Adaptive COVID-19 Treatment Trial 2 (ACTT-2)

A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults (ACTT-2)

ACTT-2 will evaluate the combination of baricitinib and remdesivir compared to remdesivir alone. Subjects will be assessed daily while hospitalized. If the subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and oropharyngeal (OP) swab and blood (serum only) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the subject to return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone. The primary outcome is time to recovery by Day 29.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Remdesivir; Drug: Baricitinib; Other: Placebo

Detailed Description

This study is an adaptive randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. The study is a multicenter trial that will be conducted in up to approximately 100 sites globally. The study will compare different investigational therapeutic agents to a control arm. New arms can be introduced according to scientific and public health needs. There will be interim monitoring to allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s). Any such change would be accompanied by an updated sample size. This adaptive platform is used to rapidly evaluate different therapeutics in a population of those hospitalized with moderate to severe COVID-19. The platform will provide a common framework sharing a similar population, design, endpoints, and safety oversight. New stages with new therapeutics can be introduced. One independent Data and Safety Monitoring Board (DSMB) will actively monitor interim data in all stages to make recommendations about early study closure or changes to study arms.

ACTT-2 will evaluate the combination of baricitinib and remdesivir compared to remdesivir alone. Subjects will be assessed daily while hospitalized. If the subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and oropharyngeal (OP) swab and blood (serum only) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the subject to return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone.

All subjects will undergo a series of efficacy, safety, and laboratory assessments. Safety laboratory tests and blood (serum and plasma) research samples and oropharyngeal (OP) swabs will be obtained on Days 1 (prior to infusion) and Days 3, 5, 8, and 11 (while hospitalized). OP swabs and blood (serum only) plus safety laboratory tests will be collected on Day 15 and 29 (if the subject attends an in-person visit or are still hospitalized).

The primary outcome is time to recovery by Day 29. A key secondary outcome evaluates treatment-related improvements in the 8-point ordinal scale at Day 15. Each stage may prioritize different secondary endpoints for the purpose of multiple comparison analyses.

Contacts:

20-0006 Central Contact

Telephone: 1 (301) 7617948

Email: DMIDClinicalTrials@niaid.nih.gov

• Study Type: Interventional
• Enrollment (Actual): 1033
• Phase: Phase 3

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • University of Copenhagen - Centre of Excellence for Health, Immunity and Infections (CHIP) - Department of Infectious Diseases
• Japan
  • Tokyo, Japan, 162-8655
    • National Center for Global Health and Medicine Hospital - Disease Control and Prevention Center
• Korea, Republic of
  • Bundang-gu Seongnam-si, Korea, Republic of, 13620
    • Seoul National University Bundang Hospital - Division of Infectious Diseases
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
• Mexico
  • Mexico City, Mexico, 14080
    • Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán - Departamento de Infectologia
  • Mexico City, Mexico, 14080
    • Instituto Nacional de Enfermedades Respiratorias (INER) - Ismael Cosío Villegas
• Singapore
  • Singapore, Singapore, 119228
    • National University Health System - Division of Infectious Diseases
  • Singapore, Singapore, 308442
    • National Centre for Infectious Diseases (NCID)
  • Singapore, Singapore, 529889
    • Changi General Hospital - Clinical Trials and Research Unit (CTRU)
  • Singapore, Singapore, 609606
    • Ng Teng Fong General Hospital - Infectious Disease Service
• Spain
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos - Enfermedades Infecciosas
  • Cataluña
    • Barcelona, Cataluña, Spain, 08036
      • Hospital Clinic Barcelona, Servicio de Salud Internacional
    • Barcelona, Cataluña, Spain, 08916
      • Hospital Germans Trias i Pujol - Servei Malalties Infeccioses
• United Kingdom
  • Brighton, United Kingdom
    • Royal Sussex County Hospital - Department of Intensive Care Medicine
  • City Of London, United Kingdom
    • Saint Thomas' Hospital - Directorate of Infection
  • Leeds, United Kingdom
    • St. James's University Hospital - Infectious Diseases
  • Newcastle Upon Tyne, United Kingdom
    • Royal Victoria Infirmary - Department of Infectious Diseases
  • Oxford, United Kingdom
    • John Radcliffe Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham School of Medicine - Infectious Disease
  • California
    • La Jolla, California, United States, 29037
      • University of California San Diego Health - Jacobs Medical Center
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles Medical Center - Westwood Clinic
    • Orange, California, United States, 92868-3298
      • University of California Irvine Medical Center - Infectious Disease
    • Palo Alto, California, United States, 94304-1207
      • VA Palo Alto Health Care System - Infectious Diseases
    • Palo Alto, California, United States, 94304-1503
      • Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases
    • Sacramento, California, United States, 95817-1460
      • University of California Davis Medical Center - Internal Medicine - Infectious Disease
    • San Diego, California, United States, 92314
      • Naval Medical Center San Diego - Infectious Disease Clinic
    • San Francisco, California, United States, 94110-2859
      • University of California San Francisco - Zuckerberg San Francisco General Hospital - Division of Human Immunodeficiency Virus, Infectious Disease, and Global Medicine
    • West Hollywood, California, United States, 90048-1804
      • Cedars Sinai Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Eastern Colorado Health Care System
    • Denver, Colorado, United States, 80204
      • Denver Health Division of Hospital Medicine - Main Campus
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center - Division of Infectious Diseases
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Health - Shands Hospital - Division of Infectious Diseases and Global Medicine
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine - Infectious Diseases
  • Georgia
    • Decatur, Georgia, United States, 30030-1705
      • Emory Vaccine Center - The Hope Clinic
    • Decatur, Georgia, United States, 30033
      • Atlanta VA Medical Center - Infectious Diseases Clinic
  • Illinois
    • Chicago, Illinois, United States, 60611-2908
      • Northwestern Hospital - Infectious Disease
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago College of Medicine - Division of Infectious Diseases
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine - Infectious Diseases
  • Louisiana
    • Kenner, Louisiana, United States, 70065
      • Ochsner Medical Center - Kenner - Department of Infectious Diseases
    • New Orleans, Louisiana, United States, 70119
      • Southeast Louisiana Veterans Health Care System (SLVHCS) - Section of Infectious Diseases
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland School of Medicine - Center for Vaccine Development - Baltimore
    • Baltimore, Maryland, United States, 21287-0005
      • Johns Hopkins Hospital - Medicine - Infectious Diseases
    • Bethesda, Maryland, United States, 20889
      • Walter Reed National Military Medical Center
    • Bethesda, Maryland, United States, 20892-1504
      • National Institutes of Health - Clinical Center, National Institute of Allergy and Infectious Diseases Laboratory Of Immunoregulation, Clinical Research Section
  • Massachusetts
    • Boston, Massachusetts, United States, 02114-2621
      • Massachusetts General Hospital - Infectious Diseases
    • Worcester, Massachusetts, United States, 01655-0002
      • University of Massachusetts Medical School - Infectious Diseases and Immunology
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455-0341
      • University of Minnesota Medical Center, Fairview - Infectious Diseases and International Medicine
  • Missouri
    • Saint Louis, Missouri, United States, 63104-1015
      • Saint Louis University - Center for Vaccine Development
  • Nebraska
    • Omaha, Nebraska, United States, 68198-5400
      • University of Nebraska Medical Center - Infectious Diseases
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Clinical and Translational Science Center
  • New York
    • Bronx, New York, United States, 10467-2401
      • Montefiore Medical Center - Infectious Diseases
    • New York, New York, United States, 10016
      • New York University School of Medicine - Langone Medical Center - Microbiology - Parasitology
    • Rochester, New York, United States, 14642-0001
      • University of Rochester Medical Center - Vaccine Research Unit
  • North Carolina
    • Durham, North Carolina, United States, 27704
      • Duke Human Vaccine Institute - Duke Vaccine and Trials Unit
    • Fort Bragg, North Carolina, United States, 28310
      • Womack Army Medical Center - Pulmonary and Respiratory Services
  • Oregon
    • Portland, Oregon, United States, 97227
      • Kaiser Permanente Northwest - Center for Health Research
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Health Milton S. Hershey Medical Center - Division of Infectious Diseases
    • Philadelphia, Pennsylvania, United States, 19104-4863
      • University of Pennsylvania Perelman School of Medicine - Penn Institute for Immunology
  • Tennessee
    • Nashville, Tennessee, United States, 37232-0011
      • Vanderbilt University Medical Center - Infectious Diseases
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor Scott & White Health - Baylor University Medical Center - North Texas Infectious Disease Consultants
    • Dallas, Texas, United States, 75390-8884
      • University of Texas Southwestern Medical Center - Internal Medicine - Infectious Diseases
    • Fort Sam Houston, Texas, United States, 78234
      • Brooke Army Medical Center
    • Galveston, Texas, United States, 77555-0435
      • University of Texas Medical Branch - Division of Infectious Disease
    • Houston, Texas, United States, 77030-3411
      • Baylor College of Medicine - Molecular Virology and Microbiology
    • San Antonio, Texas, United States, 78229-3901
      • University of Texas Health Science Center at San Antonio - Infectious Diseases
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah - Infectious Diseases
  • Virginia
    • Charlottesville, Virginia, United States, 22908-0816
      • University of Virginia - Acute Care Surgery
    • Portsmouth, Virginia, United States, 23708
      • Naval Medical Center Portsmouth - Infectious Disease Division
  • Washington
    • Kirkland, Washington, United States, 98034
      • EvergreenHealth Infectious Disease Service
    • Spokane, Washington, United States, 99204
      • Providence Sacred Heart Medical Center
    • Tacoma, Washington, United States, 98431
      • Madigan Army Medical Center - Infectious Disease Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Admitted to a hospital with symptoms suggestive of COVID-19.
2. Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures.
3. Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
4. Male or non-pregnant female adult > / = 18 years of age at time of enrollment.

