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Combining TLR9 Agonist With bNAbs for Reservoir Reduction and Immunological Control of HIV (TITAN)

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ClinicalTrials.gov Identifier: NCT03837756
Recruitment Status : Recruiting
First Posted : February 12, 2019
Last Update Posted : April 19, 2021
Sponsor:
Collaborators:
Aalborg University Hospital
Odense University Hospital
Rigshospitalet, Denmark
Hvidovre University Hospital
The Peter Doherty Institute for Infection and Immunity
University of Utah
Oslo University Hospital
Information provided by (Responsible Party):
University of Aarhus

Tracking Information
First Submitted Date  ICMJE February 7, 2019
First Posted Date  ICMJE February 12, 2019
Last Update Posted Date April 19, 2021
Actual Study Start Date  ICMJE May 6, 2019
Estimated Primary Completion Date July 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 8, 2019)
Time to re-initiation of cART during analytical treatment interruption (ATI) [ Time Frame: Up to 26 weeks. ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 8, 2019)
  • Safety and Tolerability assessment measured by AEs, Adverse Reactions (ARs), SAEs, [ Time Frame: Duration of the study ]
    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)
  • Plasma HIV RNA doubling time [ Time Frame: Duration of ATI (up to 26 weeks) ]
    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)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Combining TLR9 Agonist With bNAbs for Reservoir Reduction and Immunological Control of HIV
Official Title  ICMJE 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.
Brief Summary 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
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE 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

Masking: Double (Participant, Investigator)
Masking Description:
The participant and all study personnel who directly interact with study participants are blinded to study arm designation.
Primary Purpose: Treatment
Condition  ICMJE HIV-1-infection
Intervention  ICMJE
  • Drug: Saline
    Placebo
  • Drug: Lefitolimod
    A TLR9 agonist administered s.c. once weekly for 8 weeks.
    Other Name: MGN1703
  • Drug: 3BNC117 and 10-1074
    Broadly neutralizing antibodies against HIV env administered two times with a 3 week interval.
    Other Name: RUhumab-001 and RUhumab-002
Study Arms  ICMJE
  • Placebo Comparator: Arm A: Placebo/Placebo
    This arm will receive placebo (sterile saline) for both Lefitolimod and 3BNC117 + 10-1074.
    Intervention: Drug: Saline
  • Active Comparator: Arm B: Lefitolimod/Placebo
    This arm will receive Lefitolimod and placebo (sterile saline) for 3BNC117 + 10-1074.
    Interventions:
    • Drug: Saline
    • Drug: Lefitolimod
  • Active Comparator: Arm C: Placebo/3BNC117 + 10-1074
    This arm will receive 3BNC117 + 10-1074 and placebo (sterile saline) for Lefitolimod.
    Interventions:
    • Drug: Saline
    • Drug: 3BNC117 and 10-1074
  • Active Comparator: Arm D: Lefitolimod/3BNC117 + 10-1074
    This arm will receive both Lefitolimod and 3BNC117 + 10-1074.
    Interventions:
    • Drug: Lefitolimod
    • Drug: 3BNC117 and 10-1074
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 8, 2019)
48
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 28, 2023
Estimated Primary Completion Date July 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Documented HIV-1 infection
  • Adults age 18-65 years
  • On ART for a minimum of 18 months.
  • CD4+ T cell count >500 at screening
  • HIV-1 RNA plasma level of < 50 copies/mL by standard assays for at least 15 months (a single viral load measurement > 50 but < 500 copies/mL during this time period is allowable).
  • Able to give informed consent
  • Viral reservoir sensitivity to 3BNC117 and 10-1074. (Sensitivity of the viral reservoir to neutralization by 3BNC117 and 10-1074 will be tested following the screening visit (i.e. prior to randomization)).

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). Isolated PBMCs will be analyzed using the PhenoSense HIV mAb Assay, Monogram Biosciences. The sensitivity of an individuals archieved proviruses to bNAb neutralization will be determined by the IC50 value of PBMC derived pseudovirus inhibition. Subjects that are considered sensitive to both 3BNC117 (IC90<=1.5 μg/mL) and 10-1074 (IC90<=2.0 μg/mL) AND MPI>97 AND fulfill the other inclusion/exclusion criteria will proceed to study enrolment and randomization.

If sensitivity cannot be determined by the PhenoSense HIVmAb Assay, participants will be screened for 3BNC117 and 10-1074 sensitivity using HIV env sequencing carried out in-house (Aarhus, Denmark). The method was originally established and validated by Rockefeller University that already has this method implemented. The method utilizes HIV-1 DNA envelope sequencing and a mathematical prediction binding algoritm of known binding sites of the antibodies. Based on the individual HIV env sequence, proviruses are categorized as "sensitive" or "resistant". Subjects that are determined to be sensitive to both 3BNC117 and 10-1074 (defined as at least 90% of known sequences sensitive to either bNAb) AND fulfill the other inclusion/exclusion criteria will proceed to study enrolment and randomization.

Exclusion Criteria:

  • Any significant acute medical illness requiring hospitalization in the past 4 weeks
  • Any evidence of an active AIDS-defining opportunistic infection
  • Any condition that, in the Investigator's opinion, will prevent adequate compliance with study therapy
  • The following laboratory values at screening, the values can be repeated within the screening period, but test results must be available before baseline (Day 0) and checked for eligibility: Hepatic transaminases (AST or ALT) ≥3 x upper limit of normal (ULN) // Serum total bilirubin ≥3 ULN // Estimated glomerular filtration rate (eGFR) ≤50 mL/min (based on serum creatinine) // Platelet count ≤100 x109/L // Absolute neutrophil count ≤1x109/L
  • Hepatitis B or C infection
  • History of: Malignancy, excluding non-melanoma skin cancers, or organ transplantation
  • Receipt of strong immunosuppressive or systemic chemotherapeutic agents within 28 days prior to study entry
  • Known resistance to >2 classes of ART
  • Known hypersensitivity to the components of lefitolimod, 3BNC117, 10-1074 or their analogues
  • Pre-existing autoimmune or antibody-mediated diseases
  • Women who are pregnant or breastfeeding, or unwilling/ unable to use an acceptable method of contraception (if of child bearing potential)
  • Males or females who are unwilling or unable to use barrier contraception during sexual intercourse until plasma HIV-1 RNA is undetectable using standard assays
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ole S Søgaard, MD PhD +45 78452842 olesoega@rm.dk
Contact: Jesper F Højen, MD +45 40459718 jephns@rm.dk
Listed Location Countries  ICMJE Australia,   Denmark,   Norway,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03837756
Other Study ID Numbers  ICMJE TITAN-001
2018-001165-16 ( EudraCT Number )
AGR-2016-8833 ( Other Grant/Funding Number: Gilead Sciences, Inc. )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan 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).
Supporting Materials: Study Protocol
Supporting Materials: Informed Consent Form (ICF)
Time Frame: Data will become available following publication of the specific dataset with no planned end date.
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
Responsible Party University of Aarhus
Study Sponsor  ICMJE University of Aarhus
Collaborators  ICMJE
  • Aalborg University Hospital
  • Odense University Hospital
  • Rigshospitalet, Denmark
  • Hvidovre University Hospital
  • The Peter Doherty Institute for Infection and Immunity
  • University of Utah
  • Oslo University Hospital
Investigators  ICMJE
Principal Investigator: Ole S Søgaard, MD PhD Aarhus University Hospital
PRS Account University of Aarhus
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP