A Phase 1/2a Trial of the Intravenous Administration of the SARS-CoV-2-Neutralizing Monoclonal Antibody DZIF-10c in SARS-CoV-2-Infected and -Uninfected Individuals
Phase: PHASE1
Conditions: SARS-CoV-2 Infection
Sponsor: University of Cologne

 
DZIF-10c_Infusion_Trial Protocol_V04_0 
Universität zu Köln 
 
A Phase 1/2a Trial of the Intravenous Administration of the SARS-CoV-2-Neutralizing 
Monoclonal Antibody DZIF-10c in SARS-CoV-2-Infected and -Uninfected Individuals 
 
Sponsor 
 
University of Cologne 
Albertus-Magnus-Platz 
50923 Cologne 
Germany 
 
Sponsor Representative 
 
 
 
 
 
 
Coordinating Investigator 
 
 
 
 
 
 
 
 
EudraCT: 
 
 
 
2020-003503-34 
ClinicalTrals.gov: 
 
 
NCT04631666 
Protocol code: 
 
 
Uni-Koeln-4288 
 
 
Version V04_0, 07-APR-2021 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, authorities, trial subjects, and ethics committees or 
institutional review boards. The contents of this document shall not be disclosed to others 
without written authorization from the sponsor or the Principal Coordinating Investigator, 
unless it is necessary to obtain informed consent from potential study participants. 
 
 

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DZIF-10c_Infusion_Trial Protocol_V04_0 
 
 
 
Statement of Compliance 
The clinical trial will be conducted in compliance with the protocol, with the International 
Conference on Harmonization Good Clinical Practice E6 (ICH-GCP), as well as the 
applicable European and German law. 
 
I. Signatures 
 
                                                         
 
 
 
On behalf of the Sponsor (University of Cologne) 
Signature 
Date 
 
 
 
 
 
 
 
 
 
 
Coordinating Investigator 
Signature 
Date 
 
 
 
 
 
 
 
 
Statistician 
Signature 
 
Date 
 
 

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DZIF-10c_Infusion_Trial Protocol_V04_0 
Dose Escalation Phase 
 
During the dose escalation phase, SARS-CoV-2-uninfected (Groups 1A-D) and 
SARS-CoV-2-infected individuals (Group 2C) will receive a single intravenous 
infusion of DZIF-10c at the specified dose on day 0. 
 
Group 1A:  
 
 
2.5 mg/kg  
Group 1B:  
 
 
10 mg/kg 
Group 1C and Group 2C: 
40 mg/kg 
Group 1D: 
 
 
80 mg/kg 
 
Dose-Limiting Toxicities 
A dose-limiting toxicity (DLT) for this trial will be defined as any grade 3 or higher 
adverse event during the dose escalation phase that the investigators determine to 
be related to DZIF-10c. 
 
Dose Escalation Scheme 
During the dose escalation phase of the study, only a single individual per dose may 
be enrolled per day. 
 
Initially, three individuals will be enrolled per group during the dose escalation phase. 
 
During the dose escalation phase, the following rules will apply: 
 
- 
If no DLT occurs up to the day 7 visit in the 3 enrolled participants within a group, 
dose escalation will proceed and no additional participants will be enrolled into 
the same group (except for Group 1D, see below). 
 
- 
If a DLT occurs in one individual in a group up to the day 7 visit, three additional 
participants will be enrolled into the same group. If no additional DLTs occur up 
to the day 7 visit in these 3 additional participants, the trial will proceed to the next 
dose group. 
 
- 
If DLTs in a group occur in two or more participants, dosing will be halted, and the 
prior dose level will be declared as maximum tolerated dose (MTD). 
 
Enrollment will start in Group 1A. Decisions on dose escalation will be made by the 
Safety Monitoring Committee (SMC) who will review interim safety data after the day 
7 visit of all participants within a group has occurred. Enrollment into Group 2C can 
be initiated after a positive SMC vote once dose escalation criteria for Group 1B have 
been met. Enrollment into the randomized Group 2D can be initiated after a positive 
SMC vote once dose escalation criteria for Group 2C have been met. Should a 
maximum tolerated dose <40 mg/kg be defined during the dose escalation phase in 
healthy volunteers, participants in Group 2C or Group 2D will receive DZIF-10c at this 
maximum tolerated dose. 
 
Enrollment of Additional Participants in Group 1D 
Should no DLTs occur until the day 7 visit in all three initial Group 1D participants and 
upon a positive SMC vote, three additional participants will be enrolled. In this case, 
dose escalation phase criteria (e.g., staggered enrollment, hospitalization) will not 
apply to the additional participants. 
 
Number  
of Participants 
A total of 15 (up to 30 in case of DLTs) participants will be enrolled into the dose 
escalation component of the trial. If no DLTs occur in the dose escalation phase of 
Group 1D, three additional healthy vounteers will be enrolled. A total of 39 
participants will be enrolled into the expansion component (Group 2D).  

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Objectives 
Primary Objective 
- 
To evaluate the safety and tolerability of a single intravenous infusion of DZIF-10c 
in SARS-CoV-2-uninfected and SARS-CoV-2-infected individuals. 
 
Secondary Objectives 
- 
To determine the pharmacokinetics of DZIF-10c after a single intravenous 
infusion. 
- 
To determine the development of antibodies targeting DZIF-10c (anti-drug 
antibodies, ADA) following a single DZIF-10c infusion. 
- 
To evaluate the effect of a single DZIF-10c infusion on viral shedding in 
nasopharyngeal swabs by qRT-PCR in SARS-CoV-2-infected individuals. 
 
Exploratory Objectives 
- 
To evaluate the effect of DZIF-10c infusion on viral shedding in nasopharyngeal 
swabs determined by the presence of infectious virions in SARS-CoV-2-infected 
individuals. 
- 
To evaluate the effect of DZIF-10c infusion on viral shedding in oropharyngeal 
swabs determined by qRT-PCR in SARS-CoV-2-infected individuals. 
- 
To evaluate the effect of DZIF-10c infusion on viral shedding in oropharyngeal 
swabs determined by the presence of infectious virions in SARS-CoV-2-infected 
individuals. 
- 
To evaluate the frequency of COVID-19-related hospitalization or medical 
contacts after DZIF-10c infusion in SARS-CoV-2-infected individuals. 
- 
To evaluate the effect of DZIF-10c infusion on symptom resolution in SARS-CoV-
2-infected individuals symptomatic at baseline. 
- 
To evaluate the effects of DZIF-10c infusion on the viral sequence and the 
development of viral escape mutation that might arise. 
- 
To evaluate SARS-CoV-2-specific immune responses following DZIF-10c 
infusion. 
- 
To evaluate the effect of DZIF-10c infusion on viral replication in respiratory 
samples as determined by subgenomic mRNA levels in SARS-CoV-2-infected 
individuals. 
Endpoints 
Primary Endpoints 
- 
The rate of Adverse Events after DZIF-10c infusion. 
 
Secondary Endpoints 
- 
The pharmacokinetic profile of DZIF-10c, including elimination half-life, peak 
serum concentration, area under the curve, clearance, and volume of distribution. 
- 
The frequency and magnitude of anti-drug antibodies targeting DZIF-10c 
following DZIF-10c infusion. 
- 
SARS-CoV-2 RNA shedding in nasopharyngeal swabs determined by qRT-PCR 
in SARS-CoV-2-infected individuals. 
 
Exploratory Endpoints 
- 
Successful virus isolation from nasopharyngeal swabs in SARS-CoV-2-infected 
individuals. 
- 
SARS-CoV-2 RNA shedding in orpharyngeal swabs determined by qRT-PCR in 
SARS-CoV-2-infected individuals. 
- 
Successful virus isolation from oropharyngeal swabs in SARS-CoV-2-infected 
individuals. 
- 
Frequency of COVID19-related hospitalization and medically-attended health 
care contacts in SARS-CoV-2-infected individuals not previously hospitalized. 
- 
Time to resolution of self-assessed SARS-CoV-2-related symptoms. 
- 
Differences of viral spike gene sequences obtained before and after study drug 
administration and the investigation of the effect of observed mutations on viral 
sensitivity to DZIF-10 in neutralization assays. 

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- 
The activity and frequency of SARS-CoV-2-reactive immune cells following DZIF-
10c infusion. 
- 
Subgenomic SARS-CoV-2 mRNA levels in respiratory samples in SARS-CoV-2-
infected individuals. 
Inclusion  
and  
Exclusion 
Criteria 
Inclusion Criteria 
 
Groups 1A-1D 
- 
Age 18 to 65. 
 
- 
SARS-CoV-2-RNA negative naso- or oropharyngeal swab obtained within 3 
calendar days before study drug administration by NAAT (e.g., qRT-PCR). 
 
- 
Non-reactivity of serum antibodies (IgG; and IgA and/or IgM when tested) against 
SARS-CoV-2 by serological assay at screening. 
 
Groups 2C-2D 
- 
Age 18 to 70. 
 
- 
SARS-CoV-2-RNA positive naso- or oropharyngeal swab obtained within 3 
calendar days before study drug administration by NAAT (e.g., qRT-PCR). 
 
- 
Onset of COVID-19 symptoms (e.g., sore throat, cough, fever, chills, fatigue, dys- 
or anosmia, dys- or angeusia, headache, muscle pain, gastrointestinal symptoms) 
within 7 days prior to study drug administration 
       or 
Non-reactivity of serum or plasma antibodies (IgG; and IgA and/or IgM when 
tested) against SARS-CoV-2 by serological assay at screening. 
 
- 
Disease severity score 1-4 as defined by the WHO Clinical Progression Scale 
(WHO, Lancet Inf Dis 2020). 
 
Exclusion Criteria 
 
- 
Known hypersensitivity to any constituent of the investigational medicinal product. 
 
- 
Hepatitis B infection indicated by detectable HBsAg (Hepatitis B surface antigen) 
in blood. 
 
- 
Detectable antibodies against hepatitis C virus in blood unless active hepatitis C 
is ruled out by negative HCV-RNA. 
 
- 
HIV infection indicated by detectable HIV antigen and/or HIV antibodies in blood. 
 
- 
Blood laboratory parameter abnormalities as listed below 
- 
Neutrophil count ≤1,000 cells/µl 
- 
Hemoglobin ≤10 g/dl 
- 
Platelet count ≤100,000 cells/µl 
- 
ALT ≥2.0 x ULN 
- 
AST ≥2.0 x ULN 
- 
Total bilirubin ≥1.5 ULN  
- 
eGFR <60 ml/min/1.73m2 
 
- 
Pregnancy or lactation. 
 
- 
Any vaccination within 14 days prior to DZIF-10c administration. 
 
- 
Receipt of any SARS-CoV-2 vaccine or SARS-CoV-2 monoclonal antibody in the 
past. 
 
- 
Diagnosis of bronchial asthma or history of bronchial hyperresponsiveness, 
COPD, pulmonary fibrosis, or other chronic lung diseases. 
- 
Any chronic or clinically significant medical condition that in the opinion of 
investigator would jeopardize the safety or rights of the volunteer. 
 
- 
History of systemic corticosteroids, immunosuppressive anti-cancer, or other 
medications considered significant by the trial physician within the last 6 months 

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(a single administration of systemic corticosteroids within ≤6 months and ≥4 
weeks of enrollment is acceptable). 
 
- 
Participation in another clinical trial of an investigational medicinal product within 
the past 12 weeks or expected participation during this study. 
 
- 
Dependency on the principal investigator or study staff; or site personnel directly 
affiliated with this trial. 
 
- 
Legally incapacitated individuals. 
 
- 
Individuals held in an institution by legal or official order. 
 
- 
If engaging in sexual activity that could result in pregnancy, inability or 
unwilligness to comply with the requirements for highly effective contraception. 
Study Product 
and Placebo 
DZIF-10c is a recombinantly produced fully human monoclonal antibody of the IgG1k 
isotype that targets the spike protein (S) of SARS-CoV-2. When tested in vitro, DZIF-
10c potently neutralizes SARS-CoV-2 and prevents viral infection.  
 
Sterile normal saline (NaCl 0.9%) will be used as placebo. 
 
Dose 
DZIF-10c (or placebo) will be administered intravenously at doses of 2.5, 10, 40, or 
80 mg/kg depending on group allocation.  
 
Route of Administration 
DZIF-10c will be administered by intravenous infusion diluted in formulation buffer as 
necessary using a 0.2 µm in-line filter. 
Treatment 
Duration 
DZIF-10c or placebo will be administered as single intravenous infusion. 
 
Participants will be followed for 90 days after the administration of DZIF-10c or 
placebo. 
Tentative  
Time Plan 
First patient first visit (FPFV): 
Q4/2020 
Last patient first visit (LPFV): 
Q2/2021 
Last patient last visit (LPLV): 
Q3/2021 
End of trial: 
 
 
Q3/2021 
Final study report: 
 
Q2/2022 
Statistical 
Methodology 
Quantitative data will be summarized by mean ± standard deviation and percentiles 
(0, 25, 50, 75, 100), qualitative data by absolute and relative frequency. Listings of the 
data will be given where appropriate. Data up to the day 7 visit after infusion and 
during follow up after the day 7 visit will be evaluated separately, and in total where 
sensible. Results are described by group (dose and SARS-CoV-2-infection group in 
the dose escalation phase, treatment group in the randomized phase) and in total. 
 
Analysis cohorts include the safety population (as treated), including all trial 
participants who received any amount of the study drug, as well as the modified 
intention-to-treat (mITT) population, including all randomized trial participants 
receiving the study drug infusion who have at least a baseline (day 0) value and a 
second measurement up to the day 7 visit after infusion. 
 
Statistical analyses are descriptive by nature. The frequency of (serious) adverse 
events ((S)AEs) and adverse events of special interest (AESIs) occurring up to the 
day 7 visit after DZIF-10c infusion and during study follow up will be given. Safety 
events of the primary endpoints will be listed. Main analysis is in the safety population. 
 
Secondary and exploratory endpoints will be summarized, figures may show 
development over time where appropriate. Additionally, explorative multivariable 
methods or confidence intervals may be calculated where sensible. Endpoints will be 

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evaluated in the mITT population, and additional analysis populations can be defined. 
Viral RNA shedding determined by qRT-PCR will be evaluated as time weighted 
average change from baseline. 
 
A full description of the statistical methodology will be provided in the Statistical 
Analysis Plan. 
Funding 
This study is supported through a grant from the German Center for Infection 
Research (DZIF) and supported by Boehringer Ingelheim providing the investigational 
medicinal product and potential funding. 
 
 
 
 

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III. Table of Contents 
 
I. SIGNATURES ............................................................................................................................................... 2 
II. SYNOPSIS .................................................................................................................................................. 3 
III. TABLE OF CONTENTS ................................................................................................................................ 9 
IV. ABBREVIATIONS ..................................................................................................................................... 12 
1. 
INTRODUCTION ................................................................................................................................... 13 
1.1. 
BACKGROUND .......................................................................................................................................... 13 
1.2. 
MONOCLONAL ANTIBODIES TARGETING INFECTIOUS PATHOGENS ...................................................................... 14 
1.3. 
NEUTRALIZING ANTIBODIES TARGETING SARS-COV-2 .................................................................................... 16 
1.4. 
DZIF-10C ............................................................................................................................................... 17 
2. 
OBJECTIVES OF THE CLINICAL TRIAL ..................................................................................................... 19 
2.1. 
RATIONALE FOR THE CLINICAL TRIAL ............................................................................................................. 19 
2.2. 
PRIMARY OBJECTIVE ................................................................................................................................. 19 
2.3. 
SECONDARY OBJECTIVES ............................................................................................................................ 19 
2.4. 
EXPLORATORY OBJECTIVES ......................................................................................................................... 19 
3. 
ORGANIZATIONAL AND ADMINISTRATIVE ASPECTS OF THE TRIAL ........................................................ 20 
3.1. 
SPONSOR ................................................................................................................................................ 20 
3.2. 
COORDINATING INVESTIGATOR .................................................................................................................... 20 
3.3. 
STATISTICIAN ........................................................................................................................................... 20 
3.4. 
SAFETY MONITORING COMMITTEE............................................................................................................... 21 
3.5. 
CENTRAL ORGANIZATION UNIT .................................................................................................................... 22 
3.6. 
PRINCIPAL INVESTIGATORS AND TRIAL SITES ................................................................................................... 22 
3.7. 
FINANCING .............................................................................................................................................. 22 
4. 
TRIAL CONDUCT .................................................................................................................................. 23 
4.1. 
TRIAL DESIGN .......................................................................................................................................... 23 
4.1.1. 
Dose Escalation Scheme .............................................................................................................. 26 
4.1.2. 
Discussion of Trial Design ............................................................................................................ 27 
4.2. 
RISK-BENEFIT ASSESSMENT ........................................................................................................................ 28 
4.2.1. 
Potential Risks and Strategies for Risk Mitigation ...................................................................... 28 
4.2.2. 
Potential Benefits ........................................................................................................................ 31 
4.2.3. 
Overall Risk-/Benefit-Assessment ............................................................................................... 31 
4.3. 
SELECTION OF TRIAL POPULATION ................................................................................................................ 31 
4.3.1. 
Inclusion Criteria ......................................................................................................................... 32 
4.3.2. 
Exclusion Criteria ......................................................................................................................... 32 
4.3.2.1. 
Requirements for Effective Contraception ............................................................................................. 34 
5. 
METHODS AND PROCEDURES .............................................................................................................. 35 
5.1. 
TRIAL VISIT OVERVIEW .............................................................................................................................. 35 
5.2. 
ASSESSMENTS AND SAMPLE COLLECTION ...................................................................................................... 35 
5.2.1. 
Safety Assessments ..................................................................................................................... 35 
5.2.2. 
Pharmacokinetic Assessments .................................................................................................... 37 
5.2.3. 
Assessment of Viral Shedding ..................................................................................................... 37 
5.2.4. 
Assessment of Anti-Drug Antibodies ........................................................................................... 38 
5.2.5. 
Assessment of the Development of Viral Mutations and Antibody Resistance .......................... 38 
5.2.6. 
Assessment of COVID-19-related Hospitalizations and Medically-Attended Health Care Contacts
 
39 
5.2.7. 
Assessment of Time to Symptom Resolution .............................................................................. 39 
5.2.8. 
Assessment of Immunological Parameters ................................................................................. 39 
5.2.9. 
Sample Collection, Storage, and Shipment ................................................................................. 39 
5.3. 
RECRUITMENT .......................................................................................................................................... 40 
5.4. 
SCREENING PROCEDURES ........................................................................................................................... 40 
5.5. 
INFUSION VISIT ........................................................................................................................................ 42 
5.6. 
FOLLOW-UP VISITS ................................................................................................................................... 44 

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5.7. 
WITHDRAWAL OF TRIAL PARTICIPANTS ......................................................................................................... 45 
5.7.1. 
Follow-Up after Withdrawal ....................................................................................................... 45 
5.8. 
CLOSURE OF TRIAL SITES/PREMATURE TERMINATION OF THE CLINICAL TRIAL ....................................................... 45 
5.8.1. 
Closure of Trial Sites .................................................................................................................... 45 
5.8.2. 
Premature Termination of the Clinical Trial ................................................................................ 46 
5.9. 
TREATMENT ............................................................................................................................................ 46 
5.9.1. 
Administration ............................................................................................................................ 46 
5.9.2. 
Description of the Investigational Medicinal Product and Placebo ............................................ 47 
5.9.2.1. 
Manufacture of the Investigational Medicinal Product .......................................................................... 47 
5.9.2.2. 
Labelling of Investigational Medicinal Product ....................................................................................... 47 
5.9.2.3. 
Shipment and Storage of Investigational Medicinal Product ................................................................. 48 
5.9.3. 
Dispensing and Return of Investigational Medicinal Product ..................................................... 48 
5.9.4. 
Assignment of Trial Participants to Treatment Groups ............................................................... 48 
5.9.5. 
Selection of Dosage of DZIF-10c .................................................................................................. 49 
5.9.6. 
Blinding ....................................................................................................................................... 49 
5.9.6.1. 
Unblinding .............................................................................................................................................. 49 
5.9.7. 
Previous and Concomitant Medication ....................................................................................... 50 
5.9.8. 
Rescue Therapy for Emergencies ................................................................................................ 50 
5.9.9. 
Continuation of Treatment after the End of the Clinical Trial ..................................................... 50 
6. 
DATA QUALITY ASSURANCE ................................................................................................................. 51 
6.1. 
MONITORING AND AUDITS ......................................................................................................................... 51 
6.1.1. 
Monitoring .................................................................................................................................. 51 
6.1.2. 
Audits / Inspections ..................................................................................................................... 51 
6.2. 
DOCUMENTATION .................................................................................................................................... 52 
6.2.1. 
Data Management ...................................................................................................................... 52 
6.2.2. 
Archiving ..................................................................................................................................... 53 
7. 
ETHICAL AND REGULATORY ASPECTS ................................................................................................... 54 
7.1. 
ETHICS COMMITTEE .................................................................................................................................. 54 
7.2. 
ETHICAL AND LEGAL CONSIDERATIONS .......................................................................................................... 54 
7.3. 
REGISTRATION AND NOTIFICATION OF AUTHORITIES ........................................................................................ 54 
7.4. 
OBTAINING INFORMED CONSENT FROM TRIAL PARTICIPANTS ............................................................................ 54 
7.5. 
INSURANCE OF TRIAL SUBJECTS ................................................................................................................... 55 
7.6. 
DATA PROTECTION ................................................................................................................................... 55 
8. 
STATISTICAL METHODS AND SAMPLE SIZE CONSIDERATIONS ............................................................... 56 
8.1. 
STATISTICAL AND ANALYTICAL PLAN ............................................................................................................. 56 
8.1.1. 
Analysis Populations ................................................................................................................... 56 
8.1.2. 
Description of Trial Participants Groups ..................................................................................... 56 
8.1.3. 
Primary Outcome and Target Variables ...................................................................................... 57 
8.1.4. 
Secondary and Exploratory Outcomes and Target Variables ...................................................... 57 
8.1.5. 
Subgroup Analyses ...................................................................................................................... 59 
8.1.6. 
Interim Analysis ........................................................................................................................... 59 
8.2. 
SAMPLE SIZE CONSIDERATIONS ................................................................................................................... 59 
9. 
SAFETY ................................................................................................................................................ 61 
9.1. 
DEFINITIONS OF ADVERSE EVENTS AND ADVERSE DRUG REACTIONS ................................................................... 61 
9.1.1. 
Adverse Event.............................................................................................................................. 61 
9.1.2. 
Adverse Drug Reaction ................................................................................................................ 61 
9.1.3. 
Serious Adverse Events and Serious Adverse Reactions .............................................................. 61 
9.1.4. 
Unexpected Adverse Drug Reaction ............................................................................................ 62 
9.1.5. 
Suspected Unexpected Serious Adverse Reactions ..................................................................... 62 
9.1.6. 
Dose-Limiting Toxicities .............................................................................................................. 62 
9.2. 
DOCUMENTATION AND FOLLOW-UP OF ADVERSE EVENTS ................................................................................ 63 
9.2.1. 
Documentation of Adverse Events and Adverse Drug Reactions ................................................ 63 
9.2.2. 
Severity of Adverse Events .......................................................................................................... 64 
9.2.3. 
Causality Assessment of Adverse Events ..................................................................................... 64 
9.3. 
REPORTING OF SERIOUS ADVERSE EVENTS, ADVERSE EVENTS OF SPECIAL INTEREST, DOSE-LIMITING TOXICITIES, 
PREGNANCY AND CHANGES IN RISK-BENEFIT ASSESSMENT ............................................................................................ 65 

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9.3.1. 
SAE, AESI and DLT Reporting ....................................................................................................... 65 
9.3.2. 
Pregnancy Reporting ................................................................................................................... 66 
9.3.3. 
SAE Assessment by the Sponsor .................................................................................................. 66 
9.3.4. 
Unblinding for SUSAR when Treatment is Blinded ...................................................................... 66 
9.3.5. 
Notification of Competent Authority and Ethics Committee ...................................................... 67 
9.3.6. 
Reporting of Potential Changes in the Risk-Benefit Ratio ........................................................... 67 
9.3.7. 
Informing the Investigators......................................................................................................... 68 
9.4. 
ANNUAL SAFETY REPORT (DSUR) ............................................................................................................... 68 
10. 
REPORTING OF TRIAL RESULTS ........................................................................................................ 69 
10.1. 
REPORTS ................................................................................................................................................. 69 
10.1.1. 
Interim Reports ........................................................................................................................... 69 
10.1.2. 
Final Report ................................................................................................................................. 69 
11. 
AMENDMENTS TO THE TRIAL PROTOCOL ......................................................................................... 69 
12. 
APPENDICES .................................................................................................................................... 70 
13. 
REFERENCES .................................................................................................................................... 73 
 
 
 

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IV. Abbreviations 
ACE2 
Angiotensin-converting enzyme 2 
ADE 
Antibody-dependent enhancement 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
CA 
Competent authority 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
CRF 
Case Report Form 
Ct 
Cycle threshold 
CTCC 
Clinical Trials Center Cologne 
DLT 
Dose-limiting toxicity 
DSUR 
Development Safety Update Report 
EBOV 
Ebola virus 
EC 
Ethics Committee 
EMA 
European Medicines Agency 
Fc 
Fragment crystallizable 
FDA 
Food and Drug Administration 
HIV-1 
Human immunodeficiency virus type 1 
IC50 
50% inhibitory concentration 
ISF 
Investigator Site File 
IMSB 
Institute of Medical Statistics and Computational Biology 
IMP 
Investigational Medicinal Product 
mAb 
Monoclonal antibody 
mITT 
Modified Intention-To-Treat 
NAAT 
Nucleic acid amplification test 
PI 
Principal Investigator 
PEI 
Paul-Ehrlich-Institute 
PP 
Per Protocol 
qRT-PCR 
Quantitative real-time reverse transcription polymerase chain reaction 
RBD 
Receptor-binding domain 
RSV 
Respiratory syncytial virus 
RNA 
Ribonucleic acid 
S 
SARS-CoV-2 spike protein 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SARS 
Severe acute respiratory syndrome 
SARS-CoV 
Severe acute respiratory syndrome coronavirus 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SMC 
Safety monitoring committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
 
Trial Master File 
 

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1. Introduction 
1.1. 
Background 
After emerging at the end of 2019, the severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) has rapidly spread across the globe. By October 2020, over 40 million 
confirmed cases of SARS-COV-2 infection and more than 1,000,000 casualties of the 
associated coronavirus disease 2019 (COVID-19) have been reported1. The development of 
safe and effective options for treatment and prevention of SARS-CoV-2 infection is therefore 
of urgent concern for global public health. 
SARS-CoV-2 is an enveloped positive-sense single-stranded RNA Betacoronavirus of 
the subgenus Sarbecovirus. It is related to SARS-CoV, the causative agent of the 2002/2003 
SARS outbreak, and to coronaviruses circulating in bat populations. Although a definitive 
animal reservoir has not yet been identified, SARS-CoV-2 is likely of zoonotic origin2. 
Human-to-human transmission of SARS-CoV-2 occurs primarily through respiratory 
droplets and aerosols3. It is notable for the occurrence of superspreading events, in which a 
limited number of index cases results in the infection of a large number of contacts. Importantly, 
asymptomatic and presymptomatic individuals shedding the virus at high concentrations create 
a challenge to identify origins of transmission chains4. In addition to the respiratory route, 
transmission of SARS-CoV-2 by fomites has been suggested as plausible5. 
Following exposure, symptoms typically manifest after a median of 5-6 days, although 
this period can range from 1 to more than 14 days. In addition, a sizeable fraction of infected 
individuals appears not to develop clinically apparent signs. A majority of infections 
(approximately 80%) results in mild to moderately severe courses of disease that are 
characterized by symptoms of upper respiratory tract infections (e.g., cough, fever, rhinorrhea, 
coarse throat, or disturbances of smell or taste). More severe cases of COVID-19 primarily 
demonstrate signs of lower respiratory tract infection (e.g., dyspnea, pneumonia) and can 
result in respiratory failure with a need for mechanical ventilation or extracorporeal oxygenation 
of the blood. Beyond respiratory symptoms, an increasing number of additional manifestations 
have been associated with SARS-CoV-2 infection, including thromboembolic events, cardiac 
or systemic inflammation, and renal failure6.  
A number of investigational and approved drugs that were developed for the use in 
other indications are under evaluation for their potential use in the treatment of SARS-CoV-2 
infection. For example, remdesivir is a nucleoside analogue prodrug that acts as an inhibitor 
of viral RNA polymerase following intracellular biotransformation. Based on its demonstrated 
in vitro activity against human coronaviruses, including SARS-CoV-2, clinical investigation of 
remdesivir for SARS-CoV-2 infection was rapidly initiated. In hospitalized adults with COVID-

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19, administration of remdesivir resulted in a significantly reduced time to recovery compared 
to placebo7. Based on these observations, remdesivir has received full or conditional approval 
(e.g., by the FDA and EMA) for use in SARS-CoV-2 infected individuals requiring supplemental 
oxygen therapy. However, remdesivir requires a 5-to-10-day intravenous treatment course and 
its efficacy in prevention of SARS-CoV-2 infection has not been demonstrated yet. In addition 
to antiviral compounds, agents aimed at modulating immune-mediated organ injury are under 
investigation for their efficacy in COVID-19. Importantly, in hospitalized patients with COVID-
19 requiring oxygen therapy, the anti-inflammatory corticosteroid dexamethasone has resulted 
in reduced 28-day mortality8. However, no effects on mortality were noted in individuals not 
receiving respiratory support8. 
 
SARS-CoV-2 infection of target cells occurs through the interaction of the receptor-
binding domain (RBD) of the homotrimeric spike (S) protein on the viral surface with its host 
target cell receptor ACE29,10. Moreover, SARS-CoV-2-infected cells can be identified through 
the expression on the SARS-CoV-2 S protein on the cellular surface11. Thus, strategies that 
target the S protein are of potential interest both for the treatment and prevention of SARS-
CoV-2 infection. 
 
1.2. 
Monoclonal Antibodies Targeting Infectious Pathogens 
Human immunity is composed of an intricate network of different mechanisms aimed at 
preventing and resolving infection. Although the immune response can vary between different 
pathogens and individuals, infection as well as vaccination typically result in the induction of 
neutralizing and non-neutralizing pathogen-specific antibodies. Both types of antibodies can 
promote clearance or processing of targeted pathogens by engaging other components of the 
immune system. These functions are mediated through the antibodies’ Fc domains (Fc, 
fragment crystallizable) that interact with Fc receptors expressed on the surface of effector 
cells (e.g., NK cells, macrophages, or dendritic cells) or with components of the complement 
system12. In addition, neutralizing antibodies (nAbs) are capable of rendering pathogens non-
infectious by targeting critical surface epitopes13. For example, virus-specific neutralizing 
antibodies can prevent infection by targeting viral surface proteins that mediate attachment to 
target cells or the subsequent fusion of viral and cellular membranes13,14. Induction of 
neutralizing antibodies is therefore a key objective of many vaccination strategies and 
neutralizing antibodies are of particular relevance for antibody-mediated strategies against 
pathogens15. 
 
Administration of antibodies for treatment and prevention of infectious disease is a 
clinically well-established principle since its origins in the late 19th century when serum 
antitoxins were used against tetanus and diptheria16. For example, purified polyclonal 

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immunoglobulins enriched from human donors with high titers of pathogen-specific antibodies 
are routinely used for postexposure prophylaxis of infections including hepatitis B, rabies, or 
tetanus17. In addition, antibody-containing convalescent plasma donated by survivors of 
infection can provide a readily and rapidly available medication with clinical efficacy against 
newly emerging infectious pathogens. For example, the administration of convalescent plasma 
has been associated with reduced mortality after infection with SARS-CoV, for which no 
specific antiviral medication exists18. However, preparations of polyclonal immunoglobulins 
show donor-dependent variations resulting in difficulties for standardization and are not 
enriched for neutralizing antibodies with particularly high potency.  
In contrast, individual monoclonal antibodies (mAbs) have well-defined specifities, and 
advances in antibody production technologies have facilitated the pharmaceutical 
development of monoclonal antibodies. Such antibodies have gained widespread medical use 
with >70 approved mAbs and derived constructs, mostly for malignant and autoimmune 
diseases. In addition, monoclonal antibodies have been approved for the treatment of drug-
resistant HIV-1 (human immunodeficiency virus type 1), the prevention of recurrent Clostridium 
difficile infection, as well as for the prophylaxis of infection with RSV (respiratory syncytial 
virus)14,19.  
Monoclonal antibodies for clinical use have initially been obtained from immunized 
animals. However, recent developments in B cell cloning and antibody isolation methods have 
enabled the identification and recombinant production of fully human monoclonal antibodies 
derived from human samples14. Using these approaches, highly potent neutralizing antibodies 
targeting different viruses, including influenza virus, Ebola virus (EBOV), and HIV-1 have been 
identified14. When administered to heathy and infected individuals, potent neutralizing human 
monoclonal antibodies were generally safe and well tolerated20-25. Importantly, high in vitro 
neutralizing activity can be translated to clinical antiviral efficacy. For example, administration 
of potent human monoclonal antibodies significantly reduced mortality from Ebola virus 
compared to the antiviral agent remdesivir and a combination of antibodies obtained from 
immunized mice25. Moreover, a combination of potent human broadly neutralizing antibodies 
maintained suppression of HIV-1 without development of antibody resistance in individuals 
infected with sensitive strains20,24. Finally, human antibody-derived monoclonal antibodies 
targeting influenza and RSV resulted in significantly reduced viral titers compared to placebo 
in an influenza challenge study26 and reduced hospitalizations during RSV season27, 
respectively. 
 

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1.3. 
Neutralizing Antibodies Targeting SARS-CoV-2 
SARS-CoV-2 infection induces a humoral immune response of varying magnitude28. Total and 
neutralizing antibody titers in serum depend on several factors, including disease severity29. 
Whether the development of neutralizing antibodies contributes to protection from re-infection 
and whether neutralizing antibodies are a correlate of protection in vaccinated individuals are 
subjects of intensive research efforts that include investigations on the longevity of the immune 
response30. 
 
SARS-CoV-2-neutralizing monoclonal antibodies have been isolated from phage 
display libraries31, immunized animals32,33, survivors of infection with the related 
betacoronavirus SARS-CoV34,35, as well as from SARS-CoV-2-infected individuals33,36-48. Most 
of the identified neutralizing antibodies interfere with viral infection by targeting the RBD of the 
spike protein that interacts with the host cell receptor ACE2. However, neutralizing antibodies 
targeting other epitopes on the SARS-CoV-2 S protein have also been characterized40,44,45. 
When tested in vitro against authentic replication-competent SARS-CoV-2 or replication-
deficient viruses pseudotyped with the SARS-CoV-2 spike protein, neutralizing antibodies can 
efficiently block or reduce viral infection, although the neutralizing potency between different 
neutralizing antibodies varies considerably33,35,36,39-41,43,44,46,48. In addition, the development of 
antibody escape mutations during viral passage in vitro suggests that combinations of 
antibodies targeting different epitopes may be beneficial49. 
 
Indicating their potential for use in prevention of SARS-CoV-2 infection, administration 
of neutralizing monoclonal antibodies prior to SARS-CoV-2 challenge resulted in reduced 
clinical disease, reduced viral concentrations, and/or reduced pulmonary pathological findings 
across diverse animal models36,42,43,46,47. For example, a serum concentration of 22 µg/ml of 
the human neutralizing antibody CC12.1 at the time of intranasal viral challenge resulted in 
protection from disease in a Syrian hamster model of SARS CoV-2 infection46. Taking the 
neutralizing potency of the administered human antibody CC12.1 against SARS-CoV-2 into 
account, a serum antibody concentration of 1.160-fold the pseudovirus IC50 was considered 
fully protective in this study46. Similarly, administration of human SARS-CoV-2-neutralizing 
antibodies prior to respiratory SARS-CoV-2 challenge resulted in reduced viral replication and 
reduced pathological findings in lung biopsies in non-human primate models of SARS-CoV-2 
infection42,43. 
 
When administered in a therapeutic setting several hours after viral challenge, human 
SARS-CoV-2-neutralizing monoclonal antibodies resulted in reduced viral titers in transgenic 
mouse models expressing human ACE236,47. In addition, antibody treatment 24 h and 72 h 
after viral challenge was associated with an expedited decline of viral RNA in respiratory swabs 
and reduced pathological signs of pulmonary inflammation in rhesus macaques42.  

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These encouraging pre-clinical findings of potent human SARS-CoV-2-neutralizing 
antibodies have prompted the initiation of phase I to phase III clinical trials of different antibody 
candidates. In addition to establishing the safety and tolerability of neutralizing antibodies, 
these studies aim to evaluate antibody efficacy both in the therapeutic and preventive settings. 
For example, the SARS-CoV-2-neutralizing antibody LY-CoV555 has been investigated in 
recently SARS-CoV-2-infected outpatients with mild-to-moderate infection50. A single 
intravenous infusion of a dose of 700 to 7,000 mg was overall well tolerated50. While the effects 
on the decline of viral shedding were limited, a lower fraction of antibody-recipients reported 
COVID-19-related hospitalizations or emergency room visits compared to placebo recipients50. 
Interim results of trials investigating combinations of SARS-CoV-2 neutralizing antibodies to 
SARS-CoV-2-infected ambulatory trial participants have also suggested beneficial antibody-
mediated effects, including reduced viral shedding and impoved clinical outcomes (e.g., 
reduced symptom duration, reduced rate of COVID-19-associated medical contacts)51,52. 
Based on these results, emergency use authorizations for the first monoclonal antibodies were 
recently granted by the FDA in SARS-CoV2-infected outpatients at high risk of disesase 
progression or hospitalization. 
 
 
1.4. 
DZIF-10c 
DZIF-10c is a potent human SARS-CoV-2-neutralizing antibody that was identified from a 
blood sample of a COVID-19-convalescent patient obtained 35 days after diagnosis of 
infection48. To isolate SARS-CoV-2-neutralizing antibodies from this and 11 additional patients, 
single memory B cells reactive to the SARS-CoV-2 spike protein were sorted using flow 
cytometry. Antibody heavy and light chain sequences were subsequently amplified from 
individually lysed cells using specific reverse transcription polymerase chain reaction (RT-
PCR) and sequenced, facilitating the recombinant production of exact antibody replicates53. 
Using this approach, the human monoclonal antibody HbnC3t1p1_F4 was identified and later 
modified by eliminating the heavy chain C-terminal lysine to reduce potential charge 
heterogeneity, resulting in antibody DZIF-10c. DZIF-10c is a monoclonal antibody of the IgG1 
kappa isotype with low somatic hypermutation compared to its germline sequence (% germline 
nucleotide identity of 93.2% and 96.1% for the heavy chain and light chain variable genes, 
respectively)48. 
 
DZIF-10c targets the receptor binding domain (RBD) of the SARS-CoV-2 spike protein 
with high affinity. When tested in vitro, DZIF-10c demonstrates potent neutralizing activity both 
against authentic SARS-CoV-2 as well as SARS-CoV-2 spike-typed pseudoviruses48,54. For 
example, infection of Vero E6 cells with the SARS-CoV-2 variant BavPat1/2020 was 

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completely blocked in the presence of DZIF-10c at concentrations as low as 0.05 µg/ml as 
indicated by the absence of detectable cytopathic effects. Moreover, DZIF-10c demonstrated 
high activity against a panel of six SARS-CoV-2 pseudovirus variants with an average 50% 
inhibitory concentration (IC50) of 0.007 µg/ml in a neutralization assay using ACE2-expressing 
human 293T cells. 
 
DZIF-10c has also been studied in animal models of SARS-CoV-2-infection. Mice 
expressing human ACE2 after transtracheal transduction by a recombinant adenovirus 
encoding for ACE2 
 can be challenged with SARS-CoV-2, 
resulting in viral replication in pulmonary tissues. To investigate its therapeutic activity, DZIF-
10c was administered 
 after SARS-CoV-2 challenge either by 
intraperitoneal injection or intranasal instillation. While high titers of infectious virus could be 
detected in lung tissues of animals treated with isotype control antibodies, 
 
undectable levels of infectious SARS-CoV-2 (ACE2-transduced mice) 
were observed after DZIF-10c treatment.  
 
Thus, DZIF-10c is a highly potent human SARS-CoV-2-neutralizing monoclonal 
antibody with promising potential for use in the treatment and prevention of SARS-CoV-2 
infection. 
 
 

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2. Objectives of the Clinical Trial 
2.1. 
Rationale for the Clinical Trial 
This clinical trial is the first-in-human study for the intravenous administration of the SARS-
CoV-2-neutralizing human monoclonal antibody DZIF-10c. It is intended to investigate the 
safety and tolerability of DZIF-10c in humans and to support the further development of DZIF-
10c for treatment and prevention of SARS-CoV-2 infection.  
 
2.2. 
Primary Objective 
- 
To evaluate the safety and tolerability of a single intravenous infusion of DZIF-10c in SARS-
CoV-2-uninfected and SARS-CoV-2-infected individuals. 
2.3. 
Secondary Objectives 
- 
To determine the pharmacokinetics of DZIF-10c after a single intravenous infusion. 
- 
To determine the development of antibodies targeting DZIF-10c (anti-drug antibodies, 
ADA) following a single DZIF-10c infusion. 
- 
To evaluate the effect of DZIF-10c infusion on viral shedding in nasopharyngeal swabs by 
qRT-PCR in SARS-CoV-2-infected individuals. 
2.4. 
Exploratory Objectives 
- 
To evaluate the effect of DZIF-10c infusion on viral shedding in nasopharyngeal swabs 
determined by the presence of infectious virions in SARS-CoV-2-infected individuals. 
- 
To evaluate the effect of DZIF-10c infusion on viral shedding in oropharyngeal swabs 
determined by qRT-PCR in SARS-CoV-2-infected individuals. 
- 
To evaluate the effect of DZIF-10c infusion on viral shedding in oropharyngeal swabs 
determined by the presence of infectious virions in SARS-CoV-2-infected individuals. 
- 
To evaluate the frequency of COVID19-related hospitalization and medically-attended 
health care contacts after DZIF-10c infusion in SARS-CoV-2-infected individuals. 
- 
To evaluate the effect of DZIF-10c infusion on symptom resolution in SARS-CoV-2-infected 
individuals symptomatic at baseline. 
- 
To evaluate the effects of DZIF-10c infusion on the viral sequence and the development of 
viral escape mutations that might arise. 
- 
To evaluate SARS-CoV-2-specific immune responses following DZIF-10c infusion. 
- 
To evaluate the effect of DZIF-10c infusion on viral replication in respiratory samples by 
subgenomic mRNA in SARS-CoV-2-infected individuals. 
 

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3. Organizational and Administrative Aspects of the Trial 
3.1. 
Sponsor 
University of Cologne 
Albertus-Magnus-Platz 
50923 Cologne 
Germany 
 
Represented by 
 
 
 
  
 
 
 
3.2. 
Coordinating Investigator 
 
 
 
 
 
 
 
3.3. 
Statistician 
 
 
 
 
 
 
 

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3.4. 
Safety Monitoring Committee 
A Safety Monitoring Committee (SMC) will be established to provide assessments of the 
participants’ safety during the conduct of the clinical trial and to provide recommendations on 
dose escalation. Details are provided in the SMC charter. 
 
The SMC will be composed of three independent individuals with no connection to the 
Sponsor, who are not involved in the conduct of the clinical trial beyond their role in the SMC, 
and who do not have any direct responsibility for the clinical care of the study participants 
outside of the clinical trial. In addition, a Pharmacovigilance designee of Boehringer Ingelheim 
may be assigned as standing member of the SMC without voting right. Principal Investigators 
(PIs), designees of the Sponsor or Boehringer Ingelheim, and/or designees of the Monitor may 
be invited by the SMC for participation in SMC meetings to provide information on the conduct 
of the clinical trial and to answer questions by the SMC.  
 
Meetings of the SMC will be conducted through video conference, by phone, or in-
person as deemed necessary by the SMC. If scheduling problems prevent a timely meeting, 
review and comment may alternatively conducted by E-Mail. One member will be appointed 
chair of the SMC and be responsible for summarizing SMC meetings and informing the 
Coordinating Investigator and Sponsor about meetings and recommendations in writing. The 
SMC chair may select another SMC member as designee to perform these tasks. A quorum 
for SMC meetings will require the participation of at least two SMC members with voting rights. 
 
Ad-hoc SMC meetings will be conducted prior to enrolment into Groups 1B, 1C, 2C, 
and 2D to provide recommendations on proceeding with the dose escalation scheme. 
Additional SMC meetings may be scheduled on an as-needed-basis if deemed necessary by 
the members of the SMC, the Sponsor, or the Principal Investigators. Enrollment into Group 
1D (SARS-CoV-2-negative individuals receiving a single DZIF-10c infusion at a dose of 80 
mg/kg) will additionally require a positive vote by the SMC. 
 
On an interim basis, the SMC will also be asked to review the following data: 
 
- 
Any grade 3 or higher Adverse Events (AEs) that are deemed to be related to DZIF-10c by 
the Investigators. 
- 
These events will also be assessed as potential late-occurring dose-limiting 
toxicities (i.e., after dose-escalation has proceeded and/or been completed) to 
evaluate whether a change to study dosing is warranted. 
- 
In case of grade 3 AEs deemed related to DZIF-10c in two or more participants, 
administration of DZIF-10c will be halted until a SMC review has been completed 
to provide recommendations regarding subsequent study enrolment. 

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- 
Serious Adverse Events (SAEs) that are deemed related to DZIF-10c by the Principal 
Investigator or designee. Such events need to be reported to the SMC within one business 
day of the Sponsor becoming aware of the event. 
- 
No additional administration of DZIF-10c will occur after an SAE deemed related to 
DZIF-10c until an SMC review has been completed to provide recommendations 
regarding subsequent study enrolment. 
- 
In case of life-threatening, fatal, or permanently disabling SAEs deemed related to 
DZIF-10c, no further administration of DZIF-10c will occur until a consensus plan 
has been approved by the SMC, Investigators, the Sponsor, the principal ethics 
committee, and the PEI. 
 
3.5. 
Central Organization Unit 
Administrative trial project management, data management, monitoring, and safety 
management for this trial are delegated to the Clinical Trials Center Cologne. 
Clinical Trials Center Cologne (CTCC, ZKS Köln) 
Gleueler Str. 269 
50935 Cologne 
Germany 
Tel.:  
 
Fax:  
 
E-Mail: 
 
 
3.6. 
Principal Investigators and Trial Sites 
This trial will be conducted as a multicenter trial at up to six sites in Germany. Additional 
qualified trials sites may be recruited, if necessary, for timely recruitment.  
 
3.7. 
Financing 
This trial is funded by grants from the German Center for Infection Research (DZIF) and 
potential additional support by Boehringer Ingelheim. 
DZIF-10c is produced and provided free of charge by Boehringer Ingelheim. 
 

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4. Trial Conduct 
4.1. 
Trial Design 
This trial is the first-in-human phase I/IIa clinical trial of DZIF-10c administered by intravenous 
infusion to SARS-CoV-2-uninfected and SARS-CoV-2-infected individuals. Following a single 
infusion open-label dose-escalation phase, DZIF-10c will be administered in a randomized 
placebo-controlled double-blind manner as a single infusion to SARS-CoV-2-infected 
individuals in an exploratory expansion cohort. 
 
Table 1: 
Tentative Time Plan of the Trial 
First Patient First Visit (FPFV): 
Q4 2020 
Last Patient First Visit (LPFV): 
Q2 2021 
Last Patient Last Visit (LPLV): 
Q3 2021 
End of Trial 
Q3 2021 
Final Study Report: 
Q2 2022 
 
End of the Clinical Trial 
The end of this clinical trial is defined as the last visit of the last trial participant. 
 
 
Figure 2. Trial Design. 
 
 

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This study includes a total of 6 trial groups. 
 
Dose Escalation Phase 
 
The Dose Escalation scheme is detailed in Section 4.1.1. 
 
SARS-CoV-2-uninfected participants will receive an open-label single intravenous 
infusion of DZIF-10c dosed at (n=3-6 per group): 
 
Group 1A: 2.5 mg/kg 
Group 1B: 10 mg/kg 
Group 1C: 40 mg/kg 
Group 1D: 80 mg/kg 
 
 
 
Enrollment in Group 1D 
The first three participants in Group 1D will be enrolled under the dose 
escalation rules described below. Should no DLTs occur and upon a positive 
vote by the SMC, the remaining three participants will be enrolled outside the 
rules of the dose escalation scheme. 
 
SARS-CoV-2-infected participants will receive an open-label single intravenous 
infusion of DZIF-10c dosed at (n=3-6): 
 
Group 2C: 40 mg/kg (or highest tolerated dose) 
 
Randomized Placebo-Controlled Double-Blind Exploratory Expansion Phase 
Group 2D – SARS-CoV-2-infected participants will be randomized (2:1) to receive a 
single intravenous infusion of DZIF-10c at 40 mg/kg or the highest tested tolerated dose 
(MTD) below 40 mg/kg (n=26) or placebo (n=13) 
 
 
 
 
 

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Dose Justification 
Starting Dose: 
 it is not expected that DZIF-10c 
has pharmacological activity in healthy volunteers. DZIF-10c is a human monoclonal antibody 
isolated from a previously SARS-CoV-2-infected individual. A starting dose of 2.5 mg/kg is 
considered acceptable based on i.) the lack of detectable binding to human protein in the 
screen described above, ii.) the considerable existing experience with human monoclonal 
antibodies against viral pathogens (see Target Dose), iii.) the DZIF-10c doses investigated in 
preclinical in vivo efficacy animal models to date (see Investigator’s Brochure), as well as iv.) 
clinical trials of other SARS-CoV-2-specific human neutralizing monoclonal antibodies that 
have progressed into phase III investigation (e.g., REGN-CoV-2, 2.4 g IgG; Ly-COV555, 2.8 g 
IgG; see below). 
 
Target Dose: 
The target antibody concentration for the intravenous administration of DZIF-10c is based on 
modelling calculations suggesting that a 40 mg/kg dose provides adequate coverage for 
SARS-CoV-2 neutralization. Identical or similar doses of human monoclonal antibodies have 
previously been shown to be well-tolerated and effective against other viral pathogens in 
clinical trials, including HIV-1 and Ebola virus22-24. Limited data from small animal experiments 
suggest that protection from SARS-CoV-2-infection is achieved when antibody serum 
concentrations are approximately 1,000-fold higher than antibody IC50s determined in vitro46. 
Assuming a typical half-life of approximately 3 weeks, a single intravenous administration of 
DZIF-10c at a dose of 40 mg/kg may therefore result in protective serum concentrations for 
approximately 3 months after infusion and allow for infrequent dosing approaches in the setting 
of passive immunization. Finally, an antibody concentration of 40 mg/kg is within the range of 
reportedly effective antibody doses from non-peer reviewed interim reports of other SARS-
CoV-2-neutralizing monoclonal antibodies currently in clinical investigation (REGN-COV-2, 2.4 
g IgG; Ly-COV555, 2.8 g IgG)51,52. To determine the safety of a higher antibody doses that 
may be required to provide efficacy against viral variants with mutations conferring reduced 
antibody sensitivity, an additional higher dose of 80 mg/kg will be investigated in healthy 
volunteers (Group 1D). 
 
 
 

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4.1.1. 
Dose Escalation Scheme 
During the dose escalation phase, SARS-CoV-2-uninfected (Groups 1A-D) and SARS-CoV-
2-infected individuals (Group 2C) will receive a single intravenous infusion of DZIF-10c at the 
specified dose on day 0. 
 
Group 1A:  
 
 
2.5 mg/kg  
Group 1B:  
 
 
10 mg/kg 
Group 1C and Group 2C: 
40 mg/kg 
Group 1D: 
 
 
80 mg/kg 
 
Dose-Limiting Toxicities 
A dose-limiting toxicity (DLT) for this trial will be defined as any grade 3 or higher adverse 
event during the dose escalation phase that the investigators determine to be related to DZIF-
10c. 
 
Dose Escalation Rules 
During the dose escalation phase of the study, only a single individual per dose may be 
enrolled per day. 
Initially, three individuals will be enrolled per group during the dose escalation phase. 
During the dose escalation phase, the following rules will apply: 
- 
If no DLT occurs up to the day 7 visit in the 3 enrolled participants within a group, dose 
escalation will proceed and no additional participants will be enrolled into the same group 
(except for Group 1D, see below). 
 
- 
If a DLT occurs in one individual in a group up to the day 7 visit, three additional participants 
will be enrolled into the same group. If no additional DLTs occur up to the day 7 visit in 
these 3 additional participants, the trial will proceed to the next dose group. 
 
- 
If DLTs in a group occur in two or more participants, dosing will be halted, and the prior 
dose level will be declared as maximum tolerated dose (MTD). 
 
Enrollment will start in Group 1A. Decisions on dose escalation will be made by the Safety 
Monitoring Committee (SMC) who will review interim safety data after the day 7 visit of all 
participants within a group has occurred. Enrollment into Group 2C can be initiated after a 

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positive SMC vote once dose escalation criteria for Group 1B have been met. Enrollment into 
the randomized Group 2D can initiated after a positive SMC vote once dose escalation criteria 
for Group 2C have been met. Should a maximum tolerated dose <40 mg/kg be defined during 
the dose escalation phase in healthy volunteers, participants in Group 2C or Group 2D will 
receive DZIF-10c at this maximum tolerated dose. 
 
Enrollment of Additional Participants in Group 1D 
Should no DLTs occur until the day 7 visit in all three initial Group 1D participants and upon a 
positive SMC vote, three additional participants will be enrolled. In this case, dose escalation 
phase criteria (e.g., staggered enrollment, hospitalization) will not apply to the additional 
participants. Should DLTs occur until the day 7 visit in the first three participants of Group 1D, 
standard dose escalation rules will apply. 
4.1.2. 
Discussion of Trial Design 
During the open-label dose escalation phase of the study, a standard “3+3” phase I design will 
be used, with stopping rules based on the occurrence of dose limiting toxicities (DLTs). Dose 
escalation will be initiated in healthy volunteers (i.e., in the absence of the antibody target) to 
provide early indicators on the safety and tolerability of the infusion of DZF-10c. Based on the 
pre-specified safety criteria and upon review by the SMC, dose escalation will be performed 
as defined above.  
 
Enrollment of SARS-CoV-2-infected individuals (i.e., individuals with antigen present) 
will commence after the first two dose escalation steps in healthy volunteers. Following an 
open label lead-in phase in SARS-CoV-2-infected individuals (Group 2C), an exploratory 
expansion cohort of SARS-CoV-2-infected individuals will be recruited (Group 2D). In this 
double-blind group, infected individuals will be randomized 2:1 to receive a single intravenous 
infusion of DZIF-10c or placebo.  
In addition to analyses of safety and tolerability, pharmacokinetic parameters and the 
development of anti-drug antibodies, this trial aims to facilitate an exploratory assessment of 
the antiviral activity of DZIF-10c. This assessment will be primarily based on virological 
endpoints in respiratory tract samples. SARS-CoV-2-infected participants enrolled in this trial 
will be individuals with mild-to-moderate SARS-CoV-2 infection not requiring supplemental 
oxygen at baseline (see Inclusion and Exclusion Criteria). In this cohort, current guidelines do 
not recommend medical intervention with specific antiviral medication. Therefore, sterile 
normal saline (NaCl 0.9%) will be used as placebo and comparator to DZIF-10c infusion in 
Group 2D. 

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4.2. 
Risk-Benefit Assessment 
This is the first-in-human trial of the intravenous administration of the human monoclonal 
antibody DZIF-10c in both SARS-CoV-2-uninfected and SARS-CoV-2-infected individuals. 
Determining the safety and tolerability of DZIF-10c is the primary objective of this trial. 
 
DZIF-10c is a human monoclonal antibody of the IgG1k isotype that was isolated by 
single cell sorting of SARS-CoV-2 spike protein-reactive memory B cells and antibody 
cloning48. It was identified in a blood sample obtained 35 days after diagnosis from an individual 
who had an asymptomatic course of SARS-CoV-2 infection48. Importantly, in this individual, 
the development of B cells encoding for DZIF-10c was not associated with clinically apparent 
adverse events. 
4.2.1. 
Potential Risks and Strategies for Risk Mitigation 
Antibody-dependent enhancement  
Antibody-dependent enhancement (ADE) of disease or infection is a potential concern of all 
antibody-mediated strategies, including vaccination, against infectious pathogens. It is best, 
albeit rarely, documented for severe courses of disease after dengue virus (re)-infection in the 
presence of low neutralizing antibody titers55. However, dengue virus replicates in Fc receptor-
expressing cells (e.g., monocytes and dendritic cells). Thus, Fc-mediated cellular uptake of 
antibody-bound virus may result in increased infection, viral propagation, and enhanced 
disease for dengue virus infection56. Antibody-mediated worsening of clinical symptoms can in 
principle also result from an overstimulation of the immune response, e.g., by immune 
complex-mediated activation of the complement system. However, monoclonal antibodies 
targeting the respiratory viral pathogens RSV and influenza virus have been administered for 
treatment and prevention of disease without signs of increased disease27,57. Importantly, the 
administration of reconvalescent plasma with varying levels of neutralizing and non-
neutralizing antibodies to tens of thousands of individuals has not been reported to be 
associated with an increased severity of disease58,59. Similarly, antibody-dependent 
enhancement of disease was not reported in a phase II clinical trial of a SARS-CoV-2-
neutralizing monoclonal antibody administered to recently infected outpatients50. In addition, 
neither neutralizing nor sub-neutralizing concentrations of DZIF-10c were associated with 
increased infection or replication in CD14-derived human macrophages co-cultured with 
authentic SARS-CoV-2- in vitro.  

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Risk mitigation strategy: Infusion of DZIF-10c to SARS-CoV-2-infected individuals will 
be inititated open-label and staggered by at least 1 day for the first three participants 
(i.e., a maximum of one participant to be enrolled per dose group per day, Group 2C). 
Participants will be closely followed for clinical signs of disease enhancement (e.g., 
respiratory distress, reduced SpO2).  
 
Allergic/Anaphylactic reactions 
Administration of non-human, chimeric, or humanized antibodies can result in severe allergic 
and anaphylactic reactions because the non-human derived components can be recognized 
as foreign by the recipient’s immune system. In contrast, administration of human 
immunoglobulins (e.g., IVIG, hepatitis B immunoglobulin) is a routinely performed and safe 
clinical procedure for the treatment of autoimmune diseases or immune deficiency or to prevent 
viral infections such as hepatitis B. Similarly, monoclonal antibodies of human origin have been 
shown to be generally safe and well tolerated20-25. DZIF-10c is derived from a human antibody 
that naturally developed in response to SARS-CoV-2 infection48 and was recombinantly 
produced in a mammalian cell line without use of animal-derived media components. DZIF-
10c has not been administed to humans prior to this study and thus, no clincal data on the 
tolerability of DZIF-10c is available. 
Risk mitigation strategy: DZIF-10c will be administered slowly over an approximately 
60-minute infusion under supervision. Participants in the dose escalation phase will be 
hospitalized for the infusion for immediate access to emergency therapy. 
Antiinflammatory medication, emergency kits and an intensive-care unit are available 
on-site. Infusion-related reactions will be solicited as Adverse Events of Special Interest 
(AESIs) until the trial visit scheduled for day 7 after study drug administration. 
 
Off-target toxicity 
DZIF-10c specifically targets the spike protein of SARS-CoV-2 that is expressed on the surface 
of the virus and infected cells. 
 
 
 
 
 As DZIF-10c does not bind to human proteins, it is not expected to have 
pharmacological activity in healthy humans. Based on these results and the limited value of 
animal toxicity studies in the evaluation of human monoclonal antibodies, animal in vivo 

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toxicology studies and animal tissue cross-reactivity studies are not considered to provide 
relevant additional information. In the normal human immune system, B cell maturation and 
antibody development are tightly regulated to limit the risk for the development of self-reactivity. 
Indeed, autoreactive B cells are generally selected against and depleted from the memory B 
cell pool60. As DZIF-10c was identified from a human memory B cell in a SARS-CoV-2-
convalescent individual and based on the results of off-target profiling, the risk of off-target-
mediated toxicity of DZIF-10c can be considered as low. 
 
Risk mitigation strategy: Participants will be closely followed for unspecific toxicities. 
 
Viral resistance 
Antibody-mediated selection pressure may result in the development of viral escape mutations 
conferring antibody resistance. To date, it is not known whether the selection of antibody 
escape variants of SARS-CoV-2 within an antibody-treated host may be associated with 
changes in infectivity and/or pathogenicity. 
 
Biosampling 
Over the course of the trial, blood samples will repeatedly be obtained by venipuncture that 
can result in bleeding, infection, or nerve damage. Upper respiratory tract samples will be 
obtained by naso- and oropharyngeal swabs that may cause discomfort, tissue irritation or 
damage, or bleeding. 
 
Risk mitigation strategy: Biosamples will be obtained by trained trial staff. 
 
Visits to Trial Sites during SARS-CoV-2 Pandemic 
Trial participants will be asked for visits to trial sites that are embedded into hospital 
infrastructure.  
Risk mitigation strategy: Routine hygiene measures applicable for SARS-CoV-2 will be 
put in place at all trial sites. 
 
Blunting of Vaccine Response 
Systemic levels of DZIF-10c may blunt the response to a SARS-CoV-2 vaccine, should one 
become available to a participant. Additional or delayed vaccination may be required. 

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Risk mitigation strategy: Trial participants will be advised about the potential need to 
follow-up on anti-SARS-CoV-2 antibody levels following vaccination. 
4.2.2. 
Potential Benefits 
DZIF-10c has not been previously administered to humans and it is not known whether DZIF-
10c infusion results in beneficial clinical effects. 
It is possible that healthy volunteers are protected from SARS-CoV-2-infection or from severe 
disease after DZIF-10c infusion during the period of DZIF-10c exposure. In SARS-CoV-2-
infected individuals, administration of DZIF-10c may reduce the risk of severe disease and 
contribute to accelerated viral clearance. 
By participating in this clinicial trial, volunteers may contribute to the development of a novel 
option for the treatment and prevention of SARS-CoV-2 infection. 
4.2.3. 
Overall Risk-/Benefit-Assessment 
Taking into account the implemented procedures to mitigate risks, the potential risks to 
participants in this first-in-human trial are justified by the significant benefits that may be 
afforded to SARS-CoV-2-infected and healthy trial participants as well as the community-at-
large. 
 
4.3. 
Selection of Trial Population 
This trial is the first-in-human trial of the intravenous infusion of DZIF-10c. DZIF-10c has 
potential use both in healthy individuals (prevention of SARS-CoV-2-infection by passive 
immunization) and SARS-CoV-2-infected individuals (treatment). Adults of both potential target 
groups will be included in this trial. 
 
