Clinical trial NCT04828161
Conditions: COVID-19
Keywords: ensovibep COVID-19 treatment, symptom reduction, viral load reduction, EMPATHY SARS-CoV-2 designed ankyrin repeat protein (DARPin®) angiotensin-converting enzyme 2 (ACE2)
Sponsor: Novartis Pharmaceuticals
Start date: 2021-05-10; Completion date: 2022-01-27
Enrollment: 407 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to establish the antiviral efficacy of ensovibep against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans, identify the optimal dose, and demonstrate its clinical value for treating COVID-19 in adult ambulatory patients.

Detailed description:
Primary objectives:

Part A: The primary objective of this Part is to demonstrate superiority of ensovibep, compared to placebo, in reducing SARS-CoV-2 viral load through Day 8.

Part B: The primary objective of this Part is to demonstrate superiority of ensovibep, compared to placebo, in reducing the occurrence of hospitalizations (≥ 24 hours of acute care) and/or emergency room visits related to COVID-19 or death from any cause up to Day 29.

Secondary objectives:

Part A: The secondary objectives of this Part are:

* To assess the effect of ensovibep, compared to placebo, in reducing the occurrence of hospitalizations (≥ 24 hours of acute care) and/or emergency room visits related to COVID-19 or death from any cause up to Day 29
* To assess the effect of ensovibep, compared to placebo, in reducing COVID-19 symptoms through Day 29
* To evaluate safety and tolerability of ensovibep
* To characterize the pharmacokinetics (PK) of ensovibep

Part B: The secondary objectives of this Part are:

* To assess the effect of ensovibep, compared to placebo, in reducing SARS-CoV-2 viral load through Day 8
* To assess the effect of ensovibep, compared to placebo, in reducing COVID-19 symptoms up to Day 29
* To evaluate the immunogenicity of ensovibep during the study and its clinical relevance (PK, efficacy and safety)
* To evaluate safety and tolerability of ensovibep

Although Amendment 2 was created, modifications for this amendment are not reflected as it was never approved or implemented in the US. The study was conducted under Global Protocol Amendment 1, the last active version of the protocol.

Arms: arm 1: Phase 2 / Part A: ensovibep active treatment arm 1 arm 2: Phase 2 / Part A: ensovibep active treatment arm 2 arm 3: Phase 2 / Part A: ensovibep active treatment arm 3 arm 4: Phase 2 / Part A: Placebo arm 5: Phase 3/ Part B: ensovibep active treatment. Part B was not initiated. arm 6: Phase 3/ Part B: Placebo. Part B was not initiated.
Interventions: intervention 1: ensovibep intervention 2: Placebo
Intervention descriptions: intervention 1: IV on day 1 only. intervention 2: IV on day 1 only.

Protocol documents:
Prot_000.pdf: 
Molecular Partners AG 
Ensovibep/MP0420 
Clinical Trial Protocol MP0420-CP302 (CSKO136A12201J) / NCT04828161
Document type: 
Amended Clinical Trial Protocol 
EUDRACT number: 
2021-000890-10 
Version number: 
01 
Clinical Trial Phase: 
Phase 2 and Phase 3 
Release date: 
19-Oct-2021
Property of Molecular Partners AG 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Molecular Partners AG 
A randomized, double-blind, placebo-controlled, 
multicenter study of ensovibep (MP0420) in ambulatory 
adult patients with symptomatic COVID-19 
The “EMPATHY” Trial 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Amendment 1 dated 19-Oct-2021 (global protocol amendment) ............................................. 12 
Amendment 1 dated 17-Jun-2021 (local amendment for the sites in India only) .................... 16 
Amendment 1 dated 14-Apr-2021 (local amendment for USA sites only) ............................... 17 
Protocol summary .............................................................................................................. 18 
1 
Introduction ....................................................................................................................... 22 
1.1 
Background ............................................................................................................ 22 
1.2 
Purpose .................................................................................................................. 24 
2 
Objectives and endpoints ................................................................................................... 24 
2.1 
Primary estimands ................................................................................................. 27 
2.1.1 
Part A .................................................................................................... 27 
2.1.2 
Part B ..................................................................................................... 27 
2.2 
Secondary estimands ............................................................................................. 28 
3 
Study design ...................................................................................................................... 28 
4 
Rationale ............................................................................................................................ 29 
4.1 
Rationale for study design ..................................................................................... 29 
4.1.1 
Rationale for choice of background therapy ......................................... 31 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 31 
4.3 
Rationale for choice of control drug (placebo) ...................................................... 32 
4.4 
Purpose and timing of planned analyses/design adaptations ................................. 32 
4.5 
Risks and benefits .................................................................................................. 33 
4.5.1 
Blood sample volume ............................................................................ 34 
5 
Study population ................................................................................................................ 34 
5.1 
Inclusion criteria .................................................................................................... 34 
5.2 
Exclusion criteria ................................................................................................... 34 
6 
Treatment ........................................................................................................................... 36 
6.1 
Study treatment ...................................................................................................... 36 
6.1.1 
Investigational and control drugs .......................................................... 36 
6.1.2 
Additional study treatments .................................................................. 36 
6.1.3 
Treatment arms/group ........................................................................... 37 
6.2 
Other treatments..................................................................................................... 37 


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6.2.1 
Concomitant therapy ............................................................................. 37 
6.2.2 
Prohibited medication ........................................................................... 38 
6.2.3 
Rescue medication ................................................................................ 38 
6.3 
Patient numbering, treatment assignment, randomization ..................................... 38 
6.3.1 
Patient numbering ................................................................................. 38 
6.3.2 
Treatment assignment, randomization .................................................. 38 
6.4 
Treatment blinding................................................................................................. 39 
6.5 
Dose escalation and dose modification .................................................................. 41 
6.6 
Additional treatment guidance ............................................................................... 41 
6.6.1 
Treatment compliance ........................................................................... 41 
6.6.2 
Recommended treatment of adverse events .......................................... 41 
6.6.3 
Emergency breaking of assigned treatment code .................................. 41 
6.7 
Preparation and dispensation ................................................................................. 42 
6.7.1 
Handling of study treatment .................................................................. 42 
7 
Informed consent procedures ............................................................................................ 43 
8 
Visit schedule and assessments ......................................................................................... 43 
8.1 
Screening ............................................................................................................... 50 
8.1.1 
Information to be collected on screening failures ................................. 50 
8.2 
Patient demographics/other baseline characteristics ............................................. 50 
8.3 
Efficacy .................................................................................................................. 50 
8.3.1 
SARS-CoV-2 viral load ........................................................................ 50 
8.3.2 
Medically attended visits related to COVID-19 or death from any 
cause ...................................................................................................... 51 
8.3.3 
Patient reported outcomes ..................................................................... 51 
8.4 
Safety ..................................................................................................................... 52 
8.4.1 
Laboratory evaluations .......................................................................... 53 
8.4.2 
Electrocardiogram ................................................................................. 53 
8.4.3 
Pregnancy and assessments of fertility ................................................. 53 
8.4.4 
Appropriateness of safety measurements .............................................. 54 
8.5 
Additional assessments .......................................................................................... 54 
8.5.1 
Pharmacokinetics .................................................................................. 54 
8.5.2 
Biomarkers ............................................................................................ 55 
8.5.3 
Immunogenicity .................................................................................... 56 
 
 57 
9 
Study discontinuation and completion .............................................................................. 57 
9.1 
Discontinuation and completion ............................................................................ 57 


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9.1.1 
Interruption of study drug infusion and study discontinuation ............. 57 
9.1.2 
Withdrawal of informed consent ........................................................... 59 
9.1.3 
Lost to follow-up ................................................................................... 59 
9.1.4 
Study stopping rules .............................................................................. 59 
9.1.5 
Early study termination by the sponsor ................................................. 60 
9.2 
Study completion and post-study treatment .......................................................... 60 
10 Safety monitoring and reporting ........................................................................................ 61 
10.1 
Definition of adverse events and reporting requirements ...................................... 61 
10.1.1 
Adverse events ...................................................................................... 61 
10.1.2 
Serious adverse events .......................................................................... 62 
10.1.3 
SAE reporting........................................................................................ 63 
10.1.4 
AEs of Special Interest .......................................................................... 64 
10.1.5 
Pregnancy reporting .............................................................................. 64 
10.1.6 
Reporting of study treatment errors ...................................................... 64 
10.2 
Additional safety monitoring ................................................................................. 65 
10.2.1 
Liver safety monitoring ......................................................................... 65 
10.2.2 
Renal safety monitoring ........................................................................ 65 
10.3 
Independent data monitoring committee ............................................................... 66 
11 Data collection and database management ........................................................................ 66 
11.1 
Data collection ....................................................................................................... 66 
11.2 
Database management and quality control ............................................................ 67 
11.3 
Site monitoring ...................................................................................................... 68 
12 Data analysis and statistical methods ................................................................................ 69 
12.1 
Analysis sets .......................................................................................................... 69 
12.2 
Patient demographics and other baseline characteristics ....................................... 70 
12.3 
Treatments ............................................................................................................. 70 
12.4 
Analysis of the primary endpoints ......................................................................... 70 
12.4.1 
Definition of primary endpoints ............................................................ 70 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 71 
12.4.3 
Handling of remaining intercurrent events of primary estimand .......... 74 
12.4.4 
Handling of missing values not related to intercurrent event ............... 75 
12.4.5 
Supplementary analysis ......................................................................... 75 
12.4.6 
Supportive analysis ............................................................................... 76 
12.5 
Analysis of secondary endpoints ........................................................................... 76 
12.5.1 
Efficacy endpoints ................................................................................. 76 
12.5.2 
Safety endpoints .................................................................................... 77 


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 78 
 
 78 
 
 78 
 
 79 
 
 79 
 
 79 
12.7 
Interim analysis ...................................................................................................... 79 
12.8 
Sample size calculation .......................................................................................... 80 
12.8.1 
Primary endpoint(s) ............................................................................... 80 
13 Ethical considerations and administrative procedures....................................................... 81 
13.1 
Regulatory and ethical compliance ........................................................................ 81 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 82 
13.3 
Publication of study protocol and results............................................................... 82 
13.4 
Quality control and quality assurance .................................................................... 82 
14 Protocol adherence ............................................................................................................ 82 
14.1 
Protocol amendments............................................................................................. 83 
15 References ......................................................................................................................... 84 
16 Appendices ........................................................................................................................ 87 
16.1 
Appendix 1: Symptom questionnaire .................................................................... 87 
 
 90 
16.3 
Appendix 3: Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................................... 93 
16.4 
Appendix 4: Specific renal alert criteria and actions and event follow-up ............ 96 
16.5 
Appendix 5: Sponsor’s signature page .................................................................. 97 
16.6 
Appendix 6: Investigator’s signature page ............................................................ 98 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 24 
Table 4-1 
Rationale for study design ..................................................................... 29 
Table 6-1 
Investigational and control drug............................................................ 36 
Table 8-1 
Part A: Assessment schedule ................................................................ 45 
Table 8-2 
Part B: Assessment schedule ................................................................. 48 
Table 12-1 
Power for Part A given a range of operating characteristics given 
400 patients, 100 patients in each arm and a one sided significance 
level of 10% .......................................................................................... 80 
Table 12-2 
Power for Part B given a range of operating characteristics ................. 81 


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Table 16-1 
Liver event and laboratory trigger definitions ...................................... 93 
Table 16-2 
Follow up requirements for liver laboratory triggers with liver 
symptoms .............................................................................................. 94 
Table 16-3 
Follow up requirements for liver laboratory triggers ............................ 95 
Table 16-4 
Specific renal alert criteria and actions ................................................. 96 
List of figures 
Figure 3-1 
Study design .......................................................................................... 29 
Figure 12-1 
Candidate models for ensovibep dose ................................................... 73 


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List of abbreviations 
ACE2 
Angiotensin converting enzyme 
ADA 
Antidrug antibody 
AE 
Adverse Event 
AESI 
Adverse event of special interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
The area under the concentration-time curve 
AUCinf 
The area under the concentration-time curve from time zero to infinity 
AUClast 
The area under the concentration-time curve from time zero to the time of the last 
quantifiable concentration 
BMI 
Body mass index 
BUN 
Blood Urea Nitrogen 
CI 
Confidence interval 
CL 
Apparent total body clearance of the drug from plasma 
Cmax 
The observed maximum concentration 
COVID-19 
Coronavirus disease 2019 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CRS 
Cytokine release syndrome 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DARPin® 
Designed ankyrin repeat protein 
eCOA 
Electronic clinical outcome assessment 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EOS 
End of Study 
eSource 
Electronic Source 
EUA 
Emergency Use Authorization 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
H 
Hour 


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I 
Human Serum Albumin 
i.v. 
Intravenous 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IDMC 
independent data monitoring committee 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IP 
Investigation product 
IQR 
Interquartile range 
IRB 
Institutional Review Board 
IRR 
Infusion-related reactions 
IRT 
Interactive Response Technology 
ITT 
Intention-to-treat 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
IWRS 
Interactive web response system 
Lambda z (λz) 
The terminal elimination rate constant 
LDH 
Lactate Dehydrogenase 
LFT 
Liver function test  
LLOQ 
Lower limit of quantification 
LOCF 
Last observation carried forward 
mAb 
Monoclonal antibody 
MCS 
Mental Component Summary 
MedDRA 
Medical dictionary for regulatory activities  
MoA 
Mechanism of action 
NOAEL 
No-observed-adverse-effect-level 
NSAID 
Nonsteroidal anti-inflammatory drug 
OTC 
Over-the-counter 
PCS 
Physical Component Summary 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PP 
Per-protocol 
PRO 
Patient Reported Outcomes 
PT 
Prothrombin Time 
PT 
Preferred term 
QMS  
Quality Management System 
RAN 
Randomized set 


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RBD 
Receptor Binding Domain 
RT-PCR 
Reverse transcriptase-polymerase-chain-reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SCR 
Screened set 
SD 
Standard deviation 
SF-36 
Short Form 36 Questionnaire 
SMQ 
Standardized MedDRA Query 
SOC 
System organ class 
SRG 
Safety Review Group 
SS 
Safety set 
ß-HCG 
Beta-chorionic gonadotropin 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1/2 
The terminal elimination half-life 
TBL 
Total bilirubin 
TE-ADA 
Treatment-emergent antidrug antibody 
TEAE 
Treatment-emergent adverse event 
Tmax 
The time to reach the maximum concentration 
ULN 
Upper Limit of Normal 
Vz 
The apparent volume of distribution during terminal phase associated with λz 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 


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Glossary of terms 
Additional 
treatment 
Medicinal products that may be used during the clinical trial as described in the protocol, 
but not as an investigational medicinal product (e.g., any background therapy) 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), 
tissue, urine, 
stool, etc. taken from a study participant  
Cohort 
A specific group of participants fulfilling certain criteria and generally treated at the same 
time 
Control drug 
A study drug (active or placebo) used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g., 100 mg once a 
day, 75 mg twice a day) 
Electronic Data 
Capture 
Electronic data capture (EDC) is the electronic acquisition of clinical study data using data 
collection systems, such as web-based applications, interactive voice response systems, 
and clinical laboratory interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from paper source forms used at the 
point of care 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant  
Enrollment 
Point/time of participant entry into the study at which informed consent must be obtained  
eSource 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data electronically, 
at the point of care. eSource Platform/Applications combines source documents and case 
report forms (eCRFs) into one application, allowing for the real time collection of clinical 
trial information to sponsors and other oversight authorities, as appropriate 
Estimand  
A precise description of the treatment effect reflecting the clinical question posed by the 
trial objective. It summarizes at a population-level what the outcomes would be in the 
same patients under different treatment conditions being compared. Attributes of an 
estimand include the population, variable (or endpoint) and treatment of interest, as well 
as the specification of how the remaining intercurrent events are addressed and a 
population-level summary for the variable 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a study 
participant  
Intercurrent 
events 
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest. 
Investigational 
drug/treatment 
The drug whose properties are being tested in the study 
Medication 
number 
A unique identifier on the label of medication kits 
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for randomization and who 
did not take study treatment, but have been inadvertently randomized into the study  
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e., concomitant 
or rescue therapy) 
Part 
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a multiple dose 
part, or a part in participants with established disease and in those with newly diagnosed 
disease 
Patient 
A trial participant 
Patient number 
A unique number assigned to each participant upon signing the informed consent. This 
number is the definitive, unique identifier for the participant and should be used to identify 
the participant throughout the study for all data collected, sample labels, etc. 


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Period 
The subdivisions of the trial design (e.g., Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in clinical trial 
database setup and eventually in analysis 
Perpetrator drug 
A drug which affects the pharmacokinetics of the other drug 
Personal data 
Participant information collected by the investigator that is coded and transferred to the 
sponsor for the purpose of the clinical trial. This data includes participant identifier 
information, study information, and biological samples. 
Premature patient 
withdrawal 
Point/time when the participant exits from the study prior to the planned completion of all 
study drug administration and/or assessments; at this time all study drug administration is 
discontinued and no further assessments are planned. 
Randomization 
number 
A unique identifier assigned to each randomized participant 
Screen Failure 
A participant who did not meet one or more criteria that were required for participation in 
the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from where data 
comes. The data source can be a database, a dataset, a spreadsheet, or even hard-
coded data, such as paper or eSource 
Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed consent by the first 
participant  
Study treatment 
Any drug or combination of drugs or intervention administered to the study participants as 
part of the required study procedures; includes investigational drug(s), control(s), or 
background therapy 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) prior to the 
defined study treatment completion date (if any) for any reason; may or may not also be 
the point/time of study discontinuation  
Treatment 
arm/group  
A treatment arm/group defines the dose and regimen or the combination; may consist of 1 
or more cohorts 
Treatment of 
interest 
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations of 
interventions administered concurrently, e.g., as add-on to standard of care, or might 
consist of an overall regimen involving a complex sequence of interventions. This is the 
treatment of interest used in describing the related clinical question of interest, which 
might or might not be the same as the study treatment. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required to address 
the clinical question. The specification of the variable might include whether the 
participant experiences an intercurrent event. 
Withdrawal of 
study consent 
Withdrawal of consent (WoC) from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further collection of 
personal data 
 
 
 


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Amendment 1 dated 19-Oct-2021 (global protocol amendment) 
 
 
Amendment rationale  
As of 19-October-2021, 381 patients have been treated in the study. 
 
The purpose of this protocol amendment is to provide clarification around the data included in 
the primary analyses of Part A of the study. Clarification regarding the laboratory data available 
at the time of the database lock, unblinding after database lock and statistical analysis are the 
key changes reflected here.  
 
For the primary analysis the laboratory analysis of some of the biomarker samples may not be 
fully completed in time for the reporting out of primary analysis for Part A and for planned 
regulatory submission(s). In order to allow study results to be shared with regulatory agencies 
as early as possible with the commitment to provide additional data in a timely fashion once it 
becomes available, some of these data may therefore need to be delivered in a staggered 
approach. 
 
In this context, updates have been made to the unblinding process after the primary analysis for 
Part A and reference to the unblinding charter is included.  
 
The primary estimand wording has been updated to follow recently published guidelines (FDA 
2021). COVID-19 related hospitalizations have been added as intercurrent event for the primary 
endpoint of Part A, a composite strategy will be used to handle these intercurrent events.  
 
The definition of AESIs has been updated and is no longer limited to AE onset within 24 hours 
after dosing, it includes infusion site reactions and any type of hypersensitivity reactions 
(CTCAE Grade 2 and above). The requirements for reporting renal events have been adjusted 
and also renal follow-up testing requirements (Appendix 4) have been updated for serum 
creatinine values, to account for the study patient population with acute COVID-19 infection 
(including use of concomitant medications like NSAIDs).        
 
The EOS assessments have been clarified per a footnote in the assessment schedule to further 
guide the investigational team to make sure that, depending on when a patient`s last visit occurs, 
the correct assessments are being performed.  
 
The study stopping rules have been clarified to follow CTCAE grading and explicitly include 
laboratory findings.  
 
A clarification has been added to distinguish between hospitalizations due to worsening of 
COVID-19 (secondary endpoint) and between hospitalizations for the purpose of isolating 
patients following a positive SARS-CoV-2 test (not counted towards secondary endpoint).  
 




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Section 4 Rationale:  
Table 4-1: Per editorial update, resistance mutation was changed to mutation analysis. 
Section 4.4 was updated to reflect the changes related to planned analyses in Part A and Part 
B of the study. 
Section 5 Study population:  
Wording to exclusion criterion #2 was added to reflect changes in the local protocol 
amendment 1 for India.  
Exclusion criterion # 11 was added to reflect the wording in the local protocol amendment 1 
for the USA.   
Section 6 Treatment:  
Section 6.4: The text related to the unblinding process prior and after the primary analysis has 
been updated.  
Section 8 Visit schedule and assessments: 
Tables 8-1 and 8-2 have been corrected for defining the EOS assessments, the investigational 
product, the laboratory and the PRO assessments. 
Section 8.3.2: A clarification has been added for defining hospitalizations due to COVID-19. 
Section 8.3.3.3: Missing information related to the required study days for SF-36 assessments 
has been added. 
 
Section 9 Study discontinuation and completion:  
Section 9.1.4: Study stopping rules have been corrected. 
Section 10 Safety monitoring and reporting: 
Section 10.1.4: The definition of AESIs has been updated.  
Section 12 Data analysis and statistical methods: 
Section 12.1: Wording updated for protocol deviations.  
Section 12.2: High Level Term added for relevant medical histories and current medical 
conditions at baseline. 
Section 12.4.2: The Dose-finding step wording and the Safety endpoints wording has been 
updated. 


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Section 12.4.3: The intercurrent events of the primary estimand for Part A have been updated. 
Section 12.4.4: The wording for Handling of missing values not related to intercurrent events 
for Part A has been modified. 
Section 12.5: The text for the Analysis of secondary endpoints has been corrected. 
Section 12.5.2: The Adverse events section has been updated. 
Section 12.6.1: The version of the SF-36 questionnaire used in the study has been corrected 
from version 2 to version 1
 
 
Section 12.7: The process for the primary analysis for Part A has been clarified.  
Section 12.8.1: The text for the power calculations related to the primary endpoint for Part A 
has been updated. 
Section 15 References: 
Two references have been added. 
Section 16 Appendices: 
Appendix 1: A symptom response option has been corrected. 
Appendix 3, Table 16-2: A footnote has been added to clarify handling of isolated AST 
elevations. 
Appendix 4, Table 16-4: The follow-up testing requirements for renal AESIs have been 
updated. 
 
 
 
 
 


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Amendment 1 dated 17-Jun-2021 (local amendment for the sites in 
India only) 
 
 
Amendment rationale  
For patients in India, exclusion criterion 2 has been adjusted at the request of the Indian Subject 
Expert Committee (SEC) of the Central Drugs Standard Control Organization (CDSCO) and in 
alignment with the hospitalization criteria in AIIMS/ICMR Working Group Guidelines dated 
May 17, 2021 [A1]:  
 
Patients with a respiratory rate of ≥ 24/min or with an oxygen saturation (SpO2) ≤ 93% on room 
air are not eligible for the study. The updated exclusion criterion will be limited to India.  
 
Amendment reference:  
[A1]  All India Institute of Medical Sciences (AIIMS)/Indian Council of Medical Research 
(ICMR) COVID-19 Task Force, Joint Monitoring Group (Dte.GHS), Ministry of Health 
& Family Welfare, Government of India, Clinical Guidance for Management of Adult 
COVID-19 Patients, dated 17-May-2021 
 
Changes to the protocol 
Protocol Summary: This section has been revised to exclude patients with a respiratory rate 
of ≥ 24/min or with a SpO2 ≤ 93% (only applicable for patients to be enrolled in India).   
Section 5.2: The protocol exclusion criterion has been revised to exclude patients in India 
with a respiratory rate ≥ 24/min or with a SpO2 ≤ 93%. 
 
 
  
 
 


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Amendment 1 dated 14-Apr-2021 (local amendment for USA sites only) 
 
 
Amendment rationale  
Several monoclonal antibody (mAb) therapies are now available in the USA under EUA 
(Emergency Use Authorization) for the treatment of mild to moderate coronavirus disease 2019 
(COVID-19) in adults and pediatric patients (12 years of age and older weighing at least 40 kg) 
with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for 
progressing to severe COVID-19 and/or hospitalization.  
Since conducting a placebo-controlled trial in this population may not be appropriate, the 
protocol has been amended to exclude COVID-19 patients in the USA who are at high risk for 
developing severe COVID-19 symptoms or the need for hospitalization. This has been done in 
alignment with the FDA.  
The exclusion of high risk patients will be limited to the USA, since it is the only participating 
country where high risk patients have access to therapeutic mAbs. The change is applicable to 
Part A of the protocol.  
 
Changes to the protocol 
Protocol Summary: This section has been revised to exclude patients who are at high risk of 
progression to severe COVID-19 illness or hospitalization (only applicable for the patients to 
be enrolled at the USA sites in Part A).   
Section 3: One sentence has been added to clarify that since in the USA only non-high risk 
patients for COVID-19 disease progression will be enrolled in Part A, these patients will be 
randomized into the “not at high risk patients” stratum.   
Section 5.2: The protocol exclusion criteria have been revised to include that patients in the 
USA who are at high risk of progression to severe COVID-19 illness or hospitalization** 
must not be enrolled in Part A of the study as a placebo-controlled study may not be 
appropriate in this patient population due to the availability of anti-viral mAbs under EUA in 
the USA.   
** ”High risk of progression to severe COVID-19 illness or hospitalization” is defined to 
match the eligibility criteria for authorized therapy with therapeutic mAbs in the USA, i.e. as 
meeting at least one of the following criteria: Body mass index (BMI) ≥ 35; chronic kidney 
disease; diabetes mellitus; immunosuppressive disease; ongoing immunosuppressive 
treatment; age ≥ 65 years; or age ≥ 55 years in a patient with cardiovascular disease, or 
hypertension, or COPD / other chronic respiratory disease.  
 


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Protocol summary 
Protocol number 
MP0420-CP302 (CSKO136A12201J) 
Full title 
A randomized, double-blind, placebo-controlled, multicenter study of ensovibep 
(MP0420) in ambulatory adult patients with symptomatic COVID-19 – The “EMPATHY” 
Trial 
Brief title 
A study of ensovibep (MP0420) in ambulatory adult patients with symptoms of COVID-19 
Sponsor 
Molecular Partners AG 
Responsible for 
conducting the 
study 
Novartis Pharma AG 
Responsible CRO 
IQVIA (engaged by Novartis Pharma AG) 
Clinical phase  
Phase 2 and Phase 3 
Investigation type 
Biological 
Study type 
Interventional 
Purpose and 
rationale 
Establish the antiviral efficacy of ensovibep against severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) in humans, identify the optimal dose, and demonstrate its 
clinical value for treating COVID-19 in adult ambulatory patients 
Primary 
objectives 
Part A 
The primary objective of this Part is to demonstrate superiority of ensovibep, compared 
to placebo, in reducing SARS-CoV-2 viral load through Day 8. 
 
Part B 
The primary objective of this Part is to demonstrate superiority of ensovibep, compared 
to placebo, in reducing the occurrence of hospitalizations (≥ 24 hours of acute care) 
and/or emergency room visits related to COVID-19 or death from any cause up to Day 
29. 
Secondary 
objectives 
Part A 
The secondary objectives of this Part are: 
• 
To assess the effect of ensovibep, compared to placebo, in reducing the occurrence 
of hospitalizations (≥ 24 hours of acute care) and/or emergency room visits related to 
COVID-19 or death from any cause up to Day 29 
• 
To assess the effect of ensovibep, compared to placebo, in reducing COVID-19 
symptoms through Day 29 
• 
To evaluate safety and tolerability of ensovibep 
• 
To characterize the pharmacokinetics (PK) of ensovibep 
 
Part B 
The secondary objectives of this Part are: 
• 
To assess the effect of ensovibep, compared to placebo, in reducing SARS-CoV-2 
viral load through Day 8 
• 
To assess the effect of ensovibep, compared to placebo, in reducing COVID-19 
symptoms up to Day 29 
• 
To evaluate the immunogenicity of ensovibep and its clinical relevance 
(pharmacokinetic, efficacy, and safety). 
• 
To evaluate safety and tolerability of ensovibep 


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Study design 
This is a randomized, double-blind, placebo-controlled, multicenter study of ensovibep 
(MP0420) in ambulatory adult patients with symptomatic COVID-19. The study has two 
parts: a Phase 2 dose-ranging study to select the best dose over the therapeutic range 
(Part A) to progress into Phase 3, and a confirmatory Phase 3 safety and efficacy study 
of the dose determined in Part A (Part B). 
Screening will be used to determine eligibility. Randomization and treatment will be 
conducted on Day 1 (screening can optionally be done up to 3 days earlier, or also at 
Day 1). Study duration for individual patients is 91 ± 7 days for both Parts. 
 
Part A 
This dose-ranging part of the study will include at least 400 randomized patients in four 
arms (3 active arms and one placebo arm), randomized 1:1:1:1 to receive ensovibep (75 
mg, 225 mg, or 600 mg) or placebo, administered as a single intravenous (i.v.) infusion 
over 60 minutes, and stratified by risk for COVID-19 disease progression (“high-risk 
patients” versus “not at high-risk patients”).  
 
Part B 
Recruitment will begin in Part B once the most safe and efficacious dose has been 
selected from Part A based on the primary [day 8 viral load] analysis. Part B will recruit 
1717 patients randomized 1:1 to either the selected dose of ensovibep or placebo, 
administered as a single i.v. infusion over 60 minutes. An interim analysis for early 
efficacy will be conducted when at least 50% of patients have completed the Day 29 
assessments. Patients will be stratified by risk for COVID-19 disease progression (“high-
risk patients” versus “not at high-risk patients”). 
Study population 
The study will recruit ambulatory symptomatic adult patients diagnosed with COVID-19 
with onset of symptoms within 7 days prior to dosing and with a positive rapid antigen 
test on the day of dosing. 
Key inclusion 
criteria 
1. Men or women ≥ 18 years of age on the day of inclusion (no upper limit). 
2. Presence of two or more COVID-19 symptoms and onset within 7 days prior to 
dosing: Feeling hot or feverish, cough, sore throat, low energy or tiredness, headache, 
muscle or body aches, chills or shivering, and shortness of breath. 
3. Positive test for SARS-CoV-2 in upper respiratory swab on the day of dosing (rapid 
antigen test). 
4. Understand and agree to comply with the planned study procedures. 
5. The patient or legally authorized representative give signed informed consent. 
Key exclusion 
criteria 
1. Requiring hospitalization at time of screening, or at time of study drug administration. 
2. Oxygen saturation (SpO2) ≤ 93% on room air at sea level or ratio of arterial oxygen 
partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2) < 300, respiratory 
rate ≥ 30 per minute, and heart rate ≥ 125 per minute. 
In India, patients with a respiratory rate ≥ 24 per minute or with an oxygen saturation ≤ 
93% on room air (SpO2) are not eligible. 
3. Known allergies to any of the components used in the formulation of the ensovibep or 
placebo. 
4. Suspected or proven serious, active bacterial, fungal, viral, or other infection (besides 
SARS-CoV-2) that in the opinion of the investigator could constitute a risk when taking 
intervention. 
5. Any serious concomitant systemic disease, condition, or disorder that, in the opinion 
of the investigator, should preclude participation in this study. 
6. Any co-morbidity requiring surgery within 7 days of dosing, or that is considered life-
threatening within 29 days of dosing. 
7. Prior or concurrent use of any medication for treatment of COVID-19, including 
antiviral agents, convalescent serum, or anti-viral antibodies. Purely symptomatic 
therapies (e.g., over-the-counter [OTC] cough medications, acetaminophen, and 
nonsteroidal anti-inflammatories [NSAIDs]) are permitted. Prior vaccination for COVID-19 
is permitted. 




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formula. Two-sided 95% confidence intervals (adjusted for an interim analysis) and 
associated p-value for the test of no difference between groups will then be obtained. 
Key words 
COVID-19, COVID 19, SARS-CoV-2, Coronavirus, ensovibep, MP0420, DARPin 


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1 
Introduction 
1.1 
Background 
Coronavirus disease 2019 (COVID-19) is a respiratory disease caused by the novel severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2). While most cases are mild or 
asymptomatic, progressive disease can result in hospitalization, requirement for mechanical 
ventilation, and substantial morbidity and mortality (Johns Hopkins University). SARS-CoV-2 
is estimated to be about 10 times more deadly than seasonal influenza virus (Faust 2020). Risk 
factors for an unfavorable course include advancing age (Zhou 2020), obesity (Hamer 2020), 
and comorbidities such as diabetes mellitus (Caballero 2020) and hypertension (Wu 2020, 
Choi 2020). 
COVID-19 has a median incubation period of 4 days (interquartile range [IQR] 2 to 7 days) 
(Guan 2020) and the mean serial interval defined as the time duration between a primary 
case-patient (infector) having symptom onset and a secondary case-patient (infected) having 
symptom onset for COVID-19 was calculated as 3.96 (95% confidence interval [CI] 
3.53 to 4.39) days (Du 2020). Viral kinetic studies have demonstrated extensive SARS-CoV-2 
viral replication in the pharynx just before and early after symptom onset (He 2020). 
The clinical course of SARS-CoV-2 infection is non-specific at the beginning; the most 
common symptoms at onset of illness are fever, cough, fatigue, and myalgia (Cevik 2020). A 
majority of patients recover within 2 to 3 weeks. Those who progress to more severe symptoms 
typically develop dyspnea between Day 4 and Day 10 of illness (Cohen 2020). 
Weeks and months after the onset of acute COVID-19 some infected patients still continue to 
suffer from symptoms. This prolongation of illness after the acute COVID infection is known 
as Long-COVID-19 or Post-COVID-19 syndrome (Morley 2020). This seems to affect patients 
with mild COVID-19 as well as those with moderate-to-severe disease. The symptoms of 
Long-COVID-syndrome include shortness of breath, fatigue, coughing, and neurological 
symptoms such as altered taste, depression, and reduction in the abilities of daily living. The 
cause of these prolonged symptoms is unknown. The scale of the pandemic makes the 
prevention of Long-COVID-syndrome an imperative. It has been hypothesized that by 
managing the infection earlier post viral syndromes (including Long-COVID-syndrome) could 
be reduced in incidence and severity. 
Several vaccines against SARS-CoV-2 have become available for use, and vaccinations have 
been initiated in many countries for the most vulnerable and the most exposed population. These 
vaccines appear to have high vaccine efficacy of > 90%; however, it’s currently unknown if 
vaccine effectiveness will be maintained long-term (COVID-19 vaccines - EMA 2021). In 
addition, vaccine availability and logistics of vaccinations are current bottlenecks, anticipated 
to be overcome before the end of 2021 in high-income countries. Nevertheless, the proportion 
of individuals who are skeptical about vaccinations is globally between 40% and 80% 
(Yougov 2021). In many middle- or low-income countries, limited availability of vaccines is 


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anticipated to remain a bottleneck well beyond 2021, and herd immunity is unlikely before 2023 
(The Conversation 2021). 
In addition, since December 2020, the emergence of multiple mutated strains of SARS-CoV-2 
with higher infectivity is causing increasing concerns. Measures effective to prevent 
transmission in the wild-type strain may be insufficient to prevent spreading of more infective 
mutant strains. Mutations are mostly found in the spike protein region, which is the target for 
current vaccines. Research to evaluate the effectiveness of currently available vaccines versus 
emerging mutant strains is ongoing. 
Some treatment options for patients with severe disease requiring hospitalization have become 
available: Remdesivir, the only currently approved drug against COVID-19, reduced the time 
to discharge in early hospitalized patients, and has entered the standard of care in several 
countries, although it is not recommended by the World Health Organization (WHO) based on 
“no important effect on mortality, need for mechanical ventilation, time to clinical 
improvement, and other patient reported outcomes”. Corticosteroids have emerged as the 
treatment of choice for critically ill patients. 
Still, interventions that can be administered early during the course of infection to prevent 
disease progression and longer-term complications are urgently needed (Kim 2020). Multiple 
antiviral monoclonal antibodies (mAbs) are under development, specifically targeting 
SARS-CoV-2’s spike protein and thereby its ability to enter the host cell for viral replication. 
Recent data indicate this therapeutic mode of action is beneficial in ambulatory patients treated 
within the first 7 days after symptom onset, reducing by the need for subsequent “medically 
attended visits” (hospitalizations, emergency room visits, urgent case or other physician contact 
for COVID-19) by half (Chen 2020, Weinreich 2020, Gottlieb 2021). However, mutant strains 
are capable to escape the therapeutic effects of mAbs (Starr 2021), as well as endogenous 
immunity of recovered patients (Greany 2021). 
Ensovibep is a designed ankyrin repeat protein (DARPin®) molecule consisting of a chain of 
five covalently linked DARPin® domains with, sequentially, two N-terminal anti-human serum 
albumin (HSA) domains followed by three domains that specifically bind to the trimeric 
receptor binding domain (RBD) of the SARS-CoV-2 spike protein. The three RBD binding 
domains bind to the same epitope but their paratope sequences are different. The cooperative 
binding of these domains prevents the RBD from binding to angiotensin-converting enzyme 2 
(ACE2) on the surface of target cells. The anti-HSA domains are intended to confer an extended 
half-life in vivo. The HSA-binding domains are cross-reactive to the respective mouse, hamster, 
and cynomolgus monkey homologs. 
The rationale for the clinical development of ensovibep (MP0420) is to provide a safe and 
effective therapy for SARS-CoV-2 infections. Effective in that it prevents or reduces the need 
for hospitalization and safe in that it does not provoke excessive immunological and 
inflammatory responses in patients with pre-existing SARS-CoV-2 infection. Due to its 
multi-specificity (see below), it is expected to maintain efficacy as virus spike protein mutants 


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emerge. In addition, it is anticipated that lower doses of ensovibep will be required compared 
to monoclonal antibodies because of its smaller size and higher in vitro antiviral potency. 
The SARS-CoV-2 spike glycoprotein is key for host-cell interaction of the virus (Zhou P 2020, 
Walls 2020, Hoffmann 2020). It comprises two functional units: S1, which includes RBD 
responsible for interaction with host receptors (Hoffmann 2020) such as ACE2, and S2, which 
is responsible for virus-host cell membrane fusion by way of conformational change following 
protease cleavage (Walls 2020, Wrapp 2020). 
Ensovibep has been well-tolerated in healthy volunteers at doses of 3 mg/kg and 9 mg/kg when 
administered as a single infusion over 1 hour as a part of an ongoing Phase 1 First-in-Human 
(FIH) clinical trial (Study MP0420-CP101).    
1.2 
Purpose 
The clinical assessment of safety, tolerability, and pharmacokinetics (PK) of ensovibep is 
ongoing in Study MP0420-CP101, a dose-escalation study in healthy volunteers, exploring 
doses of 3, 9, and 20 mg/kg, under surveillance by a Safety Review Group (SRG). Doses 
(3 mg/Kg and 9 mg/Kg) have been administered as single 60-minute infusions and have been 
well tolerated; 20 mg/Kg dose cohort is pending. The safety, tolerability and PK of 
administration times less than 10 minutes (“bolus injection”) will also be assessed in additional 
cohorts of healthy volunteers within the same study. 
Study MP0420-302, is an operationally seamless two part, randomized, double-blind, 
multicenter, Phase 2 and Phase 3 study designed to assess the efficacy, safety, tolerability, and 
PK of ensovibep in adult ambulatory patients with symptomatic COVID-19. Part A is the Phase 
2 component of the study that will serve to show proof of efficacy in order to progress to Phase 
3 and to support selection of the best efficacious and safe dose; Part B is the Phase 3 component 
of the study that will confirm efficacy and safety of ensovibep at the dose selected based on the 
data from Part A. 
The study will use the acronym EMPATHY: Ensovibep Multicenter Placebo-controlled study 
in Ambulatory patients with sympTomatic COVID-19 (PHase 2 and 3 for efficacY and safety). 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Part A 
 
Primary objective 
Endpoint for primary objective 
• 
To assess the effect of ensovibep, compared to 
placebo, in reducing SARS-CoV-2 viral load through 
Day 8 
 
• 
Time-weighted change from baseline (measured 
at Day 3, Day 5, and Day 8) in log10 SARS-CoV-2 
viral load in nasopharyngeal swabs through Day 8 
 
Secondary objectives 
Endpoints for secondary objectives 
• 
To assess the effect of ensovibep, compared to 
placebo, in reducing the occurrence of hospitalizations 
• 
Proportion of patients experiencing 
hospitalizations (≥ 24 hours of acute care) and/or 






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2.1 
Primary estimands 
2.1.1 
Part A 
The primary clinical question of interest is: what is the dose response of ensovibep compared 
to placebo on log10 SARS-CoV-2 viral load through Day 8 in ambulatory adult patients with 
newly symptomatic COVID-19? 
The primary efficacy response time-weighted change from baseline in log10 SARS-CoV-2 viral 
load in nasopharyngeal swabs through Day 8 and rationale for selection as a primary objective 
can be found in Section 4.1. 
The primary estimand definition is as follows: 
1. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
population, ambulatory adult patients with newly symptomatic COVID-19 with onset of 
symptoms within 7 days prior to dosing and with a positive rapid antigen test on the day 
of dosing 
2. Treatment of interest: the randomized treatment (ensovibep 75 mg, 225 mg, 600 mg, or 
placebo) added to concomitant symptomatic/preventive treatments, including symptomatic 
therapies (e.g., antipyretics/analgesics such as ibuprofen, paracetamol/acetaminophen, 
aspirin) and anticoagulants (e.g., heparin), used for mild-to-moderate COVID-19 
3. Endpoint: time-weighted change from baseline (measured at Day 3, Day 5, and Day 8) in 
log10 SARS-CoV-2 viral load in nasopharyngeal swabs through Day 8 
4. Handling of intercurrent event(s): A combination of treatment policy and composite 
strategy will be used to handle the intercurrent events. A treatment policy strategy will be 
used to handle (1) post-treatment initiation of all antivirals (including convalescent serum, 
antiviral antibodies, and antiviral small molecules), immunomodulating medications; and, 
(2) post-treatment increase in dose of immunosuppressive medications, for the treatment 
or management of COVID-19. A composite strategy will be used to handle (3) death from 
any cause and (4) COVID-19 related hospitalization. 
5. Summary measure: adjusted mean time-weighted change from baseline (measured at 
Day 3, Day 5, and Day 8) in log10 SARS-CoV-2 viral load in nasopharyngeal swabs 
between the ensovibep 75 mg, 225 mg, and 600 mg compared to placebo arms. 
2.1.2 
Part B 
The primary clinical question is: what is the effect of ensovibep compared to placebo on 
reducing the percentage of patients requiring hospitalizations and/or emergency room visits 
related to COVID-19 or death from any cause up to Day 29 in ambulatory adult patients with 
newly symptomatic COVID-19? Hospitalization is defined as ≥ 24 hours of acute care, in a 
hospital or similar acute care facility instituted to address medical needs of those with severe 
COVID-19 during the COVID-19 pandemic. 
The primary efficacy response is hospitalizations (≥ 24 hours of acute care) and/or emergency 
room visits related to COVID-19 or death from any cause up to Day 29 and rationale for 
selection as a primary objective can be found in Section 4.1. 


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The primary estimand definition is as follows: 
1. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
population, ambulatory adult patients with newly symptomatic COVID-19 with onset of 
symptoms within 7 days prior to dosing and with a positive rapid antigen test on the day 
of dosing 
2. Treatment of interest: the randomized treatment (ensovibep [dose selected from Part A] 
or placebo) added to concomitant symptomatic/preventive treatments, including 
symptomatic therapies (e.g., antipyretics/analgesics such as ibuprofen, 
paracetamol/acetaminophen, aspirin) and anticoagulants (e.g., heparin), used for 
mild-to-moderate COVID-19 
3. Endpoint: the binary response of patients experiencing hospitalizations (≥ 24 hours of 
acute care) and/or emergency room visits related to COVID-19 or death from any cause 
up to Day 29 (Yes/No) 
4. Handling of intercurrent event(s): A treatment policy strategy will be used to handle (1) 
post-treatment initiation of all antivirals (including convalescent serum, antiviral 
antibodies, and antiviral small molecules), immunomodulating medications; and, (2) post-
treatment increase in dose of immunosuppressive medications, for the treatment or 
management of COVID-19 
5. Summary measure: difference in proportions of patients experiencing hospitalizations 
(≥ 24 hours of acute care) and/or emergency room visits related to COVID-19 or death 
from any cause up to Day 29 of ensovibep (dose selected from Part A) compared to 
placebo 
2.2 
Secondary estimands 
Not applicable. 
The secondary objectives for both Parts will be referred to as endpoints. 
3 
Study design 
This is a randomized, double-blind, placebo-controlled, multicenter study of ensovibep 
(MP0420) in ambulatory adult patients with symptomatic COVID-19. The study has two parts: 
a Phase 2 dose-ranging study to select the best dose over the therapeutic range (Part A) and a 
confirmatory Phase 3 safety and efficacy study of the dose determined in Part A (Part B). 
Screening will be used to determine eligibility. Randomization and treatment will be conducted 
on Day 1 (screening can optionally be done up to 3 days earlier, or also at Day 1) and with a 
study duration for individual patients of 91 ± 7 days for both Parts. 
Part A 
This dose-ranging part of the study will include at least 400 randomized patients in four arms 
(3 active arms and one placebo arm), randomized 1:1:1:1 (see also Figure 3-1) to receive 
ensovibep (75 mg, 225 mg, or 600 mg) or placebo, administered as a single intravenous (i.v.) 




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Study Design Aspect 
Rationale 
CoV-2 viral load in nasopharyngeal swabs through 
Day 8. 
that in the first week after symptom onset the 
effect of ensovibep is most prominent. 
Part B primary endpoint selection of proportion of 
patients with hospitalizations (≥ 24 hours of acute 
care) and/or emergency room visits related to 
COVID-19 or death from any cause up to Day 29. 
To assess a clinically meaningful endpoint as 
requested by regulatory authorities for up to 4 
weeks after treatment. 
Duration of long-term follow-up at Day 91. 
To evaluate long-term safety and track for 
long-COVID symptoms. 
Parallel design, 4 treatment arms in Part A.  
To evaluate different dose levels of ensovibep 
versus placebo and determine the optimal 
efficacious and safe dose. 
Parallel design, 2 treatment arms in Part B. 
To confirm efficacy and safety of the optimal 
dose identified based on data from Part A 
versus placebo. 
Randomization and placebo arm. 
Randomization and the inclusion of a control 
arm are essential to control unintended 
introduction of bias into the study results 
necessary to establish the safety and efficacy 
of ensovibep in COVID-19. A placebo arm is 
planned for comparison as no antiviral 
therapy is approved for treatment of 
ambulatory COVID-19 patients.  
Blinding. 
The double-blinded design is important, to 
make objective assessments of the 
pharmacological effect of the study treatment 
and to minimize the effect of assessment 
bias. 
Single-dose study. 
Based on the predicted serum half-life of two 
to three weeks in humans, a single systemic 
dose regimen is proposed for treatment of 
COVID-19. 
Phase 2 and Phase 3 study in the same protocol. 
To improve the operational efficiency between 
identifying a safe and efficacious dose in the 
dose-ranging study Part A and the initiation of 
the Phase 3 confirmatory study in Part B.  
Interim analysis in Part B. 
To allow for early stopping for efficacy using 
appropriate alpha spending. 
COVID-19 Tests: 
• Swab: Rapid SARS-CoV-2 antigen test. 
• Swab: SARS-CoV-2 PCR test. 
• Swab: SARS-CoV-2 mutation analysis. 
• Anti-SARS-CoV-2 antibody test. 
The rapid antigen test will be performed to 
quickly identify patients with ongoing 
presence of viral load at randomization; the 
RT-PCR test will be used in retrospect for 
confirmation of the rapid antigen test. For 
patients with a positive rapid test not 
confirmed by a positive PCR test (Day 1 or 
Day 3), SARS-CoV-2 infection will be 
considered uncertain. A sensitivity analysis 
excluding these patients will be conducted. 


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4.1.1 
Rationale for choice of background therapy 
Background standard of care therapy should be maintained in all treatment arms according to 
local practice. To alleviate symptoms and prevent complications related to COVID-19, 
symptomatic treatments and anticoagulants/blood thinners should be continued. Based on the 
mechanism of action (MoA) of ensovibep, no drug-drug-interactions are expected. Please also 
see Section 6.2. 
4.2 
Rationale for dose/regimen and duration of treatment 
Clinical dose and regimen projections for ensovibep are based on an integrated analysis of the 
following: pre-clinical pharmacology results, available clinical safety, tolerability and PK 
results from the ongoing Phase 1 dose-escalation FIH study (MP0420-CP101), and 
PK/pharmacodynamic (PD) modeling. Each of these elements are briefly summarized below. 
Based on these investigations a single, i.v. infusion of 75 mg is projected to have a near-
maximal effect. To allow for uncertainty within the projections, it is recommended that the 
Phase 2 dose and regimen proceed with single, i.v. infusions at 75, 225, and 600 mg in SARS-
CoV-2 patients. Parenteral administration is required because of the chemical structure 
(protein). A single administration is used because the half-life of approximately 2 weeks will 
ensure a sufficient duration of exposure for the disease. Three doses separated by approximately 
a factor of 3 are an appropriate approach for capturing an eventual dose-effect relationship. 
Preclinical pharmacology for MP0420 
In vitro pharmacology studies demonstrated that MP0420 displays sub-pM binding affinities to 
the SARS-CoV-2 RBD (SPR assessment) and has IC50 values in the range of 10-50 pM 
(1-5 ng/mL) in SARS-CoV-2 neutralizing assays against wild-type, pathogenic, and pseudo-
type viruses. Furthermore, IC50 values in the same range were observed for pseudo-type viruses 
with different spike serotypes suggesting that MP0420 could be effective against mutational 
escape. Based on non-clinical pharmacology assessment in SARS-CoV-2 infected hamsters, 
therapeutic dosing regimen for MP0420 have been identified between 3 and 20 mg/kg. When 
dosed during infection (acute) rather than prior to infection (prophylactic) efficacious doses are 
observed at 9 mg/kg and higher with significant improvement in mortality that are generally 
associated with a reduction in SARS-CoV-2 viral load. 
Initial human safety, tolerability, and PK results from MP0420-CP101 
The safety-focused no-observed-adverse-effect-level (NOAEL) approach was used to 
determine FIH doses of 3, 9 and 20 mg/kg for MP0420-CP101 (summary of the relevant pre-
clinical safety data can be found in the Investigator’s Brochure [IB]). Dosing of healthy 
volunteers with single i.v. infusions of 3 and 9 mg/kg (8 mg/kg would equate to a single dose 
of 600 mg in a 75 kg person) was completed. MP0420-CP101 Phase 1 investigation of the 
safety, tolerability, and PK of MP0420 in healthy participants is ongoing, and to date MP0420 
was assessed as safe and well-tolerated and no serious adverse effects have been reported. A 
20 mg/kg cohort will be enrolled in Q1 2021. Based on this, the proposed doses of 75, 225, and 
600 mg are expected to be safe in SARS-CoV-2 infected patients.  


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Preliminary PK data from cohort 1 (i.v., 3 mg/kg) and cohort 2 (i.v., 9 mg/kg) are available. 
The estimated half-life for MP0420 across cohorts is approximately 14.4 days (mean, range: 
11.4-24.0 days). Slightly greater than dose-proportional increases in exposure were observed 
from cohort 1 to cohort 2 (3.8-fold increase in AUC with a 3-fold increase in dose). Cohort 1 
exhibited serum concentrations on Day 14 of 31.9 ± 6.3 ug/mL (mean ± standard deviation 
[SD]), which corresponds to 378 ± 75 nM (mean ± SD), and is > 1000-fold above the IC50 
determined for MP0420 in infected Vero E6 cells. Cohort 1 exposures approximate the 225 mg 
single dose, which is the mid-dose in this dose-range finding study. 
PK/PD modeling 
The PK/PD model was constructed from publicly available data describing viral kinetics from 
SARS-CoV-2 patient throat swabs from untreated COVID-19 patients and calibrated to 
describe reported viral load data from patients treated with a neutralizing antibody therapeutic 
(LY-CoV555). The PK/PD model accounts for MP0420 PK, binding affinities, and MoA to 
predict effects in the lung. Simulations from the PK/PD model indicate that near-maximal 
binding of SARS-CoV-2 RBD is observed for MP0420 with a single, i.v. dose of 75 mg (> 95% 
reduction in free viral spike protein AUC), which is expected to correlate with clinical efficacy. 
Due to uncertainties in both the modeling predictions and the severity of disease at onset of 
therapy it is recommended that 75 mg, 225 mg, and 600 mg doses should be tested as part of a 
dose-range finding study in SARS-CoV-2 infected patients. 
4.3 
Rationale for choice of control drug (placebo) 
Given that no products have received full approval for the sponsor’s intended label claim, the 
sponsor proposes that placebo is the most appropriate comparator for this study. This approach 
is best scientific practice and has been endorsed by regulatory authorities in United States of 
America and Europe at recent Health Authority interactions. 
4.4 
Purpose and timing of planned analyses/design adaptations 
Additional interim analyses may be conducted to support decision making concerning the 
current clinical study, the sponsor’s clinical development projects in general, or in case of any 
safety concerns.  
Additional information is presented in the interim analysis section. 
Part A 
A primary analysis based on viral load up to Day 8 is planned. This analysis is planned after all 
patients have completed the Day 29 visit. Additional unplanned data analyses may be required 
to fulfill regulatory requests. A final analysis for Part A is planned once all participants in Phase 
2 complete the study, i.e. Day 91 of follow up. Additional details will be included in the SAP 
and finalized prior to the database lock for the primary analysis. 
 
 


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Part B 
A single interim analysis is planned after at least 50% of patients enrolled on Part B have 
completed Day 29 assessments. The interim analysis allows for stopping due to efficacy, to 
allow for possible accelerated development of ensovibep. A final analysis for Part B will be 
done once all patients in Phase 3 complete the study, i.e. Day 91 of follow up. 
4.5 
Risks and benefits 
Unmet medical need - There is an ongoing need for effective antiviral treatment of COVID-19. 
Vaccines have started to become available, but their ability to prevent transmission or to create 
long term immunity remains to be determined, their acceptance by the population is currently 
mixed, their effectiveness against actual and future mutant virus strains is unclear, and – most 
importantly – their limited availability (in particular, outside the Western World) will result in 
an ongoing need for therapies for the next 2-3 years or longer. The first monoclonal antibodies 
targeting SARS-CoV-2 have obtained emergency use authorizations for ambulatory patients 
with COVID-19 who are at high risking of developing severe COVID-19 and/or hospitalization, 
but their high cost of production, limited supplies, and the challenges of administration have 
resulted in very limited use outside clinical trials. 
Potential benefits - Based on non-clinical studies, ensovibep has the potential to produce 
antiviral effects which could be beneficial in patients with confirmed SARS-CoV-2 infection 
as well as prophylactically in subjects at risk of infection. The potential benefits are expected 
to be related to an early resolution of symptoms and a lower probability of progressing to severe 
disease requiring hospitalizations or leading to death. 
Potential risks - Due to its specificity for the virus target and based on non-clinical studies, 
ensovibep is expected to have an acceptable safety profile. In healthy volunteers, excellent 
tolerability has been confirmed for 3 mg/kg and 9 mg/kg doses. 
However, as ensovibep is a biological agent there is a potential risk of infusion reactions 
occurring. Consequently, guidance for infusion reaction management is provided in the clinical 
trial protocol. 
There is a potential for patients to develop antidrug antibodies (ADAs), therefore emergence of 
ADAs will be closely monitored during the study. 
The risk to patients in this trial will be minimized by adherence to the eligibility criteria and 
close clinical monitoring, including by an independent data monitoring committee (IDMC). 
Conclusion - Taking these potential benefits and risks into consideration, the sponsor is of the 
opinion that the potential benefits of ensovibep outweigh the potential risks. 
Appropriate eligibility criteria and specific dose-limiting toxicity definitions, as well as specific 
dose modification and stopping rules, are included in this protocol. 


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The risk to patients in this trial will be minimized by compliance with the eligibility criteria and 
study procedures, as well as close clinical monitoring. Refer to the IB. 
Women of child-bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. 
4.5.1 
Blood sample volume 
A volume smaller than a typical blood donation is planned to be collected over a period 
of 91 days, from each patient as part of the study. Additional samples with a volume smaller 
than a typical blood donation may be required for safety monitoring. 
Timings of blood sample collection are outlined in the assessment schedule (Table 8-1). 
A summary blood log is provided in the laboratory manual. Instructions for sample collection, 
processing, storage, and shipment information are also available in the Laboratory Manual. 
5 
Study population 
The study will recruit ambulatory symptomatic adult patients diagnosed with COVID-19, with 
onset of symptoms within 7 days prior to dosing and with a positive rapid antigen test on the 
day of dosing. 
5.1 
Inclusion criteria 
Patients eligible for inclusion in this study must meet all the following criteria: 
1. Men or women ≥ 18 years of age on the day of inclusion (no upper limit). 
2. Presence of two or more of the following COVID-19 symptoms with an onset within 
7 days of dosing: Feeling hot or feverish, cough, sore throat, low energy or tiredness, 
headache, muscle or body aches, chills or shivering, and shortness of breath. 
3. Positive test for SARS-CoV-2 in upper respiratory swab on the day of dosing (rapid 
antigen test). 
4. Understand and agree to comply with the planned study procedures. 
5. The patient or legally authorized representative give signed informed consent. 
5.2 
Exclusion criteria 
Patients meeting any of the following criteria are not eligible for inclusion in this study. 
1. Requiring hospitalization at time of screening, or at time of study drug administration. 
2. Oxygen saturation (SpO2) ≤ 93% on room air at sea level or ratio of arterial oxygen 
partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2) < 300, respiratory 
rate ≥ 30 per minute, and heart rate ≥ 125 per minute. 
In India, patients with a respiratory rate ≥ 24 per minute or with an oxygen saturation ≤ 
93% on room air (SpO2) are not eligible.   


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3. Known allergies to any of the components used in the formulation of the ensovibep or 
placebo. 
4. Suspected or proven serious, active bacterial, fungal, viral, or other infection (besides 
SARS-CoV-2) that in the opinion of the investigator could constitute a risk when taking 
intervention. 
5. Any serious concomitant systemic disease, condition or disorder that, in the opinion of the 
investigator, should preclude participation in this study.* 
6. Any co-morbidity requiring surgery within 7 days of dosing, or that is considered 
life--threatening within 29 days of dosing. 
7. Prior or concurrent use of any medication for treatment of COVID-19, including antiviral 
agents, convalescent serum, or anti-viral antibodies. Purely symptomatic therapies (e.g., 
over-the-counter [OTC] cough medications, acetaminophen, and nonsteroidal anti-
inflammatory drugs [NSAIDs]) are permitted. Prior vaccination for COVID-19 is 
permitted. 
8. Are concurrently enrolled or were enrolled within the last 30 days or within 5 half-lives 
(whichever is longer) in any other type of medical research judged not to be scientifically 
or medically compatible with this study. 
9. Are pregnant or breast feeding. 
10. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception at the 
time of dosing and for 11 weeks after dosing of study drug. Highly effective contraception 
methods include: 
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (i.e., calendar, ovulation, symptothermal, and 
postovulation methods) and withdrawal are not acceptable methods of contraception. 
b. Female sterilization (have had bilateral surgical oophorectomy [with or without 
hysterectomy], total hysterectomy, or bilateral tubal ligation at least 6 weeks before 
taking study treatment). In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow-up hormone level assessment. 
c. Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that patient. 
d. Use of oral, injected, or implanted hormonal methods of contraception or placement 
of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of 
hormonal contraception that have comparable efficacy (failure rate < 1%), for 
example hormone vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the informed consent form (ICF). 
11. For Part A only: Patients in the USA who are at high risk of progression to severe 
COVID-19 illness or hospitalization** must not be enrolled in Part A of this study as a 


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placebo-controlled study may not be appropriate in this patient population due to the 
availability of anti-viral mAbs under EUA in the USA.   
** “High risk of progression to severe COVID-19 illness or hospitalization” is defined to match the 
eligibility criteria for authorized therapy with therapeutic mAbs in the USA, i.e. as meeting at least one 
of the following criteria: Body mass index (BMI) ≥ 35; chronic kidney disease; diabetes mellitus; 
immunosuppressive disease; ongoing immunosuppressive treatment; age ≥ 65 years; or age ≥ 55 
years in a patient with cardiovascular disease, or hypertension, or COPD / other chronic respiratory 
disease.  
* Co-morbidities defining clinically vulnerable patients (with high risk for progression to serious COVID-
19 disease), for example obesity or diabetes, are generally not exclusion criteria.  
 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Sponsor (global 
or local) 
Ensovibep 
15 mg/mL for 
Part A 
Solution for infusion 
i.v. 
Non-blinded vials 
Sponsor (global) 
Placebo for Part A 
Solution for infusion 
i.v. 
Saline infusion bag 
Sponsor (global) 
Ensovibep 15 
mg/mL for Part B  
Solution for infusion 
i.v. 
Double-blind vials 
Sponsor (global) 
Placebo for Part B 
Solution for infusion 
i.v. 
Double-blind vials 
Sponsor (global) 
The investigational drug is ensovibep. 
The formulation for Part A is 15 mg/mL ensovibep provided in isotonic buffer matrix 
 
 
The formulation for Part B is 15 mg/mL ensovibep provided in isotonic buffer matrix 
 
 
Isotonic saline will be used as placebo for Part A of the study. For Part B
 
 
6.1.2 
Additional study treatments 
No other treatment beyond investigational drug and control drug are included in this trial. 


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6.1.3 
Treatment arms/group 
Part A 
Patients in Part A will be assigned on Day 1 at Visit 1 to one of the following 4 treatment 
arms in a ratio of 1:1:1:1 and will be dosed accordingly: 
• Ensovibep 75 mg 
• Ensovibep 225 mg 
• Ensovibep 600 mg 
• Placebo 
Part B 
Once the optimal safe and efficacious dose has been selected from Part A, patients in Part B 
will be assigned on Day 1 at Visit 1 to one of the following 2 treatment arms in a ratio of 1:1: 
• Ensovibep (optimal safe and efficacious dose, selected in Part A) 
• Placebo 
6.2 
Other treatments 
6.2.1 
Concomitant therapy 
Ongoing long-term medications should be continued and adjusted as needed for the 
management of underlying conditions. 
Symptomatic therapy to manage COVID-19 symptoms, such as antipyretics, analgesics, or 
oxygen, is permitted. If local standard of care includes further medications tailored to prevent 
COVID-19 complications (e.g., anticoagulation), these may be used, with the exception of 
drugs that are immunomodulators (e.g., interferon, tocilizumab, sarilumab, colchicine), 
immunosuppressives (e.g., steroids) or antivirals. Patients will be required to get upfront 
approval from the investigator to start any new prescription, OTC, and herbal medication 
treatments, with the exception of paracetamol up to 3 g/day, which does not require upfront 
investigator approval. 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the patient was enrolled into the study must be recorded 
on the appropriate Case Report Forms (CRFs). Prior concomitant therapy defined as all 
medications taken within 30 days prior to enrollment will also be recorded appropriately in the 
CRFs. 
SARS-CoV-2 vaccinations must not be scheduled up to the Day 29 visit, and if possible, should 
be postponed to take place after completion of the study (Day 91 visit) as ensovibep may 
neutralize the effectiveness of the vaccine. If such vaccinations take place prior to the last visit, 
they need to be documented in the relevant electronic Case Report Form (eCRF). 


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Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the medical monitor before randomizing 
a patient or allowing a new medication to be started. 
6.2.2 
Prohibited medication 
The following concomitant therapies are prohibited: SARS-CoV-2 antiviral medication 
(experimental or approved), including convalescent serum or anti-viral antibodies; immune-
modulating (e.g., interferon, tocilizumab, sarilumab) or immunosuppressive (e.g., steroids) 
medications initiated for management of COVID-19. However, patients who use 
immunosuppressive drugs as long-term or chronic treatment for pre-existing conditions and are 
on a stable dose and regimen may continue to use them. 
6.2.3 
Rescue medication 
Study participants who have progression of their COVID-19 such that they require treatment at 
the discretion of the investigator or treating physician should receive appropriate medical care, 
which may include: Anti-SARS-CoV-2 antiviral medication (experimental or approved), 
including convalescent serum or anti-viral antibodies; immune-modulating (e.g., interferon, 
tocilizumab, sarilumab, and colchicine) or immunosuppressive (e.g., steroids) medications for 
management of COVID-19. 
6.3 
Patient numbering, treatment assignment, randomization 
6.3.1 
Patient numbering 
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is enrolled for screening and is retained for the patient throughout his/her 
participation in the trial. A new Patient No. will be assigned at every subsequent enrollment if 
the patient is re-screened. The Patient No. consists of the Center Number (Center No.) (as 
assigned to the investigative site) with a sequential patient number suffixed to it, so that each 
patient’s participation is numbered uniquely across the entire database. Upon signing the ICF, 
the patient is assigned to the next sequential Patient No. available. 
6.3.2 
Treatment assignment, randomization 
At Visit 1, all eligible patients will be randomized via Interactive Response Technology (IRT) 
to one of the treatment arms. The investigator or his/her delegate will contact the IRT after 
confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the preparation of investigational product (IP) 
infusion to be administered to the patient. There will be a blinded and unblinded access to the 
IP allocation from IRT depending on site staff role for Part A. Part B will be fully blinded. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 


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the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced using a validated system that automates 
the random assignment of medication numbers to vials containing the study treatment. 
Stratification criteria 
Randomization will be stratified by risk of progression to severe COVID-19 and/or 
hospitalization: “high risk” or “not at high risk”. The stratum will be determined by the 
investigator according to below and entered into the interactive web response system (IWRS) 
at the time of randomization. 
Patients will be considered “high risk” if they meet at least one of the following criteria: 
• Have a body mass index (BMI) ≥ 35 
• Have chronic kidney disease 
• Have diabetes mellitus 
• Have immunosuppressive disease 
• Are currently receiving immunosuppressive treatment 
• Are ≥ 65 years of age 
• Are ≥ 55 years of age AND have 
• Cardiovascular disease, OR 
• Hypertension, OR 
• Chronic obstructive pulmonary disease/other chronic respiratory disease. 
All patients not meeting the above high-risk criteria will be considered “not at high risk”. 
6.4 
Treatment blinding 
Site firewalls to prevent unblinding and fully dedicated unblinded clinical teams managing the 
study will be assigned to ensure that the unblinded treatment assignment, the unblinded IRT 
outputs, the unblinded treatment administration and handling are overseen in such a way as to 
ensure patient safety and protocol adherence without risking unblinding the site study staff and 
the clinical teams. Refer to Pharmacy Manual for IP handling. 
This is a patient, investigator, and sponsor-blinded study. Patients, investigators, and the 
sponsor will remain blinded to study treatment throughout the study, except where indicated 
below. 
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor. 
Site staff 
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment throughout the study. 


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Unblinding a single patient at site for safety reasons (necessary for patient management) will 
occur via an emergency system in place at the site. 
Drug product will be supplied in bulk only for the 3 treatment arms in Part A, therefore an 
unblinded pharmacist who is independent of the study team will be required in order to maintain 
the blind. Patient treatment allocation can be obtained by the unblinded pharmacist through the 
IWR system. Appropriate measures must be taken by the unblinded pharmacist to ensure that 
the treatment assignments are concealed from the rest of the site staff. 
There will be fully blinded drug vials for both the active treatment arm and the placebo arm, in 
Part B of the trial, so unblinded site and clinical staff would not be needed for Part B. 
Sponsor staff or staff engaged to manage the study 
The following unblinded sponsor staff or staff (such as Contract Research Organization [CRO]) 
engaged to manage and run the study is required for this study during Part A: 
• Unblinded drug accountability monitors 
• Unblinded clinical staff managing drug re-supply to site 
• Unblinded sample analyst(s) (PK, ADA) 
In Part A, unblinded drug accountability monitors are required to review drug accountability, 
preparation, and allocation remotely. The unblinded monitors will be unblinded through review 
of source documentation compiled by the unblinded pharmacist, which details treatment 
allocation to individual patients. These unblinded monitors will also have access to the 
treatment allocation of the patients through the IWR system. 
The following unblinded staff will be applicable to both Part A and Part B: 
The external IDMC assessing unblinded results and the independent analysis team (independent 
statistician, independent programmer) will be allowed to access treatment information for the 
purpose of creating, reviewing, and assessing unblinded interim results. More details will be 
provided in an IDMC charter. 
An independent pharmacometrician and an independent pharmacokineticist may be unblinded 
prior to the database lock after all patients complete Day 29 in Part A in order to explore PK 
 The 
pharmacometrician and the pharmacokineticist will work independently and will only disclose 
results once the database is locked after all patients complete Day 29 in Part A. 
Unblinding after the primary analysis database lock in Part A 
After the database lock for the primary analysis in Part A, a small unblinded study team will 
perform the analysis and undertake submission related activities. Treatment assignment will 
continue to remain blinded to all investigators, site personnel, patients and other study team 
members until all patients have completed the entire study participation and the final database 
lock for Part A has occurred. 


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All unblinded  team members will keep randomization lists and data or information that could 
unblind other study team members confidential and secure until final clinical database lock.  
Primary analysis results and reports generated prior to the final database lock that would reveal 
subject-level data will be kept in a secure and restricted area until the end of the study. The 
detailed procedures for maintaining data integrity after primary analysis database lock will be 
described in a charter. 
Following final database lock all staff may be considered unblinded.  
 Health authorities will be granted access to unblinded data if needed. 
6.5 
Dose escalation and dose modification 
Investigational or other study treatment dose adjustments are not permitted. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The start and end date/time of each infusion as well as any infusion interruptions (stop and 
restart times) will be documented in the eCRF. The prescribed dosage, timing, and mode of 
administration may not be changed. Any departures from the intended regimen must be 
recorded in the eCRFs. 
Compliance will not be evaluated for this single-dose study. 
6.6.2 
Recommended treatment of adverse events 
For treating patients who deteriorate in their symptoms or conditions related to COVID-19, 
please refer to Section 6.2. Any infusion-related reactions should follow standard of care 
(symptomatic treatment), please see Section 9.1.1. 
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF. 
6.6.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
patient safely. Blinding codes may also be broken after a patient discontinues treatment due to 
disease progression if deemed essential to allow the investigator to select the patient’s next 
treatment regimen, and after discussion and agreement with the sponsor. Most often, study 
treatment discontinuation and knowledge of the possible treatment assignments are sufficient 
to treat a study patient who presents with an emergency condition. Emergency treatment code 
breaks are performed using the IRT. When the investigator contacts the system to break a 
treatment code for a patient, he/she must provide the requested patient identifying information 
and confirm the necessity to break the treatment code for the patient. The investigator will then 
receive details of the investigational drug treatment for the specified patient and a fax or email 
confirming this information. The system will automatically inform the clinical monitor for the 
site and the study team that the code has been broken. 


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It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide: 
• protocol number 
• name (if available) 
• patient number 
 
In addition, oral and written information to the patient must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section. 
Drug preparation and dilution according to study arm, prior to administration, is described in 
the IMP handling and administration manual. 
A unique medication number is printed on the study medication label. 
6.7.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified in the IMP handling and administration protocol. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective sponsor`s Quality Assurance. 
Study treatment will be prepared by independent pharmacist or qualified site personnel in order 
to ensure treatment masking. Following labeling and secondary packaging, the MP0420 IMP is 
supplied as a sterile solution for i.v. infusion. For clinical administration, the required volume 
of MP0420 IMP will be calculated as defined in the MP0420 clinical trial protocol. Sterile 0.9 
% NaCl infusion bags will be used. First, a sodium chloride solution volume equivalent to the 
required MP0420 IMP volume will be removed from the bag. Second, the required volume of 
MP0420 IMP will be injected into the bag. The i.v. infusion will then be performed according 
to standard clinical procedures using a 0.2 µm in-line filter, and followed by an infusion set 
flush using 25 mL from a fresh 0.9 % NaCl infusion bag. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the patient except for the medication number. 


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The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log will be returned to the CRO as part of the final drug accountability filing. 
7 
Informed consent procedures 
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-
approved informed consent. 
If applicable, in cases where the patient's representative(s) gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible given 
his/her understanding. If the patient is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the patient source documents. 
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the patient informed consent and should 
be discussed with the patient during the study as needed. Any new information regarding the 
safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an investigator notification or an aggregate 
safety finding. New information might require an update to the informed consent and then must 
be discussed with the patient. 
The following informed consents are included in this study: 
• Main study consent for Phase 2 study 
• Main study consent for Phase 3 study 
 
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study, they must adhere to the contraception requirements. 
8 
Visit schedule and assessments 
The Assessment Schedule (Part A: Table 8-1, Part B: Table 8-2) lists all of the assessments 
when they are performed. All data obtained from these assessments must be supported in the 
patient’s source documentation. 


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Patients should be seen for all visits/assessments as outlined in the assessment schedule (Part A: 
Table 8-1, Part B: Table 8-2) or as close to the designated day/time as possible. Study visits can 
be performed as home visits by a healthcare provider (e.g., a nurse). Missed or rescheduled 
visits should not lead to automatic discontinuation. Patients who prematurely discontinue the 
study for any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed for the final visit will be performed. At this final visit, AE and concomitant 
medications will be recorded on the CRF. 
When the following assessments are scheduled to be performed at the same time point, the order 
of priority will be as follows: questionnaire, vital signs, swab/blood sample. 
Every effort will be made to take the PK sample at the protocol specified time. 












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8.1 
Screening 
Screening and re-screening 
Re-screening can only occur once a patient has failed screening. It is permissible to re-screen a 
participant if he/she was potentially exposed to SARS-CoV-2 but has no positive rapid antigen 
test for SARS-CoV-2 by upper respiratory swab. 
8.1.1 
Information to be collected on screening failures 
Patients who sign an ICF form and are subsequently found to be ineligible prior to 
randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate CRF. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure patients. No other data will 
be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a serious adverse event (SAE) during the screening phase (see SAE section for 
reporting details). If the patient fails to be randomized, the IRT must be notified within 2 days 
of the screen fail that the patient was not randomized. 
Patients who are randomized and fail to start treatment, e.g., patients randomized in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate CRF. 
8.2 
Patient demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
Patient demographics: date or year of birth, sex, race, predominant ethnicity (if permitted) and 
relevant medical history/current medical conditions (until date of signature of informed 
consent) will be recorded in the eCRF. Where possible, the diagnosis and not symptoms should 
be recorded. Patient race and ethnicity are collected and analyzed to identify variations in safety 
or efficacy due to these factors as well as to assess the diversity of the study population as 
required by Health Authorities. 
All prescription medications, OTC drugs and significant non-drug therapies prior to the start of 
the study must be documented. See the protocol Section 6.2.1 Concomitant Therapy for further 
details on what information must be recorded on the appropriate page of the eCRF. 
8.3 
Efficacy 
8.3.1 
SARS-CoV-2 viral load 
The viral load will be measured by means of a nasopharyngeal swab, which will be followed 
by quantitative reverse transcriptase-polymerase-chain-reaction (RT-PCR) assay at a central 
laboratory. (Details of the nasopharyngeal swab and the RT-PCR testing will be in the Lab 
Manual.) 




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8.4 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
For details on AE collection and reporting, refer to AE section. 
 
Assessment 
Specification 
Physical examination 
A complete physical examination (Day 1) will include the 
examination of general appearance, skin, neck (including thyroid), 
eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph 
nodes, extremities, vascular, and neurological. If indicated based 
on medical history and/or symptoms, rectal, external genitalia, 
breast, and pelvic exams will be performed. 
An assessment of general physical appearance will include the 
examination of general appearance and vital signs (systolic and 
diastolic blood pressure [BP], heart rate [HR], temperature and 
pulse oximetry). An assessment of general physical appearance 
will be performed at all visits starting from Day 3. 
Information for all physical examinations must be included in the 
source documentation at the study site. Clinically relevant findings 
that are present prior to signing informed consent must be 
recorded on the appropriate CRF that captures medical history. 
Significant findings made after signing informed consent which 
meet the definition of an Adverse Event must be recorded as an 
adverse event. 
Vital signs 
Vital signs will include the collection of BP and HR. After the 
patient has been sitting for 3 minutes, with back supported and 
both feet placed on the floor, systolic and diastolic BP will be 
measured using an automated validated device, e.g., OMRON 
with an appropriately sized cuff. In case the cuff sizes available 
are not large enough for the patient's arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used. 
If vital signs are out-of-range at screening and/or baseline (see 
Section 5.2 of the protocol for details), two additional readings can 
be obtained, so that a total of three consecutive assessments are 
made, with the patient seated quietly for approximately five 
minutes preceding each repeat assessment. The last reading 
must be within the ranges provided in the eligibility criteria in order 
for the patient to qualify. 
In case of repeated vital assessments, the eCRF should contain 
all repeat measurements. 
Temperature, respiratory rate 
and oximetry 
Body temperature (in °C), respiratory rate and oxygen saturation 
(pulse oximeter) will be assessed simultaneous to vital signs. 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 
0.1 kilogram [kg] in indoor clothing, but without shoes) will be 
measured as specified in Table 8-1 and Table 8-2. 
Body mass index (BMI) will be calculated using the following 
formula: 
BMI = Body weight (kg) / (Height [m])2 


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8.4.1 
Laboratory evaluations 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. 
In all cases, the investigator must document in the source documents the clinical considerations 
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the patient to continue in the study. 
A central laboratory will be used for analysis of all safety specimens collected. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the central laboratory manual. 
All abnormal lab results must be evaluated for criteria defining an AE and reported as such if 
the criteria are met. For those lab AEs, repeated evaluations are mandatory until normalization 
of the result(s) or until the result is no longer considered to be clinically significant. 
 
Test category 
Test name 
Hematology 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils, Other)  
Chemistry 
Albumin, Alkaline phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), Gamma-glutamyl-transferase 
(GGT), Lactate dehydrogenase (LDH), Bicarbonate, Calcium, 
Magnesium, Phosphorus, Chloride, Sodium, Potassium, Creatinine, 
Creatine kinase, Direct Bilirubin, Total Bilirubin, Total Protein, Blood 
Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose 
(non-fasting), C-reactive protein (CRP), D-Dimer, Ferritin 
Coagulation 
Prothrombin time (PT), International normalized ratio (INR), Activated 
partial thromboplastin time (APTT)  
Pregnancy Test 
Serum / Urine pregnancy test  
8.4.2 
Electrocardiogram 
Not evaluated. 
8.4.3 
Pregnancy and assessments of fertility 
A condom is required for all sexually active male patients to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, 
male patients should not donate sperm for the time period specified above. 
All pre-menopausal women who are not surgically sterile will have pregnancy testing at 
screening and end of study (EOS). Additional pregnancy testing might be performed if 
requested by local requirements. 


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Screening: Women who have been on stable highly effective contraception in the last 3 months 
prior to enrollment will have a urine beta-human chorionic gonadotropin (ß-HCG) pregnancy 
test with minimum sensitivity 25 mIU/mL. In other cases, e.g., no previous contraception or 
unstable (e.g., due to missed days of oral contraceptive or change in contraceptive method), 
women will have a serum ß-HCG pregnancy test. 
EOS: Urine ß-HCG pregnancy test. In the case of a positive test at the EOS, the pregnancy will 
be reported. The site will contact the participant at least monthly and document the participant's 
status until the pregnancy has been terminated or until 6 months after the delivery. The outcome 
of the pregnancy will be reported to the sponsor without delay within 24 hours if the outcome 
is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or 
life-threatening complication to the mother or newborn). 
The result of each pregnancy test will be reported on an eCRF. 
Assessments of fertility 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of 
child-bearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy 
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, follicle stimulating hormone (FSH) testing 
is required of any female patient regardless of reported reproductive/menopausal status at 
screening/baseline, otherwise the contraception measures described for women of child-bearing 
potential apply. 
8.4.4 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/patient population. 
8.5 
Additional assessments 
8.5.1 
Pharmacokinetics 
Venous blood samples will be collected for assessment of free ensovibep (ensovibep not bound 
to target) and total ensovibep (sum of ensovibep not bound to target and ensovibep bound to 
target) concentrations in serum at the visits defined in the assessment schedule. 
Pharmacokinetic samples will be obtained and evaluated in all participants and at all dose levels 
except the placebo group. Free and total ensovibep will be determined by validated analytical 
methods. Concentrations will be expressed in mass per volume units. 
 
 
 


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Results will be presented in the Bioanalytical Data Report. 
 
 
 
 
The PK parameters will be determined using the actual recorded (elapsed) sampling times 
relative to start of infusion and non-compartmental method(s) with Phoenix WinNonlin 
(Version 6.4 or higher). 
The following PK parameters will be determined: Cmax, Tmax, AUClast, AUCinf, T1/2, λz, 
Vz, CL. Additional pharmacokinetic parameters may be calculated as necessary. Further details 
are provided in the SAP. 
The linear trapezoidal rule will be used for AUC calculation. Regression analysis of the terminal 
serum elimination phase for the determination of T1/2 will include at least 3 data points after 
Cmax. If the adjusted R2 value of the regression analysis of the terminal phase will be less than 
0.75, no values will be reported for T1/2, AUC, CL, and Vz. 
8.5.2 
Biomarkers 
8.5.2.1 
Rapid antigen test 
An immunoassay (COVID-19 Rapid Antigen Test) for the qualitative detection of 
SARS-CoV-2 antigens in nasopharyngeal swab samples will be used to confirm ongoing 
presence of viral load with SARS-CoV-2 prior to randomization. 
8.5.2.2 
SARS-CoV-2 viral load 
SARS-CoV-2 viral load will be quantified during the course of the study according to the 
Assessment Schedule (Table 8-1 and Table 8-2). Viral load will be measured to determine its 
correlation with other clinical and pharmacodynamic parameters by the use of a validated 
RT-PCR test on a sample of specimen of the respiratory mucosa (nasopharyngeal swab), 
reported as copies of viral RNA per milliliter of transport media (copies/mL). The same sample 
will be used to analyse viral genome to determine and monitor the virus genetic variants. 
Instructions for sample collection, processing, and shipment will be provided in the Laboratory 
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Patients who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 9.1.2 ‘Withdrawal of Informed Consent’ section). Where possible, 
they should return for the assessments indicated in the Assessment Schedule. If they fail to 
return for these assessments for unknown reasons, every effort (e.g., telephone, e-mail, letter) 
should be made to contact the patient/pre-designated contact as specified in the lost to follow-up 
section. This contact should preferably be done according to the study visit schedule. 
 


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9.1.2 
Withdrawal of informed consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient: 
• Does not want to participate in the study anymore, 
and 
• Does not want any further visits or assessments, 
and 
• Does not want any further study related contacts. 
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information. 
Legal framework of certain countries does not require consent to the use of personal and coded 
data. However, patients in these countries do retain the right to object to the further use of their 
personal data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits may not be collected and will be considered 
missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the patient’s study discontinuation should be made as detailed in the 
assessment table. 
All research results (data) that have already been collected for the study evaluation will 
continued to be used. 
9.1.3 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g., dates of telephone 
calls, registered letters, etc. A patient should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study. 
9.1.4 
Study stopping rules 
Overall study stopping rules 
Enrollment in the study will be placed on hold if any of the following occurs cumulatively 
across all treatment arms: 
During Part A: 




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10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation patient after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of the individual patient and 
identifying and documenting AEs. 
Qualified medical personnel will be readily available to advise on trial-related medical 
questions or problems. 
Throughout the study, the investigator will determine whether any AEs have occurred by 
evaluating the participant. These events may be directly observed, reported spontaneously by 
the patient or by questioning the patient at each study visit or by laboratory test findings. 
Patients should be questioned in a general way, without asking about the occurrence of any 
specific symptoms. 
Note that any symptoms collected by the PROs (see Section 8.3.3) will not be considered AEs 
and will not be reconciled with AEs. 
Adverse events should be described using a diagnosis whenever possible, rather than individual 
underlying signs and symptoms. Adverse events must be accompanied by the following 
information (as far as possible): 
1. Intensity, graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 
2. Its causal relationship to the study treatment. If the event is due to lack of efficacy or 
progression of underlying illness (i.e., progression of the study indication) the assessment 
of causality will usually be ‘Not suspected.’ However, worsening of COVID-19 that 
exceeds anticipated fluctuations or course of the disease should be documented as AE, and 
may qualify as an adverse event of special interest (AESI) (see Section 10.1.4). 
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE, and Section 10.1.3 
for SAE reporting) and which seriousness criteria have been met 
5. All AEs must be treated appropriately. Treatment may include interrupting or withdrawing 
of study drug 
6. Its outcome 


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Relevant conditions apart from COVID-19 infection, which were already present at the time of 
informed consent should be recorded in medical history of the patient. However, worsening of 
these conditions after study start should be recorded as an AE. 
Adverse event monitoring should be continued until EOS visit (see Table 8-1). After the EOS, 
only serious events assessed as related to study drug should continue to be reported, and only 
to the safety database. 
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g., continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the IB. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
the underlying disease. 
10.1.2 
Serious adverse events 
An SAE is defined as any AE (appearance of [or worsening of any pre-existing]) undesirable 
sign(s), symptom(s), or medical conditions(s) which meets any one of the following criteria: 
• fatal 
• life-threatening (see definition below) 
Life-threatening in the context of an SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
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• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the 
ICH-E2D Guidelines). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
10.1.3 
SAE reporting 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until last study visit must be reported to the medical monitor 
safety desk within 24 hours of learning of its occurrence. Detailed instructions regarding the 
submission process and requirements are included in the investigator folder provided to each 
site. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, further information may urgently be required from 
the investigator for health authority reporting. An Investigator Notification (IN) may need to be 
issued to inform all investigators involved in any study with the same study treatment that this 
SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 


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10.1.4 
AEs of Special Interest 
The following events are AEs of Special Interest (AESI) for this study: 
• A CTCAE Grade 2 or higher (i.e. requiring intervention) of: 
• Infusion site reactions 
• Hypersensitivity reactions (including anaphylaxis, immune complex mediated 
hypersensitivity, cytokine release syndrome and other hypersensitivity reactions) 
• Worsening of COVID-19 disease that is reported as a moderate or severe AE per 
investigator judgment, with onset within 1 week of study drug administration. 
• Liver events requiring follow-up (see Appendix 16.3) 
• Renal events requiring follow-up (see Appendix 16.4) 
The reporting of AESIs, even if non-serious, follows the same procedures and timelines as the 
reporting of SAEs: They must be reported to the medical monitor safety desk within 24 hours 
of learning of their occurrence, using the same forms. 
10.1.5 
Pregnancy reporting 
Reporting of pregnancy in female study participants follows the same procedures and timelines 
as the reporting of SAEs: They must be reported to the medical monitor safety desk within 
24 hours of learning of their occurrence, using a pregnancy form. 
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to the medical monitor safety desk within 24 hours of learning of its occurrence. The 
pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. 
Pregnancy follow-up should be reported on the same form and should include an assessment of 
the possible relationship to the study treatment for any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported. 
Pregnancy of a male participant’s female partner is not considered to be an AE. However, the 
outcome of all pregnancies occurring from dose administration until end of study (13 weeks 
after administration of IP) should, if possible, be followed up and documented. 
Information on the pregnancy of a male participant’s partner must be obtained directly from the 
patient’s partner; the male participant should not be asked to provide this information. Prior to 
obtaining information related to the pregnancy and outcome of the pregnancy, the investigator 
must obtain the participant’s partner consent. A consent form specific to this situation must be 
used. 
10.1.6 
Reporting of study treatment errors 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (European Medicines Agency [EMA] definition). 


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Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional safety monitoring 
10.2.1 
Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
Please refer to Table 16-1, Table 16-2, and Table 16-3 in Appendix 16 for complete definitions 
of liver laboratory triggers. 
Once a patient is exposed to study treatment, every liver event defined in Table 16-1 should be 
followed up by the investigator or designated personnel at the trial site, as summarized below. 
Additional details on actions required in case of liver events are outlined in Table 16-2. Repeat 
liver chemistry tests (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
total bilirubin [TBL], prothrombin time [PT]/international normalized ratio [INR], alkaline 
phosphatase [ALP] and gamma-glutamyl transferase [G-GT]) to confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the patient. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should be recorded as part of the liver AE. 
• If the initial elevation is confirmed, close observation of the patient will be initiated 
• Hospitalization of the patient if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include 
• These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more detailed 
history of symptoms and prior or concurrent diseases, history of concomitant drug use, 
exclusion of underlying liver disease. 
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF. 
10.2.2 
Renal safety monitoring 
Once a patient is exposed to study treatment, the following abnormal renal laboratory alert value 
should be assessed during the study period: 


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• Serum creatinine increase ≥ 25% compared to baseline during normal hydration status 
Abnormal renal event findings must be confirmed within 24 to 48 hours after the first 
assessment. 
Once a patient is exposed to study treatment, renal laboratory alerts or renal safety events should 
be monitored and followed up by the investigator or designated trial staff as summarized in 
Table 16-4. 
Every renal laboratory trigger or renal event as defined in Table 16-4 should be followed up by 
the investigator or designated personnel at the trial site as summarized in Table 16-4. 
10.3 
Independent data monitoring committee 
This study will include an IDMC that will function independently of all other individuals 
associated with the conduct of this clinical trial, including the site investigators participating in 
the study. The IDMC will assess at defined intervals the progress of a clinical trial, safety data, 
and critical efficacy variables and recommend to the sponsor whether to continue, modify, or 
terminate a trial. See also Section 12.7. 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of IDMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the IDMC. 
11 
Data collection and database management 
11.1 
Data collection 
Data not requiring a separate written record will be defined in the protocol and the Assessment 
Schedule (Table 8-1 and Table 8-2) and can be recorded directly on the CRFs. All other data 
captured for this study will have an external originating source (either written or electronic) 
with the CRF not being considered as source. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
Designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 
21 CFR Part 11 requirements. Investigator site staff will not be given access to the Electronic 
Data Capture (EDC) system until they have been trained. Automatic validation programs check 
for data discrepancies in the eCRFs and allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The investigator must certify that the data entered are complete and accurate. 


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After final database lock, the investigator will receive copies of the patient data for archiving at 
the investigational site. 
Certain data may be captured via other source documentation (such as safety laboratory data 
report, imaging) and then transcribed, uploaded or transferred into the eCRF RAVE system. 
This, and any additional data treated in this manner, will be source data reviewed by the study 
monitor per the monitoring plan and the location of source data (i.e., source, paper or a local 
electronic system) will be documented prior to study start. When using an electronic source 
record as the original point of data capture, there is no additional data entry step for the site for 
data collected directly into the application. Rather, the electronic source record directly 
populates the study database. 
Automatic validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected as data is entered into IQVIA EDC 
system. 
Remote monitoring of the original electronic source records will take place, due to COVID-19 
pandemic conditions. to ensure protocol adherence, to assess site operational capabilities, and 
to perform other monitoring activities that cannot be performed remotely. 
The investigator must certify that the data entered into eSource are complete and accurate. After 
database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
A CRO will review the data entered by investigational staff for completeness and accuracy. 
Electronic data queries stating the nature of the problem and requesting clarification will be 
created for discrepancies and missing values and sent to the investigational site via the EDC 
system. Designated investigator site staff are required to respond promptly to queries and to 
make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology. 
Dates of screenings, randomizations, screen failures, as well as randomization codes and all 
dosage changes will be tracked using an IRT. The system will be supplied by 
, who 
will also manage the database. The blinded data will be sent electronically to the sponsor (or a 
designated CRO) at specific timelines. 


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Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request of the 
sponsor. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by the sponsor. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a sponsor 
representative will review the protocol and data capture requirements (i.e., eCRFs) with the 
investigators and their staff. During the study, there are several methods employed to ensure 
protocol and Good Clinical Practice (GCP) compliance and the quality/integrity of the sites’ 
data. The blinded study monitor will perform remote visits to check the completeness of patient 
records, the accuracy of data capture / data entry, the adherence to the protocol and to GCP, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
study monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized CRA. Additionally, a central analytics organization may analyze 
data & identify risks & trends for site operational parameters and provide reports to clinical 
teams to assist with trial oversight. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient's file. The investigator must also keep the original ICF form signed by the patient (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed. 
 
 


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12 
Data analysis and statistical methods 
Summary statistics will be provided for: 
• continuous variables: N, mean, SD, minimum, lower quartile (25th percentile), median, 
upper quartile (75th percentile), and maximum 
• binary or discrete variables: absolute number of patients in each category and relative 
frequencies 
Presentation, unless otherwise specified, of: 
• P-values: 2-sided with a 5% significance rate 
• Confidence intervals: 95% intervals 
The baseline value is defined as the last assessment prior to treatment administration. The value 
at screening will be used, if available, if the scheduled baseline assessment value is missing. 
Following the operationally seamless design, analysis of Part A and Part B will be handled 
separately (e.g., primary, secondary, and exploratory analyses in Part A will be performed only 
on Part A patients and primary, secondary, and exploratory analyses in Part B will be performed 
only on Part B patients). 
Any data analysis carried out independently by the investigator should be submitted to the 
sponsor, as detailed in the CTAs, before publication or presentation. 
Part A: Efficacy and safety data during the Part A treatment period will be presented by 
treatment group (ensovibep 75 mg, ensovibep 225 mg, ensovibep 600 mg, and placebo) 
administered as an i.v. infusion over 60 minutes. 
Part B: Efficacy and safety data during the Part B treatment period will be presented by 
treatment group (ensovibep [dose determined in Part A] and placebo) administered as an i.v. 
infusion over 60 minutes. 
12.1 
Analysis sets 
The analysis sets are defined as follows: 
• Screened set (SCR): all unique patients who signed the informed consent (e.g., only the 
chronologically last screening data is counted in the case of re-screened patients) 
• Randomized set (RAN): all patients who received a randomization number, regardless of 
receiving study treatment 
• Full analysis set (FAS): all patients in the RAN that initiated i.v. infusion of study 
treatment during the treatment period excluding mis-randomized patients, where 
mis-randomized patients are defined as cases where IRT contacts were made by the 
investigator/qualified site staff either prematurely or inappropriately prior to confirmation 
of the patient’s final randomization eligibility and treatment was not administered to the 
patient 
• Safety set (SS): all patients who initiated i.v. infusion of study drug 


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• PK analysis set: all patients with at least one available valid (i.e., not flagged for 
exclusion) PK concentration measurement, who received any study treatment and with no 
protocol deviations that impact PK data 
For the FAS following the intention to-treat (ITT) principle, patients will be analyzed according 
to their randomized treatment assignment. Unless otherwise specified, all efficacy analysis will 
be performed on the FAS. 
For the SS following the per-protocol (PP) principle, patients will be analyzed according to the 
treatment received. Unless otherwise specified, all safety analyses will be performed on the SS. 
Important protocol deviations for exclusion from PK analysis set may be identified by the 
clinical team before the primary analysis and final database lock in Part A and interim and final 
database lock in Part B. 
12.2 
Patient demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment arm for the FAS and SS (if different from the FAS) in 
each Part. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class (SOC), high level term (HLT), preferred term (PT), and treatment arm for 
the FAS in each Part. 
12.3 
Treatments 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group using the SS in each Part. 
12.4 
Analysis of the primary endpoints 
12.4.1 
Definition of primary endpoints 
Part A 
In Part A, the primary variable for the study is a virologic endpoint defined as time-weighted 
change from baseline to Day 3, 5, and 8 (2, 4, and 7 days after dosing, respectively) in log10 
SARS-CoV-2 viral load in nasopharyngeal swabs. 
To calculate the time-weighted change from in log10 SARS-CoV-2 viral load through Day 8 
for each patient, the equation below is used: 
∑
{0.5(𝑌𝑌𝑖𝑖+ 𝑌𝑌𝑖𝑖+1)(𝑡𝑡𝑖𝑖+1 −𝑡𝑡𝑖𝑖)}
𝑏𝑏−1
𝑖𝑖=𝑎𝑎
𝑡𝑡𝑏𝑏−𝑡𝑡𝑎𝑎
 


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where 𝑌𝑌𝑖𝑖 is the change from baseline in log10 SARS-CoV-2 viral load at Visit 𝑖𝑖, 𝑡𝑡𝑖𝑖 is the time at 
the Visit 𝑖𝑖 (the actual study day), 𝑎𝑎 is the baseline assessment at Day 1, and 𝑏𝑏 is the last 
assessment at or prior to Day 8. 
The primary estimand definition for the Part A endpoint is in Section 2.1.1. 
Part B 
In Part B, the primary variable is a clinical efficacy endpoint defined as any of the following 
up to Day 29: 
• Hospitalizations (≥ 24 hours of acute care) related to COVID-19; OR, 
• Emergency room visits related to COVID-19; OR, 
• Death from any cause. 
If a patient experiences more than one of the events, the first event to occur will be counted 
towards the clinical efficacy endpoint and the date at which the first event occurred will be used 
as time date at which the clinical efficacy endpoint was achieved. 
The primary estimand definition for the Part A endpoint is in Section 2.1.2. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
Part A 
The primary objective of this Part is to demonstrate superiority of ensovibep, compared to 
placebo, on reducing SARS-CoV-2 viral load through Day 8 using the response of time-
weighted change from baseline in log10 SARS-CoV-2 viral load through Day 8. The MCP-
Mod methodology (Bretz 2005, Pinheiro 2014, EMA 2014, FDA 2016) to address this objective 
and confirm an overall dose-response signal, characterize the dose response efficacy 
relationship across the dose range of ensovibep, and estimate the smallest dose(s) that 
corresponds to the clinically relevant effect over placebo with regards to time-weighted change 
from baseline in log10 SARS-CoV-2 viral load through Day 8. 
The null hypothesis of a constant dose-response curve for the time-weighted change from 
baseline in log10 SARS-CoV-2 viral load through Day 8 will be tested at a one-sided 10% alpha 
level against the alternative hypothesis of a non-constant dose-response curve using the 
MCP-Mod methodology. 
Generalized MCP-Mod (Pinheiro 2014) will be employed in a three-step approach in the steps 
is given below: 
• Conventional step - covariate-adjusted mean response for each dose 
The data is analyzed using analysis of covariance (ANCOVA) to obtain covariate adjusted 
treatment effects and corresponding variance covariance matrix. The ANCOVA will adjust for 
baseline log10 SARS-CoV-2 viral load, treatment group, baseline risk of progression to severe 


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COVID-19 and/or hospitalization (“high risk” versus “not at high risk”) and other relevant 
parameters (specified in the SAP) as covariates. 
• Proof-of-concept step - multiple contrast tests 
The null hypothesis of flat dose-response relationship as compared to placebo for the primary 
efficacy endpoint will be tested at a significance level of one-sided 10% against the alternative 
hypothesis of a non-constant dose-response curve using a multiple contrast test as described in 
the Generalized MCP-Mod methodology (Pinheiro 2014). The contrast test statistic is a linear 
combination of the optimal contrast coefficients corresponding to the candidate dose-response 
curve with the adjusted mean responses at each individual dose obtained from Step 1. 
The contrast coefficients will be chosen to maximize the power to detect pre-specified candidate 
models (Pinheiro 2014). For that purpose, the Emax dose-response shape (E0 + Emax ∗d/(d +
ED50)) with three shapes of ED50 = 8, 40, 180 and the sigmoid Emax dose-response shape 
(E0 + Emax ∗dh/(dh + ED50
h )) with two shapes of (ED50,h) = (120, 4) and (450, 3) will be 
used where E0 is the expected placebo effect, Emax is the maximum change in effect over 
placebo, ED50 is the dose at which 50% of Emax is achieved, and h is Hill parameter (Figure 
12-1). 
The global test decision is based on the maximum of the contrast test statistics. A critical value 
𝑞𝑞 controlling the type I error rate can be derived from the fact that the contrast test statistics 
approximately follow a multivariate normal distribution and that their maximum follows the 
distribution of the maximum of a multivariate normal distribution. If the maximum contrast test 
statistic exceeds the critical value 𝑞𝑞, the overall null hypothesis of a constant dose-response 
curve is rejected and one proceeds to characterize the dose response efficacy relationship and 
estimate the optimum dose(s) that corresponds to the clinically relevant effect over placebo. 




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The cumulative proportion of experiencing hospitalizations (≥ 24 hours of acute care) and/or 
emergency room visits related to COVID-19 or death from any cause up to Day 29 will be 
estimated for each randomized group using Kaplan-Meier methods to take account of losses to 
follow-up. 
The difference between randomized groups in the estimated log cumulative proportion will be 
calculated and the variance for this difference will be obtained using Greenwood’s formula. 
Two-sided 95% CIs (adjusted for an interim analysis) and associated p-value for the test of no 
difference between groups will then be obtained. 
The hazard ratios for these comparisons for the occurrence of hospitalizations (≥ 24 hours of 
acute care) and/or emergency room visits related to COVID-19 or death from any cause and 
their corresponding 95% CIs will be computed using a stratified Cox proportional hazards 
regression model, stratified by baseline risk of progression to severe COVID-19 and/or 
hospitalization (“high risk” versus “not at high risk”). 
Time to hospitalizations (≥ 24 hours of acute care) and/or emergency room visits related to 
COVID-19 or death from any cause will be presented graphically with a Kaplan-Meier plot. 
12.4.3 
Handling of remaining intercurrent events of primary estimand 
Part A 
A combination of treatment policy and composite strategy will be used to handle the intercurrent 
events. 
A treatment policy will be used to handle (1) post-treatment initiation of all antivirals (including 
convalescent 
serum, 
antiviral 
antibodies, 
and 
antiviral 
small 
molecules) 
and 
immunosuppressive 
medications; 
and, 
(2) 
post-treatment 
increase 
in 
dose 
of 
immunosuppressive medications, for the treatment or management of COVID-19, and a patient 
will be evaluated regardless of experiencing either of these intercurrent events. 
A composite strategy will be used to handle (3) death from any cause and (4) COVID-19 related 
hospitalization. In the event a patient experiences death or COVID-19 related hospitalization, 
all values after the time of death/start of the COVID-19 related hospitalization for change from 
baseline in log10 SARS-CoV-2 viral load will be set as the worst observed value based on 
observed values at each time point within each treatment arm independently. 
Part B 
A treatment policy will be used to handle (1) post-treatment initiation of all antivirals (including 
convalescent 
serum, 
antiviral 
antibodies, 
and 
antiviral 
small 
molecules) 
and 
immunosuppressive 
medications; 
and, 
(2) 
post-treatment 
increase 
in 
dose 
of 
immunosuppressive medications, for the treatment or management of COVID-19, and a patient 
will be evaluated regardless of experiencing either of these intercurrent events. 


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12.4.4 
Handling of missing values not related to intercurrent event 
Part A 
Missing measurement in log10 SARS-CoV-2 viral load will be imputed using last observation 
carried forward (LOCF) approach. 
Part B 
Patients who prematurely discontinue the study and whose outcomes after discontinuation are 
not ascertainable will have follow up censored at the date of last known status. 
12.4.5 
Supplementary analysis 
Part A 
A supplemental analysis: 
• excluding patients who experienced a negative PCR COVID-19 test following a positive 
swab; and, 
• using multiple imputation to handle the missing data will be performed. 
Further details on supplementary analyses can be found in the SAP. 
Part B 
Simple event rate estimates (proportion of events) will be presented for the primary composite 
efficacy endpoint. 
An alternative estimand may be considered with a composite strategy account for the 
intercurrent events of (1) post-treatment initiation of all antivirals (including convalescent 
serum, antiviral antibodies and antiviral small molecules), ambulatory oxygen, and 
immunomodulating or immunosuppressive medications; and, (2) post-treatment increase in 
dose of ambulatory oxygen, and immunomodulating or immunosuppressive medications, for 
the treatment or management of COVID-19. The primary endpoint will be considered a failure 
at the time of the intercurrent event. 
The primary efficacy analysis may be repeated excluding patients who experienced a negative 
PCR COVID-19 test following a positive swab. 
A tipping point analysis will be conducted to assess the impact of the missing data strategy in 
Section 12.4.4. 
Additional analyses to address sensitivity of assumptions may be performed including inverse 
probability of censoring modeling. 
Further details on supplementary analyses can be found in the SAP. 


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12.4.6 
Supportive analysis 
The subgroup evaluation of baseline risk of progression to severe COVID-19 and/or 
hospitalization (“high risk” versus “not at high risk”) on ensovibep will be performed for both 
Parts. Further details on supportive analyses will be specified in the SAP. 
12.5 
Analysis of secondary endpoints 
For all secondary objectives analysis details are described in the SAP. 
12.5.1 
Efficacy endpoints 
12.5.1.1 Hospitalizations (≥ 24 hours of acute care) and/or emergency room 
visits related to COVID-19 or death from any cause 
This secondary objective applies only to Part A. In Part B, this endpoint is the primary 
objective. For handling of the secondary analysis on the proportion of patients experiencing 
hospitalizations (≥ 24 hours of acute care) and/or emergency room visits related to COVID-19 
or death from any cause up to Day 29, see details in the SAP. 
12.5.1.2 SARS-CoV-2 Viral load 
This secondary objective applies only to Part B. In Part A, this endpoint is the primary objective. 
For handling of the secondary analysis on log10 SARS-CoV-2 viral load in nasopharyngeal 
swabs through Day 8, see details in Section 12.4. 
12.5.1.3 COVID-19 symptoms 
Acute COVID-19 symptoms will be collected up to Day 29 to evaluate the efficacy of ensovibep 
using a COVID-19 symptoms collection tool containing a 14 symptoms questionnaire, 
collectively be referred to as the FDA COVID-19 questionnaire (FDA 2020a). This 
questionnaire will be an eCOA tool completed by the patient. Each of the symptoms is rated on 
a scale of 0 to 3: 0 – none, 1 – mild, 2 – moderate, 3 – severe. 
Sustained clinical recovery is defined as (a) all symptoms from the modified FDA COVID-19 
symptom list scored as moderate or severe at baseline are subsequently scored as mild or absent, 
AND (b) all symptoms from the modified FDA COVID-19 symptom list scored as mild or 
absent at baseline are subsequently scored as absent, with no subsequent worsening, up to 
Day 29. 
The cumulative proportion of achieving sustained clinical recovery up to Day 29 will be 
estimated for each randomized group using Kaplan-Meier methods to take account of losses to 
follow-up. Patients who prematurely discontinue the study and whose outcomes after 
discontinuation are not ascertainable will have follow up censored at the date of last known 
status. 
The difference between randomized groups in the estimated log cumulative proportion will be 
calculated and the variance for this difference will be obtained using Greenwood’s formula. 


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Two-sided 95% CIs and associated p-value for the test of no difference between groups will 
then be obtained. 
Time to sustained clinical recovery will be presented graphically with a Kaplan-Meier plot. A 
Cox proportional hazards model will be used, stratified by baseline risk of progression to severe 
COVID-19 and/or hospitalization (“high risk” versus “not at high risk”). 
12.5.2 
Safety endpoints 
Adverse events 
Adverse events (AEs) are to be coded with the MedDRA dictionary that gives PT and primary 
SOC information. The number (and percentage) of patients with treatment emergent 
• AEs 
• SAEs 
• AESIs (see Section 10.1.4) 
will be summarized for each Part by: 
• treatment, SOC, and PT; 
• treatment, SOC, PT, and CTCAE; and, 
• treatment, Standardized MedDRA Query (SMQ) and PT. 
Treatment-emergent deaths will be summarized for each Part by treatment, SOC, and PT. 
A patient with multiple AEs within a primary SOC will be only counted once towards the total 
of the primary SOC. 
AEs and SAEs will be summarized for each Part by treatment and treatment-emergent ADAs 
(TE-ADA) status as defined in Section 10.1.1. 
AEs of Special Interest are defined in Section 10.1.4. 
• The number (and percentage) of patients with each of the AESIs will be summarized for 
each Part by treatment and by treatment and maximum severity. 
Vital signs 
All vital signs data will be summarized by treatment in each Part at Day 1, Day 3, Day 5, Day 8, 
Day 29, and Day 91. Changes from baseline to values at each time point will be summarized 
for each Part by treatment. Patients with abnormalities will be listed. 
A complete list of the vital sign parameters will be provided in the SAP. 
Clinical laboratory evaluations 
All laboratory data, including hematology and biochemistry data, will be summarized by 
treatment in each Part at Day 1, Day 5, Day 8, Day 29, and Day 91. Changes from baseline to 
values at each time point will be summarized for each Part by treatment. Shift tables using the 


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low/normal/high/ (low and high) classification will be used to compare baseline to the worst 
on-treatment value. Patients with abnormalities will be listed. 
A complete list of the laboratory parameters, including hematology and biochemistry 
parameters, will be provided in the SAP. 


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12.7 
Interim analysis 
An external IDMC will be established and perform review as defined in Section 10.3. The 
details of the analysis required for IDMC will be specified in a separate IDMC charter and 
analysis plan. 


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Part A 
No interim analysis will be performed for the efficacy evaluation. Analysis of primary endpoint 
will be carried out when all patients have completed the Day 29 visit (or withdrawn 
prematurely) and have viral load data up to Day 8. Final analyses of Part A will occur when all 
patients have completed Day 91 visit (or withdrawn prematurely). However, analyses of 
primary endpoint will not be repeated. 
Part B 
There is one interim analysis after at least 50% of patients complete Day 29 and one final 
analysis after at least 1717 patients have completed Day 91. The interim analysis permits early 
stopping due to efficacy controlling overall type I error rate. The interim analysis upper stopping 
bound in Z scale is 2.963 (corresponding to alpha is 0.03). 
Further details will be provided in a separate Interim Analysis SAP. 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
Part A 
In Documentation for the EUA for emergency use of casirivimab and imdevimab, issued 
21-Nov-2020, it is shown that the treatment effect in time-weighted change from baseline 
(Day 1) to Day 8 of log10 SARS-Cov-2 viral load in nasopharyngeal swabs was -0.36 for the 
overall population and -0.68 for the subgroup of patients with at least 107 copies at baseline 
and the estimated SD was between 1.0 and 1.2. 
Assuming the published evidence to be predictive over 8 days, a sample size of at least 
100 patients per treatment group, for a total of 400 patients, would have at least 80% power 
(minimum power over the considered candidate shapes) with a one-sided Type I error rate of 
0.10 to detect a dose-response trend versus placebo using MCP-Mod to select the smallest dose 
for consideration in the decision to move into Part B. 
The power calculations given the range of operating characteristics (treatment 
effect: -0.36, -0.68, and standard deviation: 1, 1.1, 1.2) were performed based on MCP-Mod in 
R (84)and are presented in Table 12-1. 
Table 12-1 
Power for Part A given a range of operating characteristics given 
400 patients, 100 patients in each arm and a one sided significance 
level of 10% 
Treatment Effect 
Standard Deviation 
Power 
(%) 
-0.36 
1 
90.03 
1.1 
85.25 
1.2 
80.25 


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-0.68 
1 
99.98 
1.1 
99.92 
1.2 
99.73 
Part B 
Assuming the proportion of patients achieving the composite endpoint (of hospitalizations 
[≥ 24 hours of acute care] and/or emergency room visits, related to COVID-19, or death from 
any cause) up to Day 29 is 6.5% based on Gottlieb et al (2021) in the placebo group and 50% 
reduction with to 3.25%, a sample size of 1717 patients 1:1 randomized to two treatment groups 
provides at least 90% power that the primary analysis will be statistically significant using a 
two-sided log rank test with 5% significance level assuming that the survival rates are 
exponential. These results assume that the group sequential design has one interim analysis for 
stopping the trial early for efficacy after 50% of patients complete Day 29 visit (two total 
analysis including final analysis) and the O'Brien-Fleming spending function is used to 
determine the efficacy test boundary. 
Given possible enrichment for more severe COVID-19 cases, a range of operating 
characteristics were evaluated and presented in Table 12-2. 
Sample size calculations are performed in nQuery 8.4.1.0. 
Table 12-2 
Power for Part B given a range of operating characteristics 
Total Sample Size 
Placebo Event Rate (%) 
Drug Event Rate (%) 
Power 
(%) 
1717 
6.5 
3.25 
90.02 
1588 
7 
3.5 
90.01 
1476 
7.5 
3.75 
90.01 
1380 
8 
4 
90.04 
1295 
8.5 
4.25 
90.06 
1217 
9 
4.5 
90.03 
1148 
9.5 
4.75 
90.02 
1086 
10 
5 
90.02 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 


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13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written ICF, consent form updates, patient recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to monitors, auditors, the sponsor’s Quality Assurance representatives, designated 
vendors, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform the sponsor immediately 
that this request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the sponsor’s clinical 
trial results website and all required Health Authority websites (e.g., Clinicaltrials.gov, 
EudraCT etc.). 
For details on the sponsor’s publication policy including authorship criteria, please refer to the 
sponsor’s publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality control and quality assurance 
Molecular Partners AG, either itself or through Novartis Pharma AG (Novartis) that is 
responsible for conducting this study and has engaged the CRO IQVIA for that purpose, 
maintains a Quality Management System (QMS) that includes relevant activities involved in 
quality assurance and quality control, to ensure compliance with written Standard Operating 
Procedures as well as applicable GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and systems are performed by auditors, independent from 
those involved in conducting, monitoring or performing quality control of the clinical trial. The 
clinical audit process uses a knowledge/risk-based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal standard operating procedures, and are performed according to written 
processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures, and the data to be collected on 
study patients. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 


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incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to the 
sponsor and not use it for any purpose other than the study, except for the appropriate 
monitoring on study patients. 
Investigators ascertain, they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by the sponsor 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by the sponsor, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for patient safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, the sponsor 
should be notified of this action and the IRB/IEC at the study site should be informed according 
to local regulations. 


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15 
References 
References are available upon request 
Bretz, F., Pinheiro, J. C., and Branson, M. (2005). Combining multiple comparisons and 
modeling techniques in dose-response studies. Biometrics 61, p 738–748. 
Caballero AE, Ceriello A, Misra A et al (2020) COVID-19 in people living with diabetes: An 
international consensus. Journal of Diabetes and Its Complications; 34:107671. 
CDER (2020a) US Department of Health and Human Services, Food and Drug 
Administration, Guidance for Industry: Assessing COVID-19-related symptoms in outpatient 
adult and adolescent subjects in clinical trials of drugs and biological products for COVID-19 
prevention or treatment. Rockville, MD. 
Cevik M, Bamford CGG, Ho A (2020) COVID-19 pandemic—a focused review for 
clinicians. Clinical Microbiology and Infection; 26:842–7. 
Chen P, Nirula A, Heller B, et al (2020) SARS-CoV-2 neutralizing antibody LY-CoV555 in 
outpatients with Covid-19. N Engl J Med; 1-9. DOI: 10.1056/NEJMoa2029849. 
Choi MH, Ahn H, Ryu HS et al (2020) Clinical characteristics and disease progression in 
early-stage COVID-19 patients in South Korea. J Clin Med; 9(6):1959. 
Cohen P, Hall L, John J, Rapoport A (2020) The early natural history of SARS-CoV-2 
infection: Clinical observations from an urban, ambulatory COVID-19 clinic. Mayo Clin 
Proc;95(6):1124-6. 
COVID-19 vaccines: key facts | European Medicines Agency. Accessed January 23, 2021. 
//ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-
covid-19/treatments-vaccines/covid-19-vaccines-key-facts. 
Du Z, Xu X, Wu Y, et al (2020) Serial interval of COVID-19 among publicly reported 
confirmed cases. Emerg Infect Dis; 26(6). 
EMA (2014) Qualification Opinion on MCP-Mod as an efficient statistical methodology for 
model-based design and analysis of Phase II dose finding studies under model uncertainty 
[//ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2014/
02/WC500161027.pdf]. 
Faust JS and del Rio C (2020) Assessment of deaths from COVID-19 and from seasonal 
influenza. JAMA Intern Med; 180(8):1045-6. 
FDA (2016) Fit-for-purpose determination letter, 
[//fda.gov/downloads/Drugs/DevelopmentApprovalProcess/UCM508700.pdf]. 
FDA (2021). COVID-19: Developing Drugs and Biological Products for Treatment or 
Prevention. Guidance for Industry, February 2021. 
Gottlieb RL, Nirula A, Chen P, et al. Effect of Bamlanivimab as Monotherapy or in 
Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19. 
JAMA. 10.1001/jama.2021.0202 Published online January 21, 2021. 
Greany AJ, Loes AN, Crawford KHD, et al. Comprehensive mapping of mutations to the 
SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum 


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antibodies. //biorxiv.org/content/10.1101/2020.12.31.425021v1.full.pdf , accessed 25 Jan 
2021. 
Guan WJ, Zhong NS. (2020) Clinical characteristics of coronavirus disease 2019 in China. N 
Engl J Med; 382(18):1708-20. 
Hamer M, Kivimäki M, Gale CR, Batty GD (2020) Lifestyle risk factors, inflammatory 
mechanisms, and COVID-19 hospitalization: A community-based cohort study of 387,109 
adults in UK. Brain Behav Immun;87:184-7. 
He X, Lau EHY, Wu P, et al (2020) Temporal dynamics in viral shedding and transmissibility 
of COVID-19. Nat Med; 26:672–5. 
Hoffmann M, Kleine-Weber H, Schroeder S, et al (2020) SARS-CoV-2 cell entry depends on 
ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. 
Cell;16;181(2):271-80.e8. 
Johns Hopkins University and Medicine - Coronavirus Resource Center. 
//coronavirus.jhu.edu. 
Kim PS, Read SW, Fauci AS. Therapy for Early COVID-19. JAMA. 2020;324(21):2149. 
doi:10.1001/jama.2020.22813 
Morley JE. COVID-19 - The Long Road to Recovery. J Nutr Heal Aging. Published online 
2020:1. doi:10.1007/s12603-020-1473-6. 
Pinheiro J, Bornkamp B, Bretz F (2006) Design and analysis of dose-finding studies 
combining multiple comparisons and modeling procedures. Journal of Biopharmaceutical 
Statistics; 16:5,639-656. 
Pinheiro J, Bornkamp B, Glimm E, et al (2014) Model-based dose finding under model 
uncertainty using general parametric models. Statist Med; 33:1646–61. 
Starr TN, Greaney AJ, Addetia A et al. Prospective mapping of viral mutations that escape 
antibodies used to treat COVID-19. 
//biorxiv.org/content/10.1101/2020.11.30.405472v1.full.pdf accessed 25 Jan 2021. 
//theconversation.com/covid-19-vaccines-how-and-when-will-lower-income-countries-get-
access-152718, accessed 19 Jan 2021 
Walls AC, Park YJ, Tortorici MA, et al (2020) Structure, function, and antigenicity of the 
SARS-CoV-2 spike glycoprotein. Cell;181:281-92 e6. 
Weinreich DM, Sivapalasingam S, Norton T et al. REGN-COV2, a Neutralizing Antibody 
Cocktail, in Outpatients with Covid-19. Published on 17 Dec 2020 and updated on 18 Dec 
2020 at NEJM.org: NEJMoa2035002 
Wrapp D, Wang N, Corbett KS, et al (2020) Cryo-EM structure of the 2019-nCoV spike in 
the prefusion conformation. Science;367(6483):1260-3. 
Wu C, Chen X, Cai Y, et al (2020) Risk factors associated with acute respiratory distress 
syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. 
JAMA Intern Med. 
//yougov.co.uk/topics/international/articles-reports/2021/01/12/covid-19-willingness-be-
vaccinated, accessed 19 Jan 2021. 


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Zhou F, Yu T, Du R, et al (2020) Clinical course and risk factors for mortality of adult 
inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet; 395:1054–
62. 
Zhou P, Yang XL, Wang XG, et al (2020) A pneumonia outbreak associated with a new 
coronavirus of probable bat origin. Nature;579(7798):270-3. 


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16 
Appendices 
16.1 
Appendix 1: Symptom questionnaire 
Questions to evaluate the presence and severity of COVID-19 symptoms, following FDA’s 
recommended list of questions. The questionnaire is programmed onto an App that will play on 
the patient’s own device (e.g., Smartphone). Patients who don’t own a device will be given one 
for the duration of the study. 
Opening instructions: 
A variety of possibly symptoms are described and if present, should be rated by severity. If 
you don’t have the symptom, click “None”. 
 
 
Questions 
Response options 
Runny nose 
What was the severity of your stuffy 
or runny nose at its worst over the 
last 24 hours? 
☐ none 
☐ mild 
☐ moderate 
☐ severe 
Sore throat 
What was the severity of your sore 
throat at its worst over the last 24 
hours? 
☐ none 
☐ mild 
☐ moderate 
☐ severe 
Breathlessness 
What was the severity of your 
shortness of breath (difficulty 
breathing) at its worst over the last 24 
hours? 
☐ none 
☐ mild 
☐ moderate 
☐ severe 
Cough 
What was the severity of cough at its 
worst over the last 24 hours? 
☐ none 
☐ mild 
☐ moderate 
☐ severe 
Fatigue 
What was the severity of low energy 
or tiredness at its worst over the last 
24 hours? 
☐ none 
☐ mild 
☐ moderate 
☐ severe 
Body pain 
What was the severity of your muscle 
or body aches at its worst over the 
last 24 hours? 
☐ none 
☐ mild 
☐ moderate 
☐ severe 


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Questions 
Response options 
Headache 
What was the severity of your 
headache at its worst over the last 24 
hours? 
☐ none 
☐ mild 
☐ moderate 
☐ severe 
Chills 
What was the severity of your chills 
or shivering at its worst over the last 
24 hours? 
☐ none 
☐ mild 
☐ moderate 
☐ severe 
Feeling hot 
What was the severity of your feeling 
hot or feverish at its worst over the 
last 24 hours? 
☐ none 
☐ mild 
☐ moderate 
☐ severe 
Nausea 
What was the severity of your nausea 
(feeling like you wanted to throw 
up) at its worst over the last 24 hours? 
☐ none 
☐ mild 
☐ moderate 
☐ severe 
Vomiting 
How many times did you vomit 
(throw up) in the last 24 hours? 
☐ I did not vomit at all 
☐ 1-2 times 
☐ 3-4 times 
☐ 5 or more times 
Diarrhea 
How many times did you have 
diarrhea (loose or watery stools) in 
the last 24 hours? 
☐ I did not have diarrhea at all 
☐ 1-2 times 
☐ 3-4 times 
☐ 5 or more times 
Sensory: smell  
Rate you sense of smell in the last 24 
hours  
☐ My sense of smell is THE SAME AS 
usual 
☐ My sense of smell is LESS THAN 
usual 
☐ I have NO sense of smell 
Sensory: taste 
Rate you sense of taste in the last 24 
hours 
☐ My sense of taste is THE SAME AS 
usual 
☐ My sense of taste is LESS THAN 
usual 
☐ I have NO sense of taste 
Usual health 
In the past 24 hours, have you 
returned to your usual health (before 
your COVID-19 illness)? 
☐ Yes 
☐ No 
 


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Questions 
Response options 
Usual activities 
In the past 24 hours, have you 
returned to your usual activities 
(before your COVID-19 illness)? 
☐ Yes 
☐ No 
 
Overall COVID 
symptoms 
In the past 24 hours, what was the 
severity of your overall COVID-19-
related symptoms at their worst?  
☐ none 
☐ mild 
☐ moderate 
☐ severe 
 




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16.3 
Appendix 3: Liver event and laboratory trigger definitions & 
follow-up requirements 
Table 16-1 
Liver event and laboratory trigger definitions 
  
Definition/ threshold 
Liver laboratory triggers 
If ALT, AST and total bilirubin normal at 
baseline:  
• ALT or AST > 5 × ULN 
• ALP > 2 × ULN (in the absence of known bone 
pathology) 
• Total bilirubin > 3 × ULN (in the absence of known 
Gilbert syndrome) 
• ALT or AST > 3 × ULN and INR > 1.5 
• Potential Hy’s Law cases (defined as ALT or 
AST > 3 × ULN and Total bilirubin > 2 × ULN [mainly 
conjugated fraction] without notable increase in ALP to > 
2 × ULN) 
• Any clinical event of jaundice (or equivalent term) 
• ALT or AST > 3 × ULN accompanied by (general) 
malaise, fatigue, abdominal pain, nausea, or vomiting, or 
rash with eosinophilia 
• Any adverse event potentially indicative of a liver 
toxicity* 
If ALT or AST abnormal at baseline: 
• ALT or AST > 2x baseline or > 300 U/L (whichever 
occurs first) 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms ULN: 
upper limit of normal 
 


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Table 16-2 
Follow up requirements for liver laboratory triggers with liver 
symptoms 
  
ALT  
TBL 
Liver 
Symptoms 
Action 
ALT increase without bilirubin increase: 
  
  
If normal at baseline: 
ALT > 3 x ULN 
Normal 
For patients with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• Measure ALT, 
AST, ALP, GGT, TBIL, 
INR, albumin, CK, and 
GLDH in 48-72 hours. 
• Follow-up for 
symptoms. 
If elevated at baseline: 
ALT > 2 x baseline 
or > 300 U/L (whichever occurs 
ﬁrst) 
  
If normal at baseline: 
ALT > 5 x ULN for more than 
two weeks 
Normal 
For patients with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• Measure ALT, 
AST, ALP, GGT, TBIL, 
INR, albumin, CK, and 
GLDH in 48-72 hours. 
• Follow-up for 
symptoms. 
• Initiate close 
monitoring and workup 
for competing 
etiologies. 
If elevated at baseline: 
ALT > 3 x baseline 
or > 300 U/L (whichever occurs 
ﬁrst) for more than two weeks 
  
If normal at baseline: 
ALT > 8 x ULN 
Normal 
None 
ALT increase with bilirubin increase: 
  
If normal at baseline: 
ALT > 3 x ULN 
TBL > 2 x ULN 
(or INR > 1.5) 
For patients with 
Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at baseline: 
ALT > 2 x baseline 
or > 300 U/L (whichever occurs 
ﬁrst) 
  
If normal at baseline: 
ALT > 3 x ULN 
Normal or 
elevated 
Severe 
fatigue, 
nausea, 
vomiting, 
right upper 
quadrant 
pain 
If elevated at baseline: 
ALT > 2 x baseline 
or > 300 U/L (whichever occurs 
ﬁrst) 
Isolated elevation of AST >3 x ULN needs to be interpreted in context of the clinical picture and 
other liver parameters, and further investigated for non-liver related etiology. 
 


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Table 16-3 
Follow up requirements for liver laboratory triggers 
Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin (isolated) 
  
  
>1.5 – 3.0 ULN 
Repeat LFTs within 
48-72 hours 
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline 
> 3 - 10 × ULN (in the absence 
of known Gilbert syndrome) 
Repeat LFT within 48-72 hours 
Hospitalize if clinically 
appropriate 
Establish causality 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF 
Monitor LFTs weekly until 
resolutionc to ≤ Grade 1 or to 
baseline (ALT, AST, total 
bilirubin, Alb, PT/INR, ALP and 
GGT) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin) 
> 10 x ULN 
Hospitalize the participant 
Establish causality 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF 
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolutionc (frequency at 
investigator discretion) 
Any AE potentially indicative of 
a liver toxicity* 
Hospitalization if clinically 
appropriate 
Establish causality 
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF 
Investigator discretion 
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death. 
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease. 
 


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16.4 
Appendix 4: Specific renal alert criteria and actions and event 
follow-up 
Table 16-4 
Specific renal alert criteria and actions 
Serum Event 
Serum creatinine increase 25% – 49% 
compared to baseline, exceeding the normal 
range and/or considered clinically significant 
 
Confirm 25% increase after 24-48 hours 
Follow-up within 2-5 days 
Acute Kidney Injury: Serum creatinine increase  
≥ 50% compared to baseline 
Follow-up within 24-48 hours if possible 
Consider participant hospitalization /specialized 
treatment 
For all renal events: 
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and 
additional diagnostic procedures performed 
Monitor participant regularly (frequency at investigator’s discretion) until either: 
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or 
Event stabilization: sCr level with ± 10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ± 50% variability over last 6 months. 
 


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16.5 
Appendix 5: Sponsor’s signature page 
Molecular Partners AG 
Ensovibep/MP0420 
Clinical Trial Protocol MP0420-CP302 
A randomized, double-blind, placebo-controlled, 
multicenter study of ensovibep (MP0420) in ambulatory 
adult patients with symptomatic COVID-19 
Document type: 
Protocol Signature Page 
Referring to: 
Amended Protocol V01 released on 19-Oct-2021 
 
Molecular Partners AG approval signature for: 
Amended Clinical Trial Protocol MP0420-CP302 V01  
 
 
 
CMO 
 
 
 
 
Title 
 
Signature 
 
Date 
 
 
 
 


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16.6 
Appendix 6: Investigator’s signature page 
 
 
Investigator approval signatures for: 
Amended Clinical Trial Protocol MP0420-CP302 V01  
 
Investigator signature 
 
I have read the amended protocol and agree to conduct this trial in accordance with all stipulations of 
the protocol, with applicable laws and regulations and in accordance with the ethical principles outlined 
in the Declaration of Helsinki. 
 
 
 
 
 
 
Investigator  
 
Signature 
 
Date 
 
 
Center name and address 
Center name: ________________________________________________________ 
Address: ___________________________________________________________ 
 
 

SAP_001.pdf: 
Molecular Partners AG 
Ensovibep/MP0420 
MP0420-CP302 (CSKO136A12201J) / NCT04828161
A randomized, double-blind, placebo-controlled, 
multicenter study of ensovibep (MP0420) in ambulatory 
adult patients with symptomatic COVID-19 
The “EMPATHY” Trial  
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Amendment 2 (Final) 
Release date: 
07-Dec-2021
Number of pages: 
53 
Property of Molecular Partners AG 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Molecular Partners AG 


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SAP (Amendment 2)                                                                     MP0420-CP302 (CSKO136A12201J) 
 
 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
28-
Apr-
2021 
Prior to Part 
A FPFV  
Creation 
of 
first version 
N/A - First version 
NA 
3-Nov-
2021 
Prior to Part 
A 
primary 
analysis 
database 
lock 
Creation 
of 
Amendment 
1 
Changes according to protocol 
Amendment 1 implemented. 
 
All Sections 
 
 
 
Alignment of description of Part A 
primary analysis and Part A final 
analysis with protocol. 
Section 1 
 
 
 
Removed sentence that only 
listings explicitly specified in SAP 
will be done. Adjusted respective 
sections for mandatory listings. 
Other listings may only be specified 
in TFL-Shells. 
Added clarification how 
discontinuation visits and visit 
mapping for questionnaire data will 
be handled. 
Section 2.1 
 
 
 
Added subgroups of interest: Age, 
gender, risk for disease progression 
according to updated FDA definition 
and severity of COVID-19, adjusted 
categories for mutations. 
Removed subset of ADAs as ADAs 
are not available for Placebo 
patients. 
Section 2.2.1 
 
 
 
Criteria leading to discontinuation 
from analysis sets will only be 
listed.  
Section 2.3.1 
 
 
 
Regions adjusted according to 
recruiting countries. 
Baseline BMI categories adjusted to 
reflect latest FDA guidance for 
COVID-19 risk for disease 
progression. 
Adjusted categories for mutations. 
Section 2.3.2 






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Table of contents 
Table of contents ................................................................................................................. 5 
List of tables ........................................................................................................................ 7 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
1 
Introduction ......................................................................................................................... 9 
1.1 
Study design ............................................................................................................ 9 
1.2 
Study objectives and endpoints ............................................................................. 10 
2 
Statistical methods ............................................................................................................. 13 
2.1 
Data analysis general information ......................................................................... 13 
2.1.1 
General definitions ................................................................................ 14 
2.2 
Analysis sets .......................................................................................................... 18 
2.2.1 
Subgroup of interest .............................................................................. 19 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 19 
2.3.1 
Patient disposition ................................................................................. 19 
2.3.2 
Background and demographic characteristics ....................................... 20 
2.3.3 
Medical history/current medical condition ........................................... 21 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 21 
2.4.1 
Study treatment / compliance ................................................................ 21 
2.4.2 
Prior, concomitant and rescue therapies ................................................ 21 
2.5 
Analysis of the primary objective .......................................................................... 22 
2.5.1 
Primary endpoint ................................................................................... 22 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 24 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 27 
2.5.4 
Supplementary analyses ........................................................................ 27 
2.5.5 
Supportive analyses ............................................................................... 28 
2.6 
Analysis of the key secondary objective ............................................................... 28 
2.7 
Analysis of secondary efficacy objectives ............................................................. 28 
2.7.1 
Secondary endpoints ............................................................................. 29 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 29 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 31 
2.8 
Safety analyses....................................................................................................... 31 
2.8.1 
Adverse events (AEs) ............................................................................ 31 
2.8.2 
Deaths .................................................................................................... 33 
2.8.3 
Laboratory data ..................................................................................... 33 


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2.8.4 
Other safety data ................................................................................... 34 
2.9 
Pharmacokinetic endpoints .................................................................................... 34 
 
 35 
2.11 
Patient-reported outcomes (PRO) .......................................................................... 35 
2.11.1 
SF-36 ..................................................................................................... 35 
 
 35 
2.12 
Biomarkers ............................................................................................................. 36 
 
 36 
2.12.2 
SARS-CoV-2 antibodies ....................................................................... 36 
2.12.3 
Soluble Biomarker ................................................................................ 36 
 
 36 
 
 36 
 
 37 
2.14 
Interim analysis ...................................................................................................... 37 
3 
Sample size calculation ..................................................................................................... 38 
3.1 
Primary endpoint(s) ............................................................................................... 38 
3.2 
Key secondary endpoint(s) .................................................................................... 39 
3.3 
Other secondary endpoint(s) .................................................................................. 39 
4 
Change to protocol specified analyses .............................................................................. 39 
5 
Appendix ........................................................................................................................... 39 
5.1 
Imputation rules ..................................................................................................... 39 
5.1.1 
Study drug ............................................................................................. 39 
5.1.2 
AE date and hospitalization date imputation ........................................ 40 
5.1.3 
Concomitant medication and therapies date imputation ....................... 41 
5.2 
Derivation of risk of progression to severe COVID-19 and/or hospitalization ..... 43 
5.3 
Derivation of baseline COVID-19 severity ........................................................... 44 
5.4 
AEs coding/grading ............................................................................................... 44 
5.5 
Laboratory parameters derivations ........................................................................ 44 
5.6 
Vital signs – definition of clinically notable values .............................................. 47 
5.7 
Statistical models ................................................................................................... 49 
5.7.1 
Primary analysis .................................................................................... 49 
5.7.2 
Key secondary analysis ......................................................................... 52 
5.8 
Rule of exclusion criteria of analysis sets.............................................................. 52 
6 
Reference ........................................................................................................................... 53 


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List of tables 
Table 1.2-1 
Objectives and related endpoints .......................................................... 10 
Table 2.1-1 
Investigational and control drug ............................................................ 14 
Table 2.1-2 
Visit windows........................................................................................ 15 
Table 5.1-1 
Imputation logic for partial AE dates .................................................... 41 
Table 5.1-2 
Imputation logic for partial concomitant medication end dates .............. 42 
Table 5.8-1 
Subject Classification ............................................................................ 52 
List of figures 
Figure 1-1 
Study design .......................................................................................... 10 
Figure 2-1 
Candidate models for ensovibep dose ................................................... 25 


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List of abbreviations 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANCOVA 
Analysis of Covariance 
COVID-19 
Coronavirus Disease 2019 
CSR 
Clinical Study Report 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DBL 
Database Lock 
eCRF 
Electronic Case Report Form 
eCRS 
Electronic Case Retrieval Sheet 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FPFV 
First Patient First Visit 
IA 
Interim Analyses 
IDMC 
Independent Data Monitoring Committee 
IRR 
Infusion-related Reactions 
ITT 
Intention-to-treat 
MCS 
Mental Component Summary 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
PCS 
Physical Component Summary 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
PRO 
Patient-Reported Outcomes 
PT 
Preferred Term 
RAN 
Randomized Set 
RT-PCR 
Real Time Polymerase Chain Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SCR 
Screened Set 
SF-36 
Short Form 36 Health Survey Questionnaire 
SMQ 
Standard MedDRA Query 
SOC 
System Organ Class 
SS 
Safety Set 
TEAE 
Treatment-emergent Adverse Event 


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1 
Introduction 
This document presents the detailed statistical analysis plan (SAP) for Study MP0420-CP302 
(CSKO136A12201J), “A randomized, double-blind, placebo-controlled, multicenter study of 
ensovibep (MP0420) in ambulatory adult patients with symptomatic COVID-19.”  
Following the operationally seamless design, analysis of Part A and Part B will be handled 
separately (e.g., primary, secondary, and exploratory analyses in Part A will be performed only 
on Part A patients and primary, secondary, and exploratory analyses in Part B will be performed 
only on Part B patients).  
This SAP will include the details for the clinical study report (CSR) analysis of Part A and Part 
B. In this version, the full details for the CSR analysis of Part A is provided. An outline of the 
protocol-specified CSR analysis of Part B is provided in the SAP. Further details will be 
provided in a SAP amendment prior to first patient first visit (FPFV) of Part B.  
The analysis for Part A is performed in two parts: 
• Part A primary analysis: performed when all patients enrolled completed Day 29 or 
discontinued prematurely and have viral load data up to Day 8; the analysis will include 
available data on the day of cutoff. Further details are provided in Section 2.14. 
• Part A final analysis: performed when all patients completed the study at the final database 
lock (DBL); the analyses of the primary endpoint and secondary efficacy endpoints will not 
be repeated.  
The analyses will result in one clinical study report (CSR) for each Part A and Part B.  
Regular safety IDMC analyses will be performed, detailed information regarding IDMC 
analysis will be provided in the IDMC charter and a separate IDMC SAP. 
The SAP is based on the following documents: 
• Clinical Trial Protocol version 01 (Global Amendment 1) 
• Electronic case report form (eCRF)  
• Electronic case retrieval form (eCRS)  
1.1 
 Study design 
This is a randomized, double-blind, placebo-controlled, multicenter study of ensovibep 
(MP0420) in ambulatory patients with symptomatic COVID-19. The study has two parts: A 
Phase 2 dose-ranging study to select the best dose over the therapeutic range (Part A) and a 
confirmatory Phase 3 safety and efficacy study of the dose determined in Part A (Part B).  
Screening will be used to determine eligibility. Randomization and treatment will be conducted 
on Day 1 (screening can optionally be done up to 3 days earlier, or also at Day 1) and with a 
study duration for individual patients of 91 ± 7 days for both Parts. 
Part A 
This dose-ranging part of the study will include approximately 400 randomized patients in four 
arms (3 active arms and one placebo arm), randomized 1:1:1:1 (see also Figure 1-1) to receive 
ensovibep (75 mg, 225 mg, or 600 mg) or placebo, administered as a single i.v. infusion over 


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60 minutes, and stratified by risk for COVID-19 disease progression (“high-risk”, “not at high-
risk”).. 
Part B 
Recruitment will begin in Part B once the best safe and efficacious dose has been selected from 
Part A based on Day 29 data analysis. Part B will include at least 1717 patients randomized 1:1 
(see also Figure 1-1) to either the selected dose of ensovibep or placebo, administered as i.v. 
infusion over 60 minutes. An interim analysis for early efficacy will be conducted when 
approximately 50% of patients have completed the Day 29 assessments. Patients will be 
stratified by risk for COVID-19 disease progression (“high-risk patients” versus “not at high-
risk patients”). 
Figure 1-1 
Study design 
 
1.2 
Study objectives and endpoints 
The study objectives and endpoints for the primary CSR can be found in Table 1.2-1. 
Table 1.2-1 
Objectives and related endpoints  
Part A 
 
Primary Objective 
Endpoint for primary objective 
• To demonstrate superiority of ensovibep, 
compared to placebo, in reducing time-
weighted change from baseline in log10 
SARS-CoV-2 viral load through Day 8 
 
• Time-weighted change from baseline 
(measured at Day 3, Day 5, and Day 8) in 
log10 SARS-CoV-2 viral load in 
nasopharyngeal swabs through Day 8  
 
Secondary Objectives 
Endpoints for secondary objectives 


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• To assess the effect of ensovibep, compared 
to placebo, in reducing the occurrence of 
hospitalizations (≥ 24 hours of acute care) 
and/or emergency room visits related to 
COVID-19 or death from any cause up to Day 
29 
 
• Proportion of patients experiencing 
hospitalizations (≥ 24 hours of acute care) 
and/or emergency room visits related to 
COVID-19 or death from any cause up to 
Day 29 
  
• To assess the effect of ensovibep, compared 
to placebo, in reducing COVID-19 symptoms 
up to Day 29  
 
• Time to sustained clinical recovery, defined 
as (a) all symptoms from the modified FDA 
COVID-19 symptom list scored as moderate 
or severe at baseline are subsequently 
scored as mild or absent, AND (b) all 
symptoms from the modified FDA COVID-
19 symptom list scored as mild or absent at 
baseline are subsequently scored as 
absent, with no subsequent worsening up to 
Day 29 
 
• To evaluate safety and tolerability of 
ensovibep 
 
• Proportion of patients up to end of study 
with: 
o Treatment Emergent Adverse events 
(TEAEs) 
o Serious adverse events (SAEs), 
including death from any cause 
o AEs of Special Interest (AESIs),  
• Vital signs 
• Clinical laboratory measurements  
 
•  To characterize the pharmacokinetics (PK) 
of ensovibep 
 
• 
Free and total ensovibep concentration in 
serum and calculated PK parameters 
 
Exploratory Objectives 
Endpoints for exploratory objectives 


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Part B 
 
Primary Objective 
Endpoint for primary objective 
• To demonstrate superiority of ensovibep, 
compared to placebo, in reducing the 
occurrence of hospitalizations (≥ 24 hours of 
acute care) and/or emergency room visits 
related to COVID-19 or death from any cause 
up to Day 29 
 
• Proportion of patients experiencing 
hospitalizations (≥ 24 hours of acute care) 
and/or emergency room visits related to 
COVID-19 or death from any cause up to 
Day 29 
Secondary Objectives 
Endpoints for secondary objectives 
• To assess the effect of ensovibep, compared 
to placebo, in reducing SARS-CoV-2 viral 
load through Day 8 
 
• Time-weighted change from baseline 
(measured at Day 3, Day 5, and Day 8) in 
log10 SARS-CoV-2 viral load in 
nasopharyngeal swabs through Day 8 
  
• To assess the effect of ensovibep, compared 
to placebo, in reducing COVID-19 symptoms 
up to Day 29  
 
 
• Time to sustained clinical recovery, defined 
as (a) all symptoms from the modified FDA 
COVID-19 symptom list scored as moderate 
or severe at baseline are subsequently 
scored as mild or absent, AND (b) all 
symptoms from the modified FDA COVID-
19 symptom list scored as mild or absent at 
baseline are subsequently scored as 
absent, with no subsequent worsening up to 
Day 29 
• To evaluate the immunogenicity of ensovibep 
during the study 
 
• 
Proportion of patients exhibiting treatment-
emergent ADAs (TE-ADA) over time  
 
• To evaluate safety and tolerability of 
ensovibep 
 
• Proportion of patients up to end of study 
with: 
o Treatment Emergent Adverse events 
(TEAEs) 
o Serious adverse events (SAEs), 
including deaths from any cause  
o AEs of Special Interest (AESIs)  
• Vital signs 
• Clinical laboratory measurements  
 
Exploratory Objectives 
Endpoints for exploratory objectives 






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2.1.1.3 
Study days 
Study Day 1 (or Day 1 or reference start date) is defined as the day of first dose of study 
treatment. 
All other study days are labeled as the number of days relative to Day 1. Therefore, for a 
particular date, study day will be calculated as follows: 
• for dates on or after the date of first administration of study treatment:  
Study day = Assessment date – date of study drug infusion + 1 
• for dates prior to the date of first administration of study treatment: 
Study day = Assessment date – date of study drug infusion  
Moreover, duration of an event is calculated as: 
Duration of an event = Event end date – event start date + 1.  
2.1.1.4 
Baseline 
The baseline value is generally defined as the last non-missing value prior to the start of study 
drug infusion. If the date of assessment is the same as date of infusion but time is not available 
for comparison, the assessment is assumed to be prior to the administration of study treatment. 
2.1.1.5 
Post-baseline measurement 
Post-baseline measurements are defined as assessments performed after start of study drug 
infusion. 
When change from baseline is of interest the following formula will be used for each scheduled 
visit and time-point where baseline and post-baseline values are both available: 
Change from baseline = post-baseline value – baseline value. 
2.1.1.6 
Visits 
Measurements will be collected with the windowing defined in the protocol and outlined in 
Table 2.1-2.  
Table 2.1-2 
Visit windows 
Visit label 
Visit collection window (study days) 
Screening 
-3 to -1 
Day 1 
1 
Day 3 
3 
Day 5 
5 
Day 8 
8 ± 2 
Day 15 
15 ± 3 
Day 22 
22 ± 4 
Day 29 
29 ± 5 
Day 61 
61 ± 5 


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EOS (Day 91) 
91 ± 7 
Visit labels as reported in the eCRF will be used for analysis. Discontinuation visits will be 
mapped to the next scheduled visit, if within modified protocol defined visit window, otherwise 
these will be handled as unscheduled visits. For the mapping the following modification will be 
applied to the protocol defined windows to avoid overlapping days: Day 22 (22 ± 3) and Day 29 
(29  -3/+ 5) and Day 61 (± 7). 
For ePRO data visits is not captured on the eCRF, visits will be assigned using ePRO assessment 
dates based on the modified protocol defined window. 
Efficacy outputs will not include unscheduled visits. For laboratory and safety outputs, 
unscheduled visit information will be used in the summaries of the worst post-baseline 
measurement. Further details will be found in the respective Sections. 
2.1.1.7 
On-treatment/Treatment-emergent 
If not stated otherwise, all post-baseline measurements will be considered as on-
treatment/treatment emergent and included in the analyses. 
A treatment-emergent adverse event (TEAE) is defined as any AE that started after the start of 
study drug infusion. If the AE start date is the same as date of infusion but time is not available 
for comparison, the AE will be considered to be treatment emergent.  
2.1.1.8 
Last contact date 
Last contact date is defined as the date the patients completes the study or discontinues 
prematurely. If a patient discontinues the study due to "lost to follow up" the latest date out of 
assessment dates and event/medication start and end dates will be used as last contact date. 
For patients ongoing at time of primary analyses, the cut-off date will be used as last contact 
date. 
2.1.1.9 
Stratification factor 
Randomization is stratified by risk for COVID-19 disease progression (“high-risk patients” 
versus “not at high-risk patients”).  
According to the inclusion criteria for the USA only patients "not at high-risk" will be included 
in the trial, however in case of protocol deviators US patients could technically be randomized 
to the high-risk stratum 
The stratification of “high-risk” and “not at high-risk” for COVID-19 disease progression will 
be programmed based on eCRF data for the analysis.  
A comparison between COVID-19 disease progression strata recorded in the IRT data, and 
programmed risk for COVID-19 disease progression (from data reported on the eCRF) will be 
performed. 
Details on stratification definition are included in Section 5.2. 


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2.1.1.10 Blinding 
Site firewalls to prevent unblinding and fully dedicated unblinded clinical teams managing the 
study will be assigned to ensure that the unblinded treatment assignment, the unblinded IRT 
outputs, the unblinded treatment administration and handling are overseen in such a way as to 
ensure patient safety and protocol adherence without risking unblinding the site study staff and 
the clinical teams. Refer to Pharmacy Manual for IP handling.  
This is a patient, investigator, and sponsor-blinded study. Patients, investigators, and the 
sponsor will remain blinded to study treatment throughout the study, except where indicated 
below. 
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor. 
Site staff 
With the exception of any unblinded site staff identified below, all site staff (including study 
investigator and study nurse) will be blinded to study treatment throughout the study. 
Unblinding a single patient at site for safety reasons (necessary for patient management) will 
occur via an emergency system in place at the site. 
Drug product will be supplied in bulk only for the 3 treatment arms in Part A, therefore an 
unblinded pharmacist who is independent of the study team will be required in order to maintain 
the blind. Patient treatment allocation can be obtained by the unblinded pharmacist through the 
IWR system. Appropriate measures must be taken by the unblinded pharmacist to ensure that 
the treatment assignments are concealed from the rest of the site staff.  
There will be fully blinded drug vials for both the active treatment arm and the placebo arm, in 
Part B of the trial, so unblinded site and clinical staff would not be needed for Part B. 
Sponsor staff or staff engaged to manage the study 
The following unblinded sponsor staff or staff (such as CRO) engaged to manage and run the 
study is required for this study during Part A: 
• Unblinded drug accountability monitors 
• Unblinded clinical staff managing drug re-supply to site 
• Unblinded sample analyst(s) (PK, ADA) 
In Part A, unblinded drug accountability monitors are required to review drug accountability, 
preparation, and allocation remotely. The unblinded monitors will be unblinded through review 
of source documentation compiled by the unblinded pharmacist, which details treatment 
allocation to individual patients. These unblinded monitors will also have access to the 
treatment allocation of the patients through the IWR system. 
The following unblinded staff will be applicable to both Part A and Part B: 
The external independent data review committee (IDMC) assessing unblinded results and the 
independent analysis team (independent statistician, independent programmer) will be allowed 


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to access treatment information for the purpose of creating, reviewing, and assessing unblinded 
interim results. More details will be provided in an IDMC charter. 
An independent pharmacometrician and an independent pharmacokineticist may be unblinded 
prior to the database lock after all patients complete Day 29 in Part A in order to explore PK. 
The pharmacometrician and the pharmacokinetisist will work independently and will only 
disclose results once the database is locked after all patients complete Day 29 in Part A at the 
time of the Part A primary analysis. 
Unblinding after the primary analysis database lock in Part A 
After the database lock for the primary analysis in Part A, an unblinded study team will perform 
the analysis and undertake submission related activities. Treatment assignment will continue to 
remain blinded to all investigators, site personnel, patients and other study team members until 
all patients have completed the entire study participation and the final database lock for Part A 
has occurred.  
All unblinded staff will otherwise keep randomization lists and data or information that could 
unblind other study team members confidential and secure until final clinical database lock. 
Primary analysis results and reports generated prior to the final database lock that would reveal 
subject-level data will be kept in a secure and restricted area until the end of the study. The 
detailed procedures for maintaining data integrity after primary analysis database lock will be 
described in a charter. 
Following final database lock all staff may be considered unblinded.  
Health authorities will be granted access to unblinded data if needed. 
2.2 
Analysis sets 
The analysis sets are defined as follows: 
• Screened set (SCR): all unique patients who signed the informed consent (e.g. only the 
chronologically last screening data is counted in the case of re-screened patients) 
• Randomized set (RAN): all patients who received a randomization number, regardless of 
receiving study treatment 
• Full analysis set (FAS): all patients in the RAN that initiated i.v. infusion of study treatment 
during the treatment period excluding mis-randomized patients, where mis-randomized 
patients are defined as cases where IRT contacts were made by the Investigator/qualified 
site staff either prematurely or inappropriately prior to confirmation of the patient’s final 
randomization eligibility and treatment was not administered to the patient. Following the 
intention to-treat (ITT) principle, patients will be analyzed according to the randomized 
treatment arm. 
• Safety set (SS): all patients who initiated i.v. infusion of study treatment whether being 
randomized or not. Patients will be analyzed according to the actual dose received. If the 
actual dose received is not a study dose level, the analyzed dose level will be the next lowest 
active dose arm.  


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• PK analysis set: all patients with at least one available valid (i.e. not flagged for exclusion) 
PK concentration measurement, who received any study treatment and with no protocol 
deviations that impact PK data  
Unless otherwise specified, all efficacy analysis will be performed on the FAS and safety 
analyses will be performed on the SS.  
2.2.1 
Subgroup of interest 
The following subgroups will be used for the primary variable: 
• Subgroups: 
o Risk for COVID-19 disease progression (“high-risk”, “not at high-risk”) – as per 
protocol 
o Risk for COVID-19 disease progression (“high-risk”, “not at high-risk”) - as per 
FDA updated definition on May 19, 2021 
o Geographical region (North America, Europe, Africa, Asia) 
o Gender (Male, Female) 
o Age (<55 years, 55-<65 and ≥65 years) 
o Mutation type (Wild type; Alpha B.1.1.7; Beta B.1.351; Gamma P.1; Delta 
B.1.617.2; Lambda C.37; Other)*, if available 
o Baseline log10 SARS-CoV-2 viral load (log10 SARS-CoV-2 viral load < 6, log10 
SARS-CoV-2 viral load ≥ 6) 
o SARS-CoV-2 antibodies at baseline (No, Yes) 
o Baseline severity of COVID-19 (mild, moderate) 
* List of mutation types may be updated if new variants of concern are detected during the study.  
Mutation type data will only be partially available at the time of part A primary analysis, 
therefore this subgroup will be analyzed at the time of final lock i.e., day 91 analyses only. 
Subgroups may need to be combined if there is not a sufficient number of patients (e.g. at least 
10%) in a respective subgroup. Regions will only be combined if models fail to converge, 
whether or not having less than 10%. 
For tables presenting results from statistical models, the treatment effects in the subgroup will 
be derived using an additional covariate as a fixed effect and the appropriate interaction terms 
in the model, if necessary. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The number of patients in each analysis set will be presented overall for the SCR and by 
treatment group for the RAN. 
The number of patients in the FAS will be summarized by region, country, center and treatment 
group.  


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SAP (Amendment 2)                                                                     MP0420-CP302 (CSKO136A12201J) 
 
 
 
The number and percentage of patients in the SCR who were randomized or discontinued study 
prior to randomization, including the reason for discontinuation will be presented overall. 
The number and percentage of patients in the RAN who completed or discontinued study, 
including the reason for discontinuation will be presented overall and by treatment group. 
The frequency (%) of patients with CSR reportable protocol deviations will be presented for 
the RAN. Other criteria leading to exclusion from analysis sets will be listed. 
These summaries will be produced independently for Part A and Part B. 
2.3.2 
Background and demographic characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment arm for the FAS and SS (if different from the FAS).  
Demographics listed below will be summarized: 
• Age (years) 
• Gender (Male, Female) 
• Race (White, Black or African American, Asian, Native Hawaiian or Other Pacific 
Islander, American Indian or Alaska Native, Multiple, Unknown, Not reported) 
• Ethnicity (Hispanic, Non-hispanic) 
• Age group (<25 years, 25-<45 years, 45-<65 and ≥65 years) 
• Geographical region (North America, Europe, Africa, Asia) 
The following baseline characteristics will be summarized: 
• Body weight (kg) 
• BMI (kg/m2), calculated as weight in kg divided by (height in m)² 
• BMI group (<18.5 kg/m², 18.5-<25 kg/m², 25-<35 kg/m², >= 35 kg/m²) 
• Risk for COVID-19 disease progression (“high-risk”, “not at high-risk”) – as per protocol 
• Risk for COVID-19 disease progression (“high-risk”, “not at high-risk”) – as per FDA 
updated definition on May 19, 2021  
• Chronic kidney disease (No, Yes) 
• Diabetes mellitus (No, Yes) 
• Immunosuppressive disease (No, Yes) 
• Currently receiving immunosuppressive treatment (No, Yes) 
• >= 65 years of age (No, Yes) 
• >= 55 years of age and cardiovascular disease, or hypertension, or chronic obstructive 
pulmonary disease / other chronic respiratory disease (No, Yes) 
• Baseline ADA status (ADA+, ADA-)*  
• Baseline log10 SARS-CoV-2 viral load (copies per mL) 
• Baseline log10 SARS-CoV-2 viral load (log10 SARS-CoV-2 viral load < 6, log10 SARS-
CoV-2 viral load ≥ 6) 


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• Mutation type (Wild type; Alpha B.1.1.7; Beta B.1.351; Gamma P.1; Delta B.1.617.2; 
Lambda C.37; Other)*, if available 
• SARS-CoV-2 antibodies as baseline (No, Yes) 
• Baseline severity of COVID-19 (mild, moderate, severe (if appears)). Details on definition 
are included in Section 5.2.  
* ADA samples will not be analyzed for Placebo patients, therefore ADA status will be 
missing for Placebo patients. 
2.3.3 
Medical history/current medical condition 
Medical history will be coded with the Medical Dictionary for Regulatory Activities 
terminology (MedDRA) using the most recent version at the time of database lock. 
History/conditions, including pre-specified events, will be summarized for the FAS by primary 
system organ class, high level term (HLT), and preferred term.  
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The analysis of study treatment will be based on the SS. All study treatment summaries will be 
presented by treatment arm. 
The number and percentage of patients with discontinuation of study medication, if applicable, 
will be summarized by reason for discontinuation. 
2.4.2 
Prior, concomitant and rescue therapies 
Prior, concomitant, and rescue therapies will be summarized based on the FAS. 
Prior medications are defined as medications started prior to start of study drug and discontinued 
prior to start of study drug.  
Concomitant medications are defined as medications starting prior to start of study drug and are 
ongoing at Day 1, or started after/at Day 1. 
All medications will be summarized separately for prior and concomitant medications by 
anatomical main group (the 1st level of the ATC codes), ATC code (4th level or if not available 
next higher level), preferred term and treatment group. 
A patient with multiple medications of the same anatomical main group, ATC class or preferred 
term will only be counted once towards the specific anatomical main group, ATC class or 
preferred term. 
Number and percentage of patients who received COVID-19 vaccinations will be presented 
along with the number of doses received and time since most recent dose (<15 days, 15-<180 
days, >=180 days). 
In addition, the number and percentage of patients who received concomitant medications 
related 
to 
COVID-19 
will 
be 
summarized 
by 
category 
(anti-virals, 
immune-


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modulating/immunosuppressant, other) and by preferred term, separately for concomitant 
medications initiated before study medication and concomitant medications initiated after study 
medication. 
Rules for imputing incomplete dates are described in Section 5.1.3. 
2.5 
Analysis of the primary objective 
Part A 
The primary analysis in Part A is conducted on the data cut performed after the last enrolled 
Part A patient completes Day 29 visit or discontinues prematurely. 
Part B 
The primary analysis in Part B is conducted on the data cut performed after the last enrolled 
Part B patient completes Day 91 visit. 
An outline of the protocol-specified analysis of Part B is provided in the SAP. Further details 
will be provided in a SAP amendment before FPFV of Part B.  
2.5.1 
Primary endpoint 
Part A 
In Part A, the primary variable for the study is a virologic endpoint defined as time-weighted 
change from baseline to Day 3, 5, and 8 (2, 4, and 7 days after dosing, respectively) in log10 
SARS-CoV-2 viral load in nasopharyngeal swabs.  
To calculate the time-weighted change from in log10 SARS-CoV-2 viral load through Day 8 for 
each patient, the equation below is used: 
∑
{0.5(𝑌𝑌𝑖𝑖+ 𝑌𝑌𝑖𝑖+1)(𝑡𝑡𝑖𝑖+1 −𝑡𝑡𝑖𝑖)}
𝑏𝑏−1
𝑖𝑖=𝑎𝑎
𝑡𝑡𝑏𝑏−𝑡𝑡𝑎𝑎
 
where 𝑌𝑌𝑖𝑖 is the change from baseline in log10 SARS-CoV-2 viral load at Visit 𝑖𝑖, 𝑡𝑡𝑖𝑖 is the time 
at the Visit 𝑖𝑖 (the actual study day), 𝑎𝑎 is the baseline assessment at Day 1, and 𝑏𝑏 is the last 
assessment at or prior to Day 8. Viral load values below the lower limit of quantification 
(LLOQ) will be imputed as 0.5*value of the LLOQ. Viral load values above the upper limit of 
quantification (ULOQ) will be imputed as value of the ULOQ. 
The primary estimand definition is as follows: 
• Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
population, ambulatory adult patients with newly symptomatic COVID19 with onset of 
symptoms within 7 days prior to dosing and with a positive rapid antigen test on the day of 
dosing  
• Treatment of interest: the randomized treatment (ensovibep 75 mg, 225 mg, 600 mg, or 
placebo) added to concomitant symptomatic/preventive treatments, including symptomatic 
therapies (e.g., antipyretics/analgesics such as ibuprofen, paracetamol/acetaminophen, 
aspirin) and anticoagulants (e.g., heparin), used for mild-to-moderate COVID-19 


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• Endpoint: time-weighted change from baseline (measured at Day 3, Day 5, and Day 8) in 
log10 SARS-CoV-2 viral load in nasopharyngeal swabs through Day 8  
• Handling of intercurrent event(s): A combination of treatment policy and composite 
strategy will be used to handle the intercurrent events. A treatment policy strategy will be 
used to handle (1) post-treatment initiation of all antivirals (including convalescent serum, 
antiviral antibodies, and antiviral small molecules), immunomodulating medications; and, 
(2) post-treatment increase in dose of immunosuppressive medications, for the treatment 
or management of COVID-19. A composite strategy will be used to handle (3) death from 
any cause and (4) COVID-19 related hospitalization. 
• Summary measure: adjusted mean time-weighted change from baseline (measured at 
Day 3, Day 5, and Day 8) in log10 SARS-CoV-2 viral load in nasopharyngeal swabs 
between the ensovibep 75 mg, 225 mg, and 600 mg compared to placebo arms.  
Part B 
In Part B, the primary variable is a clinical efficacy endpoint defined as any of the following up 
to Day 29: 
• Hospitalizations (≥ 24 hours of acute care) related to COVID-19; OR, 
• Emergency room visits related to COVID-19; OR, 
• Death from any cause. 
If a patient experiences more than one of the events, the first event to occur will be counted 
towards the clinical efficacy endpoint and the date at which the first event occurred will be 
used as time date at which the clinical efficacy endpoint was achieved.  
The primary estimand definition is as follows: 
1. Population: defined through appropriate inclusion/exclusion criteria to reflect the targeted 
population, ambulatory adult patients with newly symptomatic COVID-19 with onset of 
symptoms within 7 days prior to dosing and with a positive rapid antigen test on the day of 
dosing 
2. Treatment of interest: the randomized treatment (ensovibep [dose selected from Part A] 
or placebo) added to concomitant symptomatic/preventive treatments, including 
symptomatic therapies (e.g., antipyretics/analgesics such as ibuprofen, 
paracetamol/acetaminophen, aspirin) and anticoagulants (e.g., heparin), used for mild-to-
moderate COVID-19 
3. Endpoint: the binary response of patients experiencing hospitalizations (≥ 24 hours of 
acute care) and/or emergency room visits related to COVID-19 or death from any cause 
up to Day 29 (Yes/No) 
4. Handling of intercurrent event(s): A treatment policy strategy will be used to handle (1) 
post-treatment initiation of all antivirals (including convalescent serum, antiviral 
antibodies, and antiviral small molecules), immunomodulating medications; and, (2) post-
treatment increase in dose of immunosuppressive medications, for the treatment or 
management of COVID-19. 


