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

Primary Purpose

COVID-19

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
RhACE2 APN01
Physiological saline solution
Sponsored by
Apeiron Biologics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for COVID-19

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Medizinische Universität Innsbruck
  • Kaiser Franz Josef Spital, 4. Medizinische Abteilung mit Infektions- und Tropenmedizin
  • Medizinische Universität Wien
  • The National University Hospital, Rigshospitalet
  • Herlev Gentofte Hospital
  • Nordsjællands Hospital
  • Hvidovre Hospital
  • Universitätsklinikum Hamburg-Eppendorf
  • Klinikum rechts der Isar, Technische Universität München
  • Regional State Budgetary Educational Institution "Clinical Hospital № 5, Barnaul"
  • State Healthcare Institution "State Clinical Hspital № 15 named after O.M. Filatov"
  • Moscow State Budgetary Healthcare Institution "City Clinical Hospital №52 of Health Department of Moscow"
  • Moscow State Budgetary Healthcare Institution "N.V. Sklifosovsky Research Institute for Emergency Medicine of Health Department of Moscow"
  • Saint Petersburg SBHI City Hospital 38 named after N A Semashko
  • Federal State Budgetary Educational Institution of Higher Education "Ryazan State Medical University named after I.P. Pavlov" HD RF
  • Alexandrovskaya Hospital
  • Saint-Petersburg State Budget Healthcare Institution City Hospital 15
  • Federal State Budgetary Educational Institution of Higher Education " Saratov State Medical University named after V.I. Razumovsky" HD RF
  • Regional State Budgetary Healthcare Institution "Clinical Hospital №1"
  • State budgetary institution of Healthcare of Tver region "Regional clinical hospital"
  • Yaroslavl Regional Clinical Hospital for Military Veterans - International Centre for Gerontological Problems "Healthy Ageing"
  • Cambridge University Hospitals NHS Trust/University of Cambridge

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Group A (active) APN01

Group B (placebo control)

Arm Description

Recombinant human angiotensin-converting enzyme 2 (rhACE2) - APN01

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Lactate Dehydrogenase (LDH) Level
Log transformed levels of LDH at Day 5 as a surrogate marker for organ damage (powered secondary endpoint).
Mortality
28-day mortality (all cause-death).
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.
Time to Death
Time to death (all causes).
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.
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.
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.
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.
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.
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.
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.
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.
Lymphocyte Count
Lymphocytes were assessed in blood samples from the patients.
C-reactive Protein Levels
C-reactive protein was assessed in blood samples from the patients.
D-Dimer
D-Dimer was assessed in blood samples from the patients.
Log-transformed Levels of LDH
Log transformed levels of LDH in blood were assessed as a surrogate marker for organ damage.

Full Information

First Posted
April 1, 2020
Last Updated
July 29, 2021
Sponsor
Apeiron Biologics
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1. Study Identification

Unique Protocol Identification Number
NCT04335136
Brief Title
Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19
Acronym
APN01-COVID-19
Official Title
Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19
Study Type
Interventional

2. Study Status

Record Verification Date
July 2021
Overall Recruitment Status
Completed
Study Start Date
April 30, 2020 (Actual)
Primary Completion Date
December 26, 2020 (Actual)
Study Completion Date
December 26, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Apeiron Biologics

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
185 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group A (active) APN01
Arm Type
Active Comparator
Arm Description
Recombinant human angiotensin-converting enzyme 2 (rhACE2) - APN01
Arm Title
Group B (placebo control)
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
RhACE2 APN01
Other Intervention Name(s)
APN01, Recombinant human angiotensin-converting enzyme 2
Intervention Description
Patients will be treated with APN01 intravenously twice daily (BID).
Intervention Type
Drug
Intervention Name(s)
Physiological saline solution
Intervention Description
Patients will be treated with placebo intravenously twice daily (BID).
Primary Outcome Measure Information:
Title
All Cause-death or Invasive Mechanical Ventilation
Description
The primary endpoint was a composite endpoint of all cause-death or invasive mechanical ventilation up to 28 days or hospital discharge.
Time Frame
28 days
Secondary Outcome Measure Information:
Title
Lactate Dehydrogenase (LDH) Level
Description
Log transformed levels of LDH at Day 5 as a surrogate marker for organ damage (powered secondary endpoint).
Time Frame
Day 5
Title
Mortality
Description
28-day mortality (all cause-death).
Time Frame
28 days
Title
Ventilator-free Days (VFD)
Description
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.
Time Frame
28 days
Title
Time to Death
Description
Time to death (all causes).
Time Frame
28 days
Title
Number of Responders, Defined as ≥2 Improvement in World Health Organization (WHO)'s 11-Point Score System at Days 7, 10, 14 and 28
Description
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.
Time Frame
Day 7, Day 10, Day 14, Day 28
Title
Time to Hospital Discharge
Description
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.
Time Frame
Up to 28 days
Title
Viral Ribonucleic Acid (RNA).
Description
Viral RNA was assessed in blood samples using quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and projected to RNA copies per mL.
Time Frame
Day 1, Day 3, Day 5, Day 7, Day 14, and Day 28/End of study (EOS)
Title
Time to a 2-point Decrease in WHO's 11-Point Score System
Description
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.
Time Frame
Up to 28 days.
Title
Number of Patients With Any Use of Invasive Mechanical Ventilation up to 28 Days or Hospital Discharge
Description
The number of patients receiving mechanical ventilation and supplemental oxygen was evaluated.
Time Frame
Up to 28 days
Title
Time to First Use of Invasive Mechanical Ventilation up to 28 Days or Hospital Discharge
Description
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.
Time Frame
Up to 28 days
Title
PaO2/FiO2 Value
Description
The ratio in partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) was assessed by analysis of patient's blood gas.
Time Frame
Day 1, Day 7, Day 10, Day 14, and Day 28
Title
Modified Sequential Organ Failure Assessment Score (mSOFA Score, Total Score)
Description
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.
Time Frame
Day -1 (Screening), Day 7, Day 10, Day 14, Day 28/End of study
Title
Lymphocyte Count
Description
Lymphocytes were assessed in blood samples from the patients.
Time Frame
Day -1, Day 3, Day 7, Day 10, Day 14, Day 28/End of study
Title
C-reactive Protein Levels
Description
C-reactive protein was assessed in blood samples from the patients.
Time Frame
Day -1, Day 3, Day 7, Day 10, Day 14, Day 28/End of study
Title
D-Dimer
Description
D-Dimer was assessed in blood samples from the patients.
Time Frame
Day -1, Day 3, Day 7, Day 10, Day 14, Day 28/End of study
Title
Log-transformed Levels of LDH
Description
Log transformed levels of LDH in blood were assessed as a surrogate marker for organ damage.
Time Frame
Day -1, Day 3, Day 7, Day 10, Day 14, Day 28/End of study

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Henning Bundgaard, MD.
Organizational Affiliation
Cap. Region's Unit of Inherited Cardiac Diseases, Faculty Health&Medical
Official's Role
Principal Investigator
Facility Information:
Facility Name
Medizinische Universität Innsbruck
City
Innsbruck
Country
Austria
Facility Name
Kaiser Franz Josef Spital, 4. Medizinische Abteilung mit Infektions- und Tropenmedizin
City
Wien
Country
Austria
Facility Name
Medizinische Universität Wien
City
Wien
Country
Austria
Facility Name
The National University Hospital, Rigshospitalet
City
Copenhagen
Country
Denmark
Facility Name
Herlev Gentofte Hospital
City
Herlev
ZIP/Postal Code
2730
Country
Denmark
Facility Name
Nordsjællands Hospital
City
Hillerød
ZIP/Postal Code
3400
Country
Denmark
Facility Name
Hvidovre Hospital
City
Hvidovre
ZIP/Postal Code
2650
Country
Denmark
Facility Name
Universitätsklinikum Hamburg-Eppendorf
City
Hamburg
Country
Germany
Facility Name
Klinikum rechts der Isar, Technische Universität München
City
München
Country
Germany
Facility Name
Regional State Budgetary Educational Institution "Clinical Hospital № 5, Barnaul"
City
Barnaul
ZIP/Postal Code
656045
Country
Russian Federation
Facility Name
State Healthcare Institution "State Clinical Hspital № 15 named after O.M. Filatov"
City
Moscow
ZIP/Postal Code
111539
Country
Russian Federation
Facility Name
Moscow State Budgetary Healthcare Institution "City Clinical Hospital №52 of Health Department of Moscow"
City
Moscow
ZIP/Postal Code
123182
Country
Russian Federation
Facility Name
Moscow State Budgetary Healthcare Institution "N.V. Sklifosovsky Research Institute for Emergency Medicine of Health Department of Moscow"
City
Moscow
ZIP/Postal Code
129090
Country
Russian Federation
Facility Name
Saint Petersburg SBHI City Hospital 38 named after N A Semashko
City
Pushkin
ZIP/Postal Code
196600
Country
Russian Federation
Facility Name
Federal State Budgetary Educational Institution of Higher Education "Ryazan State Medical University named after I.P. Pavlov" HD RF
City
Ryazan
ZIP/Postal Code
390026
Country
Russian Federation
Facility Name
Alexandrovskaya Hospital
City
Saint-Petersburg
ZIP/Postal Code
193312
Country
Russian Federation
Facility Name
Saint-Petersburg State Budget Healthcare Institution City Hospital 15
City
Saint-Petersburg
ZIP/Postal Code
198205
Country
Russian Federation
Facility Name
Federal State Budgetary Educational Institution of Higher Education " Saratov State Medical University named after V.I. Razumovsky" HD RF
City
Saratov
ZIP/Postal Code
410054
Country
Russian Federation
Facility Name
Regional State Budgetary Healthcare Institution "Clinical Hospital №1"
City
Smolensk
ZIP/Postal Code
214006
Country
Russian Federation
Facility Name
State budgetary institution of Healthcare of Tver region "Regional clinical hospital"
City
Tver
ZIP/Postal Code
170036
Country
Russian Federation
Facility Name
Yaroslavl Regional Clinical Hospital for Military Veterans - International Centre for Gerontological Problems "Healthy Ageing"
City
Yaroslavl
ZIP/Postal Code
150047
Country
Russian Federation
Facility Name
Cambridge University Hospitals NHS Trust/University of Cambridge
City
Cambridge
ZIP/Postal Code
CB2 0QQ
Country
United Kingdom

12. IPD Sharing Statement

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

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