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

Sponsor
University of Aarhus (Other)
Overall Status
Active, not recruiting
CT.gov ID
NCT03837756
Collaborator
Aalborg University Hospital (Other), Odense University Hospital (Other), Rigshospitalet, Denmark (Other), Hvidovre University Hospital (Other), The Peter Doherty Institute for Infection and Immunity (Other), University of Utah (Other), Oslo University Hospital (Other)
47
Enrollment
8
Locations
4
Arms
45.8
Anticipated Duration (Months)
5.9
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease Intervention/Treatment Phase
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
47 participants
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+10-1074Participants 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
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.
Actual Study Start Date :
May 6, 2019
Anticipated Primary Completion Date :
Jul 1, 2022
Anticipated Study Completion Date :
Feb 28, 2023

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Arm A: Placebo/Placebo

This arm will receive placebo (sterile saline) for both Lefitolimod and 3BNC117 + 10-1074.

Drug: Saline
Placebo
Active Comparator: Arm B: Lefitolimod/Placebo

This arm will receive Lefitolimod and placebo (sterile saline) for 3BNC117 + 10-1074.

Drug: Saline
Placebo

Drug: Lefitolimod
A TLR9 agonist administered s.c. once weekly for 8 weeks.
Other Names:
  • MGN1703

    		•
    Active Comparator: Arm C: Placebo/3BNC117 + 10-1074

    This arm will receive 3BNC117 + 10-1074 and placebo (sterile saline) for Lefitolimod.

    Drug: Saline
    Placebo

    Drug: 3BNC117 and 10-1074
    Broadly neutralizing antibodies against HIV env administered two times with a 3 week interval.
    Other Names:
  • RUhumab-001 and RUhumab-002

    		•
    Active Comparator: Arm D: Lefitolimod/3BNC117 + 10-1074

    This arm will receive both Lefitolimod and 3BNC117 + 10-1074.

    Drug: Lefitolimod
    A TLR9 agonist administered s.c. once weekly for 8 weeks.
    Other Names:
  • MGN1703

    • Drug: 3BNC117 and 10-1074
    Broadly neutralizing antibodies against HIV env administered two times with a 3 week interval.
    Other Names:
  • RUhumab-001 and RUhumab-002

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Time to re-initiation of cART during analytical treatment interruption (ATI) [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.

    Secondary Outcome Measures

    1. Safety and Tolerability assessment measured by AEs, Adverse Reactions (ARs), SAEs, [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)

    2. Plasma HIV RNA doubling time [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)

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Dept. of Internal Medicine, University of Utah Salt Lake City Utah United States 84132
    2 Alfred Hospital and Monash University Melbourne Australia
    3 Dept. of Infectious Diseases, Aalborg University Hospital Aalborg Denmark 9000
    4 Dept. of Infectious Diseases, Aarhus University Hospital Aarhus Denmark 8200
    5 Dept. of Infectious Diseases, Rigshospitalet Copenhagen Denmark 2100
    6 Dept. of Infectious Diseases, Amager and Hvidovre Hospitals Hvidovre Denmark 2650
    7 Dept. of Infectious Diseases, Odense University Hospital Odense Denmark 5000
    8 Oslo University Hospital Oslo Norway

    Sponsors and Collaborators

    • University of Aarhus
    • 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

    • Principal Investigator: Ole S Søgaard, MD PhD, Aarhus University Hospital

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    University of Aarhus
    ClinicalTrials.gov Identifier:
    NCT03837756
    Other Study ID Numbers:
    • TITAN-001
    • 2018-001165-16
    • AGR-2016-8833
    First Posted:
    Feb 12, 2019
    Last Update Posted:
    Mar 31, 2022
    Last Verified:
    Apr 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    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
    Additional relevant MeSH terms:
    Infections

    Study Results

    No Results Posted as of Mar 31, 2022