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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2016-002761-63
    Trial protocol
    		 GB   LT   FI   DE   CZ   ES   PT   PL   SK   BE   NL   EE   IT  
    Global end of trial date
    06 Apr 2021

    Results information
    Results version number
    		 v1
    This version publication date
    27 May 2022
    First version publication date
    27 May 2022
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    HPV-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03185013
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 US IND Number: 13683
    Sponsors
    Sponsor organisation name
    Inovio Pharmaceuticals, Inc.
    Sponsor organisation address
    660 W. Germantown Pike, Suite 110, Plymouth Meeting, United States, PA 19462
    Public contact
    Clinical Development, Inovio Pharmaceuticals, Inc., HPV301ClinicalTeam@inovio.com
    Scientific contact
    Clinical Development, Inovio Pharmaceuticals, Inc., HPV301ClinicalTeam@inovio.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Mar 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Apr 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determine the efficacy of VGX-3100 compared with placebo with respect to combined histopathologic regression of cervical HSIL and virologic clearance of HPV-16 and/or HPV-18
    Protection of trial subjects
    This protocol was implemented in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use harmonised tripartite guideline E6(R2): Good Clinical Practice. Written informed consent was to be obtained from each subject and/or from the subject’s legally authorized representative prior to screening into the clinical trial. Subjects were asked to complete a participant diary card during their clinical trial participation to record local and systemic adverse events for 7 days after each clinical trial treatment. Subjects were provided with the investigator emergency contact information and advised to report all AEs.
    Background therapy
    		 Subjects might have used supportive medications for management of anxiety and pain due to treatment (topical anesthetic, mild sedative, analgesic).
    Evidence for comparator
    		 Placebo (150 mM sodium chloride and 15 mM sodium citrate) plus EP (electroporation) with CELLECTRA™ 5PSP.
    Actual start date of recruitment
    28 Jun 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 88 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 4
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Peru: 2
    Country: Number of subjects enrolled
    Philippines: 1
    Country: Number of subjects enrolled
    South Africa: 16
    Country: Number of subjects enrolled
    Thailand: 12
    Country: Number of subjects enrolled
    United States: 56
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Slovakia: 6
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Estonia: 36
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Lithuania: 22
    Worldwide total number of subjects
    201
    EEA total number of subjects
    106
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    201
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 201 subjects were randomly assigned to receive either VGX-3100 + EP (138 subjects) or placebo + EP (63 subjects) within 10 weeks of first dose of clinical trial treatment (Day 0).

    Pre-assignment
    Screening details
    		 All screening evaluations were to be completed within 10 weeks of first dose of clinical trial treatment (Day 0), except for the safety laboratory assessments, which were to be performed within 45 days prior to Day 0.

    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    This clinical trial was double-blinded with blinding maintained throughout the clinical trial by use of identical packaging for both the active product VGX-3100 and the placebo. There was no difference in appearance for both the active product and the placebo. No personnel directly involved with the clinical trial was to be unblinded. The investigator may have requested to unblind a subject’s treatment assignment in case of an emergency or serious medical condition.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 VGX-3100 + EP
    Arm description
    		 Eligible subjects received three 6-mg doses of VGX-3100 refrigerated formulation provided as a solution followed immediately by electroporation (EP) with the CELLECTRA™ 5PSP device. Treatment was administered over 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    VGX-3100
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    6-mg dose of VGX-3100 drug product was delivered IM followed by EP. VGX-3100 drug product was provided as a solution containing 6 mg in 150 mM sodium chloride and 15 mM sodium citrate. The IP was delivered using the CELLECTRA™ 5PSP device. The device consisted of the following components: 1) Base Station; 2) Handset; and 3) Sterile single-use Array (for accepting the IP cartridge). The first clinical trial treatment was administered on Day 0, the second at Week 4, and the third (final) at Week 12.

    Arm title
    		 Placebo + EP
    Arm description
    		 Eligible subjects received three placebo, followed immediately by electroporation (EP) with the CELLECTRA™ 5PSP device. Treatment was administered over 12 weeks.
    Arm type
    		 Placebo + EP

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Injection , Intramuscular use
    Dosage and administration details
    Subjects received 1 mL placebo IM followed by EP. Placebo was delivered using the CELLECTRA™ 5PSP device. The device consisted of the following components: 1) Base Station; 2) Handset; and 3) Sterile single-use Array (for accepting the IP cartridge). The first clinical trial treatment was administered on Day 0, the second at Week 4, and the third (final) at Week 12.

    Number of subjects in period 1
    		VGX-3100 + EP Placebo + EP
    Started
    138
    63
    Completed
    129
    61
    Not completed
    9
    2
         Consent withdrawn by subject
    1
    1
         Randomized, but not treated
    2
    -
         Other
    -
    1
         Pregnancy
    2
    -
         Progressive disease
    2
    -
         Lost to follow-up
    1
    -
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    VGX-3100 + EP
    Reporting group description
    		 Eligible subjects received three 6-mg doses of VGX-3100 refrigerated formulation provided as a solution followed immediately by electroporation (EP) with the CELLECTRA™ 5PSP device. Treatment was administered over 12 weeks.

    Reporting group title
    Placebo + EP
    Reporting group description
    		 Eligible subjects received three placebo, followed immediately by electroporation (EP) with the CELLECTRA™ 5PSP device. Treatment was administered over 12 weeks.

    Reporting group values
    		 VGX-3100 + EP Placebo + EP Total
    Number of subjects
    		 138 63 201
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 138 63 201
    Age continuous
    Units: years
        median (full range (min-max))
    		 30 (20 to 55) 31 (23 to 48) -
    Gender categorical
    Units: Subjects
        Female
    		 138 63 201
        Male
    		 0 0 0
    Subject analysis sets

    Subject analysis set title
    Intent-to-Treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intent-to-Treat (ITT) set included all subjects who were randomized. Subjects in this sample were grouped to treatment as randomized. The ITT set was used for the primary analysis of efficacy in this clinical trial.

    Subject analysis set title
    Modified ITT (mITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified Intent-to-Treat (mITT) Set included all subjects who received at least one (1) dose of clinical trial treatment and who had the analysis endpoint of interest. Subjects in this sample were grouped to treatment as randomized. Analysis of the mITT set was considered supportive for the corresponding ITT set for the analysis of efficacy. The analysis of the mITT set also served as sensitivity analyses regarding missing data.

    Subject analysis set title
    Per-Protocol (PP) Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-Protocol (PP) Set was comprised of subjects who received all doses of clinical trial treatments, had no protocol violations, and had the analysis endpoint of interest. Subjects in this sample were grouped to treatment as randomized. Analyses on the PP set was considered supportive of the corresponding ITT set for the analysis of efficacy. The analysis of PP Set also served as sensitivity analyses regarding early intervention (i.e, intervention before the Week 36 timeframe).

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety set included all subjects who received at least one (1) dose of clinical trial treatment. Subjects were analyzed as to the treatment they actually received.

    Subject analysis sets values
    		 Intent-to-Treat (ITT) Modified ITT (mITT) Per-Protocol (PP) Set Safety Set
    Number of subjects
    201
    197
    184
    199
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    201
    197
    184
    199
    Age continuous
    Units: years
        median (full range (min-max))
    30 (20 to 55)
    Gender categorical
    Units: Subjects
        Female
    201
    197
    184
    199
        Male
    0
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    VGX-3100 + EP
    Reporting group description
    		 Eligible subjects received three 6-mg doses of VGX-3100 refrigerated formulation provided as a solution followed immediately by electroporation (EP) with the CELLECTRA™ 5PSP device. Treatment was administered over 12 weeks.

    Reporting group title
    Placebo + EP
    Reporting group description
    		 Eligible subjects received three placebo, followed immediately by electroporation (EP) with the CELLECTRA™ 5PSP device. Treatment was administered over 12 weeks.

    Subject analysis set title
    Intent-to-Treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intent-to-Treat (ITT) set included all subjects who were randomized. Subjects in this sample were grouped to treatment as randomized. The ITT set was used for the primary analysis of efficacy in this clinical trial.

    Subject analysis set title
    Modified ITT (mITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Modified Intent-to-Treat (mITT) Set included all subjects who received at least one (1) dose of clinical trial treatment and who had the analysis endpoint of interest. Subjects in this sample were grouped to treatment as randomized. Analysis of the mITT set was considered supportive for the corresponding ITT set for the analysis of efficacy. The analysis of the mITT set also served as sensitivity analyses regarding missing data.

    Subject analysis set title
    Per-Protocol (PP) Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Per-Protocol (PP) Set was comprised of subjects who received all doses of clinical trial treatments, had no protocol violations, and had the analysis endpoint of interest. Subjects in this sample were grouped to treatment as randomized. Analyses on the PP set was considered supportive of the corresponding ITT set for the analysis of efficacy. The analysis of PP Set also served as sensitivity analyses regarding early intervention (i.e, intervention before the Week 36 timeframe).

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety set included all subjects who received at least one (1) dose of clinical trial treatment. Subjects were analyzed as to the treatment they actually received.

    Primary: Histopathological Regression of Cervical HSIL and Virologic Clearance of HPV-16 and/or HPV-18 at Week 36 (ITT Population)

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    End point title
    		 Histopathological Regression of Cervical HSIL and Virologic Clearance of HPV-16 and/or HPV-18 at Week 36 (ITT Population)
    End point description
    The percentage of responders in each treatment group was based on the histopathological regression of cervical HSIL and virologic clearance of HPV-16 and/or HPV-18 at Week 36 and it was summarized for the ITT Population.
    End point type
    Primary
    End point timeframe
    At Week 36
    End point values
    		 VGX-3100 + EP Placebo + EP
    Number of subjects analysed
    138
    63
    Units: subjects
    number (not applicable)
        Responders (n)
    31
    7
        Responders (%)
    22.5
    11.1
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    A p-value of superiority based on a test of risk difference and corresponding 95% confidence interval (CI) using the method of Miettinen and Nurminen were computed. Superiority was concluded if the one-sided p-value was <0.025 and the corresponding lower bound of the 95% CI exceeded zero (0).
    Comparison groups
    VGX-3100 + EP v Placebo + EP
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.029 [1]
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    11.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 21.2
    Notes
    [1] - One-sided p-value

    Primary: Histopathological Regression of Cervical HSIL and Virologic Clearance of HPV-16 and/or HPV-18 at Week 36 (mITT Population)

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    End point title
    		 Histopathological Regression of Cervical HSIL and Virologic Clearance of HPV-16 and/or HPV-18 at Week 36 (mITT Population)
    End point description
    The percentage of responders in each treatment group was based on the histopathological regression of cervical HSIL and virologic clearance of HPV-16 and/or HPV-18 at Week 36 and it was summarized for the mITT population. Analyses of primary efficacy endpoint with the mITT set served as sensitivity analyses and were considered supportive of the corresponding analysis with the ITT set.
    End point type
    Primary
    End point timeframe
    At Week 36
    End point values
    		 VGX-3100 + EP Placebo + EP
    Number of subjects analysed
    134
    63
    Units: subjects
    number (not applicable)
        Subjects contributing analysis data (n)
    131
    62
        Responders (n)
    31
    7
        Responders (%)
    23.7
    11.3
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    A p-value of superiority was based on a test of risk difference and corresponding 95% CI using the method of Miettinen and Nurminen. Superiority was concluded if the one-sided p-value was <0.025 and the corresponding lower bound of the 95% CI exceeded zero (0).
    Comparison groups
    VGX-3100 + EP v Placebo + EP
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.022 [2]
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    12.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 22.5
    Notes
    [2] - One-sided p-value

    Primary: Histopathological Regression of Cervical HSIL and Virologic Clearance of HPV-16 and/or HPV-18 at Week 36 (PP Population)

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    End point title
    		 Histopathological Regression of Cervical HSIL and Virologic Clearance of HPV-16 and/or HPV-18 at Week 36 (PP Population)
    End point description
    The percentage of responders in each treatment group was based on the histopathological regression of cervical HSIL and virologic clearance of HPV-16 and/or HPV-18 at Week 36 and it was summarized for the PP Population. Analyses of primary efficacy endpoint with the PP set served as sensitivity analyses and were considered supportive of the corresponding analysis with the ITT set.
    End point type
    Primary
    End point timeframe
    At Week 36
    End point values
    		 VGX-3100 + EP Placebo + EP
    Number of subjects analysed
    124
    60
    Units: subjects
    number (not applicable)
        Subjects contributing analysis data
    122
    60
        Responders (n)
    30
    7
        Responders (%)
    24.6
    11.7
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    A p-value of superiority was based on a test of risk difference and corresponding 95% CI using the method of Miettinen and Nurminen. Superiority was concluded if the one-sided p-value was <0.025 and the corresponding lower bound of the 95% CI exceeded zero (0).
    Comparison groups
    Placebo + EP v VGX-3100 + EP
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.021 [3]
    Method
    		 Miettinen and Nurminen
    Parameter type
    		 Risk difference (RD)
    Point estimate
    12.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 23.5
    Notes
    [3] - One-sided p-value

    Secondary: Overview of Adverse Events (Safety Population)

