Clinical trial NCT03837756: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-1-infection
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: Aalborg University Hospital
name: Odense University Hospital
name: Rigshospitalet, Denmark
name: Hvidovre University Hospital
name: The Peter Doherty Institute for Infection and Immunity
name: University of Utah
name: Oslo University Hospital
First posted: 2019-02-12
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
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
Primary purpose: TREATMENT

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


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

Primary outcomes:
measure: Time to re-initiation of cART during analytical treatment interruption (ATI)
timeFrame: Up to 26 weeks.
Secondary outcomes:
measure: Safety and Tolerability assessment measured by AEs, Adverse Reactions (ARs), SAEs,
timeFrame: Duration of the study
measure: Plasma HIV RNA doubling time
timeFrame: Duration of ATI (up to 26 weeks)
Other outcomes:
Locations:
city: Salt Lake City
country: United States
facility: Dept. of Internal Medicine, University of Utah
state: Utah
city: Melbourne
country: Australia
facility: Alfred Hospital and Monash University
city: Aalborg
country: Denmark
facility: Dept. of Infectious Diseases, Aalborg University Hospital
city: Aarhus
country: Denmark
facility: Dept. of Infectious Diseases, Aarhus University Hospital
city: Copenhagen
country: Denmark
facility: Dept. of Infectious Diseases, Rigshospitalet
city: Hvidovre
country: Denmark
facility: Dept. of Infectious Diseases, Amager and Hvidovre Hospitals
city: Odense
country: Denmark
facility: Dept. of Infectious Diseases, Odense University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital
Study officials:
affiliation: Aarhus University Hospital
name: Ole S Søgaard, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: