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A Study to Evaluate the Efficacy and Safety of Remdesivir Plus Tocilizumab Compared With Remdesivir Plus Placebo in Hospitalized Participants With Severe COVID-19 Pneumonia (REMDACTA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04409262
Recruitment Status : Completed
First Posted : June 1, 2020
Results First Posted : February 14, 2022
Last Update Posted : February 14, 2022
Sponsor:
Collaborator:
Gilead Sciences
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Description
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Brief Summary:
This study will evaluate the efficacy and safety of combination therapy with remdesivir plus tocilizumab compared with remdesivir plus placebo in hospitalized patients with COVID-19 pneumonia.

Condition or disease Intervention/treatment Phase
COVID-19 Pneumonia Drug: Remdesivir Drug: Tocilizumab Drug: Placebo Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 649 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase III, Randomized, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of Remdesivir Plus Tocilizumab Compared With Remdesivir Plus Placebo in Hospitalized Patients With Severe COVID-19 Pneumonia
Actual Study Start Date : June 16, 2020
Actual Primary Completion Date : February 1, 2021
Actual Study Completion Date : March 8, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Tocilizumab

Arms and Interventions
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Arm Intervention/treatment
Experimental: Remdesivir + Tocilizumab (RDV+TCZ)
Participants assigned to the RDV+TCZ arm will receive a 10-day treatment course of RDV, plus one infusion of TCZ on Day 1.
 Drug: Remdesivir
Participants will receive intravenous (IV) RDV

Drug: Tocilizumab
Participants will receive IV TCZ
Active Comparator: Remdesivir + Placebo (RDV+Placebo)
Participants assigned to the RDV+ placebo arm will receive a 10-day treatment course of RDV, plus one infusion of TCZ-placebo on Day 1.
 Drug: Remdesivir
Participants will receive intravenous (IV) RDV

Drug: Placebo
Participants will receive IV placebo matched to TCZ


Outcome Measures
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Primary Outcome Measures :
  1. Time to Hospital Discharge or "Ready for Discharge" up to Day 28 [ Time Frame: Up to Day 28 ]

    Defined as days from randomization to hospital discharge or "Ready for Discharge" not followed by ordinal scale category >1, hospital readmission or death. Hospital discharge or "Ready for Discharge" is defined as an ordinal score of 1 on the 7-point ordinal scale. Participants who die are censored at Day 28.

    1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen)
    2. Non-intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen
    3. Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen
    4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
    5. ICU, requiring intubation and mechanical ventilation
    6. ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy)
    7. Death


Secondary Outcome Measures :
  1. Time to Mechanical Ventilation or Death up to Day 28 [ Time Frame: Up to Day 28 ]
    Time to Mechanical Ventilation or Death defined as the time from randomization to the first occurrence of death or mechanical ventilation. For participants already on mechanical ventilation at baseline, only death is counted as an event.

  2. Clinical Status as Assessed by the Investigator Using a 7-category Ordinal Scale of Clinical Status on Day 14 [ Time Frame: Day 14 ]

    Clinical status was assessed by the investigator according to the following ordinal scale categories:

    1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen)
    2. Non-intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen
    3. Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen
    4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
    5. ICU, requiring intubation and mechanical ventilation
    6. ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy)
    7. Death

  3. Time to Death up to Day 28 [ Time Frame: Up to Day 28 ]
    Time to death is defined as the time from randomization to death.

  4. Time to Death up to Day 60 [ Time Frame: Up to Day 60 ]
    Time to death is defined as the time from randomization to death.

  5. Time to Improvement of at Least 2 Categories Relative to Baseline on a 7-category Ordinal Scale of Clinical Status up to Day 28 [ Time Frame: Up to Day 28 ]

    Defined as time from randomization to the time when at least a 2-category improvement in the 7-category ordinal scale is observed. Patients who die are censored at day 28.

    Clinical status was assessed by the investigator according to the following ordinal scale categories:

    1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen)
    2. Non-intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen
    3. Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen
    4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
    5. ICU, requiring intubation and mechanical ventilation
    6. ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy)
    7. Death

  6. Clinical Status as Assessed by the Investigator Using a 7-category Ordinal Scale of Clinical Status on Day 7 [ Time Frame: Day 7 ]

    Clinical status was assessed by the investigator according to the following ordinal scale categories:

    1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen)
    2. Non-intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen
    3. Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen
    4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
    5. ICU, requiring intubation and mechanical ventilation
    6. ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy)
    7. Death

  7. Clinical Status as Assessed by the Investigator Using a 7-category Ordinal Scale of Clinical Status on Day 21 [ Time Frame: Day 21 ]

    Clinical status was assessed by the investigator according to the following ordinal scale categories:

    1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen)
    2. Non-intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen
    3. Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen
    4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
    5. ICU, requiring intubation and mechanical ventilation
    6. ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy)
    7. Death

  8. Clinical Status as Assessed by the Investigator Using a 7-category Ordinal Scale of Clinical Status on Day 28 [ Time Frame: Day 28 ]

    Clinical status was assessed by the investigator according to the following ordinal scale categories:

    1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen)
    2. Non-intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen
    3. Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen
    4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
    5. ICU, requiring intubation and mechanical ventilation
    6. ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy)
    7. Death

  9. Clinical Status as Assessed by the Investigator Using a 7-category Ordinal Scale of Clinical Status on Day 60 [ Time Frame: Day 60 ]

    Clinical status was assessed by the investigator according to the following ordinal scale categories:

    1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen)
    2. Non-intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen
    3. Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen
    4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
    5. ICU, requiring intubation and mechanical ventilation
    6. ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy)
    7. Death

  10. Proportion of Participants Requiring Initiation of Mechanical Ventilation Post-baseline (Participants Who Did Not Require Mechanical Ventilation at Baseline) [ Time Frame: Day 28 and Day 60 ]

    Day 28: Participants who withdraw or die prior to Day 28 are assumed to have required mechanical ventilation. Participants without mechanical ventilation prior to discharge are assumed not to have required mechanical ventilation unless they die by Day 28, which are counted as an event.

    Day 60: Participants who withdraw or die prior to Day 60 are assumed to have required mechanical ventilation. Participants without mechanical ventilation prior to discharge are assumed not to have required mechanical ventilation unless they die by Day 60, which are counted as an event.


  11. Proportion of Participants Who Are Alive and Free of Respiratory Failure at Day 28 and Day 60 (Participants Requiring Mechanical Ventilation at Baseline) [ Time Frame: Day 28 and Day 60 ]
  12. Duration of Mechanical Ventilation (Participants Requiring Mechanical Ventilation at Baseline) up to Day 28 [ Time Frame: Up to Day 28 ]
    Participants who die by Day 28 are assigned a duration of 28 days.

  13. Difference in Mortality at Days 14, 28, and 60 [ Time Frame: Days 14, 28, and 60 ]
  14. Time to Recovery up to Day 28 [ Time Frame: Up to Day 28 ]

    Defined as the time from randomization to the time when an ordinal scale category of 2 (non-ICU hospital ward or "ready for hospital ward" not requiring supplemental oxygen) or better is observed, not followed by ordinal scale category >2 or death. Participants who die are censored at day 28.

    1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen)
    2. Non-intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen
    3. Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen
    4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
    5. ICU, requiring intubation and mechanical ventilation
    6. ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy)
    7. Death

  15. Proportion of Participants Who Are Discharged or "Ready for Discharge" up to Day 28 [ Time Frame: Up to Day 28 ]

    Defined as hospital discharge or "Ready for Discharge" not followed by ordinal scale category >1, hospital readmission or death.

    1. Discharged (or "ready for discharge" as evidenced by normal temperature and respiratory rate, and stable oxygen saturation on ambient air or </= 2L supplemental oxygen)
    2. Non-intensive care unit (ICU) hospital ward (or "ready for hospital ward") not requiring supplemental oxygen
    3. Non-ICU hospital ward (or "ready for hospital ward") requiring supplemental oxygen
    4. ICU or non-ICU hospital ward, requiring non-invasive ventilation or high-flow oxygen
    5. ICU, requiring intubation and mechanical ventilation
    6. ICU, requiring extracorporeal membrane oxygenation (ECMO) or mechanical ventilation and additional organ support (e.g., vasopressors, renal replacement therapy)
    7. Death

  16. Proportion of Participants Who Require Initiation of Mechanical Ventilation Post-baseline or Die up to Day 28 [ Time Frame: Up to Day 28 ]
    Participants already on mechanical ventilation at baseline are only counted as an event if death occurs.


Other Outcome Measures:
  1. Percentage of Participants With Adverse Events (AEs) Tabulated by Severity [ Time Frame: Up to Day 60 ]

    AEs were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).

    Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL) Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL Grade 4: Life-threatening consequences; urgent intervention indicated Grade 5: Death related to AE

    Participants are counted at the highest AE grade experienced.


  2. Proportion of Participants With Any Post-Treatment Infection [ Time Frame: Up to Day 60 ]

Eligibility Criteria
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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Hospitalized with COVID-19 pneumonia confirmed per a positive polymerase chain reaction (PCR) of any specimen (e.g., respiratory, blood, urine, stool, other bodily fluid) and evidenced by chest X-ray or CT scan
  • Requiring more than 6 L/min supplemental oxygen to maintain SpO2 > 93%
  • Agrees to not participate in another clinical trial for the treatment of COVID-19 while participating in this study

Exclusion Criteria

  • Known severe allergic reactions to tocilizumab or other monoclonal antibodies
  • Known hypersensitivity to remdesivir, the metabolites, or formulation excipients
  • Active tuberculosis (TB) infection
  • Suspected active bacterial, fungal, viral, or other infection (besides COVID-19)
  • In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments
  • Treatment with immunosuppressive or immunomodulatory therapy (including tocilizumab) within the past 3 months
  • Concurrent treatment with other agents with actual or possible direct-acting antiviral activity against SARS-CoV-2 within 24 hours prior to study drug dosing. In addition, participants with prior or current treatment with > 2 doses of remdesivir for COVID-19 are excluded
  • Participating in other drug clinical trials
  • Estimated glomerular filtration rate (eGFR) < 30 mL/min (including patients receiving hemodialysis or hemofiltration)
  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x upper limit of normal (ULN) detected within 24 hours of screening (according to local laboratory reference ranges)
  • Absolute neutrophil count (ANC) < 1000/uL at screening
  • Platelet count < 50,000/uL at screening
  • Body weight < 40 kg
  • Treatment with an investigational drug within 5 half-lives or 30 days (whichever is longer) of randomization
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04409262


Locations
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Sponsors and Collaborators
Hoffmann-La Roche
Gilead Sciences
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
  Study Documents (Full-Text)

Documents provided by Hoffmann-La Roche:
Study Protocol  [PDF] February 22, 2021
Statistical Analysis Plan  [PDF] February 22, 2021

More Information
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT04409262    
Other Study ID Numbers: WA42511
2020-002275-34 ( EudraCT Number )
First Posted: June 1, 2020    Key Record Dates
Results First Posted: February 14, 2022
Last Update Posted: February 14, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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COVID-19
Pneumonia
Respiratory Tract Infections
Infections
Pneumonia, Viral
Virus Diseases
Coronavirus Infections
Coronaviridae Infections
Nidovirales Infections
 RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Remdesivir
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents