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

• ClinicalTrials.gov Identifier: NCT04335136
• Recruitment Status: Completed
• First Posted: April 6, 2020
• Results First Posted: August 2, 2021
• Last Update Posted: August 2, 2021
• Sponsor: Apeiron Biologics
• Information provided by (Responsible Party): Apeiron Biologics

Tracking Information

• First Submitted Date: April 1, 2020
• First Posted Date: April 6, 2020
• Results First Submitted Date: June 7, 2021
• Results First Posted Date: August 2, 2021
• Last Update Posted Date: August 2, 2021
• Actual Study Start Date: April 30, 2020
• Actual Primary Completion Date: December 26, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 7, 2021)

All Cause-death or Invasive Mechanical Ventilation [ Time Frame: 28 days ]

The primary endpoint was a composite endpoint of all cause-death or invasive mechanical ventilation up to 28 days or hospital discharge.

Original Primary Outcome Measures (submitted: April 3, 2020)

Cause of death or invasive mechanical ventilation [ Time Frame: 28 days ]

The primary endpoint is a composite endpoint of all cause-death or invasive mechanical ventilation up to 28 days or hospital discharge

Current Secondary Outcome Measures (submitted: July 29, 2021)

• Lactate Dehydrogenase (LDH) Level [ Time Frame: Day 5 ]
  Log transformed levels of LDH at Day 5 as a surrogate marker for organ damage (powered secondary endpoint).
• Mortality [ Time Frame: 28 days ]
  28-day mortality (all cause-death).
• Ventilator-free Days (VFD) [ Time Frame: 28 days ]
  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 Frame: 28 days ]
  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 [ Time Frame: Day 7, Day 10, Day 14, Day 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 [ Time Frame: Up to 28 days ]
  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). [ Time Frame: Day 1, Day 3, Day 5, Day 7, Day 14, and Day 28/End of study (EOS) ]
  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 [ Time Frame: Up to 28 days. ]
  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 [ Time Frame: Up to 28 days ]
  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 Frame: Up to 28 days ]
  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 [ Time Frame: Day 1, Day 7, Day 10, Day 14, and Day 28 ]
  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) [ Time Frame: Day -1 (Screening), Day 7, Day 10, Day 14, Day 28/End of study ]
  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 [ Time Frame: Day -1, Day 3, Day 7, Day 10, Day 14, Day 28/End of study ]
  Lymphocytes were assessed in blood samples from the patients.
• C-reactive Protein Levels [ Time Frame: Day -1, Day 3, Day 7, Day 10, Day 14, Day 28/End of study ]
  C-reactive protein was assessed in blood samples from the patients.
• D-Dimer [ Time Frame: Day -1, Day 3, Day 7, Day 10, Day 14, Day 28/End of study ]
  D-Dimer was assessed in blood samples from the patients.
• Log-transformed Levels of LDH [ Time Frame: Day -1, Day 3, Day 7, Day 10, Day 14, Day 28/End of study ]
  Log transformed levels of LDH in blood were assessed as a surrogate marker for organ damage.

Original Secondary Outcome Measures (submitted: April 3, 2020)

• LDH level [ Time Frame: Day 5 ]
  Log transformed levels of Lactate dehydrogenase (LDH) at day 5 as a surrogate marker for organ damage (powered secondary endpoint
• Mortality [ Time Frame: 28 days ]
  28-day mortality (all cause-death)
• VFD [ Time Frame: 28 days ]
  Ventilator-free days (VFD) up to 28 days or hospital discharge
• Time to death [ Time Frame: 28 days ]
  Time to death (all causes)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19
• Official Title: Recombinant Human Angiotensin-converting Enzyme 2 (rhACE2) as a Treatment for Patients With COVID-19
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: COVID-19

Intervention

• Drug: RhACE2 APN01
  Patients will be treated with APN01 intravenously twice daily (BID).
  Other Names:

  • APN01
  • Recombinant human angiotensin-converting enzyme 2
• Drug: Physiological saline solution
  Patients will be treated with placebo intravenously twice daily (BID).

Study Arms

• Active Comparator: Group A (active) APN01
  Recombinant human angiotensin-converting enzyme 2 (rhACE2) - APN01
  Intervention: Drug: RhACE2 APN01
• Placebo Comparator: Group B (placebo control)
  Intervention: Drug: Physiological saline solution

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 16, 2021): 185
• Original Estimated Enrollment (submitted: April 3, 2020): 200
• Actual Study Completion Date: December 26, 2020
• Actual Primary Completion Date: December 26, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Denmark, Germany, Russian Federation, United Kingdom
• Removed Location Countries: United States

Administrative Information

• NCT Number: NCT04335136
• Other Study ID Numbers: APN01-01-COVID19
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Apeiron Biologics
• Original Responsible Party: Same as current
• Current Study Sponsor: Apeiron Biologics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Apeiron Biologics
• Verification Date: July 2021