ACTT-2 will evaluate the combination of baricitinib and remdesivir compared to remdesivir alone. Subjects will be assessed daily while hospitalized. If the subjects are discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety laboratory tests and oropharyngeal (OP) swab and blood (serum only) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the subject to return to the clinic. In this case, these visits may be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not have laboratory tests or collection of samples and is conducted by phone. The primary outcome is time to recovery by Day 29.
This study is an adaptive randomized double-blind placebo-controlled trial to evaluate the
safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with
COVID-19. The study is a multicenter trial that will be conducted in up to approximately 100
sites globally. The study will compare different investigational therapeutic agents to a
control arm. New arms can be introduced according to scientific and public health needs.
There will be interim monitoring to allow early stopping for futility, efficacy, or safety.
If one therapy proves to be efficacious, then this treatment may become the control arm for
comparison(s) with new experimental treatment(s). Any such change would be accompanied by an
updated sample size. This adaptive platform is used to rapidly evaluate different
therapeutics in a population of those hospitalized with moderate to severe COVID-19. The
platform will provide a common framework sharing a similar population, design, endpoints, and
safety oversight. New stages with new therapeutics can be introduced. One independent Data
and Safety Monitoring Board (DSMB) will actively monitor interim data in all stages to make
recommendations about early study closure or changes to study arms.
ACTT-2 will evaluate the combination of baricitinib and remdesivir compared to remdesivir
alone. Subjects will be assessed daily while hospitalized. If the subjects are discharged
from the hospital, they will have a study visit at Days 15, 22, and 29. For discharged
subjects, it is preferred that the Day 15 and 29 visits are in person to obtain safety
laboratory tests and oropharyngeal (OP) swab and blood (serum only) samples for secondary
research as well as clinical outcome data. However, infection control or other restrictions
may limit the ability of the subject to return to the clinic. In this case, these visits may
be conducted by phone, and only clinical data will be obtained. The Day 22 visit does not
have laboratory tests or collection of samples and is conducted by phone.
All subjects will undergo a series of efficacy, safety, and laboratory assessments. Safety
laboratory tests and blood (serum and plasma) research samples and oropharyngeal (OP) swabs
will be obtained on Days 1 (prior to infusion) and Days 3, 5, 8, and 11 (while hospitalized).
OP swabs and blood (serum only) plus safety laboratory tests will be collected on Day 15 and
29 (if the subject attends an in-person visit or are still hospitalized).
The primary outcome is time to recovery by Day 29. A key secondary outcome evaluates
treatment-related improvements in the 8-point ordinal scale at Day 15. Each stage may
prioritize different secondary endpoints for the purpose of multiple comparison analyses.
Contacts:
20-0006 Central Contact
Telephone: 1 (301) 7617948
Other: Placebo
The matching Baricitinib placebo contains lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The coating for the placebo tablet is identical to that of the corresponding active tablet.
Drug: Remdesivir
Drug Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, the lyophilized formulation of Remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide.
Drug: Baricitinib
Baricitinib is a Janus kinase (JAK) inhibitor with the chemical name [1-(ethylsulfonyl)-3-(4-(7Hpyrrolo(2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile Each tablet contains 2 mg of baricitinib and the following inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, ferric oxide, lecithin (soya), polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.
Inclusion Criteria:
1. Admitted to a hospital with symptoms suggestive of COVID-19.
2. Subject (or legally authorized representative) provides informed consent prior to
initiation of any study procedures.
3. Subject (or legally authorized representative) understands and agrees to comply with
planned study procedures.
4. Male or non-pregnant female adult > / = 18 years of age at time of enrollment.
5. Has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain
reaction (PCR) or other commercial or public health assay in any specimen, as
documented by either of the following:
- PCR positive in sample collected < 72 hours prior to randomization; OR
- PCR positive in sample collected >/= 72 hours prior to randomization, documented
inability to obtain a repeat sample (e.g. due to lack of testing supplies,
limited testing capacity, results taking >24 hours, etc.) AND progressive disease
suggestive of ongoing SARS-CoV-2 infection.
6. Illness of any duration, and at least one of the following:
- Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR
- SpO2 < / = 94% on room air, OR
- Requiring supplemental oxygen, OR
- Requiring mechanical ventilation or extracorporeal membrane oxygenation (ECMO).
7. Women of childbearing potential must agree to either abstinence or use at least one
primary form of contraception not including hormonal contraception from the time of
screening through Day 29.
8. Agrees to not participate in another clinical trial for the treatment of COVID-19
through Day 29.
Exclusion Criteria:
1. Alanine Transaminase (ALT) or Aspartate Transaminase (AST) > 5 times the upper limit
of normal.
2. Estimated glomerular filtration rate (eGFR) < 30 ml/min or patient is receiving
hemodialysis or hemofiltration at time of screening.
3. Neutropenia (absolute neutrophil count <1000 cells/microliter) (<1.0 x 103/microliter
or <1.0 GI/L).
4. Lymphopenia (absolute lymphocyte count <200 cells/microliter) (<0.20 x 103/microliter
or <0.20 GI/L)
5. Pregnancy or breast feeding.
6. Anticipated discharge from the hospital or transfer to another hospital which is not a
study site within 72 hours.
7. Allergy to any study medication.
8. Received three or more doses of remdesivir, including the loading dose, outside of the
study under the EUA (or similar mechanism) for COVID-19.
9. Received convalescent plasma or intravenous immunoglobulin [IVIg]) for COVID-19, the
current illness for which they are being enrolled.
10. Received small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatibib,
genfinitib), in the 1 week prior to screening
11. Received monoclonal antibodies targeting cytokines (e.g., TNF inhibitors,
anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab]), or T-cells (e.g.,
abatacept) in the 4 weeks prior to screening.
12. Received monoclonal antibodies targeting B-cell (e.g., rituximab, and including any
targeting multiple cell lines including B-cells) in the 3 months prior to screening.
13. Received other immunosuppressants in the 4 weeks prior to screening and in the
judgement of the investigator, the risk of immunosuppression with baricitinib is
larger than the risk of COVID-19.
14. Received >/= 20 mg/day of prednisone or equivalent for >/=14 consecutive days in the 4
weeks prior to screening.
15. Use of probenecid that cannot be discontinued at study enrollment.
16. Have diagnosis of current active tuberculosis (TB) or, if known, latent TB treated for
less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by
history only, no screening required).
17. Suspected serious, active bacterial, fungal, viral, or other infection (besides
COVID-19) that in the opinion of the investigator could constitute a risk when taking
investigational product.
18. Have received any live vaccine (that is, live attenuated) within 4 weeks before
screening, or intend to receive a live vaccine (or live attenuated) during the study.
Note: Use of non-live (inactivated) vaccinations is allowed for all subjects.
19. Have a history of VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) within
12 weeks prior to screening or have a history of recurrent (>1) VTE (DVT/PE).
20. Immunocompromised patients, patients with a chronic medical condition, or those taking
a medication that cannot be discontinued at enrollment, who, in the judgment of PI,
are at increased risk for serious infections or other safety concerns given the study
products.
University of Alabama at Birmingham School of Medicine - Infectious Disease
Birmingham, Alabama, United States
University of California San Diego Health - Jacobs Medical Center
La Jolla, California, United States
University of California Los Angeles Medical Center - Westwood Clinic
Los Angeles, California, United States
University of California Irvine Medical Center - Infectious Disease
Orange, California, United States
VA Palo Alto Health Care System - Infectious Diseases
Palo Alto, California, United States
Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases
Palo Alto, California, United States
University of California Davis Medical Center - Internal Medicine - Infectious Disease
Sacramento, California, United States
Naval Medical Center San Diego - Infectious Disease Clinic
San Diego, California, United States
University of California San Francisco - Zuckerberg San Francisco General Hospital - Division of Human Immunodeficiency Virus, Infectious Disease, and Global Medicine
San Francisco, California, United States
Cedars Sinai Medical Center
West Hollywood, California, United States
Eastern Colorado Health Care System
Aurora, Colorado, United States
Denver Health Division of Hospital Medicine - Main Campus
Denver, Colorado, United States
Georgetown University Medical Center - Division of Infectious Diseases
Washington, District of Columbia, United States
University of Florida Health - Shands Hospital - Division of Infectious Diseases and Global Medicine
Gainesville, Florida, United States
University of Miami Miller School of Medicine - Infectious Diseases
Miami, Florida, United States
Emory Vaccine Center - The Hope Clinic
Decatur, Georgia, United States
Atlanta VA Medical Center - Infectious Diseases Clinic
Decatur, Georgia, United States
Northwestern Hospital - Infectious Disease
Chicago, Illinois, United States
University of Illinois at Chicago College of Medicine - Division of Infectious Diseases
Chicago, Illinois, United States
Indiana University School of Medicine - Infectious Diseases
Indianapolis, Indiana, United States
Ochsner Medical Center - Kenner - Department of Infectious Diseases
Kenner, Louisiana, United States
Southeast Louisiana Veterans Health Care System (SLVHCS) - Section of Infectious Diseases
New Orleans, Louisiana, United States
University of Maryland School of Medicine - Center for Vaccine Development - Baltimore
Baltimore, Maryland, United States
Johns Hopkins Hospital - Medicine - Infectious Diseases
Baltimore, Maryland, United States
Walter Reed National Military Medical Center
Bethesda, Maryland, United States
National Institutes of Health - Clinical Center, National Institute of Allergy and Infectious Diseases Laboratory Of Immunoregulation, Clinical Research Section
Bethesda, Maryland, United States
Massachusetts General Hospital - Infectious Diseases
Boston, Massachusetts, United States
University of Massachusetts Medical School - Infectious Diseases and Immunology
Worcester, Massachusetts, United States
University of Minnesota Medical Center, Fairview - Infectious Diseases and International Medicine
Minneapolis, Minnesota, United States
Saint Louis University - Center for Vaccine Development
Saint Louis, Missouri, United States
University of Nebraska Medical Center - Infectious Diseases
Omaha, Nebraska, United States
University of New Mexico Clinical and Translational Science Center
Albuquerque, New Mexico, United States
Montefiore Medical Center - Infectious Diseases
Bronx, New York, United States
New York University School of Medicine - Langone Medical Center - Microbiology - Parasitology
New York, New York, United States
University of Rochester Medical Center - Vaccine Research Unit
Rochester, New York, United States
Duke Human Vaccine Institute - Duke Vaccine and Trials Unit
Durham, North Carolina, United States
Womack Army Medical Center - Pulmonary and Respiratory Services
Fort Bragg, North Carolina, United States
Kaiser Permanente Northwest - Center for Health Research
Portland, Oregon, United States
Penn State Health Milton S. Hershey Medical Center - Division of Infectious Diseases
Hershey, Pennsylvania, United States
University of Pennsylvania Perelman School of Medicine - Penn Institute for Immunology
Philadelphia, Pennsylvania, United States
Vanderbilt University Medical Center - Infectious Diseases
Nashville, Tennessee, United States
Baylor Scott & White Health - Baylor University Medical Center - North Texas Infectious Disease Consultants
Dallas, Texas, United States
University of Texas Southwestern Medical Center - Internal Medicine - Infectious Diseases
Dallas, Texas, United States
Brooke Army Medical Center
Fort Sam Houston, Texas, United States
University of Texas Medical Branch - Division of Infectious Disease
Galveston, Texas, United States
Baylor College of Medicine - Molecular Virology and Microbiology
Houston, Texas, United States
University of Texas Health Science Center at San Antonio - Infectious Diseases
San Antonio, Texas, United States
University of Utah - Infectious Diseases
Salt Lake City, Utah, United States
University of Virginia - Acute Care Surgery
Charlottesville, Virginia, United States
Naval Medical Center Portsmouth - Infectious Disease Division
Portsmouth, Virginia, United States
EvergreenHealth Infectious Disease Service
Kirkland, Washington, United States
Providence Sacred Heart Medical Center
Spokane, Washington, United States
Madigan Army Medical Center - Infectious Disease Clinic
Tacoma, Washington, United States
University of Copenhagen - Centre of Excellence for Health, Immunity and Infections (CHIP) - Department of Infectious Diseases
Copenhagen, Denmark
National Center for Global Health and Medicine Hospital - Disease Control and Prevention Center
Tokyo, Japan
Seoul National University Bundang Hospital - Division of Infectious Diseases
Bundang-gu Seongnam-si, Korea, Republic of
Seoul National University Hospital
Seoul, Korea, Republic of
Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán - Departamento de Infectologia
Mexico City, Mexico
Instituto Nacional de Enfermedades Respiratorias (INER) - Ismael Cosío Villegas
Mexico City, Mexico
National University Health System - Division of Infectious Diseases
Singapore, Singapore
National Centre for Infectious Diseases (NCID)
Singapore, Singapore
Changi General Hospital - Clinical Trials and Research Unit (CTRU)
Singapore, Singapore
Ng Teng Fong General Hospital - Infectious Disease Service
Singapore, Singapore
Hospital Clinic Barcelona, Servicio de Salud Internacional
Barcelona, Cataluña, Spain
Hospital Germans Trias i Pujol - Servei Malalties Infeccioses
Barcelona, Cataluña, Spain
Hospital Clinico San Carlos - Enfermedades Infecciosas
Madrid, Spain
Royal Sussex County Hospital - Department of Intensive Care Medicine
Brighton, United Kingdom
Saint Thomas' Hospital - Directorate of Infection
City Of London, United Kingdom
St. James's University Hospital - Infectious Diseases
Leeds, United Kingdom
Royal Victoria Infirmary - Department of Infectious Diseases
Newcastle Upon Tyne, United Kingdom
John Radcliffe Hospital
Oxford, United Kingdom