A Trial of Remdesivir in Adults With Mild and Moderate COVID-19

• ClinicalTrials.gov Identifier: NCT04252664
• Recruitment Status: Suspended
• First Posted: February 5, 2020
• Last Update Posted: April 15, 2020
• Sponsor: Capital Medical University
• Collaborator: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
• Information provided by (Responsible Party): Bin Cao, China-Japan Friendship Hospital

Tracking Information

• First Submitted Date: January 31, 2020
• First Posted Date: February 5, 2020
• Last Update Posted Date: April 15, 2020
• Actual Study Start Date: February 12, 2020
• Estimated Primary Completion Date: April 10, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 13, 2020)

Time to Clinical recoveryTime to Clinical Recovery (TTCR) [ Time Frame: up to 28 days ]

TTCR is defined as the time (in hours) from initiation of study treatment (active or placebo) until normalisation of fever, respiratory rate, and oxygen saturation, and alleviation of cough, sustained for at least 72 hours, or live hospital discharge, whichever comes first. Normalisation and alleviation criteria:

• Fever - <37°C,
• Respiratory rate - ≤24/minute on room air,
• Oxygen saturation - >94% on room air,
• Cough - mild or absent on a patient reported scale of severe, moderate, mild, absent.

Original Primary Outcome Measures (submitted: January 31, 2020)

Rate of composite advers outcomes [ Time Frame: 14 days ]

Defined as SPO2≤ 94% without oxygen supplementation, PaO2/FiO2 <300mmHg or a respiratory rate ≤24 breaths per min without supplemental oxygen

Current Secondary Outcome Measures (submitted: February 3, 2020)

• All cause mortality [ Time Frame: up to 28 days ]
  baseline SpO2 during screening, PaO2/FiO2 <300mmHg or a respiratory rate ≥ 24 breaths per min without supplemental oxygen
• Frequency of respiratory progression [ Time Frame: up to 28 days ]
  Defined as SPO2≤ 94% on room air or PaO2/FiO2 <300mmHg and requirement for supplemental oxygen or more advanced ventilator support.
• Time to defervescence (in those with fever at enrolment) [ Time Frame: up to 28 days ]
• Time to cough reported as mild or absent (in those with cough at enrolment rated severe or moderate) [ Time Frame: up to 28 days ]
• Time to dyspnea reported as mild or absent (on a scale of severe, moderate, mild absent, in those with dyspnoea at enrolment rated as severe or moderate,) [ Time Frame: up to 28 days ]
• Frequency of requirement for supplemental oxygen or non-invasive ventilation [ Time Frame: up to 28 days ]
• Time to 2019-nCoV RT-PCR negative in upper respiratory tract specimen [ Time Frame: up to 28 days ]
• Change (reduction) in 2019-nCoV viral load in upper respiratory tract specimen as assessed by area under viral load curve. [ Time Frame: up to 28 days ]
• Frequency of requirement for mechanical ventilation [ Time Frame: up to 28 days ]
• Frequency of serious adverse events [ Time Frame: up to 28 days ]

Original Secondary Outcome Measures (submitted: January 31, 2020)

• time to recovery [ Time Frame: 28 days ]
  Clinical recovery was defined as sustained (48 hours) alleviation of illness based on symptom scores (fever, cough, diarrhea, myalgia, dyspnea) all being absent and no evidence for progression (newly-presented dyspnea, SpO2 decline ≥3%, respiratory rate ≥ 24 breaths per min without supplemental oxygen).
• rate of no fever [ Time Frame: 14 days ]
• rate of no cough [ Time Frame: 14 days ]
• rate of no dyspnea [ Time Frame: 14 days ]
• rate of no requring supplemental oxygen [ Time Frame: 14 days ]
• rate of undectable viral RNA [ Time Frame: 14 days ]
• rate of mechanical ventilation [ Time Frame: 28 days ]
• rate of ICU admission [ Time Frame: 28 days ]
• rate of serious adverse event [ Time Frame: 28 days ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Trial of Remdesivir in Adults With Mild and Moderate COVID-19
• Official Title: A Phase 3 Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Efficacy and Safety of Remdesivir in Hospitalized Adult Patients With Mild and Moderate COVID-19.

Brief Summary

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 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 mild or moderate COVID-19.

Detailed Description

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 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 appears to be wide, encompassing asymptomatic infection, a mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure and even death. Although the per infection risk of severe disease remains to be determined, and may differ from the initial reports of 10-15%, the large number of cases in Wuhan has resulted in a large number of patients hospitalised with pneumonia. Progression from prodromal symptoms (usually fever, fatigue, cough) to severe pneumonia requiring supplementary oxygen support, mechanical ventilation, or in some cases ECMO appears to occur most commonly during the second week of illness in association with persistent viral RNA detection. This provides a window of opportunity to test candidate antiviral therapeutics.

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, reduce risk of disease progression, speed recovery, and reduce the requirements for intensive supportive care and prolonged hospitalisation. In addition, treatments for mild cases to reduce the duration of illness and infectivity may also be of value were COVID-19 to become pandemic and/or endemic in human populations.

Given no specific antiviral therapy for COVID-19 and the 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 mild or moderate COVID-19.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• COVID-19
• SARS-CoV-2

Intervention

• Drug: Remdesivir
  RDV 200 mg loading dose on day 1 is given, followed by 100 mg iv once-daily maintenance doses for 9 days.
  Other Name: GS-5734
• Drug: Remdesivir placebo
  RDV placebo 200 mg loading dose on day 1 is given, followed by 100 mg iv once-daily maintenance doses for 9 days.

Study Arms

• Experimental: Remdesivir group
  active remdesivir
  Intervention: Drug: Remdesivir
• Placebo Comparator: Control group
  Placebos matched remdesivir
  Intervention: Drug: Remdesivir placebo

• Publications *: Ansems K, Grundeis F, Dahms K, Mikolajewska A, Thieme V, Piechotta V, Metzendorf MI, Stegemann M, Benstoem C, Fichtner F. Remdesivir for the treatment of COVID-19. Cochrane Database Syst Rev. 2021 Aug 5;8(8):CD014962. doi: 10.1002/14651858.CD014962.

Recruitment Information

• Recruitment Status: Suspended
• Estimated Enrollment (submitted: February 3, 2020): 308
• Original Estimated Enrollment (submitted: January 31, 2020): 270
• Estimated Study Completion Date: April 27, 2020
• Estimated Primary Completion Date: April 10, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age ≥18 years at time of signing Informed Consent Form
2. Laboratory (RT-PCR) confirmed COVID-19.
3. Lung involvement confirmed with chest imaging

4. Hospitalised with:

   • Fever - ≥36.7℃ -axilla or Oral temperature ≥ 38.0 ℃ or ≥38.6°C tympanic or rectal or
   • And at least one of Respiratory rate >24/min Or Cough
5. ≤8 days since illness onset
6. Willingness of study participant to accept randomization to any assigned treatment arm.
7. Must agree not to enroll in another study of an investigational agent prior to completion of Day 28 of study.

Exclusion Criteria:

1. 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.
2. Severe liver disease (e.g. Child Pugh score ≥ C, AST>5 times upper limit)
3. SaO2/SPO2≤94% in room air condition, or the Pa02/Fi02 ratio <300mgHg
4. Known allergic reaction to remdesivir
5. 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
6. Pregnant or breastfeeding, or positive pregnancy test in a predose examination
7. Will be transferred to another hospital which is not the study site within 72 hours.
8. Receipt of any experimental treatment for COVID-19 within the 30 days prior to the time of the screening evaluation.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China

Administrative Information

• NCT Number: NCT04252664
• Other Study ID Numbers: CAP-China remdesivir 1
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Bin Cao, China-Japan Friendship Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Capital Medical University
• Original Study Sponsor: Same as current
• Collaborators: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
• Investigators: Not Provided
• PRS Account: Capital Medical University
• Verification Date: April 2020