Clinical trial NCT04333420
Conditions: Severe COVID-19 Pneumonia
Keywords: COVID-19 related severe pneumonia
Sponsor: InflaRx GmbH
Start date: 2020-03-31; Completion date: 2021-12-01
Enrollment: 399 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase II \& Phase III:

This is a pragmatic, adaptive, randomized, multicenter phase II/III study evaluating IFX-1 for the treatment of COVID-19 related severe pneumonia. The study consists of two parts: Phase II, an open-label, randomized, 2-arm phase evaluating best supportive care (BSC) + IFX-1 (Arm A) and BSC alone (Arm B); and Phase III, a double-blind, placebo-controlled, randomized phase comparing standard of care (SOC) + IFX-1 (Arm A) versus SOC + placebo-to-match (Arm B)

Detailed description:
The phase II and Phase III portions enrolled patients subsequently.

1st patient was enrolled in the phase III portion on 1st October 2020.

Arms: arm 1: Phase II study part: IFX-1: 800mg intravenously administered, BSC: Best supportive care arm 2: Phase II study part: BSC: Best supportive care arm 3: Phase III study part: IFX-1: 800mg intravenously administered, SOC: Standard of care arm 4: Phase III study part: Placebo: placebo infusion intravenously administered, SOC: Standard of care
Interventions: intervention 1: IFX-1 + BSC intervention 2: BSC intervention 3: IFX-1 + SOC intervention 4: Placebo + SOC
Intervention descriptions: intervention 1: Phase II study part: IFX-1 + BSC intervention 2: Phase II study part: BSC intervention 3: Phase III study part: IFX-1 + SOC intervention 4: Phase III study part: Placebo + SOC

Protocol documents:
Prot_SAP_000.pdf: 
 
                                       CONFIDENTIAL  
The information contained in this document is confidential and the proprietary property of 
InflaRx. Any unauthorized use or disclosure of such information without the prior written 
authorization of InflaRx is expressly prohibited. 
 
CLINICAL STUDY PROTOCOL 
 
A PRAGMATIC ADAPTIVE RANDOMIZED CONTROLLED PHASE II/III 
MULTICENTER STUDY OF IFX-1 IN PATIENTS WITH SEVERE COVID-19 
PNEUMONIA --- “PANAMO” 
 
Protocol Number: IFX-1-P2.9 
Compound: IFX-1 
Phase: II -III 
Indication: Severe pneumonia in context of COVID-19  
EudraCT Number: 2020-001335-28 
Sponsor Name and Address: InflaRx GmbH 
Winzerlaer Strasse 2 
07745 Jena, Germany 
Version and Date: Version 2.0, 30 July 2020 
 


InflaRx 
Clinical Study Protocol, Version 2.0 
IFX-1 
 
                         CONFIDENTIAL  
IFX-1-P2.9 
 
PROTOCOL SIGNATURES 
Confirmation of the Final Protocol 
We hereby certify that this is the final version of the protocol: 
Protocol Number: 
IFX-1-P2.9 
Title: 
A pragmatic adaptive randomized controlled phase II/III multicenter 
study of IFX-1 in patients with severe COVID-19 pneumonia ---
“PANAMO” 
 
Sponsor Signatory: 
 
 
 
 
Date 
 
Medical monitor name and contact information will be provided separately. 
 
Statistician: 
 
 
 
 
 
 
 
 
 
Date 
 


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Signature of Coordinating Investigator 
 
Protocol Number: 
IFX-1-P2.9 
Title: 
A pragmatic adaptive randomized controlled phase II/III multicenter 
study of IFX-1 in patients with severe COVID-19 pneumonia ---
“PANAMO” 
 
Herewith I declare that I have read and understood the present protocol and agree to honor each 
part of it. By signing this study protocol, I agree to conduct the clinical study, following approval 
by an Ethics Committee, in accordance with the study protocol, the current International Council 
for Harmonization Guidelines for Good Clinical Practice (GCP), and applicable regulatory 
requirements. I will ensure that all the subjects enrolled in the study by my site will be treated, 
observed, and documented in accordance with this protocol. I will ensure that all persons 
assisting with the study under my supervision are adequately informed about the protocol, the 
investigational product, and their duties.   
 
 
 
Alexander Vlaar, MD, PhD 
Coordinating Investigator 
 
Intensive Care Volwassenen 
AmsterdamUMC  
Locatie AMC  
C3-430 
Meibergdreef 9,  
1105 AZ, Amsterdam 
 
 
Date 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................4 
ABBREVIATIONS AND DEFINITIONS OF TERMS .............................................................9 
1. 
SYNOPSIS ............................................................................................................................11 
2. 
SCHEDULE OF ASSESSMENTS .....................................................................................19 
3. 
INTRODUCTION AND BACKGROUND INFORMATION ........................................24 
3.1. 
Background ........................................................................................................................24 
3.2. 
Study Rationale ..................................................................................................................24 
3.2.1. 
Drug Profile ....................................................................................................................24 
3.2.2. 
Non-clinical and Therapeutic Studies .............................................................................25 
3.2.3. 
Experience in Humans ....................................................................................................26 
3.2.4. 
Scientific Rationale for the Study ...................................................................................27 
3.2.5. 
Justification for Dose ......................................................................................................29 
3.3. 
Benefit/Risk Assessment ...................................................................................................29 
4. 
OBJECTIVES AND ENDPOINTS ....................................................................................30 
4.1. 
Study Objectives ................................................................................................................30 
4.1.1. 
Primary Objectives .........................................................................................................30 
4.1.2. 
Secondary Objectives .....................................................................................................30 
4.2. 
Study Endpoints .................................................................................................................31 
4.2.1. 
Phase II ...........................................................................................................................31 
4.2.1.1. 
Primary Endpoint .........................................................................................................31 
4.2.1.2. 
Secondary Endpoints ...................................................................................................31 
4.2.1.3. 
Other Endpoints ...........................................................................................................31 
4.2.2. 
Phase III ..........................................................................................................................32 
4.2.2.1. 
Primary Endpoint .........................................................................................................32 
4.2.2.2. 
Secondary Endpoints ...................................................................................................32 
4.2.2.3. 
Other Endpoints ...........................................................................................................32 
5. 
STUDY DESIGN .................................................................................................................33 
5.1. 
Overall Design ...................................................................................................................33 
5.1.1. 
Method of Treatment Assignment ..................................................................................34 
5.1.2. 
Blinding ..........................................................................................................................34 
5.2. 
Patient Enrollment .............................................................................................................34 
5.3. 
Independent Safety Monitoring Board for Phase II ...........................................................34 
5.4. 
Expert Committee for Phase II ..........................................................................................35 
5.5. 
Independent Data Safety Monitoring Board for Phase III .................................................35 
5.6. 
Patient and Study Completion ...........................................................................................35 
5.6.1. 
Phase II ...........................................................................................................................35 
5.6.1.1. 
End of Treatment and Follow-up .................................................................................35 
5.6.1.2. 
End of Study ................................................................................................................36 
5.6.1.3. 
Consent Withdrawal/ Discontinuation of Study Participation .....................................36 
5.6.1.4. 
Lost to Follow-up .........................................................................................................36 


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5.6.2. 
Phase III ..........................................................................................................................37 
5.6.2.1. 
End of Treatment and Follow-up .................................................................................37 
5.6.2.2. 
End of Study ................................................................................................................37 
5.6.2.3. 
Consent Withdrawal/Discontinuation of Study Participation ......................................37 
5.6.2.4. 
Lost to Follow-up .........................................................................................................38 
6. 
STUDY POPULATION ......................................................................................................38 
6.1. 
Phase II...............................................................................................................................38 
6.1.1. 
Inclusion Criteria ............................................................................................................38 
6.1.2. 
Exclusion Criteria ...........................................................................................................39 
6.2. 
Phase III .............................................................................................................................40 
6.2.1. 
Inclusion Criteria ............................................................................................................40 
6.2.2. 
Exclusion Criteria ...........................................................................................................40 
6.3. 
Deferred Consent ...............................................................................................................41 
6.4. 
Screening Failures ..............................................................................................................42 
6.5. 
Meals and Dietary Restrictions ..........................................................................................42 
7. 
STUDY DRUG(S) AND ADMINISTRATION .................................................................43 
7.1. 
Investigational Medicinal Product .....................................................................................43 
7.1.1. 
Packaging and Labelling of Investigational Medicinal Product .....................................43 
7.1.2. 
Storage, Handling, and Accountability ...........................................................................43 
7.1.3. 
Drug Preparation and Administration Instructions .........................................................44 
7.1.4. 
Recall of IMP ..................................................................................................................44 
7.2. 
Administration and Dosage ................................................................................................44 
7.2.1. 
Treatment Administered .................................................................................................45 
7.2.1.1. 
Phase II.........................................................................................................................45 
7.2.1.1. 
Phase III .......................................................................................................................45 
7.2.2. 
Treatment Modification ..................................................................................................48 
7.2.2.1. 
Infusion Reactions .......................................................................................................48 
7.2.3. 
Re-dosing Criteria ...........................................................................................................48 
7.2.4. 
Treatment Discontinuation Criteria ................................................................................48 
7.3. 
Premedication and Postmedication ....................................................................................49 
7.4. 
Prior and Concomitant Medication/Treatments .................................................................49 
7.4.1. 
Prohibited Concomitant Medication/Treatment .............................................................49 
7.5. 
Rescue Medications and Supportive Care .........................................................................50 
7.6. 
Treatment of Overdose ......................................................................................................50 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..............................................................51 
8.1. 
Phase II...............................................................................................................................51 
8.1.1. 
Baseline Assessments .....................................................................................................51 
8.1.1.1. 
Medical History (Except COVID-19 history)..............................................................51 
8.1.1.2. 
COVID-19 History.......................................................................................................51 
8.1.1.3. 
Concomitant Disease ...................................................................................................52 
8.1.1.4. 
Prior and Concomitant Medications ............................................................................52 
8.1.2. 
Efficacy Assessments .....................................................................................................52 
8.1.2.1. 
Imaging Requirements .................................................................................................52 
8.1.2.2. 
Evaluation of Lung Function .......................................................................................52 


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8.1.2.3. 
Evaluation of Response................................................................................................53 
8.1.3. 
Safety Assessments .........................................................................................................53 
8.1.3.1. 
Adverse Events Assessments .......................................................................................53 
8.1.3.2. 
Clinical Safety Laboratory Assessments .....................................................................54 
8.1.3.3. 
Vital Signs ....................................................................................................................54 
8.1.3.4. 
Electrocardiograms ......................................................................................................55 
8.1.3.5. 
Physical Examination...................................................................................................55 
8.1.3.6. 
Survival Status .............................................................................................................55 
8.1.4. 
Pharmacokinetics/Pharmacodynamics............................................................................55 
8.1.5. 
Biobanking of Samples from Patients Treated at Amsterdam Medical Center ..............55 
8.2. 
Phase III .............................................................................................................................56 
8.2.1. 
Baseline Assessments .....................................................................................................56 
8.2.1.1. 
Medical History (Except COVID-19 history)..............................................................56 
8.2.1.2. 
COVID-19 History.......................................................................................................57 
8.2.1.3. 
Concomitant Disease ...................................................................................................57 
8.2.1.4. 
Prior and Concomitant Medications and Procedures ...................................................57 
8.2.2. 
Endpoint Assessments ....................................................................................................57 
8.2.2.1. 
Evaluation of Organ Support .......................................................................................57 
8.2.2.2. 
Ordinal Scale Evaluation .............................................................................................57 
8.2.2.3. 
Survival Status .............................................................................................................58 
8.2.2.1. 
Quality of Life Assessment ..........................................................................................58 
8.2.2.2. 
Clinical Status ..............................................................................................................58 
8.2.3. 
Safety Assessments .........................................................................................................58 
8.2.3.1. 
Adverse Events Assessments .......................................................................................58 
8.2.3.2. 
Clinical Safety Laboratory Assessments .....................................................................58 
8.2.3.3. 
Vital Signs ....................................................................................................................59 
8.2.3.4. 
Electrocardiograms ......................................................................................................59 
8.2.3.5. 
Physical Examination...................................................................................................59 
8.2.4. 
Pharmacokinetics/Pharmacodynamics............................................................................60 
9. 
ADVERSE EVENT COLLECTION AND REPORTING ..............................................60 
9.1. 
Time Period and Frequency of Collection and Reporting .................................................61 
9.1.1. 
During Treatment ............................................................................................................61 
9.1.1.1. 
During Follow-up.........................................................................................................62 
9.1.2. 
After End of Study ..........................................................................................................62 
9.2. 
Serious Adverse Event Reporting and Timelines ..............................................................62 
9.2.1. 
Initial Reporting of Serious Adverse Events ..................................................................62 
9.2.1.1. 
Follow-up Reporting of Serious Adverse Events ........................................................63 
9.2.2. 
Determination of Relatedness .........................................................................................63 
9.3. 
Death Reporting .................................................................................................................65 
9.4. 
Abnormal Laboratory Values/Vital Signs/ECG/Physical Examination ............................65 
9.5. 
Events to be Handled as SAEs ...........................................................................................66 
9.5.1. 
Overdose Reporting ........................................................................................................66 
9.5.2. 
Pregnancy Reporting.......................................................................................................66 
9.5.3. 
Drug-induced Liver Injury ..............................................................................................66 
9.5.4. 
Suspected Transmission of an Infectious Agent (pathogenic or non-pathogenic) 
via Study Drug ................................................................................................................67 


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9.6. 
Adverse Events of Special Interest ....................................................................................67 
9.7. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs ..................................................................................................................68 
9.8. 
Reporting to Competent Authorities and Ethics Committees ............................................68 
10. STATISTICAL CONSIDERATIONS ...............................................................................69 
10.1. Phase II...............................................................................................................................69 
10.1.1. 
Sample Size Determination ............................................................................................69 
10.1.2. 
Analysis Sets ...................................................................................................................69 
10.1.3. 
Statistical Analyses .........................................................................................................69 
10.1.3.1. Efficacy Analyses ........................................................................................................69 
10.1.3.2. Safety Analyses ............................................................................................................71 
10.1.3.3. Interim Analysis ...........................................................................................................71 
10.2. Phase III .............................................................................................................................71 
10.2.1. 
Sample Size Determination ............................................................................................71 
10.2.2. 
Analysis Sets ...................................................................................................................71 
10.2.3. 
Statistical Analyses .........................................................................................................71 
10.2.3.1. Primary Efficacy Analysis ...........................................................................................72 
10.2.3.2. Secondary Efficacy Analyses ......................................................................................73 
10.2.3.3. Other Efficacy Analyses ..............................................................................................74 
10.2.3.4. Safety Analyses ............................................................................................................74 
10.2.3.5. Interim Analysis ...........................................................................................................74 
11. REFERENCES ....................................................................................................................76 
12. APPENDICES ......................................................................................................................79 
Appendix 1 
Clinical Laboratory Tests .......................................................................................80 
Appendix 2 
Regulatory and Ethical Considerations ..................................................................82 
I. 
Regulatory and Ethical Considerations ..............................................................................82 
II. 
Financial Disclosure...........................................................................................................82 
III. 
Informed Consent Process .................................................................................................83 
IV. 
Data Protection...................................................................................................................83 
V. 
Publication Policy ..............................................................................................................83 
VI. 
Dissemination of Clinical Study Information ....................................................................84 
VII. 
Data Quality Assurance .....................................................................................................84 
VIII. 
Source Documents .............................................................................................................85 
IX. 
Study and Site Closure .......................................................................................................85 
Appendix 3 
Adverse Events: Definitions and Procedures for Recording, Evaluation, 
Follow-up, and Reporting ......................................................................................86 
I. 
Definitions..........................................................................................................................86 
II. 
Procedures for Recording, Evaluation, Follow-up and Reporting of an AE, 
including AESIs and SAEs ....................................................................................88 
III. 
Special Considerations for Assessment of Adverse Events in an ICU Setting..................90 
Appendix 4 
Contraceptive Guidance and Collections of Pregnancy Information .....................91 
Appendix 5 
Treatment Modification Guidelines .......................................................................95 
Appendix 6 
Conversion Tables for PaO2 / FiO2 Ratio ...............................................................97 
Appendix 7 
Ordinal Scale ..........................................................................................................98 


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Appendix 8 
New York Heart Association (NYHA) Classification ...........................................99 
Appendix 9 
Child-Pugh Classification ....................................................................................100 
Appendix 10 Special Considerations for Assessment of Prior and Concomitant 
Medications ..........................................................................................................101 
Appendix 11 Protocol Version History ......................................................................................102 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments: Phase II ...............................................................................19 
Table 2 
Schedule of Assessments: Phase III ..............................................................................21 
Table 3 
Protocol-Required Safety Laboratory Assessments: Phase II .......................................80 
Table 4 
Protocol-Required Safety Laboratory Assessments: Phase III .....................................81 
Table 5 
Highly Effective Contraceptive Methods......................................................................92 
Table 6 
Dose Modification and Toxicity Management Guidelines for Infusion 
Reactions Associated with IFX-1..................................................................................95 
Table 7 
Protocol Version History: Major Updates to Phase III ...............................................102 
Table 8 
Protocol Version History: Major Updates to Phase II ................................................104 
 
LIST OF FIGURES 
Figure 1 Patient Calendar: IMP Administrations – Phase II .......................................................46 
Figure 2 Patient Calendar: IMP Administrations – Phase III ......................................................47 
 


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ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
anti-drug antibody 
ADL 
Activities of Daily Living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AMC 
Amsterdam Medical Center 
AST 
aspartate aminotransferase 
BSC 
best supportive care 
BDB 
Beijing Deferengui Biotech 
C5a 
complement factor 5a 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIF 
cumulative incidence function 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration  
COPD 
chronic obstructive pulmonary disease 
COVID-19 
Coronavirus Disease-19 
CRO 
Contract Research Organization 
CT 
computed tomography 
EC 
Expert Committee 
eCRF 
electronic case report form 
ECG 
Electrocardiogram 
ECMO 
extracorporeal membrane oxygenation 
EU 
European Union 
eGFR 
estimated glomerular filtration rate 
EOT 
end of treatment 
EOS 
end of study 
EQ-5D 
EuroQol 5-D 
FSH 
follicle stimulating hormone 
FUV 
follow-up visit 
GCP 
Good Clinical Practice 
GDPR  
General Data Protection Regulation  
HRT 
hormone replacement therapy 
HS 
hidradenitis suppurativa 
IB 
Investigator Brochure 


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IEC 
Independent Ethic Committee 
ICH 
International Council for Harmonisation  
ICF 
informed consent form 
ICU 
intensive care unit 
IgG4 
immunoglobulin G4 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
iDMC 
independent Clinical Trial Data Monitoring Committee  
iSMB 
Independent Safety Monitoring Board 
IV 
intravenous 
IWRS 
Interactive Web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS-CoV 
Middle East Respiratory Syndrome Coronavirus  
MRI 
magnetic resonance imaging 
NIH 
National Institutes of Health 
NSAID 
non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
PaO2 / FiO2 
oxygenation index 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic 
PE 
pulmonary embolism 
PK 
pharmacokinetic 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS 
Severe Acute Respiratory Syndrome 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2  
SoA 
Schedule of Assessments 
SOC 
standard of care 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 
VTE 
venous thromboembolism 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 


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1. 
SYNOPSIS 
Title of Study:  
A PRAGMATIC ADAPTIVE RANDOMIZED, CONTROLLED PHASE II/III 
MULTICENTER STUDY OF IFX-1 IN PATIENTS WITH SEVERE COVID-19 
PNEUMONIA --- “PANAMO” 
Protocol/Study Number: IFX-1-P2.9 
EudraCT Number: 2020-001335-28 
Type of Study: 
Phase II/III Study 
Indication:  
Severe pneumonia in context of Coronavirus 
Disease-19 (COVID-19) 
Sponsor: InflaRx GmbH, Winzerlaer Strasse 2, 07745 Jena, Germany 
Coordinating Investigator: Alexander Vlaar, MD, PhD, Amsterdam UMC 
Study Site(s): 
Approximately 25 sites in approximately 7 countries in West and East Europe, United States 
(US), and Latin America 
Phase of Development: II/III 
Objectives: 
Primary Objectives: 
Phase II: To explore the effect of IFX-1 on COVID-19 related severe pneumonia (hypothesis 
generating) 
Phase III: To demonstrate the efficacy of IFX-1 to improve survival outcomes of severe 
COVID-19 pneumonia (confirmative) 
Secondary Objectives: 
Phase II and Phase III 
• 
To assess and define other parameters of efficacy 
• 
To assess the safety of IFX-1  
 
Methodology:  
This is a pragmatic, adaptive, randomized, multicenter phase II/III study evaluating IFX-1 for 
the treatment of COVID-19 related severe pneumonia. The study consists of two parts: 
Phase II, an open-label, randomized, 2-arm phase evaluating best supportive care (BSC) + 
IFX-1 (Arm A) and BSC alone (Arm B); and Phase III, a double-blind, placebo-controlled, 
randomized phase comparing standard of care (SOC) + IFX-1 (Arm A) versus SOC + placebo-
to-match (Arm B). The SOC includes venous thromboembolism prophylaxis at a minimum, 
and may include other international and country-specific recommended treatments for 
COVID-19 per the locally adopted treatment recommendations. 


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At the time of writing of Protocol Version 2.0, Phase II of the study has been completed and 
30 patients have been treated. A preliminary interim analysis has been performed to assess the 
clinical benefit of the treatment using the assessed clinical parameters. An expert committee 
has monitored safety and the supported re-definition of relevant clinical endpoint(s) for 
Phase III.  
In Phase II, patients in Arm A were treated with a maximum of 7 intravenous (IV) doses of 
IFX-1 800 mg over a period of 29 days. The first 5 treatments at days 1, 2, 4, 8, and 15 were 
administered to all patients. Treatment at day 22 was only administered in the event that a 
patient had not been extubated and discharged from the intensive care unit (ICU). In case a 
patient’s clinical situation worsened after day 8, although an initial clinical benefit was 
observed, one additional administration of 800 mg IFX-1 between day 11 and 13 could have 
been given at investigator discretion. Loss of clinical benefit could, in this situation, relate to 
the exceptionally high complement factor 5a (C5a) levels observed in some cases of 
COVID-19 related pneumonia and associated shortened IFX-1 half-life.  
Phase III of the study follows a group-sequential design (two stages) with one interim analysis 
for stopping for futility or stopping for efficacy. A total of 180 patients will be randomized 
into Arm A and Arm B using a 1:1 allocation ratio for the first stage; based on results of the 
interim analysis, up to an additional 180 patients will be randomized using the same allocation 
ratio for the second stage.  
In Phase III, patients will be treated with a maximum of 6 IV doses of IFX-1 800 mg (Arm A) 
or placebo (Arm B) at days 1, 2, 4, 8, 15, and 22, as long as the patient is still in the hospital 
(even if discharged from the ICU).  
If possible, patients will be assessed for quality of life using the EuroQol-5D (EQ-5D). 
Patients will be followed for survival and their clinical status assessed by the Glasgow 
Outcome Scale. 
 
Number of Patients: 
Phase II: 30 patients (15 arm A+ 15 arm B)  
Phase III: Total of 180 patients (approximately 90 per arm) in Stage 1 and 180 patients 
(approximately 90 per arm) in Stage 2. Simulations to evaluate the statistical properties of the 
group-sequential design yielded an overall 90% power to show superiority of IFX-1 for the 
primary endpoint of all-cause mortality. The simulations were based on the assumption that 
IFX-1 can reduce a 30% mortality under SOC by 50% to a mortality of 15%. 
 
Study Population: 
Study patients are enrolled into the study using a deferred consent procedure or another legally 
acceptable local consent procedure in this special ICU situation. 
Phase II 
Key inclusion criteria for Phase II of the study included the following: patients must have been 
at least 18 years of age or older with clinically evident or otherwise confirmed severe 


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pneumonia, oxygenation index (PaO2 / FiO2) at time of enrollment of ≤ 250 and ≥ 100, and 
had Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection confirmation 
at screening and at enrollment. 
Key exclusion criteria for Phase II of the study included the following: PaO2 / FiO2 ≤ 99 or 
≥ 250 at screening, intubated > 48h at time of enrollment, demonstrated an improvement in 
past 24h prior to enrollment in oxygenation and ventilation/support parameters, known history 
of chronic dialysis or received renal replacement therapy in past 14 days, and history of 
chronic obstructive pulmonary disease (COPD).  
All inclusion and exclusion criteria are listed for Phase II in Section 6.1. 
Phase III 
Patients must meet all the following criteria at randomization to be enrolled into Phase III of 
the study: 
1. At least 18 years of age or older 
2. Patient on invasive mechanical ventilation (but not more than 48h post intubation at time 
point of randomization) 
3. Patients with a PaO2 / FiO2 ratio of < 200 and > 60 at randomization (one representative 
measurement within 6h before randomization) 
4. SARS-CoV-2 infection confirmation (tested positive in last 14 days before randomization 
with locally available test system) 
Patients who fulfill any of the following criteria at randomization are not eligible to participate 
in Phase III of the study: 
1. Intubated > 48h at time point of randomization  
2. Expected stop of invasive ventilation or expected extubation in the next 24h without 
additional intervention according to judgment of the investigator 
3. Known history of chronic dialysis OR received renal replacement therapy in past 14 days 
OR anticipated to receive renal replacement therapy within 24h after randomization 
4. Known history of progressed COPD as evidenced by use of daily maintenance treatment 
with long-acting bronchodilators or inhaled/oral corticosteroids for > 2 months 
5. Treatment of COVID-19 with investigational antibody treatment(s) which are not 
approved or not included in locally adopted treatment guidelines (e.g., World Health 
Organization [WHO] guidance, National Institutes of Health [NIH] COVID-19 treatment 
guidelines) for this indication in the past 7 days (Note: Antibody treatment[s] given within 
past 7 days for pre-existing diseases, other than COVID-19, are allowed.)  
6. At time point of randomization, treatment of COVID-19 with investigational treatments 
which are not approved or not included in locally adopted treatment guidelines for this 
indication (e.g., WHO guidance, NIH COVID-19 treatment guidelines), including 
SARS-CoV-2 multiplication inhibitor(s) or immunomodulator(s). (Note: If a locally 
adopted treatment guideline recommends drugs such as remdesivir, dexamethasone, or 
anticoagulation, this would be allowed. Adopted guidelines and updates must be 
documented at study initiation and throughout the conduct of the study.) 


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7. Received cytokine adsorption therapy in past 3 days 
8. Known hypersensitivity to IFX-1 or any other ingredient of the study medication 
9. Serum or urine pregnancy test positive before randomization (required for women of 
childbearing potential) 
10. Received organ or bone marrow transplantation in past 3 months 
11. Known cardio-pulmonary mechanical resuscitation in past 14 days  
12. Patient moribund or expected to die in next 24h according to the judgment of the 
investigator  
13. Known to have received anti-cancer therapy for hemato-oncological disease in past 
4 weeks OR known to have active malignant disease at time point of randomization 
14. Known severe congestive heart failure (New York Heart Association [NYHA] 
Class III-IV; see Appendix 8)  
15. Known history of chronic liver disease (Child-Pugh B or C; see Appendix 9) 
16. Participating in or has participated in other investigational interventional studies (drug or 
device) within the last 7 days before randomization 
 
Test Product, Dose, and Mode of Administration: 
Phase II 
In Arm A, patients received BSC + IFX-1. IFX-1 was to be administered as a 30-60 minute IV 
infusion as follows: 800 mg on days 1, 2, 4, 8, and 15 and, if not extubated or in weaning 
process in case of tracheostomy, may have received an additional 800 mg dose at day 22. 
IFX-1 treatment was to be ceased if signs of unacceptable toxicity or intolerability occurred. In 
case a patient’s clinical situation worsened after day 8, although an initial clinical benefit was 
observed, one additional administration of 800 mg IFX-1 between day 11 and 13 may have 
been given at investigator discretion. 
Phase III 
In Arm A, patients will receive SOC + IFX-1. IFX-1 will be administered as a 30-60 minute 
IV infusion as follows: 800 mg at days 1, 2, 4, 8, 15, and 22, as long as the patient is still in the 
hospital (even if discharged from the ICU). IFX-1 treatment shall be ceased if signs of 
unacceptable toxicity or intolerability occur.  
 
Reference Therapy, Dose, and Mode of Administration: 
Phase II 
In Arm B, patients received BSC alone. 
Phase III 
In Arm B, patients will receive SOC + Placebo in the same schedule as described for Arm A. 


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Expected Study Duration: 
First patient first visit = March 2020 (Phase II) 
Last patient last follow-up visit = May 2021 (Phase III) 
Criteria for Evaluation 
Phase II 
Primary Endpoint: 
The primary endpoint was the relative change (%) from baseline (day 1 prior to study drug 
administration at ± 1h of randomization) in oxygenation index (PaO2 / FiO2) in supine position 
at day 5. 
Secondary endpoints included the number of patients (%) achieving an early and late response, 
relative change (%) from baseline (day 1 prior to study drug administration at ± 1h of 
randomization) in PaO2 / FiO2 in supine position at day 3, 7, 9, and 11, all cause 28-day 
mortality (%), and frequency, severity, and relatedness to study drug of treatment-emergent 
adverse events (TEAEs) and serious adverse events (SAEs). Further details on secondary and 
other endpoints for Phase II are provided in Section 4.2.1. 
Phase III 
Primary Endpoint: 
• 
28-day all-cause mortality 
Secondary Endpoints: 
• 
Proportion of patients free of any renal replacement therapy within 28 days upon 
randomization 
• 
Proportion of patients developing acute kidney failure (estimated glomerular filtration rate 
[eGFR] < 15 mL/min/1.73m², assessed by the Chronic Kidney Disease Epidemiology 
Collaboration [CKD-EPI] equation) during ICU stay and at day 28 
• 
Proportion of patients with an improvement in the 8-point ordinal scale (Appendix 7) 
(day 15, day 28)  
• 
Frequency, severity, and relatedness to study drug of serious and non-serious TEAEs 
Other Endpoints: 
• 
Time to first extubation 
• 
60-day mortality 
• 
Glasgow Outcome Scale score assessed at study day 60 
• 
Quality of life assessed by EQ-5D at study day 60 
 
Statistical Methods: 


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Phase II 
For efficacy analyses, the relative change (%) from baseline (day 1 prior to study drug 
administration at ± 1h of randomization) in oxygenation index (PaO2 / FiO2) in supine position 
at day 3, 5, 9, and 15 was to be analyzed with a linear repeated measures model with post-
baseline time points as outcome variables and baseline value as an explanatory variable. Least 
square mean differences between treatment arms and their 95% confidence interval (CI) were 
to be calculated and displayed for each time point separately (day 3, 5, 9 and 15), with the 
evaluation at day 5 reflecting the primary endpoint. Early response, late response, and reaching 
ICU discharge alive were to be analyzed as three separate time-to-event variables. All-cause 
mortality was to be analyzed as a censored time-to-event variable with Kaplan-Meier methods. 
Laboratory endpoints were to be analyzed descriptively by time point and treatment arm. 
Glasgow Outcome Scale was to be analyzed by ordinal regression analysis.  
For safety analyses, the occurrence of adverse events (AEs) was to be compared between 
treatment arms. The number and percentage of patients with SAEs was to be analyzed.  
Further details of statistical methods for Phase II are provided in Section 10.1. 
 
Phase III 
Efficacy: 
All efficacy analyses will be performed based on all randomized patients according to the 
intention-to-treat principle. 
The statistical study design of Phase III is a group-sequential adaptive design (two stages) with 
one interim analysis for stopping for futility or stopping for efficacy. The primary efficacy 
variable is 28-day mortality (proportion of patients deceased until day 28). 
A total of 180 patients (approximately 90 per arm) will be randomized in Stage 1 and up to 
180 patients (approximately 90 per arm) in Stage 2. This results in 90% overall power (90% 
probability to either show efficacy after Stage 1 or Stage 2). The power calculation is based on 
an overall 2.5% one-sided alpha, Pocock’s approach to account for the group-sequential 
design, a binding futility stop if the z-statistic is 0 or lower after the first stage and an assumed 
30% 28-day mortality under Placebo and 15% 28-day mortality under IFX-1 treatment. 
A total of 180 patients will be randomized to Arm A and Arm B using a 1:1 allocation ratio for 
the first stage. The interim analysis is performed after all 180 patients have been followed-up 
until day 28 (or died before). In case the interim analysis does not result in an early stop for 
efficacy or futility, 180 additional patients will be randomized in a ratio of 1:1 into Arm A 
and B. The maximum number of patients in the study will not exceed 360. 
The group sequential design to show superiority of IFX-1 + SOC compared to SOC alone will 
make use of a one-sided alpha level of 2.5% and a binding futility stop and will test for 
superiority (lower mortality among IFX-1 treated patients). The primary statistical analysis 
will be based on a logistic regression model with outcome 28-day mortality and explanatory 
variables treatment arm (Arm B versus Arm A), age, sex (male versus female), and 
PaO2 / FiO2 at randomization. 


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The critical values for the interim and the final analysis are derived according to Pocock’s 
design resulting in critical values of 2.176 for both stages. The z-statistic at each stage will be 
calculated as the proportion of the beta coefficient for the treatment arm effect and its standard 
error from the logistic regression model. The study will be stopped for futility if the z-statistic 
for the first stage is 0 or lower. 
The z-statistics of the first and the second stage will be combined using the weighted inverse 
normal combination function (Bauer and Köhne 1994; Bauer and Köhne 1996). The weights 
are chosen as w1= sqrt(180/360) and w2= sqrt(1-w12). 
Secondary efficacy endpoints will only be addressed with statistical hypothesis tests if the 
primary endpoint is statistically significant (only after the first stage or after the second stage). 
Therefore, a full overall 2.5% one-sided alpha will be spent for the secondary efficacy 
endpoints. Multiplicity in the secondary endpoints will be addressed with the fallback method. 
The secondary endpoints will be evaluated using a similar logistic regression model as for the 
primary endpoint, where instead of the 28-day mortality (proportion of patients deceased until 
day 28) the following variables will be used: 
1. Proportion of patients with an improvement in the provided ordinal scale at day 28 (at least 
one score point lower than at randomization) 
2. Proportion of patients with an improvement in the provided ordinal scale at day 15 (at least 
one score point lower than at randomization) 
3. Proportion of patients free of any renal replacement therapy within 28 days upon 
randomization 
4. Proportion of patients developing acute kidney failure (eGFR < 15 mL/min/1.73m²) during 
ICU stay and at day 28 
The ordering of the secondary endpoints for hypothesis testing will be as in above mentioned 
list. The alpha for the fallback method will be attributed to the 4 secondary endpoints in the 
following way: 2%, 0.2%, 0.2%, and 0.1%. If the preceding hypothesis test is not significant, 
subsequent tests will be performed at the aforementioned alpha level. If tests are significant, 
the alpha is added to the subsequent hypothesis test (e.g., if the primary hypothesis test is 
significant and secondary endpoints 1-3 are all significant, the fourth secondary endpoint will 
be tested at an alpha of 2.5%; if the third secondary endpoint is not significant, the fourth 
secondary endpoint will be tested at an alpha of 0.1%). 
The primary endpoint as well as all secondary endpoints will also be evaluated as censored 
time to event variables by Kaplan-Meier type methods. All time to event endpoints will also be 
evaluated via proportional hazards models with the explanatory variables treatment arm 
(Arm B versus Arm A), age, sex (male versus female) and PaO2 / FiO2 at randomization. 
Safety: 
The occurrence of TEAEs will be compared between treatment arms. TEAEs will be analyzed 
according to the number and percentage of patients who had a TEAE, as well as the number of 
TEAEs in total. Additionally, the number and percentage of patients with TEAEs will be 
further grouped by severity and causal relationship. The number and percentage of patients 
with serious TEAEs and adverse events of special interest (AESIs) and the total number of 
serious TEAEs and AESIs will be analyzed. Where TEAEs are grouped by severity or 


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relationship, the maximum severity/relationship per patient and class of TEAE will be 
considered. 
Interim Analysis: 
The interim analysis is performed after all 180 patients in Stage 1 have been followed-up until 
day 28 (or died before). The study will be stopped for futility if the z-statistic of the primary 
efficacy analysis is 0 or lower. The study will be stopped for efficacy if the z-statistic of the 
primary efficacy analysis is 2.176 or higher. If the study is not stopped for efficacy or futility, 
another 180 patients will be randomized in Stage 2. 


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2. 
SCHEDULE OF ASSESSMENTS 
Table 1 
Schedule of Assessments: Phase II 
Screening 
Period 
Treatment Period (Maximum 4 Weeks) 
Follow-up Period  
(2 Months)(Telephone) 
EOT =  
FUV 1 
EOS= 
FUV 2 
Days 
-2 – 0 
Day 
1 
 
Day 
2 
Day 
3 
Day 
4 
 
Day 
5 
Day 
7 
Day 
8 
Day 
9 
Day 
11 
Day 
13 
Day 
15 
Day 
22 
Day 29/ 
Discharge 
28 days 
after last 
IFX-1 
treatment 
28 days 
after 
FUV 1 
Deferred Informed 
consenta 
X 
 
 
Inclusion/exclusion 
criteria  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, 
medical/disease 
history, prior 
medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease/response 
assessmentsb 
X 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Imagingc 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
Concomitant disease  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
X 
 
 
 
Blood sample for 
plasma complement 
and PK assessmentd 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
IV administration of 
IFX-1e 
 
X 
X 
 
X 
 
 
X 
 
(x) 
 
X 
(x) 
 
 
 
Safety Assessments 
Weight 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
 
 
Safety laboratory testf 
 
X 
X 
 
X 
 
 
X 
 
(x) 
 
X 
X 
X 
 
 


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Pregnancy testg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Survival status  
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
CT = computed tomography; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; FUV = follow-up visit; IMP = investigational medicinal product; IV = 
intravenous; MRI = magnetic resonance imaging; PK = pharmacokinetic 
a  Obtaining of informed consent was to be deferred for the ICU patients (see Section 6.3). 
b  Disease/response assessments included evaluation of lung function and evaluation of early and late response (see Section 8.1.2). 
c  Imaging was to be performed by X-ray or CT scan or MRI, per investigator decision. Once the imaging choice was made, subsequent assessments should have been made 
using the same modality whenever possible. Imaging either at day 29 or day of discharge ± 3 days. 
d  Blood samples were to be collected for measurement of plasma concentrations and C3a and C5a of IFX-1 before administration of IMP (see Section 8.1.4), if possible. 
e  The first 5 treatments of IFX-1 at day 1, 2, 4, 8, and 15 were to be administered to all patients randomized to Arm A. Treatment at day 22 was only to be administered in the 
event that a patient had not been extubated and discharged from ICU. In case a patient’s clinical situation would worsen after day 8, although an initial clinical benefit was 
observed, one additional administration of IFX-1 between day 11 and 13 could have been given at investigator discretion, represented as (x) above. 
f  Safety laboratory tests included hematology, coagulation parameters, chemistry, urinalysis, and other screening tests (see Table 3). Blood samples for safety laboratory 
analysis should have been obtained after vital signs assessments were performed, but before administration of IMP. 
g  Blood samples for serum pregnancy testing were to be collected only for women of childbearing potential. 
h  Core body temperature, heart rate, respiratory rate, and blood pressure (diastolic and systolic) were to be assessed at each visit at pre-dose, and H0+1h, where H0 is the 
beginning of IFX 1 administration, on the days of IMP administration and at further time points whenever medically indicated. Vital signs were to be measured in a supine 
position (after a rest of at least 1h in case of position switch from prone position), preferably in the morning. 
 


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Table 2 
Schedule of Assessments: Phase III 
Screening/ 
Randomization 
Treatment Period  
Follow-up 
Period  
(Telephone 
possible) 
Week 1 
Week2 
Week 3 
Week 4 
Week 5 
Any time 
FUV 
Screening not 
more than 24h 
before 
randomization 
Day 1 
(calendar 
day of 
random-
ization) 
Day 2 
Day 4 
Day 8 
Day 15 
(if still in 
hospital) 
Day 22 
(if still in 
hospital) 
Day 28 
(if still in 
hospital) 
ICU 
discharge  
Hospital 
discharge  
Day 60 
(60 +/- 3 days 
after 
randomi-
zation  
Deferred informed consenta 
X 
Screening / Baseline Assessments 
Inclusion/exclusion criteria  
X 
 
 
Urine analysis (dipstick) 
X 
 
 
Pregnancy testb 
X 
 
 
Weight 
X 
 
 
Height 
X 
 
 
PaO2 / FiO2c 
X 
 
 
Demographics, COVID-19 
history, SARS-CoV-2 
mRNA testd  
X 
 
 
Medical history/ 
concomitant disease  
X 
 
 
Prior medications and 
procedures 
X 
 
 
Intubation date 
X 
 
 
Randomization  
Randomization 
X 
 
 
IMP Administration 
IMP administratione 
 
X 
X 
X 
X 
X 
X 
 
 
 
 


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Screening/ 
Randomization 
Treatment Period  
Follow-up 
Period  
(Telephone 
possible) 
Week 1 
Week2 
Week 3 
Week 4 
Week 5 
Any time 
FUV 
Screening not 
more than 24h 
before 
randomization 
Day 1 
(calendar 
day of 
random-
ization) 
Day 2 
Day 4 
Day 8 
Day 15 
(if still in 
hospital) 
Day 22 
(if still in 
hospital) 
Day 28 
(if still in 
hospital) 
ICU 
discharge  
Hospital 
discharge  
Day 60 
(60 +/- 3 days 
after 
randomi-
zation  
Endpoint Assessments 
Organ support (renal 
replacement therapy, 
ECMO, mechanical 
ventilation) 
 
X 
 
Extubation and 
re-intubation date(s) 
 
X 
 
Ordinal scale evaluationf 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Survival status  
 
X 
X 
Quality of life (EQ-5D) 
 
 
X 
Glasgow Outcome Scale 
 
 
X 
Safety Assessments 
Safety laboratory testsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Creatinineh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signsi 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse eventsj 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Concomitant medications 
and procedures 
 
X 
 
12-lead ECG 
X 
  
X 
 
 
PK/PD Assessments (Country-specific)k 
IFX-1 sample 
X 
 
X 
 
X 
 


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Screening/ 
Randomization 
Treatment Period  
Follow-up 
Period  
(Telephone 
possible) 
Week 1 
Week2 
Week 3 
Week 4 
Week 5 
Any time 
FUV 
Screening not 
more than 24h 
before 
randomization 
Day 1 
(calendar 
day of 
random-
ization) 
Day 2 
Day 4 
Day 8 
Day 15 
(if still in 
hospital) 
Day 22 
(if still in 
hospital) 
Day 28 
(if still in 
hospital) 
ICU 
discharge  
Hospital 
discharge  
Day 60 
(60 +/- 3 days 
after 
randomi-
zation  
ADA sample 
X 
 
X 
 
C5a sample 
X 
 
X 
 
X 
 
ADA = anti-drug antibody; C5a =  complement factor 5a; ECG = electrocardiogram; ECMO = extracorporeal membrane oxygenation; EQ-5D = EuroQol 5-D; FUV = follow-up 
visit; IMP = investigational medicinal product; IV = intravenous; PaO2 / FiO2 = oxygenation index; PK/PD = pharmacokinetic/pharmacodynamic  
a 
Obtaining of informed consent is proposed to be deferred or by any other legally acceptable local consent procedure for the ICU patients in this study ( see Section 6.3). 
b 
Serum or urine samples for pregnancy testing will be collected only for women of childbearing potential. 
c 
PaO2 / FiO2 should be assessed within 6h before randomization (one representative measurement) 
d 
SARS-CoV-2 infection confirmation will be done, if not already tested positive in last 14 days before randomization, with locally available test system 
e 
Up to 6 treatments of IMP will be administered at days 1, 2, 4, 8, 15, and 22, as long as the patient is still in the hospital, even if discharged from the ICU.  
f 
Ordinal scale score will be documented at the visits indicated, including the date (one value per assessment day, that best represents the patient’s condition at that day) 
g 
Safety laboratory tests include hematology (hemoglobin, hematocrit, platelet count, red blood cell count, red blood cells (MCV), white blood cell count with differentials 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), coagulation parameters (aPTT, PT, D-dimer), blood chemistry (ALT, AST, LDH, total bilirubin, and CRP) 
(see Appendix 1, Table 4). Blood samples for safety laboratory analysis should be obtained at indicated days during routine sampling (one representative value, if taken more 
than once a day). 
h 
Creatinine assessment should be obtained at indicated days during routine sampling (one representative value, if taken more than once a day). 
i 
Vital signs (core body temperature, heart rate, respiratory rate, blood pressure [diastolic and systolic]) will be assessed at indicated visits at pre-dose within 1h before 
administration of IMP (one representative measurement closest to IMP administration) and at further time points whenever medically indicated. Blood pressure and heart rate 
measurements will be assessed with an intra-arterial catheter, or a completely automated device. Manual techniques will be used only if an automated device is not available. 
j 
Adverse event reporting will follow special considerations for the ICU setting as described in Appendix 3. 
k 
PK/PD sampling will be conducted at sites in the US, Europe, and Russia. PK/PD samples will be taken within 1h before administration of IMP. 


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3. 
INTRODUCTION AND BACKGROUND INFORMATION 
3.1. 
Background 
There are daily increasing numbers of Severe Acute Respiratory Syndrome (SARS) 
Coronavirus 2 (SARS-CoV-2) infected individuals globally and reports on impact / mortality 
vary constantly. As of 23 July 2020, over 15 million documented cases were reported worldwide 
of which more than 619,000 died (World Health Organization [WHO] 2020). Clinical 
manifestations of Coronavirus Disease-19 (COVID-19) vary, with approximately 5% of patients 
having critical manifestations (such as respiratory failure, septic shock, and/or multiple organ 
dysfunction) and 17-35% of hospitalized patients being treated in an intensive care unit (ICU), of 
whom 29-91% require invasive mechanical ventilation (Wiersinga et al. 2020).  
The main COVID-19 characterizing clinical features are age greater than 50 years and presence 
of comorbidities such as hypertension and diabetes, whereas main laboratory findings show 
hepatic and renal dysfunction in the presence of leukopenia, lymphopenia, increase of D-dimers, 
and strong inflammatory cytokine activation (Guan et al. 2020; Huang et al. 2020; Liu et al. 
2020; Garg et al. 2020; Wiersinga et al. 2020). Elevated D-dimer values have been shown to be 
strongly associated with poorer prognosis. It is also reported that the complement cascade is 
highly activated (Gao et al. 2020). One hallmark of progressed disease in patients who become 
severely diseased is the association of blood neutrophil increases with the disease severity, and 
neutrophil infiltration in the heart and liver. 
Monoclonal antibodies directed against key inflammatory mediators, such as interleukin 1 and 6 
and complement factor 5a (C5a), aim to modulate the overwhelming inflammatory response 
following SARS-CoV-2 infection, thereby preventing organ damage (Wiersinga et al. 2020). 
These targeted immunomodulatory agents are currently being evaluated for the management of 
COVID-19 and may prevent disease progression in hospitalized patients.  
3.2. 
Study Rationale 
3.2.1. 
Drug Profile 
IFX-1 is a chimeric immunoglobulin G4 (IgG4) monoclonal anti-human C5a antibody, which 
specifically binds to the soluble human complement split product C5a. IFX-1 has been 
demonstrated to block C5a-mediated biological effects with high efficacy in vitro. C5a is one of 
the most potent inflammatory factors, triggering innate immune responses and bridging to 
adaptive immune responses (Dunkelberger and Song 2010). In blood, C5 is cleaved to C5a by 
components of the classical and alternative complement pathway, and the coagulation pathway, 
whereas in tissue, factors of the alternative complement and the coagulation pathway factors play 
a major role in C5a generation (Hess and Kemper 2016). 


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3.2.2. 
Non-clinical and Therapeutic Studies 
Non-clinical studies were conducted to assess pharmacological and toxicological aspects of 
IFX-1 and showed that IFX-1 was able to rapidly bind to its target, the human C5a, and achieve 
an almost complete blockade of C5a-induced biological effects. At the same time, cleavage of 
C5 and formation of the complement membrane attack complex was not disrupted in vitro. 
IFX-1 did not demonstrate any cross-reactivity or bioactivity in species other than humans and 
non-human primates (Section 4.2 of the Investigator Brochure [IB]). Therefore, toxicology 
studies were only conducted in cynomolgus monkeys.  
IFX-1 has been investigated in viral induced lung injury in monkeys infected with the avian flu 
virus H7N9. It had been shown that the neutrophil influx into the lung as well as the lung 
damage could be greatly reduced by this therapeutic attempt. In addition, the viral replication 
was greatly reduced as well, which is believed to be an indirect effect (Sun et al. 2015). This 
research was in line with findings generated in an H5N1 model of disease in rodents (Sun et al. 
2013). Since then, the role of complement and specifically C5a for viral induced lung injury has 
become an accepted concept in basic research (Wang et al. 2015). The same research group then 
confirmed the role of the C5a/C5a-receptor signaling axis for viral replication, for lung 
neutrophil influx and damage in a mouse model of Middle East Respiratory Syndrome 
Coronavirus (MERS-CoV) (Jiang et al. 2018). Another group of researchers then confirmed the 
role of complement activation and made similar findings on viral replication inhibition and lung 
damage reduction in complement deficient mice in a SARS virus infection model (Gralinski et 
al. 2018). One finding of this study was that complement deficient mice (C3-/-) had significantly 
less infiltration of the lungs with neutrophils and monocytes, also confirming earlier findings in 
greater detail for SARS-CoV induced viral lung injury.  
This body of research has led to the approval by the Chinese FDA of two ongoing trials in 
SARS-CoV-2 infected patients in China with the monoclonal anti-C5a antibody BDB-1 (S-FDA 
approval number 2020L00003). BDB-1 is generated from the InflaRx IFX-1 cell line which has 
been transferred and licensed to the InflaRx collaborator Beijing Deferengui Biotech Co. (BDB). 
BDB develops BDB-1 under their responsibility in China and InflaRx has all rights to any 
discoveries made by BDB-1 globally outside China, where InflaRx develops IFX-1 in the rest of 
the world. The BDB-1 trials are ongoing, however data of the first two open label treated patients 
were reported in context of a research article by Gao et al. 2020 (see Section 3.2.4). 
None of the Good Laboratory Practice-compliant studies in cynomolgus monkeys revealed 
relevant toxicological or safety concerns for IFX-1. During single-dose and repeat-dose 
administration of IFX-1 at doses of up to 50 mg/kg body weight in cynomolgus monkeys no 
direct IFX-1-related toxicological or adverse findings within an extended core battery of safety 
pharmacology assessments were observed. Results showed dose-related increases in systemic 
and maximum exposure in the investigated dose range of 1 to 50 mg/kg body weight. Anti-drug 


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antibodies (ADAs) were detected in 1 animal in the 26-week repeat-dose study. This animal 
died, most likely because of an ADA-mediated immune complex formation. 
An overview of the non-clinical toxicology studies that were conducted with IFX-1 is available 
in Table 8 of the IB. 
For further details, refer to Section 4 of the IB. 
3.2.3. 
Experience in Humans 
At the time of writing of Protocol Version 2.0, Phase II of the current study has been completed 
and all 30 enrolled patients have been treated (15 in Arm A [best supportive care (BSC) + IFX-1] 
and 15 in Arm B [BSC alone]) for up to 28 days. Relative change (%) from baseline to day 5 in 
oxygenation index was assessed as the primary endpoint along with additional clinical 
parameters until day 28. Relative change in the oxygenation index at day 5 showed no 
differences between treatment groups. However, IFX-1 treatment was associated with a lower 
28-day all-cause mortality when compared to the BSC arm, along with trends in disease 
improvement, as evidenced by fewer patients experiencing renal impairment assessed by 
estimated glomerular filtration rates (eGFR), more patients showing reversal of blood 
lymphocytopenia and a greater lowering of lactate dehydrogenase concentrations. In IFX-1-
treated patients, pulmonary embolisms (PE) reported as serious adverse events (SAEs) were 
lower compared to the BSC arm. Also, a temporary increase of D-dimer levels, as potential 
expression of induction of blood clot lysis, was detected in the first days after initiation of IFX-1 
treatment. 
Over a treatment period of 28 days, patients in the IFX-1 arm received a maximum of 7 doses of 
800 mg IFX-1 intravenously (IV) on separate days. At randomization, 18 patients (60%) were 
intubated, and 12 patients (40%) had other oxygen supply. A higher number of patients with 2 or 
more comorbidities associated with increased COVID-19 mortality were reported in the IFX-1 
treatment arm compared to the BSC arm. Twenty-eight-day all-cause mortality in the IFX-1 
treatment arm was 13% (2 out of 15) versus 27% (4 out of 15) in the BSC arm. In the BSC arm, 
4 patients died of COVID-19-induced multi-organ failure, and 3 of them had PE reported as 
SAEs. In the IFX-1 arm, one patient died after an acute ventilator tube complication (leakage) 
and one patient with a history of severe chronic obstructive pulmonary disease died of 
pulmonary failure. Serious AE rates were comparable between groups, but the rate of PE 
reported as SAEs was substantially lower in the IFX-1 treatment group. Upon review of the 
safety data, the independent data safety monitoring board has recommended continuation of the 
trial into Phase III. 
IFX-1 is also being developed for the treatment of other inflammatory diseases. Five clinical 
studies in humans have been completed so far. One Phase I study in healthy volunteers 
(Study IFX-1-P1.1) and 4 Phase II studies: 1 in patients with early septic organ dysfunction 
(Study IFX-1-P2.1), 1 in patients undergoing complex cardiac surgery (Study IFX-1-P2.2), and 


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2 in patients with hidradenitis suppurativa (HS) (Studies IFX-1-P2.3 and IFX-1-P2.4; Section 5 
of the IB).  
To date, 391 subjects (26 healthy volunteers and 365 patients) have been treated in completed 
clinical studies of these other inflammatory diseases, of which 294 have received IFX-1 and 
92 have received placebo. IFX-1 was safe and well tolerated, with no dose relationship in the 
safety findings. No specific adverse reactions emerged in clinical studies of single or multiple 
doses IFX-1 in healthy volunteers or patients with cardiac disease, sepsis, or HS. 
Currently, 4 further Phase II studies are ongoing: 1 in patients with HS (Study IFX-1-P2.4; in 
final analyses), 2 in patients with granulomatosis with polyangiitis and microscopic polyangiitis 
(also referred to as anti-neutrophil cytoplasmic antibody-associated vasculitis; Study IFX-1-P2.5 
and IFX-1-P2.6), and 1 in patients with pyoderma gangrenous (Study IFX-1-P2.7). 
Data are available from the interim analysis of the main period of the Phase II Study IFX-1-P2.4 
in HS, where 141 patients were treated with IFX-1 in 4 different IFX-1 dose cohorts (400 mg and 
800 mg every 4 weeks, 800 mg bi-weekly, and 1200 mg every 2 weeks) and 36 patients were 
treated with placebo. The total treatment duration in this study, which recently completed 
treatment, was 9 months. Treatment with IFX-1 was safe and well tolerated with rare occurrence 
of adverse events (AEs) of special interest (AESIs), defined as infusion reactions, including 
hypersensitivity or anaphylaxis, meningitis, meningococcal sepsis, and invasive infection. Four 
patients experienced AEs suggestive of hypersensitivity. The reactions were moderate, and 
treatment continued if necessary with adequate prophylactic medication. Anti-drug antibodies 
during treatment were observed in a range of 5.6% to 12.9% with a trend towards increasing 
frequency with low dose and larger administration intervals. 
3.2.4. 
Scientific Rationale for the Study  
Neutrophil driven tissue and organ damage is known to play an important role in a wide array of 
acute inflammatory diseases. The mechanism leading to damage has been largely attributed to 
two mechanisms: 1) the release of granular enzymes and 2) the generation of so-called reactive 
oxygen species in which O2 radical formation elicits a damaging effect. 
One of the strongest chemoattractant substances, which is also capable of inducing both 
mechanisms described above is the human complement split product C5a.  
Earlier research by InflaRx has demonstrated that the anti-human C5a antibody IFX-1 could 
significantly reduce the neutrophil and macrophage infiltration in a model of viral (H7N9) 
induced lung injury in monkeys (Sun et al. 2015). This was accompanied by a significantly 
reduced tissue damage in the lung of infected animals and also a significantly reduced viral 
replication when compared to mock-treated animals. The mechanism was then confirmed in a 
model of MERS–CoV induced lung injury where similar findings were made by using an anti-
C5a receptor antibody (Jiang et al. 2018) and in a model of SARS-CoV induced lung injury by 
using complement C3 knockout mice (Gralinski et al. 2018). The latter study also provided 


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evidence for a profound complement activation in SARS virus infections in animals. These 
studies all suggested a role of neutrophil driven lung damage, which was induced by generation 
of C5a in different viral-lung injury models, including SARS viruses.  
Latest data from a collaborating research group in China demonstrated strongly and significantly 
elevated C5a levels in severely diseased COVID-19 patients when compared to mildly diseased 
patients (Gao et al. 2020; Carvelli et al. 2020) and revealed evidence for a strong complement 
pathway driven activation of C5a in this disease. In addition, data from the first two severely 
diseased COVID-19 patients treated with the IFX-1 cell line derived anti-C5a antibody BDB-1, 
which InflaRx licensed to a collaborator in China, demonstrated clinical improvement in 
oxygenation index, fever reduction, and laboratory parameter normalization including liver 
enzymes and lymphocyte counts. 
From a clinical perspective, various papers have confirmed that COVID-19 infected non-
surviving patients demonstrated lung failure with close to 100% (Zhou et al. 2020) and that, in 
contrast to surviving patients, non-survivors demonstrated elevated white blood cell counts and 
neutrophils above the normal range (Wang et al. 2020; Gong et al. 2020). 
In summary, there is evidence that in COVID-19 patients who are severely affected, C5a 
activation occurs to a large extent and that neutrophil count elevation in blood is associated with 
bad outcome. These human data fit well to the scientific rationale developed in animal models of 
viral-induced lung injury that activated neutrophils attracted to the lung may cause viral-induced 
lung damage. First treatment attempts with the anti-C5a antibody technology developed by 
InflaRx (BDB-1) in severely affected COVID-19 patients provide further evidence for the 
scientific rationale.  
The completed Phase II portion of the current trial was exploratory in nature and was not 
powered to show statistically significant differences in clinical endpoints. Relative change (%) 
from baseline to day 5 in the oxygenation index, chosen as the primary endpoint for Phase II, 
showed a large variability and dependency on patient positioning and intubation status which 
excluded this endpoint from being used in a confirmatory study. Phase III of the study is an 
adequately powered, placebo-controlled, double blinded phase evaluating standard of care 
(SOC) + IFX-1 versus SOC + placebo-to-match with 28-day all-cause mortality as the primary 
endpoint, an accepted regulatory primary endpoint for critical care studies. 
At the time that Phase II of this study was initiated, there was no SOC established for this newly 
identified disease. The SOC to be utilized in Phase III of this study reflects the current 
understanding of the SOC for hospitalized patients with COVID-19, which includes venous 
thromboembolism (VTE) prophylaxis at a minimum, and may include other international and 
country-specific recommended treatments for COVID-19 per the locally adopted treatment 
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3.2.5. 
Justification for Dose 
The aim for determining the dose and administration frequency for IFX-1 is to establish a 
pragmatic administration schedule for the COVID-19 patient population. IFX-1 dose and 
administration schedule was chosen based on prior pharmacokinetic (PK)/pharmacodynamic 
(PD) observations for IFX-1 trough values and blood C5a levels, dose-response assessment in 
Study IFX-1 P2.4 in HS, and the described unprecedented high C5a levels in patients with severe 
COVID-19 related pneumonia (Gao et al. 2020; Carvelli et al. 2020). In a population PK/PD 
modelling study for IFX-1 based on the data of the 2 trials in HS patients, a reduction in C5a 
concentration was found to be dependent on all measures of drug exposure, with increasing 
exposure predicting a greater reduction in C5a.  
The observed half-life of IFX-1 with a single dose of 800 mg was 3 to 4 days in Study IFX-1 
P2.2 in patients undergoing complex cardiac surgery. Thus, an additional dose of 800 mg at 
Day 4, followed by weekly administration of 800 mg IFX-1 was chosen for Study IFX-1 P2.3 in 
patients with HS.  
In Study IFX-1 P2.3 in patients with HS, 800 mg once-weekly IFX-1 was administered for up to 
9 times including an additional dose of 800 mg at Day 4. This administration schedule resulted in 
IFX-1 trough concentrations of around 50 µg/mL and a decrease of elevated baseline C5a levels 
to approximately detection limit throughout the treatment duration in the majority of patients. 
This dosing regimen was well tolerated, with no new safety signals, and clinical improvement of 
HS was observed in some patients. 
In another clinical study in HS (Study IFX-1 P2.4), 4 different dosing schedules were explored, 
of which the highest dose was 1200 mg every 2 weeks. Safety findings were similar in all dose 
groups, and similar to safety findings in previous studies, with no new specific AESIs. 
Based on the above data, the dosing schedule of IFX-1 for this study includes an additional dose 
of 800 mg IFX-1 at day 2 in the established fractionated loading dose scheme, that foresees 
administration of 800 mg at days 1, 4, and 8. This additional dose has been chosen due to the 
reported high C5a levels in COVID-19 patients (Gao et al. 2020). Therefore, the entire dosing 
scheme contains up to 6 IFX-1 doses of 800 mg at days 1, 2, 4, 8, 15, and 22 (or less until 
hospital discharge). This regimen had been employed in Phase II of this study, leading to a lower 
death rate and supporting efficacy signals without any new signals of unknown toxicities (Vlaar 
et al 2020).  
3.3. 
Benefit/Risk Assessment 
IFX-1 is a chimeric IgG4 antibody that has the potential to elicit infusion reactions, including 
hypersensitivity or anaphylaxis. In animal studies, one unexplained death of a cynomolgus 
monkey retrospectively showed development of anti-IFX-1 antibodies. In clinical studies, few 
patients tested positive for anti-IFX-1 antibodies, and only mild to moderate signs of 
hypersensitivity reactions were occasionally observed so far (overall ADA rate in the range of 


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5% to 13%). In total, IFX-1 showed very good tolerability in clinical studies. The majority of 
observed AEs were attributed to the underlying diseases and IFX-1 AESIs occurred occasionally 
(see IB for details). 
A summarized in Section 3.2.4, there is evidence that in COVID-19 patients who are severely 
affected, C5a activation occurs to a large extent and that neutrophil count elevation in blood is 
associated with worse outcomes.  
Data from the interim analysis from the completed Phase II of the current study demonstrated 
that IFX-1 treatment was associated with a lower 28-day all-cause mortality when compared to 
the BSC arm, along with trends in disease improvement, as evidenced by fewer patients 
experiencing renal impairment, more patients showing reversal of blood lymphocytopenia, and a 
greater lowering of lactate dehydrogenase concentrations. In IFX-1-treated patients, PE reported 
as SAEs were lower compared to the BSC arm. Also, a temporary increase of D-dimer levels, as 
potential expression of induction of blood clot lysis, was detected in the first days after initiation 
of IFX-1 treatment. 
Overall, the expected clinical benefit for patients suffering from COVID-19-related severe 
pneumonia outweighs the risks in relation to the mild to moderate side effects that have been 
attributed to IFX-1 so far. 
4. 
OBJECTIVES AND ENDPOINTS 
4.1. 
Study Objectives 
4.1.1. 
Primary Objectives 
The primary objective of Phase II was: 
• 
To explore the effect of IFX-1 on COVID-19 related severe pneumonia (hypothesis 
generating) 
The primary objective of Phase III is:  
• 
To demonstrate the efficacy of IFX-1 to improve survival outcomes of severe COVID-19 
pneumonia (confirmative) 
4.1.2. 
Secondary Objectives 
The secondary objectives of Phase II and Phase III are:  
• 
To assess and define other parameters of efficacy 
• 
To assess the safety of IFX-1  


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4.2. 
Study Endpoints 
4.2.1. 
Phase II 
4.2.1.1. 
Primary Endpoint 
The primary endpoint in Phase II was the relative change (%) from baseline (day 1 prior to study 
drug administration at ± 1h of randomization) in oxygenation index (PaO2 / FiO2) in supine 
position at day 5. 
4.2.1.2. 
Secondary Endpoints 
The secondary endpoints in Phase II were: 
• 
Number of patients (%) achieving an Early Response as defined as meeting ALL of the 
following criteria at day 7 after enrollment: 
➢ Patient alive and extubated OR oxygenation index ≥ 300 OR improvement of ≥ 30% 
from baseline 
➢ Temperature < 38°C in absence of fever decreasing medication of at least 4h 
➢ White blood cell count within normal limit of local lab quantifications 
• 
Number of patients (%) reaching a Late Response as defined by either being discharged 
alive from hospital until day 28 OR meeting ALL of the following criteria at day 28 of the 
trial 
➢ Patient alive and extubated 
➢ Patient discharged from ICU 
➢ Patient free of shortness of breath (respiratory rate < 20) in absence of oxygen supply 
➢ Patient free of fever (< 37.6°C) 
• 
Relative change (%) from baseline (day 1 prior to study drug administration at ± 1h of 
randomization) in oxygenation index (PaO2 / FiO2) in supine position at day 3, 7, 9, and 11. 
• 
All cause 28-day mortality (%) 
• 
Frequency, severity, and relatedness to study drug of treatment-emergent adverse events 
(TEAEs) and SAEs 
4.2.1.3. 
Other Endpoints 
The other endpoints in Phase II were: 
• 
Change from baseline in alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST)  
• 
Change from baseline in troponin I adjusted to glomerular filtration rate  
• 
Change from baseline in creatinine 


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• 
Change from baseline in lymphocyte counts 
• 
Change from baseline in neutrophil counts 
• 
Change from baseline in D-dimers 
• 
Change from baseline in Glasgow Outcome Scale  
• 
Time to reach ICU discharge criteria as defined by ALL of the three criteria below: 
➢ Alive and extubated 
➢ No need for continued (>3h per day) non-invasive ventilation 
➢ Free of vasopressor and inotropic therapy 
• 
Assessment of complement activation parameters and plasma concentrations of IFX-1 
4.2.2. 
Phase III 
4.2.2.1. 
Primary Endpoint 
Based on the preliminary interim analysis of efficacy data from Phase II, the primary endpoint 
chosen for Phase III is 28-day all-cause mortality. 
4.2.2.2. 
Secondary Endpoints 
The secondary endpoints in Phase III are: 
• 
Proportion of patients free of any renal replacement therapy within 28 days upon 
randomization 
• 
Proportion of patients developing acute kidney failure (eGFR < 15 mL/min/1.73m², assessed 
by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) during 
ICU stay and at day 28 
• 
Proportion of patients with an improvement in the 8-point ordinal scale (Appendix 7) 
(day 15, day 28) 
• 
Frequency, severity, and relatedness to study drug of serious and non-serious TEAEs  
4.2.2.3. 
Other Endpoints 
The other endpoints in Phase III are: 
• 
Time to first extubation 
• 
60-day mortality 
• 
Glasgow Outcome Scale score assessed at study day 60 
• 
Quality of life assessed by EuroQol 5-D (EQ-5D) at study day 60 


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5. 
STUDY DESIGN 
5.1. 
Overall Design 
This is a pragmatic, adaptive, randomized, multicenter phase II/III study evaluating IFX-1 for the 
treatment of COVID-19 related severe pneumonia. The study consists of two parts: Phase II, an 
open-label, randomized, 2-arm phase evaluating BSC + IFX-1 (Arm A) and BSC alone (Arm B); 
and Phase III, a double-blind, placebo-controlled, randomized phase evaluating SOC + IFX-1 
(Arm A) and SOC + placebo-to-match (Arm B). The SOC includes VTE prophylaxis at a 
minimum, and may include other international and country-specific recommended treatments for 
COVID-19 per the locally adopted treatment recommendations. An independent safety 
monitoring board is established to monitor the safety in an ongoing manner for both parts of the 
study (see Sections 5.3 and 5.5).  
At the time of writing of Protocol Version 2.0, Phase II of the study has been completed and all 
30 patients have been treated (15 in Arm A [BSC + IFX-1] and 15 in Arm B [BSC alone]). 
A preliminary interim analysis has been performed to assess the clinical benefit of the treatment 
using the assessed clinical parameters. An expert committee (EC) has monitored safety and the 
supported re-definition of clinical endpoint(s) for Phase III.  
In Phase II, patients in Arm A were treated with a maximum of 7 IV doses of IFX-1 800 mg over 
a period of 29 days. The first 5 treatments at days 1, 2, 4, 8, and 15 were administered to all 
patients randomized into Arm A. Treatment at day 22 was only administered in the event that a 
patient has not been extubated and discharged from ICU. In case a patient’s clinical situation 
worsened after day 8, although an initial clinical benefit was observed, one additional 
administration of 800 mg IFX-1 between day 11 and 13 could have been given at investigator 
discretion. Loss of clinical benefit could in this situation relate to the exceptionally high C5a 
levels observed in some cases of COVID-19 related pneumonia and associated shortened IFX-1 
half-life.  
Phase III of the study follows a group-sequential design (two stages) with one interim analysis 
for stopping for futility or stopping for efficacy. A total of 180 patients will be randomized into 
Arm A and Arm B using a 1:1 allocation ratio for the first stage; based on results of the interim 
analysis, up to an additional 180 patients will be randomized using the same allocation ratio for 
the second stage.  
In Phase III, patients will be treated with a maximum of 6 IV doses of IFX-1 800 mg (Arm A) or 
placebo (Arm B) at days 1, 2, 4, 8, 15, and 22, as long as the patient is still in the hospital (even 
if discharged from the ICU).  
If possible, patients will be assessed for quality of life using the EQ-5D. 
Patients will be followed for survival and their clinical status assessed by the Glasgow Outcome 
Scale. 


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5.1.1. 
Method of Treatment Assignment 
In Phase II, patients were centrally assigned to a treatment arm by the Investigator via the 
randomization module of the electronic case report form (eCRF). The investigational medicinal 
product (IMP) was assigned to each patient by the investigator at the investigation site. Sites 
were each given a randomization block and instructed to assign the first patient to Arm A, the 
second patient to Arm B, etc. The site recorded the IMP assignment on the applicable eCRF, if 
required. 
In Phase III, patients will be centrally assigned to a treatment arm by the investigator via an 
Interactive Web Response System (IWRS). IMP will be assigned to each patient by the IWRS. 
IMP shipment to sites will be automatically triggered by the IWRS, and will be initiated, 
maintained, and controlled by the IWRS. 
IMP is dispensed at the study visits as summarized in the schedule of assessments (SoA, Table 1 
and Table 2). 
5.1.2. 
Blinding 
Phase II of the study was open-label and randomized, while Phase III will be double-blind, 
placebo-controlled, and randomized. 
5.2. 
Patient Enrollment 
In Phase II, patients were randomized to Group A or B. The maximum number of randomized 
patients in Phase II was set to 30. There was a recruitment stop after the planned number of 
patients for Phase II were enrolled. After the preliminary interim analysis of Phase II was 
performed and the EC recommended to proceed, the number of patients for Phase III was 
calculated according to the established hypothesis. For details on the role of the EC, see 
Section 5.4. 
In Phase III, 180 patients will be randomized into Arm A and Arm B using a 1:1 allocation ratio 
for the first stage; based on results of the interim analysis, up to an additional 180 patients will be 
randomized using the same allocation ratio for the second stage. 
5.3. 
Independent Safety Monitoring Board for Phase II  
An independent Safety Monitoring Board (iSMB) was constituted to support safety surveillance 
in both treatment arms throughout Phase II and Phase III of the study. The committee included at 
least 2 Intensive Care specialists not involved as investigators in this study and an independent 
statistician.  
The iSMB monitored the safety of all patients regularly, after 10, 20, and 30 patients completed 
their treatment in Phase II. At each review, the iSMB recommended on continuing or ending the 


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study. After completion of Phase II (30 patients), the iSMB has assessed the totality of available 
data of all patients and has recommend on proceeding to Phase III (see Section 3.2.3).  
5.4. 
Expert Committee for Phase II 
An EC was constituted to support efficacy surveillance in both treatment arms throughout 
Phase II of the study. The committee included the clinical study monitor and at least 3 Intensive 
Care specialists involved in the treatment of COVID-19 affected patients (Coordinating 
Investigator included).  
The committee monitored the efficacy of all patients regularly, after 10, 20, and 30 patients 
completed their treatment. At each review, the EC was able to recommend on continuing or 
ending the study. 
After completion of Phase II (30 patients), the EC assessed the totality of the data of all patients, 
taking into account the recommendations of the iSMB and recommend proceeding to Phase III, 
assessed appropriateness of the endpoints and scheduled assessments, and supported establishing 
an adequate hypothesis for Phase III.  
The EC has stopped meeting at the beginning of Phase III (i.e., at the time of writing of Protocol 
Version 2.0). 
5.5. 
Independent Data Safety Monitoring Board for Phase III 
In Phase III, the iSMB from Phase II will continue as an independent Clinical Trial Data 
Monitoring Committee (iDMC). The iDMC will meet every 3 months throughout Phase III of 
the study to further assess safety. In addition, the iDMC will perform an unblinded assessment of 
the data of the interim analysis and will make recommendations on whether to continue the study 
or not according to the predefined early stop criteria (see Section 10.2.3.5). All available data 
will be provided to the iDMC before each meeting. Details will be described in a separate iDMC 
Charter. 
5.6. 
Patient and Study Completion 
5.6.1. 
Phase II 
5.6.1.1. 
End of Treatment and Follow-up 
End of treatment (EOT) was defined as last planned administration or discontinuation of IMP for 
other reasons. The EOT telephone visit (Follow-up Visit [FUV] 1) was to occur 28 days after last 
study drug administration in Phase II. The visit information obtained via the telephone call 
(e.g., AEs, survival status) was to be recorded. 
Discontinuation of study treatment did not represent withdrawal from the study. 


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For details on treatment discontinuation criteria, see Section 7.2.4. 
5.6.1.2. 
End of Study  
Patients were to be followed for survival using the Glasgow Outcome Scale until the end of 
study (EOS) visit (FUV 2). If required, information could have been obtained by a telephone 
call. 
The EOS for the individual patient was defined as the date of the last contact of the 2-month 
follow-up period, date of death, date of consent withdrawal from study participation (see 
Section 5.6.1.3), or the date of last contact when patients were lost to follow-up (see 
Section 5.6.1.4). 
The entire study was to end when all patients discontinued IFX-1 AND all patients ended the 
study as described above.  
The sponsor could have prematurely terminated Phase II of the study at any time earlier than 
planned for the following reasons: 
• 
Unacceptable toxicity 
• 
Administrative reasons 
5.6.1.3. 
Consent Withdrawal/ Discontinuation of Study Participation 
A patient could have withdrawn from Phase II of the study at any time at his/her own request 
without the need to provide any reason(s). 
If the patient withdrew from study participation, the sponsor could have retained and continued 
to use any data collected before such a withdrawal of consent. However, in the case of deferred 
informed consent, if the consent was not obtained or if a legal representative denied the patient’s 
participation in the study, the patient was excluded and data were no longer to be used (see 
Section 6.3). Patients (or legal representatives) who wished to withdraw consent/discontinue the 
study while still on treatment should have been encouraged by the investigator to perform the 
EOT visit for their own safety before any further data collection for study purposes was 
terminated.  
If a patient withdrew from the study, he/she could have requested destruction of any samples 
taken and not tested, and the investigator must have documented this in the site study records. 
5.6.1.4. 
Lost to Follow-up 
A patient was to be considered lost to follow-up if he or she could not be reached after hospital 
discharge for scheduled contacts and the study site was unable to make contact as described 
below.  


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The following actions must have been taken if a patient could not be reached: 
• 
The site must have attempted to re-contact the patient as soon as possible after the failed 
first scheduled contact.  
• 
Before a patient was deemed lost to follow-up, the investigator or designee must have made 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts were to be documented in the patient’s medical record. 
• 
Should the patient have continued to be unreachable, he/she was considered to have been 
withdrawn from the study with a primary reason of lost to follow-up. 
5.6.2. 
Phase III 
5.6.2.1. 
End of Treatment and Follow-up 
End of treatment is defined as the last planned administration or discontinuation of IMP for other 
reasons. The FUV is scheduled to occur 60 days after the randomization date. The visit 
information obtained via the telephone call (e.g., AEs, survival status) should be recorded. 
Discontinuation of study treatment does not represent withdrawal from the study. 
For details on treatment discontinuation criteria, see Section 7.2.4. 
5.6.2.2. 
End of Study  
The end of study for the individual patient is defined as the date of the last contact of the 
follow-up period (i.e., 60 days after randomization), date of death, date of consent withdrawal 
from study participation (see Section 5.6.2.3), or the date of last contact when patients are lost to 
follow-up (see Section 5.6.2.4), whatever occurs earliest. 
The entire study will end when all patients have discontinued IFX-1 AND all patients ended the 
study as described above.  
The sponsor may prematurely terminate the study at any time earlier than planned for the 
following reasons: 
• 
Unacceptable toxicity 
• 
Administrative reasons 
5.6.2.3. 
Consent Withdrawal/Discontinuation of Study Participation 
A patient may withdraw from the entire study at any time at his/her own request without the need 
to provide any reason(s). 
If the patient withdraws from study participation, the sponsor may retain and continue to use any 
data collected before such a withdrawal of consent. However, in the case of deferred informed 


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consent, if the consent is not obtained or if a legal representative denies the patient’s 
participation in the study, the patient is excluded and data will no longer be used, except if local 
regulations would permit the use of such data in this situation (see Section 6.3). Patients (or legal 
representatives) who wish to withdraw consent/discontinue the study while still on treatment 
should be encouraged by the investigator to perform the FUV for their own safety before any 
further data collection for study purposes. 
If a patient withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the investigator must document this in the site study records. 
5.6.2.4. 
Lost to Follow-up 
A patient will be considered lost to follow-up if he or she cannot be reached after hospital 
discharge for scheduled contacts and the study site is unable to make contact as described below.  
The following actions must be taken if a patient cannot be reached: 
• 
The site must attempt to re-contact the patient as soon as possible after the failed first 
scheduled contact.  
• 
Before a patient is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the patient (where possible, 3 telephone calls and, if necessary, 
a certified letter to the patient’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the patient’s medical record. 
• 
Should the patient continue to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
6. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Study patients are considered enrolled into the study using a deferred consent procedure or 
another legally acceptable local consent procedure in this special ICU situation. 
6.1. 
Phase II 
6.1.1. 
Inclusion Criteria 
Patients must have met all the following criteria at screening and at enrollment to be randomized 
into Phase II of the study: 
1. At least 18 years of age or older 
2. Clinically evident or otherwise confirmed severe pneumonia as evidenced by at least one of 
the following criteria: 


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3. Chest X-ray or computed tomography (CT) scan or magnetic resonance imaging (MRI) with 
pulmonary infiltrates consistent with pneumonia 
4. Clinical history in past 14 days of newly developed severe shortness of breath (> 29 breaths 
/ minute) in the absence of oxygen supply or spontaneous peripheral oxygenation ≤ 92 with 
need for oxygen supply, or need for non-invasive or invasive ventilation (in conjunction 
with a positive test for SARS-CoV-2 infection) 
5. Oxygenation index at time of enrollment (PaO2 / FiO2) ≤ 250 and ≥ 100 in supine position  
6. SARS-CoV-2 infection confirmation (tested positive in last 14 days or test results to be 
obtained within 24h after enrollment, both with locally available test system).  
7. No use OR stop of any corticosteroid treatment at time point of enrollment (topical 
treatment and systemic dose of ≤ 10mg prednisone / day equivalent allowed) 
6.1.2. 
Exclusion Criteria 
Patients who fulfilled any of the following criteria at screening were not eligible to participate in 
Phase II of the study: 
1. Oxygenation index at time of enrollment (PaO2 / FiO2) < 100 or > 250 in supine position  
2. Intubated > 48h at time point of enrollment  
3. Patients who demonstrate an improvement in past 24h prior to enrollment in oxygenation 
and ventilation / support parameters which indicate an expected resolution of lung 
dysfunction in the next 24h without additional intervention according to judgment of the 
investigator with one or more of the following parameters present: 
4. Improvement in oxygenation index of > 30% relative to previous measure (last 24h in 
supine position) 
5. Extubation if intubated before 
6. Known history of chronic obstructive pulmonary disease (COPD) (GOLD category C or D) 
7. Known history of chronic dialysis OR received renal replacement therapy in past 14 days 
8. Received new other biologic treatment attempt for COVID-19 in the past 14 days  
9. Received treatment with a viral replication inhibitor in past 3 days 
10. Known hypersensitivity to IFX-1 or any other ingredient of the study medication 
11. Known pregnancy 
12. Received organ or bone marrow transplantation in past 3 months 
13. Known mechanically resuscitation in past 14 days  
14. Patient moribund or expected to die in next 12h according to the judgment of the 
investigator 
15. Patients otherwise considered restricted from receiving full supportive care (including ICU 
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16. Existing diagnosis of progressed cancer or other life-limiting disease with life expectancy < 
6 months 
17. Known to have received anti-cancer therapy for oncological disease in past 4 weeks 
18. Known severe congestive heart failure (New York Heart Association [NYHA] Class III-IV; 
see Appendix 8) 
6.2. 
Phase III 
6.2.1. 
Inclusion Criteria 
Patients must meet all the following criteria at randomization to be enrolled into Phase III of the 
study: 
1. At least 18 years of age or older 
2. Patient on invasive mechanical ventilation (but not more than 48h post intubation at time 
point of randomization) 
3. Patients with a PaO2 / FiO2 ratio of < 200 and > 60 at randomization (one representative 
measurement within 6h before randomization) 
4. SARS-CoV-2 infection confirmation (tested positive in last 14 days before randomization 
with locally available test system) 
6.2.2. 
Exclusion Criteria 
Patients who fulfill any of the following criteria at randomization are not eligible to participate in 
Phase III of the study: 
1. Intubated > 48h at time point of randomization  
2. Expected stop of invasive ventilation or expected extubation in the next 24h without 
additional intervention according to judgment of the investigator 
3. Known history of chronic dialysis OR received renal replacement therapy in past 14 days 
OR anticipated to receive renal replacement therapy within 24h after randomization 
4. Known history of progressed COPD as evidenced by use of daily maintenance treatment 
with long-acting bronchodilators or inhaled/oral corticosteroids for > 2 months 
5. Treatment of COVID-19 with investigational antibody treatment(s) which are not approved 
or not included in locally adopted treatment guidelines (e.g., WHO guidance, National 
Institutes of Health [NIH] COVID-19 treatment guidelines) for this indication in the past 
7 days (Note: Antibody treatment[s] given within past 7 days for pre-existing diseases, other 
than COVID-19, are allowed.) 
6. At time point of randomization, treatment of COVID-19 with investigational treatments 
which are not approved or not included in locally adopted treatment guidelines for this 
indication (e.g., WHO guidance, NIH COVID-19 treatment guidelines), including 
SARS-CoV-2 multiplication inhibitor(s) or immunomodulator(s). (Note: If a locally adopted 
treatment guideline recommends drugs such as remdesivir, dexamethasone, or 


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anticoagulation, this would be allowed. Adopted guidelines and updates must be 
documented at study initiation and throughout the conduct of the study.) 
7. Known hypersensitivity to IFX-1 or any other ingredient of the study medication 
8. Serum or urine pregnancy test positive before randomization (required for women of 
childbearing potential) 
9. Received organ or bone marrow transplantation in past 3 months 
10. Known cardio-pulmonary mechanical resuscitation in past 14 days 
11. Received cytokine adsorption therapy in past 3 days 
12. Patient moribund or expected to die in next 24h according to the judgment of the 
investigator  
13. Known to have received anti-cancer therapy for hemato-oncological disease in past 4 weeks 
OR known to have active malignant disease at time point of randomization 
14. Known severe congestive heart failure (NYHA Class III-IV; see Appendix 8) 
15. Known history of chronic liver disease (Child-Pugh B or C; see Appendix 9) 
16. Participating in or has participated in other investigational interventional studies (drug or 
device) within the last 7 days before randomization 
6.3. 
Deferred Consent 
In the Netherlands and Germany, we ask for deferred consent for patients in need of intensive 
care and we appeal to the emergency procedure for consent in medical research as stated in 
Article 6, Paragraph 4 of the WMO (Netherland), §41 (1) AMG (Germany), and other applicable 
country specific regulations, because of the following reasons: 
It is very likely that the severity of the disease (severe pneumonia/acute respiratory distress 
syndrome) will result in a large proportion of patients unable to provide informed consent before 
the beginning of the trial either in oral or written form, mainly due to being on a ventilator or 
treated with drugs with sedative effects. COVID-19 related pneumonia resulting in the need for 
intensive care is a fast progressing disease. It requires immediate adequate treatment that cannot 
be postponed. So far, no treatment has been shown to address the underlying neutrophilic, 
inflammatory lung damage. Since IFX-1 blocks C5a, it has the potential to block neutrophil 
attraction to the lung. Moreover, it has been shown that COVID-19-related severe pneumonia is 
linked to extremely high C5a blood levels and related to a worse outcome of patients (Gao et al. 
2020). In an ongoing study testing the biosimilar C5a antibody BDB-1, the first 2 patients treated 
showed a good recovery after being treated. Taken together, there is a possibility that treatment 
with IFX-1 will provide benefit specifically for patients with COVID-19-related severe 
pneumonia that require intensive care.   
These severely ill patients are incompetent to give informed consent, and obtaining informed 
consent from a legal representative may be almost impossible due to the current COVID-19-


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caused quarantine measures. Time to get informed consent from legal representatives will take at 
least half day, even by an experienced research team. 
Patients will be randomized at the ICU where the inclusion and exclusion criteria will be 
checked directly before intensive care becomes necessary or during the 24 hours before invasive 
ventilation.  
In the Netherlands, if the patient is incompetent to provide informed consent and a legal 
representative cannot be reached in time, the investigator examines the patient and confirms the 
patient’s inability to provide consent as well as the urgency of participating in the trial with 
possible benefit to the patient. Informed consent from the patients, their relatives or their legal 
representative will be requested at the earliest appropriate time thereafter as applicable in the 
participating country. At minimum, the attempt of contacting the patient’s relatives and the result 
of the contact will be documented in the patient’s file.  
In Germany, the investigator examines the patient and, if the patient is not able to consent, 
confirms together with a consulting physician, the patient’s inability to provide consent as well 
as the urgency of participating in the trial with possible benefit to the patient. Informed consent 
from the patient will be requested at the earliest appropriate time thereafter. Due to the current 
lock down and quarantine regulations in Germany the patients’ legal representative will not be 
contacted to obtain consent as it will be impossible to obtain written consent within the screening 
window.  
In other participating countries where a deferred consent procedure is not legally acceptable, 
specific requirements will be laid out that will describe the country-specific legally acceptable 
procedure for retrieving consent from patients who are incompetent to provide consent or their 
relatives or their legal representatives, whatever will be applicable.   
The hypothesis is that this group of intensive care patients can potentially benefit from 
participating in this study. While patients are exposed to the possible side effects of IFX-1, they 
will also receive SOC in Phase III. 
6.4. 
Screening Failures 
Screening failures are defined as patients who do not meet the criteria for participation in this 
study and thus, are not randomized/assigned to IMP. Screen failure data will not be recorded 
within the eCRF. 
Rescreening does not apply to this study. 
6.5. 
Meals and Dietary Restrictions 
Not applicable. 


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7. 
STUDY DRUG(S) AND ADMINISTRATION 
7.1. 
Investigational Medicinal Product 
The IMP is defined as the investigational treatment IFX-1 and Placebo-to-match (Placebo) that is 
intended to be administered to a study patient according to the study protocol. 
7.1.1. 
Packaging and Labelling of Investigational Medicinal Product 
IFX-1 concentrate solution for infusion will be supplied in 20 mL glass vials at a concentration 
of 10 mg/mL (200 mg per vial) for reconstitution and IV administration. Apart from IFX-1, the 
solution will contain sodium chloride, sodium phosphate, and polysorbate 80. 
Placebo concentrate solution for infusion will be supplied in 20 mL glass vials for reconstitution 
and IV administration. The solution will contain sodium chloride, sodium phosphate, and 
polysorbate 80. 
IFX-1 and Placebo will be packaged in cartons and labeled in accordance with all legal 
requirements. Each carton will contain 4 vials of IFX-1 or 4 vials of Placebo. Each carton and 
each vial will be labeled with a multilingual booklet label or a single panel label as applicable. 
7.1.2. 
Storage, Handling, and Accountability 
Vials of IFX-1 and Placebo must be stored in a refrigerator at 2°C to 8°C (35.6°F to 46.4°F) in 
their original cartons to protect from light and must not be frozen or shaken. All supplies of 
IFX-1 and Placebo must be stored separately or segregated from other study supplies and site 
stock in a dedicated locked facility with access limited to authorized personnel. All storage 
facilities must be temperature controlled and monitored and compliant with applicable regulatory 
requirements. 
An established and validated local temperature management system with temperature logs 
should be used to record the storage temperature. If this is not possible, the study site will be 
provided with a temperature record form by the Contract Research Organization (CRO) and the 
site personnel will maintain temperature records for the entire duration of the study. At a 
minimum, the daily (working day) minimum and maximum temperatures must be documented. 
Any deviation from the specified temperature range must be documented and reported within 
24 hours (or the next working day). Further instruction on the management and reporting of 
temperature deviations is provided in the Pharmacy Manual (or equivalent document). 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during shipment for all IMP received and any discrepancies are reported and resolved 
before use of the IMP. 


