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    Clinical Trial Results:
    A Phase IIa, randomized, double-blind, placebo-controlled study of HIV-1 Vaccines MVA.HTI and ChAdOx1.HTI with TLR7 agonist vesatolimod (GS-9620) in early treated HIV-1 infection

    Summary
    EudraCT number
    		 2018-002125-30
    Trial protocol
    		 ES  
    Global end of trial date
    16 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Aug 2023
    First version publication date
    12 Aug 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AELIX-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AELIX Therapeutics
    Sponsor organisation address
    Parc Científic de Barcelona, C/ Baldiri i Reixac, 4-8, Barcelona, Spain, 08028
    Public contact
    Jordi Naval, AELIX Therapeutics, 34 934031339, jnaval@aelixtherapeutics.com
    Scientific contact
    Jordi Naval, AELIX Therapeutics, 34 934031339, jnaval@aelixtherapeutics.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
    21 Jun 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Oct 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Dec 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety of the CCMM (ChAdOx1.HTI + MVA.HTI) + Vesatolimod regimen during Period 1 (week 0 to 48) in early treated HIV 1 infection
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles that have their origin in the Declaration of Helsinki, protocol, ICH harmonised tripartite guideline E6(R2): GCP, and all applicable AEMPS requirements. A written informed consent (including separate consent for the intensive PK substudy if applicable and potential updated or new information related to COVID 19, which could impact the study risk-benefit assessment) in compliance with AEMPS regulations was obtained from each participant.
    Background therapy
    		 The most frequently taken concomitant medications (that were ongoing on or after the first dose of the IMP) were COVID-19 vaccines (31 [93.9%] participants in the CCMM + vesatolimod group and 17 [100%] participants in the placebo group), paracetamol (21 [63.6%] participants in the CCMM + vesatolimod group and 13 [76.5%] participants in the placebo group), and ibuprofen (16 [48.5%] participants in the CCMM + vesatolimod group and 7 [41.2%] participants in the placebo group).
    Evidence for comparator
    		 Matching placebo
    Actual start date of recruitment
    20 May 2019
    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
    Spain: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    50
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Approximately 57 participants were planned to be enrolled in the study. After providing informed consent, participants were randomly assigned in a 2:1 ratio using an IRT to receive CCMM + vesatolimod or placebo.

    Pre-assignment
    Screening details
    		 The study screened participants living with HIV who had initiated ART within 180 days (6 months) of the estimated date of HIV 1 acquisition and who had achieved virological suppression for at least 1 year. A total of 65 participants were assessed for eligibility and 50 participants enrolled in the study.

    Period 1
    Period 1 title
    Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Study treatments taken during this study were double-blind. Period 1 (48 weeks) during which participants received blinded investigational medicinal product (IMP) and continued their antiretroviral therapy (ART regimen). Unblinded Roles: Pharmacist+ unblinded Study nurses, uCTM and uCRA

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CCMM + Vesatolimod
    Arm description
    		 ChAdOx1.HTI is an immunotherapeutic medicinal product that contains genetically modified organisms (ChAdOx1). MVA.HTI is an investigational immunological product (vaccine) of a biological/biotechnological origin that contains genetically modified organisms (MVA). Vesatolimod (also known as GS-9620) is an orally administered toll-like receptor 7 (TLR7) agonist currently in clinical development for the treatment and remission of HIV-1 infection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ChAdOx1.HTI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    ChAdOx1.HTI vaccine was delivered as one 0.5 mL IM injection, taken at Weeks 0 and 12.

    Investigational medicinal product name
    MVA.HTI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    MVA.HTI vaccine was delivered as one 0.5 mL IM injection, taken at Weeks 24 and 36.

    Investigational medicinal product name
    Vesatolimod
    Investigational medicinal product code
    Other name
    GS-9620
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vesatolimod was administered orally at the study site with approximately 240 mL of water after an overnight fast or after fasting period of at least 8 hours. Participants were not allowed to consume water 1 hour before and 2 hours after dosing. Vesatolimod was delivered as three 2-mg tablets and was taken at Weeks 26, 28, 30, 32, 34, 38, 40, 42, 44, and 46.

    Arm title
    		 Placebo
    Arm description
    		 The placebos matched to ChAdOx1.HTI and MVA.HTI were commercially available sterile saline solution (sodium chloride 0.9%).
    Arm type
    		 Placebo

    Investigational medicinal product name
    ChAdOx1.HTI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    ChAdOx1.HTI placebo (0.9% NaCl solution for injection) was delivered as one 0.5 mL IM injection and was taken at Weeks 0 and 12.

    Investigational medicinal product name
    MVA.HTI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    MVA.HTI (0.9% NaCl solution for injection) was delivered as one 0.5 mL IM injection and was taken at Weeks 24 and 36.

    Investigational medicinal product name
    Vesatolimod placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vesatolimod placebo was administered orally at the study site with approximately 240 mL of water after an overnight fast or after fasting period of at least 8 hours. Participants were not allowed to consume water 1 hour before and 2 hours after dosing. Vesatolimod placebo tablet was delivered as three 2-mg placebo tablets and was taken at Weeks 26, 28, 30, 32, 34, 38, 40, 42, 44, and 46.

    Number of subjects in period 1
    		CCMM + Vesatolimod Placebo
    Started
    33
    17
    Completed
    30
    17
    Not completed
    3
    0
         Withdrawal by participant
    2
    -
         Investigator decision
    1
    -
    Period 2
    Period 2 title
    Period 2 (ATI)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Participants were allowed to proceed to Period 2 if they met ATI requirements and had received at least 3 doses of vaccine/placebo and at least 3 doses of vesatolimod/placebo. During Period 2 (up to 24 weeks) participants discontinued their ART regimen (ATI period) and were monitored for pVL and CD4 counts.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CCMM + Vesatolimod
    Arm description
    		 ChAdOx1.HTI is an immunotherapeutic medicinal product that contains genetically modified organisms (ChAdOx1). MVA.HTI is an investigational immunological product (vaccine) of a biological/biotechnological origin that contains genetically modified organisms (MVA).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ChAdOx1.HTI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In Period 2 (Week 48 to Week 72), all participants discontinued ART at/after the Week 48 visit. HIV-1 plasma viremia levels were monitored weekly and CD4 counts were monitored monthly. During this period subjects did not receive study drug/ placebo.

    Investigational medicinal product name
    MVA.HTI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In Period 2 (Week 48 to Week 72), all participants discontinued ART at/after the Week 48 visit. HIV-1 plasma viremia levels were monitored weekly and CD4 counts were monitored monthly. During this period subjects did not receive study drug/ placebo.

    Investigational medicinal product name
    Vesatolimod
    Investigational medicinal product code
    Other name
    GS-9620
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In Period 2 (Week 48 to Week 72), all participants discontinued ART at/after the Week 48 visit. HIV-1 plasma viremia levels were monitored weekly and CD4 counts were monitored monthly. During this period subjects did not receive study drug/ placebo.

    Arm title
    		 Placebo
    Arm description
    		 The placebos matched to ChAdOx1.HTI and MVA.HTI were commercially available sterile saline solution (sodium chloride 0.9%).
    Arm type
    		 Placebo

    Investigational medicinal product name
    ChAdOx1.HTI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In Period 2 (Week 48 to Week 72), all participants discontinued ART at/after the Week 48 visit. HIV-1 plasma viremia levels were monitored weekly and CD4 counts were monitored monthly. During this period subjects did not receive study drug/ placebo.

    Investigational medicinal product name
    MVA.HTI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In Period 2 (Week 48 to Week 72), all participants discontinued ART at/after the Week 48 visit. HIV-1 plasma viremia levels were monitored weekly and CD4 counts were monitored monthly. During this period subjects did not receive study drug/ placebo.

    Investigational medicinal product name
    Vesatolimod placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In Period 2 (Week 48 to Week 72), all participants discontinued ART at/after the Week 48 visit. HIV-1 plasma viremia levels were monitored weekly and CD4 counts were monitored monthly. During this period subjects did not receive study drug/ placebo.

    Number of subjects in period 2
    		CCMM + Vesatolimod Placebo
    Started
    30
    17
    Entered Period 2
    30
    17
    Discontinued Period 2
    0 [1]
    0 [2]
    Completed
    30
    17
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Three (9.1%) participants in the CCMM + vesatolimod group did not complete active treatment (Period 1). All participants who entered Period 2 completed the period.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: All participants in the placebo group completed active treatment (Period 1). All participants who entered Period 2 completed the period.
    Period 3
    Period 3 title
    Period 3 (ART reinitiation)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Participants who met the requirements for restarting ART during Period 2 moved into Period 3 after restarting ART, whether during Period 2 or at the completion of Period 2 (i.e., at Week 72) underwent Week 72 procedures. During Period 3 (12 weeks) participants were monitored following the restart of their ART.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CCMM + Vesatolimod
    Arm description
    		 ChAdOx1.HTI is an immunotherapeutic medicinal product that contains genetically modified organisms (ChAdOx1). MVA.HTI is an investigational immunological product (vaccine) of a biological/biotechnological origin that contains genetically modified organisms (MVA).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ChAdOx1.HTI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In Period 3 (Week 72 to Week 84), all participants who restarted their ART during Period 2, whether during Period 2 or after completing Period 2 (i.e., at the Week 72 visit), had their viral load monitored at 4 and 12 weeks after restarting ART (Week 76 and Week 84). During this period subjects did not receive study drug/ placebo.

    Investigational medicinal product name
    MVA.HTI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In Period 3 (Week 72 to Week 84), all participants who restarted their ART during Period 2, whether during Period 2 or after completing Period 2 (i.e., at the Week 72 visit), had their viral load monitored at 4 and 12 weeks after restarting ART (Week 76 and Week 84). During this period subjects did not receive study drug/ placebo.

    Investigational medicinal product name
    Vesatolimod
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In Period 3 (Week 72 to Week 84), all participants who restarted their ART during Period 2, whether during Period 2 or after completing Period 2 (i.e., at the Week 72 visit), had their viral load monitored at 4 and 12 weeks after restarting ART (Week 76 and Week 84). During this period subjects did not receive study drug/ placebo.

    Arm title
    		 Placebo
    Arm description
    		 The placebos matched to ChAdOx1.HTI and MVA.HTI were commercially available sterile saline solution (sodium chloride 0.9%).
    Arm type
    		 Placebo

    Investigational medicinal product name
    ChAdOx1.HTI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In Period 3 (Week 72 to Week 84), all participants who restarted their ART during Period 2, whether during Period 2 or after completing Period 2 (i.e., at the Week 72 visit), had their viral load monitored at 4 and 12 weeks after restarting ART (Week 76 and Week 84). During this period subjects did not receive study drug/ placebo.

    Investigational medicinal product name
    MVA.HTI placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In Period 3 (Week 72 to Week 84), all participants who restarted their ART during Period 2, whether during Period 2 or after completing Period 2 (i.e., at the Week 72 visit), had their viral load monitored at 4 and 12 weeks after restarting ART (Week 76 and Week 84). During this period subjects did not receive study drug/ placebo.

    Investigational medicinal product name
    Vesatolimod placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    In Period 3 (Week 72 to Week 84), all participants who restarted their ART during Period 2, whether during Period 2 or after completing Period 2 (i.e., at the Week 72 visit), had their viral load monitored at 4 and 12 weeks after restarting ART (Week 76 and Week 84). During this period subjects did not receive study drug/ placebo.

    Number of subjects in period 3
    		CCMM + Vesatolimod Placebo
    Started
    30
    17
    Enter Period 3
    30
    17
    Discontinued Period 3
    0 [3]
    1 [4]
    Completed the Study
    30
    16
    Completed
    30
    16
    Not completed
    0
    1
         Withdrawal by participant
    -
    1
    Notes
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: All participants who entered Period 3 completed the study.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only 1 (5.9%) participant in the placebo group discontinued from the study during Period 3 due to withdrawal by participant.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CCMM + Vesatolimod
    Reporting group description
    		 ChAdOx1.HTI is an immunotherapeutic medicinal product that contains genetically modified organisms (ChAdOx1). MVA.HTI is an investigational immunological product (vaccine) of a biological/biotechnological origin that contains genetically modified organisms (MVA). Vesatolimod (also known as GS-9620) is an orally administered toll-like receptor 7 (TLR7) agonist currently in clinical development for the treatment and remission of HIV-1 infection.

