Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04492475
Recruitment Status : Active, not recruiting
First Posted : July 30, 2020
Last Update Posted : November 13, 2020
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
COVID-19 Drug: Interferon beta-1a Other: Placebo Drug: Remdesivir Phase 3

Detailed Description:

This study is an adaptive randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. The study is a multicenter trial that will be conducted in up to approximately 100 sites globally. The study will compare different investigational therapeutic agents to a control arm. New arms can be introduced according to scientific and public health needs. There will be interim monitoring to allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s). Any such change would be accompanied by an updated sample size. This adaptive platform is used to rapidly evaluate different therapeutics in a population of those hospitalized with moderate to severe COVID-19. The platform will provide a common framework sharing a similar population, design, endpoints, and safety oversight. New stages with new therapeutics can be introduced. One independent Data and Safety Monitoring Board (DSMB) will actively monitor interim data in all stages to make recommendations about early study closure or changes to study arms.

ACTT-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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 969 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-3)
Actual Study Start Date : August 4, 2020
Estimated Primary Completion Date : December 15, 2020
Estimated Study Completion Date : December 30, 2020

Resource links provided by the National Library of Medicine


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: 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.

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.

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.
Other: Placebo
The interferon beta-1a placebo contains either 0.5 mL 0.9% normal saline or 0.5 mL sterile water for injection.

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.




Primary Outcome Measures :
  1. Time to recovery for patients with baseline ordinal score 4, 5, and 6 [ 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, 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.


Secondary Outcome Measures :
  1. Change from baseline in alanine aminotransferase (ALT) [ Time Frame: Day 1 through Day 29 ]
    Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

  2. Change from baseline in aspartate aminotransferase (AST) [ Time Frame: Day 1 through Day 29 ]
    Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

  3. Change from baseline in C-reactive protein (CRP) [ Time Frame: Day 1 through Day 29 ]
  4. Change from baseline in creatinine [ Time Frame: Day 1 through Day 29 ]
    Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

  5. Change from baseline in d-dimer concentration [ Time Frame: Day 1 through Day 29 ]
  6. Change from baseline in hemoglobin [ Time Frame: Day 1 through Day 29 ]
    Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

  7. Change from baseline in international normalized ratio (INR) [ Time Frame: Day 1 through Day 29 ]
    Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

  8. Change from baseline in platelets [ Time Frame: Day 1 through Day 29 ]
    Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

  9. Change from baseline in total bilirubin [ Time Frame: Day 1 through Day 29 ]
    Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

  10. Change from baseline in white blood cell count (WBC) with differential [ Time Frame: Day 1 through Day 29 ]
    Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

  11. Change in National Early Warning Score (NEWS) from baseline [ 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.

  12. Cumulative incidence of Grade 3 and 4 clinical and/or laboratory adverse events (AEs) [ Time Frame: Day 1 through Day 29 ]
    Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6). 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.

  13. Cumulative incidence of serious adverse events (SAEs) [ Time Frame: Day 1 through Day 29 ]
    Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6). 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.

  14. Duration of hospitalization [ Time Frame: Day 1 through Day 29 ]
    Measured in days.

  15. Duration of invasive mechanical ventilation [ Time Frame: Day 1 through Day 29 ]
    Measured in days.

  16. Duration of new non-invasive ventilation or high flow oxygen use [ Time Frame: Day 1 through Day 29 ]
    Measured in days.

  17. Duration of new oxygen use [ Time Frame: Day 1 through Day 29 ]
    Measured in days.

  18. Duration of new ventilator or extracorporeal membrane oxygenation (ECMO) use [ Time Frame: Day 1 through Day 29 ]
    Measured in days.

  19. Duration of non invasive ventilation or high flow oxygen use [ Time Frame: Day 1 through Day 29 ]
    Measured in days.

  20. Duration of oxygen use [ Time Frame: Day 1 through Day 29 ]
    Measured in days

  21. Incidence of discontinuation or temporary suspension of study product administration [ Time Frame: Day 1 through Day 10 ]
    For any reason. Assessed overall and by baseline ordinal scale category (categories 4 and 5 versus category 6).

  22. Incidence of new non-invasive ventilation or high flow oxygen use [ Time Frame: Day 1 through Day 29 ]
  23. Incidence of new oxygen use [ Time Frame: Day 1 through Day 29 ]
  24. Incidence of new ventilator or extracorporeal membrane oxygenation (ECMO) use [ Time Frame: Day 1 through Day 29 ]
  25. Mean change from baseline in the 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) 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.

  26. Participant's clinical status at Day 15 by ordinal scale for patients with baseline ordinal score 4 and 5 [ 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: 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.

  27. Percentage of subjects reporting each severity rating on an 8 point ordinal scale [ Time Frame: Days 3, 5, 8, 11, 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: 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.

  28. Subject 14-day mortality [ Time Frame: Day 1 through Day 15 ]
    Date and cause of death (if applicable).

  29. Subject 28-day mortality [ Time Frame: Day 1 through Day 29 ]
    Date and cause of death (if applicable).

  30. 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: 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.

  31. 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) 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.

  32. Time to discharge or to a National Early Warning Score (NEWS) of </= 2 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.

  33. Time to recovery for patients with a baseline ordinal score of 4 and 5 [ 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, 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04492475


Locations
Show Show 64 study locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Layout table for additonal information
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT04492475    
Other Study ID Numbers: 20-0006 ACTT-3
First Posted: July 30, 2020    Key Record Dates
Last Update Posted: November 13, 2020
Last Verified: November 2020

Layout table for additional information
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:
Layout table for MeSH terms
Interferons
Interferon-beta
Interferon beta-1a
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs
Adjuvants, Immunologic