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Only patients enrolled in the study may receive IMP and only authorized site staff may prepare 
and administer IMP. The IMP must be prepared in a controlled area in accordance with local 
regulations/ requirements for reconstitution of products for IV administration. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for the correct storage of IMP, IMP accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused IMP are provided in the 
Pharmacy Manual (or equivalent document) provided by the CRO. 
7.1.3. 
Drug Preparation and Administration Instructions 
The IFX-1 and Placebo for infusion will be reconstituted (prepared) in a controlled area at the 
study site or at the study site’s pharmacy, in accordance (compliance) with applicable local 
regulations/ requirements for reconstitution of products for IV administration. 
The reconstituted IFX-1 or Placebo should be used within 4 hours after dilution when stored at 
room temperature. Otherwise, the reconstituted IFX-1 or Placebo has to be stored at 2°C to 8°C 
(35.6°F to 46.4°F) and used within 24 hours; if the reconstituted solution is stored in a 
refrigerator, it must be left to acclimatize to room temperature prior to administration. Details for 
the preparation of the reconstituted solution will be provided in the Pharmacy Manual (or 
equivalent document).  
The number of unused, partially used, and empty vials will be documented accurately, and the 
vials will be kept at the site until further notice by the Sponsor. 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
Further guidance and information for the final disposition of unused IMP are provided in the 
Pharmacy Manual (or equivalent document). 
7.1.4. 
Recall of IMP 
Instructions (actions to be taken by site) in the case of IMP recall are provided in the Pharmacy 
Manual (or equivalent document). 
7.2. 
Administration and Dosage 
For Phase II, patients were randomized to either receive BSC + IFX-1 in treatment Arm A or 
BSC alone in treatment Arm B. The first dose of IFX-1 was administered at Cycle 1 Day 1. 
For Phase III, patients are randomized to either receive SOC + IFX-1 in treatment Arm A or 
SOC + Placebo in treatment Arm B. The first dose of IFX-1 or Placebo is administered at Day 1. 


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Close observation of IFX-1 or Placebo infusion(s) is required for monitoring of potential 
infusion reactions. Appropriate treatment for potential infusion reactions must be available 
during this time. 
7.2.1. 
Treatment Administered 
7.2.1.1. 
Phase II 
IFX-1 800 mg was administered for a maximum of 7 doses over a period of 29 days as a 
30-minute IV infusion. However, given the variability of infusion pumps from site to site, a 
window between 5 minutes and +10 minutes was permitted (i.e., infusion time was 30 minutes 
(5 min/+10 min). IMP administrations for Phase II are detailed in Figure 1. 
The first 5 treatments at days 1, 2, 4, 8, and 15 were administered to all patients randomized into 
Arm A. Treatment at day 22 was only administered in the event that a patient had not been 
extubated and discharged from ICU. In case a patient’s clinical situation worsened after day 8, 
although an initial clinical benefit was observed, one additional administration of IFX-1 between 
day 11 and 13 could have been given at investigator discretion. 
7.2.1.1. 
Phase III 
Patients will be treated with a maximum of 6 IV doses of IFX-1 800 mg (Arm A) or placebo 
(Arm B) administered as a 30-60 minute IV infusion. The first 4 treatments at days 1, 2, 4, and 8 
shall be administered to all patients. Treatments at days 15 and 22 shall only be administered in 
the event that a patient is still in the hospital, even if discharged from ICU. IMP administrations 
for Phase III are detailed in Figure 2. 


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Figure 1 
Patient Calendar: IMP Administrations – Phase II 
 
 
D = day; D/C = discharge; EOS = end of study; EOT = end of treatment; FUV = follow-up visit; IMP = investigational medicinal product 
 


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Figure 2 
Patient Calendar: IMP Administrations – Phase III 
 
D = day; FUV = follow-up visit; IMP = investigational medicinal product 
 


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7.2.2. 
Treatment Modification 
This protocol allows some alteration from the currently outlined dosing schedule, but a dose 
reduction of IMP is generally not allowed.  
Adverse events leading to treatment modifications will be graded as mild, moderate, severe, or 
life-threatening based on the investigator’s assessment, using the definitions provided in 
Section 9.2.2.  
In case of toxicity, IMP dosing can be held by a maximum of 1 week. If therapy is continued 
during this time span, dosing will resume within the initial schedule and allowed administration 
window for a specific visit. 
For treatment discontinuation criteria, see Section 7.2.4. 
7.2.2.1. 
Infusion Reactions 
IFX-1 may cause infusion reactions, including severe or life-threatening hypersensitivity or 
anaphylactic reactions. Signs and symptoms of infusion reactions usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion with or without adequate medication. Dose modification criteria for infusion reactions 
are listed in Appendix 5, Table 6.  
7.2.3. 
Re-dosing Criteria 
The following criteria must be fulfilled to allow for re-dosing of study drug: 
• 
Absence of treatment discontinuation criteria (see Section 7.2.4). 
7.2.4. 
Treatment Discontinuation Criteria 
Discontinuation of study treatment does not represent withdrawal from the study. See 
Section 5.6.1.1 (for Phase II) or Section 5.6.2.1 (for Phase III) for the end of treatment definition 
and procedures. 
In general, patients should be treated with IMP until unacceptable toxicity, completion of the 
planned treatment, extubation, or death. 
Possible reasons for treatment discontinuation for individual patients are: 
• 
Clinical deterioration 
• 
Study participation consent withdrawal (see Sections 5.6.1.3 and 5.6.2.3) 
• 
Safety: 
o moderate infusion reactions despite adequate premedication (see Appendix 5, Table 6) 


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o severe or life-threatening infusion reactions (see Appendix 5, Table 6) 
7.3. 
Premedication and Postmedication 
Routine premedication is not required prior to the first dose of IMP. 
Patients with mild or moderate infusion reaction following IMP administration may continue to 
receive IMP with close monitoring; premedication with antipyretic and antihistamine may be 
considered.  
Patients should be observed for 60 minutes, or longer per clinical judgment, after IMP 
administrations. 
Treatment guidelines in case of occurrence of infusion reactions are detailed in Appendix 5, 
Table 6. 
7.4. 
Prior and Concomitant Medication/Treatments 
In Phase III of the study, in addition to the IMP, all patients will receive SOC for treatment of 
COVID-19, which includes VTE prophylaxis with anticoagulants at a minimum. Other 
international or country-specific recommended treatments for COVID-19 per the locally adopted 
treatment recommendations (including but not limited to corticosteroids, remdesivir, and other 
local SOC) are allowed as concomitant medications. 
Reporting of prior and concomitant medications will follow special considerations for the ICU 
setting, as described in Appendix 10. 
Reportable medications or vaccinations that the patient is receiving within 7 days prior to the 
first dose of study treatment and up to 30 days after the last dose of study treatment should be 
recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
7.4.1. 
Prohibited Concomitant Medication/Treatment 
Medications or vaccinations specifically prohibited in the exclusion criteria (see Sections 6.1.2 
and 6.2.2) are not allowed during the ongoing study. If there is a clinical indication for any 
medication or vaccination specifically prohibited during the study, discontinuation from study 
therapy may be required. The investigator should discuss any questions regarding this with the 
medical monitor. The final decision on any supportive therapy or vaccination rests with the 


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investigator and/or the patient's primary physician. However, the decision to continue the patient 
on study treatment requires the mutual agreement of the investigator and the sponsor. 
The following concomitant therapies or vaccinations are prohibited during the course of the 
study: 
• 
Antineoplastic systemic therapy 
• 
Investigational antibody treatments and other investigational agents (excluding IFX-1 but 
including SARS-CoV-2 multiplication inhibitor[s] or immunomodulator[s]) which are not 
approved or not included in locally adopted treatment recommendations for treatment of 
COVID-19 (e.g., WHO guidance, NIH COVID-19 treatment guidelines) 
• 
Cytokine adsorption therapy 
Patients who, in the assessment of the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study.  
All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. 
7.5. 
Rescue Medications and Supportive Care 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  
7.6. 
Treatment of Overdose 
No specific information is available on the treatment of overdose of IFX-1. For this study, an 
overdose of IFX-1 will be defined as any single dose of > 1200 mg. In the event of overdose, the 
participant should be observed closely for signs of toxicity. Appropriate supportive treatment 
should be provided if clinically indicated. 
In the event of an overdose, the investigator should: 
1. Contact the medical monitor immediately 
2. Closely monitor the patient for any AE/SAE and laboratory abnormalities 
3. Obtain a plasma sample for PK analysis as close as possible to the administration of 
overdose if requested by the medical monitor (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the patient. 


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Phase II 
Study procedures and their timing for Phase II are summarized in the Schedule of Assessments 
(SoA; Table 1). 
Details on the assessments and procedures are given in the following subsections.  
Safety concerns should have been discussed with the sponsor immediately upon occurrence or 
awareness to determine if the patient should continue or discontinue any IMP. 
Adherence to the study design requirements, including those specified in the SoA (Table 1), was 
essential and required for study conduct. 
All screening evaluations must have been completed and reviewed to confirm that potential 
patients met all eligibility criteria (Section 6.1). The investigator was to maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
8.1.1. 
Baseline Assessments 
The following procedures were to be performed to assess baseline characteristics during 
screening evaluations and before IMP administration: 
• 
Documentation of demographic details (age, gender, race, and ethnicity), medical and 
disease history (see Sections 8.1.1.1 and 8.1.1.2) 
• 
Disease assessments (see Section 8.1.2) 
• 
Documentation of concomitant disease and concomitant medications (see Sections 8.1.1.3 
and 8.1.1.4) 
• 
Baseline safety assessment (height, weight, physical exam, vital signs, AEs, and safety 
laboratory; see Section 8.1.3) 
8.1.1.1. 
Medical History (Except COVID-19 history) 
The documentation of the patient’s medical history were to include any details on the patient’s 
medical history before enrollment into the study. The information must have been documented as 
such in the source documentation and eCRF. 
8.1.1.2. 
COVID-19 History 
Any details on the patient’s COVID-19 disease history including any COVID-19 therapy (onset 
of symptoms, medications, oxygen support, intubation, SARS-CoV-2 testing) by verbatim name 
with start and end dates, dosages, modality) that the patient received were to be documented in 
the source documentation and in the eCRF. 


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8.1.1.3. 
Concomitant Disease  
All diseases that the patient was experiencing at enrollment into the study or after enrollment 
until EOT were to be regarded as concomitant diseases. All concomitant diseases must have been 
documented in the source documentation and in the eCRF. 
8.1.1.4. 
Prior and Concomitant Medications 
All drugs being taken by a patient at enrollment into the study or after enrollment until EOT 
were to be regarded as concomitant medication.  
All prior medications taken by the patient within 2 weeks before enrollment into the study and all 
concomitant medications must have been documented in the source documentation and in the 
eCRF. Details on prior and concomitant medications must have included the reason for use, 
administration start and stop dates, and dosing information, including dose, route, and frequency 
of administration. 
8.1.2. 
Efficacy Assessments 
8.1.2.1. 
Imaging Requirements 
CT scan, MRI, or X-ray for COVID-19 assessment were to be performed locally at each 
scheduled disease assessment time point, and at any time when disease progression was 
suspected. 
The choice of whether the imaging was by CT scan, MRI, or X-ray was an investigator decision. 
Once the imaging choice had been made, subsequent assessments should have been made using 
the same modality whenever possible. 
8.1.2.2. 
Evaluation of Lung Function 
• 
Oxygenation index (PaO2 / FiO2)  
• 
Respiratory rate 
• 
Oxygen supplementation: room air, flow O2 (L/min) if extubated 
• 
Ventilation status (invasive/non-invasive/intermittent non-invasive) 
• 
Mode of ventilation (e.g., CPAP/BIPAP) 
• 
Other oxygenation support  
➢ Type of oxygen mask or nasal canula, or other mechanical ventilation mode and 
parameters, as applicable, should have been documented 
• 
Intubation and extubation dates, as well as date of tracheostomy should have been 
documented 


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8.1.2.3. 
Evaluation of Response 
• 
SARS-CoV-2 mRNA testing was to be performed in context of enrolment procedures and at 
one to four additional time points at discretion of the investigator 
8.1.2.3.1. 
Evaluation of Early Response 
Early Response as defined as meeting ALL of the following criteria at day 7 after enrollment: 
• 
Patient alive and extubated OR oxygenation index ≥ 300 OR improvement of ≥ 30% from 
baseline,  
• 
Temperature < 38°C in absence of fever decreasing medication of at least 4h 
• 
White blood cell count within normal limit of local lab quantifications 
8.1.2.3.2. 
Evaluation of Late Response 
Late Response as defined by either being discharged alive from hospital until day 28 OR 
meeting ALL of the following criteria at day 28 of the trial: 
• 
Patient alive and extubated 
• 
Patient discharged from ICU 
• 
Patient free of shortness of breath (respiratory rate < 20) in absence of oxygen supply 
• 
Patient free of fever (< 37.6°C) 
8.1.3. 
Safety Assessments 
Safety was to be assessed based on the following variables: 
• 
AEs (see Section 8.1.3.1) 
• 
Laboratory safety parameters (see Section 8.1.3.2) 
• 
Vital signs (see Section 8.1.3.3) 
• 
Electrocardiograms (see Section 8.1.3.4) 
• 
Physical examination (see Section 8.1.3.5) 
Planned time points for all safety assessments are provided in the SoA (Table 1). 
8.1.3.1. 
Adverse Events Assessments 
Adverse events were to be assessed throughout the study from the time of enrollment to the EOT 
visit as specified in the SoA (Table 1). For details on AE collection and reporting, see 
Section 9.1. The investigator should have taken appropriate measures to follow all AEs until 
clinical recovery was complete and laboratory results had returned to normal, or until 
progression had been stabilized, or until death, in order to ensure the safety of the patients. This 
may imply that observations would continue beyond the last planned visit per protocol, and that 


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additional investigations may have been requested by the sponsor. When study treatment was 
prematurely discontinued, the patient’s observation was to be continued until the EOT visit for 
that patient as defined by the protocol. 
8.1.3.2. 
Clinical Safety Laboratory Assessments 
In general, blood samples for safety laboratory analysis should have been obtained once a day 
during a routine sampling (preferable in the morning) before administration of IMP. Additional 
tests may have been performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
See Appendix 1, Table 3 for the list of clinical laboratory tests performed and the SoA (Table 1) 
for timing and frequency.  
The investigator must have reviewed the laboratory report, documented this review, and recorded 
any clinically relevant changes (clinically relevant abnormal findings) occurring during the study 
in the AE section of the eCRF. The laboratory reports must have been filed with the source 
documents. Clinically relevant abnormal laboratory findings were those which were not 
associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the patient’s condition. 
All laboratory tests with values considered clinically relevantly abnormal and with onset before 
EOT visit should have been reported in the AE section of the eCRF and repeated until the values 
returned to normal or baseline, were no longer considered clinically relevant by the investigator 
or medical monitor, or until the EOS visit (also see Section 8.1.4 and Appendix 3). 
If such values did not return to normal/baseline within a period of time judged reasonable by the 
investigator, the etiology should have been identified, and the sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 1, Table 3, must have been 
conducted in accordance with the SoA (Table 1).  
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory required a change in patient management or were considered 
clinically relevant by the investigator (e.g., SAE or AE or dose modification), then the results 
must have been recorded in the eCRF. 
Blood samples for serum pregnancy testing were to be collected on the same day as safety 
laboratory testing. For details on pregnancy testing, refer to Appendix 4. 
8.1.3.3. 
Vital Signs 
Core body temperature, heart rate, respiratory rate, and blood pressure (diastolic and systolic) 
were to be assessed at each visit at pre-dose on the days of IMP administration and at further 
time points whenever medically indicated. 


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Blood pressure and pulse measurements were to be assessed with a completely automated 
device. Manual techniques were to be used only if an automated device was not available. 
Vital signs were to be measured in a supine position (after a rest of at least 1h in case of position 
switch from prone position), preferably in the morning. Three readings of blood pressure and 
pulse were to be taken. The first reading should have been rejected. The second and third 
readings should have been averaged to give the measurement recorded in the eCRF. 
8.1.3.4. 
Electrocardiograms 
12-lead electrocardiogram (ECG) was to be obtained as outlined in the SoA (Table 1) using an 
ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QTc 
intervals. 
8.1.3.5. 
Physical Examination 
A physical examination was to be conducted at screening and each study visit. 
The physical examination included, at a minimum, assessments of the skin, cardiovascular, 
respiratory, gastrointestinal, and neurological systems. Height (at screening) and weight was also 
to be measured and recorded as specified in the SoA (Table 1). 
Investigators should have paid special attention to clinical signs related to previous serious 
illnesses. 
8.1.3.6. 
Survival Status 
The patient survival status were to be assessed during the study and follow-up and documented 
in the eCRF. In case the patient died and the date of death was unknown, the date of the last 
personal contact should have been documented at a minimum. 
8.1.4. 
Pharmacokinetics/Pharmacodynamics 
If possible, blood samples were to be collected pre-dose for measurement of plasma 
concentrations and C3a and C5a of IFX-1 as specified in the SoA (Table 1). IFX-1 
concentrations were to be measured for all patients in citrate plasma and analyzed by a 
specialized laboratory using Enzyme-Linked ImmunoSorbent Assay. 
Detailed instructions regarding the collection, processing, etc., of samples were to follow local 
regulations and requirements. 
8.1.5. 
Biobanking of Samples from Patients Treated at Amsterdam Medical Center 
COVID-19 is a new viral disease with distinct clinical and pathophysiological features, which 
differentiate COVID-19 from other viral diseases such as Influenza. A COVID-19 dedicated 
Biobank was established at the Amsterdam Medical Center (AMC) in order to investigate further 


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COVID-19 pathophysiological characteristics. Therefore, it was planned to store all remaining 
AMC study patient derived biomaterials, including but not limited to blood, bronchial lavage 
fluid, and tissue in the AMC COVID-19 Biobank. Patients were to be asked for a separate 
informed consent.  
8.2. 
Phase III 
Study procedures and their timing for Phase III are summarized in the SoA (Table 2). 
Details on the assessments and procedures are given in the following subsections.  
Safety concerns should be discussed with the sponsor immediately upon occurrence or awareness 
to determine if the patient should continue or discontinue any IMP. 
Adherence to the study design requirements, including those specified in the SoA (Table 2), is 
essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria (Section 6.2). The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening failure, 
as applicable. 
8.2.1. 
Baseline Assessments 
The following procedures will be performed to assess baseline characteristics during 
randomization evaluations and before IMP administration: 
• 
Check inclusion and exclusion criteria 
• 
Documentation of demographic details (age, gender, race, and ethnicity), medical and 
COVID-19 history (see Sections 8.2.1.1 and 8.2.1.2) 
• 
Ordinal scale assessment (see Section 8.2.2.2) and oxygenation index (PaO2 / FiO2; one 
representative measurement within 6h before randomization) 
• 
Documentation of concomitant disease and prior medications (see Sections 8.2.1.3 and 
8.2.1.4) 
• 
Baseline safety assessment (height, weight, physical exam, AEs, ECGs, urine analysis, 
pregnancy test, and clinical safety laboratory [including creatinine assessment]); 
see Section 8.2.3) 
8.2.1.1. 
Medical History (Except COVID-19 history) 
The documentation of the patient’s medical history includes any details on the patient’s medical 
history before randomization into the study. The information must be documented as such in the 
source documentation and eCRF. 


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8.2.1.2. 
COVID-19 History 
Any details on the patient’s COVID-19 disease history including any COVID-19 therapy (onset 
of symptoms, medications, oxygen support, intubation and tracheostomy dates, SARS-CoV-2 
polymerase chain reaction (PCR) test date and result by verbatim name with start and end dates) 
that the patient received will be documented in the source documentation and in the eCRF. 
8.2.1.3. 
Concomitant Disease  
All diseases that the patient is experiencing at screening/randomization until end of treatment are 
regarded as concomitant diseases. All concomitant diseases must be documented in the source 
documentation and in the eCRF. 
8.2.1.4. 
Prior and Concomitant Medications and Procedures 
All procedures performed or medications administered within 7 days before randomization 
should be recorded as prior procedures and prior medication with generic name, start date, stop 
date, and indication for treatment. 
Reporting of prior and concomitant medications will follow special considerations for conditions 
in the ICU. A complete record of all prior and concomitant medications (but excluding 
nutritional and volume therapy, electrolyte support, vitamins, non-steroidal anti-inflammatory 
drugs (NSAIDs), and supportive therapies such as artificial tears, ointments, stool 
softeners/laxatives, etc.) will be maintained in the eCRF for each participant, beginning at 
baseline and continuing until day 28 or hospital discharge (whatever occurs earlier). 
In addition, a complete record of all steroid and antibiotic therapy, as well as any therapy 
(medications, specific treatments, etc.) associated with or used in the assessment or treatment of 
an AE will be documented for the duration of the study. 
The following information must be recorded in the eCRF for each reportable concomitant 
medication: generic name, route of administration, start date, stop date, and indication 
(Appendix 10). 
8.2.2. 
Endpoint Assessments 
8.2.2.1. 
Evaluation of Organ Support 
• 
Renal replacement therapy, extracorporeal membrane oxygenation (ECMO), mechanical 
ventilation 
• 
Extubation and re-intubation dates should be documented 
8.2.2.2. 
Ordinal Scale Evaluation 
Ordinal scale score will be documented at the visits specified in the SoA (Table 2), including the 
date (one value per assessment day, that best represents the patient’s condition at that day). 


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8.2.2.3. 
Survival Status 
The patient’s survival status will be assessed during the study and at the day 60 FUV and will be 
documented in the eCRF. In case the patient has died and the date of death is unknown, the date 
of the last personal contact should be documented at a minimum. 
8.2.2.1. 
Quality of Life Assessment 
If possible, patients will be assessed for quality of life using the EQ-5D at the day 60 FUV. 
8.2.2.2. 
Clinical Status 
Patient’s clinical status will be assessed by the Glasgow Outcome Scale at the day 60 FUV.  
8.2.3. 
Safety Assessments 
Safety will be assessed based on the following variables: 
• 
AEs (see Section 8.2.3.1) 
• 
Laboratory safety parameters, including creatinine (see Section 8.2.3.2) 
• 
Vital signs (see Section 8.2.3.3) 
• 
Electrocardiograms (see Section 8.2.3.4) 
• 
Physical examination (see Section 8.2.3.5) 
Planned time points for all safety assessments are provided in the SoA (Table 2). 
8.2.3.1. 
Adverse Events Assessments 
Adverse events will be assessed throughout the study as specified in the SoA (Table 2). Adverse 
event reporting will follow special considerations for the ICU setting as described in Appendix 3. 
8.2.3.2. 
Clinical Safety Laboratory Assessments 
In general, blood samples for safety laboratory analysis and creatinine assessment should be 
obtained at indicated visit days during routine sampling (one representative value, if taken more 
than once a day). Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.  
See Appendix 1, Table 4 for the list of clinical laboratory tests to be performed and the SoA 
(Table 2) for timing and frequency.  
In clinical studies conducted in the ICU, deviations in laboratory values are to be expected 
frequently. Clinical judgement should be applied in determining which deviations should be 
reported as an AE in the sense of an “untoward medical occurrence” and which deviations 
should be considered usual and expected findings in this setting. 


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It must be noted that clinically relevant laboratory deterioration as assessed by the investigator 
with onset before end of treatment must be documented in the respective eCRF section. 
However, it is preferred to document the condition or disease underlying the aberrant laboratory 
value (e.g., renal failure rather than hyperkalemia) rather than the laboratory value only. 
The investigator will exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant, and thus 
constitutes an AE (see also Section 9 and Appendix 3). 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory fulfill the aforementioned criteria for clinical significance, then the 
results must be recorded in the eCRF. 
All protocol-required laboratory assessments, as defined in Appendix 1, Table 4, must be 
conducted in accordance with the SoA (Table 2).  
Urine analysis (dipstick) and serum or urine samples for pregnancy testing will be collected only 
at screening/randomization. For details on pregnancy testing, refer to Appendix 4. 
8.2.3.3. 
Vital Signs 
Vital signs (core body temperature, heart rate, respiratory rate, blood pressure [diastolic and 
systolic]) will be assessed at indicated visits at pre-dose within 1h before administration of IMP 
(one representative measurement closest to IMP administration) and at further time points 
whenever medically indicated. Blood pressure and heart rate measurements will be assessed with 
an intra-arterial catheter, or a completely automated device. Manual techniques will be used only 
if an automated device is not available. 
8.2.3.4. 
Electrocardiograms 
12-lead ECG will be obtained as outlined in the SoA (Table 2) using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 
8.2.3.5. 
Physical Examination 
A physical examination will be conducted at the time of randomization and on the days of IMP 
administration, as specified in the SoA (Table 2). 
The physical examination includes, at a minimum, assessments of the skin, cardiovascular, 
respiratory, gastrointestinal, and neurological systems.  


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8.2.4. 
Pharmacokinetics/Pharmacodynamics 
PK/PD testing will be done at selected sites in the US, Europe, and Russia. Blood samples will 
be collected for measurement of plasma IFX-1 concentrations, C5a, and ADAs of IFX-1 within 
1h before administration of IMP, as specified in the SoA (Table 2).  
Detailed instructions regarding the collection, processing, etc., of samples will follow local 
regulations and requirements. 
9. 
ADVERSE EVENT COLLECTION AND REPORTING 
All AEs, serious and non-serious (see Appendix 3 I for definitions), must be collected, 
documented, and reported from randomization onwards until the end of treatment (see 
Section 9.1.1). They will be further followed up until the end of study (see Section 9.1.1.1), 
however death and related SAEs with onset during the follow-up period and after the end of 
study will be collected and reported (see Section 9.1.2). 
All AEs will be reported to the sponsor by the investigator in the appropriate sections of the 
eCRF. It will be specified whether the event is serious or not according to the definition of SAE 
(see Appendix 3 I). In case of an SAE, the SAE report will be processed by the safety vendor 
(see Section 9.2.1). The safety vendor for this study is IQVIA Pharmacovigilance. Reporting of 
AEs will be done according to the specific definitions and instructions for completing the 
respective sections of the eCRF.  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE and remain responsible for following up AEs, 
considered related to the IMPs or study procedures (see Section 9.2.2 and Appendix 3 II for 
details on causality of AEs), or that caused the patient to discontinue study treatment (see 7.2.4 
for treatment discontinuation criteria) or the study.  
Care will be taken not to introduce bias when detecting AEs. Open-ended and non-leading verbal 
questioning of the patient is the preferred method to inquire about AE occurrences.  
Due to the severity of disease of the patient population entering this study, numerous problems, 
signs, and symptoms deviating from normal will be seen during the course of the study. These 
will not necessarily constitute a reportable AE unless they require significant intervention, lead 
to discontinuation of blinded study drug, or are considered to be of concern in the investigator’s 
clinical judgement. Similarly, it is preferred to receive documentation of the underlying 
condition rather than the resulting sign (e.g., ‘agitation’ rather than ‘self-extubation’). 
In clinical studies conducted in the ICU, deviations, e.g., in laboratory values or temporary 
changes in arterial blood pressure, are to be expected frequently. Clinical judgement should be 
applied in determining which deviations should be reported as an AE in the sense of an 
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findings in this setting. It is preferred to document the condition or disease underlying the 
aberrant laboratory value (e.g., renal failure rather than hyperkalemia) rather than the laboratory 
value only. 
The records will describe (Appendix 3 II) the nature (diagnosis or single syndrome if possible, 
alternatively signs and symptoms), severity (mild, moderate, severe, life-threatening, fatal), start 
date and time, stop date and time, actions taken with respect to the IMP, corrective 
treatment/therapy given, additional investigations performed, outcome, and causality 
(relationship to study treatment according to the investigator’s assessment; see also 
Section 9.2.2). 
The terms ‘disease progression’, ‘progressive disease’, or similar, do not constitute an acceptable 
description of the nature of an AE. For example, if a patient experiences disease progression with 
hemoptysis leading to hospitalization, the investigator should file an AE and an SAE for the 
hemoptysis; data related to disease progression should be captured in the disease assessment and 
response evaluation section of the eCRF. 
Any AE not listed as an expected event in the IB or in this protocol will be considered 
unexpected. 
9.1. 
Time Period and Frequency of Collection and Reporting 
The following timeframes for reporting apply from signature of the informed consent on: 
• 
All AEs, including AESIs and SAEs until 30 days following the last IFX-1 administration 
must be reported 
• 
All pregnancies until 9 months after the last dose of treatment must be reported, as described 
in Section 9.5.2 
Any time outside of the time period specified above, in addition, any study drug related SAE 
brought to the attention of an investigator must be reported immediately to the sponsor. 
9.1.1. 
During Treatment  
All AEs, including SAEs and AESIs, must be collected from the time of patient signing the 
consent form until 30 days following the last IFX-1 administration must be reported.  
• 
All AEs must be followed until the outcome of the event is ‘recovering’ (for stabilization of 
chronic conditions), or recovered (/with sequelae), and until all queries related to these AEs 
have been resolved. 
• 
Ongoing AEs should be reviewed at each scheduled and unscheduled visit until the hospital 
discharge visit. If resolved, the details should be recorded in the eCRF. If any AE changes 
for the worse, in frequency of attacks/symptoms or in severity, a new record of the event 
must be started (i.e. distinct reports are required for differing frequencies and/or severity of 
the same event to enable comprehensive safety reports and later analysis). 


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• 
If the patient dies from an event, ongoing further AEs can be closed with an outcome 
‘unknown’, if outcome was not assessed at day of death. 
9.1.1.1. 
During Follow-up  
All ongoing AEs with onset in the treatment period will have to be followed up after the hospital 
discharge visit until the outcome of the event is ‘recovering’ (for chronic conditions), or 
recovered (/with sequelae), or until end of study and until all queries related to these AEs have 
been resolved.  
All SAEs, including fatal events related to IMP with onset during the follow-up period (from the 
hospital discharge visit until end of study) will have to be collected and followed until resolved. 
9.1.2. 
After End of Study 
After the end of study, new SAEs related to IMP must be reported to the sponsor via the regular 
SAE reporting system. 
9.2. 
Serious Adverse Event Reporting and Timelines 
9.2.1. 
Initial Reporting of Serious Adverse Events 
SAEs that should be reported within 24 hours on the SAE form are: 
• 
Events with fatal outcome 
• 
New life-threatening events, defined as: 
− 
Cardiac event requiring CPR or medical resuscitation (adrenaline use etc.) – can be 
caused by severe arrhythmia or other 
− 
Life-threatening spontaneous bleeding requiring blood transfusion and / or surgical 
intervention 
− 
Thrombo-embolic event with life-threatening hemodynamic or pulmonary instability 
− 
New life-threatening organ failure / dysfunction 
− 
Liver: AST, ALT > 20 x upper limit of normal (ULN) OR Bilirubin > 10 x ULN 
− 
Kidney: Creatinine > 6 x ULN – or newly developed anuria ≤ 100 mL urine 
production over 24h 
− 
Cardiovascular:  
− 
Norepinephrine > 1 µg/Kg/min or equivalent 
− 
Troponin I: levels consistent with myocardial infarction as defined by 
manufacturer 
− 
Coagulation: Thrombocyte count < 20.000 / µL or PTT > 2.5 x ULN 


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− 
Life-threatening infections other than COVID-19 which require immediate antibiotic 
treatment and/or additional medical / surgical intervention  
− 
Life-threatening infusion reactions which require immediate intensification of existing 
intensive care treatment, including but not limited to additional vasopressor of fluid 
support, or high dose corticosteroids and antihistamines 
All remaining SAEs should be reported at investigator’s earliest convenience. SAEs should be 
approved by the investigator (see Appendix 3 II). In addition, SAEs need to be reported in the 
(non-serious) AE section of the eCRF. The investigator will be requested to supply as much 
detailed information regarding the event as is available at the time of the initial contact. 
For transmission of the back-up paper-based SAE form, please use the following FAX line 
or e-mail account: 
Fax: +353 1 809 9501 
QLS_IFX1@iqvia.com 
In addition, care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical study are properly mentioned on any copy of a source document 
provided to the sponsor. For laboratory results, the investigator must include the laboratory 
normal ranges. 
9.2.1.1. 
Follow-up Reporting of Serious Adverse Events 
Follow-up information on SAEs must be reported by the investigator within the same time 
frames as the initial reporting.  
A follow-up report to an SAE should be prepared if any relevant change in the condition of the 
patient occurs after the initial report, or any new relevant information becomes available.  
Further information on follow-up procedures is given in Appendix 3 II. 
9.2.2. 
Determination of Relatedness 
The investigator will use medical consideration to determine the relatedness of an AE with the 
study drug based on the following definitions (see also Appendix 3 II):  
Unrelated 
This category applies to AEs that are due to extraneous causes (disease, concomitant medication, 
environment, etc.) and are not related to the administration of study drug.  


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Unlikely Related 
This category applies to AEs that are unlikely related to the administration of the study drug. The 
relationship of an AE to the study drug can be considered unlikely related if (must have first two 
criteria listed below):  
• 
The AE does not follow a reasonable temporal sequence from administration of the drug 
• 
The AE could readily have been a result of the patient’s clinical state or other underlying 
medical condition, environmental or toxic factors, or other modes of therapy administered to 
the patient 
• 
The AE does not follow a known response pattern to the suspected drug 
• 
The AE does not reappear or worsen when the study drug is re-administered 
Possibly Related 
This category applies to AEs that are unlikely to be related to the administration of the study 
drug, but the possibility cannot be ruled-out with certainty. The relationship of an AE to the 
study drug can be considered possibly related if (must have first two criteria listed below):  
• 
The AE follows a reasonable temporal sequence from administration of the study drug 
• 
The AE could readily have been a result of the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient 
• 
The AE follows a known response pattern to the suspected study drug 
Probably Related 
This category applies to AEs that are considered with a high degree of certainty to be related to 
the administration of the study drug. The relationship of an AE to the study drug can be 
considered probably related if (must have first three criteria listed below): 
• 
The AE follows a reasonable temporal sequence from administration of the study drug 
• 
The AE could not be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy administered to the 
patient 
• 
The AE disappears or decreases upon cessation of study drug or reduction in dose 
• 
The AE follows a known response pattern to the suspected study drug 
Definitely Related 
This category applies to AEs that are determined with certainty to be related to the 
administration of the study drug. The relationship of an AE to the study drug can be considered 
definitely related if (must have first three criteria listed below): 
• 
The AE follows a reasonable temporal sequence from administration of the study drug or 
study drug levels have been established in body fluids or tissues 


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• 
The AE could not be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy administered to the 
patient 
• 
The AE disappears or decreases upon cessation of study drug or reduction in dose and, if 
applicable, appears upon re-challenge 
• 
The AE follows a known response pattern to the suspected study drug 
• 
There are exceptions when an AE does not disappear upon discontinuation of the study drug, 
yet study drug relatedness clearly exists; e.g., 1) tardive dyskinesia, 2) fixed drug eruptions 
9.3. 
Death Reporting 
The site should follow all patients for survival and collect information around the death on the 
appropriate eCRF form until the end of the study. 
Primary cause of death should be reported in AE section and SAE form, as well as appropriate 
eCRF section(s). If symptoms of disease progression occurred and constitute the primary cause 
of death, these symptoms could be reported as fatal (S)AE (see Section 9.2.2). 
9.4. 
Abnormal Laboratory Values/Vital Signs/ECG/Physical Examination 
Abnormalities of laboratory results / vital signs / ECG / physical examination should be reported 
as AEs, particularly if at least one of the following is met: 
• 
Any criterion for an SAE is fulfilled 
• 
The abnormality causes the patient to discontinue from the study treatment 
• 
The abnormality causes the patient to interrupt the study treatment or a modification of 
dosing 
• 
The abnormality requires intervention as corrective treatment or consultation 
• 
The investigator judges that the abnormality is clinically relevant and should be reported as 
an (S)AE in the eCRF 
All laboratory tests for which abnormal results are collected after the initiation of study treatment 
should be repeated until the values return to normal or to a stable status. If abnormal results are 
outside of the normal laboratory range and also assessed as clinically relevant by the 
investigator, they must be reported as an AE. The frequency with which such checks should be 
made will be made by investigator’s discretion depending on the degree of abnormality. The 
reporting of laboratory/vital signs/ECG/physical examination abnormalities as both AEs and a 
specific finding of laboratory values/vital signs/ECG should be avoided.  
Abnormal laboratory value testing will follow special considerations for conditions in the ICU. It 
must be noted that clinically relevant laboratory deterioration as assessed by the investigator 
must be documented in the respective eCRF section. However, it is preferred to document the 


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condition or disease underlying the aberrant laboratory value (e.g., renal failure rather than 
hyperkalemia) rather than the laboratory value only. 
9.5. 
Events to be Handled as SAEs 
9.5.1. 
Overdose Reporting 
An overdose is defined as the accidental or intentional ingestion or infusion of any dose of a 
product that is considered both excessive and medically relevant. 
All symptoms associated with the overdose should be handled as SAEs. 
Refer to Section 7.6 for details on the treatment of overdose. 
9.5.2. 
Pregnancy Reporting 
If the patient or partner of a patient participating in the study becomes pregnant during treatment 
or within 9 months after the last dose of treatment, the investigator should report the pregnancy 
to QLS_IFX1@iqvia.com via e-mail within 24 hours of being notified. The safety vendor will 
then forward the pregnancy reporting form to the investigator for completion. In case that e-mail 
contact is not possible, the site can provide an initial pregnancy report in the SAE section of the 
SAE form and transmit this via the SAE FAX line: +353 1 809 9501. 
A patient becoming pregnant while on IMP will immediately be discontinued from treatment and 
the EOT visit will be performed. 
The patient or partner should be followed by the investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the investigator should notify 
the sponsor. At the completion of the pregnancy, the investigator will document the outcome of 
the pregnancy. If the outcome of the pregnancy meets criteria for immediate classification as an 
SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly), the investigator should follow the procedures for reporting as SAE. 
9.5.3. 
Drug-induced Liver Injury 
Potential drug induced liver injury is considered an important medical event. Although it is not 
always serious by regulatory definition, such event must be handled as SAE. 
Wherever possible, timely confirmation within 48 to 72 hours of initial liver-related laboratory 
abnormalities should occur prior to the reporting of a potential drug induced liver injury event. 
All occurrences of potential drug induced liver injuries, meeting the defined criteria, must be 
reported as SAEs. 
Potential drug induced liver injury is defined as: 
• 
ALT or AST elevation > 3 × ULN 


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AND 
• 
Total bilirubin >2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
AND  
• 
No cholestatic or other immediately apparent possible causes of AST or ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic 
9.5.4. 
Suspected Transmission of an Infectious Agent (pathogenic or 
non-pathogenic) via Study Drug 
For the purposes of reporting, any suspected transmission of an infectious agent via the 
investigational drug should be considered as an SAE. 
A transmission of an infectious agent may be suspected from clinical signs or symptoms, or 
laboratory findings indicating an infection in a patient exposed to a medicinal product.  
In the context of evaluating a suspected transmission of an infectious agent via a medicinal 
product, care should be taken to discriminate, whenever possible, between the cause (e.g., 
injection/administration) and the source (e.g., contamination) of the infection and the clinical 
conditions of the patient at the time of the infection (immuno-suppressed /vaccine). 
9.6. 
Adverse Events of Special Interest 
AESIs are events that are considered to have a special meaning or importance for a particular 
drug or class of drugs. They may be non-serious or serious. Therefore, they should be closely 
monitored. The site must report all AESIs that occur during the study period, whether considered 
to be related to IP or not, according to Appendix 3. Moreover, AESIs should be documented in 
the general AE section of the eCRF as well as in the patient file. 
This is the first study investigating IFX-1 in COVID-related pneumonia. Clinical experience 
with IFX-1 has been generated in more than 300 patients with inflammatory diseases, including 
sepsis and HS.  
For this study, the following AEs are defined as AESIs: 
• 
Infusion reactions, including hypersensitivity or anaphylaxis during or after IFX-1 infusion:  
All patients should be observed closely during the IFX-1 administration and for 
≥ 60 minutes thereafter. The intravenous line should remain open during the observation to 
allow for administration of intravenous drugs, if necessary. Medication for infusion 
reactions should be available for immediate use. Medical staff has to be trained in 
resuscitation and immediate intensive care has to be easily accessible in case of severe 


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life-threatening events. Mild to moderate reactions may be treated by slowing or interruption 
of the infusion, or with supportive treatment (Appendix 5).  
For any potential infusion event, the investigator should closely monitor for a potentially 
developing or existing anaphylactic reaction. In case an anaphylactic reaction is anticipated, 
appropriate immediate actions should be taken according to the severity or stage of the 
detected anaphylactic reaction.  
• Meningitis and meningococcal sepsis:  
In case of signs of meningitis at any time during the study, the IMP should be discontinued if 
meningitis is confirmed. The patient must be closely monitored and the guidelines for 
treatment of meningitis should be followed (Tunkel et al. 2004, van de Beek et al. 2016). 
This includes lumbar puncture, blood culture testing, immediate start of treatment with 
dexamethasone and intravenous antibiotics (combination therapy with ampicillin and third 
generation cephalosporin), and a search for the focus of the infection (e.g., CT or MRI).  
• Infections other than COVID-19 (SARS-CoV-2) infections 
In patients with bacterial infection, depending on the severity of the infections, it is important 
that concomitant antibiotic therapy is administered during treatment with IFX-1 to ensure 
appropriate control of the source of the infection. The investigator should pay close attention 
to the choice of an appropriate broad-spectrum antibiotic treatment according to applicable 
guidelines. 
Note: A severe infection can be suspected whenever an IV antibiotic, antifungal, or antiviral 
intervention would be indicated under non-ICU conditions or an invasive intervention would 
have been indicated.  
9.7. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs 
Disease progression does not constitute an AE itself; however, the symptoms/diagnosis leading 
to disease progression must be reported as AE or SAE accordingly. 
9.8. 
Reporting to Competent Authorities and Ethics Committees 
The IB(s) will be the reference document for reference safety information. 
The safety vendor is responsible for submission of suspected unexpected serious adverse 
reactions (see Appendix 3 I for a definition) to health authorities and Institutional Review Boards 
(IRB)/Independent Ethic Committees (IEC) in accordance with local regulations. 
The investigator is responsible for informing the IRB/IEC in a timely manner and in accordance 
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10. 
STATISTICAL CONSIDERATIONS 
10.1. Phase II 
10.1.1. 
Sample Size Determination 
No formal sample size calculation was performed for this trial. The sample size was based on 
pragmatic considerations in this new and urgent setting with very limited knowledge about the 
disease. 
For the Phase II part of the trial 30 patients were randomized in a 1:1 ratio to treatment Arm A 
(SBC + IFX-1) and Treatment Arm B (BSC).  
10.1.2. 
Analysis Sets 
All analyses were to be performed based on all randomized patients. 
10.1.3. 
Statistical Analyses 
The statistical analysis plan (SAP) was developed and finalized as soon as possible after clinical 
trial application approval. The SAP includes the exact definition of endpoints and variables to be 
analyzed, extensive details on the statistical analysis methods to be used together with the 
structure of tables and figures to be included as end-of-text tables and figures as well as 
appended listings for the clinical study report. It also describes procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints for Phase II of this study. 
Individual data were to be listed. Data were to be summarized using suitable descriptive 
statistics; depending on the structure of the data, summary statistics (e.g., number of 
observations, mean, standard deviation, minimum, median, maximum, lower quartile, upper 
quartile) or frequency tables may have been used.  
All data were to be displayed by treatment arm if not specified otherwise. 
10.1.3.1. 
Efficacy Analyses 
The relative change (%) from baseline (day 1 prior to study drug administration at ± 1h of 
randomization) in oxygenation index (PaO2 / FiO2) in supine position at day 3, 5, 9, and 15 was 
to be analyzed with a linear repeated measures model with post-baseline time points as outcome 
variable and baseline value as explanatory variable. Deceased patients were to be included in the 
model with an outcome of 0 after death. Patients discharged from the ICU whose oxygenation 
index was no longer be assessed were to be analyzed by last observation carried forward. 
Treatment arm, time point, the interaction between treatment arm and time point, the interaction 
between baseline and time point, age, sex, and intubation status at baseline was to be included as 
further explanatory variables. The model was to use an unstructured covariance matrix and make 


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use of the Kenward-Roger degrees of freedom approximation. Least square mean differences 
between treatment arms and their 95% confidence interval was to be calculated and displayed for 
each time point separately (day 3, 5, 9, and 15), with the evaluation at day 5 reflecting the 
primary endpoint. If oxygenation index was to be used as the primary endpoint for a Phase III 
part of the study, data from both study parts were planned to be analyzed in one combined model 
as specified above with study part as a random effect. 
Early response, late response and reaching ICU discharge alive were to be analyzed as three 
separate time-to-event variables. Withdrawing early from the study would have led to the patient 
being right-censored at the date of withdrawal provided that the reason was not an outcome of 
interest for the time-to-event endpoint. In order to adequately account for competing outcomes as 
well as potential right-censoring due to varying follow-up times, these outcomes were to be non-
parametrically analyzed using Aalen-Johansen-type estimation based on a competing risks model 
with two absorbing states (event 1: all-cause death; event 2: early response/late response/ICU 
discharge respectively). The Aalen Johansen estimator estimates the expected relative number of 
patients (cumulative incidence function [CIF]) of the event at hand. Treatment effects were to be 
derived in terms of the absolute differences between the treatment arm-specific estimators 
evaluated at day 7: 
〖Effect〗_(Y;7)=CIF_Y^A (7)- CIF_Y^B (7) 
where 〖CIF〗_Y^X (7) is the Aalen-Johansen estimator evaluated at day 7 for endpoint 
Y∈{Death, Early Response, Late Response} within treatment group X∈{A,B}. In order to test 
the hypotheses 
H0: 〖Effect〗_(Y;7)=0=0  vs 
H1: 〖Effect〗_(Y;7)≠0 
Two-sided confidence intervals (CIs) were to be constructed based on the approximate normality 
of the estimators (Beyersmann 2012). Statistical significance was to be concluded if the two-
sided 95% CI did not cover 0. 
Adjustment for relevant baseline covariates (age, sex, oxygenation index and intubation status) 
were to be realized by cause-specific Cox models. Subdistribution hazards regression modelling 
were to be applied in the presence of competing risks (Fine and Gray 1999) to explore the 
relative covariate effects in terms of the CIF of interest. Model assumptions were to be checked 
using graphical diagnostics. 
All-cause mortality was to be analyzed as a censored time-to-event variable with Kaplan-Meier 
methods. The proportion of patients still alive at 28 days was to be derived based on the product 
limits estimator in each treatment arm. Adjustment for relevant baseline covariates (age, sex, 
oxygenation index, and intubation status) was to be realized by the Cox proportional hazard 
model. 


