Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial

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Abstract

Background

Coronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30 ^th January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19.

Methods

The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed.

Discussion

This is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6 ^th February 2020.

Trial registration

ClinicalTrials.gov: NCT04257656. Registered on 6 February 2020.

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Most cited references 11

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Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Chaolin Huang, Yeming Wang, Xingwang Li … (2020)

Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.

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A Novel Coronavirus from Patients with Pneumonia in China, 2019

Na Zhu, Dingyu Zhang, Wenling Wang … (2020)

Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)

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Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China

Dawei Wang, Bo Hu, Fangfang Zhu … (2020)

In December 2019, novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited.

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Author and article information

Contributors

Bin Cao: caobin_ben@163.com

Chen Wang: cyh-birm@263.net

Journal

Journal ID (nlm-ta): Trials

Journal ID (iso-abbrev): Trials

Title: Trials

Publisher: BioMed Central (London )

ISSN (Electronic): 1745-6215

Publication date (Electronic): 24 May 2020

Publication date PMC-release: 24 May 2020

Publication date Collection: 2020

Volume: 21

Electronic Location Identifier: 422

Affiliations

[1 ]GRID grid.415954.8, ISNI 0000 0004 1771 3349, Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, , National Clinical Research Center for Respiratory Diseases, China-Japan Friendship Hospital, ; Beijing, China

[2 ]Jin Yin-tan Hospital, Wuhan, Hubei Province China

[3 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Tongji Hospital, , Tongji Medical College of Huazhong University of Science & Technology, ; Wuhan, China

[4 ]Wuhan Lung Hospital, Wuhan, China

[5 ]GRID grid.440160.7, The Central Hospital of Wuhan, ; Wuhan, China

[6 ]GRID grid.413247.7, Zhongnan Hospital of Wuhan University, ; Wuhan, China

[7 ]GRID grid.412632.0, ISNI 0000 0004 1758 2270, Renmin Hospital of Wuhan University, ; Wuhan, China

[8 ]GRID grid.33199.31, ISNI 0000 0004 0368 7223, Union Hospital, , Tongji Medical College of Huazhong University of Science & Technology, ; Wuhan, China

[9 ]GRID grid.410609.a, Wuhan First Hospital, ; Wuhan, China

[10 ]GRID grid.460060.4, Wuhan Third Hospital, ; Wuhan, China

[11 ]GRID grid.501233.6, Wuhan Fourth Hospital, ; Wuhan, China

[12 ]GRID grid.506261.6, ISNI 0000 0001 0706 7839, Institute of Medicine, , Chinese Academy of Medical Sciences, ; Beijing, China

[13 ]GRID grid.415954.8, ISNI 0000 0004 1771 3349, Institute of Clinical Medical Sciences, , China-Japan Friendship Hospital, ; Beijing, China

[14 ]GRID grid.9835.7, ISNI 0000 0000 8190 6402, Lancaster University, ; Lancaster, UK

[15 ]GRID grid.27755.32, ISNI 0000 0000 9136 933X, University of Virginia School of Medicine, ; Charlottesville, VA USA

[16 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, ISARIC, , University of Oxford, ; Oxford, UK

[17 ]GRID grid.506261.6, ISNI 0000 0001 0706 7839, Institute of Respiratory Medicine, , Chinese Academy of Medical Sciences, ; Beijing, China

[18 ]GRID grid.506261.6, ISNI 0000 0001 0706 7839, Peking Union Medical College, ; Beijing, China

Author information

Peter W. Horby http://orcid.org/0000-0002-9822-1586

Article

Publisher ID: 4352

DOI: 10.1186/s13063-020-04352-9

PMC ID: 7245636

PubMed ID: 32448345

SO-VID: 9aa9c02a-1c8e-4ae0-8375-c985703dca45

License:

Open AccessThis 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.

History

Date received : 18 February 2020

Date accepted : 27 April 2020

Funding

Funded by: look at the manuscript

Award ID: xxxx

Award Recipient : Peter W. Horby

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ScienceOpen disciplines: Medicine

Keywords: covid-19,clinical trial,remdesivir,antiviral,china ,administrative information

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ScienceOpen disciplines: Medicine

Keywords: covid-19, clinical trial, remdesivir, antiviral, china , administrative information

Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial

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Abstract

Background

Methods

Discussion

Trial registration

Related collections

Novel Coronavirus Disease COVID-19

Most cited references 11

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

A Novel Coronavirus from Patients with Pneumonia in China, 2019

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China

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