WHO R&D Blueprint

COVID-1

Informal consultation on the potential

role of chloroquine in the clinical

management of COVID 19 infection

WHO reference number
© World Health Organization 2020. All rights reserved.

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Geneva, Switzerland, 13th March 2020



COVID-19: Therapeutics Working Group consultation on the potential role of chloroquine in clinical management



Table of Contents

INTRODUCTION…………………………………………………………………………………………………………………………. 3 OBJECTIVES OF THE CONSULTATION ……………………………………………………………………………………… 3 AGENDA ITEMS…………………………………………………………………………………………………………………………. 4 PARTICIPANTS………………………………………………………………………………………………………………………….. 4 OVERVIEW OF THE DELIBERATIONS ………………………………………………………………………………………… 7 CONCLUSIONS: ………………………………………………………………………………………………………………………… 9 PROPOSED NEXT STEPS ………………………………………………………………………………………………………… 10

    



COVID-19: Therapeutics Working Group consultation on the potential role of chloroquine in clinical management



Appropriate WHO Confidentiality Undertakings were signed and submitted to WHO by all participating experts

INTRODUCTION

Currently, there are no therapeutic agents licensed and available for the treatment of COVID 19. On the 27th of January, WHO convened a meeting of experts to examine the available evidence and prioritize promising therapeutic agents for further evaluation in the ongoing outbreak. The expert panel recommended the direct-acting antiviral agent, Remdesivir, and the protease inhibitor, Lopinavir/ritonavir for evaluation in randomized clinical trials. At the time, there was insufficient evidence to support chloroquine’s further investigation. However, chloroquine has received significant attention in countries as a potentially useful prophylactic and curative agent, prompting the need to examine emerging evidence to inform a decision on its potential role. At the time of convening this meeting, about 500 clinical trials were ongoing in China, with at least 13 evaluating chloroquine’s efficacy.

This expert consultation convened clinical care partners and experts in the field of randomized controlled trials (RCTs), preclinical studies, and chloroquine pharmacology for evaluating newly available evidence.

OBJECTIVES OF THE CONSULTATION

The objectives of this consultation were:

1. Toreviewandcriticallyappraisetheexistingevidenceregardingchloroquine and hydroxychloroquine;

    

COVID-19: Therapeutics Working Group consultation on the potential role of chloroquine in clinical management



2. To decide on the further evaluation of chloroquine- based on currently available evidence – in humans infected with SARS-CoV-2 to reduce mortality and disease progression.

This Consultation represents an initial step towards the evaluation of chloroquine against the SARS-CoV-2. There are ongoing efforts to identify additional candidate therapeutics and to expand the body of evidence available on each of the candidates.

Agenda items

• Introduction and roll-call.

• Update on current evidence on chloroquine.

• Conclusions and next steps.
Participants
Chair: Marco Cavaleri

    

Name

Position

Institutional Affiliation

Marco Cavaleri

Head of Anti-infectives and Vaccines

European Medicines Agency, Netherlands

Eric Pelfrene

Office of Anti-infectives and Vaccines

European Medicines Agency, Netherlands

Sina Bavari

Independent Consultant

Karl Erlandson

Interdisciplinary Scientist

Biomedical Advanced Research and Development Authority,

COVID-19: Therapeutics Working Group consultation on the potential role of chloroquine in clinical management



Name

Position

Institutional Affiliation

US Department of Health and Human Services

Yaseen Arabi

Chairman, Intensive Care Department

King Saud bin Abdulaziz



University for Health



Sciences, Riyadh, Saudi



Arabia



John Marshall

Co-Director, Critical Illness and Injury



Research Centre, St Michael Hospital,



Canada



Co-Director, Critical Illness Research, St Michaels Hospital

Ross Upshur

Director, Primary Care Research Unit, Sunnybrook and Women’s College Health Sciences Centre, Canada Research Chair in Primary Care Research

University of Toronto, Canada

John Beigel

Associate Director for Clinical Research

NIH, USA

Thomas Fleming

Professor of Biostatistics

University of Washington

John Farley

Director, Office of Infectious Diseases

FDA, USA

Philip Krause

Deputy Director CBER/OVRR

FDA, USA

Regine Lehnert

Doctor

Federal Institute for Drugs and Medical Devices, Germany

Monalisa Chatterji

Senior Program Officer, Discovery & Translational Science

Bill & Melinda Gates Foundation, USA

Michael Kaufmann

Manager- Advisory

PriceWaterhouse Cooper,USA

    

COVID-19: Therapeutics Working Group consultation on the potential role of chloroquine in clinical management



Name

Position

Institutional Affiliation

David Vaughn

Senior Program Officer

Bill & Melinda Gates Foundation, USA

Ken Duncan

Discovery & Translational Sciences team Lead

Bill & Melinda Gates Foundation, USA

Nicholas White

Professor of Tropical Medicine

Mahidol University, Thailand

Robert Walker

Chief Medical Officer and Director, Division of Clinical Development

Biomedical Advanced Research and Development Authority, US Department of Health and Human Services

Julia Tree

Microbiological Services

Public Health England

Scott Miller

Deputy Director, medical interventions

Bill & Melinda Gates Foundation, USA

Frederick Hayden

Professor Emeritus, Medicine: Infectious Diseases and International Health

University of Virginia

Jacqueline Kirchner

Senior Program Officer

Bill & Melinda Gates Foundation, USA

Elizabeth Higgs

Global health science advisor for the Division of Clinical Research (DCR)

NIH. USA

Helen Rees

Professor, Wits Reproductive Health and HIV Institute

University of Witwatersrand, South Africa

Matthew Frieman

Associate Professor, Microbiology and Immunology

University of Maryland School of Medicine

    

COVID-19: Therapeutics Working Group consultation on the potential role of chloroquine in clinical management



Other invited experts but only those listed in the table above participated: Hilary Marston (US NIH), Philip Coyne (US PHS), Sina Bavari (Independent consultant), Marco Cavaleri (EMA), Jeremy Farrar (Wellcome Trust, UK), Markus Mueller (University of Wien), Bin Du (Peking), Yi Guan (Hong Kong); Wannian Liang (MOH China), Bruno Lina (France), Claire Madelaine William Dowling (CEPI, USA)

WHO Secretariat: Alejandro Costa, Janet Diaz, Ana Maria Henao-Restrepo, Marie- Pierre Preziosi, Vasee Moorthy, Ximena Riveros Balta, Kolawole Salami, Emer Cooke, Deusdedit Mubangizi, Matthias Mario Stahl, and Pierre Gsell.

OVERVIEW OF THE DELIBERATIONS

Overall considerations

• Chloroquine has shown in vitro activity against some viruses, including chikungunya, dengue, and influenzas, but in vivo studies in animal models and randomized controlled trials (RCTs) in humans have been largely disappointing. Chloroquine pre-treatment (prophylaxis) was associated with an enhancement of viral replication and disease with chikungunya in NHPs due to delays in immune responses. Chloroquine treatment of chikungunya infection in humans did not affect viremia or clinical parameters during the

      

acute stage of the disease. However, it reduced levels of C-reactive Protein (CRP) and specific cytokines.



• Chloroquine is reasonably active in vitro against SARS-CoV, MERS CoV, and SARS-CoV-2, the causative agent of COVID 19. In vitro studies have shown antiviral activity with an EC50 of 1.0 -1.5 μmolar in Vero cells, but it is unclear how this translates into activity in respiratory epithelial cells and in vivo. BMGF has developed a model of chloroquine penetration into tissues for malaria. This model indicates that the concentration seen in the plasma is similar to that achieved in the lungs, and even when the concentration is below the IC50 in the plasma, there could be the desired reasonable concentration in the lungs. This model is, however, not validated. Chloroquine also has the attraction of

COVID-19: Therapeutics Working Group consultation on the potential role of chloroquine in clinical management



being relatively safe, well-tolerated, and cheap to produce. Hence, it is essential to explore further its possibilities as a therapeutic agent for COVID 19.

• The selective index of chloroquine and chloroquine diphosphate for SARS-CoV in African Green Monkey kidney cells was low, ranging from 5-13 for a laboratory strain and 2-20-fold for four clinical strains (Barnard, 2006) and this

should be a cause for concern. Also, intraperitoneal delivery of chloroquine starting 4 hours before viral challenge did reduce lung titres of SARS-CoV.

