Adaptive COVID-19 Treatment Trial 2 (ACTT-2)
Condition: COVID-19
MeSH terms: COVID-19
Intervention: Placebo; Remdesivir; Baricitinib
Intervention description: The matching Baricitinib placebo contains lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. The coating for the placebo tablet is identical to that of the corresponding active tablet.; 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.; 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.
Intervention MeSH terms: Remdesivir
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 1033.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Adaptive; COVID-19; Efficacy; Multicenter; novel coronavirus; Safety

Summary:

      ACTT-2 will evaluate the combination of baricitinib and remdesivir compared to remdesivir
      alone. 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 and oropharyngeal (OP) swab and blood (serum only) samples for secondary
      research as well as clinical outcome data. However, infection control or other restrictions
      may limit the ability of the subject 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 primary outcome
      is time to recovery by Day 29.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Admitted to a hospital 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 adult > / = 18 years of age at time of enrollment.

          5. Has laboratory-confirmed SARS-CoV-2 infection as determined by polymerase chain
             reaction (PCR) or other commercial or public health assay in any specimen, as
             documented by either of the following:

               -  PCR positive in sample collected < 72 hours prior to randomization; OR

               -  PCR positive in sample collected >/= 72 hours prior to randomization, documented
                  inability to obtain a repeat sample (e.g. due to lack of testing supplies,
                  limited testing capacity, results taking >24 hours, etc.) AND progressive disease
                  suggestive of ongoing SARS-CoV-2 infection.

          6. Illness of any duration, and at least one of the following:

               -  Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), OR

               -  SpO2 < / = 94% on room air, OR

               -  Requiring supplemental oxygen, OR

               -  Requiring mechanical ventilation or extracorporeal membrane oxygenation (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 29.

          8. Agrees to not participate in another clinical trial for the treatment of COVID-19
             through Day 29.

        Exclusion Criteria:

          1. Alanine Transaminase (ALT) or Aspartate Transaminase (AST) > 5 times the upper limit
             of normal.

          2. Estimated glomerular filtration rate (eGFR) < 30 ml/min or patient is receiving
             hemodialysis or hemofiltration at time of screening.

          3. Neutropenia (absolute neutrophil count <1000 cells/microliter) (<1.0 x 103/microliter
             or <1.0 GI/L).

          4. Lymphopenia (absolute lymphocyte count <200 cells/microliter) (<0.20 x 103/microliter
             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. Allergy to any study medication.

          8. Received three or more doses of remdesivir, including the loading dose, outside of the
             study under the EUA (or similar mechanism) for COVID-19.

          9. Received convalescent plasma or intravenous immunoglobulin [IVIg]) for COVID-19, the
             current illness for which they are being enrolled.

         10. Received small molecule tyrosine kinase inhibitors (e.g. baricitinib, imatibib,
             genfinitib), in the 1 week prior to screening

         11. Received monoclonal antibodies targeting cytokines (e.g., TNF inhibitors,
             anti-interleukin-1 [IL-1], anti-IL-6 [tocilizumab or sarilumab]), or T-cells (e.g.,
             abatacept) in the 4 weeks prior to screening.

         12. Received monoclonal antibodies targeting B-cell (e.g., rituximab, and including any
             targeting multiple cell lines including B-cells) in the 3 months prior to screening.

         13. Received other immunosuppressants in the 4 weeks prior to screening and in the
             judgement of the investigator, the risk of immunosuppression with baricitinib is
             larger than the risk of COVID-19.

         14. Received >/= 20 mg/day of prednisone or equivalent for >/=14 consecutive days in the 4
             weeks prior to screening.

         15. Use of probenecid that cannot be discontinued at study enrollment.

         16. Have 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).

         17. Suspected serious, active bacterial, fungal, viral, or other infection (besides
             COVID-19) that in the opinion of the investigator could constitute a risk when taking
             investigational product.

         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 is allowed for all subjects.

         19. Have a history of VTE (deep vein thrombosis [DVT] or pulmonary embolism [PE]) within
             12 weeks prior to screening or have a history of recurrent (>1) VTE (DVT/PE).

         20. Immunocompromised patients, patients with a chronic medical condition, or those taking
             a medication that cannot be discontinued at enrollment, who, in the judgment of PI,
             are at increased risk for serious infections or other safety concerns given the study
             products.