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

• ClinicalTrials.gov Identifier: NCT04640168
• Recruitment Status: Completed
• First Posted: November 23, 2020
• Results First Posted: June 28, 2022
• Last Update Posted: June 28, 2022
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

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.

Condition or disease	Intervention/treatment	Phase
COVID-19	Drug: Baricitinib; Drug: Dexamethasone; Other: Placebo; Drug: Remdesivir	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1010 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: December 2, 2020
• Actual Primary Completion Date: May 18, 2021
• Actual Study Completion Date: June 18, 2021

Arms and Interventions

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.	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.; 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.

Outcome Measures

Primary Outcome Measures :

1. 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) [ Time Frame: Day 1 through Day 29 ]
   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.
2. 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 [ Time Frame: Day 1 through Day 29 ]
   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.
3. 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 [ Time Frame: Day 1 through Day 29 ]
   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.
4. 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 [ Time Frame: Day 1 through Day 29 ]
   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 :

1. Change From Baseline in Alanine Aminotransferase (ALT) [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
   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.
2. Change From Baseline in Aspartate Aminotransferase (AST) [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
   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.
3. Change From Baseline in C-reactive Protein (CRP) [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
   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.
4. Change From Baseline in Creatinine [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
   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.
5. Change From Baseline in D-dimer Concentration [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
   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.
6. Change From Baseline in Glucose [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
   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.
7. Change From Baseline in Hemoglobin [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
   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.
8. Change From Baseline in Platelets [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
   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.
9. Change From Baseline in Prothrombin International Normalized Ratio (INR) [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
   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.
10. Change From Baseline in Total Bilirubin [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
    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.
11. Change From Baseline in White Blood Cell Count (WBC) [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
    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.
12. Change From Baseline in Neutrophils [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
    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.
13. Change From Baseline in Lymphocytes [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
    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.
14. Change From Baseline in Monocytes [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
    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.
15. Change From Baseline in Basophils [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
    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.
16. Change From Baseline in Eosinophils [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
    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.
17. Percentage of Participants Reporting Grade 3 and 4 Clinical and/or Laboratory Adverse Events (AEs) [ Time Frame: Day 1 through Day 29 ]
    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.
18. Percentage of Participants Reporting Serious Adverse Events (SAEs) [ Time Frame: Day 1 through Day 29 ]
    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.
19. Days of Invasive Mechanical Ventilation / Extracorporeal Membrane Oxygenation (ECMO) [ Time Frame: Day 1 through Day 29 ]
    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.
20. Days of Non-invasive Ventilation/High Flow Oxygen [ Time Frame: Day 1 through Day 29 ]
    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.
21. Duration of Supplemental Oxygen Use [ Time Frame: Day 1 through Day 29 ]
    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.
22. Desirability of Outcome Ranking (DOOR) at Day 15 [ Time Frame: Day 1 through 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.
23. Desirability of Outcome Ranking (DOOR) at Day 29 [ Time Frame: Day 1 through 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.
24. Duration of Hospitalization [ Time Frame: Day 1 through Day 29 ]
    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.
25. Number of Participants With Discontinuation or Temporary Suspension of Study Product Administration [ Time Frame: Day 1 through Day 10 ]
    Discontinuation or temporary suspension of study product administration, including participants who died or were discharged, was evaluated for each study product/placebo.
26. 14-day Participant Mortality [ Time Frame: Day 1 through Day 15 ]
    The mortality rate was determined as the proportion of participants who died by study Day 15. The proportions reported are Kaplan-Meier estimates.
27. 28-day Participant Mortality [ Time Frame: Day 1 through Day 29 ]
    The mortality rate was determined as the proportion of participants who died by study Day 29. The proportions reported are Kaplan-Meier estimates.
28. Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 1 [ Time Frame: 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.
29. Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 3 [ Time Frame: 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.
30. Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 5 [ Time Frame: 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.
31. Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 8 [ Time Frame: 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.
32. Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 11 [ Time Frame: 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.
33. Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 15 [ Time Frame: 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.
34. Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 22 [ Time Frame: 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.
35. Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 29 [ Time Frame: 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.
36. Percentage of Participants Meeting Criteria for Each of the 8 Ordinal Scale Categories [ Time Frame: Day 15 ]
    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.
37. The Proportion of Participants Not Meeting Criteria for One of the Three Most Severe Ordinal Scale Categories at Any Time. [ Time Frame: Day 1 through Day 29 ]
    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.
38. Time to an Improvement of One Category From Baseline Using an Ordinal Scale [ Time Frame: Day 1 through 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, 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.
39. Time to an Improvement of Two Categories From Baseline Using an Ordinal Scale [ Time Frame: Day 1 through 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, 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.
40. Time to Recovery [ Time Frame: Day 1 through Day 29 ]
    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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham School of Medicine - Infectious Disease

Birmingham, Alabama, United States, 35233

United States, California

UCSF Fresno Center for Medical Education and Research - Clinical Research Center

Fresno, California, United States, 93701

University of California San Diego Health - Jacobs Medical Center

La Jolla, California, United States, 29037

University of California Los Angeles Medical Center - Westwood Clinic

Los Angeles, California, United States, 90095

University of California Irvine Medical Center - Infectious Disease

Orange, California, United States, 92868-3298

VA Palo Alto Health Care System - Infectious Diseases

Palo Alto, California, United States, 94304-1207

University of California Davis Medical Center - Internal Medicine - Infectious Disease

Sacramento, California, United States, 95817-1460

Kaiser Permanente San Diego Medical Center

San Diego, California, United States, 92123

Naval Medical Center San Diego - Infectious Disease Clinic

San Diego, California, United States, 92314

University of California San Francisco - Zuckerberg San Francisco General Hospital - Division of Human Immunodeficiency Virus, Infectious Disease, and Global Medicine

San Francisco, California, United States, 94110-2859

Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases

Stanford, California, United States, 94305-2200

Cedars Sinai Medical Center

West Hollywood, California, United States, 90048-1804

United States, Colorado

VA Eastern Colorado Health Care System

Aurora, Colorado, United States, 80045

Denver Health Division of Hospital Medicine - Main Campus

Denver, Colorado, United States, 80204

United States, District of Columbia

Georgetown University Medical Center - Division of Infectious Diseases

Washington, District of Columbia, United States, 20007

United States, Florida

University of Florida Health - Shands Hospital - Division of Infectious Diseases and Global Medicine

Gainesville, Florida, United States, 32610

University of Florida Health - Jacksonville - Department of Emergency Medicine

Jacksonville, Florida, United States, 32209

University of Miami Miller School of Medicine - Infectious Diseases

Miami, Florida, United States, 33136

United States, Georgia

Emory Vaccine Center - The Hope Clinic

Decatur, Georgia, United States, 30030-1705

Atlanta VA Medical Center - Infectious Diseases Clinic

Decatur, Georgia, United States, 30033

United States, Hawaii

Tripler Army Medical Center

Honolulu, Hawaii, United States, 96859

United States, Illinois

Northwestern Hospital - Infectious Disease

Chicago, Illinois, United States, 60611-2908

University of Illinois at Chicago College of Medicine - Division of Infectious Diseases

Chicago, Illinois, United States, 60612

United States, Iowa

University of Iowa Hospitals & Clinics - Department of Internal Medicine

Iowa City, Iowa, United States, 52242

United States, Louisiana

Tulane University - Section of Pulmonary Diseases, Critical Care, and Environmental Medicine

New Orleans, Louisiana, United States, 70112

United States, Maryland

University of Maryland School of Medicine - Center for Vaccine Development - Baltimore

Baltimore, Maryland, United States, 21201-1509

Johns Hopkins Hospital - Medicine - Infectious Diseases

Baltimore, Maryland, United States, 21287-0005

Walter Reed National Military Medical Center

Bethesda, Maryland, United States, 20889

National Institutes of Health - Clinical Center, National Institute of Allergy and Infectious Diseases Laboratory Of Immunoregulation, Clinical Research Section

Bethesda, Maryland, United States, 20892-1504

United States, Massachusetts

Massachusetts General Hospital - Infectious Diseases

Boston, Massachusetts, United States, 02114-2621

University of Massachusetts Medical School - Infectious Diseases and Immunology

Worcester, Massachusetts, United States, 01655-0002

United States, Michigan

University of Michigan - Infectious Disease Clinic at Taubman Center

Ann Arbor, Michigan, United States, 48109

United States, Minnesota

University of Minnesota Medical Center, Fairview - Infectious Diseases and International Medicine

Minneapolis, Minnesota, United States, 55455-0341

United States, Missouri

Saint Louis University - Center for Vaccine Development

Saint Louis, Missouri, United States, 63104-1015

United States, Nebraska

University of Nebraska Medical Center - Infectious Diseases

Omaha, Nebraska, United States, 68105

CHI Health Creighton University Medical Center - Bergan Mercy - Pulmonary Medicine

