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

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.

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

Study Overview

• Status: Completed
• Conditions: HIV-1-infection
• Intervention / Treatment: Drug: Saline; Drug: Lefitolimod; Drug: 3BNC117 and 10-1074

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Melbourne, Australia
    • Alfred Hospital and Monash University
• Denmark
  • Aalborg, Denmark, 9000
    • Dept. of Infectious Diseases, Aalborg University Hospital
  • Aarhus, Denmark, 8200
    • Dept. of Infectious Diseases, Aarhus University Hospital
  • Copenhagen, Denmark, 2100
    • Dept. of Infectious Diseases, Rigshospitalet
  • Hvidovre, Denmark, 2650
    • Dept. of Infectious Diseases, Amager and Hvidovre Hospitals
  • Odense, Denmark, 5000
    • Dept. of Infectious Diseases, Odense University Hospital
• Norway
  • Oslo, Norway
    • Oslo University Hospital
• United States
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Dept. of Internal Medicine, University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to re-initiation of cART during analytical treatment interruption (ATI)	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.	Up to 26 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability assessment measured by AEs, Adverse Reactions (ARs), SAEs,	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)	Duration of the study
Plasma HIV RNA doubling time	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)	Duration of ATI (up to 26 weeks)

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Odense University Hospital; Oslo University Hospital; Rigshospitalet, Denmark; Hvidovre University Hospital; University of Utah; Aalborg University Hospital; The Peter Doherty Institute for Infection and Immunity
• Investigators: Principal Investigator: Ole S Søgaard, MD PhD, Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 6, 2019
• Primary Completion (Actual): July 1, 2022
• Study Completion (Actual): May 1, 2023

Study Registration Dates

• First Submitted: February 7, 2019
• First Submitted That Met QC Criteria: February 8, 2019
• First Posted (Actual): February 12, 2019

Study Record Updates

• Last Update Posted (Actual): May 23, 2023
• Last Update Submitted That Met QC Criteria: May 22, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections
• Other Study ID Numbers: TITAN-001; 2018-001165-16 (EudraCT Number); AGR-2016-8833 (Other Grant/Funding Number: Gilead Sciences, Inc.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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).
• IPD Sharing Time Frame: Data will become available following publication of the specific dataset with no planned end date.
• IPD Sharing 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 Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• 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