Recombinant human angiotensin-converting enzyme 2 (rhACE2) as a treat-ment for patients with COVID-19
Latest Information Update: 04 Nov 2021
At a glance
- Drugs Alunacedase alfa (Primary)
- Indications COVID-19 respiratory infection
- Focus Therapeutic Use
- Acronyms APN01-COVID-19
- Sponsors Apeiron Biologics
- 12 Mar 2021 Primary endpoint has been met. (Cause of death or invasive mechanical ventilation), according to an Apeiron Biologics Media Release.
- 12 Mar 2021 Results published in the Apeiron Biologics Media Release
- 21 Jan 2021 Status changed from recruiting to completed.
Most Recent Events
Trial Overview
Outcome
Purpose
Recombinant human angotensin-converting enzyme 2 (rhACE2) as a treatment for patients with COVID-19 to block viral entry and decrease viral replication.
Primary Endpoints
Cause of death or invasive mechanical ventilation
description: The primary endpoint is a composite endpoint of all cause-death or invasive mechanical ventilation up to 28 days or hospital discharge
time_frame: 28 days [1]
Other Endpoints
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
Mortality
description: 28-day mortality (all cause-death).
time_frame: 28 days
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
Time to Death
description: Time to death (all causes).
time_frame: 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
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
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
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)
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.
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
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
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
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
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
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
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
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 [2]
Diseases Treated
Indication | Qualifiers | Patient Segments |
---|---|---|
COVID-19 respiratory infection | treatment | severe |
Biomarker
NCT Number | Biomarker Name | Biomarker Function |
---|---|---|
NCT04335136 | ACE2 | Arm Group Description, Brief Title, Official Title |
C-reactive protein (CRP) | Outcome Measure | |
D-dimer | Outcome Measure |
Subjects
- Subject Type patients
-
Number
Planned: 200
Actual: 185
- Sex male & female
- Age Group 18-80 years; adult; elderly
Patient Inclusion Criteria
1. Hospitalized male or female 2. Diagnosed to be COVID-19 POSITIV 3. Signed Inform Consent Form
Patient 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)
Trial Details
Identifiers
Identifier | Owner |
---|---|
NCT04335136 | ClinicalTrials.gov: US National Institutes of Health |
EudraCT2020-001172-15 | European Clinical Trials Database |
APN01-01COVID19 | - |
Organisations
- Sponsors Apeiron Biologics
- Affiliations Apeiron Biologics
Trial Dates
-
Initiation Dates
Planned : 01 Apr 2020
Actual : 30 Apr 2020
-
Primary Completion Dates
Planned : 01 Dec 2020
Actual : 26 Dec 2020
-
End Dates
Planned : 01 Dec 2020
Actual : 26 Dec 2020
Other Details
- Design double-blind; multicentre; parallel; prospective; randomised
- Phase of Trial Phase II
- Location Austria; Denmark; England; Germany; Russia; United Kingdom; USA
- Focus Therapeutic Use
Interventions
Drugs | Route | Formulation |
---|---|---|
Alunacedase alfaPrimary Drug | Intravenous | Infusion |
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 Name: APN01, Recombinant human angiotensin-converting enzyme 2
Group B (placebo control)
Drug: Physiological saline solution (Patients will be treated with placebo intravenously twice daily (BID).)
Results
Therapeutic efficacy
Results from a phase II trial in patients with COVID-2019 showed that fewer patients treated with alunacedase alfa (n=9) died or received invasive ventilation compared with placebo (n=12), although statistical significance was not achieved due to the low total number of events. Standard of care improved, resulted in fewer deaths and less use of invasive mechanical ventilation. A reduction in viral RNA load over time was observed in the alunacedase alfa treatment group [1] . Earlier results showed that the first patient treated with alunacedase alfa observed significant clinical improvement with an adaptive immune response. Alunacedase alfa effectively blocked the spike glycoprotein in COVID-19 infection. Alunacedase alfa (soluble ACE2) infusion showed the expected enzymatic activity and modulation of the renin angiotensin system. Alunacedase alfa infusion correlated with a gradual reduction in levels of multiple disease relevant inflammatory mediators over the studied time period. The APN 01 infusion also correlated with a rapid loss of detectable viremia and slightly delayed reduction in viral titers in tracheal samples and nasopharyngeal swaps. Alunacedase alfa infusion was fully compatible with an adaptive immune response and the development of high titers of neutralising antibodies against SARS-CoV-2 [3] .
