Clinical trial NCT04492475: Adaptive COVID-19 Treatment Trial 3 (ACTT-3)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COVID-19
Keywords: Adaptive
COVID-19
Efficacy
Multicenter
novel coronavirus
Safety
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2020-07-30
Enrollment: 969
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Eligibility 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.

Primary outcomes:
measure: Time to Recovery for Participants With Baseline Ordinal Score 4, 5 and 6
timeFrame: Day 1 through Day 29
measure: Time to Recovery for Participants With Baseline Ordinal Score 4, 5 and 6 by Race
timeFrame: Day 1 through Day 29
measure: Time to Recovery for Participants With Baseline Ordinal Score 4, 5 and 6 by Ethnicity
timeFrame: Day 1 through Day 29
measure: Time to Recovery for Participants With Baseline Ordinal Score 4, 5 and 6 by Sex
timeFrame: Day 1 through Day 29
Secondary outcomes:
measure: Change From Baseline in Alanine Aminotransferase (ALT)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Aspartate Aminotransferase (AST)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in C-reactive Protein (CRP)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Creatinine
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in D-dimer Concentration
timeFrame: Days 1, 3, 5, 8, 11, 15, and 29
measure: Change From Baseline in Hemoglobin
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Prothrombin International Normalized Ratio (INR)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Platelets
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Total Bilirubin
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in White Blood Cell Count (WBC)
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Neutrophils
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Lymphoctyes
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Monocytes
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Basophils
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change From Baseline in Eosinophils
timeFrame: Days 1, 3, 5, 8, 11, 15 and 29
measure: Change in National Early Warning Score (NEWS) From Baseline
timeFrame: Days 1, 3, 5, 8, 11, 15, 22, and 29
measure: Percentage of Participants Reporting Grade 3 and 4 Clinical and/or Laboratory Adverse Events (AEs)
timeFrame: Day 1 through Day 29
measure: Percentage of Participants Reporting Serious Adverse Events (SAEs)
timeFrame: Day 1 through Day 29
measure: Duration of Hospitalization
timeFrame: Day 1 through Day 29
measure: Duration of Invasive Mechanical Ventilation
timeFrame: Day 1 through Day 29
measure: Duration of New Non-invasive Ventilation or High Flow Oxygen Use
timeFrame: Day 1 through Day 29
measure: Duration of New Oxygen Use
timeFrame: Day 1 through Day 29
measure: Duration of New Ventilator or Extracorporeal Membrane Oxygenation (ECMO) Use
timeFrame: Day 1 through Day 29
measure: Duration of Non Invasive Ventilation or High Flow Oxygen Use
timeFrame: Day 1 through Day 29
measure: Duration of Oxygen Use
timeFrame: Day 1 through Day 29
measure: Number of Participants With Discontinuation or Temporary Suspension of Study Product Administration
timeFrame: Day 1 through Day 10
measure: Proportion of Participants With New Non-invasive Ventilation or High Flow Oxygen Use
timeFrame: Day 1 through Day 29
measure: Proportion of Participants With New Oxygen Use
timeFrame: Day 1 through Day 29
measure: Proportion of Participants With New Ventilator or Extracorporeal Membrane Oxygenation (ECMO) Use
timeFrame: Day 1 through Day 29
measure: Mean Change From Baseline in the Ordinal Scale
timeFrame: Day 1, 3, 5, 8, 11, 15, 22, and 29
measure: Percentage of Participants at Each Clinical Status Using Ordinal Scale at Day 15 for Participants With Baseline Ordinal Score 4 and 5
timeFrame: Day 15
measure: Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 1
timeFrame: Day 1
measure: Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 3
timeFrame: Day 3
measure: Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 5
timeFrame: Day 5
measure: Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 8
timeFrame: Day 8
measure: Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 11
timeFrame: Day 11
measure: Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 15
timeFrame: Day 15
measure: Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 22
timeFrame: Day 22
measure: Percentage of Participants Reporting Each Severity Rating on an 8 Point Ordinal Scale at Day 29
timeFrame: Day 29
measure: 14-day Participant Mortality
timeFrame: Day 1 through Day 15
measure: 28-day Participant Mortality
timeFrame: Day 1 through Day 29
measure: Time to an Improvement of One Category Using an Ordinal Scale
timeFrame: Day 1 through Day 29
measure: Time to an Improvement of Two Categories Using an Ordinal Scale
timeFrame: Day 1 through Day 29
measure: Time to Discharge or to a National Early Warning Score (NEWS) of </= 2 and Maintained for 24 Hours, Whichever Occurs First
timeFrame: Day 1 through Day 29
measure: Time to Recovery for Patients With a Baseline Ordinal Score of 4 and 5
timeFrame: Day 1 through Day 29
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham School of Medicine - Infectious Disease
state: Alabama
city: Fresno
country: United States
facility: UCSF Fresno Center for Medical Education and Research - Clinical Research Center
state: California
city: La Jolla
country: United States
facility: University of California San Diego Health - Jacobs Medical Center
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles Medical Center - Westwood Clinic
state: California
city: Orange
country: United States
facility: University of California Irvine Medical Center - Infectious Disease
state: California
city: Palo Alto
country: United States
facility: VA Palo Alto Health Care System - Infectious Diseases
state: California
city: Palo Alto
country: United States
facility: Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center - Internal Medicine - Infectious Disease
state: California
city: San Diego
country: United States
facility: Naval Medical Center San Diego - Infectious Disease Clinic
state: California
city: San Francisco
country: United States
facility: University of California San Francisco - Zuckerberg San Francisco General Hospital - Division of HIV, ID, and Global Medicine
state: California
city: West Hollywood
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Aurora
country: United States
facility: Eastern Colorado Health Care System
state: Colorado
city: Denver
country: United States
facility: Denver Health Division of Hospital Medicine - Main Campus
state: Colorado
city: Gainesville
country: United States
facility: University of Florida Health - Shands Hospital - Division of Infectious Diseases and Global Medicine
state: Florida
city: Jacksonville
country: United States
facility: University of Florida Health - Jacksonville - Department of Emergency Medicine
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine - Infectious Diseases
state: Florida
city: Decatur
country: United States
facility: Emory Vaccine Center - The Hope Clinic
state: Georgia
city: Decatur
country: United States
facility: Atlanta VA Medical Center - Infectious Diseases Clinic
state: Georgia
city: Honolulu
country: United States
facility: Tripler Army Medical Center (TAMC)
state: Hawaii
city: Chicago
country: United States
facility: Northwestern Hospital - Infectious Disease
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago Division of Infectious Diseases
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics - Department of Internal Medicine
state: Iowa
city: Kenner
country: United States
facility: Ochsner Medical Center - Kenner - Department of Infectious Diseases
state: Louisiana
city: New Orleans
country: United States
facility: Southeast Louisiana Veterans Health Care System - Section of Infectious Diseases
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland School of Medicine - Center for Vaccine Development - Baltimore
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Hospital - Medicine - Infectious Diseases
state: Maryland
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Bethesda
country: United States
facility: National Institutes of Health - Clinical Center, National Institute of Allergy and Infectious Diseases Laboratory Of Immunoregulation, Clinical Research Section
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital - Infectious Diseases
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Medical School - Infectious Diseases and Immunology
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center, Fairview - Infectious Diseases and International Medicine
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis University - Center for Vaccine Development
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center - Infectious Diseases
state: Nebraska
city: Albuquerque
country: United States
facility: University of New Mexico Clinical and Translational Science Center
state: New Mexico
city: Bronx
country: United States
facility: Montefiore Medical Center - Infectious Diseases
state: New York
city: New York
country: United States
facility: New York University School of Medicine - Langone Medical Center - Microbiology - Parasitology
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center - Vaccine Research Unit
state: New York
city: Durham
country: United States
facility: Duke Human Vaccine Institute - Duke Vaccine and Trials Unit
state: North Carolina
city: Fort Bragg
country: United States
facility: Womack Army Medical Center - Pulmonary and Respiratory Services
state: North Carolina
city: Portland
country: United States
facility: Kaiser Permanente Northwest - Center for Health Research
state: Oregon
city: Hershey
country: United States
facility: Penn State Health Milton S. Hershey Medical Center - Division of Infectious Diseases
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania - Infectious Diseases
state: Pennsylvania
city: Dallas
country: United States
facility: Baylor Scott & White Health - Baylor University Medical Center - North Texas Infectious Disease Consultants
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center - Internal Medicine - Infectious Diseases
state: Texas
city: Fort Sam Houston
country: United States
facility: Brooke Army Medical Center
state: Texas
city: Galveston
country: United States
facility: University of Texas Medical Branch - Division of Infectious Disease
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine - Molecular Virology and Microbiology
state: Texas
city: Houston
country: United States
facility: Methodist Hospital - Houston
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio - Infectious Diseases
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah - Infectious Diseases
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia - Acute Care Surgery
state: Virginia
city: Portsmouth
country: United States
facility: Naval Medical Center Portsmouth - Infectious Disease Division
state: Virginia
city: Kirkland
country: United States
facility: EvergreenHealth Infectious Disease Service
state: Washington
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center
state: Washington
city: Tacoma
country: United States
facility: Madigan Army Medical Center - Infectious Disease Clinic
state: Washington
city: Tokyo
country: Japan
facility: National Center for Global Health and Medicine Hospital - Disease Control and Prevention Center
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital - Division of Infectious Diseases
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
state: Jongno-gu
city: Mexico City
country: Mexico
facility: Instituto Nacional de Enfermedades Respiratorias (INER) - Ismael Cosío Villegas
city: Mexico City
country: Mexico
facility: Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán - Departamento de Infectologia
city: Singapore
country: Singapore
facility: National University Health System - Division of Infectious Diseases
city: Singapore
country: Singapore
facility: National Centre for Infectious Diseases (NCID)
city: Singapore
country: Singapore
facility: Changi General Hospital - Clinical Trials and Research Unit (CTRU)
city: Singapore
country: Singapore
facility: Ng Teng Fong General Hospital - Infectious Disease Service
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.