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 (TITAN)

Phase 1

• Conditions: HIV infection; MedDRA version: 20.1Level: LLTClassification code 10073675Term: HIV infection CDC category unspecifiedSystem Organ Class: 100000004862; Therapeutic area: Diseases [C] - Virus Diseases [C02]

• Registration Number: EUCTR2018-001165-16-DK
• Lead Sponsor: Department of infectious Diseases, Aarhus University Hospital

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2018-09-24
• Last Update Posted: 8 March 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 48

Inclusion Criteria

- Documented HIV-1 infection
- ?Adults age 18-65 year
- On antiretroviral therapy for a minimum of 18 months
- CD4+ 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)
- Viral reservoir sensitivity to 3BNC117 and 10-1074 (analyzed using the PhenoSense HIV mAb Assay, Monogram Biosciences).
- Able to give informed consent
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 48
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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:
o Hepatic transaminases (AST or ALT) =3 x upper limit of normal (ULN)
o Serum total bilirubin =3 ULN
o Estimated glomerular filtration rate (eGFR) =50 mL/min (based on serum creatinine)
o Platelet count =100 x109/L
o Absolute neutrophil count =1x109/L
- Hepatitis B or C infection as indicated by the presence of hepatitis B surface antigen or hepatitis C virus RNA in blood
- History of:
o 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 with a positive pregnancy test as determined by a positive urine beta- human chorionic gonadotropin test during screening or women of child bearing potential who are unwilling or unable to use an acceptable method of non-estrogen containing contraception (according to the Danish Medicines Agency guidelines) to avoid pregnancy during the study
- 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 & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To compare the effects of a TLR9 agonist (Lefitolimod) and/or administration of potent bNAbs (3BNC117 and 10-1074) on time to viral rebound during analytical treatment interruption. ;Secondary Objective: - To evaluate the safety and tolerability of the Investigational Medicinal Products (IMP)s<br>- To compare viral load (plasma HIV-1 RNA) kinetics (e.g. doubling time) between study arms <br>- To evaluate the effect of the IMPs on the amount of HIV-1 DNA in CD4+ T cells<br>- To evaluate the effect of the IMPs on the functional HIV-1 reservoir in CD4+ T cells<br>- To compare HIV-specific immunity, T cell phenotype, immune activation and cytokine production between study arms;Primary end point(s): Time from the day of cART cessation to the day of the last of three consecutive plasma HIV-1 RNA measurements >10,000 copies/mL.;Timepoint(s) of evaluation of this end point: The following visits: 5-9 and 10a-10j

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1. Safety evaluation, as measured by Adverse Events (AE), Adverse Reactions (ARs), Serious Adverse Events (SAE), Serious Adverse Reactions (SAR) and CD4 cell change from baseline to end of study<br>2. ?Rebound virus kinetics including time to >50 copies/mL and >1,000 copies/mL as well as doubling time during the analytical treatment interruption as measured by plasma HIV-1 RNA (Cobas TaqMan; Lower limit of quantitation 20 copies/mL) <br>3. To compare time without ART between study arms;Timepoint(s) of evaluation of this end point: 1. All visits<br>2. During the analytical treatment interruption (visit 5-9 and 10a-10j)<br>3. During the analytical treatment interruption (visit 5-9 and 10a-10j)