Clinical trial NCT04382755
Conditions: COVID-19
Keywords: Acute Lung Injury Hypoxia Corona virus COVID-19 SARS (Severe Acute Respiratory Syndrome) Acute Respiratory Distress Syndrome ARDS
Sponsor: University Hospital, Ghent
Start date: 2020-05-22; Completion date: 2021-04-09
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is a randomized controlled, open-label trial comparing subcutaneous Zilucoplan® with standard of care to standard of care alone.

In the active group, Zilucoplan® will be administered subcutaneously once daily for 14 days or till discharge from the hospital, whichever comes first.

The hypothesis of the proposed intervention is that Zilucoplan® (complement C5 inhibitor) has profound effects on inhibiting acute lung injury post COVID-19, and can promote lung repair mechanisms, that lead to a 25% improvement in lung oxygenation parameters. This hypothesis is based on experiments performed in mice showing that C5a blockade can prevent mortality and prevent ARDS in mice with post-viral acute lung injury.

Eligible patients include patients with confirmed COVID-19 infection suffering from hypoxic respiratory failure defined as O2 saturation below 93% on minimal 2l/min O2 therapy and/or ratio PaO2/FiO2 below 350.

Detailed description:
This investigator-initiated trial is a phase 2 academic, prospective, 2:1 randomized, open-label, multicenter interventional study designed to investigate the efficacy of subcutaneous Zilucoplan® in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure. The hypothesis of the proposed intervention is that Zilucoplan® has profound effects on inhibiting acute lung injury induced by COVID-19, and can promote lung repair mechanisms, that lead to a 25% improvement in lung oxygenation parameters. This hypothesis is based on experiments performed in mice showing that C5a blockade can prevent mortality and prevent ARDS in mice with post-viral acute lung injury.

We will randomize patients with confirmed COVID19 with acute hypoxic respiratory failure (O2 saturation below 93% on minimal 2l/min O2 therapy; and/or PaO2/FiO2 below 350 mmHg) to receive up to 14 days of SC Zilucoplan® on top of standard of care (active group A), or to receive standard of care treatment (control group B). Randomization will be done at a 2:1 ratio active: control group. In the active group A, patients will additionally receive daily antibiotics (daily 3rd generation cephalosporin IV while in hospital, followed by oral ciprofloxacin while discharged) as primary prophylaxis against meningococcal disease until 14 days after the last dose of Zilucoplan®. Control group B will receive standard of care and prophylactic antibiotics (3rd generation cephalosporin IV) for only 1 week (or until hospital discharge whichever comes first), to control for the effects of antibiotics on the clinical course of COVID-19. In case of allergies to these antibiotics, or on clinical indication, these antibiotics may be switched to antibiotics that also cover Neisseria meningitidis.

To measure the effectiveness of Zilucoplan® on restoring lung homeostasis, the primary endpoint of this intervention is measuring change in oxygenation parameters comparing baseline values (pretreatment) to values predose day 6 and to values at day 15 (or discharge whichever comes first) post-randomizationin group A and group B and the differences in these values between group A and group B.

Arms: arm 1: Standard of Care (SoC) + subcutaneous Zilucoplan® + prophylactic antibiotics until 14 days after last Zilucoplan® arm 2: Standard of Care (SoC) + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first)
Interventions: intervention 1: Zilucoplan® intervention 2: Placebo
Intervention descriptions: intervention 1: 14 days of SC Zilucoplan® on top of standard of care + prophylactic antibiotics until 14 days after last Zilucoplan® intervention 2: standard of care treatment + 1 week of prophylactic antibiotics (or until hospital discharge, whichever comes first)

Protocol documents:
Prot_000.pdf: 
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A prospective, randomized, open-label, interventional 
study to investigate the efficacy of complement C5 
inhibition with Zilucoplan® in improving oxygenation and 
short- and long-term outcome of COVID-19 patients with 
acute hypoxic respiratory failure. 
 
 
Acronym / Protocol code 
 
 
 
ZILU-COV 
Protocol version and date  
 
 
6.0 dd 9 June 2021 
Phase  
 
 
 
 
 
2 
EudraCT n°  
 
 
 
 
2020-002130-33 
Sponsor 
 
 
 
 
 
University Hospital Ghent,  
 
 
 
 
 
 
 
C. Heymanslaan 10 
 
 
 
 
 
 
 
9000 Ghent 
 
 
 
 
 
 
 
Belgium 
 
Financial/Material Support: 
 UCB 
 
Coordinating Investigator:  
 
 
Bart N. Lambrecht, MD, PhD 
Department of Internal Medicine & Pediatrics, 
Department of Respiratory Medicine 
 
 
 
 
 
 
 
University Hospital Ghent 
 
 
 
 
 
 
 
Corneel Heymanslaan  
 
 
 
 
 
 
 
9000 Ghent, Belgium 
 
 
 
 
 
 
 
+32/93329110  
 
Co-investigators:  
 
 
 
 
Multicentric trial in Belgium 
 
Cédric Bosteels, Catherine Van Der Straeten, Pieter Depuydt and Eva Van Braeckel 
contributed significantly. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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A prospective, randomized, open-label, interventional study to 
investigate the efficacy of complement C5 inhibition with 
Zilucoplan® in improving oxygenation and short- and long-term 
outcome of COVID-19 patients with acute hypoxic respiratory 
failure. 
 
Zilucoplan® in patients with acute hypoxic respiratory failure due to 
COVID-19 (ZILU-COV ) 
 
 
Protocol Co-ordinating Investigator signature page 
 
 
 
 
I certify that I will conduct the study in compliance with the protocol, any amendments, 
GCP and the declaration of Helsinki, and all applicable regulatory requirements. 
 
 
Investigator: 
 
 
Name: Prof. Dr. B. Lambrecht 
 
 
Function: Pulmonologist 
 
 
Institution: UZ Ghent 
 
 
 
Date:  
 
 
 
 
 
Signature: 
 


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A prospective, randomized, open-label, interventional study to 
investigate the efficacy of complement C5 inhibition with 
Zilucoplan® in improving oxygenation and short- and long-term 
outcome of COVID-19 patients with acute hypoxic respiratory 
failure. 
 
 
 
Protocol Site Principal Investigator signature page 
 
 
 
 
I certify that I will conduct the study in compliance with the protocol, any amendments, 
GCP and the declaration of Helsinki, and all applicable regulatory requirements. 
 
 
Investigator: 
 
 
 
 
 
 
 
Date:  
 
 
 
 
 
Signature: 
 


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Protocol Amendment History: 
 
Version 
Number 
Date 
Description of amendment 
2.0 
18 May 2020 
Section 2.1: study design added. 
Section 7.1.2: wording changed to “An Investigator must 
discontinue or withdraw a subject from the study for the 
following reason.” 
Additional reason for withdrawal from study: 
• 
Cases included in the trial with a ‘tentative’ diagnosis 
of COVID-19 in which it is not possible to get a 
confident diagnosis by serology or other means later 
in the disease course, will be withdrawn from the 
study as soon as it is clear that SARS-CoV2 was not the 
cause of the clinical presentation. 
Clarification added on prophylaxis for meningococcal 
disease: In all patients that have received Zilucoplan® as a 
study medication (group A patients), prophylaxis for 
meningococcal disease using either 3d generation 
cephalosporin IV daily or oral ciprofloxacin daily should be 
continued for 14 days after the last Zilucoplan® dose, even 
if patient retracted from the study, or was withdrawn 
from the study by the investigator.  In case reason for 
withdrawal was allergy to an antibiotic, an alternative 
antibiotic for prophylaxis should be given until 14 days 
after the last Zilucoplan® dose. 
 
Section 9.2, 9.4: Follow up visit week 12-22 after 
randomization: additional assessments were added: 
- 
WHO performance scale 
- 
6 minutes walk test (per standard of care) 
- 
HRCT scan to evaluate HRCT fibrosis score 
Section 9.4:  
- 
assessment of vital signs: values to be collected at 
morning assessment, between 7-10 AM for all 
parameters. 
- 
6-point ordinal scale: scoring updated to 
“1=Death”. 
HRCT fibrosis score: instructions on how to score HRCT 
findings. 
Section 13.5: text added: A careful assessment will be 
performed in cases where disease related events appear 
to be enhanced by the IMP. In accordance with CT-3 
guidance, a causality assessment will be performed for 
each SAE, and if the investigator considers disease 
related event to be IMP-related and the event is serious, 


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related and unexpected, then it will be reported as a 
SUSAR. 
 
Section 13.6: Additional information on DSMB Charter: 
The Charter includes the role of the committee, 
organizational flow, committee membership, committee 
meetings and will be signed by all DSMB members prior to 
the first meeting of the DSMB. 
 
 
 
Section 9.3, 9.4, 10: details on samples to be collected 
updated, cfr. updated lab manual provided by central lab, 
Covance: 
- DNA to be analysed on EDTA tube instead of PaxGene 
- PK sample to be collected on D15/discharge 
- serum samples: 2 x 6 ml instead of 5 ml 
- 6 ml EDTA tube for complement added on D1, D2, D6 and 
D15/discharge 
Section 12.1.2 information added that no data will be 
collected directly into the eCRF. 
Section 11.1: primary endpoint changed to day 6, day 15 
(or discharge).  
Section 6.1: information added on anti-conception 
requirements for male subjects. 
Section 4.2: definition of ARDS changed according to the 
Berlin criteria according to Jason Chertoff. 
Section 1., 5.1: definition of Hypoxic respiratory failure 
changed.  
3.0 
29 May 2020 
Section 1., 3.2, 4.2: secondary objectives changed. 
Section 3.1 and 4.1 Clarification for ECMO patients added. 
Section 4.2: Definition of ARDS: bullet point 4 changed. 
Section 6.1: Definition hypoxia changed. 
Section 9.2, 9.4:  
- 
laboratory assessments removed (fibrinogen and 
triglycerides at Day 6, 15 and FU) 
- 
Score assessments removed: Clinical Sign Score, 
Glasgow Come Scale and NEWS2. HScore only at 
Day 1. 
- 
Information added on timing of evaluation of 6 
point ordinal scale and HScore.6 minute walk test: 
protocol requirement, not following SOC. 
- 
 
Section 9.3:  
- 
Listing of lab assessments removed.  
- 
Day 4 was changed into day 6 
Timepoint of analysis of cytokines changed from Day 14 
to Day 15. 
General: typo’s corrected. 


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Section 10: 
D1: samples of 5ml for PK was changed into 6 ml 
One 6 ml EDTA tube was added  for complement 
(according to flowchart) 
 
 
Section 13.4: in flowchart reporting , ‘HIRUZ CTU will 
inform all participating sites’ was added for SUSARs 
 
 
Section 9.2: clinical exam and ECG added to section “at 
screening”, to correspond with 9.4. 
4.0 
10 Jun 2020 
Section 
3.1 
and 
5.1 
and 
7.1 
and 
9.4: 
statement/clarification on use of alternative antibiotics in 
case of allergy to cephalosporin or ciprofloxacin 
 
 
Section 6.2: Exclusion Criteria added: patient on ECMO at 
screening 
 
 
Section 8.1.4: clarification added on administration of IMP 
during 24 hours dialysis. 
 
 
Section 9.4: Physical Examination: to be assessed on 
clinical grounds, as per standard of care. 
Clarification for ECMO patients added 
5.0 
27 Apr 2021 
Section 4.2: Typo “≥60” corrected to “≥ 50”. 
 
 
Section 4.2: Secondary endpoints updated according to 
SAP 
 
 
Section 4.3 has been added and describes the 
pharmacodynamics and pharmacokinetic endpoints 
 
 
Section 7.3, 9.4: information added on assessment of 
arterial blood gas: if an arterial blood gas value is available 
of less than 24 hours before randomization, there’s no 
need to have a new ABG done on Day 0/1. 
 
 
Section 9.4: correction in footnote: time window of 
assessment of vital signs is not applicable for the follow-
up visit. 
 
 
Section 13.3: Reporting address for SAEs changed to 
DS_ICT@ucb.com 
 
 
Section 13.7: clarification added on timelines of 
submission of DSUR. 
 
 
Section 10.3, 10.4: clarification added on analysis and 
storage by selected centres of optional samples.  
 
 
Section 10.5: identification of FAGG certified biobank to 
store remaining samples for future use. 
 
 
Section 9.2: volume of DNA EDTA changed from 5 ml to 4 
ml (typo). 
 
 
Section 11.0: Update of statistical analysis team 
 
 
Section 5.1: “Group B” removed from sentence about 
prophylactic antibiotic treatment for patient randomized 
to Group A. 
6.0 
9 june 2021 
Section 4.2 : All secondary endpoints not related to 
secondary objectives have been moved to new section 
4.3 “exploratory endpoints” section. 
Duplicates within secondary endpoint section have been 
removed. 


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Removal of analytical language e.g. ‘means’ has been 
updated to reflect the endpoint itself not the analytical 
approach 
 
 
Section 4.3 Exploratory Endpoints was added. The content 
of this section concerns endpoints previously listed under 
section 4.2 which have been moved to the current section 
4.3.  For some of the endpoints, analytical language e.g. 
‘means’ has been updated to reflect the endpoint itself 
not the analytical approach 
 
 
Section 4.4: clarification was added related to the 
exploratory 
nature 
of 
pharmacodynamic 
and 
pharmacokinetic endpoints 
 
 
Section 4.4: aPTT and PT have been removed from 
Pharmacodynamic endpoints 
 
 
Section 11.1 : name of individual UCB statistician Trevor 
Smart replaced by UCB 
 
 
Section 11.2: Clarification was added regarding the 
endpoints to be summarized.   
 
 
Section 11.2: the sentence “Data from SOC in another 
study with a very similar protocol will be incorporated into 
the analysis using a Bayesian frame work.  This will be 
described more fully in the statistical analysis plan (SAP).” 
Has been replaced by “Data from SOC in another study 
with a very similar protocol may be incorporated into the 
analysis using a Bayesian frame work.  This will be 
described more fully in the statistical analysis plan (SAP).” 
 
 
Section 12.4: The sentence “Pseudonymized biological 
analyses and study results will also be shared with the 
provider of Zilucoplan® (UCB Pharma)” has been replaced 
by “Pseudonymized biological analyses, study data and 
study results will also be shared with the provider of 
Zilucoplan® (UCB Pharma) “ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
 
LIST OF ABBREVIATIONS ............................................................................................................... 11 
1. 
Protocol Summary ...................................................................................................................... 12 
2. 
Rationale and background ........................................................................................................ 14 
2.1. 
Rationale .............................................................................................................................. 14 
2.2. 
Risk/Benefit Assessment ................................................................................................... 15 
2.3. 
Limitations ............................................................................................................................ 16 
3. 
Objectives .................................................................................................................................... 17 
3.1. 
Primary Objectives ............................................................................................................. 17 
3.2. 
Secondary Objectives ........................................................................................................ 17 
4. 
End Points + Time Points .......................................................................................................... 18 
4.1. 
Primary End Points + Time Points ................................................................................... 18 
4.2. 
Secondary End Points + Time Points .............................................................................. 18 
4.3. 
Pharmacodynamic and Pharmacokinetic endpoints ..................................................... 20 
5. 
Study design ................................................................................................................................ 22 
5.1. 
Description of study design ............................................................................................... 22 
5.2. 
End of Study Definition ...................................................................................................... 23 
5.2.1. 
For an individual subject ............................................................................................ 23 
5.2.2. 
For the whole study .................................................................................................... 23 
5.3. 
Estimated duration of the study ........................................................................................ 23 
6. 
Inclusion and Exclusion Criteria ............................................................................................... 24 
6.1. 
Inclusion Criteria ................................................................................................................. 24 
6.2. 
Exclusion Criteria ................................................................................................................ 25 
6.2.1. 
Screen failures ............................................................................................................... 25 
7. 
Target Population ....................................................................................................................... 26 
7.1. 
Subjects ................................................................................................................................ 26 
7.1.1. 
Number of subjects and planned recruitment rate................................................. 26 
7.1.2. 
Withdrawal and replacement of subjects ................................................................ 26 
7.2. 
Method of recruitment ........................................................................................................ 27 


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7.3. 
Screening ............................................................................................................................. 27 
8. 
Investigational Medicinal Product (IMP) .................................................................................. 28 
8.1. 
Name of the IMP ................................................................................................................. 28 
8.1.1. 
Composition and active substance of the IMP ....................................................... 28 
8.1.2. 
Producer and Distributor of the IMP ........................................................................ 28 
8.1.3. 
Preparation + Dosage + administration of the IMP ............................................... 28 
8.1.4. 
Permitted dose adjustments and interruption of treatment .................................. 30 
8.1.5. 
Duration of treatment.................................................................................................. 30 
8.1.6. 
Packaging and Labeling of the IMP ......................................................................... 30 
8.1.7. 
Storage conditions of the IMP ................................................................................... 31 
8.1.8. 
Known side effects of the medication ...................................................................... 31 
8.2. 
Concomitant / Rescue Medication ................................................................................... 32 
9. 
Study Specific Procedures ........................................................................................................ 33 
9.1. 
Randomization .................................................................................................................... 33 
9.2. 
Study specific interventions ............................................................................................... 33 
9.3. 
Overview of collected data ................................................................................................ 35 
9.4. 
Schematic overview of the data collection & interventions (see next page).............. 35 
9.5. 
Restrictions for subjects during the study ....................................................................... 39 
10. 
Sampling .................................................................................................................................. 39 
10.1. 
Types and number of samples ..................................................................................... 39 
10.2. 
Timepoints of sampling .................................................................................................. 39 
10.3. 
Sample Handling & Analysis ......................................................................................... 39 
10.4. 
Sample Storage and/or shipping .................................................................................. 39 
10.5. 
Future use of stored samples ....................................................................................... 39 
11. 
Statistical Considerations ...................................................................................................... 40 
11.1. 
Sample size calculation ................................................................................................. 40 
11.2. 
Type of statistical methods ............................................................................................ 40 
11.3. 
Statistical analysis team ................................................................................................ 41 
12. 
Data handling .......................................................................................................................... 41 
12.1. 
Method of data collection ............................................................................................... 41 
12.1.1. 
Case Report Form .................................................................................................. 41 
12.1.2. 
Data directly collected in the CRF (no source available) .................................. 41 
12.2. 
Data storage .................................................................................................................... 42 
12.3. 
Archiving of data ............................................................................................................. 42 
12.4. 
Access to data ................................................................................................................. 42 
13. 
Safety ........................................................................................................................................ 43 


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13.1. 
Definitions ........................................................................................................................ 43 
13.2. 
Reporting requirements ................................................................................................. 44 
13.2.1. 
AE reporting ............................................................................................................. 44 
13.2.2. 
SAE reporting .......................................................................................................... 44 
13.2.3. 
SUSAR reporting .................................................................................................... 45 
13.3. 
List of contact details for safety reporting ................................................................... 45 
13.4. 
Flowchart Reporting ....................................................................................................... 46 
13.5. 
Events, excluded from reporting ................................................................................... 46 
13.6. 
Data Safety Monitoring Board (DSMB) ....................................................................... 46 
13.7. 
Development Safety Update Report ............................................................................ 47 
14. 
Monitoring/Auditing/Inspection ............................................................................................. 48 
14.1. 
Monitoring ........................................................................................................................ 48 
14.1.1. 
General ..................................................................................................................... 48 
14.1.2. 
Monitoring team ...................................................................................................... 48 
14.1.3. 
Scope ........................................................................................................................ 48 
14.2. 
Inspection ......................................................................................................................... 48 
14.3. 
Protocol Deviation policy ............................................................................................... 48 
14.4. 
Serious breach to GCP and/or the protocol ................................................................ 48 
15. 
Ethical and legal aspects ....................................................................................................... 49 
15.1. 
Good Clinical Practice .................................................................................................... 49 
15.2. 
Informed Consent ........................................................................................................... 49 
15.3. 
Approval of the study protocol ...................................................................................... 49 
15.3.1. 
General ..................................................................................................................... 49 
15.3.2. 
Protocol amendments ............................................................................................ 50 
15.4. 
Confidentiality and Data Protection .............................................................................. 50 
15.5. 
Liability and Insurance ................................................................................................... 50 
15.6. 
End of Study Notification ............................................................................................... 50 
16. 
Publication policy .................................................................................................................... 51 
17. 
Reference List ......................................................................................................................... 51 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
 
= 
Adverse Event 
AECC  
= 
American-European Consensus Conference  
ARDS  
=  
Acute Respiratory Distress Syndrome 
CI 
 
= 
Coordinating Investigator 
COVID-19 
= 
Coronavirus induced disease-2019 
CT 
 
= 
Clinical Trial Unit 
DSMB  
= 
Data Safety Monitoring Board 
DSUR  
= 
Development Safety Update Report 
EC 
 
= 
Ethics Committee 
ECG  
= 
Electrocardiogram 
eCRF  
= 
electronic Case Report Form 
EDC  
= 
Electronic Data Capture 
EPD  
= 
Electronic Patient Dossier 
FAMHP 
= 
Federal Agency for Medicines and Health Products 
FiO2  
= 
Fraction of inspired oxygen 
FPI 
 
= 
First Patient In 
FVC  
= 
Forced vital capacity 
GCP  
= 
Good Clinical Practice 
GDPR  
= 
General Data Protection Regulation 
gMG  
=  
generalized myasthenia gravis 
GMP  
= 
Good Manufacturing Practice 
HIRUZ 
= 
Health, Innovation and Research Institute UZ Ghent 
IB 
 
= 
Investigator’s Brochure 
ICF 
 
= 
Informed Consent Form 
ICH 
 
= 
International Council for Harmonisation 
IMNM  
= 
Immune Mediated Necrotic Myopathy 
IMP 
 
= 
Investigational Medicinal Product 
IMPD  
= 
Investigational Medicinal Product Dossier 
LVLS  
= 
Last Visit, Last Subject 
PCWP 
= 
Pulmonary Capillary Wedge Pressure 
PEEP  
= 
Positive End Expiratory Pressure 
PI 
 
= 
Principal Investigator 
PaO₂  
= 
Partial pressure of oxygen 
PNH  
=  
Paroxysmal Nocturnal Hemoglobinuria 
SC 
 
= 
Subcutaneous 
SAE  
= 
Serious Adverse Event 
SC 
 
= 
Subcutaneous 
sHLH  
= 
secondary hemophagocytic lymphohistiocytosis 
SmPC  
= 
Summary of Product Characteristics 
SOP  
= 
Standard Operating Procedure 
SUSAR 
= 
Suspected Unexpected Serious Adverse Reaction 
TERENA 
= 
Trans-European Research and Education Networking Association 
TLC 
 
= 
Total Lung Capacity 
TLS 
 
= 
Transport Layer Security 
 
 


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1. Protocol Summary 
 
ZILU-COV trial : Use of Zilucoplan® in patients with acute hypoxic respiratory failure due to COVID-19 
 
Title 
A prospective, randomized, open-label, interventional study to 
investigate the efficacy of Zilucoplan® in improving oxygenation and 
short- and long-term outcome of COVID-19 patients with acute 
hypoxic respiratory failure. 
Protocol number 
ZILU-COV 
Protocol version 
V6.0 
EudraCT number 
2020-002130-33 
Sponsor 
University Hospital Ghent 
Co-ordinating Investigator 
Bart N. Lambrecht 
Type of study 
Interventional 
Fase 
Phase 2a (Proof-of-concept) 
Study design 
prospective, 2:1  randomized, open-label study 
Study duration 
22 weeks 
Purpose of study 
To investigate the efficacy and safety of Zilucoplan® in improving 
oxygenation and short- and long-term outcome of COVID-19 patients 
with acute hypoxic respiratory failure.  
Primary Objective  
To study if complement C5 inhibition on top of standard of care 
improves measures of oxygenation versus standard of care in 
patients with COVID-19 
Secondary Objectives  
- to study if early intervention with Zilucoplan® is safe (number of 
AEs/SAEs) 
- to study if early intervention with subcutaneous (sc) Zilucoplan® 
affects clinical outcome defined by duration of hospital stay, 6-point 
ordinal scale and SOFA 
- to study if early intervention with Zilucoplan® affects the rate of 
nosocomial infection  
- to study if early intervention with Zilucoplan® affects progression to 
mechanical ventilation and/or ARDS 
- to study if treatment with Zilucoplan® affects all-cause mortality rate 
at D28  and 12-22 weeks post-randomization 
- to study if treatment with Zilucoplan® has a favourable effect on long 
term at follow up 12-22 weeks post-randomization 
Primary Endpoint 
Improvement of oxygenation as measured by mean and/or median 
change in normalized PaO2/FiO2 and P(A-a)O2 gradient between 
enrolment (baseline) and at predose D6 and D15 (or discharge, 
whichever comes first).  
Number of participants 
81 


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Study population and main 
inclusion criteria 
Patients with confirmed COVID-19 infection 
Presence of hypoxic respiratory failure defined as  
1) O2 saturation below 93% on minimal 2l/min O2 therapy; and/or  
2) PaO2/FiO2 below 350 mmHg (Strongly recommended: patient in 
upright position, after minimal 3 minutes without supplemental 
oxygen; In ventilated patients PaO2 can be taken from invasive 
arterial line and FiO2 taken directly from mechanical ventilation 
settings). 
Control arm 
Standard of Care (SoC) + 1 week of prophylactic antibiotics (or until 
hospital discharge, whichever comes first) = Group B (control) 
Experimental Arm 
Standard of Care (SoC) + subcutaneous Zilucoplan® + prophylactic 
antibiotics until 14 days after last Zilucoplan®= Group A (active) 
Investigational drug, 
dose, route 
subcutaneous Zilucoplan®, 32.4 mg once daily for 14 days or until 
hospital discharge, whichever comes first 
Treatment duration 
14 days or until hospital discharge, whichever comes first. 
Prophylactic antibiotics will be continued for 14 days after the last 
Zilucoplan® administration 
Follow-up duration 
12-22 weeks post-randomization 
Study Duration 
From first patient in to final report 
12 months 
 
 
 


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2. Rationale and background 
2.1. 
Rationale 
 
The proposed development plan was guided by three specific considerations: 
 
1. Supportive Scientific Rationale:  
The complement system performs a broad range of functions, including defense against invading 
pathogens, removal of cellular debris, modulation of adaptive immune system responses, and 
maintenance of homeostasis. The complement cascade is triggered by diverse mechanisms which lead 
to the generation of effector molecules that clear susceptible pathogens and cellular debris or promote 
inflammation, and is also closely regulated.  
Acute respiratory distress syndrome (ARDS) is characterized by severe, acute inflammatory responses 
in the lung, resulting in diffuse damage to the alveolar-capillary barrier, flooding the airspaces with 
protein-rich edema fluid, with severe gas-exchange abnormalities and disordered ventilation-
perfusion mismatch as a result, leading to profound hypoxia1.  
Among well-known causes of ARDS is viral pneumonia caused by influenza and corona viruses such as 
SARS-CoV, MERS-CoV and SARS-CoV2. Cytokine responses induced by these viruses can be so 
excessive, which is known as “cytokine storm”, that they not only enhance local inflammatory 
reactions in the lungs but also induce widespread inflammation elsewhere in the body. ARDS is a 
frequent complication of COVID-19. It is a main cause of death and the main reason for the current 
need of intensive care (IC) beds and ventilators to treat patients with SARS-CoV2 infection2-4. 
Excessive production of cytokines is not the only inflammatory response of the body to severe viral 
infections. Rather this cytokine storm is part of a broader response involving multiple inflammatory 
systems. Among the systems activated is the complement system. This system has been studied for 
decades regarding its role in ARDS. In particular the effects of activated complement on neutrophils 
leading to their lodging in lung capillaries where they damage the blood-air barrier by releasing oxygen 
radicals and aggressive proteases, are key in the pathogenesis of ARDS 5,6.  
Indirect evidence suggests that complement activation likely contributes to the pathogenesis of ARDS 
and multiple organ failure (MOF) in COVID-19. A severe viral infection (including influenza, SARS-CoV, 
MERS-CoV, SARS-CoV2) can trigger a cytokine storm in the lungs and lead to a systemic 
hyperinflammatory response.  
Studies in animal models in mice and monkeys for influenza and corona virus-induced lung injury have 
shown that this leads to activation of complement in the lungs, as evidenced by deposition of several 
complement factors in the damaged tissues, as well as to an increase of complement activation 
products in the circulation7,8. Though the exact molecular mechanism of this activation process needs 
to identified, it likely involves C-reactive protein (CRP) and natural IgM which bind to damaged cells, 
microparticles, cell debris and molecules released by damaged cells, (ie, damage-associated molecular 
patterns [DAMPs]), and which subsequently activate complement. The physiological role of this 
activation is to remove damaged cells and debris via complement receptors on phagocytes. However, 
in case of excessive activation, complement may do more harm than good, as it further amplifies 
inflammation and causes additional tissue damage. For example, C3a and C5a, which are generated 
during complement activation are potent inflammatory peptides, and because of these properties 
referred to as the anaphylatoxins. C3a and C5a can directly by interaction with their receptors C3aR 
and C5aR, respectively, interact with endothelial cells and mast cells to increase local vasopermeability. 
Secondly, C3a and in particular C5a are also chemoattractants that recruit immune effector cells which 
contributes to lung inflammation. Both recruited monocytes and neutrophils highly express C5aR CD88 


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in COVID-19 patients. Their effects on neutrophils can be deleterious as they not only recruit these 
cells to the lungs but also activate and degranulate these cells, leading to further damage of the 
endothelial-epithelial barrier of the alveoli. Finally, the anaphylatoxins, and also terminal membrane 
attack complex (MAC, C5b-9) can enhance cytokine responses by mononuclear cells and exacerbate 
the cytokine storm. 
Observations in patients with viral pneumonia suggest that the progression towards ARDS is associated 
with complement activation. Levels of CRP and C4 were significantly increased in patients with SARS. 
Moreover, levels of C3a and C5a are increased in patients with 2009 H1N1 infection. Furthermore, 
increased levels of cleaved (presumably activated) C3 distinguish SARS patients from controls, and 
correlate with LDH and CRP levels. Evidence for complement activation in patients with COVID-19 has 
recently been documented, showing deposition of MASP2, C4 complement and C5-C9 membrane 
attack complex in the lungs and skin of 5 patients with severe COVID-19, 2 of which died9. Pathological 
examination suggests that complement activation might be at the heart of a thrombotic micro-
angiopathy that is typically seen in COVID-19 and might be at the basis of increased LDH, 
thrombocytopenia, mild anemia and elevated D-dimers. The N protein of SARS-CoV2 has the potential 
to activate MASP-2 and in this way promote the alternative activation of complement10. These 
observations as well as those made in the animal models for virus-induced lung injury, strongly suggest 
involvement of complement in thrombotic events, acute lung injury, diffuse alveolar damage and 
ultimately development of ARDS and SIRS during COVID-19 infection.  
Multiple studies in animal models not only show that virus (influenza, corona)-induced lung injury 
triggers activation of complement, but also that inhibition of this activation can improve outcome. 
Deficiency of C3, or inhibition of C5aR or C3aR by receptor antagonist or monoclonal antibody, 
attenuate virus-induced lung injury in various influenza and SARS models both in mice and 
monkeys11,12. Notably, these animal studies not only show an improved survival, but also decreased 
viral load in the lungs7.  
Though experimental evidence for involvement of complement in severe complications of COVID-19 
is currently lacking, clinical observations in related syndromes and pathological descriptions of 
complement deposition at sites of microthrombosis in the lung and skin in COVID-19 patients and data 
obtained in multiple animal models for virus-induced lung injury, including injury induced by SARS-CoV 
and MERS-CoV support involvement of complement activation in patients with severe complications 
of COVID-19.  Two small series in COVID-19 patients have reported initial success blocking either C3 
complement using AMY101 or C5 complement using eculizumab13 14, and one trial is currently 
underway in China blocking C5a using the antibody BDB-001 (ref10).  A genetic association study across 
54 countries has identified a polymorphism in complement C3 as a major genetic risk association locus 
for severity of COVID-19 (Prof Joris De Lange, oral communication). 
 
