COVID-19 Study at the Russian Clinical and Research Center of Gerontology of the Pirogov RNRMU

Study Overview
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Brief Summary
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This is a retrospective observational cohort study. About 1000 hospital charts of adult patients admitted to the hospital with mild-to-moderate COVID-19 from February to August 2020 were analyzed to evaluate the inflammatory markers and clinical outcomes. The aim of this study was to compare the observed results of targeted immunosuppressive therapy, anti-IL-6R (Tocilizumab), anti-IL-17A (Netakimab), and JAK1/JAK2 inhibitor (Baricitinib), with standard-of-care (SOC) therapy. The investigators hypothesize that, as compared to SOC therapy, all target drugs will demonstrate at least similar beneficial effects. This observation may additionally support a rational choice for mild-to-moderate COVID-19 treatment strategy, considering the general safety profile and patient-specific limitations.

Detailed Description
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The clinical data from 154 patients were retrospectively collected according to Inclusion and Exclusion criteria. Finally all patients were divided into four groups depending on therapy: 38 patients who received Baricitinib and SOC; 34 patients who received Tocilizumab and SOC; 48 patients who received Netakimab and SOC and 34 patients who received only SOC. For all patients the investigators assessed the National Early Warning Score2 (NEWS2), absolute neutrophil count (ANC), absolute lymphocyte count (ALC) and blood neutrophil-to-lymphocyte ratio (NLR) at baseline (0 h, the day of therapy started) and after 72 hours (3 days) and 120 hours (5 days) of therapy. The individual dynamics of c-reactive protein (CRP) and lactate dehydrogenase (LDH) were assessed for patients with known parameters at baseline and 72 h (Δ0-72) or at baseline and 120 h (Δ0-120) to avoid excluding from the analysis patients who lacked CRP or LDH data at one of the time points. The individual dynamics of CRP and LDH for patients for whom the results of sequential measurements were available for all three time points was also assessed separately. Additionally, the clinical outcomes (death or hospital discharge) and amount of days in hospital after starting therapy were estimate for all 154 patients.

Official Title
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Tocilizumab, Netakimab, and Baricitinib Versus Standard of Care Therapy in Patients With Mild to Moderate COVID-19 - a Retrospective Observational Study

Conditions
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COVID-19, Mild to Moderate

Intervention / Treatment
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* Drug: Baricitinib Oral Tablet
* Drug: Tocilizumab Injection
* Drug: Netakimab
* Other: Standard of care therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who meet all of the following criteria were included in the study: Patients were hospitalized in two Moscow specialized COVID-19 care units from 02/01/2020 to 08/31/2020. Patients had symptoms of acute respiratory infection (fever, muscle pain, cough) and radiologically-defined viral pneumonia as assessed by computed tomography All patients written informed consent for 'off-label' drug use for persons who received tocilizumab, netakimab, or baricitinib Exclusion Criteria: Subjects who meet any of the following criteria were excluded from participation in the study: Pregnant women Patients with unknown National Early Warning Score 2 (NEWS2) metric or with NEWS2 > 6 points on the first day of therapy Patients with the plasma level of CRP > 140 mg/l on the first day of therapy Information about the outcome of patients (death or discharge from the hospital) was absent Patients who first time got the investigational drug later than 72 hours after hospitalization Patients who received a combination of the investigational drugs or application was differed to study design Patients with severe hematological, renal, or liver function impairment or evidence of concomitant bacterial infections.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Baricitinib<br>group included patients received Baricitinib in addition to standard of care therapy | Drug: Baricitinib Oral Tablet<br>* Baricitinib was administered at a dose of 4 mg once or twice per day for 3-8 days (5 days on average) depending on the individual patients' condition<br>* Other names: Olumiant;|
| Tocilizumab<br>group included patients received Tocilizumab in addition to standard of care therapy | Drug: Tocilizumab Injection<br>* Tocilizumab was administered by a single intravenous dose of 400 mg<br>* Other names: Actemra;|
| Netakimab<br>group included patients received Netakimab in addition to standard of care therapy | Drug: Netakimab<br>* Netakimab was administered by a single subcutaneous injection of 120 mg<br>* Other names: Efleira;|
| Control<br>group included patients received only standard of care therapy at the time of hospital admission according to the corresponding COVID-19 Russian guidelines 2020. | Other: Standard of care therapy<br>* SOC treatment included hydroxychloroquine (400 mg twice on day 1, followed by 200 mg twice per day on days 5-10), azithromycin (500 mg once per day for 5 days), lopinavir-ritonavir (400/100 mg twice per day for 14 days), and low molecular-weight heparin according to personal indicators<br>* Other names: SOC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changing in the level of C-reactive protein | The level of C-reactive protein (mg/L ) was measured by ELISA on the day of the start of therapy and then after 72 hours and 120 hours | 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changing in the level of Lactate dehydrogenase | The blood level of lactate dehydrogenase (LDH, U/L) was estimate by enzymatic UV-Kinetic method on the day of the start of therapy and then after 72 hours and 120 hours. | 5 days | 
| Assessment of the absolute lymphocyte count in dynamic | The absolute lymphocyte count (ALC) was assessed by using an automatic hematology analyzer on the day of the start of therapy and then after 72 hours and 120 hours. | 5 days | 
| Assessment of the absolute neutrophil count in dynamic | The absolute neutrophil count (ANC) was assessed by using an automatic hematology analyzer on the day of the start of therapy and then after 72 hours and 120 hours. | 5 days | 
| Assessment of the neutrophil-to-lymphocyte ratio | The mathematical ratio of ANC to ALC were calculated for timepoints 0 ( the day of the start of therapy), 3 (72 hours after the start of the therapy) and 5 (120 hours after the start of the therapy) | 5 days | 
| Changing of the National Early Warning Score2 | The National Early Warning Score2 (NEWS2) metric based on physiological variables including blood pressure, heart rate, respiratory rate, temperature, oxygen saturation, and level of consciousness and falls on a scale of 0 to 20. NEWS2 value at 0-4 points corresponds to low clinical risk, 5-6 points to medium risk and 7 or more points to high clinical risk. NEWS2 was estimate on the day of the start of therapy and then after 72 hours and 120 hours. | 5 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tocilizumab, baricitinib, netakimab, anti-IL-17, c-reactive protein, lactic dehydrogenase, neutrophil-to-lymphocyte ratio