5. Has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay in any specimen, as documented by either of the following:

   • PCR positive in sample collected < 72 hours prior to randomization; OR
   • PCR positive in sample collected >/= 72 hours prior to randomization, documented inability to obtain a repeat sample (e.g. due to lack of testing supplies, limited testing capacity, results taking >24 hours, etc.) AND progressive disease suggestive of ongoing SARS-CoV-2 infection.

6. Illness of any duration, and at least one of the following:

   • Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR
   • SpO2 < / = 94% on room air, OR
   • Requiring supplemental oxygen, OR
   • Requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO).
7. Women of childbearing potential must agree to either abstinence or use at least one primary form of contraception not including hormonal contraception from the time of screening through Day 29.
8. Agrees to not participate in another clinical trial for the treatment of COVID-19 through Day 29.

Exclusion Criteria:

1. Alanine Transaminase (ALT) or Aspartate Transaminase (AST) > 5 times the upper limit of normal.
2. Estimated glomerular filtration rate (eGFR) < 30 ml/min or patient is receiving hemodialysis or hemofiltration at time of screening.
3. Neutropenia (absolute neutrophil count <1000 cells/microliter) (<1.0 x 103/microliter or <1.0 GI/L).
4. Lymphopenia (absolute lymphocyte count <200 cells/microliter) (<0.20 x 103/microliter or <0.20 GI/L)
5. Pregnancy or breast feeding.
6. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours.
7. Allergy to any study medication.
8. Received three or more doses of remdesivir, including the loading dose, outside of the study under the EUA (or similar mechanism) for COVID-19.
9. Received convalescent plasma or intravenous immunoglobulin [IVIg]) for COVID-19, the current illness for which they are being enrolled.
10. Received small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatibib, genfinitib), in the 1 week prior to screening
11. Received monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab]), or T-cells (e.g., abatacept) in the 4 weeks prior to screening.
12. Received monoclonal antibodies targeting B-cell (e.g., rituximab, and including any targeting multiple cell lines including B-cells) in the 3 months prior to screening.
13. Received other immunosuppressants in the 4 weeks prior to screening and in the judgement of the investigator, the risk of immunosuppression with baricitinib is larger than the risk of COVID-19.
14. Received >/= 20 mg/day of prednisone or equivalent for >/=14 consecutive days in the 4 weeks prior to screening.
15. Use of probenecid that cannot be discontinued at study enrollment.
16. Have diagnosis of current active tuberculosis (TB) or, if known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history only, no screening required).
17. Suspected serious, active bacterial, fungal, viral, or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking investigational product.
18. Have received any live vaccine (that is, live attenuated) within 4 weeks before screening, or intend to receive a live vaccine (or live attenuated) during the study. Note: Use of non-live (inactivated) vaccinations is allowed for all subjects.
19. Have a history of VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) within 12 weeks prior to screening or have a history of recurrent (>1) VTE (DVT/PE).
20. Immunocompromised patients, patients with a chronic medical condition, or those taking a medication that cannot be discontinued at enrollment, who, in the judgment of PI, are at increased risk for serious infections or other safety concerns given the study products.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Remdesivir plus Baricitinib; 200 mg of Remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of Remdesivir while hospitalized for up to a 10-day total course and 4 mg (2 tablets of 2 mg) of Baricitinib administered orally daily for the duration of the hospitalization up to a 14-day total course.	Drug: Remdesivir; Drug Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, the lyophilized formulation of Remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide.; Drug: Baricitinib; Baricitinib is a Janus kinase (JAK) inhibitor with the chemical name [1-(ethylsulfonyl)-3-(4-(7Hpyrrolo(2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile Each tablet contains 2 mg of baricitinib and the following inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, ferric oxide, lecithin (soya), polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.
Placebo Comparator: Remdesivir plus Placebo; 200 mg of Remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of Remdesivir while hospitalized for up to a 10-day total course and 4 mg (2 tablets of 2 mg) of Baricitinib Placebo administered orally daily for the duration of the hospitalization up to a 14-day total course.	Drug: Remdesivir; Drug Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, the lyophilized formulation of Remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide.; Other: Placebo; The matching Baricitinib placebo contains lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The coating for the placebo tablet is identical to that of the corresponding active tablet.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Recovery	Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care.	Day 1 through Day 29
Time to Recovery by Race	Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care.	Day 1 through Day 29
Time to Recovery by Ethnicity	Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care.	Day 1 through Day 29
Time to Recovery by Sex	Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care.	Day 1 through Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Alanine Transaminase (ALT)	Blood to evaluate ALT was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in Aspartate Transaminase (AST)	Blood to evaluate AST was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in Creatinine	Blood to evaluate serum creatinine was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in Glucose	Blood to evaluate serum glucose was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in Hemoglobin	Blood to evaluate hemoglobin was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in Platelets	Blood to evaluate platelets was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in Prothrombin International Normalized Ratio (INR)	Blood to evaluate INR was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in Total Bilirubin	Blood to evaluate total bilirubin was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in White Blood Cell Count (WBC)	Blood to evaluate WBC was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in Neutrophils	BBlood to evaluate neutrophils was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in Lymphocytes	Blood to evaluate lymphocytes was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in Monocytes	Blood to evaluate monocytes was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in Basophils	Blood to evaluate basophils was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in Eosinophils	Blood to evaluate eosinophils was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29
Change in National Early Warning Score (NEWS) From Baseline	The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure. The minimum score is 0, representing the better outcome, and the maximum value is 19, representing the worse outcome.	Days 1, 3, 5, 8, 11, 15, 22, and 29
Percentage of Participants Reporting Grade 3 and 4 Clinical and/or Laboratory Adverse Events (AEs)	Grade 3 AEs are defined as events that interrupt usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. Severe events are usually incapacitating. Grade 4 AEs are defined as events that are potentially life threatening.	Day 1 through Day 29
Percentage of Participants Reporting Serious Adverse Events (SAEs)	An SAE is defined as an AE or suspected adverse reaction is considered serious if, in the view of either the investigator or the sponsor, it results in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.	Day 1 through Day 29
Duration of Hospitalization	Duration of hospitalization was determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die.	Day 1 through Day 29
Duration of New Non-invasive Ventilation or High Flow Oxygen Use	Duration of new non-invasive ventilation or high flow oxygen use was measured in days among participants who were not on non-invasive ventilation or high-flow oxygen use at baseline, determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die	Day 1 through Day 29
Duration of New Oxygen Use	Duration of new oxygen use was measured in days among participants who were not on oxygen at baseline, determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die	Day 1 through Day 29
Duration of New Ventilator or Extracorporeal Membrane Oxygenation (ECMO) Use	Duration of new ventilator or ECMO use was measured in days among participants who were not on a ventilator or ECMO at baseline, determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die	Day 1 through Day 29
Duration of Oxygen Use	Duration of oxygen use was measured in days among participants who were on oxygen in based, calculated in two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die.	Day 1 through Day 29
Percentage of Participants Discontinued or Temporarily Suspended From Investigational Therapeutics	Participants may have been discontinued from investigational therapeutics due to discharge or death. The halting or slowing of the infusion for any reason was collected, as was missed doses in the series of 10 doses of Remdesivir, or in the 14 doses of Baricitinib/placebo.	Day 1 through Day 14
Percentage of Participants Requiring New Ventilator or Extracorporeal Membrane Oxygenation (ECMO) Use	The percentage of participants requiring new ventilator or ECMO use was determined as the percentage not on a ventilator or ECMO at baseline	Day 1 through Day 29
Percentage of Participants Requiring New Oxygen Use	The percentage of participants requiring new oxygen use was determined as the percentage of participants not requiring oxygen at baseline	Day 1 through Day 29
Mean Change in the Ordinal Scale	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. A positive change indicates a worsening and a negative change is an improvement.	Day 1, 3, 5, 8, 11, 15, 22, and 29
Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 15	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. Data was imputed using last observation carried forward or worst possible score based on hospitalization status (2 if not hospitalized, 7 if hospitalized) when there was a change in hospitalization status since last score. Deaths were imputed as an 8.	Day 15
Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 1	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.	Day 1
Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 3	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.	Day 3
Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 5	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.	Day 5
Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 8	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.	Day 8
Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 11	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.	Day 11
Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 22	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.	Day 22
Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 29	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.	Day 29
14-day Participant Mortality	The mortality rate was determined as the proportion of participants who died by study Day 15. The proportions reported are Kaplan-Meier estimates.	Day 1 through Day 15
28-day Participant Mortality	The mortality rate was determined as the proportion of participants who died by study Day 29. The proportions reported are Kaplan-Meier estimates.	Day 1 through Day 29
Time to an Improvement of One Category Using an Ordinal Scale	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. Time to improvement by at least one category was determined for each participant	Day 1 through Day 29
Time to an Improvement of Two Categories Using an Ordinal Scale	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities. Time to improvement by at least two categories was determined for each participant	Day 1 through Day 29
Time to Discharge or to a NEWS of 2 or Less and Maintained for 24 Hours, Whichever Occurs First	The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure. The minimum score is 0, representing the better outcome, and the maximum value is 19, representing the worse outcome. The time to discharge or a NEWS of less than or equal to 2 was determined for each participant.	Day 1 through Day 29
Change From Baseline in C-reactive Protein (CRP)	Blood to evaluate CRP was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in D-dimer Concentration	Blood to evaluate d-dimer concentration was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.	Days 1, 3, 5, 8, 11, 15 and 29

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.
• Kramer A, Prinz C, Fichtner F, Fischer AL, Thieme V, Grundeis F, Spagl M, Seeber C, Piechotta V, Metzendorf MI, Golinski M, Moerer O, Stephani C, Mikolajewska A, Kluge S, Stegemann M, Laudi S, Skoetz N. Janus kinase inhibitors for the treatment of COVID-19. Cochrane Database Syst Rev. 2022 Jun 13;6:CD015209. doi: 10.1002/14651858.CD015209. Review.
• Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V, Marconi VC, Ruiz-Palacios GM, Hsieh L, Kline S, Tapson V, Iovine NM, Jain MK, Sweeney DA, El Sahly HM, Branche AR, Regalado Pineda J, Lye DC, Sandkovsky U, Luetkemeyer AF, Cohen SH, Finberg RW, Jackson PEH, Taiwo B, Paules CI, Arguinchona H, Erdmann N, Ahuja N, Frank M, Oh MD, Kim ES, Tan SY, Mularski RA, Nielsen H, Ponce PO, Taylor BS, Larson L, Rouphael NG, Saklawi Y, Cantos VD, Ko ER, Engemann JJ, Amin AN, Watanabe M, Billings J, Elie MC, Davey RT, Burgess TH, Ferreira J, Green M, Makowski M, Cardoso A, de Bono S, Bonnett T, Proschan M, Deye GA, Dempsey W, Nayak SU, Dodd LE, Beigel JH; ACTT-2 Study Group Members. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. 2021 Mar 4;384(9):795-807. doi: 10.1056/NEJMoa2031994. Epub 2020 Dec 11.
• Azzi Y, Bartash R, Scalea J, Loarte-Campos P, Akalin E. COVID-19 and Solid Organ Transplantation: A Review Article. Transplantation. 2021 Jan 1;105(1):37-55. doi: 10.1097/TP.0000000000003523.

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2020
• Primary Completion (Actual): July 31, 2020
• Study Completion (Actual): July 31, 2020

Study Registration Dates

• First Submitted: May 22, 2020
• First Submitted That Met QC Criteria: May 22, 2020
• First Posted (Actual): May 26, 2020

Study Record Updates

• Last Update Posted (Actual): March 14, 2022
• Last Update Submitted That Met QC Criteria: March 9, 2022
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Safety; Efficacy; COVID-19; Adaptive; Multicenter; novel coronavirus
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Remdesivir
• Other Study ID Numbers: 20-0006 ACTT-2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No