2. Experience: Use of Zilucoplan® has been performed in phase III studies 
 
3. Expediency: Toxicology, pharmacologic and safety data supports the immediate clinical use of 
Zilucoplan® in hypoxic respiratory failure and ARDS due to COVID-19. Investigator brochure is available 
and contains detailed information on toxicity. 
 
2.2. 
Risk/Benefit Assessment 
  
COVID-19 poses a very significant risk of mortality of 3-7% and this percentage rises to mortality of 
20% in patients with co-morbidity. Of all infected patients, some 15-20% develop severe respiratory 
symptoms necessitating hospital admission. Around 5% of infected patients will require invasive 


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mechanical ventilation, and many of those (40-50% will die). The current world-wide pandemic of 
COVID-19 is putting unforeseen stress on the entire primary, secondary and tertiary medical system, 
leading to unseen triage of patients that potentially benefit or not from admission to ICU units when 
they develop respiratory failure. 
Immune protection against coronavirus infection is understood to rely primarily upon neutralizing 
humoral immunity and CD8 cytotoxic adaptive T cell cellular immunity, rather than innate immunity 
and the complement system. Therefore, C5 inhibition is not expected mechanistically to impair the 
immune response to coronavirus (or indeed to a vaccine once one is available).  
Treatment with the approved C5 inhibitors eculizumab and ravulizumab, as well as rare genetic 
deficiencies in C5, are associated with a markedly increased risk for infection with encapsulated 
bacteria, most notably Neisseria meningitidis and H. influenzae, but not for viral infections generally, 
or for coronavirus infections in particular. 
Despite the important potential risk of Neisseria meningitidis, no other important risks have been 
identified with Zilucoplan®.  To prevent the risk of meningococcal disease and prevent other infections 
with encapsulated bacteria, patients will receive prophylactic antibiotics (e.g. intravenous 3rd 
generation cephalosporin while in hospital, followed by oral ciprofloxacin upon discharge until 14 days 
after the last Zilucoplan® administration). Antibiotics that have been used previously to prevent 
infections under Zilucoplan® in clinical trials include:  
Antibiotic (trade) 
Usual dosage 
Cefotaxime (Claforan) 
1-2 g IV every 8 hrs 
Ceftriaxone (Rocephine, generics) 
2 g IV once daily 
Vancomycin 
1 gr IV every 12 hrs, 
Pharmacokinetics recommended; 
not recommended in monotherapy 
Ciprofloxacin (Ciproxine) 
400 mg IV every 12 hrs or  
500 mg PO every 12 hrs 
Levofloxacin (Tavanic, generics) 
750 mg IV/PO daily 
Moxifloxacin (Avelox, generics) 
400 mg IV/PO every 24 hours 
Imipenem (not available in Belgium) 
500 mg IV every 6 hrs 
Meropenem (Meronem) 
1 gr IV every 8 hrs 
 
2.3. 
Limitations 
There is a large number of COVID-19 infected patients that are currently being hospitalized across the 
globe. In just 30 days time, our COVID-19 ward at Ghent University Hospital has admitted 225 
confirmed cases, of which a significant portion (30%) would have fulfilled eligibility criteria for the 
current proposed protocol. We believe that given the current descending part of the epidemiology 
curve in Belgium, with numbers of hospital-admitted patients declining rapidly, there will be some 
delay in obtaining high patient numbers initially.  With the release of social distancing measures, and 
release of government-enforced quarantine measures, the number of cases may increase again after 
mid May 2020.  
 


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3. Objectives 
 
3.1. 
Primary Objectives 
Justification for our objective is that preventing progression from early acute hypoxic respiratory 
failure to frank ARDS via complement C5 inhibition could have a huge impact on the overflow of the 
ICU units, that is happening in some countries and is bound to happen on a global scale. The outcome 
of our study could thus have large impact from a medical, ethical and economic perspective. 
 
The hypothesis of the proposed intervention is that complement C5 has profound effects on acute 
lung injury present in patients with severe COVID-19 and hypoxia, prior to mechanical intubation, and 
that C5 inhibition can lead to a 25% improvement in lung oxygenation parameters.  
 
The primary objective of this intervention is to study if Zilucoplan® affects the the median and/or 
mean change in oxygenation between enrolment (baseline) and at predose day 6 and day 15 (or 
discharge, whichever comes first) through assessment of the PaO2/FiO2 ratio and through 
measurement of the P(A-a)O2 gradient, which can easily be performed in the setting of clinical 
observation of patients admitted to the COVID-19 ward or ICU COVID-19 unit. For patients on 
ECMO the PaO2/FiO2 ratio and Aa-gradient cannot be calculated as in this case the FiO2 will be 
missing. Therefore, the last available value of PaO2/FiO2 ratio and Aa gradient prior to ECMO can be 
used at that timepoint. 
Comparison will be between active group A receiving Zilucoplan® on top of standard of care and 
control group B receiving standard of care. Prophylaxis against meningococcal disease will be given in 
group A  in the form of IV antibiotic prophylaxis with a third generation cephalosporin (ceftriaxone or 
cefotaxime while in hospital, followed by oral ciprofloxacin upon discharge until at least 14 days after 
the last Zilucoplan® dose), since there is no time for immunization against meningococci. To control 
for the effects of 3d generation cephalosporin on clinical course of COVID-19, the control group B will 
also receive 1 week (or until hospital discharge whichever comes first) of IV 3rd generation 
cephalosporin. In case of allergies to these antibiotics, or on clinical indication, these antibiotics may 
be switched to antibiotics that also cover Neisseria meningitidis. 
 
3.2. 
Secondary Objectives 
 
-to study if early intervention with Zilucoplan® is safe (number of AEs/SAEs) 
 
-to study if early intervention with Zilucoplan® affects clinical outcome defined by duration of 
hospital stay, 6-point ordinal scale, time to defervescence, supplemental oxygen use and SOFA score 
 
- to study if early intervention with Zilucoplan® affects progression to mechanical ventilation and/or 
ARDS and duration of ICU stay 
 
-to study if early intervention with Zilucoplan® affects the rate of nosocomial infection  
 
-to study if treatment with Zilucoplan® has a favourable effect on long term at follow up 12-22 weeks 
post-randomization 
 
-to study if treatment with Zilucoplan® affects all-cause mortality rate at day 28 and at 12-22 weeks 
post-randomization 
 


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4. End Points + Time Points 
4.1. 
Primary End Points + Time Points 
To measure the effectiveness of SC Zilucoplan® treatment on restoring lung homeostasis, the primary 
endpoint of this intervention is measuring oxygenation at predose day 6 and day 15  (or at discharge, 
whichever comes first) through assessment of the mean and/or median change from pretreatment 
(day 1) to post-treatment (day 6 and 15 or at discharge, whichever comes first) PaO2/FiO2 ratio, P(A-
a)O2 gradient and  a/A pO2 ratio, which can easily be performed in the setting of clinical observation of 
patients admitted to the COVID-19 ward or ICU COVID-19 unit. These measurements derived from an 
arterial blood gas sampling are taken when the patient is sitting upright and breathing room air. Since 
supplemental oxygen will be indispensable in some patients, the A-a gradient will be normalized 
against age and FiO2 expected A-a gradient, according to validated formulas. If patients leave hospital 
between day 6 and day 15, that day of discharge will be taken as measurement point for primary 
endpoint instead of day 15. For patients on ECMO the PaO2/FiO2 ratio and Aa-gradient cannot 
be calculated as in this case the FiO2 will be missing. Therefore, the last available value of 
PaO2/FiO2 ratio and Aa gradient prior to ECMO can be used at that timepoint. 
 
 
4.2. 
Secondary End Points + Time Points 
 
-To study if early intervention with Zilucoplan® is safe (number of AEs/SAEs) 
 
-To study if early intervention with Zilucoplan® affects clinical outcome  
defined by 6-point ordinal scale change between day 1 and respectively day 6, day 15 (or discharge, 
whichever comes first) and day 28 (by phone call). 6-point ordinal scale defined as  
1. Death 
2. Hospitalized, on invasive mechanical ventilation or ECMO; 
3. Hospitalized, on non-invasive ventilation or high flow oxygen devices; 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, not requiring supplemental oxygen 
Not hospitalized 
-Number of days requiring supplemental oxygen after randomization to Day 28 (or discharge, 
whichever comes first) 
 
-Number of days with fever (defined as 37.1°C or more) during 28-day assessment period 
 
- change from baseline in SOFA score to D6, D15 (or on discharge, whichever is first) 
 
- Time to at least a 2-point improvement or discharge sustained up to D28 on the 6-point ordinal 
scale during 28-day assessment period  
 
-Incidence of nosocomial bacterial or invasive fungal infection during 28-day assessment period 
Patients with viral respiratory infection are at risk of secondary bacterial infections. As part of routine 
clinical care, sputum or BAL samples will be collected in patients suspected of secondary bacterial 


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pneumonia, and checked for the presence of bacteria. Measurements of procalcitonin levels will be 
performed at least three times per week until day 14 or hospital discharge. 
 
- All-cause mortality rate at 28 days post randomization (all treated participants) 
 
-All-cause mortality rate at 28 days post randomization (excluding participants that required invasive 
mechanical ventilation or ECMO, non-invasive mechanical ventilation or high-flow oxygen devices 
within 24 hours prior to or after randomization) 
 
-All-cause mortality rate at 28 days post randomization (excluding participants that required invasive 
mechanical ventilation or ECMO within 24 hours prior to or after randomization) 
 
-All-cause mortality rate at 28 days post randomization (only including patients that required 
invasive mechanical ventilation or ECMO within 24 hours prior to or after randomization) 
 
-Incidence of patients in each category of the 6-point Ordinal Scale at follow up 12-22 weeks post-
randomization 
 
-All cause mortality at follow up 12-22 weeks post-randomization for all treated participants 
 
- Results from 6 minute walking test 
 
- Incidence of participants in each category of the WHO performance scale 
 
 
 
4.3. 
 Exploratory Endpoints 
-Time since randomization until improvement in oxygenation, (defined as independence from 
supplemental oxygen) during 28-day assessment period (or discharge, whichever comes earlier) 
 
-Number of days with hypoxia defined as SpO2 < 93% breathing room air or the dependence on 
supplemental oxygen after randomization to Day 28 (or discharge, whichever comes earlier) 
 
-Time since randomization until absence of last fever (defined as 37.1°C or more) for more than 48h 
without antipyretics 
 
- change in CRP levels between day 1 and day 6, and between day 1 and day 15 (or discharge in each 
case  
 
- change in ferritin levels between day 1 and day 6, and between day 1 and day 15 (or discharge in 
each case). 
 
-Incidence of SARs/SUSARs during 28 days 
 
-Duration of hospital stay  
 
-Duration of hospital stay in survivors 
 
- Change from baseline in 6-point ordinal scale to Day 6, Day 15 and D28 (by phonecall) post 
randomization 
 


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- Percentage of participants reporting at least a 2-point improvement sustained to D28 or discharge  
 
- AUEC/Time using the 6-point score recorded daily – up to D15, D28 and all data recorded  
 
- Percentage of participants who record a 2-point improvement from baseline or discharge at D6, 
D15 and D28  
 
- Percentage of participants not deteriorating according to the ordinal scale by 1 or 2 points on D6, 
D15 and D28  
 
-6-point Ordinal Scale at 6 and 15 days (or discharge whichever comes first) and day 28 (phone call), 
in relation to serum D-dimers and complement C5a levels at baseline 
 
-Time since randomization until first use of high-flow oxygen devices or non-invasive mechanical 
ventilation or invasive mechanical ventilation or ECMO in non-ventilated patients (i.e. excluding 
patients who are ventilated within 24h prior to or after randomization) during 28-day assessment 
period 
 
- duration of ventilator-free days after randomization to Day 28 (or discharge, whichever comes 
earlier) 
 
-Duration of invasive mechanical (including ECMO) and non-invasive mechanical ventilation in 
ventilated patients 
 
-Duration of ICU stay in patients that enrolled in trial on invasive or non-invasive mechanical 
ventilation for less than 24h prior to or after randomization during 28-day assessment period 
 
-Duration of ICU stay in patients that enrolled in trial that were on invasive or non-invasive 
mechanical ventilation or high-flow oxygen devices within 24h prior to or after randomization during 
28-day assessment period 
 
-Time since randomization to progression to ARDS  
criteria-defined ARDS according to the adapted Berlin criteria as follow: 
* Within 1 week of a known clinical insult or new or worsening respiratory symptoms 
* bilateral infiltrates not supposed to be of cardiac origin or fluid overload 
* PaO2/FiO2 < 300 mmHg 
* PEEP > 5 cm H2O on invasive or non-invasive ventilation or flow ≥ 50L/min on HFOT (Optiflow) 
-Time since randomization to progression to ARDS according to D-dimers and complement C5a at 
randomization 
 
-Incidence of lung function abnormalities at follow up 12-22 weeks post-randomization 
 
-Incidence of lung fibrosis on chest high-resolution computed tomography (HRCT) scan at follow up 
12-22 weeks post-randomization 
 
 


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4.4. 
Pharmacodynamic and Pharmacokinetic endpoints (exploratory) 
 
Pharmacodynamic endpoints: 
Plasma and serum samples will be collected for summary and exploratory analysis as appropriate , may 
include but are not limited to (see also Section 9.3):  
• ADA – D1 and long-term follow-up from serum samples (Summary only to indicate presence or not)  
• Local safety labs such as D-dimers, LDH, ferritin, CRP, fibrinogen  
• Complement system assessment (EDTA tubes) – D1, D2, D6 and D15 (or at hospital discharge, if 
earlier)  
 
• Cytokines and biomarkers (from selected centres) on D1, D6 and D15 (or at hospital discharge, if 
    earlier)  
o Cytokines may include, but not limited to:  
▪ IL-1beta, IL-1RA, IL-2, IL-8, IL-6, TNFa, GM-CSF, G-CSF, IP-10, MCP-1, MIP-1a, IFNg, and IL-10  
o Biomarkers may include but not limited to  
▪ sRAGE, Angiopoietin-2), KL6 
• 
DNA for pharmacogenomic research (Paxgene tube, D1 only)  
Pharmacokinetic endpoints: 
Blood samples will be taken from participants in Arm A only on D1, D2, D6 and day 15/discharge– all 
pre-dose. 
 
 
 
 


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5. Study design  
 
5.1. 
Description of study design 
 
 
 
This investigator-initiated trial is a phase 2 academic, prospective, 2:1 randomized, open-label, multi-
center interventional study designed to investigate the efficacy of subcutaneous Zilucoplan® in 
improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic 
respiratory failure. There are currently no treatments reducing lung damage in COVID-19 patients, and 
no treatment that attempts to halt the progression from manageable acute hypoxic respiratory failure 
to acute lung injury or ARDS in patients with COVID-19 infection. Justification for our objective is that 
preventing progression from early acute hypoxic respiratory failure to ARDS could have a huge impact 
on the foreseeable overflow of the ICU units, that is already happening in some countries and is bound 
to happen on a global scale. 
 
Several academic and non-academic centers in Belgium will participate in this trial. Study coordination, 
monitoring and data management will be performed under the responsibility of the Health Innovation 
and Research Institute UZ Ghent (HIRUZ) Clinical Trial Unit and Data Management Unit.  
 
The hypothesis of the proposed intervention is that Zilucoplan® has profound effects on inhibiting 
acute lung injury induced by COVID-19, and can promote lung repair mechanisms, that lead to a 25% 


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improvement in lung oxygenation parameters. This hypothesis is based on experiments performed in 
mice showing that C5a blockade can prevent mortality and prevent ARDS in mice with post-viral acute 
lung injury. 
 
We will randomize patients with confirmed COVID19 with acute hypoxic respiratory failure (1. O2 
saturation 
below 
93% 
on 
minimal 
2l/min 
O2 
therapy; 
and/or  
2. PaO2/FiO2 below 350 mmHg) to receive up to 14 days of SC Zilucoplan® on top of standard of care 
(active group A), or to receive standard of care treatment (control group B). Randomization will be 
done at a 2:1 ratio active: control group. In the active group A, patients will additionally receive daily 
antibiotics (daily 3rd generation cephalosporin IV while in hospital, followed by oral ciprofloxacin while 
discharged) as primary prophylaxis against meningococcal disease until 14 days after the last dose of 
Zilucoplan®. Control group B will receive standard of care and prophylactic antibiotics (3rd generation 
cephalosporin IV) for only 1 week (or until hospital discharge whichever comes first), to control for the 
effects of antibiotics on the clinical course of COVID-19. In case of allergies to these antibiotics, or on 
clinical indication, these antibiotics may be switched to antibiotics that also cover Neisseria 
meningitidis. 
 
To measure the effectiveness of Zilucoplan® on restoring lung homeostasis, the primary endpoint of 
this intervention is measuring change in oxygenation parameters comparing baseline values 
(pretreatment) to  values predose day 6 and to values at day 15 (or discharge whichever comes first) 
post-randomizationin group A and group B and the differences in these values between group A and 
group B.  
 
5.2. 
End of Study Definition 
5.2.1. For an individual subject 
 
The subject has completed the study if he or she has completed all phases of the study, including the 
last visit (week 12-22 post-randomization clinical follow up visit) or the last scheduled procedures, as 
described in this protocol (see section “9. Study Specific Procedures”). 
 
5.2.2. For the whole study 
 
Overall, the end of the study is reached when the last study procedure for the last subject has occurred: 
last subject, last visit (LSLV). 
As soon as the whole study has ended (cfr. the definition above), the coordinating investigator shall 
notify the HIRUZ Clinical Trial Unit, so that the Competent Authority and the Ethics Committee can be 
informed in a timely manner according to the regulatory requirements (within 90 days after end of the 
study, or if the study had to be terminated early, this period must be reduced to 15 days and the 
reasons should clearly explained). 
 
5.3. 
Estimated duration of the study 
 
We estimate the study to terminate in 52 weeks, including last clinical follow up visits.  
 
 
 
 
 
 
 


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6. Inclusion and Exclusion Criteria 
 
6.1. 
Inclusion Criteria 
 
-Recent (≥6 days and ≤16 days of flu-like symptoms or malaise prior to randomization) infection with 
COVID-19. 
 
-COVID-19 diagnosis confirmed by antigen detection test and/or PCR and/or positive serology, or any 
emerging and validated diagnostic laboratory test for COVID-19 within this period. For patients with a 
negative SARS-CoV-2 PCR and either a positive SARS-CoV-2 antigen or antibody test, the presence of 
suggestive lesions for COVID-19 on chest-CT scan is mandatory. 
 
-In some patients, it may be impossible to get a confident laboratory confirmation of COVID-19 
diagnosis after 24h of hospital admission because viral load is low and/or problems with diagnostic 
sensitivity. In those cases, in absence of an alternative diagnosis, and with highly suspect bilateral 
ground glass opacities on recent (<24h) chest-CT scan (confirmed by a radiologist and pulmonary 
physician as probable COVID-19), and a typical clinical and chemical diagnosis with signs of cytokine 
release syndrome, a patient can be enrolled as probable SARS-CoV-2-infected. In all cases, this needs 
confirmation by later seroconversion. 
 
-Presence of hypoxia defined as  
1)O2 saturation below 93% on minimal 2l/min O2 therapy;  
and/or  
2) PaO2/FiO2 below 350 mmHg (Strongly recommended: patient in upright position, after minimal 3 
minutes without supplemental oxygen; In ventilated patients PaO2 can be taken from invasive arterial 
line and FiO2 taken directly from mechanical ventilation settings). 
 
-Signs of acute lung injury and/or cytokine release syndrome defined as  
ANY of the following 
-serum ferritin concentration >1000 mcg/L and rising since last 24h 
-single ferritin above 2000 mcg/L in patients requiring immediate high flow oxygen device 
(Optiflow) or non-invasive or invasive mechanical ventilation 
-lymphopenia  defined as <800 lymphocytes/microliter and two of the following extra criteria 
 
 
-Ferritin > 700 mcg/L and rising since last 24h 
 
-increased LDH (above 300 IU/L) and rising since last 24h 
 
 
-D-Dimers > 1000 ng/mL and rising since last 24h 
 
 
-CRP above 70 mg/L and rising since last 24h and absence of bacterial infection 
 
 
-if three of the above are present at admission, no need to document 24h rise 
 
-Low dose Chest CT or HRCT or Angio Chest CT scan showing bilateral infiltrates within last 2 days prior 
to randomization 
-Admitted to specialized COVID-19 ward or an ICU ward taking care of COVID-19 patients 
-Age ≥ 18 years 
- Women of childbearing potential must have a negative serum pregnancy test pre-dose on day 1. 
Women of childbearing potential must consistently and correctly use (during the entire treatment 
period and 4weeks after last Zilucoplan® administration ) at least 1 highly effective method for 
contraception.  
Male subjects (who have not been surgically sterilized by vasectomy) must agree to use effective 
contraception during the study. 
-Willing and able to provide informed consent or legal representative willing to provide informed 
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6.2. 
Exclusion Criteria  
 
-Patients with known history of serious allergic reactions, including anaphylaxis, to Zilucoplan® or 
inability to receive antibiotic prophylaxis due to allergy to ALL of the antibiotics that can be given for 
prophylaxis of meningococcal disease 
 
-History of active or past meningococcal disease 
 
-Invasive mechanical ventilation > 24 h at randomization 
 
-Patient on ECMO at screening 
 
-Clinical frailty scale above 3 before onset of the COVID-19 episode 
-Weight below 54 kg as measured max 1 week prior to inclusion 
-Weight above 150 kg as measured max 1 week prior to inclusion 
-Active bacterial or fungal infection  
-Unlikely to survive beyond 48h 
-Neutrophil count below 1500 cells/microliter 
-Platelets below 50.000/microliter 
-Patients enrolled in another investigational drug study 
-Patients on high dose systemic steroids (> 8 mg methylprednisolone or equivalent for more than 1 
month) or other moderately immunosuppressive drugs (in the opinion of the investigator) for COVID-
19 unrelated disorder 
-Patients on current complement inhibiting drugs  
-Serum transaminase levels >5 times upper limit of normal, unless there are clear signs of cytokine 
release syndrome defined by LDH >300 IU/L and ferritin >700 ng/ml 
-Pregnant or breastfeeding females (all female subjects deemed of childbearing potential by the 
investigator must have negative pregnancy test at screening) 
 
 
 
6.2.1. Screen failures 
 
Screen failures are defined as subjects who consent to participate in the clinical study but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information will be kept to ensure transparent reporting of screen failure subjects.  
 
 
 


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7. Target Population 
 
7.1. 
Subjects 
 
7.1.1. Number of subjects and planned recruitment rate 
 
The number of subjects that will be included in this study is: 81. 
These are divided into following sub-groups: 54 patients will be randomized to receive daily 
Zilucoplan® SC for a maximum of 14 days plus prophylactic antibiotics (3rd generation cephalosporin 
IV, followed by oral ciprofloxacin, or appropriate alternative) daily, maintained for at least 2 weeks 
after last Zilucoplan® dose)(group A); 27 patients will be randomized to receive standard of care (Group 
B) plus one week (or until hospital discharge whichever comes first) of 3rd generation cephalosporin 
IV (or appropriate alternative).  
 
The sample size calculation is elaborated in the Statistics section in section 11.  
 
 
7.1.2. Withdrawal and replacement of subjects 
 
Subjects are free to withdraw from participation in the study at any time upon request. If patient 
decides to leave hospital between day 6 and day 15, treatment with Zilucoplan® will be terminated, 
and day of discharge will be used to calculate the day 15 endpoint. 
 
An investigator must discontinue or withdraw a subject from the study for the following reasons:  
• allergic reactions (anaphylactic shock) to Zilucoplan® or antibiotic used for prophylaxis of 
meningococcal disease. Allergy to an antibiotic, should lead to a switch to another antibiotic 
so that patients receive prophylaxis against meningococcal disease for at least 14 days after 
the last dose of Zilucoplan®. 
• Pregnancy 
• Significant study intervention non-compliance  
• If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best interest 
of the subject 
• If the subject meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation  
• 
Cases included in the trial with a ‘tentative’ diagnosis of COVID-19 in which it is not possible 
to get a confident diagnosis by serology or other means later in the disease course, will be 
withdrawn from the study as soon as it is clear that SARS-CoV2 was not the cause of the 
clinical presentation. 
 
 
In all cases, the reason why subjects are withdrawn must be recorded in detail in the eCRF and in the 
subject’s medical records. 
 
In all patients that have received Zilucoplan® as a study medication (group A patients), prophylaxis for 
meningococcal disease using either 3d generation cephalosporin IV daily or oral ciprofloxacin daily (or 
appropriate alternative) should be continued for 14 days after the last Zilucoplan® dose, even if patient 
retracted from the study, or was withdrawn from the study by the investigator.  In case reason for 


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withdrawal was allergy to an antibiotic, an alternative antibiotic for prophylaxis should be given until 
14 days after the last Zilucoplan® dose. 
 
The following actions must be taken if a subject fails to return to the clinic for a required study visit 
(visit at 12-22 weeks post-randomization):  
• The site will attempt to contact the subject and reschedule the missed visit within 4 weeks 
and counsel the subject on the importance of maintaining the assigned visit schedule and 
ascertain if the subject wishes to and/or should continue in the study.  
• Before a subject is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the subject (where possible, 3 telephone calls and, if necessary, a 
certified letter to the subject’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the subject’s medical record or study file.  
• Should the subject continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
 
7.2. 
Method of recruitment 
 
Subjects will be recruited at the COVID-19 hospitalization ward at the participating centers. The study 
will be proposed by the treating physician to COVID-19 subjects that fulfill inclusion and exclusion 
criteria. 
There will be no compensation for study participation. UCB is providing Zilucoplan® to the study 
subjects, free of charge. Cost of prophylactic antibiotics will be part of the per patient budget per 
center and will be purchased by the study site pharmacy. 
Since this is a hospital-based trial, in which patients are severely ill, we suspect the retention in the 
trial to be high.  
 
 
7.3. 
Screening 
 
Patients will be informed about the study by the treating physician.  
After receiving full explanation, including the risk of meningococcal disease when blocking C5, having 
received sufficient time to considerer the trial, asking questions and receiving satisfying responses to 
all questions, patients will be asked to sign ICF. 
 
A serum pregnancy test will be done (female patients of childbearing potential only). 
Medical history will be checked for review of exclusion criteria and relevant subject information. 
 
Patients will be under continuous medical supervision on the COVID-19 ward. 
Exams (standard of care) include, but are not limited to: 
- 
ECG 
- 
Low dose chest CT-scan 
- 
Laboratory  tests for leukocyte formula, kidney and liver function, ferritin levels 
- 
Vital signs 
- 
Pulse oximetry 
- 
Arterial blood gas: If an arterial blood gas value is available of less than 24 hours before 
randomization, there’s no need to have a new ABG done on Day 0/1. 
As soon as all in- and exclusion criteria are checked and patient is considered eligible, patient can be 
randomized in the RedCAP system. The maximal time window between screening and randomization 
of the patient is 24h. 
 


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8. Investigational Medicinal Product (IMP) 
 
 
8.1. 
Name of the IMP 
ZILUCOPLAN® 
 
8.1.1. Composition and active substance of the IMP 
Zilucoplan® drug product is supplied as a sterile, preservative-free solution (40 mg/mL) for 
subcutaneous injection 
Supplied in a single-use 1-mL long glass syringe with a 29 gauge, ½” staked needle and stoppered with 
a Daikyo B2-40 coated butyl rubber stopper and filled with Zilucoplan® bulk solution is an isotonic 
buffered solution of Zilucoplan® drug substance, sodium phosphate monobasic/sodium phosphate 
dibasic (phosphate buffer), sodium chloride, and Water for Injection.  
The prefilled syringe is placed into a Becton Dickinson (BD) UltraSafe Plus device assembled with a 
finger flange and plunger rod on the dose 32.4 mg (0.810 mL). 
 
8.1.2. Producer and Distributor of the IMP 
 
Zilucoplan® 40mg/mL (32.4 mg/0.810 mL) will be supplied by Ra Pharmaceuticals, Inc. as pre-filled 1mL 
syringes with a 29-gauge, half-inch staked needle placed within an administration device. Study drug 
will be packaged and labeled in accordance with applicable local and regulatory requirements. 
 
8.1.3. Preparation + Dosage + administration of the IMP 
Investigational drug product will be provided in prefilled syringes containing 32.4 mg of Zilucoplan® for 
subcutaneous injection in the abdomen (preferred site), thigh, or upper arm. This dose is equivalent 
to that administered to the highest weight bracket in prior weight-based dosing regimens and is 
expected to achieve rapid, profound, and sustained complement inhibition with acceptable safety and 
tolerability. 
Subjects who present with very low body weight (<54kg) are excluded from enrolment. Subjects with 
very high body weight (>150 kg) are also excluded. 
 
Dosage justification : 
Based on prior studies, a well-characterized nominal dose level of 0.3 mg/kg (dispensed as a fixed dose 
of 32.4 mg daily) has been selected for this study based on its superior efficacy, greater inhibition of 
the terminal complement pathway, and similar safety profile as compared with the 0.1 mg/kg and 
placebo arms in completed Phase 2 studies in patients with general myasthenia gravis (gMG) and 
paroxysmal nocturnal hemoglobinuria (PNH). Although previous trials of Zilucoplan® implemented 
weight-based dosing with 3 weight brackets, for this study we have selected only the fixed dose from 
the highest weight bracket in order to most rapidly and efficiently achieve complete complement 
inhibition, and to account for any reduction in skin perfusion or cardiac output in the setting of critical 
illness and/or cardiovascular compromise. 
A fixed dose of 32.4 mg will result in the potential for a range of actual doses to be received per unit 
weight, from a minimum of 0.22 mg/kg daily (e.g. patient weight 150 kg) to a maximum dose of 0.6 
mg/kg daily (e.g. patient weight 54kg).  The anticipated exposure at 0.6 mg/kg provides a safety margin 
of approximately 1.3- and 1.6-fold (area under the drug concentration versus time curve [AUC] and 
Cmax, respectively) to the maximum tolerated dose (MTD) in the 39-week non-human primate (NHP) 
toxicology study. Of note, the maximum possible actual dose of 0.6mg/kg daily for 7 days has already 


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been administered in an ongoing phase 1 clinical study with no major safety or tolerability concerns 
identified to date. 
 
In a completed Phase 2 Study in gMG patients (RA101495-02.201), the magnitude and speed of 
improvement on the primary (QMG) and key secondary (MG-ADL) efficacy endpoints were greater 
with the 0.3 mg/kg dose than the 0.1 mg/kg dose, and both active doses were superior to placebo. The 
dose response seen in the clinical outcome measures is consistent with the known pharmacodynamic 
effect of Zilucoplan® that resulted, as expected, in rapid, sustained and complete (97%) inhibition of 
the terminal complement pathway in all gMG patients receiving the 0.3 mg/kg dose while the 0.1 
mg/kg group achieved only submaximal (88%) inhibition of the terminal complement pathway. 
 
There was no apparent difference with respect to the pattern and distribution of adverse events or 
tolerability between the Zilucoplan® treated and the placebo groups. No dose response in the safety 
profile was seen between the 0.1 mg/kg and 0.3 mg/kg Zilucoplan® groups.  
Similarly, in the Phase 2 studies in patients with PNH, the starting dose of 0.1 mg/kg daily tested did 
not consistently achieve complete inhibition of complement activity in the sRBC lysis assay. The 0.3 
mg/kg daily dose, by contrast, consistently achieved complete inhibition in the sheep red blood cells 
(sRBC) lysis assay (≥95% inhibition at trough) and reduced LDH to levels similar to those observed in 
patients receiving eculizumab.  
 
It is expected that the same pharmacodynamic response to Zilucoplan® as seen in patients with MG 
and PNH, i.e. complete complement inhibition, will be needed to achieve the optimal therapeutic 
response in patients with COVID-19. Therefore, the nominal dose level previously-tested in PNH and 
MG, i.e. 0.3 mg/kg daily dosing has again been selected for use in this study, with preference given to 
the highest fixed dose presentation in order to most rapidly and efficiently achieve complete 
complement inhibition in this acute indication, and to account for any reduction in skin perfusion or 
cardiac output in the setting of critical illness and/or cardiovascular compromise. 
 


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8.1.4. Permitted dose adjustments and interruption of treatment 
No dose adjustments and interruptions are permitted during this trial. In case of anaphylaxis or severe 
AE, the drug will be immediately interrupted. In case a patient is well enough to leave hospital before 
14 days of treatment, drug administration will be terminated.  
 
Patients on hemodialysis: on days of dialysis the dose of Zilucoplan® should be administered after the 
procedure is completed. Since a single dose leads to complete complement inhibition within approx. 
3h, subjects should continue to be fully complement inhibited even when treated with hemodialysis.  
If patient undergoes a 24 hours dialysis, it is recommended to administer Zilucoplan® as per protocol 
while dialysis is ongoing. 
 
 
8.1.5. Duration of treatment 
14 days, or until hospital discharge, whichever comes first 
 
8.1.6. Packaging and Labeling of the IMP 
Study drug will be packaged and labeled in accordance with applicable local and regulatory 
requirements.  Via its partner RaPharmaceuticals, UCB had prefilled syringes ready for a Phase III trial 
in Myastenia gravis in various European countries, labeled on the syringe as RA101495 plus the study 
number identification.  The syringes are too small to be individually relabeled, but the kit containing 7 
syringes will be relabeled on the external packaging following communication and as per instructions 
eFigure 3. Mean Complement Activity as Measured by Sheep Red Blood Cell Assay (% Hemolysis) 
 
 
LLOQ, lower limit of quantification. 


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of FAMHP.  All the syringes in the kit will have the same number as on the label on the corrected 
external packaging, making it possible to link it with the corrected trial reference and sponsor marked 
on the external packaging.  In any case, at the various trial sites, IMP will be administered by study 
staff, to minimalize errors. 
 
8.1.7. Storage conditions of the IMP 
The IMP, Zilucoplan®, will be directly delivered to the study sites by UCB in a relabeled format. The 
study medication should be stored at 2°C to 8°C at the study site. Once dispensed to the hospital ward, 
Zilucoplan® may be stored at room temperature [20°C to 25°C (68°F to 77°F)] for up to 45 days 
protected from sources of heat, light, and damage. However, storage of Zilucoplan® outside of room 
temperatures should be avoided. 
 
8.1.8. Known side effects of the medication 
 
To date Zilucoplan® has shown a favorable safety and good tolerability profile across all studies in 
healthy volunteers and patients with gMG, PNH, immune mediated necrotic myopathy (IMNM), and 
renal impairment. No major safety risks have been identified to date, with over 100 patient years of 
exposure across and >40,000 injections administered in clinical trials. A difference in the overall 
adverse event profiles was seen between the clinical trials in different populations: few adverse events 
occurred in healthy controls and stable renally impaired patients; the adverse event profile in PNH 
reflected the hemolytic anemia characteristic of the underlying disease; and in the gMG population, 
many adverse events were reflective of multiple comorbidities, longstanding use of corticosteroid and 
immunosuppressive therapies, and the more advanced age of this population.  
 
Although no meningococcal infections were identified with Zilucoplan® treatment to date, it is well 
established that inhibition of complement C5 and the terminal complement pathway increases the 
susceptibility to infection with encapsulated bacteria, in particular Neisseria meningitidis. This risk is 
also described in the prescribing information for the approved complement C5 inhibitor eculizumab 
(Soliris® USPI 2017).  
Given the increased risk for Neisseria meningitidis infection with complement C5 inhibition or deficit, 
patients who have received Zilucoplan® in ambulatory clinical trials were required to have 
documentation of Neisseria meningitidis vaccination (and booster if appropriate) prior to treatment 
initiation. In addition, while on Zilucoplan®, subjects were monitored closely for signs and symptoms 
of Neisseria meningitidis infection, including self- monitoring based on detailed instruction about signs 
and symptoms of possible meningococcal infections.  
 
Considering the acuteness of the indication and short duration of treatment (maximum of 14 days 
inhibition of C5 with Zilucoplan®, followed by a post-dosing inhibition of C5 for a maximum of 14 
days) in the hospital, vaccination and induction of humoral immunity prior to initiation of 
Zilucoplan® therapy is not feasible in the context of COVID-19 with hypoxia. Vaccination during the 
period of COVID-19 with high fever and complement activation, is also not a safe option. Therefore, 
the risk of neisserial infection must be mitigated by concomitant administration of appropriate 
antibiotics (e.g. 3rd generation cephalosporin IV, ciprofloxacin PO) from the beginning of Zilucoplan® 
administration until 14 days after cessation of Zilucoplan®. In the hospital setting this will be 
achieved by daily IV administration of ceftriaxone (or cefotaxime). As soon as the patient is 
discharged, oral daily ciprofloxacin will be given until at least 14 days after the last dose of 
Zilucoplan®. To correct for the effects of antibiotics on the course of COVID-19 disease, the control 
group B will receive 1 week (or until hospital discharge whichever comes first) of IV ceftriaxone (or 
cefotaxime) during the hospital stay. In the control group, oral ciprofloxacin post ceftriaxone or 
cefotaxime is not required. In case of allergies to these antibiotics, or on clinical indication, these 
antibiotics may be switched to antibiotics that also cover Neisseria meningitidis. 


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8.2. 
Concomitant / Rescue Medication 
 
There are no restrictions regarding concomitant/rescue medication, except for complement inhibiting 
drugs or other investigational drugs (see exclusion criteria). 
 
PROPHYLACTIC ANTIBIOTICS USE 
 
Group A patients will receive a daily IV infusion of 2g of ceftriaxone until hospital discharge (or until 
28 days after randomization when still in hospital, whichever comes first). If patient is discharged 
before day 28 after randomization, patient will switch to oral ciprofloxacin 1x500 mg per day until at 
least 14 days after the last Zilucoplan® administration. In case of unavailability, ceftriaxone can be 
replaced by cefotaxime 1gr every 8 hours. 
 
Group B patients will receive daily IV infusion of 2g of ceftriaxone daily IV during one week or until 
hospital discharge, whichever comes first. In case of unavailability, ceftriaxone can be replaced by 
cefotaxime 1g every 8 hours. 
 
Prophylactic ceftriaxone will replace any amoxicillin/clavulanic acid that would be given to treat 
concomitant community acquired pneumonia. In the case that, on clinical grounds, antibiotics need to 
be switched, in all instances, Neisseria meningitidis and Streptococcus pneumoniae need to be covered 
by the new antibiotic regimen (e.g. meropenem or piperacillin/tazobactam). In all instances, 
prophylactic antimeningococcal antibiotics need to be given until at least 14 days after the last 
Zilucoplan® administration. 
 
 
 


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9. Study Specific Procedures 
Patients will be informed about the study by the treating physician. 
After receiving full explanation, having received sufficient time to considerer the trial, asking questions 
and receiving satisfying responses to all questions, patients will be asked to sign ICF. 
The ICF process will be performed before any other study related procedure. 
 
9.1. 
Randomization 
In this open label trial patients will be randomized in a 2:1 ratio. Randomization in all centers will be 
done using REDCap (electronic IWRS system).  
 
9.2. 
Study specific interventions 
This is a hospital based intervention trial, in which patients with COVID-19 will be treated for a 
maximum of 14 days with Zilucoplan®. Patients with COVID-19 infection and respiratory failure are 
severely ill, and will require multiple daily clinical exams, blood sampling, vital parameter 
measurements, blood oxygenation measurements, and chest X-rays and/or CT. These are all part of 
the clinical management plan of the patients, and data stored in the electronic patient file will be used 
as part of the assessment of efficacy and safety profile of Zilucoplan® 
 
At screening, a blood sample will be taken, preferentially during routine blood sampling, to determine 
exclusion criteria (minimally includes Ferritin, LDH, haptoglobin, D-dimers, CRP, creatinine, 
triglycerides, fibrinogen, eosinophils, lymphocytes, neutrophils, haemoglobin, WBC count, platelets, 
bilirubin, ALT and AST, procalcitonin and bHCG (females)). A clinical exam and ECG to be performed at 
screening or day 1 before administration of study mediation. Any form of chest CT scan within 48h 
before randomization (low dose, HRCT, or Angio CT scan) must document a presence of bilateral 
ground glass infiltrates or bilateral consolidation. 
 
On day 1, prior to Zilucoplan® treatment in group A, and during the day in group B control patients, 
two tubes of blood serum (2 x 6 ml), one EDTA 6 ml tube, one 4 ml DNA EDTA tube, and two optional 
EDTA tubes (2 x 10 ml, optional) will be collected for measuring blood cytokine and chemokine levels, 
complement, and activation of immune cells. Additionally, one extra EDTA 6 ml tube will be collected 
from patients in the active group for pharmacokinetics (PK). In both groups, an arterial blood gas 
determination via arterial puncture will be taken in upright position, after minimal 3 minutes without 
supplemental oxygen. In case of inability to sit upright: same position should be used for all 
measurements of PaO2. In ventilated patients or ECMO patients ABG can be obtained from invasive 
arterial line. In ventilated patients the FiO2 can be directly derived from mechanical ventilation 
settings.  The FiO2 at moment of ABG is documented in the eCRF, except for patients on ECMO.. Scores 
to be assessed include 6-point ordinal scale, SOFA score and HScore. Both scores to be evaluated at 
time of first drug administration (Arm A and Arm B). 
 
On day 2, one  EDTA 6 ml tube for patients in both groups for complement assays (prior to Zilucoplan® 
treatment in group A) and one tube of blood EDTA (6ml) prior to Zilucoplan® treatment in group A will 
be collected for pharmacokinetics. 
 
On day 6, prior to Zilucoplan® treatment in group A (i.e. pre-dosing) and during the day in group B, two 
tubes of blood serum (2 x 6ml), plus 1 EDTA 6 ml tube for PK in active group,  one EDTA 6 ml tube and 
two optional EDTA tubes (2 x 10 ml, optional) will be collected for measuring blood cytokine and 
chemokine levels, complement activation,  and activation of immune cells. Additionally, one extra 
EDTA 6 ml tube will be collected from patients in the active group for PK. Routine laboratory 
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eosinophils, lymphocytes, haemoglobin, WBC count, platelets, bilirubin, ALT and AST. Also, an arterial 
blood gas determination via arterial puncture will be taken in upright position, after minimal 3 minutes 
without supplemental oxygen. In case of inability to sit upright: same position should be used for all 
measurements of PaO2. In ventilated patients or ECMO patients ABG can be obtained from invasive 
arterial line. In ventilated patients the FiO2 can be directly derived from mechanical ventilation 
settings.  The FiO2 at moment of ABG is documented in the eCRF, except for patients on ECMO. Scores 
to be assessed include 6-point ordinal scale and SOFA score 
 
On day 15 (or on discharge whichever comes first), two tubes of blood serum (2 x 6 ml), 1 EDTA 6 ml 
tube and optional 2 EDTA tubes (2 x 10 ml, optional) will be collected for measuring blood cytokine 
and chemokine levels, complement activation and activation of immune cells. . Additionally, one extra 
EDTA 6 ml tube will be collected from patients in the active group for PK. Routine laboratory 
assessment should minimally include Ferritin, LDH, haptoglobin, D-dimers, CRP, creatinine, fibrinogen, 
eosinophils, lymphocytes, haemoglobin, WBC count, platelets, bilirubin, ALT and AST. Also, an arterial 
blood gas determination via arterial puncture will be taken in upright position, after minimal 3 minutes 
without supplemental oxygen. In case of inability to sit upright: same position should be used for all 
measurements of PaO2. In ventilated patients or ECMO patients ABG can be obtained from invasive 
arterial line. In ventilated patients the FiO2 can be directly derived from mechanical ventilation 
settings.  The FiO2 at moment of ABG is documented in the eCRF, except for patients on ECMO. Scores 
to be assessed include 6-point ordinal scale and SOFA score. Measurements of procalcitonin levels will 
be performed at least three times per week until day 14, to exclude bacterial infection. 
 
On days 1-14 (or until discharge, whichever comes first), patients in group A will receive Zilucoplan® 
on top of standard of care. They will additionally receive prophylactic antibiotics (IV ceftriaxone during 
hospital stay followed by daily ciprofloxacin for 14 days after the last Zilucoplan® administration).  
Patients in control group B will only receive one week of ceftriaxone IV (or until hospital discharge 
whichever comes first) on top of standard of care, to control for a modifying effect of antibiotics on 
the clinical course. In case patients in group A and group B would need a switch to another antibiotic 
for intermittent therapeutic indications, in all instances N. meningitidis, H. Influenzae and S. 
pneumoniae should be covered in the antibiotic spectrum of the new antibiotic.  Patients in groups A 
or group B who are already receiving amoxicillin/clavulanic acid for treatment of possible bacterial 
pneumonia co-infection at randomization should be switched to IV ceftriaxone, in order for S. 
pneumoniae and N. meningitidis to be covered. 
 
Upon progression of disease, need for mechanical ventilation and transfer to the ICU within the 14 day 
period, in patients in the active group, Zilucoplan® will be administered also via SC administration and 
at all instances presence of edema will be noted. If edema is noted, where possible drug will be 
administered subcutaneously in non-edematous area, with a preference for the upper leg.  
 
At day 28 post-randomization (or within next 3 days) patients will be inquired by phone for 6-point 
ordinal scale, (S)AE, supplemental oxygen need (Y/N), therapy compliance (antibiotics) and 
concomitant medication since hospital discharge or day 15.  
 
On a final clinical visit between week 12-22 after randomization two additional serum tubes (2 x 6 
ml) and optional 2 EDTA tubes (2 x 10 ml) will be taken. Routine laboratory assessment should 
minimally include Ferritin, LDH, haptoglobin, D-dimers, CRP, creatinine, fibrinogen, eosinophils, 
lymphocytes, haemoglobin, WBC count, platelets, bilirubin, ALT and AST. Also, an arterial blood gas 
determination via arterial puncture will be taken. WHO-score, Lung function data (FVC, FEV1, FRC, RV, 
DLCO), a 6 minute walk test and HRCT scan to assess the HRCT fibrosis score. 
 
 
 


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9.3. 
Overview of collected data 
1. patient demographics and biometry 
 
age, sex, ethnicity, day of admission, weight, length  
2. day of confident or highly suspicious COVID-19 diagnosis 
3. Clinical and laboratory parameters on screening day and as frequent as possible during trial 
 
-first day of illness (defined by myalgia, or fever, or coughing)  
-clinically relevant abnormalities found during physical examination  
 
-vital signs (temperature, blood pressure, heart rate, breathing rate) 
 
-pulse oximetry data (SpO2) 
 
-clinical blood gas sampling (pH, PaO2, PaCO2, HCO3, SaO2) 
-clinical chemistry sampling (will be measured on day 1, 6,day 15 or discharge and FU) 
-Chest X-ray and/or CT characteristics and radiology clinical report 
4. All standard care drugs used during the trial and on day of enrolment of the trial, including oxygen 
flow rate. 
5. Basic clinical data on prior medical history (prior lung diseases, smoking history, prior lung function 
measurements (preferentially within 5 preceding years), prior gas exchange measurements) and 
medication use will be collected from electronic medical record. 
6. Study specific measurements  
 Plasma and serum samples will be collected at each of the indicated timepoints for exploratory 
analysis that may include but not limited to: 
• 
ADA (Day 1, and week 12-22 follow-up) 
• 
Complement system assessment on EDTA tube 
• 
Cytokines such as IL-1beta, IL-1RA, IL-2, IL-8, IL-6, TNFa, GM-CSF, G-CSF, IP-10, MCP-
1, MIP-1a, IFNg, and IL-10 as well as biomarkers (sRAGE, Angiopoietin-2) will be 
measured on samples collected at the various centers at day 1, day 6 and day 15 or 
discharge (whichever comes first) 
• 
DNA EDTA tube for pharmacogenomic research (Day 1 predose only) 
 
7. Phamacokinetics (PK) measurements (predose D1, predose D2, predose D6 and D15/discharge) 
only in group A. 
 
 
9.4. 
Schematic overview of the data collection & interventions (see next 
page) 


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Procedure 
Screening (D0 or D1) 
D1a 
D2 
D6 
Hospital discharge or D15b 
D28c  
Follow-upd 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Medical history & biometry 
X 
 
 
 
 
 
6 minute walk test  
 
 
 
 
 
X 
Lung function 
 
 
 
 
 
X 
Physical examinationh 
Per SOC 
Vital signse,h 
X 
                                     Daily until discharge from hospital 
 
X 
Daily (S)AE inquiry 
 
 
Concomitant medication 
X 
 
Xc 
X 
ECGh 
X 
On clinical grounds 
 
 
Any chest CT scan 
Xp 
On clinical grounds 
 
 
HRCTq 
 
 
 
X 
Routine laboratory assessments on clinical 
grounds, except: 
- D0/1, D6, discharge/D15 and FU 
- Procalcitonin 3x/week until D15 
Xf,h 
 
Xg,h 
Xg 
 
Xg 
Study blood samplingh 
 
 
 
 
 
 
- 2 x 6 ml serum tubes 
 
X 
 
X 
X 
 
X 
- 1 x 4 ml EDTA tube (DNA) 
 
X 
 
 
 
 
 
- 2 x 10 ml EDTA tube (optional, selected sites) 
 
X 
 
X 
X 
 
X 
- 1 x 6 ml EDTA tube (complement) 
 
X 
X 
X 
X 
 
 
- 1 x 6 ml EDTA tube for PK (arm A only) 
 
X 
X 
X 
X 
 
 
- Arterial blood gas 
Xh 
 
Xi,h 
Xi 
 
X 
Score assessments 
 
 
 
 
 
 
- 6-point ordinal scalej,h 
        Daily until discharge from hospital  
X 
- SOFA scorek,h 
 
X 
 
X 
X 
 
 
- HScorel,h 
 
X 
 
 
 
 
 
- WHO performance scaler 
 
 
 
 
 
 
X 
IMP Zilucoplan® (arm A only) 
 
                                          Daily SC until D14 or discharge 
 
 
Third generation cephalosporin (arm A only)m 
 
   Daily IV until discharge 
 
Third generation cephalosporin (arm B only)n 
 
 Daily IV until D7 
 
 
 
Oral ciprofloxacin (arm A only)o 
 
 
                     o 
 
 
Daily drug compliance inquiry 
 
 
Xc 
 


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a Prior to first Zilucoplan® administration in arm A, and during the day in arm B 
 
b Hospital discharge or D15, whichever comes first 
 
c Inquiry by phone on D28 post-randomization (or within next 3 days) for 6-point ordinal scale, (S)AE, supplemental oxygen need (Y/N) and concomitant medication since discharge 
or D15 
 
d Follow-up visit at 12-22 weeks post-randomization 
 
e Values between 7-10AM Includes T°C (actual  and highest last 24h), Pulse rate, Blood Pressure, Respiratory Rate, SpO2 by pulsoximetry, FiO2 and ventilator parameters (if patient 
admitted to ICU) Time window of assessment of vital signs (7-10 AM) is not applicable for follow-up visit. 
 
f Minimally includes Ferritin, LDH, haptoglobin, D-dimers, CRP, creatinine, triglycerides, fibrinogen, eosinophils, lymphocytes, neutrophils, haemoglobin, WBC count, platelets, 
bilirubin, ALT and AST, procalcitonin and bHCG (females) (For exclusion criteria, HScore and SOFA) 
 
g Should minimally include Ferritin LDH, haptoglobin, D-dimers, CRP, creatinine, fibrinogen, eosinophils, lymphocytes, haemoglobin, WBC count, platelets, bilirubin, ALT and AST (For 
SOFA) 
 
h If arm A: Pre-dose Zilucoplan®  
Arterial blood gas: If an arterial blood gas value is available of less than 24 hours before randomization, there’s no need to have a new ABG done on Day 0/1. 
 
i Mandatory: patient in upright position, after minimal 3 minutes without supplemental oxygen. In case of inability to sit upright: same position is to be used for all measurements of 
PaO2. In ventilated patients PaO2 can be taken from invasive arterial line and FiO2 taken directly from mechanical ventilation settings, document FiO2 at moment of ABG. For 
patients on ECMO the PaO2/FiO2 ratio and Aa-gradient cannot be calculated as in this case the FiO2 will be missing. Therefore, the last available value of PaO2/FiO2 ratio and Aa 
gradient prior to ECMO can be used at that timepoint. 
j Defined as 1 = Death; 2 = Hospitalized, on invasive mechanical ventilation or ECMO; 3 = Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4 = Hospitalized, 
requiring supplemental oxygen; 5 = Hospitalized, not requiring supplemental oxygen; 6 = Not hospitalized 
 
k SOFA score (see https://www.mdcalc.com/sequential-organ-failure-assessment-sofa-score): requires PaO2, FiO2, platelet count, GCS, bilirubin, MAP and creatinine. To be 
evaluated between 6 and 10 am. Score to be calculated based on the worst values in the previous 24h at time of evaluation. 
 
l HScore (see https://www.mdcalc.com/hscore-reactive-hemophagocytic-syndrome): requires T°C, haemoglobin, wbc count, platelets, ferritin, fibrinogen, triglycerides and AST (BM 
aspirate is not required) To be evaluated at time of randomization. 
 


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m Third generation cephalosporin replaces empiric amoxicillin/clavulanic acid to treat concomitant community acquired pneumonia. In case of allergies or clinical indication for 
antibiotic switch, N. menigitidis and S. pneumoniae need to be covered by the new antibiotic treatment (e.g. meropenem or piperacilin/tazobactam). Third generation cephalosporin 
is given until D28 or hospital discharge whichever comes first.  
 
n Group B patients receive daily injection of 2g ceftriaxone IV (or appropriate alternative in case of allergies or on clinical indication) during one week or until hospital discharge, 
whichever comes first.  
 
o Upon discharge before D28 post-randomization, patients will switch to daily oral ciprofloxacin (500 mg 1x/d) until at least 14 days after the last dose of Zilucoplan® (only in arm A). 
 
p any form of chest CT scan  within 48h before randomization (low dose, HRCT, or Angio CT scan) must document  a presence of bilateral ground glass infiltrates or bilateral consolidation 
q HRCT scoring: A subjective assessment of the overall extent of normal attenuation, reticular abnormalities, honeycombing and traction bronchiectasis will be performed.  A reticular 
abnormality is defined as a collection of innumerable areas of small linear opacity. Honeycombing is defined as the presence of a cystic airspace measuring 3–10 mm in diameter, with 
1- to 3-mm thick walls. Traction bronchiectasis is defined as irregular bronchial dilatation within the surrounding areas showing parenchymal abnormalities. The morphological criteria 
on HRCT scans include bronchial dilatation with respect to the accompanying pulmonary artery, a lack of tapering of the bronchi and the identification of bronchi within 10 mm of the 
pleural surface. The HRCT findings will be graded on a scale of 1–4 based on the classification system: 1. normal attenuation; 2. reticular abnormality; 3. traction bronchiectasis; and 
4. honeycombing. The presence of each of the above four HRCT findings will be assessed independently in three (upper, middle and lower) zones of each lung. The upper lung zone is 
defined as the area of the lung above the level of the tracheal carina, the lower lung zone is defined as the area of the lung below the level of the inferior pulmonary vein and the 
middle lung zone is defined as the area of the lung between the upper and lower zones. The extent of each HRCT finding will be determined by visually estimating the percentage (to 
the nearest 5%) of parenchymal involvement in each zone. The score for each zone will be calculated by multiplying the percentage of the area by the grading scale score. The six zone 
scores will be averaged to determine the total score for each patient. The highest score is 400 points and the lowest score is 100 points using this calculation method. The total score 
is the “HRCT fibrosis score”. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922654/pdf/1465-9921-15-10.pdf) 
r WHO performance scale: 0. Able to carry out all normal activity without restrictions; 1. Restricted in physically strenuous activity but ambulatory and able to carry out light work; 2. 
Ambulatory and capable of all self-care but unable to carry out any work: up and more than 50% of waking hours; 3. Capable of only limited self-care: confined to bed or chair more 
than 50% if waking hours; 4. Completely disabled: cannot carry on any self-care: totally confined to bed or chair. 
 


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9.5. 
Restrictions for subjects during the study 
There are no subject restrictions during this trial.  
10. 
Sampling 
10.1. Types and number of samples 
D1: pre-dose serum blood sample 2 x 6ml serum, one EDTA 6ml tube for PK in active group A, one 4 
ml DNA EDTA tube, one EDTA 6 ml tube for complement and optional EDTA blood sample, 2 x 10 ml 
D2: predose 1 x 6ml EDTA tube for PK in active group A only, 1 x 6ml EDTA tube for patients in both 
groups 
D6: serum blood sample 2 x 6ml serum tube, one 6 ml EDTA tube for PK in group A, 1 x 6ml EDTA tube 
for patients in both groups and optional EDTA blood sample, 2 x 10 ml 
D15 or at discharge: serum blood sample 2 x 6ml, one 6 ml EDTA tube for PK in group A, 1 x 6ml EDTA 
tube for patients in both groups and optional EDTA blood sample, 2 x 10 ml 
Week 12-22 post-randomization follow-up visit: serum blood sample 2 x 6ml, optional EDTA blood 
sample, 2 x 10 ml 
 
10.2. Timepoints of sampling 
These samples are to be taken predose on D1, D2, D6 and D15 (or discharge whichever comes first) 
and on final follow up visit between week 12 and 22.  
 
10.3. Sample Handling & Analysis 
Samples will be taken during hospitalization preferably together with the blood draw for standard of 
care and will be used for measurements of pharmacodynamics and pharmacokinetic endpoints 
described under section 4.3 
 
For sample handling and analysis, see lab manual provided by Covance. 
 
OPTIONAL sampling per center 
In selected centers (to be decided by the local investigator after consulting with the coordinating 
principle investigator), additional 2 x 10 ml EDTA blood tubes will be taken at day 1, 6 and 15, or at 
hospital discharge whichever comes first and safety follow-up, for flow cytometric analysis and  COVID-
19 related research purposes. The samples will be stored in the FAGG-certified biobank mentioned in 
section 10.5 until further use in the context of COVID-19 related research takes place. 
 
Separate submission to the Ethics Committee will be initiated before execution of any research activity 
on the blood samples stored in the biobank. 
 
 
10.4. Sample Storage and/or shipping 
See lab manual provided by Covance.  
Optional EDTA samples (selected sites) to be shipped to UZ Ghent for analysis and storage.   
 
10.5. Future use of stored samples 
Initially samples will be stored for the use as described within this protocol. If at a later time point 
samples will be stored for future use, they will be stored  in the FAGG certified biobank “prospectieve 
biobank CF, bronchiëctasieën en respiratoire infecties” managed by biobank manager Prof. Dr. E. Van 
Braeckel. For each future project with samples collected from the current protocol, a separate Ethics 
Committee approval will be obtained.  
 


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11. 
Statistical Considerations 
 
11.1. Sample size calculation 
The outcome(s) on which the sample size calculation is based upon, is the primary endpoint 
measurement of oxygenation, defined as ratio of PaO2/FiO2. 
Sample calculation and power analysis have been performed by UCB. The target difference is the 
difference measured at the primary endpoint (day 6 and day 15 or discharge) between the control and 
the treated group. Given a sample size of 81 patients, 54 on Zilucoplan® and standard of care and 27 
on standard of care there would be >85% power to show a significant difference from standard of care 
at the 2 sided 5% level if the true underlying treatment difference was an 80 point difference (25% of 
320, being the mean at hospital admission) in the PaO2/FiO2 ratio.  This assumes a standard deviation 
of 105 and a dropout rate of less than 10%.   
 
11.2. Type of statistical methods 
 
All primary and secondary endpoints will be summarized and where relevant represented graphically 
 
Primary endpoint:   
The change from baseline in PaO2/FiO2 ratio will be analyzed using a Mixed Model Repeated Measures 
(MMRM) analysis with a fixed effect for Baseline PaO2/FiO2 ratio, treatment, day and treatment by 
day interaction, where day is categorical. Subject will be fitted as a random effect and an unstructured 
covariance will be used unless it fails to converge, where other covariance structures will be 
considered.  Other covariates, such as gender, may also be included in the model, if by the time of the 
analysis these have been identified as key differentiators in terms of COVID-19 recovery.  If the 
variability is shown to be inappropriate for this additive model, then a log transformation of the 
PaO2/FiO2 ratio may be considered. 
 
Data from SOC in another study with a very similar protocol may be incorporated into the analysis 
using a Bayesian frame work.  This will be described more fully in the statistical analysis plan (SAP). 
 
A similar analysis for the P(A-a)O2 gradient will be completed 
 
Other Endpoints: 
Other continuous endpoints will be analyzed in a similar way using an MMRM.   
Response rates, such as 28 day all-cause mortality a logistic regression will be used. 
Count data will use a generalized linear model with a log link unless the model is either over or under 
dispersed and then an alternative approach will be used.  If it is counts out of a fixed number of days, 
then a logistic regression will be considered. 
 
For the final follow up, a survival analysis with Kaplan-Meir plots will be created covering from Day 1 
to end of follow up. 
 
The detail around the analyses will be explained in more detail in the SAP and as this is an 
exploratory study, additional analyses may be considered to explore the data more fully. 
 
Interim analyses: will be performed when 42 patients have reached primary endpoint analysis. 
 


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After half the patients have completed day 15 an interim analysis will be completed to understand if 
there is already enough evidence to prompt further work on COVID-19 treatment with Zilucoplan®.  
There is no plan to stop the study at this stage. 
Analyses will also be completed when all patients have finished day 28 to assess all pre-follow up 
assessments and 28 day mortality (via phone call).  This will enable key results to be understood as 
soon as possible without compromising the study. 
 
11.3. Statistical analysis team 
The statistical analysis will be performed by UCB. 
 
 
12. 
Data handling 
 
 
12.1. Method of data collection 
 
Subjects that are included in the study at Ghent University Hospital or other Belgian centers, will be 
assigned a unique study number upon their registration in REDCap. On all documents submitted to the 
coordinating center, sponsor or CI, patients will only be identified by their study number. The subject 
identification list will be safeguarded by the site. The name and any other directly identifying details 
will not be included in the study database. 
 
12.1.1. 
Case Report Form 
An electronic data capture (EDC) system, i.e. REDCap, will be used for data collection. Data reported 
on each eCRF should be consistent with the source data. If information is not known, this must be 
clearly indicated on the eCRF. All missing and ambiguous data will be clarified.  
Only the data required by the protocol are captured in the eCRF. The eCRFs and the database will be 
developed, based on the protocol. The final eCRF design will be approved by the Co-ordinating 
Investigator. 
All data entries and corrections will only be performed by study site staff, authorized by the 
investigator. Data will be checked by trained personnel (monitor, data manager) and any errors or 
inconsistencies will be clarified. The investigator must verify that all data entries in the eCRF are 
accurate and correct. 
 
REDCap is provided and maintained by Vanderbilt University; a license for use was granted to the 
Health, Innovation and Research Institute (HIRUZ). REDCap is a web-based system intended for 
academic clinical trials.  
The study site staff is responsible for data entry in REDCap.  
 
12.1.2. 
Data directly collected in the CRF (no source available) 
All data is to be collected in accordance with the latest version of the ICH E6 (R2) GCP guidelines. There 
will be no data directly collected in the CRF. 
 
 
 
 
 


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12.2. Data storage 
The data is accessed through a web browser directly on the secure REDCap server. The server is hosted 
within the UZ Ghent campus and meets hospital level security and back-up requirements.  
 
Privacy and data integrity between the user's browser and the server is provided by mandatory use of 
Transport Layer Security (TLS), and a server certificate issued by TERENA (Trans-European Research 
and Education Networking Association). All study sites will have access to REDCap. Site access is 
controlled with IP restriction. 
 
12.3. Archiving of data 
The investigator and sponsor specific essential documents will be retained for at least 25 years. At that 
moment, it will be judged whether it is necessary to retain them for a longer period, according to 
applicable regulatory or other requirement(s). 
 
12.4. Access to data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit study-related monitoring, audits and inspections. 
Pseudonymized biological analyses, study data and study results will also be shared with the provider 
of Zilucoplan® (UCB Pharma)  
Login in REDCap is password controlled. Each user will receive a personal login name and password 
and will have a specific role which has predefined restrictions on what is allowed in REDCap. 
Furthermore, users will only be able to see data of subjects of their own site. Any activity in the 
software is traced and transparent via the audit trail and log files. 
 
 


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13. 
Safety  
 
13.1. Definitions 
 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a subject to whom a medicinal product 
has been administered, including occurrences which are not necessarily 
caused by or related to that product. An AE can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product. 
Unexpected Adverse 
Event 
An adverse event, the nature or severity of which is not consistent with the 
applicable product information (e.g., Investigator's Brochure for an 
unapproved investigational product or package insert/summary of product 
characteristics for an approved product). 
Adverse Reaction (AR) 
 
An untoward and unintended response in a subject to an investigational 
medicinal product which is related to any dose administered to that subject. 
The phrase "response to an investigational medicinal product" means that a 
causal relationship between a study medication and an AE is at least a 
reasonable possibility, i.e. the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional or the 
Sponsor as having a reasonable suspected causal relationship to the study 
medication qualify as adverse reactions. 
Serious Adverse Event 
(SAE) 
A serious adverse event is any untoward medical occurrence that: 
• results in death 
• is life-threatening 
• requires inpatient hospitalisation or prolongation of existing 
hospitalisation 
• results in persistent or significant disability/incapacity 
• consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if they 
jeopardise the subject or require an intervention to prevent one of the above 
consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were 
more severe. 
Serious Adverse 
Reaction (SAR) 
An adverse event that is both serious and, in the opinion of the reporting 
Investigator, believed with reasonable probability to be due to one of the 
study treatments, based on the information provided. 
Suspected Unexpected 
Serious Adverse 
Reaction (SUSAR) 
A serious adverse reaction, the nature and severity of which is not consistent 
with the information about the medicinal product in question set out: 
• in the case of a product with a marketing authorisation, in the summary 
of product characteristics (SmPC) for that product 
• in the case of any other investigational medicinal product, in the 
investigator’s brochure (IB) relating to the study in question 
 


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Attribution definitions 
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable or definitive, in the opinion of the investigator. 
 
Not related 
An adverse event which is not related to the use of the drug. 
 
Unlikely 
An adverse event for which an alternative explanation is more likely - e.g. concomitant drug(s), 
concomitant disease(s), and/or the relationship in time suggests that a causal relationship is unlikely. 
 
Possible 
An adverse event which might be due to the use of the drug. An alternative explanation - e.g. 
concomitant drug(s), concomitant disease(s), - is inconclusive. The relationship in time is reasonable; 
therefore the causal relationship cannot be excluded. 
 
Probable 
An adverse event which might be due to the use of the drug. The relationship in time is suggestive (e.g. 
confirmed by dechallenge). An alternative explanation is less likely - e.g. concomitant drug(s), 
concomitant disease(s). 
 
Definitely 
An adverse event which is listed as a possible adverse reaction and cannot be reasonably explained by 
an alternative explanation - e.g. concomitant drug(s), concomitant disease(s). The relationship in time 
is very suggestive (e.g. it is confirmed by dechallenge and rechallenge). 
 
13.2. Reporting requirements 
13.2.1. 
AE reporting 
 
AE’s will be recorded from the first drug administration until the end of the study, as defined in section 
5.2.  
Special attention will be given to those subjects who have discontinued the study for an AE, or who 
experienced a severe or a serious AE. All AE’s should be recorded in the patient’s file and in the CRF.  
 
13.2.2. 
SAE reporting 
 
SAE’s occurring during the entire study period will be reported as below. 
 
All serious adverse events (initial and follow up information) and pregnancies occurring during this 
study must be reported by the local Principal Investigator within 24 hours after becoming aware of the 
SAE to: 
- 
The local ethics committee (it is the responsibility of the local PI to report the local SAE’s to 
the local EC) 
- 
HIRUZ CTU of the University Hospital Ghent 
- 
The National Coordinating Investigator (in case of multicenter studies) 
The company UCB that provides the IMP  
This reporting is done by using the appropriate SAE form. For the contact details, see below. 
 
 
 


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13.2.3. 
SUSAR reporting 
 
In case the Coordinating Investigator, in consultation with HIRUZ CTU, decides the SAE is a SUSAR 
(Suspected Unexpected Serious Adverse Reaction), HIRUZ CTU will report the SUSAR to the Central EC 
and the FAMHP within the timelines as defined in national legislation. The Coordinating Investigator 
reports the SUSAR to all local PI’s. 
In case of a life-threatening and fatal SUSAR the entire reporting process must be completed within 7 
calendar days. In case of a non life-threatening SUSAR the reporting process must be completed within 
15 calendar days.  
 
 
13.3. List of contact details for safety reporting 
Contact details for serious adverse drug reactions and serious adverse events: 
 
HIRUZ CTU: 
 
 
 
Ghent University Hospital 
C. Heymanslaan 10, 1K5 
9000 Ghent, Belgium 
e-mail: hiruz.ctu@uzgent.be   
Tel: 
+32 9 332 05 00 
Fax:  
+32 9 332 05 20 
 
Coordinating Investigator: 
 
Prof. dr. Bart Lambrecht 
Ghent University Hospital 
Department of pneumology 
C. Heymanslaan 10, 1K5 
9000 Ghent, Belgium 
email: bart.lambrecht@ugent.be  
Tel: 
+32 9 332 91 10 
 
Marketing Authorisation Holder: 
 
N.A.  
 
Partner providing the IMP (serious adverse drug reactions only):         
DS_ICT@ucb.com 
 
 
 
 
 
 
 
 
 
 
 


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13.4. Flowchart Reporting 
 
Type of Adverse Event 
Action to be taken 
AE 
List all AE’s per subject in the patient’s file and 
add this information to the CRF. 
SAE 
Notify to HIRUZ CTU within 24 hours after 
becoming aware of the SAE + add the SAE to a 
list that will be reported yearly (see section 13.8) 
SAR 
Notify to HIRUZ CTU within 24 hours after 
becoming aware of the SAE 
→ HIRUZ CTU will submit to the central EC 
→ HIRUZ CTU informs company that provides 
the IMP 
SUSAR 
Notify to HIRUZ CTU within 24 hours after 
becoming aware of the SUSAR 
→ HIRUZ CTU will submit to the central EC. 
→ HIRUZ CTU will submit to the FAMHP 
→ HIRUZ CTU informs company that provides 
the IMP 
→HIRUZ CTU will inform all participating sites 
 
In case the (SU)SAR occurs at a local participating site, the local PI or study team should also contact: 
- 
The local Ethics Committee 
- 
The Co-ordinating Investigator 
 
13.5. Events, excluded from reporting 
COVID-19 infection is a very recent syndrome, on which few data are available. Normal symptoms and 
natural disease course symptoms that will not be reported as adverse events are dyspnea, coughing, 
malaise, fever, drop in oxygen saturation, progression to respiratory failure, progression to ARDS, drop 
in blood pressure. However, progression to multi-organ failure, may have other etiologies and will be 
reported as SAE.  
 
A careful assessment will be performed in cases where disease related events appear to be enhanced 
by the IMP. In accordance with CT-3 guidance, a causality assessment will be performed for each SAE, 
and if the investigator considers disease related event to be IMP-related and the event is serious, 
related and unexpected, then it will be reported as a SUSAR. 
 
 
 
13.6. Data Safety Monitoring Board (DSMB) 
Considering the known safety profile of the study medications and study design, however in a new 
disease indication, a DSMB (chaired by Prof. Sylvie Rottey) is foreseen after enrolment of the first 10 
active patients in the trial. The Charter includes the role of the committee, organizational flow, 
committee membership, committee meetings and will be signed by all DSMB members prior to the 
first meeting of the DSMB. 
 
 


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13.7. Development Safety Update Report 
The Coordinating Investigator will provide DSURs once a year throughout the entire duration of the 
clinical study, or on request, to the Competent Authority, Central Ethics Committee and Sponsor. This 
DSUR will include all SAE’s (who were not categorized as SAR’s and were not immediately reported to 
the EC). 
The report will be submitted 1 year (+ maximum 60 days) after the ‘Development International Birth 
Date (DIBD)’, and will subsequently be submitted each year until the study is declared ended. This DIBD 
is the date of the sponsor’s first overall authorisation to conduct the clinical trial in any country 
worldwide. 
HIRUZ CTU can provide a template that can be used to complete this DSUR. 
 
 


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14. 
Monitoring/Auditing/Inspection 
 
14.1. Monitoring 
14.1.1. 
General 
Monitoring of the study will be performed in compliance with GCP E6(R2) and the applicable regulatory 
requirements. The study team will be trained in an initiation visit by the monitor. A training and 
delegation log will be held. A detailed description of the monitoring tasks can be found in the latest 
version of the (study-specific) ‘Monitoring plan’. 
 
14.1.2. 
Monitoring team 
Monitoring services will be provided by HIRUZ CTU. All relevant contact details (e.g. primary contact 
person, can be found in the ‘Monitoring plan’. 
 
14.1.3. 
Scope 
Monitoring services will consist of the following (non-exhaustive list): 
- review of informed consents and the followed process 
- check on recruitment status 
- checking for protocol deviations/violations 
- checking GCP compatibility 
- check on safety reporting compliance 
- IMP handling and storage 
- review of study data 
… 
 
14.2. Inspection 
This study can be inspected at any time by regulatory agencies during or after completion of the study. 
Therefore access to all study records, including source documents, must be accessible to the inspection 
representatives. Subject privacy must be respected at all times, in accordance to GDPR, GCP and all 
other applicable local regulations. 
The investigator/study team should immediately notify the sponsor if he or she has been contacted by 
a regulatory agency concerning an upcoming inspection. 
 
14.3. Protocol Deviation policy 
Sponsor and all investigators agree to take any reasonable actions to correct protocol 
deviations/violations noted during monitoring/inspection, in consultation with the monitoring team. 
All deviations must be documented on a protocol deviation log by the study team that is kept available 
at any time for monitoring/inspection purposes. Under emergency circumstances, deviations from the 
protocol to protect the rights, safety or well-being of human subjects may proceed without prior 
approval of the sponsor and the EC. 
 
14.4. Serious breach to GCP and/or the protocol 
Critical issues that significantly affect patient safety, data integrity and/or study conduct should be 
clearly documented and will be communicated with the Coordinating Investigator, HIRUZ CTU and 
possibly both the applicable Ethics Committee(s) and Competent authority. (Please contact HIRUZ CTU 
asap in case of a serious breach: hiruz.ctu@uzgent.be and/or +3293320500). 
Early determination of the study (in a specific center or overall) may be necessary in case of major non-
compliance. 
 


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15. 
Ethical and legal aspects 
 
15.1. Good Clinical Practice 
The study will be conducted cfr the latest version of the ICH E6 (R2) GCP guidelines, creating a standard 
for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of 
clinical studies that provides assurance that the data and reported results are accurate and that the 
rights, integrity and confidentiality of study subjects are protected. 
 
15.2. Informed Consent 
Eligible subjects may only be included in the study after providing written (witnessed, if needed) 
Ethics Committee-approved informed consent, or, if incapable of doing so, after such consent has been 
provided by a legally acceptable representative(s) of the subject. 
Informed consent must be obtained before conducting any study-specific procedures (as described in 
this protocol).  
 
Prior to entry in the study, the investigator must explain to potential subjects or their legal 
representatives the study and the implication of participation. Subjects will be informed that their 
participation is voluntary and that they may withdraw consent to participate at any time. Participating 
subjects will be told that their records may be accessed by competent authorities and by authorized 
persons without violating the confidentiality of the subject, to the extent permitted by the applicable 
law(s) and/or regulations. By signing the Informed Consent Form (ICF), the subjects or legally 
acceptable representatives are authorizing such access. 
After this explanation and before entry to the study, written, dated and signed informed consent 
should be obtained from the subject or legally acceptable representative. The ICF should be provided 
in a language sufficiently understood by the subject. Subjects must be given the opportunity to ask 
questions. 
The subject or legally acceptable representative will be given sufficient time to read the ICF and to ask 
additional questions. After this explanation and before entry to the study, consent should be 
appropriately recorded by means of either the subject's or his/her legal representative's dated 
signature or the signature of an independent witness who certifies the subject's consent in writing. 
After having obtained the consent, a copy of the ICF must be given to the subject. 
In case the subject or legally acceptable representative is unable to read, an impartial witness must 
attest the informed consent. 
Subjects who are unable to comprehend the information provided or pediatric subjects can only be 
enrolled after consent of a legally acceptable representative. 
The following information should be added to the electronic medical record (EMR):   
• 
which version of the ICF was obtained 
• 
who signed the ICF  
• 
if sufficient time has been given to consider participation into the study 
• 
which investigator obtained ICF with the date of signature 
• 
if a copy was provided to the patient 
• 
start and end of participation in the study 
 
15.3. Approval of the study protocol 
15.3.1. 
General 
The protocol has been reviewed and approved by the Ethics Committee of the Ghent University 
(Hospital), designated as the central Ethics Committee, after consultation with the local Ethics 
Committees, and the Federal Agency for Medicine and Health Products (FAMHP). This study cannot 
start before both approvals have been obtained. 
 


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15.3.2. 
Protocol amendments 
Any significant change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by the Central Ethics Committee (and the FAMHP if applicable). 
Only amendments that are intended to eliminate an apparent immediate safety threat to patients may 
be implemented immediately. 
Notwithstanding the need for approval of formal protocol amendments, the investigators are expected 
to take any immediate action, required for the safety of any subject included in this study, even if this 
action represents a deviation from the protocol. These actions should always be notified to the 
sponsor. 
 
15.4. Confidentiality and Data Protection 
All study data will be handled in accordance with the law on General Data Protection Regulation (GDPR) 
and institutional rules 
[Belgian law dated on 30 July 2018 and 22 Aug. 2002]. 
 
The collection and processing of personal data from subjects enrolled in this study will be limited to 
those data that are necessary to fulfill the objectives of the study. These data must be collected and 
processed with adequate precautions to ensure confidentiality and compliance with applicable data 
privacy protection laws and regulations. 
  
Appropriate technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be put 
in place. Sponsor and site personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential. 
The informed consent obtained from the subject includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original medical 
records (source data/documents) for study-related monitoring, audit, Ethics Committee review and 
regulatory inspection. This consent also addresses the transfer of the data to other entities, if 
applicable. 
 
Privacy and confidentiality of data generated in the future on stored samples will be protected by the 
same standards applicable to all other clinical data. 
Stored samples will be pseudonymized throughout the sample storage and analysis process and will 
not be labeled with personal identifiers. 
 
 
15.5. Liability and Insurance 
The sponsor has taken a no fault insurance for this study, in accordance with the relevant legislation 
(article 29, Belgian Law of May 7, 2004). 
Sponsor: Ghent University Hospital 
Insurance Details: Allianz Global Corporate & Specialty; Uitbreidingstraat 86, 2600 Berchem; Tel: +32 
33 04 16 00 
Polis number: BEL000862 
 
 
15.6. End of Study Notification 
If all subjects have completed the study, a notification of the end of the study should be submitted to 
the (Central) Ethics Committee and FAMHP. This notification should be made within 90 days of the end 
of the clinical study. In case of early termination (definition in CT-1, 4.2), this is reduced to 15 days. 


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16. 
Publication policy 
 
This study will be registered at EudraCT and ClinicalStudies.gov, and results information from this study 
will be submitted to ClinicalStudies.gov. In addition, every attempt will be made to publish results in 
peer-reviewed journals. 
17. 
Reference List 
 
1. 
Thompson BT, Chambers RC, Liu KD. Acute Respiratory Distress Syndrome. N Engl 
J Med 2017;377:1904-5. 
2. 
Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress 
Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. 
JAMA Intern Med 2020. 
3. 
Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 
2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 2020. 
4. 
Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to 
COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care 
Med 2020. 
5. 
Huppert LA, Matthay MA, Ware LB. Pathogenesis of Acute Respiratory Distress 
Syndrome. Semin Respir Crit Care Med 2019;40:31-9. 
6. 
Weinberg PF, Matthay MA, Webster RO, Roskos KV, Goldstein IM, Murray JF. 
Biologically active products of complement and acute lung injury in patients with the sepsis 
syndrome. Am Rev Respir Dis 1984;130:791-6. 
7. 
Gralinski LE, Sheahan TP, Morrison TE, et al. Complement Activation Contributes to 
Severe Acute Respiratory Syndrome Coronavirus Pathogenesis. mBio 2018;9. 
8. 
Mulvey JJ, Magro CM, Ma LX, Nuovo GJ, Baergen RN. Analysis of complement 
deposition and viral RNA in placentas of COVID-19 patients. Ann Diagn Pathol 
2020;46:151529. 
9. 
Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and 
thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases. Transl 
Res 2020. 
10. 
Gao T. Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-
mediated 
complement 
over-activation. 
MedRxiv 
2020;https://doi.org/10.1101/2020.03.29.20041962. 
11. 
Jiang Y, Zhao G, Song N, et al. Blockade of the C5a-C5aR axis alleviates lung damage 
in hDPP4-transgenic mice infected with MERS-CoV. Emerg Microbes Infect 2018;7:77. 
12. 
Jiang Y, Li J, Teng Y, et al. Complement Receptor C5aR1 Inhibition Reduces 
Pyroptosis in hDPP4-Transgenic Mice Infected with MERS-CoV. Viruses 2019;11. 
13. 
Mastaglio S, Ruggeri A, Risitano AM, et al. The first case of COVID-19 treated with 
the complement C3 inhibitor AMY-101. Clin Immunol 2020:108450. 
14. 
Diurno F, Numis FG, Porta G, et al. Eculizumab treatment in patients with COVID-19: 
preliminary results from real life ASL Napoli 2 Nord experience. Eur Rev Med Pharmacol Sci 
2020;24:4040-7. 
 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
Study: ZILU-COV 
Product: Zilucoplan® 
A prospective, randomized, open-label, interventional study to 
investigate the efficacy of complement C5 inhibition with Zilucoplan® 
in improving oxygenation and short- and long-term outcome of COVID-
19 participants with acute hypoxic respiratory failure. 
 
