Baricitinib, Placebo and Antiviral Therapy for the Treatment of Patients With Moderate and Severe COVID-19
Baricitinib, Placebo and Antiviral Therapy for the Treatment of Patients With Moderate and Severe COVID-19
This phase II trial studies the effect of baricitinib in combination with antiviral therapy
 for the treatment of patients with moderate or severe coronavirus disease-2019 (COVID-19).
 Treatment with antiviral medications such as hydroxychloroquine, lopinavir/ritonavir, and/or
 remdesivir may act against infection caused by the virus responsible for COVID-19.
 Baricitinib may reduce lung inflammation. Giving baricitinib in combination with antiviral
 therapy may reduce the risk of the disease from getting worse and may help prevent the need
 for being placed on a ventilator should the disease worsen compared to antiviral therapy
 alone.
PRIMARY OBJECTIVE:

 I. To determine the efficacy of baricitinib combined with antiviral therapy in participants
 with COVID-19-related moderate and severe disease in terms of reduction of the proportion of
 participants requiring invasive mechanical ventilation or dying or requiring anti-IL6
 monoclonal antibodies compared to that seen with antiviral alone within 60 days.

 SECONDARY OBJECTIVES:

 I. To describe the clinical findings in a cohort of symptomatic COVID-19-infected
 participants.

 II. To test whether cytokine signatures predict progression to invasive ventilatory support
 or death.

 III. To describe adverse events (AEs) associated with baricitinib when administered at 4mg in
 combination with antivirals.

 EXPLORATORY OBJECTIVES:

 I. Describe the decay in quantitative viral burden from saliva samples collected sequentially
 under treatment with baricitinib in combination with antivirals.

 II. To obtain preliminary data on efficacy and tolerability of baricitinib in combination
 with antivirals in participants with cancer.

 OUTLINE: Patients are randomized to 1 of 2 groups.

 GROUP I: Patients receive baricitinib orally (PO) daily, and standard of care
 hydroxychloroquine PO three times daily (TID). Treatment continues for 14 days in the absence
 of disease progression or unacceptable toxicity.

 GROUP II: Patients receive placebo PO daily, and standard of care hydroxychloroquine PO TID.
 Treatment continues for 14 days in the absence of disease progression or unacceptable
 toxicity.

 Patients are followed for 60 days after enrollment to treatment.
Inclusion Criteria:

 -  Positive polymerase chain reaction (PCR) for severe acute respiratory syndrome
 coronavirus 2 (SARS-CoV2) in a respiratory tract sample OR positive anti-SARS CoV2 IgM
 antibody test that is approved by Food and Drug Administration (FDA) or allowed under
 an emergency use authorization; either result obtained within 5 days prior to study
 entry

 -  Cough and/or pneumonia on chest imaging

 -  Moderate disease with risk factor(s): Peripheral capillary oxygen saturation (SpO2) >=
 92% on room air with one of the following risk factors for development of severe
 disease: age >= 60 years, receiving medication for hypertension, diagnosed diabetes
 mellitus, known cardiac disease, chronic lung disease, obesity (body mass index [BMI]
 >= 35 kg/m^2), active malignancy, immunosuppression (receiving biologics or
 glucocorticoids >= 20 mg/d prednisone equivalent for > 2 weeks)

 -  Severe disease: SpO2 =< 92% on room air

 -  Ability to understand and the willingness to sign a written informed consent. Adults
 not competent to consent will be enrolled with the use of an appropriate legally
 authorized representative (per California Code, Health and Safety Code - HSC)

 -  FDA regulations generally require that the informed consent of a participant be
 documented by the use of a written consent form approved by the IRB and signed
 and dated by the participant or the participant's legally authorized
 representative at the time of consent (21 case form report [CFR] 50.27[a]). In
 light of COVID-19 infection control measures, the following procedure would
 satisfy documentation of this requirement if the participant signing the informed
 consent is in COVID-19 isolation. If the technology is available, electronic
 methods of obtaining informed consent will be taken. The electronic consent and
 Health Insurance Portability and Accountability Act (HIPAA) forms will be
 uploaded and available through REDCap

 -  Women of child-bearing potential and men must agree to use adequate contraception
 (hormonal or barrier method of birth control; abstinence) prior to study entry, for
 the duration of study participation, and for 7 days following completion of therapy.
 NOTE: Should a woman become pregnant or suspect she is pregnant while participating in
 this study, she should inform her treating physician immediately. Women of
 child-bearing potential should use highly effective methods of birth control. These
 are those methods of contraception, alone or in combination, that result in a low
 failure rate (i.e, less than 1% per year) when used consistently and correctly

 Exclusion Criteria:

 -  Mechanical ventilation, high-flow nasal oxygen, biphasic positive airway pressure
 (BiPAP)

 -  Venous thromboembolism within 12 weeks or previously diagnosed thrombophilic
 conditions or conditions that increase the risk of thrombosis. Individuals with > 1
 episode of venous thromboembolism or pulmonary embolism in the past will also be
 excluded

 -  Prior receipt of other immunomodulatory drugs (e.g., any JAK inhibitors,
 immunomodulatory biologics, or other immunomodulatory investigational products) within
 14 days prior to enrollment

 -  Current treatment with probenecid

 -  Known infection with human immunodeficiency syndrome (HIV), or active infection with
 hepatitis B or hepatitis C

 -  Participant with known active or latent tuberculosis infection

 -  Pregnancy and lactation

 -  Any serious acute infections or known active or latent tuberculosis

 -  All enrolled participants will be screened for latent tuberculosis infection by
 testing QuantiFERON-TB Gold Plus, but a documented negative test will not be
 required prior to entry. If a participant is found to have positive QuantiFERON
 that results after enrollment, baricitinib will be discontinued

 -  Solid organ transplant recipient

 -  Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x upper limit
 of normal

 -  Absolute neutrophil count < 1000/mm^3

 -  Absolute lymphocyte count < 200/mm^3

 -  Hemoglobin < 8 g/dl

 -  Estimated glomerular filtration rate (GFR) < 30 mL/min/1.73 m^2

 -  Any medical condition in the opinion of the investigator that would place the
 participant at undue high risk for participation in the trial

 -  Hypersensitivity to the active substance or to any of the excipients