<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03837756</url>
  </required_header>
  <id_info>
    <org_study_id>TITAN-001</org_study_id>
    <secondary_id>2018-001165-16</secondary_id>
    <secondary_id>AGR-2016-8833</secondary_id>
    <nct_id>NCT03837756</nct_id>
  </id_info>
  <brief_title>Combining TLR9 Agonist With bNAbs for Reservoir Reduction and Immunological Control of HIV</brief_title>
  <acronym>TITAN</acronym>
  <official_title>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.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Aarhus</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Aalborg University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Odense University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Rigshospitalet, Denmark</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hvidovre University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Peter Doherty Institute for Infection and Immunity</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Utah</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Oslo University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Aarhus</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is designed to evaluate the safety and efficacy of lefitolimod and 3BNC117/10-1074&#xD;
      in HIV-1-infected individuals on ART and during ATI as intervention to reduce the HIV-1&#xD;
      reservoir&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 6, 2019</start_date>
  <completion_date type="Actual">May 1, 2023</completion_date>
  <primary_completion_date type="Actual">July 1, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Factorial Assignment</intervention_model>
    <intervention_model_description>Participants will be randomized 1:1:1:1 in a blinded fashion to receive:&#xD;
Arm A: Placebo and Placebo Arm B: Lefitolimod and Placebo Arm C: Placebo and 3BNC117+10-1074 Arm D: Lefitolimod and 3BNC117+10-1074</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>The participant and all study personnel who directly interact with study participants are blinded to study arm designation.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Time to re-initiation of cART during analytical treatment interruption (ATI)</measure>
    <time_frame>Up to 26 weeks.</time_frame>
    <description>Time from date of cART cessation to the date of the last of three consecutive plasma HIV-1 RNA measurements &gt;10,000 copies/mL, CD4 cell count &lt;350 on two consecutive measurements, or end of ATI (i.e. 26 weeks after cessation of cART) - whichever comes first.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety and Tolerability assessment measured by AEs, Adverse Reactions (ARs), SAEs,</measure>
    <time_frame>Duration of the study</time_frame>
    <description>Subject who receives at least one dose of the IMP(s) will be included in the evaluation for safety, measured by AEs, Adverse Reactions (ARs), SAEs, Serious ARs (SARs) and (SUSAR)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma HIV RNA doubling time</measure>
    <time_frame>Duration of ATI (up to 26 weeks)</time_frame>
    <description>Plasma HIV RNA doubling time from first measurement &gt;50 copies/mL to first measurement &gt;1,000 copies/mL during the analytical treatment interruption (plasma HIV RNA measured by standard clinical assays, e.g. Cobas TaqMan; Lower limit of quantitation 20 copies/mL)</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">47</enrollment>
  <condition>HIV-1-infection</condition>
  <arm_group>
    <arm_group_label>Arm A: Placebo/Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>This arm will receive placebo (sterile saline) for both Lefitolimod and 3BNC117 + 10-1074.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B: Lefitolimod/Placebo</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This arm will receive Lefitolimod and placebo (sterile saline) for 3BNC117 + 10-1074.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm C: Placebo/3BNC117 + 10-1074</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This arm will receive 3BNC117 + 10-1074 and placebo (sterile saline) for Lefitolimod.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm D: Lefitolimod/3BNC117 + 10-1074</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This arm will receive both Lefitolimod and 3BNC117 + 10-1074.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Saline</intervention_name>
    <description>Placebo</description>
    <arm_group_label>Arm A: Placebo/Placebo</arm_group_label>
    <arm_group_label>Arm B: Lefitolimod/Placebo</arm_group_label>
    <arm_group_label>Arm C: Placebo/3BNC117 + 10-1074</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lefitolimod</intervention_name>
    <description>A TLR9 agonist administered s.c. once weekly for 8 weeks.</description>
    <arm_group_label>Arm B: Lefitolimod/Placebo</arm_group_label>
    <arm_group_label>Arm D: Lefitolimod/3BNC117 + 10-1074</arm_group_label>
    <other_name>MGN1703</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>3BNC117 and 10-1074</intervention_name>
    <description>Broadly neutralizing antibodies against HIV env administered two times with a 3 week interval.</description>
    <arm_group_label>Arm C: Placebo/3BNC117 + 10-1074</arm_group_label>
    <arm_group_label>Arm D: Lefitolimod/3BNC117 + 10-1074</arm_group_label>
    <other_name>RUhumab-001 and RUhumab-002</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Documented HIV-1 infection&#xD;
&#xD;
          -  Adults age 18-65 years&#xD;
&#xD;
          -  On ART for a minimum of 18 months.&#xD;
&#xD;
          -  CD4+ T cell count &gt;500 at screening&#xD;
&#xD;
          -  HIV-1 RNA plasma level of &lt; 50 copies/mL by standard assays for at least 15 months (a&#xD;
             single viral load measurement &gt; 50 but &lt; 500 copies/mL during this time period is&#xD;
             allowable).&#xD;
&#xD;
          -  Able to give informed consent&#xD;
&#xD;
          -  Viral reservoir sensitivity to 3BNC117 and 10-1074. (Sensitivity of the viral&#xD;
             reservoir to neutralization by 3BNC117 and 10-1074 will be tested following the&#xD;
             screening visit (i.e. prior to randomization)).&#xD;
&#xD;
        Sensitivity of the viral reservoir to neutralization by 3BNC117 and 10-1074 will be tested&#xD;
        following the screening visit (i.e. prior to enrollment and randomization). Isolated PBMCs&#xD;
        will be analyzed using the PhenoSense HIV mAb Assay, Monogram Biosciences. The sensitivity&#xD;
        of an individuals archieved proviruses to bNAb neutralization will be determined by the&#xD;
        IC50 value of PBMC derived pseudovirus inhibition. Subjects that are considered sensitive&#xD;
        to both 3BNC117 (IC90&lt;=1.5 μg/mL) and 10-1074 (IC90&lt;=2.0 μg/mL) AND MPI&gt;97 AND fulfill the&#xD;
        other inclusion/exclusion criteria will proceed to study enrolment and randomization.&#xD;
&#xD;
        If sensitivity cannot be determined by the PhenoSense HIVmAb Assay, participants will be&#xD;
        screened for 3BNC117 and 10-1074 sensitivity using HIV env sequencing carried out in-house&#xD;
        (Aarhus, Denmark). The method was originally established and validated by Rockefeller&#xD;
        University that already has this method implemented. The method utilizes HIV-1 DNA envelope&#xD;
        sequencing and a mathematical prediction binding algoritm of known binding sites of the&#xD;
        antibodies. Based on the individual HIV env sequence, proviruses are categorized as&#xD;
        &quot;sensitive&quot; or &quot;resistant&quot;. Subjects that are determined to be sensitive to both 3BNC117&#xD;
        and 10-1074 (defined as at least 90% of known sequences sensitive to either bNAb) AND&#xD;
        fulfill the other inclusion/exclusion criteria will proceed to study enrolment and&#xD;
        randomization.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any significant acute medical illness requiring hospitalization in the past 4 weeks&#xD;
&#xD;
          -  Any evidence of an active AIDS-defining opportunistic infection&#xD;
&#xD;
          -  Any condition that, in the Investigator's opinion, will prevent adequate compliance&#xD;
             with study therapy&#xD;
&#xD;
          -  The following laboratory values at screening, the values can be repeated within the&#xD;
             screening period, but test results must be available before baseline (Day 0) and&#xD;
             checked for eligibility: Hepatic transaminases (AST or ALT) ≥3 x upper limit of normal&#xD;
             (ULN) // Serum total bilirubin ≥3 ULN // Estimated glomerular filtration rate (eGFR)&#xD;
             ≤50 mL/min (based on serum creatinine) // Platelet count ≤100 x109/L // Absolute&#xD;
             neutrophil count ≤1x109/L&#xD;
&#xD;
          -  Hepatitis B or C infection&#xD;
&#xD;
          -  History of: Malignancy, excluding non-melanoma skin cancers, or organ transplantation&#xD;
&#xD;
          -  Receipt of strong immunosuppressive or systemic chemotherapeutic agents within 28 days&#xD;
             prior to study entry&#xD;
&#xD;
          -  Known resistance to &gt;2 classes of ART&#xD;
&#xD;
          -  Known hypersensitivity to the components of lefitolimod, 3BNC117, 10-1074 or their&#xD;
             analogues&#xD;
&#xD;
          -  Pre-existing autoimmune or antibody-mediated diseases&#xD;
&#xD;
          -  Women who are pregnant or breastfeeding, or unwilling/ unable to use an acceptable&#xD;
             method of contraception (if of child bearing potential)&#xD;
&#xD;
          -  Males or females who are unwilling or unable to use barrier contraception during&#xD;
             sexual intercourse until plasma HIV-1 RNA is undetectable using standard assays&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ole S Søgaard, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Aarhus University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Dept. of Internal Medicine, University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84132</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Alfred Hospital and Monash University</name>
      <address>
        <city>Melbourne</city>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dept. of Infectious Diseases, Aalborg University Hospital</name>
      <address>
        <city>Aalborg</city>
        <zip>9000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dept. of Infectious Diseases, Aarhus University Hospital</name>
      <address>
        <city>Aarhus</city>
        <zip>8200</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dept. of Infectious Diseases, Rigshospitalet</name>
      <address>
        <city>Copenhagen</city>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dept. of Infectious Diseases, Amager and Hvidovre Hospitals</name>
      <address>
        <city>Hvidovre</city>
        <zip>2650</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dept. of Infectious Diseases, Odense University Hospital</name>
      <address>
        <city>Odense</city>
        <zip>5000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oslo University Hospital</name>
      <address>
        <city>Oslo</city>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Denmark</country>
    <country>Norway</country>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>February 7, 2019</study_first_submitted>
  <study_first_submitted_qc>February 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 12, 2019</study_first_posted>
  <last_update_submitted>May 22, 2023</last_update_submitted>
  <last_update_submitted_qc>May 22, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 23, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Individual deidentified participant data (including data dictionaries) will be shared following the publication of the primary and secondary endpoints as outlined in this protocol. Data to be shared includes deidentified data points in published, peer-reviewed articles. Additional, related documents will also be available (study protocol, informed consent form, statistical analysis plan).</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>Data will become available following publication of the specific dataset with no planned end date.</ipd_time_frame>
    <ipd_access_criteria>Access to the data sharing will be given to researchers who provide a methodologically sound proposal for any type of analysis and requires IRB/Ethics committee approval (if applicable). Proposal should be addressed to olesoega@rm.dk</ipd_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03837756
org study id: TITAN-001
secondary id: 2018-001165-16
secondary id: AGR-2016-8833
nct id: NCT03837756
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This study is designed to evaluate the safety and efficacy of lefitolimod and 3BNC117/10-1074
      in HIV-1-infected individuals on ART and during ATI as intervention to reduce the HIV-1
      reservoir
allocation: Randomized
intervention model: Factorial Assignment
intervention model description: Participants will be randomized 1:1:1:1 in a blinded fashion to receive:
Arm A: Placebo and Placebo Arm B: Lefitolimod and Placebo Arm C: Placebo and 3BNC117+10-1074 Arm D: Lefitolimod and 3BNC117+10-1074
primary purpose: Treatment
masking: Double (Participant, Investigator)
masking description: The participant and all study personnel who directly interact with study participants are blinded to study arm designation.
measure: Time to re-initiation of cART during analytical treatment interruption (ATI)
time frame: Up to 26 weeks.
description: Time from date of cART cessation to the date of the last of three consecutive plasma HIV-1 RNA measurements >10,000 copies/mL, CD4 cell count <350 on two consecutive measurements, or end of ATI (i.e. 26 weeks after cessation of cART) - whichever comes first.
measure: Safety and Tolerability assessment measured by AEs, Adverse Reactions (ARs), SAEs,
time frame: Duration of the study
description: Subject who receives at least one dose of the IMP(s) will be included in the evaluation for safety, measured by AEs, Adverse Reactions (ARs), SAEs, Serious ARs (SARs) and (SUSAR)
measure: Plasma HIV RNA doubling time
time frame: Duration of ATI (up to 26 weeks)
description: Plasma HIV RNA doubling time from first measurement >50 copies/mL to first measurement >1,000 copies/mL during the analytical treatment interruption (plasma HIV RNA measured by standard clinical assays, e.g. Cobas TaqMan; Lower limit of quantitation 20 copies/mL)
arm group label: Arm A: Placebo/Placebo
arm group type: Placebo Comparator
description: This arm will receive placebo (sterile saline) for both Lefitolimod and 3BNC117 + 10-1074.
arm group label: Arm B: Lefitolimod/Placebo
arm group type: Active Comparator
description: This arm will receive Lefitolimod and placebo (sterile saline) for 3BNC117 + 10-1074.
arm group label: Arm C: Placebo/3BNC117 + 10-1074
arm group type: Active Comparator
description: This arm will receive 3BNC117 + 10-1074 and placebo (sterile saline) for Lefitolimod.
arm group label: Arm D: Lefitolimod/3BNC117 + 10-1074
arm group type: Active Comparator
description: This arm will receive both Lefitolimod and 3BNC117 + 10-1074.
intervention type: Drug
intervention name: Saline
description: Placebo
arm group label: Arm A: Placebo/Placebo
arm group label: Arm B: Lefitolimod/Placebo
arm group label: Arm C: Placebo/3BNC117 + 10-1074
intervention type: Drug
intervention name: Lefitolimod
description: A TLR9 agonist administered s.c. once weekly for 8 weeks.
arm group label: Arm B: Lefitolimod/Placebo
arm group label: Arm D: Lefitolimod/3BNC117 + 10-1074
other name: MGN1703
intervention type: Drug
intervention name: 3BNC117 and 10-1074
description: Broadly neutralizing antibodies against HIV env administered two times with a 3 week interval.
arm group label: Arm C: Placebo/3BNC117 + 10-1074
arm group label: Arm D: Lefitolimod/3BNC117 + 10-1074
other name: RUhumab-001 and RUhumab-002
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Ole S Søgaard, MD PhD
role: Principal Investigator
affiliation: Aarhus University Hospital
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Australia
country: Denmark
country: Norway
country: United States
responsible party type: Sponsor
mesh term: Infections
sharing ipd: Yes
ipd description: Individual deidentified participant data (including data dictionaries) will be shared following the publication of the primary and secondary endpoints as outlined in this protocol. Data to be shared includes deidentified data points in published, peer-reviewed articles. Additional, related documents will also be available (study protocol, informed consent form, statistical analysis plan).
ipd info type: Study Protocol
ipd info type: Informed Consent Form (ICF)
ipd time frame: Data will become available following publication of the specific dataset with no planned end date.
ipd access criteria: Access to the data sharing will be given to researchers who provide a methodologically sound proposal for any type of analysis and requires IRB/Ethics committee approval (if applicable). Proposal should be addressed to olesoega@rm.dk