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    Clinical Trial Results:
    An Exploratory Safety and Immunogenicity Study of Human Papillomavirus (HPV16+) Immunotherapy VB10.16 in Women with High Grade Cervical Intraepithelial Neoplasia (HSIL; CIN 2/3)

    Summary
    EudraCT number
    		 2014-005576-28
    Trial protocol
    		 DE  
    Global end of trial date
    17 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Oct 2019
    First version publication date
    04 Oct 2019
    Other versions
    Summary report(s)
    		 VB C-01 CSR Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    VB C-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02529930
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    VACCIBODY A.S.
    Sponsor organisation address
    Gaustadalléen 21, Oslo, Norway, 0349
    Public contact
    Irene Skjørestad, VACCIBODY A.S., Head of Quality Assurance/Clinical Program Director, 0047 22958193, ISkjorestad@vaccibody.com
    Scientific contact
    Dr Agnete Fredriksen, VACCIBODY A.S., President and Chief Scientific Officer, 0047 22958193, ABFredriksen@vaccibody.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
    07 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was: - To assess the safety/tolerability of 3 mg VB10.16 immunotherapy in patients with HPV16+ Cervical Intraepithelial Neoplasia Grade 2/3 (CIN 2/3). The secondary objectives of the trial were: - To assess immunogenicity of 3 mg VB10.16 immunotherapy in patients with HPV16+ Cervical Intraepithelial Neoplasia Grade 2/3 (CIN 2/3). - To make a preliminary assessment of efficacy of VB10.16 immunotherapy.
    Protection of trial subjects
    As per attached synopsis.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 34
    Worldwide total number of subjects
    34
    EEA total number of subjects
    34
    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)
    34
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a multicenter study that involved four participating sites in Germany.

    Pre-assignment
    Screening details
    		 This was an exploratory, open-label, multicenter study with two phases; a Dosing Phase and an Expansion Phase, in patients with histologically confirmed HPV16+ associated CIN 2/3 HSIL which assessed the safety/tolerability, immunogenicity and efficacy of VB10.16 immunotherapy.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label, single arm study. No blinding of the patients or investigators was necessary

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1
    Arm description
    		 Three 3 mg/mL VB10.16 immunotherapy vaccinations administered on Day 1 (Visit 1), Day 21-25 (Visit 2) and 20-24 days after the date of the second vaccination (Visit 3).
    Arm type
    		 Experimental

    Investigational medicinal product name
    VB10.16
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in needle-free injector
    Routes of administration
    Intramuscular use
    Dosage and administration details
    VB10.16 is a naked DNA plasmid vaccine supplied as a sterile, ready to use solution at a concentration of 3 mg/mL in 1 mL glass vials. VB10.16 was administered using the PharmaJet® Stratis 0.5 mL needle-free injection system to deliver the plasmid intramuscularly in the area over the lateral deltoid muscle. The delivery volume was 0.5 mL per injection. Two injections were administered at each vaccination time point. The two injections were given in different arms.

    Arm title
    		 Cohort 2
    Arm description
    		 Three 3 mg/mL VB10.16 immunotherapy vaccinations administered on Day 1 (Visit 1), Day 27-32 (Visit 2) and 54-60 days after the date of the second vaccination (Visit 3).
    Arm type
    		 Experimental

    Investigational medicinal product name
    VB10.16
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in needle-free injector
    Routes of administration
    Intramuscular use
    Dosage and administration details
    VB10.16 is a naked DNA plasmid vaccine supplied as a sterile, ready to use solution at a concentration of 3 mg/mL in 1 mL glass vials. VB10.16 was administered using the PharmaJet® Stratis 0.5 mL needle-free injection system to deliver the plasmid intramuscularly in the area over the lateral deltoid muscle. The delivery volume was 0.5 mL per injection. Two injections were administered at each vaccination time point. The two injections were given in different arms.

    Arm title
    		 Expansion Cohort
    Arm description
    		 Four 3 mg/mL VB10.16 immunotherapy vaccinations administered on Day 1 (Visit 1), Day 21-25 (Visit 2), 20-24 days after the date of the second vaccination (Visit 3) and at Week 16 (Visit 4).
    Arm type
    		 Experimental

    Investigational medicinal product name
    VB10.16
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in needle-free injector
    Routes of administration
    Intramuscular use
    Dosage and administration details
    VB10.16 is a naked DNA plasmid vaccine supplied as a sterile, ready to use solution at a concentration of 3 mg/mL in 1 mL glass vials. VB10.16 was administered using the PharmaJet® Stratis 0.5 mL needle-free injection system to deliver the plasmid intramuscularly in the area over the lateral deltoid muscle. The delivery volume was 0.5 mL per injection. Two injections were administered at each vaccination time point. The two injections were given in different arms.

    Number of subjects in period 1
    		Cohort 1 Cohort 2 Expansion Cohort
    Started
    8
    8
    18
    Completed
    8
    8
    17
    Not completed
    0
    0
    1
         Retrospectively determined as HPV16 negative
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Three 3 mg/mL VB10.16 immunotherapy vaccinations administered on Day 1 (Visit 1), Day 21-25 (Visit 2) and 20-24 days after the date of the second vaccination (Visit 3).

    Reporting group title
    Cohort 2
    Reporting group description
    		 Three 3 mg/mL VB10.16 immunotherapy vaccinations administered on Day 1 (Visit 1), Day 27-32 (Visit 2) and 54-60 days after the date of the second vaccination (Visit 3).

    Reporting group title
    Expansion Cohort
    Reporting group description
    		 Four 3 mg/mL VB10.16 immunotherapy vaccinations administered on Day 1 (Visit 1), Day 21-25 (Visit 2), 20-24 days after the date of the second vaccination (Visit 3) and at Week 16 (Visit 4).

    Reporting group values
    		 Cohort 1 Cohort 2 Expansion Cohort Total
    Number of subjects
    		 8 8 18 34
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 8 8 18 34
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 8 8 18 34
        Male
    		 0 0 0 0
    Cervical Dysplasia Categorisation at Baseline
    Units: Subjects
        CIN 2
    		 8 8 8 24
        CIN 3
    		 0 0 10 10
    HPV16 Status
    Units: Subjects
        HPV16 present
    		 8 8 17 33
        HPV16 not present
    		 0 0 1 1
    Subject analysis sets

    Subject analysis set title
    Safety Evaluable Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received any amount of VB10.16.

    Subject analysis set title
    Efficacy Evaluable Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All evaluable patients with at least one post-baseline colposcopic assessment and positive COBAS® HPV test.

    Subject analysis set title
    Immunogenicity Evaluable Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All evaluable patients with an immunologic assessment performed during the study.

    Subject analysis sets values
    		 Safety Evaluable Population Efficacy Evaluable Population Immunogenicity Evaluable Population
    Number of subjects
    34
    33
    33
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    34
    33
    33
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
    Age continuous
    Units:
        
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    34
    33
    33
        Male
    0
    0
    0
    Cervical Dysplasia Categorisation at Baseline
    Units: Subjects
        CIN 2
    24
    23
    23
        CIN 3
    10
    10
    10
    HPV16 Status
    Units: Subjects
        HPV16 present
    33
    33
    33
        HPV16 not present
    1
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Three 3 mg/mL VB10.16 immunotherapy vaccinations administered on Day 1 (Visit 1), Day 21-25 (Visit 2) and 20-24 days after the date of the second vaccination (Visit 3).

    Reporting group title
    Cohort 2
    Reporting group description
    		 Three 3 mg/mL VB10.16 immunotherapy vaccinations administered on Day 1 (Visit 1), Day 27-32 (Visit 2) and 54-60 days after the date of the second vaccination (Visit 3).

    Reporting group title
    Expansion Cohort
    Reporting group description
    		 Four 3 mg/mL VB10.16 immunotherapy vaccinations administered on Day 1 (Visit 1), Day 21-25 (Visit 2), 20-24 days after the date of the second vaccination (Visit 3) and at Week 16 (Visit 4).

    Subject analysis set title
    Safety Evaluable Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received any amount of VB10.16.

    Subject analysis set title
    Efficacy Evaluable Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All evaluable patients with at least one post-baseline colposcopic assessment and positive COBAS® HPV test.

    Subject analysis set title
    Immunogenicity Evaluable Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All evaluable patients with an immunologic assessment performed during the study.

    Primary: Safety

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    End point title
    		 Safety [1]
    End point description
    Number of patients with adverse events, including any dose limiting toxicities, laboratory assessments and physical findings.
    End point type
    Primary
    End point timeframe
    Safety data was collected from the date of informed consent until 30 days after the last administration of VB10.16. Potential late-emerging AEs considered related to study treatment were recorded during the extended follow-up period for up to 12 months.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Safety parameters were analysed using descriptive statistics.
    End point values
    		 Cohort 1 Cohort 2 Expansion Cohort Safety Evaluable Population
    Number of subjects analysed
    8
    8
    18
    34
    Units: Number of patients with events
        Any TEAEs
    8
    8
    17
    33
        Any drug-related TEAEs
    8
    8
    17
    33
        Any Grade 3, 4 or 5 TEAEs
    1
    0
    1
    2
        Any Grade 3, 4 or 5 drug-related TEAEs
    0
    0
    1
    1
        Any serious TEAEs
    0
    0
    0
    0
        Any serious drug-related TEAEs
    0
    0
    0
    0
        Any TEAEs leading to discontinuation
    0
    0
    0
    0
        Any dose limiting toxicities
    0
    0
    0
    0
        Any deaths due to TEAEs
    0
    0
    0
    0
        Any late-emergent AEs
    0
    2
    6
    8
        Any drug-related late-emergent AEs
    0
    1
    2
    3
        Any Grade 3, 4 or 5 late-emergent AEs
    0
    1
    0
    1
        Any Grade 3, 4 or 5 drug-related late-emergent AEs
    0
    0
    0
    0
        Any serious late-emergent AEs
    0
    0
    0
    0
        Any serious drug-related late-emergent AEs
    0
    0
    0
    0
        Any late-emergent AEs leading to discontinuation
    0
    0
    0
    0
        Any deaths due to late-emergent AEs
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Immunogenicity of VB10.16

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    End point title
    		 Immunogenicity of VB10.16
    End point description
    The monitoring of immune response by means of: - The percentage of patients with E6/E7 specific cellular immune response in the blood.
    End point type
    Secondary
    End point timeframe
    Blood sampling for peripheral immune response in Cohorts 1 and 2 took place on Visit 1, Visit 1B, Visit 2A, Visit 3A, Visit 5 and Visit 6. In the expansion cohort, sampling took place on Visit 1, Visit 3, Visit 4, Visit 5 and Visit 6.
    End point values
    		 Cohort 1 Cohort 2 Expansion Cohort Immunogenicity Evaluable Population
    Number of subjects analysed
    7
    7
    17
    31
    Units: Percentage of patients
        Systemic T cell response against E6/E7 antigens
    6
    7
    17
    30
        No systemic T cell response against E6/E7 antigens
    1
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Efficacy - HPV16 Clearance

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    End point title
    		 Efficacy - HPV16 Clearance
    End point description
    HPV16 testing performed using the Cobas® HPV test. Summary results presented in the additional attachment.
    End point type
    Secondary
    End point timeframe
    Patients were assessed for HPV16 clearance at Visit 4 (week 8), Visit 5 (Week 16), Visit 6 (Week 24), Visit 7 (Month 9) and Visit 8 (Month 12).
    End point values
    		 Cohort 1 Cohort 2 Expansion Cohort Efficacy Evaluable Population
    Number of subjects analysed
    8
    8
    17
    33
    Units: Number of patients
    8
    8
    17
    33
    Attachments
    		 Untitled (Filename: VB C-01_EudraCT Summary Attachment_HPV Clearance_12Sep19.pdf)
    No statistical analyses for this end point

    Secondary: Efficacy - CIN Categorisation

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    End point title
    		 Efficacy - CIN Categorisation
    End point description
    Patients had colposcopy performed at the time points specified. Histological grading of CIN lesions was based on the pathological assessment of representative biopsies of all visible lesions. Summary results presented in the additional attachment.
    End point type
    Secondary
    End point timeframe
    CIN assessment was performed at Visit 1 (baseline), Visit 4 (Week 8), Visit 5 (Week 16), Visit 6 (Week 24), Visit 7 (Month 9) and Visit 8 (Month 12).
    End point values
    		 Cohort 1 Cohort 2 Expansion Cohort Efficacy Evaluable Population
    Number of subjects analysed
    8
    8
    17
    33
    Units: Number of patients
    8
    8
    17
    33
    Attachments
    		 Untitled (Filename: VB C-01_EudraCT Summary Attachment_CIN Categorisation_12Sep19.pdf)
    No statistical analyses for this end point

    Secondary: Efficacy - Lesion Regression (Best Overall Responses)

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    End point title
    		 Efficacy - Lesion Regression (Best Overall Responses)
    End point description
    As part of the CIN regression assessment, a response assessment was performed by the investigator at Visits 4-8. This table shows a summary of the best responses based on the investigator's assessments during the study.
    End point type
    Secondary
    End point timeframe
    Lesion regression assessment was performed at Visit 4 (Week 8), Visit 5 (Week 16), Visit 6 (Week 24), Visit 7 (Month 9) and Visit 8 (Month 12).
    End point values
    		 Cohort 1 Cohort 2 Expansion Cohort Efficacy Evaluable Population
    Number of subjects analysed
    8
    8
    17
    33
    Units: Number of patients
        Complete response
    1
    1
    2
    4
        Partial response
    4
    3
    14
    21
        Stable disease
    3
    4
    1
    8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety data was collected from the time of informed consent until 30 days after the last administration of VB10.16. Potential late-emerging AEs considered related to study treatment were recorded during the extended follow-up period for up to 12 months.
    Adverse event reporting additional description
    Safety was assessed by means of physical examination, vital signs, performance status, laboratory evaluations (haematology and biochemistry), recording of concurrent illness/therapy and adverse events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    		 Three 3 mg/mL VB10.16 immunotherapy vaccinations administered on Day 1 (Visit 1), Day 21-25 (Visit 2) and 20-24 days after the date of the second vaccination (Visit 3).

    Reporting group title
    Cohort 2
    Reporting group description
    		 Three 3 mg/mL VB10.16 immunotherapy vaccinations administered on Day 1 (Visit 1), Day 27-32 (Visit 2) and 54-60 days after the date of the second vaccination (Visit 3).

    Reporting group title
    Expansion Cohort
    Reporting group description
    		 Four 3 mg/mL VB10.16 immunotherapy vaccinations administered on Day 1 (Visit 1), Day 21-25 (Visit 2), 20-24 days after the date of the second vaccination (Visit 3) and at Week 16 (Visit 4).

    Reporting group title
    Safety Evaluable Population
    Reporting group description
    		 All patients who received any amount of VB10.16.

    Serious adverse events
    		 Cohort 1 Cohort 2 Expansion Cohort Safety Evaluable Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    0 / 34 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort 1 Cohort 2 Expansion Cohort Safety Evaluable Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    8 / 8 (100.00%)
    17 / 18 (94.44%)
    33 / 34 (97.06%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital warts
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    1
    2
    Hot flush
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Hypotension
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Surgical and medical procedures
    Dental care
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Electrocauterisation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    8 / 8 (100.00%)
    3 / 8 (37.50%)
    16 / 18 (88.89%)
    27 / 34 (79.41%)
         occurrences all number
    17
    8
    51
    76
    Injection site erythema
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 8 (25.00%)
    12 / 18 (66.67%)
    17 / 34 (50.00%)
         occurrences all number
    5
    4
    28
    37
    Injection site hypersensitivity
         subjects affected / exposed
    6 / 8 (75.00%)
    1 / 8 (12.50%)
    7 / 18 (38.89%)
    14 / 34 (41.18%)
         occurrences all number
    11
    2
    14
    27
    Injection site hyperaesthesia
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 8 (25.00%)
    8 / 18 (44.44%)
    13 / 34 (38.24%)
         occurrences all number
    8
    4
    30
    42
    Injection site swelling
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 8 (25.00%)
    6 / 18 (33.33%)
    11 / 34 (32.35%)
         occurrences all number
    5
    4
    15
    24
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    5 / 18 (27.78%)
    6 / 34 (17.65%)
         occurrences all number
    1
    0
    9
    10
    Pain
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 8 (50.00%)
    1 / 18 (5.56%)
    6 / 34 (17.65%)
         occurrences all number
    1
    6
    1
    8
    Swelling
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    3 / 18 (16.67%)
    6 / 34 (17.65%)
         occurrences all number
    1
    3
    3
    7
    Influenza like illness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    4 / 18 (22.22%)
    4 / 34 (11.76%)
         occurrences all number
    0
    0
    5
    5
    Injection site haematoma
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    1
    2
    Injection site pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    2 / 18 (11.11%)
    3 / 34 (8.82%)
         occurrences all number
    0
    1
    3
    4
    Malaise
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 18 (11.11%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    4
    4
    Pyrexia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 18 (11.11%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    3
    3
    Administration site bruise
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Application site haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Asthenia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Feeling hot
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Injection site bruising
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Injection site discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Injection site haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    3
    3
    Injection site induration
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Local swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    3 / 18 (16.67%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    4
    4
    Dysmenorrhoea
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    2
    1
    0
    3
    Menstruation delayed
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Vaginal discharge
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    1
    0
    2
    Emotional distress
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Listless
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Mood swings
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Nervousness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Thermal burn
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    0
    2
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Tachycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 8 (50.00%)
    6 / 8 (75.00%)
    8 / 18 (44.44%)
    18 / 34 (52.94%)
         occurrences all number
    4
    10
    10
    24
    Hyperaesthesia
         subjects affected / exposed
    2 / 8 (25.00%)
    4 / 8 (50.00%)
    7 / 18 (38.89%)
    13 / 34 (38.24%)
         occurrences all number
    3
    10
    13
    26
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 18 (11.11%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    2
    Migraine
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    2
    0
    3
    Disturbance in attention
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Paraesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Sciatica
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    2
    2
    Eye disorders
    Eye irritation
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 8 (12.50%)
    1 / 18 (5.56%)
    4 / 34 (11.76%)
         occurrences all number
    2
    3
    1
    6
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 8 (25.00%)
    1 / 18 (5.56%)
    3 / 34 (8.82%)
         occurrences all number
    0
    2
    1
    3
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    2 / 18 (11.11%)
    3 / 34 (8.82%)
         occurrences all number
    0
    1
    2
    3
    Abdominal pain upper
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 18 (11.11%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    3
    3
    Abdominal pain lower
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Constipation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Gastritis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    2 / 8 (25.00%)
    4 / 8 (50.00%)
    6 / 18 (33.33%)
    12 / 34 (35.29%)
         occurrences all number
    3
    8
    9
    20
    Hyperhidrosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 18 (11.11%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    3
    3
    Night sweats
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    2
    2
    Pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Rash
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    3
    3
    Alopecia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Haematuria
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    0 / 18 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    1
    2
    0
    3
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 8 (25.00%)
    1 / 18 (5.56%)
    3 / 34 (8.82%)
         occurrences all number
    0
    4
    1
    5
    Myalgia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    1
    0
    2
    Pain in extremity
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 8 (25.00%)
    0 / 18 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    5
    0
    5
    Bone pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    2
    2
    Muscle tightness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Arthritis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    0
    2
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    5 / 18 (27.78%)
    7 / 34 (20.59%)
         occurrences all number
    2
    1
    5
    8
    Bacterial vaginosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Gastrointestinal infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Influenza
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Laryngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Paronychia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Rhinitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    0
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Fungal infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1
    Tonsillitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 18 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    0
    1
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 18 (5.56%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Sep 2015
    This amendment resulted in protocol version 4.0, dated 24 September 2015. The following changes were made: Wording changes requested by the regulatory agency were implemented. Urine pregnancy tests before each vaccination were introduced for all patients. The pre-screening period was increased from 4 to 6 weeks. Colposcopy and documentation of the size of the CIN lesions with digital photography had to be repeated in case it was performed more than 4 weeks prior to the first vaccination. The timing of visits was clarified further. Additional minor corrections (spelling mistakes, formatting) were made.
    23 Aug 2016
    This amendment resulted in protocol version 5.0, dated 23 August 2016. The following changes were made: Rationale was provided for the selection of the Cohort 1 dosing schedule for the Expansion Phase of the study. This decision by the Cohort Review Committee was based on the results of the interim analysis of the safety, immunogenicity and clinical outcome data from the 16 women enrolled in the parallel dosing schedules (Cohorts 1 and 2). Introduction of the requirement for documentation of disease status and potential late emergent adverse events during the extended follow up and implementation of additional Visits 7 and 8, at 9 and 12 months, respectively. Patients were required to attend the site for the extended follow up examinations. Pregnancy testing was made mandatory prior to each vaccination and during all follow up visits to ensure any unexpected pregnancies were brought to the attention of VACCIBODY A.S. and pregnancy outcomes documented accordingly. Additional minor corrections (spelling mistakes, formatting) were made.
    09 Mar 2017
    This amendment resulted in protocol version 6.0, dated 09 March 2017. The following changes were made: Addition of a fourth vaccination in the Expansion Phase of the study. This decision was based on the results of the safety, immunogenicity and clinical outcome data from the 16 women enrolled in the parallel dosing schedules (Cohorts 1 and 2) during the Dosing Phase. Introduction of a pregnancy test at Visit 5, before the fourth vaccination. Additional exploratory analysis of the potentially relevant immune markers was performed on the blood and tissue samples to gain a better understanding of the immune response after dose administration. Additional minor corrections (spelling mistakes, formatting) were made.
    27 Mar 2018
    This amendment resulted in protocol version 7.0, dated 27 March 2018. The amendment was submitted to inform about a change in the analyses arrangement. It made reference to a final CSR at Week 24 of the Expansion Phase of the study, with a follow up report including data from Visit 7 (Month 9) and Visit 8 (Month 12). However, this CSR was finalised after the full data set for all patients was available, after Visit 8 (Month 12). The amended protocol stated: 'An interim analysis was done in the Dosing Phase after 16 weeks and a final analysis done after 24 weeks of the Expansion Phase, which is included in this CSR. Following study completion after 12 months of the Expansion Phase, a CSR addendum with applicable data will be produced.'

    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.
    6 patients underwent a conization procedure during the study. The conizations affected the efficacy and/or immunogenicity results in each cohort and are therefore, after conization, presented separately in the tables.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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