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

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: COVID-19
• Interventions: Drug: RhACE2 APN01; Drug: Physiological saline solution
• Enrollment: 185

Participant Flow

Recruitment Details	185 Patients were screened of whom 181 patients were randomized.
Pre-assignment Details

Arm/Group Title	Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description	Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Period Title: Overall Study
Started [1]	91	90
Treated	88	90
Completed	77	83
Not Completed	14	7
Reason Not Completed
Death	8	4
Lost to Follow-up	2	0
Protocol Violation	1	0
Withdrawal by Subject	1	1
Health-threatening condition	0	1
Adverse Event	0	1
Erroneously randomized	2	0
[1] Patients randomized.

Baseline Characteristics

Arm/Group Title		Group A (Active) APN01	Group B (Placebo Control)	Total
Arm/Group Description		Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).	Total of all reporting groups
Overall Number of Baseline Participants		88	90	178
Baseline Analysis Population Description		All randomized patients who received at least 1 dose of investigational medicinal product (IMP).
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	88 participants	90 participants	178 participants
		59.6 (11.3)	58.5 (12.4)	59.0 (11.9)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	88 participants	90 participants	178 participants
	Female	33 37.5%	31 34.4%	64 36.0%
	Male	55 62.5%	59 65.6%	114 64.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	88 participants	90 participants	178 participants
	Hispanic or Latino	0 0.0%	0 0.0%	0 0.0%
	Not Hispanic or Latino	88 100.0%	90 100.0%	178 100.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	88 participants	89 participants	177 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	1 1.1%	1 1.1%	2 1.1%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 1.1%	0 0.0%	1 0.6%
	White	86 97.7%	88 98.9%	174 98.3%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
		[1] Measure Analysis Population Description: Data of 1 patient in the placebo group are missing.
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
Austria	Number Analyzed	88 participants	90 participants	178 participants
		19	20	39
Germany	Number Analyzed	88 participants	90 participants	178 participants
		2	3	5
Russia	Number Analyzed	88 participants	90 participants	178 participants
		67	67	134

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All randomized patients who had received at least 1 dose of investigational medicinal product (IMP).

Arm/Group Title	Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:	Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed	88	90
Measure Type: Count of Participants; Unit of Measure: Participants
	9 10.2%	12 13.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group A (Active) APN01, Group B (Placebo Control)
	Comments	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.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.5207
	Comments	The level of significance was 5% (2-sided).
	Method	Chi-squared
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group A (Active) APN01, Group B (Placebo Control)
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3588
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	Degree of freedom: 1
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.23 to 1.70
	Estimation Comments	[Not Specified]

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All randomized patients who had received at least 1 dose of IMP and had an LDH measurement at Day 5.

Arm/Group Title	Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:	Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed	74	74
Mean (Standard Deviation); Unit of Measure: Log U/L
	5.82 (0.470)	5.80 (0.433)

3. Secondary Outcome

Title	Mortality
Description	28-day mortality (all cause-death).
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

All randomized patients who had received at least 1 dose of IMP.

Arm/Group Title	Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:	Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed	88	90
Measure Type: Count of Participants; Unit of Measure: Participants
	9 10.2%	7 7.8%

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title		Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:		Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed		88	90
Mean (Standard Deviation); Unit of Measure: days
VFD (death not censored)	Number Analyzed	88 participants	90 participants
		17.2 (8.8)	16.7 (8.4)
VFD (death censored)	Number Analyzed	88 participants	90 participants
		17.4 (8.6)	16.7 (8.4)
VFD (subgroup: alive patients)	Number Analyzed	80 participants	84 participants
		18.9 (7.3)	17.9 (7.4)
mVFD (death not censored)	Number Analyzed	88 participants	90 participants
		25.7 (8.4)	25.1 (8.7)
mVFD (death censored)	Number Analyzed	88 participants	90 participants
		26.3 (6.6)	25.6 (7.6)
mVFD (subgroup: alive patients)	Number Analyzed	79 participants	83 participants
		28.2 (1.9)	26.9 (5.8)

5. Secondary Outcome

Title	Time to Death
Description	Time to death (all causes).
Time Frame	28 days

Outcome Measure Data

Analysis Population Description

All randomized patients who had received at least 1 dose of IMP.

Arm/Group Title	Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:	Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed	88	90
Median (Full Range); Unit of Measure: days
	NA [1]; (6 to 22)	NA [1]; (2 to 28)

[1]

Median time to death could not be estimated due to an insufficient number of patients with events.

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title		Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:		Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed		88	90
Measure Type: Count of Participants; Unit of Measure: Participants
Day 7	Number Analyzed	88 participants	88 participants
		2 2.3%	0 0.0%
Day 10	Number Analyzed	86 participants	85 participants
		17 19.8%	13 15.3%
Day 14	Number Analyzed	83 participants	85 participants
		38 45.8%	32 37.6%
Day 28	Number Analyzed	79 participants	83 participants
		72 91.1%	74 89.2%

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients who had received at least 1 dose of IMP.

Arm/Group Title	Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:	Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed	88	90
Median (95% Confidence Interval); Unit of Measure: days
	14; (12 to 15)	14; (13 to 15)

8. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

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/Group Title		Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:		Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed		88	90
Mean (Standard Deviation); Unit of Measure: copies/mL
Day 1	Number Analyzed	59 participants	49 participants
		27996 (78877)	3900 (5848)
Day 3	Number Analyzed	47 participants	58 participants
		20931 (53182)	13681 (45287)
Day 5	Number Analyzed	56 participants	64 participants
		9825 (32979)	11912 (75457)
Day 7	Number Analyzed	65 participants	61 participants
		5229 (24514)	2094 (8742)
Day 14	Number Analyzed	73 participants	73 participants
		9274 (78304)	53 (455)
Day 28/EOS	Number Analyzed	37 participants	0 participants
		36 (217)

9. Secondary Outcome

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.

Outcome Measure Data

Analysis Population Description

All randomized patients who had received at least 1 dose of IMP.

Arm/Group Title	Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:	Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed	88	90
Median (95% Confidence Interval); Unit of Measure: days
	27; (14 to 27)	27; (17 to 27)

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All randomized patients who had received at least 1 dose of IMP.

Arm/Group Title	Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:	Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed	88	90
Measure Type: Count of Participants; Unit of Measure: Participants
Mechanical ventilation	7 8.0%	7 7.8%
Mechanical ventilation and oxygen supplementation	86 97.7%	88 97.8%

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All randomized patients who had received at least 1 dose of IMP.

Arm/Group Title	Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:	Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed	88	90
Median (Full Range); Unit of Measure: days
	NA [1]; (0 to 14)	NA [1]; (0 to 20)

[1]

Median time to first invasive mechanical ventilation could not be estimated due to an insufficient number of patients with events.

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title		Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:		Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed		88	90
Mean (Standard Deviation); Unit of Measure: mmHg
Day 1	Number Analyzed	30 participants	28 participants
		223.07 (99.70)	185.14 (79.79)
Day 7	Number Analyzed	19 participants	24 participants
		218.74 (91.66)	192.21 (92.71)
Day 10	Number Analyzed	14 participants	13 participants
		290.00 (204.70)	186.62 (87.83)
Day 14	Number Analyzed	9 participants	11 participants
		197.00 (99.42)	185.00 (67.20)
Day 28	Number Analyzed	1 participants	3 participants
		261.00 [1] (NA)	185.00 (116.73)

[1]

Data of only 1 patient were available.

13. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title		Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:		Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed		88	90
Mean (Standard Error); Unit of Measure: score on a scale
Day -1	Number Analyzed	80 participants	80 participants
		2.6 (1.2)	2.2 (1.4)
Day 7	Number Analyzed	83 participants	77 participants
		1.8 (2.5)	1.6 (2.1)
Day 10	Number Analyzed	80 participants	77 participants
		1.0 (1.7)	1.0 (1.6)
Day 14	Number Analyzed	79 participants	75 participants
		1.0 (2.4)	0.9 (1.7)
Day 28/EOS	Number Analyzed	39 participants	38 participants
		0.2 (0.6)	0.8 (1.8)

14. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title		Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:		Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed		88	90
Mean (Standard Deviation); Unit of Measure: 10^9 cells/L
Day -1	Number Analyzed	82 participants	82 participants
		1.13 (0.694)	1.06 (0.629)
Day 3	Number Analyzed	85 participants	83 participants
		1.25 (0.843)	1.16 (0.662)
Day 7	Number Analyzed	82 participants	80 participants
		1.45 (0.948)	1.62 (0.940)
Day 10	Number Analyzed	81 participants	75 participants
		1.74 (1.444)	1.79 (0.782)
Day 14	Number Analyzed	77 participants	73 participants
		1.70 (0.773)	1.71 (0.730)
Day 28/EOS	Number Analyzed	37 participants	37 participants
		2.28 (3.420)	1.72 (0.559)

15. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title		Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:		Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed		88	90
Mean (Standard Deviation); Unit of Measure: mg/L
Day -1	Number Analyzed	77 participants	79 participants
		56.0 (64.53)	62.8 (51.75)
Day 3	Number Analyzed	80 participants	74 participants
		36.1 (53.75)	43.7 (45.13)
Day 7	Number Analyzed	78 participants	76 participants
		21.7 (41.58)	26.1 (38.71)
Day 10	Number Analyzed	74 participants	71 participants
		13.9 (24.24)	26.3 (48.75)
Day 14	Number Analyzed	69 participants	73 participants
		15.8 (29.66)	38.3 (133.24)
Day 28/EOS	Number Analyzed	36 participants	37 participants
		4.9 (5.69)	8.5 (11.54)

16. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All randomized patients who had received at least 1 dose of IMP and who had a D-Dimer measurement at the respective timepoint.

Arm/Group Title		Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:		Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed		88	90
Mean (Standard Deviation); Unit of Measure: µg/L
Day -1	Number Analyzed	71 participants	73 participants
		1341 (2757)	1187 (3994)
Day 3	Number Analyzed	69 participants	74 participants
		1109 (1316)	881 (959)
Day 7	Number Analyzed	73 participants	68 participants
		1208 (1485)	1139 (1590)
Day 10	Number Analyzed	70 participants	66 participants
		988 (1135)	1219 (2228)
Day 14	Number Analyzed	70 participants	66 participants
		1015 (1520)	1013 (2243)
Day 28/EOS	Number Analyzed	32 participants	31 participants
		573 (629)	685 (939)

17. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

All randomized patients who had received at least 1 dose of IMP and who had an LDH measurement at the respective timepoints.

Arm/Group Title		Group A (Active) APN01	Group B (Placebo Control)
Arm/Group Description:		Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).	Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
Overall Number of Participants Analyzed		88	90
Mean (Standard Error); Unit of Measure: Log U/L
Day -1	Number Analyzed	78 participants	77 participants
		5.91 (0.442)	5.87 (0.489)
Day 3	Number Analyzed	76 participants	76 participants
		5.86 (0.440)	5.88 (0.422)
Day 7	Number Analyzed	78 participants	74 participants
		5.77 (0.459)	5.75 (0.387)
Day 10	Number Analyzed	72 participants	74 participants
		5.66 (0.464)	5.67 (0.401)
Day 14	Number Analyzed	69 participants	71 participants
		5.55 (0.467)	5.52 (0.406)
Day 28/EOS	Number Analyzed	38 participants	38 participants
		5.43 (0.305)	5.50 (0.383)

Adverse Events

Time Frame	28 days
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Group A (Active) APN01		Group B (Placebo Control)
Arm/Group Description	Patients were treated with APN01 (Recombinant human angiotensin-converting enzyme 2 [rhACE2]) intravenously twice daily (BID).		Patients were treated with placebo (physiological saline solution) intravenously twice daily (BID).
All-Cause Mortality
	Group A (Active) APN01		Group B (Placebo Control)
	Affected / at Risk (%)		Affected / at Risk (%)
Total	9/88 (10.23%)		7/90 (7.78%)
Serious Adverse Events
	Group A (Active) APN01		Group B (Placebo Control)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/88 (11.36%)		12/90 (13.33%)
General disorders
General physical health deterioration * 1	1/88 (1.14%)	1	1/90 (1.11%)	1
Infections and infestations
Sepsis * 1	1/88 (1.14%)	1	0/90 (0.00%)	0
Injury, poisoning and procedural complications
Muscle rupture * 1	0/88 (0.00%)	0	1/90 (1.11%)	1
Nervous system disorders
Cerebral infarction * 1	0/88 (0.00%)	0	1/90 (1.11%)	1
Haemorrhagic stroke * 1	0/88 (0.00%)	0	1/90 (1.11%)	1
Syncope * 1	0/88 (0.00%)	0	1/90 (1.11%)	1
Renal and urinary disorders
Renal failure * 1	1/88 (1.14%)	1	0/90 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure * 1	1/88 (1.14%)	1	0/90 (0.00%)	0
Pulmonary embolism * 1	1/88 (1.14%)	1	0/90 (0.00%)	0
Pulmonary oedema * 1	1/88 (1.14%)	1	0/90 (0.00%)	0
Respiratory distress * 1	0/88 (0.00%)	0	1/90 (1.11%)	1
Respiratory failure * 1	6/88 (6.82%)	6	7/90 (7.78%)	7
Vascular disorders
Infarction * 1	1/88 (1.14%)	1	1/90 (1.11%)	1
Thrombosis * 1	1/88 (1.14%)	1	0/90 (0.00%)	0
1 Term from vocabulary, MedDRA (23.0); * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Group A (Active) APN01		Group B (Placebo Control)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/88 (15.91%)		24/90 (26.67%)
Investigations
Alanine aminotransferase increased * 1	10/88 (11.36%)	10	11/90 (12.22%)	11
Blood potassium increased * 1	5/88 (5.68%)	5	4/90 (4.44%)	4
Electrocardiogram QT prolonged * 1	2/88 (2.27%)	2	6/90 (6.67%)	6
Hepatic enzyme increased * 1	0/88 (0.00%)	0	5/90 (5.56%)	5
1 Term from vocabulary, MedDRA (23.0); * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Dr. Romana Gugenberger
• Organization: APEIRON Biologics AG
• Phone: +4366488506236
• EMail: romana.gugenberger@apeiron-biologics.com

• Responsible Party: Apeiron Biologics
• ClinicalTrials.gov Identifier: NCT04335136
• Other Study ID Numbers: APN01-01-COVID19
• First Submitted: April 1, 2020
• First Posted: April 6, 2020
• Results First Submitted: June 7, 2021
• Results First Posted: August 2, 2021
• Last Update Posted: August 2, 2021