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The individual components of the composite time-to-event endpoints early and late response and 
ICU discharge were to be analyzed descriptively. 
Laboratory endpoints as well as the Glasgow Outcome Scale were to be analyzed descriptively 
by time point and treatment arm. 
10.1.3.2. 
Safety Analyses 
The occurrence of AEs was to be compared between treatment arms. Treatment-emergent AEs 
(TEAEs) were to be analyzed according to the number and percentage of patients who had a 
TEAE, as well as the number of TEAEs with the respective Medical Dictionary for Regulatory 
Activities (MedDRA) System Organ Class and Preferred Term. Additionally, the number and 
percentage of patients with TEAEs were to be further grouped by severity and causal 
relationship. The number and percentage of patients with SAEs and the number of SAEs were to 
be analyzed. Where AEs were grouped by severity or relationship, the maximum 
severity/relationship per patient and class of AE was to be considered. 
10.1.3.3. 
Interim Analysis 
An interim analysis was performed after the first 30 patients treated in Phase II reached at least 
day 15 of the study schedule to assess the clinical benefit of the treatment using the assessed 
clinical parameters.  
10.2. Phase III 
10.2.1. 
Sample Size Determination 
A total of 180 patients (90 per arm) will be randomized in Stage 1 and up to 180 patients (90 per 
arm) in Stage 2. This results in 90% overall power (90% probability to either show efficacy after 
Stage 1 or Stage 2). The power calculation is based on an overall 2.5% one-sided alpha, 
Pocock’s approach to account for the group-sequential design, a binding futility stop if the 
z-statistic is 0 or lower after the first stage and an assumed 30% 28-day mortality under Placebo 
and 15% 28-day mortality under IFX-1 treatment. 
10.2.2. 
Analysis Sets 
All efficacy analyses will be performed based on all randomized patients according to the 
intention to treat principle. Safety analyses will also be based on all randomized patients, but 
patients will be analyzed according to the treatment they actually receive. 
10.2.3. 
Statistical Analyses 
The SAP will be developed and finalized before the study will be unblinded. The SAP will 
include the exact definition of endpoints and variables to be analyzed, extensive details on the 
statistical analysis methods to be used together with the structure of tables and figures to be 


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included as end-of-text tables and figures as well as appended listings for the clinical study 
report. It will also describe procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary, secondary, and other 
endpoints. 
Individual data will be listed. Data will be summarized using suitable descriptive statistics; 
depending on the structure of the data, summary statistics (e.g., number of observations, mean, 
standard deviation, minimum, median, maximum, lower quartile, upper quartile) or frequency 
tables may be used.  
All data will be displayed by treatment arm if not specified otherwise. 
10.2.3.1. 
Primary Efficacy Analysis 
All efficacy analyses will be performed based on all randomized patients according to the 
intention-to-treat principle. 
The statistical study design of Phase III is a group-sequential adaptive design (two stages) with 
one interim analysis for stopping for futility or stopping for efficacy. The primary efficacy 
variable is 28-day mortality (proportion of patients deceased until day 28). The primary 
statistical hypotheses to be tested are: 
H0: pIFX-1 = pPlacebo 
versus 
H1: pIFX-1 < pPlacebo 
where pIFX-1 is the proportion of patients deceased until day 28 in the SOC + IFX-1 treatment 
arm (Arm A) and pPlacebo is the proportion of patients deceased until day 28 in the SOC + Placebo 
treatment arm (Arm B). 
A total of 180 patients will be randomized to Arm A and Arm B using a 1:1 allocation ratio for 
the first stage. The interim analysis is performed after all 180 patients have been followed-up 
until day 28 (or died before). In case the interim analysis does not result in an early stop for 
efficacy or futility, 180 additional patients will be randomized in a ratio of 1:1 to Arm A and B. 
The maximum number of patients in the study will not exceed 360. 
The group sequential design to show superiority of IFX-1 + SOC compared to SOC alone will 
make use of a one-sided alpha level of 2.5% and a binding futility stop and will test for 
superiority (lower mortality among IFX-1 treated patients). The primary statistical analysis will 
be based on a logistic regression model with outcome 28-day mortality and explanatory variables 
treatment arm (Arm B versus Arm A), age, sex (male versus female), and PaO2 / FiO2 at 
randomization. 


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The critical values for the interim and the final analysis are derived according to Pocock’s design 
resulting in critical values of 2.176 for both stages. The z-statistic at each stage will be calculated 
as the proportion of the beta coefficient for the treatment arm effect and its standard error from 
the logistic regression model. The study will be stopped for futility if the z-statistic for the first 
stage is 0 or lower. 
The z-statistics of the first and the second stage will be combined using the weighted inverse 
normal combination function (Bauer and Köhne 1994; Bauer and Köhne 1996). The weights are 
chosen as w1= sqrt(180/360) and w2= sqrt(1-w12). 
10.2.3.2. 
Secondary Efficacy Analyses 
Secondary efficacy endpoints will only be addressed with statistical hypothesis tests if the 
primary endpoint is statistically significant (only after the first stage or after the second stage). 
Therefore, a full overall 2.5% one-sided alpha will be spent for the secondary efficacy endpoints. 
Multiplicity in the secondary endpoints will be addressed with the fallback method. The 
secondary endpoints will be evaluated using a similar logistic regression model as for the 
primary endpoint, where instead of the 28-day mortality (proportion of patients deceased until 
day 28) the following variables will be used: 
1. Proportion of patients with an improvement in the provided ordinal scale at day 28 (at least 
one score point lower than at randomization) 
2. Proportion of patients with an improvement in the provided ordinal scale at day 15 (at least 
one score point lower than at randomization) 
3. Proportion of patients free of any renal replacement therapy within 28 days upon 
randomization  
4. Proportion of patients developing acute kidney failure (eGFR < 15 mL/min/1.73m²) during 
ICU stay and at day 28  
The ordering of the secondary endpoints for hypothesis testing will be as in above mentioned list. 
The alpha for the fallback method will be attributed to the 4 secondary endpoints in the following 
way 2%, 0.2%, 0.2%, and 0.1%. If the preceding hypothesis test is not significant, subsequent 
tests will be performed at the aforementioned alpha level. If tests are significant, the alpha is 
added to the subsequent hypothesis test (e.g., if the primary hypothesis test is significant and 
secondary endpoints 1-3 are all significant, the fourth secondary endpoint will be tested at an 
alpha of 2.5%; if the third secondary endpoint is not significant, the fourth secondary endpoint 
will be tested at an alpha of 0.1%). 
The primary endpoint as well as all secondary endpoints will also be evaluated as censored time 
to event variables by Kaplan-Meier type methods. All time to event endpoints will also be 
evaluated via proportional hazards models with the explanatory variables treatment arm (Arm B 
versus Arm A), age, sex (male versus female), and PaO2 / FiO2 at randomization. 


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10.2.3.3. 
Other Efficacy Analyses 
Time to First Extubation 
Time to first extubation will be analyzed as a censored time to event variable. Withdrawing early 
from the study will lead to the patient being right-censored at the date of withdrawal provided 
that the reason is not an outcome of interest (extubation or death). In order to adequately account 
for competing outcomes as well as potential right-censoring due to varying follow-up times, the 
outcome will be non-parametrically analyzed using Aalen-Johansen-type estimation based on a 
competing risks model with two absorbing states (event 1: all-cause death; event 2: extubation). 
Adjustment for relevant baseline covariates (age, sex, and PaO2 / FiO2 at randomization) will be 
realized by regression modeling accounting for competing risks. 
60-Day Mortality 
The 60-day mortality will be derived from the above-mentioned Kaplan-Meier analysis of 
all-cause mortality. 
Glasgow Outcome Scale 
Glasgow Outcome Scale assessed at study day 60 will be analyzed via ordinal logistic regression 
with explanatory variables treatment arm (Arm B versus Arm A), age, sex (male versus female), 
and PaO2 / FiO2 at randomization. 
Quality of Life 
Quality of life will be assessed by EQ-5D at study day 60. The visual analogue scale as well as 
an index value based on the 5 health states (cross-walk index value using the United States value 
set) will be analyzed by an ANCOVA model with explanatory variables treatment arm (Arm B 
versus Arm A), age, sex (male versus female), and PaO2 / FiO2 at randomization. 
10.2.3.4. 
Safety Analyses 
The occurrence of TEAEs will be compared between treatment arms. TEAEs will be analyzed 
according to the number and percentage of patients who had a TEAE, as well as the number of 
TEAEs in total. Additionally, the number and percentage of patients with TEAEs will be further 
grouped by severity and causal relationship. The number and percentage of patients with serious 
TEAEs and AESIs and the number of serious TEAEs and AESIs will be analyzed. Where 
TEAEs are grouped by severity or relationship, the maximum severity/relationship per patient 
and class of TEAE will be considered. 
10.2.3.5. 
Interim Analysis 
The interim analysis is performed after all 180 patients in Stage 1 have been followed-up until 
day 28 (or died before). The study will be stopped for futility if the z-statistic of the primary 


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efficacy analysis is 0 or lower. The study will be stopped for efficacy if the z-statistic of the 
primary efficacy analysis is 2.176 or higher. If the study is not stopped for efficacy or futility, 
another 180 patients will be randomized in Stage 2.  


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11. 
REFERENCES 
Bauer P, Köhne K. Evaluation of experiments with adaptive interim analyses. Biometrics. 
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Bauer P, Köhne K. Erratum: Evaluation of experiments with adaptive interim analysis. 
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Beyersmann J, Schumacher M, Alignol A. Competing risks and multistate models with R. 
Springer. 2012. doi: 10.1007/978-1-4614-2035-4. 
Carvelli, J. et al. Association of COVID-19 inflammation with activation of the C5a–C5aR1 
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Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. 
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Fine JP, Gray RP. A proportional hazards model for the subdistribution of a competing risk. 
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Gao T, Hu M, Zhang X, et al. Highly pathogenic coronavirus N protein aggravates lung injury by 
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Garg S, Kim L, Whitaker M, et al. Hospitalization rates and characteristics of patients 
hospitalized with laboratory-confirmed coronavirus disease 2019—COVID-NET, 14 States, 
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Global Initiative for Chronic Obstructive Lung Disease. 2020 GOLD Pocket Guide. Available at: 
http://goldcopd.org/gold-reports. 
Gong J, Dong H, Xia Q, et al. Correlation analysis between disease severity and inflammation-
related parameters in patients with COVID-19 pneumonia. 2020 Feb 25; medRxiv preprint: 
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Gralinski LE, Sheahan TP, Morrison TE, et al. Complement activation contributes to severe 
acute respiratory syndrome coronavirus pathogenesis. mBio 2018;9(5):e01753-18. 
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Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl 
J Med. 2020 Feb 28; doi: 10.1056/ NEJMoa2002032. 


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Hess C, Kemper C. complement-mediated regulation of metabolism and basic cellular processes. 
Immunity. 2016;45(2):240-54. 
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus 
in Wuhan, China. Lancet 2020;395:497-506. 
Investigator’s Brochure (IFX-1) Version 7.1. 11 Dec 2019.Jiang Y, Zhao G, Song N, et al. 
Blockade of the C5a–C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with 
MERS-CoV. Emerging Microbes & Infections. 2018;7:77. doi: 0.1038/s41426-018-0063-8.  
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peripheral blood of SARS-CoV-2 infected patients. 2020 Feb 22; medRxiv preprint: 
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Sun S, Zhao G, Liu C, et al. Treatment with anti-C5a antibody improves the outcome of H7N9 
virus infection in African green monkeys. Clin Infect Dis. 2015;60(4):586-95.  
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acute bacterial meningitis. Clin Microbiol Infect. 2016;22 Suppl 3:S37 62. 
Vlaar APJ, de Bruin S, Busch M et al. Anti-C5a Antibody (IFX-1) Treatment of Severe COVID-
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10.1038/emi.2015.28. 
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treatment of Coronavirus Disease 2019 (COVID-19), a review. JAMA. 2020 Jul 10. 
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World Health Organization (WHO) Coronavirus Disease (COVID-19) Situation Report – 185. 
23 July 2020. Available at: https://www.who.int/docs/default-source/coronaviruse/situation-
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12. 
APPENDICES 


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Appendix 1 
Clinical Laboratory Tests 
The protocol-required laboratory assessments are detailed in Table 3 for Phase II and in Table 4 
for Phase III. Protocol-specific requirements for inclusion or exclusion of patients are detailed in 
Section 6.1 and Section 6.2 of the protocol. In general, blood samples for safety laboratory 
analysis should be obtained once a day during a routine sampling (preferable in the morning). 
Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Table 3 
Protocol-Required Safety Laboratory Assessments: Phase II 
Assessment 
Parameters 
Hematology 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
Red blood cells (MCV) 
White blood cell count with 
differentials (neutrophils, 
lymphocytes, monocytes, 
eosinophils, basophils) 
Coagulation parameters 
APTT  
PT 
D-Dimer 
Clinical chemistry a 
ALT (SGPT) 
AST (SGOT) 
LDH 
Total bilirubin 
Creatinine 
Procalcitonin  
Sodium 
Potassium 
Calcium 
Magnesium 
Glucose 
CRP 
 
Urinalysis (Dipstick) 
PH 
Glucose Leucocytes 
Protein 
Blood 
Other screening tests 
Troponin ISerum or urine hCG pregnancy test (as needed in 
women of childbearing potential) 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring are given in Section 9.5.3. All events of ALT ≥3 × ULN and bilirubin ≥2 × ULN (35% direct 
bilirubin) or ALT ≥3 ULN and INR >1.5 (if INR is measured), may indicate severe liver injury (possible Hy’s 
Law) and must be reported as an SAE. 
 


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Table 4 
Protocol-Required Safety Laboratory Assessments: Phase III 
Assessment 
Parameters 
Screening/Randomization Only (as indicated in SoA Table 2) 
Urinalysis (Dipstick) 
PH 
Glucose  
Leucocytes 
Protein 
Blood 
Other screening tests 
Serum or urine hCG pregnancy test (in women of childbearing 
potential) 
Screening/Randomization and Treatment (as indicated in SoA Table 2) 
Hematology 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
Red blood cells (MCV) 
White blood cell count with differentials (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils) 
Coagulation parameters 
APTT  
PT 
D-Dimer 
Clinical chemistry a 
ALT (SGPT) 
AST (SGOT) 
LDH 
Total bilirubin 
CRP 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring are the same as in Phase II (listed in Section 9.5.3). All events of ALT ≥3 × ULN and bilirubin 
≥2 × ULN (35% direct bilirubin) or ALT ≥3 ULN and INR >1.5 (if INR is measured), may indicate severe 
liver injury (possible Hy’s Law) and must be reported as an SAE. 
Investigators must document their review of each laboratory safety report. 
 


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Appendix 2 Regulatory and Ethical Considerations 
I. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines 
• 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
• 
Applicable laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), IB, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients.  
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
• 
Notifying the IRB/IEC of SAEs or other relevant safety findings as required by IRB/IEC 
procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations 
II. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 


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III. 
Informed Consent Process 
Obtaining of informed consent is proposed to be deferred for the ICU patients in this study or by 
any other legally acceptable local procedure specific for patients treated in the ICU setting (see 
Section 6.3). 
The ICF could contain a separate section or an additional ICF may be issued that addresses the 
use of remaining samples for optional exploratory research. The investigator or authorized 
designee will explain to each patient/legal representative the objectives of the exploratory 
research. Patients/legal representatives will be told that they are free to refuse to participate and 
may withdraw their consent at any time and for any reason during the storage period. A separate 
signature will be required to document a patient’s agreement to allow any remaining specimens 
to be used for exploratory research. Patients who decline to participate in this optional research 
will not provide this separate signature. 
IV. 
Data Protection 
Patients will be assigned a unique identifier by the sponsor. Any patient records or datasets that 
are transferred to the sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred.  
The patient and/or the legal representative must be informed that patients’ personal study-related 
data will be used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the patient.  
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
The sponsor will ensure that all safeguards are in place to minimize any eventual risk of 
breaches, and complies otherwise with the requirements of European Union (EU) General Data 
Protection Regulation (GDPR [EU] 2016/679). The sponsor will regularly check all procedures 
relevant to the processing of personal data, as to ensure privacy by design and compliance with 
this regulation. 
V. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. Individual 
publications are allowed only after publication of the entire study. If this is foreseen, the 
investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. This 
allows the sponsor to protect proprietary information and to provide comments.  
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 


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multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
In accordance with consistent editorial practice, the sponsor supports publication of multicenter 
studies in their entirety and not as individual center data unless as ancillary study/data.  
All publications in peer-reviewed medical journals resulting from this study will be listed in the 
original study protocol registration record (e.g., on ClinicalTrials.gov). 
VI. 
Dissemination of Clinical Study Information 
The sponsor will provide the relevant study protocol information in a public database (e.g., 
ClinicalTrials.gov, https://clinicaltrials.gov/) before or at commencement of the study. The 
sponsor may also provide study information for inclusion in national registries according to local 
regulatory requirements.  
If a potential patient contacts the sponsor regarding participation in the study, the investigator 
agrees that the sponsor may forward the study site and contact details to the patient. Based on the 
inclusion and exclusion criteria for the study, the investigator will assess the suitability of the 
patient for enrollment into the study. 
Results of this study will be disclosed according to the relevant regulatory requirements. All 
publications in peer-reviewed medical journals resulting from this study will be listed in the 
original study protocol registration record (e.g., on ClinicalTrials.gov). 
VII. 
Data Quality Assurance 
All patient data relating to the study will be recorded on the eCRF unless transmitted to the 
sponsor or designee electronically (e.g., laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
It is the responsibility of the site to comply with the protocol-defined procedures and 
assessments. Details about the handling of protocol deviations will be included in a separate 
Protocol Deviation Plan. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  


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The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a different retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor.  
VIII. 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records, depending on the study.  
IX. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines 
• 
Inadequate recruitment of patients by the investigator 
• 
Discontinuation of further IMP development 


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Appendix 3 
Adverse Events: Definitions and Procedures for Recording, 
Evaluation, Follow-up, and Reporting 
I. 
Definitions 
Definition of an AE 
An AE is any untoward medical occurrence in a patient or clinical study patient, temporally 
associated with the use of IMP, whether or not considered related to the IMP. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of IMP. 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including 
those that worsen from baseline. Laboratory tests are considered abnormal, if 
− 
Any criterion for an SAE is fulfilled 
− 
The abnormality causes the patient to discontinue from the study treatment 
− 
The abnormality causes the patient to interrupt the study treatment or a modification of 
dosing 
− 
The investigator judges that the abnormality is clinically relevant and should be 
reported as an (S)AE in the eCRF 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after IMP administration even though it may have 
been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either IMP or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should 
be reported regardless of sequelae. 
• 
Signs, symptoms, and/or clinical sequelae resulting from disease progression will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. The terms ‘disease 
progression’, ‘progressive disease’, or similar, per se will not be reported as an AE or SAE. 
Such instances will be captured in the efficacy assessments.  
Events NOT Meeting the AE Definition 
• 
The terms ‘progressive disease’ or ‘progression of disease’ per se will not be reported as an 
AE or SAE. Such instances will be captured in the efficacy assessments.  


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• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
 
Definition of an SAE 
If an event is not an AE according to the above definition, then it cannot be an SAE even if 
serious conditions are met. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
• 
Results in death 
• 
Is life-threatening  
Life-threatening in the definition of ‘serious’ refers to an event in which the patient was at risk of 
death at the time of the event. It does not refer to an event which hypothetically might have 
caused death, if it were more severe. 
• 
Required inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether ‘hospitalization’ occurred 
or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
• 
Results in persistent disability or incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
• 
Is a congenital anomaly or birth defect 
• 
Other situations: 
− 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 


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patient or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
 
Definition of an Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction is defined (as per ICH Topic E2A) as all noxious and 
unintended responses to a medicinal product related to any dose which nature or severity is not 
consistent with the relevant source document, i.e., current IB. When reported as serious, the 
unexpected adverse reaction is defined as suspected unexpected serious adverse reaction. The 
safety vendor is responsible for notifying suspected unexpected serious adverse reactions to 
concerned regulatory bodies in accordance with local regulations. 
II. 
Procedures for Recording, Evaluation, Follow-up and Reporting of an 
AE, including AESIs and SAEs 
Recording of AEs, including AESIs and SAEs 
• 
When an AE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the 
event. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE. 
• 
The investigator will then record all relevant information in the eCRF. 
• 
It is not acceptable for the investigator to send photocopies of the patient’s medical records 
to the safety vendor in lieu of completion of the respective sections of the eCRF. 
• 
There may be instances when copies of medical records for certain cases are requested by 
the safety vendor. In this case, all patient identifiers, with the exception of the patient 
number, must be redacted on the copies of the medical records before submission to the 
safety vendor. 
SAE Reporting to the Safety Vendor via the eCRF 
• 
The safety vendor for this study is IQVIA Pharmacovigilance and is responsible for SAE 
processing and reporting. 
• 
The primary mechanism for reporting an SAE to the safety vendor will be the eCRF. 
• 
Investigators and other site personnel must report those SAEs that are outlined under 
Section 9.2 within 24 hours of becoming aware. The same applies for follow-up information 
on SAEs. 
• 
A paper SAE reporting form needs to be completed by the investigator or other relevant site 
staff, signed by the investigator, and faxed to +353 1 809 9501 or QLS_IFX1@iqvia.com. 


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Assessment of Intensity for AEs, including AESIs and SAEs 
The investigator will make an assessment of intensity for each AE reported during the study and 
assign it to 1 of the following categories (NCI CTCAE v5.0):  
• 
Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• 
Grade 2 (Moderate): minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL)* 
• 
Grade 3 (Severe/medically relevant but not immediately life-threatening); hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL** 
• 
Grade 4 (Life-threatening): Life-threatening consequences; urgent intervention indicated 
• 
Grade 5 (Death): Death related to AE 
 
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden 
Assessment of Causality of AEs, including AESIs and SAEs 
• 
The investigator is obligated to assess the relationship between IMP and each occurrence of 
each AE. 
• 
A ‘reasonable possibility‘ of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to IMP administration will be 
considered, investigated, and reported. 
• 
The investigator will also consult the IB and/or Product Information, for marketed products, 
in his/her assessment. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the safety vendor. However, it is very important 
that the investigator always makes an assessment of causality for every event before the 
initial transmission of the SAE data to the safety vendor. 
• 
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 


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Follow-up of AEs, including AESIs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
the safety vendor to elucidate the nature and/or causality of the AE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• 
In case of persisting SAEs, follow-up must continue until the AEs have resolved to grade ≤1 
or baseline or are deemed irreversible by the investigator. 
• 
If a patient dies during participation in the study or during a recognized follow-up period, 
the investigator will provide the safety vendor with a copy of any post-mortem findings 
including histopathology, if any would become available. 
• 
The investigator will submit any updated SAE data to the safety vendor within 24 hours of 
receipt of the information. 
III. 
Special Considerations for Assessment of Adverse Events in an ICU 
Setting 
Due to the severity of disease of the patient population entering this study, numerous problems, 
signs, and symptoms deviating from normal will be seen during the course of the study. These 
will not necessarily constitute a reportable AE unless they require significant intervention, lead 
to discontinuation of blinded study drug, or are considered to be of concern in the investigator’s 
clinical judgement. Similarly, it is preferred to receive documentation of the underlying 
condition rather than the resulting sign (e.g., ‘agitation’ rather than ‘self-extubation’). 
In clinical studies in intensive care, deviations, e.g., in laboratory values or temporary changes in 
arterial blood pressure, are to be expected frequently. Clinical judgement should be applied in 
determining which deviations should be reported as an AE in the sense of an “untoward medical 
occurrence” and which deviations should be considered usual and expected findings in this 
setting. 
It must be noted that clinically relevant laboratory deterioration as assessed by the investigator 
must be documented in the respective eCRF section. However, it is preferred to document the 
condition or disease underlying the aberrant laboratory value (e.g., renal failure rather than 
hyperkalemia) rather than the laboratory value only. 
The investigator will exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant, and thus 
constitutes an AE. 


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Appendix 4 
Contraceptive Guidance and Collections of Pregnancy 
Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
− 
Documented hysterectomy 
− 
Documented bilateral salpingectomy 
− 
Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the patient’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female: 
− 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
− 
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
Contraception Guidance 
Male Patients 
Male patients with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following during the study and until 3 months after last dose of IFX-1:  
• 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent 
• 
Agree to use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 5 when having penile-vaginal intercourse with a woman 
of childbearing potential who is not currently pregnant 


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Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile vaginal 
intercourse or use a male condom during each episode of penile penetration [during the 
protocol-defined time frame]. 
 
Female Patients 
Female patients of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception (from the day of study medication initiation throughout the 
study period and up to 3 months for IFX-1 after the last dose of study medication) consistently 
and correctly as described in Table 5. During the treatment period of the study conception is 
assumed to be precluded by the severe clinical conditions for included patients and applicability 
of sexual abstinence as a contraceptive method can be assessed by the investigator in case a 
patient confirmation cannot be gained. 
 
Table 5 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
(failure rate of <1% per year when used consistently and correctly) 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: b 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Highly Effective Methods That Are User Independent a 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation: b 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 


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Vasectomized partner: 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used. 
Sexual abstinence: 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the IMP. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the patient. 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for patients participating 
in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the 
efficacy of the contraceptive method. In this case, two highly effective methods of contraception 
should be utilized during the treatment period and for at least 3 months after the last dose of IFX-1. 
Pregnancy Testing 
WOCBP should only be included after a negative serum or urine pregnancy test. 
Collection of Pregnancy Information  
Male Patients with Partners who Become Pregnant  
The investigator will attempt to collect pregnancy information on any male patient’s female 
partner who becomes pregnant while the male patient is in this study. This applies only to male 
patients who receive IFX-1. 
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the investigator will record pregnancy information on the appropriate form and submit it to the 
sponsor within 24 hours of learning of the partner’s pregnancy. The female partner will also be 
followed to determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the sponsor. Generally, the follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
Female Patients who Become Pregnant  
The investigator will collect pregnancy information on any female patient who becomes pregnant 
while participating in this study. Information will be recorded on the appropriate form and 


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submitted to the sponsor within 24 hours of learning of a patient’s pregnancy. The patient will be 
followed at least monthly to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on the patient and the neonate and the information will be 
forwarded to the sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous abortion is 
always considered to be an SAE and will be reported as such. Any post-study pregnancy related 
SAE considered reasonably related to the IMP by the investigator will be reported to the safety 
vendor as described in Appendix 3. While the investigator is not obligated to actively seek this 
information in former study patients, he or she may learn of an SAE through spontaneous 
reporting.  
Any female patient who becomes pregnant while participating in the study will discontinue IMP. 
 
 


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Appendix 5 
Treatment Modification Guidelines 
Table 6 
Dose Modification and Toxicity Management Guidelines for Infusion Reactions 
Associated with IFX-1 
Grade 
Treatment 
Premedication at 
Subsequent Dosing 
mild 
 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
• Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator. 
None 
moderate 
 
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs. 
• Stop Infusion. 
• Additional appropriate medical therapy may 
include but is not limited to: 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator. 
• If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 
mL/hr. to 50 mL/hr.). Otherwise dosing will be 
held until symptoms resolve and the patient 
should be premedicated for the next scheduled 
dose. 
 
Patients who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment 
 
Patient may be premedicated 
1.5 h (± 30 minutes) prior to 
infusion of IMP with: 
 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic). 
severe 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicated for other 
clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
 
• Stop Infusion. 
• Additional appropriate medical therapy may 
include but is not limited to: 
• Epinephrine** 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Oxygen 
• Pressors 
• Corticosteroids 
• Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator. 
• Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used 
immediately. 
No subsequent dosing 


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life-threatening: 
Life-threatening; 
pressor or ventilator 
support indicated 
Patient is permanently discontinued from further 
study drug treatment. 
 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration. For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 
(CTCAE) at http://ctep.cancer.gov. 
 
 
 


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Appendix 6 
Conversion Tables for PaO2 / FiO2 Ratio 
The following conversion tables should be used if a blood gas analysis is not available.  
Estimating PaO2 from a measured SO2  
SO2 
Calculated 
PaO2 (mmHg) 
SO2 
Calculated 
PaO2 (mmHg) 
SO2 
Calculated 
PaO2 (mmHg) 
80 
44 
87 
53 
94 
73 
81 
45 
88 
55 
95 
79 
82 
46 
89 
57 
96 
86 
83 
47 
90 
60 
97 
96 
84 
49 
91 
62 
98 
112 
85 
50 
92 
65 
99 
145 
86 
52 
93 
69 
 
 
 
Estimating FiO2 with known O2 Application Flow 
Method 
O2-Flow (l/min) 
Estimated 
FiO2 ( %) 
Nasal O2 Tube 
Nasal Prong 
1 
2 
3 
4 
5 
6 
24 
28 
32 
36 
40 
44 
Nasopharyngeal 
Catheter 
4 
5 
6 
40 
50 
60 
Oxygen Mask 
5 
6–7 
7–8 
40 
50 
60 
Oxygen Mask with 
Reservoir 
6 
7 
8 
9 
10 
60 
70 
80 
90 
95 


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Appendix 7 
Ordinal Scale 
 


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Appendix 8 
New York Heart Association (NYHA) Classification 
Class 
Patient symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, dyspnea (shortness of breath) 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea (shortness of 
breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than 
ordinary activity causes fatigue, palpitation, or dyspnea 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of 
heart failure at rest. If any physical activity is undertaken, discomfort 
increases. 
 


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Appendix 9 
Child-Pugh Classification 
Category 
Hepatic Function 
Score 
Child-Pugh A 
Good  
5 to 6 points 
Child-Pugh B 
Moderately impaired 
7 to 9 points 
Child-Pugh C 
Advanced hepatic dysfunction 
10 to 15 points 
 
 
1 point 
2 points 
3 points 
Encephalopathy: 
None 
Grade 1 and 2  
Grade 3 and 4  
Ascites:   
None  
Slight  
Moderate  
Bilirubin: 
< 2 mg/mL 
2 to 3 mg/mL  
> 3 mg/mL 
Albumin: 
> 3.5mg/mL 
2.8 to 3.5mg/mL  
< 2.8mg/mL 
Prothrombin Time 
OR 
INR 
< 4 sec  
 
< 1.7 
4 to 6 sec  
 
1.7 to 2.2 
> 6 sec  
 
> 2.2 


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Appendix 10 
Special Considerations for Assessment of Prior and 
Concomitant Medications 
A complete record of all prior and concomitant drugs (but excluding nutritional and volume 
therapy, electrolyte support, vitamins, NSAIDs, and supportive therapies such as artificial tears, 
ointments, stool softeners/laxatives, etc.) will be maintained in the eCRF for each participant, 
beginning at baseline and continuing until day 28 or hospital discharge (whatever occurs earlier). 
In addition, a complete record of all steroid and antibiotic therapy and any therapy (drugs, 
specific treatments, etc.) associated with or used in the assessment or treatment of an adverse 
event will be documented for the duration of the study. 
The following information must be recorded in the eCRF for each concomitant medication: 
generic name, route of administration, start date, stop date, and indication. 
All medications administered within 7 days before randomization should be recorded with 
generic name, route of administration, start date, stop date, and indication. 


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Appendix 11 
Protocol Version History 
VERSION 2.0: 30 JULY 2020 
This protocol version is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the EU. 
Overall Rationale for Version 2.0 
After completion of the explorative Phase II (30 patients) of this adaptive study, the Expert 
Committee has recommended on proceeding to a confirmatory Phase III study based on interim 
analysis results suggesting that multi-organ failure is the leading cause of death for critically ill 
COVID-19 patients on mechanical ventilation. According to the findings from the preliminary 
interim analysis and after discussion with the Expert Committee, the Phase III design was 
established. In particular, the primary endpoint was modified to all-cause 28-day mortality, and 
secondary endpoints were adapted.  
Major updates made in Protocol Version 2.0 for Phase III of the study include the addition of 
information on the updated study design, endpoints, conduct, treatment administration, and 
statistical methods, as described in the table below. 
Table 7 
Protocol Version History: Major Updates to Phase III 
Section(s)  
Description of Change 
Brief Rationale 
 
Overall 
Where applicable, protocol sections were separated into 
subsections for Phase II and Phase III. 
This version includes study design elements applicable to 
Phase III of the study. 
1, 4.1.1 
Primary study objective 
updated 
To align with new primary endpoint and primary analysis for 
Phase III 
1, 10.2 
Number of sites increased 
from 6 in 3 countries to 
approximately 25 in 
7 countries 
Given the currently unpredictable epidemiology of COVID-19, 
additional sites in more countries will improve the ability to 
enroll the study in a timely manner. 
1, 5.2, 10.2 
Number of patients to be 
enrolled in Phase III increased 
from an estimated 100 patients 
to up to 360 patients 
The sample size was changed to ensure a sufficient sample size to 
yield an overall 90% power to show superiority of IFX-1 over 
SOC for the endpoint of 28-day all-cause mortality.  
1, 5 
Added details on the study 
design for Phase III  
Phase III will be a double-blind, placebo-controlled study in a 
group-sequential adaptive design (two stages) with one interim 
analysis for stopping for futility or stopping for efficacy in order 
to fulfill regulatory requirements for a confirmatory study. 
1, 5, 7.2.1 
The maximum number of IMP 
doses to be administered was 
decreased from 7 in Phase II 
to 6 in Phase III. 
The additional IMP administration between day 11 and 13 that 
was given in Phase II was removed in Phase III because 
experience from Phase II provided no evidence of the benefit of 
an additional dose. 
1, 6 
Clarified that all study patients 
are enrolled using a deferred 
consent.  
This was the same approach used in Phase II, due to the 
likelihood that a large proportion of patients or no patient will be 
unable to provide informed consent before the beginning of the 


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Description of Change 
Brief Rationale 
study. In Phase III, only patients requiring mechanical ventilation 
are eligible. 
1, 6.2 
Added inclusion and exclusion 
criteria for Phase III 
Only patients on mechanical ventilation are enrolled in Phase III 
because the Phase II preliminary interim results suggest that these 
patients benefit the most from IFX-1 treatment. 
1 
Expected study duration was 
increased by approximately 
6 months 
The increased sample size for Phase III was taken into 
consideration. 
1, 4.2.2 
Primary endpoint for Phase III 
was changed to all-cause 
mortality at day 28. 
Based on the interim analysis results of lower mortality rates in 
the IFX-1 arm compared with the BSC arm, the primary endpoint 
chosen for Phase III is 28-day all-cause mortality, which is an 
accepted regulatory primary endpoint for critical care studies. 
1, 4.2.2, 
Appendix 7 
Ordinal scale was added as a 
secondary endpoint 
The ordinal scale is commonly used in COVID-19 trials to assess 
patient’s clinical status. 
1, 4.2.2 
EQ-5D was added as a 
secondary endpoint 
EQ-5D is a commonly used patient-reported outcome in 
confirmatory studies and a recommended tool for COVID-19 
studies by several regulatory bodies. 
1, 4.2.2 
Additional secondary and 
other endpoints were added 
for Phase III 
These endpoints were added based on interim analysis results 
from Phase II.  
1, 10.2 
Statistical methods were added 
for Phase III 
To reflect the updated study design 
2 
Schedule of Assessments was 
added for Phase III 
To reflect the updated study design 
3 
Background and dose 
justification updated 
To reflect current understanding of SARS-CoV-2, COVID-19, 
and new data from interim analysis of Phase II. 
5.1.1, 
5.1.2, 7.1, 
7.2 
Text updated to reflect that 
Phase III will be double-
blinded and placebo-
controlled; Figure 2 added to 
show IMP administrations in 
Phase III 
To reflect the updated study design 
5.5 
Added section on iDMC 
Includes information on how and by whom the interim analysis 
during Phase III will be performed 
5.5.2 and 
subsections 
Definitions of end of treatment 
and end of study were added 
for Phase III 
Phase III included 1 less follow-up visit than Phase II, since 
follow-up of patients discharged from hospital in the COVID-19 
situation is expected to be difficult and a longer follow up would 
lead to a high proportion of missing information. 
7.3, 7.4, 
8.2.1, 
Appendix 
10 
Reporting of prior and 
concomitant medications will 
follow special considerations. 
Requirements for recording of prior and concomitant medications 
were simplified for the ICU setting. 
7.4.1 
Additional prohibited 
concomitant medications 
added 
To reflect the exclusion criteria for Phase III 
8.2 
Study assessments and 
procedures are added for 
Phase III. 
Efficacy and safety assessments were simplified for the ICU 
setting, based on clinical experience derived from Phase II of the 
study. 
9, 
Appendix 3 
AE collection and reporting 
requirements updated 
AE collection and reporting were simplified for the ICU setting, 
based on clinical experience derived from Phase II of the study 
9.8, 
Appendix 2 
Updated some text on 
regulatory and ethical 
considerations 
Phase III of the study will be conducted at US sites, so IRB is 
added where IEC is mentioned. Informed consent and data 


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Section(s)  
Description of Change 
Brief Rationale 
protection language updated to adapt to ICU setting. Storage of 
records updated to 15 years. Other minor updates are made. 
11 
Reference list updated 
To reflect updated Background section 
Appendix 8 
Added NYHA Classification 
scale 
For reference 
Appendix 9 
Added Child-Pugh 
Classification scale 
For reference 
Appendix 
11 
Added protocol version 
history 
To reflect changes to current protocol version. 
Additional major updates made in Protocol Version 2.0 that were retrospectively applied to 
Phase II mainly include text that was simplified or adapted to an ICU setting, as described in the 
table below. 
Table 8 
Protocol Version History: Major Updates to Phase II 
Section(s)  
Description of Change 
Brief Rationale 
 
Overall 
Where applicable, protocol sections were separated into 
subsections for Phase II and Phase III. 
Because Phase II is now completed, all information relevant only 
to Phase II of the study has been changed to past tense and font 
color changed to grey. 
“Subject(s)” changed to “Patient(s)” throughout to reflect the 
COVID-19 diseased population, and not healthy subjects, in the 
trial. 
5.5.1.3 
Clarification made 
Removed “In such a case the EOS visit information will be added 
to the EOT visit information.”, as this language was unclear. 
5.5.1.4 
Text on patients lost to follow-
up updated 
Text adapted to an ICU setting 
6.4 
Revised definition of 
screening failures 
Text adapted to an ICU setting 
6.5 
Removed dietary requirements 
Text adapted to an ICU setting 
7.2, 7.3, 
9.2.1, 9.6, 
Appendix 5 
“Infusion-related reactions” 
was changed to “infusion 
reactions” 
"Infusion reactions” is more a more accurate description of these 
events. 
7.2.4 
Removed “disease 
progression” 
Text adapted to an ICU setting 
7.3 
Removed “in the treatment 
facility” 
Text adapted to an ICU setting 
7.4 
Requirements for recording of 
prior and concomitant 
medications were revised  
Requirements were simplified and adapted to an ICU setting 
9.1 
Text on frequency of 
collection and reporting 
revised 
AESIs were included in the specified AEs to be reported until 
30 days following the last IFX-1 administration. SAEs was 
moved to the first bullet; bullets 1 and 2 combined since they 
follow the same timelines 
9.1.1, 
9.1.1.1, 
9.1.2 
Headings renamed and text 
updated accordingly 
Removed visit names that were used only in Phase II, to make the 
text applicable to Phase III as well. 
9.1.1.1, 
9.2.1 
“Death” was revised to 
“Events with fatal outcome” 
Death is not an SAE, but the outcome of an SAE. 


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Section(s)  
Description of Change 
Brief Rationale 
9.2.2 
“Not Related” was changed to 
“Unrelated” 
Harmonization of terminology 
 


 
                                       CONFIDENTIAL  
The information contained in this document is confidential and the proprietary property of 
InflaRx. Any unauthorized use or disclosure of such information without the prior written 
authorization of InflaRx is expressly prohibited. 
 
CLINICAL STUDY PROTOCOL 
 
A PRAGMATIC ADAPTIVE RANDOMIZED CONTROLLED PHASE II/III 
MULTICENTER STUDY OF IFX-1 IN PATIENTS WITH SEVERE COVID-19 
PNEUMONIA --- “PANAMO” 
 
Protocol Number: IFX-1-P2.9 
Compound: IFX-1 
Phase: II - III 
Indication: Severe pneumonia in context of COVID-19  
EudraCT Number: 2020-001335-28 
Sponsor Name and Address: InflaRx GmbH 
Winzerlaer Strasse 2 
07745 Jena, Germany 
Version and Date: Version 4.0, 12 May 2021 
 


InflaRx 
Clinical Study Protocol, Version 4.0, 12 May 2021 
IFX-1                          
                         CONFIDENTIAL  
IFX-1-P2.9 
 
PROTOCOL SIGNATURES 
 
Confirmation of the Final Protocol 
We hereby certify that this is the final version of the protocol: 
Protocol Number: 
IFX-1-P2.9 
Title: 
A pragmatic adaptive randomized controlled phase II/III multicenter 
study of IFX-1 in patients with severe COVID-19 pneumonia ---
“PANAMO” 
 
Sponsor Signatory: 
 
 
InflaRx GmbH 
Fraunhofer Strasse 22 
82152 Planegg / Martinsried 
Germany 
Date 
 
Medical monitor name and contact information will be provided separately. 
 
Statistician: 
 
 
 
 
 
 
 
 
Date 
 


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Signature of Coordinating Investigator 
 
Protocol Number: 
IFX-1-P2.9 
Title: 
A pragmatic adaptive randomized controlled phase II/III multicenter 
study of IFX-1 in patients with severe COVID-19 pneumonia ---
“PANAMO” 
 
Herewith I declare that I have read and understood the present protocol and agree to honor each 
part of it. By signing this study protocol, I agree to conduct the clinical study, following approval 
by an Ethics Committee, in accordance with the study protocol, the current International Council 
for Harmonization Guidelines for Good Clinical Practice (GCP), and applicable regulatory 
requirements. I will ensure that all the subjects enrolled in the study by my site will be treated, 
observed, and documented in accordance with this protocol. I will ensure that all persons 
assisting with the study under my supervision are adequately informed about the protocol, the 
investigational product, and their duties.   
 
 
 
Alexander Vlaar, MD, PhD 
Coordinating Investigator 
 
Intensive Care Volwassenen 
Amsterdam University Medical Center 
Locatie AMC  
C3-430 
Meibergdreef 9,  
1105 AZ, Amsterdam 
The Netherlands 
Date 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................4 
ABBREVIATIONS AND DEFINITIONS OF TERMS .............................................................9 
1. 
SYNOPSIS ............................................................................................................................12 
2. 
SCHEDULE OF ASSESSMENTS .....................................................................................20 
3. 
INTRODUCTION AND BACKGROUND INFORMATION ........................................25 
3.1. 
Background ......................................................................................................................25 
3.2. 
Study Rationale ................................................................................................................25 
3.2.1. 
Drug Profile ....................................................................................................................25 
3.2.2. 
Non-clinical and Therapeutic Studies .............................................................................26 
3.2.3. 
Experience in Humans ....................................................................................................27 
3.2.4. 
Scientific Rationale for the Study ...................................................................................28 
3.2.5. 
Justification for Dose ......................................................................................................29 
3.3. 
Benefit/Risk Assessment ..................................................................................................30 
4. 
OBJECTIVES AND ENDPOINTS ....................................................................................31 
4.1. 
Study Objectives...............................................................................................................31 
4.1.1. 
Primary Objectives .........................................................................................................31 
4.1.2. 
Secondary Objectives .....................................................................................................31 
4.2. 
Study Endpoints ...............................................................................................................32 
4.2.1. 
Phase II ...........................................................................................................................32 
4.2.1.1. 
Primary Endpoint .........................................................................................................32 
4.2.1.2. 
Secondary Endpoints ...................................................................................................32 
4.2.1.3. 
Other Endpoints ...........................................................................................................32 
4.2.2. 
Phase III ..........................................................................................................................33 
4.2.2.1. 
Primary Endpoint .........................................................................................................33 
4.2.2.2. 
Secondary Endpoints ...................................................................................................33 
4.2.2.3. 
Other Endpoints ...........................................................................................................33 
5. 
STUDY DESIGN .................................................................................................................34 
5.1. 
Overall Design ..................................................................................................................34 
5.1.1. 
Method of Treatment Assignment ..................................................................................35 
5.1.2. 
Blinding ..........................................................................................................................35 
5.2. 
Patient Enrollment ...........................................................................................................36 
5.3. 
Independent Safety Monitoring Board for Phase II .....................................................36 
5.4. 
Expert Committee for Phase II .......................................................................................36 
5.5. 
Independent Data Monitoring Committee for Phase III..............................................37 
5.6. 
Patient and Study Completion ........................................................................................37 
5.6.1. 
Phase II ...........................................................................................................................37 
5.6.1.1. 
End of Treatment and Follow-up .................................................................................37 
5.6.1.2. 
End of Study ................................................................................................................37 
5.6.1.3. 
Consent Withdrawal/ Discontinuation of Study Participation .....................................38 


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5.6.1.4. 
Lost to Follow-up .........................................................................................................38 
5.6.2. 
Phase III ..........................................................................................................................39 
5.6.2.1. 
End of Treatment and Follow-up .................................................................................39 
5.6.2.2. 
End of Study ................................................................................................................39 
5.6.2.3. 
Consent Withdrawal/Discontinuation of Study Participation ......................................39 
5.6.2.4. 
Lost to Follow-up .........................................................................................................40 
6. 
STUDY POPULATION ......................................................................................................40 
6.1. 
Phase II .............................................................................................................................40 
6.1.1. 
Inclusion Criteria ............................................................................................................40 
6.1.2. 
Exclusion Criteria ...........................................................................................................41 
6.2. 
Phase III ............................................................................................................................42 
6.2.1. 
Inclusion Criteria ............................................................................................................42 
6.2.2. 
Exclusion Criteria ...........................................................................................................42 
6.3. 
Deferred Consent and Other Forms of Informed Consent ..........................................43 
6.4. 
Screening Failures ............................................................................................................44 
6.5. 
Meals and Dietary Restrictions.......................................................................................44 
7. 
STUDY DRUG(S) AND ADMINISTRATION .................................................................45 
7.1. 
Investigational Medicinal Product .................................................................................45 
7.1.1. 
Packaging and Labelling of Investigational Medicinal Product .....................................45 
7.1.2. 
Storage, Handling, and Accountability ...........................................................................45 
7.1.3. 
Drug Preparation and Administration Instructions .........................................................46 
7.1.4. 
Recall of IMP ..................................................................................................................46 
7.2. 
Administration and Dosage .............................................................................................46 
7.2.1. 
Treatment Administered .................................................................................................47 
7.2.1.1. 
Phase II.........................................................................................................................47 
7.2.1.2. 
Phase III .......................................................................................................................47 
7.2.2. 
Treatment Modification ..................................................................................................50 
7.2.2.1. 
Infusion Reactions .......................................................................................................50 
7.2.3. 
Re-dosing Criteria ...........................................................................................................50 
7.2.4. 
Treatment Discontinuation Criteria ................................................................................50 
7.3. 
Premedication and Postmedication ................................................................................51 
7.4. 
Prior and Concomitant Medication/Treatments ...........................................................51 
7.4.1. 
Prohibited Concomitant Medication/Treatment .............................................................52 
7.5. 
Rescue Medications and Supportive Care .....................................................................52 
7.6. 
Treatment of Overdose ....................................................................................................52 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..............................................................53 
8.1. 
Phase II .............................................................................................................................53 
8.1.1. 
Baseline Assessments .....................................................................................................53 
8.1.1.1. 
Medical History (Except COVID-19 history)..............................................................54 
8.1.1.2. 
COVID-19 History.......................................................................................................54 
8.1.1.3. 
Concomitant Disease ...................................................................................................54 
8.1.1.4. 
Prior and Concomitant Medications ............................................................................54 
8.1.2. 
Efficacy Assessments .....................................................................................................54 
8.1.2.1. 
Imaging Requirements .................................................................................................54 


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8.1.2.2. 
Evaluation of Lung Function .......................................................................................54 
8.1.2.3. 
Evaluation of Response................................................................................................55 
8.1.3. 
Safety Assessments .........................................................................................................55 
8.1.3.1. 
Adverse Events Assessments .......................................................................................56 
8.1.3.2. 
Clinical Safety Laboratory Assessments .....................................................................56 
8.1.3.3. 
Vital Signs ....................................................................................................................57 
8.1.3.4. 
Electrocardiograms ......................................................................................................57 
8.1.3.5. 
Physical Examination...................................................................................................57 
8.1.3.6. 
Survival Status .............................................................................................................57 
8.1.4. 
Pharmacokinetics/Pharmacodynamics............................................................................58 
8.1.5. 
Biobanking of Samples from Patients Treated at Amsterdam Medical Center ..............58 
8.2. 
Phase III ............................................................................................................................58 
8.2.1. 
Baseline Assessments (Screening)..................................................................................58 
8.2.1.1. 
Medical History (Except COVID-19 History) .............................................................59 
8.2.1.2. 
COVID-19 History.......................................................................................................59 
8.2.1.3. 
Concomitant Disease ...................................................................................................59 
8.2.1.4. 
Prior and Concomitant Medications and Procedures ...................................................59 
8.2.2. 
Endpoint Assessments ....................................................................................................60 
8.2.2.1. 
Evaluation of Organ Support .......................................................................................60 
8.2.2.2. 
Ordinal Scale Evaluation .............................................................................................60 
8.2.2.3. 
Survival Status .............................................................................................................60 
8.2.2.4. 
Quality of Life Assessment ..........................................................................................60 
8.2.2.5. 
Clinical Status ..............................................................................................................60 
8.2.3. 
Safety Assessments .........................................................................................................60 
8.2.3.1. 
Adverse Events Assessments .......................................................................................61 
8.2.3.2. 
Clinical Safety Laboratory Assessments .....................................................................61 
8.2.3.3. 
Vital Signs ....................................................................................................................62 
8.2.3.4. 
Electrocardiograms ......................................................................................................62 
8.2.3.5. 
Physical Examination...................................................................................................62 
8.2.4. 
Pharmacokinetics/Pharmacodynamics............................................................................62 
9. 
ADVERSE EVENT COLLECTION AND REPORTING ..............................................62 
9.1. 
Time Period and Frequency of Collection and Reporting ...........................................64 
9.1.1. 
During Treatment ............................................................................................................64 
9.1.1.1. 
During Follow-up.........................................................................................................64 
9.1.2. 
After End of Study ..........................................................................................................65 
9.2. 
Serious Adverse Event Reporting and Timelines .........................................................65 
9.2.1. 
Initial Reporting of Serious Adverse Events ..................................................................65 
9.2.1.1. 
Follow-up Reporting of Serious Adverse Events ........................................................66 
9.2.2. 
Determination of Relatedness .........................................................................................66 
9.3. 
Death Reporting ...............................................................................................................68 
9.4. 
Abnormal Laboratory Values/Vital Signs/ECG/Physical Examination .....................68 
9.5. 
Events to be Handled as SAEs ........................................................................................68 
9.5.1. 
Overdose Reporting ........................................................................................................68 
9.5.2. 
Pregnancy Reporting.......................................................................................................69 
9.5.3. 
Drug-induced Liver Injury ..............................................................................................69 


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9.5.4. 
Suspected Transmission of an Infectious Agent (Pathogenic or Non-pathogenic) 
via Study Drug ................................................................................................................70 
9.6. 
Adverse Events of Special Interest .................................................................................70 
9.7. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs ..........................................................................................................71 
9.8. 
Reporting to Competent Authorities and Ethics Committees .....................................71 
10. STATISTICAL CONSIDERATIONS ...............................................................................71 
10.1. Phase II .............................................................................................................................71 
10.1.1. 
Sample Size Determination ............................................................................................71 
10.1.2. 
Analysis Sets ...................................................................................................................72 
10.1.3. 
Statistical Analyses .........................................................................................................72 
10.1.3.1. Efficacy Analyses ........................................................................................................72 
10.1.3.2. Safety Analyses ............................................................................................................73 
10.1.3.3. Interim Analysis ...........................................................................................................74 
10.2. Phase III ............................................................................................................................74 
10.2.1. 
Sample Size Determination ............................................................................................74 
10.2.2. 
Analysis Sets ...................................................................................................................74 
10.2.3. 
Statistical Analyses .........................................................................................................74 
10.2.3.1. Primary Efficacy Analysis ...........................................................................................75 
10.2.3.2. Secondary Efficacy Analyses ......................................................................................76 
10.2.3.3. Other Efficacy Analyses ..............................................................................................77 
10.2.3.4. Safety Analyses ............................................................................................................77 
10.2.3.5. Interim Analysis ...........................................................................................................78 
11. REFERENCES ....................................................................................................................79 
12. APPENDICES ......................................................................................................................81 
Appendix 1 Clinical Laboratory Tests ....................................................................................82 
Appendix 2 Regulatory and Ethical Considerations .............................................................84 
I. 
Regulatory and Ethical Considerations .........................................................................84 
II. 
Financial Disclosure .........................................................................................................84 
III. 
Informed Consent Process ..............................................................................................85 
IV. 
Data Protection.................................................................................................................85 
V. 
Publication Policy.............................................................................................................85 
VI. 
Dissemination of Clinical Study Information ................................................................86 
VII. 
Data Quality Assurance ...................................................................................................86 
VIII. Source Documents ............................................................................................................87 
IX. 
Study and Site Closure ....................................................................................................87 
Appendix 3 Adverse Events: Definitions and Procedures for Recording, 
Evaluation, Follow-up, and Reporting ...............................................................88 
I. 
Definitions .........................................................................................................................88 
II. 
Procedures for Recording, Evaluation, Follow-up and Reporting of an AE, 
including AESIs and SAEs ..................................................................................90 
III. 
Special Considerations for Assessment of Adverse Events in an ICU Setting ...........92 
Appendix 4 Contraceptive Guidance and Collections of Pregnancy Information .............94 
Appendix 5 Treatment Modification Guidelines ...................................................................98 


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Appendix 6 Conversion Tables for PaO2 / FiO2 Ratio .........................................................100 
Appendix 7 Ordinal Scale ......................................................................................................101 
Appendix 8 Glasgow Outcome Scale .....................................................................................102 
Appendix 9 EQ-5D Health Questionnaire ............................................................................103 
Appendix 10 New York Heart Association (NYHA) Classification .....................................105 
Appendix 11 Child-Pugh Classification ..................................................................................106 
Appendix 12 Special Considerations for Assessment of Prior and Concomitant 
Medications .........................................................................................................107 
Appendix 13 Protocol Version History ...................................................................................108 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments: Phase II ...............................................................................20 
Table 2 
Schedule of Assessments: Phase III ..............................................................................22 
Table 3 
Protocol-Required Safety Laboratory Assessments: Phase II .......................................82 
Table 4 
Protocol-Required Safety Laboratory Assessments: Phase III .....................................83 
Table 5 
Highly Effective Contraceptive Methods......................................................................95 
Table 6 
Dose Modification and Toxicity Management Guidelines for Infusion 
Reactions Associated with IFX-1..................................................................................98 
Table 7 
Protocol Version History: Major Updates to Version 3.0, Phase III ..........................108 
Table 8 
Protocol Version History: Major Updates to Phase II ................................................108 
 
LIST OF FIGURES 
Figure 1 Patient Calendar: IMP Administrations – Phase II .......................................................48 
Figure 2 Patient Calendar: IMP Administrations – Phase III ......................................................49 
 


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ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADA 
Anti-drug antibody 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AMC 
Amsterdam Medical Center 
AMG 
German Medicines Act (in German: “Arzneimittelgesetz”) 
aPTT/APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
BSC 
Best supportive care 
BDB 
Beijing Deferengui Biotech 
C5a 
Complement factor 5a 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIF 
Cumulative incidence function 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration  
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
Coronavirus Disease-19 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
EC 
Expert committee 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 
EU 
European Union 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
EOT 
End of treatment 
EQ-5D 
EuroQol 5-D (quality of life assessment tool) 
FAS 
Full analysis set 
FSH 
Follicle-stimulating hormone 
FUV 
Follow-up visit 


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GCP 
Good Clinical Practice 
GDPR  
General Data Protection Regulation  
HR 
Hazard ratio 
HRT 
Hormone replacement therapy 
HS 
Hidradenitis suppurativa 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
ICU 
Intensive care unit 
IDMC 
Independent Data Monitoring Committee  
IEC 
Independent ethics committee 
IgG4 
Immunoglobulin G4 
IMP 
Investigational Medicinal Product 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
iSMB 
Independent Safety Monitoring Board 
IV 
Intravenous 
IWRS 
Interactive Web Response System 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MERS-CoV 
Middle East Respiratory Syndrome Coronavirus  
MRI 
Magnetic resonance imaging 
NIH 
National Institutes of Health 
NSAID 
Non-steroidal anti-inflammatory drug 
NYHA 
New York Heart Association 
PaO2 / FiO2 
Oxygenation index 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PE 
Pulmonary embolism 
PK 
Pharmacokinetic 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 


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SARS 
Severe Acute Respiratory Syndrome 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2  
SoA 
Schedule of assessments 
SOC 
Standard of care 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
USA 
United States of America 
VTE 
Venous thromboembolism 
WHO 
World Health Organization 
WMO 
The Dutch Medical Research Involving Human Subjects Act (in 
Dutch: Wet medisch-wetenschappelijk onderzoek met mensen) 
WOCBP 
Women of childbearing potential 


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1. 
SYNOPSIS 
Title of Study:  
A PRAGMATIC ADAPTIVE RANDOMIZED, CONTROLLED PHASE II/III 
MULTICENTER STUDY OF IFX-1 IN PATIENTS WITH SEVERE COVID-19 
PNEUMONIA --- “PANAMO” 
Protocol/Study Number: IFX-1-P2.9 
EudraCT Number: 2020-001335-28 
Type of Study: 
Phase II/III Study 
Indication:  
Severe pneumonia in context of Coronavirus 
Disease-19 (COVID-19) 
Sponsor: InflaRx GmbH, Winzerlaer Strasse 2, 07745 Jena, Germany 
Coordinating Investigator: Alexander Vlaar, MD, PhD, Amsterdam University Medical 
Center, The Netherlands 
Study Site(s): Approximately 60 sites in approximately 10 countries in Europe, Russia, South 
Africa, United States of America (USA), and Latin America 
 
Phase of Development: II/III 
Objectives: 
Primary Objectives: 
Phase II: To explore the effect of IFX-1 on COVID-19 related severe pneumonia (hypothesis 
generating) 
Phase III: To demonstrate the efficacy of IFX-1 to improve survival outcomes of severe 
COVID-19 pneumonia (confirmative) 
Secondary Objectives: 
Phase II and Phase III 
• 
To assess and define other parameters of efficacy 
• 
To assess the safety of IFX-1  
 
Methodology:  
This is a pragmatic, adaptive, randomized, multicenter phase II/III study evaluating IFX-1 for 
the treatment of COVID-19 related severe pneumonia. The study consists of two parts: 
Phase II, an open-label, randomized, 2-arm phase evaluating best supportive care (BSC) + 
IFX-1 (Arm A) and BSC alone (Arm B); and Phase III, a double-blind, placebo-controlled, 
randomized phase comparing standard of care (SOC) + IFX-1 (Arm A) versus SOC + placebo-
to-match (Arm B). The SOC includes venous thromboembolism prophylaxis at a minimum, 


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and may include other international and country-specific recommended treatments for 
COVID-19 per the locally adopted treatment recommendations. 
At the time of writing of Protocol Version 2.0, Phase II of the study has been completed and 
30 patients have been treated. A preliminary interim analysis has been performed to assess the 
clinical benefit of the treatment using the assessed clinical parameters. An expert committee 
has monitored safety and the supported re-definition of relevant clinical endpoint(s) for 
Phase III.  
In Phase II, patients in Arm A were treated with a maximum of 7 intravenous (IV) doses of 
IFX-1 800 mg over a period of 29 days. The first 5 treatments at days 1, 2, 4, 8, and 15 were 
administered to all patients. Treatment at day 22 was only administered in the event that a 
patient had not been extubated and discharged from the intensive care unit (ICU). In case a 
patient’s clinical situation worsened after day 8, although an initial clinical benefit was 
observed, one additional administration of 800 mg IFX-1 between day 11 and 13 could have 
been given at investigator discretion. Loss of clinical benefit could, in this situation, relate to 
the exceptionally high complement factor 5a (C5a) levels observed in some cases of 
COVID-19 related pneumonia and associated shortened IFX-1 half-life.  
Phase III of the study will randomize up to 400 patients with one interim analysis for stopping 
for futility. A total of 180 patients are planned to be randomized into Arm A and Arm B using 
a 1:1 allocation ratio for the first stage; based on results of the interim analysis, up to an 
additional 180 patients are planned to be randomized using the same allocation ratio for the 
second stage. For patients randomized in error (screening failures) and patients for whom 
consent is withdrawn within 48 hours after randomization, additional patients will be 
randomized. 
In Phase III, patients will be treated with a maximum of 6 IV doses of IFX-1 800 mg (Arm A) 
or placebo (Arm B) at days 1, 2, 4, 8, 15, and 22, as long as the patient is still in the hospital 
(even if discharged from the ICU).  
Patients will be assessed for quality of life using the EuroQol-5D (EQ-5D). 
Patients will be followed for survival and their clinical status assessed by the Glasgow 
Outcome Scale. 
 
Number of Patients: 
Phase II: 30 patients (15 arm A+ 15 arm B)  
Phase III: Total of 180 patients (approximately 90 per arm) in Stage 1 and 180 patients 
(approximately 90 per arm) in Stage 2 are planned. The assumed rate for randomization of 
additional patients, i.e. patients randomized in error (screening failures) and patients for whom 
consent is withdrawn within 48 hours after randomization, is 10%. The planned maximum 
number of patients in the study is 400, 200 patients per treatment arm. The sample size ensures 
90% power to show superiority of IFX-1 for the primary endpoint of 28-day all-cause 
mortality. Sample size calculations were based on the assumption that IFX-1 can reduce a 30% 
mortality under SOC by 50% to a mortality of 15% and that at least 360 patients are evaluable 
for the primary endpoint for the final analysis.  
 


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Study Population: 
Study patients are enrolled into the study using a deferred consent procedure or another legally 
acceptable local consent procedure in this special ICU situation. 
Phase II 
Key inclusion criteria for Phase II of the study included the following: patients must have been 
at least 18 years of age or older with clinically evident or otherwise confirmed severe 
pneumonia, oxygenation index (PaO2 / FiO2) at time of enrollment of ≤ 250 and ≥ 100, and 
had Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection confirmation 
at screening and at enrollment. 
Key exclusion criteria for Phase II of the study included the following: PaO2 / FiO2 ≤ 99 or 
≥ 250 at screening, intubated > 48h at time of enrollment, demonstrated an improvement in 
past 24h prior to enrollment in oxygenation and ventilation/support parameters, known history 
of chronic dialysis or received renal replacement therapy in past 14 days, and history of 
chronic obstructive pulmonary disease (COPD).  
All inclusion and exclusion criteria are listed for Phase II in Section 6.1. 
Phase III 
Patients must meet all the following criteria at randomization to be enrolled into Phase III of 
the study: 
1. At least 18 years of age or older 
2. Patient on invasive mechanical ventilation (but not more than 48 h post intubation at time 
point of first IMP administration) 
3. Patients with a PaO2 / FiO2 ratio of < 200 and > 60 at randomization (one representative 
measurement within 6h before randomization) 
4. SARS-CoV-2 infection confirmation (tested positive in last 14 days before randomization 
with locally available test system) 
 
Patients who fulfill any of the following criteria at randomization are not eligible to participate 
in Phase III of the study: 
1. Intubated > 48 h at time point of first IMP administration  
2. Expected stop of invasive ventilation or expected extubation in the next 24h without 
additional intervention according to judgment of the investigator 
3. Known history of chronic dialysis OR received renal replacement therapy in past 14 days 
OR anticipated to receive renal replacement therapy within 24h after randomization 
4. Known history of progressed COPD as evidenced by use of daily maintenance treatment 
with long-acting bronchodilators or inhaled/oral corticosteroids for > 2 months 
5. Treatment of COVID-19 with investigational antibody treatment(s) which are not 
approved or not included in locally adopted treatment guidelines (e.g., World Health 
Organization [WHO] guidance, National Institutes of Health [NIH] COVID-19 treatment 


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guidelines) for this indication in the past 7 days (Note: Antibody treatment[s] given within 
past 7 days for pre-existing diseases, other than COVID-19, are allowed.)  
6. At time point of randomization, treatment of COVID-19 with investigational treatments 
which are not approved or not included in locally adopted treatment guidelines for this 
indication (e.g., WHO guidance, NIH COVID-19 treatment guidelines), including 
SARS-CoV-2 multiplication inhibitor(s) or immunomodulator(s). (Note: If a locally 
adopted treatment guideline recommends drugs such as remdesivir, dexamethasone, or 
anticoagulation, this would be allowed. Adopted guidelines and updates must be 
documented at study initiation and throughout the conduct of the study.) 
7. Received cytokine adsorption therapy in past 3 days 
8. Known hypersensitivity to IFX-1 or any other ingredient of the study medication 
9. Serum or urine pregnancy test positive before randomization (required for women of 
childbearing potential) 
10. Received organ or bone marrow transplantation in past 3 months 
11. Known cardio-pulmonary mechanical resuscitation in past 14 days  
12. Patient moribund or expected to die in next 24h according to the judgment of the 
investigator  
13. Known to have received anti-cancer therapy for hemato-oncological disease in past 
4 weeks OR known to have active malignant disease at time point of randomization 
14. Known severe congestive heart failure (corresponding to e.g. New York Heart Association 
[NYHA] Class III-IV, left ventricular ejection fraction <40%; see Appendix 8)  
15. Known history of chronic liver disease (Child-Pugh B or C; see Appendix 11) 
16. Participating in or has participated in other investigational interventional studies (drug or 
device) within the last 7 days before randomization 
 
Test Product, Dose, and Mode of Administration: 
Phase II 
In Arm A, patients received BSC + IFX-1. IFX-1 was to be administered as a 30-60 minute IV 
infusion as follows: 800 mg on days 1, 2, 4, 8, and 15 and, if not extubated or in weaning 
process in case of tracheostomy, may have received an additional 800 mg dose at day 22. 
IFX-1 treatment was to be ceased if signs of unacceptable toxicity or intolerability occurred. In 
case a patient’s clinical situation worsened after day 8, although an initial clinical benefit was 
observed, one additional administration of 800 mg IFX-1 between day 11 and 13 may have 
been given at investigator discretion. 
Phase III 
In Arm A, patients will receive SOC + IFX-1. IFX-1 will be administered as a 30-60-minute 
IV infusion as follows: 800 mg at days 1, 2, 4, 8, 15, and 22, as long as the patient is still in the 
hospital (even if discharged from the ICU). IFX-1 treatment shall be ceased if signs of 
unacceptable toxicity or intolerability occur.  


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Reference Therapy, Dose, and Mode of Administration: 
Phase II 
In Arm B, patients received BSC alone. 
Phase III 
In Arm B, patients will receive SOC + Placebo in the same schedule as described for Arm A. 
SOC treatment start and stop is not defined by the protocol and can start at any time. SOC 
treatment will be given according to investigator’s discretion. 
 
Expected Study Duration: 
First patient first visit: March 2020 (Phase II) 
Last patient last follow-up visit: August 2021 (Phase III) 
Criteria for Evaluation 
Phase II 
Primary Endpoint: 
The primary endpoint was the relative change (%) from baseline (day 1 prior to study drug 
administration at ± 1h of randomization) in oxygenation index (PaO2 / FiO2) in supine position 
at day 5. 
Secondary endpoints included the number of patients (%) achieving an early and late response, 
relative change (%) from baseline (day 1 prior to study drug administration at ± 1h of 
randomization) in PaO2 / FiO2 in supine position at day 3, 7, 9, and 11, all cause 28-day 
mortality (%), and frequency, severity, and relatedness to study drug of treatment-emergent 
adverse events (TEAEs) and serious adverse events (SAEs). Further details on secondary and 
other endpoints for Phase II are provided in Section 4.2.1. 
Phase III 
Primary Endpoint: 
• 
28-day all-cause mortality 
Secondary Endpoints: 
• 
60-day all-cause mortality (proportion of patients deceased until Day 60) 
• 
Proportion of patients with an improvement in the 8-point ordinal scale (Appendix 7) 
(day 15, day 28)  
• 
Proportion of patients developing acute kidney failure (estimated glomerular filtration rate 
[eGFR] < 15 mL/min/1.73m², assessed by the Chronic Kidney Disease Epidemiology 
Collaboration [CKD-EPI] equation requiring race information) during ICU stay and at 
day 28 


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• 
Proportion of patients free of any renal replacement therapy within 28 days upon 
randomization 
• 
Frequency, severity, and relatedness to study drug of serious and non-serious TEAEs 
Other Endpoints: 
• 
Time to first extubation 
• 
Proportion of patients achieving 8-point ordinal scale score 3 or below (patients alive and 
free of respiratory failure) at day 15 and day 28  
• 
Glasgow Outcome Scale score assessed at study day 60 
• 
Quality of life assessed by EQ-5D at study day 60. 
 
Statistical Methods: 
Phase II 
For efficacy analyses, the relative change (%) from baseline (day 1 prior to study drug 
administration at ± 1h of randomization) in oxygenation index (PaO2 / FiO2) in supine position 
at day 3, 5, 9, and 15 was to be analyzed with a linear repeated measures model with post-
baseline time points as outcome variables and baseline value as an explanatory variable. Least 
square mean differences between treatment arms and their 95% confidence interval (CI) were 
to be calculated and displayed for each time point separately (day 3, 5, 9 and 15), with the 
evaluation at day 5 reflecting the primary endpoint. Early response, late response, and reaching 
ICU discharge alive were to be analyzed as three separate time-to-event variables. All-cause 
mortality was to be analyzed as a censored time-to-event variable with Kaplan-Meier methods. 
Laboratory endpoints were to be analyzed descriptively by time point and treatment arm. 
Glasgow Outcome Scale was to be analyzed by ordinal regression analysis.  
For safety analyses, the occurrence of adverse events (AEs) was to be compared between 
treatment arms. The number and percentage of patients with SAEs was to be analyzed.  
Further details of statistical methods for Phase II are provided in Section 10.1. 
 
Phase III 
Efficacy: 
The primary statistical analysis will be based on all randomized patients except patients 
randomized in error (reason for early termination documented as “Randomized by mistake” in 
the eCRF) who did not get IMP treatment. For patients randomized in error (screening 
failures) and patients for whom consent is withdrawn within 48 hours after randomization, 
additional patients will be randomized. 
The primary efficacy variable is 28-day mortality (proportion of patients deceased until day 
28). 
The planned maximum number of patients in the study is 400. Up to 200 patients are planned 
to be randomized to Arm A and Arm B using a 1:1 allocation ratio for the first and for the 


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second stage each. The sample size calculation is based on an assumed rate of about 10% for 
additional patient randomization. A total of 180 patients (approximately 90 per arm) in Stage 1 
and up to 180 patients (approximately 90 per arm) in Stage 2 are planned to be analyzed in a 
combined fashion for the final efficacy analyses. This results in 90% overall power to show 
superiority of IFX-1. The power calculation is based on an overall 2.5% one-sided alpha and 
an assumed 30% 28-day mortality under Placebo and 15% 28-day mortality under IFX-1 
treatment. 
The interim analysis is performed after 180 patients, not counting patients being randomized in 
error, have been followed-up until day 28 (or died before). In case the interim analysis does 
not result in an early stop for futility, up to 180 additional patients are planned to be 
randomized in a ratio of 1:1 into Arm A and B. 
The primary analysis of IFX-1 + SOC compared to SOC alone will make use of a one-sided 
alpha level of 2.5%  and will test for superiority (lower mortality among IFX-1 treated 
patients). The primary statistical analysis will be based on a Cox proportional hazards 
regression model with outcome all-cause mortality as a censored time-to-event variable and 
explanatory variables randomized treatment arm (Arm B versus Arm A) and age. The primary 
statistical analysis will be based on all randomized patients except patients randomized in error 
(screening failures). For the primary analysis, all-cause mortality will be censored at day 28 
for subjects who died after day 28 or who have more than 28 days follow-up alive. 
The z-statistic for the interim and final analysis will be calculated as the proportion of the beta 
coefficient for the treatment arm effect and its standard error from the Cox proportional 
hazards regression model. The study will be stopped for futility if the z-statistic for the first 
stage is 0 or lower. 
The first secondary efficacy endpoint will only be addressed with statistical hypothesis tests if 
the primary endpoint is statistically significant, using the full overall 2.5% one-sided alpha. If 
the first secondary endpoint is also statistically significant, the full 2.5% one-sided alpha will 
be passed to the 4 remaining secondary endpoints. Multiplicity in the secondary endpoints will 
be addressed with the fallback method. 60-day mortality will be analyzed similar to 28-day 
mortality, and the other secondary endpoints will be evaluated using a logistic regression 
model with the explanatory variables randomized treatment arm (Arm B versus Arm A) and 
age: 
1. 60-day all-cause mortality 
2. Proportion of patients with an improvement in the provided 8-point ordinal scale at day 15 
(at least one score point lower than at randomization) 
3. Proportion of patients with an improvement in the provided 8-point ordinal scale at day 28 
(at least one score point lower than at randomization) 
4. Proportion of patients developing acute kidney failure (eGFR < 15 mL/min/1.73m²) during 
ICU stay and at day 28 
5. Proportion of patients free of any renal replacement therapy within 28 days upon 
randomization 
The ordering of the secondary endpoints 2 to 5 for hypothesis testing will be as in above 
mentioned list. The full 2.5% one-sided alpha for the fallback method will be attributed to 


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these 4 secondary endpoints in the following way: 2%, 0.2%, 0.2%, and 0.1%. If the preceding 
hypothesis test is not significant, subsequent tests will be performed at the aforementioned 
alpha level. If tests are significant, the alpha is added to the subsequent hypothesis test (e.g., if 
the primary hypothesis test is significant and secondary endpoints 1-4 are all significant, the 
fifth secondary endpoint will be tested at an alpha of 2.5%; if the fourth secondary endpoint is 
not significant, the fifth secondary endpoint will be tested at an alpha of 0.1%). 
The primary endpoint as well as all secondary endpoints will also be evaluated as censored 
time to event variables by Kaplan-Meier type methods. 
Safety: 
The occurrence of TEAEs will be compared between treatment arms. TEAEs will be analyzed 
according to the number and percentage of patients who had a TEAE, as well as the number of 
TEAEs in total. Additionally, the number and percentage of patients with TEAEs will be 
further grouped by severity and causal relationship. The number and percentage of patients 
with serious TEAEs and adverse events of special interest (AESIs) and the total number of 
serious TEAEs and AESIs will be analyzed. Where TEAEs are grouped by severity or 
relationship, the maximum severity/relationship per patient and class of TEAE will be 
considered. 
Interim Analysis: 
The interim analysis is performed after 180 patients, not counting patients being randomized in 
error, in Stage 1 have been followed-up until day 28 (or died before). The study will be 
stopped for futility if the z-statistic of the primary efficacy analysis is 0 or lower. If the study 
is not stopped for futility, another up to 180 patients will be randomized in Stage 2. Depending 
on the number of patients meeting criteria for additional randomization, more than 360 
patients will be randomized but not more than a total of 400. 


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2. 
SCHEDULE OF ASSESSMENTS 
Table 1 
Schedule of Assessments: Phase II 
Screening 
Period 
Treatment Period (Maximum 4 Weeks) 
Follow-up Period  
(2 Months)(Telephone) 
EOT =  
FUV 1 
EOS= 
FUV 2 
Days 
-2 – 0 
Day 
1 
 
Day 
2 
Day 
3 
Day 
4 
 
Day 
5 
Day 
7 
Day 
8 
Day 
9 
Day 
11 
Day 
13 
Day 
15 
Day 
22 
Day 29/ 
Discharge 
28 days 
after last 
IFX-1 
treatment 
28 days 
after 
FUV 1 
Deferred Informed 
consenta 
X 
 
 
Inclusion/exclusion 
criteria  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, 
medical/disease 
history, prior 
medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease/response 
assessmentsb 
X 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Imagingc 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
Concomitant disease  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
 
X 
 
 
X 
 
X 
 
 
X 
X 
 
 
 
Blood sample for 
plasma complement 
and PK assessmentd 
 
X 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
IV administration of 
IFX-1e 
 
X 
X 
 
X 
 
 
X 
 
(x) 
 
X 
(x) 
 
 
 
Safety Assessments 
Weight 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
X 
 
 
Safety laboratory testf 
 
X 
X 
 
X 
 
 
X 
 
(x) 
 
X 
X 
X 
 
 


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Pregnancy testg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Survival status  
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
CT = computed tomography; ECG = electrocardiogram; EOS = end of study; EOT = end of treatment; FUV = follow-up visit; IMP = investigational medicinal product; IV = 
intravenous; MRI = magnetic resonance imaging; PK = pharmacokinetic 
a  Obtaining of informed consent was to be deferred for the ICU patients (see Section 6.3). 
b  Disease/response assessments included evaluation of lung function and evaluation of early and late response (see Section 8.1.2). 
c  Imaging was to be performed by X-ray or CT scan or MRI, per investigator decision. Once the imaging choice was made, subsequent assessments should have been made 
using the same modality whenever possible. Imaging either at day 29 or day of discharge ± 3 days. 
d  Blood samples were to be collected for measurement of plasma concentrations and C3a and C5a of IFX-1 before administration of IMP (see Section 8.1.4), if possible. 
e  The first 5 treatments of IFX-1 at day 1, 2, 4, 8, and 15 were to be administered to all patients randomized to Arm A. Treatment at day 22 was only to be administered in the 
event that a patient had not been extubated and discharged from ICU. In case a patient’s clinical situation would worsen after day 8, although an initial clinical benefit was 
observed, one additional administration of IFX-1 between day 11 and 13 could have been given at investigator discretion, represented as (x) above. 
f  Safety laboratory tests included hematology, coagulation parameters, chemistry, urinalysis, and other screening tests (see Table 3). Blood samples for safety laboratory 
analysis should have been obtained after vital signs assessments were performed, but before administration of IMP. 
g  Blood samples for serum pregnancy testing were to be collected only for women of childbearing potential. 
h  Core body temperature, heart rate, respiratory rate, and blood pressure (diastolic and systolic) were to be assessed at each visit at pre-dose, and H0+1h, where H0 is the 
beginning of IFX 1 administration, on the days of IMP administration and at further time points whenever medically indicated. Vital signs were to be measured in a supine 
position (after a rest of at least 1h in case of position switch from prone position), preferably in the morning. 
 


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Table 2 
Schedule of Assessments: Phase III 
Screening/ 
Randomization 
Treatment Period  
IMP administration and assessments as long as in ICU / Hospital 
Follow-up 
Period  
(Telephone 
possible) 
Week 1 
Week2 
Week 3 
Week 4 
Week 5 
Any time 
FUV 
Screening  
not more than  
24h before 
randomization 
Day 1 
(at or up 
to 24h 
after 
random-
ization)  
Day 2 
Day 4 
Day 8 
Day 15 
 
Day 22 
 
Day 28 
(if still in 
hospital) 
ICU  
discharge  
 
 
Hospital 
discharge  
Day 28  
 
Day 60
(+/- 
3 days) 
after  
randomization  
Deferred informed consenta 
X 
Screening / Baseline Assessments 
Inclusion/exclusion criteria  
X 
 
 
 
Urine analysis  
X 
 
 
 
Pregnancy testb 
X 
 
 
 
Weight 
X 
 
 
 
Height 
X 
 
 
 
PaO2 / FiO2c 
X 
 
 
 
Demographics, COVID-19 
history, SARS-CoV-2 
mRNA testd  
X 
 
 
 
Medical history/ 
concomitant disease  
X 
 
 
 
Prior medications and 
procedures 
X 
 
 
 
Intubation date 
X 
 
 
 
Randomization  
Randomization 
X 
 
 
 
IMP Administration 
IMP administratione 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 


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Screening/ 
Randomization 
Treatment Period  
IMP administration and assessments as long as in ICU / Hospital 
Follow-up 
Period  
(Telephone 
possible) 
Week 1 
Week2 
Week 3 
Week 4 
Week 5 
Any time 
FUV 
Screening  
not more than  
24h before 
randomization 
Day 1 
(at or up 
to 24h 
after 
random-
ization)  
Day 2 
Day 4 
Day 8 
Day 15 
 
Day 22 
 
Day 28 
(if still in 
hospital) 
ICU  
discharge  
 
 
Hospital 
discharge  
Day 28  
 
Day 60
(+/- 
3 days) 
after  
randomization  
Endpoint Assessments 
Organ support  
(renal replacement therapy, 
ECMO, mechanical 
ventilation) 
 
X 
 
 
Extubation and 
re-intubation date(s) 
 
X 
 
 
Ordinal scale evaluationf 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Survival status  
 
X 
X 
X 
Quality of life (EQ-5D) 
 
 
 
X 
Glasgow Outcome Scale 
 
 
 
X 
Safety Assessments 
Safety laboratory testsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Creatinineh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signsi 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse eventsj 
X 
X 
X 
X 
Physical examinationl 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Concomitant medications 
and procedures 
 
X 
 
 
12-lead ECG 
X 
  
X 
 
 
 
PK/PD Assessments (Country-specific)k 
IFX-1 sample 
X 
 
X 
 
X 
 
 


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Screening/ 
Randomization 
Treatment Period  
IMP administration and assessments as long as in ICU / Hospital 
Follow-up 
Period  
(Telephone 
possible) 
Week 1 
Week2 
Week 3 
Week 4 
Week 5 
Any time 
FUV 
Screening  
not more than  
24h before 
randomization 
Day 1 
(at or up 
to 24h 
after 
random-
ization)  
Day 2 
Day 4 
Day 8 
Day 15 
 
Day 22 
 
Day 28 
(if still in 
hospital) 
ICU  
discharge  
 
 
Hospital 
discharge  
Day 28  
 
Day 60
(+/- 
3 days) 
after  
randomization  
ADA sample 
X 
 
X 
 
 
C5a sample 
X 
 
X 
 
X 
 
 
ADA = anti-drug antibody; C5a =  complement factor 5a; COVID-19 = Coronavirus Disease-19; ECG = electrocardiogram; ECMO = extracorporeal membrane oxygenation; EQ-
5D = EuroQol 5-D; FUV = follow-up visit; ICU = intensive care unit; IMP = investigational medicinal product; IV = intravenous; PaO2 / FiO2 = oxygenation index; 
PK/PD = pharmacokinetic/pharmacodynamic; SARS-CoV-2 = Severe acute respiratory syndrome Coronavirus 2.  
a 
Obtaining of informed consent is proposed to be deferred or by any other legally acceptable local consent procedure for the ICU patients in this study (see Section 6.3). 
b 
Serum or urine samples for pregnancy testing will be collected only for women of childbearing potential. 
c 
PaO2 / FiO2 should be assessed within 6h before randomization (one representative measurement) 
d 
SARS-CoV-2 infection confirmation will be done, if not already tested positive in last 14 days before randomization, with locally available test system 
e 
Up to 6 treatments of IMP will be administered at days 1, 2, 4, 8, 15, and 22 as long as the patient is still in the hospital, even if discharged from the ICU.  
f 
8-point ordinal scale score will be documented at the visits indicated, including the date (one value per assessment day, that best represents the patient’s condition at that day) 
g 
Day 1 assessment has to be done prior to IMP administration only, if more than 12 h elapsed between screening assessment and IMP administration. Safety laboratory tests 
include hematology (hemoglobin, hematocrit, platelet count, red blood cell count, red blood cells (MCV), white blood cell count with differentials (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils), coagulation parameters (activated partial thromboplastin time [aPTT], prothrombin time [PT], D-dimer), blood chemistry (ALT, AST, 
lactate dehydrogenase [LDH], total bilirubin, and c-reactive protein [CRP]) (see Appendix 1, Table 4). Blood samples for safety laboratory analysis should be obtained at 
indicated days during routine sampling (one representative value, if taken more than once a day). 
h 
Creatinine assessment should be obtained at indicated days during routine sampling (one representative value, if taken more than once a day). Day 1 assessment has to be done 
prior to IMP administration only, if more than 12 h elapsed between screening assessment and IMP administration. 
i 
Vital signs (core body temperature, heart rate, respiratory rate, blood pressure [diastolic and systolic]) will be assessed at indicated visits at pre-dose within 1h before 
administration of IMP (one representative measurement closest to IMP administration) and at further time points whenever medically indicated. Blood pressure and heart rate 
measurements will be assessed with an intra-arterial catheter, or a completely automated device. Manual techniques will be used only if an automated device is not available. 
j 
Adverse event reporting will follow special considerations for the ICU setting as described in Section 9.1 ff and Appendix 3. 
k 
PK/PD sampling will be conducted at selected countries/sites. PK/PD samples will be taken within 1h before administration of IMP. 
l 
Day 1 assessment has to be done prior to IMP administration only, if more than 24 h elapsed between screening assessment and IMP administration. 
 