    Reporting group title
    Placebo
    Reporting group description
    		 The placebos matched to ChAdOx1.HTI and MVA.HTI were commercially available sterile saline solution (sodium chloride 0.9%).

    Reporting group values
    		 CCMM + Vesatolimod Placebo Total
    Number of subjects
    		 33 17 50
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 33 17 50
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.4 ( 8.77 ) 36.8 ( 12.42 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 33 17 50
    HLA with potential for superior viral control (Corrected)
    Baseline was defined as the last nonmissing assessment prior to the first administration of any IMP. A total of 10 (20.0%) participants (6 [18.2%] in the CCMM + vesatolimod group and 4 [23.5%] in the placebo group) had potential for superior viral control due to the presence of human leukocyte antigen (HLA allele(s)) associated with natural control of HIV. Median time since HIV acquisition to screening visit was 43.08 months (41.79 months in the CCMM + vesatolimod group and 46.45 months in the placebo group).
    Units: Subjects
        Yes
    		 6 4 10
        No
    		 27 13 40
    Time from HIV acquisition to ART initiation
    Time from HIV acquisition to ART initiation = the ART initiation date — the estimated date of HIV-1 acquisition.
    Units: days
        median (full range (min-max))
    		 61.0 (7 to 170) 86.0 (16 to 167) -
    Subject analysis sets

    Subject analysis set title
    ITT set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    ITT set was defined as all randomized participants who took at least one dose of IMP. Numbers were based on planned treatment group.

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety set was defined as all randomized participants who took at least one dose of IMP. Numbers were based on actual treatment group.

    Subject analysis sets values
    		 ITT set Safety set
    Number of subjects
    50
    50
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    17
    33
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    37.9 ( 10.06 )
    37.9 ( 10.06 )
    Gender categorical
    Units: Subjects
        Female
    0
    0
        Male
    50
    50
    HLA with potential for superior viral control (Corrected)
    Baseline was defined as the last nonmissing assessment prior to the first administration of any IMP. A total of 10 (20.0%) participants (6 [18.2%] in the CCMM + vesatolimod group and 4 [23.5%] in the placebo group) had potential for superior viral control due to the presence of human leukocyte antigen (HLA allele(s)) associated with natural control of HIV. Median time since HIV acquisition to screening visit was 43.08 months (41.79 months in the CCMM + vesatolimod group and 46.45 months in the placebo group).
    Units: Subjects
        Yes
    10
    10
        No
    40
    40
    Time from HIV acquisition to ART initiation
    Time from HIV acquisition to ART initiation = the ART initiation date — the estimated date of HIV-1 acquisition.
    Units: days
        median (full range (min-max))
    67.0 (7 to 170)
    67.0 (7 to 170)

    End points

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    End points reporting groups
    Reporting group title
    CCMM + Vesatolimod
    Reporting group description
    		 ChAdOx1.HTI is an immunotherapeutic medicinal product that contains genetically modified organisms (ChAdOx1). MVA.HTI is an investigational immunological product (vaccine) of a biological/biotechnological origin that contains genetically modified organisms (MVA). Vesatolimod (also known as GS-9620) is an orally administered toll-like receptor 7 (TLR7) agonist currently in clinical development for the treatment and remission of HIV-1 infection.

    Reporting group title
    Placebo
    Reporting group description
    		 The placebos matched to ChAdOx1.HTI and MVA.HTI were commercially available sterile saline solution (sodium chloride 0.9%).
    Reporting group title
    CCMM + Vesatolimod
    Reporting group description
    		 ChAdOx1.HTI is an immunotherapeutic medicinal product that contains genetically modified organisms (ChAdOx1). MVA.HTI is an investigational immunological product (vaccine) of a biological/biotechnological origin that contains genetically modified organisms (MVA).

    Reporting group title
    Placebo
    Reporting group description
    		 The placebos matched to ChAdOx1.HTI and MVA.HTI were commercially available sterile saline solution (sodium chloride 0.9%).
    Reporting group title
    CCMM + Vesatolimod
    Reporting group description
    		 ChAdOx1.HTI is an immunotherapeutic medicinal product that contains genetically modified organisms (ChAdOx1). MVA.HTI is an investigational immunological product (vaccine) of a biological/biotechnological origin that contains genetically modified organisms (MVA).

    Reporting group title
    Placebo
    Reporting group description
    		 The placebos matched to ChAdOx1.HTI and MVA.HTI were commercially available sterile saline solution (sodium chloride 0.9%).

    Subject analysis set title
    ITT set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    ITT set was defined as all randomized participants who took at least one dose of IMP. Numbers were based on planned treatment group.

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety set was defined as all randomized participants who took at least one dose of IMP. Numbers were based on actual treatment group.

    Primary: Proportion of participants who developed solicited Grade 3 or 4 local reactions in the 7-day period following administration of IMPs during Period 1

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    End point title
    		 Proportion of participants who developed solicited Grade 3 or 4 local reactions in the 7-day period following administration of IMPs during Period 1 [1]
    End point description
    The incidence of Grade 3 or 4 solicited local reactions in the CCMM + vesatolimod group was higher than in the placebo group. 95% CI of the proportion was calculated based on the exact method and was (5.1, 31.9) for CCMM + vesatolimod group and (0.0, 19.5) for placebo group. Diary event severity was assessed by the participant. AE severity was assessed by the investigator, Grade 1 was presented as 'Mild', Grade 2 was presented as 'Moderate'; Grade 3,4 or death were presented as 'Severe'.
    End point type
    Primary
    End point timeframe
    From administration of IMP within the 7 days following IMP dosing (during Period 1)
    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: No statistical analyses have been provided for safety end points since data was summarized using descriptive statistics.
    End point values
    		 CCMM + Vesatolimod Placebo Safety set
    Number of subjects analysed
    33
    17
    50
    Units: number of subjects
        Grade 3
    5
    0
    5
        Grade 4
    1
    0
    1
    No statistical analyses for this end point

    Primary: Proportion of participants who developed solicited Grade 3 or 4 systemic reactions in the 7-day period following administration of IMPs during Period 1

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    End point title
    		 Proportion of participants who developed solicited Grade 3 or 4 systemic reactions in the 7-day period following administration of IMPs during Period 1 [2]
    End point description
    The incidence of Grade 3 solicited systemic reactions in the CCMM + vesatolimod group was higher than in the placebo group, whereas all Grade 4 solicited systemic reactions were reported in the placebo group. Ten (30.3%) participants in the CCMM + vesatolimod group had 40 and 3 (17.6%) participants in the placebo group had twenty Grade 3 solicited systemic reactions during Period 1. 95% CI of the proportion was calculated based on the exact method and was (15.6, 48.7) for CCMM + vesatolimod group and (3.8, 43.4) for placebo group. Diary event severity is assessed by the participant. AE severity was assessed by the investigator, Grade 1 was presented as 'Mild', Grade 2 was presented as 'Moderate'; Grade 3,4 or death were presented as 'Severe'.
    End point type
    Primary
    End point timeframe
    From administration of IMP within the 7 days following IMP dosing (during Period 1)
    Notes
    [2] - 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: No statistical analyses have been provided for safety end points since data was summarized using descriptive statistics.
    End point values
    		 CCMM + Vesatolimod Placebo Safety set
    Number of subjects analysed
    33
    17
    50
    Units: number of subjects
        Grade 3
    10
    3
    13
        Grade 4
    0
    2
    2
    No statistical analyses for this end point

    Primary: Proportion of participants who developed treatment-emergent SAEs during Period 1

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    End point title
    		 Proportion of participants who developed treatment-emergent SAEs during Period 1 [3]
    End point description
    The serious TEAE was considered severe and was reported as recovered/resolved. The median duration for the serious TEAE during Period 1 was 10 days (range: 10.0 to 10.0). It was considered not related to the IMP.
    End point type
    Primary
    End point timeframe
    From administration of IMP up to 48 weeks (during Period 1)
    Notes
    [3] - 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: No statistical analyses have been provided for safety end points since data was summarized using descriptive statistics.
    End point values
    		 CCMM + Vesatolimod Placebo Safety set
    Number of subjects analysed
    33
    17
    50
    Units: subjects
        number (confidence interval 95%)
    1 (0.1 to 15.8)
    0 (0 to 19.5)
    1 (0.1 to 10.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (including SAEs) would be collected beginning from the time the participant signs the ICF and until the completion of the study.
    Adverse event reporting additional description
    ChAdOx1.HTI, MVA.HTI, and vesatolimod were found to be generally safe and well-tolerated, no new safety signal detected. A TEAE is defined as any event not present before exposure to IMP or any event already present that worsens in either intensity or frequency after exposure to IMP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    CCMM + Vesatolimod
    Reporting group description
    		 ChAdOx1.HTI is an immunotherapeutic medicinal product that contains genetically modified organisms (ChAdOx1). MVA.HTI is an investigational immunological product (vaccine) of a biological/biotechnological origin that contains genetically modified organisms (MVA). Vesatolimod (also known as GS-9620) is an orally administered toll-like receptor 7 (TLR7) agonist currently in clinical development for the treatment and remission of HIV-1 infection.

    Reporting group title
    Placebo
    Reporting group description
    		 The placebos matched to ChAdOx1.HTI and MVA.HTI were commercially available sterile saline solution (sodium chloride 0.9%).

