COVID-19
Conditions
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.
Interventions
DRUGRhACE2 APN01
Patients will be treated with APN01 intravenously twice daily (BID).
Patients will be treated with placebo intravenously twice daily (BID).
Sponsors
Apeiron Biologics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All Cause-death or Invasive Mechanical Ventilation | 28 days | The primary endpoint was a composite endpoint of all cause-death or invasive mechanical ventilation up to 28 days or hospital discharge. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mortality | 28 days | 28-day mortality (all cause-death). |
| Ventilator-free Days (VFD) | 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 | 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 | 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 | 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). | 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 | 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. |
| Lactate Dehydrogenase (LDH) Level | Day 5 | Log transformed levels of LDH at Day 5 as a surrogate marker for organ damage (powered secondary endpoint). |
| Time to First Use of Invasive Mechanical Ventilation up to 28 Days or Hospital Discharge | 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 | 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) | 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 | 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 | 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 | 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 | 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. |
| Number of Patients With Any Use of Invasive Mechanical Ventilation up to 28 Days or Hospital Discharge | Up to 28 days | The number of patients receiving mechanical ventilation and supplemental oxygen was evaluated. |
Countries
Austria, Denmark, Germany, Russia, United Kingdom
Participant flow
Recruitment details
185 Patients were screened of whom 181 patients were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Group A (Active) APN01 Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 \[rhACE2\]) intravenously twice daily (BID). | 88 |
| Group B (Placebo Control) Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID). | 90 |
| Total | 178 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Death | 8 | 4 |
| Overall Study | Erroneously randomized | 2 | 0 |
| Overall Study | Health-threatening condition | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Group B (Placebo Control) | Total | Group A (Active) APN01 |
|---|---|---|---|
| Age, Continuous | 58.5 years STANDARD_DEVIATION 12.4 | 59.0 years STANDARD_DEVIATION 11.9 | 59.6 years STANDARD_DEVIATION 11.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 90 Participants | 178 Participants | 88 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 88 Participants | 174 Participants | 86 Participants |
| Region of Enrollment Austria | 20 participants | 39 participants | 19 participants |
| Region of Enrollment Germany | 3 participants | 5 participants | 2 participants |
| Region of Enrollment Russia | 67 participants | 134 participants | 67 participants |
| Sex: Female, Male Female | 31 Participants | 64 Participants | 33 Participants |
| Sex: Female, Male Male | 59 Participants | 114 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 88 | 7 / 90 |
| other Total, other adverse events | 14 / 88 | 24 / 90 |
| serious Total, serious adverse events | 10 / 88 | 12 / 90 |
Outcome results
Primary
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.
Time frame: 28 days
Population: All randomized patients who had received at least 1 dose of investigational medicinal product (IMP).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (Active) APN01 | All Cause-death or Invasive Mechanical Ventilation | 9 Participants |
| Group B (Placebo Control) | All Cause-death or Invasive Mechanical Ventilation | 12 Participants |
Comparison: Hypothesis tested: H0: pAPN01 = pPlacebo; H1: pAPN01 ≠ pPlacebo (with p=proportion of patients with event).~A total of 186 patients (93 per group) was estimated to yield 80% power to detect a 20% absolute risk reduction in the primary, from 50% in the placebo group to 30% in the APN01 group, at a 2-sided alpha of 0.05. To consider patients who would be randomized but not treated, a total of 200 patients (100 per group) were planned to be enrolled.p-value: 0.5207Chi-squared
p-value: 0.358895% CI: [0.23, 1.7]Regression, Logistic
Secondary
C-reactive Protein Levels
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
Population: All randomized patients who had received at least 1 dose of IMP and who had a C-reactive protein measurement at the respective timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A (Active) APN01 | C-reactive Protein Levels | Day -1 | 56.0 mg/L | Standard Deviation 64.53 |
| Group A (Active) APN01 | C-reactive Protein Levels | Day 3 | 36.1 mg/L | Standard Deviation 53.75 |
| Group A (Active) APN01 | C-reactive Protein Levels | Day 7 | 21.7 mg/L | Standard Deviation 41.58 |
| Group A (Active) APN01 | C-reactive Protein Levels | Day 10 | 13.9 mg/L | Standard Deviation 24.24 |
| Group A (Active) APN01 | C-reactive Protein Levels | Day 14 | 15.8 mg/L | Standard Deviation 29.66 |
| Group A (Active) APN01 | C-reactive Protein Levels | Day 28/EOS | 4.9 mg/L | Standard Deviation 5.69 |
| Group B (Placebo Control) | C-reactive Protein Levels | Day 14 | 38.3 mg/L | Standard Deviation 133.24 |
| Group B (Placebo Control) | C-reactive Protein Levels | Day -1 | 62.8 mg/L | Standard Deviation 51.75 |
| Group B (Placebo Control) | C-reactive Protein Levels | Day 10 | 26.3 mg/L | Standard Deviation 48.75 |
| Group B (Placebo Control) | C-reactive Protein Levels | Day 3 | 43.7 mg/L | Standard Deviation 45.13 |
| Group B (Placebo Control) | C-reactive Protein Levels | Day 28/EOS | 8.5 mg/L | Standard Deviation 11.54 |
| Group B (Placebo Control) | C-reactive Protein Levels | Day 7 | 26.1 mg/L | Standard Deviation 38.71 |
Secondary
D-Dimer
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
Population: All randomized patients who had received at least 1 dose of IMP and who had a D-Dimer measurement at the respective timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A (Active) APN01 | D-Dimer | Day -1 | 1341 µg/L | Standard Deviation 2757 |
| Group A (Active) APN01 | D-Dimer | Day 7 | 1208 µg/L | Standard Deviation 1485 |
| Group A (Active) APN01 | D-Dimer | Day 28/EOS | 573 µg/L | Standard Deviation 629 |
| Group A (Active) APN01 | D-Dimer | Day 10 | 988 µg/L | Standard Deviation 1135 |
| Group A (Active) APN01 | D-Dimer | Day 3 | 1109 µg/L | Standard Deviation 1316 |
| Group A (Active) APN01 | D-Dimer | Day 14 | 1015 µg/L | Standard Deviation 1520 |
| Group B (Placebo Control) | D-Dimer | Day 3 | 881 µg/L | Standard Deviation 959 |
| Group B (Placebo Control) | D-Dimer | Day 28/EOS | 685 µg/L | Standard Deviation 939 |
| Group B (Placebo Control) | D-Dimer | Day -1 | 1187 µg/L | Standard Deviation 3994 |
| Group B (Placebo Control) | D-Dimer | Day 14 | 1013 µg/L | Standard Deviation 2243 |
| Group B (Placebo Control) | D-Dimer | Day 7 | 1139 µg/L | Standard Deviation 1590 |
| Group B (Placebo Control) | D-Dimer | Day 10 | 1219 µg/L | Standard Deviation 2228 |
Secondary
Lactate Dehydrogenase (LDH) Level
Log transformed levels of LDH at Day 5 as a surrogate marker for organ damage (powered secondary endpoint).
Time frame: Day 5
Population: All randomized patients who had received at least 1 dose of IMP and had an LDH measurement at Day 5.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A (Active) APN01 | Lactate Dehydrogenase (LDH) Level | 5.82 Log U/L | Standard Deviation 0.47 |
| Group B (Placebo Control) | Lactate Dehydrogenase (LDH) Level | 5.80 Log U/L | Standard Deviation 0.433 |
Secondary
Log-transformed Levels of LDH
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
Population: All randomized patients who had received at least 1 dose of IMP and who had an LDH measurement at the respective timepoints.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A (Active) APN01 | Log-transformed Levels of LDH | Day -1 | 5.91 Log U/L | Standard Error 0.442 |
| Group A (Active) APN01 | Log-transformed Levels of LDH | Day 3 | 5.86 Log U/L | Standard Error 0.44 |
| Group A (Active) APN01 | Log-transformed Levels of LDH | Day 7 | 5.77 Log U/L | Standard Error 0.459 |
| Group A (Active) APN01 | Log-transformed Levels of LDH | Day 10 | 5.66 Log U/L | Standard Error 0.464 |
| Group A (Active) APN01 | Log-transformed Levels of LDH | Day 14 | 5.55 Log U/L | Standard Error 0.467 |
| Group A (Active) APN01 | Log-transformed Levels of LDH | Day 28/EOS | 5.43 Log U/L | Standard Error 0.305 |
| Group B (Placebo Control) | Log-transformed Levels of LDH | Day 14 | 5.52 Log U/L | Standard Error 0.406 |
| Group B (Placebo Control) | Log-transformed Levels of LDH | Day -1 | 5.87 Log U/L | Standard Error 0.489 |
| Group B (Placebo Control) | Log-transformed Levels of LDH | Day 10 | 5.67 Log U/L | Standard Error 0.401 |
| Group B (Placebo Control) | Log-transformed Levels of LDH | Day 3 | 5.88 Log U/L | Standard Error 0.422 |
| Group B (Placebo Control) | Log-transformed Levels of LDH | Day 28/EOS | 5.50 Log U/L | Standard Error 0.383 |
| Group B (Placebo Control) | Log-transformed Levels of LDH | Day 7 | 5.75 Log U/L | Standard Error 0.387 |
Secondary
Lymphocyte Count
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
Population: All randomized patients who had received at least 1 dose of IMP and who had a measurement of lymphocyte count at the respective timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A (Active) APN01 | Lymphocyte Count | Day -1 | 1.13 10^9 cells/L | Standard Deviation 0.694 |
| Group A (Active) APN01 | Lymphocyte Count | Day 3 | 1.25 10^9 cells/L | Standard Deviation 0.843 |
| Group A (Active) APN01 | Lymphocyte Count | Day 7 | 1.45 10^9 cells/L | Standard Deviation 0.948 |
| Group A (Active) APN01 | Lymphocyte Count | Day 10 | 1.74 10^9 cells/L | Standard Deviation 1.444 |
| Group A (Active) APN01 | Lymphocyte Count | Day 14 | 1.70 10^9 cells/L | Standard Deviation 0.773 |
| Group A (Active) APN01 | Lymphocyte Count | Day 28/EOS | 2.28 10^9 cells/L | Standard Deviation 3.42 |
| Group B (Placebo Control) | Lymphocyte Count | Day 14 | 1.71 10^9 cells/L | Standard Deviation 0.73 |
| Group B (Placebo Control) | Lymphocyte Count | Day -1 | 1.06 10^9 cells/L | Standard Deviation 0.629 |
| Group B (Placebo Control) | Lymphocyte Count | Day 10 | 1.79 10^9 cells/L | Standard Deviation 0.782 |
| Group B (Placebo Control) | Lymphocyte Count | Day 3 | 1.16 10^9 cells/L | Standard Deviation 0.662 |
| Group B (Placebo Control) | Lymphocyte Count | Day 28/EOS | 1.72 10^9 cells/L | Standard Deviation 0.559 |
| Group B (Placebo Control) | Lymphocyte Count | Day 7 | 1.62 10^9 cells/L | Standard Deviation 0.94 |
Secondary
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.
Time frame: Day -1 (Screening), Day 7, Day 10, Day 14, Day 28/End of study
Population: All randomized patients who had received at least 1 dose of IMP and who had a measurement of the mSOFA score at the respective timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A (Active) APN01 | Modified Sequential Organ Failure Assessment Score (mSOFA Score, Total Score) | Day 7 | 1.8 score on a scale | Standard Error 2.5 |
| Group A (Active) APN01 | Modified Sequential Organ Failure Assessment Score (mSOFA Score, Total Score) | Day 14 | 1.0 score on a scale | Standard Error 2.4 |
| Group A (Active) APN01 | Modified Sequential Organ Failure Assessment Score (mSOFA Score, Total Score) | Day 10 | 1.0 score on a scale | Standard Error 1.7 |
| Group A (Active) APN01 | Modified Sequential Organ Failure Assessment Score (mSOFA Score, Total Score) | Day 28/EOS | 0.2 score on a scale | Standard Error 0.6 |
| Group A (Active) APN01 | Modified Sequential Organ Failure Assessment Score (mSOFA Score, Total Score) | Day -1 | 2.6 score on a scale | Standard Error 1.2 |
| Group B (Placebo Control) | Modified Sequential Organ Failure Assessment Score (mSOFA Score, Total Score) | Day 28/EOS | 0.8 score on a scale | Standard Error 1.8 |
| Group B (Placebo Control) | Modified Sequential Organ Failure Assessment Score (mSOFA Score, Total Score) | Day -1 | 2.2 score on a scale | Standard Error 1.4 |
| Group B (Placebo Control) | Modified Sequential Organ Failure Assessment Score (mSOFA Score, Total Score) | Day 7 | 1.6 score on a scale | Standard Error 2.1 |
| Group B (Placebo Control) | Modified Sequential Organ Failure Assessment Score (mSOFA Score, Total Score) | Day 10 | 1.0 score on a scale | Standard Error 1.6 |
| Group B (Placebo Control) | Modified Sequential Organ Failure Assessment Score (mSOFA Score, Total Score) | Day 14 | 0.9 score on a scale | Standard Error 1.7 |
Secondary
Mortality
28-day mortality (all cause-death).
Time frame: 28 days
Population: All randomized patients who had received at least 1 dose of IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (Active) APN01 | Mortality | 9 Participants |
| Group B (Placebo Control) | Mortality | 7 Participants |
Secondary
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 frame: Up to 28 days
Population: All randomized patients who had received at least 1 dose of IMP.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Active) APN01 | Number of Patients With Any Use of Invasive Mechanical Ventilation up to 28 Days or Hospital Discharge | Mechanical ventilation | 7 Participants |
| Group A (Active) APN01 | Number of Patients With Any Use of Invasive Mechanical Ventilation up to 28 Days or Hospital Discharge | Mechanical ventilation and oxygen supplementation | 86 Participants |
| Group B (Placebo Control) | Number of Patients With Any Use of Invasive Mechanical Ventilation up to 28 Days or Hospital Discharge | Mechanical ventilation | 7 Participants |
| Group B (Placebo Control) | Number of Patients With Any Use of Invasive Mechanical Ventilation up to 28 Days or Hospital Discharge | Mechanical ventilation and oxygen supplementation | 88 Participants |
Secondary
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 frame: Day 7, Day 10, Day 14, Day 28
Population: All randomized patients who had received at least 1 dose of IMP and who had a measurement of the WHO 11-Point Score System at the respective timepoint.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Active) APN01 | Number of Responders, Defined as ≥2 Improvement in World Health Organization (WHO)'s 11-Point Score System at Days 7, 10, 14 and 28 | Day 7 | 2 Participants |
| Group A (Active) APN01 | Number of Responders, Defined as ≥2 Improvement in World Health Organization (WHO)'s 11-Point Score System at Days 7, 10, 14 and 28 | Day 10 | 17 Participants |
| Group A (Active) APN01 | Number of Responders, Defined as ≥2 Improvement in World Health Organization (WHO)'s 11-Point Score System at Days 7, 10, 14 and 28 | Day 14 | 38 Participants |
| Group A (Active) APN01 | Number of Responders, Defined as ≥2 Improvement in World Health Organization (WHO)'s 11-Point Score System at Days 7, 10, 14 and 28 | Day 28 | 72 Participants |
| Group B (Placebo Control) | Number of Responders, Defined as ≥2 Improvement in World Health Organization (WHO)'s 11-Point Score System at Days 7, 10, 14 and 28 | Day 28 | 74 Participants |
| Group B (Placebo Control) | Number of Responders, Defined as ≥2 Improvement in World Health Organization (WHO)'s 11-Point Score System at Days 7, 10, 14 and 28 | Day 7 | 0 Participants |
| Group B (Placebo Control) | Number of Responders, Defined as ≥2 Improvement in World Health Organization (WHO)'s 11-Point Score System at Days 7, 10, 14 and 28 | Day 14 | 32 Participants |
| Group B (Placebo Control) | Number of Responders, Defined as ≥2 Improvement in World Health Organization (WHO)'s 11-Point Score System at Days 7, 10, 14 and 28 | Day 10 | 13 Participants |
Secondary
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.
Time frame: Day 1, Day 7, Day 10, Day 14, and Day 28
Population: All randomized patients who had received at least 1 dose of IMP and who had a measurement of PaO2/FiO2 at the respective timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A (Active) APN01 | PaO2/FiO2 Value | Day 7 | 218.74 mmHg | Standard Deviation 91.66 |
| Group A (Active) APN01 | PaO2/FiO2 Value | Day 14 | 197.00 mmHg | Standard Deviation 99.42 |
| Group A (Active) APN01 | PaO2/FiO2 Value | Day 1 | 223.07 mmHg | Standard Deviation 99.7 |
| Group A (Active) APN01 | PaO2/FiO2 Value | Day 28 | 261.00 mmHg | — |
| Group A (Active) APN01 | PaO2/FiO2 Value | Day 10 | 290.00 mmHg | Standard Deviation 204.7 |
| Group B (Placebo Control) | PaO2/FiO2 Value | Day 28 | 185.00 mmHg | Standard Deviation 116.73 |
| Group B (Placebo Control) | PaO2/FiO2 Value | Day 7 | 192.21 mmHg | Standard Deviation 92.71 |
| Group B (Placebo Control) | PaO2/FiO2 Value | Day 10 | 186.62 mmHg | Standard Deviation 87.83 |
| Group B (Placebo Control) | PaO2/FiO2 Value | Day 14 | 185.00 mmHg | Standard Deviation 67.2 |
| Group B (Placebo Control) | PaO2/FiO2 Value | Day 1 | 185.14 mmHg | Standard Deviation 79.79 |
Secondary
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.
Time frame: Up to 28 days.
Population: All randomized patients who had received at least 1 dose of IMP.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Active) APN01 | Time to a 2-point Decrease in WHO's 11-Point Score System | 27 days |
| Group B (Placebo Control) | Time to a 2-point Decrease in WHO's 11-Point Score System | 27 days |
Secondary
Time to Death
Time to death (all causes).
Time frame: 28 days
Population: All randomized patients who had received at least 1 dose of IMP.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Active) APN01 | Time to Death | NA days |
| Group B (Placebo Control) | Time to Death | NA days |
Secondary
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.
Time frame: Up to 28 days
Population: All randomized patients who had received at least 1 dose of IMP.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Active) APN01 | Time to First Use of Invasive Mechanical Ventilation up to 28 Days or Hospital Discharge | NA days |
| Group B (Placebo Control) | Time to First Use of Invasive Mechanical Ventilation up to 28 Days or Hospital Discharge | NA days |
Secondary
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.
Time frame: Up to 28 days
Population: All patients who had received at least 1 dose of IMP.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Active) APN01 | Time to Hospital Discharge | 14 days |
| Group B (Placebo Control) | Time to Hospital Discharge | 14 days |
Secondary
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 frame: 28 days
Population: All randomized patients who had received at least 1 dose of IMP. In addition, a subgroup analysis was performed including only patients who were still alive at Day 28 (or discharged from the hospital/early terminated).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A (Active) APN01 | Ventilator-free Days (VFD) | VFD (death not censored) | 17.2 days | Standard Deviation 8.8 |
| Group A (Active) APN01 | Ventilator-free Days (VFD) | VFD (death censored) | 17.4 days | Standard Deviation 8.6 |
| Group A (Active) APN01 | Ventilator-free Days (VFD) | VFD (subgroup: alive patients) | 18.9 days | Standard Deviation 7.3 |
| Group A (Active) APN01 | Ventilator-free Days (VFD) | mVFD (death not censored) | 25.7 days | Standard Deviation 8.4 |
| Group A (Active) APN01 | Ventilator-free Days (VFD) | mVFD (death censored) | 26.3 days | Standard Deviation 6.6 |
| Group A (Active) APN01 | Ventilator-free Days (VFD) | mVFD (subgroup: alive patients) | 28.2 days | Standard Deviation 1.9 |
| Group B (Placebo Control) | Ventilator-free Days (VFD) | mVFD (death censored) | 25.6 days | Standard Deviation 7.6 |
| Group B (Placebo Control) | Ventilator-free Days (VFD) | VFD (death not censored) | 16.7 days | Standard Deviation 8.4 |
| Group B (Placebo Control) | Ventilator-free Days (VFD) | mVFD (death not censored) | 25.1 days | Standard Deviation 8.7 |
| Group B (Placebo Control) | Ventilator-free Days (VFD) | VFD (death censored) | 16.7 days | Standard Deviation 8.4 |
| Group B (Placebo Control) | Ventilator-free Days (VFD) | mVFD (subgroup: alive patients) | 26.9 days | Standard Deviation 5.8 |
| Group B (Placebo Control) | Ventilator-free Days (VFD) | VFD (subgroup: alive patients) | 17.9 days | Standard Deviation 7.4 |
Secondary
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 frame: Day 1, Day 3, Day 5, Day 7, Day 14, and Day 28/End of study (EOS)
Population: All randomized patients who had received at least 1 dose of IMP and who had a measurement of viral RNA at the respective timepoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A (Active) APN01 | Viral Ribonucleic Acid (RNA). | Day 28/EOS | 36 copies/mL | Standard Deviation 217 |
| Group A (Active) APN01 | Viral Ribonucleic Acid (RNA). | Day 1 | 27996 copies/mL | Standard Deviation 78877 |
| Group A (Active) APN01 | Viral Ribonucleic Acid (RNA). | Day 3 | 20931 copies/mL | Standard Deviation 53182 |
| Group A (Active) APN01 | Viral Ribonucleic Acid (RNA). | Day 5 | 9825 copies/mL | Standard Deviation 32979 |
| Group A (Active) APN01 | Viral Ribonucleic Acid (RNA). | Day 7 | 5229 copies/mL | Standard Deviation 24514 |
| Group A (Active) APN01 | Viral Ribonucleic Acid (RNA). | Day 14 | 9274 copies/mL | Standard Deviation 78304 |
| Group B (Placebo Control) | Viral Ribonucleic Acid (RNA). | Day 5 | 11912 copies/mL | Standard Deviation 75457 |
| Group B (Placebo Control) | Viral Ribonucleic Acid (RNA). | Day 1 | 3900 copies/mL | Standard Deviation 5848 |
| Group B (Placebo Control) | Viral Ribonucleic Acid (RNA). | Day 14 | 53 copies/mL | Standard Deviation 455 |
| Group B (Placebo Control) | Viral Ribonucleic Acid (RNA). | Day 3 | 13681 copies/mL | Standard Deviation 45287 |
| Group B (Placebo Control) | Viral Ribonucleic Acid (RNA). | Day 7 | 2094 copies/mL | Standard Deviation 8742 |