Adaptive COVID-19 Treatment Trial 4 (ACTT-4)

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-4)

ACTT-4 will evaluate the combination of baricitinib and remdesivir compared to dexamethasone and remdesivir. 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, oropharyngeal (OP) swabs, plasma (Day 29), and serum for secondary research as well as clinical outcome data. However, if infection control or other restrictions limit the ability of the subject to return to the clinic, 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 objective is to evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir as assessed by the mechanical ventilation free survival by Day 29.

Study Overview

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

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-4 will evaluate the combination of baricitinib and remdesivir compared to dexamethasone and remdesivir. 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, oropharyngeal (OP) swabs, plasma (Day 29), and serum for secondary research as well as clinical outcome data. However, if infection control or other restrictions limit the ability of the subject to return to the clinic, 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 objective is to evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir as assessed by the mechanical ventilation free survival by Day 29. The key secondary objective is to evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir according to clinical status (8-point ordinal scale) at Day 15.

Contacts:

20-0006 Central Contact

Telephone: 1 (301) 7617948

Email: DMIDClinicalTrials@niaid.nih.gov

• Study Type: Interventional
• Enrollment (Actual): 1010
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Tokyo, Japan, 162-8655
    • National Center for Global Health and Medicine Hospital - Disease Control and Prevention Center
  • Tokyo, Japan, 113-8519
    • Tokyo Medical and Dental University - Medical Hospital - Department of Respiratory Medicine
• Korea, Republic of
  • Gyeonggi-do
    • Bundang-gu Seongnam-si, Gyeonggi-do, Korea, Republic of, 13620
      • Seoul National University Bundang Hospital - Division of Infectious Diseases
  • Jongno-gu
    • Seoul, Jongno-gu, 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, 529889
    • Changi General Hospital - Clinical Trials and Research Unit (CTRU)
  • Singapore, Singapore, 609606
    • Ng Teng Fong General Hospital - Infectious Disease Service
  • Singapore, Singapore, 308442
    • National Centre for Infectious Diseases
  • Singapore, Singapore, 159964
    • National University Health System - Alexandra Hospital - Division of Infectious Diseases
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham School of Medicine - Infectious Disease
  • California
    • Fresno, California, United States, 93701
      • UCSF Fresno Center for Medical Education and Research - Clinical Research Center
    • 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
    • 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 Diego, California, United States, 92123
      • Kaiser Permanente San Diego Medical Center
    • 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
    • Stanford, California, United States, 94305-2200
      • Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases
    • West Hollywood, California, United States, 90048-1804
      • Cedars Sinai Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • VA 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
    • Jacksonville, Florida, United States, 32209
      • University of Florida Health - Jacksonville - Department of Emergency 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
  • Hawaii
    • Honolulu, Hawaii, United States, 96859
      • Tripler Army Medical Center
  • 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
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinics - Department of Internal Medicine
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University - Section of Pulmonary Diseases, Critical Care, and Environmental Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21287-0005
      • Johns Hopkins Hospital - Medicine - Infectious Diseases
    • Baltimore, Maryland, United States, 21201-1509
      • University of Maryland School of Medicine - Center for Vaccine Development - Baltimore
    • 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
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan - Infectious Disease Clinic at Taubman Center
  • 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, 68105
      • University of Nebraska Medical Center - Infectious Diseases
    • Omaha, Nebraska, United States, 68124
      • CHI Health Creighton University Medical Center - Bergan Mercy - Pulmonary Medicine
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Atlantic Health System - Morristown Medical Center
  • 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, 10016-6402
      • 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
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Science Center - Surgery
  • 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, 19104-4238
      • Hospital of the University of Pennsylvania - Infectious Diseases
    • Pittsburgh, Pennsylvania, United States, 15213-2582
      • University of Pittsburgh - Medicine - 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
    • Houston, Texas, United States, 77030-2703
      • Methodist Hospital - Houston
    • 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, 84132-0002
      • 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. Hospitalized with symptoms suggestive of COVID-19.
2. Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures and understands and agrees to comply with planned study procedures.
3. Male or non-pregnant female adult > / = 18 years of age at time of enrollment.
4. Illness of any duration and has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay (e.g. NAAT, antigen test) in any respiratory specimen or saliva < / = 14 days prior to randomization.
5. Within the 7 days prior to randomization requiring new use of supplemental oxygen (or increased oxygen requirement if on chronic oxygen) and requires at the time of randomization low or high flow oxygen devices or use of non-invasive mechanical ventilation (ordinal scale category 5 or 6).
6. 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.
7. Agrees not to participate in another blinded clinical trial (both pharmacologic and other types of interventions) for the treatment of COVID-19 through Day 29.

Exclusion Criteria:

1. Prior enrollment in ACTT-3 or ACTT-4. Note: this includes subjects whose participation in ACTT was terminated early.
2. On invasive mechanical ventilation at the time of randomization (ordinal scale category 7).
3. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours of randomization.
4. Positive test for influenza virus during the current illness (influenza testing is not required by protocol).

5. Subjects with a low glomerular filtration rate (eGFR), specifically:

   1. Subjects with an eGFR 15-30 mL/min are excluded unless in the opinion of the PI, the potential benefit of participation outweighs the potential risk of study participation.
   2. All subjects with an eGFR <15 mL/min
   3. All subjects on hemodialysis and/or hemofiltration at screening, irrespective of eGFR are excluded.
6. Neutropenia (absolute neutrophil count <700 cells/microliter, 0.7 x 10^3/microliter).
7. Lymphopenia (absolute lymphocyte count <200 cells/microliter, 0.20 x 10^3/microliter).
8. Received five or more doses of remdesivir including the loading dose, outside of the study as treatment for COVID-19.
9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 1 until two weeks after the last study product is given are not excluded).
10. Allergy to any study medication.
11. Received convalescent plasma or intravenous immunoglobulin [IVIg] for COVID-19, the current illness for which they are being enrolled.

12. Received any of the following in the two weeks prior to screening as treatment of COVID-19:

    • More than one dose of baricitinib for the treatment of COVID-19;
    • Other small molecule tyrosine kinase inhibitors (e.g. imatinib, gefitinib, acalabrutinib, etc.);
    • monoclonal antibodies targeting cytokines (e.g., TNF inhibitors, anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], etc.);
    • monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19. Note: receipt of anti-SARS-CoV-2 monoclonal antibody (mAb) prior to enrollment (e.g. bamlanivimab) for their current COVID-19 illness is not exclusionary
13. Use of probenecid that cannot be discontinued at study enrollment.
14. Received 6 mg or more of dexamethasone by mouth (po) or Intravenous (IV) (or equivalent for other glucocorticoids) in one day, on more than one day, in the 7 days prior to time of randomization. Note: 6 mg dexamethasone dose equivalents include 40 mg prednisone, 32 mg methylprednisolone and 160 mg hydrocortisone.
15. Received > / = 20 mg/day of prednisone po or IV (or equivalent for other glucocorticoids) for > / = 14 consecutive days in the 4 weeks prior to screening.
16. Have diagnosis of current active or latent tuberculosis (TB), if known, treated for less than 4 weeks with appropriate therapy (by history only, no screening required).
17. Serious infection (besides COVID-19), immunosuppressive state, or immunosuppressive medications that in the opinion of the investigator could constitute a risk when taking baricitinib or dexamethasone.
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 including SARS-CoV-2 vaccine is allowed for all subjects.
19. Had a known Venous thromboembolism (VTE)(deep vein thrombosis [DVT] or pulmonary embolism [PE]) during the current COVID-19 illness.

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; 4 mg of baricitinib administered as 2 tablets taken orally daily while hospitalized for up to a 14-day total course; and dexamethasone placebo administered as an intravenous injection daily while hospitalized for up to a 10-day total course.	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.; Other: Placebo; Placebo matching oral baricitinib or intravenous dexamethasone.; 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.
Experimental: Remdesivir plus Dexamethasone; 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; baricitinib placebo administered as 2 tablets taken orally daily while hospitalized for up to a 14-day total course; and 6 mg of dexamethasone administered as an intravenous injection daily while hospitalized for up to a 10-day total course.	Other: Placebo; Placebo matching oral baricitinib or intravenous dexamethasone.; 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: Dexamethasone; Dexamethasone Sodium Phosphate Injection, USP, is an adrenocortical steroid anti-inflammatory drug. It is a water-soluble inorganic ester of dexamethasone. Each mL contains dexamethasone sodium phosphate equivalent to dexamethasone phosphate 4 mg or dexamethasone 3.33 mg; benzyl alcohol 10 mg added as preservative; sodium citrate dihydrate 11 mg; sodium sulfite 1 mg as an antioxidant.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Proportion of Participants Not Meeting Criteria for One of the Following Two Ordinal Scale Categories at Any Time: 8) Death; 7) Hospitalized, on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO)	Mechanical ventilation-free survival was assessed through Day 29, defined as the proportion of participants who had not died nor were hospitalized on invasive mechanical ventilation or ECMO as of Day 29. Results are reported as Kaplan Meier estimates.	Day 1 through Day 29
The Proportion of Participants Not Meeting Criteria for One of the Following Two Ordinal Scale Categories at Any Time: 8) Death; 7) Hospitalized, on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO) by Race	Mechanical ventilation-free survival was assessed through Day 29, defined as the proportion of participants who had not died nor were hospitalized on invasive mechanical ventilation or ECMO as of Day 29. Results are reported as Kaplan Meier estimates.	Day 1 through Day 29
The Proportion of Participants Not Meeting Criteria for One of the Following Two Ordinal Scale Categories at Any Time: 8) Death; 7) Hospitalized, on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO) by Ethnicity	Mechanical ventilation-free survival was assessed through Day 29, defined as the proportion of participants who had not died nor were hospitalized on invasive mechanical ventilation or ECMO as of Day 29. Results are reported as Kaplan Meier estimates.	Day 1 through Day 29
The Proportion of Participants Not Meeting Criteria for One of the Following Two Ordinal Scale Categories at Any Time: 8) Death; 7) Hospitalized, on Invasive Mechanical Ventilation or Extracorporeal Membrane Oxygenation (ECMO) by Sex	Mechanical ventilation-free survival was assessed through Day 29, defined as the proportion of participants who had not died nor were hospitalized on invasive mechanical ventilation or ECMO as of Day 29. Results are reported as Kaplan Meier estimates.	Day 1 through Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 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 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
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
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
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
Change From Baseline in Neutrophils	Blood 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 Alanine Aminotransferase (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 Aminotransferase (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 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 Glucose	Blood to evaluate 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
Days of Invasive Mechanical Ventilation / Extracorporeal Membrane Oxygenation (ECMO)	Duration of invasive ventilation/ECMO was measured in days among participants who required invasive ventilation, 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
Days of Non-invasive Ventilation/High Flow Oxygen	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 Supplemental Oxygen Use	Duration of supplemental oxygen use was measured in days among participants who were on oxygen at baseline, 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
Desirability of Outcome Ranking (DOOR) at Day 15	Desirability of Outcome Ranking (DOOR) based on ordinal scale: 1) Recovered (category 1, 2 or 3 on ordinal scale); 2) Improved (> / = 1 category improvement of ordinal scale compared with baseline) & no serious adverse event (SAE); 3) Improved (> / = 1 category improvement of the ordinal scale compared with baseline) & SAE (related or unrelated); 4) No change in ordinal scale from baseline & no SAE; 5) No change in ordinal scale from baseline & SAE (related or unrelated); 6) Worsening (> / = 1 category worse in ordinal scale from baseline); 7) Death.	Day 1 through Day 15
Desirability of Outcome Ranking (DOOR) at Day 29	Desirability of Outcome Ranking (DOOR) based on ordinal scale: 1) Recovered (category 1, 2 or 3 on ordinal scale); 2) Improved (> / = 1 category improvement of ordinal scale compared with baseline) & no serious adverse event (SAE); 3) Improved (> / = 1 category improvement of the ordinal scale compared with baseline) & SAE (related or unrelated); 4) No change in ordinal scale from baseline & no SAE; 5) No change in ordinal scale from baseline & SAE (related or unrelated); 6) Worsening (> / = 1 category worse in ordinal scale from baseline); 7) Death.	Day 1 through Day 29