    Serious adverse events
    		 CCMM + Vesatolimod Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 17 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 17 (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
    		 CCMM + Vesatolimod Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 33 (96.97%)
    17 / 17 (100.00%)
    Vascular disorders
    Varicose vein
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    29 / 33 (87.88%)
    5 / 17 (29.41%)
         occurrences all number
    64
    9
    Influenza like illness
         subjects affected / exposed
    12 / 33 (36.36%)
    4 / 17 (23.53%)
         occurrences all number
    40
    5
    Fatigue
         subjects affected / exposed
    11 / 33 (33.33%)
    4 / 17 (23.53%)
         occurrences all number
    17
    17
    Asthenia
         subjects affected / exposed
    5 / 33 (15.15%)
    5 / 17 (29.41%)
         occurrences all number
    11
    12
    Injection site induration
         subjects affected / exposed
    7 / 33 (21.21%)
    2 / 17 (11.76%)
         occurrences all number
    10
    3
    Injection site erythema
         subjects affected / exposed
    6 / 33 (18.18%)
    2 / 17 (11.76%)
         occurrences all number
    6
    3
    Malaise
         subjects affected / exposed
    5 / 33 (15.15%)
    1 / 17 (5.88%)
         occurrences all number
    7
    1
    Pyrexia
         subjects affected / exposed
    4 / 33 (12.12%)
    2 / 17 (11.76%)
         occurrences all number
    5
    2
    Chills
         subjects affected / exposed
    4 / 33 (12.12%)
    1 / 17 (5.88%)
         occurrences all number
    4
    3
    Injection site reaction
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 17 (5.88%)
         occurrences all number
    5
    1
    Injection site pruritus
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Vaccination site pain
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    2
    Injection site bruising
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Injection site warmth
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Testicular pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    5 / 33 (15.15%)
    6 / 17 (35.29%)
         occurrences all number
    16
    9
    Cough
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 17 (5.88%)
         occurrences all number
    3
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 17 (23.53%)
         occurrences all number
    3
    4
    Insomnia
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Affective disorder
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Substance abuse
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Investigations
    Mycoplasma test positive
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    2
    Vaccination complication
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Limb injury
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Penis injury
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 33 (48.48%)
    10 / 17 (58.82%)
         occurrences all number
    38
    21
    Tension headache
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 17 (11.76%)
         occurrences all number
    2
    2
    Dizziness
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Migraine with aura
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Myoclonus
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    3 / 33 (9.09%)
    3 / 17 (17.65%)
         occurrences all number
    3
    4
    Lymph node pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Ear pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Photopsia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    6 / 33 (18.18%)
    6 / 17 (35.29%)
         occurrences all number
    6
    11
    Diarrhoea
         subjects affected / exposed
    5 / 33 (15.15%)
    6 / 17 (35.29%)
         occurrences all number
    6
    7
    Abdominal pain
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 17 (11.76%)
         occurrences all number
    4
    2
    Proctalgia
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 17 (5.88%)
         occurrences all number
    3
    1
    Dyspepsia
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    2
    Toothache
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 17 (5.88%)
         occurrences all number
    1
    2
    Constipation
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Odynophagia
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 17 (11.76%)
         occurrences all number
    3
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 33 (33.33%)
    1 / 17 (5.88%)
         occurrences all number
    12
    3
    Myalgia
         subjects affected / exposed
    9 / 33 (27.27%)
    2 / 17 (11.76%)
         occurrences all number
    12
    4
    Back pain
         subjects affected / exposed
    4 / 33 (12.12%)
    2 / 17 (11.76%)
         occurrences all number
    5
    2
    Muscle spasms
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Temporomandibular joint syndrome
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    9 / 33 (27.27%)
    7 / 17 (41.18%)
         occurrences all number
    9
    7
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 33 (18.18%)
    4 / 17 (23.53%)
         occurrences all number
    6
    5
    Nasopharyngitis
         subjects affected / exposed
    5 / 33 (15.15%)
    2 / 17 (11.76%)
         occurrences all number
    7
    3
    Syphilis
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 17 (11.76%)
         occurrences all number
    3
    2
    Proctitis gonococcal
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 17 (11.76%)
         occurrences all number
    2
    2
    Tonsillitis
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 17 (11.76%)
         occurrences all number
    1
    2
    Bronchitis
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Folliculitis
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Hordeolum
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Oral herpes
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Oropharyngeal gonococcal infection
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Pharyngeal chlamydia infection
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Tinea versicolour
         subjects affected / exposed
    1 / 33 (3.03%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Urethritis gonococcal
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Furuncle
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Gastroenteritis shigella
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Genital herpes simplex
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Gonorrhoea
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Latent syphilis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    Proctitis chlamydial
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Ureaplasma infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Viral infection
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 33 (9.09%)
    3 / 17 (17.65%)
         occurrences all number
    5
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Oct 2019
    The following is a summary of the major changes implemented with Protocol Amendment 2 (substantial), dated 07 Oct 2019: • The vesatolimod dose was reduced from 8 mg to 6 mg and study monitoring plan following the first dose of vesatolimod and subsequent doses was updated to include a 24-hour on-site admission period following the first dose and an 8-hour observation period following subsequent doses to monitor for CRS. • The study was simplified by removing the GALT substudy, eliminating 2 treatment arms (and reducing the number of participants), and eliminating the sentinel dosing cohort (based on safety data from another study). • The size of intensive PK substudy was reduced from 18 to 15 participants. • The number of participants was changed to 57 (38 in the CCMM + vesatolimod group and 19 in the placebo group). • The randomization stratification by sentinel and non-sentinel cohorts was removed. • Stratification based on the potential for superior viral control (based on HLA genotype) was added.
    24 Sep 2020
    The following is a summary of the major changes implemented with Protocol Amendment 4 (substantial), dated 24 Sep 2020: • Text was added to introduce the conduct of the study during the COVID-19 pandemic, including the benefit-risk assessment of ChAdOx1. HTI, MVA.HTI, and vesatolimod, and the measures taken during the COVID-19 pandemic, such as SARS CoV 2 PCR, serological tests, and remote visits in relation to vesatolimod/placebo administration and certain non-IMP dosing visits. • Safety data of the relevant clinical studies on the study vaccines were updated based on the latest DSUR, dated on 08 Apr 2020.

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

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