Adaptive COVID-19 Treatment Trial 2 (ACTT-2)

NCT04401579 | Completed Phase 3 Results FDA Drug

• 1 other identifier: 20-0006 ACTT-2
• Study Type: interventional
• Target: 1,033
• Locations: 8 countries
• Sites: 71

Brief Summary

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.

Conditions

COVID-19

Keywords

Adaptive; COVID-19; Efficacy; Multicenter; novel coronavirus; Safety

Outcome Measures

Primary Outcomes (4)

• Time to Recovery

  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

• Time to Recovery 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, 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

• Time to Recovery 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, 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

• Time to Recovery 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, 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

Secondary Outcomes (41)

• Change From Baseline in Alanine Transaminase (ALT)

  Days 1, 3, 5, 8, 11, 15 and 29

• Change From Baseline in Aspartate Transaminase (AST)

  Days 1, 3, 5, 8, 11, 15 and 29

• Change From Baseline in Creatinine

  Days 1, 3, 5, 8, 11, 15 and 29

• Change From Baseline in Glucose

  Days 1, 3, 5, 8, 11, 15 and 29

• Change From Baseline in Hemoglobin

  Days 1, 3, 5, 8, 11, 15 and 29

Study Arms (2)

Remdesivir plus Baricitinib

EXPERIMENTAL

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 4 mg (2 tablets of 2 mg) of Baricitinib administered orally daily for the duration of the hospitalization up to a 14-day total course.

Drug: Remdesivir; Drug: Baricitinib

Remdesivir plus Placebo

PLACEBO COMPARATOR

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 4 mg (2 tablets of 2 mg) of Baricitinib Placebo administered orally daily for the duration of the hospitalization up to a 14-day total course.

Other: Placebo; Drug: Remdesivir

Interventions

Placebo OTHER

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.

Remdesivir plus Placebo

Remdesivir DRUG

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 Baricitinib; Remdesivir plus Placebo

Baricitinib DRUG

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.

Remdesivir plus Baricitinib

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Admitted to a hospital with symptoms suggestive of COVID-19.
• Subject (or legally authorized representative) provides informed consent prior to initiation of any study procedures.
• Subject (or legally authorized representative) understands and agrees to comply with planned study procedures.
• Male or non-pregnant female adult \> / = 18 years of age at time of enrollment.
• 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.
• 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).
• 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.
• Agrees to not participate in another clinical trial for the treatment of COVID-19 through Day 29.

You may not qualify if:

• Alanine Transaminase (ALT) or Aspartate Transaminase (AST) \> 5 times the upper limit of normal.
• Estimated glomerular filtration rate (eGFR) \< 30 ml/min or patient is receiving hemodialysis or hemofiltration at time of screening.
• Neutropenia (absolute neutrophil count \<1000 cells/microliter) (\<1.0 x 103/microliter or \<1.0 GI/L).
• Lymphopenia (absolute lymphocyte count \<200 cells/microliter) (\<0.20 x 103/microliter or \<0.20 GI/L)
• Pregnancy or breast feeding.
• Anticipated discharge from the hospital or transfer to another hospital which is not a study site within 72 hours.
• Allergy to any study medication.
• Received three or more doses of remdesivir, including the loading dose, outside of the study under the EUA (or similar mechanism) for COVID-19.
• Received convalescent plasma or intravenous immunoglobulin \[IVIg\]) for COVID-19, the current illness for which they are being enrolled.
• Received small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatibib, genfinitib), in the 1 week prior to screening
• 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.
• 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.
• 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.
• Received \>/= 20 mg/day of prednisone or equivalent for \>/=14 consecutive days in the 4 weeks prior to screening.
• Use of probenecid that cannot be discontinued at study enrollment.

Sponsors & Collaborators

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

Study Sites (71)

University of Alabama at Birmingham School of Medicine - Infectious Disease

Birmingham, Alabama, 35233, United States

Location

University of California San Diego Health - Jacobs Medical Center

La Jolla, California, 29037, United States

Location

University of California Los Angeles Medical Center - Westwood Clinic

Los Angeles, California, 90095, United States

Location

University of California Irvine Medical Center - Infectious Disease

Orange, California, 92868-3298, United States

Location

VA Palo Alto Health Care System - Infectious Diseases

Palo Alto, California, 94304-1207, United States

Location

Stanford University - Stanford Hospital and Clinics - Pediatrics - Infectious Diseases

Palo Alto, California, 94304-1503, United States

Location

University of California Davis Medical Center - Internal Medicine - Infectious Disease

Sacramento, California, 95817-1460, United States

Location

Naval Medical Center San Diego - Infectious Disease Clinic

San Diego, California, 92314, United States

Location

University of California San Francisco - Zuckerberg San Francisco General Hospital - Division of Human Immunodeficiency Virus, Infectious Disease, and Global Medicine

San Francisco, California, 94110-2859, United States

Location

Cedars Sinai Medical Center

West Hollywood, California, 90048-1804, United States

Location

Eastern Colorado Health Care System

Aurora, Colorado, 80045, United States

Location

Denver Health Division of Hospital Medicine - Main Campus

Denver, Colorado, 80204, United States

Location

Georgetown University Medical Center - Division of Infectious Diseases

Washington D.C., District of Columbia, 20007, United States

Location

University of Florida Health - Shands Hospital - Division of Infectious Diseases and Global Medicine

Gainesville, Florida, 32610, United States

Location

University of Miami Miller School of Medicine - Infectious Diseases

Miami, Florida, 33136, United States

Location

Emory Vaccine Center - The Hope Clinic

Decatur, Georgia, 30030-1705, United States

Location

Atlanta VA Medical Center - Infectious Diseases Clinic

Decatur, Georgia, 30033, United States

Location

Northwestern Hospital - Infectious Disease

Chicago, Illinois, 60611-2908, United States

Location

University of Illinois at Chicago College of Medicine - Division of Infectious Diseases

Chicago, Illinois, 60612, United States

Location

Indiana University School of Medicine - Infectious Diseases

Indianapolis, Indiana, 46202, United States

Location

Ochsner Medical Center - Kenner - Department of Infectious Diseases

Kenner, Louisiana, 70065, United States

Location

Southeast Louisiana Veterans Health Care System (SLVHCS) - Section of Infectious Diseases

New Orleans, Louisiana, 70119, United States

Location

University of Maryland School of Medicine - Center for Vaccine Development - Baltimore

Baltimore, Maryland, 21201, United States

Location

Johns Hopkins Hospital - Medicine - Infectious Diseases

Baltimore, Maryland, 21287-0005, United States

Location

Walter Reed National Military Medical Center

Bethesda, Maryland, 20889, United States

Location

National Institutes of Health - Clinical Center, National Institute of Allergy and Infectious Diseases Laboratory Of Immunoregulation, Clinical Research Section

Bethesda, Maryland, 20892-1504, United States

Location

Massachusetts General Hospital - Infectious Diseases

Boston, Massachusetts, 02114-2621, United States

Location

University of Massachusetts Medical School - Infectious Diseases and Immunology

Worcester, Massachusetts, 01655-0002, United States

Location

University of Minnesota Medical Center, Fairview - Infectious Diseases and International Medicine

Minneapolis, Minnesota, 55455-0341, United States

Location

Saint Louis University - Center for Vaccine Development

St Louis, Missouri, 63104-1015, United States

Location

University of Nebraska Medical Center - Infectious Diseases

Omaha, Nebraska, 68198-5400, United States

Location

University of New Mexico Clinical and Translational Science Center

Albuquerque, New Mexico, 87106, United States

Location

New York University School of Medicine - Langone Medical Center - Microbiology - Parasitology

New York, New York, 10016, United States

Location

University of Rochester Medical Center - Vaccine Research Unit

Rochester, New York, 14642-0001, United States

Location

Montefiore Medical Center - Infectious Diseases

The Bronx, New York, 10467-2401, United States

Location

Duke Human Vaccine Institute - Duke Vaccine and Trials Unit

Durham, North Carolina, 27704, United States

Location

Womack Army Medical Center - Pulmonary and Respiratory Services

Fort Bragg, North Carolina, 28310, United States

Location

Kaiser Permanente Northwest - Center for Health Research

Portland, Oregon, 97227, United States

Location

Penn State Health Milton S. Hershey Medical Center - Division of Infectious Diseases

Hershey, Pennsylvania, 17033, United States

Location

University of Pennsylvania Perelman School of Medicine - Penn Institute for Immunology

Philadelphia, Pennsylvania, 19104-4863, United States

Location

Vanderbilt University Medical Center - Infectious Diseases

Nashville, Tennessee, 37232-0011, United States

Location

Baylor Scott & White Health - Baylor University Medical Center - North Texas Infectious Disease Consultants

Dallas, Texas, 75246, United States

Location

University of Texas Southwestern Medical Center - Internal Medicine - Infectious Diseases

Dallas, Texas, 75390-8884, United States

Location

Brooke Army Medical Center

Fort Sam Houston, Texas, 78234, United States

Location

University of Texas Medical Branch - Division of Infectious Disease

Galveston, Texas, 77555-0435, United States

Location

Baylor College of Medicine - Molecular Virology and Microbiology

Houston, Texas, 77030-3411, United States

Location

University of Texas Health Science Center at San Antonio - Infectious Diseases

San Antonio, Texas, 78229-3901, United States

Location

University of Utah - Infectious Diseases

Salt Lake City, Utah, 84132, United States

Location

University of Virginia - Acute Care Surgery

Charlottesville, Virginia, 22908-0816, United States

Location

Naval Medical Center Portsmouth - Infectious Disease Division

Portsmouth, Virginia, 23708, United States

Location

EvergreenHealth Infectious Disease Service

Kirkland, Washington, 98034, United States

Location

Providence Sacred Heart Medical Center

Spokane, Washington, 99204, United States

Location

Madigan Army Medical Center - Infectious Disease Clinic

Tacoma, Washington, 98431, United States

Location

University of Copenhagen - Centre of Excellence for Health, Immunity and Infections (CHIP) - Department of Infectious Diseases

Copenhagen, 2100, Denmark

Location

National Center for Global Health and Medicine Hospital - Disease Control and Prevention Center

Tokyo, 162-8655, Japan

Location

Instituto Nacional de Ciencias Medicas y Nutrición Salvador Zubirán - Departamento de Infectologia

Mexico City, 14080, Mexico

Location

Instituto Nacional de Enfermedades Respiratorias (INER) - Ismael Cosío Villegas

Mexico City, 14080, Mexico

Location

National University Health System - Division of Infectious Diseases

Singapore, 119228, Singapore

Location

National Centre for Infectious Diseases (NCID)

Singapore, 308442, Singapore

Location

Changi General Hospital - Clinical Trials and Research Unit (CTRU)

Singapore, 529889, Singapore

Location

Ng Teng Fong General Hospital - Infectious Disease Service

Singapore, 609606, Singapore

Location

Seoul National University Bundang Hospital - Division of Infectious Diseases

Bundang-gu Seongnam-si, 13620, South Korea

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Hospital Clinic Barcelona, Servicio de Salud Internacional

Barcelona, Catalonia, 08036, Spain

Location

Hospital Germans Trias i Pujol - Servei Malalties Infeccioses

Barcelona, Catalonia, 08916, Spain

Location

Hospital Clinico San Carlos - Enfermedades Infecciosas

Madrid, 28040, Spain

Location

Royal Sussex County Hospital - Department of Intensive Care Medicine

Brighton, United Kingdom

Location

Saint Thomas' Hospital - Directorate of Infection

City of London, United Kingdom

Location

St. James's University Hospital - Infectious Diseases

Leeds, United Kingdom

Location

Royal Victoria Infirmary - Department of Infectious Diseases

Newcastle upon Tyne, United Kingdom

Location

John Radcliffe Hospital

Oxford, United Kingdom

Location

Related Publications (6)

• Paules CI, Wang J, Tomashek KM, Bonnett T, Singh K, Marconi VC, Davey RT Jr, Lye DC, Dodd LE, Yang OO, Benson CA, Deye GA, Doernberg SB, Hynes NA, Grossberg R, Wolfe CR, Nayak SU, Short WR, Voell J, Potter GE, Rapaka RR. A Risk Profile Using Simple Hematologic Parameters to Assess Benefits From Baricitinib in Patients Hospitalized With COVID-19: A Post Hoc Analysis of the Adaptive COVID-19 Treatment Trial-2. Ann Intern Med. 2024 Mar;177(3):343-352. doi: 10.7326/M23-2593. Epub 2024 Feb 27.

  PMID: 38408357 DERIVED

• 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.

  PMID: 36442063 DERIVED

• Kramer A, Prinz C, Fichtner F, Fischer AL, Thieme V, Grundeis F, Spagl M, Seeber C, Piechotta V, Metzendorf MI, Golinski M, Moerer O, Stephani C, Mikolajewska A, Kluge S, Stegemann M, Laudi S, Skoetz N. Janus kinase inhibitors for the treatment of COVID-19. Cochrane Database Syst Rev. 2022 Jun 13;6(6):CD015209. doi: 10.1002/14651858.CD015209.

  PMID: 35695334 DERIVED

• 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.

  PMID: 34473343 DERIVED

• Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V, Marconi VC, Ruiz-Palacios GM, Hsieh L, Kline S, Tapson V, Iovine NM, Jain MK, Sweeney DA, El Sahly HM, Branche AR, Regalado Pineda J, Lye DC, Sandkovsky U, Luetkemeyer AF, Cohen SH, Finberg RW, Jackson PEH, Taiwo B, Paules CI, Arguinchona H, Erdmann N, Ahuja N, Frank M, Oh MD, Kim ES, Tan SY, Mularski RA, Nielsen H, Ponce PO, Taylor BS, Larson L, Rouphael NG, Saklawi Y, Cantos VD, Ko ER, Engemann JJ, Amin AN, Watanabe M, Billings J, Elie MC, Davey RT, Burgess TH, Ferreira J, Green M, Makowski M, Cardoso A, de Bono S, Bonnett T, Proschan M, Deye GA, Dempsey W, Nayak SU, Dodd LE, Beigel JH; ACTT-2 Study Group Members. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. 2021 Mar 4;384(9):795-807. doi: 10.1056/NEJMoa2031994. Epub 2020 Dec 11.

  PMID: 33306283 DERIVED

• 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.

  PMID: 33148977 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

remdesivir; baricitinib

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: John Beigel, MD
• Organization: NIAID

jbeigel@niaid.nih.gov

3014519881

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 22, 2020
• First Posted: May 26, 2020
• Study Start: May 8, 2020
• Primary Completion: July 31, 2020
• Study Completion: July 31, 2020
• Last Updated: March 14, 2022
• Results First Posted: April 26, 2021

Record last verified: 2020-04

Locations

US (53); JP (1); SG (4); ES (3); KR (2); DK (1); ME (2); GB (5)