Omaha, Nebraska, United States, 68124

United States, New Jersey

Atlantic Health System - Morristown Medical Center

Morristown, New Jersey, United States, 07960

United States, New Mexico

University of New Mexico Clinical and Translational Science Center

Albuquerque, New Mexico, United States, 87106

United States, New York

Montefiore Medical Center - Infectious Diseases

Bronx, New York, United States, 10467-2401

New York University School of Medicine - Langone Medical Center - Microbiology - Parasitology

New York, New York, United States, 10016-6402

University of Rochester Medical Center - Vaccine Research Unit

Rochester, New York, United States, 14642-0001

United States, North Carolina

Duke Human Vaccine Institute - Duke Vaccine and Trials Unit

Durham, North Carolina, United States, 27704

Womack Army Medical Center - Pulmonary and Respiratory Services

Fort Bragg, North Carolina, United States, 28310

United States, Oklahoma

University of Oklahoma Health Science Center - Surgery

Oklahoma City, Oklahoma, United States, 73104

United States, Oregon

Kaiser Permanente Northwest - Center for Health Research

Portland, Oregon, United States, 97227

United States, Pennsylvania

Penn State Health Milton S. Hershey Medical Center - Division of Infectious Diseases

Hershey, Pennsylvania, United States, 17033

Hospital of the University of Pennsylvania - Infectious Diseases

Philadelphia, Pennsylvania, United States, 19104-4238

University of Pittsburgh - Medicine - Infectious Diseases

Pittsburgh, Pennsylvania, United States, 15213-2582

United States, Texas

Baylor Scott & White Health - Baylor University Medical Center - North Texas Infectious Disease Consultants

Dallas, Texas, United States, 75246

University of Texas Southwestern Medical Center - Internal Medicine - Infectious Diseases

Dallas, Texas, United States, 75390-8884

Brooke Army Medical Center

Fort Sam Houston, Texas, United States, 78234

University of Texas Medical Branch - Division of Infectious Disease

Galveston, Texas, United States, 77555-0435

Methodist Hospital - Houston

Houston, Texas, United States, 77030-2703

Baylor College of Medicine - Molecular Virology and Microbiology

Houston, Texas, United States, 77030-3411

University of Texas Health Science Center at San Antonio - Infectious Diseases

San Antonio, Texas, United States, 78229-3901

United States, Utah

University of Utah - Infectious Diseases

Salt Lake City, Utah, United States, 84132-0002

United States, Virginia

University of Virginia - Acute Care Surgery

Charlottesville, Virginia, United States, 22908-0816

Naval Medical Center Portsmouth - Infectious Disease Division

Portsmouth, Virginia, United States, 23708

United States, Washington

EvergreenHealth Infectious Disease Service

Kirkland, Washington, United States, 98034

Providence Sacred Heart Medical Center

Spokane, Washington, United States, 99204

Madigan Army Medical Center - Infectious Disease Clinic

Tacoma, Washington, United States, 98431

Japan

Tokyo Medical and Dental University - Medical Hospital - Department of Respiratory Medicine

Tokyo, Japan, 113-8519

National Center for Global Health and Medicine Hospital - Disease Control and Prevention Center

Tokyo, Japan, 162-8655

Korea, Republic of

Seoul National University Bundang Hospital - Division of Infectious Diseases

Bundang-gu Seongnam-si, Gyeonggi-do, Korea, Republic of, 13620

Seoul National University Hospital

Seoul, Jongno-gu, Korea, Republic of, 03080

Mexico

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

Mexico City, Mexico, 14080

Singapore

National University Health System - Division of Infectious Diseases

Singapore, Singapore, 119228

National University Health System - Alexandra Hospital - Division of Infectious Diseases

Singapore, Singapore, 159964

National Centre for Infectious Diseases

Singapore, Singapore, 308442

Changi General Hospital - Clinical Trials and Research Unit (CTRU)

Singapore, Singapore, 529889

Ng Teng Fong General Hospital - Infectious Disease Service

Singapore, Singapore, 609606

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

  Study Documents (Full-Text)

Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):

Study Protocol  [PDF] January 18, 2021

Statistical Analysis Plan  [PDF] June 9, 2021

Informed Consent Form  [PDF] January 22, 2021

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT04640168
• Other Study ID Numbers: 20-0006 ACTT-4
• First Posted: November 23, 2020
• Results First Posted: June 28, 2022
• Last Update Posted: June 28, 2022
• Last Verified: April 2021

• 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

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

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

Additional relevant MeSH terms:

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Remdesivir; Dexamethasone; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents