Adaptive COVID-19 Treatment Trial 4 (ACTT-4)
Condition: COVID-19
MeSH terms: COVID-19
Intervention: Baricitinib; Dexamethasone; Placebo; Remdesivir
Intervention description: Baricitinib is a Janus kinase (JAK) inhibitor with the chemical name [1-(ethylsulfonyl)-3-(4-(7Hpyrrolo(2,3-d)pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl]acetonitrile. Each tablet contains 2 mg of baricitinib and the following inactive ingredients: croscarmellose sodium, magnesium stearate, mannitol, microcrystalline cellulose, ferric oxide, lecithin (soya), polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide.; Dexamethasone Sodium Phosphate Injection, USP, is an adrenocortical steroid anti-inflammatory drug. It is a water-soluble inorganic ester of dexamethasone. Each mL contains dexamethasone sodium phosphate equivalent to dexamethasone phosphate 4 mg or dexamethasone 3.33 mg; benzyl alcohol 10 mg added as preservative; sodium citrate dihydrate 11 mg; sodium sulfite 1 mg as an antioxidant.; Placebo matching oral baricitinib or intravenous dexamethasone.; Drug remdesivir is a single diastereomer monophosphoramidate prodrug designed for the intracellular delivery of a modified adenine nucleoside analog GS-441524. In addition to the active ingredient, the lyophilized formulation of remdesivir contains the following inactive ingredients: water for injection, sulfobutylether beta-cyclodextrin sodium (SBECD), and hydrochloric acid and/or sodium hydroxide.
Intervention MeSH terms: Remdesivir; Dexamethasone
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 1010.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: ACTT; Adaptive; COVID-19; Efficacy; Multicenter; novel coronavirus; Safety

Summary:

      ACTT-4 will evaluate the combination of baricitinib and remdesivir compared to dexamethasone
      and remdesivir. Subjects will be assessed daily while hospitalized. If the subjects are
      discharged from the hospital, they will have a study visit at Days 15, 22, and 29. For
      discharged subjects, it is preferred that the Day 15 and 29 visits are in person to obtain
      safety laboratory tests, oropharyngeal (OP) swabs, plasma (Day 29), and serum for secondary
      research as well as clinical outcome data. However, if infection control or other
      restrictions limit the ability of the subject to return to the clinic, 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 primary objective is
      to evaluate the clinical efficacy of baricitinib + remdesivir versus dexamethasone +
      remdesivir as assessed by the mechanical ventilation free survival by Day 29.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Hospitalized with symptoms suggestive of COVID-19.

          2. Subject (or legally authorized representative) provides informed consent prior to
             initiation of any study procedures and understands and agrees to comply with planned
             study procedures.

          3. Male or non-pregnant female adult > / = 18 years of age at time of enrollment.

          4. Illness of any duration and has laboratory-confirmed SARS-CoV-2 infection as
             determined by polymerase chain reaction (PCR) or other commercial or public health
             assay (e.g. NAAT, antigen test) in any respiratory specimen or saliva < / = 14 days
             prior to randomization.

          5. Within the 7 days prior to randomization requiring new use of supplemental oxygen (or
             increased oxygen requirement if on chronic oxygen) and requires at the time of
             randomization low or high flow oxygen devices or use of non-invasive mechanical
             ventilation (ordinal scale category 5 or 6).

          6. 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 29.

          7. 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. Prior enrollment in ACTT-3 or ACTT-4. Note: this includes subjects whose participation
             in ACTT was terminated early.

          2. On invasive mechanical ventilation at the time of randomization (ordinal scale
             category 7).

          3. Anticipated discharge from the hospital or transfer to another hospital which is not a
             study site within 72 hours of randomization.

          4. Positive test for influenza virus during the current illness (influenza testing is not
             required by protocol).

          5. Subjects with a low glomerular filtration rate (eGFR), specifically:

               1. Subjects with an eGFR 15-30 mL/min are excluded unless in the opinion of the PI,
                  the potential benefit of participation outweighs the potential risk of study
                  participation.

               2. All subjects with an eGFR <15 mL/min

               3. All subjects on hemodialysis and/or hemofiltration at screening, irrespective of
                  eGFR are excluded.

          6. Neutropenia (absolute neutrophil count <700 cells/microliter, 0.7 x 10^3/microliter).

          7. Lymphopenia (absolute lymphocyte count <200 cells/microliter, 0.20 x 10^3/microliter).

          8. Received five or more doses of remdesivir including the loading dose, outside of the
             study as treatment for COVID-19.

          9. Pregnancy or breast feeding (lactating women who agree to discard breast milk from Day
             1 until two weeks after the last study product is given are not excluded).

         10. Allergy to any study medication.

         11. Received convalescent plasma or intravenous immunoglobulin [IVIg] for COVID-19, the
             current illness for which they are being enrolled.

         12. Received any of the following in the two weeks prior to screening as treatment of
             COVID-19:

               -  More than one dose of baricitinib for the treatment of COVID-19;

               -  Other small molecule tyrosine kinase inhibitors (e.g. imatinib, gefitinib,
                  acalabrutinib, etc.);

               -  monoclonal antibodies targeting cytokines (e.g., TNF inhibitors,
                  anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab], etc.);

               -  monoclonal antibodies targeting T-cells or B-cells as treatment for COVID-19.
                  Note: receipt of anti-SARS-CoV-2 monoclonal antibody (mAb) prior to enrollment
                  (e.g. bamlanivimab) for their current COVID-19 illness is not exclusionary

         13. Use of probenecid that cannot be discontinued at study enrollment.

         14. Received 6 mg or more of dexamethasone by mouth (po) or Intravenous (IV) (or
             equivalent for other glucocorticoids) in one day, on more than one day, in the 7 days
             prior to time of randomization. Note: 6 mg dexamethasone dose equivalents include 40
             mg prednisone, 32 mg methylprednisolone and 160 mg hydrocortisone.

         15. Received > / = 20 mg/day of prednisone po or IV (or equivalent for other
             glucocorticoids) for > / = 14 consecutive days in the 4 weeks prior to screening.

         16. Have diagnosis of current active or latent tuberculosis (TB), if known, treated for
             less than 4 weeks with appropriate therapy (by history only, no screening required).

         17. Serious infection (besides COVID-19), immunosuppressive state, or immunosuppressive
             medications that in the opinion of the investigator could constitute a risk when
             taking baricitinib or dexamethasone.

         18. Have received any live vaccine (that is, live attenuated) within 4 weeks before
             screening, or intend to receive a live vaccine (or live attenuated) during the study.
             Note: Use of non-live (inactivated) vaccinations including SARS-CoV-2 vaccine is
             allowed for all subjects.

         19. Had a known Venous thromboembolism (VTE)(deep vein thrombosis [DVT] or pulmonary
             embolism [PE]) during the current COVID-19 illness.