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3. 
INTRODUCTION AND BACKGROUND INFORMATION 
3.1. 
Background 
There are daily increasing numbers of Severe Acute Respiratory Syndrome (SARS) 
Coronavirus 2 (SARS-CoV-2) infected individuals globally and reports on impact / mortality 
vary constantly. As of 23 July 2020, over 15 million documented cases were reported worldwide 
of which more than 619,000 died (World Health Organization [WHO] 2020). Clinical 
manifestations of Coronavirus Disease-19 (COVID-19) vary, with approximately 5% of patients 
having critical manifestations (such as respiratory failure, septic shock, and/or multiple organ 
dysfunction) and 17-35% of hospitalized patients being treated in an intensive care unit (ICU), of 
whom 29-91% require invasive mechanical ventilation (Wiersinga et al. 2020).  
The main COVID-19 characterizing clinical features are age greater than 50 years and presence 
of comorbidities such as hypertension and diabetes, whereas main laboratory findings show 
hepatic and renal dysfunction in the presence of leukopenia, lymphopenia, increase of D-dimers, 
and strong inflammatory cytokine activation (Guan et al. 2020; Huang et al. 2020; Liu et al. 
2020; Garg et al. 2020; Wiersinga et al. 2020). Elevated D-dimer values have been shown to be 
strongly associated with poorer prognosis. It is also reported that the complement cascade is 
highly activated (Gao et al. 2020). One hallmark of progressed disease in patients who become 
severely diseased is the association of blood neutrophil increases with the disease severity, and 
neutrophil infiltration in the heart and liver. 
Monoclonal antibodies directed against key inflammatory mediators, such as interleukin 1 and 6 
and complement factor 5a (C5a), aim to modulate the overwhelming inflammatory response 
following SARS-CoV-2 infection, thereby preventing organ damage (Wiersinga et al. 2020). 
These targeted immunomodulatory agents are currently being evaluated for the management of 
COVID-19 and may prevent disease progression in hospitalized patients.  
3.2. 
Study Rationale 
3.2.1. 
Drug Profile 
IFX-1 is a chimeric immunoglobulin G4 (IgG4) monoclonal anti-human C5a antibody, which 
specifically binds to the soluble human complement split product C5a. IFX-1 has been 
demonstrated to block C5a-mediated biological effects with high efficacy in vitro. C5a is one of 
the most potent inflammatory factors, triggering innate immune responses and bridging to 
adaptive immune responses (Dunkelberger and Song 2010). In blood, C5 is cleaved to C5a by 
components of the classical and alternative complement pathway, and the coagulation pathway, 
whereas in tissue, factors of the alternative complement and the coagulation pathway factors play 
a major role in C5a generation (Hess and Kemper 2016). 


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3.2.2. 
Non-clinical and Therapeutic Studies 
Non-clinical studies were conducted to assess pharmacological and toxicological aspects of 
IFX-1 and showed that IFX-1 was able to rapidly bind to its target, the human C5a, and achieve 
an almost complete blockade of C5a-induced biological effects. At the same time, cleavage of 
C5 and formation of the complement membrane attack complex was not disrupted in vitro. 
IFX-1 did not demonstrate any cross-reactivity or bioactivity in species other than humans and 
non-human primates (Section 4.2 of the Investigator Brochure [IB]). Therefore, toxicology 
studies were only conducted in cynomolgus monkeys.  
IFX-1 has been investigated in viral-induced lung injury in monkeys infected with the avian flu 
virus H7N9. It had been shown that the neutrophil influx into the lung as well as the lung 
damage could be greatly reduced by this therapeutic attempt. In addition, the viral replication 
was greatly reduced as well, which is believed to be an indirect effect (Sun et al. 2015). This 
research was in line with findings generated in an H5N1 model of disease in rodents (Sun et al. 
2013). Since then, the role of complement and specifically C5a for viral-induced lung injury has 
become an accepted concept in basic research (Wang et al. 2015). The same research group then 
confirmed the role of the C5a/C5a-receptor signaling axis for viral replication, for lung 
neutrophil influx and damage in a mouse model of Middle East Respiratory Syndrome 
Coronavirus (MERS-CoV) (Jiang et al. 2018). Another group of researchers then confirmed the 
role of complement activation and made similar findings on viral replication inhibition and lung 
damage reduction in complement deficient mice in a SARS virus infection model (Gralinski et 
al. 2018). One finding of this study was that complement deficient mice (C3-/-) had significantly 
less infiltration of the lungs with neutrophils and monocytes, also confirming earlier findings in 
greater detail for SARS-CoV induced viral lung injury.  
This body of research has led to the approval by the Chinese FDA of two ongoing trials in 
SARS-CoV-2 infected patients in China with the monoclonal anti-C5a antibody BDB-1 (S-FDA 
approval number 2020L00003). BDB-1 is generated from the InflaRx IFX-1 cell line which has 
been transferred and licensed to the InflaRx collaborator Beijing Deferengui Biotech Co. (BDB). 
BDB develops BDB-1 under their responsibility in China and InflaRx has all rights to any 
discoveries made by BDB-1 globally outside China, where InflaRx develops IFX-1 in the rest of 
the world. The BDB-1 trials are ongoing, however data of the first two open label treated patients 
were reported in context of a research article by Gao et al. 2020 (see Section 3.2.4). 
None of the Good Laboratory Practice-compliant studies in cynomolgus monkeys revealed 
relevant toxicological or safety concerns for IFX-1. During single-dose and repeat-dose 
administration of IFX-1 at doses of up to 50 mg/kg body weight in cynomolgus monkeys no 
direct IFX-1-related toxicological or adverse findings within an extended core battery of safety 
pharmacology assessments were observed. Results showed dose-related increases in systemic 
and maximum exposure in the investigated dose range of 1 to 50 mg/kg body weight. Anti-drug 


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antibodies (ADAs) were detected in 1 animal in the 26-week repeat-dose study. This animal 
died, most likely because of an ADA-mediated immune complex formation. 
An overview of the non-clinical toxicology studies that were conducted with IFX-1 is available 
in Table 8 of the IB. 
For further details, refer to Section 4 of the IB. 
3.2.3. 
Experience in Humans 
At the time of writing of Protocol Version 2.0, Phase II of the current study has been completed 
and all 30 enrolled patients have been treated (15 in Arm A [best supportive care (BSC) + IFX-1] 
and 15 in Arm B [BSC alone]) for up to 28 days. Relative change (%) from baseline to day 5 in 
oxygenation index was assessed as the primary endpoint along with additional clinical 
parameters until day 28. Relative change in the oxygenation index at day 5 showed no 
differences between treatment groups. However, IFX-1 treatment was associated with a lower 
28-day all-cause mortality when compared to the BSC arm, along with trends in disease 
improvement, as evidenced by fewer patients experiencing renal impairment assessed by eGFR, 
more patients showing reversal of blood lymphocytopenia and a greater lowering of lactate 
dehydrogenase concentrations. In IFX-1-treated patients, pulmonary embolisms (PE) reported as 
serious adverse events (SAEs) were lower compared to the BSC arm. Also, a temporary increase 
of D-dimer levels, as potential expression of induction of blood clot lysis, was detected in the 
first days after initiation of IFX-1 treatment. 
Over a treatment period of 28 days, patients in the IFX-1 arm received a maximum of 7 doses of 
800 mg IFX-1 intravenously (IV) on separate days. At randomization, 18 patients (60%) were 
intubated, and 12 patients (40%) had other oxygen supply. A higher number of patients with 2 or 
more comorbidities associated with increased COVID-19 mortality were reported in the IFX-1 
treatment arm compared to the BSC arm. Twenty-eight-day all-cause mortality in the IFX-1 
treatment arm was 13% (2 out of 15) versus 27% (4 out of 15) in the BSC arm. In the BSC arm, 
4 patients died of COVID-19-induced multi-organ failure, and 3 of them had PE reported as 
SAEs. In the IFX-1 arm, one patient died after an acute ventilator tube complication (leakage) 
and one patient with a history of severe chronic obstructive pulmonary disease died of 
pulmonary failure. Serious AE rates were comparable between groups, but the rate of PE 
reported as SAEs was substantially lower in the IFX-1 treatment group. Upon review of the 
safety data, the independent data safety monitoring board has recommended continuation of the 
trial into Phase III. 
IFX-1 is also being developed for the treatment of other inflammatory diseases. Five clinical 
studies in humans have been completed so far. One Phase I study in healthy volunteers 
(Study IFX-1-P1.1) and 4 Phase II studies: 1 in patients with early septic organ dysfunction 
(Study IFX-1-P2.1), 1 in patients undergoing complex cardiac surgery (Study IFX-1-P2.2), and 
2 in patients with hidradenitis suppurativa (HS) (Studies IFX-1-P2.3 and IFX-1-P2.4; Section 5 
of the IB).  


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To date, 391 subjects (26 healthy volunteers and 365 patients) have been treated in completed 
clinical studies of these other inflammatory diseases, of which 294 have received IFX-1 and 
92 have received placebo. IFX-1 was safe and well tolerated, with no dose relationship in the 
safety findings. No specific adverse reactions emerged in clinical studies of single or multiple 
doses IFX-1 in healthy volunteers or patients with cardiac disease, sepsis, or HS. 
Currently, 4 further Phase II studies are ongoing: 1 in patients with HS (Study IFX-1-P2.4; in 
final analyses), 2 in patients with granulomatosis with polyangiitis and microscopic polyangiitis 
(also referred to as anti-neutrophil cytoplasmic antibody-associated vasculitis; Study IFX-1-P2.5 
and IFX-1-P2.6), and 1 in patients with pyoderma gangrenosum (Study IFX-1-P2.7). 
Data are available from the interim analysis of the main period of the Phase II Study IFX-1-P2.4 
in HS, where 141 patients were treated with IFX-1 in 4 different IFX-1 dose cohorts (400 mg and 
800 mg every 4 weeks, 800 mg bi-weekly, and 1200 mg every 2 weeks) and 36 patients were 
treated with placebo. The total treatment duration in this study, which recently completed 
treatment, was 9 months. Treatment with IFX-1 was safe and well tolerated with rare occurrence 
of AESIs, defined as infusion reactions, including hypersensitivity or anaphylaxis, meningitis, 
meningococcal sepsis, and invasive infection. Four patients experienced AEs suggestive of 
hypersensitivity. The reactions were moderate, and treatment continued, if necessary with 
adequate prophylactic medication. Anti-drug antibodies during treatment were observed in a 
range of 5.6% to 12.9% with a trend towards increasing frequency with low dose and larger 
administration intervals. 
3.2.4. 
Scientific Rationale for the Study  
Neutrophil driven tissue and organ damage is known to play an important role in a wide array of 
acute inflammatory diseases. The mechanism leading to damage has been largely attributed to 
two mechanisms: 1) the release of granular enzymes and 2) the generation of so-called reactive 
oxygen species in which O2 radical formation elicits a damaging effect. 
One of the strongest chemoattractant substances, which is also capable of inducing both 
mechanisms described above is the human complement split product C5a.  
Earlier research by InflaRx has demonstrated that the anti-human C5a antibody IFX-1 could 
significantly reduce the neutrophil and macrophage infiltration in a model of viral (H7N9)-
induced lung injury in monkeys (Sun et al. 2015). This was accompanied by a significantly 
reduced tissue damage in the lung of infected animals and also a significantly reduced viral 
replication when compared to mock-treated animals. The mechanism was then confirmed in a 
model of MERS–CoV-induced lung injury where similar findings were made by using an anti-
C5a receptor antibody (Jiang et al. 2018) and in a model of SARS-CoV-induced lung injury by 
using complement C3 knockout mice (Gralinski et al. 2018). The latter study also provided 
evidence for a profound complement activation in SARS virus infections in animals. These 
studies all suggested a role of neutrophil driven lung damage, which was induced by generation 
of C5a in different viral-lung injury models, including SARS viruses.  


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Latest data from a collaborating research group in China demonstrated strongly and significantly 
elevated C5a levels in severely diseased COVID-19 patients when compared to mildly diseased 
patients (Gao et al. 2020; Carvelli et al. 2020) and revealed evidence for a strong complement 
pathway driven activation of C5a in this disease. In addition, data from the first two severely 
diseased COVID-19 patients treated with the IFX-1 cell line derived anti-C5a antibody BDB-1, 
which InflaRx licensed to a collaborator in China, demonstrated clinical improvement in 
oxygenation index, fever reduction, and laboratory parameter normalization including liver 
enzymes and lymphocyte counts. 
From a clinical perspective, various papers have confirmed that COVID-19 infected non-
surviving patients demonstrated lung failure with close to 100% (Zhou et al. 2020) and that, in 
contrast to surviving patients, non-survivors demonstrated elevated white blood cell counts and 
neutrophils above the normal range (Wang et al. 2020; Gong et al. 2020). 
In summary, there is evidence that in COVID-19 patients who are severely affected, C5a 
activation occurs to a large extent and that neutrophil count elevation in blood is associated with 
bad outcome. These human data fit well to the scientific rationale developed in animal models of 
viral-induced lung injury that activated neutrophils attracted to the lung may cause viral-induced 
lung damage. First treatment attempts with the anti-C5a antibody technology developed by 
InflaRx (BDB-1) in severely affected COVID-19 patients provide further evidence for the 
scientific rationale.  
The completed Phase II portion of the current trial was exploratory in nature and was not 
powered to show statistically significant differences in clinical endpoints. Relative change (%) 
from baseline to day 5 in the oxygenation index, chosen as the primary endpoint for Phase II, 
showed a large variability and dependency on patient positioning and intubation status which 
excluded this endpoint from being used in a confirmatory study. Phase III of the study is an 
adequately powered, placebo-controlled, double blinded phase evaluating standard of care 
(SOC) + IFX-1 versus SOC + placebo-to-match with 28-day all-cause mortality as the primary 
endpoint, an accepted regulatory primary endpoint for critical care studies. 
At the time that Phase II of this study was initiated, there was no SOC established for this newly 
identified disease. The SOC to be utilized in Phase III of this study reflects the current 
understanding of the SOC for hospitalized patients with COVID-19, which includes venous 
thromboembolism (VTE) prophylaxis at a minimum, and may include other international and 
country-specific recommended treatments for COVID-19 per the locally adopted treatment 
recommendations. 
3.2.5. 
Justification for Dose 
The aim for determining the dose and administration frequency for IFX-1 is to establish a 
pragmatic administration schedule for the COVID-19 patient population. IFX-1 dose and 
administration schedule was chosen based on prior pharmacokinetic (PK)/pharmacodynamic 
(PD) observations for IFX-1 trough values and blood C5a levels, dose-response assessment in 


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Study IFX-1 P2.4 in HS, and the described unprecedented high C5a levels in patients with severe 
COVID-19 related pneumonia (Gao et al. 2020; Carvelli et al. 2020). In a population PK/PD 
modelling study for IFX-1 based on the data of the 2 trials in HS patients, a reduction in C5a 
concentration was found to be dependent on all measures of drug exposure, with increasing 
exposure predicting a greater reduction in C5a.  
The observed half-life of IFX-1 with a single dose of 800 mg was 3 to 4 days in Study IFX-1 
P2.2 in patients undergoing complex cardiac surgery. Thus, an additional dose of 800 mg at 
Day 4, followed by weekly administration of 800 mg IFX-1 was chosen for Study IFX-1 P2.3 in 
patients with HS.  
In Study IFX-1 P2.3 in patients with HS, 800 mg once-weekly IFX-1 was administered for up to 
9 times including an additional dose of 800 mg at Day 4. This administration schedule resulted in 
IFX-1 trough concentrations of around 50 µg/mL and a decrease of elevated baseline C5a levels 
to approximately detection limit throughout the treatment duration in the majority of patients. 
This dosing regimen was well tolerated, with no new safety signals, and clinical improvement of 
HS was observed in some patients. 
In another clinical study in HS (Study IFX-1 P2.4), 4 different dosing schedules were explored, 
of which the highest dose was 1200 mg every 2 weeks. Safety findings were similar in all dose 
groups, and similar to safety findings in previous studies, with no new specific AESIs. 
Based on the above data, the dosing schedule of IFX-1 for this study includes an additional dose 
of 800 mg IFX-1 at day 2 in the established fractionated loading dose scheme, that foresees 
administration of 800 mg at days 1, 4, and 8. This additional dose has been chosen due to the 
reported high C5a levels in COVID-19 patients (Gao et al. 2020). Therefore, the entire dosing 
scheme contains up to 6 IFX-1 doses of 800 mg at days 1, 2, 4, 8, 15, and 22 (or less until 
hospital discharge). This regimen had been employed in Phase II of this study, leading to a lower 
death rate and supporting efficacy signals without any new signals of unknown toxicities (Vlaar 
et al 2020).  
3.3. 
Benefit/Risk Assessment 
IFX-1 is a chimeric IgG4 antibody that has the potential to elicit infusion reactions, including 
hypersensitivity or anaphylaxis. In animal studies, one unexplained death of a cynomolgus 
monkey retrospectively showed development of anti-IFX-1 antibodies. In clinical studies, few 
patients tested positive for anti-IFX-1 antibodies, and only mild to moderate signs of 
hypersensitivity reactions were occasionally observed so far (overall ADA rate in the range of 
5% to 13%). In total, IFX-1 showed very good tolerability in clinical studies. The majority of 
observed AEs were attributed to the underlying diseases and IFX-1 AESIs occurred occasionally 
(see IB for details). 


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A summarized in Section 3.2.4, there is evidence that in COVID-19 patients who are severely 
affected, C5a activation occurs to a large extent and that neutrophil count elevation in blood is 
associated with worse outcomes.  
Data from the interim analysis from the completed Phase II of the current study demonstrated 
that IFX-1 treatment was associated with a lower 28-day all-cause mortality when compared to 
the BSC arm, along with trends in disease improvement, as evidenced by fewer patients 
experiencing renal impairment, more patients showing reversal of blood lymphocytopenia, and a 
greater lowering of lactate dehydrogenase concentrations. In IFX-1-treated patients, PE reported 
as SAEs were lower compared to the BSC arm. Also, a temporary increase of D-dimer levels, as 
potential expression of induction of blood clot lysis, was detected in the first days after initiation 
of IFX-1 treatment. 
Overall, the expected clinical benefit for patients suffering from COVID-19-related severe 
pneumonia outweighs the risks in relation to the mild to moderate side effects that have been 
attributed to IFX-1 so far. 
4. 
OBJECTIVES AND ENDPOINTS 
4.1. 
Study Objectives 
4.1.1. 
Primary Objectives 
The primary objective of Phase II was: 
• 
To explore the effect of IFX-1 on COVID-19 related severe pneumonia (hypothesis 
generating) 
The primary objective of Phase III is:  
• 
To demonstrate the efficacy of IFX-1 to improve survival outcomes of severe COVID-19 
pneumonia (confirmative) 
4.1.2. 
Secondary Objectives 
The secondary objectives of Phase II and Phase III are:  
• 
To assess and define other parameters of efficacy 
• 
To assess the safety of IFX-1  


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4.2. 
Study Endpoints 
4.2.1. 
Phase II 
4.2.1.1. 
Primary Endpoint 
The primary endpoint in Phase II was the relative change (%) from baseline (day 1 prior to study 
drug administration at ± 1h of randomization) in oxygenation index (PaO2 / FiO2) in supine 
position at day 5. 
4.2.1.2. 
Secondary Endpoints 
The secondary endpoints in Phase II were: 
• 
Number of patients (%) achieving an Early Response as defined as meeting ALL of the 
following criteria at day 7 after enrollment: 
➢ Patient alive and extubated OR oxygenation index ≥ 300 OR improvement of ≥ 30% 
from baseline 
➢ Temperature < 38°C in absence of fever decreasing medication of at least 4h 
➢ White blood cell count within normal limit of local lab quantifications 
• 
Number of patients (%) reaching a Late Response as defined by either being discharged 
alive from hospital until day 28 OR meeting ALL of the following criteria at day 28 of the 
trial 
➢ Patient alive and extubated 
➢ Patient discharged from ICU 
➢ Patient free of shortness of breath (respiratory rate < 20) in absence of oxygen supply 
➢ Patient free of fever (< 37.6°C) 
• 
Relative change (%) from baseline (day 1 prior to study drug administration at ± 1h of 
randomization) in oxygenation index (PaO2 / FiO2) in supine position at day 3, 7, 9, and 11. 
• 
All cause 28-day mortality (%) 
• 
Frequency, severity, and relatedness to study drug of treatment-emergent adverse events 
(TEAEs) and SAEs 
4.2.1.3. 
Other Endpoints 
The other endpoints in Phase II were: 
• 
Change from baseline in alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST)  
• 
Change from baseline in troponin I adjusted to glomerular filtration rate  
• 
Change from baseline in creatinine 


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• 
Change from baseline in lymphocyte counts 
• 
Change from baseline in neutrophil counts 
• 
Change from baseline in D-dimers 
• 
Change from baseline in Glasgow Outcome Scale  
• 
Time to reach ICU discharge criteria as defined by ALL of the three criteria below: 
➢ Alive and extubated 
➢ No need for continued (>3h per day) non-invasive ventilation 
➢ Free of vasopressor and inotropic therapy 
• 
Assessment of complement activation parameters and plasma concentrations of IFX-1 
4.2.2. 
Phase III 
4.2.2.1. 
Primary Endpoint 
Based on the preliminary interim analysis of efficacy data from Phase II, the primary endpoint 
chosen for Phase III is 28-day all-cause mortality. 
4.2.2.2. 
Secondary Endpoints 
The secondary endpoints in Phase III are: 
• 
60-day all-cause mortality (proportion of patients deceased until Day 60) 
• 
Proportion of patients with an improvement in the 8-point ordinal scale (Appendix 7) 
(day 15, day 28) 
• 
Proportion of patients developing acute kidney failure (eGFR < 15 mL/min/1.73m², assessed 
by the CKD-EPI equation requiring race information) during ICU stay and at day 28 
• 
Proportion of patients free of any renal replacement therapy within 28 days upon 
randomization 
• 
Frequency, severity, and relatedness to study drug of serious and non-serious TEAEs  
4.2.2.3. 
Other Endpoints 
The other endpoints in Phase III are: 
• 
Time to first extubation 
• 
Proportion of patients achieving 8-point ordinal scale score 3 or below (patients alive and 
free of respiratory failure) at day 15 and day 28  
• 
Glasgow Outcome Scale score assessed at study day 60 
• 
Quality of life assessed by EuroQol 5-D (EQ-5D) at study day 60. 


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5. 
STUDY DESIGN 
5.1. 
Overall Design 
This is a pragmatic, adaptive, randomized, multicenter phase II/III study evaluating IFX-1 for the 
treatment of COVID-19 related severe pneumonia. The study consists of two parts: Phase II, an 
open-label, randomized, 2-arm phase evaluating BSC + IFX-1 (Arm A) and BSC alone (Arm B); 
and Phase III, a double-blind, placebo-controlled, randomized phase evaluating SOC + IFX-1 
(Arm A) and SOC + placebo-to-match (Arm B). The SOC includes VTE prophylaxis at a 
minimum, and may include other international and country-specific recommended treatments for 
COVID-19 per the locally adopted treatment recommendations. An independent safety 
monitoring board in phase II part and an independent data monitoring board (IDMC) in phase III 
part are established to monitor the patients’ safety in an ongoing manner (see Sections 5.3 and 
5.5).  
At the time of writing of Protocol Version 2.0, Phase II of the study has been completed and all 
30 patients have been treated (15 in Arm A [BSC + IFX-1] and 15 in Arm B [BSC alone]). 
A preliminary interim analysis has been performed to assess the clinical benefit of the treatment 
using the assessed clinical parameters. An expert committee (EC) has monitored safety and the 
supported re-definition of clinical endpoint(s) for Phase III.  
In Phase II, patients in Arm A were treated with a maximum of 7 IV doses of IFX-1 800 mg over 
a period of 29 days. The first 5 treatments at days 1, 2, 4, 8, and 15 were administered to all 
patients randomized into Arm A. Treatment at day 22 was only administered in the event that a 
patient has not been extubated and discharged from ICU. In case a patient’s clinical situation 
worsened after day 8, although an initial clinical benefit was observed, one additional 
administration of 800 mg IFX-1 between day 11 and 13 could have been given at investigator 
discretion. Loss of clinical benefit could in this situation relate to the exceptionally high C5a 
levels observed in some cases of COVID-19 related pneumonia and associated shortened IFX-1 
half-life.  
Phase III of the study will randomize up to 400 patients with one interim analysis for stopping 
for futility. A total of 180  patients are planned to be randomized into Arm A and Arm B using a 
1:1 allocation ratio for the first stage; based on results of the interim analysis, up to an additional 
180 patients are planned to be randomized using the same allocation ratio for the second stage. 
Additional patients will be randomized under the following conditions: 
• For patients who were erroneously randomized (screening failures) and did not get IMP 
treatment. 
• For patients who were randomized but consent was withdrawn (either by the patient or 
patient representative) within the first 48 hours after randomization, irrespective of 
whether IMP was administered or not. 
 


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The primary statistical analysis will be based on all randomized patients except patients 
randomized in error (reason for early termination documented as “Randomized by mistake” in 
the eCRF) who did not get IMP treatment.  
In Phase III, patients will be treated with a maximum of 6 IV doses of IFX-1 800 mg (Arm A) or 
placebo (Arm B) at days 1, 2, 4, 8, 15, and 22, as long as the patient is still in the hospital (even 
if discharged from the ICU).  
Patients will be assessed for quality of life using the EQ-5D. 
Patients will be followed for survival and their clinical status assessed by the Glasgow Outcome 
Scale. 
5.1.1. 
Method of Treatment Assignment 
In Phase II, patients were centrally assigned to a treatment arm by the Investigator via the 
randomization module of the electronic case report form (eCRF). The investigational medicinal 
product (IMP) was assigned to each patient by the investigator at the investigation site. Sites 
were each given a randomization block and instructed to assign the first patient to Arm A, the 
second patient to Arm B, etc. The site recorded the IMP assignment on the applicable eCRF, if 
required. 
In Phase III, patients will be centrally assigned to a treatment arm by the investigator via an 
Interactive Web Response System (IWRS). IMP will be assigned to each patient by the IWRS. 
IMP shipment to sites will be automatically triggered by the IWRS, and will be initiated, 
maintained, and controlled by the IWRS. 
IMP is dispensed at the study visits as summarized in the schedule of assessments (SoA, Table 1 
and Table 2). 
5.1.2. 
Blinding 
Phase II of the study was open-label and randomized, while Phase III will be double-blind, 
placebo-controlled, and randomized. 
Phase III: Emergency Identification of Investigational Medicinal Product 
Breaking of the treatment-assigned blind will be performed in the IWRS (please refer to the 
Interactive Response Technology Study User Guide for instructions on unblinding). Any 
premature breaking of the blind should be confined to emergency cases in which knowledge of 
the IMP received is necessary, e.g., to be able to provide appropriate emergency medical 
treatment. Before breaking the blind, the investigator should contact the medical monitor 
whenever possible, unless this would delay the emergency treatment. Subject safety must always 
be the primary consideration when determining whether to break the blind.  


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Investigators will be provided with the appropriate IWRS access to unblind the treatment 
assignment of an individual subject.  
If a subject’s treatment assignment is unblinded, the required personnel will receive an alert from 
the IWRS. In addition, the investigator must inform the medical monitor within 24 hours of 
breaking the blind and the subject will be discontinued from further IMP treatment. The date and 
reason why the blind was broken must be provided by the investigator and recorded in the source 
documentation and in the eCRF, as applicable. 
5.2. 
Patient Enrollment 
In Phase II, patients were randomized to Group A or B. The maximum number of randomized 
patients in Phase II was set to 30. There was a recruitment stop after the planned number of 
patients for Phase II were enrolled. After the preliminary interim analysis of Phase II was 
performed and the EC recommended to proceed, the number of patients for Phase III was 
calculated according to the established hypothesis. For details on the role of the EC, see 
Section 5.4. 
In Phase III, 180 patients are planned to be randomized into Arm A and Arm B using a 1:1 
allocation ratio for the first stage; based on results of the interim analysis, up to an additional 180 
patients are planned to be randomized using the same allocation ratio for the second stage.  
For patients randomized in error (screening failures) and patients for whom consent is withdrawn 
within 48 hours after randomization, additional patients will be randomized. Depending on the 
number of patients meeting criteria for additional randomization, more than 360 patients will be 
randomized but not more than 400. 
5.3. 
Independent Safety Monitoring Board for Phase II  
An independent Safety Monitoring Board (iSMB) was constituted to support safety surveillance 
in both treatment arms throughout Phase II and Phase III of the study. The committee included at 
least 2 Intensive Care specialists not involved as investigators in this study and an independent 
statistician.  
The iSMB monitored the safety of all patients regularly, after 10, 20, and 30 patients completed 
their treatment in Phase II. At each review, the iSMB recommended on continuing or ending the 
study. After completion of Phase II (30 patients), the iSMB has assessed the totality of available 
data of all patients and has recommend on proceeding to Phase III (see Section 3.2.3).  
5.4. 
Expert Committee for Phase II 
An EC was constituted to support efficacy surveillance in both treatment arms throughout 
Phase II of the study. The committee included the clinical study monitor and at least 3 Intensive 


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Care specialists involved in the treatment of COVID-19 affected patients (Coordinating 
Investigator included).  
The committee monitored the efficacy of all patients regularly, after 10, 20, and 30 patients 
completed their treatment. At each review, the EC was able to recommend on continuing or 
ending the study. 
After completion of Phase II (30 patients), the EC assessed the totality of the data of all patients, 
taking into account the recommendations of the iSMB and recommend proceeding to Phase III, 
assessed appropriateness of the endpoints and scheduled assessments, and supported establishing 
an adequate hypothesis for Phase III.  
The EC has stopped meeting at the beginning of Phase III (i.e., at the time of writing of Protocol 
Version 2.0). 
5.5. 
Independent Data Monitoring Committee for Phase III 
In Phase III, the iSMB from Phase II will continue as an Independent (Clinical Trial) Data 
Monitoring Committee (IDMC). The IDMC will meet every 3 months throughout Phase III of 
the study to further assess safety. In addition, the IDMC will perform an unblinded assessment of 
the data of the interim analysis and will make recommendations on whether to continue the study 
or not according to the predefined early stop criterion (see Section 10.2.3.5). All available data 
will be provided to the IDMC before each meeting. Details will be described in a separate IDMC 
Charter. 
5.6. 
Patient and Study Completion 
5.6.1. 
Phase II 
5.6.1.1. 
End of Treatment and Follow-up 
End of treatment (EOT) was defined as last planned administration or discontinuation of IMP for 
other reasons. The EOT telephone visit (Follow-up Visit [FUV] 1) was to occur 28 days after last 
study drug administration in Phase II. The visit information obtained via the telephone call 
(e.g., AEs, survival status) was to be recorded. 
Discontinuation of study treatment did not represent withdrawal from the study. 
For details on treatment discontinuation criteria, see Section 7.2.4. 
5.6.1.2. 
End of Study  
Patients were to be followed for survival using the Glasgow Outcome Scale until the end of 
study (EOS) visit (FUV 2). If required, information could have been obtained by a telephone 
call. 


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The EOS for the individual patient was defined as the date of the last contact of the 2-month 
follow-up period, date of death, date of consent withdrawal from study participation (see 
Section 5.6.1.3), or the date of last contact when patients were lost to follow-up (see 
Section 5.6.1.4). 
The entire study was to end when all patients discontinued IFX-1 AND all patients ended the 
study as described above.  
The sponsor could have prematurely terminated Phase II of the study at any time earlier than 
planned for the following reasons: 
• 
Unacceptable toxicity 
• 
Administrative reasons 
5.6.1.3. 
Consent Withdrawal/ Discontinuation of Study Participation 
A patient could have withdrawn from Phase II of the study at any time at his/her own request 
without the need to provide any reason(s). 
If the patient withdrew from study participation, the sponsor could have retained and continued 
to use any data collected before such a withdrawal of consent. However, in the case of deferred 
informed consent, if the consent was not obtained or if a legal representative denied the patient’s 
participation in the study, the patient was excluded and data were no longer to be used (see 
Section 6.3). Patients (or legal representatives) who wished to withdraw consent/discontinue the 
study while still on treatment should have been encouraged by the investigator to perform the 
EOT visit for their own safety before any further data collection for study purposes was 
terminated.  
If a patient withdrew from the study, he/she could have requested destruction of any samples 
taken and not tested, and the investigator must have documented this in the site study records. 
5.6.1.4. 
Lost to Follow-up 
A patient was to be considered lost to follow-up if he or she could not be reached after hospital 
discharge for scheduled contacts and the study site was unable to make contact as described 
below.  
The following actions must have been taken if a patient could not be reached: 
• 
The site must have attempted to re-contact the patient as soon as possible after the failed 
first scheduled contact.  
• 
Before a patient was deemed lost to follow-up, the investigator or designee must have made 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts were to be documented in the patient’s medical record. 


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• 
Should the patient have continued to be unreachable, he/she was considered to have been 
withdrawn from the study with a primary reason of lost to follow-up. 
5.6.2. 
Phase III 
5.6.2.1. 
End of Treatment and Follow-up 
End of treatment (EOT) is defined as the last planned administration or discontinuation of IMP 
for other reasons.  
The FUV is scheduled to occur 28 days (if patient has been discharged) and 60 days after the 
randomization date. The visit information obtained at a site visit or via telephone call (e.g., AEs, 
survival status, according to the SoA, Table 2) should be recorded. 
Discontinuation of study treatment does not represent withdrawal from the study. 
For details on treatment discontinuation criteria, see Section 7.2.4. 
5.6.2.2. 
End of Study  
The end of study for the individual patient is defined as the date of the last contact of the 
follow-up period (i.e., 60 days after randomization), date of death, date of consent withdrawal 
from study participation (see Section 5.6.2.3), or the date of last contact when patients are lost to 
follow-up (see Section 5.6.2.4), whatever occurs earliest. 
The entire study will end when all patients have discontinued IFX-1 AND all patients ended the 
study as described above.  
The sponsor may prematurely terminate the study at any time earlier than planned for the 
following reasons: 
• 
Unacceptable toxicity 
• 
Administrative reasons 
5.6.2.3. 
Consent Withdrawal/Discontinuation of Study Participation 
A patient may withdraw from the entire study at any time at his/her own request without the need 
to provide any reason(s). 
If the patient withdraws /patient is withdrawn by legal representatives/relatives from study 
participation, the sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. However, in the case of deferred informed consent, if the consent is not 
obtained or if a legal representative denies the patient’s participation in the study, the patient is 
excluded and data will no longer be used, except if local regulations would permit the use of 
such data in this situation (see Section 6.3). Patients (or legal representatives/relatives) who wish 
to withdraw consent/discontinue the study while still on treatment should be encouraged by the 


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investigator to perform the FUV for their own safety before any further data collection will be 
stopped. 
If a patient (or legal representatives/relatives) withdraws from the study, he/she may request 
destruction of any samples taken and not tested, and the investigator must document this in the 
site study records. 
5.6.2.4. 
Lost to Follow-up 
A patient will be considered lost to follow-up if he or she cannot be reached after hospital 
discharge for scheduled contacts and the study site is unable to make contact as described below.  
The following actions must be taken if a patient cannot be reached: 
• 
The site must attempt to re-contact the patient as soon as possible after the failed first 
scheduled contact.  
• 
Before a patient is deemed lost to follow-up, the investigator or designee must make every 
effort to regain contact with the patient (where possible, 3 telephone calls and, if necessary, 
a certified letter to the patient’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the patient’s medical record. 
• 
Should the patient continue to be unreachable, he/she will be considered to have withdrawn 
from the study with a primary reason of lost to follow-up. 
6. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Study patients are considered enrolled into the study using a deferred consent procedure or 
another legally acceptable local consent procedure in this special ICU situation. 
6.1. 
Phase II 
6.1.1. 
Inclusion Criteria 
Patients must have met all the following criteria at screening and at enrollment to be randomized 
into Phase II of the study: 
1. At least 18 years of age or older 
2. Clinically evident or otherwise confirmed severe pneumonia as evidenced by at least one of 
the following criteria: 
3. Chest X-ray or computed tomography (CT) scan or magnetic resonance imaging (MRI) with 
pulmonary infiltrates consistent with pneumonia 
4. Clinical history in past 14 days of newly developed severe shortness of breath (> 29 breaths 
/ minute) in the absence of oxygen supply or spontaneous peripheral oxygenation ≤ 92 with 


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need for oxygen supply, or need for non-invasive or invasive ventilation (in conjunction 
with a positive test for SARS-CoV-2 infection) 
5. Oxygenation index at time of enrollment (PaO2 / FiO2) ≤ 250 and ≥ 100 in supine position  
6. SARS-CoV-2 infection confirmation (tested positive in last 14 days or test results to be 
obtained within 24h after enrollment, both with locally available test system).  
7. No use OR stop of any corticosteroid treatment at time point of enrollment (topical 
treatment and systemic dose of ≤ 10mg prednisone / day equivalent allowed) 
6.1.2. 
Exclusion Criteria 
Patients who fulfilled any of the following criteria at screening were not eligible to participate in 
Phase II of the study: 
1. Oxygenation index at time of enrollment (PaO2 / FiO2) < 100 or > 250 in supine position  
2. Intubated > 48h at time point of enrollment  
3. Patients who demonstrate an improvement in past 24h prior to enrollment in oxygenation 
and ventilation / support parameters which indicate an expected resolution of lung 
dysfunction in the next 24h without additional intervention according to judgment of the 
investigator with one or more of the following parameters present: 
4. Improvement in oxygenation index of > 30% relative to previous measure (last 24h in 
supine position) 
5. Extubation if intubated before 
6. Known history of chronic obstructive pulmonary disease (COPD) (GOLD category C or D) 
7. Known history of chronic dialysis OR received renal replacement therapy in past 14 days 
8. Received new other biologic treatment attempt for COVID-19 in the past 14 days  
9. Received treatment with a viral replication inhibitor in past 3 days 
10. Known hypersensitivity to IFX-1 or any other ingredient of the study medication 
11. Known pregnancy 
12. Received organ or bone marrow transplantation in past 3 months 
13. Known mechanically resuscitation in past 14 days  
14. Patient moribund or expected to die in next 12h according to the judgment of the 
investigator 
15. Patients otherwise considered restricted from receiving full supportive care (including ICU 
support) 
16. Existing diagnosis of progressed cancer or other life-limiting disease with life expectancy < 
6 months 
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18. Known severe congestive heart failure (New York Heart Association [NYHA] Class III-IV; 
see Appendix 8) 
6.2. 
Phase III 
6.2.1. 
Inclusion Criteria 
Patients must meet all the following criteria at randomization to be enrolled into Phase III of the 
study: 
1. At least 18 years of age or older 
2. Patient on invasive mechanical ventilation (but not more than 48h post intubation at time 
point of first IMP administration) 
3. Patients with a PaO2 / FiO2 ratio of < 200 and > 60 at randomization (one representative 
measurement within 6h before randomization) 
4. SARS-CoV-2 infection confirmation (tested positive in last 14 days before randomization 
with locally available test system) 
6.2.2. 
Exclusion Criteria 
Patients who fulfill any of the following criteria at randomization are not eligible to participate in 
Phase III of the study: 
1. Intubated > 48 h at time point of first IMP administration  
2. Expected stop of invasive ventilation or expected extubation in the next 24h without 
additional intervention according to judgment of the investigator 
3. Known history of chronic dialysis OR received renal replacement therapy in past 14 days 
OR anticipated to receive renal replacement therapy within 24h after randomization 
4. Known history of progressed COPD as evidenced by use of daily maintenance treatment 
with long-acting bronchodilators or inhaled/oral corticosteroids for > 2 months 
5. Treatment of COVID-19 with investigational antibody treatment(s) which are not approved 
or not included in locally adopted treatment guidelines (e.g., WHO guidance, National 
Institutes of Health [NIH] COVID-19 treatment guidelines) for this indication in the past 
7 days (Note: Antibody treatment[s] given within past 7 days for pre-existing diseases, other 
than COVID-19, are allowed.) 
6. At time point of randomization, treatment of COVID-19 with investigational treatments 
which are not approved or not included in locally adopted treatment guidelines for this 
indication (e.g., WHO guidance, NIH COVID-19 treatment guidelines), including 
SARS-CoV-2 multiplication inhibitor(s) or immunomodulator(s). (Note: If a locally adopted 
treatment guideline recommends drugs such as remdesivir, dexamethasone, or 
anticoagulation, this would be allowed. Adopted guidelines and updates must be 
documented at study initiation and throughout the conduct of the study.) 
7. Received cytokine adsorption therapy in past 3 days 


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8. Known hypersensitivity to IFX-1 or any other ingredient of the study medication 
9. Serum or urine pregnancy test positive before randomization (required for women of 
childbearing potential) 
10. Received organ or bone marrow transplantation in past 3 months 
11. Known cardio-pulmonary mechanical resuscitation in past 14 days 
12. Patient moribund or expected to die in next 24h according to the judgment of the 
investigator  
13. Known to have received anti-cancer therapy for hemato-oncological disease in past 4 weeks 
OR known to have active malignant disease at time point of randomization 
14. Known severe congestive heart failure (corresponding to e.g. NYHA Class III-IV, left 
ventricular ejection fraction <40%; see Appendix 8) 
15. Known history of chronic liver disease (Child-Pugh B or C; see Appendix 11) 
16. Participating in or has participated in other investigational interventional studies (drug or 
device) within the last 7 days before randomization 
6.3. 
Deferred Consent and Other Forms of Informed Consent 
In the Netherlands and Germany, we ask for deferred consent for patients in need of intensive 
care and we appeal to the emergency procedure for consent in medical research as stated in 
Article 6, Paragraph 4 of the Medical Research Involving Human Subjects Act (WMO, the 
Netherlands), §41 (1) of the Medicines Act (AMG, Germany), and other applicable country 
specific regulations, because of the following reasons: 
It is very likely that the severity of the disease (severe pneumonia/acute respiratory distress 
syndrome) will result in a large proportion of patients unable to provide informed consent before 
the beginning of the trial either in oral or written form, mainly due to being on a ventilator or 
treated with drugs with sedative effects. COVID-19 related pneumonia resulting in the need for 
intensive care is a fast progressing disease. It requires immediate adequate treatment that cannot 
be postponed. So far, no treatment has been shown to address the underlying neutrophilic, 
inflammatory lung damage. Since IFX-1 blocks C5a, it has the potential to block neutrophil 
attraction to the lung. Moreover, it has been shown that COVID-19-related severe pneumonia is 
linked to extremely high C5a blood levels and related to a worse outcome of patients (Gao et al. 
2020). In an ongoing study testing the biosimilar C5a antibody BDB-1, the first 2 patients treated 
showed a good recovery after being treated. Taken together, there is a possibility that treatment 
with IFX-1 will provide benefit specifically for patients with COVID-19-related severe 
pneumonia that require intensive care.   
These severely ill patients are incompetent to give informed consent, and obtaining informed 
consent from a legal representative/relative may be almost impossible due to the current COVID-
19-caused quarantine measures. Time to get informed consent from legal 
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Patients have to be randomized at the ICU after inclusion and exclusion criteria have been 
checked and patients have been found to be eligible.  
In the Netherlands, if the patient is incompetent to provide informed consent and a legal 
representative/relative cannot be reached in time, the investigator examines the patient, confirms 
and documents the patient’s inability to provide consent as well as the urgency of participating in 
the trial with possible benefit to the patient. Informed consent from the patients, their relatives or 
their legal representative will be requested at the earliest appropriate time thereafter as applicable 
in the participating country. At minimum, the attempt of contacting the patient’s relatives and the 
result of the contact will be documented in the patient’s file.  
In Germany, the investigator examines the patient and, if the patient is not able to consent, 
confirms and documents together with a consulting physician the patient’s inability to provide 
consent as well as the urgency of participating in the trial with possible benefit to the patient. 
Informed consent from the patient will be requested at the earliest appropriate time thereafter. A 
further option in Germany may be the signing of the informed consent by the patients’ legal 
representative.  
In other participating countries where a deferred consent procedure is not legally acceptable, 
specific requirements will be laid out that will describe the country-specific legally acceptable 
procedure for retrieving consent from patients who are incompetent to provide consent or their 
relatives or their legal representatives, whatever will be applicable.   
The hypothesis is that this group of intensive care patients can potentially benefit from 
participating in this study. While patients are exposed to the possible side effects of IFX-1, they 
will also receive SOC in Phase III. 
6.4. 
Screening Failures 
Screening failures are defined as patients who do not meet the criteria for participation in this 
study and thus, are either not randomized/assigned to IMP or randomized in error and do/did not 
receive IMP. Screen failure data for not randomized patients will not be recorded in the eCRF, 
for those patients who are randomized in error, screen failure data are to be recorded in the 
eCRF. 
Rescreening does not apply to this study. 
6.5. 
Meals and Dietary Restrictions 
Not applicable. 


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7. 
STUDY DRUG(S) AND ADMINISTRATION 
7.1. 
Investigational Medicinal Product 
The IMP is defined as the investigational treatment IFX-1 and Placebo-to-match (Placebo) that is 
intended to be administered to a study patient according to the study protocol. 
7.1.1. 
Packaging and Labelling of Investigational Medicinal Product 
IFX-1 concentrate solution for infusion will be supplied in 20 mL glass vials at a concentration 
of 10 mg/mL (200 mg per vial) for reconstitution and IV administration. Apart from IFX-1, the 
solution will contain sodium chloride, sodium phosphate, and polysorbate 80. 
Placebo concentrate solution for infusion will be supplied in 20 mL glass vials for reconstitution 
and IV administration. The solution will contain sodium chloride, sodium phosphate, and 
polysorbate 80. 
IFX-1 and Placebo will be packaged in cartons and labeled in accordance with all legal 
requirements. Each carton will contain 4 vials of IFX-1 or 4 vials of Placebo. Each carton and 
each vial will be labeled with a multilingual booklet label or a single panel label as applicable. 
7.1.2. 
Storage, Handling, and Accountability 
Vials of IFX-1 and Placebo must be stored in a refrigerator at 2°C to 8°C (35.6°F to 46.4°F) in 
their original cartons to protect from light and must not be frozen or shaken. All supplies of 
IFX-1 and Placebo must be stored separately or segregated from other study supplies and site 
stock in a dedicated locked facility with access limited to authorized personnel. All storage 
facilities must be temperature controlled and monitored and compliant with applicable regulatory 
requirements. 
An established and validated local temperature management system with temperature logs 
should be used to record the storage temperature. If this is not possible, the study site will be 
provided with a temperature record form by the Contract Research Organization (CRO) and the 
site personnel will maintain temperature records for the entire duration of the study. At a 
minimum, the daily (working day) minimum and maximum temperatures must be documented. 
Any deviation from the specified temperature range must be documented and reported within 
24 hours (or the next working day). Further instruction on the management and reporting of 
temperature deviations is provided in the Investigator Manual (or equivalent document). 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during shipment for all IMP received and any discrepancies are reported and resolved 
before use of the IMP. 


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Only patients enrolled in the study may receive IMP and only authorized site staff may prepare 
and administer IMP. The IMP must be prepared in a controlled area in accordance with local 
regulations/ requirements for reconstitution of products for IV administration. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for the correct storage of IMP, IMP accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused IMP are provided in the 
Investigator Manual (or equivalent document) provided by the CRO. 
7.1.3. 
Drug Preparation and Administration Instructions 
The IFX-1 and Placebo for infusion will be reconstituted (prepared) in a controlled area at the 
study site or at the study site’s pharmacy, in accordance (compliance) with applicable local 
regulations/ requirements for reconstitution of products for IV administration. 
The reconstituted IFX-1 or Placebo should be used within 4 hours after dilution when stored at 
room temperature. Otherwise, the reconstituted IFX-1 or Placebo has to be stored at 2°C to 8°C 
(35.6°F to 46.4°F) and used within 24 hours; if the reconstituted solution is stored in a 
refrigerator, it must be left to acclimatize to room temperature prior to administration. Details for 
the preparation of the reconstituted solution will be provided in the Investigator Manual (or 
equivalent document).  
The number of unused, partially used, and empty vials will be documented accurately, and the 
vials will be kept at the site until further notice by the Sponsor. 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
Further guidance and information for the final disposition of unused IMP are provided in the 
Investigator Manual (or equivalent document). 
7.1.4. 
Recall of IMP 
Instructions (actions to be taken by site) in the case of IMP recall are provided in the Investigator 
Manual (or equivalent document). 
7.2. 
Administration and Dosage 
For Phase II, patients were randomized to either receive BSC + IFX-1 in treatment Arm A or 
BSC alone in treatment Arm B. The first dose of IFX-1 was administered at Cycle 1 Day 1. 
For Phase III, patients are randomized to either receive SOC + IFX-1 in treatment Arm A or 
SOC + Placebo in treatment Arm B. The first dose of IFX-1 or Placebo is administered at Day 1. 
SOC may start at any time according to their administration schedule. 


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Close observation of IFX-1 or Placebo infusion(s) is required for monitoring of potential 
infusion reactions. Appropriate treatment for potential infusion reactions must be available 
during this time. 
7.2.1. 
Treatment Administered 
7.2.1.1. 
Phase II 
IFX-1 800 mg was administered for a maximum of 7 doses over a period of 29 days as a 
30-minute IV infusion. However, given the variability of infusion pumps from site to site, a 
window between 5 minutes and +10 minutes was permitted (i.e., infusion time was 30 minutes 
(5 min/+10 min). IMP administrations for Phase II are detailed in Figure 1. 
The first 5 treatments at days 1, 2, 4, 8, and 15 were administered to all patients randomized into 
Arm A. Treatment at day 22 was only administered in the event that a patient had not been 
extubated and discharged from ICU. In case a patient’s clinical situation worsened after day 8, 
although an initial clinical benefit was observed, one additional administration of IFX-1 between 
day 11 and 13 could have been given at investigator discretion. 
7.2.1.2. 
Phase III 
Patients will be treated with a maximum of 6 IV doses of IFX-1 800 mg (Arm A) or placebo 
(Arm B) administered as a 30-60-minute IV infusion. The 6 treatments are at days 1, 2, 4, 8, 15, 
and 22 as long as the patient is still in the hospital, even if discharged from ICU. IMP 
administrations for Phase III are detailed in Figure 2. 


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Figure 1 
Patient Calendar: IMP Administrations – Phase II 
 
 
D = day; D/C = discharge; EOS = end of study; EOT = end of treatment; FUV = follow-up visit; IMP = investigational medicinal product 
 
 


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Figure 2 
Patient Calendar: IMP Administrations – Phase III 
 
D = day; FUV = follow-up visit; ICU = intensive care unit; IMP = investigational medicinal product 
 


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7.2.2. 
Treatment Modification 
This protocol allows some alteration from the currently outlined dosing schedule, but a dose 
reduction of IMP is generally not allowed.  
Adverse events leading to treatment modifications will be graded as mild, moderate, severe, or 
life-threatening based on the investigator’s assessment, using the definitions provided in 
Section 9.2.2.  
In case of toxicity, IMP dosing can be held by a maximum of 1 week. If therapy is continued 
during this time span, dosing will resume at the initially planned next dosing day according to 
the initial schedule and allowed administration window. 
For treatment discontinuation criteria, see Section 7.2.4. 
7.2.2.1. 
Infusion Reactions 
IFX-1 may cause infusion reactions, including severe or life-threatening hypersensitivity or 
anaphylactic reactions. Signs and symptoms of infusion reactions usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion with or without adequate medication. Dose modification criteria for infusion reactions 
are listed in Appendix 5, Table 6.  
7.2.3. 
Re-dosing Criteria 
The following criteria must be fulfilled to allow for re-dosing of study drug: 
• 
Absence of treatment discontinuation criteria (see Section 7.2.4). 
7.2.4. 
Treatment Discontinuation Criteria 
Discontinuation of study treatment does not represent withdrawal from the study. See 
Section 5.6.1.1 (for Phase II) or Section 5.6.2.1 (for Phase III) for the end of treatment definition 
and procedures. 
In general, patients should be treated with IMP until unacceptable toxicity, completion of the 
planned treatment, or death. 
Possible reasons for treatment discontinuation for individual patients are: 
• 
Clinical deterioration 
• 
Study participation consent withdrawal (see Sections 5.6.1.3 and 5.6.2.3) 
• 
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• 
Safety: 
o moderate infusion reactions despite adequate premedication (see Appendix 5, Table 6) 
o severe or life-threatening infusion reactions (see Appendix 5, Table 6) 
7.3. 
Premedication and Postmedication 
Routine premedication is not required prior to the first dose of IMP. 
Patients with mild or moderate infusion reaction following IMP administration may continue to 
receive IMP with close monitoring; premedication with antipyretic and antihistamine may be 
considered.  
Patients should be observed for 60 minutes, or longer per clinical judgment, after IMP 
administrations. 
Treatment guidelines in case of occurrence of infusion reactions are detailed in Appendix 5, 
Table 6. 
7.4. 
Prior and Concomitant Medication/Treatments 
In Phase III of the study, in addition to the IMP, all patients will receive SOC for treatment of 
COVID-19, which includes VTE prophylaxis with anticoagulants at a minimum. Other 
international or country-specific recommended treatments for COVID-19 per the locally adopted 
treatment recommendations (including but not limited to corticosteroids, remdesivir, and other 
local SOC) are allowed as concomitant medications. SOC treatment start and stop is not defined 
by the protocol and can start at any time. SOC treatment will be given according to investigator’s 
discretion. 
Reporting of prior and concomitant medications will follow special considerations for the ICU 
setting, as described in Appendix 12. 
Reportable medications or vaccinations that the patient is receiving within 7 days prior to  
randomization and up to 30 days after the last dose of study treatment should be recorded along 
with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 


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7.4.1. 
Prohibited Concomitant Medication/Treatment 
Medications or vaccinations specifically prohibited in the exclusion criteria (see Sections 6.1.2 
and 6.2.2) are not allowed during the ongoing study. If there is a clinical indication for any 
medication or vaccination specifically prohibited during the study, discontinuation from study 
therapy may be required. The investigator should discuss any questions regarding this with the 
medical monitor. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the patient's primary physician. However, the decision to continue the patient 
on study treatment requires the mutual agreement of the investigator and the sponsor. 
The following concomitant therapies or vaccinations are prohibited during the course of the 
study: 
• 
Antineoplastic systemic therapy 
• 
Investigational antibody treatments and other investigational agents (excluding IFX-1 but 
including SARS-CoV-2 multiplication inhibitor[s] or immunomodulator[s]) which are not 
approved or not included in locally adopted treatment recommendations for treatment of 
COVID-19 (e.g., WHO guidance, NIH COVID-19 treatment guidelines) 
• 
Cytokine adsorption therapy 
Patients who, in the assessment of the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study.  
All treatments that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. 
7.5. 
Rescue Medications and Supportive Care 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  
7.6. 
Treatment of Overdose 
No specific information is available on the treatment of overdose of IFX-1. For this study, an 
overdose of IFX-1 will be defined as any single dose of > 1,200 mg. In the event of overdose, the 
participant should be observed closely for signs of toxicity. Appropriate supportive treatment 
should be provided if clinically indicated. 
In the event of an overdose, the investigator should: 
1. Contact the medical monitor immediately 
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3. Obtain a plasma sample for PK analysis as close as possible to the administration of 
overdose if requested by the medical monitor (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the patient. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Phase II 
Study procedures and their timing for Phase II are summarized in the Schedule of Assessments 
(SoA; Table 1). 
Details on the assessments and procedures are given in the following subsections.  
Safety concerns should have been discussed with the sponsor immediately upon occurrence or 
awareness to determine if the patient should continue or discontinue any IMP. 
Adherence to the study design requirements, including those specified in the SoA (Table 1), was 
essential and required for study conduct. 
All screening evaluations must have been completed and reviewed to confirm that potential 
patients met all eligibility criteria (Section 6.1). The investigator was to maintain a screening log 
to record details of all patients screened and to confirm eligibility or record reasons for screening 
failure, as applicable. 
8.1.1. 
Baseline Assessments 
The following procedures were to be performed to assess baseline characteristics during 
screening evaluations and before IMP administration: 
• 
Documentation of demographic details (age, gender, race, and ethnicity), medical and 
disease history (see Sections 8.1.1.1 and 8.1.1.2) 
• 
Disease assessments (see Section 8.1.2) 
• 
Documentation of concomitant disease and concomitant medications (see Sections 8.1.1.3 
and 8.1.1.4) 
• 
Baseline safety assessment (height, weight, physical exam, vital signs, AEs, and safety 
laboratory; see Section 8.1.3) 


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8.1.1.1. 
Medical History (Except COVID-19 history) 
The documentation of the patient’s medical history were to include any details on the patient’s 
medical history before enrollment into the study. The information must have been documented as 
such in the source documentation and eCRF. 
8.1.1.2. 
COVID-19 History 
Any details on the patient’s COVID-19 disease history including any COVID-19 therapy (onset 
of symptoms, medications, oxygen support, intubation, SARS-CoV-2 testing) by verbatim name 
with start and end dates, dosages, modality) that the patient received were to be documented in 
the source documentation and in the eCRF. 
8.1.1.3. 
Concomitant Disease  
All diseases that the patient was experiencing at enrollment into the study or after enrollment 
until EOT were to be regarded as concomitant diseases. All concomitant diseases must have been 
documented in the source documentation and in the eCRF. 
8.1.1.4. 
Prior and Concomitant Medications 
All drugs being taken by a patient at enrollment into the study or after enrollment until EOT 
were to be regarded as concomitant medication.  
All prior medications taken by the patient within 2 weeks before enrollment into the study and all 
concomitant medications must have been documented in the source documentation and in the 
eCRF. Details on prior and concomitant medications must have included the reason for use, 
administration start and stop dates, and dosing information, including dose, route, and frequency 
of administration. 
8.1.2. 
Efficacy Assessments 
8.1.2.1. 
Imaging Requirements 
CT scan, MRI, or X-ray for COVID-19 assessment were to be performed locally at each 
scheduled disease assessment time point, and at any time when disease progression was 
suspected. 
The choice of whether the imaging was by CT scan, MRI, or X-ray was an investigator decision. 
Once the imaging choice had been made, subsequent assessments should have been made using 
the same modality whenever possible. 
8.1.2.2. 
Evaluation of Lung Function 
• 
Oxygenation index (PaO2 / FiO2)  
• 
Respiratory rate 
• 
Oxygen supplementation: room air, flow O2 (L/min) if extubated 


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• 
Ventilation status (invasive/non-invasive/intermittent non-invasive) 
• 
Mode of ventilation (e.g., CPAP/BIPAP) 
• 
Other oxygenation support  
➢ Type of oxygen mask or nasal canula, or other mechanical ventilation mode and 
parameters, as applicable, should have been documented 
• 
Intubation and extubation dates, as well as date of tracheostomy should have been 
documented 
8.1.2.3. 
Evaluation of Response 
• 
SARS-CoV-2 mRNA testing was to be performed in context of enrolment procedures and at 
one to four additional time points at discretion of the investigator 
8.1.2.3.1. 
Evaluation of Early Response 
Early Response as defined as meeting ALL of the following criteria at day 7 after enrollment: 
• 
Patient alive and extubated OR oxygenation index ≥ 300 OR improvement of ≥ 30% from 
baseline,  
• 
Temperature < 38°C in absence of fever decreasing medication of at least 4h 
• 
White blood cell count within normal limit of local lab quantifications 
8.1.2.3.2. 
Evaluation of Late Response 
Late Response as defined by either being discharged alive from hospital until day 28 OR 
meeting ALL of the following criteria at day 28 of the trial: 
• 
Patient alive and extubated 
• 
Patient discharged from ICU 
• 
Patient free of shortness of breath (respiratory rate < 20) in absence of oxygen supply 
• 
Patient free of fever (< 37.6°C) 
8.1.3. 
Safety Assessments 
Safety was to be assessed based on the following variables: 
• 
AEs (see Section 8.1.3.1) 
• 
Laboratory safety parameters (see Section 8.1.3.2) 
• 
Vital signs (see Section 8.1.3.3) 
• 
Electrocardiograms (see Section 8.1.3.4) 
• 
Physical examination (see Section 8.1.3.5) 


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Planned time points for all safety assessments are provided in the SoA (Table 1). 
8.1.3.1. 
Adverse Events Assessments 
Adverse events were to be assessed throughout the study from the time of enrollment to the EOT 
visit as specified in the SoA (Table 1). For details on AE collection and reporting, see 
Section 9.1. The investigator should have taken appropriate measures to follow all AEs until 
clinical recovery was complete and laboratory results had returned to normal, or until 
progression had been stabilized, or until death, in order to ensure the safety of the patients. This 
may imply that observations would continue beyond the last planned visit per protocol, and that 
additional investigations may have been requested by the sponsor. When study treatment was 
prematurely discontinued, the patient’s observation was to be continued until the EOT visit for 
that patient as defined by the protocol. 
8.1.3.2. 
Clinical Safety Laboratory Assessments 
In general, blood samples for safety laboratory analysis should have been obtained once a day 
during a routine sampling (preferable in the morning) before administration of IMP. Additional 
tests may have been performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
See Appendix 1, Table 3 for the list of clinical laboratory tests performed and the SoA (Table 1) 
for timing and frequency.  
The investigator must have reviewed the laboratory report, documented this review, and recorded 
any clinically relevant changes (clinically relevant abnormal findings) occurring during the study 
in the AE section of the eCRF. The laboratory reports must have been filed with the source 
documents. Clinically relevant abnormal laboratory findings were those which were not 
associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the patient’s condition. 
All laboratory tests with values considered clinically relevantly abnormal and with onset before 
EOT visit should have been reported in the AE section of the eCRF and repeated until the values 
returned to normal or baseline, were no longer considered clinically relevant by the investigator 
or medical monitor, or until the EOS visit (also see Section 8.1.4 and Appendix 3). 
If such values did not return to normal/baseline within a period of time judged reasonable by the 
investigator, the etiology should have been identified, and the sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 1, Table 3, must have been 
conducted in accordance with the SoA (Table 1).  
If laboratory values from non-protocol specified laboratory assessments performed at the 
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clinically relevant by the investigator (e.g., SAE or AE or dose modification), then the results 
must have been recorded in the eCRF. 
Blood samples for serum pregnancy testing were to be collected on the same day as safety 
laboratory testing. For details on pregnancy testing, refer to Appendix 4. 
8.1.3.3. 
Vital Signs 
Core body temperature, heart rate, respiratory rate, and blood pressure (diastolic and systolic) 
were to be assessed at each visit at pre-dose on the days of IMP administration and at further 
time points whenever medically indicated. 
Blood pressure and pulse measurements were to be assessed with a completely automated 
device. Manual techniques were to be used only if an automated device was not available. 
Vital signs were to be measured in a supine position (after a rest of at least 1h in case of position 
switch from prone position), preferably in the morning. Three readings of blood pressure and 
pulse were to be taken. The first reading should have been rejected. The second and third 
readings should have been averaged to give the measurement recorded in the eCRF. 
8.1.3.4. 
Electrocardiograms 
12-lead electrocardiogram (ECG) was to be obtained as outlined in the SoA (Table 1) using an 
ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QTc 
intervals. 
8.1.3.5. 
Physical Examination 
A physical examination was to be conducted at screening and each study visit. 
The physical examination included, at a minimum, assessments of the skin, cardiovascular, 
respiratory, gastrointestinal, and neurological systems. Height (at screening) and weight was also 
to be measured and recorded as specified in the SoA (Table 1). 
Investigators should have paid special attention to clinical signs related to previous serious 
illnesses. 
8.1.3.6. 
Survival Status 
The patient survival status were to be assessed during the study and follow-up and documented 
in the eCRF. In case the patient died and the date of death was unknown, the date of the last 
personal contact should have been documented at a minimum. 


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8.1.4. 
Pharmacokinetics/Pharmacodynamics 
If possible, blood samples were to be collected pre-dose for measurement of plasma 
concentrations and C3a and C5a of IFX-1 as specified in the SoA (Table 1). IFX-1 
concentrations were to be measured for all patients in citrate plasma and analyzed by a 
specialized laboratory using Enzyme-Linked ImmunoSorbent Assay. 
Detailed instructions regarding the collection, processing, etc., of samples were to follow local 
regulations and requirements. 
8.1.5. 
Biobanking of Samples from Patients Treated at Amsterdam Medical Center 
COVID-19 is a new viral disease with distinct clinical and pathophysiological features, which 
differentiate COVID-19 from other viral diseases such as Influenza. A COVID-19 dedicated 
Biobank was established at the Amsterdam Medical Center (AMC) in order to investigate further 
COVID-19 pathophysiological characteristics. Therefore, it was planned to store all remaining 
AMC study patient derived biomaterials, including but not limited to blood, bronchial lavage 
fluid, and tissue in the AMC COVID-19 Biobank. Patients were to be asked for a separate 
informed consent.  
8.2. 
Phase III 
Study procedures and their timing for Phase III are summarized in the SoA (Table 2). 
Details on the assessments and procedures are given in the following subsections.  
Safety concerns should be discussed with the sponsor immediately upon occurrence or awareness 
to determine if the patient should continue or discontinue any IMP. 
Adherence to the study design requirements, including those specified in the SoA (Table 2), is 
essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria (Section 6.2). The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening failure, 
as applicable. 
8.2.1. 
Baseline Assessments (Screening) 
The following procedures will be performed to assess baseline characteristics during screening 
evaluations and before randomization and IMP administration: 
• 
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• 
Documentation of demographic details (age, gender, race, and ethnicity), medical and 
COVID-19 history (see Sections 8.2.1.1 and 8.2.1.2). Race information is required for eGFR 
calculation using the CKD-EPI equation 
• 
8-point ordinal scale assessment (see Section 8.2.2.2) and oxygenation index (PaO2 / FiO2; 
one representative measurement within 6h before randomization) 
• 
Documentation of concomitant disease and prior medications (see Sections 8.2.1.3 and 
8.2.1.4) 
• 
Baseline safety assessment (height, weight, physical exam, AEs, ECG, urine analysis, 
pregnancy test, and clinical safety laboratory [including creatinine assessment]); 
see Section 8.2.3) 
8.2.1.1. 
Medical History (Except COVID-19 History) 
The documentation of the patient’s medical history includes any details on the patient’s medical 
history before randomization into the study. The information must be documented as such in the 
source documentation and eCRF. 
8.2.1.2. 
COVID-19 History 
Any details on the patient’s COVID-19 disease history including any COVID-19 therapy (onset 
of symptoms, medications, oxygen support, intubation and tracheostomy dates, SARS-CoV-2 
polymerase chain reaction (PCR) test date and result by verbatim name with start and end dates) 
that the patient received will be documented in the source documentation and in the eCRF. 
8.2.1.3. 
Concomitant Disease  
All diseases that the patient is experiencing at screening/randomization until end of treatment are 
regarded as concomitant diseases. All concomitant diseases must be documented in the source 
documentation and in the eCRF. 
8.2.1.4. 
Prior and Concomitant Medications and Procedures 
All procedures performed or medications administered within 7 days before randomization 
should be recorded as prior procedures and prior medication with generic name, start date, stop 
date, and indication for treatment. 
Reporting of prior and concomitant medications will follow special considerations for conditions 
in the ICU. A complete record of all prior and concomitant medications (but excluding 
nutritional and volume therapy, electrolyte support, vitamins, non-steroidal anti-inflammatory 
drugs (NSAIDs), and supportive therapies such as artificial tears, ointments, stool 
softeners/laxatives, etc.) will be maintained in the eCRF for each participant, beginning 7 days 
before randomization and continuing up to 30 days after the last dose of study treatment). 


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In addition, a complete record of all steroid and antibiotic therapy, as well as any therapy 
(medications, specific treatments, etc.) associated with or used in the assessment or treatment of 
an AE will be documented for the duration of the study. 
The following information must be recorded in the eCRF for each reportable concomitant 
medication: generic name, route of administration, start date, stop date, and indication 
(Appendix 12). 
8.2.2. 
Endpoint Assessments 
8.2.2.1. 
Evaluation of Organ Support 
• 
Renal replacement therapy, extracorporeal membrane oxygenation (ECMO), mechanical 
ventilation 
• 
Extubation and re-intubation dates should be documented 
8.2.2.2. 
Ordinal Scale Evaluation 
8-point ordinal scale score will be documented at the visits specified in the SoA (Table 2), 
including the date (one value per assessment day, that best represents the patient’s condition at 
that day). 
8.2.2.3. 
Survival Status 
The patient’s survival status will be assessed during the study and at the day 28 and day 60 FUV 
and will be documented in the eCRF. In case the patient has died and the date of death is 
unknown, the date of the last personal contact should be documented at a minimum. 
8.2.2.4. 
Quality of Life Assessment 
Patients will be assessed for quality of life using the EQ-5D at the day 60 FUV. 
8.2.2.5. 
Clinical Status 
Patient’s clinical status will be assessed by the Glasgow Outcome Scale at the day 60 FUV.  
8.2.3. 
Safety Assessments 
Safety will be assessed based on the following variables: 
• 
AEs (see Section 8.2.3.1) 
• 
Laboratory safety parameters, including creatinine (see Section 8.2.3.2) 
• 
Vital signs (see Section 8.2.3.3) 
• 
Electrocardiograms (see Section 8.2.3.4) 
• 
Physical examination (see Section 8.2.3.5) 


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Planned time points for all safety assessments are provided in the SoA (Table 2). 
8.2.3.1. 
Adverse Events Assessments 
Adverse events will be assessed throughout the study as specified in the SoA (Table 2). Adverse 
event reporting will follow special considerations for the ICU setting as described in Appendix 3. 
8.2.3.2. 
Clinical Safety Laboratory Assessments 
In general, blood samples for safety laboratory analysis and creatinine assessment should be 
obtained at indicated visit days during routine sampling (one representative value, if taken more 
than once a day). Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.  
See Appendix 1, Table 4 for the list of clinical laboratory tests to be performed and the SoA 
(Table 2) for timing and frequency.  
In clinical studies conducted in the ICU, deviations in laboratory values are to be expected 
frequently. Clinical judgement should be applied in determining which deviations should be 
reported as an AE in the sense of an “untoward medical occurrence” and which deviations 
should be considered usual and expected findings in this setting. 
It must be noted that clinically significant laboratory deterioration as assessed by the investigator 
with onset before end of treatment must be documented in the respective eCRF section. 
However, it is preferred to document the condition or disease underlying the aberrant laboratory 
value (e.g., renal failure rather than hyperkalemia) rather than the laboratory value only. 
The investigator will exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant, and thus 
constitutes an AE (see also Section 9 and Appendix 3). 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory fulfill the aforementioned criteria for clinical significance, then the 
results must be recorded in the eCRF. 
All protocol-required laboratory assessments, as defined in Appendix 1, Table 4, must be 
conducted in accordance with the SoA (Table 2). Please note that day 1 safety laboratory 
assessment, including creatinine assessment, has to be done prior to IMP administration only, if 
more than 12 h elapsed between the screening assessment and the IMP administration. 
Urine analysis and serum or urine samples for pregnancy testing will be collected only at 
screening/randomization. For details on pregnancy testing, refer to Appendix 4. 


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8.2.3.3. 
Vital Signs 
Vital signs (core body temperature, heart rate, respiratory rate, blood pressure [diastolic and 
systolic]) will be assessed at indicated visits at pre-dose within 1h before administration of IMP 
(one representative measurement closest to IMP administration) and at further time points 
whenever medically indicated. Blood pressure and heart rate measurements will be assessed with 
an intra-arterial catheter, or a completely automated device. Manual techniques will be used only 
if an automated device is not available. 
8.2.3.4. 
Electrocardiograms 
12-lead ECG will be obtained as outlined in the SoA (Table 2) using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 
8.2.3.5. 
Physical Examination 
A physical examination will be conducted at the time of screening/randomization, on day 1 prior 
to IMP administration only, if more than 24 h elapsed between screening assessment and IMP 
administration, and on the days of further IMP administration, as specified in the SoA (Table 2). 
The physical examination includes, at a minimum, assessments of the skin, cardiovascular, 
respiratory, gastrointestinal, and neurological systems.  
8.2.4. 
Pharmacokinetics/Pharmacodynamics 
PK/PD testing will be done at selected countries/sites. Blood samples will be collected for 
measurement of plasma IFX-1 concentrations, C5a, and ADAs of IFX-1 within 1h before 
administration of IMP, as specified in the SoA (Table 2).  
Detailed instructions regarding the collection, processing, etc., of samples will follow local 
regulations and requirements. 
9. 
ADVERSE EVENT COLLECTION AND REPORTING 
All AEs, serious and non-serious (see Appendix 3 I for definitions), must be collected, 
documented, and reported from signature of the informed consent or, where informed consent is 
deferred, from the documented decision timepoint of the responsible investigator and/or 
physicians to enroll the patient until the end of treatment (see Section 9.1.1). They will be further 
followed up until the end of study (see Section 9.1.1.1), however death and related SAEs with 
onset during the follow-up period and after the end of study will be collected and reported (see 
Section 9.1.2). 
All AEs will be reported to the sponsor by the investigator in the appropriate sections of the 
eCRF. It will be specified whether the event is serious or not according to the definition of SAE 
(see Appendix 3 I). In case of an SAE, the SAE report will be processed by the safety vendor 


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(see Section 9.2.1). The safety vendor for this study is IQVIA Pharmacovigilance. Reporting of 
AEs will be done according to the specific definitions and instructions for completing the 
respective sections of the eCRF.  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE and remain responsible for following up AEs, 
considered related to the IMPs or study procedures (see Section 9.2.2 and Appendix 3 II for 
details on causality of AEs), or that caused the patient to discontinue study treatment (see 7.2.4 
for treatment discontinuation criteria) or the study.  
Care will be taken not to introduce bias when detecting AEs. Open-ended and non-leading verbal 
questioning of the patient is the preferred method to inquire about AE occurrences.  
Due to the severity of disease of the patient population entering this study, numerous problems, 
signs, and symptoms deviating from normal will be seen during the course of the study. These 
will not necessarily constitute a reportable AE unless they require significant intervention, lead 
to discontinuation of blinded study drug, or are considered to be of concern in the investigator’s 
clinical judgement. Similarly, it is preferred to receive documentation of the underlying 
condition rather than the resulting sign (e.g., ‘agitation’ rather than ‘self-extubation’). 
In clinical studies conducted in the ICU, deviations, e.g., in laboratory values or temporary 
changes in arterial blood pressure, are to be expected frequently. Clinical judgement should be 
applied in determining which deviations should be reported as an AE in the sense of an 
“untoward medical occurrence” and which deviations should be considered usual and expected 
findings in this setting. It is preferred to document the condition or disease underlying the 
aberrant laboratory value (e.g., renal failure rather than hyperkalemia) rather than the laboratory 
value only. 
The records will describe (Appendix 3 II) the nature (diagnosis or single syndrome if possible, 
alternatively signs and symptoms), severity (mild, moderate, severe, life-threatening, fatal), start 
date and time, stop date and time, actions taken with respect to the IMP, corrective 
treatment/therapy given, additional investigations performed, outcome, and causality 
(relationship to study treatment according to the investigator’s assessment; see also 
Section 9.2.2). 
The terms ‘disease progression’, ‘progressive disease’, or similar, do not constitute an acceptable 
description of the nature of an AE. For example, if a patient experiences disease progression with 
hemoptysis leading to hospitalization, the investigator should file an AE and an SAE for the 
hemoptysis; data related to disease progression should be captured in the disease assessment and 
response evaluation section of the eCRF. 
Any AE not listed as an expected event in the IB or in this protocol will be considered 
unexpected. 


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9.1. 
Time Period and Frequency of Collection and Reporting 
The following timeframes for reporting apply from signature of the informed consent or, where 
informed consent is deferred, from the documented decision timepoint of the responsible 
investigator and/or physicians to enroll the patient, on: 
• 
All AEs, including AESIs and SAEs until 30 days following the last IFX-1 administration 
must be reported 
• 
All pregnancies until 30 days after the last dose of treatment with IFX-1 must be reported 
until completion of the pregnancy, as described in Section 9.5.2 
Any time outside of the time period specified above, in addition, any study drug-related SAEs 
brought to the attention of an investigator must be reported immediately to the sponsor. 
9.1.1. 
During Treatment  
All AEs, including SAEs and AESIs, must be collected and reported appropriately from the time 
of patient/others signing the consent form or, where informed consent is deferred, from the 
documented decision timepoint of the responsible investigator and/or physicians to enroll the 
patient until 30 days following the last IFX-1 administration.  
• 
All AEs must be followed until the outcome of the event is ‘recovering’ (for stabilization of 
chronic conditions), or recovered (/with sequelae), and until all queries related to these AEs 
have been resolved. 
• 
Ongoing AEs should be reviewed at each scheduled and unscheduled visit until the hospital 
discharge visit. All details should be recorded in the eCRF. If any AE changes for the worse, 
in frequency of attacks/symptoms or in severity, a new record of the event must be started 
(i.e. distinct reports are required for differing frequencies and/or severity of the same event 
to enable comprehensive safety reports and later analysis). 
• 
If the patient dies from an event, ongoing further AEs can be closed with an outcome 
‘unknown’, if outcome was not assessed at day of death. 
9.1.1.1. 
During Follow-up  
All ongoing AEs with onset in the treatment period will have to be followed up after the hospital 
discharge visit until the outcome of the event is ‘recovering’ (for chronic conditions), or 
recovered (/with sequelae), or until end of study and until all queries related to these AEs have 
been resolved.  
All SAEs, including fatal events, related to IMP with onset during the follow-up period (from the 
hospital discharge visit until end of study) will have to be collected and followed until resolved. 


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9.1.2. 
After End of Study 
After the end of study, new SAEs related to IMP must be reported to the sponsor via the regular 
SAE reporting system. 
9.2. 
Serious Adverse Event Reporting and Timelines 
9.2.1. 
Initial Reporting of Serious Adverse Events 
SAEs that should be reported within 24 hours on the SAE form are: 
• 
Events with fatal outcome 
• 
New life-threatening events, defined as: 
− 
Cardiac event requiring CPR or medical resuscitation (adrenaline use etc.) – can be 
caused by severe arrhythmia or other 
− 
Life-threatening spontaneous bleeding requiring blood transfusion and / or surgical 
intervention 
− 
Thrombo-embolic event with life-threatening hemodynamic or pulmonary instability 
− 
New life-threatening organ failure / dysfunction 
− 
Liver: AST, ALT > 20 x upper limit of normal (ULN) OR Bilirubin > 10 x ULN 
− 
Kidney: Creatinine > 6 x ULN – or newly developed anuria ≤ 100 mL urine 
production over 24h 
− 
Cardiovascular:  
− 
Norepinephrine > 1 µg/kg/min or equivalent 
− 
Troponin I: levels consistent with myocardial infarction as defined by 
manufacturer 
− 
Coagulation: Thrombocyte count < 20.000 / µL or partial thromboplastin time (PTT) 
> 2.5 x ULN 
− 
Life-threatening infections other than COVID-19 which require immediate antibiotic 
treatment and/or additional medical / surgical intervention  
− 
Life-threatening infusion reactions which require immediate intensification of existing 
intensive care treatment, including but not limited to additional vasopressor of fluid 
support, or high dose corticosteroids and antihistamines 
All remaining SAEs should be reported at investigator’s earliest convenience. SAEs should be 
approved by the investigator (see Appendix 3 II). In addition, SAEs need to be reported in the 
(non-serious) AE section of the eCRF. The investigator will be requested to supply as much 
detailed information regarding the event as is available at the time of the initial contact. 


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For transmission of the back-up paper-based SAE form, please use the following FAX line 
or e-mail account: 
Fax: +353 1 809 9501 
QLS_IFX1@iqvia.com 
In addition, care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical study are properly mentioned on any copy of a source document 
provided to the sponsor. For laboratory results, the investigator must include the laboratory 
normal ranges. 
9.2.1.1. 
Follow-up Reporting of Serious Adverse Events 
Follow-up information on SAEs must be reported by the investigator within the same time 
frames as the initial reporting.  
A follow-up report to an SAE should be prepared if any relevant change in the condition of the 
patient occurs after the initial report, or any new relevant information becomes available.  
Further information on follow-up procedures is given in Appendix 3 II. 
9.2.2. 
Determination of Relatedness 
The investigator will use medical consideration to determine the relatedness of an AE with the 
study drug based on the following definitions (see also Appendix 3 II):  
Unrelated 
This category applies to AEs that are due to extraneous causes (disease, concomitant medication, 
environment, etc.) and are not related to the administration of study drug.  
Unlikely Related 
This category applies to AEs that are unlikely related to the administration of the study drug. The 
relationship of an AE to the study drug can be considered unlikely related if (must have first two 
criteria listed below):  
• 
The AE does not follow a reasonable temporal sequence from administration of the drug 
• 
The AE could readily have been a result of the patient’s clinical state or other underlying 
medical condition, environmental or toxic factors, or other modes of therapy administered to 
the patient 
• 
The AE does not follow a known response pattern to the suspected drug 
• 
The AE does not reappear or worsen when the study drug is re-administered 


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Possibly Related 
This category applies to AEs that are unlikely to be related to the administration of the study 
drug, but the possibility cannot be ruled-out with certainty. The relationship of an AE to the 
study drug can be considered possibly related if (must have first two criteria listed below):  
• 
The AE follows a reasonable temporal sequence from administration of the study drug 
• 
The AE could readily have been a result of the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient 
• 
The AE follows a known response pattern to the suspected study drug 
Probably Related 
This category applies to AEs that are considered with a high degree of certainty to be related to 
the administration of the study drug. The relationship of an AE to the study drug can be 
considered probably related if (must have first three criteria listed below): 
• 
The AE follows a reasonable temporal sequence from administration of the study drug 
• 
The AE could not be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy administered to the 
patient 
• 
The AE disappears or decreases upon cessation of study drug or reduction in dose 
• 
The AE follows a known response pattern to the suspected study drug 
Definitely Related 
This category applies to AEs that are determined with certainty to be related to the 
administration of the study drug. The relationship of an AE to the study drug can be considered 
definitely related if (must have first three criteria listed below): 
• 
The AE follows a reasonable temporal sequence from administration of the study drug or 
study drug levels have been established in body fluids or tissues 
• 
The AE could not be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors, or other modes of therapy administered to the 
patient 
• 
The AE disappears or decreases upon cessation of study drug or reduction in dose and, if 
applicable, appears upon re-challenge 
• 
The AE follows a known response pattern to the suspected study drug 
• 
There are exceptions when an AE does not disappear upon discontinuation of the study drug, 
yet study drug relatedness clearly exists; e.g., 1) tardive dyskinesia, 2) fixed drug eruptions 


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9.3. 
Death Reporting 
The site should follow all patients for survival and collect information around the death on the 
appropriate eCRF form until the end of the study. 
Primary cause of death should be reported in AE section and SAE form, as well as appropriate 
eCRF section(s). If symptoms of disease progression occurred and constitute the primary cause 
of death, these symptoms could be reported as fatal (S)AE (see Section 9.2.2). 
9.4. 
Abnormal Laboratory Values/Vital Signs/ECG/Physical Examination 
Abnormalities of laboratory results / vital signs / ECG / physical examination should be reported 
as AEs, particularly if at least one of the following is met: 
• 
Any criterion for an SAE is fulfilled 
• 
The abnormality causes the patient to discontinue from the study treatment 
• 
The abnormality causes the patient to interrupt the study treatment or a modification of 
dosing 
• 
The abnormality requires intervention as corrective treatment or consultation 
• 
The investigator judges that the abnormality is clinically significant and should be reported 
as an (S)AE in the eCRF 
All laboratory tests for which clinically significant abnormal results are observed after the 
initiation of study treatment should be repeated until the values return to normal or to a stable 
status. Clinically significant abnormal laboratory results must be reported as an AE. The 
frequency with which such checks should be made will be made by investigator’s discretion 
depending on the degree of abnormality. The reporting of laboratory/vital signs/ECG/physical 
examination abnormalities as both AEs and a specific finding of laboratory values/vital 
signs/ECG should be avoided.  
Abnormal laboratory value testing will follow special considerations for conditions in the ICU 
(refer also to Appendix 3, III Special Considerations for Assessment of Adverse Events in an 
ICU Setting). It must be noted that clinically significant laboratory deterioration as assessed by 
the investigator must be documented in the respective eCRF section. However, it is preferred to 
document the condition or disease underlying the aberrant laboratory value (e.g., renal failure 
rather than hyperkalemia) rather than the laboratory value only. 
9.5. 
Events to be Handled as SAEs 
9.5.1. 
Overdose Reporting 
An overdose is defined as the accidental or intentional ingestion or infusion of any dose of a 
product that is considered both excessive and medically relevant. 


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All symptoms associated with the overdose should be handled as SAEs. 
Refer to Section 7.6 for details on the treatment of overdose. 
9.5.2. 
Pregnancy Reporting 
If the patient or partner of a patient participating in the study becomes pregnant during treatment 
or within 30 days after the last dose of treatment with IFX-1, the investigator should report the 
pregnancy to QLS_IFX1@iqvia.com via e-mail within 24 hours of being notified. The safety 
vendor will then forward the pregnancy reporting form to the investigator for completion. In case 
that e-mail contact is not possible, the site can provide an initial pregnancy report in the SAE 
section of the SAE form and transmit this via the SAE FAX line: +353 1 809 9501. 
A patient becoming pregnant while on IMP will immediately be discontinued from treatment and 
the EOT visit will be performed. 
The patient or partner should be followed by the investigator until completion of the pregnancy. 
If the pregnancy ends for any reason before the anticipated date, the investigator should notify 
the sponsor. At the completion of the pregnancy, the investigator will document the outcome of 
the pregnancy. If the outcome of the pregnancy meets criteria for immediate classification as an 
SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, neonatal death, or 
congenital anomaly), the investigator should follow the procedures for reporting as SAE. 
9.5.3. 
Drug-induced Liver Injury 
Potential drug-induced liver injury is considered an important medical event. Although it is not 
always serious by regulatory definition, such event must be handled as SAE. 
Wherever possible, timely confirmation within 48 to 72 hours of initial liver-related laboratory 
abnormalities should occur prior to the reporting of a potential drug-induced liver injury event. 
All occurrences of potential drug-induced liver injuries, meeting the defined criteria, must be 
reported as SAEs. 
Potential drug-induced liver injury is defined as: 
• 
ALT or AST elevation > 3 × ULN 
AND 
• 
Total bilirubin >2 × ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase) 
AND  
• 
No cholestatic or other immediately apparent possible causes of AST or ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic 


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9.5.4. 
Suspected Transmission of an Infectious Agent (Pathogenic or 
Non-pathogenic) via Study Drug 
For the purposes of reporting, any suspected transmission of an infectious agent via the 
investigational drug should be considered as an SAE. 
A transmission of an infectious agent may be suspected from clinical signs or symptoms, or 
laboratory findings indicating an infection in a patient exposed to a medicinal product.  
In the context of evaluating a suspected transmission of an infectious agent via a medicinal 
product, care should be taken to discriminate, whenever possible, between the cause (e.g., 
injection/administration) and the source (e.g., contamination) of the infection and the clinical 
conditions of the patient at the time of the infection (immuno-suppressed /vaccine). 
9.6. 
Adverse Events of Special Interest 
AESIs are events that are considered to have a special meaning or importance for a particular 
drug or class of drugs. They may be non-serious or serious. Therefore, they should be closely 
monitored. The site must report all AESIs that occur during the study period, whether considered 
to be related to IP or not, according to Appendix 3. Moreover, AESIs should be documented in 
the general AE section of the eCRF as well as in the patient file. 
This is the first study investigating IFX-1 in COVID-related pneumonia. Clinical experience 
with IFX-1 has been generated in more than 300 patients with inflammatory diseases, including 
sepsis and HS.  
For this study, the following AEs are defined as AESIs: 
• 
Infusion reactions, including hypersensitivity or anaphylaxis during or after IFX-1 infusion:  
All patients should be observed closely during the IFX-1 administration and for 
≥ 60 minutes thereafter. The intravenous line should remain open during the observation to 
allow for administration of intravenous drugs, if necessary. Medication for infusion 
reactions should be available for immediate use. Medical staff has to be trained in 
resuscitation and immediate intensive care has to be easily accessible in case of severe 
life-threatening events. Mild to moderate reactions may be treated by slowing or interruption 
of the infusion, or with supportive treatment (Appendix 5).  
For any potential infusion event, the investigator should closely monitor for a potentially 
developing or existing anaphylactic reaction. In case an anaphylactic reaction is anticipated, 
appropriate immediate actions should be taken according to the severity or stage of the 
detected anaphylactic reaction.  
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In case of signs of meningitis at any time during the study, the IMP should be discontinued if 
meningitis is confirmed. The patient must be closely monitored and the guidelines for 
treatment of meningitis should be followed (Tunkel et al. 2004, van de Beek et al. 2016). 
This includes lumbar puncture, blood culture testing, immediate start of treatment with 
dexamethasone and intravenous antibiotics (combination therapy with ampicillin and third 
generation cephalosporin), and a search for the focus of the infection (e.g., CT or MRI).  
• Infections other than COVID-19 (SARS-CoV-2) infections 
In patients with bacterial infection, depending on the severity of the infections, it is important 
that concomitant antibiotic therapy is administered during treatment with IFX-1 to ensure 
appropriate control of the source of the infection. The investigator should pay close attention 
to the choice of an appropriate broad-spectrum antibiotic treatment according to applicable 
guidelines. 
Note: A severe infection can be suspected whenever an IV antibiotic, antifungal, or antiviral 
intervention would be indicated under non-ICU conditions or an invasive intervention would 
have been indicated.  
9.7. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs 
Disease progression does not constitute an AE itself; however, the symptoms/diagnosis leading 
to disease progression must be reported as AE or SAE accordingly. 
9.8. 
Reporting to Competent Authorities and Ethics Committees 
The IB(s) will be the reference document for reference safety information. 
The safety vendor is responsible for submission of suspected unexpected serious adverse 
reactions (see Appendix 3 I for a definition) to health authorities and Institutional Review Boards 
(IRB)/Independent Ethic Committees (IEC) in accordance with local regulations. 
The investigator is responsible for informing the IRB/IEC in a timely manner and in accordance 
with local procedures. 
10. 
STATISTICAL CONSIDERATIONS 
10.1. Phase II 
10.1.1. 
Sample Size Determination 
No formal sample size calculation was performed for this trial. The sample size was based on 
pragmatic considerations in this new and urgent setting with very limited knowledge about the 
disease. 


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For the Phase II part of the trial 30 patients were randomized in a 1:1 ratio to treatment Arm A 
(SBC + IFX-1) and Treatment Arm B (BSC).  
10.1.2. 
Analysis Sets 
All analyses were to be performed based on all randomized patients. 
10.1.3. 
Statistical Analyses 
The statistical analysis plan (SAP) was developed and finalized as soon as possible after clinical 
trial application approval. The SAP includes the exact definition of endpoints and variables to be 
analyzed, extensive details on the statistical analysis methods to be used together with the 
structure of tables and figures to be included as end-of-text tables and figures as well as 
appended listings for the clinical study report. It also describes procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints for Phase II of this study. 
Individual data were to be listed. Data were to be summarized using suitable descriptive 
statistics; depending on the structure of the data, summary statistics (e.g., number of 
observations, mean, standard deviation, minimum, median, maximum, lower quartile, upper 
quartile) or frequency tables may have been used.  
All data were to be displayed by treatment arm if not specified otherwise. 
10.1.3.1. 
Efficacy Analyses 
The relative change (%) from baseline (day 1 prior to study drug administration at ± 1h of 
randomization) in oxygenation index (PaO2 / FiO2) in supine position at day 3, 5, 9, and 15 was 
to be analyzed with a linear repeated measures model with post-baseline time points as outcome 
variable and baseline value as explanatory variable. Deceased patients were to be included in the 
model with an outcome of 0 after death. Patients discharged from the ICU whose oxygenation 
index was no longer be assessed were to be analyzed by last observation carried forward. 
Treatment arm, time point, the interaction between treatment arm and time point, the interaction 
between baseline and time point, age, sex, and intubation status at baseline was to be included as 
further explanatory variables. The model was to use an unstructured covariance matrix and make 
use of the Kenward-Roger degrees of freedom approximation. Least square mean differences 
between treatment arms and their 95% confidence interval was to be calculated and displayed for 
each time point separately (day 3, 5, 9, and 15), with the evaluation at day 5 reflecting the 
primary endpoint. If oxygenation index was to be used as the primary endpoint for a Phase III 
part of the study, data from both study parts were planned to be analyzed in one combined model 
as specified above with study part as a random effect. 
Early response, late response and reaching ICU discharge alive were to be analyzed as three 
separate time-to-event variables. Withdrawing early from the study would have led to the patient 


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being right-censored at the date of withdrawal provided that the reason was not an outcome of 
interest for the time-to-event endpoint. In order to adequately account for competing outcomes as 
well as potential right-censoring due to varying follow-up times, these outcomes were to be non-
parametrically analyzed using Aalen-Johansen-type estimation based on a competing risks model 
with two absorbing states (event 1: all-cause death; event 2: early response/late response/ICU 
discharge respectively). The Aalen Johansen estimator estimates the expected relative number of 
patients (cumulative incidence function [CIF]) of the event at hand. Treatment effects were to be 
derived in terms of the absolute differences between the treatment arm-specific estimators 
evaluated at day 7: 
〖Effect〗_(Y;7)=CIF_Y^A (7)- CIF_Y^B (7) 
where 〖CIF〗_Y^X (7) is the Aalen-Johansen estimator evaluated at day 7 for endpoint 
Y∈{Death, Early Response, Late Response} within treatment group X∈{A,B}. In order to test 
the hypotheses 
H0: 〖Effect〗_(Y;7)=0=0  vs 
H1: 〖Effect〗_(Y;7)≠0 
Two-sided confidence intervals (CIs) were to be constructed based on the approximate normality 
of the estimators (Beyersmann 2012). Statistical significance was to be concluded if the two-
sided 95% CI did not cover 0. 
Adjustment for relevant baseline covariates (age, sex, oxygenation index and intubation status) 
were to be realized by cause-specific Cox models. Subdistribution hazards regression modelling 
were to be applied in the presence of competing risks (Fine and Gray 1999) to explore the 
relative covariate effects in terms of the CIF of interest. Model assumptions were to be checked 
using graphical diagnostics. 
All-cause mortality was to be analyzed as a censored time-to-event variable with Kaplan-Meier 
methods. The proportion of patients still alive at 28 days was to be derived based on the product 
limits estimator in each treatment arm. Adjustment for relevant baseline covariates (age, sex, 
oxygenation index, and intubation status) was to be realized by the Cox proportional hazard 
model. 
The individual components of the composite time-to-event endpoints early and late response and 
ICU discharge were to be analyzed descriptively. 
Laboratory endpoints as well as the Glasgow Outcome Scale were to be analyzed descriptively 
by time point and treatment arm. 
10.1.3.2. 
Safety Analyses 
The occurrence of AEs was to be compared between treatment arms. Treatment-emergent AEs 
(TEAEs) were to be analyzed according to the number and percentage of patients who had a 


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TEAE, as well as the number of TEAEs with the respective Medical Dictionary for Regulatory 
Activities (MedDRA) System Organ Class and Preferred Term. Additionally, the number and 
percentage of patients with TEAEs were to be further grouped by severity and causal 
relationship. The number and percentage of patients with SAEs and the number of SAEs were to 
be analyzed. Where AEs were grouped by severity or relationship, the maximum 
severity/relationship per patient and class of AE was to be considered. 
10.1.3.3. 
Interim Analysis 
An interim analysis was performed after the first 30 patients treated in Phase II reached at least 
day 15 of the study schedule to assess the clinical benefit of the treatment using the assessed 
clinical parameters.  
10.2. Phase III 
10.2.1. 
Sample Size Determination 
A total of 180 patients (90 per arm) are planned to be randomized in Stage 1 and up to 180 
patients (90 per arm) in Stage 2. For patients randomized in error (screening failures) and 
patients for whom consent is withdrawn within 48 hours after randomization, additional patients 
will be randomized. This results in 90% overall power to show efficacy in the final efficacy 
analysis. The power calculation is based on an overall 2.5% one-sided alpha and an assumed 
30% 28-day mortality under Placebo and 15% 28-day mortality under IFX-1 treatment. 
10.2.2. 
Analysis Sets 
Full analysis set (FAS): The primary statistical analysis will be based on all randomized patients 
except patients randomized in error (reason for early termination documented as “Randomized 
by mistake” in the eCRF) who did not get IMP treatment. 
Safety analysis set (SAF): Safety analyses will be based on all patients who received at least 
one infusion of IMP, and patients will be analyzed according to the treatment they actually 
received.  
10.2.3. 
Statistical Analyses 
The SAP will be developed and finalized before the study will be unblinded. The SAP will 
include the exact definition of endpoints and variables to be analyzed, extensive details on the 
statistical analysis methods to be used together with the structure of tables and figures to be 
included as end-of-text tables and figures as well as appended listings for the clinical study 
report. It will also describe procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary, secondary, and other 
endpoints. 


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Individual data will be listed. Data will be summarized using suitable descriptive statistics; 
depending on the structure of the data, summary statistics (e.g., number of observations, mean, 
standard deviation, minimum, median, maximum, lower quartile, upper quartile) or frequency 
tables may be used.  
All data will be displayed by treatment arm if not specified otherwise. 
10.2.3.1. 
Primary Efficacy Analysis 
The primary analysis will be performed based on the FAS.  
 
The primary efficacy variable is 28-day mortality (proportion of patients deceased until day 28). 
The primary statistical hypotheses to be tested are: 
H0: HR = 1 
versus 
H1: HR > 1 
where HR is the hazard ratio derived from the beta coefficient of the primary statistical analysis 
Cox regression model comparing the SOC + Placebo treatment arm (Arm B) with the SOC + 
IFX-1 treatment arm (Arm A). 
A total of 180 patients are planned to be randomized to Arm A and Arm B using a 1:1 allocation 
ratio for the first stage. The interim analysis is performed after 180 patients, not counting patients 
being randomized in error, have been followed-up until day 28 (or died before). In case the 
interim analysis does not result in an early stop for futility, 180 additional patients are planned to 
be randomized in a ratio of 1:1 to Arm A and B. The planned maximum number of patients in 
the study is 360. Depending on the number of patients meeting criteria for additional 
randomization, more patients will be randomized but not more than 400. 
The primary statistical analysis of IFX-1 + SOC compared to SOC alone will make use of a one-
sided alpha level of 2.5% and will test for superiority (lower mortality among IFX-1 treated 
patients). The primary statistical analysis will be based on a Cox proportional hazards regression 
model with outcome 28-day all-cause mortality as a censored time-to-event variable and 
explanatory variables treatment arm (Arm B versus Arm A) and age. The primary statistical 
analysis will be based on all randomized patients except patients randomized in error (reason for 
early termination documented as “Randomized by mistake” in the eCRF) who did not get IMP 
treatment.. For the primary analysis, all-cause mortality will be censored at day 28 for subjects 
who died after day 28 or who have more than 28 days follow-up alive. 
The z-statistic for the interim and final analysis will be calculated as the proportion of the beta 
coefficient for the treatment arm effect and its standard error from the Cox proportional hazards 


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regression model. The study will be stopped for futility if the z-statistic for the first stage is 0 or 
lower. 
 
10.2.3.2. 
Secondary Efficacy Analyses 
The secondary efficacy analyses will be performed based on the FAS.  
The first secondary efficacy endpoint will only be addressed with statistical hypothesis tests if 
the primary endpoint is statistically significant using the full overall 2.5% one-sided alpha. If the 
first secondary endpoint is also statistically significant, the full 2.5% one-sided alpha will be 
passed to the 4 remaining secondary endpoints. Multiplicity in the secondary endpoints will be 
addressed with the fallback method. 60-day mortality will be analyzed similar to 28-day 
mortality and the other secondary endpoints will be evaluated using a logistic regression model 
with the explanatory variables randomized treatment arm (Arm B versus Arm A) and age for: 
1. 60-day all-cause mortality 
2. Proportion of patients with an improvement in the provided 8-point ordinal scale at day 15 
(at least one score point lower than at randomization) 
3. Proportion of patients with an improvement in the provided 8-point ordinal scale at day 28 
(at least one score point lower than at randomization) 
4. Proportion of patients developing acute kidney failure (eGFR < 15 mL/min/1.73m²) during 
ICU stay and at day 28 
5. Proportion of patients free of any renal replacement therapy within 28 days upon 
randomization  
6.  
The ordering of the secondary endpoints 2 to 5 for hypothesis testing will be as in above 
mentioned list. The full 2.5% one-sided alpha for the fallback method will be attributed to the 4 
secondary endpoints in the following way 2%, 0.2%, 0.2%, and 0.1%. If the preceding 
hypothesis test is not significant, subsequent tests will be performed at the aforementioned alpha 
level. If tests are significant, the alpha is added to the subsequent hypothesis test (e.g., if the 
primary hypothesis test is significant and secondary endpoints 1-4 are all significant, the fifth 
secondary endpoint will be tested at an alpha of 2.5%; if the fourth secondary endpoint is not 
significant, the fifth secondary endpoint will be tested at an alpha of 0.1%). 
The primary endpoint as well as all secondary endpoints will also be evaluated as censored time 
to event variables by Kaplan-Meier type methods. Kaplan-Meier analyses will be performed 
comparing the two treatment arms overall and within the following stratifications: 
• Stratification by site 
• Stratification by country 


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• Stratification by sex 
• Stratification by age 
• Stratification by comorbidities 
• Stratification by standard or care.  
10.2.3.3. 
Other Efficacy Analyses 
Time to First Extubation 
Time to first extubation will be analyzed as a censored time to event variable. Withdrawing early 
from the study will lead to the patient being right-censored at the date of withdrawal provided 
that the reason is not an outcome of interest (extubation or death). In order to adequately account 
for competing outcomes as well as potential right-censoring due to varying follow-up times, the 
outcome will be non-parametrically analyzed using Aalen-Johansen-type estimation based on a 
competing risks model with two absorbing states (event 1: all-cause death; event 2: extubation). 
Adjustment for age will be realized by regression modeling accounting for competing risks. 
Patients Alive and Free of Respiratory Failure 
Patients achieving 8-point ordinal scale score 3 or below (patients alive and free of respiratory 
failure) at day 15 and day 28 are defined as alive and free of respiratory failure at the respective 
study day. The corresponding endpoint will be analyzed using logistic regression with 
explanatory variables age and treatment group. 
Glasgow Outcome Scale 
Glasgow Outcome Scale assessed at study day 60 will be analyzed via ordinal logistic regression 
with explanatory variables treatment arm (Arm B versus Arm A) and age. 
Quality of Life 
Quality of life will be assessed by EQ-5D at study day 60. The visual analogue scale as well as 
an index value based on the 5 health states (cross-walk index value using the United States value 
set) will be analyzed by an ANCOVA model with explanatory variables treatment arm (Arm B 
versus Arm A), age, and sex (male versus female). 
10.2.3.4. 
Safety Analyses 
Safety analyses will be performed based on the SAF. 
The occurrence of TEAEs will be compared between treatment arms. TEAEs will be analyzed 
according to the number and percentage of patients who had a TEAE, as well as the number of 
TEAEs in total. Additionally, the number and percentage of patients with TEAEs will be further 
grouped by severity and causal relationship. The number and percentage of patients with serious 


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TEAEs and AESIs and the number of serious TEAEs and AESIs will be analyzed. Where 
TEAEs are grouped by severity or relationship, the maximum severity/relationship per patient 
and class of TEAE will be considered. 
10.2.3.5. 
Interim Analysis 
The interim analysis is performed after the first 180 patients, not counting patients being 
randomized in error, in Stage 1 have been followed-up until day 28 (or died before). The study 
will be stopped for futility if the z-statistic of the primary efficacy analysis is 0 or lower. If the 
study is not stopped for futility, another up to 180 patients will be randomized in Stage 2. 
Depending on the number of patients meeting criteria for additional randomization, more than 
360 patients will be randomized but not more than a total of 400. 


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11. 
REFERENCES 
Beyersmann J, Schumacher M, Alignol A. Competing risks and multistate models with R. 
Springer. 2012. doi: 10.1007/978-1-4614-2035-4. 
Carvelli, J. et al. Association of COVID-19 inflammation with activation of the C5a–C5aR1 
axis. Nature https://doi.org/10.1038/s41586-020-2600-6 (2020). 
Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. 
Cell Res. 2010;20(1):34-50. 
Fine JP, Gray RP. A proportional hazards model for the subdistribution of a competing risk. 
J Am Statistical Assoc. 1999;94(446):496-509. 
Gao T, Hu M, Zhang X, et al. Highly pathogenic coronavirus N protein aggravates lung injury by 
MASP-2-mediated complement over-activation. BMJ. 18 June 2020. Draft publication ahead of 
print. doi: https://doi.org/10.1101/2020.03.29.20041962. 
Garg S, Kim L, Whitaker M, et al. Hospitalization rates and characteristics of patients 
hospitalized with laboratory-confirmed coronavirus disease 2019—COVID-NET, 14 States, 
March 1-30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(15):458-464. 
doi:10.15585/mmwr.mm6915e3. 
Global Initiative for Chronic Obstructive Lung Disease. 2020 GOLD Pocket Guide. Available at: 
http://goldcopd.org/gold-reports. 
Gong J, Dong H, Xia Q, et al. Correlation analysis between disease severity and inflammation-
related parameters in patients with COVID-19 pneumonia. 2020 Feb 25; medRxiv preprint: 
doi: 10.1101/2020.02.25.20025643. 
Gralinski LE, Sheahan TP, Morrison TE, et al. Complement activation contributes to severe 
acute respiratory syndrome coronavirus pathogenesis. mBio 2018;9(5):e01753-18. 
doi: 10.1128/mBio.01753-18. 
Guan W, Ni Z, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl 
J Med. 2020 Feb 28; doi: 10.1056/ NEJMoa2002032. 
Hess C, Kemper C. complement-mediated regulation of metabolism and basic cellular processes. 
Immunity. 2016;45(2):240-54. 
Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus 
in Wuhan, China. Lancet 2020;395:497-506. 
Investigator’s Brochure (IFX-1) Version 7.1. 11 Dec 2019. 


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Jiang Y, Zhao G, Song N, et al. Blockade of the C5a–C5aR axis alleviates lung damage in 
hDPP4-transgenic mice infected with MERS-CoV. Emerging Microbes & Infections. 2018;7:77. 
doi: 0.1038/s41426-018-0063-8.  
Liu et al. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the 
peripheral blood of SARS-CoV-2 infected patients. 2020 Feb 22; medRxiv preprint: 
doi: 10.1101/2020.02.16.20023671. 
Sun S, Zhao G, Liu C, et al. Treatment with anti-C5a antibody improves the outcome of H7N9 
virus infection in African green monkeys. Clin Infect Dis. 2015;60(4):586-95.  
Sun S, Zhao G, Liu C, et al. Inhibition of complement activation alleviates acute lung injury 
induced by highly pathogenic avian influenza H5N1 virus infection. Am J Respir Cell Mol Biol. 
2013;49(2):221-230. 
Tunkel A, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial 
meningitis. Clin Infect Dis. 2004;39(9):1267-84. 
van de Beek D, Cabellos C, Dzupova O et al. ESCMID guideline: diagnosis and treatment of 
acute bacterial meningitis. Clin Microbiol Infect. 2016;22 Suppl 3:S37 62. 
Vlaar APJ, de Bruin S, Busch M et al. Anti-C5a Antibody (IFX-1) Treatment of Severe COVID-
19: An Exploratory Phase 2 Randomized Controlled Trial. Available at SSRN: 
https://ssrn.com/abstract=3658226 or http://dx.doi.org/10.2139/ssrn.3658226  
Wang R, Xiao H, Guo R, et al. The role of C5a in acute lung injury induced by highly 
pathogenic viral infections. Emerging Microbes & Infections. 2015;e28. doi: 
10.1038/emi.2015.28. 
Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel 
Coronavirus–infected pneumonia in Wuhan, China. JAMA 2020;323(11):1061-1069. 
doi: 10.1001/jama.2020.1585. 
Wiersinga WJ, Rhodes A, Cheng AC, et al. Pathophysiology, transmission, diagnosis, and 
treatment of Coronavirus Disease 2019 (COVID-19), a review. JAMA. 2020 Jul 10. 
doi: 10.1001/jama.2020.12839 
World Health Organization (WHO) Coronavirus Disease (COVID-19) Situation Report – 185. 
23 July 2020. Available at: https://www.who.int/docs/default-source/coronaviruse/situation-
reports/20200723-covid-19-sitrep-185.pdf?sfvrsn=9395b7bf_2.  
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with 
COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 09; doi: 10.1016/ 
S0140-6736(20)30566-3. 
 


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12. 
APPENDICES 


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Appendix 1 
Clinical Laboratory Tests 
The protocol-required laboratory assessments are detailed in Table 3 for Phase II and in Table 4 
for Phase III. Protocol-specific requirements for inclusion or exclusion of patients are detailed in 
Section 6.1 and Section 6.2 of the protocol. In general, blood samples for safety laboratory 
analysis should be obtained once a day during a routine sampling (preferable in the morning) 
prior to IMP administration. Additional tests may be performed at any time during the study as 
determined necessary by the investigator or required by local regulations. 
Table 3 
Protocol-Required Safety Laboratory Assessments: Phase II 
Assessment 
Parameters 
Hematology 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
Red blood cells (MCV) 
White blood cell count with 
differentials (neutrophils, 
lymphocytes, monocytes, 
eosinophils, basophils) 
Coagulation parameters 
APTT  
PT 
D-Dimer 
Clinical chemistry a 
ALT (SGPT) 
AST (SGOT) 
LDH 
Total bilirubin 
Creatinine 
Procalcitonin  
Sodium 
Potassium 
Calcium 
Magnesium 
Glucose 
CRP 
 
Urinalysis (Dipstick) 
PH 
Glucose Leucocytes 
Protein 
Blood 
Other screening tests 
Troponin ISerum or urine hCG pregnancy test (as needed in 
women of childbearing potential) 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring are given in Section 9.5.3. All events of ALT ≥3 × ULN and bilirubin ≥2 × ULN (35% direct 
bilirubin) or ALT ≥3 ULN and INR >1.5 (if INR is measured), may indicate severe liver injury (possible Hy’s 
Law) and must be reported as an SAE. 
 


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Table 4 
Protocol-Required Safety Laboratory Assessments: Phase III 
Assessment 
Parameters 
Screening/Randomization Only (as indicated in SoA Table 2) 
Urinalysis  
PH 
Glucose  
Leucocytes 
Protein 
Blood 
Other screening tests 
Serum or urine human chorionic gonadotropin/hCG pregnancy 
test (in women of childbearing potential) 
Screening/Randomization and Treatment (as indicated in SoA Table 2) 
Hematology 
Hemoglobin 
Hematocrit 
Platelet count 
Red blood cell count 
Red blood cells (MCV) 
White blood cell count with differentials (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils) 
Coagulation parameters 
APTT  
PT 
D-Dimer 
Clinical chemistry a 
ALT (SGPT) 
AST (SGOT) 
LDH 
Total bilirubin 
CRP 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping 
or monitoring are the same as in Phase II (listed in Section 9.5.3). All events of ALT ≥3 × ULN and bilirubin 
≥2 × ULN (35% direct bilirubin) or ALT ≥3 ULN and international normalized ratio (INR) >1.5 (if INR is 
measured), may indicate severe liver injury (possible Hy’s Law) and must be reported as an SAE. 
Investigators must document their review of each laboratory safety report. 
 


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Appendix 2 Regulatory and Ethical Considerations 
I. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• 
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines 
• 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines 
• 
Applicable laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), IB, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients.  
The investigator will be responsible for the following: 
• 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
• 
Notifying the IRB/IEC of SAEs or other relevant safety findings as required by IRB/IEC 
procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations 
II. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 


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III. 
Informed Consent Process 
Obtaining of informed consent is proposed to be deferred for the ICU patients in this study or by 
any other legally acceptable local procedure specific for patients treated in the ICU setting (see 
Section 6.3). 
The ICF could contain a separate section or an additional ICF may be issued that addresses the 
use of remaining samples for optional exploratory research. The investigator or authorized 
designee will explain to each patient/legal representative the objectives of the exploratory 
research. Patients/legal representatives will be told that they are free to refuse to participate and 
may withdraw their consent at any time and for any reason during the storage period. A separate 
signature will be required to document a patient’s agreement to allow any remaining specimens 
to be used for exploratory research. Patients who decline to participate in this optional research 
will not provide this separate signature. 
IV. 
Data Protection 
Patients will be assigned a unique identifier by the sponsor. Any patient records or datasets that 
are transferred to the sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred.  
The patient and/or the legal representative/relative must be informed that patients’ personal 
study-related data will be used by the sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the patient.  
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
The sponsor will ensure that all safeguards are in place to minimize any eventual risk of breaches 
and complies otherwise with the requirements of European Union (EU) General Data Protection 
Regulation (GDPR [EU] 2016/679). The sponsor will regularly check all procedures relevant to 
the processing of personal data, as to ensure privacy by design and compliance with this 
regulation. 
V. 
Publication Policy 
The results of this study may be published or presented at scientific meetings. Individual 
publications are allowed only after publication of the entire study. If this is foreseen, the 
investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. This 
allows the sponsor to protect proprietary information and to provide comments.  
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 


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multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
In accordance with consistent editorial practice, the sponsor supports publication of multicenter 
studies in their entirety and not as individual center data unless as ancillary study/data.  
All publications in peer-reviewed medical journals resulting from this study will be listed in the 
original study protocol registration record (e.g., on ClinicalTrials.gov). 
VI. 
Dissemination of Clinical Study Information 
The sponsor will provide the relevant study protocol information in a public database (e.g., 
ClinicalTrials.gov, https://clinicaltrials.gov/) before or at commencement of the study. The 
sponsor may also provide study information for inclusion in national registries according to local 
regulatory requirements.  
If a potential patient contacts the sponsor regarding participation in the study, the investigator 
agrees that the sponsor may forward the study site and contact details to the patient. Based on the 
inclusion and exclusion criteria for the study, the investigator will assess the suitability of the 
patient for enrollment into the study. 
Results of this study will be disclosed according to the relevant regulatory requirements. All 
publications in peer-reviewed medical journals resulting from this study will be listed in the 
original study protocol registration record (e.g., on ClinicalTrials.gov). 
VII. 
Data Quality Assurance 
All patient data relating to the study will be recorded on the eCRF unless transmitted to the 
sponsor or designee electronically (e.g., laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
It is the responsibility of the site to comply with the protocol-defined procedures and 
assessments. Details about the handling of protocol deviations will be included in a separate 
Protocol Deviation Plan. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  


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The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing on-site or remote source data verification to confirm that 
data entered into the eCRF by authorized site personnel are accurate, complete, and verifiable 
from source documents, that the safety and rights of patients are being protected, and that the 
study is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study, must be 
retained by the investigator for 25 years after study completion unless local regulations or 
institutional policies require a different retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor.  
VIII. 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records, depending on the study.  
IX. 
Study and Site Closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor’s procedures, or GCP guidelines 
• 
Inadequate recruitment of patients by the investigator 
• 
Discontinuation of further IMP development 


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Appendix 3 
Adverse Events: Definitions and Procedures for Recording, 
Evaluation, Follow-up, and Reporting 
I. 
Definitions 
Definition of an AE 
An AE is any untoward medical occurrence in a patient or clinical study patient, temporally 
associated with the use of IMP, whether or not considered related to the IMP. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of IMP. 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECG, radiological scans, vital signs measurements), including 
those that worsen from baseline. Laboratory tests are considered abnormal, if 
− 
Any criterion for an SAE is fulfilled 
− 
The abnormality causes the patient to discontinue from the study treatment 
− 
The abnormality causes the patient to interrupt the study treatment or a modification of 
dosing 
− 
The investigator judges that the abnormality is clinically significant and hence is to be 
reported as an (S)AE in the eCRF 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after IMP administration even though it may have 
been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either IMP or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should 
be reported regardless of sequelae. 
• 
Signs, symptoms, and/or clinical sequelae resulting from disease progression will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. The terms ‘disease 
progression’, ‘progressive disease’, or similar, per se will not be reported as an AE or SAE. 
Such instances will be captured in the efficacy assessments.  
Events NOT Meeting the AE Definition 
• 
The terms ‘progressive disease’ or ‘progression of disease’ per se will not be reported as an 
AE or SAE. Such instances will be captured in the efficacy assessments.  


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• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
 
Definition of an SAE 
If an event is not an AE according to the above definition, then it cannot be an SAE even if 
serious conditions are met. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
• 
Results in death 
• 
Is life-threatening  
Life-threatening in the definition of ‘serious’ refers to an event in which the patient was at risk of 
death at the time of the event. It does not refer to an event which hypothetically might have 
caused death, if it were more severe. 
• 
Required inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually involving at least 
an overnight stay) at the hospital or emergency ward for observation and/or treatment that would 
not have been appropriate in the physician’s office or outpatient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether ‘hospitalization’ occurred 
or was necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
• 
Results in persistent disability or incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
• 
Is a congenital anomaly or birth defect 
• 
Other situations: 
− 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 


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patient or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
 
Definition of an Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction is defined (as per ICH Topic E2A) as all noxious and 
unintended responses to a medicinal product related to any dose which nature or severity is not 
consistent with the relevant source document, i.e., current IB. When reported as serious, the 
unexpected adverse reaction is defined as suspected unexpected serious adverse reaction. The 
safety vendor is responsible for notifying suspected unexpected serious adverse reactions to 
concerned regulatory bodies in accordance with local regulations. 
II. 
Procedures for Recording, Evaluation, Follow-up and Reporting of an 
AE, including AESIs and SAEs 
Recording of AEs, including AESIs and SAEs 
• 
When an AE occurs, it is the responsibility of the investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the 
event. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE. 
• 
The investigator will then record all relevant information in the eCRF. 
• 
It is not acceptable for the investigator to send photocopies of the patient’s medical records 
to the safety vendor in lieu of completion of the respective sections of the eCRF. 
• 
There may be instances when copies of medical records for certain cases are requested by 
the safety vendor. In this case, all patient identifiers, with the exception of the patient 
number, must be redacted on the copies of the medical records before submission to the 
safety vendor. 
SAE Reporting to the Safety Vendor via the eCRF 
• 
The safety vendor for this study is IQVIA Pharmacovigilance and is responsible for SAE 
processing and reporting. 
• 
The primary mechanism for reporting an SAE to the safety vendor will be the eCRF. 
• 
Investigators and other site personnel must report those SAEs that are outlined under 
Section 9.2 within 24 hours of becoming aware. The same applies for follow-up information 
on SAEs. 


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• 
A paper SAE reporting form needs to be completed by the investigator or other relevant site 
staff, signed by the investigator, and faxed to +353 1 809 9501 or QLS_IFX1@iqvia.com in 
case eCRF SAE reporting is not possible. 
Assessment of Intensity for AEs, including AESIs and SAEs 
The investigator will make an assessment of intensity for each AE reported during the study and 
assign it to 1 of the following categories (National Cancer Institute Common Terminology 
Criteria for Adverse Events [CTCAE] v5.0):  
• 
Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• 
Grade 2 (Moderate): minimal, local or non-invasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL)* 
• 
Grade 3 (Severe/medically relevant but not immediately life-threatening); hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL** 
• 
Grade 4 (Life-threatening): Life-threatening consequences; urgent intervention indicated 
• 
Grade 5 (Death): Death related to AE 
 
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden 
Assessment of Causality of AEs, including AESIs and SAEs 
• 
The investigator is obligated to assess the relationship between IMP and each occurrence of 
each AE. 
• 
A ‘reasonable possibility‘ of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to IMP administration will be 
considered, investigated, and reported. 
• 
The investigator will also consult the IB and/or Product Information, for marketed products, 
in his/her assessment. 
• 
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to the safety vendor. However, it is very important 
that the investigator always makes an assessment of causality for every event before the 
initial transmission of the SAE data to the safety vendor. 


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• 
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs, including AESIs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
the safety vendor to elucidate the nature and/or causality of the AE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
• 
In case of persisting SAEs, follow-up must continue until the AEs have resolved to grade ≤1 
or baseline or are deemed irreversible by the investigator. 
• 
If a patient dies during participation in the study or during a recognized follow-up period, 
the investigator will provide the safety vendor with a copy of any post-mortem findings 
including histopathology, if any would become available. 
• 
The investigator will submit any updated SAE data to the safety vendor within 24 hours of 
receipt of the information. 
III. 
Special Considerations for Assessment of Adverse Events in an ICU 
Setting 
Due to the severity of disease of the patient population entering this study, numerous problems, 
signs, and symptoms deviating from normal will be seen during the course of the study. These 
will not necessarily constitute a reportable AE unless they require significant intervention, lead 
to discontinuation of blinded study drug, or are considered to be of concern in the investigator’s 
clinical judgement, i.e. classified as “clinically significant”. Similarly, it is preferred to receive 
documentation of the underlying condition rather than the resulting sign (e.g., ‘agitation’ rather 
than ‘self-extubation’). 
In clinical studies in intensive care, deviations, e.g., in laboratory values or temporary changes in 
arterial blood pressure, are to be expected frequently. Clinical judgement should be applied in 
determining which deviations should be reported as an AE in the sense of an “untoward medical 
occurrence” and which deviations should be considered usual and expected findings in this 
setting. To support the investigators, a separate list of non-reportable findings will be provided 
defining the parameters as well as the conditions when to report a deviation as an AE and when 
not. 
It must be noted that clinically significant laboratory deterioration as assessed by the investigator 
must be documented in the respective eCRF section. However, it is preferred to document the 
condition or disease underlying the aberrant laboratory value (e.g., renal failure rather than 
hyperkalemia) rather than the laboratory value only. 


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The investigator will exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant, and thus 
constitutes an AE. 


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Appendix 4 
Contraceptive Guidance and Collections of Pregnancy 
Information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
− 
Documented hysterectomy 
− 
Documented bilateral salpingectomy 
− 
Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the patient’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female: 
− 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
− 
Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-hormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
Contraception Guidance 
Male Patients 
Male patients with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following during the study and until 3 months after last dose of IFX-1:  
• 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent 
• 
Agree to use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 5 when having penile-vaginal intercourse with a woman 
of childbearing potential who is not currently pregnant 


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Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile vaginal 
intercourse or use a male condom during each episode of penile penetration [during the 
protocol-defined time frame]. 
 
Female Patients 
Female patients of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception (from the day of study medication initiation throughout the 
study period and up to 3 months for IFX-1 after the last dose of study medication) consistently 
and correctly as described in Table 5. During the treatment period of the study conception is 
assumed to be precluded by the severe clinical conditions for included patients and applicability 
of sexual abstinence as a contraceptive method can be assessed by the investigator in case a 
patient confirmation cannot be gained. 
 
Table 5 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User-Dependent a  
(failure rate of <1% per year when used consistently and correctly) 
Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation: b 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
Highly Effective Methods That Are User-Independent a 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation: b 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 


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Vasectomized partner: 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used. 
Sexual abstinence: 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the IMP. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the patient. 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for patients participating 
in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the 
efficacy of the contraceptive method. In this case, two highly effective methods of contraception 
should be utilized during the treatment period and for at least 3 months after the last dose of IFX-1. 
Pregnancy Testing 
WOCBP should only be included after a negative serum or urine pregnancy test. 
Collection of Pregnancy Information  
Male Patients with Partners who Become Pregnant  
The investigator will attempt to collect pregnancy information on any male patient’s female 
partner who becomes pregnant while the male patient is in this study. This applies only to male 
patients who receive IFX-1. 
After obtaining the necessary signed informed consent from the pregnant female partner directly, 
the investigator will record pregnancy information on the appropriate form and submit it to the 
sponsor within 24 hours of learning of the partner’s pregnancy. The female partner will also be 
followed to determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the sponsor. Generally, the follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
Female Patients who Become Pregnant  
The investigator will collect pregnancy information on any female patient who becomes pregnant 
while participating in this study. Information will be recorded on the appropriate form and 


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submitted to the sponsor within 24 hours of learning of a patient’s pregnancy. The patient will be 
followed at least monthly to determine the outcome of the pregnancy. The investigator will 
collect follow-up information on the patient and the neonate, and the information will be 
forwarded to the sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous abortion is 
always considered to be an SAE and will be reported as such. Any post-study pregnancy related 
SAE considered reasonably related to the IMP by the investigator will be reported to the safety 
vendor as described in Appendix 3. While the investigator is not obligated to actively seek this 
information in former study patients, he or she may learn of an SAE through spontaneous 
reporting.  
Any female patient who becomes pregnant while participating in the study will discontinue IMP. 
 
 


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Appendix 5 
Treatment Modification Guidelines 
Table 6 
Dose Modification and Toxicity Management Guidelines for Infusion Reactions 
Associated with IFX-1 
Grade 
Treatment 
Premedication at 
Subsequent Dosing 
mild 
 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
• Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator. 
None 
moderate 
 
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs. 
• Stop Infusion. 
• Additional appropriate medical therapy may 
include but is not limited to: 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator. 
• If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 
mL/hr. to 50 mL/hr.). Otherwise dosing will be 
held until symptoms resolve and the patient 
should be premedicated for the next scheduled 
dose. 
 
Patients who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment 
 
Patient may be premedicated 
1.5 h (± 30 minutes) prior to 
infusion of IMP with: 
 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic). 
severe 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicated for other 
clinical sequelae (e.g., 
renal impairment, 
pulmonary infiltrates) 
 
• Stop Infusion. 
• Additional appropriate medical therapy may 
include but is not limited to: 
• Epinephrine** 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Oxygen 
• Pressors 
• Corticosteroids 
• Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator. 
• Hospitalization may be indicated. 
** In cases of anaphylaxis, epinephrine should be used 
immediately. 
No subsequent dosing 


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life-threatening: 
Life-threatening; 
pressor or ventilator 
support indicated 
Patient is permanently discontinued from further 
study drug treatment. 
 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration. For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 
(CTCAE) at http://ctep.cancer.gov. 
 
 
 


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Appendix 6 
Conversion Tables for PaO2 / FiO2 Ratio 
The following conversion tables should be used if a blood gas analysis is not available.  
Estimating PaO2 from a measured SO2  
SO2 
Calculated 
PaO2 (mmHg) 
SO2 
Calculated 
PaO2 (mmHg) 
SO2 
Calculated 
PaO2 (mmHg) 
80 
44 
87 
53 
94 
73 
81 
45 
88 
55 
95 
79 
82 
46 
89 
57 
96 
86 
83 
47 
90 
60 
97 
96 
84 
49 
91 
62 
98 
112 
85 
50 
92 
65 
99 
145 
86 
52 
93 
69 
 
 
 
Estimating FiO2 with known O2 Application Flow 
Method 
O2-Flow (l/min) 
Estimated 
FiO2 ( %) 
Nasal O2 Tube 
Nasal Prong 
1 
2 
3 
4 
5 
6 
24 
28 
32 
36 
40 
44 
Nasopharyngeal 
Catheter 
4 
5 
6 
40 
50 
60 
Oxygen Mask 
5 
6–7 
7–8 
40 
50 
60 
Oxygen Mask with 
Reservoir 
6 
7 
8 
9 
10 
60 
70 
80 
90 
95 


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Appendix 7 
Ordinal Scale 
 
 
 


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Appendix 8 
Glasgow Outcome Scale 
The Glasgow Outcome Scale is a global scale for functional outcome that rates patient status 
into one of five categories: 
Rate 
Category 
1 
Death 
2 
Persistent vegetative state 
3 
Severe disability (conscious but disabled) 
4 
Moderate disability (disabled but independent) 
5 
Good recovery 
 
 
 


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Appendix 9 
EQ-5D Health Questionnaire 
The EQ-5D is a widely used multi attribute utility instrument for measuring health-related 
quality of life. 
 


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Appendix 10 
New York Heart Association (NYHA) Classification 
 
Class 
Patient symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, dyspnea (shortness of breath) 
II 
Slight limitation of physical activity. Comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea (shortness of 
breath). 
III 
Marked limitation of physical activity. Comfortable at rest. Less than 
ordinary activity causes fatigue, palpitation, or dyspnea 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of 
heart failure at rest. If any physical activity is undertaken, discomfort 
increases. 
 


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Appendix 11 
Child-Pugh Classification 
 
Category 
Hepatic Function 
Score 
Child-Pugh A 
Good  
5 to 6 points 
Child-Pugh B 
Moderately impaired 
7 to 9 points 
Child-Pugh C 
Advanced hepatic dysfunction 
10 to 15 points 
 
 
1 point 
2 points 
3 points 
Encephalopathy: 
None 
Grade 1 and 2  
Grade 3 and 4  
Ascites:   
None  
Slight  
Moderate  
Bilirubin: 
< 2 mg/mL 
2 to 3 mg/mL  
> 3 mg/mL 
Albumin: 
> 3.5mg/mL 
2.8 to 3.5mg/mL  
< 2.8mg/mL 
Prothrombin Time: 
OR 
INR: 
< 4 sec  
 
< 1.7 
4 to 6 sec  
 
1.7 to 2.2 
> 6 sec  
 
> 2.2 


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Appendix 12 
Special Considerations for Assessment of Prior and 
Concomitant Medications 
A complete record of all prior and concomitant drugs (but excluding nutritional and volume 
therapy, electrolyte support, vitamins, NSAIDs, and supportive therapies such as artificial tears, 
ointments, stool softeners/laxatives, etc.) will be maintained in the eCRF for each participant, 
beginning 7 days before randomization and continuing until up to 30 days after the last dose of 
study treatment. 
In addition, a complete record of all steroid and antibiotic therapy and any therapy (drugs, 
specific treatments, etc.) associated with or used in the assessment or treatment of an adverse 
event will be documented for the duration of the study. 
The following information must be recorded in the eCRF for each concomitant medication: 
generic name, route of administration, start date, stop date, and indication. 
All medications administered within 7 days before randomization should be recorded with 
generic name, route of administration, start date, stop date, and indication. 


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Appendix 13 
Protocol Version History 
VERSION 4.0: 12 MAY 2021 
This protocol version is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the EU. 
Overall Rationale for Version 4.0 
Following Scientific Advice recommendations of the USA Federal Drug Administration and the 
European Medical Agency, the statistical ‘stop for efficacy’ criterion for the interim analysis has 
been removed, including adaptation of the power calculation, the randomization of additional 
patients clarified, and the order of secondary endpoints adapted.  
Corresponding updates have been implemented in Protocol Version 4.0 for Phase III part of the 
study as described in Table 7 below. 
Table 7 
Protocol Version History: Updates to Version 4.0, Phase III 
Section(s)  
Description of Change 
Brief Rationale 
 
Overall 
Separation of protocol sections into subsections for Phase II and 
Phase III has been maintained, as study is designed as a 
combined Phase II/III study. 
Amended topics refer only to study design elements applicable to 
Phase III part of the study. 
1 Synopsis,  Number of sites have been 
increased from 45 sites to 60 
sites. 
Given the still unpredictable epidemiology of COVID-19, 
additional sites will improve the ability to enroll the study in a 
timely manner. 
1 Synopsis, 
4.2.2.2, 
5.1, 5.2, 
10.2.1, 
10.2.3.1, 
10.2.3.2, 
10.2.3.3, 
10.2.3.5 
Statistical ‘stop for efficacy’ 
criterion for the interim 
analysis has been removed, 
power calculation adapted, 
randomization of additional 
patients clarified, ’60-day 
mortality’ endpoint upgraded 
to the first secondary endpoint, 
and the order of the secondary 
endpoints adapted. Addition of 
an exploratory endpoint. 
Adaptations performed to eliminate statistical concerns of 
regulatory authorities about the early stop for efficacy at interim 
analysis and to clarify final analysis. 
Additional major updates made in Protocol Version 2.0 that were retrospectively applied to 
Phase II mainly include text that was simplified or adapted to an ICU setting, as described in the 
table below. 
Table 8 
Protocol Version History: Major Updates to Phase II 
Section(s)  
Description of Change 
Brief Rationale 
 
Overall 
Where applicable, protocol sections were separated into 
subsections for Phase II and Phase III. 


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Section(s)  
Description of Change 
Brief Rationale 
Because Phase II is now completed, all information relevant only 
to Phase II of the study has been changed to past tense and font 
color changed to grey. 
“Subject(s)” changed to “Patient(s)” throughout to reflect the 
COVID-19 diseased population, and not healthy subjects, in the 
trial. 
5.5.1.3 
Clarification made 
Removed “In such a case the EOS visit information will be added 
to the EOT visit information.”, as this language was unclear. 
5.5.1.4 
Text on patients lost to follow-
up updated 
Text adapted to an ICU setting 
6.4 
Revised definition of 
screening failures 
Text adapted to an ICU setting 
6.5 
Removed dietary requirements 
Text adapted to an ICU setting 
7.2, 7.3, 
9.2.1, 9.6, 
Appendix 5 
“Infusion-related reactions” 
was changed to “infusion 
reactions” 
"Infusion reactions” is more a more accurate description of these 
events. 
7.2.4 
Removed “disease 
progression” 
Text adapted to an ICU setting 
7.3 
Removed “in the treatment 
facility” 
Text adapted to an ICU setting 
7.4 
Requirements for recording of 
prior and concomitant 
medications were revised  
Requirements were simplified and adapted to an ICU setting 
9.1 
Text on frequency of 
collection and reporting 
revised 
AESIs were included in the specified AEs to be reported until 
30 days following the last IFX-1 administration. SAEs was 
moved to the first bullet; bullets 1 and 2 combined since they 
follow the same timelines 
9.1.1, 
9.1.1.1, 
9.1.2 
Headings renamed and text 
updated accordingly 
Removed visit names that were used only in Phase II, to make the 
text applicable to Phase III as well. 
9.1.1.1, 
9.2.1 
“Death” was revised to 
“Events with fatal outcome” 
Death is not an SAE, but the outcome of an SAE. 
9.2.2 
“Not Related” was changed to 
“Unrelated” 
Harmonization of terminology