLAINTS 
A product complaint (or device deficiency) involves any written, electronic, or oral 
communication that alleges deficiencies related to the identity, quality, durability, reliability, 
safety, effectiveness, or performance of a device such as malfunction, misuse or use error 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. All product complaints that meet this definition 
must be reported to the sponsor with 10 days of discovery. Any product complaint that involves 
an AE or SAE must be also reported per Section 7.4. 
Any problems experienced including potential malfunctions of the device, error messages 
displayed on the device screen following treatment or errors that occur during the treatment 
procedure must be reported to the Sponsor or designee immediately for evaluation.  
Additional instructions on reporting to be provided separately. 
7.5 
STUDY DISCONTINUATION 
Inovio Pharmaceuticals reserves the right to discontinue the study at this site or at multiple sites for 
safety or administrative reasons at any time. In particular, a site that does not recruit at a reasonable 
rate may be discontinued. Should the study be terminated and/or the site closed for whatever reason, 
all non-source documentation and study product pertaining to the study must be returned to Inovio 
Pharmaceuticals or its representative. 
The study may be discontinued at any time by an IRB, Inovio Pharmaceuticals Inc., the FDA or 
other government agencies as part of their duties to ensure that research subjects are protected. 
8 STATISTICAL ANALYSIS PLAN 
8.1 
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 
with a histologic diagnosis of cervical HSIL. The study’s primary endpoint is binary: regression to 
CIN1/normal and clearance of HPV-16 and/or HPV-18 infection, based on tissue collected at Week 
36. The primary hypothesis is that VGX-3100 will be superior to placebo regarding the proportion 
who achieve the primary endpoint.  Secondary efficacy analyses involve regression to CIN1/normal, 
clearance of HPV-16 and/or HPV-18 infection from cervical tissue and non-progression of cervical 
lesions. Other secondary analyses concern safety and humoral and cellular immunological measures. 
Exploratory analyses concern tissue immunological measures, durability of clearance of HPV-16 
and/or HPV-18 infection from cervical tissue, association of colposcopy, cytology, virology, other 
microRNA (miRNA) profiles, and DNA methylation profile and efficacy, patient-reported 
outcomes, and association of Immunoscore and efficacy. 
8.2 
RANDOMIZATION AND BLINDING 
Subjects will be randomized (2 VGX-3100:1 Placebo) in a stratified manner according to a) the 
degree of CIN observed in the biopsy specimens at screening (CIN2 vs. CIN3), b) BMI category 
525

(≤25 vs. >25 kg/m2) on Day 0, and c) age category (<25 years vs. ≥25 years) on Day 0. There will 
be no pre-determined number of subjects required to be randomized within each stratum. To ensure 
that milder CIN2 disease is not over-represented in the study, the percentage of subjects enrolled 
with CIN2 will not exceed 50% of the total enrolled. A group of sequential allocation numbers will 
be designated for use by each participating country. 
The study is double-blinded. 
8.3 
SAMPLE SIZE/POWER 
A sample of 198 subjects will be randomized to receive either 6 mg VGX-3100 or placebo IM 
followed by EP in a 2:1 ratio. This sample size provides 90% power to declare VGX-3100 superior 
to placebo, assuming the true proportion of subjects who achieve the primary endpoints is 35% and 
14% for VGX-3100 and placebo, respectively. These proportions also incorporate missing data 
(~10%) classified as non-regressors (failures). The assumptions are based on the Phase 2 study 
results. 
8.4 
ANALYSES POPULATIONS 
Analysis populations will include: 
• 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 primary for the analysis of efficacy in this study. 
• The modified intention to treat (mITT) population includes all subjects who receive at least one 
dose of Study Treatment and who have the analysis endpoint of interest. Subjects in this sample 
will be grouped to treatment arms as randomized.  Analysis of the mITT population will be 
considered supportive for the corresponding ITT population for the analysis of efficacy. 
• The per-protocol (PP) population comprises subjects who receive all doses of Study Treatments 
and have no protocol violations and who have the analysis endpoint of interest. Subjects in this 
sample will be grouped to treatment arms as randomized.  Analyses on the PP population will 
be considered supportive of the corresponding ITT population for the analysis of efficacy.  
Subjects excluded from the PP population will be identified and documented prior to unblinding 
of the study database. 
• The safety analysis set includes all subjects who receive at least one does of Study Treatment. 
Subjects will be analyzed as to the treatment they received.  
8.5 
SUBJECT 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. 
8.6 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and baseline data will be summarized with descriptive statistics: mean standard 
deviation, minimum, median, and maximum values for continuous variables, and percentages for 
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categorical variables, by treatment arm, for the ITT population.  Prior and concomitant medications 
will also be summarized with percentages in this fashion.  
8.7 
MEDICAL HISTORY 
The percentage of subjects with abnormal medical history findings will be summarized by body 
system, by treatment arm, for the ITT population. 
8.8 
PRIOR AND CONCOMITANT MEDICATIONS 
Prior medications are those that were used before the start of the trial (prior to Day 0).  Concomitant 
medications are those used during the course of the trial (on or after Day 0).  Partial stop dates of 
prior and 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 prior and concomitant medications will be 
summarized with percentages by treatment arm, for the mITT population. 
8.9 
EFFICACY ANALYSES 
The true treatment effect on the primary endpoint is δ = pV – pP, where pV and pP denote the true 
population probabilities of the primary endpoint for VGX-3100 and Placebo, respectively.  The 
primary hypothesis of superiority is:  
H0: δ ≤ 0 vs. H1: δ > 0. 
A p-value for this hypothesis test and corresponding 95% confidence interval will be computed 
based on the method of Miettinen and Nurminen [29].  Superiority will be concluded if the one-
sided p-value is <0.025 and the corresponding lower bound of the 95% CI exceeds zero. 
The secondary efficacy endpoints will be analyzed in the same manner as the primary hypothesis, 
but without the hypothesis test p-values. 
The histopathologic efficacy time frame is defined by those who have undergone a biopsy or surgical 
excision at any time starting from 14 days prior to the protocol-specified target date of Week 36.  It 
also includes subjects who undergo early excision or biopsy on or after Dose 1 but prior to this time 
frame or subjects who have no endpoint data for this time frame; these subjects are considered as 
failures for the efficacy endpoints.  Table 7 through Table 11 provide details for the definition of the 
endpoint responses.   
An exploratory analysis will examine the relationship between the primary efficacy endpoint and 
also the secondary efficacy endpoints of regression and clearance individually and the Immunoscore 
results.  Relationships will be examined by using logistic regression models which model the 
efficacy outcomes versus the Immunoscore results and treatment group as regressor variables. 
An exploratory analyses will examine the relationship between the primary efficacy endpoint and a) 
miRNA results, b) DNA methylation results, c) colposcopy results, d) cytology results, and e) HPV 
results.  Relationships will be examined by using logistic regression models which model the 
primary endpoint outcome versus these results and treatment group as regressor variables. 
Other exploratory analyses will examine durability of clearance of HPV-16 and/or HPV-18 infection 
from cervical tissue at Weeks 62 and 88.  Descriptive statistics will be utilized; percentages of 
subjects who cleared will be presented by time point or anatomic location and treatment group. 
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8.10     IMMUNOGENICITY ANALYSES 
Post-baseline cellular and humoral responses will be compared between treatment groups using a 
difference in medians and associated exact non-parametric 95% CI.  Increases from baseline in 
interferon-γ ELISpot response magnitudes and HPV E6 and E7 titers from ELISA at Weeks 15 and 
36 visits will be evaluated.  Increases from baseline in CD8+ / CD137+ PBMCs Perforin+ results at 
the Week 15 visit will be evaluated. 
Changes from baseline in tissue response will be compared between treatment groups using a 
difference in means and associated t-distribution based 95% CIs. 
Valid samples for statistical analysis purposes will be those collected within 7 or 14 days of the 
specified time points (see Table 1).  Baseline is defined as the last measurement prior to the first 
treatment administration. 
The mITT population will be used for immunogenicity analyses. 
8.11  SAFETY ANALYSES 
8.11.1 
ADVERSE EVENTS 
All AEs 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 28 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 
[29].  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. 
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. 
8.12 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. 
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8.13 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 ITT population. 
8.14 PATIENT REPORTED OUTCOMES 
As an exploratory endpoint, patient reported outcomes will be compared between treatment arms, 
based on PRO endpoints. Median changes from baseline for the SF-36 and EQ-5D-5L responses 
and median days of worsened quality of life for the Week 40 Quality of Life questionnaire will be 
analyzed using exact non-parametric 95% confidence intervals for the differences in medians.  The 
proportion of subjects who report a worsened quality of life for the Week 40 Quality of Life 
questionnaire will be analyzed using a 95% Miettinen and Nurminen confidence interval for the 
difference in proportions. 
 
In addition, the Week 36 and beyond outcomes will be summarized according to those with 
excision versus those without excision. 
 
The mITT population will be used for PRO analyses. 
8.15 MISSING VALUES 
Missing data will be considered as non-regressors (failures) for the ITT efficacy analysis.  A 
subject’s regression outcome is missing if her CIN grade and HPV clearance at Week 36 cannot be 
determined. Also, any subject who undergoes an unscheduled excision or biopsy in which tissue 
sample was obtained after Dose 1 and before Week 36 will be considered a non-regressor regardless 
of the Week 36 result. Efficacy analyses using the mITT population will be conducted and will serve 
as sensitivity analyses regarding missing data. 
8.16 SUBGROUP ANALYSES 
Primary and secondary efficacy endpoints will be analyzed by history of exposure to prophylactic 
HPV vaccines. 
8.17 INTERIM ANALYSIS 
For reasons of futility (early evidence of poor efficacy of VGX-3100) or safety issues, the DSMB 
could recommend stopping enrollment at any time; no formal interim analysis will be performed for 
this purpose.  The type I error of 0.05 will not be adjusted for possible early stopping due to futility. 
Group-level unblinded (VGX-3100, Placebo) summaries and analyses of efficacy will be produced 
once the primary endpoint Week 36 visit 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 88 visit.  The summaries and analyses will allow the 
Sponsor to have results with respect to the primary endpoint and all other efficacy endpoints 
corresponding to the cervix and the Week 36 visit on which to make decisions regarding the VGX-
3100 program, while still gathering secondary and exploratory endpoint and safety data through 
the final Week 88 visit.  The planned set of summaries and analyses is comprised of a) the primary 
composite endpoint of histopathologic regression and virologic clearance, b) the secondary 
529

endpoint of histopathologic regression, c) the secondary endpoint of virologic clearance, d) the 
secondary composite endpoint of histopathologic regression to normal and virologic clearance, e) 
the secondary endpoint of histopathologic regression to normal, and f) the secondary endpoint of 
histopathologic non-progression.  None of these summaries or analyses will be provided if the total 
count of subjects who experience the event of interest is greater than 0 and the count for any 
treatment group relative to this total count is less than 3% for a given summary/analysis.  Also, 
items a) through f) are planned to be produced in the order in which they are listed, but as there are 
intersecting endpoints among these items, items among b) through f) will not be produced if the 
difference in total count of subjects who experience the event of interest is greater than 0 and the 
count for any treatment group is 0, relative to any preceding item in the set.  The group-level 
unblinded (VGX-3100, Placebo) production of the summaries and analyses will not include anyone 
directly involved with the trial or any additional unblinded personnel; only the external Contract 
Research Organization (CRO), PPD, which has already been 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. 
9 DATA COLLECTION, MONITORING AND REPORTING 
9.1 
CONFIDENTIALITY AND PRIVACY 
A report of the results of this study may be published or sent to the appropriate health authorities in 
any country in which the study products are legally marketed or may ultimately be marketed, but 
the subject’s name will not be disclosed in these documents. The subject’s name may be disclosed 
to the study sponsor, Sponsor, the governing health authorities or the Food and Drug Administration 
(FDA), if they inspect the study records. Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information. 
Written Authorization and other documentation in accordance with the relevant country and local 
privacy requirements (where applicable) are to be obtained from each subject prior to enrollment 
into the study, and/or from the subject’s legally authorized representative in accordance with the 
applicable privacy requirements (e.g., the Health Insurance Portability and Accountability Act 
Standards for Privacy of Individually Identifiable Health Information (HIPAA). 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of the research subject to revoke their authorization for use of their PHI 
The rights of the research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the sponsor retains the ability 
to use all information collected prior to the revocation of subject authorization. For subjects that 
530

have revoked authorization to collect or use PHI, attempts should be made to obtain permission to 
collect at least vital status (i.e., that the subject is alive) at the end of their scheduled study period. 
9.2 
SOURCE DOCUMENTS 
Source data is all information, original records or clinical findings, laboratory results, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source 
data are contained in original source documents. Examples of these original documents, and data 
records include: hospital records, clinical and office charts, laboratory notes, memoranda, subject’s 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records 
kept at the pharmacy, at the laboratories, and at medical records and within information technology 
systems that are involved in the clinical trial. 
A medical history must be present in the source documents. A medication history must be present 
in the source documents. All prescription and nonprescription medications taken within l week prior 
to entry must be recorded on the CRF. Actual or estimated start and stop dates must be provided. 
9.3 
RECORDS RETENTION 
Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution 
should make available for direct access all requested 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 study essential documents for at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product. This retention period 
may be superseded by applicable regulatory requirements (e.g. minimum of 25 years for Health 
Canada). The sponsor will inform the investigator/institution as to when these documents are no 
longer needed to be retained. 
9.4 
SAFETY AND QUALITY MONITORING  
9.4.1 
DATA & SAFETY MONITORING BOARD 
A Data & Safety Monitoring Board (DSMB) will be established to protect the research subjects 
through independent analysis of emerging data from the trial.  The DSMB will meet quarterly to 
review unblinded safety data and regression/clearance results.  If there are no new safety data or 
regression/clearance results to review for a quarterly scheduled meeting the DSMB will be notified 
and the meeting may be cancelled; Ad hoc meetings may be scheduled to review new data as 
applicable. The DSMB will be charged with advising the Sponsor if there appears to be a safety 
issue and with advising the Sponsor if it appears that regression in the VGX-3100 group is 
unacceptably low compared to the placebo group; no formal interim analysis will be performed 
for this purpose. The DSMB Chair, upon consultation with the other voting members of the 
DSMB, has the authority to recommend suspension or stopping the study and to request a full 
531

DSMB review and ad hoc statistical analyses. The DSMB charter will define the membership, 
responsibilities and procedures for the meeting.  
9.4.2 
PATHOLOGY ADJUCATION COMMITTEE 
All histology slides (i.e. cervical biopsies or surgical excision tissue) will be read by a Pathology 
Adjudication Committee (PAC) to ensure consistent assignment of disease status for both study 
eligibility and the efficacy analysis. The PAC will consist of a total of four pathologists in separate 
locations. Each specimen will be read by two pathologists independently in a blinded fashion.    
 
9.4.3 
CLINICAL MONITORING 
Clinical Monitoring of the clinical trial will be performed by experienced monitors, who will 
report to the Sponsor or the Sponsor designee. Records for all clinical subjects in this trial will be 
monitored. The following clinical site monitoring tasks will be performed at all sites: 
• Prior to trial initiation, a site visit will be conducted to review all relevant forms and 
documentation, to ensure the site is qualified and compliant with all applicable requirements. 
• All clinical site monitoring visits will be documented. 
• Periodic site visits will be performed throughout the study. 
• The site monitor will be responsible for addressing and documenting the following study 
conduct activities and obligations and will: 
o Assure that the study is being conducted in accordance with the protocol, applicable 
regulatory agency regulations, and IRB policies 
o Discuss study conduct issues and incidents of noncompliance with the Investigator and/or 
study 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 serious 
adverse events (SAE) and provide subsequent follow-up report of the final outcome to the 
IRB 
o Throughout the study, inspect all source documents to ensure they are complete, logical, 
consistent, attributable, legible, contemporaneous, original, and accurate (ALCOA).  
o Assure that the study facilities continue to be acceptable 
o Compare the study 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 per 
laboratory manual requirements 
532

10 ETHICS 
10.1  INVESTIGATOR AND SPONSOR RESPONSIBILITIES 
The investigator and Sponsor are responsible for ensuring that the clinical study is performed in 
accordance with the protocol, the Declaration of Helsinki, principles of Good Clinical Practice 
(GCP), and applicable regulatory requirements.  
10.2 INSTITUTIONAL REVIEW BOARD OR INSTITUTIONAL ETHICS 
COMMITTEE (IRB/IEC) 
The investigator will undertake the study after full approval of the protocol and adjunctive materials 
(e.g., informed consent form, advertising) has been obtained from the applicable IRB/IEC and a 
copy of this approval has been received by the sponsor. 
Investigator responsibilities relevant to the IRB include the following: 
• During the conduct of the study, submit progress reports to the IRB/IEC as required.  
• Notify the Sponsor immediately of any SAEs or serious unanticipated adverse device effects. 
• If Sponsor notifies you about any reportable safety events notify the IRB immediately. 
• As required, obtain approval from the IRB/IEC for protocol amendments and for revisions to 
the consent form or subject recruitment advertisements; 
• Reports on, and reviews of, the trial and its progress will be submitted to the IRB by the 
investigator at intervals stipulated in their guidelines and in accordance with pertinent 
regulations and guidelines. 
• Maintain a file of study-related information that includes all correspondence with the IRB; 
• Notify IRB when study is completed (i.e. after the last study visit of the final study subject); 
• After study completion provide the IRB with a final report on the study. 
10.3 OFFICE OF BIOTECHNOLOGY ACTIVITIES (OBA) 
The investigator and Sponsor are responsible for ensuring that the clinical study is reviewed and 
approved according to local and applicable global regulations (e.g., NIH Office of Biotechnology 
Activities) governing research that involves recombinant or synthetic nucleic acid molecules.   
11 PROTECTION OF HUMAN SUBJECTS 
11.1  COMPLIANCE WITH INFORMED CONSENT REGULATIONS  
Written informed consent is to be obtained from each subject prior to Screening into the study, 
and/or from the subject’s legally authorized representative.  The process for obtaining informed 
consent must also be documented in the subject’s medical record.  
11.2  COMPLIANCE WITH IRB/IEC REQUIREMENTS 
This study is to be conducted in accordance with applicable IRB/IEC regulations.  The Investigator 
must obtain approval from a properly constituted IRB/IEC prior to initiating the study and re-
approval or review at least annually.  Sponsor is to be notified immediately if the responsible 
IRB/IEC has been disqualified or if proceedings leading to disqualification have begun.  Copies of 
all IRB/IEC correspondence with the investigator must be provided to Sponsor. 
533

11.3  COMPLIANCE WITH GOOD CLINICAL PRACTICE 
This protocol is to be conducted in accordance with the applicable GCP regulations and guidelines.  
11.4  COMPLIANCE WITH ELECTRONIC RECORDS/SIGNATURES 
REGULATIONS (21CFR PART 11) 
When applicable, this study is to be conducted in compliance with the regulations on electronic 
records and electronic signature. 
11.5  COMPLIANCE WITH PROTOCOL 
Subjects are not required to follow special instructions specific to the Investigational Product used 
in this study however will be asked to complete a participant diary card during their study 
participation.  Subjects will be provided with Investigator emergency contact information and 
advised to report all adverse events. While every effort should be made to avoid protocol deviations, 
should a deviation be discovered, Sponsor must be informed immediately. Any protocol deviation 
impacting Subject safety must be reported to the Medical Monitor immediately. 
11.6  CHANGES TO THE PROTOCOL 
The Investigator should not implement any deviation from or changes to the protocol without 
approval by Sponsor and prior review and documented approval/favorable opinion from the IRB of 
a protocol amendment, except where necessary to eliminate immediate hazards to study subjects, or 
when the changes involve only logistical or administrative aspects of the study (e.g., change in 
monitors, change of telephone numbers).  
12 FINANCING AND INSURANCE 
Inovio Pharmaceuticals is the sponsor in all participating countries and is fully supporting the study.  
Clinical trial insurance has been taken out according to the laws of the countries where the study 
will be conducted. 
13 PUBLICATION POLICY 
Publication of the results of this trial in its entirety will be allowed. The proposed presentation, 
abstract and/or manuscript must be made available to The Sponsor 60 days prior to submission for 
publication. The Sponsor shall have thirty (30) days after receipt of the copies to object to the 
proposed presentation or publication because there is patentable subject matter that needs protection. 
In the event that The Sponsor makes such objection, the researcher(s) shall refrain from making such 
publication or presentation for a maximum of three (3) months from the date of receipt of such 
objection in order for patent application(s) (directed to the patentable subject matter contained in the 
proposed publication or presentation) to be filed with the United States Patent and Trademark Office 
and/or foreign patent office(s). 
 
 
534

14  REFERENCES 
1. 
Centers for Disease C, Prevention. Human papillomavirus-associated cancers - United States, 2004-
2008. MMWR Morb Mortal Wkly Rep 2012,61:258-261. 
2. 
Satterwhite CL, Torrone E, Meites E, Dunne EF, Mahajan R, Ocfemia MC, et al. Sexually 
transmitted infections among US women and men: prevalence and incidence estimates, 2008. Sex 
Transm Dis 2013,40:187-193. 
3. 
Hariri S, Unger ER, Sternberg M, Dunne EF, Swan D, Patel S, et al. Prevalence of genital human 
papillomavirus among females in the United States, the National Health And Nutrition Examination 
Survey, 2003-2006. J Infect Dis 2011,204:566-573. 
4. 
American Cancer Society. Cancer Facts & Figures. In. Atlanta; 2016. 
5. 
Bruni L, Alberto G, Aldea M, Serrano B, Valencia S, Brotons M, et al. Human Papillomavirus and 
Related Diseases in theWorld. Summary Report 2015-12-23. ICO Information Centre on HPV and 
Cancer (HPV Information Centre). In; 2015. 
6. 
Guan P, Howell-Jones R, Li N, Bruni L, de Sanjose S, Franceschi S, et al. Human papillomavirus 
types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. Int J 
Cancer 2012,131:2349-2359. 
7. 
Apgar BS, Zoschnick L, Wright TC, Jr. The 2001 Bethesda System terminology. Am Fam Physician 
2003,68:1992-1998. 
8. 
McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW, et al. Natural history of 
cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a 
retrospective cohort study. Lancet Oncol 2008,9:425-434. 
9. 
McIndoe WA, McLean MR, Jones RW, Mullins PR. The invasive potential of carcinoma in situ of 
the cervix. Obstet Gynecol 1984,64:451-458. 
10. 
Future Ii Study Group. Supplementary Material: Quadrivalent vaccine against human papillomavirus 
to prevent high-grade cervical lesions. N Engl J Med 2007,356:1915-1927. 
11. 
The American College of Obstetricians and Gynecologists. FAQs Loop Electrosurgical Excision 
Procedure (LEEP). In; 2014. 
12. 
Aihara H, Miyazaki J. Gene transfer into muscle by electroporation in vivo. Nat.Biotechnol. 
1998,16:867-870. 
13. 
Gehl J, Mir LM. Determination of optimal parameters for in vivo gene transfer by electroporation, 
using a rapid in vivo test for cell permeabilization. Biochemical and Biophysical Research 
Communications 1999,261:377-380. 
14. 
Sardesai NY, Weiner DB. Electroporation delivery of DNA vaccines: prospects for success. 
Curr.Opin.Immunol. 2011,23:421-429. 
15. 
van Drunen Littel-van den H, Hannaman D. Electroporation for DNA immunization: clinical 
application. Expert.Rev.Vaccines. 2010,9:503-517. 
16. 
Bodles-Brakhop AM, Heller R, Draghia-Akli R. Electroporation for the Delivery of DNA-based 
Vaccines and Immunotherapeutics: Current Clinical Developments. Mol Ther. 2009. 
535

17. 
Hirao 
LA, 
Wu 
L, 
Khan 
AS, 
Satishchandran 
A, 
Draghia-Akli 
R, 
Weiner 
DB. 
Intradermal/subcutaneous immunization by electroporation improves plasmid vaccine delivery and 
potency in pigs and rhesus macaques. Vaccine 2008,26:440-448. 
18. 
Khan AS, Pope MA, Draghia-Akli R. Highly efficient constant-current electroporation increases in 
vivo plasmid expression. DNA & Cell Biology 2005,24:810-818. 
19. 
Bagarazzi ML, Yan J, Morrow MP, Shen X, Parker RL, Lee JC, et al. Immunotherapy against 
HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci.Transl.Med. 
2012,4:155ra138. 
20. 
Diehl MC, Lee JC, Daniels SE, Tebas P, Khan AS, Giffear M, et al. Tolerability of intramuscular 
and intradermal delivery by CELLECTRA((R)) adaptive constant current electroporation device in 
healthy volunteers. Hum Vaccin Immunother 2013,9:2246-2252. 
21. 
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. 
22. 
Xiang L, Li J, Yang W, Xu X, Wu X, Wang H, et al. Conization Using an Electrosurgical Knife for 
Cervical Intraepithelial Neoplasia and Microinvasive Carcinoma. PLoS One 2015,10:e0131790. 
23. 
Stoler MH, Vichnin MD, Ferenczy A, Ferris DG, Perez G, Paavonen J, et al. The accuracy of 
colposcopic biopsy: analyses from the placebo arm of the Gardasil clinical trials. Int J Cancer 
2011,128:1354-1362. 
24. 
Kahwati LC, Haigler L, Rideout S, Markova T. What is the best way to diagnose menopause? J Fam 
Pract 2005,54:1000-1002. 
25. 
Sarri G, Davies M, Lumsden MA, Guideline Development G. Diagnosis and management of 
menopause: summary of NICE guidance. BMJ 2015,351:h5746. 
26. 
Maruish ME. User’s manual for the SF-36v2 Health Survey. 3rd ed. Lincoln, RI: Quality Metric 
Incorporated; 2011. 
27. 
EuroQol G. EuroQol--a new facility for the measurement of health-related quality of life. Health 
Policy 1990,16:199-208. 
28. 
Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, et al. Measurement properties 
of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual 
Life Res 2013,22:1717-1727. 
29. 
Miettinen O, Nurminen M. Comparative analysis of two rates. Stat Med 1985,4:213-226. 
 
 
 
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15 APPENDIX 
15.1 APPENDIX A:  GUIDELINES FOR COLPOSCOPY, BIOPSY, AND 
SURGICAL EXCISION 
Colposcopy Procedure 
It is recommended that all study colposcopies performed after informed consent be according the procedures 
recommended by the American Society of Colposcopy and Cervical Pathology (ASCCP): 
1. Use warm, clean water to lubricate the vaginal speculum.  Avoid other lubricant substances which could 
obscure results. 
2. If the vaginal walls are lax, a lateral vaginal sidewall retractor aligned perpendicular to the speculum may 
facilitate visualization. 
3. Examine the cervico-vaginal secretions and remove any excess mucus from the cervix with saline-soaked 
cotton swabs. 
4. Obtain any required specimens required for cytology and HPV testing. 
5. Using low-power magnification (5x to 10 x) inspect the cervix for obvious areas of abnormalities. 
6. Swab or spray the cervix with 3-5% acetic acid.  Reapply every 2-3 minutes during the examination. 
7. Use the green or blue filter to examine blood vessels.  Increase magnification (15x) 
8. Identify the distal and proximal boarders of the transformation zone. 
a. The inner border is the entire 360-degree circumference of the squamocolumnar junction 
i. If the junction is proximal to the external os, in the canal, use a cotton-tipped 
applicator to pry either the anterior lip up or the posterior lip down or use an 
endocervical speculum 
ii. If the junction is not visualized in its entire circumference, the colposcopy is deemed  
inadequate  
b. The distal limit of the transformation zone may be identified by finding the most distal crypt 
openings or nabothian follicles in the lips of the cervix and drawing an imaginary line 
connecting these landmarks 
9. Inspect the entire new squamocolumnar junction and detect and evaluate any abnormal areas.   
10. Evaluate the upper third portion of the vagina. 
11. Lugol or Schiller’s solution may be applied to further define previously identified lesions.   
Cervical Biopsies  
 Endocervical Curettage 
ECC is to be performed using a kervorkian curette or equivalent instrument.  Rotate and scrape the curette 
360○ in the endocervical canal and use a cytobrush to remove the specimen.  Deposit the specimen onto a 
Telfa pad before depositing in the specimen vial containing 10% neutral buffered formalin solution and 
labeled with the subject identification (SID) number. 
Ectocervical Biopsies 
Ectocervical biopsies should only be performed prior to Week 36 if disease progression is suspected.  Only 
the suspect lesion should be biopsied in that circumstance.   
If the subject is eligible for 4 quadrant biopsy at the Week 36 visit, the following procedure should be 
followed: 
537

1. Label each specimen vial containing 10% neutral buffered formalin solution with the subject’s ID number 
and the quadrant number according to the figure below. 
2. Perform and record colposcopy findings from each quadrant according to the following categories 
a. Negative (no lesion present) 
b. Low Grade  (e.g. pale acetowhite lesion on or off the squamocolumnar junction 
c. High Grade  (e.g. dense acetowhite lesion often with mosaic pattern or punctation) 
d. Suspicion of invasive cancer 
e. Invasive cancer 
3. Perform colposcopic directed biopsies from all quadrants. 
4. Multiple biopsies can be obtained of a lesion at the discretion of the investigator but must be uniquely 
labeled  
5. If a quadrant is free of lesions, obtain a random biopsy at the squamocolumnar junction in that quadrant 
at 2, 4, 8, or 10 o’clock. 
6. Prepare the biopsy specimen vials for shipment according to the Laboratory Manual. 
 
Figure 1 – Biopsy Quadrant Numbers 
 
 
Surgical Excision 
For subjects undergoing surgical excision at the Week 36 visit, the following procedure should be followed: 
1. Label each specimen vial containing 10% neutral buffered formalin solution with the SID number and 
the specimen type. 
2. Record colposcopy findings from each quadrant according to the following categories 
a. Negative (no lesion present) 
b. Low Grade  (e.g. pale acetowhite lesion on or off the squamocolumnar junction 
c. High Grade  (e.g. dense acetowhite lesion often with mosaic pattern or punctation) 
d. Suspicion of invasive cancer 
e. Invasive cancer 
3. Perform the LEEP or CKC per usual practice. 
4. Specimen should be marked at 12 o’clock with suture or gentian violet ink for purposes of orientation 
5. Prepare the biopsy specimen vials for shipment according to the Laboratory Manual. 
 
538

C O N FI D E N TI A L 
• 
• 
' 
' 
,-
, 
1 n o v 1 0 
F O R M 
TI T L E 
Pr ot o c ol A p pr o v al P a g e 
S E C TI O N 1: C LI NI C A L T RI A L P R O T O C O L I N F O R M A TI O N 
Pr ot o c ol #: 
H P V- 3 0 1 
A P R O S P E C TI V E, R A N D O MI Z E D, D O U B L E- B LI N D, P L A C E B O- C O N T R O L L E D 
P H A S E 3 S T U D Y O F V G X- 3 1 0 0 D E LI V E R E D I N T R A M U S C U L A R L Y 
F ull Pr ot o c ol Titl e: 
F O L L O W E D B Y E L E C T R O P O R A TI O N WI T H C E L L E C T R A ™ 5 P S P F O R T H E 
T R E A T M E N T O F H P V- 1 6 A N D/ O R H P V- 1 8 R E L A T E D HI G H G R A D E 
S Q U A M O U S I N T R A E PI T H E LI A L L E SI O N ( H SI L) O F T H E C E R VI X 
Pr ot o c ol V er si o n #: 
V er si o n 5. 0 
Pr ot o c ol V er si o n D at e: 
2 0 N o v e m b er 2 0 1 9 
( d d M m m y y y y) 
S E C TI O N 2: A U T H O R SI G N A T U R E 
I wr ot e t h e pr ot o c ol li st e d a b o v e a n d c o nfir m t h at t h e c o nt e nt i s c o m pl et e a n d a c c ur at e. 
 
 
D at e ( d d M m m y y y y) 
S E C TI O N 3: A P P R O V A L SI G N A T U R E S 
M y si g n at ur e i n di c at e s t h at I h a v e r e vi e w e d a n d a p pr o v e t h e c o nt e nt of t h e pr ot o c ol li st e d a b o v e . 
 
 
 
 
 
 
C L- F R M- 0 0 9 1 
F or m V er si o n: B 
D at e ( d d M m m y y y y) 
D at e ( d d M m m y y y y) 
D at e ( d d M m m y y y y) 
D at e ( d d M m m y y y y) 
D at e ( d d M m m y y y y) 
F or m Eff e cti v e D at e: 1 4 N o v 2 0 1 9 
P a g e 1 of 1 
5 3 9
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
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I 0 
1 0 
Pr ot o c ol A p pr o v al P a g e 
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: n•,e, .. , ... ,., A P R O S P E C TI V E, R A N D O MI Z E D, D O U B L E- B LI N D, P L A C E B O- C O N T R O L L E D 
P H A S E 3 S T U D Y O F V G X- 3 1 0 0 D E LI V E R E D I N T R A M U S C U L A R L Y 
F O L L O W E D B Y E L E C T R O P O R A TI O N WI T H C E L L E C T R A T M 5 P S P F O R T H E 
T R E A T M E N T O F H P V- 1 6 A N D/ O R H P V- 1 8 R E L A T E D HI G H G R A D E 
.... , w.•• Y•• .. ;; .... :·.•: .. , S Q U A M O U S I N T R A E PI T H E LI A L L E SI O N ( H SI L) O F T H E C E R VI X 
I wr ot e t h e pr ot o c ol li st e d a b o v e a n d c o nfir m t h at t h e c o nt e nt i s c o m pl et e a n d a c c ur at e. 
 
 
D at e ( d d M m m y y y y) 
M y si g n at ur e i n di c at e s t h at I h a v e r e vi e w e d a n d a p pr o v e t h e c o nt e nt of t h e pr ot o c ol li st e d a b o v e. 
 
 
 
 
 
 
 
C L- F R M- 0 0 9 1 
F or m V er si o n: B 
D at e ( d d M m m y y y y) 
D at e ( d d M m m y y y y) 
D at e ( d d M m m y y y y) 
D at e ( d d M m m y y y y) 
D at e ( d d M m m y y y y) 
F or m Eff e cti v e D at e: 1 4 N o v 2 0 1 9 
P a g e 1 of 1 
5 4 0
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

Pr ot o c ol A d mi ni str ati v e M e m o ( P A M) Si g n at ur e P a g e 
H P V- 3 0 1 
A P R O S P E C TI V E, R A N D O MI Z E D, D O U B L E- B LI N D, P L A C E B O- C O N T R O L L E D 
P H A S E 3 S T U D Y O F V G X- 3 1 0 0 D E LI V E R E D I N T R A M U S C U L A R L Y F O L L O W E D B Y 
E L E C T R O P O R A TI O N WI T H C E L L E C T R A ™ 5 P S P F O R T H E T R E A T M E N T O F H P V-
1 6 A N D/ O R H P V- 1 8 R E L A T E D HI G H G R A D E S Q U A M O U S I N T R A E PI T H E LI A L 
L E SI O N ( H SI L) O F T H E C E R VI X 
P A M # 1 
D at e: 1 0 S e p 2 0 1 8 
Writt e n b y: 
 
R e vi e w e d a n d A p pr o v e d b y: 
N, C R N P, M B A 
 
 M D, P h. D. 
 
C O N FI D E N TI A L 
D at e ( D D M M M Y Y Y Y) 
D at e ( D D M M M Y Y Y Y) 
P a g e 1 of 1 
5 4 1
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

• 
• 
VIO 
PHARMACEUTICALS 
Protocol Administrative Memo {PAM)# 1 
PAM Date: 1 0SEP2018 
To 
HPV-301 
A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
PHASE 3 STUDY OF VGX-3100 DELIVERED INTRAMUSCULARLY FOLLOWED BY 
ELECTROPORATION WITH CELLECTRA™ 5PSP FOR THE TREATMENT OF HPV-
16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS INTRAEPITHELIAL 
LESION (HSIL) OF THE CERVIX 
Protocol Version: 4.0 
Protocol Version Date: 29 March 2018 
Sponsored by: 
lnovio Pharmaceuticals, Inc. 
IND#: 13683 
EudraCT #2016-002761-63 
542

V G X- 3 1 0 0 
l n o vi o P h ar m a c e uti c al s, I n c. 
Pr ot o c ol #: H P V- 3 0 1 
Pr ot o c ol A d mi ni str ati v e M e m o #: 1 
M e di c al M o nit or A p pr o v al P a g e 
M e di c al M o nit or Si g n at ur e: 
 
l n o vi o P h ar m a c e uti c a l s, I n c. 
D at e 
T hi s m e m o c o nt ai n s i nf or m ati o n t h at i s c o n si d er e d t o b e a d mi ni str ati v e or cl arif yi n g 
i n n at ur e a n d d o e s n ot m e et t h e crit eri a of a n i m m e di at e pr ot o c ol a m e n d m e nt. 
Pl e a s e di stri b ut e t hi s m e m o t o all a p pr o pri at e st aff m e m b er s, a n d fil e it wit h t h e 
sit e' s pr ot o c ol d o c u m e nt s. C o n s ult t h e l o c al I n stit uti o n al R e vi e w B o ar d (I R B)/ Et hi c s 
C o m mitt e e ( E C) r e g ar di n g s u b mi s si o n r e q uir e m e nt s f or Pr ot o c ol A d mi ni str ati v e 
M e m o s ( P A M s). 
Pr ot o c ol V er si o n D at e: 2 9 M ar 2 0 1 8 
C O N FI D E N TI A L 
P a g e 2 of 4 
Pr ot o c ol V er si o n: 4. 0 
5 4 3
P P D
P P D
P P D

VGX-3100 
lnovio Pharmaceuticals, Inc. 
Protocol #: HPV-301 
Protocol Administrative Memo #: 1 
PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT 
I have read and understood this Protocol Administrative Memo (PAM) #1 and will 
incorporate it as part of the protocol. I will provide a copy of this PAM to the Institutional 
Review Board or Independent Ethics Committee (IRB/IEC) overseeing the conduct of 
the trial. 
The signature of the Principal Investigator (Pl) constitutes the Pl's acknowledgement of, 
and agreement with, this PAM and provides the necessary assurances that this trial will 
be conducted in accordance with ICH/GCP and ISO guidelines, local legal and 
regulatory requirements, and all stipulations of the protocol. 
Principal Investigator Signature: _____________ _ 
Printed Name of Principal Investigator 
Site Number: ----------
Site Name: -------------
Protocol Version Date: 29Mar2018 
CONFIDENTIAL 
Page 3 of 4 
Date (DDMMMYYYY) 
Protocol Version: 4.0 
544

VGX-3100 
lnovio Pharmaceuticals, Inc. 
Protocol#: HPV-301 
Protocol Administrative Memo #: 1 
Item 1: 
Clarification of Section 6.1.1 Screening Evaluations 
The current protocol reads as below: 
Additionally, Investigators may discuss with the Sponsor on a case-by-case basis the screening 
of subjects with abnormal cytology findings (i.e. HSIL or ASC-H with or without local HPV-16 or 
18 genotype results) obtained as part of standard of care. 
It should be read: 
Additionally, Investigators may discuss with the Sponsor on a case-by-case basis the screening 
of subjects with abnormal cytology findings (e.g., HSIL or ASC-H with or without local HPV-16 or 
18 genotype results) obtained as part of standard of care. 
This memo is being provided to clarify that screening based on abnormal cytology findings is not 
limited to HSIL or ASC-H. A subject with any abnormal Pap smear cytology finding (including 
LSIL, ASCUS) with or without HPV typing may be eligible for screening upon written approval 
from the Medical Monitor. 
Protocol Version Date: 29Mar2018 
CONFIDENTIAL 
Page 4 of 4 
Protocol Version: 4.0 
545

• 
• 
VIO 
PHARMACEUTICALS 
Protocol Administrative Memo (PAM)# 2 
PAM Date: 29APR2019 
To 
HPV-301 
A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
PHASE 3 STUDY OF VGX-3100 DELIVERED INTRAMUSCULARLY FOLLOWED BY 
ELECTROPORATION WITH CELLECTRA™ SPSP FOR THE TREATMENT OF HPV-
16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS INTRAEPITHELIAL 
LESION (HSIL) OF THE CERVIX 
Protocol Version: 4.0 
Protocol Version Date: 29 March 2018 
Sponsored by: 
lnovio Pharmaceuticals, Inc. 
IND#: 13683 
EudraCT #2016-002761-63 
546

V G X- 3 1 0 0 
l n o vi o P h ar m a c e uti c al s, I n c. 
Pr ot o c ol #: H P V- 3 0 1 
Pr ot o c ol A d mi ni str ati v e M e m o #: 2 
M e di c al M o nit or A p pr o v al P a g e 
M e di c al M o nit or Si g n at ur e: 
l n o vi o P h ar m a c e uti c al s, I n c. 
D at e 
T hi s m e m o c o nt ai n s i nf or m ati o n t h at i s c o n si d er e d t o b e a d mi ni str ati v e or cl arif yi n g 
i n n at ur e a n d d o e s n ot m e et t h e crit eri a of a n i m m e di at e pr ot o c ol a m e n d m e nt. T h e 
c h a n g e s d o n ot aff e ct t h e o v er all d e si g n, s af et y, or q u alit y of t h e tri al. Pl e a s e 
di stri b ut e t hi s m e m o t o all a p pr o pri at e st aff m e m b er s, a n d fil e it wit h t h e sit e' s 
pr ot o c ol d o c u m e nt s. C o n s ult t h e l o c al I n stit uti o n al R e vi e w B o ar d (I R B)/ Et hi c s 
C o m mitt e e ( E C) r e g ar di n g s u b mi s si o n r e q uir e m e nt s f or Pr ot o c ol A d mi ni str ati v e 
M e m o s ( P A M s). 
Pr ot o c ol V er si o n D at e: 
2 9 M ar 2 0 1 8 
C O N FI D E N TI A L 
P a g e 2 of 7 
Pr ot o c ol V er si o n: 4. 0 
5 4 7
P P D
P P D

VGX-3100 
lnovio Pharmaceuticals, Inc. 
Protocol#: HPV-301 
Protocol Administrative Memo #:2 
PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT 
I have read and understood this Protocol Administrative Memo (PAM) #2 and will 
incorporate it as part of the protocol. I will provide a copy of this PAM to the Institutional 
Review Board or Independent Ethics Committee (IRB/IEC) overseeing the conduct of 
the trial. 
The signature of the Principal Investigator (Pl) constitutes the Pl's acknowledgement of, 
and agreement with, this PAM and provides the necessary assurances that this trial will 
be conducted in accordance with ICH/GCP and ISO guidelines, local legal and 
regulatory requirements, and all stipulations of the protocol. 
Principal Investigator Signature: _____________ _ 
Printed Name of Principal Investigator 
Site Number: ----------
Site Name: -------------
Protocol Version Date: 29Mar201 B 
CONFIDENTIAL 
Page 3 of 7 
Date (DDMMMYYYY) 
Protocol Version: 4.0 
548

VGX-3100 
lnovio Pharmaceuticals, Inc. 
Protocol #: HPV-301 
Protocol Administrative Memo #:2 
Item 1: 
Clarification of HIV Testing time window-within 45 
DaysofDayO 
Exclusion Criteria # 8a (Pages 22 and 49 of Protocol) 
The current protocol reads as below: 
a) 
History of or positive serologic test for HIV at screening (performed within 30 days prior to 
Day0) 
It should read: 
a) 
History of or positive serologic test for HIV at screening (performed within 45 days prior 
to Day 0) 
This change will make the HIV testing window consistent with Section 6.1.1 Screening 
Evaluations of the Protocol which reads Serology (HIV Antibody, within 45 days of Day 0). This 
memo is being provided to clarify that serology HIV testing must be completed within 45 Days of 
Daya. 
Item 2: 
Clarification of Body Mass Index (BMI) calculation 
The protocol does not currently specify whether to calculate stratification BMI based on 
screening measurements or Day O measurements. BMI should be calculated using height and 
weight measurements taken at Day O prior to dosing. 
Sites are encouraged to calculate BMI manually using the below kg/m2 formula, to calculate BMI 
for the determination of the stratification group within YPrime at Day 0. 
BM/= weight (kg) I [height (m)f 
or if using pounds and inches 
BM/= 703 x weight (lbs) I [height (in)f 
Item 3: 
Clarifications to Procedures for Documenting 
Pregnancy During Study 
Section 7.1.9: 
The current protocol reads as below: 
All pregnancies that occur from the time of first screening procedure through the follow up 
visits must be reported. The investigator will monitor the subject and follow the outcome of the 
pregnancy. If the end of the pregnancy occurs after the study has been completed, the 
outcome will be reported directly to the study team and the medical monitor. 
Protocol Version Date: 29Mar2018 
CONFIDENTIAL 
Page 4 of 7 
Protocol Version: 4.0 
549

VGX-3100 
lnovio Pharmaceuticals, Inc. 
It should read: 
Protocol#: HPV-301 
Protocol Administrative Memo #:2 
All pregnancies that occur from the time of first study treatment through the follow up visits must 
be reported. The investigator will monitor the subject and follow the outcome of the pregnancy. If 
the end of the pregnancy occurs after the study has been completed, the outcome will be reported 
directly to the study team and the medical monitor. 
This memo is to update the pregnancy reporting time frame for those participants that become 
pregnant while participating in the trial. The protocol had erroneously reflected that pregnancies 
occurring following the first screening procedure will be followed through outcome, however, this 
would require the Investigator to follow pregnancies even for subjects that are not eligible for the 
study and are considered screen failures. It is not the Sponsor's intent to collect information 
regarding pregnancy outcome for subjects that are not exposed to lnvestigational Product. 
Item 4: 
Clarifications to Section 8, Statistical Analysis Plan 
Section 8.1: 
The current protocol reads as below: 
Other secondary analyses concern safety and humoral and cellular immunological measures, 
and association of lmmunoscores and efficacy. Exploratory analyses concern tissue 
immunological measures, durability of clearance of HPV-16 and/or HPV-18 infection from 
cervical tissue, effect of HLA type on efficacy, association of colposcopy, cytology, virology, 
other microRNA (miRNA) profiles, and DNA methylation profile and efficacy, and patient-
reported outcomes. 
It should read: 
Other secondary analyses concern safety and humoral and cellular immunological measures. 
Exploratory analyses concern tissue immunological measures, durability of clearance of HPV-
16 and/or HPV-18 infection from cervical tissue, effect of HLA type on efficacy, association of 
colposcopy, cytology, virology, other microRNA (miRNA) profiles, and DNA methylation profile 
and efficacy, patient-reported outcomes, and association of lmmunoscores and efficacy. 
This memo is to clarify the association of lmmunoscores and efficacy is an exploratory 
objective. 
Section B. 10: 
The current protocol reads as below: 
Post-baseline cellular and humoral responses will be compared between treatment groups 
using a difference in medians and associated exact non-parametric 95% Cl. Increases from 
baseline in interferon-y EL/Spot response magnitudes and in COB+ I CD137+ PBMCs Perforin+ 
results and HPV E6 and El titers from ELISA at Weeks 8, 15 and 36 visits will be evaluated. 
Protocol Version Date: 29Mar2018 
CONFIDENTIAL 
Page 5 of 7 
Protocol Version: 4.0 
550

VGX-3100 
lnovio Pharmaceuticals, Inc. 
It should read: 
Protocol#: HPV-301 
Protocol Administrative Memo #:2 
Post-baseline cellular and humoral responses will be compared between treatment groups 
using a difference in medians and associated exact non-parametric 95% Cl. Increases from 
baseline in interferon-y EL/Spot response magnitudes and in COB+ I CD137+ PBMCs Perforin+ 
results and HPV E6 and El titers from ELISA at Weeks 15 and 36 visits will be evaluated. 
This memo is to clarify that immunogenicity assessments will be conducted post-baseline at 
Weeks 15 and 36. Week 8 was removed to make this section consistent with other protocol 
sections that refer to post-baseline immunogenicity assessments only at Week 15 and 36 visits. 
Section 8. 11.2: 
The current protocol reads as below: 
Continuous response variables per time point and changes from baseline will be summarized 
with mean, median, minimum, and maximum values, and categorical response variables will be 
summarized per time point with percentages, by treatment arm. Baseline is defined as the last 
measurement prior to the first treatment administration. 
It should be disregarded, as there are no safety laboratory post-baseline measurements, and 
therefore this section is not applicable. 
Section 8.14 
The current protocol reads as below: 
As an exploratory endpoint, patient reported outcomes among subjects who receive VGX-3100 
will be compared between those with excision versus those without excision, based on PRO 
endpoints. This comparison will utilize the median endpoint or the proportion of subjects with 
endpoints and associated Wilcoxon rank-sum test or Pearson chi-square test/Fisher's exact 
test, for continuous responses and categorical responses, respectively. 
The mlTT population will be used for PRO analyses. 
It should read: 
As an exploratory endpoint, patient reported outcomes will be compared between treatment 
arms, based on PRO endpoints. Median changes from baseline for the SF-36 and EQ-5O-SL 
responses and median days of worsened quality of life for the Week 40 Quality of Life 
questionnaire will be analyzed using exact non-parametric 95% confidence intervals for the 
differences in medians. The proportion of subjects who report a worsened quality of life for the 
Week 40 Quality of Life questionnaire will be analyzed using a 95% Miettinen and Nurminen 
confidence interval for the difference in proportions. 
In addition, the Week 36 and beyond outcomes will be summarized according to those with 
excision versus those without excision. 
Protocol Version Date: 29Mar2018 
CONFIDENTIAL 
Page 6 of 7 
Protocol Version: 4.0 
551

VGX-3100 
lnovio Pharmaceuticals, Inc. 
Protocol#: HPV-301 
Protocol Administrative Memo #:2 
The mlTT population will be used for PRO analyses. 
This memo is to provide further clarity and specification of these analyses. 
Item 5: 
Clarification to referencing Tables 4 and 5: Minimally 
Required Procedure at Week 36 
The current protocol indicates that Table 5 and 6 reference "Minimally Required Procedures at 
Week 36", however the actual table numbers showing the minimally required procedures at 
Week 36 are Table 4 and 5. These tables are references throughout the protocol in the 
following sections: 
Study Design 
Schedule of Events Footnotes 
Section 1.3.2 Potential Risks of Study Participation 
Section 2.3 Safety Monitoring Plan 
Section 6.2.1 0 Week 36 
Section 6.13.1 Ectocervical Biopsies 
Item 6: 
Clarification to Appendix: Ectocervical biopsy Section. 
4 Quadrant Biopsy: 
Appendix: 
The current protocol reads as below: 
3. 
Perform colposcopic directed biopsies from all quadrants with lesions. 
It should read: 
3. 
Perform colposcopic directed biopsies from all quadrants. 
Study participants qualifying for 4 quadrant biopsies should have biopsies collected from all four 
quadrants regardless of visible lesion being present. 
Protocol Version Date: 29Mar2018 
CONFIDENTIAL 
Page 7 of 7 
Protocol Version: 4.0 
552

CONFIDENTIAL
Page 1 of 4
Protocol Administrative Memo (PAM) # 3
PAM Date:26Mar2021
To
HPV-301
A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
PHASE 3 STUDY OF VGX-3100 DELIVERED INTRAMUSCULARLY FOLLOWED BY 
ELECTROPORATION WITH CELLECTRA™ 5PSP FOR THE TREATMENT OF HPV-
16 AND/OR HPV-18 RELATED HIGH GRADE SQUAMOUS INTRAEPITHELIAL 
LESION (HSIL) OF THE CERVIX  
Protocol Version:  5.0
Protocol Version Date: 20Nov2019
Sponsored by:
Inovio Pharmaceuticals, Inc.
Investigational New Drug Application (IND) #:  13683
EudraCT #:  #2016-002761-63
553

V G X- 3 1 0 0
        Pr ot o c ol #: H P V- 3 0 1
I n o vi o P h ar m a c e uti c al s, I n c.
Pr ot o c ol A d mi ni str ati v e M e m o #: 3
C O N FI D E N TI A L
P a g e 2 of 4
M e di c al M o nit or A p pr o v al P a g e
M e di c al M o nit or Si g n at ur e:
I n o vi o P h ar m a c e uti c al s, I n c.
D at e ( d d M m m y y y y)
T his m e m o c o nt ai ns i nf or m ati o n t h at is c o n si d er e d t o b e a d mi ni str ativ e or cl arif yi n g i n n at ur e a n d d o e s n ot 
m e et t h e crit eri a of a n i m m e di at e pr ot o c ol a m e n d m e nt. Pl e a s e distri b ut e t his m e m o t o all a p pr o pri at e st aff 
m e m b er s, a n d fil e it wit h t h e sit e’s pr ot oc ol d o c u m e nt s. C o n s ult t h e l o c al I n stit uti o n al R e vi e w B o ar d (I R B)/
R e s e arc h Et hic s B o ar d ( R E B)/ Et hi cs C o m mitt e e ( E C) r e g ar di n g s u b mis si o n r e q uir e m e nt s f or Pr ot o c ol 
A d mi ni str ativ e M e m os ( P A M s).
5 5 4
P P D
P P D
P P D
P P D

VGX-3100
Protocol #: HPV-301
Inovio Pharmaceuticals, Inc. 
 
Protocol Administrative Memo #: 3 
 
 
 
CONFIDENTIAL
Page 3 of 4 
 
 
Principal Investigator Acknowledgement
I have read and understood this Protocol Administrative Memo (PAM) and will incorporate it as 
part of the Protocol. I will submit this PAM, if required, to the Institutional Review Board
(IRB)/Research Ethics Board (REB)/Ethics Committee (EC) overseeing the conduct of the 
clinical trial in accordance with their policies and procedures and local requirements. 
 
The Principal Investigator’s (PI’s) signature constitutes the PI’s acknowledgement of, and 
agreement with, this PAM 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 (first and last) 
 
Principal Investigator Signature 
Date (ddMmmyyyy) 
Clinical Trial Site Number: 
Clinical Trial Site Name:
 
555

V G X- 3 1 0 0
Pr ot o c ol #: H P V- 3 0 1
I n o vi o P h ar m a c e uti c al s, I n c. 
 
Pr ot o c ol A d mi ni str ati v e M e m o #: 3 
 
 
 
C O N FI D E N TI A L
P a g e 4  of 4 
 
It e m 1:
M e di c al M o nit or h a s b e e n u p d at e d fr o m 
, M. D., 
P h. D. t o 
 , M. D. 
 
 
T h e H P V- 3 0 1 Pr ot o c ol V er si o n 5. 0 c urr e ntl y st at e s: 
O n P a g e 2 of 9 4: 
M e di c al M o nit or:
, M. D., P h. D.
 
 
 I n o vi o P h ar m a c e uti c al s, I n c. 
 
T h e H P V- 3 0 1 Pr ot o c ol V er si o n 5. 0 s h o ul d st at e:
O n P a g e 2 of 9 4:
M e di c al M o nit or:  
 
, M. D. 
 
  
 I n o vi o P h ar m a c e uti c al s, I n c. 
 
 
5 5 6
P P D
P P D
P P D
P P D
P P D
P P D