Adaptive COVID-19 Treatment Trial 2 (ACTT-2)
Adaptive COVID-19 Treatment Trial 2 (ACTT-2)
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.
This study is an adaptive randomized double-blind placebo-controlled trial to evaluate the
 safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with
 COVID-19. The study is a multicenter trial that will be conducted in up to approximately 100
 sites globally. The study will compare different investigational therapeutic agents to a
 control arm. New arms can be introduced according to scientific and public health needs.
 There will be interim monitoring to allow early stopping for futility, efficacy, or safety.
 If one therapy proves to be efficacious, then this treatment may become the control arm for
 comparison(s) with new experimental treatment(s). Any such change would be accompanied by an
 updated sample size. This adaptive platform is used to rapidly evaluate different
 therapeutics in a population of those hospitalized with moderate to severe COVID-19. The
 platform will provide a common framework sharing a similar population, design, endpoints, and
 safety oversight. New stages with new therapeutics can be introduced. One independent Data
 and Safety Monitoring Board (DSMB) will actively monitor interim data in all stages to make
 recommendations about early study closure or changes to study arms.

 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.

 All subjects will undergo a series of efficacy, safety, and laboratory assessments. Safety
 laboratory tests and blood (serum and plasma) research samples and oropharyngeal (OP) swabs
 will be obtained on Days 1 (prior to infusion) and Days 3, 5, 8, and 11 (while hospitalized).
 OP swabs and blood (serum only) plus safety laboratory tests will be collected on Day 15 and
 29 (if the subject attends an in-person visit or are still hospitalized).

 The primary outcome is time to recovery by Day 29. A key secondary outcome evaluates
 treatment-related improvements in the 8-point ordinal scale at Day 15. Each stage may
 prioritize different secondary endpoints for the purpose of multiple comparison analyses.

 Contacts:

 20-0006 Central Contact

 Telephone: 1 (301) 7617948

 Email: DMIDClinicalTrials@niaid.nih.gov
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.