Adverse events
Results from a phase II trial in patients with COVID-2019 infections, showed that treatment with alunacedase alfa was safe and well tolerated and no drug-related severe adverse events were observed [1] .
Pharmacodynamics
Results from a phase II trial in patients with COVID-2019 infections showed that treatment with alunacedase alfa reduced plasma levels of Ang II compared to control group. Alunacedase alfa treatment showed increased Ang 1-7 and Ang 1-5 levels while no increase in these anti-inflammatory factors was seen in the placebo group. Suppression of Ang II and increase of Ang 1-7 and Ang 1-5 in addition to the observed reduction in viral RNA load under alunacedase alfa treatment [1] .
Publications
-
Apeiron Biologics. APEIRON's APN01 shows clinical benefits for severely ill COVID-19 patients in phase 2 trial. Media-Rel 2021;.
Media Release
Trial Centres
Investigators
Investigator | Centre Name | Trial Centre Country |
---|---|---|
Alexander Popov, MD | Saint Petersburg SBHI City Hospital 38 named after N A Semashko | Russia |
Alexander Zoufaly, Priv.-Doz. Dr. | Kaiser Franz Josef Spital, 4. Medizinische Abteilung mit Infektions- und Tropenmedizin | Austria |
Boris Goloshchekin, MD | Saint-Petersburg State Budget Healthcare Institution City Hospital 15 | Russia |
Christian Søborg | Herlev Gentofte Hospital | Denmark |
Christoph D. Spinner, PD DR. med. | Klinikum rechts der Isar, Technische Universität München | Germany |
Claudia Haider, Mag.
43 1 8656577 110
show details
claudia.haider@apeiron-biologics.com |
Apeiron Biologics |
-
|
Daria Formina, MD | Moscow State Budgetary Healthcare Institution "City Clinical Hospital №52 of Health Department of Moscow" | Russia |
Elena Simakina, MD | Regional State Budgetary Healthcare Institution "Clinical Hospital №1" | Russia |
Galina Trufanova, MD | State budgetary institution of Healthcare of Tver region "Regional clinical hospital" | Russia |
Günter Weiss, Univ.-Prof. Dr. | Medizinische Universität Innsbruck | Austria |
Henning Bundgaard, MD. | Cap. Region's Unit of Inherited Cardiac Diseases, Faculty Health&Medical |
-
|
Ivan Gordeev, MD | State Healthcare Institution "State Clinical Hspital № 15 named after O.M. Filatov" | Russia |
Jan Gerstoft, Prof. Dr. med. | The National University Hospital, Rigshospitalet | Denmark |
Jeffrey Reeves, MD | Norton Infectious Disease Institute | USA |
Joseph Cheriyan, MD | Cambridge University Hospitals NHS Trust/University of Cambridge | United-Kingdom |
Maria Mozheiko | Yaroslavl Regional Clinical Hospital for Military Veterans - International Centre for Gerontological Problems "Healthy Ageing" | Russia |
Oleg Burlaka, MD | Alexandrovskaya Hospital | Russia |
Peter Hou, MD | Brigham and Women's Hospital | USA |
Roman Ullrich, Prof. Dr. | Medizinische Universität Wien | Austria |
Sergey Zhuravel, MD | Moscow State Budgetary Healthcare Institution "N.V. Sklifosovsky Research Institute for Emergency Medicine of Health Department of Moscow" | Russia |
Sonja Höller, Dr.
43 1 865 65 77 128
show details
sonja.hoeller@apeiron-biologics.com |
, Apeiron Biologics |
-
|
SPONSOR
Campus-Vienna-Biocenter 5,
show details
Vienna, 1030, Austria. sonja.hoeller@apeiron-biologics.com |
APEIRON Biologics AG | Austria |
Stefan Schmiedel, Dr. med. | Universitätsklinikum Hamburg-Eppendorf | Germany |
Tatyana Martynenko | Regional State Budgetary Educational Institution "Clinical Hospital № 5, Barnaul" | Russia |
Thomas L. Benfield, Prof. | Hvidovre Hospital | Denmark |
Troels B. Knudsen | Nordsjællands Hospital | Denmark |
Vladimir Martynov, MD | Federal State Budgetary Educational Institution of Higher Education "Ryazan State Medical University named after I.P. Pavlov" HD RF | Russia |
Centres
Centre Name | Location | Trial Centre Country |
---|---|---|
- |
-
|
-
|
Alexandrovskaya Hospital | Saint-Petersburg | Russia |
Apeiron Biologics |
-
|
-
|
APEIRON Biologics AG | Vienna | Austria |
Brigham and Women's Hospital | Boston, Massachusetts | USA |
Cambridge University Hospitals NHS Trust/University of Cambridge | Cambridge | United-Kingdom |
Cap. Region's Unit of Inherited Cardiac Diseases, Faculty Health&Medical |
-
|
-
|
Federal State Budgetary Educational Institution of Higher Education " Saratov State Medical University named after V.I. Razumovsky" HD RF | Saratov | Russia |
Federal State Budgetary Educational Institution of Higher Education "Ryazan State Medical University named after I.P. Pavlov" HD RF | Ryazan | Russia |
Herlev Gentofte Hospital | Herlev | Denmark |
Hvidovre Hospital | Hvidovre | Denmark |
Kaiser Franz Josef Spital, 4. Medizinische Abteilung mit Infektions- und Tropenmedizin | Wien | Austria |
Klinikum rechts der Isar, Technische Universität München | München | Germany |
Medizinische Universität Innsbruck | Innsbruck | Austria |
Medizinische Universität Wien | Wien | Austria |
Moscow State Budgetary Healthcare Institution "City Clinical Hospital №52 of Health Department of Moscow" | Moscow | Russia |
Moscow State Budgetary Healthcare Institution "N.V. Sklifosovsky Research Institute for Emergency Medicine of Health Department of Moscow" | Moscow | Russia |
Nordsjællands Hospital | Hillerød | Denmark |
Norton Infectious Disease Institute | Louisville, Kentucky | USA |
Regional State Budgetary Educational Institution "Clinical Hospital № 5, Barnaul" | Barnaul | Russia |
Regional State Budgetary Healthcare Institution "Clinical Hospital №1" | Smolensk | Russia |
Saint Petersburg SBHI City Hospital 38 named after N A Semashko | Pushkin | Russia |
Saint-Petersburg State Budget Healthcare Institution City Hospital 15 | Saint-Petersburg | Russia |
State budgetary institution of Healthcare of Tver region "Regional clinical hospital" | Tver | Russia |
State Healthcare Institution "State Clinical Hspital № 15 named after O.M. Filatov" | Moscow | Russia |
The National University Hospital, Rigshospitalet | Copenhagen | Denmark |
Universitätsklinikum Hamburg-Eppendorf | Hamburg | Germany |
Yaroslavl Regional Clinical Hospital for Military Veterans - International Centre for Gerontological Problems "Healthy Ageing" | Yaroslavl | Russia |
Trial History
Event Date | Event Type | Comment |
---|---|---|
04 Aug 2021 | Other trial event | Last checked against ClinicalTrials.gov record. Updated 04 Aug 2021 |
02 Aug 2021 | Biomarker Update | Biomarkers information updated Updated 04 Nov 2021 |
12 Mar 2021 | Endpoint met | Primary endpoint has been met. (Cause of death or invasive mechanical ventilation), according to an Apeiron Biologics Media Release. Updated 16 Mar 2021 |
12 Mar 2021 | Results | Results published in the Apeiron Biologics Media Release Updated 16 Mar 2021 |
01 Feb 2021 | Other trial event | Last checked against the European Clinical Trials Database record Updated 01 Feb 2021 |
21 Jan 2021 | Status change - completed | Status changed from recruiting to completed. Updated 27 Jan 2021 |
15 Jan 2021 | Other trial event | This trial has been completed in Denmark, according to European Clinical Trials Database record. (2020-12-26) Updated 15 Jan 2021 |
07 Jan 2021 | Other trial event | This trial has been completed in Germany, according to European Clinical Trials Database record. Updated 07 Jan 2021 |
26 Nov 2020 | Other trial event | This trial has been Discontinued in Denmark, according to European Clinical Trials Database record. Updated 30 Nov 2020 |
30 Sep 2020 | Completion date | Planned End Date changed from 1 Nov 2020 to 1 Dec 2020. Updated 18 Jan 2021 |
30 Sep 2020 | Other trial event | Planned primary completion date changed from 1 Sep 2020 to 1 Dec 2020. Updated 18 Jan 2021 |
24 Sep 2020 | Other trial event | According to an Apeiron Biologics media release, Case study from promising first COVID-19 patient treatment with APN01 published in the peer-reviewed journal The Lancet Respiratory Medicine, supports this ongoing clinical trial Updated 28 Sep 2020 |
05 Jun 2020 | Other trial event | According to an Apeiron Biologics media release, the company plans to expand the trial to USA and Russia. Updated 05 Jun 2020 |
04 May 2020 | Status change - recruiting | Status changed from not yet recruiting to recruiting. Updated 06 May 2020 |
08 Apr 2020 | Other trial event | New source identified and integrated: (ClinicalTrials.gov: US National Institutes of Health: NCT04335136). Updated 08 Apr 2020 |
07 Apr 2020 | Other trial event | New source identified and integrated: (European Clinical Trials Database: EudraCT2020-001172-15). Updated 07 Apr 2020 |
03 Apr 2020 | New trial record | New trial record Updated 03 Apr 2020 |
02 Apr 2020 | Other trial event | According to an Apeiron Biologics media release, the University Medical Center Hamburg-Eppendorf and the Klinikum rechts der Isar of the Technical University of Munich; the Medical University of Vienna, the Kaiser Franz-Josef-Spital, Vienna, the Medical University of Innsbruck and the University Medical Center Salzburg; the National University Hospital, Rigshospitalet, the Herlev Gentofte Hospital, the Hvido Hospital, and the Nordsaellands Hospital will participate in this study. Updated 03 Apr 2020 |
02 Apr 2020 | Other trial event | According to an Apeiron Biologics media release, the Austrian Government has agreed to fund a significant portion of this trial. Prof. Henning Bundgaard is the principal investigator of this study. Updated 03 Apr 2020 |
02 Apr 2020 | Other trial event | According to an Apeiron Biologics media release, the company announced that it has received regulatory approvals in Austria, Germany and Denmark to initiate a Phase II clinical trial of APN01 to treat COVID-19 and the first patients are expected to be dosed shortly. Updated 03 Apr 2020 |
Table of Contents
References
-
Apeiron Biologics. APEIRON's APN01 shows clinical benefits for severely ill COVID-19 patients in phase 2 trial. Media-Rel 2021;.
Media Release -
ClinicalTrials.gov: US National Institutes of Health. Trial-Reg 2023;.
Available from: URL: http://clinicaltrials.gov -
Apeiron Biologics. THE LANCET publishes promising data of APEIRON's APN01 (rhsACE2) to treat COVID-19 in named patient use. Media-Rel 2020;.
Media Release -
Apeiron Biologics. APEIRON Biologics Initiates Phase II Clinical Trial of APN01 for Treatment of COVID-19. Media-Rel 2020;.
Media Release -
European Clinical Trials Database. Trial-Reg 2023;.
Available from: URL: https://www.clinicaltrialsregister.eu -
Apeiron Biologics. APEIRON Biologics closes oversubscribed financing round of EUR 17.5 million for the development of APN01 against COVID-19. Media-Rel 2020;.
Media Release
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