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

COVER PAGE 
Official Title: 
NCT Number: NCT03721978 
Document Date: 01 June 2022 
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REVEAL 2
(Randomized Evaluation of VGX-3100 and Electroporation 
 the Treatment of CervicAl 
HSIL)
HPV – 303
Sponsored by:
Inovio Ph rmaceuticals, Inc.
U.S. IND #13683
Eu r CT #: 2018-004114-17
Version 4.1
01Jun2022
FINAL
REVEAL 2: 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
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CONFIDENTIAL
The information in this document is considered privileged and confidential by Inovio Pharmaceuticals and may 
not be disclosed to others except to the extent necessary to obtain Institutional Review Board/Ethics Committee 
approval and informed consent, or as required by local regulatory authorities. Persons to whom this 
information is disclosed must be informed that this information is privileged and confidential and that it should 
not be further disclosed without the written permission of Inovio Pharmaceuticals. Any supplemental 
information added to this document is also confidential and proprietary information of Inovio Pharmaceuticals 
and must be kept in confidence in the same manner as the contents of this document.
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Summary of Changes 
The following is a list of protocol changes organized categorically and secondarily in order of appearance 
from HPV-303 Protocol version 3.0 dated 15 November 2018 to Protocol version 4.1 dated 01 June 2022. 
All other changes are administrative and do not significantly affect the safety of subjects, study scope, or 
scientific quality of the protocol. These are deemed to be non-significant. The discrepancies between the 
Protocol version 3.0 and Protocol Synopsis version 3.0 have been corrected in Protocol Version 4.1. 
1.
The primary population to which the primary objective will be applied has been changed from 
“all subjects” to “subjects defined as biomarker-positive at baseline,” as identified by microRNA 
(miRNA) profiling performed from peripheral blood prior to dosing with VGX-3100 (Section 
6.10). This change has been made in order to define a population of patients in whom VGX-3100 
is more likely to be efficacious as defined by the pr
 n point of regression of cervical HSIL 
and clearance of HPV-16/18.  
2.
The protocol has been revised to remove 4-quadrant biopsy as a potential procedure at Week 36
throughout the protocol. 
3.
Stopping Rules (Criteria for Pausing of Study) added to Data Safety Monitoring Board Charter 
version 3.0. 
4.
Update to acceptable contraception methods in Protocol Synopsis, Inclusion Criteria and Section 
4.1, Inclusion Criteria. A footnote has been added to clarify that use of condoms or condoms and 
spermicide are not acceptable forms of contraception.
5.
Update to Table 1: Schedule of Events and Sections 6.1.1, 6.1.2, and 6.4.12, Method of 
collection for cervical di
e™ samples. Text was changed to update the method of collection 
of cervical digene™ samples from swabs to brushes at Screening, Day 0, Weeks 15, 28, and 36. 
6.
Clarification of previous footnote “K” for Table 1: Schedule of Events. The footnote has been 
updated to indicate that a biopsy is only done at the Screening visits. 
7.
Clarification of previous footnote “M” for Table 1: Schedule of Events. The footnote has been 
updated to indicate that 4-quadrant biopsies will not be completed at Week 36. 
8.
Clarification of Section 3, Study Design and Endpoints and Section 8.7, Randomization and 
Blinding. 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.
9.
Clarification of Section 3, Study Design and Endpoints. Text was included to clarify that the 
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at randomization should be performed using the age at Day 0.
10. Clarification of the definition of Responder and Non-Responder in Section 3.1.4, 8.5.1 and 
8.5.9. The definition of non-responder was clarified to comprise subjects who undergo excision, 
or subjects whose cervix is biopsied, at any time between their initial dose of study drug and the 
Week 36 endpoint tissue collection.
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11. Clarification of HPV clearance result to Table 4 in Section 3.1.4 and Tables 6 and 7 in Section
3.2.
12. Clarification of Exclusion Criteria 3 in Section 4.2, Exclusion Criteria. The text has been 
updated to correspond with Exclusion Criteria 3 in the Clinical Protocol Synopsis. 
13. Clarification of Exclusion Criteria 7 in Section 4.2, Exclusion Criteria. The text has been 
updated to correspond with Exclusion Criteria 7 in the Clinical Protocol Synopsis.
14. Clarification of Exclusion Criteria 12 in Section 4.2, Exclusion Criteria. The text has been 
updated to correspond with Exclusion Criteria 12 in the Clinical Protocol Synopsis. 
15. Clarification of Section 6.1.1, Screening Evaluations. Text has been updated that Serology 
testing must be completed and negative within 60 days of Day 0. 
16. Clarification of Section 6.1.1, Screening Evaluations. 
 
 
17. Clarification of Section 6.1.2, Week 40 (Study Co
lus on)  
hole blood and serum samples are 
not obtained at Week 40 as indicated in Table 1, S
e of Events. “Whole blood and serum 
for immunology” has been removed from the t
t  
18. Clarification of Section 6.4.3, Height and Weigh  
 
 
s clarified to include that height 
and weight should be collected at Screening and on Day 0, Weeks 4 and 12, and that the BMI at 
Day 0 will be used to determine BMI Stratum for randomization.
19. Clarification of Table 13: Grading Scale for Injection Site Reactions in Protocol Section 6.9, 
Assessment of Injection Site Reactions. Daily activity is defined for the Injection Site Reactions 
table.  
20. Clarification of Section 8.5
Planned 
rim Analysis. Language was added to this section to 
explain that group-level unblinding summaries and analyses may be produced once the primary 
endpoint data are com
ed for all subjects, if deemed necessary.
21. Clarification of Section 8.5.10.4, Vital Signs. The summary will be performed on the Safety 
population instead of the mITT population.
22. Clarification of Sectio  5
Compliance with Good Clinical Practice. The text has been 
updated to define GCP regulati ns as including ICH, ISO, and local regulations. 
23. Clarification of Section 11, Source Documents. All prescription and nonprescription medications 
taken within 8 weeks prior to entry must be recorded on the CRF as stated in Section 6.12,
Concomitant Medications/Treatment. 
24. Clarification of Section 17, Appendices. Appendix A was updated to remove the procedure for 
collecting 4-quadrant biopsies at Week 36. 
Administrative Changes:
25. Administrative Change to Inclusion Criteria 5 in the Clinical Protocol Synopsis. The text has 
been updated to correspond with Inclusion Criteria 5 in Section 4.1, Inclusion Criteria. 
26. Administrative Change to Exclusion Criteria 3 in Section 4.2, Exclusion Criteria. The text has 
been updated to correspond with Exclusion Criteria 3 in the Clinical Protocol Synopsis. 
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27. Administrative Change to Section 5.3, CELLECTRA™ 5PSP device. A statement was added for 
informational purposes indicating that CELLECTRA™5PSP device is CE Marked in the 
European Union.
28. Administrative Change to Section 6.4.13, Colposcopy and Cervical Biopsies and Section 6.4.15, 
Unscheduled Biopsies. The guidelines for Colposcopy and Surgical Excision is in Appendix A.
29. Administrative Change to Section 7.2, Adverse Events (AEs), and Section 7.11, Procedure for 
Reporting Pregnancy During the Study. The additional information on pregnancy reporting is 
referenced there. 
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PRINCIPAL INVESTIGATOR ACKNOWLEDGEMENT
I have read and understood this Protocol and agree that it contains all necessary details for 
carrying out the trial described. I understand that it must be reviewed by the Institutional Review 
Board or Independent Ethics Committee overseeing the conduct of the trial and approved or 
given favorable opinion before implementation.
The signature of the Principal Investigator (PI) constitutes the PI’s approval of this protocol and 
provides the necessary assurances that this trial will be conducted in accordance with ICH/GCP 
and ISO guidelines, local legal and regulatory requirem
s  nd all stipulations of the protocol.
_________________________________
_________________________
Principal Investigator Signature 
Date (DDMMYYYY)      
__________________________________
Printed Name
Site Number: ___________________________
Site Name: _____________________________
EudraCT #: 2018-004114-17
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TABLE OF CONTENTS
CLINICAL PROTOCOL SYNOPSIS .................................................................................. 13
STUDY DESIGN.................................................................................................................. 16
1
INTRODUCTION ................................................................................................................ 22
1.1
BACKGROUND AND SCIENTIFIC RATIONALE ................................................ 22
1.2
BACKGROUND INFORMATION ........................................................................... 22
1.3
PRODUCT DEVELOPMENT OVERVIEW ............................................................. 22
1.3.1
INVESTIGATIONAL PRODUCT ......................................................................... 22
1.3.2
CELLECTRA™ DEVICE DEVELOPMENT ....................................................... 23
1.3.3
RATIONALE .......................................................................................................... 24
1.4
POTENTIAL RISKS AND BENEFIT ....................................................................... 25
1.4.1
POTENTIAL RISKS .............................................................................................. 25
1.4.2
POTENTIAL BENEFITS ....................................................................................... 26
1.5
RISKS FOR CURRENT TR
NT ................................................................... 26
2
OBJECTIVES AND PURPOSE 
.............................................................. 27
2.1
HYPOTHESIS ............................................................................................................ 27
3
STUDY DESIGN AND ENDPOINTS ................................................................................. 27
3.1
PRIMARY OBJECT
 
....................................................................................... 28
3.1.1
PRIMARY ENDPOINT & EFFICACY ASSESSMENT ...................................... 28
3.1.2
HISTOLOGY ASSESSM NT ............................................................................... 28
3.1.3
VIROLOGIC ASS S
ENT ................................................................................ 29
3.1.4
DEFINITION OF RESPONDER AND NON-RESPONDER ............................... 29
3.2
SECONDARY OBJECTIVES AND ENDPOINTS .................................................. 30
3.2.1
HISTOLOGY ASSESSMENT ............................................................................... 31
3.2.2
VIROLOGIC ASSESSMENT ................................................................................ 31
3.2.3
DEFINITION OF RESPONDER AND NON-RESPONDER ............................... 32
3.3
EXPLORATORY OBJECTIVES AND ENDPOINTS ............................................. 33
3.4
IMMUNOGENICITY ASSESSMENT ...................................................................... 34
3.5
SAFETY ASSESSMENT........................................................................................... 34
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3.5.1
SUMMARY OF LONG TERM FOLLOW UP DATA FROM PHASE 2B STUDY
 
35
4
STUDY POPULATION ....................................................................................................... 39
4.1
INCLUSION CRITERIA ........................................................................................... 39
4.2
EXCLUSION CRITERIA .......................................................................................... 40
4.3
DISCONTINUATION/WITHDRAWAL OF STUDY SUBJECTS .......................... 41
5
STUDY TREATMENT ........................................................................................................ 43
5.1
INVESTIGATIONAL PRODUCTS .......................................................................... 43
5.2
BLINDING ................................................................................................................. 43
5.3
CELLECTRA™ 5PSP DEVICE ...................... ......................................................... 44
5.4
TREATMENT REGIMENS....................................................................................... 46
5.5
PACKAGING AND LABELING .............................................................................. 46
5.6
HANDLING AND STORAGE .................................................................................. 48
5.7
PREPARATION AND DISPENS
 
................................................ 48
5.8
USE OF CELLECTRA™ 5PS  D
ICE 
..................................................... 48
5.9
INVESTIGATIONAL DRU  A
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5.9.1
INVESTIGATIONAL 
U
 
............................................................... 49
5.9.2
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.................................................................... 49
5.10
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49
5.10.1
INVESTIGATI
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5.10.2
CELLECTRA™ 5P
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6
STUDY PROCEDURES AND SCHEDULE ....................................................................... 50
6.1
PROCEDURES BY VISIT ........................................................................................ 50
6.1.1
SCREENING EVALUATIONS ............................................................................. 50
SCREENING VISIT ............................................................................................................. 52
6.1.2
STUDY EVALUATIONS AND PROCEDURES ................................................. 52
DAY 0 ................................................................................................................................... 52
8-14 DAYS POST DOSE 1 PHONE CALL ........................................................................ 53
WEEK 4 (±4 DAYS) ............................................................................................................ 53
8-14 DAYS POST DOSE 2 PHONE CALL ........................................................................ 53
WEEK 8 (±4 DAYS) ............................................................................................................ 54
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WEEK 12 (±4 DAYS) .......................................................................................................... 54
8-14 DAYS POST DOSE 3 PHONE CALL ........................................................................ 54
WEEK 15 (± 1 WEEK) ......................................................................................................... 54
WEEK 28 .............................................................................................................................. 55
WEEK 36 .............................................................................................................................. 55
WEEK 40 (STUDY CONCLUSION) .................................................................................. 55
6.2
INFORMED CONSENT ............................................................................................ 56
6.3 ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS ................................. 56
6.4 SAFETY EVALUATIONS ................................................................................................ 56
6.4.1 PHYSICAL EXAMINATION ........................................................................................ 56
6.4.2 VITAL SIGNS ................................................................................................................. 56
6.4.3 HEIGHT AND WEIGHT ............................................................................................ 56
6.4.4 MEDICAL HISTORY ................................................................................................. 57
6.4.5 SOCIO-BEHAVIORAL ASSESSM NT .................................................................... 57
6.4.6 LABORATORY EVALUATIO
 
................................................................. 57
6.4.7 URINALYSIS (UA) .................................................................................................... 57
6.4.8 DEMOGRAPHICS ...................................................................................................... 57
6.4.9 URINE PREGNANCY TESTING .............................................................................. 58
6.4.10 ECG............................................................................................................................ 58
6.4.11 PARTICIPANT DIARY CAR  (PDC) SUBJECT SELF EVALUATION ............. 58
6.4.12 PAP SMEAR  
D PV ESTING ....................................................................... 58
6.4.13 COLPOSCOP  AND CERVICAL BIOPSIES......................................................... 59
6.4.14 ECTOCERVICA  IOPSIES ................................................................................... 59
6.4.15 UNSCHEDULED BIOPSIES .................................................................................... 59
6.5 INJECTION AND ELECTROPORATION (EP) ........................................................... 60
6.6 MANAGEMENT OF ANXIETY AND PAIN DUE TO EP PROCEDURE ................. 60
6.7 ASSESSMENT OF LABORATORY ABNORMALITIES ........................................... 60
6.8 ASSESSMENT OF CLINICAL STUDY ADVERSE EVENTS ................................... 60
6.9 ASSESSMENT OF INJECTION SITE REACTIONS................................................... 60
6.10 PERIPHERAL BLOOD IMMUNOGENICITY ASSESSMENT ................................ 61
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6.12 CONCOMITANT MEDICATIONS/TREATMENTS ................................................. 62
6.13 RESTRICTIONS .......................................................................................................... 63
7
EVALUATION OF SAFETY AND MANAGEMENT OF TOXICITY ............................. 63
7.1
SAFETY PARAMETERS .......................................................................................... 63
7.2
ADVERSE EVENTS (AES) ...................................................................................... 63
7.3
SERIOUS ADVERSE EVENTS (SAES) .................................................................. 64
7.4
UNEXPECTED ADVERSE DRUG REACTIONS AND EXPEDITED REPORTING
 
65
7.5
UNANTICIPATED (SERIOUS) ADVERSE DEVICE EFFECT (UADE) .............. 66
7.6
ASSESSING SEVERITY (INTENSITY) .................................................................. 66
7.7
CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS
 
66
7.8
ABNORMAL LABORATORY VALUE  ................................................................ 67
7.9
POST-STUDY REPORTING REQUIREMENTS .................................................... 67
7.10
EVENT REPORTING FOR DISEASE PR GRESSION OR EXCLUSIONARY 
HISTOLOGIC FINDINGS POST-STUDY TREATMENT .................................................... 68
7.11
PROCEDURE FOR REP RT
G 
ANCY DURING THE STUDY ........... 68
7.12
METHODS AND TIMING O  COLLECTION OF SAFETY DATA ..................... 68
7.13
SAFETY AND TOXICITY M N
EMENT .......................................................... 69
7.14
ADVERSE EVENT  OF SPECIAL INTEREST ...................................................... 69
7.15
ADVERSE EXPERIENCE (AE) REPORTING ........................................................ 69
7.15.1
STUDY REPORTING PERIOD OF ADVERSE EVENTS .................................. 69
7.15.2
STUDY REPORTING PERIOD FOR ADVERSE EVENTS OF SPECIAL 
INTEREST ............................................................................................................................ 70
7.15.3
STUDY REPORTING PERIOD OF SERIOUS ADVERSE EVENTS ................. 70
7.16
NOTIFICATIONS OF SERIOUS ADVERSE EVENTS .......................................... 71
7.17
REPORTING OF DEVICE RELATED COMPLAINTS OR DEFICIENCIES ........ 71
7.18
STUDY DISCONTINUATION ................................................................................. 71
8
STATISTICAL CONSIDERATIONS.................................................................................. 72
8.1
STATISTICAL AND ANALYTICAL PLAN ........................................................... 72
8.2
GENERAL CONSIDERATIONS .............................................................................. 72
8.3
STATISTICAL HYPOTHESES ................................................................................ 72
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12
SAFETY AND QUALITY MONITORING ........................................................................ 80
12.1
LONG TERM SAFETY FOLLOW-UP ..................................................................... 80
12.2
DATA SAFETY MONITORING BOARD ............................................................... 80
12.3
PATHOLOGY ADJUDICATION COMMITTEE .................................................... 80
12.4
CLINICAL MONITORING ....................................................................................... 80
13
FINANCING AND INSURANCE ....................................................................................... 81
14
PUBLICATION POLICY .................................................................................................... 81
15
LIST OF ABBREVIATIONS ............................................................................................... 82
16
REFERENCES ..................................................................................................................... 84
17
APPENDICES ...................................................................................................................... 86
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Clinical Protocol Synopsis
Protocol Title: REVEAL 2, A Prospective, Randomized, Double-blind, Placebo-Controlled Phase 3 
Study of VGX-3100 Delivered Intramuscularly (IM) followed by Electroporation with 
CELLECTRA™ 5PSP for the Treatment of HPV-16 and/or HPV-18 related High Grade Squamous 
Intraepithelial Lesion (HSIL)1 of the Cervix
Protocol Number: HPV-303
Trial Phase: 3
Estimated Number of Trial Centers and Countries/Regions: Approximately 50 study centers in 
approximately 9 countries
Formulation: VGX-3100 delivered with CELLECTRA™ 5PSP Electroporation Device
Trial design: Prospective, Randomized, Double-blind, Placebo-Controlled
Criteria for evaluation:
Hypothesis: Among baseline biomarker-positive women, three 6 mg doses of VGX-3100 (DNA 
Plasmids encoding E6 and E7 proteins of HPV-16 and HP
) 
livered by intramuscular (IM) 
injection followed by electroporation (EP) with CELLE
A™ 5P
 to adult women with 
histologically confirmed high-grade squamous intraepi
al e
s HSIL), Cervical Intraepithelial 
Neoplasia, (CIN2, 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 PV-18 compared to placebo delivered IM 
followed by EP with CELLECTRA™ 5PSP at the W
k 36 visit.2
Primary Objective: Among baseline biomarker-positive w
n, determine the efficacy of VGX-3100 
compared with placebo with respect to combined histopat
gic regression of cervical HSIL and 
virologic clearance of HPV-16 and/or HP -18.
Primary Endpoint: Proportion of baseline bio arker-positive women with no evidence of cervical 
HSIL on histology sample and no evidence of HPV-16 and/or HPV-18 in cervical samples by type 
specific HPV testing at Week 36 
.
___________________________________________________________________________________________________________________________
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.
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Secondary Objectives
Associated Secondary Endpoints
vagina and intra-anal) at Week 36 Visit
compared to baseline.
9.
Among i) baseline biomarker-positive women 
and ii) all women, determine the humoral and 
cellular immune response of VGX-3100 
compared with placebo at post dose 3 and 
Week 36 visit as assessed relative to baseline.
9a. Levels of serum anti-HPV-16 and anti-HPV-
18 antibody concentrations at Weeks 15 and
36 visits
9b. Interferon-Ȗ (/,6SRW UHVSRQVH PDJQLWXGHV DW
baseline, Weeks 15 and 36 visits
9c. Flow Cytometry response magnitudes at 
baseline and Week 15 visits.
Exploratory Objectives
Associated Exploratory Endpoints
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Study Design
Trial Treatment: 6 mg (1 ml) VGX-3100 Intramuscular injection followed by EP with the 
CELLECTRA™ 5PSP device given at Day 0, Week 4 and Week 12
Efficacy Assessment: The primary endpoint for the Phase 3 study (HPV-303) is based upon the results 
of the Phase 2b study (HPV-003) and the Phase 3 study (HPV-301). Given that HPV persistence is an 
important factor in the clinical progression of cervical dysplasia and also based upon the findings of the 
secondary objective of the HPV-003 study, the responder definition for the HPV-303 primary endpoint 
determination will take into consideration both histological regression of cervical HSIL and clearance 
of high-risk HPV-16 and HPV-18.  
Regression of cervical HSIL will be determined by histopathological assessment of cervical tissue, 
which is considered the definitive method for diagnosis of cervical dysplasia. Tissue to be analyzed for 
evidence of histopathologic regression will be obtained at Week 36. Cervical cytology samples will be 
obtained to characterize HPV infection at screening, Day 0 (prior to dosing) and Weeks 8, 15, 28 and 
36. Also, if there is residual tissue in the paraffin block after h s
ogic diagnoses have been rendered, 
then unstained slides and/or the relevant paraffin blocks m y 
 
ted for testing of HPV-16 and 
/or HPV-18. Vaginal, oropharyngeal, and optional intra- nal a ple  will be obtained 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.  
Immunogenicity Assessment: Humoral and cell m diate  imm
 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.
 
Safety Assessment: Based upon the HP
 
u ts, the risk of HSIL progression to cancer or 
recurrence of HSIL is considered low and comparable to the rates observed post-LEEP/CKC [1]. The 
long-term follow-up planned for this HPV-303 stud  will include safety, cytology and HPV-16 and/or 
HPV-18 testing up to 7 months f
 
 
t dose of Study Treatment.  
A Data Safety Monitoring Bo d (D
) w l review safety data and histopathological regression 
results. The DSMB will be 
 
 
sing the Sponsor if there appears to be a safety issue and 
if it appears that the proportion o  
 subjects with histopathologic regression in the VGX-3100 group 
is unacceptably low compared to the la ebo group. No formal interim analysis will be performed.
Trial Population: Women 18 years of age and older will be recruited in this multi-center global trial.
VGX-3100 is being developed as a non-surgical therapeutic option for the treatment of the precursor 
to cervical cancer, precancerous cervical HSIL, and the underlying pathogenic HPV-16 and/or     
HPV-18 infection.
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Inclusion Criteria:
Each subject must meet all of the following criteria to be enrolled in the study:
1.
Women aged 18 years and above that meet 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 Pathological Adjudication Committee (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(s) 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 Pot nt
 (
O B ) is willing to use a contraceptive method with 
failure rate of less than 1% per yeara w
n used onsistently and correctly from screening until 
Week 36. The following methods are acceptable:
•
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);
•
Abstinence from penile-vaginal intercourse when this is the subject’s mode of sexual 
activity;
•
Intrauterine device or intrauterine system;
•
Male partner steriliz
n 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 Electrocardiogram (ECG) or screening ECG with no clinically significant 
findings, as judged by the investigator.
a Use of condoms alone or condoms with spermicide does not have a failure rate of <1% per year and is 
therefore not an acceptable form of contraception.
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Exclusion Criteria:
Subjects meeting any of the following criteria will be excluded from enrollment or continuation 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 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™, SilgardTM, Cervarix™);
7.
Presence of any unresolved abnormal clinical scree
 ab
atory 
lues of Grade 1 or greater per 
Common Toxicity Criteria for Adverse Events (CTCAE) v 4.03 a
 deemed clinically significant 
by the investigator 60 days prior to Day 0;
8.
Immunosuppression as a result of underlying illness or treatment including:
a)
History of or positive serologic test for H V t 
een n  (performed within 60 days prior to 
Day 0);
b) Primary immunodeficiencies;
c)
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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, cyclophos
m
, 
r ne, methotrexate), and biologic disease modifying 
drugs such as TNF-Į LQKibitors (e.g. infliximab, adalimumab or etanercept);
e)
History of solid or
n or bone marrow transplantation;
f)
Any prior history 
 oth r 
 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 m l o
shed (i.e. medically significant unintentional weight loss) based on 
screening labs, medical h story 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 (locally treated ano-
genital malignancy and superficial skin cancers 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;
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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 (except HPV-
301 REVEAL 1) 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 (in
lun r y nc
erated) for treatment of either 
a psychiatric or physical (i.e. infectious disease) i
25. Active military service personnel;
26. Study-related staff or family member of study-r lated staff;
27. Any illness or condition that in the opinion of h  investigator may affect the safety of the subject 
or the evaluation of any study endpoint.
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Schedule of Events
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 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)
Informed consent
X
Medical History
X
Demographics
X
Socio-behavioral a
X
X
X
Inclusion / Exclusion
X
X
Randomization
X
Physical exam/assessment b
X
X
X
X
X
X
X
X
Vital signs
X c
X
X
X
X
X
X
Screening safety d
X
Pregnancy Test e
X
X
X
X
X
X
X
HIV Antibody Testing
X q
Blood immunologic samples f
X q
X
X g
X
Cervical digene brushes i, j
X q
X
X
X
ThinPrep™ h, i
X q
X
X
X
X
Colposcopyk
Xl, q
X
X
X
X
X
Ectocervical biopsy m
X q
Surgical excision m
X n
OP rinse, vaginal swabs, intra-
anal swabs o
X
X
Inject VGX-3100/Placebo
X
X
X
Post treatment assessment
X
X
X
X
X
X
X p
X
AE/SAE assessment
X
X
X
X
X
X
X
X
X
X
X
X
Distribute Participant Diary Card
(PDC)
X
X
X
Review PDC
X
X
X
X p
a Socio-behavioral assessments, e.g. self-reported smoking and alcohol history;
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b Complete physical examination (PE) mandatory at screening and study discharge (Week 40), otherwise 
targeted physical assessment as determined by the investigator or per subject complaints unless signs or 
symptoms dictate the need for a complete PE;
c Screening vital signs must include a measured height and weight. Height and weight will be collected on 
Day 0, Weeks 4 and 12;
d Screening safety procedures includes 12-Lead ECG, complete blood count (CBC), serum electrolytes, 
blood urea nitrogen (BUN), serum creatinine (Cr), serum Albumin, serum glucose, serum ALT, serum 
CPK and urinalysis performed within 60 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;
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 prio  t  cervical specimen collection;
j Collected prior to the ThinPrep™ sample;
k Acetic acid should be applied to lesions b f
 co
pi  e aminations for the Screening and Week 36 
visits; 
l Screening colposcopy is optional if ad
 c
o y as performed upon collection of initial biopsy;
mScreening biopsy of the lesion should be collected 
 paraffin-embedded cervical tissue, fresh cervical 
tissue, or H&E slides. In the absence of par
in-embedded or fresh tissue, unstained slides will be 
required in addition to H&E slide  Tissue to be analyzed for evidence of histopathologic regression will 
be obtained at Week 36 by excision (e.g. LEEP, LLETZ, CKC);
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 assessment 
of 
 as well as HPV testing;
o Please refer to the Laboratory 
nual for specific information regarding biological sample collection;
p Activities at 8 to 14 days Post-Dose 3 phone call may be done at Week 15 if timing overlaps;
q Results and activities performed as part of the screening process in the HPV-301 trial can be used as 
qualifying historical information to satisfy screening activities for HPV-303 provided that they were 
assessed within the required timeframes for HPV-303 screening.
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1 INTRODUCTION
1.1 BACKGROUND AND SCIENTIFIC RATIONALE
Infection with human papillomavirus (HPV) can lead to malignant neoplasia, localized primarily in the ano-
genital area and aero-digestive 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 [2]. In the US alone, approximately 14 million new genital HPV 
infections occur annually, and approximately half of these infections are with a high-risk HPV type [3, 4].  
Up to 13,000 women in the US alone are diagnosed with cervical cancer each year, with an estimated 4,120 
deaths annually in year 2017 [5]. 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 [6],[7].
Incident infection by HPV is characterized by ongoing viral replication and shedding and is associated with 
early histologic changes (grade 1 cervical intraepithelial neo
i ) 
en the female cervix is infected with 
HPV. Most cases of genital HPV infection clear spontan
ly  bu  
r istent 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) [8]. Over time, typically years, cervical HSIL can progress to invasive 
cancer of the cervix [9, 10]. The basis for these changes are attributed to the viral proteins E6 and E7.  
Infected cells produce E6 and E7 constitutively 
i
 i
s
 the degradation of cell cycle regulation 
proteins p53 and pRb, respectively, resulting in unrest c
 ce  growth and neoplasia.
1.2 BACKGROUND INFORMATION
While the currently available prophylac ic 
V 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 an  other 
 
 the prophylactic vaccines have no therapeutic effect 
upon existing HPV infection or ex s
 
