ACTIV-5 / Big Effect Trial (BET-B) for the Treatment of COVID-19
Condition: COVID-19
MeSH terms: COVID-19
Intervention: Lenzilumab; Placebo; Remdesivir
Intervention description: Lenzilumab is a first-in-class recombinant monoclonal antibody targeting soluble human GM-CSF, with potential immunomodulating activity, high binding affinity in the pM range, and 94% specificity to the human germline, which reduces immunogenicity.; Placebo for lenzilumab is commercially sourced 0.9% sodium chloride.; Remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524.
Intervention MeSH terms: Remdesivir; Lenzilumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 527.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Adults; COVID-19; Multicenter; Putative; Therapeutics

Summary:

      This is a platform trial to conduct a series of randomized, double-blind, placebo-controlled
      trials using common assessments and endpoints in hospitalized adults diagnosed with
      Coronavirus Disease 2019 (COVID-19). Big Effect Trial (BET) is a proof-of-concept study with
      the intent of identifying promising treatments to enter a more definitive study. The study
      will be conducted in up to 70 domestic sites and 5 international sites. The study will
      compare different investigational therapeutic agents to a common control arm and determine
      which have relatively large effects. In order to maintain the double blind, each intervention
      will have a matched placebo. However, the control arm will be shared between interventions
      and may include participants receiving the matched placebo for a different intervention.

      The goal is not to determine clear statistical significance for an intervention, but rather
      to determine which products have clinical data suggestive of efficacy and should be moved
      quickly into larger studies. Estimates produced from BET will provide an improved basis for
      designing the larger trial, in terms of sample size and endpoint selection. Products with
      little indication of efficacy will be dropped on the basis of interim evaluations. In
      addition, some interventions may be discontinued on the basis of interim futility or efficacy
      analyses.

      One or more interventions may be started at any time. The number of interventions enrolling
      are programmatic decisions and will be based on the number of sites and the pace of
      enrollment. At the time of enrollment, subjects will be randomized to receive any one of the
      active arms they are eligible for or placebo. Approximately 200 (100 treatment and 100 shared
      placebo) subjects will be assigned to each arm entering the platform and a given site will
      generally have no more than 3 interventions at once.

      The BET-B stage will evaluate the combination of remdesivir with lenzilumab vs remdesivir
      with a lenzilumab placebo. The primary objective is to evaluate the clinical efficacy of
      different investigational therapeutics relative to the control arm in adults hospitalized
      with COVID-19 according to clinical status (8-point ordinal scale) at Day 8.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Admitted to a hospital with symptoms suggestive of Coronavirus Disease 2019 (COVID-19)
             and requires ongoing medical care.

          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 adult >/= 18 years of age at time of enrollment.

          5. Illness of any duration and has laboratory-confirmed severe acute respiratory syndrome
             coronavirus 2 (SARS-CoV-2) infection as determined by polymerase chain reaction (PCR)
             or other commercial or public health assay (e.g., Nucleic Acid Amplification Test
             [NAAT], antigen test) in any respiratory specimen, or saliva </=14 days prior to
             randomization.

          6. Illness of any duration, and requiring, just prior to randomization, supplemental
             oxygen (any flow), mechanical ventilation or Extracorporeal Membrane Oxygenation
             (ECMO) (ordinal score 5, 6, or 7).

          7. Women of childbearing potential must agree to either abstinence or use at least one
             acceptable method of contraception* from the time of screening through 5 months post
             study intraperitoneal (IP) dosing.

             * Acceptable methods include barrier contraceptives (condoms or diaphragm) with
             spermicide, intrauterine devices (IUDs), hormonal contraceptives, oral contraceptive
             pills, and surgical sterilization.

          8. Agrees not to participate in another blinded clinical trial (both pharmacologic and
             other types of interventions) for the treatment of COVID-19 through Day 29.

        Exclusion Criteria:

          1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 times the upper
             limit of normal.

          2. Subjects with a low glomerular filtration rate (eGFR), specifically:

               1. Subjects with a glomerular filtration rate (eGFR) 20-30 mL/min are excluded
                  unless in the opinion of the principal investigator (PI), the potential benefit
                  of participation outweighs the potential risk of study participation.

               2. All subjects with a glomerular filtration rate (eGFR) <20 mL/min (including
                  hemodialysis and hemofiltration) are excluded.

          3. Pregnancy or breast feeding.

          4. Anticipated discharge from the hospital or transfer to another hospital which is not a
             study site within 72 hours of enrollment.

          5. Allergy to any study medication.

          6. Received five or more doses of remdesivir prior to screening.

          7. Received small molecule tyrosine kinase inhibitors, including Janus kinase (JAK)
             inhibitors (e.g., baricitinib, ibrutinib, acalabrutinib, imatinib, gefitinib), in the
             4 weeks prior to screening.

          8. Received monoclonal antibodies targeting cytokines (e.g., tumor necrosis factor (TNF)
             inhibitors, anti-IL-1 [e.g., anakinra, canakinumab], anti-IL-6 [e.g., tocilizumab,
             sarilumab, sitlukimab]), or T-cells (e.g., abatacept) in the 4 weeks prior to
             screening.

          9. Received monoclonal antibodies targeting B-cells (e.g., rituximab, and including any
             targeting multiple cell lines including B-cells) in the 3 months prior to screening.

         10. Received granulocyte-macrophage colony-stimulating factor (GM-CSF) agents (e.g.,
             sargramostim) within 2 months prior to screening.

         11. Received other immunosuppressants in the 4 weeks prior to screening and in the
             judgement of the investigator, the risk of immunosuppression with lenzilumab is larger
             than the risk of Coronavirus Disease 2019 (COVID-19).

         12. Received any live vaccine in the 4 weeks prior to screening.

         13. Known active tuberculosis.

         14. Known history of Human Immunodeficiency Virus (HIV), Hepatitis B (HBV) or untreated
             hepatitis C (HCV) infection.

         15. History of pulmonary alveolar proteinosis (PAP).

         16. Has a malignancy currently receiving immunosuppressive chemotherapy, immunodeficiency,
             uncontrolled opportunistic infection, or uncontrolled cirrhosis.

         17. Has a medical condition that could, in the judgment of the investigator, limit the
             interpretation and generalizability of trial results.

         18. Positive test for influenza virus during the current illness (influenza testing is not
             required by protocol).

         19. Previous participation in an ACTIV-5/Big Effect Trial (BET).