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    Clinical Trial Results:
    Combining a TLR9 agonist with broadly neutralizing antibodies for reservoir reduction and immunological control of HIV infection: An investigator-initiated randomized, placebo-controlled, phase IIa trial (TITAN)

    Summary
    EudraCT number
    		 2018-001165-16
    Trial protocol
    		 DK   NO  
    Global end of trial date
    09 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Oct 2024
    First version publication date
    03 Oct 2024
    Other versions
    Summary report(s)
    		 Paper

    Trial information

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    Trial identification
    Sponsor protocol code
    TITAN-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03837756
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juul-Jensens Boulevard 45, Aarhus, Denmark,
    Public contact
    Ole Schmeltz Søgaard, Department of Infectious Diseases, Aarhus University Hospital, 0045 78452842, olesoega@rm.dk
    Scientific contact
    Ole Schmeltz Søgaard, Department of Infectious Diseases, Aarhus University Hospital, 0045 78452842, olesoega@rm.dk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Jun 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jun 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effects of a TLR9 agonist (Lefitolimod) and/or administration of potent bNAbs (3BNC117 and 10-1074) on time to viral rebound during analytical treatment interruption.
    Protection of trial subjects
    Blood samples and participant-specific documents will not contain information that directly identifies the participant, but will be supplied with a study identification code unique for each subject. All study material will be treated in accordance with the national law and Data Protection Agency.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Dec 2018
    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
    Norway: 14
    Country: Number of subjects enrolled
    Denmark: 27
    Country: Number of subjects enrolled
    Australia: 5
    Worldwide total number of subjects
    46
    EEA total number of subjects
    41
    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)
    46
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible study subjects will be recruited according to local norms. To direct the information for potential eligible participants, screening on inclusion and exclusion criterias can be done by nurses or doctors at local sites involved in the study.

    Pre-assignment
    Screening details
    		 Sensitivity of the viral reservoir to neutralization by 3BNC117 and 10-1074 will be tested following the screening visit (i.e. prior to enrollment and randomization).

    Pre-assignment period milestones
    Number of subjects started
    		 46
    Number of subjects completed
    		 46

    Period 1
    Period 1 title
    Inclusion and dosing
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Because the placebo is not specifically manufactured by the producers of the IMPs, it is not possible for the placebo packaging to mimic that of the IMPs. Therefore, in order to ensure the continued blinding of the administering personnel and the participant, a nurse or similarly qualified point-of-care designee will prepare the IMP(s) in a manner so that the administering personnel remains blinded to the IMP packaging.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo/placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    Lefitolimod (120 mg) or placebo was dosed subcutaneously (s.c.) once weekly for 8 weeks starting 2 weeks before the ATI and ending at the beginning of week 6 of the ATI

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3BNC117 (30 mg kg−1) and 10-1074 (20 mg kg−1) or placebo were given as sequential intravenous (i.v.) infusions the day before starting the ATI and 3 weeks into the ATI.

    Arm title
    		 TLR9/placebo
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lefitolimod
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    Lefitolimod (120 mg) or placebo was dosed subcutaneously (s.c.) once weekly for 8 weeks starting 2 weeks before the ATI and ending at the beginning of week 6 of the ATI

    Arm title
    		 Placebo/bNAb
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    Lefitolimod (120 mg) or placebo was dosed subcutaneously (s.c.) once weekly for 8 weeks starting 2 weeks before the ATI and ending at the beginning of week 6 of the ATI

    Arm title
    		 TLR9/bNAb
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lefitolimod
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    Lefitolimod (120 mg) or placebo was dosed subcutaneously (s.c.) once weekly for 8 weeks starting 2 weeks before the ATI and ending at the beginning of week 6 of the ATI

    Investigational medicinal product name
    bNAbs
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3BNC117 (30 mg kg−1) and 10-1074 (20 mg kg−1) or placebo were given as sequential intravenous (i.v.) infusions the day before starting the ATI and 3 weeks into the ATI.

    Number of subjects in period 1
    		Placebo/placebo TLR9/placebo Placebo/bNAb TLR9/bNAb
    Started
    11
    11
    12
    12
    Completed
    10
    10
    10
    12
    Not completed
    1
    1
    2
    0
         Consent withdrawn by subject
    1
    1
    1
    -
         Adverse event, non-fatal
    -
    -
    1
    -
    Period 2
    Period 2 title
    ATI
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo/placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    Lefitolimod (120 mg) or placebo was dosed subcutaneously (s.c.) once weekly for 8 weeks starting 2 weeks before the ATI and ending at the beginning of week 6 of the ATI

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3BNC117 (30 mg kg−1) and 10-1074 (20 mg kg−1) or placebo were given as sequential intravenous (i.v.) infusions the day before starting the ATI and 3 weeks into the ATI.

    Arm title
    		 TLR9/placebo
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lefitolimod
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    Lefitolimod (120 mg) or placebo was dosed subcutaneously (s.c.) once weekly for 8 weeks starting 2 weeks before the ATI and ending at the beginning of week 6 of the ATI

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3BNC117 (30 mg kg−1) and 10-1074 (20 mg kg−1) or placebo were given as sequential intravenous (i.v.) infusions the day before starting the ATI and 3 weeks into the ATI.

    Arm title
    		 Placebo/bNAb
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    Lefitolimod (120 mg) or placebo was dosed subcutaneously (s.c.) once weekly for 8 weeks starting 2 weeks before the ATI and ending at the beginning of week 6 of the ATI

    Investigational medicinal product name
    bNAbs
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3BNC117 (30 mg kg−1) and 10-1074 (20 mg kg−1) or placebo were given as sequential intravenous (i.v.) infusions the day before starting the ATI and 3 weeks into the ATI.

    Arm title
    		 TLR9/bNAb
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lefitolimod
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Injection
    Dosage and administration details
    Lefitolimod (120 mg) or placebo was dosed subcutaneously (s.c.) once weekly for 8 weeks starting 2 weeks before the ATI and ending at the beginning of week 6 of the ATI

    Investigational medicinal product name
    bNAbs
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    3BNC117 (30 mg kg−1) and 10-1074 (20 mg kg−1) or placebo were given as sequential intravenous (i.v.) infusions the day before starting the ATI and 3 weeks into the ATI.

    Number of subjects in period 2
    		Placebo/placebo TLR9/placebo Placebo/bNAb TLR9/bNAb
    Started
    10
    10
    10
    12
    Completed
    10
    10
    10
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Inclusion and dosing
    Reporting group description
    		 -

    Reporting group values
    		 Inclusion and dosing Total
    Number of subjects
    		 46 46
    Age categorical
    Median age at enrollment was 50 years (interquartile range (IQR): 41–54)
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 46 46
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 50 (41 to 54) -
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 39 39

    End points

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    End points reporting groups
    Reporting group title
    Placebo/placebo
    Reporting group description
    		 -

    Reporting group title
    TLR9/placebo
    Reporting group description
    		 -

    Reporting group title
    Placebo/bNAb
    Reporting group description
    		 -

    Reporting group title
    TLR9/bNAb
    Reporting group description
    		 -
    Reporting group title
    Placebo/placebo
    Reporting group description
    		 -

    Reporting group title
    TLR9/placebo
    Reporting group description
    		 -

    Reporting group title
    Placebo/bNAb
    Reporting group description
    		 -

    Reporting group title
    TLR9/bNAb
    Reporting group description
    		 -

    Primary: Time to loss of virologic control after ATI

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    End point title
    		 Time to loss of virologic control after ATI
    End point description
    End point type
    Primary
    End point timeframe
    25-week of ATI
    End point values
    		 Placebo/placebo TLR9/placebo Placebo/bNAb TLR9/bNAb
    Number of subjects analysed
    10
    10
    10
    12
    Units: week
        median (inter-quartile range (Q1-Q3))
    4.5 (3.0 to 11)
    5.0 (4.0 to 6.0)
    17 (11 to 25)
    14 (10 to 17)
    Statistical analysis title
    		 Time to event
    Comparison groups
    Placebo/placebo v TLR9/placebo v Placebo/bNAb v TLR9/bNAb
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Logrank
    Confidence interval

    Secondary: Safety

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    End point title
    		 Safety
    End point description
    End point type
    Secondary
    End point timeframe
    Entire study
    End point values
    		 Placebo/placebo TLR9/placebo Placebo/bNAb TLR9/bNAb
    Number of subjects analysed
    10
    10
    10
    11
    Units: adverse events
    51
    53
    52
    98
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5
    Reporting groups
    Reporting group title
    Placebo/placebo
    Reporting group description
    		 -

    Reporting group title
    TLR9/placebo
    Reporting group description
    		 -

    Reporting group title
    Placebo/bNAb
    Reporting group description
    		 -

    Reporting group title
    TLR9/bNAb
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo/placebo TLR9/placebo Placebo/bNAb TLR9/bNAb
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Vasovagal reaction
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo/placebo TLR9/placebo Placebo/bNAb TLR9/bNAb
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    10 / 10 (100.00%)
    10 / 11 (90.91%)
    12 / 12 (100.00%)
    Injury, poisoning and procedural complications
    Injection site reaction
         subjects affected / exposed
    5 / 10 (50.00%)
    3 / 10 (30.00%)
    2 / 11 (18.18%)
    8 / 12 (66.67%)
         occurrences all number
    5
    12
    4
    27
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 10 (30.00%)
    3 / 11 (27.27%)
    2 / 12 (16.67%)
         occurrences all number
    1
    5
    3
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 10 (60.00%)
    4 / 10 (40.00%)
    3 / 11 (27.27%)
    7 / 12 (58.33%)
         occurrences all number
    8
    5
    3
    8
    Hot flush
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0

    More information

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

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Feb 2020
    Study procedures were unfortunately severely impacted by the coronavris disease 2019 (COVID-19) pandemic, and enrollment had to be paused for longer periods in 2020 and 2021.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The reported results have limitations and may not be generalizable to all PWH. Specifically, our ability to predict proviral bNAb sensitivity based on the PhenoSense assay or sequence analysis is limited. Most enrolled participants were male.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/3769693
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    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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