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5. Summary measure: difference in proportions of patients experiencing hospitalizations (≥ 
24 hours of acute care) and/or emergency room visits related to COVID-19 or death from 
any cause up to Day 29 of ensovibep (dose selected from Part A) compared to placebo 
2.5.2 
Statistical hypothesis, model, and method of analysis  
Part A 
The primary objective of this Part is to demonstrate a dose-response effect of ensovibep 
compared to placebo defined as time-weighted change from baseline in log10 SARS-CoV-2 
viral load through Day 8. The MCP-Mod methodology (Bretz et al 2005, Pinheiro et al 2014, 
Qualification Opinion on MCP-Mod EMA 2014, FDA endorsement 2016) to address this 
objective and confirm an overall dose-response signal, characterize the dose response efficacy 
relationship across the dose range of ensovibep, and estimate the smallest dose(s) that 
corresponds to the clinically relevant effect over placebo with regards to time-weighted change 
from baseline in log10 SARS-CoV-2 viral load through Day 8.  
The null hypothesis of a constant dose-response curve for the time-weighted change from 
baseline in log10 SARS-CoV-2 viral load through Day 8 will be tested at a one-sided 10% alpha 
level against the alternative hypothesis of a non-constant dose-response curve using the MCP-
Mod methodology.  
Generalized MCP-Mod (Pinheiro et al 2014) will be employed in a three-step approach in the 
steps is given below:  
• Conventional step – covariate-adjusted mean response for each dose  
The data are analyzed using analysis of covariance (ANCOVA) to obtain covariate 
adjusted treatment effects and corresponding variance covariance matrix. The 
ANCOVA will adjust for baseline log10 SARS-CoV-2 viral load, treatment group, 
baseline risk of progression to severe COVID-19 and/or hospitalization (“high risk” vs. 
“not at high risk”) and presence of SARS-CoV-2 antibodies (Yes vs. No) and 
Geographical region (North America, Europe, Africa, Asia) as covariates.  
The estimated treatment difference and the associated 95% confidence intervals will be 
presented for the treatment contrast of each dose versus placebo. 
• Proof-of-concept step – multiple contrast tests 
The null hypothesis of flat dose-response relationship as compared to placebo for the 
primary efficacy endpoint will be tested at a significance level of one-sided 10% against 
the alternative hypothesis of a non-constant dose-response curve using a multiple 
contrast test as described in the Generalized MCP-Mod methodology (Pinheiro et al 
2014). The contrast test statistic is a linear combination of the optimal contrast 
coefficients corresponding to the candidate dose-response curve with the adjusted mean 
responses at each individual dose obtained from Step 1.  
The contrast coefficients will be chosen to maximize the power to detect pre-specified 
candidate models (Pinheiro et al 2014). For that purpose, the Emax dose-response shape 
(E0 + Emax ∗d/(d + ED50)) with three shapes of ED50 = 8, 40, 180 and the sigmoid 


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Emax dose-response shape ( E0 + Emax ∗dh/(dh + ED50
h ) ) with two shapes of 
(ED50, h) = (120, 4)  and (450, 3) will be used where E0  is the expected placebo 
effect, Emax is the maximum change in effect over placebo, ED50 is the dose at which 
50% of Emax is achieved, and h is Hill parameter (Figure 2-1).  
The global test decision is based on the maximum of the contrast test statistics. A critical 
value 𝑞𝑞 controlling the type I error rate can be derived from the fact that the contrast test 
statistics approximately follow a multivariate normal distribution and that their 
maximum follows the distribution of the maximum of a multivariate normal distribution. 
If the maximum contrast test statistic exceeds the critical value 𝑞𝑞, the overall null 
hypothesis of a constant dose-response curve is rejected and one proceeds to 
characterize the dose response efficacy relationship and estimate the optimum dose(s) 
that corresponds to the clinically relevant effect over placebo.  
Figure 2-1 
Candidate models for ensovibep dose 
 
For each candidate dose-response curve, the test statistics and corresponding adjusted 
p-values will be presented. 
• Dose-finding step – dose-response model fitting 
A bootstrap sample (from a normal distribution with LSMeans and corresponding 
covariance matrix from an ANCOVA) is used to fit the non-linear dose-response 
functions and obtain parameter estimates for each model. Bootstrap model averaging 
based on AIC over all significant model families considered in the analysis will be used 
to estimate the final dose-response shape, to calculate the optimum dose(s) by 
substituting the values for the placebo-adjusted dose response in the model and solving 
for dose, and to derive the 95% confidence intervals. Bootstrap simulation will be 
performed using the multivariate normal distribution of the adjusted estimates of the 
population means for each dose and generalized least-squares fitting of the resulting 


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simulated values (Pinheiro et al 2014). The dose-response estimate will be the median 
across the bootstrap model predictions and 95% confidence intervals based on bootstrap 
quantiles.  
The dose-response curve estimate with the model-based two-sided 95% confidence 
interval will be presented graphically. In addition, the plot will include the mean 
responses from the ANCOVA and the associated 95% confidence intervals for each of 
the studied dose groups. 
Further details on the MCP-mod are described in Section 5.7.1. 
The target dose(s) will be estimated from MCP-mod for a delta of 0.36 and 0.68 based on the 
estimated dose-response curve (median of bootstrap estimates). The target dose is the smallest 
dose among the investigated doses which reaches the effect of delta.. 
The target dose(s) suggested by MCP-Mod based on viral endpoint serves as an important 
consideration in dose selection. However, the final dose selection for Part B will be determined 
based on the following 
• Efficacy of doses based on rate of occurrence of hospitalizations (≥ 24 hours of acute care) 
and/or emergency room visits related to COVID 19 or death from any cause up to day 29, 
FDA/modified FDA symptom score; AND, 
• Safety endpoints including 
 AESIs, AEs, and SAEs. 
Part B 
The primary objective of this Part is to demonstrate superiority of ensovibep, compared to 
placebo, in reducing the occurrence of hospitalizations (≥ 24 hours of acute care) and/or 
emergency room visits related to COVID 19 or death from any cause up to Day 29.  
The cumulative proportion of experiencing hospitalizations (≥ 24 hours of acute care) and/or 
emergency room visits related to COVID 19 or death from any cause up to Day 29 will be 
estimated for each randomized group using Kaplan-Meier methods to take account of losses to 
follow-up.  
The difference between randomized groups in the estimated log cumulative proportion will be 
calculated and the variance for this difference will be obtained using Greenwood’s formula. 
Two-sided 95% confidence intervals (adjusted for an interim analysis) and associated p-value 
for the test of no difference between groups will then be obtained. 
The hazard ratios for these comparisons for the occurrence of hospitalizations (≥ 24 hours of 
acute care) and/or emergency room visits related to COVID 19 or death from any cause and 
their corresponding 95% confidence intervals will be computed using a stratified Cox 
proportional hazards regression model, stratified by baseline risk of progression to severe 
COVID-19 and/or hospitalization (“high risk” vs. “not at high risk”). 
Time to hospitalizations (≥ 24 hours of acute care) and/or emergency room visits related to 
COVID 19 or death from any cause will be presented graphically with a Kaplan-Meier plot. 


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2.5.3 
Handling of missing values/censoring/discontinuations 
Part A 
A combination of treatment policy and composite strategy will be used to handle the intercurrent 
events.  
A treatment policy will be used to handle (1) post-treatment initiation of all antivirals (including 
convalescent 
serum, 
antiviral 
antibodies, 
and 
antiviral 
small 
molecules) 
and 
immunosuppressive 
medications; 
and, 
(2) 
post-treatment 
increase 
in 
dose 
of 
immunosuppressive medications, for the treatment or management of COVID-19, and a patient 
will be evaluated regardless of experiencing either of these intercurrent events. 
A composite strategy will be used to handle (3) death from any cause and (4) COVID-19 related 
hospitalization. In the event a patient experiences death or COVID-19 related hospitalization, 
all values after the time of death/start of the COVID-19 related hospitalization for change from 
baseline in log10 SARS-CoV-2 viral load will be set as the worst observed value based on 
observed values at each time point within each treatment arm independently.  
All measurements in log10 SARS-CoV-2 viral load missing for other reason than death or 
COVID-19 related hospitalization will be imputed using last observation carried forward 
(LOCF) approach.  
Part B 
A treatment policy will be used to handle (1) post-treatment initiation of all antivirals (including 
convalescent 
serum, 
antiviral 
antibodies, 
and 
antiviral 
small 
molecules) 
and 
immunosuppressive 
medications; 
and, 
(2) 
post-treatment 
increase 
in 
dose 
of 
immunosuppressive medications, for the treatment or management of COVID-19, and a patient 
will be evaluated regardless of experiencing either of these intercurrent events. 
Patients who prematurely discontinue the study and whose outcomes after discontinuation are 
not ascertainable will have follow up censored at the date of last known status. 
2.5.4 
Supplementary analyses 
Part A 
The following supplemental analysis will be performed: 
• excluding patients who experienced a negative PCR COVID-19 test following a positive 
swab; and,  
• imputing values below the LLOQ with the LLOQ value; and  
• using the approach for the handling of the intercurrent events specified and jump-to-
reference (J2R), a control-based pattern imputation method, for the handling of the 
remaining missing data. 
Further details on supplementary analyses can be found in Section 5.7.1. 


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Part B 
Analysis will be specified a future SAP amendment as outlined in Section 1. 
2.5.5 
Supportive analyses 
For all analyses specified in this section, the estimand in Section 2.5.1 and the missing data plan 
in Section 2.5.3 2.5.3for the primary analysis will be applied.  
Part A 
Subgroup analyses as described in Section 2.2.1 will be performed as supportive analysis on 
primary variable. Subgroup analysis will be performed using ANCOVA but not the full MCP-
mod procedure.  
Change from baseline in log10 SARS-CoV-2 viral load at visits (Day 3, Day 5 and Day 8) will 
be analyzed using a repeated measures ANCOVA (MMRM) including terms of treatment, 
baseline log10 SARS-CoV-2 viral load, baseline risk of COVID-19 progression, presence of 
SARS-CoV-2 antibodies (Yes vs. No) and Geographical region (North America, Europe, Africa, 
Asia), visit, treatment*visit and baseline*visit interaction. Estimated treatment differences at 
visit and corresponding 95% CI will be tabulated and presented graphically. 
MCP-mod procedure will be conducted for change from baseline at Day 8 in log10 SARS-CoV-
2 viral load as outlined in Section 2.5.2. LSMeans and covariance estimates from the MMRM 
on change from baseline at Day 8 in log10 SARS-CoV-2 viral load will be used to conduct the 
MCP-mod procedure. Similar outputs will be provided as in the primary analysis.  
A descriptive summary will be provided for time-weighted change from baseline in log10 
SARS-CoV-2 viral load through Day 8. Additionally, for absolute values and change from 
baseline in log10 SARS-CoV-2 viral load will be presented by visit.  
Further details on supplementary analyses can be found in Section 5.7.1. 
Part B 
Analysis will be specified a future SAP amendement as outlined in Section 1. 
2.6 
Analysis of the key secondary objective 
Not applicable. See Section 2.7 for secondary objectives.  
2.7 
Analysis of secondary efficacy objectives 
Part A 
Secondary efficacy objectives for Part A are: 
• To assess the effect of ensovibep, compared to placebo, in reducing the occurrence of 
hospitalizations (≥ 24 hours of acute care) and/or emergency room visits related to 
COVID-19 or death from any cause up to Day 29 
• To assess the effect of ensovibep, compared to placebo, in reducing COVID-19 symptoms 
up to Day 29  


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All secondary efficacy endpoints will be analyzed using the FAS. 
Part B 
Analysis will be specified a future SAP amendment as outlined in Section 1. 
2.7.1 
Secondary endpoints 
2.7.1.1 
Hospitalizations (≥ 24 hours of acute care) and/or emergency room 
visits related to COVID-19 or death from any cause up to Day 29 
This secondary variable is defined as the event of experiencing 
• Hospitalizations (≥ 24 hours of acute care) related to COVID-19; OR, 
• Emergency room visits related to COVID-19; OR, 
• Death from any cause. 
If a patient experiences more than one of the events, the first event to occur will be counted 
towards the clinical efficacy endpoint and the date at which the first event occurred will be used 
as time date at which the clinical efficacy endpoint was achieved.   
2.7.1.2 
COVID-19 symptoms 
Acute COVID-19 symptoms will be collected using a COVID-19 symptoms collection tool 
containing a 14-symptom questionnaire: feeling hot or feverish, chills or shivering, cough, sore 
throat, low energy or tiredness, headache, muscle or body aches, shortness of breath, nausea, 
vomiting, diarrhea, stuffy or runny nose, impaired sense of smell, and impaired sense of taste. 
The 14-symptoms will collectively be referred to as the FDA COVID-19 questionnaire (FDA 
2020a).  
At baseline, patients will have two or more COVID-19 symptoms as per inclusion critera. 
The endpoint to assess the reduction of COVID-19 symptoms up to Day 29 is time to sustained 
clinical recovery. 
Sustained clinical recovery is defined as (a) all symptoms from the modified FDA COVID-19 
symptom list scored as moderate or severe at baseline are subsequently scored as mild or absent, 
AND (b) all symptoms from the modified FDA COVID-19 symptom list scored as mild or 
absent at baseline are subsequently scored as absent, with no subsequent worsening, up to Day 
29.  
2.7.2 
Statistical hypothesis, model, and method of analysis 
2.7.2.1 
Hospitalizations (≥ 24 hours of acute care) and/or emergency room 
visits related to COVID-19 or death from any cause up to Day 29 
Proportion of patients experiencing hospitalizations (≥ 24 hours of acute care) and/or 
emergency room visits related to COVID 19 or death from any cause up to Day 29 will be 
presented along with relative risk to Placebo. 


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In addition, the number and percentage of patients with hospitalizations (≥ 24 hours of acute 
care) and/or emergency room visits related to COVID-19 or death from any cause up to day 29 
will be summarized overall and separately for hospitalizations (≥ 24 hours of acute care), 
emergency room visits related to COVID-19 and death from any cause. 
2.7.2.2 
COVID-19 symptoms 
The cumulative proportion of achieving sustained clinical recovery up to Day 29 will be 
estimated for each treatment group using Kaplan-Meier methods to take account of losses to 
follow-up. 
The treatment differences in the estimated log cumulative proportion will be calculated and the 
variance for this difference will be obtained using Greenwood’s formula. Two-sided 95% 
confidence intervals and associated p-value for the test of no difference between groups will 
then be obtained.  
Number and percentage of patients with and without event will be tabulated along with the time 
at risk, event rates and corresponding 95%CI. Additionally, a Kaplan-Meier plot will be 
presented. 
Time to sustained clinical recovery will be presented graphically with a Kaplan-Meier plot. A 
Cox proportional hazards model will be used, stratified by baseline risk of progression to severe 
COVID-19 and/or hospitalization (“high risk” vs. “not at high risk”). The model will include 
treatment, presence of SARS-CoV-2 antibodies (Yes vs. No), Geographical region (North 
America, Europe, Africa, Asia). Time of onset of COVID-19 symptoms (days relative to Day 
1) will also be evaluated as a predictor in the model. 
As a descriptive summary, shift tables presenting shifts from baseline to post-baseline will be 
provided for each question by selected visits (Day 3, Day 8, Day 15, and Day 29) and treatment 
group. Question on return to usual health and return to usual activities will be summarized for 
post-baseline visits only. Further a descriptive summary of the COVID-19 symptom score will 
be provided by scheduled timepoint. The symptom score ranges from 0 to 24 and includes eight 
domains (cough, breathlessness, feeling hot, fatigue, body pain, sore throat, chills and 
headache), each is graded on a scale of 0 (no symptoms) to 3 (severe symptoms). 
Prior to database lock for primary analyses it was detected that due to non-compliance at sites 
some patients did not complete the COVID-19 symptom questionnaire prior to start of infusion. 
These patients do not have valid baseline data for COVID-19 symptom questionnaire. Therefore 
the following supportive analysis will be performed: 
1) Time to sustained recovery analyses will be repeated using extended definition of 
sustained recovery: Sustained recovery is defined as (a) all symptoms from the 
modified FDA COVID-19 symptom list scored as moderate or severe at baseline are 
subsequently scored as mild or absent, AND (b) all symptoms from the modified FDA 
COVID-19 symptom list scored as mild or absent at baseline are subsequently scored 
as absent, with no subsequent worsening up to Day 29. For patients with missing 
baseline COVID-19 symptom questionnaire sustained recovery is defined as all 
symptoms from the modified FDA COVID-19 symptom list are scored as absent, with 
no subsequent worsening up to Day 29.  


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2) Time to event analyses will be repeated modifying baseline definition for COVID-19 
symptom questionnaire. All values up to the end of infusion at Day 1 will be 
considered as baseline. Since the COVID-19 symptom questionnaire has a recall 
period of last 24 hours, study medication is unlikely to have an impact on patients’ 
assessment of their symptoms over the last 24 hours, before infusion is completed. 
2.7.3 
Handling of missing values/censoring/discontinuations 
2.7.3.1 
Hospitalizations (≥ 24 hours of acute care) and/or emergency room 
visits related to COVID-19 or death from any cause up to Day 29 
Missing data will not be imputed. 
2.7.3.2 
COVID-19 symptoms 
Missing data due to premature discontinuations prior to Day 29 are covered with the censoring 
approach.  
Patients being too ill to complete the questionnaire will be considered as not achieving sustained 
recovery and will be censored at the earlier date or (last contact date, visit date of Day 29). 
Patients who complete the questionnaire due to other reasons than 'being too ill to complete the 
questionnaire', do not achieve sustained recovery up to Day 29 and discontinue prior to Day 29 
visit will be censored at the last date questionnaire was completed.  
For any missing questionnaires between non-missing assessments, if reason for this is that 
patient is too ill to complete the questionnaire, the respective day will be considered as not 
achieving recovery. 
2.8 
Safety analyses 
For all analyses in this section, the safety set will be used, if not specified otherwise. 
2.8.1 
Adverse events (AEs) 
Adverse events (AEs) will be coded based on the latest available MedDRA version practically 
possible (version 23.0 or above) that gives preferred term (PT) and primary system organ class 
(SOC) information. The MedDRA version will be displayed in the respective output footnotes. 
AEs will be graded using the common toxicity criteria for adverse events (CTCAE) version 5.0. 
The number (and percentage) of patients with treatment-emergent 
• Treatment emergent AEs (TEAEs) 
• Serious adverse events (SAEs)  
• AEs of Special Interest (AESIs; see Section 2.8.1.1)  
will be summarized by: 
• treatment, SOC and PT; 
• treatment, SOC, PT, and CTCAE grade; and, 
• treatment, Standardized MedDRA Query (SMQ) and PT. 


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In addition, the following events will be summarized by treatment, SOC and PT as well as by 
SOC, PT and maximum CTCAE grade: 
• TEAEs leading to discontinuation of study drug; 
• and,  
• TEAEs suspected to be study drug related. 
Deaths will be summarized by SOC and PT. 
Dot plots of the most frequent TEAEs of CTCAE grade 3 or higher, and serious TEAEs will be 
provided. 
AEs , SAEs, and AESIs will be listed, treatment emergent events will be flagged. 
In AE summaries, the primary SOC will be presented alphabetically and the PTs will be sorted 
within the primary SOC in descending frequency of the highest ensovibep dose. If a patient 
reported more than one AE with the same preferred term, the AE with the greatest severity will 
be presented. If a patient reported more than one AE within the same primary system organ 
class, the patient will be counted only once with the greatest severity at the SOC level, where 
applicable. An AE with missing CTCAE grade will be included in ‘All grades’ of the summary 
tables only. 
AEs and SAEs will be summarized by SOC, PT and ensovibep treatment arms for each 
treatment-emergent Anti-Drug Antibodies (TE-ADA) status (TE-ADA-, TE-ADA+induced, 
TE-ADA+boosted, and a combined TE-ADA+). ADA status is assessed at Day 1, 15, 29, 61 
and 91. AE will be summarized according to the TE-ADA status at start of the event. For the 
event start date, the TE-ADA status used will be the TE-ADA status assessed on the date of the 
event, if available, or on the first assessment after the event start date. If TE-ADA status 
following the event is not available, the last available TE-ADA status will be used. Percentages 
will be based on the number of patients with the respective ADA status at any time post-baseline. 
For more detail regarding TE-ADAs refer to Section 2.13.1. 
ADA data will only be partially available at the time of part A primary analysis, therefore 
adverse event analyses by TE-ADA status will be analyzed only at the time of final lock i.e., 
day 91 analyses.  
2.8.1.1 
Adverse events of special interest / grouping of AEs 
The following events are AEs of Special Interest (AESI) for this study:  
• A CTCAE grade 2 or higher (i.e. requiring intervention) of:Infusion site reactions:  
• Hypersensitivity reactions (including anaphylaxis, immune complex mediated 
hypersensitivity, cytokine release syndrome and other hypersensitivity reactions) 
• Worsening of COVID-19 disease that is reported as a moderate or severe AE per 
investigator judgement, with onset within 1 week of study drug administration.  
• Liver events requiring follow-up 
• Renal events requiring follow-up 
The number (and percentage) of patients with each of the AESIs will be summarized for each 
Part  


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• by treatment;  
• by treatment and maximum CTCAE grade; and, 
• and by treatment, primary system organ class, and preferred term.  
A listing of AESIs will be provided. AESIs will be analyzed as flagged by the investigator on 
the eCRF. 
Safety topics of interest are defined in the electronic case retrieval sheet (eCRS). These will by 
summarized for each part 
• by safety topic of interest  
• by safety topic of interest and preferred term 
• by safety topic of interest and preferred term for those AEs marked as AESI by the 
investigator 
AESIs and safety topics of interest will be in addition will be summarized for each treatment-
emergent Anti-Drug Antibodies (TE-ADA) status. ADA data will only be partially available at 
the time of part A primary analysis, therefore this analysis will only be done at the time of final 
lock i.e., day 91 analyses. 
2.8.2 
Deaths 
See Section 2.8.1. A listing will be provided for all deaths by treatment for each Part.  
2.8.3 
Laboratory data 
Laboratory data include measurements of all parameters below: 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, 
Other)  
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase 
(GGT), Lactate dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, 
Phosphorus, Chloride, Sodium, Potassium, Creatinine, Creatine kinase, Direct 
Bilirubin, Total Bilirubin, Total Protein, Blood Urea Nitrogen (BUN) or Urea, 
Uric Acid, Amylase, Lipase, Glucose (non-fasting), CRP, D-Dimer, Ferritin 
Coagulation 
Prothrombin time (PT), International normalized ratio [INR]), Activated 
partial thromboplastin time (APTT)  
Pregnancy Test 
Serum / Urine pregnancy test  
Clinically notable abnormalities and abnormalities in liver function tests (LFT) are described 
in Section 5.5. 
Absolute values and change from baseline will be summarized for continuous laboratory 
parameters by treatment and scheduled visit, including the worst post-baseline value. The 
direction of interest for worst post-baseline value for selected hematology and biochemistry 
parameters is shown in Section 5.4. 
For selected laboratory tests, the number and percentage of patients with newly occurring or 
worsening laboratory abnormalities meeting the clinically notable criteria at any time post-


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baseline, considering all post-baseline data from scheduled, unscheduled and premature 
discontinuation visits, will be summarized by treatment and laboratory parameter.  
Furthermore, the number and percentage of patients with newly occurring or worsening 
abnormalities in liver function tests (LFT) will be summarized by treatment and at any time 
post-baseline considering all post-baseline data from scheduled, unscheduled and premature 
discontinuation visit.  
The number (%) of patients with newly occurring or worsening of notable laboratory values 
will be provided.  
Shift tables using the low/normal/high/ (low and high) classification will be used to compare 
baseline to the worst post-baseline value.  
Listing of all laboratory data of patients with notable abnormal laboratory values will be 
provided with the classifications relative to the laboratory normal ranges. 
Urine pregnancy test data will be summarized using frequency and percentage by treatment. A 
listing of all pregnancy test data will be provided.  
2.8.4 
Other safety data 
2.8.4.1 
Vital signs 
Vital signs variables include measurements of systolic and diastolic blood pressure, heart rate, 
body temperature, respiratory rate, oximetry and weight. Clinically notable abnormalities are 
described in Section 5.6. 
Absolute values and change from baseline will be summarized for all vital signs parameter by 
treatment and scheduled visit.  
For selected vital sign parameter, the number and percentage of patients with newly occurring 
or worsening abnormalities meeting the clinically notable criteria at any time post-baseline, 
considering all post-baseline data from scheduled, unscheduled and premature discontinuation 
visits, will be summarized by treatment and parameter.  
 A listing of all vital signs of patients with notable abnormal vital signs values (with clinically 
notable abnormalities being flagged) will be generated. 
2.9 
Pharmacokinetic endpoints 
For all analyses in this section, the PK analysis set will be used. 
The PK analysis is specified as a secondary objective in Part A 
 
  
Free (ensovibep not bound to target) and total (sum of ensovibep not bound and ensovibep 
bound to target) concentration in serum will be summarized by treatment in each Part at Day 1 
pre-dose, Day 1 post-dose (at minute 15 and minute 90), Day 3, Day 8, Day 15, Day 29, Day 
61 and Day 91, including the frequency (n, %) of concentrations below the LLOQ and reported 
as zero. Median concentrations and median log(concentration) over scheduled time-points will 
be presented graphically by treatment group. 








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Part B 
There will be one interim analysis after 50% of patients complete Day 29 and one final analysis 
after at least 1717 patients have completed Day 91. The interim analysis permits early stopping 
due to efficacy controlling overall type I error rate. The interim analysis upper stopping bound 
in Z scale is 2.963 (corresponding to alpha is 0.03). 
3 
Sample size calculation 
3.1 
Primary endpoint(s) 
Part A  
In Documentation for the EUA for emergency use of casirivimab and imdevimab, issued 21 
Nov 2020, it is shown that the treatment effect in time-weighted change from baseline (Day 1) 
to 
Day 
8 
of 
log10 
SARS-Cov-2 
viral 
load 
in 
nasopharyngeal 
swabs 
was  
-0.36 for the overall population and -0.68 for the subgroup of patients with at least 107 copies 
at baseline and the estimated standard deviation was between 1.0 and 1.2. 
Assuming the published evidence to be predictive over 8 days, a sample size of at least 100 
patients per treatment group, for a total of 400 patients, would have at least 80% power 
(minimum power over the considered candidate shapes) with a one-sided Type I error rate of 
0.10 to detect a dose-response trend versus placebo using MCP-Mod to select the smallest dose 
for consideration in the decision to move into Part B. 
The power calculation given the range of operating characteristics (treatment effect: -0.36, -
0.68, and standard deviation: 1, 1.1, 1.2) were performed based on MCP-Mod in R (Pinheiro 
2006) and are presented in Table 3.1-1. 
Table 3.1-1 
Power for Part A given a range of operating characteristics given 400 
patients, 100 patients in each arm and a one sided significance level of 10% 
Treatment Effect 
Standard 
Deviation 
Power  
(%) 
-0.36 
1 
90.03 
1.1 
85.25 
1.2 
80.25 
-0.68 
1 
99.98 
1.1 
99.92 
1.2 
99.73 
Part B 
Assuming the proportion of patients achieving the composite endpoint (of hospitalizations (≥ 
24 hours of acute care) and/or emergency room visits, related to COVID-19, or death from any 
cause) up to Day 29 is 6.5% based on Gottlieb et al (2021) in the placebo group and 50% 
reduction with to 3.25%, a sample size of 1717 patients 1:1 randomized to two treatment groups 
provides at least 90% power that the primary analysis will be statistically significant using a 
two-sided log rank test with 5% significance level assuming that the survival rates are 
exponential. These results assume that the group sequential design has one interim analysis for 


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stopping the trial early for efficacy after 50% of patients complete Day 29 visit (two total 
analysis including final analysis) and the O'Brien-Fleming spending function is used to 
determine the efficacy test boundary.  
Given possible enrichment for more severe COVID-19 cases, a range of operating 
characteristics were evaluated and presented in Table 3.1-2. 
Sample size calculations are performed in nQuery 8.4.1.0.  
Table 3.1-2 
Power for Part B given a range of operating characteristics  
Total Sample Size 
Placebo Event 
Rate (%) 
Drug Event Rate 
(%) 
Power  
(%) 
1717 
6.5 
3.25 
90.02 
1588 
7 
3.5 
90.01 
1476 
7.5 
3.75 
90.01 
1380 
8 
4 
90.04 
1295 
8.5 
4.25 
90.06 
1217 
9 
4.5 
90.03 
1148 
9.5 
4.75 
90.02 
1086 
10 
5 
90.02 
3.2 
Key secondary endpoint(s) 
Not Applicable. 
3.3 
Other secondary endpoint(s) 
Not Applicable. 
4 
Change to protocol specified analyses 
 
Not applicable. 
5 
Appendix 
5.1 
Imputation rules 
Any date incompletely reported is split into its day, month, and year components. In SAS, a 
numerical date value can only be defined if all these date components are known; incomplete 
dates are to be handled as text strings (character-type variables); as such, they could not be 
easily processed. An imputation rule for incomplete dates will be performed. 
5.1.1 
Study drug 
Missing/partial start date/time or end date/time of study treatment will not be imputed. 


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5.1.2 
AE date and hospitalization date imputation 
This algorithm is expressed in the Variable Source Derivation column as #IMPUTAEV(event) 
where event is the partial start date of the AE. Table 5.1-1 explains the notation used in the logic 
matrix. Please note that missing start dates will not be imputed. Note, if the imputed AE (or 
HO) start is after AE (or HO) end date, then set AE (or HO) start equal to AE (or HO) end date. 
Missing AE (or HO) end dates will not be imputed. 








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• Neurodevelopmental disorders (for example, cerebral palsy) or other conditions that 
confer medical complexity (for example, genetic or metabolic syndromes and severe 
congenital anomalies) 
• Having a medical-related technological dependence (for example, tracheostomy, 
gastrostomy, or positive pressure ventilation (not related to COVID-19)) 
5.3 
Derivation of baseline COVID-19 severity 
Baseline COVID-19 severity will be calculated based on the FDA guidance (CDER 2020b). 
Derivation for severe or critical COVID-19 are not included as these patients will not be 
enrolled in the trial. 
Mild COVID-19: 
• No presence of dyspnea (as found in the eCRF); AND, 
• Respiratory rate < 20 breaths/minute; AND, 
• Heart rate < 90 beats/minute. 
• AND no criterion for moderate or severe COVID-19 
Moderate COVID-19: 
• Presence of dyspnea with exertion (as found in the eCRF); OR, 
• Respiratory rate 20 - < 30 breaths/minutes; OR, 
• Heart rate 90 - < 125 beats/minute 
• AND no criterion for severe COVID-19.  
Severe COVID-19: 
• Presence of dyspnea at rest (as found in the eCRF); OR, 
• Respiratory rate ≥ 30 breaths/minutes; OR, 
• Heart rate ≥ 125 beats/minute; OR  
• Oxygen saturation SpO2 <=93% 
5.4 
AEs coding/grading 
Adverse events (AEs) are to be coded with the MedDRA dictionary based on the latest version 
available at the time of the analyses (version 24 or above) gives preferred term (PT) and primary 
system organ class (SOC) information. AEs will be graded using the common toxicity criteria 
for adverse events (CTCAE) version 5.0. 
5.5 
Laboratory parameters derivations 
Table 5.5-1 shows the criteria for clinically notable laboratory values and includes the direction 
of interest when analyzing worst case values in form of maximum and/or minimum post-
baseline values.  


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Not all parameters have notable criteria defined. 
If the direction of interest is given as "High" the maximum value will be calculated and used as 
worst value, if the direction is given as "Low" the minimum value will be taken, and if it is 
given as "Low and high", both the minimum value and the maximum value will be calculated 
and presented in summary tables. 
Table 5.5-1  
    Clinical notable criteria for selected laboratory tests 
Laboratory parameter (unit) 
Lower bound of 
clinically 
notable range 
Upper bound of 
clinically 
notable range 
Direction of 
interest for 
worst case 
value 
A. Hematology 
 
 
 
Hematocrit (v/v) 
 
 
 
     Male 
0.37 
 
Low 
     Female 
0.32 
 
Low 
Hemoglobin (g/L) 
 
 
 
     Male 
115 
 
Low 
     Female 
95 
 
Low 
Erythrocytes 
 
 
Low 
WBC (x10E9/L) 
2.8 
16.0 
Low and High 
Basophils 
- 
 
High 
Eosinophils 
- 
 
High 
Lymphocytes (x10E9/L) 
0.5 
4 
Low and High 
Monocytes 
- 
 
High 
Neutrophils (x10E9/L) 
1.5 
10 
Low and High 
Platelets (x10E9/L) 
75 
700 
Low and High 
B. Chemistry 
 
 
 
Albumin (g/L) 
 
 
25 
- 
Low 
Alkaline Phosphatase (U/L) 
- 
3xULN 
High 
ALT/SGPT (U/L) 
- 
3xULN 
High 
AST/SGOT (U/L) 
- 
3xULN 
High 
Bilirubin Total (mmol/L) 
- 
34.2 
High 
Direct bilirubin 
- 
 
High 
BUN (mmol/L) 
- 
10.7 
High 
Creatinine (umol/L) 
- 
177 
High 
Creatinine kinase 
- 
3 x ULN 
High 
Gamma GT (U/L) 
- 
3 x ULN 
High 
Bicarbonate 
 
 
Low and High 
Chloride 
90 
115 
Low and High 
Potassium (mmol/L) 
3 
5.5 
Low and High 
Magnesium (mmol/L) 
0.51 
1.07 
Low and High 
Calcium 
1.75 
3.0 
Low and High 
LDH 
- 
 
High 
Phosphorus 
0.6 
1.6 
Low and High 
Sodium (mmol/L) 
130 
150 
Low and High 
C-Reactive Protein (CRP) (mg/L) 
- 
100 
High 


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Laboratory parameter (unit) 
Lower bound of 
clinically 
notable range 
Upper bound of 
clinically 
notable range 
Direction of 
interest for 
worst case 
value 
Fibrinogen 
- 
 
High 
Total protein (g/L) 
45 
- 
Low 
Uric Acid 
 
 
 
    Male 
- 
595 
High 
    Female 
- 
476 
High 
Amylase 
- 
1.5 x ULN 
High 
Lipase 
- 
1.5 x ULN 
High 
Glucose (mmol/L) 
3.0 
11 
Low and High 
D-dimer 
- 
3 x ULN 
High 
Ferritin (ng/mL) 
 
3 x ULN 
High 
C. Coagulation 
 
 
 
PT 
 
- 
Low 
INR 
 
1.5 x ULN 
High 
APTT 
 
1.5 x ULN 
High 
v = volume, ULN = upper limit of normal 
Table 5.5-2 shows the criteria for clinically notable liver test values.  
When a criterion contains multiple laboratory parameters, the criterion will only be considered 
to have been met when all conditions occur within a 3-day window. A case where all criteria 
are met at a post-baseline time point will be considered as newly occurring if the criteria are not 
met at baseline and will be considered as worsening if the criteria are met at baseline and at 
least one component is worsening from baseline irrespective of whether the other(s) are better. 


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Table 5.5-2  
    Notable liver function test values 
Criterion 
ALT > 3 x the upper limit of normal range (ULN) 
ALT > 5 x ULN 
ALT > 8 x ULN 
ALT > 10 x ULN 
ALT > 20 x ULN 
ALT or AST > 3 x ULN 
ALT or AST > 5 x ULN 
ALT or AST > 8 x ULN 
ALT or AST > 10 x ULN 
ALT or AST > 20 x ULN 
Total bilirubin > 1 x ULN 
Total bilirubin > 1.5 x ULN 
Total bilirubin > 2 x ULN 
Total bilirubin > 3 x ULN 
ALP > 1.5 x ULN 
ALP > 2 x ULN 
ALP > 3 x ULN 
ALP > 5 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 1.5 x ULN 
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 5 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 8 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 10 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 20 x ULN and total bilirubin > 2 x ULN 
ALP > 3 x ULN and total bilirubin > 2 x ULN 
ALP > 5 x ULN and total bilirubin > 2 x ULN 
ALT or AST > 3 x ULN and Total Bilirubin > 2 x ULN and ALP < 2 x ULN (Hy's law) 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, ALP = alkaline phosphatase 
5.6 
Vital signs – definition of clinically notable values 
Table 5.6-1 shows the clinical notable criteria for vital signs. 
Table 5.6-1  
    Clinical notable criteria for vital signs 
Vital sign 
Direction 
Patient age at screening 
< 18 years 
≥ 18 years 
Systolic blood 
pressure [mmHg] 
High 
≥ 95th percentile of the age and 
height group1 
≥ 180 with increase from baseline of 
≥20 mmHg 
Low 
≤ 5th percentile of the age and 
height group1 
≤ 90 with decrease from baseline of 
≥20 mmHg 
Diastolic blood 
pressure [mmHg] 
High 
≥ 95th percentile of the age and 
height group1 
≥ 105 with increase from  baseline of 
≥15 mmHg 
Low 
≤ 5th percentile of the age and 
height group1 
≤ 50 with decrease from baseline of 
≥15 mmHg 
High 
≥ 38.4°C 
≥ 39.1°C 


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Vital sign 
Direction 
Patient age at screening 
< 18 years 
≥ 18 years 
Oral body 
temperature [°C] 
Low 
≤ 35.0°C 
Pulse rate [bpm] 2 
High 
1-6 months 
> 160 
≥120 with increase from  baseline of 
≥15 bpm 
6-12 months 
>150 
12-18 months 
> 140 
18-24 months 
> 135 
2-3 years 
> 128 
3-4 years 
> 123 
4-6 years 
> 117 
6-8 years 
> 111 
8-12 years 
> 103 
12-15 years 
> 96 
≥ 15 years 
> 92 
Low 
1-6 months 
<120 
≤50 with decrease from baseline of 
≥15 bpm 
6-12 months 
<110 
12-18 months 
< 103 
18-24 months 
< 98 
2-3 years 
< 92 
3-4 years 
< 86 
4-6 years 
< 81 
6-8 years 
< 74 
8-12 years 
< 67 
12-15 years 
< 62 
≥ 15 years 
< 58 
Weight 
High 
increase from baseline3 of ≥ 2 
BMI- for-age percentile 
categories4 
Weight increase from  baseline of ≥ 
10% 
Low 
decrease from baseline3 of ≥ 2 
BMI- for-age percentile 
categories4 
Weight decrease from baseline of ≥ 
10% 
Respiratory rate 
[breath per 
minute]2,6,7 
High 
1-6 months 
>55 
≥30bpm 
6-12 months 
>50 
12-18 months 
> 46 
18-24 months 
> 40 
2-3 years 
> 34 
3-4 years 
> 29 
4-6 years 
> 27 
6-8 years 
> 24 
8-12 years 
> 22 
12-15 years 
> 21 
≥ 15 years 
> 20 
Low 
1-6 months 
<33 
≤ 10bpm 
6-12 months 
< 30 


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Vital sign 
Direction 
Patient age at screening 
< 18 years 
≥ 18 years 
12-18 months 
<28 
18-24 months 
< 25 
2-3 years 
< 22 
3-4 years 
< 21 
4-6 years 
< 20 
6-8 years 
< 18 
8-12 years 
< 16 
12-15 years 
< 15 
≥ 15 years 
< 13 
Oxygen saturation Low <=93% 
bpm=beats per minute; NHLBI= National Heart, Lung, and Blood Institute; 
1 Blood pressure percentiles are calculated for each blood BP record using the method described in 
Appendix B of the following reference: The Fourth Report on Diagnosis, Evaluation and Treatment of 
High Blood Pressure in Children and Adolescents. Pediatrics 2004; 114; 555. 
2 Fleming S, Thompson M, Stevens R, et al. Normal ranges of heart rate and respiratory rate in children 
from birth to 18 years of age: a systematic review of observational studies. Lancet 2011; published online 
March 15. DOI:10.1016/S0140-6736(10)62226-X. 
3 Baseline BMI-for-age weight status categories are underweight (less than the 5th percentile), healthy 
weight (5th percentile to less than the 85th percentile), overweight (85th to less than the 95th percentile) 
and obese (equal to or greater than the 95th percentile); 
4 BMI-for-age percentiles categories (P3, P5, P10, P25, P50, P75, P85, P90, P95, P97) are obtained 
from the WHO Growth Charts (http://www.who.int/childgrowth/en/); 
Note: For patients less than 2 years old, growth charts are based on recumbent length instead of height, 
which is not collected in the study. As an approximation, height collected in the study is considered as 
equal to the recumbent length; 
6 Eldridge L. What is a Normal Respiratory Rate?, Updated May 16, 2014; 
7.Kou .R., Shuei L., Bradypnea, Department of Physiology, School of Medicine, National Yang-Ming 
University, Taipei, Taiwan, http://rd.springer.com/referenceworkentry/10.1007%2F978-3-540-29676- 
8_246 
5.7 
Statistical models  
5.7.1 
Primary analysis 
The following ANCOVA will be used for time-weighted change from baseline in log10 SARS-
Cov-2 viral load through Day 8: 
Dependent variable = intercept + treatment + baseline in log10 SARS-CoV-2 viral load + 
baseline risk for COVID-19 disease progression + presence of SARS-Cov-2 antibodies at 
baseline + geographic region + error. 
The SAS procedure PROC MIXED will be used for analysis. Results will be presented with 
LSM and standard error (SE) for treatment effects and LSM, SE, associated two-sided 95% 
confidence interval, and two-sided p-value for treatment contrasts of each ensovibep dose 
versus Placebo. 
• MCP-Mod 


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The Multiple Comparison Procedure – Modelling (MCP-Mod) methodology (see 
Bretz et al 2005 and Pinheiro et al 2014) will be employed to assess the primary objective. The 
following steps for the MCP-Mod methodology will be performed. The analysis will be 
implemented in SAS (used for ANCOVA) and R (MCP-Mod) using DoseFinding R package:  
Step 1 (Testing an overall dose-response signal - MCP part): 
a. Fit ANCOVA model. Extract estimates and variance-covariance matrix from fitted model. 
b. Perform multiple contrast test with pre-defined model types and optimal contrasts, using 
variance-covariance matrix from the ANCOVA.  
Consider the following candidate models: 
- 
Emax (ED50=8) 
- 
Emax (ED50=40) 
- 
Emax (ED50=180) 
- 
sigEmax (ED50=120, h=4) 
- 
sigEmax (ED50=450, h=3) 
Present t-statistics and corresponding adjusted p-values for each candidate model. 
If there is at least one significant DR relationship, the DR signal is declared and Step 2 will 
be performed. 
Step 2 (Estimation of the dose-response curve and target dose – Mod part): 
a. Draw bootstrap samples (at least 1000) from a multivariate normal distributions N(µ,sigma) 
with parameter µ and sigma populated with the corresponding LSMeans and variance-
covariance from the ANCOVA of step 1a. Fit each of the pre-defined models to the data of 
each sample. Select the model with the best fit based on generalized AIC and predict the 
dose-response curve with this model in each sample. 
b. Derive median and other quantiles for predicted response over the dose range from the 
bootstrap samples. This will result in an averaged model. 
c. Estimate the target dose(s) for a delta of 0.3, 0.8, and 1.5 using inverse regression techniques 
using the best model for each of the bootstrap samples. If at least 50% of the target doses 
are within the investigated dose range the target dose will be derived as the median of the 
bootstrap samples, the 95% interval will be derived from the respective quantiles. For this 
derivation only target doses within the boundaries for the parameter are included (i.e. range 
of 0 – 1.5*maxdose for Emax and sigEmax, 0 – 2*maxdose for exponential). 
• Multiple imputation for supplementary analysis 
A treatment policy will be used to handle (1) post-treatment initiation of all antivirals (including 
convalescent 
serum, 
antiviral 
antibodies, 
and 
antiviral 
small 
molecules) 
and 
immunosuppressive 
medications; 
and, 
(2) 
post-treatment 
increase 
in 
dose 
of 
immunosuppressive medications, for the treatment or management of COVID-19, and a patient 
will be evaluated regardless of experiencing either of these intercurrent events. 
A composite strategy will be used to handle (3) death from any cause and (4) COVID-19 related 
hospitalization. In the event a patient experiences death or COVID-19 related hospitalization, 
all values after the time of death/start of COVID-19 related hospitalization for change from 


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baseline in log10 SARS-CoV-2 viral load will be set as the worst observed value based on 
observed values at each time point within each treatment arm independently.  
All measurements in log10 SARS-CoV-2 viral load missing for other reason than death or 
COVID-19 related hospitalization will be multiply imputed assuming patients in the ensovibep 
treatment arms behave as patients in the placebo arm, i.e. using jump-to-reference (J2R). 
Missing data of patients in the placebo treatment arm will be imputed using missing at random 
(MAR) assumption.  
For supplemental analysis using multiple imputation the following imputation steps need to be 
performed for missing data.  
Missing data will be imputed for the visits before deriving the time-weighted change from 
baseline Imputations will be done for change from baseline log10 SARS-CoV-2 viral load, not 
for the absolute value:  
1. Impute missing data using MAR for patient in the placebo arm: 
Select all patients from the placebo arm, impute missing values at Day 3, 5 and 8 using the 
MI approach based on the fully conditional specification (FCS) method for 100 time and 
obtain 100 imputed datasets. Missing Day 3 values will be imputed using a model with the 
imputed values of baseline risk of COVID-19 progression, baseline in log10 SARS-CoV-2 
viral load, presence of SARS-Cov-2 antibodies at baseline and geographic region as 
predictors. Missing Day 5 values will be imputed using a model with the values of Day 3, 
baseline risk of progression, baseline in log10 SARS-CoV-2 viral load presence of SARS-
Cov-2 antibodies at baseline and geographic region as predictors. Repeat the same for 
subsequent visits.  
This results in at least 100 imputed datasets.  
2. Impute missing for patients in the ensovibep treatment groups using J2R:  
Select all patients, impute missing values at Day 3, 5 and 8 using the MI approach, under 
assumption of missing not at random (MNAR) that patients in ensovibep treatment groups 
will behave as patients treated with Placebo, based on the fully conditional specification 
(FCS) method for 100 time and obtain 100 imputed datasets. Missing Day 3 values will be 
imputed using a model with the imputed values of baseline risk of COVID-19 progression, 
baseline in log10 SARS-CoV-2 viral load, presence of SARS-Cov-2 antibodies at baseline 
and geographic region as predictors. Missing Day 5 values will be imputed using a model 
with the values of Day 3, baseline risk of progression, baseline in log10 SARS-CoV-2 viral 
load presence of SARS-Cov-2 antibodies at baseline and geographic region as predictors. 
Repeat the same for subsequent visits. 
This results in 100 imputed datasets.  
3. Set datasets from step 1 and step 2.  
4. Derive time weighted change from baseline for each patient and each imputed dataset. 
5. Data of the final multiply-imputed dataset where all missing values are filled will be 
analyzed (by imputed dataset) using the ANCOVA as specified for the primary analysis. 
6. The results for the treatment effect from at least 100 datasets will then be combined using 
Rubin’s rule. 
Step 1 to 6 will be implemented before MCP-Mod is used.  


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Step 5 and 6 will be used within MCP-Mod for step 1a Step 1b and 2a of the MCP-Mod will 
use the combined estimate and variance-covariance matrix of step 6. 
• Repeated measures ANCOVA (MMRM) for supportive analyses 
The following repeated measure ANCOVA (MMRM) will be used for change from baseline in 
log10 SARS-CoV-2 viral load: 
Dependent variable = intercept + treatment + baseline log10 SARS-CoV-2 viral load + baseline 
risk for COVID-19 disease progression + presence of SARS-Cov-2 antibodies at baseline + 
geographic region + visit + treatment*visit + baseline log10 SARS-CoV-2 viral load *visit + 
error. 
The within-patient correlation will be modeled using an unstructured covariance matrix in the 
mixed model. The Kenward-Roger approximation will be used to estimate denominator degrees 
of freedom (Kenward and Roger 1997).  
If the model fails to converge with unstructured covariance matrix, either a compound 
symmetry (first choice) or first order autoregressive (AR1) (second choice) covariance structure 
will be used.  
The SAS procedure PROC MIXED will be used for analysis. Results will be presented with 
LSM and standard error (SE) for treatment effects and LSM, SE, associated two-sided 95% 
confidence interval, and two-sided p-value for treatment contrasts of each ensovibep dose 
versus placebo. 
Handling of intercurrent events follows the primary analysis. Any missing data for other reason 
than death/COVID-29 related hospitalization are considered MAR and handled as such in the 
MMRM. 
5.7.2 
Key secondary analysis 
Not applicable. 
5.8 
Rule of exclusion criteria of analysis sets  
Table 5.8-1 
Subject Classification 
Analysis Set 
PD ID that 
  
cause patients to be excluded 
Non-PD criteria that cause  
patients to be excluded 
SCR 
NA 
Not having ICF;  
Not having screening epoch disposition page 
RAN 
NA 
Patients not being randomized. 
FAS 
NA 
Not in RAN; 
Mistakenly randomized and no study drug taken 
SS 
NA 
No study drug taken 
PK analysis 
set 
To be defined 
Patients not having at least one available valid 
(i.e. not flagged for exclusion) PK concentration 
measurement 
No study drug taken. 


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6 
Reference 
Bretz, F., Pinheiro, J. C., and Branson, M. (2005). Combining multiple comparisons and 
modeling techniques in dose-response studies. Biometrics 61, p 738–748. 
CDER (2020a) US Department of Health and Human Services, Food and Drug 
Administration, Guidance for Industry: Assessing COVID-19-related symptoms in outpatient 
adult and adolescent subjects in clinical trials of drugs and biological products for COVID-19 
prevention or treatment. Rockville, MD. 
CDER (2020b) US Department of Health and Human Services, Food and Drug 
Administration, Guidance for Industry: COVID-19: Developing drugs and biological products 
for treatment or prevention. Rockville, MD.  
EMA (2014) Qualification Opinion on MCP-Mod as an efficient statistical methodology for 
model-based design and analysis of Phase II dose finding studies under model uncertainty 
[http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guide
line/2014/02/WC500161027.pdf]. 
FDA (2016) Fit-for-purpose determination letter, 
[https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/UCM508700.pdf]. 
Gottlieb RL, Nirula A, Chen P, et al. Effect of Bamlanivimab as Monotherapy or in 
Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19. 
JAMA. 10.1001/jama.2021.0202 Published online January 21, 2021. 
Pinheiro J, Bornkamp B, Glimm E, et al (2014) Model-based dose finding under model 
uncertainty using general parametric models. Statist Med; 33:1646–61. 
Kenward, M. G., & Roger, J. H. (1997). Small sample inference for fixed effects from 
restricted maximum likelihood. Biometrics, 983-997.