The RIO trial: rationale, design, and the role of community involvement in a randomised placebo-controlled trial of antiretroviral therapy plus dual long-acting HIV-specific broadly neutralising antibodies (bNAbs) in participants diagnosed with recent HIV infection-study protocol for a two-stage randomised phase II trial

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Title: The RIO trial: rationale, design, and the role of community involvement in a randomised placebo-controlled trial of antiretroviral therapy plus dual long-acting HIV-specific broadly neutralising antibodies (bNAbs) in participants diagnosed with recent HIV infection-study protocol for a two-stage randomised phase II trial
Authors: Lee, MJ
Collins, S
Babalis, D
Johnson, N
Falaschetti, E
Prevost, AT
Ashraf, A
Jacob, M
Cole, T
Hurley, L
Pace, M
Ogbe, A
Khan, M
Zacharopoulou, P
Brown, H
Sutherland, E
Box, H
Fox, J
Deeks, S
Horowitz, J
Nussenzweig, MC
Caskey, M
Frater, J
Fidler, S
Item Type: Journal Article
Abstract: Background: Antiretroviral therapy (ART) has led to dramatic improvements in survival for people living with HIV, but is unable to cure infection, or induce viral control off therapy. Designing intervention trials with novel agents with the potential to confer a period of HIV remission without ART remains a key scientific and community goal. We detail the rationale, design, and outcomes of a randomised, placebo-controlled trial of two HIV-specific long-acting broadly neutralising antibodies (bNAbs): 3BNC117-LS and 10-1074-LS, which target CD4 binding site and V3 loop respectively, on post-treatment viral control. Methods: RIO is a randomised, placebo-controlled, double-blinded prospective phase II study. Eligible individuals will have started ART within 3 months of primary HIV infection and have viral sequences that appear to be sensitive to both bNAbs. It will randomise 72 eligible participants 1:1 to the following arms via a two-stage design. In Stage 1, arm A participants are given dual long-acting (LS-variants) bNAbs infusions, followed by intensively monitored Analytical Treatment Interruption (ATI) (n = 36); in arm B, participants receive placebo infusions followed by ATI. The primary endpoint will be time to viral rebound within 36 weeks after ATI. Upon viral rebound, the participant and researcher are unblinded. Participants in arm A recommence ART and complete the study. Participants in arm B are invited to restart ART and enroll into Stage 2 where they will receive open-label LS bNAbs, followed by a second ATI 24 weeks after. Secondary and exploratory endpoints include adverse events, time to undetectable viraemia after restarting ART, immunological markers, HIV proviral DNA, serum bNAb concentrations in blood, bNAb resistance at viral rebound, and quality of life measures. Discussion: The two-stage design was determined in collaboration with community involvement. This design allows all participants the option to receive bNAbs. It also tests the hypothesis that bNAbs may drive sustained HIV control beyond the duration of detectable bNAb concentrations. Community representatives were involved at all stages. This included the two-stage design, discussion on the criteria to restart ART, frequency of monitoring visits off ART, and reducing the risk of onward transmission to HIV-negative partners. It also included responding to the challenges of COVID-19. Trial registration: The protocol is registered on Clinical.trials.gov and EudraCT and has approval from UK Ethics and MHRA.
Issue Date: 5-Apr-2022
Date of Acceptance: 4-Mar-2022
URI: http://hdl.handle.net/10044/1/96608
DOI: 10.1186/s13063-022-06151-w
ISSN: 1745-6215
Publisher: BioMed Central
Journal / Book Title: Trials
Volume: 23
Issue: 1
Copyright Statement: © The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Sponsor/Funder: Bill and Melinda Gates Foundation
Funder's Grant Number: OPP1210792
Keywords: Science & Technology
Life Sciences & Biomedicine
Medicine, Research & Experimental
Research & Experimental Medicine
HIV
Primary infection
Broadly neutralising antibodies
Antiretroviral therapy
Virological remission
T cell Immunity
Antiretroviral therapy
Broadly neutralising antibodies
HIV
Primary infection
T cell Immunity
Virological remission
Broadly Neutralizing Antibodies
COVID-19
Clinical Trials, Phase II as Topic
Community Participation
HIV Antibodies
HIV Infections
HIV-1
Humans
Prospective Studies
Quality of Life
Randomized Controlled Trials as Topic
SARS-CoV-2
Treatment Outcome
Humans
HIV-1
HIV Infections
HIV Antibodies
Treatment Outcome
Prospective Studies
Quality of Life
Randomized Controlled Trials as Topic
Clinical Trials, Phase II as Topic
Community Participation
Broadly Neutralizing Antibodies
COVID-19
SARS-CoV-2
Science & Technology
Life Sciences & Biomedicine
Medicine, Research & Experimental
Research & Experimental Medicine
HIV
Primary infection
Broadly neutralising antibodies
Antiretroviral therapy
Virological remission
T cell Immunity
General & Internal Medicine
Cardiovascular System & Hematology
1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
Publication Status: Published
Open Access location: https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-022-06151-w
Article Number: ARTN 263
Appears in Collections:Department of Infectious Diseases
School of Public Health



This item is licensed under a Creative Commons License Creative Commons