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

Ming Jie Lee; Simon Collins; Daphne Babalis; Nicholas Johnson; Emanuela Falaschetti; A. Toby Prevost; Ambreen Ashraf; Milaana Jacob; Tom Cole; Lisa Hurley; Matthew Pace; Ane Ogbe; Maryam Khan; Panagiota Zacharopoulou; Helen Brown; Euan Sutherland; Hanna Box; Julie Fox; Steven Deeks; Jill Horowitz; Michel C. Nussenzweig; Marina Caskey; John Frater; Sarah Fidler

doi:10.1186/s13063-022-06151-w

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

Ming Jie Lee^*, Simon Collins, Daphne Babalis, Nicholas Johnson, Emanuela Falaschetti, A. Toby Prevost, Ambreen Ashraf, Milaana Jacob, Tom Cole, Lisa Hurley, Matthew Pace, Ane Ogbe, Maryam Khan, Panagiota Zacharopoulou, Helen Brown, Euan Sutherland, Hanna Box, Julie Fox, Steven Deeks, Jill HorowitzMichel C. Nussenzweig, Marina Caskey, John Frater, Sarah Fidler

^*Corresponding author for this work

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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.

Keywords: HIV, Primary infection, Broadly neutralising antibodies, Antiretroviral therapy, Virological remission, T cell Immunity

Original language	English
Article number	263
Number of pages	26
Journal	Trials
Volume	23
Issue number	1
Early online date	5 Apr 2022
DOIs	https://doi.org/10.1186/s13063-022-06151-w
Publication status	Published - 5 Apr 2022

Keywords

Antiretroviral therapy
Broadly neutralising antibodies
HIV
Primary infection
T cell Immunity
Virological remission

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Lee, M. J., Collins, S., Babalis, D., Johnson, N., Falaschetti, E., Prevost, A. T., 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., ... Fidler, S. (2022). 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. Trials, 23(1), Article 263. https://doi.org/10.1186/s13063-022-06151-w

Lee, Ming Jie ; Collins, Simon ; Babalis, Daphne et al. / 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. In: Trials. 2022 ; Vol. 23, No. 1.

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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",

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 thechallenges of COVID-19.Trial registration: The protocol is registered on Clinical.trials.gov and EudraCT and has approval from UK Ethics and MHRA.Keywords: HIV, Primary infection, Broadly neutralising antibodies, Antiretroviral therapy, Virological remission, T cell Immunity",

keywords = "Antiretroviral therapy, Broadly neutralising antibodies, HIV, Primary infection, T cell Immunity, Virological remission",

author = "Lee, {Ming Jie} and Simon Collins and Daphne Babalis and Nicholas Johnson and Emanuela Falaschetti and Prevost, {A. Toby} and Ambreen Ashraf and Milaana Jacob and Tom Cole and Lisa Hurley and Matthew Pace and Ane Ogbe and Maryam Khan and Panagiota Zacharopoulou and Helen Brown and Euan Sutherland and Hanna Box and Julie Fox and Steven Deeks and Jill Horowitz and Nussenzweig, {Michel C.} and Marina Caskey and John Frater and Sarah Fidler",

note = "Funding Information: The study was funded by the Bill and Melinda Gates Foundation. This research was supported by the NIHR Biomedical Research Centre based at Imperial College Healthcare National Health Service (NHS) Trust and Imperial College London. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS, or the Department of Health. SF is the chief investigator. JFr is the laboratory lead and protocol co-chair. MJL is the trial physician at Imperial College Clinical Trials Unit. SC is the community representative for people living with HIV. NJ, EF, and TP are the trial statisticians. DB, AA, MJ, and HBo are responsible for the management, coordination, and administration of the study. TC and LH manage the Imperial College Research Facility and designed the ICRF protocol for the randomisation and dosing of bNAbs/placebo infusions. HBr, MP, AO, MK, and PZ are responsible for the participant bNAb sensitivity screening, HIV immunology and viral laboratory endpoints assays. MJL, SF, JFo, and ES are clinical investigators responsible for recruitment. SD, JH, MN, and MC designed and developed the investigational medicinal products and contributed to the study design. All authors contributed to the writing and review of the manuscript. Authorship eligibility for this manuscript and all future manuscript output related to this study will be in accordance with the International Committee of Medical Journal Editors criteria for authorship (http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-of-authors-and-contributors.html). No professional writers were involved in this work or are intended to be involved in future manuscripts. This research is funded by the Bill and Melinda Gates Foundation, P.O. Box 23350, Seattle, WA 9810, USA. Funders have had a limited role in study design, and no role in data collection, analysis, decision to publish, or preparation of future manuscripts. Information concerning the study, patent applications, processes, scientific data, or other pertinent information is confidential and remains the property of the Sponsor. The investigator may use this information for the purposes of the study only. Permission from the Trial Management Group is necessary prior to disclosing any information relative to this study outside of the Trial Steering Committee. Any request by site investigators or other collaborators to access the study dataset must be formally reviewed by the TSC. Funding Information: This research is funded by the Bill and Melinda Gates Foundation, P.O. Box 23350, Seattle, WA 9810, USA. Funders have had a limited role in study design, and no role in data collection, analysis, decision to publish, or preparation of future manuscripts. Funding Information: This research was supported by the NIHR Biomedical Research Centre based at Imperial College Healthcare National Health Service (NHS) Trust and Imperial College London. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS, or the Department of Health. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = apr,

day = "5",

doi = "10.1186/s13063-022-06151-w",

language = "English",

volume = "23",

journal = "Trials",

issn = "1745-6215",

publisher = "BioMed Central",

number = "1",

}

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 2022, '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', Trials, vol. 23, no. 1, 263. https://doi.org/10.1186/s13063-022-06151-w

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. / Lee, Ming Jie; Collins, Simon; Babalis, Daphne et al.
In: Trials, Vol. 23, No. 1, 263, 05.04.2022.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - The RIO trial

T2 - 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

AU - Lee, Ming Jie

AU - Collins, Simon

AU - Babalis, Daphne

AU - Johnson, Nicholas

AU - Falaschetti, Emanuela

AU - Prevost, A. Toby

AU - Ashraf, Ambreen

AU - Jacob, Milaana

AU - Cole, Tom

AU - Hurley, Lisa

AU - Pace, Matthew

AU - Ogbe, Ane

AU - Khan, Maryam

AU - Zacharopoulou, Panagiota

AU - Brown, Helen

AU - Sutherland, Euan

AU - Box, Hanna

AU - Fox, Julie

AU - Deeks, Steven

AU - Horowitz, Jill

AU - Nussenzweig, Michel C.

AU - Caskey, Marina

AU - Frater, John

AU - Fidler, Sarah

N1 - Funding Information: The study was funded by the Bill and Melinda Gates Foundation. This research was supported by the NIHR Biomedical Research Centre based at Imperial College Healthcare National Health Service (NHS) Trust and Imperial College London. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS, or the Department of Health. SF is the chief investigator. JFr is the laboratory lead and protocol co-chair. MJL is the trial physician at Imperial College Clinical Trials Unit. SC is the community representative for people living with HIV. NJ, EF, and TP are the trial statisticians. DB, AA, MJ, and HBo are responsible for the management, coordination, and administration of the study. TC and LH manage the Imperial College Research Facility and designed the ICRF protocol for the randomisation and dosing of bNAbs/placebo infusions. HBr, MP, AO, MK, and PZ are responsible for the participant bNAb sensitivity screening, HIV immunology and viral laboratory endpoints assays. MJL, SF, JFo, and ES are clinical investigators responsible for recruitment. SD, JH, MN, and MC designed and developed the investigational medicinal products and contributed to the study design. All authors contributed to the writing and review of the manuscript. Authorship eligibility for this manuscript and all future manuscript output related to this study will be in accordance with the International Committee of Medical Journal Editors criteria for authorship (http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-of-authors-and-contributors.html). No professional writers were involved in this work or are intended to be involved in future manuscripts. This research is funded by the Bill and Melinda Gates Foundation, P.O. Box 23350, Seattle, WA 9810, USA. Funders have had a limited role in study design, and no role in data collection, analysis, decision to publish, or preparation of future manuscripts. Information concerning the study, patent applications, processes, scientific data, or other pertinent information is confidential and remains the property of the Sponsor. The investigator may use this information for the purposes of the study only. Permission from the Trial Management Group is necessary prior to disclosing any information relative to this study outside of the Trial Steering Committee. Any request by site investigators or other collaborators to access the study dataset must be formally reviewed by the TSC. Funding Information: This research is funded by the Bill and Melinda Gates Foundation, P.O. Box 23350, Seattle, WA 9810, USA. Funders have had a limited role in study design, and no role in data collection, analysis, decision to publish, or preparation of future manuscripts. Funding Information: This research was supported by the NIHR Biomedical Research Centre based at Imperial College Healthcare National Health Service (NHS) Trust and Imperial College London. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS, or the Department of Health. Publisher Copyright: © 2022, The Author(s).

PY - 2022/4/5

Y1 - 2022/4/5

N2 - 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 thechallenges of COVID-19.Trial registration: The protocol is registered on Clinical.trials.gov and EudraCT and has approval from UK Ethics and MHRA.Keywords: HIV, Primary infection, Broadly neutralising antibodies, Antiretroviral therapy, Virological remission, T cell Immunity

AB - 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 thechallenges of COVID-19.Trial registration: The protocol is registered on Clinical.trials.gov and EudraCT and has approval from UK Ethics and MHRA.Keywords: HIV, Primary infection, Broadly neutralising antibodies, Antiretroviral therapy, Virological remission, T cell Immunity

KW - Antiretroviral therapy

KW - Broadly neutralising antibodies

KW - HIV

KW - Primary infection

KW - T cell Immunity

KW - Virological remission

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Lee MJ, Collins S, Babalis D, Johnson N, Falaschetti E, Prevost AT et al. 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. Trials. 2022 Apr 5;23(1):263. Epub 2022 Apr 5. doi: 10.1186/s13063-022-06151-w