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    Clinical Trial Results:
    Quadrivalent HPV vaccination after effective treatment of Anal Intraepithelial Neoplasia in HIV+ men

    Summary
    EudraCT number
    		 2013-002009-70
    Trial protocol
    		 NL  
    Global end of trial date
    01 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Sep 2021
    First version publication date
    07 Sep 2021
    Other versions
    Summary report(s)
    		 Paper

    Trial information

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    Trial identification
    Sponsor protocol code
    VACCAIN-P
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02087384
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Academic Medical Center
    Sponsor organisation address
    Meibergdreef 9, Amsterdam, Netherlands, 1105AZ
    Public contact
    prof.dr. J.M. Prins, Academic Medical Center, 31 205664380, j.m.prins@amc.nl
    Scientific contact
    prof.dr. J.M. Prins, Academic Medical Center, 31 205664380, j.m.prins@amc.nl
    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
    01 Nov 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Nov 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of qHPV vaccination in preventing recurrence of high-grade AIN in HIV+ MSM with CD4 counts >350 x 10E6/l who were successfully treated in the past year for high-grade intra-anal AIN.
    Protection of trial subjects
    Regular follow-up at outpatient clinic.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Mar 2014
    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
    Netherlands: 126
    Worldwide total number of subjects
    126
    EEA total number of subjects
    126
    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)
    120
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Enrolment started on March 27, 2014 and was completed on June 1, 2017

    Pre-assignment
    Screening details
    		 A total of 207 HIV+ MSM were screened for eligibility. One hundred twenty-seven (61.4%) men were enrolled and randomised. Ineligible (n=80): - Not meeting inclusion/meeting exclusion criteria (n=77) - Retracted informed consent (n=1) - Procedural planning not feasible for patient (n=2) One patient incorrectly enrolled and excluded

    Pre-assignment period milestones
    Number of subjects started
    		 126
    Number of subjects completed
    		 126

    Period 1
    Period 1 title
    overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Vaccine or placebo prepared by pharmacy.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 qHPV
    Arm description
    		 qHPV L1 virus-like particle (VLP) vaccine (Gardasil-4®, Merck Sharp & Dohme (MSD), Kenilworth, NJ, USA) or a placebo (0.9% saline). The first qHPV or placebo vaccine was administered within three months after the first screening HRA and six weeks after the second screening HRA, and subsequent vaccines two months (±1 week), and six months (±2 weeks) after first vaccination. Injections, 0.5 ml in the deltoid muscle, were generally given on the same side throughout the study.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    qHPV L1 virus-like particle (VLP) vaccine (Gardasil-4®, Merck Sharp & Dohme (MSD), Kenilworth, NJ, USA
    Investigational medicinal product code
    Other name
    Gardasil
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    qHPV L1 virus-like particle (VLP) vaccine (Gardasil-4®, Merck Sharp & Dohme (MSD), Kenilworth, NJ, USA) or a placebo (0.9% saline). The first qHPV or placebo vaccine was administered within three months after the first screening HRA and six weeks after the second screening HRA, and subsequent vaccines two months (±1 week), and six months (±2 weeks) after first vaccination. Injections, 0.5 ml in the deltoid muscle, were generally given on the same side throughout the study

    Arm title
    		 placebo
    Arm description
    		 placebo injection
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    The first placebo vaccine was administered within three months after the first screening HRA and six weeks after the second screening HRA, and subsequent vaccines two months (±1 week), and six months (±2 weeks) after first vaccination. Injections, 0.5 ml in the deltoid muscle, were generally given on the same side throughout the study.

    Number of subjects in period 1
    		qHPV placebo
    Started
    64
    62
    Completed
    62
    60
    Not completed
    2
    2
         Lost to follow-up
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    qHPV
    Reporting group description
    		 qHPV L1 virus-like particle (VLP) vaccine (Gardasil-4®, Merck Sharp & Dohme (MSD), Kenilworth, NJ, USA) or a placebo (0.9% saline). The first qHPV or placebo vaccine was administered within three months after the first screening HRA and six weeks after the second screening HRA, and subsequent vaccines two months (±1 week), and six months (±2 weeks) after first vaccination. Injections, 0.5 ml in the deltoid muscle, were generally given on the same side throughout the study.

    Reporting group title
    placebo
    Reporting group description
    		 placebo injection

    Reporting group values
    		 qHPV placebo Total
    Number of subjects
    		 64 62 126
    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)
    		 63 57 120
        From 65-84 years
    		 1 5 6
        85 years and over
    		 0 0 0
    Gender categorical
    Correctly enrolled and randomized
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 64 62 126

    End points

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    End points reporting groups
    Reporting group title
    qHPV
    Reporting group description
    		 qHPV L1 virus-like particle (VLP) vaccine (Gardasil-4®, Merck Sharp & Dohme (MSD), Kenilworth, NJ, USA) or a placebo (0.9% saline). The first qHPV or placebo vaccine was administered within three months after the first screening HRA and six weeks after the second screening HRA, and subsequent vaccines two months (±1 week), and six months (±2 weeks) after first vaccination. Injections, 0.5 ml in the deltoid muscle, were generally given on the same side throughout the study.

    Reporting group title
    placebo
    Reporting group description
    		 placebo injection

    Primary: Recurrences of HGAIN

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    End point title
    		 Recurrences of HGAIN
    End point description
    cumulative recurrence of biopsy-proven intra-anal or peri-anal HGAIN at 12 months after last vaccination (FU18)
    End point type
    Primary
    End point timeframe
    12 months after last vaccination (FU18)
    End point values
    		 qHPV placebo
    Number of subjects analysed
    64
    62
    Units: patients
        recurrences
    44
    38
    Statistical analysis title
    		 Prim endpoint
    Statistical analysis description
    Prim endpoint
    Comparison groups
    qHPV v placebo
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -7.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.1
         upper limit
    		 9.2

    Secondary: Occurrence of LGAIN

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    End point title
    		 Occurrence of LGAIN
    End point description
    cumulative occurrence of LGAIN at 12 months after last vaccination (FU18)
    End point type
    Secondary
    End point timeframe
    12 months after last vaccination (FU18)
    End point values
    		 qHPV placebo
    Number of subjects analysed
    28
    27
    Units: patients
        occurrence of LGAIN
    21
    18
    Statistical analysis title
    		 Sec endpoint LGAIN
    Comparison groups
    placebo v qHPV
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -8.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.3
         upper limit
    		 15.6

    Secondary: occurrence of anogenital condylomata

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    End point title
    		 occurrence of anogenital condylomata
    End point description
    cumulative occurrence of anogenital condylomata at 12 months after last vaccination (FU18)
    End point type
    Secondary
    End point timeframe
    12 months after last vaccination (FU18)
    End point values
    		 qHPV placebo
    Number of subjects analysed
    38
    43
    Units: patients
        occurrence of warts
    21
    19
    Statistical analysis title
    		 warts
    Comparison groups
    qHPV v placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Chi-squared
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -11.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -32.8
         upper limit
    		 10.6

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    first vaccination until 12 months after last vaccination
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    qHPV ITT
    Reporting group description
    		 -

    Reporting group title
    placebo ITT
    Reporting group description
    		 -

    Serious adverse events
    		 qHPV ITT placebo ITT
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 64 (4.69%)
    4 / 62 (6.45%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Fracture
    Additional description: and accidents
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 64 (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
    Renal and urinary disorders
    Nephrolithiasis
    Additional description: and renal insufficiency - by dehydration
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychiatric decompensation
         subjects affected / exposed
    1 / 64 (1.56%)
    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
    		 qHPV ITT placebo ITT
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 64 (90.63%)
    55 / 62 (88.71%)
    Nervous system disorders
    Nervous system disorder
         subjects affected / exposed
    32 / 64 (50.00%)
    26 / 62 (41.94%)
         occurrences all number
    32
    26
    Gastrointestinal disorders
    GI
         subjects affected / exposed
    22 / 64 (34.38%)
    27 / 62 (43.55%)
         occurrences all number
    22
    27
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorder
         subjects affected / exposed
    15 / 64 (23.44%)
    7 / 62 (11.29%)
         occurrences all number
    15
    7
    Skin and subcutaneous tissue disorders
    Skin disorder
         subjects affected / exposed
    25 / 64 (39.06%)
    13 / 62 (20.97%)
         occurrences all number
    25
    13
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorder
         subjects affected / exposed
    19 / 64 (29.69%)
    8 / 62 (12.90%)
         occurrences all number
    19
    8
    Infections and infestations
    Infection
         subjects affected / exposed
    46 / 64 (71.88%)
    54 / 62 (87.10%)
         occurrences all number
    46
    54

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33966029
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