A Phase 3 Randomized Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734*) in Participants with Moderate COVID-19 Compared to Standard of Care Treatment

In December 2019, a series of pneumonia cases of unknown cause emerged in
Wuhan, Hubei, China. Sequencing analysis from the patients* respiratory tract
samples indicated a novel coronavirus (CoV), which was named COVID-19. As of 23
February 2020, more than 78,000confirmed cases have been identified in Wuhan,
other provinces in China, and in multiple countries outside China {World Health
Organisation (WHO) 2020}. More than 2400 deaths associated with COVID-19 have
been reported, making COVID-19 a major health emergency. Antiviral drugs that
are being evaluated as potential treatments for COVID-19 include
lopinavir/ritonavir (LPV/RTV; used in the treatment of HIV infection) and
remdesivir (RDV, GS-5734*). In a study of Severe Acute Respiratory Syndrome
(SARS), a significant reduction in acute respiratory distress
syndrome/mortality was observed in 41 patients treated with the combination of
LPV/RTV, compared with 111 patients receiving monotherapy ribavirin (2.4 % vs
28.8%, p = 0.001). However, the use of historical control data does not allow
for a reliable estimation of efficacy. Additionally, LPV/RTV has multiple known
adverse reactions such as prolonged QT interval, severe gastrointestinal
reactions, abnormal blood glucose, pancreatitis, hepatic impairment, and
elevated blood lipids. It has multiple drug-to-drug interactions with many
commonly used drugs in clinical practice; thus, its clinical safety is not
determined. Remdesivir shows potent in vitro activity against the human
pathogenic CoVs Middle East Respiratory Syndrome (MERS)-CoV and SARS-CoV in
multiple relevant human cell types. In a mouse model of MERS-CoV infection,
both prophylactic and therapeutic RDV significantly improved pulmonary function
and reduce lung viral loads and severe lung pathology compared with vehicle
control animals. In contrast, prophylactic LPV/RTV + interferon-beta
(LPV/RTV-IFNb) slightly reduced viral loads without impacting other disease
parameters. Therapeutic LPV/RTV-IFNbimproves pulmonary function but did not
reduce virus replication or severe lung pathology {Sheahan 2020}.

The evaluation of the safety and potential efficacy of RDV in people with
COVID-19 is urgently needed.

The purpose of this study is to provide remdesivir (RDV) to participants with
moderate COVID-19. The primary objective of this study is as follows:
To evaluate the efficacy of 2 remdesivir (RDV) regimens compared to standard of
care (SOC), with respect to clinical status assessed by a 7-
point ordinal scale on Day 11


The secondary objective of this study is as follows:
To evaluate the safety and tolerability of RDV compared to SOC

This is a Phase 3 randomized, open-labeled, multi-center study RDV therapy in
participants with moderate COVID-19. The study will be conducted in two parts.
In Part A,
approximately 600 participants who meet all eligibility criteria may be
randomized in 1:1:1 ratio into one of the following treatment groups:
Treatment Group 1: continued SOC therapy together with intravenous (IV) RDV 200
mg on Day 1 followed by IV RDV 100 mg on Days 2, 3, 4, and 5
Treatment Group 2: continued SOC therapy together with IV RDV 200 mg on Day 1
followed by IV RDV 100 mg on Days 2,3, 4, 5, 6, 7, 8, 9, and 10
Treatment Group 3: continued SOC therapy

Part B will be enrolled after enrollment to Part A is complete. In Part B, an
additional approximately 1000 participants who meet all of the eligibility
criteria may receive:
Extension Treatment Group: continued standard of care therapy together with IV
RDV 200 mg on Day 1 followed by IV RDV 100 mg on Days 2, 3, 4, 5, 6, 7, 8, 9,
and 10

If Treatment Group 1 of Part A is selected for Part B, or if treatment for 5
days is selected in a study of more severe disease, all participants in the
Extension Treatment Group and all new participants will be reassigned to
receive treatment for a total of 5 days. National and local regulatory
authorities will be informed.
Participants in Part A of the study will be the primary efficacy population.
Participants enrolled in Part B, will have data reported descriptively at study
completion.

Treatment Group 1:continued SOCtherapy together with IV RDV200 mg on Day 1
followed by IV RDV 100mg on Days 2, 3, 4, and 5
Treatment Group 2:continued SOC therapy together with IV RDV200 mg on Day 1
followed by IV RDV 100mg on Days 2, 3, 4, 5, 6, 7, 8, 9, and 10
Treatment Group 3:continued SOC therapy

A pertinent specific risk for participantsin this study is the potential for
transient,Grade <=2, treatment-emergent elevations in alanine aminotransferase
(ALT) and aspartate aminotransferase (AST), which were observed after multiple
daily RDV administrations in Studies GS-US-399-1954 and GS-US-399-5505. To date
in human studies, no serious adverse events (SAEs) have occurred in healthy
individuals who have received at least 1 dose of RDV. Remdesivir has been
tested in healthy volunteers as a single ascending dose over a dose range of 3
to 225 mg and in a multi-dose study of 150 mg for up to 14 days and at 200 mg
loading dose followed by 100 mg for a total of 10 days. In nonclinical animal
studies, toxicity findings were consistent with dose-dependent and reversible
kidney injury and dysfunction.The clinical significance of the nephrotoxicity
noted in animal species is unknown.The etiology of reversible kidney injury
observed in rats is consistent with the ability of rat renal organic anion
transporters (OATs), but not human OATs, to efficiently interact with blood
metabolites of RDV, particularly GS-704277. This effect may lead to
proportionally higher intracellular accumulation of drug metabolites in renal
rat tubules, leading to kidney injury. The 200 mg loading dose with 8 g of
sulfobutylether β-cyclodextrin sodium(SBECD) on Day 1 will be followed by 100
mg of RDV each day for 4 or 9 days with 4 g of SBECD, which is within the range
of daily SBECD administration considered safe in humans. A total of 250
mg/kg/day of SBECD is considered safe by the European Medicines Agency and is
therefore safe for all adults with weight over 32 kg. The 100 mg dose prepared
in 0.9% saline will be hypertonic relative to human serum osmolality but
approaches the normal physiological osmolar range for humans. The RDV regimen
consisting of a loading dose of 200 mg followed by RDV 100 mg daily for up to 9
days is not anticipated to pose a safety risk to participants enrolled in this
study. There are currently no data available on the interaction of RDV and
other investigational agents. Administering RDV concurrent with other
investigational anti-CoV agents may lead to antagonismorsynergy or have no
effect. The risk mitigation strategy for this study includes restriction of the
study population to those without a history of significant renal or hepatic
disease:
- Exclusion of participants with ALT > 5 ULN
- Exclusion of participants with an estimated glomerular filtration rate (eGFR)
<50mL/min
- Exclusion of coadministration of other investigational agents against
COVID-19

Serum chemistry assessments, including liver function testing, will be closely
monitored during the study period.

There are currently no investigational agents with demonstrated clinical
efficacy or approved treatments for COVID-19. The timely evaluation of a safe
and effective antiviral agent that works by directly and selectively blocking
the virus replication and is broadly efficacious against SARS-CoV-2 addresses a
serious unmet medical need.In consideration of the information included in this
protocol, the overall risks to participants are outweighed by the potential
benefits of RDV experimental therapy for the treatment of COVID-19.The
benefit-risk balance for this study is considered positive.