Evaluation of Antiretroviral Therapy Combined with 10-1074-LS and Teropavimab in Primary or Early HIV Infection: A Randomized, Placebo-Controlled Trial
- Trial ID
- 2024-514564-13-00
- Protocol
- 19IC5249
Trial statistics
Diseases & Conditions
Objectives
The primary objective of the RIO Trial is to determine the **efficacy** of dual broadly neutralising antibody (bNAb) infusion of 10-1074-LS and 3BNC117-LS in sustaining virological control within 20 weeks following initial analytical treatment interruption (ATI) compared with placebo infusion. This is clinically relevant as it explores a potential strategy for maintaining viral suppression in individuals with primary or early-stage **HIV** infection, potentially reducing the need for continuous antiretroviral therapy (ART).
Secondary objectives include:
- Evaluating the safety of dual bNAb infusion of 10-1074-LS and 3BNC117-LS.
- Determining the role of viraemia at the time of bNAb administration in subsequent virological control.
- Assessing the contribution of circulating bNAbs to virological control compared with a sustained impact following antibody elimination.
- Documenting the experiences and determining the attitudes of participants towards the interventions and the treatment interruption.
Participants
The clinical trial involves a total of **66 participants** diagnosed with **HIV**. The study population includes both male and female subjects, aged between **18 to 60 years**. Participants are required to have a current CD4 count greater than 500 cells/μl or a CD4:CD8 ratio greater than 1.0, and must be on an integrase inhibitor or boosted protease inhibitor-based regimen at the time of randomization. The trial excludes individuals with significant co-morbidities and those with evidence of viral insensitivity to the antibodies 10-1074 or 3BNC117. Participants must have been vaccinated against COVID-19 at least four weeks prior to enrollment. Lifestyle considerations include maintaining a weight of at least 50 kg and, for females capable of becoming pregnant, agreeing to use effective contraception or complete abstinence during the study period. The trial does not involve a vulnerable population, and all participants must be willing and able to comply with the visit schedule and provide blood samples as required.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of dual **broadly neutralizing antibodies** (bNAbs) infusion, specifically 10-1074-LS and 3BNC117-LS, in maintaining virological control in individuals with **HIV** following an analytical treatment interruption (ATI). This is a randomized, placebo-controlled trial with a double-blind design, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The trial is expected to conclude by March 31, 2027, with recruitment having commenced on April 28, 2023.
Participants will undergo a series of study visits, beginning with an inclusion visit to assess eligibility based on criteria such as age, CD4 count, and current antiretroviral therapy (ART) regimen. The inclusion visit will also involve obtaining informed consent and ensuring compliance with the study protocol. Following randomization, participants will receive either the bNAbs or placebo via **intravenous infusion**. The primary endpoint is the time to viral rebound within 20 weeks post-ATI, while secondary endpoints include safety assessments, CD4 T cell counts, and the duration of viral remission.
Study visits will occur at regular intervals, including weeks 12, 20, 32, and 44 after randomization, with additional visits every 12 weeks until the end of the study. These visits will involve clinical assessments, blood sampling, and monitoring for adverse events. The end-of-study visit will mark the conclusion of participant involvement, which is anticipated to last approximately four years. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety.
Treatment
The clinical trial involves the administration of **Sodium Chloride 0.9% Intravenous Infusion BP** as a non-experimental treatment. This solution, manufactured by Baxter Healthcare Ltd., is utilized as a placebo in the study. It is a **solution for infusion** with a pharmaceutical form of **intravenous infusion BP**. The active substance is **sodium chloride**, a chemical compound, and the maximum daily dose is 150 mg/ml. The administration route is intravenous infusion, and the treatment period is limited to one day.
The experimental treatment includes the administration of **10-1074-LS**, a solution for injection developed by INSERM-ANRS. This investigational product is a protein-based substance, specifically a broadly neutralizing antibody (bNAb) targeting HIV. The pharmaceutical form is a solution for injection, and it is administered via intravenous infusion. The maximum daily dose is 150 mg/ml, with a treatment period of one day. The study aims to evaluate the efficacy of this bNAb in sustaining virological control in HIV-infected individuals.
Another experimental treatment in the trial is **3BNC117-LS**, also a solution for injection produced by INSERM-ANRS. This investigational product is a humanized IgG1-kappa monoclonal antibody against the HIV-1 gp120 envelope glycoprotein, specifically targeting the CD4 binding site. The pharmaceutical form is a solution for injection, administered through intravenous infusion. The maximum daily dose is 150 mg/ml, with a treatment period of one day. This bNAb is evaluated for its potential to maintain virological control in the context of HIV infection.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the **time to viral rebound** within 20 weeks after the initial analytical treatment interruption (ATI). This will be measured to determine the efficacy of dual broadly neutralizing antibodies (bNAbs) infusion of 10-1074-LS and 3BNC117-LS in sustaining virological control compared to placebo infusion.
Secondary endpoints include several parameters: safety, defined by the occurrence of adverse events and serious adverse events by group; the length of time the viral load remains undetectable in days following ATI; CD4 T cell counts and CD4:CD8 ratios at specified weeks post-randomization; the percentage of participants with undetectable viral load at various time points; quantitation of proviral HIV DNA and cell-associated RNA; duration of remission by different viral load parameters; time to re-starting antiretroviral therapy (ART) after ATI; time to undetectable HIV viral load after re-starting ART; presence of ART in blood during ATI; bNAb levels in blood; bNAb resistance/sensitivity; and HIV quality of life measures.
These efficacy parameters will be collected and analyzed at specific time points, including weeks 12, 20, 32, and 44 after randomization, and every 12 weeks until the end of the study. The trial is designed to provide comprehensive data on the efficacy of the treatment regimen in maintaining viral control and improving patient outcomes in the context of primary or early-stage HIV infection.
Inclusion and Exclusion 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 or Early stage infection. Estimated time of primary infection will be based on one of the following six criteria: a. 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. b. The date of a positive p24 antigen result with or without a negative HIV antibody test depending on local lab reporting c. The date of a negative antibody test with either detectable HIV RNA or proviral DNA d. 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. e. The date of a weakly reactive or equivocal 4th generation HIV antibody antigen test f. The date of an 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 >1.0
- On integrase inhibitor (INSTI) or boosted protease inhibitor (bPI) 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 ≥ 50kg
- 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/placebo 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 may be 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 and 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 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 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 a. Moderate to severe hepatic impairment as defined by significant liver impairment with evidence of advanced fibrosis or cirrhosis with decompensation b. ALT >5 x ULN c. eGFR <60 d. uPCR >30 mg/mmol e. 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 28 Apr 2023 | 2 |
 Denmark | Recruiting | 28 Apr 2023 | 6 |
 Germany | Recruiting | 28 Apr 2023 | 3 |
 The Netherlands | Recruiting | 28 Apr 2023 | — |
 Spain | Recruiting | 28 Apr 2023 | 5 |
 Sweden | Recruiting | 28 Apr 2023 | 2 |
| Netherlands | — | — | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
10-1074-LS | Test | SOLUTION FOR INJECTION | INTRAVENOUS INFUSION | 150 | 1 | PRD11221895 |
3BNC117-LS | Test | SOLUTION FOR INJECTION | INTRAVENIOUS INFUSION | 150 | 1 | PRD11221887 |
Sodium Chloride 0.9% Intravenous Infusion BP | Placebo | INTRAVENOUS INFUSION BP | INTRAVENOUS INFUSION | 150 | 1 | PRD382062 |