P - e ted intraepithelial neoplasia [11]. This means that the 
large number of women who already h ve high grade cervical dysplasia, either because they were too old 
to have received the prophylactic vaccine or they did not respond to vaccination, must currently rely upon 
surgery and the chance of spontaneous regression to treat their condition and avoid progression to cancer.  
Furthermore, the number of US
 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 [12]. 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. 
1.3 PRODUCT DEVELOPMENT OVERVIEW
1.3.1 INVESTIGATIONAL PRODUCT
VGX-3100 contains plasmids that encode HPV-16 E6/E7 and HPV-18 E6/E7 antigens. The plasmids were 
designed and constructed using Inovio’s proprietary SynCon™ (synthetic consensus) technology. This 
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process involves synthetically deriving consensus genes across multiple strains and optimizing DNA inserts 
at the genetic level to allow high expression in human cells. The initial formulation of VGX-3100 was water 
for injection with 1% w/w poly-L-glutamate (WFI/LGS) that required frozen storage and was administered
by the CELLECTRA™ 2000 device. The frozen formulation has been administered to more than 250 
subjects in Phase 1 and 2 clinical trials. Proof of concept was demonstrated in the prospective, randomized, 
double blind, placebo-controlled HPV-003 study of VGX-3100 (frozen formulation) followed by EP in the 
treatment of high-grade cervical dysplasia, cervical HSIL associated with HPV-16 and/or HPV-18. HPV-
003 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, frozen formulation) or the 
placebo arm, respectively. All subjects received treatment on Day 0, Week 4 and Week 12. All subjects 
repeated cervical biopsy or LEEP of the cervix at Week 36 to assess efficacy defined as regression of high 
grade CIN by histology. 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 C
1 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. T-cell activity was detected in VGX-3100 
recipients compared to placebo recipients. VGX-310  demonstrated an acceptable safety profile when 
administered intramuscularly followed by electroporation  
In preparation for the Phase 3 program, a buffered refrigerated (2– q C storage) formulation of VGX-3100 
was developed using a saline sodium citr
 S
 
 The refrigerated formulation requires 
administration using the next generation device, the CELLECTRA™ 5PSP. This refrigerated formulation 
of VGX-3100 was first administered to 1
 s
ct   a P
se 1 clinical trial, HPV-101. Roughly half the 
healthy volunteers in the HPV-101 study, received 
r e 6 mg IM doses of VGX-3100 (refrigerated
formulation) followed by EP. Base  
 n 
l sis of the data, the refrigerated formulation was 
determined to be non-inferior to the frozen
r
n based upon a 2-fold rise in overall Spot Forming 
Units (SPU) to the antigens encoded 
 
 
s
ds per 106 peripheral blood mononuclear cells (PBMC) 
as measured from baseline to Week 14 using the interferon-Ȗ (/,6SRW assay. 
1.3.2 CELLECTRA™ DEVICE DEVELOPMENT 
CELLECTRA™2000 & 
P a e l c roporation (EP) devices. EP is a physical method of tissue 
transfection whereby the gen a on 
 hort, controlled electrical pulses creates a localized electrical field 
at the injection site which increas
 
l membrane permeability and improves the transfection of DNA and 
subsequent immunogenicity [13, 14]. EP is believed to increase the uptake and processing of plasmid DNA, 
thereby enabling increased expression and enhanced immunogenicity by 10 to 100-fold [15, 16]. 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 [13]. 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) [14, 15].  
In preparation for the Phase 3 program, a next generation device, CELLECTRA™ 5PSP, was created to 
address ergonomic functionality and automate the delivery of VGX-3100 and EP. The technology 
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differences between the CELLECTRA™ 2000 and CELLECTRA™ 5PSP design do not affect the intended 
mechanism of EP on the activity of VGX-3100 and will not present any new risks. The device design 
change does not affect the indications for use, operating principle, energy type, or sterilization 
specifications. The CELLECTRA™ 5PSP has been approved for investigational use in the US with VGX-
3100 and is being used in a Phase 3 clinical study HPV-301, titled “A Prospective, Randomized, Double-
blind, Placebo-Controlled Phase 3 Study of VGX-3100 Delivered Intramuscularly (IM) 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”.
Together, VGX-3100 and the CELLECTRA™ device represent an integrated product designed as a non-
surgical treatment for HPV-16/18-related cervical HSIL (CIN2, CIN3) via an immune response directed 
against HPV-16/18. Therefore, the refrigerated formulation of VGX-3100 and the CELLECTRA™ 5PSP 
device were chosen to progress into Phase 3 clinical development. Full preclinical design verification 
testing and a non-significant risk device functionality study have been completed prior to the start of Phase 
3. The intent is to support that the dimensional changes, change to the ergonomics of the patient user 
interface and injection method result in the CELLECTRA™ 5PSP de ice design meeting its safety and 
performance specifications. The mechanical process f ad
nistration has changed from manual to 
automatic, but the overall administration of VGX-3100 foll
d by electroporation is the same as in the 
CELLECTRA™ 2000. Inovio’s device experienc  de
ns a e  hat delivery of its proprietary 
electroporation pulses into muscle immediately fol
i g injection f DNA plasmids (including VGX-
3100) is well-tolerated in humans and no signific
 
f t  ssues have been identified [1], [14], [16]. For 
further information concerning the 5PSP de
e plea
 
r to the User Manual and the Investigator’s 
Brochure.
1.3.3 RATIONALE
A total dose of 6 mg VGX-3100 DNA 
 be
 el
t d or this study based on previous human experience 
with both the frozen and refrigera e  or
n  f VGX-3100, preclinical data with VGX-3100 and 
DNA vaccines, and the safety and immunogenicity data generated in the HPV-001, HPV-003, and 
HPV- 101 studies. In the HPV-001 trial, the 6 m  dose was delivered IM followed by EP, which showed 
trends toward higher response rates and magn
des of IFN-Ȗ (/,6SRW UHVSRQVHV FRPSDUHG WR WKH ORZ 
mg) and mid-dose (2 mg) cohorts (Table 2) without significant safety issues [14]. 
This dose-trend was consistent w h 
or 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 een 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 HPV-003. The results obtained in 
HPV-003 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 [1].
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Table 2:  Percent of Protocol HPV-001 Subjects Responding and Average SFU/106 PBMC 
in Responders for each Antigen by Cohort in Interferon-Ȗ (/,6SRW
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
1.4 POTENTIAL RISKS AND BENEFIT
1.4.1 POTENTIAL RISKS
Risks associated with VGX-3100 for the treatment of i
rade ce vical dysplasia are injection site 
reactions related to the IM injection and/or electroporati
.  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 potential risk is the delay of surgical intervent on of the high-grade cervical dysplasia and possible missed 
diagnosis of an occult early invasive cerv
 c
r 
 the VGX-3100 non-responders or placebo 
recipients, who do not spontaneously regress. Alth
 
rofessional guidelines typically advocate 
immediate excisional therapy for adult  w th 
v
 HSIL, scientific data indicates that the rate of 
progression from pre-invasive to inva
 
 
a
 is slow, typically thought to take several years 
[8]. The risk of a missed diagnosis o  
 o c
 
sive 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 
rence of dysplasia following surgical intervention [8], which illustrates 
that current standard of care for cervical dysplasia requires improvement. To mitigate these potential risks
the study design includes numerous s feguards to detect disease progression or the presence of an 
undiagnosed occult earl  invas
 c
l cancer. These include careful selection of immunocompetent 
patients, thorough screening and baseline evaluation, frequent cervical colposcopy, cytology and high-risk 
HPV testing throughout the tr
 
e t gators will be comprised of experienced gynecologists, who will 
have the discretion to obtain biopsies at any point if disease progression is suspected. 
A Data Safety Monitoring Board (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 of progression of the cervical HSIL and the risk of harboring an undiagnosed 
occult early invasive cervical cancer. Secondary to the potential risk of progression to cancer during the 
course of the trial described above, all subjects with the suggestion of residual disease will undergo 
excisional therapy (e.g. CKC, LEEP, LLETZ) at Week 36 as part of the efficacy assessment. In the HPV-
003 study, the percentage of subjects with micro-invasive cancer 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 that reported under standard of care settings [17]; never the less, all subjects will 
undergo excision at Week 36 to ensure no evidence of occult progression. 
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For further information concerning the risks associated with VGX-3100 and the CELLECTRA™ 5PSP 
device please refer to the User Manual and the Investigator’s Brochure.
1.4.2 POTENTIAL BENEFITS
Subjects that participate in the study may potentially see benefit from the investigational treatment if it 
proves efficacious. The close follow-up required by this study will also enable careful monitoring of the 
existing precancerous lesion(s). Overall, the study results will provide new information that may benefit 
other subjects in the future.  
1.5 RISKS FOR CURRENT TREATMENT
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 3.
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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 elated low birth weight
Incomplete treatment f 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) [12].
More importantly, none of the currently avail ble 
gi a  t
tments 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 t r sk for recur
 cervical HSIL as well as high grade dysplasia 
of the vulva and vagina due to the potentially broader infection of the genitourinary area.
2 OBJECTIVES AND U
SE 
Among baseline biomarker-posi ve women, d
mine the efficacy of VGX-3100 compared to placebo 
with respect to combined histopathologic regression of cervical HSIL and virologic clearance of HPV-16 
and/or HPV-18.
2.1 HYPOTHESIS
Among baseline biomarker-positi e women, 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 histopathologic 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 STUDY DESIGN AND ENDPOINTS
The HPV-303 study design is based upon the HPV-003 and HPV-301 study designs and results. It will also
provide confirmation of the initial Phase 3 study, HPV-301, with regard to histologic regression of cervical 
HSIL and clearance of the underlying HPV 16/18 infection. HPV-303 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 the CELLECTRA™ 5PSP device in adult 
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ica
rth and elate
nd ela
G
ete trea m
 
 cerv
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G
treatment of an occult
ment of an oc
HG
H
on Procedure (LEEP) 
cedure (LE
vaila
 
ical trea
ble surg
dysplasia, persistent
plasia, per
 at ri
 o  
rrent 
sk for recur
entially broader infec
ly broader
PURPOSE
POSE 
sitive women,
e women deter
eter
stopathologi
ologic regress
c regress
tive wo
v
V
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women with histologically confirmed cervical HSIL (CIN2, CIN3) associated with HPV-16/18. 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.
To be eligible for the study, subjects at least 18 years age and above the age of consent must agree 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 the PAC in a blinded manner to establish the presence of cervical HSIL within 
screening. In order to be eligible for randomization, 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.
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 among biomarker-positive women, assuming, based upon HPV-301 study results, 
that the true proportion of subjects whose lesion(s) regress a
 hose HPV-16/18 clear is 66% and 15% 
for VGX-3100 and placebo, respectively, and that the proportion of biomarker-positive women is 33%.  
Biomarker positivity in this context is defined as being predicted to exhibit lesion regression concomitant 
with HPV-16/18 clearance after interrogation of a pre-de i
d 
NA (miRNA) signature in subject 
plasma which is assessed prior to the administration 
 
X-3100 or placebo. Those subjects who are not 
predicted to exhibit lesion regression and HPV-16/18 clearanc  based on this signature prior to dosing with 
VGX-3100 or placebo are considered biomarker-ne
Subjects will be randomized in a stratified manner according to (a) the CIN severity observed in the biopsy 
specimens at screening (iH &,1 YV &,1 
, D HJRU\  25 vs. > 25 kg/m2) on Day 0, and (c) age 
category (<  \HDUV YV  25 years) on Day 0.
 
e 
2 disease is not over-represented in the study, 
the percentage of subjects enrolled wi  IN2 will not exceed 50% of the total enrolled. Each country will 
receive a group of sequential allocation numbers.
3.1 PRIMARY OBJECTIVE
Among baseline biomarker-positive women, d ermine the efficacy of VGX-3100 compared with placebo 
with respect to combined histop thologic regression of cervical HSIL and virologic clearance of HPV-16 
and/or HPV-18.
3.1.1 PRIMARY ENDPOINT & EFFICACY ASSESSMENT
The primary endpoint for HPV-303 is based upon the results of HPV-003 and HPV-301 and is identical to 
the primary endpoint of the HPV-301 study, but for a biomarker-positive population. 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 HPV-003 study, the responder definition for the HPV-303 primary 
endpoint determination will take into consideration both histological regression of cervical HSIL and 
clearance of high-risk HPV-16/18. The composite endpoint of histologic regression and virologic clearance 
will be primary in the HPV-303 study, and histologic regression will be a secondary endpoint.
3.1.2 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. Tissue to be analyzed for evidence 
of histopathologic regression will be obtained at Week 36by excision (e.g., LEEP, LLETZ, CKC). 
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ative.
anner according to (
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 
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Day 0. To ensu e
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th CIN2 will not exc
IN2 will no
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VE
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3.1.3 VIROLOGIC ASSESSMENT
Cervical cytology samples will be obtained to characterize HPV infection at screening, Day 0 (prior to 
dosing) and Weeks 8, 15, 28 and 36, for all subjects. 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, intra-anal, and oropharyngeal samples will be obtained 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. 
3.1.4 DEFINITION OF RESPONDER AND NON-RESPONDER
Responder and non-responder definitions (Table 4) 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 
after their initial dose and before the Week 36 endpoint tissue collection time frame. This exclusion is 
included to reduce the potential for artefactual increases in t
 
t effect caused by removal of HSIL
tissue and potentially HPV-16/18 by unplanned interval biopsies.   
To qualify as a responder for the primary endpoint, t
 
t 
 hav : 
1) An acceptable histology specimen at the Week 
time frame, w
h is interpretable by the 
independent PAC 
2) An acceptable HPV ThinPrep™ sample at the Wee  6 time frame, with an associated valid HPV-
testing result. 
 A responder is defined as a subject wi
  
 
- No histologic evidence of cervical HSIL 
 
- No evidence of HPV-16 or HPV-18  
- The subject must not have had an unscheduled excision or biopsy sample obtained between 
initial dose and the Week 36 evaluation.
To be qualified as a non-responder any sub ect with: 
- Histologic evidence of cervica  HSIL, or 
- Evidence of HPV-16 or HPV-18, or  
- An excision or biopsy sample obtained between initial dose and the Week 36 evaluation, or  
- No Week 36 visit sample/result
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 have
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 6
Week 3 time f
th: 
cervical HSIL
cal HSIL
6 or HPV-18  
HPV-18 
ot have had an unsch
e had an unsch
Week 36 evaluation
Week 36 evaluatio
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Table 4: Definition of Composite Regression and Clearance 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 36 visitb
AND
Subject in whom 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 with evidence of HPV-16 or HPV-18 at Week 36 visit
OR
Subject in whom an excision or biopsy sample 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 rem
al sample determines the histology endpoint. The most 
recent HPV clearance result prior to tissue removal, which includes results from the same date, within the timeframe determines 
the HPV clearance endpoint.
c Excludes ECC-only samples.
3.2 SECONDARY OBJECTIVES AND ENDPOINTS
Secondary Objectives
Associated Secondary Endpoints
1.
Among i) baseline biomarker-positive w men 
and ii) all women, evaluate the safety and 
tolerability of VGX-3100 delivered IM 
followed by EP with CELLECTRA™5PSP.
1a.
ence and severity of local and systemic 
events for 7 and 28 days following each 
investigational treatment and for the duration 
of the study (i.e., 40 weeks).
1b. Incidence and severity of all adverse events 
including Serious adverse events (SAEs) 
(e.g., Serious unexpected serious adverse 
reaction (SUSAR), Unexpected adverse 
device effect (UADE) and other unexpected 
AEs) for the duration of the study (through 
Week 40 visit).
2.
Among all women, determi
 t e 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.
2.
Proportion of all women with no evidence of 
cervical HSIL on histology sample and no 
evidence of HPV-16 and/or HPV-18 in 
cervical samples by type specific HPV 
testing at Week 36 visit.
3.
Among i) baseline biomarker-positive women 
and ii) all women, determine VGX-3100 
efficacy compared to placebo as measured by 
histopathologic regression of cervical HSIL.
3.
Proportion of women with no evidence of   
cervical HSIL on histology sample at Week 
36 visit.
4.
Among i) baseline biomarker-positive women 
and ii) all women, determine VGX-3100 
efficacy compared to placebo as measured by 
4.
Proportion of women with 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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RY
RY
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safety and 
delivered IM
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Secondary Objectives
Associated Secondary Endpoints
virologic clearance of HPV-16 and/or HPV-
18.
5.
Among i) baseline biomarker-positive women 
and ii) all women, determine VGX-3100 
efficacy compared to placebo as measured by 
complete histopathologic regression of 
cervical HSIL to normal.
5.
Proportion of women  with no evidence of 
Low grade squamous intraepithelial lesion 
(LSIL) or HSIL (i.e., no evidence of CIN1, 
CIN2 or CIN3) on histology sample at Week 
36 visit.
6.
Among i) baseline biomarker-positive women 
and ii) all women, 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.
6.
Proportion of women with no evidence of 
LSIL or HSIL (i.e., no evidence of CIN1, 
CIN2 or CIN3) on histology sample and no 
evidence of HPV-16 and/or HPV-18 by type 
spe f c HPV testing at Week 36 visit.
7.
Among i) baseline biomarker-positive women 
and ii) all women, determine VGX-3100 
efficacy compared to placebo as measured by 
histopathologic non-progression.
7.
Proportion of w men with no progression of 
cervical HSIL to cervical carcinoma from 
baseline on histology sample at Week 36 
visit.
8.
Among i) baseline biomarker-positive w
en 
and ii) all women, describe the clearan
 f 
HPV-16 and/or HPV-18 infection from non-
cervical anatomic locations.
8.
P oportion of women 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
compared to baseline.
9.
Among i) baseline biomarker-positive women 
and ii) all women, determine the humoral and 
cellular immune respon
 f V X-3100 
compared with placebo t post dose 3 and 
Week 36 visit as assessed relativ  to baseline. 
9a. Levels of serum anti-HPV-16 and anti-HPV-
18 antibody concentrations at Weeks 15 and 
36 visits
9b. Interferon-Ȗ (/,6SRW UHVSRQVH PDJQLWXGHV DW
baseline, Weeks 15 and 36 visits
9c. Flow Cytometry response magnitudes at 
baseline and Week 15 visits.
3.2.1 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, for all subjects. Tissue to be analyzed 
for evidence of histopathologic regression will be obtained at Week 36 by excision (e.g., LEEP, LLETZ, 
CKC).
3.2.2 VIROLOGIC ASSESSMENT
Cervical cytology samples will be obtained to characterize HPV infection at screening, Day 0 (prior to 
dosing) and Weeks 8, 15, 28 and 36, for all subjects. 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, intra-anal, and oropharyngeal samples will be obtained to 
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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.
3.2.3 DEFINITION OF RESPONDER AND NON-RESPONDER
Table 5: 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 whom 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 whom an excision or biopsy sample 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 r
al s
 determines the histology endpoint.
c Excludes ECC-only samples
Table 6: Definition of Secondary Complete Re ression 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 whom an excision or biopsy sampleb wa  
NOT obtained between initial dose up to We k 36 
visit
Subje t with histologic evidence of cervical HSIL, squamous 
atypia, LSIL, AIS, cervical or carcinoma at Week 36 visit
OR
Subjec  in whom an excision or biopsy sample 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 b  
 h  
 
gone 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 determines the histology endpoint.
b Excludes ECC-only samples.
Table 7: 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 whom 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 whom an excision or biopsy sample 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 determines the histology endpoint.
b Excludes ECC-only samples
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Table 8: Definition of Secondary Composite 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 whom 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 whom an excision or biopsy sample 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 remov l 
le determines the histology endpoint.  The 
most recent HPV clearance result prior to tissue removal, which includes results f
m the same date, within the timeframe 
determines the HPV clearance endpoint.
c Excludes ECC-only samples
Table 9: 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 whom an excision or biopsy sampleb was 
NOT obtainedc between initial dose up to Wee  36 
visit
Subject with evidence of HPV-16 or HPV-18 at Week 36 visit
OR
Subjec   hom excision or biopsy sample 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 tho
 h  
 u d gone HPV testing at any time starting from 14 days prior to the 
protocol-specified target date of Week 36. The first tis
 
ov l sample determines the histology endpoint. The most recent 
HPV clearance result prior to tissue re
al wit in e timef a e determines the HPV clearance endpoint.
b Excludes ECC-only samples
c This applies only to the cervical clearance endpoint.
3.3 EXPLORATORY OBJECTIV
 AND ENDPOINTS
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Histology is the gold standard for the diagnosis of cervical HSIL. Therefore, the definitive histopathologic 
assessment in the Phase 2b study was determined by an independent blinded Pathology Adjudication Panel, 
comprised of experienced cytopathologists from independent medical centers in the US, who are also 
adjudicating the HPV-301 study.  This will enable the highest certainty of the diagnosis for study entry with 
the exclusion of individuals with carcinoma and also enable a consistent and accurate histologic endpoint 
evaluation.  
Cervical disease will be monitored 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. The increased frequency of monitoring is designed to afford an even 
wider margin of safety and an opportunity to explore predictors of efficacy. 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 s
l  t
i ally over years, which makes close, 
active follow-up possible.  All subjects will undergo excision  thera
 
 EEP, LLETZ or CKC at Week 
36 as part of the efficacy assessment [18].  
Importantly, investigators in the HPV-303 stud  will be chosen o ly if they are experienced in the 
management of cervical cancer as was the case in the HPV-003 study. Phase 3 investigators are instructed 
to perform additional, ad hoc colposcopic exa
 
 ce
i a  
opsies if they suspect potential disease 
progression. Subjects that undergo an unscheduled biop y 
l be classified as a non-responder in the 
efficacy analysis as outlined in Table 4. T
 measures s
 minimize the risk of progression of cervical 
HSIL and the risk of harboring an undia
ed 
ult 
 vasive cervical cancer. The frequency of close 
monitoring by experienced investigat r  sh uld minimize the risk of cancer progression on the study what 
is expected with standard of care.  
An independent Data and Safety Monitoring Board (DSMB) will also provide safety oversight as is being 
done for the HPV-301 study.
 
B 
ll 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 unac
pt bl  ow compared to the placebo group. 
3.5.1 SUMMARY OF LONG TERM FOLLOW UP DATA FROM PHASE 2B 
STUDY
In HPV-003, cervical tissue samples were 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. 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 
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which micro-invasive cancer was found based on confirmed cases in larger surgical excision samples in 
subjects who had no evidence of invasive cancer by initial biopsy in the VGX-3100+EP arm was 1.8%, 
(2/114 with specimens) and across both arms was 1.3% (2/155 with specimens), which is consistent with 
that reported under standard of care settings [19].  
In the HPV-003 study, all subjects were scheduled to be followed for approximately 1 year (Week 88) after 
the histopathologic assessment of the primary endpoint. 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). Investigators were instructed to perform a LEEP/CKC in 
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 10).
Cytology and HPV-16/18 clearance from the cervix was 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 cl
r d their underlying HPV-16/18 cervical 
infection by the Week 62 and 88 visits. For Weeks 62 and 8  
ere 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 10 which 
summarizes the HPV and cytology results following Week 36   
Table 10:  HPV-003 HPV and Cytology R
lt  at We
 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
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Biopsyc
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%(n/N)
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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 (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 10). Based upon the Phase 2b results, the risk of recurrence of cervical dysplasia
and the risk of persistent High Risk HPV infection under these clinical trial conditions is lower than the 
rates observed post-LEEP/CKC in clinical practice. For example, Xi et al. showed that in a prospective 
cohort of women with HPV-16 who participated in the ASCUS and LSIL triage study (ALTS), 6.0% 
(12/201) subjects had a recurrence of CIN 2 or CIN 3 at 12 months post-LEEP [20]. In a very large 
retrospective cohort study (n = 3,273 women treated for CIN2, C N3, or AIS) Katki et al found, in the 
subgroup of patients who had an AGC, ASC-H, OR H I
 
etreat
t screening result (n = 1,461 
women), a CIN2+ recurrence at 12 months post-treatment of 6.1% in wom n treated for CIN2 and 9.8% in 
women treated for CIN3 [21]. Nobbenhuis et al. have reported a rate 
 igh Risk HPV persistence of 14% 
(26/181) at 12 months post-LEETZ [22], as did Moore   
h 12 months post-treatment (LEEP, cone, 
or laser ablation) persistence of: HR-HPV at 29.7% (260/874), HPV-16 at 14% (58/416), and HPV-18 at 
11% (11/99) [23]. 
The collection of cytology and virology da a f r 
 a
onal year of follow-up after the removal of tissue 
at Week 36 was reassuring in that no significant recurrence of cytological or virological disease was noted. 
However, the removal of tissue at Week 36 did appear to obfuscate the differences between the treatment 
groups that were present at that time but normalized across groups after that visit presumably due to the 
removal of infected and/or dys
tic tissue. A uming the longer term virologic and cytologic data 
collected in the companion HPV-301 Phase 3 stud  are similar to what was seen in the HPV-003 Phase 2b 
study, the collection of virologic nd or cytol
c data beyond the Week 36 primary endpoint visit would 
not be expected to yield significant results in t is companion Phase 3 study.   
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V-301 P
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4 STUDY POPULATION
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 that meet 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(s)  
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 r
ins after Screening biopsy;
10. Must meet one of the following criteria with respect to their rep oductive capacity:
a)
Post-menopausal as defined by spontaneous amenorrhea for more than 12 months;
b) Surgically sterile due to absence of ova ie  o  
e t   bilateral tubal ligation/occlusion performed 
more than 12 months prior to screening;
c)
Women of Child Bearing Potential (WOC
 ar
illing to use a contraceptive method with failure 
rate of less than 1% per yeara when use  
sistently and correctly from Screening until Week 36. 
The following methods are acce
b e
•
Hormonal contraception: either com
ed 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);
•
Abstinence from 
a nal intercourse when this is the subject’s preferred mode of sexual 
activity;
•
Intrauterine device or intrauterine system;
•
Male partner sterilizat
 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.
a Use of condoms alone or condoms with spermicide does not have a failure rate of <1% per year and is therefore not 
an acceptable form of contraception.
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 either com
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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 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;
6. History of previous therapeutic HPV vaccination (licensed prophylactic HPV vaccines are allowed, e.g. 
Gardasil™, 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.
 
