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

NCT03837756 | Completed Phase 2 DMC FDA Drug

• 3 other identifiers: TITAN-0012018-001165-16AGR-2016-8833
• Study Type: interventional
• Target: 47
• Locations: 4 countries
• Sites: 8

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

Conditions

HIV-1-infection

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Safety and Tolerability assessment measured by AEs, Adverse Reactions (ARs), SAEs,

  Duration of the study

• Plasma HIV RNA doubling time

  Duration of ATI (up to 26 weeks)

Study Arms (4)

Arm A: Placebo/Placebo

PLACEBO COMPARATOR

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

Drug: Saline

Arm B: Lefitolimod/Placebo

ACTIVE COMPARATOR

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

Drug: Saline; Drug: Lefitolimod

Arm C: Placebo/3BNC117 + 10-1074

ACTIVE COMPARATOR

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

Drug: Saline; Drug: 3BNC117 and 10-1074

Arm D: Lefitolimod/3BNC117 + 10-1074

ACTIVE COMPARATOR

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

Drug: Lefitolimod; Drug: 3BNC117 and 10-1074

Interventions

Saline DRUG

Placebo

Arm A: Placebo/Placebo; Arm B: Lefitolimod/Placebo; Arm C: Placebo/3BNC117 + 10-1074

Lefitolimod DRUG

A TLR9 agonist administered s.c. once weekly for 8 weeks.

Also known as: MGN1703

Arm B: Lefitolimod/Placebo; Arm D: Lefitolimod/3BNC117 + 10-1074

3BNC117 and 10-1074 DRUG

Broadly neutralizing antibodies against HIV env administered two times with a 3 week interval.

Also known as: RUhumab-001 and RUhumab-002

Arm C: Placebo/3BNC117 + 10-1074; Arm D: Lefitolimod/3BNC117 + 10-1074

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)).

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Aarhus: lead
• Aalborg University Hospital: collaborator
• Odense University Hospital: collaborator
• Rigshospitalet, Denmark: collaborator
• Hvidovre University Hospital: collaborator
• The Peter Doherty Institute for Infection and Immunity: collaborator
• University of Utah: collaborator
• Oslo University Hospital: collaborator

Study Sites (8)

Dept. of Internal Medicine, University of Utah

Salt Lake City, Utah, 84132, United States

Location

Alfred Hospital and Monash University

Melbourne, Australia

Location

Dept. of Infectious Diseases, Aalborg University Hospital

Aalborg, 9000, Denmark

Location

Dept. of Infectious Diseases, Aarhus University Hospital

Aarhus, 8200, Denmark

Location

Dept. of Infectious Diseases, Rigshospitalet

Copenhagen, 2100, Denmark

Location

Dept. of Infectious Diseases, Amager and Hvidovre Hospitals

Hvidovre, 2650, Denmark

Location

Dept. of Infectious Diseases, Odense University Hospital

Odense, 5000, Denmark

Location

Oslo University Hospital

Oslo, Norway

Location

Related Publications (1)

• Gunst JD, Hojen JF, Pahus MH, Rosas-Umbert M, Stiksrud B, McMahon JH, Denton PW, Nielsen H, Johansen IS, Benfield T, Leth S, Gerstoft J, Ostergaard L, Schleimann MH, Olesen R, Stovring H, Vibholm L, Weis N, Dyrhol-Riise AM, Pedersen KBH, Lau JSY, Copertino DC Jr, Linden N, Huynh TT, Ramos V, Jones RB, Lewin SR, Tolstrup M, Rasmussen TA, Nussenzweig MC, Caskey M, Reikvam DH, Sogaard OS. Impact of a TLR9 agonist and broadly neutralizing antibodies on HIV-1 persistence: the randomized phase 2a TITAN trial. Nat Med. 2023 Oct;29(10):2547-2558. doi: 10.1038/s41591-023-02547-6. Epub 2023 Sep 11.

  PMID: 37696935 DERIVED

MeSH Terms

Interventions

Sodium Chloride; MGN1703

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Ole S Søgaard, MD PhD

  Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: The participant and all study personnel who directly interact with study participants are blinded to study arm designation.
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: February 7, 2019
• First Posted: February 12, 2019
• Study Start: May 6, 2019
• Primary Completion: July 1, 2022
• Study Completion: May 1, 2023
• Last Updated: May 23, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, 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

Locations

AU (1); NO (1); DK (5); US (1)