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)

• 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: Hoffmann-La Roche
• Collaborator: Gilead Sciences
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

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

• 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

Arms and Interventions

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

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

• 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

Locations

United States, Arizona

Valleywise Health Medical Center

Phoenix, Arizona, United States, 85008

United States, California

eStudySite - Chula Vista - PPDS

Chula Vista, California, United States, 91911

Hoag Hospital Irvine

Irvine, California, United States, 92612

Providence St Johns Health Center

Santa Monica, California, United States, 90404

United States, Connecticut

Yale University School of Medicine; HIV Clinical Trials Program

New Haven, Connecticut, United States, 06501

United States, District of Columbia

Medstar Georgetown University Hospital

Washington, District of Columbia, United States, 20007

United States, Florida

Holy Cross Hospital Inc

Fort Lauderdale, Florida, United States, 33308

Larkin Community Hospital Palm Springs Campus (Hialeah)

Hialeah, Florida, United States, 33012

University of Miami Miller School of Medicine; Clinical Reseach Building

Miami, Florida, United States, 33136

Larkin Community Hospital

South Miami, Florida, United States, 33143

United States, Idaho

St Luke's Health System; Rheumatology Research

Boise, Idaho, United States, 83702

United States, Illinois

Advocate Christ Medical Center

Oak Lawn, Illinois, United States, 60453

United States, Louisiana

Ochsner Clinic Foundation

New Orleans, Louisiana, United States, 70121

United States, Maryland

University of Maryland

Baltimore, Maryland, United States, 21201

United States, Massachusetts

Boston Medical Center

Boston, Massachusetts, United States, 02118-2393

Baystate Medical Center

Springfield, Massachusetts, United States, 01199

United States, Michigan

Henry Ford Medical Center

Novi, Michigan, United States, 48322

United States, New Jersey

St. Michael'S Medical Center

Newark, New Jersey, United States, 07102

United States, New Mexico

San Juan Oncology Associates

Farmington, New Mexico, United States, 87401

United States, New York

Wyckoff Heights Medical Center

Staten Island, New York, United States, 11237

United States, North Carolina

Novant Health Clinical Research

Charlotte, North Carolina, United States, 28204

United States, Ohio

OhioHealth Research Institute

Columbus, Ohio, United States, 43214

United States, Oregon

Providence Saint Vincent's Medical Center

Portland, Oregon, United States, 97225

United States, Pennsylvania

Lehigh Valley Hospital

Allentown, Pennsylvania, United States, 18103

Thomas Jefferson University

Philadelphia, Pennsylvania, United States, 19107

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

United States, Texas

The Liver Institute at Methodist Dallas

Arlington, Texas, United States, 76012

Baylor Scott and White Medical Center - College Station

College Station, Texas, United States, 77845

Baylor University Medical Center

Dallas, Texas, United States, 75231

Baylor St. Luke's Medical Center

Houston, Texas, United States, 77030

Ben Taub General Hospital - HCHD

Houston, Texas, United States, 77030

Houston Methodist Hospital

Houston, Texas, United States, 77030

Baylor Scott & White Medical Center - Irving

Irving, Texas, United States, 75061

Baylor Scott & White Hospital - Plano

Plano, Texas, United States, 75093

Baylor Scott & White Health

Temple, Texas, United States, 76502

United States, Utah

Intermountain LDS Hospital

Salt Lake City, Utah, United States, 84143

United States, Washington

The Providence Regional Medical Center Everett

Everett, Washington, United States, 98201

United States, West Virginia

West Virginia University Hospital

Morgantown, West Virginia, United States, 26506

Brazil

Santa Casa de Misericordia de Belo Horizonte

Belo Horizonte, MG, Brazil, 30150-221

Hospital Nossa Senhora das Graças; Setor de Pesquisa em Neurologia

Curitiba, PR, Brazil, 80810-040

Instituto de Pesquisa Clinica Evandro Chagas - IPEC FIOCRUZ

Rio de Janeiro, RJ, Brazil, 21045-900

CEMEC - Centro Multidisciplinar de Estudos Clínicos

Sao Bernardo Do Campo, SP, Brazil, 09715-090

Hospital de Base de Sao Jose do Rio Preto

Sao Jose do Rio Preto, SP, Brazil, 15090-000

Instituto de Infectologia Emilio Ribas

Sao Paulo, SP, Brazil, 01246-000

Instituto do Coração - HCFMUSP

Sao Paulo, SP, Brazil, 05403-900

Russian Federation

Medsi Clinic

Moscow, Adygeja, Russian Federation, 143442

O.M. Filatov City Clinical Hospital #15; Department of Surgery

Moskva, Moskovskaja Oblast, Russian Federation, 111539

City Pokrovskaya Hospital

Sankt-peterburg, Sankt Petersburg, Russian Federation, 199106

City Clinical Hospital # 52

Moscow, Russian Federation, 123182

Spain

Hospital Universitario de Bellvitge

Hospitalet de Llobregat, Barcelona, Spain, 08907

Hospital Universitario Principe de Asturias; Medicina Interna - Servicio de Enfermedades Infecciosas

Alcala de Henares, Madrid, Spain, 28005

Hospital Universitario HM Torrelodones

Torrelodones, Madrid, Spain, 28250

Hospital General Universitario de Guadalajara

Guadalajara, Spain, 19002

Hospital Universitario Fundacion Jimenez Diaz.

Madrid, Spain, 28040

Sponsors and Collaborators

Hoffmann-La Roche

Gilead Sciences

Investigators

• 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

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT04409262
• Other Study ID Numbers: WA42511; 2020-002275-34 ( EudraCT Number )
• First Posted: June 1, 2020
• 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).

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

Additional relevant MeSH terms:

Remdesivir; COVID-19; Pneumonia; Pneumonia, Viral; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents