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    Clinical Trial Results:
    A phase IIa randomized, placebo controlled, double blinded study to evaluate the safety and immunogenicity of iHIVARNA-01 in chronically HIV-infected patients under stable combined antiretroviral therapy.

    Summary
    EudraCT number
    		 2016-002724-83
    Trial protocol
    		 BE   ES   NL  
    Global end of trial date
    27 Nov 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    02 Aug 2019
    First version publication date
    14 Jun 2019
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    On request of the AEMPS, the following warning has been added to the description arm of the relevant treatment groups: "see limitations and caveats section"
    Summary report(s)
    		 SAR

    Trial information

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    Trial identification
    Sponsor protocol code
    iHIVARNA-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02888756
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IDIBAPS
    Sponsor organisation address
    Villaroell, Barcelona, Spain,
    Public contact
    Hospital Clínic, IDIBAPS, 34 9322754002884, fgarcia@clinic.cat
    Scientific contact
    Hospital Clínic, IDIBAPS, 34 9322754002884, fgarcia@clinic.cat
    Sponsor organisation name
    Erasmus MC
    Sponsor organisation address
    Wytemaweg 80, Rotterdam, Netherlands, 3015 GE
    Public contact
    Dr R Gruters, Erasmus MC, 31 107032100, r.gruters@erasmusmc.nl
    Scientific contact
    Dr R Gruters, Erasmus MC, 31 107032100, r.gruters@erasmusmc.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
    27 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Nov 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    • safety and tolerability, as measured by the total number of adverse events. • immunogenicity of an immunization schedule with HIV-TriMix-mRNA as measured by the increase in frequency of the HIV-specific T-cell responses between baseline and 2 weeks after the last injection as compared to both control groups, immunized with TriMix-mRNA only or WFI only
    Protection of trial subjects
    In every visit subjects were attended by the study team (at least a physician and a nurse), during this visits all vitals were checked and information about any side effect collected. This team accompanied the subject during all procedures (blood extraction, product administration..) and made everything possible to minimize distress. In case of a painful procedure a painkiller could have been prescribed. Subject had a direct telephone line to contact the study team in any case they considered this necessary.
    Background therapy
    		 cART therapy for chronic HIV-1 infection, before and during immunization. Two weeks after the last immunization cART was interrupted. cART was restarted at week 12 after interruption or earlier at the doctor's decision.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    27 Mar 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 19
    Worldwide total number of subjects
    33
    EEA total number of subjects
    33
    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)
    33
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment period started March 27, 2017 and ended June 19, 2017 in Spain. The recruitment period in Belgium was April 3, 2017 until June 30, 2017. In The Netherlands two patients were screened on May 29 and June 14, 2017.

    Pre-assignment
    Screening details
    		 patients were eligible for enrollment in case of a stably treated HIV-1 infection, as determined by a viral load ≤ 50copies/mL, a current CD4+ cell count ≥ 450 cells/μl and a nadir CD4+ cell count of ≥ 350 cells/μl. No chronic co-infections with hepatitis B and/or C virus were allowed.

    Pre-assignment period milestones
    Number of subjects started
    		 38 [1]
    Number of subjects completed
    		 33

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Physician decision: 3
    Reason: Number of subjects
    		 Consent withdrawn by subject: 2
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Five subjects that were screened, were not included in the trial due to the decision of the physician (n=3) or withdrawn consent (n=2).
    Period 1
    Period 1 title
    vaccination 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
    A randomization code list was generated by an independent statistician prior to start of the study (using R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria). The label containing the randomization code was attached to the appropriate IMP at the central production facility in order to keep the blind for both the sponsor and investigators.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HTI/TriMix
    Arm description
    		 HTI HIVACAT immunogen with TriMix adjuvans both in form of mRNA. See limitations and caveats section
    Arm type
    		 Experimental

    Investigational medicinal product name
    iHIVARNA-01
    Investigational medicinal product code
    Other name
    HTI/TriMix, HIVACAT/TriMix
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    300 microgram TriMix and 900 microgram HIVACAT. Echo-guided intranodal injection in lymph nodes of the groin.

    Arm title
    		 TriMix
    Arm description
    		 TriMix adjuvans alone. TriMix mRNA encodes for CD40L, caTLR4 and CD70
    Arm type
    		 adjuvans alone

    Investigational medicinal product name
    TriMix
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    300 microgram TriMix. Echo-guided intranodal injection in lymph nodes of the groin.

    Arm title
    		 Water for Injection WFI
    Arm description
    		 Water for injection
    Arm type
    		 Placebo

    Investigational medicinal product name
    WFI
    Investigational medicinal product code
    Other name
    water for injection
    Pharmaceutical forms
    Injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    Intranodal injection of placebo, water for injection.

    Number of subjects in period 1
    		HTI/TriMix TriMix Water for Injection WFI
    Started
    16
    9
    8
    Completed
    16
    9
    8
    Period 2
    Period 2 title
    Analytical treatment interruption
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    See vaccination period

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 HTI/TriMix
    Arm description
    		 HTI HIVACAT immunogen with TriMix adjuvans both in form of mRNA See limitations and caveats section
    Arm type
    		 Experimental

    Investigational medicinal product name
    iHIVARNA-01
    Investigational medicinal product code
    Other name
    HTI/TriMix, HIVACAT/TriMix
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    300 microgram TriMix and 900 microgram HIVACAT. Echo-guided intranodal injection in lymph nodes of the groin.

    Arm title
    		 TriMix
    Arm description
    		 TriMix adjuvans alone. TriMix mRNA encodes for
    Arm type
    		 adjuvans alone

    Investigational medicinal product name
    TriMix
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    300 microgram TriMix mRNA

    Arm title
    		 Water for Injection WFI
    Arm description
    		 Water for injection
    Arm type
    		 Placebo

    Investigational medicinal product name
    WFI
    Investigational medicinal product code
    Other name
    water for injection
    Pharmaceutical forms
    Injection
    Routes of administration
    Intralymphatic use
    Dosage and administration details
    Intranodal injection of placebo, water for injection.

    Number of subjects in period 2 [2]
    		HTI/TriMix TriMix Water for Injection WFI
    Started
    15
    9
    8
    Completed
    5
    3
    3
    Not completed
    10
    6
    5
         Physician decision
    10
    6
    5
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: One subject experienced an SAE and it was decided that the subject should not stop cART.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    HTI/TriMix
    Reporting group description
    		 HTI HIVACAT immunogen with TriMix adjuvans both in form of mRNA. See limitations and caveats section

    Reporting group title
    TriMix
    Reporting group description
    		 TriMix adjuvans alone. TriMix mRNA encodes for CD40L, caTLR4 and CD70

    Reporting group title
    Water for Injection WFI
    Reporting group description
    		 Water for injection

    Reporting group values
    		 HTI/TriMix TriMix Water for Injection WFI Total
    Number of subjects
    		 16 9 8 33
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 16 9 8 33
    Age continuous
    Age reported by group
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 44.5 (36.0 to 54.0) 46.0 (37.0 to 51.0) 40 (35.0 to 54.0) -
    Gender categorical
    Units: Subjects
        Female
    		 1 0 0 1
        Male
    		 15 9 8 32
    Mode of HIV transmission reported per roup
    Units: Subjects
        men having sex with men
    		 14 8 7 29
        heterosexual
    		 1 0 1 2
        Intravenous Drug Abuse
    		 0 1 0 1
        Unknown
    		 1 0 0 1
    Median CD4+ T cell count at baseline
    Units: cells/microlitre
        median (inter-quartile range (Q1-Q3))
    		 793 (689 to 1041) 708 (592 to 961) 742 (679 to 918) -

    End points

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    End points reporting groups
    Reporting group title
    HTI/TriMix
    Reporting group description
    		 HTI HIVACAT immunogen with TriMix adjuvans both in form of mRNA. See limitations and caveats section

    Reporting group title
    TriMix
    Reporting group description
    		 TriMix adjuvans alone. TriMix mRNA encodes for CD40L, caTLR4 and CD70