• A recent in vitro study shows hydroxychloroquine to have greater antiviral activity against SARS CoV-2 in Vero cell lines than chloroquine. However, another recently published RCT study in China with hydroxychloroquine involving 30 COVID 19 patients with mild to moderate symptoms shows no significant reduction in time to clinical improvement or viral clearance in the hydroxychloroquine arm compared to the conventional therapy control group.

• An experiment in murine models with SARS-CoV (MA15) in BALB/c mice and MERS-CoV (in the Ad5/hDPP4 mouse model) at the University of Maryland School of Medicine, involving the daily administration of 40ml/kg and 80 ml/kg dose of chloroquine resulted in protection from weight loss, lung pathology, and clinical symptoms but no reduction in viral titters. Further experiments to delineate the antiviral and immunomodulating effects are ongoing.

• A placebo-controlled trial of longer-term chloroquine prophylaxis is currently being planned and could commence as early as two weeks. The study would involve 20,000 healthcare workers. For this study, chloroquine will be tested daily as used in the treatment of rheumatoid arthritis. A loading dose of 10 mg base/kg, followed by 100 mg daily, will be taken for three months or until they are diagnosed with COVID-19. Higher doses would be considered for treatment, i.e., 10mg/kg base, followed by 5mg/kg twice daily for seven days. BMGF is also developing a post-exposure prophylaxis clinical trial protocol for hydroxychloroquine that would be made available next week. No prophylactic trials involving chloroquine have been reported from in China.

    

COVID-19: Therapeutics Working Group consultation on the potential role of chloroquine in clinical management





Conclusions:

• It is expected that there would be some results from animal model studies

involving chloroquine in the coming days. However, the decision about the global clinical trial protocol needs to be made ASAP, andWHOwould appreciate the possibility of taking this decision from this panel discussion if possible. WHO to contact colleagues from NIH and animal model group to determine the type of animal studies ongoing and the dose of chloroquine being used.

• Both post-exposure prophylaxis and longer-term prophylactic use of hydroxychloroquine & chloroquine should also be considered.

• BMGF and other global health partners are developing protocols for this prophylactic use. Since WHO also has a prophylaxis protocol, and all must work in unison and avoid duplicate efforts. WHO has proposed a TC involving partners working on prophylaxis to have a common approach. The date and time will be communicated soon by WHO.

• There are more than 20 treatment studies ongoing in China utilizing

chloroquine, and it would be better to get these data, provided studies design allows interpretation of data, rather than wait for animal studies from the NIH. WHO is engaging with Chinese colleagues at the mission in Geneva and have received assurances of improved collaboration; however, no data has been shared regarding the chloroquine studies. It should be noted that the RCTs in China are small and may not be powered enough to reach the conclusions that are needed.

• Animal studies could be useful to conclude that there are no disease enhancement signals, but making firm conclusions about clinical efficacy is uncertain. It should be possible to assess antiviral efficacy in animal models, but the immunomodulatory effects of chloroquine will depend on the pathogenesis of the model. Current limited evidence from preclinical studies

    

COVID-19: Therapeutics Working Group consultation on the potential role of chloroquine in clinical management



with coronaviruses would not suggest a scenario similar to what was observed with chikungunya. Moreover, it would not be expected that the data from the ongoing animal studies would provide definitive findings before proceeding to clinical evaluation.

PROPOSED NEXT STEPS

•

• •

As the decision should be taken rapidly based on available data, it was agreed that there is equipoise for the inclusion of chloroquine in clinical trials and to proceed with the evaluation of chloroquine in COVID 19 patients.

Members of the expert panel were invited to share with the WHO R&D Blueprint any additional information on chloroquine that should be considered.

The panel will be convened again in a week to discuss the various protocols available for the evaluation of chloroquine’s efficacy as a pre or post- exposure prophylaxis agent in COVID 19, and to align efforts for maximal synergy.



  

Note that above prioritization decisions are preliminary and may change as further information is provided to WHO.