 
emed clinically significant by the 
investigator 60 days prior to Day 0;
8. Immunosuppression as a result of underlying illnes  
 reatment in
ing:
a)
History of or positive serologic test or IV  screening (performed within 60 days prior 
to Day 0)
b) Primary immunodeficiencies
c)
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d) Current or anticipated use of disease modifying doses of anti-rheumatic drugs (e.g., 
azathioprine, cyclophosp
 
yclosporine, methotrexate), and biologic disease 
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History of solid organ or bone marrow transplantation
f)
Any prior history  other clinically significant immunosuppressive or clinically diagnosed 
autoimmune diseas  that may jeopardize the safety of the subject or require therapy that 
would inter
 wit  s
 
sessments or endpoint evaluation, or otherwise impact the 
validity of the study results.
g) Subjects who 
 malnourished based on screening labs, medical history (e.g. clinically 
significant unintentional weight loss) and physical exam, as determined by investigator’s
clinical judgment
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 systemic treatment for malignancy within 2 years of screening (locally treated ano-
genital malignancy and superficial skin cancers are allowed);
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4.2        EXCLUSION CRITERIA (continued)
13. Presence of acute or chronic bleeding or clotting disorder that would contraindicate intramuscular (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 onsidering 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 preven   life-threatening arrhythmia) that is located in 
ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist);
22. Metal implants or implantable medical device wit
 t
 lectroporation 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 t e op nion of the investigator may affect the safety of the subject or the 
evaluation of any study endpoint.
4.3 DISCONTINUATION/WI
AWAL OF STUDY SUBJECTS
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 safety 
follow-up assessments through study disc arge 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. 
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), 
to 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 
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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). If these attempts to 
contact the subject are unsuccessful the subject can be considered as withdrawn from the study (i.e. lost to 
follow-up). If contact with the subject is re-established, the site should contact the Medical Monitor to 
discuss whether the 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. 
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 
blood samples collected as indicated in the Schedule of Events in 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.
The primary reason for a subject discontinuing further do n  o  
thdrawal 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. 
x
Death of subject, (including manner of de th if known)  
x
Subject voluntarily withdrew consent: The subje  
sir d o withdraw from further participation in the 
study in the absence of an investiga
-determ
d me ical need to withdraw. If the subject gave a 
reason for withdrawal, it must be recorded on he CRF. This reason does not allow for further data 
collection and should not be selected if foll
-up data collection of this subject is anticipated by the 
subject. 
x
Investigator decision to with
 
e 
t rom participation: Investigator determined a medical 
need to withdraw the s
t. 
tig or must consult the Sponsor’s Medical Monitor before 
withdrawing a subject rom participation n the study. 
x
Protocol Deviation: T
 
bject’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 deviation should be discussed with the Sponsor’s Medical Monitor prior to 
discontinuation of study treatment  or study withdrawal. 
x
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. 
x
Other: The subject was terminated for a reason other than those listed above, such as the termination of 
the study by the Sponsor. 
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. 
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5 STUDY TREATMENT
5.1 INVESTIGATIONAL PRODUCTS
The active and placebo formulations to be used in this study are described in Table 11. Both Investigational 
Products (IPs) will be presented in clear glass cartridges and injected intramuscularly.
VGX-3100 and placebo will be provided by Inovio Pharmaceuticals, Inc. or its designee.
Table 11:  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 m
 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 n  
f
e  appe rance between 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 stud  tr atm nt is es ential for proper clinical management of 
the subject, as judged by the investigator. It is preferred, b  
t 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 co
 Medical Mo
or to discuss the options before unblinding the 
subject’s treatment assignment. 
The Sponsor’s or designee’s pha
a
i
e t f  may unblind the treatment assignment for any subject 
with an SAE, UADE, or AE of 
t. N  pe s
nel directly involved with the study will be unblinded. If 
expedited regulatory reporting is required 
 
 event, the report may be submitted to regulatory authorities 
with the subject’s treatment assignment  in accordance with local regulations.
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ovigilance sta
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5.4 TREATMENT REGIMENS
The three-dose regimen of VGX-3100 appeared to be safe and well tolerated in the HPV-003 study, 
therefore all eligible subjects who consent to participate in the HPV-303 study will receive three 6 mg doses 
of VGX-3100 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. 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, concurrent with the positive 
testing for HPV-16/18.
5.5 PACKAGING AND LABELING
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-of . Bo h VGX-3100 and placebo labels will 
include, at minimum, the following information in Table 12:  
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5.6 HANDLING AND STORAGE
The CELLECTRA™ 5PSP device and its components must be stored in a secure location according to the 
instructions in the User Manual. For the specific temperature guidelines for storing, please refer to the 
CELLECTRA™ 5PSP User Manual. 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 records 
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.
5.7 PREPARATION AND DISPENSING
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 pe
l 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 mus  
t e r
 r m the pouch until immediately prior to 
administration. 
The pouch must not be discarded until:
1) Administration is completed and 
2) All pertinent information fro  the pouch label has been documented in source. 
The product must be used within 4 hours of removal from the refrigerator. If the IP is not used within this 
time frame it must be discarded after reconciliation.
5.8 USE OF CELLECTRA™5P P DEVICE
The instructions for use of 
 
E LECTRA™5PSP are located in the CELLECTRA™ 5PSP User 
Manual. Users of the CELLECTR
 5PSP device must successfully complete training before using the 
device. Training will include review of the entire device User Manual as well as hands-on training. After 
training on the proper use of the CELLECTRA™ 5PSP device, the intended users at each site will be 
required to demonstrate their competency in its use to Inovio personnel 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.
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5.9 INVESTIGATIONAL DRUG AND DEVICE ACCOUNTABILITY
5.9.1 INVESTIGATIONAL PRODUCT
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:
x
Amount received and placed in storage area;
x
Amount currently in storage area;
x
Label ID number and use date or expiry date;
x
Dates and initials of person responsible for each investigational product inventory/movement;
x
Amount dispensed to each subject, including unique subject identifiers;
x
Amount transferred to another area/site for dispensing or storage;
x
Amount returned to Sponsor;
x
Amount destroyed at study site, if applicable.
5.9.2 CELLECTRA™ 5PSP DEVICE
The site is responsible for maintaining the device and its account
 logs. The device must have full 
traceability from receipt of the components through the device
 
 return of the device. The site must 
document acknowledgement of receipt and then notify Inovio upon eceipt of the device. This includes the 
content shipped and condition of the items upon r
 
For each subject treatment, there must be  
or  f each p o
ct used for that subject, i.e. CELLECTRA™ 
5PSP Base Station & Handset serial number  
ay 
 number and the study drug lot number. The used 
Array attachment must be disposed of in accordance with institutional policy regarding disposal of sharp 
needles/instruments.
5.10
RETURN AND DESTRUCT
 
INVESTIGATIONAL DRUG AND DEVICES
5.10.1 INVESTIGATIONAL PRODUCT
Upon completion or term
on o  
 udy, all unused IP must be destroyed at site per institution policy 
or returned to Inovio Pharmaceuti
ls, 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. personal 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 
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a record of each produ
rd of each p
umber, Array
rr
lot num
l
of in accordance wit
accordance
STRUCTION OF
RUCTION OF
IGATIONAL PR
GATIONAL PR
ination of the stud
on of the
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returned to Inovio Pharmaceuticals, Inc. The return of unused IP(s) should be arranged with the responsible 
Inovio personnel and/or Clinical Monitor. 
5.10.2 CELLECTRA™5PSP DEVICE
Upon completion or termination of Inovio’s 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 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. 
x
Written authorization must be granted by Inovio Pharmace icals, Inc., or its designee of the disposal,  
x
Ensure that proper procedures for disposal have been esta
d and followed according to applicable 
local regulations, guidelines and institutional procedures,  
x
Appropriate records of the disposal have been documented.
6 STUDY PROCEDURES AND S
DUL
This section lists the procedures and param
 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 spe ific procedures are performed. Results and activities 
performed as part of the screening process in the HPV-301 trial can be used as qualifying historical 
information to satisfy screening c viti
 f
 
V-303 provided that they were assessed within the 
required timeframes for HPV-303 screening. Participants will be consented for the HPV-303 trial and 
asked that their historical results be applied to HPV-303. All participants will be screen failed as part of 
HPV-301 regardless of parti ipati
  PV-303.
Protocol waivers or exemptions will not be granted. Immediate safety concerns will be dealt with as deemed 
necessary by the investigator. Adherence to the study design requirements, as outlined in the Schedule of 
Events Table are essential and requ ed for study conduct. Subject eligibility should be reconfirmed at every 
study visit.
6.1 PROCEDURES BY VISIT
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 the PAC for evaluation prior to enrollment.  
Figure 7 below illustrates the information in order of priority that could help in the identification of 
potential subjects for screening.
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 HPV
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x
Post treatment adverse event and injection site reaction evaluation
x
Review Week 4 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)
WEEK 8 (±4 DAYS)
The following study evaluation will be performed during the visit:
x
Targeted physical assessment
x
Vital signs
x
Collect and review PDC for dose 2
x
Post treatment adverse event and injection site reaction evaluation
x
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)
WEEK 12 (±4 DAYS)
The following study evaluation will be performed on We
 
 rior to study treatment:
x
Targeted physical assessment
x
Vital signs including weight
x
Urine pregnancy test
x
Study treatment will be administered 
The following study evaluations will be performed at Week 12 post treatment:
x
Post treatment adverse event and nje
on te 
tion assessment within a minimal of 30 minutes after 
study treatment
x
Distribute PDC
**Please remember to download EP data from device within 24-48 hours of study treatment. **
8-14 DAYS POST DOSE 3 PHONE CALL
The following informatio  wil  b  evaluated during phone call:
x
Post treatment adverse event and injection site reaction evaluation
x
Review Week 12 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.)
WEEK 15 (± 1 WEEK)
The following study evaluations will be performed at Week 15:
x
Targeted physical assessment
x
Vital signs
x
Post-treatment injection site reaction assessment
x
Urine pregnancy test
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6.2 INFORMED CONSENT
All subjects must sign the informed consent prior to any study related procedures being performed. The 
informed consent documentation must be in accordance with applicable regulations and Good Clinical 
Practice (GCP). Qualified study personnel will meet with prospective study participants, 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 or subject’s 
legally acceptable representative is then requested to sign and date the ICF. A copy of the signed informed 
consent documentation must be provided to the subject or subject’s legally acceptable representative. 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. 
6.3 ASSIGNMENT OF SUBJECT IDENTIFICATION NUMBERS
Each subject who consents will be assigned a unique subject identification number (SID), which identifies 
the subject for all study-related procedures. Once assigned, SID  
ot be reused for any reason. 
Information regarding the SID and screen date 
ill 
 ocu e
 on a screening and enrollment 
log/system and in the eCRF.
Subjects meeting eligibility criteria listed in the protocol will be randomized by a computer-generated 
allocation schedule. 
6.4 SAFETY EVALUATIONS
6.4.1 PHYSICAL EXAMINATION
A complete physical examination (P
 
i  
 
nducted during screening and study discharge.  It will 
include an assessment of the following: general appearance, skin, head, eyes, ears, nose, and throat, lymph 
nodes, respiratory, cardiovascular, gastrointestinal, genitourinary, musculoskeletal, and neurological 
systems. 
A targeted physical assessment will be performed at other visits as determined by the investigator or 
directed per subject complaints. 
6.4.2 VITAL SIGNS
Vital signs will be measured at specified visits and will include:
x
Sitting systolic and diastolic blood pressures with subject sitting at rest for at least 5 minutes before 
measurement
x
Respiration rate
x
Heart rate 
x
Oral temperature measured with an automated thermometer 
6.4.3 HEIGHT AND WEIGHT
Height and weight will be collected at Screening and on Day 0, Weeks 4 and 12. 
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on (P
 
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n
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following: general ap
ing: general ap
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ascular, gastroint
sment will be p
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The BMI at the Day 0 visit will be used to determine the BMI stratum for randomization.
6.4.4 MEDICAL HISTORY
All relevant past and present conditions at screening, as well as prior surgical procedures will be recorded 
for the main body systems (as judged by the investigator). The medical history will include 
a) Any prior history of CIN diagnosed – with diagnosis date(s) and respective CIN 
level(s),
b) If treated previously for CIN, the respective treatment type(s) and date(s).
6.4.5 SOCIO-BEHAVIORAL ASSESSMENT
Socio-behavioral assessment, including self-reported smoking history, history of exposure to second-hand 
smoke, alcohol intake history, recreational drug use, contraceptive use and type of contraceptive if known, 
reproductive history, history of prior cervical dysplasia, and pregnancy history will be obtained at 
Screening, Weeks 36 and 40. Socio-behavioral assessmen  
 
 erformed to document any change 
from Screening.
6.4.6 LABORATORY EVALUATIONS
At Screening, blood samples will be taken to be te
 o  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:
• Albumin
• Glucose
• Serum glut
c-pyruvic transaminase (SGPT)/Alanine aminotransferase (ALT)
• Blood urea nitro
 B N)
• Creatinine
• Electrolytes (Sodium, Potassium, Chloride, Carbon Dioxide or Bicarbonate)
• Creatine Phosphokinase (CPK)
6.4.7 URINALYSIS (UA) 
Urine samples will be tested at screening by dipstick for glucose, protein, and hematuria. If abnormal 
(presence of protein, KHPDWXULD RU JOXFRVH   D PLFURVFRSLF H[DPLQDWLRQ VKRXOG EH SHUIRUPHG
6.4.8 DEMOGRAPHICS
Demographic information will be collected via self-report (unless noted otherwise), including the 
following:
x
Age
x
Race/ethnicity
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x
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6.4.9 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. A final pregnancy test will also be done at Week 40 to capture 
pregnancy status at study completion.
6.4.10 ECG
A single 12-lead ECG will be obtained during Screening after the subject has been in a supine position for 
at least 10 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.
6.4.11 PARTICIPANT DIARY CARD (PDC) SUBJECT SELF EVALUATION
Subjects will be provided and trained on a PDC and w
 
 a k d 
 r cord the following the evening of 
study treatment through Day 6:
x
Oral temperature and time taken (before 11:59 pm)
x
General symptoms of feeling unwell
x
Pain and itching at injection site
x
Measure redness, swelling, bruising at injection site
x
Medications taken
The completed PDC will be reviewed wit  
 subject by the study staff at the 8 -14 day post-dose phone 
call and at the next in-person visit.
The study staff will review the P C fo  g
r  
mptoms (e.g. malaise, fatigue, headache, nausea, and 
myalgia/arthralgia), injection ite 
 y p oms (e.g. pain, erythema and edema), medical events and 
medications. 
Any PDC entry determined to meet the TCAE criteria for a Grade 1 or higher adverse event should be 
documented as an adverse ev nt 
less deemed part of the subject’s ongoing medical history. If the PDC
entry does not meet the criteria o  a rade 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.
6.4.12 PAP SMEARS AND HPV TESTING
Pap smears will be obtained using ThinPrep™ test kits at screening, Day 0, Weeks 8, 15, 28 and 36. They 
will be sent to 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.
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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, Weeks 15, 28 and 36) 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 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. Non-cervical swabs (vaginal and intra-anal) along with an oropharynx  
rinse will be collected at specified visits for HPV typing. 
6.4.13 COLPOSCOPY AND CERVICAL BIOPSIE
Colposcopy at Screening must be adequate, defined as full vis
t
 of the squamo-columnar junction 
(Type I or II transformation zone) and complete visualization of the u per 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 
 er
d at Screening if adequate colposcopy 
was previously obtained upon collection of initi l 
 
l  colposcopies performed after informed 
consent should be conducted according to the guideli e  outli ed in Appendix A. 
Interval colposcopies will be performed a  
  W
ks 1 , 28 and 36.  An unscheduled colposcopy may 
be performed at the discretion of the investigator if there is suspicion of disease worsening or progression. 
6.4.14 ECTOCERVICA  BIOPSIES
Ectocervical biopsies are requi
  creening to confirm eligibility.   
Biopsies should not be performed at any other visit unless there is suspicion of disease progression.  
Removal of additional tissue by biops  
re Week 36 will bias results toward improvement regardless of 
whether the subject is in th  ct ve or placebo group. For this reason, if biopsies are obtained prior to the 
Week 36 visit, 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.
6.4.15 UNSCHEDULED BIOPSIES
In the event an unscheduled biopsy is performed prior to the Week 36 visit, the subject will be classified as 
a non-responder in the efficacy analyses. The subject may 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.   
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6.5 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. 
6.6 MANAGEMENT OF ANXIETY AND PAIN DUE TO EP PROCEDURE
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 s ould 
 e 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, ket
olac) after injection/EP. Subjects who are 
allergic to or have contraindications to EMLA, ibupr f
 k
olac 
 a mild sedative may be offered a 
suitable alternative. Medication taken for anxiety or pa  m na
 should be added to the concomitant 
medications.
6.7 ASSESSMENT OF LABORATORY AB ORM
TIES
Blood will be drawn for serum chemistry, hematology and serology assessments as well as urine pregnancy 
testing at Screening and will be performed for incl s
 
 the study as listed in the Schedule of Events. 
6.8 ASSESSMENT OF CLINICAL STUDY ADVERSE EVENTS
The injection site will be assessed by stu
 
el prior to and of 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 P
. 
 
r e event assessment will be conducted at each visit during 
which subjects will be q
ed 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 f
m the time of the informed consent to study discharge. These events will 
be recorded on the subject’s CRF. 
6.9 ASSESSMENT OF INJECTION SITE REACTIONS
When evaluating injection site reactions throughout the study, the investigator will be instructed to use the 
following grading scale in Table 13.
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The following medications and treatments are prohibited:
x
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equivalent; use of inhaled otic and ophthalmic corticosteroids are allowed
x
Disease modifying doses of anti-rheumatic drugs (e.g., azathioprine, cyclophosphamide, cyclosporine, 
methotrexate), and biologic disease modifying drugs such as TNF-Į LQKLELWRUV HJ LQIOL[LPDE
adalimumab or etanercept) at screening and throughout the study
x
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
x
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)
The decision to administer a prohibited medication/treatment is done with the safety of the study participant 
as the primary consideration. When possible, the Sponsor should be notified before the prohibited 
medication/treatment is administered. All medications should 
 
orded in the appropriate sections of the 
subject’s eCRF.
6.13 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
As a requirement for inclusio  in the HPV-303 study investigators will only be chosen if they are 
experienced in the management of cervical cancer. HPV-303 investigators are instructed to perform 
additional, ad hoc colposcopic exams and cervical biopsies if they suspect potential disease progression. 
Subjects that undergo an early unscheduled biopsy will be classified as a non-responder in the efficacy 
analyses. These precautions should minimize the risk of progression of cervical HSIL. The increased 
frequency of close monitoring by experienced investigators should minimize the risk of cancer progression 
and the risk of an underlying misdiagnosis of invasive cancer. 
7.2 ADVERSE EVENTS (AES)
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 
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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:
x
Pre- or post-treatment complications that occur as a result of protocol mandated procedure during or 
after screening (before the administration of study drug).
x
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.
x
Complications of pregnancy; (e.g., spontaneous abortion, miscarriage, ectopic pregnancy, fetal death, 
still birth, congenital anomaly of the fetus/newborn); see Section 7.11 for additional information on 
pregnancy reporting.
x
All AEs that occur from when the informed consent is obtained onwards and throughout the duration 
of the study, including the follow-up off study drug p
 
 be 
rded as an AE.
AEs do not include the following:
x
Medical or surgical procedures (e.g., surgery, endosco
, to t  
raction, transfusion) performed; the 
condition that leads to the procedure is an AE
x
Pre-existing diseases or conditions or labor t r  
n
ities present or detected before the Screening 
visit that do not worsen.
x
Situations where an untoward medica  o currence has not occurred (e.g., hospitalization for elective 
surgery, social and/or convenience 
sions
x
Overdose without clinical sequelae.
x
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 his o y RF.
x
Uncomplicated pregnancy.
x
An induced elective abortion to terminate a pregnancy without medical reason.
7.3 SERIOUS ADVERS  VEN
 (SAES)
A serious adverse event (SAE) is any AE that meets one of the following conditions:
x
Death during the period of surveillance defined by the protocol;
x
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;
x
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;
x
Results in persistent or significant disability/incapacity or substantial disruption of the ability to conduct 
normal life functions;
x
Results in congenital anomaly or birth defect;
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x
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:
o
allergic bronchospasm requiring intensive treatment in an emergency room or at home,
o
blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
o
the development of drug dependency or drug abuse or 
o
development of a malignancy
x
Is medically significant or requires intervention to prevent one or other of the outcomes listed above.
Clarification of Serious Adverse Events:
x
Death is an outcome of an AE, and not an adverse event in itself.
x
The subject may not have been on investigational medicinal product at the occurrence of the event. 
x
Dosing may have been given as treatment cycles or interru te  temporarily before the onset of the SAE, 
but may have contributed to the event. 
x
“Life-threatening” means that the subject was at immediate risk
 eath from the event as it occurred. 
This does not include an event that might have led to death if it had o
urred with greater severity.
x
Complications that occur during hospitaliza
 
e AE . I  a complication prolongs the 
hospitalization, it is an SAE.
x
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 7.15.3.
7.4 UNEXPECTED ADVERSE DRUG REACTIONS AND EXPEDITED REPORTING 
An adverse drug reaction (A
)  ny noxious and unintended responses to a medicinal product related to
any dose; for which a causal rel tions ip 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 adverse event or ADR is considered unexpected if it is not listed in the applicable product 
information (Investigator’s Brochure, Protocol, or User Manual) or is not listed at the specificity or severity 
which is consistent with the risk information provided. The Sponsor will assess each serious adverse drug 
reaction 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 
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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 patient population, or a 
major safety finding from a study conducted in animals.  
7.5 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 4 hours. Sponsor will assess each device 
related SAE to determine if anticipated based on prior ide
fi a ion 
in the investigational plan.
7.6 ASSESSING SEVERITY (INTENSITY)
Adverse events should be captured once on the CRF at t
 
m severity reported. 
The investigator will grade laboratory AEs wit  e
ct  
 
o ing levels of severity as defined in the 
document “Toxicity Grading Scale” for appli
ble 
 po
lations:
x
Mild (Grade 1)
x
Moderate (Grade 2)
x
Severe (Grade 3)
x
Potentially Life Threatening (Grade 4)
x
Death (Grade 5)
The investigator will grade c
 
Es or SAEs (based on discussions with study participants) in 
accordance with the Com
n 
m ology Criteria for Adverse Events (CTCAE) v 4.03.
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.
7.7 CAUSAL RELATIONSHIP OF CLINICAL MATERIAL TO ADVERSE EVENTS
A causally related AE is one judged to have a possible, probable or definite relationship to the 
administration of the IP and/or the device. An AE may also be assessed as not related to the investigational 
product 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 EP 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.
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Investigators should use their knowledge of the study subject, the circumstances surrounding the event, 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 related to drug or related to device or related to both drug and device (i.e. 
indiscernible) by the following criteria:
x
Yes – there is a reasonable possibility that administration of the Study Treatment (drug or device 
or both drug and device) contributed to the event;
x
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:
x
Temporal relationship of event to administration of IP and/or EP;
x
Course of the event, considering especially the effects of dose reduction, discontinuation of IP, or 
reintroduction of IP (where applicable);
x
Known association of the event with the IP, EP or with similar treatments;
x
Known association of the event with the disease under study;
x
Presence of risk factors in the study subject or use of concomitant medications known to increase 
the occurrence of the event.
7.8
ABNORMAL LABORATORY VALUES
Laboratory abnormalities are usually not r c
de  
 AE  
 AEs. However, laboratory abnormalities 
(e.g., serum chemistry, CBC, CPK, urinalysis) independent of the underlying medical condition that require 
medical or surgical intervention or lead t  
 
upti n 
 discontinuation must be recorded as an AE, as 
well as an 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:
x
Requires therapeutic intervention or diagnostic tests
x
Leads to discontinuation of study treatment
x
Has accompanying or inducing symptoms or signs
x
Is judged by the investigator as clinically significant
Severity will be assessed as detailed in Section 7.6.
7.9
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 
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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 Sponsor.
7.10
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.
7.11
PROCEDURE FOR REPORTING PREGNANCY DURING THE STUDY
Subjects who are pregnant or expect to become pregnant prior to Week 36 of the study will be excluded 
from participation in the study. Should a subject become pregn
 f er randomization, she will not be given 
any further treatments with the investigational product. 
 Pr
ncy Form will be completed by the 
investigator and submitted to the sponsor study team and edic  
r 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 7.15.3. The investigator will also report thi  e e  o the IRB/EC within 24 hours of 
becoming aware of the pregnancy. Sites must requ
 e subject’s 
ission to query pregnancy outcome 
and follow each subject to determine the outcom  of the pregnan y. Results will be summarized in the 
Clinical Study Report (CSR). 
Subjects who become pregnant at any po
 u ing 
e study will continue to be followed for safety 
assessments without receiving further IP. Procedures that are contraindicated during pregnancy, including 
additional treatments, must not be performed. In est ators 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 occu  
o  he time of first study treatment through the follow up visits must be 
reported. The investigator w ll monitor the subject and follow the outcome of the pregnancy. If the end of 
the pregnancy occurs after the st
 
 b en completed, the outcome will be reported directly to the study 
team and the Medical Monitor.
7.12
METHODS AND TIMING OF COLLECTION 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 40.
The sources of AEs cover:
x
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).
x
Symptoms spontaneously reported by the subject.
x
Evaluations and examinations where the findings are assessed by the investigator to be clinically 
significant changes or abnormalities.
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x
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.
7.13
SAFETY AND TOXICITY MANAGEMENT
The Medical Monitor will be responsible for the overall safety monitoring of the study. 
Safety assessments include the following:
x
Incidence of all adverse events classified by system organ class (SOC), preferred term, severity, 
and relationship to study treatment
x
Local and systemic injection site review; special atten
n will be paid to the examination of the 
injection site. Administration site reactions and the s bject's complaints will be documented
7.14
ADVERSE EVENTS OF SPECIAL INTER ST
Adverse Events of special interest (AESI) are the adverse event  
d related to VGX-3100/Placebo 
delivered with the CELLECTRA™device that requi  expe i ed c
munication from the site to the 
Sponsor and meet any of the following criteria:
x
Grade 3 or greater persistent aGPLQLVWUDWLRQ VLWH HU\WKHPD DQGRU LQGXUDWLRQ UHFRUGHG   KRXUV
immediately after Study Treatment
x
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after Study Treatment
x
Grade 3 or greater fever
x
Grade 3 or greater systemic symptoms
.g , malaise, chills, fatigue), including generalized pruritus
Sites will inform the Sponsor via the m
 
scribed in Section 7.15.2 within 24 hours to discuss 
whether further dosing for th  p
l  
ct should continue.
7.15
ADVERSE EXPERIENCE (AE) REPORTING
To assure the safety of the participants, information about all AEs (see Section 7.2), whether volunteered 
by the subject, discovered by investigator or study staff questioning, or detected through physical 
examination, laboratory test or other means, will be collected and recorded in the subject’s source 
documents and followed as appropriate.
7.15.1 STUDY REPORTING PERIOD OF ADVERSE EVENTS
All solicited and unsolicited adverse events will be collected throughout the study and recorded in the EDC 
system. The Study Report will analyze and summarize all adverse events throughout the study. Emphasis 
will be placed on the following: 
x
Certain AEs of interest will be solicited during the 7 days following each administration of Study 
Treatment and summarized separately
x
Unsolicited AEs will be collected and summarized for the entire study period
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7.15.2 STUDY REPORTING PERIOD FOR ADVERSE EVENTS OF SPECIAL 
INTEREST
Adverse events of special interest (AESI) (see Section 7.14) require expedited communication from the site 
to the Sponsor. Within 24 hours of the site's awareness of the event, AESI must be reported by the
investigator through data entry in the Adverse Event electronic case report form (eCRF) via the Medidata 
RAVE electronic data capture (EDC) system. In the event that the Medidata RAVE EDC system is 
unavailable, the investigator must notify the Sponsor via email or phone. 
AESI reporting if EDC system is unavailable
EMAIL:     
   
SAFETY PHONE:
7.15.3 STUDY REPORTING PERIOD OF S
O S ADVERSE EVENTS
The reporting period for SAEs (without regard to caus
ty 
 r la i
ship) is comprised of the period 
following the signing of the informed consent form unt  the end of the study. 
Each AE will be assessed to determine whether it meets seriousness criteria. If the AE is considered serious, 
the investigator should report this event to the Sponsor within 24 hours of becoming aware of the event. 
The investigator may also directly report this ev nt to the IR
C according to its standard operating 
procedures. Expectedness of SAEs will be determined by the S onsor using reference safety information 
specified in the Investigator’s Brochure. 
 
t m y qualify for expedited reporting to regulatory 
authorities if it is an SAE, unexpected pe  reference safety information and considered related following 
the guidelines in Section 7.4 (Suspected Unexpected Serious Adverse Reaction, SUSAR) and 7.5 
(Unanticipated [Serious] Adverse 
evice 
 ine with relevant legislation. All investigators will 
receive a safety letter notifying t
 o all SUSA  reports. The investigator should notify the IRB/EC as 
soon as is practical, of serious events in w ting w ere this is required by local regulatory authorities, and 
in accordance with the local institutional policy.  
Within 24 hours of the site's awareness of the event, all SAEs (regardless of relationship to investigational 
product) must be reported by the investiga or through data entry in the Adverse Event electronic case report 
form (eCRF) via the Medidata R
E electronic data capture (EDC) system.  In the event that the Medidata 
RAVE EDC system is unavailable, the paper SAE Report form should be used and faxed to the 
PPD Pharmacovigilance (PVG) Safety Hotline Fax Number shown below:
Facsimile (FAX) reporting if requireda: 
Americas FAX#: 
 
Europe FAX#: 
 
a Reporting by FAX is required for paper SAE Report Forms if electronic data capture (EDC) 
is not available, redacted supporting medical records, and Pregnancy Report Forms. 
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 patient identifying 
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information present on SAE supporting documents prior to sending the report to the Sponsor. The 
supporting documents for SAE reports should be sent by fax to the PPD PVG Safety Hotline Fax Number, 
shown above. 
Investigator will supply the Sponsor and the IRB/EC with more information as it becomes available and 
any additional requested information. 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. 
7.16
NOTIFICATIONS 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 drug reaction that is both serious and 
unexpected and any significant new safety informati
 hat might m
ially influence the benefit-risk 
assessment of a medicinal product, sufficient to consid r changes i  product administration or overall 
conduct of a clinical investigation. The Sponsor will n
y 
ry agencies within the time frame 
specified by local requirements but no later tha  10 worki
 days for UADE, 7 days for a fatal or 
life-threatening SUSAR, and 15 days for a  ot er SUS
s see Section 7.5 and 7.4). Results of 
investigations of other safety information s
ll b  
tted, as appropriate, in an information amendment 
or annual report. 
7.17
REPORTING OF DEVIC  RELATED COMPLAINTS OR DEFICIENCIES
A product complaint/device deficiency is defined as any written, electronic, or oral communication that 
alleges deficiencies or inadequacies of the device o  components related to the identity, quality, durability, 
reliability, safety, effectiveness, o  e f
 of the device or components after it is released for 
distribution within the clinical investigation. All product complaints that meet this definition (with the 
exception of SAEs requiring 24 hr reporting) must be reported to the Sponsor with 10 days of discovery. 
Device deficiencies include malfunctions, use errors and inadequate labeling. A malfunction is defined as 
the failure of a device to meet its performance specifications or otherwise perform as intended. The intended 
performance of a device refers to the intended use for which the device is labeled or marketed.  
Any problems experienced during the treatment procedure including 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:
or fax to
. 
7.18
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 
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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 received.
8.5 DESCRIPTION OF STATISTICAL METHODS
8.5.1 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT
The true treatment effect on the primary endpoint is G= pV – pP, where pV and pP denote the true biomarker-
positive population probabilities of the primary endpoint for VGX-3100 and Placebo, respectively. The 
primary hypothesis of superiority is:  
H0: G d 0 vs. H1: G > 0.
A p-value for this hypothesis test and corresponding 95% confidence interval will be computed based on 
the method of Miettinen and Nurminen [17]. Superiority w
 
 o
uded if the one-sided p-value is 
<0.025 and the corresponding lower bound of the two-sided 95% CI exceeds zero.
The efficacy time frame is defined by those who have unde g
e  iopsy 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 
e  ut 
ior to this time frame or subjects who have no 
endpoint data for this time frame; these su
 ar  
s
red as failures for the primary efficacy 
endpoints. Table 4 provides details for the definition of the primary endpoint response.   
The ITT biomarker-positive populatio  
 be p
 
r the analysis of efficacy in this study. Missing 
data will be considered as non-regr sso  
ures) for the ITT efficacy analysis. Efficacy analysis using 
the mITT population will also be onduc
 
 w
 serve as sensitivity analyses regarding missing data. 
The PP population will also be 
ed 
  s
rtive analysis. An additional analysis on the PP population 
will utilize the Week 36 timefram  
 
a dless of excision or biopsy performed before the Week 36 
time frame, thus serving as a sensitivity analysis regarding early intervention. Additional analyses will be 
performed on all subjects reg
 
 
arker status.
8.5.2 ANALYSIS OF THE SECONDARY ENDPOINTS
8.5.2.1 Efficacy
The secondary efficacy endpoints will be analyzed in the same manner as the primary hypothesis, but 
without the hypothesis test p-values. The efficacy time frame is the same as for the primary endpoint.
Table 5 through Table 9 provide details for the definitions of the secondary endpoint responses. 
The ITT biomarker-positive population will be used for the analyses of these endpoints. Missing data will 
be considered as non-regressors (failures) for the ITT efficacy analyses. Efficacy analyses using the mITT 
population will also be conducted and will serve as sensitivity analyses regarding missing data. The PP 
population will also be used for supportive analyses.  Additional analyses on the PP population will utilize 
the Week 36 timeframe result regardless of excision or biopsy performed before the Week 36 time frame, 
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thus serving as sensitivity analyses regarding early intervention. Additional analyses will be performed on 
all subjects regardless of biomarker status.
8.5.2.2 Immunogenicity
Post-baseline cellular and humoral response magnitude will be compared between treatment groups using 
a difference in medians and associated non-parametric 95% CIs.
Increases from baseline in interferon-Ȗ (/,6SRW UHVSRQVH PDJQLWXGHV DQG HPV E6 and E7 titers from 
ELISA at Weeks 15 and 36 visits will be evaluated. Valid samples for statistical analysis purposes will be 
those collected within 7 days of the specified visit. Baseline is defined as the last measurement prior to the 
first treatment administration.
The mITT biomarker-positive population will be used for immunogenicity analyses. Additional analyses 
will be performed on all subjects regardless of biomarker status.
8.5.3 SAFETY ANALYSES
All AEs will be summarized among the safety population by frequency per treatment arm. These 
frequencies will be presented overall and separatel  
 
e, and will depict overall, by system organ class 
and by preferred term, the percentage of subjects af
. d it onal 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 
orst-case approach with respect to severity and 
relationship to Study Treatment. All serious AE  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 t m 
ts will be compared between study arms with risk differences 
and 95% confidence intervals, using the method of Miettinen and Nurminen [17]. 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 
ll 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 th  
rliest 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.
Analyses and summaries will be performed on biomarker-positive subjects and on all subjects regardless 
of biomarker status separately.
8.5.4 DISPOSITION
Disposition will be summarized by treatment arm for the ITT population and will include the number and 
percentage randomized, the number and percentage who received each dose and the number who completed 
the trial.  The number and percentage of subjects who discontinued will be summarized overall and by 
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reason. The number in each analysis population will also be presented. Summaries will be performed on 
biomarker-positive subjects and on all subjects regardless of biomarker status separately.
8.5.5 BASELINE CHARACTERISTICS
8.5.5.1 Demographics
Demographic data will be summarized with descriptive statistics: mean standard deviation, minimum, 
median, and maximum values for continuous variables, and percentages for categorical variables, by 
treatment arm, for the ITT population. Summaries will be performed on biomarker-positive subjects and
on all subjects regardless of biomarker status separately.  
8.5.5.2 Medical History
The percentage of subjects with abnormal medical history findings will be summarized by body system, by 
treatment arm, for the ITT population.  Summaries will be pe
d on biomarker-positive subjects and
on all subjects regardless of biomarker status separately.
8.5.5.3 Prior Medications
Prior medications are those that were used before the start of the trial (prior to Day 0). Partial stop dates of 
prior medications will be assumed to be the lat
t pos i l  ate 
sistent with the partial date; start dates 
will not be imputed. Data for all prior medications will be summarized with percentages by treatment arm, 
for the mITT population.  Summaries will be pe formed 
 bi marker-positive subjects and on all subjects 
regardless of biomarker status separately.
8.5.6 PLANNED INTERIM ANALYSES
No formal interim analyses will e pe f
 f
 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 
 
t d 
 
le early stopping due to futility.
Group-level unblinded (VGX-3100, Placebo) summaries and analyses may be produced once the primary 
endpoint Week 36 visit da  
 completed for all subjects; subject-level blinding will be maintained. The 
summaries and analyses will allow e S onsor to have results with respect to the primary endpoint and key 
safety outcomes on which to make decisions regarding the VGX-3100 program while awaiting final 
database lock. The planned set of summaries and analyses is comprised of a) the primary composite 
endpoint of histopathologic regression and virologic clearance and b) adverse events of progression to 
cervical cancer.  Both will be performed on the biomarker-positive set of subjects and on all subjects. 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. 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.
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8.5.7 SUBGROUP ANALYSES
Primary and secondary efficacy endpoints will be analyzed by history of exposure to prophylactic HPV 
vaccines.
8.5.8 MULTIPLICITY
Not applicable, there is one hypothesis that will be tested.
8.5.9 MISSING VALUES
Missing data will be considered as non-regressors (failures) for the ITT efficacy analyses. A subject’s 
regression outcome is missing if the CIN grade and HPV clearance at the Week 36 time frame cannot be 
determined. Also, any subject who undergoes an unscheduled excision or biopsy in which cervical tissue 
sample is obtained after Dose 1 and before the Week 36 timeframe will be considered a non-regressor 
regardless of the Week 36 timeframe result. 
Efficacy analyses using the mITT population will be co
t d and will serve as sensitivity analyses 
regarding missing data.
8.5.10 EXPLORATORY ANALYSES
8.5.10.1
Efficacy
8.5.10.3
Concomitant Medications
Concomitant medications are those used during the course of the trial (on or after Day 0). Partial stop dates 
of concomitant medications will be assumed to be the latest possible date consistent with the partial date; 
start dates will not be imputed. Data for all concomitant medications will be summarized with percentages 
by treatment arm, for the mITT population.
8.5.10.4
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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8.5.10.5
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.
8.6 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 among 
biomarker-positive women, utilizing the methodology described in Section 8.5.1, and assuming that the 
true proportion of subjects who achieve the primary endpoint is 66% and 15% for VGX-3100 and placebo, 
respectively, and that the proportion of biomarker-positive women is 33%. These proportions also 
incorporate missing data classified as non-regressors (failures) in accordance with the ITT analysis 
approach. The assumptions are based on the HPV-301 study results.
8.7 RANDOMIZATION AND BLINDING
Subjects will be randomized (2 VGX-3100:1 Placebo) in a stratifi d m nner according to a) the degree of 
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um. To ens
 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 nu b
 i  b  e ig
ted for use by each participating country.
The study is double blinded. Randomization and blinding will avoid bias in the assignment of participants
to treatment, increase the likelihood that known and unkn wn subject attributes (e.g., demographics and 
other baseline characteristics) are even  balanced be
en treatment groups, and enable valid statistical 
comparisons between treatment groups.
9 ETHICS
9.1 INVESTIGATOR 
D 
N
 RESPONSIBILITIES
The investigator and Spons
 
 
ons le for ensuring that the clinical study is performed in accordance 
with the protocol, the principles of the Declaration of Helsinki, GCP, and applicable regulatory 
requirements. 
9.2 INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE (IRB/EC)
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/EC and a copy of this 
approval has been received by the Sponsor.
Investigator responsibilities relevant to the IRB/EC include the following:
x
During the conduct of the study, submit progress reports to the IRB/EC as required, and request re-
review and approval of the study at least once a year;
x
Notify the Sponsor immediately of any suspected unexpected adverse drug or device events/effects;
x
If Sponsor notifies you about any reportable safety events notify the IRB/EC immediately;
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x
As required, obtain approval from the IRB/EC for protocol amendments and for revisions to the 
consent form or patient recruitment advertisements;
x
Reports on, and reviews of, the trial and its progress will be submitted to the IRB/EC by the 
investigator at intervals stipulated in their guidelines and in accordance with pertinent regulations 
and guidelines;
x
Maintain a file of study-related information (see study files) that includes all correspondence with 
the IRB/EC;
x
Notify IRB/EC when study is completed (i.e. after the last study visit of the final study patient);
x
After study completion (within 3 months is recommended) provide the IRB/EC with a final report 
on the study.
9.3 IBC APPROVAL AND REPORTING
Investigator will ensure responsibilities relevant to Institutional Biosafety Committee (IBC) approval and 
reporting if applicable per local regulations.
9.4 ADDITIONAL APPROVAL AND REPORTING
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. a
 
itutes of Health/Office of Science 
Policy) governing research that involves recombinant 
 
n he
 
leic molecules.
9.5 PROTECTION OF HUMAN SUBJECTS
9.5.1 COMPLIANCE WITH INFORMED CONSENT REGULATIONS 
Written informed consent is to be obtained from each subject prior to enrollment 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 recor  ( e  S c on 6.2).    
9.5.2 COMPLIANCE WITH IRB/EC REQUIREMENTS
This study is to be cond
 in accordance with applicable IRB/EC regulations. The investigator must 
obtain approval from a properly constituted IRB/EC prior to initiating the study and re-approval or review 
at least annually.  Sponsor is to be notified immediately if the responsible IRB/EC has been disqualified or 
if proceedings leading to disqualification have begun. Copies of all IRB/EC correspondence with the 
investigator should be provided to Sponsor. 
9.5.3 COMPLIANCE WITH GOOD CLINICAL PRACTICE
This protocol is to be conducted in accordance with the applicable GCP regulations and guidelines. 
GCP regulations and guidelines include International Council of Harmonization (ICH) and International 
Organization for Standardization (ISO) and applicable local regulations.  
9.5.4 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.
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9.5.5 COMPLIANCE WITH PROTOCOL
Subjects are not required to follow special instructions specific to the Investigational Product used in this 
study. 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.  
9.5.6 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/EC 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). While every effort should be made to avoid protocol deviations, should a deviation be 
discovered, Sponsor must be informed immediately. Any prot
 eviation impacting subject safety must 
be reported to the Medical Monitor immediately.  
10 DATA COLLECTION, MONITORING 
 REPORTING
10.1
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 legall  m r
ted 
 a  ultimately be marketed, but the subject’s 
name will not be disclosed in these documents. The subject’s name may be disclosed to the Sponsor, the 
governing health authorities or the Food and D ug Ad
istration (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 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 all applicable laws, 
regulations or directives rel
g  pr
y 
d data protection.
11 SOURCE DOCUMENTS
Source data is all information, i i
l ecords or clinical findings, laboratory results, observations, or other 
activities in a clinical trial neces
y 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. The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review, and 
regulatory inspections by providing direct access to source data/documents related to this study.
A medical history and history of medications must be present in the source documents. All prescription and 
nonprescription medications taken within 8 weeks prior to entry must be recorded on the CRF. Actual or 
estimated start and stop dates must be provided.
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11.1
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 their country and until there are no pending or contemplated 
marketing applications in their country 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 
country requirements. The Sponsor will inform the investigator/institution as to when these documents 
are no longer needed to be retained.
12 SAFETY AND QUALITY MONITORING
12.1
LONG TERM SAFETY FOLLOW-UP
Subjects will be followed for safety for 7 months after the last dose of VGX-3100. During this time they 
will be attending scheduled visits with qualified vestigators to monitor their health and condition. The 
investigators have the ability to perform unscheduled biopsies if deemed necessary.
12.2
DATA SAFETY MONITORING B ARD
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 appear  to be a safety issue and with advising the Sponsor if it appears that 
the proportion of the subjects w h 
s
 i  the VGX-3100 group is unacceptably low compared to 
the placebo group. However, no formal inter m analysis will be performed.
12.3
PATHOLOGY ADJUDICATION COMMITTEE
All histology slides (i.e. cervical biopsies or surgical excision tissue) will be read by a Pathology 
Adjudication Committee (P
) 
 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 at least two pathologists independently in a blinded fashion.  
12.4
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. 
Clinical site monitoring tasks will include but not be limited to the following at all sites:
x
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,
x
All clinical site monitoring visits will be documented,
x
Periodic site visits will be performed throughout the study,
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x
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/EC 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/EC,
o
Throughout the study, inspect all source documents to ensure they are attributable, legible, 
contemporaneous, original, accurate, and correct (ALCOAC),
o
Assure that the study facilities continue to be acceptable,
o
Compare the study CRFs with source docum nts to assure that the data are accurate and 
complete and that the protocol is being follow
o
Assure that investigational drug and devic  ac
 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.
13 FINANCING AND INSURAN
Inovio Pharmaceuticals is the Sponsor in a  pa ti ip ing countries and is fully supporting the study.  
Clinical trial insurance has been taken out acco
n  
 
 laws of the countries where the study will be 
conducted.
14 PUBLICATION POLICY
Publication of the results of this tr
 n its en ir t  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 afte  
c
t of the copies to object to the proposed presentation or 
publication because there is 
 
t matter that needs protection. In the event that the Sponsor 
makes such objection, the res
he
) shall refrain from making such publication or presentation for a 
maximum of three (3) months from t e date of receipt of such objection in order for patent application(s) 
(directed to the patentable subjec  
er 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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15 LIST OF ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIS
Adenocarcinoma-in-situ
AGC
Atypical Glandular Cell
ALCOAC
Attributable, legible, contemporaneous, original, accurate, and correct
ASC-H 
Atypical Squamous Cells, cannot exclude High grade squamous 
intraepithelial lesion
ASC-US 
Atypical squamous cells of undetermined significance
BMI
Body Mass Index
CFR
Code of Federal Regulations
CIN
Cervical Intraepithelial Neoplasia
CKC
Cold knife conization
CRF
Case Report Forms
CPK
Creatine Phosphokinase
CTCAE
Common Terminology
r
 f
 Adverse Events
CSR
Clinical Study Report
DNA
Deoxyribonucleic A d
ECC
Endocervical C
t ge
EP
Electroporation 
DSMB
Data and Safety Monitoring Board
ECG
Electrocardiogram
eCRF
E ectronic Case Report Form
ELISA
Enz
 
n
 Immunosorbent Assay
ELISpot
Enzyme 
n ed Immunosorbent Spot-forming Assay
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HSIL
High grade squamous intraepithelial lesion
HIV
Human Immunodeficiency Virus
HPV
Human Papillomavirus
HPV-16/18
HPV-16 and/or HPV-18
ICF
Informed Consent Form
ICH
International Conference on Harmonization
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Electronic Case Re
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IFN-Ȗ
Interferon Gamma
IM
Intramuscular
IND
Investigational New Drug Application
IP
Investigational Product
IRB
Institutional Review Board
ISO
International Organization of Standardization
ITT
Intent to Treat
LAST
Lower Anogenital Squamous Terminology
LEEP
Loop Electrosurgical Excision Procedure
LLETZ
Large Loop Excision of Transformation Zone
LSIL
Low grade squamous intraepithelial 
n
MedDRA®
Medical Dictionary for Drug Regulatory Aff rs
MM
Medical Monitor
mITT
Modified Intent to Treat
NILM
Negative for intraepithelial lesion or malignancy
NIH
National Institutes of Health
OP
Oropharyngeal 
PAC 
Pathology Adjudic i n 
e
PBMC
Peripheral Blood Mononuclear Cells
PDC
Participant Diary Card
PE
Physical Exami
on
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
TNF
Tumor Necrosis Factor
WOCBP
Women of Childbearing Potential
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16 REFERENCES
1.
Trimble, C.L., 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(10008): p. 2078-88.
2.
Centers for Disease, C. and Prevention, Human papillomavirus-associated cancers - United States,
2004-2008. MMWR Morb Mortal Wkly Rep, 2012. 61: p. 258-61.
3.
Satterwhite, C.L., et al., Sexually transmitted infections among US women and men: prevalence
and incidence estimates, 2008. Sex Transm Dis, 2013. 40(3): p. 187-93.
4.
Hariri, 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(4): p.
566-73.
5.
SEER, Surveillance, Epidemiology, and End Results Program National Cancer Institue, 2017.
6.
Bruni L, B.-R.L., Albero G, Serrano B, Mena M, Gómez D, Muñoz J, Bosch FX, de Sanjosé ICO
Information Centre on HPV and Cancer (HPV Informati
 C
re). Human Papillomavirus and
Related Diseases in USA. 2016(Summary Report 15 December 2016.).
7.
Guan, P., et al., Human papillomavirus 
 n 115,789 HPV-positive women: a meta-analysis
from cervical infection to cancer. Int J Cancer, 2012. 131(10): p. 2349-59.
8.
Apgar, B.S., L. Zoschnick, and T.C. Wr ght, Jr., The 2001 Bethesda System terminology. Am Fam
Physician, 2003. 68(10): p. 1992
9.
McCredie, M.R., et al., Natural history of cervical neoplasia and risk of invasive cancer in women
with cervical intraepithelial neoplasia 3: a r trospective cohort study. Lancet Oncol, 2008. 9(5):
p. 425-34.
10.
McIndoe, W.A., et al., The invasive potential of carcinoma in situ of the cervix. Obstet Gynecol,
1984. 64(4): p. 451-8.
11.
Group, T.F.I.S., Quadrivalent Vaccine against Human Papillomavirus to Prevent High-Grade
Cervical Lesions. New En land Journal of Medicine, 2007. 356(19): p. 1915-1927.
12.
The American College f 
tetricians and Gynecologists, FAQs Loop Electrosurgical Excision
Procedure (LEEP). 2014.
13.
Hirao, L.A., et al., Intradermal/subcutaneous immunization by electroporation improves plasmid
vaccine delivery and potency in pigs and rhesus macaques. Vaccine, 2008. 26(3): p. 440-8.
14.
Bagarazzi, M.L., et al., Immunotherapy against HPV16/18 generates potent TH1 and cytotoxic
cellular immune responses. Sci Transl Med, 2012. 4(155): p. 155ra138.
15.
Khan, A.S., M.A. Pope, and R. Draghia-Akli, Highly efficient constant-current electroporation
increases in vivo plasmid expression. DNA Cell Biol, 2005. 24(12): p. 810-8.
16.
Diehl, M.C., et al., Tolerability of intramuscular and intradermal delivery by CELLECTRA((R))
adaptive constant current electroporation device in healthy volunteers. Hum Vaccin Immunother,
2013. 9(10): p. 2246-52.
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ogram
M, Gómez D, Muñoz
ez D, Mu
PV Information Cent
formation C
Report 15 December 
rt 15 Decem
types in 115,789 H
es in 11
J Cancer, 2012.
ncer, 2012. 131(
C. Wright, Jr.,
right, Jr., The 20
-8.
ral history of cervica
story of cer
al neoplasia 3: a retr
plasia 3: a
., The invasive poten
invasive poten
-8.8.
Quadrivalent Vacc
drivalent Vacc
New England Jo
Eng
o  Obs
f
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17.
Miettinen, O. and M. Nurminen, Comparative analysis of two rates. Stat Med, 1985. 4(2): p. 213-
26.
18.
Stoler, M.H., et al., The accuracy of colposcopic biopsy: analyses from the placebo arm of the
Gardasil clinical trials. Int J Cancer, 2011. 128(6): p. 1354-62.
19.
Xiang, L., et al., Conization Using an Electrosurgical Knife for Cervical Intraepithelial Neoplasia
and Microinvasive Carcinoma. PLoS One, 2015. 10(7): p. e0131790.
20.
Xi, L.F., et al., Risk of cervical intraepithelial neoplasia grade 2 or 3 after loop electrosurgical
excision procedure associated with human papillomavirus type 16 variants. J Infect Dis, 2007.
195(9): p. 1340-4.
21.
Katki, H.A., et al., Five-year risk of recurrence after treatment of CIN 2, CIN 3, or AIS:
performance of HPV and Pap cotesting in posttreatment management. J Low Genit Tract Dis, 2013. 
17(5 Suppl 1): p. S78-84.
22.
Nobbenhuis, M.A., et al., Addition of high-risk HPV esting improves the current guidelines on
follow-up after treatment for cervical intraepithelial neoplasia. Br J Cancer, 2001. 84(6): p. 796-
801.
23.
Moore, E.E., et al., Clearance of human papillom virus in wo en treated for cervical dysplasia.
Obstet Gynecol, 2011. 117(1): p. 101-8.
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V testing
lial neoplasia.
eoplasia. B
pilloma
mavirus n wom
virus in
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17 APPENDICES
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 a d HP  
t ng.
5.
Using low-power magnification (5x to 10 x) inspect h  e v x 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.  
 magnification (15x)
8.
Identify the distal and proximal boarders of the transformatio  zone.
a.
The inner border is the entire 360-
 
cumference 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 ante o  ip up or the posterior lip down or use an 
endocervical speculum
ii.
If the junction is n  
alized in its entire circumference, the colposcopy is 
deemed  inadequ
 
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 soluti n m
 e 
p ied 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 
360ż 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.  
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Version Date: 01Jun2022
CONFIDENTIAL
Version 4.1
Page 87 of 87
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, LLETZ 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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