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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Recombinant human angotensin-converting enzyme 2 (rhACE2) as a treatment for patients with COVID-19 to block viral entry and decrease viral replication.

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

Conditions
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COVID-19

Intervention / Treatment
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* Drug: RhACE2 APN01
* Drug: Physiological saline solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hospitalized male or female Diagnosed to be COVID-19 POSITIV Signed Inform Consent Form Exclusion Criteria: Any patient whose clinical condition is deteriorating rapidly Known history of positive Hepatitis B surface antigen, Hepatitis C antibody or HIV antibody History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation Pregnant females as determined by positive serum or urine hCG test prior to dosing Lung transplantation Pre-existing renal failure, i.e. requiring renal replacement therapy with hemodialysis or peritoneal dialysis There are other uncontrolled co-morbidities that increase the risks associated with the study drug administration, that are assessed by the medical expert team as unsuitable Patient in clinical trials for COVID-19 within 30 days before ICF Immunocompromised patients (chemotherapy, HIV, organ transplants, stem cell transplants)

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A (active) APN01<br>Recombinant human angiotensin-converting enzyme 2 (rhACE2) - APN01 | Drug: RhACE2 APN01<br>* Patients will be treated with APN01 intravenously twice daily (BID).<br>* Other names: Recombinant human angiotensin-converting enzyme 2;|
| Placebo Comparator: Group B (placebo control)<br> | Drug: Physiological saline solution<br>* Patients will be treated with placebo intravenously twice daily (BID).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All Cause-death or Invasive Mechanical Ventilation | The primary endpoint was a composite endpoint of all cause-death or invasive mechanical ventilation up to 28 days or hospital discharge. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lactate Dehydrogenase (LDH) Level | Log transformed levels of LDH at Day 5 as a surrogate marker for organ damage (powered secondary endpoint). | Day 5 | 
| Mortality | 28-day mortality (all cause-death). | 28 days | 
| Ventilator-free Days (VFD) | VFD up to 28 days or hospital discharge. VFD and mechanical-VFD (mVFD) were calculated as time in the study minus duration of ventilation and were set to zero if the duration of ventilation exceeded the time in the study. Three analysis approaches were used: 1) Death not censored: (m)VFD was set to zero for patients who died. 2) Death censored: patients who died before or on Day 28 were censored at the day before death. 3) Alive patients analyzed: only patients who were alive at Day 28, hospital discharge, or early termination were included in the analysis. | 28 days | 
| Time to Death | Time to death (all causes). | 28 days | 
| Number of Responders, Defined as ≥2 Improvement in World Health Organization (WHO)'s 11-Point Score System at Days 7, 10, 14 and 28 | The WHO Clinical Progression Scale provides a measure of illness severity across an 11 point range from 0 (not infected) to 10 (dead) as follows (scores 4-9 contain measures of respiratory failure): Uninfected, no viral deoxyribonucleic acid (DNA) detected = 0; Asymptomatic, viral DNA detected = 1; Symptomatic, independent = 2; Symptomatic, assistance needed = 3; Hospitalized, no oxygen therapy = 4; Hospitalized, oxygen by mask or nasal prongs = 5; Hospitalized, oxygen by non-invasive ventilation (NIV) or high flow = 6; Intubation and mechanical ventilation, partial pressure of oxygen (pO2)/fraction of inspired oxygen (FiO2)≥ 150 or oxygen saturation (SpO2)/FiO2≥200 = 7; Mechanical ventilation, pO2/FiO2 < 150 (SpO2/FiO2 < 200) or vasopressors = 8; Mechanical ventilation, pO2/FiO2 < 150 and vasopressors, dialysis, or extracorporeal membrane oxygenation (ECMO) = 9; Dead = 10. A decrease in the score reflects an improvement. | Day 7, Day 10, Day 14, Day 28 | 
| Time to Hospital Discharge | The number of days from randomization to discharge from hospital was calculated (Kaplan-Meier analysis). Patients without hospitalization or without documented hospital discharge who completed the study or were early terminated before Day 28 were censored at the date of study completion or discontinuation, respectively. Patients who died before Day 28 were censored at the date of death even if early terminated before. | Up to 28 days | 
| Viral Ribonucleic Acid (RNA). | Viral RNA was assessed in blood samples using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and projected to RNA copies per mL. | Day 1, Day 3, Day 5, Day 7, Day 14, and Day 28/End of study (EOS) | 
| Time to a 2-point Decrease in WHO's 11-Point Score System | The time from randomization to an at least 2-point decrease in the WHO scale was calculated. The WHO Clinical Progression Scale provides a measure of illness severity across an 11 point range from 0 (not infected) to 10 (dead) as follows (scores 4-9 contain measures of respiratory failure): Uninfected, no viral DNA detected = 0; Asymptomatic, viral DNA detected = 1; Symptomatic, independent = 2; Symptomatic, assistance needed = 3; Hospitalized, no oxygen therapy = 4; Hospitalized, oxygen by mask or nasal prongs = 5; Hospitalized, oxygen by non-invasive ventilation (NIV) or high flow = 6; Intubation and mechanical ventilation, pO2/FiO2 ≥ 150 or SpO2/FiO2≥200 = 7; Mechanical ventilation, pO2/FiO2 < 150 (SpO2/FiO2 < 200) or vasopressors = 8; Mechanical ventilation, pO2/FiO2 < 150 and vasopressors, dialysis, or ECMO = 9; Dead = 10. A decrease in the score reflects an improvement in disease status. | Up to 28 days. | 
| Number of Patients With Any Use of Invasive Mechanical Ventilation up to 28 Days or Hospital Discharge | The number of patients receiving mechanical ventilation and supplemental oxygen was evaluated. | Up to 28 days | 
| Time to First Use of Invasive Mechanical Ventilation up to 28 Days or Hospital Discharge | Time from randomization to first use of invasive mechanical ventilation was calculated (Kaplan-Meier analysis). Patients without documented invasive mechanical ventilation who completed the study, were early terminated or discharged from hospital before Day 28 were censored at the date of study completion, discontinuation or discharge from hospital, respectively. | Up to 28 days | 
| PaO2/FiO2 Value | The ratio in partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) was assessed by analysis of patient's blood gas. | Day 1, Day 7, Day 10, Day 14, and Day 28 | 
| Modified Sequential Organ Failure Assessment Score (mSOFA Score, Total Score) | The mSOFA score predicts intensive care unit mortality using clinical and laboratory variables. 5 organ systems (respiratory SpO2/FiO2; liver; cardiovascular/hypotension; Central nervous System/Glasgow Coma Score; renal/creatinine), all, except for liver, scored on a 0 to 4 scale (liver: 2-point scale: 0 or 3) according to specified criteria indicating severity, with the total score ranging from 0 to a maximum score of 19. A higher score reflects a worse disease state. | Day -1 (Screening), Day 7, Day 10, Day 14, Day 28/End of study | 
| Lymphocyte Count | Lymphocytes were assessed in blood samples from the patients. | Day -1, Day 3, Day 7, Day 10, Day 14, Day 28/End of study | 
| C-reactive Protein Levels | C-reactive protein was assessed in blood samples from the patients. | Day -1, Day 3, Day 7, Day 10, Day 14, Day 28/End of study | 
| D-Dimer | D-Dimer was assessed in blood samples from the patients. | Day -1, Day 3, Day 7, Day 10, Day 14, Day 28/End of study | 
| Log-transformed Levels of LDH | Log transformed levels of LDH in blood were assessed as a surrogate marker for organ damage. | Day -1, Day 3, Day 7, Day 10, Day 14, Day 28/End of study |