Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
1971 participants
INTERVENTIONAL
2020-10-15
2022-03-05
Brief Summary
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The study population corresponds to moderately and severely ill patients infected with the coronavirus disease 2019 (COVID-19) virus. Recruitment will target patients already hospitalized for treatment of COVID-19 infection as well as patients being treated for COVID-19 infection in Emergency Departments while waiting to be admitted to the hospital. Patients both in and out of the ICU are included in the study population.
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Detailed Description
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The effectiveness of each therapeutic agent as add-on therapy to SoC plus remdesivir (provided) will be evaluated based on the primary endpoint of time to recovery by Day 29. The sample size requirements are based on the ability to detect a moderate improvement in time to recovery (3-4 fewer days) for each agent. A total of 788 recoveries are required for each comparison to provide approximately 85% power to detect a recovery rate ratio of 1.25. Assuming 73% of participants achieve recovery in 28 days, consistent with the ACTT-1 results, the total sample size to evaluate 1, 2, and 3 agents in ACTIV-1 IM is approximately 1080, 1620, and 2160, respectively. Because each agent is being compared to SoC with no between-agent comparisons, no multiplicity adjustments for multiple agents are planned.
The CVC arm of the study was closed to enrollment on 3-Sep-2021.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
All test agents are evaluated as add-on therapies to the local SoC at each clinic. The master protocol design allows for the efficacy and safety of each agent to be determined based on comparisons with a pooled control group, consisting of patients receiving SoC plus placebo. Sharing control patients across all test agents substantially reduces the sample size requirements for the study.
TREATMENT
TRIPLE
Study Groups
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Standard of Care + infliximab or matching placebo
infliximab (single dose IV 5mg/kg given on day 1) or matching placebo
Infliximab
study drug or matching placebo
Remdesivir
Standard of Care
Standard of Care + abatacept or matching placebo
abatacept (single dose IV 10 mg/kg up to 1,000 mg given on day 1) or matching placebo
Abatacept
study drug or matching placebo
Remdesivir
Standard of Care
Standard of Care + cenicriviroc or matching placebo (closed to enrollment as of 3-Sep-2021)
cenicriviroc \[tablet, Day 1/Loading Dose: 450 mg (300mg morning and 150mg evening) Day 2 - 29/Maintenance Dose: 300 mg (150 mg BID) through Day 29\]. or matching placebo
Remdesivir
Standard of Care
cenicriviroc (closed to enrollment as of 3-Sep-2021)
study drug or matching placebo
Interventions
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Infliximab
study drug or matching placebo
Abatacept
study drug or matching placebo
Remdesivir
Standard of Care
cenicriviroc (closed to enrollment as of 3-Sep-2021)
study drug or matching placebo
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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 adults ≥18 years of age at time of enrollment.
5. Has laboratory-confirmed (within 14 days prior to enrollment) SARS-CoV-2 infection as determined by PCR or other commercial or public health assay in any specimen.
6. Ongoing illness of any duration, and at least one of the following:
* Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR
* Blood oxygen saturation (SpO2) ≤94% on room air, OR
* Requiring supplemental oxygen, OR
* Requiring mechanical ventilation or ECMO.
7. Women of childbearing potential must agree to either abstinence or use of at least one primary form of contraception not including hormonal contraception from the time of screening through Day 60.
8. Agrees to not to participate in another interventional trial for the treatment of COVID-19 through Day 60.
Exception 1: Participant may co-enroll in ACTIV-4 (ACTIV-4A and ACTIV-4C). Exception 2: Participants in ACTIV-2 who have been hospitalized may be enrolled in ACTIV-1 as long as ACTIV-2 study therapy has been discontinued. They will remain in ACTIV-2 follow-up.
Exclusion Criteria
2. Estimated glomerular filtration rate (eGFR) \<30 mL/min (including patients receiving hemodialysis or hemofiltration).
Exception: Participants with an eGFR \<30 mL/min may enroll as long as their renal insufficiency has been stable without renal replacement therapy for ≥1 month and they are not current candidates for renal replacement therapy. These participants will not receive remdesivir.
3. Neutropenia (absolute neutrophil count \<1000 cells/μL) (\<1.0 x 103/μL or \<1.0 GI/L).
4. Lymphopenia (absolute lymphocyte count \<200 cells/μL) (\<0.20 x 103/μL 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. Known allergy to any study medication.
8. Received cytotoxic or biologictargeted immune-modulator treatments (such as anti-interleukin-1 \[IL-1\], anti-IL-6 \[tocilizumab or sarilumab\], anti-IL-17, or T-cell or B-cell targeted therapies (\[e.g., rituximab), tyrosine kinase\], JAK inhibitors \[including baricitinib,\], TNF inhibitors, or interferon) within 4 weeks or 5 half-lives prior to screening., whichever is longer. Steroid dependency, defined as need for prednisone at a dose \>10 mg (or equivalent) for \>1 month within 2 weeks of screening, is exclusionary. Note Exception 1: Dexamethasone (at a dose of 6 mg per day for up to 10 days) is permitted for the treatment of COVID-19 in patients who are already mechanically ventilated and in patients who require supplemental oxygen at screening, but who are not mechanically ventilated in accordance with national guidelines. Note Exception 2: Infusion of convalescent plasma given for treatment of COVID-19 while on-study is also allowed.
Exception 3: Monoclonal antibody therapy given for COVID-19 treatment at any time prior to enrollment is also allowed.
9. BasedKnown or suspected history of untreated tuberculosis (TB). TB diagnosis may be suspected based on medical history and concomitant therapies that would suggest TB infection, have suspected clinical diagnosis of current active tuberculosis (TB) or, if. Participants are also excluded if they have known, latent TB treated for less than 4 weeks with appropriate anti-tuberculosis therapy per local guidelines (by history only, no screening required).
10. Based on medical history and concomitant therapies that would suggest infection,Known or suspected serious, active bacterial, fungal, or viral (infection (excepting SARS-CoV-2 and including, but not limited to, active HBV, HCV, or HIV/AIDS). with the latter defined as a CD4 count \<200 or an unsuppressed HIV viral load), or other infection (besides COVID-19) that in the opinion of the investigator could constitute a risk when taking investigational product.
Note: Broad-spectrum empiric antibiotic usage does not exclude participation.
11. Have received any live vaccine (that is,or live attenuated) within 3 months before screening, or intend to receive a live vaccine (or live attenuated) during the study. Note Exception: Use of prior non-live (inactivated) vaccinations is allowed for all participants, including any vaccine for COVID-19.
12. Severe hepatic impairment (defined as liver cirrhosis Child stage C).
13. CurrentKnown severe heart failure (New York Heart Association \[NYHA\] III-IV).) or new-onset left-systolic or global cardiac dysfunction in the setting of COVID-19.
Exception: Right-sided heart dysfunction or pulmonary hypertension thought related to COVID-19 is permitted.
14. In the Investigator's judgment, the patient has any advanced organ dysfunction that would not make participation appropriate.
18 Years
ALL
No
Sponsors
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National Center for Advancing Translational Sciences (NCATS)
NIH
Biomedical Advanced Research and Development Authority
FED
Daniel Benjamin
OTHER
Responsible Party
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Daniel Benjamin
Kiser-Arena Distinguished Professor, Duke University Pediatrics
Principal Investigators
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Daniel K Benjamin, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Duke University
Bill Powderly, MD
Role: STUDY_CHAIR
Washington University School of Medicine
Locations
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Banner University Medical Center
Phoenix, Arizona, United States
University of Arkansas Medical Sciences
Little Rock, Arkansas, United States
Scripps Clinical Medical Group
La Jolla, California, United States
UCLA - Ronald Reagan Medical Center
Los Angeles, California, United States
Riverside University
Moreno Valley, California, United States
UC Irvine Medical Center
Orange, California, United States
Stanford University Medical Center
Palo Alto, California, United States
UCLA Medical Center- Santa Monica
Santa Monica, California, United States
Medstar Washington Hospital Center
Washington D.C., District of Columbia, United States
University of Florida-Jacksonville
Jacksonville, Florida, United States
University of Illinois at Chicago
Chicago, Illinois, United States
Northwestern University
Chicago, Illinois, United States
Loyola University Medical Center
Maywood, Illinois, United States
University of Iowa
Iowa City, Iowa, United States
University of Kansas
Kansas City, Kansas, United States
University of Kentucky
Lexington, Kentucky, United States
Tulane School of Medicine
New Orleans, Louisiana, United States
University Medical Center New Orleans
New Orleans, Louisiana, United States
Ochsner Medical Center
New Orleans, Louisiana, United States
Anne Arundel Medical Center
Annapolis, Maryland, United States
Johns Hopkins Medical Center
Baltimore, Maryland, United States
Tufts Medical Center
Boston, Massachusetts, United States
Brigham and Women's Hospital
Boston, Massachusetts, United States
Boston Medical Center
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
U Mass Memorial Medical Center
Worcester, Massachusetts, United States
U Mass University Medical Center
Worcester, Massachusetts, United States
MidMichigan Medical Center- Gratiot
Alma, Michigan, United States
MidMichigan Medical Center - Midland
Midland, Michigan, United States
Mayo Clinic
Rochester, Minnesota, United States
University of Mississippi Medical Center
Jackson, Mississippi, United States
University of Missouri Health Care
Columbia, Missouri, United States
Washington University School of Medicine
St Louis, Missouri, United States
Trinitas Hospital
Elizabeth, New Jersey, United States
Hackensack University Medical Center
Hackensack, New Jersey, United States
Rutgers New Jersey Medical School
New Brunswick, New Jersey, United States
NYU Brooklyn
Brooklyn, New York, United States
University at Buffalo
Buffalo, New York, United States
Flushing Hospital Medical Center
Flushing, New York, United States
Jamaica Hospital Medical Center
Jamaica, New York, United States
NYU Long Island
Long Island City, New York, United States
New York University Langone Medical Center
New York, New York, United States
Harlem Hospital Center
New York, New York, United States
Weill Cornell Medicine
New York, New York, United States
St Lawrence Health System
Potsdam, New York, United States
University of Rochester Medical Center-Strong Memorial Hospital
Rochester, New York, United States
University of North Carolina - Chapel Hill
Chapel Hill, North Carolina, United States
Duke University
Durham, North Carolina, United States
Wake Forest University
Winston-Salem, North Carolina, United States
Mercy Saint Vincent Medical Center
Toledo, Ohio, United States
University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma, United States
Oregon Health and Science University
Portland, Oregon, United States
Temple University Hospital
Philadelphia, Pennsylvania, United States
Reading Hospital Study
Wyomissing, Pennsylvania, United States
Avera McKennan Hospital
Sioux Falls, South Dakota, United States
University of Tennessee Medical Center
Knoxville, Tennessee, United States
Methodist Health System Clinical Research Institute
Dallas, Texas, United States
University of Texas Health Science Center - Houston
Houston, Texas, United States
University of Texas Health Science Center at San Antonio
San Antonio, Texas, United States
Trinity Mother Frances Hospital
Tyler, Texas, United States
University of Texas Health Center at Tyler
Tyler, Texas, United States
University of Utah
Salt Lake City, Utah, United States
Virginia Commonwealth University Medical Center
Richmond, Virginia, United States
University of Washington Medical Center
Seattle, Washington, United States
Providence Medical Research Center
Spokane, Washington, United States
West Virginia University
Morgantown, West Virginia, United States
Gundersen Health System
La Crosse, Wisconsin, United States
Hospital Interzonal Dr Jose Penna Bahia Blanca
Bahía Blanca, Buenos Aires, Argentina
Sanatorio Ramon Cereijo
CABA, Buenos Aires, Argentina
Instituto Medico Platense
La Plata, Buenos Aires, Argentina
Clinica Central S.A.
Villa Regina, Río Negro Province, Argentina
Hospital Ramos Mejia
Buenos Aires, , Argentina
Hospital Rawson
Córdoba, , Argentina
Sanatorio Allende
Córdoba, , Argentina
Sanatorio Britanico
Rosario, , Argentina
Sanatorio Diagnóstico/ Instituto del Buen Aire
Santa Fe, , Argentina
Hospital Brasília
Brasília, Federal District, Brazil
Hospital Felício Rocho
Belo Horizonte, Minas Gerais, Brazil
Instituto DOR de Ensino e Pesquisa Hospital Glória D'Or
Rio de Janeiro, Rio de Janeiro / RJ, Brazil
Hospital Ernesto Dornelles
Porto Alegre, Rio Grande D Sul /RS, Brazil
Hospital de Clinicas de Porto Alegre HCPA
Porto Alegre, Rio Grande Do Sul / RS, Brazil
Santa Casa de Misericordia de Porto Alegre
Porto Alegre, Rio Grande Do Sul/RS, Brazil
Hospital e Maternidade Celso Pierro - PUC Campinas
Campinas, São Paulo/SP, Brazil
Nuevo Hospital Civil de Guadalajara "Dr. Juan I. Menchaca"
Guadalajara, Guadalajara Jalisco, Mexico
Hospital Universitario "Dr. Jose Eleuterio Gonzalez"
Nuevo León, Monterrey, Mexico
Hospital Central FAP
Lima, Lima/Lima, Peru
Hospital Regional Lambayeque
Chiclayo, , Peru
Hospitala Nacional Hipólito Unánue
Lima, , Peru
Hospital Nacional Aezobispo Loayza
Lima, , Peru
Hospital de Chancay y Servicios Basicos de Salud
Lima, , Peru
Clínica Belén SANNA
Piura, , Peru
Countries
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References
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Lachiewicz AM, Shah M, Der T, Cyr D, Al-Khalidi HR, Lindsell C, Iyer V, Khan A, Panettieri R, Rauseo AM, Maillo M, Schmid A, Jagpal S, Powderly WG, Bozzette SA; ACTIV-1 IM study group members. Resource Use in the Randomized Master Protocol for Immune Modulators for Treating COVID-19 (ACTIV-1 IM): A Secondary Data Analysis. CHEST Crit Care. 2024 Dec;2(4):100095. doi: 10.1016/j.chstcc.2024.100095. Epub 2024 Aug 22.
