Adaptive COVID-19 Treatment Trial 3 (ACTT-3)

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-3)

ACTT-3 will evaluate the combination of interferon beta-1a 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.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Remdesivir; Drug: Interferon beta-1a; Other: Placebo

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-3 will evaluate the combination of interferon beta-1a 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 for patients with baseline ordinal score 4, 5 and 6. 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 Type: Interventional
• Enrollment (Actual): 969
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Tokyo, Japan, 162-8655
    • National Center for Global Health and Medicine Hospital - Disease Control and Prevention Center
• Korea, Republic of
  • Gyeonggi-do
    • Seongnam, Gyeonggi-do, Korea, Republic of
      • Seoul National University Bundang Hospital - Division of Infectious Diseases
  • Jongno-gu
    • Seoul, Jongno-gu, Korea, Republic of, 03080
      • Seoul National University Hospital
• Mexico
  • Mexico City, Mexico, 14080
    • Instituto Nacional de Enfermedades Respiratorias (INER) - Ismael Cosío Villegas
  • Mexico City, Mexico
    • Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán - Departamento de Infectologia
• Singapore
  • Singapore, Singapore, 119228
    • National University Health System - Division of Infectious Diseases
  • Singapore, Singapore, 308442
    • National Centre for Infectious Diseases (NCID)
  • Singapore, Singapore, 529889
    • Changi General Hospital - Clinical Trials and Research Unit (CTRU)
  • Singapore, Singapore
    • Ng Teng Fong General Hospital - Infectious Disease Service
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham School of Medicine - Infectious Disease
  • California
    • Fresno, California, United States, 93701
      • UCSF Fresno Center for Medical Education and Research - Clinical Research Center
    • La Jolla, California, United States, 29037
      • University of California San Diego Health - Jacobs Medical Center
    • Los Angeles, California, United States, 90095
      • University of California Los Angeles Medical Center - Westwood Clinic
    • Orange, California, United States, 92868-3298
      • University of California Irvine Medical Center - Infectious Disease
    • Palo Alto, California, United States, 94304-1207
      • VA Palo Alto Health Care System - Infectious Diseases
    • Palo Alto, California, United States, 94304-1503
      • Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases
    • Sacramento, California, United States, 95817-1460
      • University of California Davis Medical Center - Internal Medicine - Infectious Disease
    • San Diego, California, United States, 92314
      • Naval Medical Center San Diego - Infectious Disease Clinic
    • San Francisco, California, United States, 94110-2859
      • University of California San Francisco - Zuckerberg San Francisco General Hospital - Division of HIV, ID, and Global Medicine
    • West Hollywood, California, United States, 90048-1804
      • Cedars Sinai Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Eastern Colorado Health Care System
    • Denver, Colorado, United States, 80204
      • Denver Health Division of Hospital Medicine - Main Campus
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Health - Shands Hospital - Division of Infectious Diseases and Global Medicine
    • Jacksonville, Florida, United States, 32209
      • University of Florida Health - Jacksonville - Department of Emergency Medicine
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine - Infectious Diseases
  • Georgia
    • Decatur, Georgia, United States, 30030-1705
      • Emory Vaccine Center - The Hope Clinic
    • Decatur, Georgia, United States, 30033
      • Atlanta VA Medical Center - Infectious Diseases Clinic
  • Hawaii
    • Honolulu, Hawaii, United States, 96859
      • Tripler Army Medical Center (TAMC)
  • Illinois
    • Chicago, Illinois, United States, 60611-2908
      • Northwestern Hospital - Infectious Disease
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago Division of Infectious Diseases
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinics - Department of Internal Medicine
  • Louisiana
    • Kenner, Louisiana, United States, 70065
      • Ochsner Medical Center - Kenner - Department of Infectious Diseases
    • New Orleans, Louisiana, United States, 70119
      • Southeast Louisiana Veterans Health Care System - Section of Infectious Diseases
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland School of Medicine - Center for Vaccine Development - Baltimore
    • Baltimore, Maryland, United States, 21287-0005
      • Johns Hopkins Hospital - Medicine - Infectious Diseases
    • Bethesda, Maryland, United States, 20889
      • Walter Reed National Military Medical Center
    • Bethesda, Maryland, United States, 20892-1504
      • National Institutes of Health - Clinical Center, National Institute of Allergy and Infectious Diseases Laboratory Of Immunoregulation, Clinical Research Section
  • Massachusetts
    • Boston, Massachusetts, United States, 02114-2621
      • Massachusetts General Hospital - Infectious Diseases
    • Worcester, Massachusetts, United States, 01655-0002
      • University of Massachusetts Medical School - Infectious Diseases and Immunology
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455-0356
      • University of Minnesota Medical Center, Fairview - Infectious Diseases and International Medicine
  • Missouri
    • Saint Louis, Missouri, United States, 63104-1015
      • Saint Louis University - Center for Vaccine Development
  • Nebraska
    • Omaha, Nebraska, United States, 68198-5400
      • University of Nebraska Medical Center - Infectious Diseases
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Clinical and Translational Science Center
  • New York
    • Bronx, New York, United States, 10467-2401
      • Montefiore Medical Center - Infectious Diseases
    • New York, New York, United States, 10016-6402
      • New York University School of Medicine - Langone Medical Center - Microbiology - Parasitology
    • Rochester, New York, United States, 14642-0001
      • University of Rochester Medical Center - Vaccine Research Unit
  • North Carolina
    • Durham, North Carolina, United States, 27704
      • Duke Human Vaccine Institute - Duke Vaccine and Trials Unit
    • Fort Bragg, North Carolina, United States, 28310
      • Womack Army Medical Center - Pulmonary and Respiratory Services
  • Oregon
    • Portland, Oregon, United States, 97227
      • Kaiser Permanente Northwest - Center for Health Research
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Health Milton S. Hershey Medical Center - Division of Infectious Diseases
    • Philadelphia, Pennsylvania, United States, 19104-4238
      • Hospital of the University of Pennsylvania - Infectious Diseases
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor Scott & White Health - Baylor University Medical Center - North Texas Infectious Disease Consultants
    • Dallas, Texas, United States, 75390-8884
      • University of Texas Southwestern Medical Center - Internal Medicine - Infectious Diseases
    • Fort Sam Houston, Texas, United States, 78234
      • Brooke Army Medical Center
    • Galveston, Texas, United States, 77555
      • University of Texas Medical Branch - Division of Infectious Disease
    • Houston, Texas, United States, 77030-3411
      • Baylor College of Medicine - Molecular Virology and Microbiology
    • Houston, Texas, United States, 77030
      • Methodist Hospital - Houston
    • San Antonio, Texas, United States, 78229-3901
      • University of Texas Health Science Center at San Antonio - Infectious Diseases
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah - Infectious Diseases
  • Virginia
    • Charlottesville, Virginia, United States, 22908-0816
      • University of Virginia - Acute Care Surgery
    • Portsmouth, Virginia, United States, 23708
      • Naval Medical Center Portsmouth - Infectious Disease Division
  • Washington
    • Kirkland, Washington, United States, 98034
      • EvergreenHealth Infectious Disease Service
    • Spokane, Washington, United States, 99204
      • Providence Sacred Heart Medical Center
    • Tacoma, Washington, United States, 98431
      • Madigan Army Medical Center - Infectious Disease Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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 respiratory specimen or saliva, as documented by either of the following:

   • PCR or other assay positive in sample collected < 72 hours prior to randomization; OR
   • PCR or other assay positive in sample collected >/= 72 hours but < 7 days prior to randomization AND progressive disease suggestive of ongoing SARS-CoV-2 infection.

   Note: if written documentation of the positive test result is not available at enrollment (e.g., report from other institution), the subject may be enrolled but the PCR should be repeated at the time of enrollment.

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.
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 (both pharmacologic and other types of interventions) for the treatment of COVID-19 through Day 29.

Exclusion Criteria:

1. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours.
2. Subject meets criteria for ordinal scale category 6 or 7 at the time of screening.
3. Subject has a positive test for influenza virus during this current hospital admission.
4. Subjects with an estimated glomerular filtration rate (eGFR) < 30 mL/min are excluded unless in the opinion of the PI, the potential benefit of receiving remdesivir outweighs the potential risk of study participation.
5. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 times the upper limits of normal.
6. Total white cell blood cell count (WBC) <1500 cells/microliter.
7. Platelet count <50,000/microliter.
8. History of chronic liver disease (e.g., jaundice, ascites, hepatic encephalopathy, history of bleeding esophageal or gastric varices). No laboratory testing is needed.
9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 1 until three weeks after the last study product is given are not excluded).
10. Allergy to any study medication including history of hypersensitivity to natural or recombinant interferon beta or human albumin.
11. Patient has a chronic or acute medical condition or is taking a medication that cannot be discontinued at enrollment, that in the judgement of the PI, places them at unacceptable risk for a poor clinical outcome if they were to participate in the study.
12. Received three or more doses of remdesivir, including the loading dose, outside of the study for COVID-19.
13. Received convalescent plasma or intravenous immunoglobulin [IVIg] for the treatment of COVID-19.
14. Received any interferon product within two weeks of screening, either for the treatment of COVID-19 or for a chronic medical condition (e.g., multiple sclerosis, HCV infection).

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

    • Small molecule tyrosine kinase inhibitors (e.g. baricitinib, 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.
16. Prior enrollment in ACTT-3.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Remdesivir plus Interferon Beta-1a; 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 44 mcg of interferon beta-1a administered by a 0.5 mL subcutaneous injection on Days 1, 3, 5, and 7 while hospitalized for a total of 4 doses.	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: Interferon beta-1a; Rebif (R) is a purified 166 amino acid human interferon beta glycoprotein with an amino acid sequence identical to natural fibroblast derived human interferon beta. Each 0.5 mL prefilled syringe contains 44 mcg of interferon beta-1a, 4 mg human albumin, USP; 27.3 mg mannitol, USP; 0.4 mg sodium acetate; and water for injection, USP.
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 a 0.5 mL placebo injection administered subcutaneously on Days 1, 3, 5, and 7 while hospitalized for a total of 4 doses.	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.; Other: Placebo; The interferon beta-1a placebo contains either 0.5 mL 0.9% normal saline or 0.5 mL sterile water for injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Recovery for Participants With Baseline Ordinal Score 4, 5 and 6	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, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care.	Day 1 through Day 29
Time to Recovery for Participants With Baseline Ordinal Score 4, 5 and 6 by Race	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, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care.	Day 1 through Day 29
Time to Recovery for Participants With Baseline Ordinal Score 4, 5 and 6 by Ethnicity	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, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care.	Day 1 through Day 29
Time to Recovery for Participants With Baseline Ordinal Score 4, 5 and 6 by Sex	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, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen and no longer requires ongoing medical care.	Day 1 through Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	Day 1 through Day 29
Percentage of Participants Reporting Serious Adverse Events (SAEs)	An SAE is defined as an AE or suspected adverse reaction is considered serious if, in the view of either the investigator or the sponsor, it results in death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.	Day 1 through Day 29
Duration of Hospitalization	Duration of hospitalization was determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die.	Day 1 through Day 29
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	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	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.	Day 1 through Day 29
28-day Participant Mortality	The mortality rate was determined as the proportion of participants who died by study Day 29. The proportions reported are Kaplan-Meier estimates.	Day 1 through Day 29
Change From Baseline in Alanine Aminotransferase (ALT)	Blood to evaluate ALT was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The measure was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6).	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in Aspartate Aminotransferase (AST)	Blood to evaluate AST was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The measure was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6).	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in C-reactive Protein (CRP)	Blood to evaluate CRP was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The measure was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6).	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. The measure was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6).	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.	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. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6).	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. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6).	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. The outcome was assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).	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. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6).	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. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6).	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in Neutrophils	Blood to evaluate neutrophils was collected at Days 1, 3, 5, 8, and 11 while participants were inpatient, and at Days 15 and 29, with the Day 1 assessment serving as baseline. Participants who had been discharged had blood collected if infection control measures allowed for in-person visits after discharge. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6).	Days 1, 3, 5, 8, 11, 15 and 29
Change From Baseline in Lymphoctyes	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. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6).	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. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6).	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. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6).	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. The outcome was assessed by baseline ordinal scale category (categories 4 and 5 versus category 6).	Days 1, 3, 5, 8, 11, 15 and 29
Duration of Invasive Mechanical Ventilation	Duration of invasive ventilation was measured in days among participants who required invasive ventilation, determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die	Day 1 through Day 29
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.	Day 1 through Day 29
Duration of Non Invasive Ventilation or High Flow Oxygen Use	Duration of non invasive ventilation or high flow oxygen use was measured in days, determined two ways. The first includes imputations for participants who died. The second method is restricted to participants who did not die.	Day 1 through Day 29
Number of Participants With Discontinuation or Temporary Suspension of Study Product Administration	Discontinuation or temporary suspension of study product administration, including participants who died or were discharged, was evaluated by baseline ordinal scale category (categories 4 and 5 versus category 6).	Day 1 through Day 10
Proportion of Participants With New Non-invasive Ventilation or High Flow Oxygen Use	Proportion of participants with new non-invasive ventilation or high flow oxygen use was assessed as for participants in Ordinal Score 4 and 5.	Day 1 through Day 29
Proportion of Participants With New Oxygen Use	Incidence of new oxygen use was assessed as for participants in Ordinal Score 4 and 5 who were not on oxygen at baseline.	Day 1 through Day 29
Proportion of Participants With New Ventilator or Extracorporeal Membrane Oxygenation (ECMO) Use	Incidence of new ventilator or extracorporeal membrane oxygenation (ECMO) use was assessed among participants not on ventilator or extracorporeal membrane oxygenation (ECMO) use at baseline.	Day 1 through Day 29
Mean Change From Baseline 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: 1) Not hospitalized, no limitations on activities; 2) Not hospitalized, but new or increased limitation on activities and/or new or increased requirement for home oxygen; 3) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 4) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 5) Hospitalized, requiring supplemental oxygen; 6) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 7) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 8) Death. A positive change indicates a worsening and a negative change is an improvement.	Day 1, 3, 5, 8, 11, 15, 22, and 29
Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 15 for Participants With Baseline Ordinal Score 4 and 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. 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.	Day 15
Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 1	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or 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.	Day 1
Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 3	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or 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.	Day 3
Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 5	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or 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.	Day 5
Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 8	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or 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.	Day 8
Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 11	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or 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.	Day 11
Percentage of Participants Reporting Each Severity Rating on an 8 Point 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.	Day 15
Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 22	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or 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.	Day 22
Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 29	The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 8) Death; 7) Hospitalized, on invasive mechanical ventilation or 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.	Day 29
14-day Participant Mortality	The mortality rate was determined as the proportion of participants who died by study Day 15. The proportions reported are Kaplan-Meier estimates	Day 1 through Day 15
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.	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.	Day 1 through Day 29
Time to Discharge or to a National Early Warning Score (NEWS) of </= 2 and Maintained for 24 Hours, Whichever Occurs First	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.	Day 1 through Day 29
Time to Recovery for Patients With a Baseline Ordinal Score of 4 and 5	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.	Day 1 through Day 29

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.
• Kalil AC, Mehta AK, Patterson TF, Erdmann N, Gomez CA, Jain MK, Wolfe CR, Ruiz-Palacios GM, Kline S, Regalado Pineda J, Luetkemeyer AF, Harkins MS, Jackson PEH, Iovine NM, Tapson VF, Oh MD, Whitaker JA, Mularski RA, Paules CI, Ince D, Takasaki J, Sweeney DA, Sandkovsky U, Wyles DL, Hohmann E, Grimes KA, Grossberg R, Laguio-Vila M, Lambert AA, Lopez de Castilla D, Kim E, Larson L, Wan CR, Traenkner JJ, Ponce PO, Patterson JE, Goepfert PA, Sofarelli TA, Mocherla S, Ko ER, Ponce de Leon A, Doernberg SB, Atmar RL, Maves RC, Dangond F, Ferreira J, Green M, Makowski M, Bonnett T, Beresnev T, Ghazaryan V, Dempsey W, Nayak SU, Dodd L, Tomashek KM, Beigel JH; ACTT-3 study group members. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial. Lancet Respir Med. 2021 Dec;9(12):1365-1376. doi: 10.1016/S2213-2600(21)00384-2. Epub 2021 Oct 18.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 5, 2020
• Primary Completion (ACTUAL): December 21, 2020
• Study Completion (ACTUAL): December 21, 2020

Study Registration Dates

• First Submitted: July 28, 2020
• First Submitted That Met QC Criteria: July 28, 2020
• First Posted (ACTUAL): July 30, 2020

Study Record Updates

• Last Update Posted (ACTUAL): March 14, 2022
• Last Update Submitted That Met QC Criteria: March 9, 2022
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Safety; Efficacy; COVID-19; Adaptive; Multicenter; novel coronavirus
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Adjuvants, Immunologic; Interferons; Interferon beta-1a; Interferon-beta; Remdesivir
• Other Study ID Numbers: 20-0006 ACTT-3

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No