Immune Modulators for Treating COVID-19
Condition: Covid19
MeSH terms: COVID-19
Intervention: Infliximab; Abatacept; Remdesivir; cenicriviroc (closed to enrollment as of 3-Sep-2021)
Intervention description: study drug or matching placebo; study drug or matching placebo; Standard of Care; study drug or matching placebo
Intervention MeSH terms: Remdesivir; Cenicriviroc; Infliximab; Abatacept
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
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
Enrollment: 1971.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: COVID19

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.
    

Eligibility 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 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.