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

Primary Purpose

COVID-19

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Baricitinib

Dexamethasone

Placebo

Remdesivir

About this trial

This is an interventional treatment trial for COVID-19 focused on measuring ACTT, Adaptive, COVID-19, Efficacy, Multicenter, novel coronavirus, Safety

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Hospitalized with symptoms suggestive of COVID-19.
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.
Male or non-pregnant female adult > / = 18 years of age at time of enrollment.
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.
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).
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.
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:

Prior enrollment in ACTT-3 or ACTT-4. Note: this includes subjects whose participation in ACTT was terminated early.
On invasive mechanical ventilation at the time of randomization (ordinal scale category 7).
Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours of randomization.
Positive test for influenza virus during the current illness (influenza testing is not required by protocol).
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.
Neutropenia (absolute neutrophil count <700 cells/microliter, 0.7 x 10^3/microliter).
Lymphopenia (absolute lymphocyte count <200 cells/microliter, 0.20 x 10^3/microliter).
Received five or more doses of remdesivir including the loading dose, outside of the study as treatment for COVID-19.
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).
Allergy to any study medication.
Received convalescent plasma or intravenous immunoglobulin [IVIg] for COVID-19, the current illness for which they are being enrolled.
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
Use of probenecid that cannot be discontinued at study enrollment.
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.
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.
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).
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.
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.
Had a known Venous thromboembolism (VTE)(deep vein thrombosis [DVT] or pulmonary embolism [PE]) during the current COVID-19 illness.

Sites / Locations

University of Alabama at Birmingham School of Medicine - Infectious Disease
UCSF Fresno Center for Medical Education and Research - Clinical Research Center
University of California San Diego Health - Jacobs Medical Center
University of California Los Angeles Medical Center - Westwood Clinic
University of California Irvine Medical Center - Infectious Disease
VA Palo Alto Health Care System - Infectious Diseases
University of California Davis Medical Center - Internal Medicine - Infectious Disease
Kaiser Permanente San Diego Medical Center
Naval Medical Center San Diego - Infectious Disease Clinic
University of California San Francisco - Zuckerberg San Francisco General Hospital - Division of Human Immunodeficiency Virus, Infectious Disease, and Global Medicine
Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases
Cedars Sinai Medical Center
VA Eastern Colorado Health Care System
Denver Health Division of Hospital Medicine - Main Campus
Georgetown University Medical Center - Division of Infectious Diseases
University of Florida Health - Shands Hospital - Division of Infectious Diseases and Global Medicine
University of Florida Health - Jacksonville - Department of Emergency Medicine
University of Miami Miller School of Medicine - Infectious Diseases
Emory Vaccine Center - The Hope Clinic
Atlanta VA Medical Center - Infectious Diseases Clinic
Tripler Army Medical Center
Northwestern Hospital - Infectious Disease
University of Illinois at Chicago College of Medicine - Division of Infectious Diseases
University of Iowa Hospitals & Clinics - Department of Internal Medicine
Tulane University - Section of Pulmonary Diseases, Critical Care, and Environmental Medicine
University of Maryland School of Medicine - Center for Vaccine Development - Baltimore
Johns Hopkins Hospital - Medicine - Infectious Diseases
Walter Reed National Military Medical Center
National Institutes of Health - Clinical Center, National Institute of Allergy and Infectious Diseases Laboratory Of Immunoregulation, Clinical Research Section
Massachusetts General Hospital - Infectious Diseases
University of Massachusetts Medical School - Infectious Diseases and Immunology
University of Michigan - Infectious Disease Clinic at Taubman Center
University of Minnesota Medical Center, Fairview - Infectious Diseases and International Medicine
Saint Louis University - Center for Vaccine Development
University of Nebraska Medical Center - Infectious Diseases
CHI Health Creighton University Medical Center - Bergan Mercy - Pulmonary Medicine
Atlantic Health System - Morristown Medical Center
University of New Mexico Clinical and Translational Science Center
Montefiore Medical Center - Infectious Diseases
New York University School of Medicine - Langone Medical Center - Microbiology - Parasitology
University of Rochester Medical Center - Vaccine Research Unit
Duke Human Vaccine Institute - Duke Vaccine and Trials Unit
Womack Army Medical Center - Pulmonary and Respiratory Services
University of Oklahoma Health Science Center - Surgery
Kaiser Permanente Northwest - Center for Health Research
Penn State Health Milton S. Hershey Medical Center - Division of Infectious Diseases
Hospital of the University of Pennsylvania - Infectious Diseases
University of Pittsburgh - Medicine - Infectious Diseases
Baylor Scott & White Health - Baylor University Medical Center - North Texas Infectious Disease Consultants
University of Texas Southwestern Medical Center - Internal Medicine - Infectious Diseases
Brooke Army Medical Center
University of Texas Medical Branch - Division of Infectious Disease
Methodist Hospital - Houston
Baylor College of Medicine - Molecular Virology and Microbiology
University of Texas Health Science Center at San Antonio - Infectious Diseases
University of Utah - Infectious Diseases
University of Virginia - Acute Care Surgery
Naval Medical Center Portsmouth - Infectious Disease Division
EvergreenHealth Infectious Disease Service
Providence Sacred Heart Medical Center
Madigan Army Medical Center - Infectious Disease Clinic
Tokyo Medical and Dental University - Medical Hospital - Department of Respiratory Medicine
National Center for Global Health and Medicine Hospital - Disease Control and Prevention Center
Seoul National University Bundang Hospital - Division of Infectious Diseases
Seoul National University Hospital
Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán - Departamento de Infectologia
Instituto Nacional de Enfermedades Respiratorias (INER) - Ismael Cosío Villegas
National University Health System - Division of Infectious Diseases
National University Health System - Alexandra Hospital - Division of Infectious Diseases
National Centre for Infectious Diseases
Changi General Hospital - Clinical Trials and Research Unit (CTRU)
Ng Teng Fong General Hospital - Infectious Disease Service

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Remdesivir plus Baricitinib

Remdesivir plus Dexamethasone

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Desirability of Outcome Ranking (DOOR) at 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.

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.

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.

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.

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.

Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 3

Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 5

Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 8

Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 11

Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 15

Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 22

Percentage of Participants at Each Clinical Status Using Ordinal Scale at 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.

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.

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.

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.

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.

Full Information

NCT ID

NCT04640168

First Posted

November 19, 2020

Last Updated

June 22, 2022

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

1. Study Identification

Unique Protocol Identification Number

NCT04640168

Brief Title

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

Official Title

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)

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Completed

Study Start Date

December 2, 2020 (Actual)

Primary Completion Date

May 18, 2021 (Actual)

Study Completion Date

June 18, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

5. Study Description

Brief Summary

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.

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

COVID-19

Keywords

ACTT, Adaptive, COVID-19, Efficacy, Multicenter, novel coronavirus, Safety

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

1010 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Remdesivir plus Baricitinib

Arm Type

Experimental

Arm Description

Arm Title

Remdesivir plus Dexamethasone

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Baricitinib

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Dexamethasone

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Placebo

Intervention Description

Placebo matching oral baricitinib or intravenous dexamethasone.

Intervention Type

Drug

Intervention Name(s)

Remdesivir

Intervention Description

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.

Primary Outcome Measure Information:

Title

Description

Time Frame

Day 1 through Day 29

Title

Description

Time Frame

Day 1 through Day 29

Title

Description

Time Frame

Day 1 through Day 29

Title

Description

Time Frame

Day 1 through Day 29

Secondary Outcome Measure Information:

Title

Change From Baseline in Alanine Aminotransferase (ALT)

Description

Time Frame