Participation in the cohort of SARS-CoV-2-infected individuals for this first-in-human 
trial will be restricted to adults aged 18-70 with mild-to-moderate infection not requiring 
supplemental oxygen at baseline (based on the inclusion criterion of the WHO Clinical 
Progression Scale, see Appendix I) as well as probable early infection (based on the duration 
of symptoms and/or absence of antibodies against SARS-CoV-2). In these individuals, current 
guidelines do not recommend the use of approved antiviral drugs. In addition, the exclusion of 
elderly individuals (>70 years) or individuals with significant co-morbidities will result in the 
enrolment of SARS-CoV-2-infected individuals at a relatively low risk of clinical progression 
into this first-in-human study that will focus the on safety and tolerability of DZIF-10c. 

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Gender Distribution 
We expect the gender distribution in this clinical trial to reflect the population-at-large. 
Enrollment of SARS-CoV-2-infected individuals will primarily be driven by local epidemiological 
characteristics, but all efforts will be made to ensure equal trial access to all genders. 
 
4.3.1. 
Inclusion Criteria 
 
Groups 1A-1D 
- 
Age 18-65. 
 
- 
SARS-CoV-2-RNA negative in naso- or oropharyngeal swab obtained within 3 calendar 
days before study drug administration by NAAT (e.g., qRT-PCR). 
 
- 
Non-reactivity of serum antibodies (IgG; and IgA and/or IgM when tested) against SARS-
CoV-2 by serological assay. 
 
Groups 2C-2D 
- 
Age 18-70. 
 
- 
SARS-CoV-2-RNA positive in naso- or oropharyngeal swab obtained within 3 calendar 
days before study drug administration by NAAT (e.g., qRT-PCR). 
 
- 
Onset of COVID-19 symptoms (e.g., sore throat, cough, fever, chills, fatigue, dys- or 
anosmia, dys- or angeusia, headache, muscle pain, gastrointestinal symptoms) within 7 
days prior to study drug administration 
or 
Non-reactivity of serum or plasma antibodies (IgG; and IgA and/or IgM when tested) 
against SARS-CoV-2 by serological assay at screening. 
 
- 
Disease severity 1-4 as defined by the WHO Clinical Progression Scale (WHO, Lancet Inf 
Dis 2020). 
4.3.2. 
Exclusion Criteria 
- 
Known hypersensitivity to any constituent of the investigational medicinal product. 
 
- 
Hepatitis B infection indicated by detectable HBsAg (Hepatitis B surface antigen) in blood. 
 
- 
Detectable antibodies against hepatitis C virus in blood unless active hepatitis C is ruled 
out by negative HCV-RNA. 

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- 
HIV infection indicated by detectable HIV antigen and/or HIV antibodies in blood. 
 
- 
Blood laboratory parameter abnormalities as listed below 
- 
Neutrophil count ≤1,000 cells/µl 
- 
Hemoglobin ≤10 g/dl 
- 
Platelet count ≤100,000 cells/µl 
- 
ALT ≥2.0 x ULN 
- 
AST ≥2.0 x ULN 
- 
Total bilirubin ≥1.5 ULN  
- 
eGFR <60 ml/min/1.73m2 
- 
Pregnancy or lactation. 
 
- 
Any vaccination within 14 days prior to DZIF-10c administration. 
 
- 
Receipt of any SARS-CoV-2 vaccine or SARS-CoV-2 monoclonal antibody in the past. 
 
- 
Diagnosis of bronchial asthma or history of bronchial hyperresponsiveness, COPD, 
pulmonary fibrosis, or other chronic lung diseases. 
 
- 
Any chronic or clinically significant medical condition that in the opinion of investigator 
would jeopardize the safety or rights of the volunteer. 
 
- 
History of systemic corticosteroids, immunosuppressive anti-cancer, or other medications 
considered significant by the trial physician within the last 6 months (a single administration 
of systemic corticosteroids within ≤6 months and ≥4 weeks of enrollment is acceptable). 
 
- 
Participation in another clinical trial of an investigational medicinal product within the past 
12 weeks or expected participation during this study. 
 
- 
Dependency on the principal investigator or study staff; or site personnel directly affiliated 
with this trial. 
 
- 
Legally incapacitated individuals. 
 
- 
Individuals held in an institution by legal or official order. 
 
- 
If engaging in sexual activity that could result in pregnancy, inability or unwilligness to 
comply with the requirements for highly effective contraception (see section 4.3.2.1). 
 
 

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4.3.2.1. 
Requirements for Effective Contraception 
Female participants 
For the purpose of this trial, a woman is considered of childbearing potential following 
menarche and until becoming post-menopausal unless permanently sterile (e.g., by 
hysterectomy, bilateral salpingectomy, or bilateral oophorectomy). A postmenopausal state is 
defined as no menses for 12 months without an alternative medical cause.  
Women of childbearing potential are eligible to participate if they are not pregnant or 
breastfeeding and agree to use a highly effective contraceptive method during the trial period 
and for at least 3 months after the administration of the study drug. 
Highly effective contraceptive methods are methods with a failure rate of <1% per year when 
used consistently and correctly. Acceptable highly effective contraceptive methods for the 
purpose of this trial are: 
 
- 
Combined (estrogen- and progestogen-containing) hormonal contraception methods 
associated with inhibition of ovulation (oral, intravaginal, or transdermal application) 
- 
Progestogen-only hormonal contraception that prevent ovulation (oral, injectable, or 
implantable application) 
o Note that progestogen-only hormonal contraception where inihibition is 
ovulation is not the primary mode of action is not considered as highly effective 
- 
Intrauterine devices (IUDs) 
- 
Intrauterine hormone-releasing systems (IUSs) 
- 
Bilateral tubal occlusion 
- 
Vasectomized partner (if partner is sole sexual partner and has received medical 
assessment of surgical success) 
- 
Abstinence from heterosexual intercourse if this is the preferred and usual lifestyle of 
the subject 
 
Male participants 
Male participants who engage in heterosexual intercourse with women of childbearing potential 
must be willing to use barrier contraception (i.e., condom) from the start of study drug 
administration until 3 months after infusion, and ensure their partner is using an additional 
highly effective method of contraception (listed above) until at least 3 months after study drug 
administration. Men with pregnant partners should use condoms during the pregnancy of the 
partner.  
 

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5. Methods and Procedures 
5.1. 
Trial Visit Overview 
A summary overview of study visits and corresponding procedures is provided in the Visit 
Schedule (Appendix II). 
 
5.2. 
Assessments and Sample Collection 
5.2.1. 
Safety Assessments 
Adverse Events 
Adverse Events will be assessed by open questions or upon spontaneous reporting by the trial 
participants. All adverse events will be followed to resolution or until completion for the trial of 
the subject concerned. Serious Adverse Events (SAEs) will be collected during the entire study 
period for each individual trial subject until completion of the trial of the subject concerned (see 
also section 9.3). In the interest of participants’ safety, follow-up for up to 30 days after the 
individual participants’s study termination is required for SAEs that are not sufficiently resolved 
at the participant’s final trial visit. The CTCAE (Common Terminology Criteria for Adverse 
Events) grading table (v5.0) will be used by trial investigators to report and grade Adverse 
Events. The development of Adverse Events will be followed until the day 90 visit (i.e., until the 
end of the trial).  
 
Adverse Events of Special Interest (AESI) 
Infusion-related reactions presenting as hypersensitivity/allergic reaction, anaphylaxis, or 
cytokine release sydrome are designated as Adverse Events of Special Interest (AESIs). 
Infusion of biological products including monoclonal antibodies may be associated with the 
development of infusion-related reactions that can occur during and/or within hours of the 
infusion. Symptoms of infusion-related reactions may be related to immediate hypersensivity 
(allergic reaction, anaphylaxis) or cytokine release syndrome. Symptoms of cytokine release 
syndrome may include, but are not limited to, fever, tachypnea, headache, tachycardia, 
hypotension, all types of rashes including flushing, and/or hypoxia. 
The presence or absence of infusion-related reactions presenting as hypersensitivity/allergic 
reaction, anaphylaxis, or cytokine release sydrome will be solicited and documented until the 
study visit seven days after study drug administration.  

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Adverse Events of Special Interest should be communicated to the Sponsor in an expedited 
manner (see section 9.3.1 for requirements). 
 
Dose-Limiting Toxicities 
During the dose-escalation phase of the trial (Groups 1A-1D, Group 2C), grade 3 or higher 
Adverse Events that are deemed to be related to DZIF-10c by the Investigator are considered 
as Dose-Limiting Toxicities (DLTs). DLTs should be reported to the Sponsor in an expedited 
manner (see section 9.3.1 for requirements). 
 
Routine Laboratory Parameters 
Routine laboratory parameters from blood and urine samples will be assessed as indicated in 
the Visit Schedule (see Appendix II). Laboratory parameters will include a complete blood 
count with white blood cell differential, clinical chemistry (Na, K, Cl, Ca, AST, ALT, AP, total 
bilirubin, creatinine including eGFR, CRP, lipase), coagulation parameters (INR, PTT), 
urinalysis, and pregnancy testing in women of childbearing potential.  
In female participants of childbearing age, the negative result of a serum beta-HCG test or a 
negative urine dipstick pregnancy test from a sample obtained on the day of administration 
must be available prior to infusion. 
In the event of abnormal laboratory results, participants may be asked to have additional 
samples collected at the discretion of the investigator or designee. 
Abnormal laboratory parameters determined to be clinically significant by the investigator or 
designee will be graded according to the CTCAE (Common Terminology Criteria for Adverse 
Events) grading table (v5.0) and reported as Adverse Events. 
 
Physical Examination and Vital Signs 
A general physical examination including weight, height, and examination of skin, respiratory, 
cardiovascular, nervous, and gastrointestinal systems will be performed at screening. 
Symptom-directed physical examinations will be performed at later visits as indicated and 
include vital signs and any further examination indicated by history or observation. 
Vital signs to be determined are systolic and diastolic blood pressure, heart rate, respiratory 
rate, body temperature, and peripheral oxygen saturation. 
 

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ECG 
A 12-lead ECG will be performed at screening and assessed by the Investigators. 
5.2.2. 
Pharmacokinetic Assessments 
Non-compartmental analysis methods will be used to calculate pharmacokinetic parameters, 
and descriptive results will be presented for each dose group. Parameters to be assessed will 
include  
• 
AUC0-672 (the area under the concentration-time curve of DZIF-10c in serum over the 
time interval from 0 to 672 hours (Day 28)) 
• 
AUC0-504 (the area under the concentration-time curve of DZIF-10c in serum over the 
time interval from 0 to 504 hours) in healthy volunteers 
• 
AUC0-inf (the area under the concentration-time curve of DZIF-10c in serum over the 
time interval from 0 extrapolated to infinity) 
• 
Cmax (maximum measured concentration of DZIF-10c in serum) 
• 
tmax (time from dosing to Cmax of DZIF-10c in serum) 
• 
t1/2 (the terminal elimination half-life of DZIF-10c in serum) 
• 
CL (total clearance of DZIF-10c in serum following i.v. administration) 
• 
Vss (volume of distribution at steady state following i.v. administration) 
• 
Vz (volume of distribution during the terminal phase following i.v. administration) 
Further PK parameters may be calculated, if considered reasonable.  
Serum levels of DZIF-10c will be determined using a validated immunoassay
 
. 
Exploratory assays for PK analyses under development include serum/plasma neutralization 
assays against pseudoviruses and authentic SARS-CoV-2. These assays will be performed at 
the Institutes of Virology at the University Hospital Cologne and/or at the University of Marburg. 
5.2.3. 
Assessment of Viral Shedding 
SARS-CoV-2 RNA assessment 
SARS-CoV-2 RNA levels will be determined from frozen (-80°C) transport medium using a 
clinically validated quantitative reverse-transcripase real-time PCR assay (qRT-PCR) assay. 
Results will be provided as Ct (Cycle threshold) values as well as quantitatively (copies/ml) 
based on a reference standard. These assays will be performed at the Institute of Virology at 
the University Hospital Cologne. 

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At the screening visit, a single naso- and/or oropharyngeal swab is sufficient to document the 
absence or presence of SARS-CoV-2 infection by qRT-PCR. This assay is performed at the 
trial site’s local laboratory. In any case, in SARS-CoV-2-infected individuals, both 
nasopharyngeal and oropharyngeal swabs must be obtained for the central laboratory prior to 
study drug administration. 
 
To provide participants with early results about the presence or absence of SARS-CoV-2 in 
swab samples prior to the determination of results at the central laboratory, an additional 
oropharyngeal swab may be obtained and sent for NAAT (e.g., qRT-PCR) at the local routine 
laboratory. This optional additional swab is to be obtained after the oropharyngeal swab for 
central laboratory evaluation. 
 
Assessment of the presence of infectious SARS-CoV-2 
Viral transport medium will be incubated on VeroE6 cells to determine the presence of 
infectious virions. Cell culture supernatants will be assessed for virus production by qRT-PCR 
and/or cells will be visually inspected for the development of cytopathic effects. These assays 
will be performed at the Institutes of Virology at the University Hospital Cologne and/or the 
University of Marburg. 
 
Assessment of viral replication by subgenomic RNA 
Levels of subgenomic mRNA that is transcribed in infected cells but not packaged into virions 
will be determined from RNA extracted from swab samples by qRT-PCR. These assays will 
be performed at the Institutes of Virology at the University Hospital Cologne and/or the 
University of Marburg. 
5.2.4. 
Assessment of Anti-Drug Antibodies 
Serum samples will be analyzed for reactivity against DZIF-10c by a validated immunoassay. 
 
5.2.5. 
Assessment of the Development of Viral Mutations and Antibody Resistance 
Viral RNA will be extracted from transport medium and cDNA will be generated by reverse 
transcription. Spike sequences will be amplified from cDNA using polymerase chain reaction 

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(PCR) and purified PCR products will be sequenced by Sanger sequencing or next-generation 
sequencing. Sequences from samples obtained prior to infusion will be compared to 
sequences obtained after infusion.  
Selected recurrent or individual mutations observed in the SARS-CoV-2 S gene will be 
introduced into plasmids encoding the SARS-CoV-2 S gene by site-directed mutagenesis. 
Modified plasmids will be used to generate replication-deficient SARS-CoV-2 pseudoviruses 
and the DZIF-10c sensitivity of unmodified and modified variants will be compared to evaluate 
the effect of individual spike mutations on antibody sensitivity. 
These assays will be performed at the Institutes of Virology at the University Hospital Cologne 
and/or the University of Marburg. 
5.2.6. 
Assessment of COVID-19-related Hospitalizations and Medically-Attended 
Health Care Contacts 
Any hospitalization and medically-attended health care contact (i.e., health care contacts that 
were not routine/scheduled visits; including, but not limited to, emergency room visits, 
unscheduled visits to primary care physicians) reported by participants during the trial duration 
will be assessed by the investigators based on the available medical information on its 
relatedness to COVID-19 and conditions associated with SARS-CoV-2-infection.  
5.2.7. 
Assessment of Time to Symptom Resolution 
Participants will be asked to self-record selected SARS-CoV-2 symptoms (cough, 
feverishness, body ache, headache, sore throat, shortness of breath, changes in/loss of taste 
of taste and smell) from the day of study drug administration through the day 28 visit and grade 
them as absent, mild, moderate, or severe using a participant diary (Groups 2C and 2D only). 
5.2.8. 
Assessment of Immunological Parameters 
SARS-CoV-2-reactive T cell responses will be evaluated in T cells purified from peripheral 
blood mononuclear cells by multiparametric cytokine flow cytometry and the expression of 
immune activation and exhaustion markers. These assays will be performed at the Institute of 
Virology at the University Hospital Cologne and/or collaborating Institutes. 
5.2.9. 
Sample Collection, Storage, and Shipment 
Blood samples will be obtained by venipuncture. 

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Nasopharyngeal swabs will be obtained by inserting a swab in one nostril along the nasal 
septum to the nasopharynx until resistance is felt, reaching a depth that is proximately the 
length from the outer nostril opening to the ear. Once resistance is felt, the swab will be left in 
place for a few seconds to allow for absorption of secretions and is slowly removed while 
rotating. 
Oropharyngeal swabs will be obtained by swabbing the posterior pharynx and tonsillar areas. 
Care should be taken to avoid accidental swabbing of the gums, tongue, or teeth. 
All biospecimens will be handled according to Standard Operating Procedures (SOPs) defined 
in a Lab Manual that will be provided to all trial sites. Blood (serum, plasma, PBMCs) and 
respiratory swab samples will be processed at the trial site, aliquoted as needed, and stored 
as indicated in the lab manual. Long-term storage of samples will be located at the Institute of 
Virology at the University Hospital Cologne. 
 
5.3. 
Recruitment 
SARS-CoV-2-uninfected participants will be recruited through advertisements and the CTCC 
volunteer database. SARS-CoV-2-infected individuals will additionally be recruited by referrals 
of primary care physicians or following a patient contact by the diagnosing health care 
institution or health care authorities to determine potential interest in trial participation. 
 
5.4. 
Screening Procedures 
Pre-Screening 
Healthy volunteers and SARS-CoV-2-infected individuals may undergo a pre-screening 
procedure conducted by phone or video call to inform them about the aims and nature of the 
trial, potential risks, and the trial schedule. In addition, potential participants will be provided 
with the opportunity to discuss all questions and concerns they may have about the trial. 
Moreover, study recruiters will preliminarily assess study eligibility based on the previous 
medical history as well as the trial inclusion and exclusion criteria.  
 
Screening Visit 
At the screening visit, the Principal Investigator or subinvestigator will explain and discuss the 
aims and nature of the trial, potential risks, and the trial schedule with potential participants 
who will be provided the opportunity to address all questions and concerns they may have with 

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study staff, relatives, and friends. Prior to the initiation of any study-related procedures, written 
informed consent will obtained from each participant. 
If the potential participant provides informed consent to participate in this trial, study staff will 
- 
Obtain a complete medical history including the use of concomitant medication (including 
medication within the last 4 weeks prior to screening) 
- 
Perform a general physical exam, including height, weight, vital signs (heart rate, blood 
pressure, body temperature, respiratory rate, and pulse oximetry), and examination of the 
skin and respiratory, cardiovascular, abdominal, and neurological systems 
- 
Provide pregnancy counseling 
- 
Determine the clinical score based on the WHO Clinical Progression Scale (Groups 2C 
and 2D only) 
- 
Collect blood, urine, and swab samples for all tests indicated in the Visit Schedule 
(Appendix II) 
- 
At the screening visit, a single nasopharyngeal and/or oropharyngeal swab may be 
obtained to document absence or presence of SARS-CoV-2 infection. This swab is to 
be analyzed at the trial site’s routine laboratory. An available SARS-CoV-2-RNA NAAT 
result documented in writing from a sample obtained within three days prior to infusion 
is considered as an acceptable alternative. In all cases, nasopharyngeal and 
oropharyngeal swabs must be obtained at baseline prior to study drug administration 
in SARS-CoV-2-infected individuals. 
 
Screening and Infusion Visit Procedures may occur on the same day during the expansion 
phase of the trial (Group 2D). 
 
Screening Failures 
Participants who have provided informed consent to participate in the clinical trial but do not 
receive any study drug administration are defined as Screening Failures. Information on 
demography, details on the cause for the screen failure and inclusion/exclusion criteria, as well 
as any Adverse Events should be recorded to facilitate transparent reporting. Individuals with 
a Screening Failure may not be rescreened unless for Screening Failures due to scheduling 
issues in healthy volunteers (Groups 1A-1D). In case of Screening Failures due to 
abnormalities in blood laboratory parameters (hematology and/or clinical chemistry), the 
deviating parameter may be retested once during the Screening window. 
 

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• 
Immediate observation by trial staff 
during and until at least 15 min after 
infusion; nursing staff on the ward at all 
times; dedicated physician available 
(24/7 availability on premises or ward) 
 
• 
Immediate observation by trial staff for 
at least 10 min after the start of the 
infusion; continuous presence by trial 
staff on the ward during the treatment 
and observation period (at least 1 hour 
post end of infusion); physician on the 
ward during treatment and available on 
premises during observation period  
 
 
• 
Immediate access to emergency medication (e.g., antihistamines, glucocorticoids, 
epinephrine, bronchodilators) and emergency ventilation equipment 
 
 
• 
Resuscitation ICU team availability at all times   
 
 
• 
Intensive monitoring with continuous 
ECG, automated blood pressure 
assessments (at least every 30 
minutes), and pulse oximetry during and 
for at least 4 hours after the end of the 
infusion. Continuous ECG monitoring 
and pulse oximetry will be continued for 
at least 12 hours after the end of the 
infusion and until at least 6 am. 
Continuous monitoring may be 
intermittently interrupted for mobilization 
on the ward. 
 
 
• 
ECG, blood pressure cuffs, pulse 
oximetry readily available on demand. 
 
• 
Assessment of vital signs by trial staff 
15 min (+/-5 min) after infusion start, at 
the end of the infusion, and 1 h (+/- 10 
min) and 4 h (+/- 15 min) after the end 
of the infusion 
 
 
• 
Assessment of vital signs by trial staff 
15 min (+/-5 min) after infusion start, at 
the end of the infusion, and 1 h (+/- 10 
min) and 2 h (+/- 10 min) after the end 
of the infusion 
 
 
• 
Discharge assessment by trial physician 
after day 1 visit procedures 
 
 
• 
Assessment of discharge qualification 
by trial physician at the end of the 
observation period (at least 2 h after the 
end of the infusion) 
 
 * If no DLT develops in the first three participants enrolled in Group 1D and upon a positive vote by the SMC, the    
  remaining participants may be observed as defined for the Expansion Cohort (Group 2D).       
 
Should infusion-related adverse events (e.g., hypersensitivity, anaphylaxis, or cytokine release 
syndrome) occur, it is typically expected that such events develop within the first hour of the 
antibody administration as a consequence of antibody exposure and/or high serum antibody 
concentrations.  

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To enable intensive monitoring in the lead-in phase of the trial, participants in the dose 
escalation phase (Groups 1A-1D and Group 2C) will be admitted to an Intermediate Care 
Unit or ward with equivalent monitoring and observational capacity (e.g., phase I unit, ICU). 
Participants will be intensively monitored by continuous ECG, automated blood pressure cuffs, 
and pulse oximetry during the infusion and for at least 4 hours after the end of the infusion, 
followed by at least ECG monitoring and pulse oximetry for at least 12 hours after the end and 
overnight (until at least 6 am). Prior to discharge, participants will be assessed by a study 
physician. 
 
Participants in the expansion cohort Group 2D will be clinically observed for at least 
two hours after the end of the trial drug administration and may be discharged only after a final 
assessment by a trial physician. If no DLT develops in the first three participants enrolled in 
Group 1D and upon a positive SMC vote, this can also be applied to the remaining three 
participants in Group 1D. 
 
The presence or absence of infusion-related reactions will be assessed and documented for 
all participants 1 h after the end of the infusion. 
 
Samples for PK analysis will be obtained prior to infusion, at the end of the infusion, 1 h (+/- 
10 min) after the end of the infusion, and (hospitalized participants in Groups 1A-1D and 
Group 2C) 4 h (+/- 15 min) after the end of the infusion. 
  
5.6. 
Follow-up Visits 
Participants will be followed for a total of 90 days (+/- 7 days) after the infusion. 
 
At these follow-up visits, trial staff will 
- 
Review the interim medical history including concomitant medication 
- 
Review safety laboratory results 
- 
Perform symptom-directed physical exams 
- 
Perform procedures and obtain samples as outlined in the Visit Schedule (Appendix II) 
 
For SARS-CoV-2-infected indivduals, trial visits may be conducted at home during the period 
of quarantine. Trial visits on days 5 and days 10 are considered optional for SARS-CoV-2-
infected individuals in quarantine. 
 
Should trial participants become hospitalized during the follow-up phase, the visit schedule 
should be followed as possible. 

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5.7. 
Withdrawal of Trial Participants 
Participants may be withdrawn from the trial for any of the following reasons: 
- 
Any participant may withdraw from the trial at any time and for any reason if he or she 
wishes to do so 
- 
At the discretion of an investigator or designee following an Adverse Event 
- 
At the discretion of an investigator or designee if the participant is judged to be at risk of 
failing to comply with the study protocol which may result in harm or interfere with the 
validity of the study results 
- 
At the discretion of the primary care provider if he or she thinks that further participations 
is no longer in the best interest of the participant 
5.7.1. 
Follow-Up after Withdrawal 
In case of an early termination of a trial participant, the date and reason for early termination 
should be collected and reported to the Principal Investigator who will provide this information 
to the Sponsor and to the SMC. At the time of withdrawal and if the participant agrees, all 
procedures specified in the Final Study Visit according to the corresponding Visit Schedule 
(Appendix II) will be performed. 
 
Any Adverse Event resulting in withdrawal of a participant will be followed up until 
resolution or until the adverse event is judged by the principal investigator or designee to have 
stabilized where possible. 
 
Should a study participant become pregnant during the conduct of the clinical trial, 
separate informed consent for follow-up until delivery and for assessment of the newborn’s 
health status or a report by the responsible pediatrician will be sought. 
 
Participants who are withdrawn from the trial after DZIF-10c administration will not be 
replaced, except for participants during the dose-escalation phase of the trial that are not 
followed until at least the day 7 visit after the infusion for reasons not related to safety events. 
 
5.8. 
Closure of Trial Sites/Premature Termination of the Clinical Trial 
5.8.1. 
Closure of Trial Sites 
At any time, the study can be terminated at an individual trial site if: 

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• 
The trial site cannot comply with the requirements of the protocol. 
• 
The trial site cannot comply with GCP standards. 
• 
The trial sites first patient is not recruited within 6 weeks after initiation of the trial site. 
 
Should the study be prematurely terminated, all study materials (IMPs, etc.) must be returned 
to the Sponsor. After consultation with the Sponsor, IMP may be also destroyed at the site 
according to the local procedures. 
5.8.2. 
Premature Termination of the Clinical Trial 
The sponsor has the right to terminate the trial prematurely if there are any relevant medical 
or ethical concerns, or if completing the trial is no longer practicable. If such action is taken, 
the reasons for terminating the trial must be documented in detail. All trial subjects still under 
treatment at the time of termination shall undergo a final examination which must be 
documented.  
Premature termination of the trial will be considered if: 
- 
The risk-benefit balance for the trial subject changes markedly 
- 
It is no longer ethical to continue treatment with the IMP 
- 
The sponsor considers that the trial must be discontinued for safety reasons (e.g., on 
the advice of the SMC) 
- 
It is no longer practicable to complete the trial 
 
A decision on premature termination by the Sponsor will be made in consultation with the 
Principal Coordinating Investigator, the trial statistician, and the SMC. 
 
5.9. 
Treatment 
5.9.1. 
Administration 
DZIF-10c or placebo will be administered as a single intravenous infusion using a peripherally 
inserted catheter, preferably into an upper extremity vein, using a 0.2 µm in-line filter and 
polyurethane-based infusion system. In individuals receiving a DZIF-10c dose ≤5 g, a volume 
of 100 ml will be administered within 60 min (+/- 10 min). In individuals receiving a higher dose, 
the infusion volume will be increased as required to administer the calculated dose of DZIF-

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10c without further dilution; in these cases, the duration of the infusion will be extended 
accordingly to maintain a flow rate of 1.67 ml/min. Polypropylene-coated infusion bags 
containing the appropriate quantitify of diluted or undiluted DZIF-10c or placebo will be 
provided by the local study pharmacy after preparation according to the handling instructions. 
At the end of the infusion, the infusion system will be flushed using at least 25 ml of sterile 
normal saline at the infusion flow rate. The dose of DZIF-10c or the amount of placebo will be 
body weight-adjusted.  
5.9.2. 
Description of the Investigational Medicinal Product and Placebo 
DZIF-10c is a human monoclonal antibody of the IgG1 kappa isotype (see section 1.4). 
 
 
 
 
 
 
Sterile normal saline (NaCl 0.9%) procured from a commercial source and approved for clinical 
application will be used as placebo. 
 
5.9.2.1. 
Manufacture of the Investigational Medicinal Product 
 
 
 
 
 
 
 
 
 
 
5.9.2.2. 
Labelling of Investigational Medicinal Product 
DZIF-10c stock vials and vials with solvent for dilution (diluent) will be labelled by Boehringer 
Ingelheim. For potential shelf-life extensions after shipment of DZIF-10c and diluent to the trial 
sites, labels for re-labelling at the trial sites will be provided by Boehringer Ingelheim. 

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Bags of DZIF-10c or normal sterile saline prepared for infusion will be labelled by the 
local pharmacies according to national requirements. 
 
5.9.2.3. 
Shipment and Storage of Investigational Medicinal Product 
DZIF-10c stock vials and diluent will be transported to the trial sites in temperature-controlled 
conditions using a temperature logger following a qualified order by the sponsor. Study 
pharmacies will acknowledge receipt of DZIF-10c and diluent, and document integrity of the 
shipment and the logged temperature in writing to be stored in the Pharmacy Trial File. DZIF-
10c stock vials and diluent will be stored at the local pharmacies at the recommended storage 
temperature of 5±3°C. In case of temperature excursions during shipment or storage, the 
product shall not be administered, and the sponsor is to be informed about the temperature 
deviation without undue delay.   
5.9.3. 
Dispensing and Return of Investigational Medicinal Product 
During the open-label dose escalation phase, DZIF-10c for administration will be ordered 
based on the individual participant’s body weight using local standard procedures.  
 
DZIF-10c or placebo will be prepared for infusion by the unblinded local study 
pharmacist. For participants assigned to receive DZIF-10c, the appropriate volume of DZIF-
10c stock solution based on the individual participant’s body weight will be diluted in diluent to 
or provided undiluted, as appropriate. For participants assigned to receive placebo, an infusion 
bag containing normal sterile saline at the nominal volume that would be provided for weight-
adjusted DZIF-10c will be prepared. 
 
DZIF-10c or placebo will be provided to the blinded study team by the local study 
pharmacy in infusion bags of identical visual appearance. 
 
Following completion of the infusion, the used infusion bags will be discarded as per 
local standard procedures. 
Product Accountability and Product Dispensions Forms will be maintained by the local study 
pharmacy and stored in the Pharmacy Trial File. Following completion or termination of the 
clinical trial, unused material of DZIF-10c will be destroyed as per local guidelines after 
consultation with the Sponsor. Destruction of study material will be documented in writing. 
5.9.4. 
Assignment of Trial Participants to Treatment Groups 
In the expansion cohort (Group 2D) participants are randomized 2:1 (DZIF-10c:placebo) into 
the study groups without stratification. Randomization will be implemented by a 24/7-Internet 

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service (ALEA 17.1, FormsVision BV, Abcoude, NL) and prepared centrally by the Institute of 
Medical Statistics and Computational Biology (IMSB) at the University of Cologne. 
5.9.5. 
Selection of Dosage of DZIF-10c 
Starting, interim, and target doses for DZIF-10c are based on previous experiences of safe 
and well-tolerated doses for the intravenous infusion of human virus-neutralizing monoclonal 
antibodies, expected pharmacokinetics based on previous clinical experience with human 
antibodies and pre-clinical data on DZIF-10c, and based on expected exposure required for in 
vivo efficacy. 
5.9.6. 
Blinding 
During the open-label dose-escalation phase of this clinical trial (Groups 1A-1D and 2C), study 
participants as well as the study team will be aware of group and dose assignments. 
 
During the expansion cohort of SARS-CoV-2-infected individuals (Group 2D), 
participants and study investigators will be blinded to the treatment assignment (DZIF-10c or 
placebo). Infusions will be prepared by the unblinded local pharmacist who will provide the 
infusions bags in a blinded manner (i.e., in a way that does not reveal the content of the 
infusion). Study pharmacists will be informed about the participants’ group assignments 
through the randomization software. Blinding for participants will be maintained until the end 
of the trial, while the sponsor may be unblinded on the visit scheduled for day 7 after the final 
study drug administration of the trial. 
 
5.9.6.1. Unblinding 
Emergency unblinding of the treatment assignment for a patient may be necessary due to a 
medical emergency, a serious adverse event (SAE) that is unexpected and for which a causal 
relationship to IMP cannot be ruled out, or any other significant medical event (e.g., 
pregnancy).  
If unblinding is required for a medical emergency:  
- 
Only the investigator will make the decision to unblind the treatment assignment.  
- 
Only the affected patient will be unblinded.  
- 
An emergency envelope will provide the treatment assignment to the investigator.  
The investigator will notify the sponsor and/or designee immediately that the patient has 
been unblinded. 
 

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Emergency unblinding will be done by unsealing unblinding envelopes. The envelopes will be 
prepared centrally by IMSB and sealed by the study pharmacists. Study pharmacists receive 
a request for a specific patient ID and randomise the patient using his or her patient ID via 
ALEA 17.1. The study pharmacists then write the patient ID on a prepared letter that contains 
the randomized treatment for this patient and seal the letter so that the patient ID can be seen 
in the window of the envelope. 
Data will be unblinded after the last participant has completed the day 7 visit after infusion for 
a first data analysis of the expansion cohort (Group 2D). Unblinding is done by the IMSB. 
Results are not communicated to participants during the trial and are used to inform the further 
development of DZIF-10c. 
5.9.7. 
Previous and Concomitant Medication 
Following trial drug infusion, the standard of care may be provided as required by the medical 
condition and deemed appropriate by health care providers.  
5.9.8. 
Rescue Therapy for Emergencies 
All trial sites are embedded into a maximum-care hospital facility capable of providing 
immediate emergency therapy including specialized medical intensive care. 
 
No specific rescue therapy for DZIF-10c is available. In case of an acute infusion 
reaction, the infusion will be interrupted and not be re-initiated. For infusion reactions requiring 
medical 
intervention, 
rescue 
medication 
including, 
but 
not 
limited 
to, 
acetaminophen/paracetamol, antihistamines, glucocorticoids, and IV fluids must be available 
on-site. 
5.9.9. 
Continuation of Treatment after the End of the Clinical Trial 
Study participants will receive no additional infusions of DZIF-10c beyond the planned 
administration as per group assignment. 
 
 

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6. Data Quality Assurance 
6.1. 
Monitoring and Audits 
6.1.1. 
Monitoring 
Regularly scheduled monitoring will be performed by the Clinical Trials Center Cologne 
(CTCC) Monitoring team at all trial sites. This monitoring process aims to ensure the study 
participants’ safety, that data is collected accurately and completely, that the clinical trial is 
conducted according to the trial protocol, and that all principles of GCP and applicable 
guidance are followed.  
A monitoring plan will define the specific extent of the monitoring procedures for all sites. All 
Principal Investigators will agree to regularly performed monitoring and provide appropriate 
support to the delegate of the CTCC Monitoring team to fully conduct the monitoring 
procedures and ensure access to all relevant trial-related documentation including source 
documents. Monitoring procedures will additionally include drug accountability checks at the 
local study pharmacies to ensure accurate documentation and handling of study drug, as well 
as monitoring of local study research laboratories to ensure proper sample handling and 
storage. 
Each monitoring visit will be followed by a written visit report summarizing the visit and any 
potential findings. 
6.1.2. 
Audits / Inspections 
For purposes of quality assurance, the sponsor or a delegate assigned by the sponsor will 
have the right to audit trial sites and other institutions involved in this clinical trial. The 
objectives of such audits include the ensurance of trial participants’ safety, and the verification 
of data accuracy, validity, and completeness. To perform these tasks, auditors will receive 
access to all relevant trial documentation including source documentation, drug accountability 
documentation, and any trial-related correspondence. 
Inspections may be performed by competent authorities as indicated by applicable law and 
guidelines. 
The sponsor and all trial sites will commit to support auditors and inspectors of competent 
authorities at all times, and to provide all necessary original documentation. 
 

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6.2. 
Documentation 
Principal Investigators will oversee and coordinate data collection, entry, and protection. Trial-
specific data will be collected by the clinical trial staff using designated source documents. 
Standard GCP practices will be followed to ensure accurate, reliable and consistent data 
collection. Any correction to source documentation needs to ensure a valid correction trail, 
including leaving original entries legible and signed or initialed dated corrections.  
 
All trial data must be verifiable to the source documentation. All source documents will 
be kept in a locked facility at the clinical site. Source documents include but are not limited to  
- 
Informed Consent Forms 
- 
Reported laboratory results 
- 
Lists of adverse events 
- 
Lists of concomitant medication 
- 
Documentations of existing conditions. 
Medical records will be archived by the Medical Record Department of the hospital. 
All data relevant to the trial are documented by the Principal Investigators (PI) or designees in 
corresponding electronic case report forms (eCRFs). All eCRFs and laboratory reports will be 
reviewed by the clinical team to ensure that they are accurate and complete. 
The Principal Investigators may authorize trial staff members to sign the eCRFs to confirm 
accuracy of the data. At the completion of the follow-up visits, final sign-off must be performed 
by the Principal Investigators. 
6.2.1. 
Data Management 
The IT infrastructure and dedicated staff will be provided by the Clinical Trials Center Cologne 
(CTCC, ZKS Köln). A trial-specific database will be developed and validated prior to data entry 
based on standard operating procedures established at the CTCC. The data management 
system is based on commercial, validated trial software. 
All changes to data stored within the trial database will be documented in an audit trail. The 
trial software has a user and role concept that can be adjusted on a trial-specific basis. Access 
to the trial database is restricted, and the database is embedded into an IT infrastructure with 
a dedicated safety concept including a firewall and backup systems. Data within the trial 
database are backed up daily.  
Data will be entered online at the local trial sites via the internet. During data entry, automated 
plausibility checks will be performed, thereby detecting many discrepancies immediately. 
CTCC staff will conduct additional checks for data completeness and plausibility and clarify 
any questions with the local trial staff using an electronic query system of the trial software. 

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These electronic queries have to be answered by the trial site without unreasonable delay. 
Further details will be specified in the data management plan.  
eCRF Completion Requirements will be provided to the trial sites for detailed descriptions of 
the respective procedures.  
After completion or termination of the clinical trial and data cleaning, the database will be 
locked and the data exported for statistical analysis. 
6.2.2. Archiving 
All essential trial documents including investigator and sponsor parts of the TMF will be 
archived for 15 years according to ICH-GCP (Chapter 8).  
The trial master file, the eCRFs, the code envelopes and other material supplied for the 
performance will be archived according to applicable regulations and laws. 
 
 

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7. Ethical and Regulatory Aspects 
7.1. 
Ethics Committee 
A favorable opinion by the competent ethics committee will be obtained before initiating any 
trial procedures. 
7.2. 
Ethical and Legal considerations  
This trial will be conducted in agreement with the principles of the Declaration of Helsinki as 
well as the Good Clinical Practice guidelines by the International Council for Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH-GCP), and 
all applicable law.  
7.3. 
Registration and Notification of Authorities 
This clinical trial has been registered at the EU Clinical Trials Register (EudraCT: 2020-
003503-34) and ClinicalTrials.gov (NCT04631666). 
Prior to study initiation, approval will be obtained from the federal competent authority (Paul-
Ehrlich-Institute), and state and local authorities will be notified as per applicable regulations. 
7.4. 
Obtaining Informed Consent from Trial Participants 
Prior to the initiation of any clinical trial-related procedures, potential trial participants will be 
provided with a copy of the most recent informed consent form approved by the local ethics 
committee to read. In addition, the Principal Investigator or a Subinvestigator will discuss the 
specifics of the clinical trial with the potential participants verbally. This discussion will include 
but not be limited to the purpose for conducting the clinical trial, the procedures to be 
conducted, the time commitment required by the participant, the drug and placebo to be 
administered, potential benefits and risks of participation, alternative options for treatment, 
patient confidentiality, and potential access to data by representatives of the sponsor (e.g., 
monitors or auditors) and competent authorities. As part of this discussion, potential 
participants will be informed that participation in the clinical trial is completely voluntary, and 
that withdrawal of consent is possible at any time without the need to provide reasons and will 
not jeopardize the participant’s future medical treatment. The informed consent discussion will 
be led in a comprehensible manner using language that is readily understandable by the 
potential participant. 

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Potential participants will be given the opportunity to ask questions to the investigators 
and express potential concerns, and to discuss potential participation in the clinical trial with 
family, friends, and/or other health care providers.  
Originals of the signed informed consent forms will be stored in the investigator site file, and 
trial participants will be provided with a copy of the participant information sheet and the signed 
informed consent form. Receipt of this copy will be confirmed by the participants by signature 
on the informed consent form. 
7.5. 
Insurance of Trial Subjects 
All study participants will be provided insurance in accordance with § 40 AMG. The insurer's 
name, contact details, and policy number will be provided in the participant’s information sheet. 
7.6. 
Data Protection 
All investigational materials and data will be pseudonymized using unique alphanumerical 
codes for each trial participant, and all applicable provision of the data protection legislation 
will be followed. As part of the informed consent process, potential trial participants will be 
informed about the requirement to agree to handling of pseudonymized data in accordance 
with applicable legislation to be eligible to participate in the trial. 
The sponsor (University of Cologne) is responsible for data processing (University of Cologne, 
Albertus-Magnus-Platz, 50923 Cologne; 
 
). In this trial, the sponsor is 
represented by 
. Data processing will be carried out by the Clinical Trials 
Center Cologne at the University of Cologne (CTCC, Gleueler Str. 269, 50935 Cologne). 
 
 

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8. Statistical Methods and Sample Size Considerations 
8.1. 
Statistical and Analytical Plan 
For each study phase (dose escalation and randomized) a first analysis is planned after the 
data from up to the day 7 visit after administration of the study drug is collected and data is 
cleaned. In the expansion cohort (Group 2D), data will be unblinded for this analysis. The final 
analysis will take place after the follow up for all subjects of both phases is completed. The 
final CTR will include all study phases. 
In group 2D, no adjustments for dropouts are planned. 
8.1.1. 
Analysis Populations 
Dose-Escalation Phase (Groups 1A-1D and Group 2C) 
Analyses are conducted “as treated”, which includes all participants who received any amount 
of the study drug. 
 
Randomized Placebo-Controlled Phase (Group 2D) 
The primary dataset for analysis is the safety population (as treated). This population includes 
all trial subjects who received any amount of the study drug. 
The secondary dataset for analysis is a modified intention-to-treat (mITT) population. This 
dataset includes all randomized trial participants receiving the study drug infusion and who 
have at least a baseline (day 0) value and a second measurement in the first week (up to the 
day 7 visit) of viral RNA shedding in nasopharyngeal swabs by qRT-PCR. The evaluation is 
carried out strictly in accordance with the allocation by randomization. 
Additional analysis populations can be defined in the SAP. 
8.1.2. 
Description of Trial Participants Groups 
Quantitative data will be summarized by mean ± standard deviation and percentiles (0, 25, 50, 
75, 100). Qualitative data will be summarized by absolute and relative frequency. Confidence 
intervals can support interpretation, if sensible. Listings of the data will be given where 
appropriate. Data up to the day 7 visit after infusion of the study drug and during follow up will 
be evaluated separately and in aggregate as appropriate. 
 
 

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Dose-Escalation Phase (Groups 1A-1D and Group 2C) 
Descriptions will be provided by DZIF-10c dose and infection status, as well as in aggregate. 
Listings of the data by participant will be provided for all safety data. 
 
Randomized Placebo-Controlled Phase (Group 2D) 
Descriptions will be provided separated by treatment group and in aggregate. Listings of the 
data by participant will be provided for all safety data. 
 
Screening failures 
Screening failures will be listed with available information on demography, the cause for the 
screen failure and Adverse Events. 
8.1.3. 
Primary Outcome and Target Variables 
Primary target variables are Adverse Events (including Serious Adverse Events and Adverse 
Events of Special Interest), as defined in chapter 5.2.1 and chapter Fehler! Verweisquelle 
konnte nicht gefunden werden.. Evaluation will be performed in the safety population. Safety 
events will be listed by participant. Safety events are reported in total, by seriousness, 
relatedness, and severity. 
Analysis is descriptive. Safety events will be evaluated as rate and frequency of participants 
who experienced the event and also as number of events.  
Safety events will be evaluated in the time period until the day 7 visit after infusion, after the 
day 7 visit until the end of study, and in aggregate. An exception are AESIs, which will be 
documented as AESIs until the day 7 visit only. 
8.1.4. 
Secondary and Exploratory Outcomes and Target Variables 
Analysis is descriptive in nature. Secondary and exploratory endpoints will be evaluated by 
dose or treatment group and visit. Endpoints will be evaluated mainly in the safety population 
(dose escalation phase) or in the mITT population (Group 2D). Figures may show 
development over time where sensible. Endpoints can additionally be analysed by suitable 
multivariable models, including covariates. Substitution of missing values is not planned; the 
main efficacy analysis of time weighted average change of viral RNA shedding is possible in 
the mITT without substitutions. Complete methods will be specified in the SAP. 

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Outcomes and Target Variables 
 
Laboratory Parameters, Vital Signs, Symptoms 
Changes in safety laboratory parameters, vital signs and symptoms will be summarized 
descriptively. Changes in laboratory parameters and vital signs will additionally be calculated 
relative to the results obtained at baseline (day 0 prior to study drug administration). 
 
Pharmacokinetic Parameters 
Pharmacokinetic parameters of DZIF-10c in antibody recipients will be calculated using 
standard non-compartmental analysis methods and described. Parameters calculated will 
include the area under the curve (AUC), the maximum concentration, and terminal half-life. 
 
Anti-Drug Antibodies 
The frequency of participants with antibodies and magnitude of antibodies targeting DZIF-10c 
will be calculated and described in tables. 
 
Viral Shedding Determined by qRT-PCR  
Viral RNA shedding in nasopharygeal and oropharyngeal swabs will be measured by qRT-
pCR as Ct values and copies/ml. Viral RNA shedding will be evaluated as original values and 
difference to baseline by visit, and as time weighted average change between baseline and 
the day 7 visit, as well as between baseline and the day 14 visit (Groups 2C-2D). In addition, 
the proportion of SARS-CoV-2-RNA positive participants per group and swab type will be 
determined (Groups 2C-2D). 
 
Viral Shedding Determined by the Isolation of Infectious Virus 
Frequency of viral shedding as determined by successful isolation of infectious virus in virus 
isolation assays will be analysed by visit (Groups 2C-2D). 
 
Viral Replication Determined by Subgenomic SARS-CoV-2 mRNA 
Levels of subgenomic SARS-CoV-2 mRNA will be determined in swab samples by qRT-PCR 
and summarized (Groups 2C-2D). 
 
Frequency of COVID-19-related hospitalizations and medically-attended contacts 

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The frequency of unplanned hospitalizations and medically-attended contacts deemed to be 
related to COVID-19 by the Investigator will be described (Groups 2C-2D). 
 
Time to symptom resolution 
The duration of COVID-19-related symptoms will be described based on participants’s self-
assessment documented on patient diaries (Groups 2C-2D).  
 
Differences in Viral Sequences and Change in Neutralization Sensitivity 
Sequencing results of SARS-CoV-2 spike genes will be described. The impact of individual 
mutations (e.g., within the antibody epitope or recurrent mutations) on DZIF-10c sensitivity will 
be determined by neutralization assays and 50% inhibitory concentrations (IC50s) and/or 100% 
inhibitory concentrations (IC100s) will be determined (Groups 2C-2D). 
 
Activity and Frequency of SARS-CoV-2-reactive immune responses 
The frequency and response magnitude of SARS-CoV-2-reactive lymphocytes or lymphocyte 
subset will be evaluated and summarized per participant (Groups 2C-2D). 
8.1.5. 
Subgroup Analyses 
All subgroup analyses will be descriptive only. A subgroup analyses for sex will be performed 
for the primary endpoint. 
Additional subgroup analyses are planned in the expansion cohort (Group 2D) for age, sex, 
BMI, viral RNA shedding at baseline, and trial center. The definition of Subgroup categories 
and minimum number of participants for a subgroup analysis will be specified in the SAP. 
8.1.6. 
Interim Analysis 
No formal interim analysis is planned. 
 
8.2. 
Sample Size Considerations 
During the dose escalation phase of the trial, a routine 3+3 trial design will be employed. 
Since this is a hypothesis-generating trial, no formal sample size calculation is done for the 
randomized expansion study part. Selection of the group size included considerations of 

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feasibility for an early phase first-in-human trial in quarantined individuals while facilitating 
outcome measures that can inform later stage trials. 39 participants will be included in the 
expansion study, randomized 2:1 (DZIF-10c : placebo). Assuming a similar rate of participants 
having Adverse Events as observed in a previous clinical trial of a SARS-CoV-2 neutralizing 
antibody in ambulatory SARS-CoV-2-infected participants50, the following confidence intervals 
for the rate of Adverse Events in the expansion cohort can be calculated:  
 
90% confidence interval 
(Participants with AEs) 
Rate of AEs 
(Participants) 
DZIF-10c  
(n=26) 
Placebo  
(n=13) 
20% 
[7% ; 33%] 
[2% ; 38%] 
25% 
[11% ; 39%] 
[5% ; 45%] 
 
While this exploratory trial is not powered to determine statistically significant differences in the 
change of the viral load between the treatment arms in the expansion cohort, simulations 
based on previously reported SARS-CoV-2 neutralizing antibody responses61,62 indicate that 
the group size (DZIF-10c, n=26; placebo, n=13) gives a >80% probability to observe an AUC 
ratio of >1.45. 
 
 
 

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9. Safety 
9.1. 
Definitions of Adverse Events and Adverse Drug Reactions 
9.1.1. 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a clinical trial participant 
administered a study drug (i.e., IMP or placebo), even if the event is not considered to be 
caused by study drug. The adverse event may be, but is not restricted, to any new illness, 
worsening of a sign or symptom of COVID-19, or deterioration of a pre-existing medical 
condition. Abnormal laboratory results and results of physical examinations after the screening 
examination constitute Adverse Events to be reported and graded according to the CTCAE 
Grading table (v 5.0) if they are considered as clinically significant and/or require treatment.  
Pregnancy 
For reasons of drug safety, the occurrence of a pregnancy during the conduct of this 
trial is to be regarded as an AE. For details of special reporting requirements for 
pregnancy, see section 9.3.2. 
 
 
Adverse Events of Special Interest 
Infusion-related reactions presenting as hypersensitivity/allergic reaction, anaphylaxis, 
or cytokine release sydrome are designated as Adverse Events of Special Interest. For 
details of reporting requirements, see section 9.3.1. 
9.1.2. 
Adverse Drug Reaction 
All adverse events judged by either the investigator or the sponsor as having a reasonable 
suspected causal relationship to the study drug product qualify as adverse drug reactions 
(ADR). 
9.1.3. 
Serious Adverse Events and Serious Adverse Reactions 
A serious adverse event (SAE) or serious adverse drug reaction (SAR) is any adverse event 
or adverse drug reaction that 
- 
results in death, and/or 
- 
is life-threatening at the time of the event, and/or 
- 
requires inpatient hospitalization or prolongation of existing hospitalization, and/or 

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- 
results in persistent or significant disability/incapacity, and/or 
- 
is a congenital anomaly/birth defect, and/or 
- 
is any other medically important event in the opinion of the investigator (e.g., an event 
that may jeopardize the trial subject or may require intervention to prevent one of the 
outcomes listed above) 
Inpatient hospitalization is defined as any stay in a hospital that includes at least one night 
(midnight to 6 am).  
Admission to hospital that was planned before the first study drug administration will not 
considered as SAE but must be documented in the trial subject’s medical records and CRF. 
Inpatient hospitalization for the purpose of IMP administration is not considered as SAE, but 
must be documented in a proper manner in the trial subject’s medical record and CRF. 
Prolongation of hospitalization must be documented and reported as SAE. 
9.1.4. 
Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction is an ADR that is not consistent with the potential ADRs 
listed in the Investigator’s Brochure in severity, nature and/or outcome.  
9.1.5. 
Suspected Unexpected Serious Adverse Reactions 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse event (SAE) 
the nature or severity of which is not consistent with the potential ADRs listed in the 
Investigator’s Brochure, and that has at least a possible causal relationship to the study drug. 
9.1.6. 
Dose-Limiting Toxicities 
A dose-limiting toxicity (DLT) will be defined as any adverse event of grade 3 or greater toxicity 
during the dose escalation phase of the trial (Groups 1A-1D, Group 2C) that is assessed by 
the trial investigators to be related to DZIF-10c. For details on reporting requirements see 
section 9.3.2. 
 

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9.2. 
Documentation and Follow-Up of Adverse Events 
9.2.1. 
Documentation of Adverse Events and Adverse Drug Reactions  
The occurrence of (S)AEs and ADRs will be documented starting with the provision of informed 
consent and until the termination of the clinical trial for the individual participant using the 
applicable case report form (CRF).  
All adverse events, regardless of whether a causal relationship between the AE and study drug 
is suspected, will be followed-up until the associated symptoms have subsided, abnormal 
laboratory results have returned to pre-event levels, or the study has been completed or 
terminated for the individual participant.  
Persistent AEs that do no resolve between individual visits will be recorded once. The initial 
severity will be documented at the time the event is first reported, and the highest severity will 
be documented should the persistent AE become more severe.  
Should an AE become serious within the reporting period, it should be reported to the sponsor 
immediately (i.e., no more than 24 hours after learning that the event became serious) by using 
the trial-specific SAE form. Additionally, as soon as a documented Adverse Event becomes 
serious, the SAE information should be amended on the AE eCRF page by providing the date 
that the event became serious as onset date of the SAE and completing all data fields related 
to serious adverse event. 
Documentation of AEs includes 
- 
Description of AE 
- 
Date and time of onset and resolution 
- 
Grading/Severity 
- 
Relationship to study drug  
- 
Seriousness 
- 
Effect on the infusion schedule 
- 
Need for treatment and action taken 
- 
Outcome 
- 
Written summary / narrative (for SAEs, AESIs, and DLTs) 
Pre-existing diseases (i.e., medical conditions starting before study drug administration) are 
not documented as AEs but as medical history. However, worsening of pre-existing diseases 
will be documented as AEs.  

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9.2.2. 
Severity of Adverse Events 
The CTCAE (Common Terminology Criteria for Adverse Events) grading table (v5.0) will be 
used by trial investigators to classify adverse events. It comprises the following categories:  
- 
Grade 1: Mild. 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
- 
Grade 2: Moderate. 
Minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
activities of daily living* (ADL). 
- 
Grade 3: Severe or medically significant but not immediately life-threatening. 
Hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
- 
Grade 4: Life-threatening consequences. 
Urgent intervention indicated. 
- 
Grade 5: Death related to AE. 
 
*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. 
9.2.3. 
Causality Assessment of Adverse Events 
Every AE will be assessed by a trial investigator for potential causal relationship to the study 
drug. This assessment will include consideration of the nature and type of reaction, the 
temporal relationship with the study drug, the clinical status of the trial participant, concomitant 
medication and other relevant clinical factors. If the event is considered to be a consequence 
of lack of study drug efficacy or to be a symptom or sign of the underlying disorder, no causal 
relationship to the study drug will be assumed. 
AEs/SAEs will be assessed according to the causality determinations of CIOMS VI-Group 
(Council for International Organizations of Medical Sciences) as follows: 
• 
Related: There is a reasonable possibility that the AE is related to the IMP 
• 
Not related: There is not a reasonable possibility that the AE is related to the IMP. 

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Events for which no causal relationship to the IMP is given or which are classified as “not 
assessable” will be regarded as related until enough information is provided to allow a proper 
assessment of the causal relationship. 
 
The causality assessment given by the investigator should not be downgraded by the Sponsor. 
If the Sponsor disagrees with the Investigator’s causality assessment, the more critical 
assessment is to be used for further processing of the case and the opinion of both, the 
Investigator and the Sponsor, will be provided the report narrative. 
 
9.3. 
Reporting of Serious Adverse Events, Adverse Events of Special Interest, Dose-
Limiting Toxicities, Pregnancy and Changes in Risk-Benefit Assessment 
Every SAE that occurs from the provision of infomed consent to participate in the trial until the 
trial participant’s last study visit must be documented on the appropriate CRF and in addition 
be reported on a SAE form to the sponsor. In the interest of participants’ safety, follow-up for 
up to 30 days after the individual participants’s study termination is required for SAEs that are 
not sufficiently resolved at the participant’s final trial visit. 
Adverse Events of Special Interest (AESIs) and Dose-Limiting Toxicites (DLTs) should be 
reported to the sponsor within 24 h of the site becoming aware of the event. 
Pregnancies must be documented on a separate pregnancy form and reported to the sponsor 
within the defined periods (see Section 7.3.2.). 
An Investigator Handout providing detailed information of reporting procedures will be provided 
to the trial sites.  
9.3.1. 
SAE, AESI and DLT Reporting 
All serious adverse events (SAEs) occurring between the provision of informed consent to 
participant in the trial and the participant’s last trial visit must be reported by the local trial 
investigator to the sponsor without delay and at the latest within 24 hours of becoming aware 
of the SAE. 
To this end, the provided SAE report forms must be completed and submitted by fax or E-Mail 
to the Clinical Trials Center Cologne (CTCC, ZKS Köln) to which the sponsor has delegated 
the SAE management procedures: 
 

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SAE Dedicated Facsimile:  
 
 
SAE Reporting E-Mail: 
 
 
Similarly, AESIs should be reported on AESI report forms and must be completed and 
submitted by fax or E-Mail to the Clinical Trials Center Cologne (CTCC, ZKS Köln) within 24 h 
of the site becoming aware of the event. 
Finally, DLTs occurring during the dose-escalation phase of the trial (Groups 1A-1D, Group 
2C) must be reported by submitting the AE/DLT report form by fax or E-Mail to the Clinical 
Trials Center Cologne (CTCC, ZKS Köln) within 24 h of the site becoming aware of the event. 
9.3.2. 
Pregnancy Reporting 
The trial investigator will inform the sponsor of any pregnancy in a female trial participant 
reported during the conduct of the trial within 24 hours of the investigator becoming aware of 
the pregnancy.  
To this end, the provided pregnancy report forms must be completed and submitted by fax or 
E-Mail to the Clinical Trials Center Cologne (CTCC, ZKS Köln) to which the sponsor has 
delegated the safety management procedures: 
 
Pregnancy Dedicated Facsimile: 
 
 
Pregnancy Reporting E-Mail: 
 
Pregnant trial participants will be asked to provide separate informed consent for pregnancy 
follow up, and the parents will be asked to provide separate informed consent for follow-up of 
the child until 4 weeks after life birth. 
9.3.3. 
SAE Assessment by the Sponsor 
All cases of suspected SAEs will additionally be assessed by the Coordinating Investigator or 
its delegate (Sponsor assessors) with regard to seriousness, causality, and expectedness, 
regardless of the investigator’s assessments. 
9.3.4. 
Unblinding for SUSAR when Treatment is Blinded 
The trial treatment is unblinded by the Sponsor in the individual trial subject to verify causality 
before reporting the event to the responsible ethics committee, the competent authority and 
SMC members.  

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The Sponsor will notify the Investigator (blinded SUSAR) of relevant information about 
SUSARs that could adversely affect the safety of subjects in a timely fashion. Follow-up 
information may be submitted if necessary.  
Details on emergency unblinding are described in section 5.9.6.1. 
9.3.5. 
Notification of Competent Authority and Ethics Committee 
Every SUSAR (suspected unexpected serious adverse reaction) will be reported by the 
sponsor to the competent authority and the responsible ethics committee. 
 
- 
Fatal and life-threatening SUSARs 
The competent authority and responsible ethics committee must be informed by the 
sponsor without delay, and at the latest within 7 calendar days of becoming aware of the 
minimum criteria for reporting. In all cases, attempts will be made to obtain further relevant 
information which will be supplied within an additional 8 days. 
- 
SUSARs that are not fatal or life-threatening 
The competent authority and the responsible ethics committee must be informed without 
delay by the sponsor, at the latest within 15 calendar days of becoming aware of the 
minimum criteria for reporting. Additional relevant details will be passed on as soon as 
possible. 
If the information provided at the time of reporting is incomplete for a final assessment, 
additional information will be requested from the investigator or other available sources. 
9.3.6. 
Reporting of Potential Changes in the Risk-Benefit Ratio 
The sponsor will inform the competent authority and the responsible ethics committee of any 
occurrences that may change the risk-benefit ratio of the IMP. This will be done without delay, 
and at the latest within 15 calendar days of becoming aware of such an occurrence. Such 
occurrences include, but are not restricted to: 
• 
Reports of expected serious adverse drug reactions (SARs) with an unexpected 
outcome 
• 
An unexpected high frequency of expected SARs 
• 
SUSARs in trial participants occurring following trial completion (end-of-trial visit) 

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• 
Events in connection with the conduct of the study or the development of the IMP that 
may affect the safety of the trial subjects. 
In case of any new event or safety issues relating to the conduct of the trial or the development 
of the investigational medicinal product where that new event is likely to affect the safety of the 
trial participants, the Sponsor and the Investigator must take appropriate urgent safety 
measures to protect the participants against any immediate hazard. The Sponsor has to inform 
the competent authority, ethics committee and SMC of those new events and the measures 
taken. 
9.3.7. 
Informing the Investigators 
All site investigators will be informed by the sponsor on all SUSARs in blinded form including 
all relevant further information within the periods defined by the competent authority. 
In addition, the sponsor will communicate any changes resulting in the risk-benefit-assessment 
to all site investigators. 
 
9.4. 
Annual Safety Report (DSUR) 
An annual report (Development Safety Update Report, DSUR) compiled according to ICH 
guideline E2F and comprising all available and relevant information concerning trial 
participants’ safety will be provided by the sponsor to the competent authority and ethics 
committee. 
This report will be submitted annually within 60 calendar days of the DSUR data lock point, 
defined as one year from the first authorization to conduct the clinical trial by the sponsor. 
 
 

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10. Reporting of Trial Results 
10.1. Reports 
10.1.1. Interim Reports 
No formal interim reports are planned. 
10.1.2. Final Report 
Within 90 days of the end of the trial, the competent authority and ethics committee will be 
informed about the end the trial. 
Within one year of the end of the trial, a final study report will be provided to the competent 
authority and a summary will be provided to the ethics committee. 
11. Amendments to the Trial Protocol 
Amendments to the trial protocol may only be implemented in joint agreement between the 
sponsor, the sponsor’s representative, the Coordinating Investigator, and the trial statistician. 
Substantial amendments will be implemented only after approval by the competent authority 
and after receiving a favourable opinion of the ethics committee. Amendments necessary to 
avoid immediate danger to the trial participants are exempt from this requirement. 
 
 

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12. Appendices 
Appendix I 
WHO Clinical Progression Scale 
 
 
* If hospitalized for isolation only, record status as for ambulatory patient. 
 
 
 
 

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Appendix II Visit Schedule 
 
 
 
 

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