Number of Participants With Discontinuation or Temporary Suspension of Study Product Administration	Discontinuation or temporary suspension of study product administration, including participants who died or were discharged, was evaluated for each study product/placebo.	Day 1 through Day 10
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 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, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, participant is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use.	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 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, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, participant is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use.	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 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, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, participant is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use.	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 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, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, participant is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use.	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 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, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, participant is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use.	Day 11
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 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, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, participant is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use.	Day 15
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 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, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, participant is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use.	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 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, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, participant is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use.	Day 29
Percentage of Participants Meeting Criteria for Each of the 8 Ordinal Scale Categories	The ordinal scale categories are defined as: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or 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, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use.	Day 15
The Proportion of Participants Not Meeting Criteria for One of the Three Most Severe Ordinal Scale Categories at Any Time.	The three most severe ordinal scale categories are: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices.	Day 1 through Day 29
Time to an Improvement of One Category From Baseline 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 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, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use. 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 From Baseline 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 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, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use. Time to improvement by at least two categories was determined for each participant.	Day 1 through Day 29
Time to Recovery	Day of recovery is defined as the first day on which the participant satisfies one of the following three ordinal scale categories: 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care; 2) Not hospitalized, but has new or increased limitation on activities and/or new or increased requirement for home oxygen over baseline, pre-COVID-19 status; 1) Not hospitalized, patient is back to their baseline, pre-COVID-19 status, that is, no new or increased limitations on activities and no new or increased oxygen use.	Day 1 through Day 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.
• Wolfe CR, Tomashek KM, Patterson TF, Gomez CA, Marconi VC, Jain MK, Yang OO, Paules CI, Palacios GMR, Grossberg R, Harkins MS, Mularski RA, Erdmann N, Sandkovsky U, Almasri E, Pineda JR, Dretler AW, de Castilla DL, Branche AR, Park PK, Mehta AK, Short WR, McLellan SLF, Kline S, Iovine NM, El Sahly HM, Doernberg SB, Oh MD, Huprikar N, Hohmann E, Kelley CF, Holodniy M, Kim ES, Sweeney DA, Finberg RW, Grimes KA, Maves RC, Ko ER, Engemann JJ, Taylor BS, Ponce PO, Larson L, Melendez DP, Seibert AM, Rouphael NG, Strebe J, Clark JL, Julian KG, de Leon AP, Cardoso A, de Bono S, Atmar RL, Ganesan A, Ferreira JL, Green M, Makowski M, Bonnett T, Beresnev T, Ghazaryan V, Dempsey W, Nayak SU, Dodd LE, Beigel JH, Kalil AC; ACTT-4 Study Group. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial. Lancet Respir Med. 2022 Sep;10(9):888-899. doi: 10.1016/S2213-2600(22)00088-1. Epub 2022 May 23.

Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2020
• Primary Completion (Actual): May 18, 2021
• Study Completion (Actual): June 18, 2021

Study Registration Dates

• First Submitted: November 19, 2020
• First Submitted That Met QC Criteria: November 19, 2020
• First Posted (Actual): November 23, 2020

Study Record Updates

• Last Update Posted (Actual): June 28, 2022
• Last Update Submitted That Met QC Criteria: June 22, 2022
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Safety; Efficacy; COVID-19; Adaptive; Multicenter; novel coronavirus; ACTT
• 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Anti-Inflammatory Agents; Antimetabolites; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone; Remdesivir
• Other Study ID Numbers: 20-0006 ACTT-4

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