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

• ClinicalTrials.gov Identifier: NCT03837756
• Recruitment Status: Completed
• First Posted: February 12, 2019
• Last Update Posted: May 23, 2023
• Sponsor: University of Aarhus
• 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: February 7, 2019
• First Posted Date: February 12, 2019
• Last Update Posted Date: May 23, 2023
• Actual Study Start Date: May 6, 2019
• Actual Primary Completion Date: July 1, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Combining TLR9 Agonist With bNAbs for Reservoir Reduction and Immunological Control of HIV
• 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.
• 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: Interventional
• Study Phase: Phase 2

Study Design

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: HIV-1-infection

Intervention

• 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

• 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

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 30, 2022): 47
• Original Estimated Enrollment (submitted: February 8, 2019): 48
• Actual Study Completion Date: May 1, 2023
• Actual Primary Completion Date: July 1, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Denmark, Norway, United States

Administrative Information

• NCT Number: NCT03837756
• Other Study ID Numbers: 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

• 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

• Current Responsible Party: University of Aarhus
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Aarhus
• Original Study Sponsor: Same as current

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

Investigators

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

• PRS Account: University of Aarhus
• Verification Date: May 2023