Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
1010 participants
INTERVENTIONAL
2020-12-02
2021-06-18
Brief Summary
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Detailed Description
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ACTT-4 will evaluate the combination of baricitinib and remdesivir compared to dexamethasone and remdesivir. 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, oropharyngeal (OP) swabs, plasma (Day 29), and serum for secondary research as well as clinical outcome data. However, if infection control or other restrictions limit the ability of the subject to return to the clinic, 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 objective is to evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir as assessed by the mechanical ventilation free survival by Day 29. The key secondary objective is to evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone + remdesivir according to clinical status (8-point ordinal scale) at Day 15.
Contacts:
20-0006 Central Contact
Telephone: 1 (301) 7617948
Email: [email protected]
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
DOUBLE
Study Groups
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Remdesivir plus Baricitinib
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; 4 mg of baricitinib administered as 2 tablets taken orally daily while hospitalized for up to a 14-day total course; and dexamethasone placebo administered as an intravenous injection daily while hospitalized for up to a 10-day total course.
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.
Placebo
Placebo matching oral baricitinib or intravenous dexamethasone.
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.
Remdesivir plus Dexamethasone
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; baricitinib placebo administered as 2 tablets taken orally daily while hospitalized for up to a 14-day total course; and 6 mg of dexamethasone administered as an intravenous injection daily while hospitalized for up to a 10-day total course.
Dexamethasone
Dexamethasone Sodium Phosphate Injection, USP, is an adrenocortical steroid anti-inflammatory drug. It is a water-soluble inorganic ester of dexamethasone. Each mL contains dexamethasone sodium phosphate equivalent to dexamethasone phosphate 4 mg or dexamethasone 3.33 mg; benzyl alcohol 10 mg added as preservative; sodium citrate dihydrate 11 mg; sodium sulfite 1 mg as an antioxidant.
Placebo
Placebo matching oral baricitinib or intravenous dexamethasone.
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.
Interventions
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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.
Dexamethasone
Dexamethasone Sodium Phosphate Injection, USP, is an adrenocortical steroid anti-inflammatory drug. It is a water-soluble inorganic ester of dexamethasone. Each mL contains dexamethasone sodium phosphate equivalent to dexamethasone phosphate 4 mg or dexamethasone 3.33 mg; benzyl alcohol 10 mg added as preservative; sodium citrate dihydrate 11 mg; sodium sulfite 1 mg as an antioxidant.
Placebo
Placebo matching oral baricitinib or intravenous dexamethasone.
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.
Eligibility Criteria
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Inclusion Criteria
2. Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures and understands and agrees to comply with planned study procedures.
3. Male or non-pregnant female adult \> / = 18 years of age at time of enrollment.
4. Illness of any duration and has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain reaction (PCR) or other commercial or public health assay (e.g. NAAT, antigen test) in any respiratory specimen or saliva \< / = 14 days prior to randomization.
5. Within the 7 days prior to randomization requiring new use of supplemental oxygen (or increased oxygen requirement if on chronic oxygen) and requires at the time of randomization low or high flow oxygen devices or use of non-invasive mechanical ventilation (ordinal scale category 5 or 6).
6. 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.
7. Agrees not to participate in another blinded clinical trial (both pharmacologic and other types of interventions) for the treatment of COVID-19 through Day 29.
Exclusion Criteria
2. On invasive mechanical ventilation at the time of randomization (ordinal scale category 7).
3. Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours of randomization.
4. Positive test for influenza virus during the current illness (influenza testing is not required by protocol).
5. Subjects with a low glomerular filtration rate (eGFR), specifically:
1. Subjects with an eGFR 15-30 mL/min are excluded unless in the opinion of the PI, the potential benefit of participation outweighs the potential risk of study participation.
2. All subjects with an eGFR \<15 mL/min
3. All subjects on hemodialysis and/or hemofiltration at screening, irrespective of eGFR are excluded.
6. Neutropenia (absolute neutrophil count \<700 cells/microliter, 0.7 x 10\^3/microliter).
7. Lymphopenia (absolute lymphocyte count \<200 cells/microliter, 0.20 x 10\^3/microliter).
8. Received five or more doses of remdesivir including the loading dose, outside of the study as treatment for COVID-19.
9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day 1 until two weeks after the last study product is given are not excluded).
10. Allergy to any study medication.
11. Received convalescent plasma or intravenous immunoglobulin \[IVIg\] for COVID-19, the current illness for which they are being enrolled.
12. Received any of the following in the two weeks prior to screening as treatment of COVID-19:
* More than one dose of baricitinib for the treatment of COVID-19;
* Other small molecule tyrosine kinase inhibitors (e.g. 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. Note: receipt of anti-SARS-CoV-2 monoclonal antibody (mAb) prior to enrollment (e.g. bamlanivimab) for their current COVID-19 illness is not exclusionary
13. Use of probenecid that cannot be discontinued at study enrollment.
14. Received 6 mg or more of dexamethasone by mouth (po) or Intravenous (IV) (or equivalent for other glucocorticoids) in one day, on more than one day, in the 7 days prior to time of randomization. Note: 6 mg dexamethasone dose equivalents include 40 mg prednisone, 32 mg methylprednisolone and 160 mg hydrocortisone.
15. Received \> / = 20 mg/day of prednisone po or IV (or equivalent for other glucocorticoids) for \> / = 14 consecutive days in the 4 weeks prior to screening.
16. Have diagnosis of current active or latent tuberculosis (TB), if known, treated for less than 4 weeks with appropriate therapy (by history only, no screening required).
17. Serious infection (besides COVID-19), immunosuppressive state, or immunosuppressive medications that in the opinion of the investigator could constitute a risk when taking baricitinib or dexamethasone.
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 including SARS-CoV-2 vaccine is allowed for all subjects.
19. Had a known Venous thromboembolism (VTE)(deep vein thrombosis \[DVT\] or pulmonary embolism \[PE\]) during the current COVID-19 illness.
18 Years
99 Years
ALL
No
Sponsors
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National Institute of Allergy and Infectious Diseases (NIAID)
NIH
Responsible Party
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Locations
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University of Alabama at Birmingham School of Medicine - Infectious Disease
Birmingham, Alabama, United States
UCSF Fresno Center for Medical Education and Research - Clinical Research Center
Fresno, California, 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
University of California Davis Medical Center - Internal Medicine - Infectious Disease
Sacramento, California, United States
Kaiser Permanente San Diego Medical Center
San Diego, 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
Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases
Stanford, California, United States
Cedars Sinai Medical Center
West Hollywood, California, United States
VA 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 D.C., District of Columbia, United States
University of Florida Health - Shands Hospital - Division of Infectious Diseases and Global Medicine
Gainesville, Florida, United States
University of Florida Health - Jacksonville - Department of Emergency Medicine
Jacksonville, 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
Tripler Army Medical Center
Honolulu, Hawaii, 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
University of Iowa Hospitals & Clinics - Department of Internal Medicine
Iowa City, Iowa, United States
Tulane University - Section of Pulmonary Diseases, Critical Care, and Environmental Medicine
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 Michigan - Infectious Disease Clinic at Taubman Center
Ann Arbor, Michigan, United States
