A Trial of Remdesivir in Adults With Severe COVID-19

• ClinicalTrials.gov Identifier: NCT04257656
• Recruitment Status: Terminated
• First Posted: February 6, 2020
• Last Update Posted: April 15, 2020
• Sponsor: Capital Medical University
• Information provided by (Responsible Party): Bin Cao, China-Japan Friendship Hospital

Tracking Information

• First Submitted Date: January 31, 2020
• First Posted Date: February 6, 2020
• Last Update Posted Date: April 15, 2020
• Actual Study Start Date: February 6, 2020
• Actual Primary Completion Date: March 30, 2020 (Final data collection date for primary outcome measure)

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

Time to Clinical Improvement (TTCI) [Censored at Day 28] [ Time Frame: up to 28 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. 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.

Original Primary Outcome Measures (submitted: February 3, 2020)

Time to Clinical Improvement (TTCI) [Censored at Day 28] [ Time Frame: up to 28 days ]

TTCI is defined as the time (in days) from initiation of study treatment (active or placebo) until a decline of two categories from admission status on a six-category ordinal scale of clinical status which ranges from 1 (discharged) to 6 (death). 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. Abbreviation: IMV, invasive mechanical ventilation; NIV, non-invasive mechanical ventilation; HFNC, High-flow nasal cannula.

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

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

• Original Secondary Outcome Measures: Same as current
• 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 Severe 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 Severe 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 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

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.

• 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
• Remdesivir
• 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.
• Wang Y, Zhou F, Zhang D, Zhao J, Du R, Hu Y, Cheng Z, Gao L, Jin Y, Luo G, Fu S, Lu Q, Du G, Wang K, Lu Y, Fan G, Zhang Y, Liu Y, Ruan S, Liu W, Jaki T, Hayden FG, Horby PW, Cao B, Wang C. 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. Trials. 2020 May 24;21(1):422. doi: 10.1186/s13063-020-04352-9.
• Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, Fu S, Gao L, Cheng Z, Lu Q, Hu Y, Luo G, Wang K, Lu Y, Li H, Wang S, Ruan S, Yang C, Mei C, Wang Y, Ding D, Wu F, Tang X, Ye X, Ye Y, Liu B, Yang J, Yin W, Wang A, Fan G, Zhou F, Liu Z, Gu X, Xu J, Shang L, Zhang Y, Cao L, Guo T, Wan Y, Qin H, Jiang Y, Jaki T, Hayden FG, Horby PW, Cao B, Wang C. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020 May 16;395(10236):1569-1578. doi: 10.1016/S0140-6736(20)31022-9. Epub 2020 Apr 29. Erratum In: Lancet. 2020 May 30;395(10238):1694.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: April 13, 2020): 237
• Original Estimated Enrollment (submitted: February 3, 2020): 452
• Actual Study Completion Date: April 10, 2020
• Actual Primary Completion Date: March 30, 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. Hospitalized with a SaO2/SPO2≤94% on room air or Pa02/Fi02 ratio <300mgHg
5. ≤12 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. Pregnant or breastfeeding, or positive pregnancy test in a predose examination
4. 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
5. Will be transferred to another hospital which is not the study site within 72 hours.
6. 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: NCT04257656
• Other Study ID Numbers: CAP-China remdesivir 2
• Has Data Monitoring Committee: No

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: Not Provided
• Investigators: Not Provided
• PRS Account: Capital Medical University
• Verification Date: April 2020