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

• ClinicalTrials.gov Identifier: NCT04401579
• Recruitment Status: Completed
• First Posted: May 26, 2020
• Results First Posted: April 26, 2021
• Last Update Posted: March 14, 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-2 will evaluate the combination of baricitinib and remdesivir compared to remdesivir alone. Subjects will be assessed daily while hospitalized. If the subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and oropharyngeal (OP) swab and blood (serum only) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the subject to return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone. The primary outcome is time to recovery by Day 29.

Condition or disease	Intervention/treatment	Phase
COVID-19	Other: Placebo; Drug: Remdesivir; Drug: Baricitinib	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-2 will evaluate the combination of baricitinib and remdesivir compared to remdesivir alone. Subjects will be assessed daily while hospitalized. If the subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and oropharyngeal (OP) swab and blood (serum only) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the subject to return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone.

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

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

Contacts:

20-0006 Central Contact

Telephone: 1 (301) 7617948

Email: DMIDClinicalTrials@niaid.nih.gov

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1033 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-2)
• Actual Study Start Date: May 8, 2020
• Actual Primary Completion Date: July 31, 2020
• Actual Study Completion Date: July 31, 2020

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 and 4 mg (2 tablets of 2 mg) of Baricitinib administered orally daily for the duration of the hospitalization up to a 14-day total course.	Drug: Remdesivir; Drug Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, the lyophilized formulation of Remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide.; Drug: Baricitinib; Baricitinib is a Janus kinase (JAK) inhibitor with the chemical name [1-(ethylsulfonyl)-3-(4-(7Hpyrrolo(2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile Each tablet contains 2 mg of baricitinib and the following inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, ferric oxide, lecithin (soya), polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.
Placebo Comparator: Remdesivir plus Placebo; 200 mg of Remdesivir administered intravenously on Day 1, followed by a 100 mg once-daily maintenance dose of Remdesivir while hospitalized for up to a 10-day total course and 4 mg (2 tablets of 2 mg) of Baricitinib Placebo administered orally daily for the duration of the hospitalization up to a 14-day total course.	Other: Placebo; The matching Baricitinib placebo contains lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The coating for the placebo tablet is identical to that of the corresponding active tablet.; 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. Time to Recovery [ Time Frame: Day 1 through Day 29 ]
   Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care.
2. Time to Recovery by Race [ Time Frame: Day 1 through Day 29 ]
   Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care.
3. Time to Recovery by Ethnicity [ Time Frame: Day 1 through Day 29 ]
   Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care.
4. Time to Recovery by Sex [ Time Frame: Day 1 through Day 29 ]
   Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care.

Secondary Outcome Measures :

1. Change From Baseline in Alanine Transaminase (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 Transaminase (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 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.
4. Change From Baseline in Glucose [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
   Blood to evaluate serum glucose was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. Change From Baseline in Neutrophils [ Time Frame: Days 1, 3, 5, 8, 11, 15 and 29 ]
    BBlood to evaluate neutrophils was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.
11. 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.
12. 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.
13. 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.
14. 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.
15. Change in National Early Warning Score (NEWS) From Baseline [ Time Frame: Days 1, 3, 5, 8, 11, 15, 22, and 29 ]
    The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure. The minimum score is 0, representing the better outcome, and the maximum value is 19, representing the worse outcome.
16. 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.
17. 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.
18. 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.
19. Duration of New Non-invasive Ventilation or High Flow Oxygen Use [ 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
20. Duration of New Oxygen Use [ Time Frame: Day 1 through Day 29 ]
    Duration of new oxygen use was measured in days among participants who were not on oxygen at baseline, determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die
21. Duration of New Ventilator or Extracorporeal Membrane Oxygenation (ECMO) Use [ Time Frame: Day 1 through Day 29 ]
    Duration of new ventilator or ECMO use was measured in days among participants who were not on a ventilator or ECMO at baseline, determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die
22. Duration of Oxygen Use [ Time Frame: Day 1 through Day 29 ]
    Duration of oxygen use was measured in days among participants who were on oxygen in based, calculated in two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die.
23. Percentage of Participants Discontinued or Temporarily Suspended From Investigational Therapeutics [ Time Frame: Day 1 through Day 14 ]
    Participants may have been discontinued from investigational therapeutics due to discharge or death. The halting or slowing of the infusion for any reason was collected, as was missed doses in the series of 10 doses of Remdesivir, or in the 14 doses of Baricitinib/placebo.
24. Percentage of Participants Requiring New Ventilator or Extracorporeal Membrane Oxygenation (ECMO) Use [ Time Frame: Day 1 through Day 29 ]
    The percentage of participants requiring new ventilator or ECMO use was determined as the percentage not on a ventilator or ECMO at baseline
25. Percentage of Participants Requiring New Oxygen Use [ Time Frame: Day 1 through Day 29 ]
    The percentage of participants requiring new oxygen use was determined as the percentage of participants not requiring oxygen at baseline
26. Mean Change in the Ordinal Scale [ Time Frame: Day 1, 3, 5, 8, 11, 15, 22, and 29 ]
    The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. A positive change indicates a worsening and a negative change is an improvement.
27. 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 extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. Data was imputed using last observation carried forward or worst possible score based on hospitalization status (2 if not hospitalized, 7 if hospitalized) when there was a change in hospitalization status since last score. Deaths were imputed as an 8.
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 extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.
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 extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.
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 extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.
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 extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.
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 extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.
33. 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 extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.
34. 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 extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities.
35. 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.
36. 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.
37. Time to an Improvement of One Category 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 extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. Time to improvement by at least one category was determined for each participant
38. Time to an Improvement of Two Categories 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: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities. Time to improvement by at least two categories was determined for each participant
39. Time to Discharge or to a NEWS of 2 or Less and Maintained for 24 Hours, Whichever Occurs First [ Time Frame: Day 1 through Day 29 ]
    The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure. The minimum score is 0, representing the better outcome, and the maximum value is 19, representing the worse outcome. The time to discharge or a NEWS of less than or equal to 2 was determined for each participant.
40. 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.
41. 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.

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

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

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

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

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

Exclusion Criteria:

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

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

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

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

Palo Alto, California, United States, 94304-1503

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

Sacramento, California, United States, 95817-1460

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

Cedars Sinai Medical Center

West Hollywood, California, United States, 90048-1804

United States, Colorado

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 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, 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, Indiana

Indiana University School of Medicine - Infectious Diseases

Indianapolis, Indiana, United States, 46202

United States, Louisiana

Ochsner Medical Center - Kenner - Department of Infectious Diseases

Kenner, Louisiana, United States, 70065

Southeast Louisiana Veterans Health Care System (SLVHCS) - Section of Infectious Diseases

New Orleans, Louisiana, United States, 70119

United States, Maryland

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

Baltimore, Maryland, United States, 21201

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, 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, 68198-5400

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

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, 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

University of Pennsylvania Perelman School of Medicine - Penn Institute for Immunology

Philadelphia, Pennsylvania, United States, 19104-4863

United States, Tennessee

Vanderbilt University Medical Center - Infectious Diseases

Nashville, Tennessee, United States, 37232-0011

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

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

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

Denmark

University of Copenhagen - Centre of Excellence for Health, Immunity and Infections (CHIP) - Department of Infectious Diseases

Copenhagen, Denmark, 2100

Japan

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, Korea, Republic of, 13620

Seoul National University Hospital

Seoul, 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 Centre for Infectious Diseases (NCID)

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

Spain

Hospital Clinic Barcelona, Servicio de Salud Internacional

Barcelona, Cataluña, Spain, 08036

Hospital Germans Trias i Pujol - Servei Malalties Infeccioses

Barcelona, Cataluña, Spain, 08916

Hospital Clinico San Carlos - Enfermedades Infecciosas

Madrid, Spain, 28040

United Kingdom

Royal Sussex County Hospital - Department of Intensive Care Medicine

Brighton, United Kingdom

Saint Thomas' Hospital - Directorate of Infection

City Of London, United Kingdom

St. James's University Hospital - Infectious Diseases

Leeds, United Kingdom

Royal Victoria Infirmary - Department of Infectious Diseases

Newcastle Upon Tyne, United Kingdom

John Radcliffe Hospital

Oxford, United Kingdom

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] May 25, 2020

Statistical Analysis Plan  [PDF] August 20, 2020

Informed Consent Form  [PDF] June 4, 2020

More Information

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

Kramer A, Prinz C, Fichtner F, Fischer AL, Thieme V, Grundeis F, Spagl M, Seeber C, Piechotta V, Metzendorf MI, Golinski M, Moerer O, Stephani C, Mikolajewska A, Kluge S, Stegemann M, Laudi S, Skoetz N. Janus kinase inhibitors for the treatment of COVID-19. Cochrane Database Syst Rev. 2022 Jun 13;6(6):CD015209. doi: 10.1002/14651858.CD015209.

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.

Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V, Marconi VC, Ruiz-Palacios GM, Hsieh L, Kline S, Tapson V, Iovine NM, Jain MK, Sweeney DA, El Sahly HM, Branche AR, Regalado Pineda J, Lye DC, Sandkovsky U, Luetkemeyer AF, Cohen SH, Finberg RW, Jackson PEH, Taiwo B, Paules CI, Arguinchona H, Erdmann N, Ahuja N, Frank M, Oh MD, Kim ES, Tan SY, Mularski RA, Nielsen H, Ponce PO, Taylor BS, Larson L, Rouphael NG, Saklawi Y, Cantos VD, Ko ER, Engemann JJ, Amin AN, Watanabe M, Billings J, Elie MC, Davey RT, Burgess TH, Ferreira J, Green M, Makowski M, Cardoso A, de Bono S, Bonnett T, Proschan M, Deye GA, Dempsey W, Nayak SU, Dodd LE, Beigel JH; ACTT-2 Study Group Members. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. 2021 Mar 4;384(9):795-807. doi: 10.1056/NEJMoa2031994. Epub 2020 Dec 11.

Azzi Y, Bartash R, Scalea J, Loarte-Campos P, Akalin E. COVID-19 and Solid Organ Transplantation: A Review Article. Transplantation. 2021 Jan 1;105(1):37-55. doi: 10.1097/TP.0000000000003523.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT04401579
• Other Study ID Numbers: 20-0006 ACTT-2
• First Posted: May 26, 2020
• Results First Posted: April 26, 2021
• Last Update Posted: March 14, 2022
• Last Verified: April 2020

• 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):

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; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antiviral Agents; Anti-Infective Agents