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    Clinical Trial Results:
    Early administration of anti-latency reversing therapy and broadly neutralizing antibodies to limit the establishment of the HIV-1 reservoir during initiation of antiretroviral treatment - a randomized controlled trial (eCLEAR)

    Summary
    EudraCT number
    		 2015-002234-53
    Trial protocol
    		 DK   GB  
    Global end of trial date
    17 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    eCLEAR-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03041012
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Department of Infectious Diseases, Aarhus University Hospital
    Sponsor organisation address
    Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark, 8200
    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 Feb 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of early viral reactivation by latency reversing agents (LRA) and/or administration of potent broadly neutralizing antibodies (bNAbs) on the size of the latent HIV-1 reservoir in treatment naïve HIV-1 patients initiating ART
    Protection of trial subjects
    There is now considerable experience with the human safety profile of romidepsin. As of 31 December 2011, more than 1300 patients have been treated with romidepsin in clinical studies, and of those a total of 891 patients with at least one dose of romidepsin as monotherapy. The experience with 3BNC177 is sparse, but both uninfected and HIV-1infected individuals were given a single dose IV and monitored for 56 days. A total of 37 individuals have received 3BNC117 at doses ranging from 1 to 30 mg/kg, and there have been no significant AE related to 3BNC117 to date. Romidepsin is better characterized than 3BNC117, but both IMPs require monitoring and safety monitoring is described below: Safety will be monitored by vital signs, clinical laboratory tests, history and physical examinations if needed and the rate and severity of AE. If indicated in the opinion of the investigator, a physical examination will be performed prior to and after completed infusion. Routine biochemistry (safety) will be performed prior to infusion. Infusion is postponed in case of unacceptable laboratory values prior to infusion, and laboratory tests may be repeated, as clinically indicated, to obtain acceptable values before withdraw from the study: o Hepatic transaminases (AST or ALT) ≥3 x upper limit of normal (ULN) o Serum total bilirubin ≥3 ULN o Estimated glomerular filtration rate (eGFR) ≤60 mL/min (based on serum creatinine or other appropriate validated markers) o Platelet count ≤100 x10^9/L o Absolute neutrophil count ≤1x10^9/L o Serum potassium, magnesium, phosphorus outside ≥1.5 ULN/LLN o Total calcium (corrected for serum albumin) or ionized calcium ≥1.5 ULN/LLN A baseline ECG will be obtained at screening. Upon completion of follow-up specified in this protocol at day 365, study subjects who do not enter the ATI will resume routine treatment and control following standard treatment guidelines.
    Background therapy
    		 All four arms were started on integrase-inhibitor-based triple-ART regimen.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Jan 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Denmark: 47
    Worldwide total number of subjects
    59
    EEA total number of subjects
    47
    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)
    57
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible individuals were given written information upon diagnosed with HIV-1 to participate in the study unless the individual refuses. Eligible individuals were recruited from 16 January 2017 to 3 March 2020.

    Pre-assignment
    Screening details
    		 Screening occurred within 4 weeks before the baseline visit at day 0. Newly diagnosed ART-naive participants aged 18 with a confirmed HIV-1 diagnosis and a CD4+ T cell count of >200 cells per mm3 at screening were recruited by study physicians. During screening, we excluded 25% of the newly diagnosed individuals due to low CD4+ T cell count.

    Period 1
    Period 1 title
    Main
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ART alone
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 ART+3BNC117
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    3BNC117
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg/kg

    Arm title
    		 ART+romidepsin
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    romidepsin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg per m2

    Arm title
    		 ART+3BNC117+romidepsin
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    3BNC117
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg/kg

    Investigational medicinal product name
    romidepsin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg per m2

    Number of subjects in period 1
    		ART alone ART+3BNC117 ART+romidepsin ART+3BNC117+romidepsin
    Started
    15
    15
    13
    16
    Completed
    15
    13
    10
    14
    Not completed
    0
    2
    3
    2
         Consent withdrawn by subject
    -
    -
    1
    2
         Adverse event, non-fatal
    -
    1
    -
    -
         Lost to follow-up
    -
    1
    2
    -
    Period 2
    Period 2 title
    ATI
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ART alone
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 ART+3BNC117
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    3BNC117
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg/kg

    Arm title
    		 ART+romidepsin
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    romidepsin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg per m2

    Arm title
    		 ART+3BNC117+romidepsin
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    3BNC117
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg/kg

    Investigational medicinal product name
    romidepsin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5 mg per m2

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Yes, period 1 is baseline.
    Number of subjects in period 2 [2] [3]
    		ART alone ART+3BNC117 ART+romidepsin ART+3BNC117+romidepsin
    Started
    4
    5
    5
    6
    ATI
    4
    5
    5
    6
    Completed
    4
    5
    5
    6
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: ATI was optional.
    [3] - 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: ATI was optional.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ATI
    Reporting group description
    		 -

    Reporting group values
    		 ATI Total
    Number of subjects
    		 20 20
    Age categorical
    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)
    		 20 20
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 37 (29 to 46) -
    Gender categorical
    Units: Subjects
        Female
    		 2 2
        Male
    		 18 18

    End points

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    End points reporting groups
    Reporting group title
    ART alone
    Reporting group description
    		 -

    Reporting group title
    ART+3BNC117
    Reporting group description
    		 -

    Reporting group title
    ART+romidepsin
    Reporting group description
    		 -

    Reporting group title
    ART+3BNC117+romidepsin
    Reporting group description
    		 -
    Reporting group title
    ART alone
    Reporting group description
    		 -

    Reporting group title
    ART+3BNC117
    Reporting group description
    		 -

    Reporting group title
    ART+romidepsin
    Reporting group description
    		 -

    Reporting group title
    ART+3BNC117+romidepsin
    Reporting group description
    		 -

    Primary: HIV-1 reservoir

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    End point title
    		 HIV-1 reservoir
    End point description
    Median decline
    End point type
    Primary
    End point timeframe
    Day 0-365
    End point values
    		 ART alone ART+3BNC117 ART+romidepsin ART+3BNC117+romidepsin
    Number of subjects analysed
    14
    14
    10
    14
    Units: intact proviruses710^6 CD4+ T cells
        median (inter-quartile range (Q1-Q3))
    2709 (734 to 11442)
    5032 (2013 to 26165)
    5382 (2583 to 8695)
    10274 (355 to 18846)
    Statistical analysis title
    		 Size of HIV-1 reservoir
    Comparison groups
    ART+3BNC117+romidepsin v ART alone
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.36
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Size of HIV-1 reservoir
    Comparison groups
    ART alone v ART+3BNC117
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.21
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Size of HIV-1 reservoir
    Comparison groups
    ART+romidepsin v ART alone
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.53
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Primary: ATI

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    End point title
    		 ATI
    End point description
    ART-free virological control
    End point type
    Primary
    End point timeframe
    Day 400
    End point values
    		 ART alone ART+3BNC117 ART+romidepsin ART+3BNC117+romidepsin
    Number of subjects analysed
    4
    5
    5
    6
    Units: %
    2
    1
    1
    3
    Statistical analysis title
    		 ATI
    Comparison groups
    ART alone v ART+3BNC117+romidepsin v ART+3BNC117 v ART+romidepsin
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.025 [1]
    Method
    		 Log-rank test
    Confidence interval
    Notes
    [1] - We compared 3BNC117-sensitive individuals to all other ATI participants, but the difference in virologic control between the groups remained significant (P = 0.025)

    Secondary: FISH flow

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    End point title
    		 FISH flow
    End point description
    End point type
    Secondary
    End point timeframe
    Day 0-30
    End point values
    		 ART+3BNC117 ART+romidepsin
    Number of subjects analysed
    9
    9
    Units: p24+ cells per 10^6 CD4+ T cells
        median (inter-quartile range (Q1-Q3))
    167 (62 to 359)
    80 (20 to 132)
    No statistical analyses for this end point

    Secondary: HIV-1 specific immunity

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    End point title
    		 HIV-1 specific immunity
    End point description
    End point type
    Secondary
    End point timeframe
    Day 0-365
    End point values
    		 ART alone ART+3BNC117+romidepsin
    Number of subjects analysed
    14
    14
    Units: %
        median (inter-quartile range (Q1-Q3))
    0.31 (0.07 to 0.57)
    0.95 (0.52 to 1.74)
    Statistical analysis title
    		 HIV-1 immunity
    Comparison groups
    ART alone v ART+3BNC117+romidepsin
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Post-hoc: 3BNC117 sensitivity

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    End point title
    		 3BNC117 sensitivity [2]
    End point description
    End point type
    Post-hoc
    End point timeframe
    End of study
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only done for individuals given 3BNC117.
    End point values
    		 ART+3BNC117 ART+3BNC117+romidepsin ART+3BNC117 ART+3BNC117+romidepsin
    Number of subjects analysed
    15
    16
    5
    6
    Units: 18
    8
    10
    2
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Start to end of study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    ART alone
    Reporting group description
    		 -

    Reporting group title
    ART+3BNC117+romidepsin
    Reporting group description
    		 -

    Serious adverse events
    		 ART alone ART+3BNC117+romidepsin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 16 (12.50%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Radiculitis brachial
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ART alone ART+3BNC117+romidepsin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 15 (93.33%)
    15 / 16 (93.75%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 15 (20.00%)
    4 / 16 (25.00%)
         occurrences all number
    3
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 16 (18.75%)
         occurrences all number
    1
    3
    Musculoskeletal and connective tissue disorders
    Fatigue
         subjects affected / exposed
    2 / 15 (13.33%)
    5 / 16 (31.25%)
         occurrences all number
    4
    5
    Infections and infestations
    Sexually transmitted disease
         subjects affected / exposed
    6 / 15 (40.00%)
    5 / 16 (31.25%)
         occurrences all number
    11
    6
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 15 (13.33%)
    4 / 16 (25.00%)
         occurrences all number
    2
    5

    More information

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

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Our study also has some limitations and may not be generalizable to all newly diagnosed individuals due to the study’s stringent exclusion criteria.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/3625360
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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
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