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

National Institute of Allergy and Infectious Diseases (NIAID)1,033 enrolled

Overview

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.

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

Interventions

PlaceboOTHER

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.

RemdesivirDRUG

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.

BaricitinibDRUG

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 99 Years

Medical Language ↔ Plain English

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.

Locations (71)

University of Alabama at Birmingham School of Medicine - Infectious Disease

Birmingham, Alabama, United States

University of California San Diego Health - Jacobs Medical Center

La Jolla, California, United States

University of California Los Angeles Medical Center - Westwood Clinic

Los Angeles, California, United States

University of California Irvine Medical Center - Infectious Disease

Orange, California, United States

VA Palo Alto Health Care System - Infectious Diseases

Palo Alto, California, United States

Outcomes

Primary Outcomes

Time to Recovery

Day of recovery is defined as the first day on which the subject satisfies one of the following three categories from the ordinal scale: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care.

Time frame: Day 1 through Day 29

Time to Recovery by Race

Time frame: Day 1 through Day 29

Time to Recovery by Ethnicity

Time frame: Day 1 through Day 29

Time to Recovery by Sex

Time frame: Day 1 through Day 29

Secondary Outcomes

Change From Baseline in Alanine Transaminase (ALT)

Blood to evaluate ALT was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

Change From Baseline in Aspartate Transaminase (AST)

Blood to evaluate AST was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

Change From Baseline in Creatinine

Blood to evaluate serum creatinine was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

Change From Baseline in Glucose

Blood to evaluate serum glucose was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

Change From Baseline in Hemoglobin

Blood to evaluate hemoglobin was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

Change From Baseline in Platelets

Blood to evaluate platelets was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

Change From Baseline in Prothrombin International Normalized Ratio (INR)

Blood to evaluate INR was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

Change From Baseline in Total Bilirubin

Blood to evaluate total bilirubin was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

Change From Baseline in White Blood Cell Count (WBC)

Blood to evaluate WBC was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

Change From Baseline in Neutrophils

BBlood to evaluate neutrophils was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

Change From Baseline in Lymphocytes

Blood to evaluate lymphocytes was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

Change From Baseline in Monocytes

Blood to evaluate monocytes was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

Change From Baseline in Basophils

Blood to evaluate basophils was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

Change From Baseline in Eosinophils

Blood to evaluate eosinophils was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

Change in National Early Warning Score (NEWS) From Baseline

The NEW score has demonstrated an ability to discriminate patients at risk of poor outcomes. This score is based on 7 clinical parameters (respiration rate, oxygen saturation, any supplemental oxygen, temperature, systolic blood pressure, heart rate, level of consciousness). The NEW Score is being used as an efficacy measure. The minimum score is 0, representing the better outcome, and the maximum value is 19, representing the worse outcome.

Time frame: Days 1, 3, 5, 8, 11, 15, 22, and 29

Percentage of Participants Reporting Grade 3 and 4 Clinical and/or Laboratory Adverse Events (AEs)

Grade 3 AEs are defined as events that interrupt usual activities of daily living, or significantly affects clinical status, or may require intensive therapeutic intervention. Severe events are usually incapacitating. Grade 4 AEs are defined as events that are potentially life threatening.

Time frame: Day 1 through Day 29

Percentage of Participants Reporting Serious Adverse Events (SAEs)

An SAE is defined as an AE or suspected adverse reaction is considered serious if, in the view of either the investigator or the sponsor, it results in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.

Time frame: Day 1 through Day 29

Duration of Hospitalization

Duration of hospitalization was determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die.

Time frame: Day 1 through Day 29

Duration of New Non-invasive Ventilation or High Flow Oxygen Use

Duration of new non-invasive ventilation or high flow oxygen use was measured in days among participants who were not on non-invasive ventilation or high-flow oxygen use at baseline, determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die

Time frame: Day 1 through Day 29

Duration of New Oxygen Use

Duration of new oxygen use was measured in days among participants who were not on oxygen at baseline, determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die

Time frame: Day 1 through Day 29

Duration of New Ventilator or Extracorporeal Membrane Oxygenation (ECMO) Use

Duration of new ventilator or ECMO use was measured in days among participants who were not on a ventilator or ECMO at baseline, determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die

Time frame: Day 1 through Day 29

Duration of Oxygen Use

Duration of oxygen use was measured in days among participants who were on oxygen in based, calculated in two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die.

Time frame: Day 1 through Day 29

Percentage of Participants Discontinued or Temporarily Suspended From Investigational Therapeutics

Participants may have been discontinued from investigational therapeutics due to discharge or death. The halting or slowing of the infusion for any reason was collected, as was missed doses in the series of 10 doses of Remdesivir, or in the 14 doses of Baricitinib/placebo.

Time frame: Day 1 through Day 14

Percentage of Participants Requiring New Ventilator or Extracorporeal Membrane Oxygenation (ECMO) Use

The percentage of participants requiring new ventilator or ECMO use was determined as the percentage not on a ventilator or ECMO at baseline

Time frame: Day 1 through Day 29

Percentage of Participants Requiring New Oxygen Use

The percentage of participants requiring new oxygen use was determined as the percentage of participants not requiring oxygen at baseline

Time frame: Day 1 through Day 29

Mean Change in the Ordinal Scale

The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. A positive change indicates a worsening and a negative change is an improvement.

Time frame: Day 1, 3, 5, 8, 11, 15, 22, and 29

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

The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. Data was imputed using last observation carried forward or worst possible score based on hospitalization status (2 if not hospitalized, 7 if hospitalized) when there was a change in hospitalization status since last score. Deaths were imputed as an 8.

Time frame: Day 15

Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 1

Time frame: Day 1

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

Time frame: Day 3

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

Time frame: Day 5

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

Time frame: Day 8

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

Time frame: Day 11

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

Time frame: Day 22

Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 29

Time frame: Day 29

14-day Participant Mortality

The mortality rate was determined as the proportion of participants who died by study Day 15. The proportions reported are Kaplan-Meier estimates.

Time frame: Day 1 through Day 15

28-day Participant Mortality

The mortality rate was determined as the proportion of participants who died by study Day 29. The proportions reported are Kaplan-Meier estimates.

Time frame: Day 1 through Day 29

Time to an Improvement of One Category Using an Ordinal Scale

The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 5) Hospitalized, requiring supplemental oxygen; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 2) Not hospitalized, limitation on activities and/or requiring home oxygen; 1) Not hospitalized, no limitations on activities. Time to improvement by at least one category was determined for each participant

Time frame: Day 1 through Day 29

Time to an Improvement of Two Categories Using an Ordinal Scale

The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities. Time to improvement by at least two categories was determined for each participant

Time frame: Day 1 through Day 29

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

Change From Baseline in C-reactive Protein (CRP)

Blood to evaluate CRP was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

Change From Baseline in D-dimer Concentration

Blood to evaluate d-dimer concentration was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge.

Time frame: Days 1, 3, 5, 8, 11, 15 and 29

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

Overview

Conditions

Interventions

Eligibility

Locations (71)

Outcomes

Primary Outcomes

Secondary Outcomes