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Immune Modulators for Treating COVID-19 (ACTIV-1 IM)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04593940
Recruitment Status : Recruiting
First Posted : October 20, 2020
Last Update Posted : November 16, 2020
Sponsor:
Collaborators:
National Center for Advancing Translational Science (NCATS)
Biomedical Advanced Research and Development Authority
Information provided by (Responsible Party):
Daniel Benjamin, Duke University

Brief Summary:

ACTIV-1 IM is a master protocol designed to evaluate multiple investigational agents for the treatment of moderately or severely ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The research objectives are to evaluate each agent with respect to speed of recovery, mortality, illness severity, and hospital resource utilization. Each agent will be evaluated as add-on therapy to the standard of care (SoC) in use at the local clinics, including remdesivir (provided). The SoC may change during the course of the study based on other research findings. Comparisons of the agents among themselves is not a research objective.

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.


Condition or disease Intervention/treatment Phase
Covid19 Drug: Infliximab Drug: Abatacept Drug: Remdesivir Drug: cenicriviroc Phase 3

Detailed Description:

ACTIV-1 IM is a master protocol designed to evaluate immune modulators for the treatment of moderately or severely ill hospitalized patients infected with COVID-19. Trial participants will be assessed daily while hospitalized. If the participants are discharged from the hospital prior to Day 29, they will have follow-up study visits at Days 8, 11, 15, 22, and 29. For discharged participants, it is preferred that the Day 8, 11, 15, and 29 visits are in person to obtain safety laboratory tests and blood (serum/plasma) samples for secondary research as well as clinical outcome data. However, infection control or other restrictions may limit the ability of the participant 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 Day 60 assessment will be conducted by phone.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2160 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

ACTIV-1 IM builds upon findings and the model used for other network COVID studies. Including multiple therapeutic agents under a single protocol avoids duplication of effort in terms of infrastructure, trial governance, information systems (EDC, web-based randomization, etc.) and other aspects of study management. Implementation of the master protocol facilitates discontinuation of less promising agents and addition of possibly newly emergent agents that become available after the study begins, without stopping and starting the study itself for extended pauses.

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.

Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description: Study Drug and Matching Placebo
Primary Purpose: Treatment
Official Title: Randomized Master Protocol for Immune Modulators for Treating COVID-19
Actual Study Start Date : October 15, 2020
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : September 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Remdesivir + infliximab or matching placebo
infliximab (single dose IV 5mg/kg given on day 1) or matching placebo
Drug: Infliximab
study drug or matching placebo
Other Name: remicade

Drug: Remdesivir
Standard of Care

Active Comparator: Remdesivir + abatacept or matching placebo
abatacept (single dose IV 10 mg/kg up to 1,000 mg given on day 1) or matching placebo
Drug: Abatacept
study drug or matching placebo
Other Name: orencia

Drug: Remdesivir
Standard of Care

Active Comparator: Remdesivir + cenicriviroc or matching placebo
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
Drug: Remdesivir
Standard of Care

Drug: cenicriviroc
study drug or matching placebo




Primary Outcome Measures :
  1. Number of patients that recovered from COVID-19 [ Time Frame: days 1-29 ]
    time to recovery by Day 29


Secondary Outcome Measures :
  1. Change in number of patients hospitalized on invasive mechanical ventilation [ Time Frame: Days 15 and 29 ]
    Number of patients hospitalized on invasive mechanical ventilation

  2. number of patients that improved clinically [ Time Frame: Days 3, 5, 8, 11, 15, 29, and 60 ]
    8-point ordinal clinical scale assessed

  3. Number of patient deaths [ Time Frame: Day 14 ]
    mortality rate

  4. Number of patients with decreased supplemental oxygenation needed [ Time Frame: Day 29 ]
    compared to baseline the amount of supplementation oxygen

  5. Change in number of patients needing non-invasive ventilation/ high flow oxygen [ Time Frame: Day 29 ]
    assessment of non-invasive ventilation/ high flow oxygen up to day 29

  6. Number of days patients are in the hospital [ Time Frame: Days 3, 5, 8, 11, 15, 22, and 29 ]
    number of days in the hospital

  7. Number of SAEs and AEs of grade 3 and 4 [ Time Frame: Days 3, 5, 8, 11, 15, 22, and 29 ]
    Cumulative incidence of SAEs and AEs of grade 3 and 4

  8. Number of patients with changes in abnormal WBC counts [ Time Frame: Days 3, 5, 8, 11, 15, and 29 ]
    Number of patients with changes in abnormal WBC counts


Other Outcome Measures:
  1. Number of patients with National Early Warning Scores (NEWS) <=2 [ Time Frame: Days 3, 5, 8, 11, 15, and 29 ]
    time to discharge or to a NEWS of <=2 and maintained for 24 hours



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Admitted to a hospital or awaiting admission in the ED 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 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 at least one primary form of contraception not including hormonal contraception from the time of screening through Day 60.
  8. Agrees to not participate in another intervention trial for the treatment of COVID-19 through Day 60.

