Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19

Study Overview
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Brief Summary
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This is an open label, randomized, controlled, pilot clinical study in patients with COVID-19, to obtain preliminary biologic, physiologic, and clinical data in patients with COVID-19 treated with rhACE2 or control patients, to help determine whether a subsequent Phase 2B trial is warranted.

Detailed Description
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This is a small pilot study investigating whether there is any efficacy signal that warrants a larger Phase 2B trial, or any harm that suggests that such a trial should not be done. It is not expected to produce statistically significant results in the major endpoints. The investigators will examine all of the biologic, physiological, and clinical data to determine whether a Phase 2B trial is warranted. Primary efficacy analysis will be carried only on patients receiving at least 4 doses of active drug. Safety analysis will be carried out on all patients receiving at least one dose of active drug. It is planned to enroll more than or equal to 24 subjects with COVID-19. It is expected to have at least 12 evaluable patients in each group. Experimental group: 0.4 mg/kg rhACE2 IV BID and standard of care Control group: standard of care Intervention duration: up to 7 days of therapy No planned interim analysis.

Official Title
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A Randomized, Open Label, Controlled Clinical Study to Evaluate the Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) in Adult Patients With COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Recombinant human angiotensin-converting enzyme 2 (rhACE2)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Laboratory diagnosis: Respiratory specimen is positive for SARS-CoV-2 nucleic acid by RT-PCR; OR, The viral gene sequencing of the respiratory specimen is highly homologous to known novel coronavirus. Fever: Axillary temperature >37.3℃ Respiratory variables (meets one of the following criteria): Respiratory rate: RR ≥25 breaths/min Oxygen saturation ≤93% at rest on room air PaO2/FiO2 ≤300 mmHg（1 mmHg=0.133 KPa） Pulmonary imaging showed that the lesions progressed more than 50% within 24-48 hours, and the patients were managed as severe HBsAg negative, or HBV DNA ≤10^4 copy/ml if HBsAg positive; anti-HCV negative; HIV negative two weeks prior to signed Informed Consent Form (ICF) Appropriate ethics approval and ICF Exclusion Criteria: Age <18 years; Age >80 years Pregnant or breast feeding woman or with positive pregnancy test result P/F <100 mmHg Moribund condition (death likely in days) or not expected to survive for >7 days Refusal by attending MD Not hemodynamically stable in the preceding 4 hours (MAP ≤65 mmHg, or SAP <90 mmHg, DAP <60 mmHg, vasoactive agents are required) Patient on invasive mechanical ventilation or ECMO Patient in other therapeutic clinical trial within 30 days before ICF Receive any other ACE inhibitors (ACEI), angiotensin-receptor blockers (ARB) treatment within 7 days before ICF Chronic immunosuppression: current autoimmune diseases or patients who received immunotherapy within 30 days before ICF Hematologic malignancy (lymphoma, leukemia, multiple myeloma) Other patient characteristics (not thought to be related to underlying COVID-19) that portend a very poor prognosis (e.g, severe liver failure, and ect) Known allergy to study drug or its ingredients related to renin-angiotensin system (RAS), or frequent and/or severe allergic reactions with multiple medications Other uncontrolled diseases, as judged by investigators Body weight ≥85 kg

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 2-arm pilot study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: rhACE2 group<br>0.4 mg/kg IV BID for 7 days (unblinded) + standard of care | Drug: Recombinant human angiotensin-converting enzyme 2 (rhACE2)<br>* In this study, the experimental group will receive 0.4 mg/kg rhACE2 IV BID for 7 days.<br>|
| No Intervention: Control group<br>Standard of care; no placebo | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time course of body temperature (fever) | Compare the time course of body temperature (fever) between two groups over time. | 14 days | 
| Viral load over time | Compare viral load between two groups over time. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| P/F ratio over time | PaO2/FiO2 ratio | 14 days | 
| Sequential organ failure assessment score(SOFA score) over time | SOFA, including assessment of respiratory, blood, liver, circulatory, nerve, kidney, from 0 to 4 scores in each systems, the higher scores mean a worse outcome. | 14 days | 
| Pulmonary Severity Index (PSI) |  | 14 days | 
| Image examination of chest over time | Based on radiologist's assessment of inflammatory exudative disease, category as follows: significant improvement, partial improvement, no improvement, increase of partial exudation, significant increase in exudation, unable to judge. | 14 days | 
| Proportion of subjects who progressed to critical illness or death |  | 14 days | 
| Time from first dose to conversion to normal or mild pneumonia |  | 14 days | 
| T-lymphocyte counts over time |  | 14 days | 
| C-reactive protein levels over time |  | 14 days | 
| Angiotensin II (Ang II) changes over time |  | 14 days | 
| Angiotensin 1-7 (Ang 1-7) changes over time |  | 14 days | 
| Angiotensin 1-5 (Ang 1-5) changes over time |  | 14 days | 
| Renin changes over time |  | 14 days | 
| Aldosterone changes over time |  | 14 days | 
| Angiotensin-converting enzyme (ACE) changes over time |  | 14 days | 
| Angiotensin-converting enzyme 2 (ACE2) changes over time |  | 14 days | 
| Interleukin 6 (IL-6) changes over time |  | 14 days | 
| Interleukin 8 (IL-8) changes over time |  | 14 days | 
| Soluble tumor necrosis factor receptor type II (sTNFrII) changes over time |  | 14 days | 
| Plasminogen activator inhibitor type-1 (PAI-1) changes over time |  | 14 days | 
| Von willebrand factor (vWF) changes over time |  | 14 days | 
| Tumor necrosis factor-α (TNF-α) changes over time |  | 14 days | 
| Soluble receptor for advanced glycation end products (sRAGE) changes over time |  | 14 days | 
| Surfactant protein-D (SP-D) changes over time |  | 14 days | 
| Angiopoietin-2 changes over time |  | 14 days | 
| Frequency of adverse events and severe adverse events |  | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV-2, Renin-angiotensin-system (RAS)