University of Minnesota Medical Center, Fairview - Infectious Diseases and International Medicine
Minneapolis, Minnesota, United States
Saint Louis University - Center for Vaccine Development
St Louis, Missouri, United States
University of Nebraska Medical Center - Infectious Diseases
Omaha, Nebraska, United States
CHI Health Creighton University Medical Center - Bergan Mercy - Pulmonary Medicine
Omaha, Nebraska, United States
Atlantic Health System - Morristown Medical Center
Morristown, New Jersey, United States
University of New Mexico Clinical and Translational Science Center
Albuquerque, New Mexico, 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
Montefiore Medical Center - Infectious Diseases
The Bronx, 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
University of Oklahoma Health Science Center - Surgery
Oklahoma City, Oklahoma, 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
Hospital of the University of Pennsylvania - Infectious Diseases
Philadelphia, Pennsylvania, United States
University of Pittsburgh - Medicine - Infectious Diseases
Pittsburgh, Pennsylvania, 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
Methodist Hospital - Houston
Houston, 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
Tokyo Medical and Dental University - Medical Hospital - Department of Respiratory Medicine
Tokyo, , Japan
National Center for Global Health and Medicine Hospital - Disease Control and Prevention Center
Tokyo, , Japan
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 University Health System - Alexandra Hospital - Division of Infectious Diseases
Singapore, , Singapore
National Centre for Infectious Diseases
Singapore, , Singapore
Changi General Hospital - Clinical Trials and Research Unit (CTRU)
Singapore, , Singapore
Ng Teng Fong General Hospital - Infectious Disease Service
Singapore, , Singapore
Seoul National University Bundang Hospital - Division of Infectious Diseases
Bundang-gu Seongnam-si, Gyeonggi-do, South Korea
Seoul National University Hospital
Seoul, Jongno-gu, South Korea
Countries
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References
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Potter GE, Bonnett T, Rubenstein K, Lindholm DA, Rapaka RR, Doernberg SB, Lye DC, Mularski RA, Hynes NA, Kline S, Paules CI, Wolfe CR, Frank MG, Rouphael NG, Deye GA, Sweeney DA, Colombo RE, Davey RT Jr, Mehta AK, Whitaker JA, Castro JG, Amin AN, Colombo CJ, Levine CB, Jain MK, Maves RC, Marconi VC, Grossberg R, Hozayen S, Burgess TH, Atmar RL, Ganesan A, Gomez CA, Benson CA, Lopez de Castilla D, Ahuja N, George SL, Nayak SU, Cohen SH, Lalani T, Short WR, Erdmann N, Tomashek KM, Tebas P. Temporal Improvements in COVID-19 Outcomes for Hospitalized Adults: A Post Hoc Observational Study of Remdesivir Group Participants in the Adaptive COVID-19 Treatment Trial. Ann Intern Med. 2022 Dec;175(12):1716-1727. doi: 10.7326/M22-2116. Epub 2022 Nov 29.
Wolfe CR, Tomashek KM, Patterson TF, Gomez CA, Marconi VC, Jain MK, Yang OO, Paules CI, Palacios GMR, Grossberg R, Harkins MS, Mularski RA, Erdmann N, Sandkovsky U, Almasri E, Pineda JR, Dretler AW, de Castilla DL, Branche AR, Park PK, Mehta AK, Short WR, McLellan SLF, Kline S, Iovine NM, El Sahly HM, Doernberg SB, Oh MD, Huprikar N, Hohmann E, Kelley CF, Holodniy M, Kim ES, Sweeney DA, Finberg RW, Grimes KA, Maves RC, Ko ER, Engemann JJ, Taylor BS, Ponce PO, Larson L, Melendez DP, Seibert AM, Rouphael NG, Strebe J, Clark JL, Julian KG, de Leon AP, Cardoso A, de Bono S, Atmar RL, Ganesan A, Ferreira JL, Green M, Makowski M, Bonnett T, Beresnev T, Ghazaryan V, Dempsey W, Nayak SU, Dodd LE, Beigel JH, Kalil AC; ACTT-4 Study Group. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial. Lancet Respir Med. 2022 Sep;10(9):888-899. doi: 10.1016/S2213-2600(22)00088-1. Epub 2022 May 23.
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.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Document Type: Informed Consent Form
Other Identifiers
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20-0006 ACTT-4
Identifier Type: -
Identifier Source: org_study_id
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