Balevic SJ, Benjamin DK Jr, Powderly WG, Smith PB, Gonzalez D, McCarthy MW, Shaw LK, Lindsell CJ, Bozzette S, Williams D, Linas BP, Blamoun J, Javeri H, Hornik CP; ACTIV-1 IM Study Group. Abatacept Pharmacokinetics and Exposure Response in Patients Hospitalized With COVID-19: A Secondary Analysis of the ACTIV-1 IM Randomized Clinical Trial. JAMA Netw Open. 2024 Apr 1;7(4):e247615. doi: 10.1001/jamanetworkopen.2024.7615.
O'Halloran JA, Ko ER, Anstrom KJ, Kedar E, McCarthy MW, Panettieri RA Jr, Maillo M, Nunez PS, Lachiewicz AM, Gonzalez C, Smith PB, de Tai SM, Khan A, Lora AJM, Salathe M, Capo G, Gonzalez DR, Patterson TF, Palma C, Ariza H, Lima MP, Blamoun J, Nannini EC, Sprinz E, Mykietiuk A, Alicic R, Rauseo AM, Wolfe CR, Witting B, Wang JP, Parra-Rodriguez L, Der T, Willsey K, Wen J, Silverstein A, O'Brien SM, Al-Khalidi HR, Maldonado MA, Melsheimer R, Ferguson WG, McNulty SE, Zakroysky P, Halabi S, Benjamin DK Jr, Butler S, Atkinson JC, Adam SJ, Chang S, LaVange L, Proschan M, Bozzette SA, Powderly WG; ACTIV-1 IM Study Group Members. Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA. 2023 Jul 25;330(4):328-339. doi: 10.1001/jama.2023.11043.
Ko ER, Anstrom KJ, Panettieri RA, Lachiewicz AM, Maillo M, O'Halloran JA, Boucher C, Smith PB, McCarthy MW, Segura Nunez P, Mendivil Tuchia de Tai S, Khan A, Mena Lora AJ, Salathe M, Kedar E, Capo G, Rodriguez Gonzalez D, Patterson TF, Palma C, Ariza H, Patelli Lima M, Blamoun J, Nannini EC, Sprinz E, Mykietiuk A, Wang JP, Parra-Rodriguez L, Der T, Willsey K, Benjamin DK, Wen J, Zakroysky P, Halabi S, Silverstein A, McNulty SE, O'Brien SM, Al-Khalidi HR, Butler S, Atkinson J, Adam SJ, Chang S, Maldonado MA, Proscham M, LaVange L, Bozzette SA, Powderly WG; ACTIV-1 IM study group members. Abatacept for Treatment of Adults Hospitalized with Moderate or Severe Covid-19. medRxiv [Preprint]. 2022 Sep 26:2022.09.22.22280247. doi: 10.1101/2022.09.22.22280247.
O'Halloran JA, Kedar E, Anstrom KJ, McCarthy MW, Ko ER, Nunez PS, Boucher C, Smith PB, Panettieri RA, de Tai SMT, Maillo M, Khan A, Mena Lora AJ, Salathe M, Capo G, Gonzalez DR, Patterson TF, Palma C, Ariza H, Lima MP, Lachiewicz AM, Blamoun J, Nannini EC, Sprinz E, Mykietiuk A, Alicic R, Rauseo AM, Wolfe CR, Witting B, Benjamin DK, McNulty SE, Zakroysky P, Halabi S, Butler S, Atkinson J, Adam SJ, Melsheimer R, Chang S, LaVange L, Proschan M, Bozzette SA, Powderly WG; ACTIV-1 IM study group members. Infliximab for Treatment of Adults Hospitalized with Moderate or Severe Covid-19. medRxiv [Preprint]. 2022 Sep 26:2022.09.22.22280245. doi: 10.1101/2022.09.22.22280245.
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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Pro00106301
Identifier Type: -
Identifier Source: org_study_id
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