    Reporting group title
    Water for Injection WFI
    Reporting group description
    		 Water for injection
    Reporting group title
    HTI/TriMix
    Reporting group description
    		 HTI HIVACAT immunogen with TriMix adjuvans both in form of mRNA See limitations and caveats section

    Reporting group title
    TriMix
    Reporting group description
    		 TriMix adjuvans alone. TriMix mRNA encodes for

    Reporting group title
    Water for Injection WFI
    Reporting group description
    		 Water for injection

    Primary: Safety

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    End point title
    		 Safety
    End point description
    grade 3 or above adverse events during the entire study period
    End point type
    Primary
    End point timeframe
    Entire study period 30 weeks
    End point values
    		 HTI/TriMix TriMix Water for Injection WFI
    Number of subjects analysed
    16
    9
    8
    Units: Adverse Events
        Adverse Events
    2
    0
    1
    Statistical analysis title
    		 Safety
    Comparison groups
    HTI/TriMix v TriMix v Water for Injection WFI
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.38
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Primary: Immunogenicity

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    End point title
    		 Immunogenicity
    End point description
    Difference in log10 mean Elispspot results between groups, with WFI as reference
    End point type
    Primary
    End point timeframe
    Log10(week6 Elispot)-log10(baseline Elispot), Log10(week10 Elispot)-log10(baseline Elispot), Log10(week18 Elispot)-log10(baseline Elispot)
    End point values
    		 HTI/TriMix TriMix Water for Injection WFI
    Number of subjects analysed
    16 [1]
    9 [2]
    8
    Units: Spot Forming Units
    log mean (confidence interval 95%)
        week 6
    -0.07 (-0.35 to 0.20)
    0.18 (-0.17 to 0.52)
    0.01 (-0.57 to 0.60)
        week 10
    0.16 (-0.42 to 0.75)
    0.26 (-0.52 to 1.05)
    0.04 (-0.86 to 0.94)
        week 18
    -0.08 (-0.57 to 0.42)
    -0.12 (-0.61 to 0.36)
    0.45 (-0.52 to 1.42)
    Notes
    [1] - multiple imputation for week 10 and week 18
    [2] - multiple imputation for week 10 and week 18
    Statistical analysis title
    		 linear mixed effects regression
    Comparison groups
    HTI/TriMix v TriMix v Water for Injection WFI
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.14 [4]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [3] - multiple imputation for later time points
    [4] - week 6
    Statistical analysis title
    		 linear mixed effects regression
    Comparison groups
    HTI/TriMix v TriMix v Water for Injection WFI
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3 [5]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [5] - week 10
    Statistical analysis title
    		 mixed linear effects regression
    Comparison groups
    HTI/TriMix v TriMix v Water for Injection WFI
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38 [6]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [6] - week 18

    Secondary: T cell responses W6, W30

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    End point title
    		 T cell responses W6, W30
    End point description
    Difference between vaccination arms in HIV-specific T cell responses, with WFI as reference
    End point type
    Secondary
    End point timeframe
    Log10(W6 Elispot), log10 (W30 Elispot)
    End point values
    		 HTI/TriMix TriMix Water for Injection WFI
    Number of subjects analysed
    13
    7
    6 [7]
    Units: Spot Forming Units
    log mean (confidence interval 95%)
        week 6
    0.01 (-0.56 to 0.57)
    0.17 (-0.47 to 0.81)
    2.65 (1.94 to 3.37)
        week 30
    0.03 (-0.54 to 0.49)
    0.12 (-0.48 to 0.71)
    3.19 (2.64 to 3.73)
    Notes
    [7] - for week 30 there were 8 subjects available for analysis
    Statistical analysis title
    		 linear mixed effects regression
    Statistical analysis description
    linear mixed effects regression with fixed effect for intervention group and random intercept by site.
    Comparison groups
    HTI/TriMix v TriMix v Water for Injection WFI
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.79 [8]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [8] - week 6
    Statistical analysis title
    		 linear mixed effects regression
    Comparison groups
    HTI/TriMix v TriMix v Water for Injection WFI
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86 [9]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [9] - week 30

    Secondary: Time to viral rebound

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    End point title
    		 Time to viral rebound
    End point description
    median time to viral rebound (days)
    End point type
    Secondary
    End point timeframe
    Analytical Treatment Interruption period: week 6 week 30
    End point values
    		 HTI/TriMix TriMix Water for Injection WFI
    Number of subjects analysed
    15 [10]
    9
    8
    Units: time (days)
        median (confidence interval 95%)
    50 (33 to 57)
    55.5 (43 to 77)
    58 (36 to 72)
    Notes
    [10] - One participant did not stop cART, due to unrelated SAE
    Statistical analysis title
    		 frailty model
    Statistical analysis description
    A shared frailty model was fitted with intervention group as independent variable and frailties for site to compare time from W6 until viral rebound between the three intervention groups; the cause-specific hazard ratio with 95% confidence interval was estimated where events such as restart of cART and death were handled as competing risks.
    Comparison groups
    HTI/TriMix v TriMix v Water for Injection WFI
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 Regression, Cox
    Confidence interval

    Secondary: Reduction in plasma viral load

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    End point title
    		 Reduction in plasma viral load
    End point description
    difference in log10 copies/ml pvl, compared to placebo WFI
    End point type
    Secondary
    End point timeframe
    week 6- restart of cART
    End point values
    		 HTI/TriMix TriMix Water for Injection WFI
    Number of subjects analysed
    15
    9
    8
    Units: copies/ml
        log mean (confidence interval 95%)
    -0.17 (-1.10 to 0.77)
    -0.14 (-1.18 to 0.90)
    1.26 (0.21 to 2.31)
    Statistical analysis title
    		 linear mixed effects model
    Statistical analysis description
    This model includes (nested) random intercepts for subject and site and fixed effects for randomization group, time (days since W6) and the interaction term between time and randomization group
    Comparison groups
    HTI/TriMix v TriMix v Water for Injection WFI
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.63
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Functional cure at week 18

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    End point title
    		 Functional cure at week 18
    End point description
    Number of participants with suppression of HIV to undetectable levels, at the end of the cART interruption period (week 18. This could be explained as functional cure.
    End point type
    Secondary
    End point timeframe
    week 18
    End point values
    		 HTI/TriMix TriMix Water for Injection WFI
    Number of subjects analysed
    15
    7
    8
    Units: participants with pvl <50 copies/ml
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Primary immune response.

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    End point title
    		 Primary immune response.
    End point description
    Number of participants with an increase in frequency of at least 0.7 log10 HIV-specific T-cell responses between baseline and week 6, two weeks after the last vaccination.
    End point type
    Secondary
    End point timeframe
    week 6
    End point values
    		 HTI/TriMix TriMix Water for Injection WFI
    Number of subjects analysed
    13
    7
    5
    Units: participants
    0
    0
    0
    No statistical analyses for this end point

    Secondary: CD8 T cell-mediated virus suppression

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    End point title
    		 CD8 T cell-mediated virus suppression
    End point description
    Mean change in CD8+ T-cell HIV suppressive capacity measured after in vitro re-stimulation: (log10 virus CD4-(log10 virus CD4CD8). Suppressive capacity is measured in the decrease in HIV p24 production in te supernatant. Value for WFI is mean change from baseline. other arms are mean difference from WFI.
    End point type
    Secondary
    End point timeframe
    week 4 compared to baseline
    End point values
    		 HTI/TriMix TriMix Water for Injection WFI
    Number of subjects analysed
    10
    9
    5
    Units: copies/ml
    log mean (confidence interval 95%)
        Ex vivo (2:1)
    -0.10 (-0.78 to 0.57)
    -0.60 (-1.36 to 0.16)
    0.07 (-0.50 to 0.63)
        Ex vivo (0.1:1)
    0.17 (-0.37 to 0.72)
    -0.09 (-0.70 to 0.51)
    -0.05 (-0.51 to 0.40)
        Stimulated (2:1)
    0.15 (-0.69 to 0.99)
    0.22 (-0.73 to 1.16)
    0.18 (-0.48 to 0.85)
        Stimulated (0.1:1)
    -0.65 (-1.26 to -0.05)
    -1.32 (-2.00 to -0.65)
    0.41 (-0.08 to 0.90)
    Statistical analysis title
    		 mixed effects linear regression
    Statistical analysis description
    This model included (nested) random intercepts for subject and site and fixed effects for time and the interaction term between time and randomization group.
    Comparison groups
    HTI/TriMix v TriMix v Water for Injection WFI
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.21
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [11] - Ex vivo 2:1
    Statistical analysis title
    		 mixed effects linear regression
    Statistical analysis description
    This model included (nested) random intercepts for subject and site and fixed effects for time and the interaction term between time and randomization group.
    Comparison groups
    HTI/TriMix v TriMix v Water for Injection WFI
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.55
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [12] - Ex vivo 0.1:1
    Statistical analysis title
    		 mixed effects linear regression
    Statistical analysis description
    This model included (nested) random intercepts for subject and site and fixed effects for time and the interaction term between time and randomization group.
    Comparison groups
    HTI/TriMix v TriMix v Water for Injection WFI
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.89
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [13] - Stimulated 2:1
    Statistical analysis title
    		 mixed effects linear re...
    Statistical analysis description
    This model included (nested) random intercepts for subject and site and fixed effects for time and the interaction term between time and randomization group.
    Comparison groups
    HTI/TriMix v TriMix v Water for Injection WFI
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.002
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [14] - Stimulated 0.1:1

    Secondary: Effect on reservoir as measured by cell associated RNA

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    End point title
    		 Effect on reservoir as measured by cell associated RNA
    End point description
    change per day in log 10 RNA copies/ million CD4 T cells
    End point type
    Secondary
    End point timeframe
    0-30 days, 30-80 daays, 80-150 days, >150 days
    End point values
    		 HTI/TriMix TriMix Water for Injection WFI
    Number of subjects analysed
    16
    9
    8
    Units: Log RNA copies
    log mean (confidence interval 95%)
        0-30 days
    -0.001 (-0.009 to 0.007)
    -0.002 (-0.012 to 0.008)
    -0.004 (-0.011 to 0.003)
        30-80 days
    -0.006 (-0.015 to 0.003)
    -0.001 (-0.013 to 0.010)
    0.032 (0.024 to 0.040)
        80-150 days
    0.002 (-0.008 to 0.012)
    0.003 (-0.008 to 0.015)
    -0.016 (-0.024 to -0.008)
        >150 days
    0.002 (-0.008 to 0.011)
    -0.001 (-0.012 to 0.010)
    -0.004 (-0.011 to 0.003)
    Statistical analysis title
    		 mixed effects linear regression
    Statistical analysis description
    This model includes (nested) random intercepts for subject and site and fixed effects for time (days since W0) and the interaction term between time and randomization group
    Comparison groups
    HTI/TriMix v TriMix v Water for Injection WFI
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.69
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [15] - a piecewise linear model was fitted with breakpoints chosen based on lowess graphs

    Secondary: Effect on reservoir as measured by proviral DNA

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    End point title
    		 Effect on reservoir as measured by proviral DNA
    End point description
    Change per day in log10 HIV proviral cp/million CD4+ T cells
    End point type
    Secondary
    End point timeframe
    Time periods were based on the breakpoints of a piecewise linear model, Figure 5 in SAR
    End point values
    		 HTI/TriMix TriMix Water for Injection WFI
    Number of subjects analysed
    16
    9
    8
    Units: log10 copies/million CD4 T cells
    log mean (confidence interval 95%)
        0-90 days
    -0.002 (-0.007 to 0.003)
    -0.001 (-0.007 to 0.004)
    0.007 (0.003 to 0.011)
        90-130 days
    0.004 (-0.010 to 0.019)
    0.004 (-0.013 to 0.020)
    -0.003 (-0.015 to 0.008)
        >130 days
    -0.001 (-0.007 to 0.005)
    -0.002 (-0.010 to 0.006)
    -0.003 (-0.007 to 0.002)
    Statistical analysis title
    		 mixed effects linear regression
    Statistical analysis description
    This model includes (nested) random intercepts for subject and site and fixed effects for time (days since W0) and the interaction term between time and randomization group
    Comparison groups
    HTI/TriMix v TriMix v Water for Injection WFI
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.99
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [16] - a piecewise linear model was fitted with breakpoints chosen based on lowess graphs

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire study period 30 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    HTI/TriMix
    Reporting group description
    		 HTI HIVACAT immunogen with TriMix adjuvans both in form of mRNA

    Reporting group title
    TriMix
    Reporting group description
    		 TriMix adjuvans alone. TriMix mRNA encodes for

    Reporting group title
    Water for Injection WFI
    Reporting group description
    		 Water for injection

    Serious adverse events
    		 HTI/TriMix TriMix Water for Injection WFI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 HTI/TriMix TriMix Water for Injection WFI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 16 (100.00%)
    9 / 9 (100.00%)
    8 / 8 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    1
    Chills
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    2
    2
    2
    Cyst
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    2 / 16 (12.50%)
    3 / 9 (33.33%)
    2 / 8 (25.00%)
         occurrences all number
    3
    5
    4
    Influenza like illness
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    2
    1
    0
    Infusion site extravasation
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    2
    Injection site pain
         subjects affected / exposed
    3 / 16 (18.75%)
    2 / 9 (22.22%)
    2 / 8 (25.00%)
         occurrences all number
    3
    3
    4
    Injection site pruritus
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    2
    Injection site reaction
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    1
    1
    0
    Malaise
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    6
    1
    2
    Pyrexia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    Tenderness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Urethritis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Erectile dysfunction
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    2
    Dysphonia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Productive cough
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Burnout syndrome
         subjects affected / exposed
    0 / 16 (0.00%)
    2 / 9 (22.22%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    0
    Depression
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    Mental disorder
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Nightmare
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    1
    Injury, poisoning and procedural complications
    Accidental exposure to product
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Wrist fracture
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Disturbance in attention
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    2
    Dizziness
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    2
    Headache
         subjects affected / exposed
    6 / 16 (37.50%)
    1 / 9 (11.11%)
    4 / 8 (50.00%)
         occurrences all number
    7
    1
    8
    Hypoaesthesia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    2
    Muscle contractions involuntary
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Neuralgia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Somnolence
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Syncope
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Vitreous floaters
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Anal fissure
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Aphthous ulcer
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
    4 / 9 (44.44%)
    2 / 8 (25.00%)
         occurrences all number
    1
    4
    2
    Dry mouth
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    1
    Dysphagia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Enterocolitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    Food poisoning
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    1
    0
    3
    Oesophageal pain
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    1
    Oral dysaesthesia
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    1
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    1
    Night sweats
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    1
    2
    0
    Rash macular
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Skin swelling
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Skin ulcer
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Back pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Groin pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Myalgia
         subjects affected / exposed
    5 / 16 (31.25%)
    1 / 9 (11.11%)
    2 / 8 (25.00%)
         occurrences all number
    6
    1
    5
    Neck pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Eyelid infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Furuncle
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatitis viral
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Laryngitis
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Lung infection
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    Oral herpes
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Sexually transmitted disease
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Skin infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    2
    Tonsillitis
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    2
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
         occurrences all number
    0
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    4 / 16 (25.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    5
    0
    1
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Apr 2017
    Temporary hold of recruitment for interim analysis. As a result of poor immunogenicity results from the phase I trial. After analysis the study was stopped for reasons of futility.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    16 Nov 2017
    After interim analysis the trial was stopped for futility as the specified difference of 0.7 log10 mean Elispot increase in the vaccine group compared with placebo, was not observed.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Limited number of subjects for statistical analysis due to early termination. An error in the vaccine was discovered after the trial. An extra startcodon 5' of the HIVACAT startcodon is likely to greatly impair its expression and immunogenicity.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30289805
    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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