SAP/Amendment Number Date 
Final SAP 
Approved 18DEC2020 
Confidentiality Statement 
Confidential 
This document is the property of UCB and may not – in full or in part – be passed on, 
reproduced, published, or otherwise used without the express permission of UCB. 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................. 7 
2 
PROTOCOL SUMMARY ................................................................................................. 7 
2.1 
Study Objectives ............................................................................................................ 8 
2.1.1 
Primary objective(s) ............................................................................................... 8 
2.1.2 
Secondary objective(s) ........................................................................................... 8 
2.2 
Study endpoint(s) ........................................................................................................... 9 
2.2.1 
 Efficacy endpoint(s) ............................................................................................ 13 
2.2.1.1 
Primary efficacy endpoint(s) ..................................................................... 13 
2.2.1.2 
Secondary efficacy endpoint(s) ................................................................. 13 
2.2.2 
Pharmacodynamic endpoint(s) ............................................................................ 19 
2.2.3 
Pharmacokinetic endpoint(s) ............................................................................... 20 
2.2.4 
Safety endpoint(s) ................................................................................................ 20 
2.2.4.1 
Key safety endpoint(s) ............................................................................... 20 
2.2.4.2 
Safety endpoint(s) of special interest ........................................................ 20 
2.2.4.3 
Other safety endpoint(s) ............................................................................ 20 
2.3 
Study design and conduct ............................................................................................ 22 
2.4 
Determination of sample size ....................................................................................... 23 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 24 
3.1 
General presentation of summaries and analyses ........................................................ 24 
3.2 
General study level definitions .................................................................................... 25 
3.2.1 
Analysis time points ............................................................................................ 25 
3.2.1.1 
Relative day ............................................................................................... 25 
3.2.1.2 
Study periods ............................................................................................. 26 
3.2.1.3 
Nominal Days ............................................................................................ 26 
3.2.2 
Definition of Baseline values ............................................................................... 27 
3.2.2.1 
General baseline ........................................................................................ 27 
3.2.2.2 
Alternate baseline ...................................................................................... 28 
3.3 
Protocol deviations....................................................................................................... 28 
3.4 
Treatment assignment and treatment groups ............................................................... 28 
3.5 
Analysis sets................................................................................................................. 28 
3.5.1 
Enrolled Set ......................................................................................................... 29 
3.5.2 
Randomized Set ................................................................................................... 29 
3.5.3 
Safety Set ............................................................................................................. 29 
3.5.4 
Full Analysis Set .................................................................................................. 29 
3.5.5 
Completer Analysis Set ....................................................................................... 29 
3.5.6 
Per Protocol Set ................................................................................................... 29 


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3.5.7 
Pharmacokinetic Analysis Set ............................................................................. 29 
3.6 
Centres ......................................................................................................................... 29 
3.6.1 
Centre pooling strategy ........................................................................................ 29 
3.6.2 
Change of Centres ................................................................................................ 30 
3.7 
Coding dictionaries ...................................................................................................... 30 
3.8 
Changes to protocol-defined analyses ......................................................................... 30 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 31 
4.1 
Adjustments for covariates .......................................................................................... 31 
4.2 
Handling of dropouts or missing data .......................................................................... 31 
4.2.1 
Safety laboratory data .......................................................................................... 32 
4.2.2 
Dates and times .................................................................................................... 32 
4.3 
Handling of repeated and unscheduled measurements ..................................... 32 
4.4 
Interim analyses and data monitoring .......................................................................... 32 
4.4.1 
Interim 1 ............................................................................................................... 32 
4.4.2 
Interim 2 ............................................................................................................... 33 
4.4.3 
Safety Data Interim Look .................................................................................... 33 
4.5 
Multiple comparisons/multiplicity ............................................................................... 33 
4.6 
Use of an efficacy subset of participants ..................................................................... 33 
4.7 
Examination of subgroups ........................................................................................... 34 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 34 
5.1 
Participant disposition .................................................................................................. 34 
5.2 
Protocol deviations....................................................................................................... 36 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 37 
6.1 
Demographics .............................................................................................................. 37 
6.2 
Other Baseline characteristics ...................................................................................... 37 
6.3 
Medical history and concomitant diseases ................................................................... 40 
6.4 
Prior and concomitant medications .............................................................................. 40 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 41 
8 
EFFICACY ANALYSES ................................................................................................ 41 
8.1 
Statistical analysis of the primary efficacy endpoint(s) ............................................... 42 
8.1.1 
Derivations of primary efficacy endpoint(s) ........................................................ 42 
8.1.2 
Primary analysis of the primary efficacy endpoint(s) .......................................... 43 
8.1.3 
Sensitivity analyses of the primary efficacy endpoint(s) ..................................... 44 
8.1.3 Supplementary analyses of the primary efficacy endpoint(s) .... Error! Bookmark not 
defined. 
8.2 
Statistical analysis of the secondary efficacy endpoint(s) ........................................... 45 
9 
PHARMACOKINETICS AND PHARMACODYNAMICS .......................................... 59 
9.1 
Pharmacokinetics ......................................................................................................... 59 


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9.2 
Pharmacodynamics ...................................................................................................... 59 
10 SAFETY ANALYSES ..................................................................................................... 59 
10.1 
Extent of exposure ....................................................................................................... 59 
10.2 
Adverse events ............................................................................................................. 59 
10.3 
Clinical laboratory evaluations .................................................................................... 61 
10.4 
Vital signs, physical findings, and other observations related to safety ...................... 61 
10.4.1 
Vital signs ............................................................................................................ 61 
10.4.2 
Electrocardiograms (if applicable) ...................................................................... 61 
11 REFERENCES ................................................................................................................ 62 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 63 
 


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LIST OF ABBREVIATIONS 
AE  
 Adverse Event  
AECC  
 American-European Consensus Conference  
ARDS  
 Acute Respiratory Distress Syndrome  
CI  
 Coordinating Investigator  
COVID-19  
 Coronavirus induced disease-2019  
CT  
 Clinical Trial Unit  
DSMB  
 Data Safety Monitoring Board  
DSUR  
 Development Safety Update Report  
EC  
 Ethics Committee  
ECG  
 Electrocardiogram  
eCRF  
 electronic Case Report Form  
EDC  
 Electronic Data Capture  
EPD  
 Electronic Participant Dossier  
FAMHP  
 Federal Agency for Medicines and Health 
Products  
FiO2  
 Fraction of inspired oxygen  
FPI  
 First Participant In  
FVC  
 Forced vital capacity  
GCP  
 Good Clinical Practice  
GDPR  
 General Data Protection Regulation  
gMG  
 generalized myasthenia gravis  
GMP  
 Good Manufacturing Practice  
HIRUZ  
 Health, Innovation and Research Institute UZ 
Ghent  
IB  
 Investigator’s Brochure  
ICF  
 Informed Consent Form  
ICH  
 International Council for Harmonisation  
IMNM  
 Immune Mediated Necrotic Myopathy  
IMP  
 Investigational Medicinal Product  
IMPD  
 Investigational Medicinal Product Dossier  
LVLS  
 Last Visit, Last Subject  
PCWP  
 Pulmonary Capillary Wedge Pressure  
PEEP  
 Positive End Expiratory Pressure  
PI  
 Principal Investigator  
PaO₂  
 Partial pressure of oxygen  
PNH  
 Paroxysmal Nocturnal Hemoglobinuria  
SC  
 Subcutaneous  
SAE  
 Serious Adverse Event  
SC  
 Subcutaneous  
sHLH  
 secondary hemophagocytic 
lymphohistiocytosis  
SmPC  
 Summary of Product Characteristics  
SOP  
 Standard Operating Procedure  


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SUSAR  
 Suspected Unexpected Serious Adverse 
Reaction  
TERENA  
 Trans-European Research and Education 
Networking Association  
TLC  
 Total Lung Capacity  
TLS  
 Transport Layer Security 


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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide all information that is necessary 
to perform the required statistical analysis of this study to support the final clinical study report 
(CSR). It also defines the summary tables, figures and listings (TFLs) to be generated (specific 
shells will be provided in a separate document) to be included in the report. 
The SAP is based on the following study documents: Protocol version 3.0 dated 29May2020.  
If a future protocol amendment necessitates a substantial change to the analysis of the study data, 
this SAP will be amended accordingly. In addition, if the methodology for the analysis of key 
study endpoints must be modified or updated prior to database lock, an SAP amendment will be 
required. If, after database lock, additional analyses are required to supplement the planned 
analyses described in this SAP, these changes will be described in the clinical study report 
together with the associated rationale. 
The content of this SAP is compatible with the International Conference on Harmonization 
(ICH)/ Food and Drug Administration (FDA) E9 Guidance documents. 
 
2 
PROTOCOL SUMMARY 
Details of the study design are described in the protocol and Section 5 of this SAP, but a brief 
outline is as follows.  
 
The purpose of this phase 2a (proof of concept), multi-center,open-label 2:1 randomised 
(Experimental Arm: Control Arm) study is to investigate the efficacy and safety of Zilucoplan® 
in improving oxygenation and short- and long-term outcome of COVID-19 participants with 
early acute hypoxic respiratory failure (Acute hypoxemic respiratory failure is severe arterial 
hypoxemia that is refractory to supplemental oxygen) The participant population are participants 
with confirmed (see inclusion criteria) COVID-19 infection and with presence of hypoxic 
respiratory failure defined as O2 saturation below 93% on minimal 2l/min O2 therapy and/or 
PaO2/Fi O2 ratio below 350 mmHg.  A sufficient number of participants will be enrolled in order 
to randomise 81 participants onto one of the 2 treatment arms in a 2:1 ratio. A 2:1 randomisation 
ratio was chosen to give the opportunity for more participants to potentially benefit from 
treatment with Zilucoplan and also it may be possible to include participant level data from 
another trial to augment the control arm. 
 
Participants in the experimental arm (Arm A) will receive standard of care (SoC) + subcutaneous 
Zilucoplan® once daily and prophylactic antibiotics once daily (until 14 days after the last 
Zilucoplan® dose). Participants in the Control Arm (Arm B) will receive SOC+1 week of 
prophylactic antibiotics once daily (or until hospital discharge, whichever comes first). 
 
The study consists of a screening day, 28-day primary assessment period, D28 (by phone call, 
unless still in hospital) and a final follow-up visit sometime between 12 to 22 weeks post-
randomisation. For Arm A, the 28-day primary assessment period includes an in-participant 
treatment duration of up to 14 days (less if discharged from hospital before D15) of Standard of 
Care (SoC) + subcutaneous Zilucoplan® once daily + IV prophylactic antibiotics once daily, 
followed by 14 days of SoC +IV prophylactic antibiotics. It is required that the participant 


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should continue prophylactic antibiotics once daily for 14 days after the last dose of 
Zilucoplan®. If the participant is discharged before D28, daily prophylactic antibiotic treatment 
will be taken orally until 14 days after last dose of Zilucoplan®. For Arm B, the 28-day 
assessment period comprises SOC treatment up to 28 days post randomization or hospital 
discharge, when the D28 nominal day procedures. Arm B will only have 1 week of IV 
prophylactic antibiotics once daily, starting on D1. If hospital discharge occurs before D28 post-
randomisation, both SOC and antibiotic treatment will cease and the D28 nominal day 
procedures will occur by telephone. 
 
For both arms, whilst in hospital, assessments will continue on a daily basis as possible, until 
discharge or Day 28 is reached. If discharge is prior to D28, no daily assessments will be carried 
out – just the D28 telephone call.   
 
The maximum time window for an eligible participant signing the informed consent document 
(and starting screening) and being randomised is 24 hours. It is assumed that first dose occurs 
very soon after randomisation. 
 
An interim analysis (Interim 1) of the primary endpoints is planned after approximately half the 
planned number of participants have been dosed and had the opportunity to complete D15 
assessments. The purpose of the interim analysis is to understand if there is already enough 
evidence to prompt further work on COVID-19 treatment with Zilucoplan®. There is currently 
no plan to stop the study based on interim results at this stage. Other endpoints may be 
summarised as the data allows. Safety data will also be reviewed and summarised as appropriate. 
 
There will also be an interim analysis (Interim 2) when all participants have had the opportunity 
to complete D28 procedures (by phone call) to assess the primary endpoints, response rate, time 
to response, time to discharge and 28-day mortality, as appropriate. These analyses will enable 
key results to be understood as soon as possible, without compromising the study. In addition, 
safety will be summarised by incidence of TEAE and SAE by treatment arm. Graphs showing 
the time course for oxygen levels and 6-point ordinal score and Kaplan-Meier plots for time-to -
event variables will be provided. 
 
Final analyses will be carried out after all participants have either discontinued prematurely from 
or completed the study, by completing the follow-up visit. 
2.1 
Study Objectives 
2.1.1 
Primary objective(s) 
The primary objective of this intervention is to study if Zilucoplan® plus standard of care 
improves the median and/or mean change in oxygenation between enrolment (baseline) and at 
predose day 6 and day 15 (or discharge, whichever comes first)  compared to standard of care 
through assessment of the PaO2/FiO2 ratio and through measurement of the P(A-a)O2 gradient, 
which can easily be performed in the setting of clinical observation of participants admitted to 
the COVID-19 ward or ICU COVID-19 unit. 
2.1.2 
Secondary objective(s) 
The secondary objectives are: 


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• to study if early intervention with Zilucoplan® is safe  
• to study if early intervention with Zilucoplan® affects clinical outcome defined by 
duration of hospital stay, 6-point ordinal scale, time to defervescence, supplemental 
oxygen use SOFA score,  
• to study if early intervention with Zilucoplan® affects progression to mechanical 
ventilation and/or ARDS and duration of ICU stay 
• to study if early intervention with Zilucoplan® affects the rate of nosocomial infection  
• to study if treatment with Zilucoplan® has a favourable effect on long term at follow up 
12-22 weeks post-randomisation  
• to study if treatment with Zilucoplan® affects all-cause mortality rate at day 28 and at 12-
22 weeks post-randomisation 
2.2 
Study endpoint(s) 
Endpoints listed in these subsections are definitions of the measures that are collected from each 
participant. How each of these are handled to assess the effectiveness of the intervention is 
described in the analysis sections.  
Table 1.1 provides details of the schedule of events and when it is mandatory to take 
measurements of each endpoint. However, where possible, clinical and laboratory endpoints will 
be taken as frequently as possible; ideally daily up until hospital discharge. 
 


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Table 1.1  
Procedure  
Screening (D0 or D1)  
D1a 
D2  
D6  
Hospital discharge or D15b  
D28c  
Follow-upd  
Informed consent  
X 
 
 
 
 
 
Inclusion/exclusion criteria  
X 
 
 
 
 
 
Randomisation  
 
X 
 
 
 
 
 
Medical history & biometry  
X 
 
 
 
 
 
6-minute walk test  
 
 
 
 
 
 
X 
Lung function  
 
 
 
 
 
 
X 
Physical examinationh,  
X 
-------------------------------Per SOC------------------------------ 
 
 
Vital signse,h  
X 
----------------------------Daily until discharge------------------------- 
 
X 
Daily (S)AE inquiry  
 
-------------------------------------------------------------------------------------------------------- 
Concomitant medication  
X 
----------------------------Daily until discharge---------------------- 
Xc 
X 
ECGh  
X 
On clinical grounds 
 
 
Any chest CT scan  
Xp 
On clinical grounds 
 
 
HRCTq 
 
 
 
 
 
 
X 
Routine laboratory assessments on clinical 
grounds, except:  
- D0/1, D6, discharge/D15 and FU  
- Procalcitonin 3x/week until D15  
Xf,h 
 
Xg,h 
Xg 
 
Xg 
Study blood samplingh  
 
 
 
 
 
 
 
- 2 x 6 ml serum tubes  
 
X 
 
X 
X 
 
X 
- 1 x 4 ml EDTA tube (DNA) 
 
X 
 
 
 
 
 
- 2 x 10 ml EDTA tube (optional,selected 
sites)  
 
X 
 
X 
X 
 
X 
 - 1 x6 ml EDTA tube (complement) 
 
X 
X 
X 
X 
 
 
- 1 x 6 ml EDTA tube for PK (arm A only)  
 
X 
X 
X 
X 
 
 
- Arterial blood gas  
Xh 
 
Xi.h 
Xi 
 
X 
Score assessments 
 
 
 
 
 
 
- 6-point ordinal scale j,h  
----------------------------------------------Daily until discharge---------------------------------- 
X 
- SOFA score k,h  
 
X  
 
X  
 
X  
 
- HScore l,h 
 
X  
 
 
 
 
 
- WHO performance scale r 
 
 
 
 
 
 
X 
IMP Zilucoplan® (arm A only)  
 
------------------Daily SC until D14 or discharge-----------------  
 
 
Third generation cephalosporin (arm A 
only)m 
 
------------------Daily IV until discharge---------------------------------------  
 


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Procedure  
Screening (D0 or D1)  
D1a 
D2  
D6  
Hospital discharge or D15b  
D28c  
Follow-upd  
Third generation cephalosporin (arm B 
only)n 
 
--------Daily IV until D7------- 
 
 
 
Oral ciprofloxacin (arm A only)o 
 
 
-------------o 
 
 
Daily drug compliance enquiry 
 
---------------------------------------------------------------------------- 
Xc 
 
a  Prior to first Zilucoplan® administration in arm A, and during the day in arm B 
b Hospital discharge or D15, whichever comes first 
c Enquiry by phone on D28 post-randomisation (or within next 3 days) for 6-point ordinal scale, (s)AE, supplemental oxygen (Y/N) and concomitant medication since 
discharge or D15 
d Follow-up visit at 12-22 weeks post-randomisation 
e Values between 7-10am includes T°C (actual and highest last 24h), Pulse Rate, Blood Pressure, Respiratory Rate, SpO2 by pulsoximetry, FiO2 and ventilator 
parameters (if participant admitted to ICU) 
f Minimally includes Ferritin, LDH, haptoglobin, D-dimers, CRP, creatinine, fibrinogen, eosinophils, lymphocytes, haemoglobin, WBC count, platelets, bilirubin, ALT and 
AST, procalcitonin and bHCG (females) (for exclusion criteria, HScore and SOFA) 
g Should minimally include Ferritin, LDH, haptoglobin, D-dimers, CRP, creatinine, fibrinogen, eosinophils, lymphocytes, haemoglobin, WBC count, platelets, bilirubin, 
ALT and AST (for SOFA) 
h If arm A: Pre-dose Zilucoplan®  
i Mandatory: participant in upright position, after minimal 3 minutes without supplemental oxygen. In case of inability to sit upright: same position is to be used for all 
measurements of PaO2. In ventilated participants or ECMO participants PaO2 can be taken from invasive arterial line and FiO2 taken directly from mechanical 
ventilation settings, document FiO2 at moment of ABG. For patients on ECMO the PaO2/FiO2 ratio and Aa-gradient cannot be calculated as in this case the FiO2 will be 
missing. Therefore, the last available value of PaO2/FiO2 ratio and Aa gradient prior to ECMO can be used at that timepoint. 
j Defined as 1 = Death; 2 = Hospitalized, on invasive mechanical ventilation or ECMO; 3 = Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4 = 
Hospitalized, requiring supplemental oxygen; 5 = Hospitalized, not requiring supplemental oxygen; 6 = Not hospitalized  
k SOFA score (see https://www.mdcalc.com/sequential-organ-failure-assessment-sofa-score): requires PaO2, FiO2, platelet count, GCS, bilirubin, MAP and creatinine. 
To be evaluated between 6 and 10 am. Score to be calculated based on the worst values in the previous 24h at time of evaluation.  
l HScore (see https://www.mdcalc.com/hscore-reactive-hemophagocytic-syndrome): requires T°C, haemoglobin, wbc count, platelets, ferritin, fibrinogen, triglycerides 
and AST (BM aspirate is not required) To be evaluated at time of randomization. 
m Third generation cephalosporin replaces empiric amoxicillin/clavulanic acid to treat concomitant community acquired pneumonia. In any case that antibiotics need to 
be switched, N. menigitidis and S. pneumoniae need to be covered by the new antibiotic treatment (e.g. meropenem or piperacilin/tazobactam). Third generation 
cephalosporin is given until D28 or hospital discharge whichever comes first.  
n Group B participants receive daily injection of 2g ceftriaxone IV (or appropriate alternative in case of allergies or on clinical indication) during one week or until 
hospital discharge, whichever comes first.  
o Upon discharge before D28 post-randomization, participants will switch to daily oral ciprofloxacin (500 mg 1x/d) until at least 14 days after the last dose of Zilucoplan® 
(only in arm A).  
p any form of chest CT scan within 48h before randomization (low dose, HRCT, or Angio CT scan) must document a presence of bilateral ground glass infiltrates or 
bilateral consolidation  
q HRCT scoring: A subjective assessment of the overall extent of normal attenuation, reticular abnormalities, honeycombing and traction bronchiectasis will be 
performed. A reticular abnormality is defined as a collection of innumerable areas of small linear opacity. Honeycombing is defined as the presence of a cystic airspace 
measuring 3–10 mm in diameter, with 1- to 3-mm thick walls. Traction bronchiectasis is defined as irregular bronchial dilatation within the surrounding areas showing 


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parenchymal abnormalities. The morphological criteria on HRCT scans include bronchial dilatation with respect to the accompanying pulmonary artery, a lack of 
tapering of the bronchi and the identification of bronchi within 10 mm of the pleural surface. The HRCT findings will be graded on a scale of 1–4 based on the 
classification system: 1. normal attenuation; 2. reticular abnormality; 3. traction bronchiectasis; and 4. honeycombing. The presence of each of the above four HRCT 
findings will be assessed independently in three (upper, middle and lower) zones of each lung. The upper lung zone is defined as the area of the lung above the level of 
the tracheal carina, the lower lung zone is defined as the area of the lung below the level of the inferior pulmonary vein and the middle lung zone is defined as the area 
of the lung between the upper and lower zones. The extent of each HRCT finding will be determined by visually estimating the percentage (to the nearest 5%) of 
parenchymal involvement in each zone. The score for each zone will be calculated by multiplying the percentage of the area by the grading scale score. The six zone 
scores will be averaged to determine the total score for each participant. The highest score is 400 points and the lowest score is 100 points using this calculation 
method. The total score is the “HRCT fibrosis score”. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922654/pdf/1465-9921-15-10.pdf)  
r WHO performance scale: 0. Able to carry out all normal activity without restrictions; 1. Restricted in physically strenuous activity but ambulatory and able to carry out 
light work; 2. Ambulatory and capable of all self-care but unable to carry out any work: up and more than 50% of waking hours; 3. Capable of only limited self-care: 
confined to bed or chair more than 50% if waking hours; 4. Completely disabled: cannot carry on any self-care: totally confined to bed or chair.


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2.2.1  
Efficacy endpoint(s) 
2.2.1.1 
Primary efficacy endpoint(s) 
• Change from baseline in PaO2/FiO2 ratio to Day 6 and Day 15 (or at discharge, 
whichever comes first)  
• Change from baseline in P(A-a)O2 gradient to Day 6 and Day 15 (or at discharge, 
whichever comes first). 
• Change from baseline in a/A pO2 ratio to Day 6 and Day 15 (or at discharge, whichever 
comes first 
These endpoints are derived from variables obtained from arterial blood gas sampling. 
2.2.1.2 
Secondary efficacy endpoint(s) 
All time to event endpoints are measured from date of randomization. It is expected that there 
will be approximately 24 hours between randomization and dosing.  
All endpoints associated with each secondary objective are listed together. The key endpoints are 
written in bold to be analysed/summarized at the second interim analysis when all participants 
have had the opportunity to complete Day 28 Procedures. Collected endpoints and their timing 
that may be used to derive the endpoints are listed in the third column. Alternative sources of the 
same information may be available and used. 
There is overlap on some of the measurements across endpoints. Some may be taken once for 
each endpoint or taken once and used for more than one endpoint.  
Details of the items in the 6-point ordinal score are provided below this table. Brief details of 
SOFA, are provided and further information can be obtained from the hyperlink. 


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Secondary 
Objective 
Endpoint 
Measurement 
1)  To study if early 
intervention with 
Zilucoplan® affects 
clinical outcome 
defined by duration 
of hospital stay, 6-
point ordinal scale, 
time to 
defervescence, 
supplemental 
oxygen use, SOFA 
score  
Incidents of participants reporting each 
severity rating in 6-point ordinal scale at 
D1, D6, D15 and D28 
Change from baseline in 6-point ordinal 
scale to Day 6, Day 15 and Day 28 (by 
phone call) weeks post randomisation  
Time to at least a 2-point improvement 
or discharge sustained up to D28 on the 
6-point ordinal scale during 28-day 
assessment period 
Percentage of participants reporting at 
least a 2-point improvement sustained 
to D28 or discharge 
AUEC/Time using the 6-point score 
recorded daily – up to D15, D28 and all 
data recorded 
Percentage of participants who record a 
2-point improvement from baseline or 
discharge at D6, D15 and D28 
Percentage of participants not 
deteriorating according to the ordinal 
scale by 1 or 2 points on D6, D15 and 
D28  
6-point ordinal Scale at D6 and D15 and 
D28 in relation to D-Dimers and 
complement C5a levels at baseline 
6-point ordinal scale 
measured daily up to 
discharge, D28 and 
follow-up 
Lab values at baseline for 
D-Dimers and C5a 
Change from baseline in SOFA score 
(https://www.mdcalc.com/sequential-
organ-failure-assessment-sofa-score) to 
Day 6, Day 15 (or at discharge, whichever 
comes first) 
SOFA score measured at 
D1, D6 and D15 
 


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Secondary 
Objective 
Endpoint 
Measurement 
1)continued:  
To study if early 
intervention with 
Zilucoplan® affects 
clinical outcome 
defined by duration 
of hospital stay, 6-
point ordinal scale, 
time to 
defervescence, 
supplemental 
oxygen use, SOFA 
score 
Number of days with fever (defined as 
37.1ºC or more) during 28-day assessment 
period 
Time since randomization until absence of 
LAST fever (defined as 37. 1ºC or more) 
for more than 48 h without antipyretics 
(use last fever to account for possibility 
that participants have intermittent fever 
per this definition) 
 
Temperature Vital 
Parameters  
Antipyretic use in last 24 
hours is collected on eCRF 
on every day. Use highest 
temperature recorded in 
last 24 hours, not the 7-
10am temperature 
 
Duration of hospital stay 
From DATES eCRF 
Duration of hospital stay of survivors 
From DATES  
Number of days requiring supplemental 
oxygenation after randomisation to Day 
28 (or discharge, whichever comes 
earlier) 
Time since randomization until 
improvement in oxygenation (defined as 
independence from supplemental oxygen) 
during 28-day assessment period (or 
discharge, whichever comes earlier) 
Number of days where 
Suppl O2 = ‘Y’ from Vital 
parameters 
Independence from 
supplementary oxygen 
means nor further ‘Y’ after 
a ‘N’ 
Number of days with hypoxia (defined as 
SpO2 <93% breathing room air or the 
dependence on supplemental oxygen after 
randomisation to Day 28 (or discharge, 
whichever comes earlier) 
Use SpO2 (%) and Supple 
O2 (Y/N) from Vital 
parameters 
 


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Secondary 
Objective 
Endpoint 
Measurement 
2) To study if early 
intervention with 
Zilucoplan® affects 
progression to 
mechanical 
ventilation and/or 
ARDS  
And  
Duration of ICU 
stay 
Duration of ventilator free days after 
randomisation to Day 28 (or discharge, 
whichever comes earlier) 
Duration of invasive mechanical 
(including ECMO) and non-invasive 
mechanical ventilation in ventilated 
participants 
Use data from Vital 
parameters (include all 
days, where NIV, IV and 
ECMO=’N’) 
 
Complement of above 
(exclude participants who 
are not ventilated i.e. do 
not include these with a 
duration of 0) 
  
Time since randomization until first use of 
high-flow oxygen devices or non-invasive 
mechanical ventilation or invasive 
mechanical ventilation or ECMO in non-
ventilated participants (i.e. excluding 
participants who are ventilated within 24h 
prior to or after randomization) during 28-
day assessment period 
 
Use Vital Parameter CRF,  
 
Time since randomization to progression 
to ARDS  
Randomisation date 
Date of ARDS diagnosis 
 
Duration of ICU stay in participants that 
enrolled in trial that were on invasive or 
non-invasive mechanical ventilation or 
high-flow oxygen devices within 24h 
prior to or after randomization during 28-
day assessment period 
Duration of ICU stay in participants that 
enrolled in trial that were on invasive or 
non-invasive mechanical ventilation for 
less than 24h prior to or after 
randomization during 28-day assessment 
period 
 
Use DATES  and Vital 
Signs dataset 
 


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Secondary 
Objective 
Endpoint 
Measurement 
3) To study if 
treatment with 
Zilucoplan® affects 
all-cause mortality 
rate at day 28 and 
at 12-22 weeks 
post-randomisation 
All-cause mortality rate at 28 days post 
randomisation (all treated participants) 
 
All-cause mortality rate at 28 days post 
randomisation (excluding participants that 
required invasive mechanical ventilation 
or ECMO, non-invasive mechanical 
ventilation or high-flow oxygen devices 
within 24 hours prior to or after 
randomisation) 
 
All-cause mortality rate at 28 days post 
randomisation (excluding participants that 
required invasive mechanical ventilation 
or ECMO within 24 hours prior to or after 
randomisation) 
 
All-cause mortality rate at 28 days post 
randomisation (excluding participants that 
required invasive mechanical ventilation 
or ECMO, non-invasive mechanical 
ventilation or high-flow oxygen devices 
within 24 hours prior to or after 
randomisation) 
 
 
All-cause mortality rate at 28 days post 
randomisation (only including participants 
that required invasive mechanical 
ventilation or ECMO within 24 hours 
prior to or after randomisation) 
 
All-cause mortality at follow up 12-22 
weeks post-randomisation for all treated 
participants  
6-point ordinal scores, 
DATES and VITAL 
SIGNS datasets 
 


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Secondary 
Objective 
Endpoint 
Measurement 
4) To study if 
treatment with 
Zilucoplan® has a 
favourable effect on 
long term at follow 
up 12-22 weeks 
post-randomisation 
Incidents of participants in each category 
of the 6 point ordinal scale at follow-up 
12-22 weeks post randomisation 
 
6-point ordinal score 
Incidents of lung fibrosis on chest high-
resolution computed tomography (HRCT) 
scan at follow up 12-22 weeks post-
randomisation  
 
Incidents of lung function abnormalities at 
follow up 12-22 weeks post-
randomisation  
 
HRCT results 
 
Lung function results – 
dataset should list all  
abnormalities in a 
consistent way across 
participants, including 
‘None’ 
Results from the 6 minute walk test 
 
 
Incidents of participants in each category 
of the WHO performance scale 
WHO score 
5) To study if early 
intervention with 
Zilucoplan® affects 
the rate of 
nosocomial 
infection 
Incidents of nosocomial bacterial or 
invasive fungal infection during 28-day 
assessment period 
 
Note: Participants with viral respiratory 
infection are at risk of secondary bacterial 
infections. As part of clinical routine care, 
sputum or BAL samples will be collected 
in participants suspected of secondary 
bacterial pneumonia and checked for 
presence of bacteria. Measurements of 
procalcitonin levels will be performed at 
least 3x/week until 14 days or hospital 
discharge 
 
Data for bacteria will be 
presence/absence at each 
day tested.  
 
Procalcitonin will be 
concentrations 
6) Change from 
baseline in specific 
labs 
Mean change in ferritin levels between D1 
and D6 and between D1 and D15 (or 
discharge in each case) 
 
Mean change in CRP levels between D1 
and D6 and between D1 and D15 (or 
discharge in each case) 
Laboratory values 
Note: Please refer to Section 3.2.1.3 for details about assigning the correct nominal day in the 
event that participants are discharged from hospital due to clinical improvement prior to D28.  
 


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The 6-point ordinal score is collected daily and the 6 points are defined by:  
▪ 1. Death 
▪ 2. Hospitalized, on invasive mechanical ventilation or ECMO 
▪ 3. Hospitalized, on non-invasive mechanical ventilation or high flow 
oxygen devices 
▪ 4. Hospitalized, requiring supplemental oxygen 
▪ 5. Hospitalized, not requiring supplemental oxygen 
▪ 6. Not hospitalized 
For Grade 3, ‘high-flow oxygen’ consists of a heated, humidified high-flow nasal cannula delivering 
up to 100% heated and humidified oxygen at a maximum flow of 60 L/minute via nasal prongs or 
cannula to a participant at rates of flow higher than traditional low-flow therapy. In high-flow 
oxygen, the fraction of inspired oxygen (FiO2) can be titrated from 21% to 100% independent of the 
flow rate. 
SOFA score – This is a measure of mortality risk of participants admitted into an ICU. The 
higher the total score, the greater the risk of death. The score can be mapped to a probability of 
death, but the analysis will use the raw total score data. (https://www.mdcalc.com/sequential-
organ-failure-assessment-sofa-score) 
Additional endpoints may be explored using analytical models and graphs to help inform 
interpretation of the results, as required upon sight of the data. 
2.2.2 
Pharmacodynamic endpoint(s) 
Plasma and serum samples will be collected for summary and exploratory analysis as appropriate 
(e.g. descriptive statistics, compare change from baseline between the two treatment arms), may 
include but are not limited to: 
• ADA – D1 and long-term follow-up from serum samples (Summary only to indicate 
presence or not) 
• Local safety labs such as D-dimers, LDH, ferritin, CRP, fibrinogen, aPTT, PT 
• Complement system assessment (EDTA tubes) – D1, D2, D6 and D15 (or at hospital 
discharge, if earlier) 
The following may be collected but will be analysed at a later stage, and not as part of the main 
analyses for the study 
• Cytokines and biomarkers (from selected centres) on D1, D6 and D15 (or at hospital 
discharge, if earlier) 
o Cytokines may include, but not limited to: 
▪ IL-1beta, IL-1RA, IL-2, IL-8, IL-6, TNFa, GM-CSF, G-CSF, IP-10, MCP-
1, MIP-1a, IFNg, and IL-10 
o Biomarkers may include but not limited to 
▪ sRAGE, Angiopoietin-2) 


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• DNA for pharmacogenomic research (Paxgene tube, D1 only) 
2.2.3 
Pharmacokinetic endpoint(s) 
Blood samples will be taken from participants in Arm A only on D1, D2, D6 and day 
15/discharge– all pre-dose. 
2.2.4 
Safety endpoint(s) 
2.2.4.1 
Key safety endpoint(s) 
The key safety endpoints of this study are the incidence/number of adverse events (AE), serious 
adverse events (SAE) and the severity of AEs from first dose of study treatment on D1 until D28. 
Each AE will be categorized as a Treatment Emergent Adverse Event (TEAE) or not. All cases 
will be assessed by the reporting medically qualified professional or Sponsor as to having a 
reasonable suspected causal relationship to study treatment or not and categorized on the eCRF 
as 
1. Not related 
2. Unlikely 
3. Possible 
4. Probable 
5. Definitely 
All AE/SAEs that fall into the last 3 categories are deemed as related to study treatment and will 
be classified as an Adverse Reaction (AR) or Serious Adverse Reaction (SAR) respectively. 
Each SAEs will also assessed as to whether it was an unexpected SAR (Suspected Unexpected 
Serious Adverse Event, SUSAR)  
2.2.4.2 
Safety endpoint(s) of special interest 
Endpoints associated with nosocomial infection: 
• Number of participants with at least one occurrence of nosocomial bacterial or invasive 
fungal infection for 28 days (phone call) after enrolment in trial  
Participants with viral respiratory infection are at risk of secondary bacterial infections. As part 
of routine clinical care, sputum or BAL samples will be collected in participants suspected of 
secondary bacterial pneumonia, and checked for the presence of bacteria. Measurements of 
procalcitonin levels will be performed at least three times per week until day 14 or hospital 
discharge 
2.2.4.3 
Other safety endpoint(s) 
• ECG – at screening and on clinical grounds  
• CT scan – at screening and on clinical grounds 
• Routine laboratory assessments – on clinical grounds but also on Screening, D6, D15 (or 
at discharge whichever is earlier) and long-term follow-up  
o At a minimum the following will be collected at  Screening: 


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▪ Ferritin, LDH, haptoglobin, D-dimers, CRP, creatinine, tryglycerides, 
fibrinogrn, eosinophils, lymphocytes, haemoglobin,WBC count, platelets, 
bilirubin, ALT and AST  
▪ bHCG for females  
o At a minimum the following will be collected at on D6, D15 (or at discharge 
whichever is earlier) and long term follow-up: 
▪ Ferritin, LDH, haptoglobin, D-dimers, CRP, creatinine, tryglycerides, 
fibrinogrn, eosinophils, lymphocytes, haemoglobin,WBC count, platelets, 
bilirubin, ALT, AST 
o Procalcitonin – Screening and 3x week for 14 days or hospital discharge 
• Physical examination – at Screening, as required by standard of care (SOC) treatment and 
long term follow-up 
o including but not limited to  
▪ cyanosis, crepitation and rales, heart murmurs and peripheral edema 
• Vital Signs – at Screening,  daily until discharge andlong term follow-up 
o Temperature (actual 8-10 am and highest in last 24 hours) 
o Pulse rate 
o Blood pressure 
o Respiratory rate 
o SpO2 by pulse oximetry 
o Supplemental Oxygen (Y/N) and Ventilation Method (plus flow rate when 
appropriate) 
o FiO2(%) – for each method used 
▪ If participant is admitted to ICU the following invasive mechanical 
ventilation monitoring data 
• Arterial blood pressure 
• PCWP 
• Continuous O2 saturation  
• Continuous ECG  
• Ventilatory parameters (tidal volume, FiO2, PEEP pressure, peak 
pressure, minute ventilation) 
• 6 minute walk test – long term follow-up only 
• Lung Function – long term follow-up only 
o FVC, FEV1, FRC, RV, DLCO 
• HRCT Scan – at long term follow-up  


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• HScore  - taken at screening only. This is an algorithm that results in an integer value 
ranging from 0 to 337. Different scores are grouped together and each mapped onto a 
range of probabilities of hemophagocytic syndrome. In addition, an HScore >169 are 
93% sensitive and 86% specific for HLH.  
2.3 
Study design and conduct 
This investigator-initiated trial is a phase 2 academic, prospective, 2:1 randomized, open-label, 
multi-center interventional study designed to investigate the efficacy of subcutaneous 
Zilucoplan® in improving oxygenation and short- and long-term outcome of COVID-19 
participants with acute hypoxic respiratory failure. 
 Several academic and non-academic centers in Belgium will participate in this trial. Study 
coordination, monitoring and data management will be performed under the responsibility of the 
Health Innovation and Research Institute UZ Gent (HIRUZ) Clinical Trial Unit and Data 
Management Unit. 
81 participants with confirmed COVID19 with acute hypoxic respiratory failure (saturation 
below 93% on minimal 2 L/min supplemental O2 or PaO2/FiO2 <350) will be randomised to 
receive up to 14 days of SC Zilucoplan® on top of standard of care (active Arm A), or to receive 
standard of care treatment (control Arm B). Randomization will be done at a 2:1 ratio active: 
control group. In the active Arm A and in the control Arm B, participants will additionally 
receive daily antibiotics (daily 3rd generation cephalosporin IV while in hospital, followed by 
oral ciprofloxacin while discharged) as primary prophylaxis against meningococcal disease until 
14 days after the last dose of Zilucoplan®. Control Arm B will receive standard of care and 
prophylactic antibiotics (3rd generation cephalosporin IV) for only 1 week (or until hospital 
discharge whichever comes first), to control for the effects of antibiotics on the clinical course of 
COVID-19.  
A schematic of the study design is provided in Figure 1. 
To measure the effectiveness of Zilucoplan® on restoring lung homeostasis, the primary 
endpoints of this intervention is measuring change in oxygenation comparing change from 
baseline values (pre-treatment) to values pre-dose day 6 (or discharge whichever comes first) and 
to values at day 15 (or discharge whichever comes first) post-randomization between Arm A and 
Arm B.  
The study is estimated to terminate 52 weeks after the first participant is dosed, including last 
clinical follow up visits. 
 
 
 
 
 
 


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Figure 1 Description of Study Design 
 
 
 
2.4 
Determination of sample size 
The outcome(s) on which the sample size calculation is based upon, is the primary endpoint 
measurement of oxygenation, defined as ratio of PaO2/FiO2. 
  
The target difference is the difference from baseline measured at the primary endpoint (at day 6 
and day 15) between the control and the treated group. Given a sample size of 81 participants, 54 
on Zilucoplan® and standard of care and 27 on standard of care there would be >85% power to 
show a significant difference from standard of care at the 2 sided 5% level if the true underlying 
treatment difference was an 80 point difference (25% of 320, being the mean at hospital 
admission) in the PaO2/FiO2 ratio. This assumes a standard deviation of 105 and a dropout rate 
of less than 10%. 


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3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Statistical analysis and generation of tables, figures, participant data listings, and statistical 
output will be performed using SAS Version 9.1 or higher. 
Descriptive statistics will be displayed to provide an overview of the study results. For 
categorical parameters, the number and percentage of participants in each category will be 
presented. The denominator for percentages will be based on the number of participants 
appropriate for the purpose of analysis. Unless otherwise noted, all percentages will be displayed 
to 1 decimal place. No percentage will be displayed for zero counts, and no decimal will be 
presented when the percentage is 100%. For continuous parameters, descriptive statistics will 
include number of participants with available measurements (n), mean, standard deviation (SD), 
median, minimum, and maximum. 
Decimal places for descriptive statistics will always apply the following rules: 
• 
“n” will be an integer. 
• 
Mean, SD, and median will use 1 additional decimal place compared to the original data. 
• 
Coefficient of variance (CV[%]) will be presented with 1 decimal place. 
• 
Minimum and maximum will have the same number of decimal places as the original value. 
Statistical tests of the primary efficacy endpoints will be presented as 2-sided p-values rounded 
to 4 decimal places. P-values less than 0.0001 will be presented as “<0.0001” and p-values 
greater than 0.9999 will be presented as “>0.9999.”. Appropriate statistical models will be fit to 
the various data collected for the secondary objectives, as described in their respective sub-
sections in Section 8 for the purposes of estimation. No p-values will be provided for the analysis 
of endpoints associated with the secondary objectives, rather 95% confidence limits of the results 
of various comparisons of interest will be provided. 
Data listings containing documented and calculated data (eg, change from Baseline) may be 
generated if it supports the interpretation of any analysis. Unless otherwise stated, listings will be 
sorted by treatment arm, participant number within arm, parameter (if applicable), nominal day 
and relative day respective to first dose and relative day with respect to last dose for any data 
collected after discontinuation from treatment.  All listings will include all measurements which 
will appear in chronological order together with the scheduled nominal days. In all listings dates 
will be presented in the format ‘YYYY-MMM-DD’ and times will be presented as ‘hh:mm’ or 
hh:mm:ss’ as needed. 
A listing of reasons for screen fail will be provided for participants who fail screening. A listing 
of reasons for not being dosed will be provided for participants who were randomized but not 
dosed. will also be provided. 
Appropriate descriptive statistics will be provided in summary tables by treatment and Nominal 
Day for all endpoints, collected or derived. A total column will always be presented.  
Figures will be generated to visualise all the raw data (not just those that fall on the nominal 
days) to aid interpretation of the results as indicated in their respective sub-sections in Section 8. 


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Treatment labels for TFLs 
Full treatment regimen 
Summary tables label 
Listings label 
Group A: Standard of Care + 
Zilucoplan 32.4mg i.v. + 
prophylactic antibiotics 
Zilucoplan 32.4mg i.v. + 
Standard of Care 
Group A:  Zilucoplan 32.4mg 
i.v. + Standard of Care + 
prophylactic antibiotics 
Group B: Standard of Care + 
prophylactic antibiotics 
Standard of Care 
Group B:  Standard of Care + 
prophylactic antibiotics 
Notes: 
Standard of Care maybe 
abbreviated to ‘SoC’ if 
so add Footnote: 
SoC=Standard of Care 
Standard of Care maybe 
abbreviated to ‘SoC’ if so add 
Footnote: SoC=Standard of 
Care  
If the label is still too long for 
some listings the ‘Group A/B’ 
may be dropped’. 
 
 
3.2 
General study level definitions 
3.2.1 
Analysis time points 
3.2.1.1 
Relative day 
The relative day of an event or assessment will be derived using the date/time of first dose of 
study treatment as reference. This is the date/time of first dose of Zilucoplan® for participants 
randomised to Arm A and first dose of IV antibiotic for participants randomised to Arm B. 
For the purposes of reporting, there is no relative Day 0. Note that the protocol refers to 
‘Screening (D0 or D1)’. This is to indicate that it is expected that screening will only take 24 
hours and ends at first dose on D1. However, for some participants this is two days (D0 and D1) 
and for others it is only 1 day (D1) Hence the SAP/TFLs will state ’Day -1’ if the day before 
dosing and ‘Day 1’ if the day of dosing to ensure differentiation of the days. 
Relative days for an event or assessment occurring before the date/time of first dose are 
calculated as follows and preceded by ‘-‘: 
Relative Day = Event/Assessment Date/Time – Date/Time of First Dose 
If Time has not been collected for the event/assessment, checks must be made to ensure that any 
Event/Assessment made on the same day, but PRIOR to first dose, is indicated as this will form 
part of the calculation to identify baseline values.  
The relative day for an event or assessment occurring on or after the first dose to the date of the 
last dose of study treatment will be calculated as follows: 


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Relative Day = (Event/Assessment Date – Date of First Dose) + 1 
For events or assessments occurring after the date of the last dose, relative day will be prefixed 
with ‘+’ in the data listings and will be calculated as follows: 
Relative Day = Event/Assessment Date – Date of Last Dose 
Relative day will not be calculated in cases where dates are partial and should be presented as “--
”in the relevant data listing. 
3.2.1.2 
Study periods 
The following are defined as study periods: 
Screening  
Prior to the time of first dose of 
Zilucoplan® (Arm A) or IV antibiotic (Arm 
B) 
Primary Assessment Period  
For Arm A, from the date/time of first dose 
of Zilucoplan® to the end date* of the 
Primary Assessment Period 
For Arm B, from the date/time of first dose 
of IV antibiotic to the end date* of the 
Primary Assessment Period 
Planned Active Treatment Duration 
For both arms the planned active treatment 
duration is from D1 up to D14 or hospital 
discharge, whichever is earlier. 
D28 (minimal assessments carried out (6-
point ordinal scale, (S)AE supplemental 
oxygen need (Y/N), concomitant 
medication) 
28 days post randomization (by phone call, 
unless still hospitalised) 
Follow-up 
12-22 weeks post randomisation 
* The end date of the primary assessment period for each participant will be 28 days post-
randomisation  
The end of the study is defined by the date of the Follow-up visit for the last participant to 
complete their Follow-up visit. In the event that participants are lost to follow-up, the study is not 
deemed to have ended until the last participant dosed has had the opportunity to complete their 
follow-up visit as scheduled. 
3.2.1.3 
Nominal Days 
The pre-specified protocol nominal days are labelled as follows: 
• Day -1 
• D1  
• D2 


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• D6 
• D15 
• D28 
• Follow-up  
 
 
The study protocol specifies that clinical and laboratory parameters be collected as frequently as 
possible, which would be daily. A window of +/- 1 relative day for each specified nominal day 
after D2 (+ 1 day for D2) will be allowed if a measurement was not collected on the specified 
relative day. The window for D28 is +/- 3 days. If a large proportion of data fall outside this 
window, then increasing the window to +/-2 days for nominal D6, nominal D15 and D28 will be 
considered.  
 
An additional indicator variable will be derived, DISCHARGE DAY (Y/N), which will identify 
the relative day that the participants was discharged from hospital. If discharge is on or earlier 
than relative day 6, between relative day 7 and relative day 15 inclusive or between relative day 
16 and relative day 28 inclusive, an additional row mapping the results of the discharge visit to 
nominal D6, or nominal D15 and nominal D28 respectively. For the primary endpoints a LOCF 
approach will be utilized for the participants who discharge i.e. if a participant discharges at Day 
4 then that oxygenation measure will be mapped to Day 6, Day 15 and Day 28. The approach 
may be extended to secondary parameters.  Data from participants who leave hospital for reasons 
other than clinical improvement will not be mapped to the nominal days as described above. 
Participants who die whilst in hospital are not considered as ‘discharged’. Separate indicator 
variables will be derived to indicate whether a participant has died on a specific relative day and 
if treatment was discontinued due to an adverse event. 
 
The Nominal Day variable with the above labels will be derived from the relative days and 
allowable window for all collected endpoints. Since the ideal is to take measurements as 
frequently as possible, some measurements of some endpoints will not have a Nominal Day 
associated with them. When these values (without an associated Nominal Day) are to be 
summarized, graphed or analysed in statistical models, Relative Day will be used as either a 
continuous variable or categorical as defined in the respective sections. Nominal Day will only 
ever be used as a categorical variable. 
 
3.2.2 
Definition of Baseline values 
3.2.2.1 
General baseline 
In general, Baseline values for efficacy and safety endpoints will be determined from the last 
non-missing data value collected prior to the first dose of Zilucoplan®, unless otherwise noted 
for a specific type of data in Arm A. For Arm B, baseline values will be the first value taken on 
the designated Day 1 of study medication, defined as the day the participant first receives IV 
antibiotic. For endpoints which measurements are not taken on Day 1, Baseline will be the value 
taken at Screening. 
Note that for the Nominal Day variable, identified baseline values (whether they were actually 
taken at Day -1/Screening or pre-dose D1) will be mapped to D1. If this value was taken at Day -


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1 (Screening), there will be a missing value associated with the Day -1(Screening) level in order 
not to duplicate results. 
3.2.2.2 
Alternate baseline 
Due to the severity of disease in hospitals and the pandemic conditions some participants may 
not have a baseline recorded prior to their first dose. In the event there is no measurement at all 
prior to dosing for the key parameters then a measurement up to 2 hours postdose (this time 
frame may change based on PK/PD data) may be included as baseline for that participant. This 
baseline will be referred to as the ‘alternate baseline’ and will be used in sensitivity analyses. 
 
3.3 
Protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on study conduct or on the primary efficacy (effectiveness) or safety for an 
individual participant. The criteria for identifying important protocol deviations may be defined 
within the appropriate protocol-specific document. Important protocol deviations will be 
reviewed as part of the ongoing data cleaning process and data evaluation documented in a 
protocol deviation log. All important deviations will be identified and documented prior to final 
database lock to confirm exclusion from analysis sets.  
Note: whilst protocol deviations maybe listed for Interim1 it is unlikely sufficient determination 
on the effect of the deviations will have been reviewed and hence no one will be excluded from 
the PPS (section 3.5.6) for Interim1. 
3.4 
Treatment assignment and treatment groups 
Participants will be randomized onto one of the two treatment arms (Arm A:Zilucoplan®+SOC, 
Arm B: SOC only) in a 2:1 ratio. The 2:1 randomisation will be carried out using REDCap 
(electronic IWRS system) by centre. No other stratification factors are planned. 
 
3.5 
Analysis sets 
All safety analyses will be carried out on the Safety Set. All efficacy analyses will be carried out 
on the Full Analysis Set. They may be repeated on the Randomised and Per Protocol Set if these 
are generated. PK analyses will be carried out on the Pharmacokinetic Analysis Set. 
It is expected that participants will receive treatment as randomized. However, if it is determined 
that participants received treatment other than what they were randomized to, then all analysis 
sets participants will be allocated to the actual treatment they received (SS-as treated, FAS – as 
treated, RS – as treated, PPS, PKS – as treated).  
It is always appropriate to assess safety and PK based on actual treatment received. Since this is 
a PoC study, it is appropriate that treatment assignment for the FAS will be also be actual 
treatment received. 
 


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3.5.1 
Enrolled Set 
The Enrolled Set (ES) will consist of all participants who have given informed and will consist 
of all screened participants, including screen failures. 
3.5.2 
Randomized Set 
The Randomized Set (RS) will consist of all participants randomized into the study. This will 
only be created if any participant was not dosed after randomization.  
3.5.3 
Safety Set 
The Safety Set (SS) will consist of all participants who have received at least 1 dose of 
Zilucoplan®  on Arm A and all participants who have had at least one dose of IV prophylactic 
antibiotic on Arm B. 
3.5.4 
Full Analysis Set 
The Full Analysis Set will consist of all participants who have received at least 1 dose of 
Zilucoplan® on Arm A and who have had at least one dose of IV prophylactic antibody on Arm 
B. This is clearly the same as the SS but the FAS will be referred to when reporting results for 
efficacy endpoints.  
3.5.5 
Completer Analysis Set 
The completer analysis set comprises participants who have received treatments per protocol 
(including patients who are discharged due to clinical improvement prior to completing the 
specified maximum number of days of treatment) and have complete data available up to D28 or 
up to date of death, whichever is sooner (Section 5.1) 
3.5.6 
Per Protocol Set 
The Per Protocol Set (PPS) will consist of participants in the FAS without any major protocol 
deviations that may influence the validity of the data. If there are no major protocol deviations, 
this analysis set will not be created. This set will not be used for Interim1 as no protocol 
deviation meeting will have taken place. 
3.5.7 
Pharmacokinetic Analysis Set 
The Pharmacokinetic Set (PKS) will be all participants in Arm A in SS who have at least one 
evaluable PK concentration. 
3.6 
Centres 
3.6.1 
 Centre pooling strategy 
All by participant listings will include the various centers. Summary statistics of all endpoints 
will be provided by center and treatment, as well as by treatment. The data from all centers will 
be pooled for both safety and efficacy summaries. Statistical models may include center as a 
covariate (center is included as a stratifying factor in the randomization). Centre by treatment 
interaction may be included if appropriate. 


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3.6.2 
Change of Centres  
Due to the ongoing pandemic participants may be required to move hospitals. No IMP will move 
with the participants and hence dosing will stop. Prophylactic antibiotic use will continue where 
appropriate. 
If participants are moved to a hospital within the study then safety (conmeds, AEs, labs and 
temperature) and key efficacy data (primary oxygenation endpoint, ordinal scale, respiration data 
and mortality) will be prioritised. 
If participants are moved to a hospital outside the conduct of the study then only key safety data 
(conmeds, AEs, SAEs) will be collected. 
Centre changes will be captured and reported as well as day of transfer. Data collected for 
participants after transfer to another hospital may not be included in any formal analyses, but will 
be listed. 
3.7 
Coding dictionaries 
Adverse events and medical history will be coded using CTCAE V5.0 and the latest available 
version of the Medical Dictionary for Regulatory Activities (MedDRA®) (Version v 22.0 or 
higher).  
Medications may be coded using the World Health Organization Drug Reference List (WHO-
DRL).  
Medical procedures will not be coded. 
3.8 
Changes to protocol-defined analyses 
The analysis of the primary endpoint described in the protocol omitted to add that baseline*day 
would be included as a fixed effect in the Mixed Model Repeated Measures (MMRM) analysis. 
This is needed in order to account for the fact that values from days closer to baseline are likely 
to be more correlated than values at days further apart from baseline. This is important if we 
include D28 and long-term follow-up in some of our analyses.  
The primary analyses will be using Nominal Day as the categorical time point, and not strict 
relative day. This is because whilst the ideal is to take measurements as frequently as possible, 
the protocol only specifies specific days, which are the primary days for comparing between 
treatment arms. Therefore, windowing has been incorporated into the derivation of Nominal Day 
to ensure data that may not have been collected on the specific day of interest, but are within the 
window, are used. Sensitivity analyses using Relative Day (continuous and/or categorical) will 
be carried out as described in the relevant sections. 
An additional variable will be created to indicate day of discharge and where needed, the results 
on the day of discharge will be mapped to the appropriate nominal day (Section 3.2.1.3).. This is 
to match with the sentence in Section 7.1.2 where it describes how to treat data if the day of 
discharge is prior to D15. 
The SAP will not be amended for any changes to planned analyses or any additional analyses 
that are made after database lock 


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4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
Covariates such as sex, age, BMI (measure of obesity) and race may also be included in the 
models if by the time of analysis these have been identified as key differentiators in terms of 
COVID-19 recovery.  
Weight may also be used (independently of BMI) as a covariate to explore the impact of weight 
on results as the usual dosing regimen for Zilucoplan® is to dose by weight. 
In addition, the impact on the results of disease severity at baseline may be explored using the 4 
middle categories of the 6 point ordinal scale to define disease severity at baseline as a covariate 
Where indicated, some secondary endpoints will explore the impact of baseline laboratory values 
on efficacy endpoints eg Baseline D-Dimers and C5a values. 
The addition of the interaction of any baseline covariate with treatment may be explored to 
identify any evidence to suggest a differential impact on results. 
Prior to fitting any model, all data will be explored graphically. 
4.2 
Handling of dropouts or missing data 
The SOE indicates some endpoints are listed as only being collected on the specified days where 
comparisons between treatments are required, but all clinical and laboratory endpoints will be 
collected as frequently as possible, preferably daily, whilst in hospital. The primary assessment 
period is for 28 days post randomization, but some endpoints cannot be collected once a 
participant has been discharged from hospital e.g. vital signs (including the primary endpoints) 
and laboratory endpoints. 
See Section 5.1 for definitions for Completed Treatment and Completed Study and their 
complements. 
Missing values from participants take 4 forms: 
• Missing due to death (no longer ‘at risk’ of recovery) 
• Missing due to hospital discharge prior to end of primary assessment period (on any 
day up to D28) 
• Missing values from the ideal of having daily collection of laboratory and clinical 
endpoints whilst participants are in hospital 
• Missing values due to premature withdrawal from study 
How missing data are to be handled is described in the analysis sections for each endpoint. 
Participants who discontinue study treatment for reasons other than death or hospital discharge 
(for example, withdraw consent or adverse event, may still continue on study and will have 
measurements taken, so data from timepoints following discontinuation from study treatment 
will not be missing. These participants/data may be considered differently as part of a sensitivity 
analysis as they did not receive treatment per protocol.  


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4.2.1 
Safety laboratory data 
BLQ values should be set to half the LLOQ and any values above the limit of quantification 
(ALQ) will be assigned as the value of upper limit of quantification. 
 
4.2.2 
Dates and times 
A description of how these are to be handled is in Section 13.1. 
4.3 
Handling of repeated and unscheduled measurements 
No measurements are considered as unscheduled as the ideal is to take all clinical and laboratory 
measurements as frequently as possible.  
Repeated measurements are defined as more than 1 measurement at the same timepoint. For 
example, the same ECG parameters assessed twice due to issues with the first assessment. The 
use of either the original or repeated measurement performed in any summary or analysis will 
depend on the reason for repeating the measurement. If repeated measurements are used in any 
analysis or summary, it will be clearly stated and the reason articulated. 
Since the ideal is to take as many measurements as possible, it is possible that more than one 
measurement will be taken at  different times on the same day but is not really considered a 
repeated measurement under the usual definition. In these cases, the first value taken on any day 
will be used in any analyses as these should hopefully be taken at the same time on each day and 
this should avoid any potential bias caused by diurnal variation. 
Any listings and graphs of these data over time will include the repeated and/or unscheduled 
assessments. Sensitivity analyses may be performed using the original and repeated 
measurements. When more than 1 assessment is available for a specific study moment, these 
assessments are organized as first the original assessment, assigned to the nominal visit, and then 
the repeated assessment(s), assigned to unscheduled visits. The date and time of measurement 
are used to sort the data 
4.4 
Interim analyses and data monitoring 
4.4.1 
Interim 1 
It is assumed that all data for the primary endpoints will not have been cleaned for this interim 
analysis. 
The analyses of the primary endpoints will be as described in Section 8.1. In addition, the results 
of the secondary endpoints associated with a 2-point improvement in the 6-point ordinal scale 
may be analysed, if upon data exploration, formal comparison is meaningful – the percentage of 
participants who have achieved a sustained (to D15) 2-point improvement or discharge will be 
compared between treatments and the time to achieving the sustained 2 point improvement or 
discharge will be estimated. See Section 8.2.1 for a description of the analysis methods. 
Safety data will also be reviewed (including adverse events) and presented as described in 
Sections 10.2 and 10.3 respectively. Mortality will be listed and/or summarized by nominal 
timepoint and treatment depending on if there is sufficient data to warrant a treatment summary. 


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There is no plan to stop the study based on results at this stage and no adjustment to control the 
overall Type 1 error at the final analysis is needed.  
4.4.2 
Interim 2 
Interim 2 analyses will be carried out when all participants have had the opportunity to complete 
D28 procedures (in clinic or by a phone call if previously discharged) to assess 28 day mortality 
endpoints and endpoints associated with a 2 point improvement or discharge in the 6-point 
ordinal scale. 
If all data from every participant for the primary objective and 6-point ordinal scale is available 
and clean at this time, this may form the final analysis for the primary objective and key 
secondary endpoints and be used to guide further research. i.e. there would be no need to wait for 
the final analysis planned to occur 12-22 weeks post randomization 
The analyses of the primary endpoints, 28 day mortality and endpoints associated with a 2 point 
improvement in the 6-point ordinal score or discharge will be as described in Section 8.1 and 
Section 8.2.1 respectively.   
Safety data will also be reviewed (Adverse events and clinical laboratory parameters) and 
presented as described in Sections 10.2 and 10.3 respectively. 
 
4.4.3 
Safety Data Interim Look 
In addition to these interim analyses a Data Safety Monitoring Board is likely to happen after 10 
participants have been dosed in Arm A. Additional DSMBs may occur as indicated. UzGhent 
will manage the DSMB (including the charter) however, the TFLs will be produced by UCB 
when the 10th active participant is entered in the database with data up to Day 15. The protocol 
does not state the timeframe of data required, however, it is judged that 15 days of data from 10 
active participants will be sufficient to assess safety. AEs, Conmeds, laboratory values, vital 
signs, exposure will be investigated in Spotfire visualisations and summarized in TFLs if there 
are sufficient data. To put the safety data in context oxygenation levels, clinical scores, medical 
history and demography may be considered.  
4.5 
Multiple comparisons/multiplicity 
Three endpoints are listed that are associated with the primary objective. There are no plans to 
control for multiplicity in the primary objectives as the endpoints are different parameterizations 
of the same underlying endpoint measured on separate days. This means there is effectively only 
one primary endpoint, PaO2/FiO2 ratio which was used to calculate sample size. The comparison 
of the differences from baseline to two days (D6/Early Discharge and D15/Early discharge) are 
of specific interest. 
There are no plans to control for multiplicity in the secondary objectives as these hypotheses are 
considered exploratory. Therefore, any findings will need to be confirmed in subsequent studies. 
4.6 
Use of an efficacy subset of participants 
Not applicable. 


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4.7 
Examination of subgroups 
Not applicable. 
 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Participant disposition 
Participants are considered screenfails if they were deemed not eligible for randomisation. 
Since this is initially an in participant study the Nominal Days are not considered a scheduled 
protocol visit.  
A participant who dies at any time during the study is considered as having completed the study 
and primary assessment period. If they discontinued early from planned active treatment 
duration (i.e. not including hospital discharge), the participant is considered as having completed 
the study and primary assessment period, but not completed planned active treatment 
duration. 
In addition, a participant is considered to have completed the study if they have completed D28 
and the follow-up visit. Participants can be discharged from hospital at any time, and as long as 
they have completed D28 and the follow-up visit, they have completed the study. 
Participants have completed primary assessment period if they have: 
• Arm A: completed up to 14 days of treatment with study drug followed by 14 days of 
either IV or oral prophylactic antibiotic treatment (as an in-participant or after discharge 
from hospital) AND completed D28 procedures 
• Arm B: Completed up to 14 days of treatment with study drug (SOC+ 1 week of 
prophylactic antibiotic treatment) AND completed D28 procedures 
Participants have not completed primary assessment period: 
• are discontinued treatment prior to end of planned active treatment duration due to an 
adverse event - they may still complete D28 and/or follow-up visits 
• discontinue treatment prior to end of planned active treatment duration as they meet an 
exclusion criterion (either newly developed or not previously recognized) that precludes 
further study treatment participation - they still may complete D28 and/or follow-up 
visits 
• withdraw consent from being treated prior to end of planned active treatment duration – 
they may agree to complete D28 and/or follow-up visits 
• Complete the treatment as planned but do not complete D28 procedures 
Participants have prematurely withdrawn from the study if they: 
• are lost to follow-up, after hospital discharge (i.e. do not complete D28 and follow-up 
visits or do not complete follow-up visit). 
• Withdraw consent from being treated prior to end of planned active treatment duration 
and from D28 and follow-up visits 


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• Withdraw consent for D28 and follow-up visit procedures visit after completing planned 
active treatment duration  
A listing of participants who failed screening at the beginning of the study will be presented for 
the ES, providing dates of informed consent and primary reason for screenfail.  
In addition, the disposition of participants screened and treated will be summarized by site.  This 
table may include, for each site, the site number, principal investigator name, the dates of the 
first participant in and the last participant out, the number of participants screened (ES), 
randomized (RS), treated (SS) and included in the FAS, PPS and PKS (if RS and PPS 
generated).  
Disposition (completed study, completed primary assessment period, completed planned 
treatment duration or prematurely withdrawn from study and subsets) in each analysis set will be 
summarized by treatment group, and overall.  
The number of participants who enrolled (overall only) and the number and percentage of 
screenfails (overall only) will be provided. 
The following will be provided for the FAS, by treatment arm and overall. 
• The number of participants randomized (used as basis for following percentages) 
• The number of participants who started treatment  
o The number and percentage of participants who complete the study  
▪ Of these,  
• The number and percentage of participants who were discharged 
prior to D15 
• The number and percentage who died and how many of these died 
prior to D15  
o The number and percentage of participants who complete the primary 
assessment period 
▪ Of these,  
• The number and percentage of participants who were discharged 
prior to D15 
• The number and percentage who died and how many of these died 
prior to D15 
o The number and percentage of participants who did not complete the primary 
assessment period 
▪ Of these,  
• The number and percentage of participants who discontinued 
active treatment  
o Due to Adverse Event 
o Due to withdrawing consent 


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o Due to not meeting exclusion criteria 
• The number and percentage who did not complete D28 
assessments 
o The number and percentage of participants who withdrew from study 
▪ Due to lost to follow-up 
▪ Due to withdrawing consent 
o The number and percentage who completed planned active treatment duration 
o The number and percentage who completed the D28 assessment 
o The number and percentage who completed 12-22 week follow-up visit 
o The number and percentage of participants who died 
 
The number and percentage of participants who discontinued due to AEs will be summarized 
separately for all participants, based on the FAS. This will be used for European Union Drug 
Regulating Authorities Clinical Trials (EudraCT) reporting. 
In addition, the following listings will be presented: 
• Study participant disposition (ES) 
• Study discontinuation (ES) 
• Analysis sets (ES) 
The listing of study participant disposition will be presented by treatment group and by site, and 
will include the date of informed consent, date and time of first and last dose of study treatment, 
number of days on treatment, date of decision to terminate study treatment early and primary 
reason, date of D28 visit, date of the follow-up visit (if completed). 
The number of days on study treatment will be calculated as follows: 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝐷𝑎𝑦𝑠 𝑜𝑛 𝑆𝑡𝑢𝑑𝑦 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡
= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐿𝑎𝑠𝑡 𝐷𝑜𝑠𝑒 𝑅𝑒𝑐𝑒𝑖𝑣𝑒𝑑−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒 𝑅𝑒𝑐𝑒𝑖𝑣𝑒𝑑) + 1 
5.2 
Protocol deviations 
Important protocol deviations will be identified and classified by the deviation types defined in 
the IPD document, as per Section 3.4. 
A listing of all IPDs identified at a data review meeting and will be presented for all study 
participants based on the FAS and will include the deviation type and description. The number 
and percentage of participants in the FAS with IPDs will be summarized by treatment group and 
for all participants for each deviation type. The number and percentage of participants who were 
excluded from the PPS will also be presented. The denominator for the percentage calculations 
will be the number of participants in the FAS. 


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6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
Additional endpoints to those mentioned below may be collected at baseline and will be 
summarized appropriately.  
6.1 
Demographics 
A by-participant listing of demographics will be presented based on the ES. This will include the 
year of birth, age (calculated in years from date of randomisation), sex, race, height (in cm), 
weight (in kg) and body mass index (BMI, in kg/m2). The height will be the measurement 
obtained at the Screening visit. Weight will be the last non-missing value prior to the first dose of 
study treatment. 
The BMI will be derived using the height and weight measurements recorded at the Screening 
visit and will be reported to 1 decimal place.  
All demographic characteristics will be summarized by treatment group using the FAS. The 
summary of age will include descriptive statistics and categorical summaries, the latter based on 
requirements for EudraCT and clinicaltrials.gov reporting. 
For the EudraCT reporting, the categories will include: 
• 18 to <65 years 
• 65 to <85 years 
For clinicaltrials.gov reporting, the categories will include: 
• ≤18 years 
• 19 to <65 years 
• ≥65 years 
No statistical analysis will be performed on demographic data. 
6.2 
Other Baseline characteristics 
All other baseline characteristics collected based on eligibility criteria will be listed for the FAS. 
The following baseline characteristics will be summarized by treatment group using the FAS 
COVID-19 tests 
• Number and percentage on COVID-19 ward and ICU 
• Number and percentage with positive PCR for COVID-19 
• Number and percentage of Multiple PCRs 
• Number and percentage of each type of sampling for COVID-PCR 
o Nasopharyngeal 
o BAL (bronchoalveolar lavage) 
o Anal 


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o Sputum 
o Blood 
o Urine 
o Other (specify) 
• Number and Percentage of PCR for other micro-organisms 
o Number and percentage positive for  
▪ Influenza 
▪ RSV 
▪ Other (Specify) 
• Number and percentage of positive antigen tests for COVID-19 
• Number and percentage of serology/other validated COVID-19 diagnostic tests 
 
• Number and percentage of hypoxic respiratory failure 
 
BASELINE ORDINAL SCALE Category 
• Number and percentage with each score: 1 Death, 2 Hospitalized, requiring ECMO, 
invasive mechanical ventilation, or both, 3 Hospitalized, requiring nasal high-flow 
oxygen therapy, non-invasive mechanical ventilation, or both, 4 Hospitalized, requiring 
supplemental oxygen, 5 Hospitalized, not requiring supplemental oxygen, 6 Not 
hospitalized 
• Note: these are worded slightly differently on the CRF 
CYTOKINE RELEASE SYNDROME 
• Summary of absolute score and probabilities for presence of sHLH by treatment arm 
(involves mapping the provided HScore to the appropriate point on the probability scale 
using linear interpolation to a probability based on the information contained in the 
following table) 
 
HScore 
Probability of hemophagocytic syndrome  
≤90 
<1% 
91-100 
~1% 
101-110 
1-3% 
111-120 
3-5% 
121-130 
5-9% 


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131-140 
9-16% 
141-150 
16-25% 
151-160 
25-40% 
161-170 
40-54% 
171-180 
54-70% 
181-190 
70-80% 
191-200 
80-88% 
201-210 
88-93% 
211-220 
93-96% 
221-230 
96-98% 
231-240 
98-99% 
≥241 
>99% 
Note: the best cutoff value for HScore was 169, corresponding to a sensitivity of 93%, specificity of 86%, and 
accurate classification of 90% of the participants. 
Reference: https://www.mdcalc.com/hscore-reactive-hemophagocytic-syndrome#evidence 
 
• Number and percentage of BOTH highly suspect bilateral ground opacities on chest CT-
scan AND typical clinical and chemical diagnosis with signs of cytokine release 
syndrome  
• Number and percentage of Radiography showing bilateral infiltrates in last 2 days 
(should be 100%) 
• Number and percentage of signs of Cytokine Syndrome (should be 100%) 
o As shown by: 
▪ Number and percentage of single ferritin >2000 ng/ml (denominator 
participants with high flow nasal oxygen or mechanical ventilation i.e. 
total of participants on ordinal score 2 or 3 (which should be our 
participant population))  OR 
▪ Number and percentage of Ferritin > 1000 ng/ml and rising since last 24 
hours 
OR 
• Lymphopenia < 800 /µL AND ≥ 2 of: 
o Ferritin > 700 mcg/L and rising since last 24h   


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o CRP > 70 mg/dL and rising since last 24h without bacterial 
infection  
o LDH > 300 IU/L and rising since last 24h  
o D-dimers > 1000 ng/mL and rising for 24h 
OR 
• Lymphopenia < 800 /µL AND ≥ 3 of: 
o Ferritin > 700 mcg/L    
o CRP > 70 mg/dL  
o LDH > 300 IU/L  
o D-dimers > 1000 ng/mL  
Summary statistics and distribution plots of laboratory parameters listed here will be 
provided by treatment arm. 
6.3 
Medical history and concomitant diseases 
A listing of all basic clinical data will be provided (such as prior lung diseases, smoking history, 
prior lung function measurements (within last 5 years), prior gas exchange measurements). These 
data will be collected from electronic medical records for each participant, and may not entered 
directly into the eCRF. All data received will be summarized as their data type suggests (see 
Section 3.1) by treatment arm. 
The frequency of historical and ongoing conditions will be summarized by treatment 
(Y/N/ongoing). 
Prior lung function test carried out (within last 5 years) (Y/N) 
In addition to the above, any continuous data collected on lung function will be summarized by 
treatment arm ( eg FEV1 (L) 
Summary of substance use (alcohol (No, Daily, Sporadic, smoking (Never, Former, Current) or 
Other (No, Yes (other)) will be provided by treatment arm. Quantities may be summarized 
depending on quality of data provided. 
6.4 
Prior and concomitant medications 
Prior medications include any medications that ended prior to the date of the first dose of study 
treatment. 
Concomitant medications include medications with a start date before, on or after the first dose 
of study treatment and either ended post-first dose or continued after study treatment 
discontinuation.  
Any medication that started prior to the first dose and stopped or continued after study treatment 
discontinuation after will be classified as both prior and concomitant. 
Any medications with partially missing dates will be handled as described in Section 4.2.3 to 
classify them as prior or concomitant. 


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Medication use, both prior and concomitant, and all standard of care drugs (SOC) for Arm B will 
be collected on eCRFs. Drugs considered as SOC and the concomitant antibiotics, as opposed to 
prior and/or concomitant medication, will be clearly indicated and listed and summarized as 
described in Section 10.1 Extent of Exposure.  
If the data allow, all prior and concomitant medications will be listed for the SS by treatment 
group and by WHODD Anatomical Main Group [Level 1 term text], Pharmacological Subgroup 
[Level 3 term text] and PT. The reported term will be included in the listing. Additional 
endpoints to be listed will be described in the TFL shells.  
Separate summaries will be presented for prior medications and concomitant medications. Prior 
medications which continued into the Treatment Period will also be classified as concomitant 
and will be included in both summaries. 
If medication is not coded, then all summaries will be based on the reported term. 
If coded, all tabulations will be sorted alphabetically by Level 1 term, alphabetical Level 3 term 
within Level, otherwise by reported term, and decreasing frequency of PT in all study 
participants. 
A glossary of all prior and concomitant medications will be presented for the FAS including the 
Anatomical Main Group (Level 1), Pharmacological Subgroup (Level 3), PT and reported term.  
 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Administration of study treatment (including the administration of appropriate antibiotics) will 
be performed at the study site under the supervision of the designated site personnel. Compliance 
will be monitored at the site through a review of the pharmacy and dispensing records to ensure 
that each study participant received the correct dose level. 
Compliance with taking oral daily antibiotics for at least 14 days after hospital discharge in Arm 
A will be monitored during the planned phone call at D28. The taking of antibiotics after hospital 
discharge is not required for Arm B. 
Any dosing deviations will be reviewed as IPDs at the DEM and assessed for possible impact on 
the PPS.  If considered important, these deviations will be included in the summary and listing of 
IPDs. 
8 
EFFICACY ANALYSES 
All raw data collected will be displayed graphically, over time (relative day as continuous and 
nominal day as categorical) and by treatment arm, as appropriate. Plots may be trellised by 
factors to explore for potential patterns if there are too many data for meaningful review in a 
single plot e.g. by treatment arm for each site. The y-axis may be logarithmic or natural, 
depending on the endpoints being visualized. Means (and 95% CI) and Median and IQ range will 
be included where possible on the plots – this may not be appropriate when using relative day on 
the x-axis, depending on the number of participants who had measurements taken on each day, 
but should be possible for all plots using Nominal Day on the x-axis. If the data are presented on 
the log scale, then the geometric mean and 95% CI will be displayed, instead of the mean and 
95% CI. 
 


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Of general note, since the protocol is not written using an estimand framework, this SAP will 
describe primary analyses for both primary and secondary endpoints. In addition, some pre-
planned sensitivity and supplementary analyses are described.  
 
In this context a sensitivity analysis is an additional analysis carried out on the same endpoint to 
determine how robust inferences based on the endpoint are to limitations in the data and 
assumptions behind the model used in the primary analysis. The analyses could use different 
transformations of the raw data, using different variance-covariance structures and different 
methods for handling missing data. 
 
A supplementary analysis to support any clinical inference could use different methods of 
statistical analysis and/or different, but related, endpoints. 
 
8.1 
Statistical analysis of the primary efficacy endpoint(s) 
The primary efficacy endpoints are PaO2/FiO2 ratio, P(A-a) O2 gradient and a/A PO2 ratio and of 
interest are comparisons between treatments of: 
▪ Change from baseline to nominal D6in PaO2/FiO2 ratio (units=mm Hg) 
▪ Change from baseline to nominal D6 in P(A-a) O2 gradient (units=mm Hg) 
▪ Change from baseline to nominal D6in a/A PO2 ratio (unitless) 
▪ Change from baseline to nominal D15in PaO2/FiO2 ratio 
▪ Change from baseline to nominal D15 in P(A-a) O2 gradient 
▪ Change from baseline to nominal D15in a/A PO2 ratio 
Mapping of results to nominal days in the event that a participant is discharged from hospital 
before nominal D6 and/or nominal D15 is described in Section 3.2.1.3. 
Residual plots, including plots against potential covariates, will be produced to investigate the 
validity of the assumptions behind the analyses for each of the 3 primary endpoints and if 
necessary, sensitivity analyses will be carried out (Section 8.1.3). Results from the most 
appropriate analysis will be presented.  
 
8.1.1 
Derivations of primary efficacy endpoint(s) 
Measurements to derive PaO2/FiO2 ratio (measure of severity of hypoxemia), P(A-a) O2 gradient 
(always positive and a reflection of the difficulty oxygen has at crossing the alveolar capillary 
membrane and increases with age and FiO2 related to determine if it is normal.) and a/A PO2 ratio 
are to be taken at Baseline, and at least at pre-dose (for arm A) on Day 6 and Day 15 (or at 
discharge, whichever comes first). Measurements for Arm B can be taken at any time, but 
preferably at the same time on each Day for every participant to allow for diurnal variation, at 
least on Days 1, 6, 15 (or at discharge, whichever comes first). Where possible, more frequent 
measurements will be taken in both arms, preferably daily. 
eCRFs indicate that FiO2 will be taken daily, however PaO2 and PaCO2 only at Screening/Day-1, 
nominal D1, nominal D6 and nominal D15. 


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Therefore, the derived parameters should be calculated using the data from the arterial blood gas 
(ABG) eCRF and not from Vital Signs. 
Calculation 
PaO2 is the partial pressure of oxygen in the arterial blood and provided on the CRF. The 
Alveolar Gas Equation provides an estimate of PAO2. 
PAO2 =(Patm-PH20)FiO2 - PaCO2/RQ 
 
(=partial pressure of oxygen in the alveoli) 
Where: 
 
Patm is atmospheric pressure at sea level = constant 760 mm Hg 
PH2O is partial pressure of water in alveoli= constant 45 mm Hg 
FiO2 is fractional concentration of O2 in inspired air, from eCRF (or 21% (0.21) if participant 
is not on supplemental oxygen 
PaCO2 is partial pressure of carbon dioxide in alveoli from eCRF 
RQ = respiratory quotient = constant 0.82 (for typical human diet) 
P(A-a) O2 gradient = A-a gradient = PAO2 - PaO2  
a/A PO2 ratio = PaO2/PAO2 
Given that ABG is only measured on specified days, change from baseline to each of these days 
will be calculated for each of these endpoints for each participant [For example, (D6 - Baseline), 
(D15 - Baseline)]. 
Note:  
All the above calculations should be carried out and used to verify the result for variables that are 
directly collected on the eCRF. Any discrepancy should be listed but the ones on the eCRF 
should be primarily used. 
Increasing values for PaO2/FiO2 ratio indicates improvement over time (normal considered ~470 
mmHg ) 
Decreasing values of P(A-a) O2 gradient indicates improvement over time (normal A-a gradient 
is (Age/4) +4) and in addition increases with higher FiO2 
No similar statement for a/A PO2 is appropriate. 
8.1.2 
Primary analysis of the primary efficacy endpoint(s) 
Summary descriptive statistics for each endpoint and change from baseline for each endpoint, 
including to follow-up, will be provided by treatment and Nominal Day (D1(Baseline), D2, D6, 
D15 and Follow-Up). 
Each endpoint (PaO2/FiO2 ratio, P(A-a)/O2 gradient, a/A PO2 ratio) will be analyzed separately 
using a Mixed Model Repeated Measures (MMRM) analysis with fixed effects for Baseline, 
treatment, Nominal Day (using Nominal Days, D6 and D15), Baseline*Nominal Day interaction 
and treatment*Nominal Day interaction where Nominal Day is categorical. Participant will be 
fitted as a random effect and an unstructured covariance will be used, unless it fails to converge, 


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when other covariance structures will be considered. Mean change from baseline to D6 and D15 
for each treatment arm and differences between treatments in mean change from baseline to D6 
and D15, their 95% confidence intervals and p-values will be estimated directly from the model.  
The primary analysis will not adjust for missing data, other than how they are handled in 
MMRM under the assumption that the data are missing at random. This assumption implies that 
the behaviour of the post dropout observations can be predicted from the observed endpoints, 
and therefore the response can be estimated without bias using exclusively the observed data.  
The following results from the model will be tabulated: 
▪ LSMEANS (adjusted for baseline levels) and 95% confidence intervals for change from 
baseline by treatment and Nominal Day for each endpoint (PaO2/FiO2 ratio, P(A-a)/O2 
gradient, a/A PO2 ratio) 
▪ Estimates of the differences between treatments in mean change from baseline, 95% 
confidence interval and p-value at D6 and D15 for each endpoint (PaO2/FiO2 ratio, P(A-
a)/O2 gradient, a/A PO2 ratio). 
▪ Mean percentage change from baseline will be estimated from the results of the MMRM 
model for D6 and D15 for each Treatment Arm, together with 95% confidence intervals. 
Plots of the results from the MMRM will be provided for LSMEANS (adjusted) of change from 
baseline and 95% CI by treatment on each Nominal Day of Interest and the mean differences of 
the LSMEANS between treatments and their 95% CI. Distribution plots for the estimated mean 
differences (Arm A -Arm B) between treatments will be provided for each nominal day where 
the x-axis will represent the range of differences between treatments and the area under the curve 
will present the probability of the mean difference in means being greater than specified values.  
 
8.1.3 
Sensitivity analyses of the primary efficacy endpoint(s) 
In order to explore the validity of assumptions behind the primary analyses and after review of 
residual plots, the data for each endpoint (data only come from the set of positive real numbers) 
(PaO2/FiO2 ratio, P(A-a)/O2 gradient, a/A PO2 ratio) may be first log transformed and each 
endpoint will be analysed separately using a MMRM model with fixed effects for Baseline, 
treatment, Nominal Day (D1,D6, D15), Baseline*Nominal Day interaction and 
treatment*Nominal Day interaction where Nominal Day is categorical. Participant will be fitted 
as a random effect and an unstructured covariance will be used, unless it fails to converge, when 
other covariance structures will be considered. 
Mean change from baseline to D6 and D15 for each treatment arm and differences in the means 
on the log scale between Arm A and Arm B (Arm A- Arm B) for each VISIT (Day 6, 15) will be 
estimated directly from the models. 
The following results from the model will be first back-transformed and then tabulated:  
• LS geometric means (adjusted for baseline) and 95% confidence intervals for by 
treatment and Nominal Day for each endpoint (PaO2/FiO2 ratio, P(A-a)/O2 gradient, a/A 
PO2 ratio) to provide geometric LSMEANS(adjusted for baseline) and 95% confidence 
limits 


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▪ Estimates of the treatment differences on the log scale between treatments and 95% 
confidence interval at D6 and D15 for each endpoint (PaO2/FiO2 ratio, P(A-a)/O2 
gradient, a/A PO2 ratio) to provide the ratio of geometric means and 95% confidence 
limits. The p-values for these differences will also be provided in the table. 
 
These analyses will be repeated using the alternate baseline (section 3.2.2.2) to include 
participants with a baseline soon after dosing. 
An additional sensitivity analysis will repeat both the primary analysis and sensitivity analysis 
above using LOCF for participants with missing data on either D6 or D15 that was not due to 
discharge: 
• due to death prior to D15, which could mean both D6 and D15 are missing or just D15. 
The impact of both being missing will be explored using residuals, as the LOCF method 
will necessarily mean that the change from baseline for these participants is nominally 0, 
as the baseline value will be carried forward 
To explore the impact of age, sex, weight and ethnicity on the results, the analyses described 
above and in section 8.1.2 will be repeated including sex, age (in years), BMI and weight and 
ethnicity as additional covariates. 
8.2 
Statistical analysis of the secondary efficacy endpoint(s) 
There are several secondary endpoints that cover each of the secondary objectives and a list is 
provided in the table listing the secondary endpoints in Section 2.2.1.2. Some of these endpoints 
are different derivations from the same collected data. In addition, some of the endpoints 
collected for one objective, may be the inputs to derivations for endpoints for the same objective 
or for another objective.  
 
Data types for the secondary efficacy endpoints fall into the following main categories: 
continuous (for example, change from baseline (including the various ordinal categorical 
endpoints), number of days with ‘condition’), ordinal categorical, binary (‘responder’ Y/N), time 
to event or duration of event. 
 
Table 8.1 describes the analyses of each secondary endpoint listed in Section 2.2.1.2 and 
identifies which efficacy objective (2-6) the endpoint is addressing. Brief details of any 
derivations and analysis methods used are provided. Further details are included in the mock 
TFL shell document. In the event the data for some of these endpoints indicate that analysis 
through fitting models is not appropriate, for example too few events for a formal analysis on 
response or mortality rates, or time to event analyses, the analyses will not be carried out and 
only listings, figures and summaries provided. 
Some patients may withdraw from the study or be transferred to another hospital prior to 
discharge through medical improvement. If data have been collected from another hospital post 
discharge from the first hospital, these data will be listed. This will be for variables or derived 
variables which would have included data from these patients. For example, duration of stay in 
hospital. However, for variables only including data up to a relative day prior to 
discharge/transfer from the first hospital, these patients will be included in the analysis/summary 


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for that period but set as missing for the other periods. Residual plots will be reviewed to 
determine any influence these participants may have had on the results. 
 
 
 
 


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Table 8.1 
 
Endpoint 
Derivation 
Analysis 
Objective 2 
Incidents of participants reporting 
each severity rating in 6-point ordinal 
scale at D1, D6, D15 and D28 
Percentages for each ordinal score on each 
day are based on N in each treatment arm 
on D1. An additional category (score=7) to 
be created to indicate participants who 
have withdrawn from the study for any 
reason or transferred to another hospital. 
Add label for score category=7 as 
‘Withdrawn’. Participants who die 
(score=1) or are discharged from hospital 
due to medical improvement (score=6) or 
are withdrawn (score=7) remain in both the 
numerator and denominator for these 
categories on subsequent days by using 
LOCF for discharge, death and withdrawal. 
Only use LOCF for participants whose 
final recorded score is 1, 6 or 7. For the 
interim, all other subjects whose final 
recorded score during the period up to 28 
days is not equal to 1, 6 or 7, impute a 
score of 8 for their remaining days (up to 
D28). This is to indicate the percentage of 
participants who are still on treatment 
without imputing what their future values 
may be.  
Check that ordinal score matches whether 
participant has been discharged or has died 
PROC FREQ to create summary table of actual 
counts and percentages for each of the 6-points on 
the ordinal scale on each nominal day (D1, D6, 
D15 and D28) for each treatment 
 
Stacked 100% bar chart indicating a snapshot of 
counts in each category (color coded for scores 1-7 
(including 8 in the interim analyses)) on each 
relative day by treatment arm. A separate graph 
for each treatment, placed side by side.  
 
For final analysis: 
Logistic regression for data from specified nominal 
days (D1, D6, D15 and D28). Fixed effect of 
Score*Treatment indicating whether the pattern 
across scores is different between treatments on each 
day.  
Note: If D1 is pre-dose and therefore baseline, 
exclude from table and plot.  
 


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Endpoint 
Derivation 
Analysis 
 
Objective 2 
Change from baseline in 6-point 
ordinal scale to Day 6, Day 15 and 
Day 28  
Change from baseline at each relative day 
for each participant. If a participant has 
died (score=1) or discharged from hospital 
(score=6), these values will carry forward 
onto subsequent days. For participants who 
are missing values after any day for any 
other reason, the value will remain 
missing. For participants who miss some 
intermediate values, the latest value prior 
to the missing value will be carried 
forward until the day where data are 
recorded again. 
The additional scores derived for the 
previous endpoint will not be used in 
change from baseline 
(One line per day per participant dataset) 
Summary table providing n, mean change from 
baseline, SD change from baseline, median, 
minimum and maximum on each specified 
nominal day by treatment arm 
 
Graph of change from baseline over time for each 
participant by treatment, and the average lines 
for each treatment. 
For final analysis: MMRM fitting response variable 
change from baseline against fixed effects for 
specified nominal days, treatment and 
treatment*nominal day interaction. Baseline score as 
covariate and baseline score*nominal day as 
additional terms. Participant as random effect. 
Objective 2 
Time to at least a 2-point improvement 
or discharge sustained up to (D15 for 
interim analysis 1) D28 on the 6-point 
ordinal scale during 28-day 
assessment period (=Response) 
Note: for both the interim analyses and 
final analyses up to D15 and D28 
respectively, if the 2-point change 
occurred on D15 or D28, and the 
Create TTE dataset for cumulative 
response rate analysis with 2 variables 
each for analysis up to D15 and up to D28 
with one line per participant providing 
time to response and censor status. Censor 
status=0 for patients with response and =1 
on relative day for: patients who have: 
withdrawn from treatment and/or study; 
discharged from first hospital for reasons 
other than improvement; have no response 
by analysis date (censor=1 at analysis 
Kaplan-Meier analysis using PROC LIFETEST. 
Strata ACTARM. 
Request Failure plot adjusting axis and heading 
titles to reflect responder and not failure 
Output statistics: 
Appropriate statistics from analysis as indicated 
in mock shell 


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Endpoint 
Derivation 
Analysis 
patient remained in hospital, the 
patient will be classified as a 
responder, even though the 2-point 
change had not been ‘sustained’. 
 
date). If Time to Response >15 and 
censor=1 for analysis up to D15, Time to 
Response=15. If Time to Response >28 
and censor=1 for analysis up to D28, Time 
to Response=28. For patients who have 
died Time to Response is set to D15 or 
D28 respectively and censored at this time. 
Note: Treatment will be merged into the 
TTE dataset. In addition to other variables 
that may be used as covariates in final 
analysis.  
(one line per participant dataset) 
Objective 2 
Percentage of participants reporting at 
least a 2-point improvement sustained 
to D28 or discharge 
 
Use D28 response indicator variable 
defined above 
PROC FREQ/PROC LOGISTIC(if covariates are 
added) 
Model: Response=ACTARM +covariates (if added) 
Output percentage response on each treatment. 
Odds ratio and 95% confidence interval 
Objective 2 
AUEC/Time using the 6-point score 
recorded daily – up to D15, D28 and 
all data recorded 
 
For each participant calculate the area 
under the curve and divide by 15 for up to 
D15 and by 28 for up to D28 (higher 
average score per day the better the 
response). Use last value brought forward 
for any missing values until next data 
entry. For discharge, carry forward 
score=6 for each day post discharge day. 
For death, carry forward score=1 for each 
day post death day. 
Analyse AUEC/Time using analysis of variance with 
ACTARM as a two-level factor and baseline score as 
a covariate 
 
 


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Endpoint 
Derivation 
Analysis 
 
Objective 2 
Percentage of participants who record 
at least 2-point improvement from 
baseline or discharge (response) 
between D1-D6, D7-D15 and D16-
D28  
 
Responder classified as above. Create 
indicator variable (3 levels) if the relative 
day of START of response is between D1 
and D6, between D7 and D15 or between 
D16 and D28. Each responder participant 
can only be within one of these categories. 
Participants who have a missing value are 
classified as non-responders 
Frequency table and percentage responders in 
each of the categories defined by the indicator 
variable, by treatment. Exact 95% confidence 
intervals for each percentage 
Objective 2 
Percentage of participants not 
deteriorating according to the ordinal 
scale by 1 point between D1and D6, 
between D7 and D15 and between 
D16 and D28 – not deteriorating 
corresponds to Stable + Responders    
 
A participant is classified as Stable + 
Response if at no time CfB < -1. Create 
indicator variable (3 levels) if the relative 
day of START of Stable or Response falls 
between D1and D6, between D7 and D15 
and between D16 and D28 for each 
participant  
Frequency table and percentage responders in each of 
the categories defined by the indicator variable, by 
treatment. Exact 95% confidence intervals for each 
percentage 
Objective 2 
6-point ordinal Scale at D6 and D15 
and D28 in relation to D-Dimers and 
complement C5a levels at baseline 
 
Box-whisker plot of baseline D-Dimers and 
complement C5a for each score (x-axis) reported on 
each of D6, D15 and D28 
Objective 2 
Change from baseline in SOFA score 
(https://www.mdcalc.com/sequential-
organ-failure-assessment-sofa-score) 
Change from baseline to D6 and D15 in 
SOFA score  
Summary statistics for raw data and change from 
baseline 


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Endpoint 
Derivation 
Analysis 
to Day 6, Day 15 (or at discharge, 
whichever comes first) 
Objective 2 
Number of days with fever (defined as 
37.1ºC or more) during 28-day 
assessment period 
 
Create indicator variable for each 
participant on each day where temperature 
is above 37.1 ºC  
Create variable with total number of days 
where temperature was above 37.1 ºC for 
each participant  
Create variable for each participant giving 
total number of days where temperature 
was recorded 
Summary statistics to provide n, average number of 
days, SD, median, minimum and maximum where 
temperature was above 37.1 ºC by treatment 
Produce line plot of temperature over time for each 
patient together with average line per treatment 
group.  
Temperatures are due to be taken daily until 
discharge – indicate the number of subjects on each 
day in each treatment arm 
Objective 2 
Time since randomization until 
absence of LAST fever (defined as 37. 
1ºC or more) for more than 48 h 
without antipyretics (use last fever to 
account for possibility that participants 
have intermittent fever per this 
definition) 
 
Antipyretic use in last 24 hours is collected 
on eCRF on every day. Use highest 
temperature recorded in last 24 hours, not 
the 7-10am temperature to identify the date 
when the last fever ended per definition. 
Create variable which contains number of 
days between this date and date of 
randomisation for each participant. If a 
participant has had no episodes of the 
fever, the number of days is 0. 
Create indicator variable (censor) to 
indicate if participant has recovered from 
the last fever at time of analysis 
(0=recovered, 1=fever is ongoing at time 
of analysis). If a participant has had no 
fever, (i.e. time=0), censor=0. 
Kaplan-Meier analysis using PROC LIFETEST. 
Strata ACTARM. 
Request Failure plot adjusting axis and heading titles 
to reflect responder and not failure 
Output statistics: 
Appropriate statistics from analysis as indicated in 
mock shell  


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Endpoint 
Derivation 
Analysis 
Objective 2 
Duration of hospital stay 
 
Duration of hospital stay of survivors 
Calculate duration of hospital stay in days 
(Hospital Discharge date-Hospital 
Admission date) 
Create indicator variable to flag survivors 
Summary statistics: n, nmissing, mean, SD, median, 
minimum, maximum 
By treatment arm 
 
Objective 2 
Number of days requiring 
supplemental oxygenation after 
randomisation to Day 28 (or 
discharge, whichever comes earlier) 
Number of days where Suppl O2 = ‘Y’ 
from Vital parameters 
 
 
Summary statistics: n, nmissing, mean, SD, median, 
minimum, maximum 
By treatment arm 
Objective 2 
Time since randomization until 
improvement in oxygenation (defined 
as independence from supplemental 
oxygen) during 28 day assessment 
period (or discharge, whichever comes 
earlier) 
Independence from supplementary oxygen 
means no further ‘Y’ after a ‘N’ 
Kaplan-Meier analysis using PROC LIFETEST. 
Strata ACTARM. 
Request Failure plot adjusting axis and heading titles 
to reflect responder and not failure 
Output statistics: 
Appropriate statistics from analysis as indicated in 
mock shell 
Objective 2 
Number of days with hypoxia (defined 
as SpO2 <93% breathing room air or 
the dependence on supplemental 
oxygen after randomisation to Day 28 
(or discharge, whichever comes 
earlier) 
Use SpO2 (%) and Supp O2 (Y/N) from 
Vital parameters to derive indicator 
variable which flags each day where this 
condition holds.  
Derive variable per participant that gives 
total number of days with condition 
Summary statistics of variable with Total number of 
days: n, mean, SD, median, minimum, maximum 
By treatment arm 
 


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Endpoint 
Derivation 
Analysis 
Objective 3 
Duration of ventilator free days after 
randomisation to Day 28 (or 
discharge, whichever comes earlier) 
Use data from Vital parameters (include all 
days, where NIV, IV and ECMO=’N’) 
 
Summary statistics of variable with Total number of 
days: n, mean, SD, median, minimum, maximum 
By treatment arm 
Objective 3 
Duration of invasive mechanical 
(including ECMO) and non-invasive 
mechanical ventilation in ventilated 
participants 
Complement of above (exclude 
participants who are not ventilated i.e. do 
not include these with a duration of 0) 
 
Summary statistics of variable with Total number of 
days: n, mean, SD, median, minimum, maximum 
By treatment arm 
 
Objective 3 
Time since randomization until first 
use of high-flow oxygen devices or 
non-invasive mechanical ventilation or 
invasive mechanical ventilation or 
ECMO in non-ventilated participants 
(i.e. excluding participants who are 
ventilated within 24h prior to or after 
randomization) during 28-day 
assessment period 
 
Use Vital Parameter CRF and the method 
of supplementary oxygen variable. Use the 
date from this CRF to identify when first 
use occurred.  
Indicator variable to identify sub-group to 
be included. 
Censor if never used any of these 
ventilation methods at Day 28 
  
 
Kaplan-Meier analysis using PROC LIFETEST. 
Strata ACTARM. 
Request Survival plot adjusting axis and heading 
titles to reflect progression and not response 
Output statistics: 
Appropriate statistics from analysis as indicated in 
mock shell 
Objective 3 
Time since randomization to 
progression to ARDS 
Randomisation date 
Date of ARDS diagnosis 
Derive time variable (days) from date of 
randomization to date of ARDs diagnosis 
for each participant. For participants who 
Kaplan-Meier analysis using PROC LIFETEST. 
Strata ACTARM. 
Request Survival plot adjusting axis and heading 
titles to reflect progression and not response 


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Endpoint 
Derivation 
Analysis 
do not progress to ARDs, time is from date 
of randomization to date of discharge from 
hospital or 28 days, whichever is earlier. 
Derive Censor variable indicating whether 
Progression to ARDS (censor=0, otherwise 
censor=1) 
 
Output statistics: 
Appropriate statistics from analysis as indicated in 
mock shell 
Objective 3 
Duration of ICU stay in participants 
that enrolled in trial that were on 
invasive or non-invasive mechanical 
ventilation or high-flow oxygen 
devices within 24h prior to or after 
randomization during 28-day 
assessment period 
Duration of ICU stay in participants 
that enrolled in trial that were on 
invasive or non-invasive mechanical 
ventilation for less than 24h prior to or 
after randomization during 28-day 
assessment period 
 
Use DATES and Vital Signs dataset to 
calculate variable giving total number of 
days in ICU for sub-group of patients 
Summary statistics of variable with Total number of 
days: n, mean, SD, median, minimum, maximum 
By treatment arm 
 


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Endpoint 
Derivation 
Analysis 
Objective 6 
All-cause mortality rate at 28 days 
post randomisation (all treated 
participants) 
 
All-cause mortality rate at 28 days 
post randomisation (excluding 
participants that required invasive 
mechanical ventilation or ECMO, 
non-invasive mechanical ventilation or 
high-flow oxygen devices within 24 
hours prior to or after randomisation) 
 
All-cause mortality rate at 28 days 
post randomisation (excluding 
participants that required invasive 
mechanical ventilation or ECMO 
within 24 hours prior to or after 
randomisation) 
 
All-cause mortality rate at 28 days 
post randomisation (excluding 
participants that required invasive 
mechanical ventilation or ECMO, 
non-invasive mechanical ventilation or 
high-flow oxygen devices within 24 
hours prior to or after randomisation) 
 
All-cause mortality rate at 28 days 
post randomisation (only including 
participants that required invasive 
Using  6 point ordinal scores, DATES 
and VITAL SIGNS and SuppO2 
variables : 
Derive indicator variable identifying each 
sub-group of patients identified in the 
Endpoint column 
Derive Mortality variable identifying 
whether a patient has died within 28 days 
of randomisation 
For each mortality sub-group: 
PROC LOGISTIC 
Model: Mortality=ACTARM 
Output percentage died on each treatment and 95% 
confidence interval. 
Odds ratio and 95% confidence interval 
 


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Endpoint 
Derivation 
Analysis 
mechanical ventilation or ECMO 
within 24 hours prior to or after 
randomisation) 
 
All-cause mortality at follow up 12-22 
weeks post-randomisation for all 
treated participants 
Objective 5 
Incidents of participants in each 
category of the 6-point ordinal scale at 
follow-up 12-22 weeks post 
randomisation 
6-point ordinal score 
PROC FREQ to create summary table of actual 
counts and percentages for each of the 6-points on 
the ordinal scale at follow-up by treatment arm 
 
Objective 5 
Incidents of lung fibrosis on chest 
high-resolution computed tomography 
(HRCT) scan at follow up 12-22 
weeks post-randomisation  
 
 
Incidents of lung function 
abnormalities at follow up 12-22 
weeks post-randomisation  
HRCT results 
 
 
 
 
 
 
 
Lung function results – dataset should list 
all abnormalities in a consistent way across 
participants, including ‘None’ 
Summarise Left lower, Left middle and Left Upper 
Total Scores by treatment 
Summarise Right lower, Right middle and Right 
Upper Total Scores by treatment 
Provide 100% stacked bars for each of the above 6 
areas, coding by score (normal, reticular, bronch and 
honeycomb) – a separate graph for each treatment  
 
 
Objective 5 
Results from the 6-minute walk test 
 
 
 
 
 
 
 
 
 
 
 


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Endpoint 
Derivation 
Analysis 
Objective 5 
Incidents of participants in each 
category of the WHO performance 
scale 
WHO score 
Summary statistics of WHO Score by treatment at 
follow-up 
Objective 4 
Incidence of nosocomial bacterial or 
invasive fungal infection during 28-
day assessment period 
 
Note: Participants with viral 
respiratory infection are at risk of 
secondary bacterial infections. As part 
of clinical routine care, sputum or 
BAL samples will be collected in 
participants suspected of secondary 
bacterial pneumonia and checked for 
presence of bacteria. Measurements of 
procalcitonin levels will be performed 
at least 3x/week until 14 days or 
hospital discharge 
Procalcitonine will be concentrations.  
Concentrations are to be taken 3 times a 
week. The actual day each week may differ 
between participants. Allocate 1, 2 or 3 to 
each concentration taken in chronological 
order in each week. 
 
Replace ‘Not Dectectable’ with the lower 
limit of quantification and include in the 
summary statistics. 
 
Data for bacteria will be presence/absence 
at each day tested (if collected) 
 
 
Summarise procalcitonine concentrations by 
occasion (1,2,3) within each period of 7 relative days 
post first-dose for each treatment. 
 
Summary statistics to include n, nmissing, Mean, SD, 
Median, Minimum, Maximum. n in each case will be 
N-Not Done(nmissing).  
 
Provide line plots over relative day by treatment. A 
separate line for each participant 
 
Depending on distribution of data the above 
summary statistics will be provided using the log 
scale, and presented after back transforming 
 
No specific objective 
Change in ferritin levels between D1 
and D6 and between D1 and D15 (or 
discharge in each case) 
 
Change in CRP levels between D1 and 
D6 and between D1 and D15 (or 
discharge in each case) 
Laboratory values – derive change from 
D1 (i.e the last pre-dose value) to D6 and 
D15 or day of discharge 
Summarise change from D1 in concentrations to D6 
and to D15 (or day of discharge) for each treatment. 
 
Summary statistics to include n, nmissing, Mean, SD, 
Median, Minimum, Maximum. n in each case will be 
N-Not Done(nmissing).  
 


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Endpoint 
Derivation 
Analysis 
Provide line plots over relative by treatment, for both 
absolute values and change from D1. A separate line 
for each participant 
 


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9 
PHARMACOKINETICS AND PHARMACODYNAMICS  
9.1 
Pharmacokinetics 
Pharmacokinetic data are only collected pre-dose on Days 1, 2 and 6 in Group A. Concentration 
data will be listed and summarized. 
9.2 
Pharmacodynamics 
Plasma and serum samples were collected for summary and exploratory analysis as appropriate 
(e.g. compare change from baseline between the two treatment arms). Listings, summaries 
graphs and figures for raw values and change from baseline (if appropriate) over time will be 
generated. Associations with response may be explored. 
10 
SAFETY ANALYSES 
All safety summaries and listings will be presented by treatment group and overall based on the 
SS as defined in in Section 3.5 unless otherwise stated. 
10.1 
Extent of exposure 
Details of study treatment administration will be listed, including administration of the 
concomitant antibiotics, by treatment arm and participant, ordered by date of administration 
within participant. This listing will include all medications that are considered as SOC for Arm 
B. The actual endpoints to be listed will be defined in the TFL shells, but at a minimum should 
contain date and time of each dose of Zilucoplan® and concomitant antibiotics for participants 
on Arm A, and for each of the SOC medications and concomitant antibiotics for participants on 
Arm B. 
Frequency counts and percentages for the number of doses of study treatment received and 
summary statistics for the duration of exposure to study treatment will be presented overall and 
broken down by age (<75yr, >=75yrs) and sex. Duration of exposure will be calculated as 
follows: 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒= (𝐷𝑎𝑡𝑒 𝑜𝑓 𝐿𝑎𝑠𝑡 𝐷𝑜𝑠𝑒−𝐷𝑎𝑡𝑒 𝑜𝑓 𝐹𝑖𝑟𝑠𝑡 𝐷𝑜𝑠𝑒)  
Antibiotics after discharge for the Zilucoplan® arm were not collected by day (due to be taken 
for 14 days after discharge) in the CRF. Hence for Day 28-31 just the information of ‘were 
antibiotics’ taken (Y/N) will be listed, but the detail of compliance in this period will not be able 
to be captured. 
 
10.2 
Adverse events 
An AE is any untoward medical occurrence in a participant or clinical investigation participant 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
 
AEs are further characterised as pre-treatment or treatment emergent.  


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A pre-treatment AE are events whose onset date and time is prior to the first administration of 
study drug (Zilucoplan® for Arm A and IV antibiotic for Arm B). 
A TEAE is defined as any AE with a start date/time on or after the first dose of study treatment 
up until the D28 visit. Any AE with an onset date later than the D28 visit for a participant will 
not be considered as treatment-emergent and therefore will not be included in the tabulations of 
TEAEs. Where dates are missing or partially missing, AEs will be assumed to be treatment-
emergent, unless there is clear evidence to suggest that the AE started prior to the first dose of 
study treatment. Missing or partially missing dates for AEs will be handled as described in 
Section 4.2.3. All AEs for a participant will be recorded in the eCRF from the time of informed 
consent until completion or early study discontinuation.  
For each AE the following information should be provided in the eCRF: AE term (verbatim), 
date and time of onset, whether or not the AE was classified as an SAE, relationship to study 
treatment, severity, action taken with study treatment, other action taken, outcome, date and time 
of outcome and whether the AE led to study treatment discontinuation or to study 
discontinuation. 
 
COVID-19 infection is a very recent syndrome, on which few data are available. Therefore, 
normal symptoms and natural disease course symptoms that will not be reported as adverse 
events are dyspnea, coughing, malaise, fever, drop in oxygen saturation, progression to 
respiratory failure, progression to ARDS, drop in blood pressure. However, progression to multi-
organ failure may have other etiologies and will be reported as an SAE. 
 
The number and percentage of participants who experience TEAEs will be summarized by 
MedDRA preferred term (PT) and treatment.  
Summaries of TEAEs may include the following:  
• Incidence of overall TEAEs (overview including number and percentage of participants with 
any TEAEs, serious TEAEs, discontinuations due to TEAEs, drug-related TEAEs, severe 
TEAEs and TEAEs leading to death; event counts will also be included) 
• Incidence of TEAEs  
• Incidence of TEAEs by maximum intensity 
• Incidence of TEAEs by maximum CTCAE grade 
• Incidence of TEAEs by maximal relationship  
• Incidence of non-serious TEAEs above reporting threshold of 5% of study participants  
Summary tables will contain counts of study participant, percentages of study participants in 
parentheses and the number of events where applicable. A participant who has multiple events in 
the same SOC and PT during a given treatment will be counted only once in the participant 
counts for that treatment, but all events will be included.  
In summaries including relationship, the following relationships will be summarized: Any,‘Not 
related’, ‘Related’. eCRF entries of ‘Not applicable’ and ‘Unlikely’ will be classified as ‘Not 


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Related’. eCRF entries of ‘Possibly’, ‘Probably’ and ‘Definitely’ will be classified as ‘Related’. 
Participants who experience the same event multiple times will be included in the most related 
category for tabulations by maximum relationship. Events with missing relationship will be 
considered as ‘Related’ but recorded as missing in the listings.   
In summaries including intensity using CTCAE v5.0 grades, the following intensity categories 
will be summarized: ‘Grade 1 -Mild’, ‘Grade 2 - Moderate’, ‘Grade 3 -Severe’, ‘Grade 4 – life 
threatening’, ‘Grade 5 – Death’. Participants who experience the same event multiple times will 
be included in the most severe category for tabulations by maximum intensity. Events with 
missing intensity will be considered as ‘Severe’ events for summary purposes but recorded as 
missing in the listings.  
Adverse event summaries will be ordered alphabetically by System Organ Class (SOC) and 
decreasing frequency of PT within SOC in the group column for tables including event counts. 
For tables including only number and percentage of study participants, summaries will be 
ordered alphabetically by SOC and decreasing incidence of PT within SOC in the group column.  
Listings of AEs and TEAEs will include the following:   
• 
All AEs  
• 
Incidence of all TEAEs   
• 
All Related TEAEs   
• 
All Serious AEs  
• 
Discontinuation due to AEs  
All listings (except incidence of all TEAEs) will be presented by study participant and treatment 
and will include the onset date/time and outcome date/time of the event, the event duration 
(derived), time to onset (derived), pattern of event, intensity, relationship, action taken, outcome 
and AEs that led to discontinuation. 
The listing of incidence of all TEAEs will be presented by treatment and will include intensity, 
relationship, serious, number of participants reporting at least one TEAE within SOC/PT, 
number of individual occurrences of TEAE and site-participant number. 
 
10.3 
Clinical laboratory evaluations 
Clinical chemistry and hematology parameters may be summarized graphically and listed by 
treatment and timepoint for both absolute values and changes from baseline. 
10.4 
Vital signs, physical findings, and other observations related to 
safety 
10.4.1 
Vital signs 
Vital signs measurements maybe summarized graphically and listed by treatment and timepoint 
including changes from Baseline.  
10.4.2 
Electrocardiograms (if applicable) 
ECG data maybe listed. 


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11 
REFERENCES 
None at this time. 
 
12. 
APPENDICES 
None at this time. 
 
13. 
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP) 
(IF APPLICABLE) 
This is the first version of the SAP 


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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
 
 
Review and Approval of Clinical Documents 
for reviewer(s)/approver(s) not captured in ECMS 
 
Project code/Study Number: 
Compound Name: 
Indication (if applicable): 
ZILU-COV 
  Zilucoplan® 
  
 
Document(s) submitted 
for: (check one) 
 
Review 
 
 
X 
Approval 
 
 
Document(s) submitted: 
Statistical Analysis Plan 
 
 
Version Date: 
18December2020 
 
Submitted by: 
 
 
SSI - CTStat 
(Printed Name and Date) 
 
(Department and Function) 
 
Document distributed to: 
(Add rows as needed) 
Rolea 
 
Nameb 
SPhys 
 
 
Statistical 
Rep 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a As defined within sop-af-009924 
b Please name the person or persons to review or approve the document(s). 
 
Signed by: 
 
(Printed Author Name) 
 
(Author Signature)                                                 (Date) 
 
 


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Signed by: 
 
(Printed Author Name) 
(Author Signature)                                                 (Date) 
Note: For an approval not captured in ECMS, documentation of the approval (eg, printed Email) should be appended 
to this form. 
18 DEC 2020