Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19 (APN01-COVID-19)

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

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: RhACE2 APN01; Drug: Physiological saline solution

• Study Type: Interventional
• Enrollment (Actual): 185
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Innsbruck, Austria
    • Medizinische Universität Innsbruck
  • Wien, Austria
    • Medizinische Universität Wien
  • Wien, Austria
    • Kaiser Franz Josef Spital, 4. Medizinische Abteilung mit Infektions- und Tropenmedizin
• Denmark
  • Copenhagen, Denmark
    • The National University Hospital, Rigshospitalet
  • Herlev, Denmark, 2730
    • Herlev Gentofte Hospital
  • Hillerød, Denmark, 3400
    • Nordsjællands Hospital
  • Hvidovre, Denmark, 2650
    • Hvidovre Hospital
• Germany
  • Hamburg, Germany
    • Universitätsklinikum Hamburg-Eppendorf
  • München, Germany
    • Klinikum rechts der Isar, Technische Universität München
• Russian Federation
  • Barnaul, Russian Federation, 656045
    • Regional State Budgetary Educational Institution "Clinical Hospital № 5, Barnaul"
  • Moscow, Russian Federation, 111539
    • State Healthcare Institution "State Clinical Hspital № 15 named after O.M. Filatov"
  • Moscow, Russian Federation, 123182
    • Moscow State Budgetary Healthcare Institution "City Clinical Hospital №52 of Health Department of Moscow"
  • Moscow, Russian Federation, 129090
    • Moscow State Budgetary Healthcare Institution "N.V. Sklifosovsky Research Institute for Emergency Medicine of Health Department of Moscow"
  • Pushkin, Russian Federation, 196600
    • Saint Petersburg SBHI City Hospital 38 named after N A Semashko
  • Ryazan, Russian Federation, 390026
    • Federal State Budgetary Educational Institution of Higher Education "Ryazan State Medical University named after I.P. Pavlov" HD RF
  • Saint-Petersburg, Russian Federation, 193312
    • Alexandrovskaya Hospital
  • Saint-Petersburg, Russian Federation, 198205
    • Saint-Petersburg State Budget Healthcare Institution City Hospital 15
  • Saratov, Russian Federation, 410054
    • Federal State Budgetary Educational Institution of Higher Education " Saratov State Medical University named after V.I. Razumovsky" HD RF
  • Smolensk, Russian Federation, 214006
    • Regional State Budgetary Healthcare Institution "Clinical Hospital №1"
  • Tver, Russian Federation, 170036
    • State Budgetary Institution of Healthcare of Tver region "Regional clinical hospital"
  • Yaroslavl, Russian Federation, 150047
    • Yaroslavl Regional Clinical Hospital for Military Veterans - International Centre for Gerontological Problems "Healthy Ageing"
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Cambridge University Hospitals NHS Trust/University of Cambridge

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Hospitalized male or female
2. Diagnosed to be COVID-19 POSITIV
3. Signed Inform Consent Form

Exclusion Criteria:

1. Any patient whose clinical condition is deteriorating rapidly
2. Known history of positive Hepatitis B surface antigen, Hepatitis C antibody or HIV antibody
3. 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
4. Pregnant females as determined by positive serum or urine hCG test prior to dosing
5. Lung transplantation
6. Pre-existing renal failure, i.e. requiring renal replacement therapy with hemodialysis or peritoneal dialysis
7. 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
8. Patient in clinical trials for COVID-19 within 30 days before ICF
9. Immunocompromised patients (chemotherapy, HIV, organ transplants, stem cell transplants)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Apeiron Biologics
• Investigators: Principal Investigator: Henning Bundgaard, MD., Cap. Region's Unit of Inherited Cardiac Diseases, Faculty Health&Medical

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2020
• Primary Completion (Actual): December 26, 2020
• Study Completion (Actual): December 26, 2020

Study Registration Dates

• First Submitted: April 1, 2020
• First Submitted That Met QC Criteria: April 3, 2020
• First Posted (Actual): April 6, 2020

Study Record Updates

• Last Update Posted (Actual): August 2, 2021
• Last Update Submitted That Met QC Criteria: July 29, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: APN01-01-COVID19

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No