Clinical trial NCT04319367: A Randomised Placebo Controlled Trial of ART Plus Dual Long-acting HIV-specific Broadly Neutralising Antibodies (bNAbs).
Official title: A Randomised Placebo Controlled Trial of ART Plus Dual Long-acting HIV-specific Broadly Neutralising Antibodies (bNAbs) vs ART Plus Placebo in Treated Primary or Early Stage HIV Infection on Viral Control Off ART
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: HIV/AIDS and Infections
Lead sponsor: Imperial College London
Sponsor class: OTHER
Collaborators: name: Bill and Melinda Gates Foundation
name: University of Oxford
name: Rockefeller University
First posted: 2020-03-24
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RIO is a placebo-controlled double-blinded two arm prospective phase II randomised controlled trial . This study will test the use of broadly neutralising antibodies (bNAbs) in participants with treated primary HIV infection (PHI).

Detailed description: This study proposes a trial of a novel combination of long-acting broadly neutralising antibodies in participants initiating ART early after HIV acquisition, during primary HIV infection (PHI). The aim of this study is to investigate the effect of dual long-acting versions of bNABs (3BNC117-LS and 10-1074-LS) in a randomised clinical trial powered to answer the question whether these bNAbs are effective at controlling HIV replication in the absence of ART.

The study aims to enrol 72 individuals across multiple UK collaborating clinical centres. Participants will have been previously diagnosed with primary HIV-1 infection, will have started ART during early phase of Primary HIV infection, and who have remained on suppressive ART without interruption for at least 12 months. Study duration will vary by participant, depending on the time to viral rebound.

The results from this trial will demonstrate whether or not the combination of two long-acting (LS) broadly neutralising antibodies, 3BNC117-LS and 10-1074-LS, will prevent HIV viral rebound after stopping antiretroviral therapy for an extended period of time in adults living with HIV who initiated ART during early HIV infection.

Eligibility criteria: Inclusion Criteria:

* Aged ≥18 to ≤60 years old at screening
* Able to give informed written consent including consent to long-term follow-up
* Willing and able to comply with visit schedule and provide blood sampling
* Started ART within a maximum of six months of estimated time of primary infection. Estimated time of primary infection will be based on one of the following six criteria

  1. Positive HIV-1 serology within a maximum of 24 weeks of a documented negative HIV-1 serology test result (can include point of care test (POCT) using blood for both tests) - The estimated time of infection is taken as the midpoint between the dates of the negative HIV-1 serology or POCT test and positive HIV test at diagnosis
  2. The date of a positive p24 antigen result with or without a negative HIV antibody test depending on local laboratory reports
  3. The date of a negative antibody test with either detectable HIV RNA or proviral DNA
  4. PHE RITA test algorithm reported as "Incident" confirming the HIV-1 antibody avidity is consistent with recent infection (within the preceding 16 weeks). The estimated date of infection is assumed to be two months prior to the date of the incident test result. Asanté™ HIV-1 Rapid Recency® Assay can also be used for recency testing.
  5. The date of a weakly reactive or equivocal 4th generation HIV antibody antigen test
  6. Equivocal or reactive antibody test with \<4 bands on western blot
* OR, started ART in early stage infection, with nadir CD4 \> 500 cells and stable on ART with suppressed undetectable HIV VL 'target not detected' (TND) using local assays for \>= 1 years (a single viral load measurement \> 50 but \< 500 copies/mL during this time period is allowable)
* No evidence of viral insensitivity to either 10-1074 or 3BNC117 antibodies based on proviral sequencing algorithm
* HBV sAg or HBV DNA, HCV Ag or HCV RNA negative or anti-core antibody negative
* No significant co-morbidities
* Nadir CD4 \> 250 cells/μL for those diagnosed with confirmed PHI
* Current CD4 count \> 500 cells/µL or CD4:CD8 ratio \>1
* On integrase inhibitor (INSTI) or boosted protease inhibitor (PI) based regimen at time of randomisation, if previously on non-nucleoside reverse transcriptase inhibitor (NNRTI) has switched at least 4 weeks prior to randomisation
* Adequate haemoglobin (Hb≥12 g/dL for males, ≥11 g/dL for females)
* Weight ≥50 kg
* Have been vaccinated against coronavirus (COVID-19), at least 4 weeks prior to enrolment
* Females capable of becoming pregnant\* must agree to use hormonal contraception, intrauterine device, intrauterine hormone-releasing system, or to complete abstinence\*\* from at least two weeks before the first bNAb/placebo infusion and for 20 months after the last bNAb infusion.

Exclusion Criteria:

* Previous ischaemic heart disease (ST or non-ST myocardial infarction, Q3-risk \> 20, stable angina, unstable angina, stroke)
* Any current or past history of malignancy, excluding squamous cell skin cancers
* Concurrent opportunistic infection or other comorbidity or comorbidity likely to occur during the trial e.g. malabsorption syndromes, autoimmune disease
* Any contraindication to receipt of BHIVA recommended combination antiretrovirals
* HTLV-1 co-infection
* SARS-Cov-2 infection confirmed by SARS-Cov-2 RT-PCR positive result from nasopharyngeal swab up to 72 hours prior to randomisation/dosing visit (as per current local NHS guidelines or until such guidelines/practices are no longer applicable/relevant)
* Individuals at high risk from severe COVID-19 disease who maybe defined in accordance with NHSE guidance as vulnerable and shielded (as per the view of participant's physician)
* Current or planned systemic immunosuppressive therapy (inhaled or topical corticosteroids are allowed)
* Participation in any other clinical trial of an experimental agent or any non-interventional study where additional blood draws are required; participation in an observational studies is permitted
* History of anaphylaxis or severe adverse reaction to antibody infusions, or hypersensitivity to 3BNC117-LS or 10-1074-LS or to or any constituent products or excipients thereof
* Treatment with IV immunoglobulin or other monoclonal antibody treatments planned during the duration of the trial
* Clinically significant abnormal blood test results at screening including

  1. Moderate to severe hepatic impairment as defined by significant liver impairment with evidence of advanced fibrosis or cirrhosis with decompensation
  2. ALT \>5 x ULN
  3. eGFR \<60
  4. uPCR \>30 mg/mmol
  5. INR \>1.5
* Physical examination findings: Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination and/or vital signs that the investigator believes is a preclusion from enrolment into the study.
* Active alcohol or substance use that, in the Investigator's opinion, will prevent adequate adherence with study requirements
* Insufficient venous access that will allow scheduled blood draws as per protocol
* Concern regarding likelihood of participant not taking precautions to prevent HIV transmission during treatment interruption period
* Pregnancy or breastfeeding

Primary outcomes:
measure: Time to viral rebound within 20 weeks after initial ATI
timeFrame: up to 20 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Aarhus
country: Denmark
facility: Aarhus University Hospital
city: Brighton
country: United Kingdom
facility: University Hospitals Sussex NHS Foundation Trust
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: London
country: United Kingdom
facility: Imperial College NHS Healthcare Trust
city: London
country: United Kingdom
facility: Barts Health NHS Trust
city: London
country: United Kingdom
facility: Chelsea And Westminster Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Foundation Trust
city: London
country: United Kingdom
facility: Mortimer Market CNWL Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust
city: London
country: United Kingdom
facility: St Georges Hospital NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: Manchester University NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals
Study officials:
affiliation: Imperial College London
name: Sarah Fidler, MBBS, Ph.D
role: PRINCIPAL_INVESTIGATOR
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