A Trial of Remdesivir in Adults With Severe COVID-19

Study Overview
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Brief Summary
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In December 2019, Wuhan, in Hubei province, China, became the center of an outbreak of pneumonia of unknown cause. In a short time, Chinese scientists had shared the genome information of a novel coronavirus (SARS-CoV-2) from these pneumonia patients and developed a real-time reverse transcription PCR (real-time RT-PCR) diagnostic assay. Given no specific antiviral therapy for COVID-19 and the ready availability of remdesvir as a potential antiviral agent, based on pre-clinical studies in SARS-CoV and MERS-CoV infections, this randomized, controlled, double blind trial will evaluate the efficacy and safety of remdesivir in patients hospitalized with severe COVID-19.

Detailed Description
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In December 2019, Wuhan, in Hubei province, China, became the center of an outbreak of pneumonia of unknown cause. In a short time, Chinese scientists had shared the genome information of a novel coronavirus (SARS-CoV-2) from these pneumonia patients and developed a real-time reverse transcription PCR (real-time RT-PCR) diagnostic assay. Whilst the outbreak is likely to have started from a zoonotic transmission event associated with a large seafood market that also traded in live wild animals, it soon became clear that person-to-person transmission was also occurring. The number of cases of infection with COVID-19 identified in Wuhan increased markedly over the later part of January 2020, with cases identified in multiple other Provinces of China and internationally. Mathematical models of the expansion phase of the epidemic suggested that sustained person-to-person transmission is occurring, and the R-zero is substantially above 1, the level required for a self-sustaining epidemic in human populations. The clinical spectrum of COVID-19 illness appears to be wide, encompassing asymptomatic infection, a mild upper respiratory tract infection, and severe viral pneumonia with respiratory failure and even death. Although the per infection risk of severe disease remains to be determined, case-fatality risk of 11-14% has been reported in several initial studies of seriously ill patients and case-fatality has been estimated approximately at 2% overall. Also the large number of cases in Wuhan has resulted in a large number of patients hospitalised with pneumonia requiring supplemental oxygen and sometimes more advance ventilator support. This new coronavirus, and previous experiences with SARS and MERS-CoV, highlight the need for therapeutics for human coronavirus infections that can improve clinical outcomes, speed recovery, and reduce the requirements for intensive supportive care and prolonged hospitalisation. Given no specific antiviral therapy for COVID-19 and the ready availability of remdesvir as a potential antiviral agent, based on pre-clinical studies in SARS-CoV and MERS-CoV infections, this randomized, controlled, double blind trial will evaluate the efficacy and safety of remdesivir in patients hospitalized with severe COVID-19.

Official Title
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A Phase 3 Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Remdesivir in Hospitalized Adult Patients With Severe COVID-19.

Conditions
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COVID-19, Remdesivir, SARS-CoV-2

Intervention / Treatment
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* Drug: Remdesivir
* Drug: Remdesivir placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years at time of signing Informed Consent Form Laboratory (RT-PCR) confirmed COVID-19. Lung involvement confirmed with chest imaging Hospitalized with a SaO2/SPO2≤94% on room air or Pa02/Fi02 ratio <300mgHg ≤12 days since illness onset Willingness of study participant to accept randomization to any assigned treatment arm. Must agree not to enroll in another study of an investigational agent prior to completion of Day 28 of study. Exclusion Criteria: Physician makes a decision that trial involvement is not in patients' best interest, or any condition that does not allow the protocol to be followed safely. Severe liver disease (e.g. Child Pugh score ≥ C, AST>5 times upper limit) Pregnant or breastfeeding, or positive pregnancy test in a predose examination Patients with known severe renal impairment (estimated glomerular filtration rate ≤30 mL/min/1.73 m2) or receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis Will be transferred to another hospital which is not the study site within 72 hours. Receipt of any experimental treatment for COVID-19 within the 30 days prior to the time of the screening evaluation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Remdesivir group<br>active remdesivir | Drug: Remdesivir<br>* RDV 200 mg loading dose on day 1 is given, followed by 100 mg iv once-daily maintenance doses for 9 days.<br>* Other names: GS-5734;|
| Placebo Comparator: Control group<br>Placebos matched remdesivir | Drug: Remdesivir placebo<br>* RDV placebo 200 mg loading dose on day 1 is given, followed by 100 mg iv once-daily maintenance doses for 9 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Clinical Improvement (TTCI) [Censored at Day 28] | 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. Six-category ordinal scale: 6. Death; 5. ICU, requiring ECMO and/or IMV; 4. ICU/hospitalization, requiring NIV/ HFNC therapy; 3. Hospitalization, requiring supplemental oxygen (but not NIV/ HFNC); 2. Hospitalization, not requiring supplemental oxygen; 1. Hospital discharge or meet discharge criteria (discharge criteria are defined as clinical recovery, i.e. fever, respiratory rate, oxygen saturation return to normal, and cough relief). Abbreviation: IMV, invasive mechanical ventilation; NIV, non-invasive mechanical ventilation; HFNC, High-flow nasal cannula. | up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical status | Clinical status, assessed by the ordinal scale at fixed time points (days 7, 14, 21, and 28). | days 7, 14, 21, and 28 | 
| Time to Hospital Discharge OR NEWS2 (National Early Warning Score 2) of ≤ 2 maintained for 24 hours. | Time to Hospital Discharge OR NEWS2 (National Early Warning Score 2) of ≤ 2 maintained for 24 hours. | up to 28 days | 
| All cause mortality |  | up to 28 days | 
| Duration (days) of mechanical ventilation |  | up to 28 days | 
| Duration (days) of extracorporeal membrane oxygenation |  | up to 28 days | 
| Duration (days) of supplemental oxygenation |  | up to 28 days | 
| Length of hospital stay (days) |  | up to 28 days | 
| Time to 2019-nCoV RT-PCR negativity in upper and lower respiratory tract specimens |  | up to 28 days | 
| Change (reduction) in 2019-nCoV viral load in upper and lower respiratory tract specimens as assessed by area under viral load curve. |  | up to 28 days | 
| Frequency of serious adverse drug events |  | up to 28 days |