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    End point title
    		 Overview of Adverse Events (Safety Population)
    End point description
    Treatment-Emergent Adverse Events (TEAE) was defined as AE with onset date on or after clinical trial treatment. One subject excluded due to receiving mixed treatment.
    End point type
    Secondary
    End point timeframe
    With onset date on or after clinical trial treatment
    End point values
    		 VGX-3100 + EP Placebo + EP
    Number of subjects analysed
    136
    62
    Units: subjects
        Any AE
    131
    61
        Any pretreatment AE
    18
    7
        Any TEAE
    131
    61
        Any serious TEAE
    13
    6
        Any IP- or EP-related TEAE
    114
    56
        Any IP- or EP-related serious TEAE
    0
    0
        Any TEAE with CTCAE ≥3
    19
    7
        Any IP- or EP-related TEAE with CTCAE ≥3
    3
    2
        Any TEAE of special interest
    0
    0
        Any TEAE with treatment permanently discontinued
    1
    0
        Any TEAE leading to death
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Onset date on or after clinical trial treatment
    Adverse event reporting additional description
    Treatment-Emergent Adverse Events (TEAE) was defined as AE with onset date on or after clinical trial treatment. One subject excluded due to receiving mixed treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    VGX-3100 + EP
    Reporting group description
    		 Eligible subjects received three 6-mg doses of VGX-3100 refrigerated formulation followed immediately by electroporation (EP) with the CELLECTRA™ 5PSP device. The first clinical trial treatment was administered on Day 0, the second at Week 4, and the third (final) at Week 12. The first clinical trial treatment was given as soon as possible following confirmation of the cervical HSIL diagnosis and HPV-16 and/or HPV-18 status but no more than 10 weeks following collection of the subject’s biopsy specimen used for diagnosis by the PAC during screening, contemporaneous with the positive testing for HPV-16 and/or HPV-18.

    Reporting group title
    Placebo + EP
    Reporting group description
    		 Eligible subjects received three placebo, followed immediately by electroporation (EP) with the CELLECTRA™ 5PSP device. The first clinical trial treatment was administered on Day 0, the second at Week 4, and the third (final) at Week 12. The first clinical trial treatment was given as soon as possible following confirmation of the cervical HSIL diagnosis and HPV-16 and/or HPV-18 status but no more than 10 weeks following collection of the subject’s biopsy specimen used for diagnosis by the PAC during screening, contemporaneous with the positive testing for HPV-16 and/or HPV-18.

    Serious adverse events
    		 VGX-3100 + EP Placebo + EP
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 136 (9.56%)
    6 / 62 (9.68%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenosquamous carcinoma of the cervix
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carcinoma stage 0
         subjects affected / exposed
    3 / 136 (2.21%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    5 / 136 (3.68%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ligament injury
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ectopic pregnancy
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diaphragmatic hernia
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 136 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar disorder
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Kidney infection
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 136 (0.74%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 VGX-3100 + EP Placebo + EP
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    131 / 136 (96.32%)
    61 / 62 (98.39%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    45 / 136 (33.09%)
    19 / 62 (30.65%)
         occurrences all number
    67
    29
    General disorders and administration site conditions
    Injection-site pain
         subjects affected / exposed
    107 / 136 (78.68%)
    50 / 62 (80.65%)
         occurrences all number
    246
    114
    Fatigue
         subjects affected / exposed
    39 / 136 (28.68%)
    17 / 62 (27.42%)
         occurrences all number
    65
    29
    Injection-site erythema
         subjects affected / exposed
    34 / 136 (25.00%)
    14 / 62 (22.58%)
         occurrences all number
    64
    28
    Injection-site pruritus
         subjects affected / exposed
    34 / 136 (25.00%)
    14 / 62 (22.58%)
         occurrences all number
    53
    21
    Injection-site swelling
         subjects affected / exposed
    28 / 136 (20.59%)
    15 / 62 (24.19%)
         occurrences all number
    69
    29
    Injection-site bruising
         subjects affected / exposed
    14 / 136 (10.29%)
    9 / 62 (14.52%)
         occurrences all number
    26
    11
    Malaise
         subjects affected / exposed
    11 / 136 (8.09%)
    5 / 62 (8.06%)
         occurrences all number
    17
    7
    Injection-site haematoma
         subjects affected / exposed
    9 / 136 (6.62%)
    6 / 62 (9.68%)
         occurrences all number
    12
    10
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    25 / 136 (18.38%)
    11 / 62 (17.74%)
         occurrences all number
    36
    13
    Abdominal pain
         subjects affected / exposed
    8 / 136 (5.88%)
    2 / 62 (3.23%)
         occurrences all number
    11
    2
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    29 / 136 (21.32%)
    15 / 62 (24.19%)
         occurrences all number
    47
    22
    Arthralgia
         subjects affected / exposed
    13 / 136 (9.56%)
    7 / 62 (11.29%)
         occurrences all number
    17
    10
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 136 (9.56%)
    4 / 62 (6.45%)
         occurrences all number
    15
    4
    Bacterial vaginosis
         subjects affected / exposed
    9 / 136 (6.62%)
    3 / 62 (4.84%)
         occurrences all number
    10
    3
    Vulvovaginal candidiasis
         subjects affected / exposed
    9 / 136 (6.62%)
    3 / 62 (4.84%)
         occurrences all number
    9
    3
    Urinary tract infection
         subjects affected / exposed
    7 / 136 (5.15%)
    4 / 62 (6.45%)
         occurrences all number
    7
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jun 2016
    The main changes in Protocol version 2.0 include the following: • Added rationale for selection of nonfrozen formulation for Phase 3 clinical trial. • Added additional background information to Section 2 Study Design. • Clarified inclusion and exclusion criteria. • Administrative changes made throughout the protocol for clarification, that did not significantly affect the safety of subjects, clinical trial scope, or scientific quality of the protocol.
    10 Jun 2016
    The main changes in Protocol version 2.1 include the following: • Administrative and formatting changes were made to protocol version 2.0 dated 06Jun2016 resulting in protocol version 2.1 dated 10Jun2016.
    23 Sep 2016
    The main changes in Protocol version 3.0 include the following: • Name of the investigational product (IP) was changed from VGX-3100X to VGX-3100. The term VGX-3100 as used in protocol version 3.0 denoted 3.0 ± 0.2 mg/mL pGX3001 bulk plasmid and 3.0 ± 0.2 mg/mL pGX3002 bulk plasmid in SSC buffer, refrigerated formulation. • The population for the primary analysis for the clinical trial was changed from mITT based on complete data to intent-to-treat (ITT) analysis. Based on this change, the number of subjects to be enrolled in the clinical trial was now 198 instead of 165. • Modifications in objectives and endpoints • Modifications in inclusion and exclusion criteria • Modifications to the clinical trial evaluations • Section 2.1.3 Definition of Responder and Nonresponde • Added information on supplementation of subjects in case more than 10% of subjects randomly assigned to clinical trial treatment discontinued prior to the Week 36 primary endpoint procedure. • Section 5.7 Return and Destruction of Investigational Product • Section 6.1.1 Screening Evaluations • Section 6.15.1 Prohibited Concomitant Medications and Treatments • Added that progression of HSIL to microinvasive or invasive squamous cell carcinoma should be reported as an SAE. • Section 7.3.1 was modified to replace the term “events requiring expedited reporting” to “adverse events of special interest (AESI)”. Added clarification on reporting requirements to sponsor. • Section 7.4.2 was updated to reflect change in reporting contact details in event of SAE. • Section 8 Statistical Analysis section • Section 9.4.2 Pathology Adjudication Committee • Additional administrative clarifications were made to the protocol that did not significantly affect the safety of subjects, clinical trial scope, or scientific quality of the protocol.
    29 Mar 2018
    The main changes in Protocol version 4.0 include the following: • Modifications and updates to the hypothesis, objectives, and endpoints • Revisions to the inclusion and exclusion criteria • Updates were made to the Schedule of Events table to align with the protocol text and above-mentioned changes to the clinical trial endpoints and inclusion and exclusion criteria. • General updates and clarifications • Section 7.3 (Safety and Toxicity Management) was modified to align with safety assessments as stated in the section describing clinical trial design of clinical protocol synopsis. • Section 8 (Statistical Analysis Plan) was revised to align with the changes made to objectives and endpoints. • Section 9.4.2 (Pathology Adjudication Committee) was modified to refer to the PAC charter, which had the most current information regarding the PAC review process. • The PDC was unchanged but was removed from the Appendix since the PDC was a separate document. • Additional minor grammatical and administrative changes were made throughout the document for improving the general readability of the protocol.
    20 Nov 2019
    The main changes in Protocol version 5.0 include the following: • Human leukocyte antigen (HLA) testing and associated exploratory endpoint 2 was removed from the protocol in consideration of the HPV-003 clinical trial results which showed no clear association of HLA background as a predictor of response. • Group-level unblinded (VGX-3100, placebo) summaries and analyses of efficacy were to be produced once the primary endpoint Week 36 visit data were collected for all subjects. • The stopping rules outlined in Section 7.3.2, Stopping Rules (Criteria for Pausing of Study), were clarified to focus on unexpected, verified events and not include events that were already described as known adverse drug reactions. • Additional administrative clarifications were made to the protocol that did not significantly affect the safety of subjects, clinical trial scope, or scientific quality of the protocol.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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