An Open Non-comparative Study of the Efficacy and Safety of Aprotinin in Patients Hospitalized With COVID-19

Study Overview
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Brief Summary
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The observational study will be carried out in two stages. At the first stage, the efficacy and safety of Aprotinin intravenous infusion as add-on therapy to the standard of care will be studied. At the second stage, two groups will be included: the first group will be the inhaled Aprotinin add-on therapy, the second group will be intravenous Aprotinin in combination with Favipiravir.

Detailed Description
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Primary objective of the study is to evaluate the efficacy of Aprotinin as add-on therapy in patients hospitalized with COVID-19 using the following parameters: The time to elimination of SARS-CoV-2 virus until Day 10; The time to C-reactive protein (CRP) normalization until Day 10; The time to D-dimer normalization until Day 10. Secondary objectives are to evaluate the following parameters of efficacy and safety of Aprotinin add-on therapy in patients hospitalized with COVID-19: The time to body temperature normalization (<37oC); Changes from baseline of the laboratory parameters during 14 days: hematology, CRP, coagulogram; Changes of lung injury on CT scan on Day 7 and Day 14 from baseline; Frequency of clinical status improvement by 2 scores in accordance with the WHO Ordinal scale of clinical improvement (WHO-OSCI) or discharge from the hospital before Day 14; Frequency of transfer to the Intensive Care Unit (ICU), frequency of the non-invasive ventilation, frequency of the invasive ventilation and mortality rate; Frequency of Adverse Events (AEs) and Serious Adverse Events (SAEs) of various severity according to subjective complains, physical examination, vital signs, laboratory tests and ECG.

Official Title
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An Open Non-comparative Study of the Efficacy and Safety of Aprotinin in Patients Hospitalized With COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Aprotinin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Patient Information Sheet and Informed Consent Form for participation in the study; Adult male or female ≥18 years of age; Body mass < 90 kg; Positive qualitative RNA SARS-CoV-2 PCR analysis at screening; Score 4 on the WHO-OSCI (added at Stage 2); Subjects with moderate-to-severe disease with the follow conditions and symptoms: Pneumonia; Fever > 38°C; Blood serum CRP > 10 mg/L. Agreement to use medically acceptable forms of birth control during the study (contraceptive with spermicide). Exclusion Criteria: Severe disease with one of the follow criteria: Respiratory rate > 35 per minute that doesn't decrease after body temperature reducing to normal or subfebrile level; Saturation ≤ 93% at rest; Partial pressure of arterial oxygen (PaO2) < 60 mmHg; Oxygenation index (РаО2/FiO2) ≤ 200 mmHg; Partial pressure of arterial CO2 (PaCO2) > 60 mmHg; Septic shock. Chronic liver and kidney diseases in terminal stage; Other organs failure requiring control and treatment in the ICU; Subjects with HIV; Using of Aprotinin during 6 months prior to screening; hypersensitivity to any of the drug components; Participation in any other clinical trial or using of other study drugs during 28 days prior to screening; Pregnant or lactating women or women planning pregnancy during the clinical study; women with child-bearing potential (including women non-sterilized surgically and in postmenopause for less than 2 years) not using medically acceptable forms of birth control; Inability to read or write; unwillingness to understand and follow the Protocol procedures; non-compliance with the regimen of taking medications or performing procedures that, according to the Investigator, may affect the results of the study or the safety of the patient and prevent the patient from further participation in the study; any other comorbid medical or serious mental conditions that make patient ineligible for participation in the clinical study, limits the ability to obtain informed consent, or may affect patient's ability to participate in the study.

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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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: A non-comparative study of the efficacy and safety
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1/Group 1<br>Intravenous Aprotinin in addition to standard care: 1 000 000 KIU IV daily during 3 days | Drug: Aprotinin<br>* Intravenous or inhalation<br>* Other names: Gordox®;|
| Experimental: Stage 2/Group 2<br>Inhaled Aprotinin in addition to standard care: 625 KIU 4 times per day during 5 days | Drug: Aprotinin<br>* Intravenous or inhalation<br>* Other names: Gordox®;|
| Experimental: Stage 2/Group 3<br>Intravenous Aprotinin in addition to standard care that includes Favipiravir: 1 000 000 KIU IV daily during 5 days | Drug: Aprotinin<br>* Intravenous or inhalation<br>* Other names: Gordox®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to elimination of SARS-CoV-2 virus | Time to two negative PCR tests with at least 24 hours interval [days] | 10 days | 
| Time to CRP normalization | Time to CRP <10 mg/L [days] | 10 days | 
| Time to D-dimer normalization | Time to D-dimer <243 ng/mL [days] | 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to body temperature normalization | Time to body temperature <37oC [days] | 14 days | 
| Change in absolute neutrophil count (ANC) | Change of ANC [cells/L] | Baseline to Day 14 | 
| Change in white blood cells (WBC) | Change of WBC [cells/L] | Baseline to Day 14 | 
| Change of CRP | Change of CRP [mg/L] | Baseline to Day 14 | 
| Change of D-dimer | Change of D-dimer [ng/mL] | Baseline to Day 14 | 
| Change in fibrinogen | Change of fibrinogen [g/L] | Baseline to Day 14 | 
| Change of Quick's value | Change of Quick's value [%] | Baseline to Day 14 | 
| Change of international normalized ratio (INR) | Change of INR [score] | Baseline to Day 14 | 
| Changes of lung injury on CT scan | Improvement, no change or worsening of the lung injury on CT scan [proportion of patients] | Baseline to Day 14 | 
| Frequency of clinical status improvement by 2 scores in accordance with the WHO-OSCI or discharge from the hospital | Frequency of clinical status improvement by 2 scores in accordance with the WHO-OSCI or discharge from the hospital [proportion of patients] | 14 days | 
| Frequency of deterioration of the patients' status | Frequency of transfer to the ICU, non-invasive ventilation, invasive ventilation and mortality rate [proportion of patients] | 14 days | 
| Frequency of AEs and SAEs | Frequency of AEs and SAEs of various severity according to subjective complains, physical examination, vital signs, laboratory tests and ECG [% of patients] | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, SARS-CoV-2, pneumonia, inpatients