Exclusion Criteria:

  1. ALT or AST >5 times the upper limit of normal.
  2. Estimated glomerular filtration rate (eGFR) <30 mL/min (including patients receiving hemodialysis or hemofiltration).
  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 biologic treatments (such as anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], IL-17, or T-cell or B-cell targeted therapies (e.g., rituximab), tyrosine kinase inhibitors including baricitinib, TNF inhibitors, or interferon within 4 weeks or 5 half-lives prior to screening. 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 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 2: Infusion of convalescent plasma is also allowed.
  9. Based on medical history and concomitant therapies that would suggest infection, have suspected clinical 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).
  10. Based on medical history and concomitant therapies that would suggest infection, suspected serious, active bacterial, fungal, viral (including, but not limited to, active HBV, HCV, or HIV/AIDS).
  11. Have received any live vaccine (that is, live attenuated) within 3 months 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 participants.
  12. Severe hepatic impairment (defined as liver cirrhosis Child stage C).
  13. Current severe heart failure (New York Heart Association [NYHA] III-IV).
  14. In the Investigator's judgment, the patient has any advanced organ dysfunction that would not make participation appropriate.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04593940


Contacts
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Contact: Theresa Jasion, MS 919-338-4307 theresa.jasion@duke.edu
Contact: Lori Hudson, PhD 919-259-5579 lori.hudson@duke.edu

Locations
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United States, Arkansas
University of Arkansas Medical Sciences Recruiting
Little Rock, Arkansas, United States, 72205
Contact: Cindy Witkowski    501-526-5282    witkowskicynthial@uams.edu   
Principal Investigator: Ryan Dare, MD         
United States, Kansas
University of Kansas Recruiting
Kansas City, Kansas, United States, 66160
Contact: Carolina Aguiar    913-945-9295    caguiar@kumc.edu   
Contact: Kimberly Lovell       klovell@kumc.edu   
Principal Investigator: Matthias Salathe, MD         
United States, Massachusetts
Boston Medical Center Recruiting
Boston, Massachusetts, United States, 02118
Contact: Ridiane Denis    617-358-7561    ridianed@bu.edu   
Principal Investigator: Benjamin Linas, MD         
United States, Mississippi
University of Mississippi Medical Center Recruiting
Jackson, Mississippi, United States, 39216
Contact: Cathy Hudgins    601-815-5000    chudgins@umc.edu   
Principal Investigator: Gailen Marshall, MD         
United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Lisa Kessels    314-747-1096    lkessels@wustl.edu   
Principal Investigator: Jane O'Halloran, MD         
United States, New Jersey
Rutgers New Jersey Medical School Recruiting
New Brunswick, New Jersey, United States, 08901
Contact: Deborah McCloskey    732-418-8484    mcclosda@rwjms.rutgers.edu   
Principal Investigator: Reynold Panettieri, MD         
United States, North Carolina
University of North Carolina - Chapel Hill Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Nayeem Choudhury    417-379-6389    nayeem_choudhury@med.unc.edu   
Principal Investigator: Anne Lachiewicz, MD         
Duke University Recruiting
Durham, North Carolina, United States, 27710
Contact: Jacob Craven    919-681-9997    jacob.craven@duke.edu   
Principal Investigator: Wolfe Cameron, MBBS         
Wake Forest University Recruiting
Winston-Salem, North Carolina, United States, 27157
Contact: Elizabeth Zieser-Misenheimer    336-716-5685    ezieserm@wakehealth.edu   
Contact: Lashaunda Holmes    1-336-716-4267    laholmes@wakehealth.edu   
Principal Investigator: Caryn Morse, MD         
United States, Utah
University of Utah Recruiting
Salt Lake City, Utah, United States, 84108
Contact: Macy Barrios    801-581-5811    macy.barrios@hsc.utah.edu   
Principal Investigator: Estelle Harris, MD         
United States, Virginia
Virginia Commonwealth University Medical Center Recruiting
Richmond, Virginia, United States, 23298
Contact: Rebecca Collen    804-628-4376    rebecca.collen@vcuhealth.org   
Principal Investigator: Arun Sanyal, MD         
United States, Washington
Providence Medical Research Center Recruiting
Spokane, Washington, United States, 99204
Contact: Carissa Urbat    509-474-4345    carissa.urbat@providence.org   
Principal Investigator: Radica Alicic, MD         
United States, Wisconsin
Gundersen Health System Recruiting
La Crosse, Wisconsin, United States, 54601
Contact: Cindy Murphy    608-775-6782    camurphy@gundersenhealth.org   
Principal Investigator: Arick Sabin, MD         
Sponsors and Collaborators
Daniel Benjamin
National Center for Advancing Translational Science (NCATS)
Biomedical Advanced Research and Development Authority
Investigators
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Principal Investigator: Daniel K Benjamin, MD, PhD Duke University
Study Chair: Bill Powderly, MD Washington University School of Medicine
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Responsible Party: Daniel Benjamin, Kiser-Arena Distinguished Professor, Duke University Pediatrics, Duke University
ClinicalTrials.gov Identifier: NCT04593940    
Other Study ID Numbers: Pro00106301
First Posted: October 20, 2020    Key Record Dates
Last Update Posted: November 16, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Daniel Benjamin, Duke University:
COVID19
Additional relevant MeSH terms:
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TAK-652
Infliximab
Abatacept
Dermatologic Agents
Gastrointestinal Agents
Antirheumatic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
CCR5 Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents