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

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ClinicalTrials.gov Identifier: NCT04593940
Recruitment Status : Recruiting
First Posted : October 20, 2020
Last Update Posted : May 11, 2021
Sponsor:
Collaborators:
National Center for Advancing Translational Science (NCATS)
Biomedical Advanced Research and Development Authority
Information provided by (Responsible Party):
Daniel Benjamin, Duke University

Tracking Information
First Submitted Date  ICMJE September 23, 2020
First Posted Date  ICMJE October 20, 2020
Last Update Posted Date May 11, 2021
Actual Study Start Date  ICMJE October 15, 2020
Estimated Primary Completion Date August 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 19, 2020)
Number of patients that recovered from COVID-19 [ Time Frame: days 1-29 ]
time to recovery by Day 29
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 19, 2020)
  • Change in number of patients hospitalized on invasive mechanical ventilation [ Time Frame: Days 15 and 29 ]
    Number of patients hospitalized on invasive mechanical ventilation
  • number of patients that improved clinically [ Time Frame: Days 3, 5, 8, 11, 15, 29, and 60 ]
    8-point ordinal clinical scale assessed
  • Number of patient deaths [ Time Frame: Day 14 ]
    mortality rate
  • Number of patients with decreased supplemental oxygenation needed [ Time Frame: Day 29 ]
    compared to baseline the amount of supplementation oxygen
  • 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
  • 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
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: October 19, 2020)
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
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Immune Modulators for Treating COVID-19
Official Title  ICMJE Randomized Master Protocol for Immune Modulators for Treating COVID-19
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.

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE 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
Condition  ICMJE Covid19
Intervention  ICMJE
  • Drug: Infliximab
    study drug or matching placebo
    Other Name: remicade
  • Drug: Abatacept
    study drug or matching placebo
    Other Name: orencia
  • Drug: Remdesivir
    Standard of Care
  • Drug: cenicriviroc
    study drug or matching placebo
Study Arms  ICMJE
  • Active Comparator: Remdesivir + infliximab or matching placebo
    infliximab (single dose IV 5mg/kg given on day 1) or matching placebo
    Interventions:
    • Drug: Infliximab
    • Drug: Remdesivir
  • 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
    Interventions:
    • Drug: Abatacept
    • Drug: Remdesivir
  • 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
    Interventions:
    • Drug: Remdesivir
    • Drug: cenicriviroc
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 2, 2020)
2160
Original Estimated Enrollment  ICMJE
 (submitted: October 19, 2020)
2190
Estimated Study Completion Date  ICMJE September 2021
Estimated Primary Completion Date August 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 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.

Exception 3: If participant is already participating in a COVID-19 vaccine trial but develops COVID-19 disease that requires hospitalization, participant is eligible for this study, assuming all other inclusion/exclusion criteria are met.

Exclusion Criteria:

  1. ALT or AST >10 times the upper limit of normal.
  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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Theresa Jasion, MS 919-338-4307 theresa.jasion@duke.edu
Contact: Lori Hudson, PhD 919-259-5579 lori.hudson@duke.edu
Listed Location Countries  ICMJE Argentina,   Brazil,   Peru,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04593940
Other Study ID Numbers  ICMJE Pro00106301
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Daniel Benjamin, Duke University
Study Sponsor  ICMJE Daniel Benjamin
Collaborators  ICMJE
  • National Center for Advancing Translational Science (NCATS)
  • Biomedical Advanced Research and Development Authority
Investigators  ICMJE
Principal Investigator: Daniel K Benjamin, MD, PhD Duke University
Study Chair: Bill Powderly, MD Washington University School of Medicine
PRS Account Duke University
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP