A Randomized, Open-label, Adaptive, Proof-of-concept Clinical Trial of Donated Antibodies Working Against With COVID-19: DAWN-PLASMA
Phase: PHASE2
Conditions: COVID-19
Sponsor: Universitaire Ziekenhuizen KU Leuven

 
 Protocol: DAWN-Plasma 
Internal Ref.: S63992 
 
 
Version: v 2.5  27/10/2020  
 
 
 
 
 
 
 
 
 
 
 
                       
 
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interventional clinical Trial with Convalescent Plasma  
  
CLINICAL TRIAL PROTOCOL 
 
A randomized, open-label, adaptive, proof-of-concept clinical trial of 
Donated Antibodies Working agaiNst COVID-19: DAWN-PLASMA 
 
DAWN-Plasma  
 
Version number: v 2.5  date 27/10/2020 
 
 
 
 
 
Sponsor  
University Hospitals Leuven (UZ Leuven) 
Herestraat 49, B-3000 Leuven 
 
 
Coordinating Investigator 
Professor Dr. Geert Meyfroidt 
 
 
 
DAWN study coordination 
Professor Dr. Peter Verhamme 
 
 
 
 
 
 
Confidentiality Statement 
The information in this document is strictly confidential and is available for review to Investigators, potential 
Investigators and appropriate Ethics Committees, Institutional Review Boards or Competent Authorities.  No 
disclosure should take place without written authorization from the Sponsor. 
 
 
 
 

 
 
 
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CLINICAL TRIAL PROTOCOL HISTORY 
 
CTP / Amendment # 
Date 
Reason for amendment 
 
 
 
DAWN-Plasma v1.0  
 
6-4-2020 
 
DAWN-Plasma v2.0  
 
DAWN-Plasma v2.1 
 
DAWN-PLASMA V2.2 
10-4-2020 
 
15-4-2020 
 
24-4-2020 
 
  DAWN-PLASMA V2.3 
 
     27-4-2020 
  
DAWN-PLASMA V2.4 
 
   24/07/2020 
 
Minor revisions 
DAWN-Plasma V2.5 
 
  27/10/2020 
 
 
LIST OF PARTICIPATING SITES 
(as applicable) 
List Of Participating Sites 
Principal Investigator 
UZ Leuven 
Professor Dr Timothy Devos 
CHU Brugmann 
Dr Evelyne Maillart 
Erasmus Ziekenhuis Brussel 
Professor Dr David Grimaldi 
UZ Brussel 
Dr Lucie Seyler 
UMC Sint-Pieter Brussel 
Dr Nicolas Dauby 
AZ Delta Roeselare 
Dr Bernard Bouckaert 
CHU Liège Sart-Tilman 
Professor Dr Michel Moutschen 
Cliniques Universitaires St Luc 
Professor Dr Jean Cyr Yombi 
CHC Liège Mont Légia 
Dr Laurent Jadot 
Institut Bordet 
Dr Georgala Aspasia 
ZNA  Antwerpen 
Dr Niels Van Regenmortel 
AZ Groeninge 
Dr Matthias Leys 
CHR Jolimont Mons-Hainaut 
Dr Clotilde Visée 
CHR Citadelle Liège 
Dr Martial Moonen 
CHU Ambroise Paré 
Dr Camelia Rossi 
Sint-Trudo Ziekenhuis 
Dr Kristof Cuppens 

 
 
 
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Imelda Ziekenhuis Bonheiden 
Dr Emmanuel Van der Hauwaert
AZ Maria Middelares Gent 
Dr. Sarah Loof 
AZ Sint-Vincentius Deinze 
Dr. Sarah Loof 
Centre Hospitalier de Wallonie 
Picarde (CHwapi) 
Dr Mélanie Delvallee 
AZ Sint-Lucas Gent 
Elke Govaerts 
AZ West Veurne 
Bernard Vandooren 
 
 
 
 

 
 
 
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SIGNATURES 
 
Title:  A randomized, open-label, adaptive, proof-of-concept clinical trial of 
Donated Antibodies Working agaiNst COVID-19: DAWN-PLASMA 
Protocol: DAWN-Plasma 
 
The undersigned confirm that the above referenced protocol has been acknowledged and accepted, and 
agree to conduct the Trial in compliance with the approved protocol, and will adhere to: the principles 
outlined in the requirements for the conduct of clinical trials in the EU as provided for in Directive 
2001/20/EC or the EU Regulation 536/2014 (as soon as in effect) and any subsequent amendments thereto, 
the ICH guidelines, the most recent version of the Declaration of Helsinki,  the Belgian law of May 7th 2004 
regarding experiments on the human person (as amended) or the Belgian law of May 7th 2017 related to 
clinical trials on medicinal products for human use (as soon as in effect), the EU General Data Protection 
Regulation 2016/679 (GDPR), the relevant Belgian laws implementing the GDPR, the Belgian Law of August 
22nd 2002 on patient rights, the Sponsor’s applicable SOPs, and other regulatory requirements as applicable. 
The undersigned agree not to disclose the confidential information 
contained in this document for any purpose other than the evaluation or conduct of the Trial, without 
prior written consent of the Sponsor. 
The undersigned also commit to making the findings of the Trial publicly available through publication 
and/or other dissemination tools, in accordance with this protocol and applicable regulations, without any 
unnecessary delay and to provide an honest, accurate and transparent account of the Trial; and to explain 
any discrepancies or deviations from the approved Trial protocol.  
 
Coordinating Investigator 
Professor Dr Geert Meyfroidt 
………………………… 
………………………… 
 
Name & Title 
Signature 
Date 
 
Principal Investigator (Participating Site) (in case of monocentric Trial, the Principal Investigator is the 
same as the Coordinating Investigator) 
Professor Dr Timothy Devos 
 
………………………… 
………………………… 
 
Name & Title 
Signature 
Date 
 
 
Coordination Dawn trials 
Professor Dr Peter Verhamme 
 
………………………… 
………………………… 
 
Name & Title 
Signature 
Date 
 
 
 

 
 
 
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TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL................................................................................................................................... 2-1 
CLINICAL TRIAL PROTOCOL HISTORY .................................................................................................................. 2 
LIST OF PARTICIPATING SITES .................................................................................................................................... 2 
SIGNATURES ....................................................................................................................................................................... 4 
TABLE OF CONTENTS .................................................................................................................................................... 2 
LIST OF ABBREVIATIONS ............................................................................................................................................... 5 
FUNDING AND SUPPORT ............................................................................................................................................. 9 
ROLES AND RESPONSIBILITIES .................................................................................................................................... 9 
TRIAL SYNOPSIS ............................................................................................................................................................... 10 
TRIAL FLOWCHART DAWN-PLASMA .................................................................................................................... 13 
2 
Background and Rationale ...................................................................................................................................... 15 
3 
Trial Objectives and Design ................................................................................................................................... 16 
3.1 
Trial objectives ................................................................................................................................................ 16 
3.2 
Trial outcomes ................................................................................................................................................ 17 
3.2.1 
Primary outcome ....................................................................................................................................... 17 
3.2.2 
Secondary outcome................................................................................................................................... 17 
3.2.3 
Exploratory outcomes .............................................................................................................................. 18 
3.3 
Trial Design ...................................................................................................................................................... 18 
3.4 
Expected Duration of the Trial ................................................................................................................... 19 
4 
Trial Population / Eligibility Criteria ..................................................................................................................... 19 
4.1 
Inclusion criteria.............................................................................................................................................. 19 
4.2 
Exclusion criteria ............................................................................................................................................ 20 
5 
Trial Procedures ....................................................................................................................................................... 20 
5.1 
Participant Consent and withdrawal of consent ..................................................................................... 20 
5.2 
Selection of Participants / Recruitment ..................................................................................................... 21 
5.3 
Randomization Procedure ............................................................................................................................ 21 
5.4 
Trial Procedures ............................................................................................................................................. 21 
5.4.1 
By visit ........................................................................................................................................................... 21 
5.4.2 
Laboratory tests ......................................................................................................................................... 22 
5.4.3 
Other investigations .................................................................................................................................. 22 
5.4.4 
Exploratory investigations ....................................................................................................................... 22 
5.5 
Premature discontinuation of Trial treatment ........................................................................................ 23 
6 
Trial Intervention ...................................................................................................................................................... 24 
6.1 
Collection of convalescent plasma ............................................................................................................. 24 
6.2 
Convalescent Plasma and Dosing Regimen .............................................................................................. 25 
6.3 
Concomitant / Prohibited Medication / Treatment ............................................................................... 26 

 
 
 
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7 
Safety ............................................................................................................................................................................ 27 
7.1 
Specification, timing and recording of safety parameters ..................................................................... 27 
7.1.1 
Definitions.................................................................................................................................................... 27 
7.1.2 
Adverse Events that do not require reporting ................................................................................... 27 
7.1.3 
Recording and reporting of Adverse Events ....................................................................................... 28 
7.1.4 
Assessment .................................................................................................................................................. 28 
7.1.5 
Timelines for reporting ............................................................................................................................ 29 
7.1.6 
Follow-up ..................................................................................................................................................... 29 
7.1.7 
Death ............................................................................................................................................................ 29 
7.1.8 
Reporting requirements to Ethics Committee’s (EC’s) and Competent Authorities (CA’s) . 29 
7.1.9 
Hemovigilance ............................................................................................................................................. 29 
7.1.10 Annual reporting ........................................................................................................................................ 30 
7.1.11 Data and safety monitoring committee (DSMB) and treatment stopping rules ......................... 30 
8 
Statistics and Data Analysis. ................................................................................................................................... 31 
8.1 
Sample Size Determination .......................................................................................................................... 31 
8.2 
Statistical Analysis ........................................................................................................................................... 32 
8.3 
Data & Safety Monitoring Board (DSMB) ................................................................................................. 35 
9 
Data handling ............................................................................................................................................................. 35 
9.1 
Data Collection Tools and Source Document Identification .............................................................. 35 
9.1.2 
Legal requirements .................................................................................................................................... 36 
9.2 
Audits and Inspections................................................................................................................................... 36 
9.3 
Monitoring ........................................................................................................................................................ 36 
9.4 
Archiving ........................................................................................................................................................... 37 
10 Ethical and Regulatory Considerations ................................................................................................................ 37 
10.1 
Ethics Committee (EC) review & reports ................................................................................................ 37 
10.2 
Regulatory Compliance ................................................................................................................................. 37 
10.3 
Protocol / GCP compliance ......................................................................................................................... 37 
10.4 
Data protection and participant confidentiality ...................................................................................... 38 
10.5 
Insurance ........................................................................................................................................................... 38 
10.6 
Access to the Study Data by KCE and similar institutes in the EU ................................................... 38 
10.7 
Amendments .................................................................................................................................................... 39 
10.8 
Post-Trial activities ......................................................................................................................................... 40 
11 Research Registration, Dissemination of Results and Publication Policy .................................................... 40 
12 Intellectual Property ................................................................................................................................................. 40 
13 Joint Commission International (JCI) ................................................................................................................... 41 
References ........................................................................................................................................................................... 42 
APPENDICES ...................................................................................................................................................................... 44 
14 Appendix 1: Data Processing Annex (DPA) ...................................................................................................... 44 

 
 
 
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Definitions: ........................................................................................................................................................................... 44 
 
 
 
 
 
 

 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
(e)CRF 
(electronic) Case Report Form 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
APR 
Annual Progress Report 
ASR 
Annual Safety Report 
AR 
Adverse Reaction 
CA 
Competent Authority 
CI 
Coordinating Investigator 
CIOMS 
Council for International Organizations of Medical Sciences 
CM 
Concomitant Medication 
CSR 
Clinical Study Report 
CTP 
Clinical Trial Protocol 
DMP 
Data Management Plan 
DPA 
Data Processing Annex 
DSMB 
DSUR 
Data and Safety Monitoring Committee 
Development Safety Update Report 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EoT 
End of Trial 
FPFV 
First Patient First Visit 
GCP 
Good Clinical Practice (latest version of ICH E6) 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ISF 
KCE 
Investigator Site File 
Federaal Kenniscentrum voor de gezondheidszorg - Federal Knowledge 
Centre   for Health Care 
LPLV 
Last Patient Last Visit 
MAH 
Marketing Authorisation Holder 
MP 
Monitoring Plan 
PI 
Principal Investigator (Participating Site) 
PRO 
Patient Reported Outcome 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
SOC 
Serious Adverse Reaction 
Standard of Care / Best supportive care 
SmPC 
Summary of Product Characteristics 

 
 
 
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SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File 
TSC 
Trial Steering Committee 
 
 
 
 
 
 
 
 
 
 

 
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FUNDING AND SUPPORT 
Funder: KCE
Type of Financial or Non-Financial Support
No fault liability insurance has been taken out by UZ Leuven for treating and/or compensating Trial 
participants who are harmed as a consequence of participation in the Trial. 
 
 
ROLES AND RESPONSIBILITIES 
The Principle Investigator (PI) is responsible for the conduct of the Trial at his/her Participating Site, and 
for protecting the rights, safety and well-being of the Trial participants. As such the PI must ensure 
adequate supervision of the Trial conduct at the Participating Site. If any tasks are delegated, the PI will 
maintain a log of appropriately qualified persons to whom he/she has delegated specified Trial-related 
duties. The PI will ensure that adequate training is provided and documented for all Trial staff, prior to 
conducting assigned Trial-related activities.  
It is the Coordinating Investigator's (CI’s) responsibility to supervise the general conduct (e.g. Trial 
progress, communication, protocol training and support of the participating sites, annual reporting to the 
Ethics Committee (EC), end of Trial notification(s) and results reporting…) of the Trial.  The CI fulfils 
both  Investigator and Sponsor responsibilities, as outlined in International Conference on Harmonisation 
– Good Clinical Practice (ICH-GCP) E6(R2) and applicable regulations. 
PI and CI shall each be referred to as « Investigator(s)». 
 
 
 
 
 

 
 
 
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TRIAL SYNOPSIS 
 
Title of clinical Trial 
(«Trial») 
A randomized, open-label, adaptive, proof-of-concept clinical trial of 
Donated Antibodies Working agaiNst COVID-19: DAWN-PLASMA 
Protocol Short Title 
Acronym 
DAWN-Plasma 
Trial Phase (I, II, III, IV) 
phase II proof-of-concept study 
Sponsor name 
University Hospitals Leuven (UZ Leuven) 
Coordinating Investigator 
Prof. Dr. Geert Meyfroidt 
           Contact Address CI 
Herestraat 49, 3000 Leuven (UZ Leuven) 
           E-mail 
geert.meyfroidt@uzleuven.be  
           Phone 
+32 16 34 40 21 
Medical condition or disease 
under investigation 
COVID-19 
Trial rationale  
To evaluate clinical efficacy and safety of convalescent plasma for COVID-
19 
Primary objective 
The overall objective of the study is to evaluate the clinical efficacy and 
safety of best supportive care combined with convalescent plasma versus 
best supportive care only in patients hospitalized with COVID-19. 
Secondary objective(s) 
To evaluate clinical efficacy of convalescent plasma vs. SOC as assessed by 
Clinical Severity, Oxygenation, Ventilation, Hospitalisation. 
Trial Design 
Randomized, Open-label, Multicentre, Adaptive Study design 
Other public database nbr  
/ 
Principal Investigators and 
Participating Sites 
University Hospitals Leuven (UZ Leuven): local PI = Prof. Dr. Timothy 
Devos 
 
Cfr list op participating sites page 2 
Medical condition or disease 
under investigation 
COVID-19 
Outcomes 
Primary outcome
Patients requiring mechanical ventilation or death 
 
Key secondary outcome 
Clinical status of subject at day 15 and day 30 (on a 10-point “WHO 
progression” ordinal scale):  
0. Uninfected. Non viral RNA detected 
1. Ambulatory, Asymptomatic, viral RNA detected 
2. Ambulatory, Symptomatic, Independent 
3. Ambulatory, Symptomatic, Assistance needed  
4. Hospitalized, mild disease, No oxygen therapy needed 
5. Hospitalized, mild disease, Oxygen by mask of nasal prongs 
6. Hospitalized, severe disease, Oxygen by NIV or High flow 
7. Hospitalized, severe disease, Intubation and mechanical 
ventilation (pO2/FiO2>=150 OR SpO2/FIO2>=200) 

 
 
 
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8.
Hospitalized, severe disease, Mechanical ventilation 
(pO2/FiO2<150 OR SpO2/FIO2<200) OR vasopressors 
(norepinephrine >0.3 microg/kg/min) 
9. Hospitalized, severe disease, Mechanical ventilation 
pO2/FiO2<150 AND vasopressors (norepinephrine >0.3 
microg/kg/min), OR Dialysis OR ECMO 
10. Death, Dead 
 
 

 
 
 
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Sample Size 
483 patients with 2:1 randomization 
• 
322 patients receiving plasma 
• 
161 patients receiving SOC 
Blood product, dosage and 
route of administration 
4 units of convalescent plasma:
• 
2 units of plasma are administered within 12h after 
randomization, but preferably as soon as practically possible 
• 
2 units of plasma should be administered between 24h and 36h 
after the first infusion 
 
Other investigational products may be added as part of the adaptive 
study design. 
Labs conducting neutralizing 
antibody testing 
REGA institute Leuven (Piet Maes); Sciensano (Cyril Barbezange), 
University of Liège (Daniel Desmecht), ITG (Kevin Arïen). 
 
Active comparator 
product(s) 
none 
Maximum duration of 
treatment and Follow Up of 
a Participant 
90 days of follow-up  
Maximum duration of entire 
Trial 
18 months 
Date anticipated First 
Participant First Visit (FPFV) 
To be determined 
Date anticipated Last Patient 
Last Visit (LPLV) 
Unknown 
 
 
 
 
 
 

 
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TRIAL FLOWCHART DAWN-PLASMA 
Schedule of Events – Trial specific Procedures / Assessments 
 
Screen 
Baseline 
 
 
 
 
 
 
 
Day +/- window 
-1 or 0 
0 
Daily until discharge 
Within 12 
hours after 
randomization* 
24-36 hours 
afer 1st 
administration* 
6 +/- 2 
15 +/- 2 
30 +/- 3 
Day 
90+/-5  
 
 
 
 
Assesments/Procedures 
 
 
 
 
ELIGIBILITY 
 
 
 
 
Informed consent 
X 
 
 
 
 
Demographics & Medical History 
X 
 
 
 
 
Review COVID-19 criteria 
X 
 
 
 
 
In- and exclusion criteria 
X 
 
 
 
 
ABO D typing *1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY INTERVENTION 
 
 
 
 
Randomization 
X 
 
 
 
 
Administration of Plasma 
X    
X 
 
 
 
 
 
 
STUDY PROCEDURES 
 
 
 
 
Vital signs including SpO2 
X 
Daily until discharge 
 
 
 
 
 
 
Clinical data collection 
X 
Daily until discharge 
 
 
 
 
 
 
Targeted medication review 
X 
Daily until discharge 
 
 
 
 
 
 
Targeted Adverse event evaluation 
when it occurs 
X 
Daily until discharge 
 
 
 
 
 
 

 
 
 
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ECG 
 
X 
 
 
 
 
 
 
 
Evaluation by telephone 
 
 
 
 
X 
X 
X 
LABORATORY 
 
 
 
 
CRP, haematology, chemistry, kidney 
and liver test 
X 
At 
clinician’s 
discretion 
At clinician’s discretion 
 
 
 
 
Pregnancy test for females of 
childbearing potential 
X 
 
 
 
 
Viral qPCR (Nasopharyngeal swab) 
X 
 
 
 
 
If 
feasible 
 
 
 
Blood for COVID-19 antibody titer 
testing and immunoparesis (optional) 
*2 
X 
 
 
 
 
X 
 
 
 
Quality of life scoring *3 
X 
 
 
 
 
 
 
X 
X 
VAS Pain Score *4 
X 
 
Daily until discharge 
 
 
 
 
 
 
 
*1 ABO D typing has to be performed twice at two different, independent time points and the two ABO D results have to be identical before the blood institution can 
release the plasma units. Before randomisation the ABO D typing should be done at least once and the result should be known. 
*2  one serum tube of 10 ml and one EDTA tube of 10 mL. This blood is drawn if feasible and in sites that agree to participate. 
*3 Q of L scoring using the EQ-5D-5L questionnaire. QofL scoring at day+30 is optional if the patient is still hospitalized; if patient is at home at day+30, scoring will be 
done by telephone call. 
*4 Daily until discharge 
 
 
 

 
 
 
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2 Background and Rationale 
In December 2019, the Wuhan Municipal Health Committee identified an outbreak of viral pneumonia 
cases of unknown cause. Coronavirus RNA was quickly identified in some of these patients. This novel 
coronavirus has been designated SARS-CoV-2, and the disease caused by this virus has been designated 
COVID-19. Currently there are no approved therapeutic agents available for coronaviruses1.  
 
The Direct antivirals working against nCoV (DAWN) master study protocol allow to investigate promising 
drug compounds or convalescent plasma in a proof-of-concept study. The study complies with the 
recommendations 
for 
outcomes 
as 
outlined 
by 
the 
WHO 
master 
template 
protocol 
(https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/early-
investigations; and https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-
novel-coronavirus-2019-ncov assessed on March 20th 2020). The design is adaptive, i.e. it allows to add and 
remove treatment arms and or strata for based on the most updated information. 
 
Based on the current information, different strategies hold promise for a successful reduction of COVID-
19 disease burden. The first is anti-viral therapy to reduce viral replication.  The second strategy is to 
modify the inappropriate host inflammatory response. Widespread systemic inflammation and 
subsequent activation of the coagulation and complement system have repeatedly been described in severe 
COVID-193,4.  
 
Another potentially attractive treatment option for COVID-19 infection is the administration of 
convalescent plasma.  
 
Plasma collected from patients who have recovered from a SARS-CoV-2 infection, contains antiviral 
antibodies. This could help newly diagnosed patients with SARS-CoV-2 infection to clear the infection more 
rapidly. This plasma provides passive polyclonal antibody administration and thus immediate immunity. The 
treatment effect of plasma has already been shown in other viral infections but has not been studied in 
patients with SARS-CoV-2  infection. A recent meta-analysis has shown that convalescent plasma reduces 
mortality compared to standard of care in patients with SARS and severe influenza infections. Importantly, 
these studies were heterogeneous on the timing of plasma adminitstration and the threshold on anti-virus 
antibodies in convalescent patients. It is particularly successful when administered early after symptom 
onset (PMID 25030060).  
 
Information on immune response on SARS-CoV-2 infection is rather limited at this point. It seems that 
seroconversion occurs within 2 weeks after infection. Recently, case series showed that convalescent 
plasma possibly had a contributory effect on clinical improvement of 5 critically ill patients with SARS-CoV-
2 and acute respiratory distress syndrome (PMID 32219428) . This study will evaluate the effect of passive 
immunotherapy with recovalsescent plasma for the treatment of patients with a newly diagnosed SARS-
CoV-2 infection.  
 
However, convalescent plasma has proven not to be effective against other viral infection (e.g. Ebola) and 
carries a risk of ADE (antibody-dependent enhancement), which could result in worsening of the ARDS. 
Hence, the efficacy and safety of convalescent plasma should be studied in a randomized controlled setting.  
 
The amount of administered plasma varied in studies investigating the added value of convalescent plasma 
in the SARS epidemic in 2003. The volume of plasma infused ranged from 160mL to 640mL (PMID 
15616839). There is no consensus in literature on the optimal volume of convalescent plasma for maximum 
treatment effect.  In this study, we will investigate the added value of 4 units of plasma. This allows to 
administer plasma of different donors with a variable titer of anti-COVID 19 antibodies to the same patient, 
ensuring that enough anti-COVID19 antibiodies will provide passive immunisation. 

 
 
 
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Eligible adult patients who tested positive for SARS-CoV-2 and are admitted to the hospital will be 
randomized and assessed daily during hospitalization. Discharged patients will be contacted by telephone 
at days 15, 30 and 90. All subjects will undergo efficacy and safety assessments, including laboratory assays, 
which are aligned with clinical care. Only an extra blood sample will be drawn at baseline. Also blood 
samples and nasopharyngeal swabs will be done according to clinical need (standard of care). If feasible, an 
additional nasopharyngeal swab will be taken on day 6. The study should not put an extra burden on 
healthcare workers and on the hospital’s resources.  
 
3 
Trial Objectives and Design 
3.1 Trial objectives 
The study objectives are adapted from the WHO master protocol that was proposed to streamline 
interventional studies in patients with COVID-19.  (https://www.who.int/emergencies/diseases/novel-
coronavirus-2019/technical-guidance/early-investigations; 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-
2019-ncov assessed on March 20th 2020). 
 
The overall objective of the DAWN-plasma study is to evaluate the clinical efficacy and safety of 
convalescent plasma relative to the standard of care in patients hospitalized with COVID-19.  
 
Secondary objectives are to evaluate clinical efficacy of convalescent plasma as compared to the control 
arm.  
Clinical Severity 
Ordinal scale: 
o 
time to an improvement of one category from admission on an ordinal scale. 
o 
subject clinical status on an ordinal scale at days 3, 5, 8, 11, 15 and 30. 
o 
mean change in the ranking on an ordinal scale from baseline to days 3, 5, 8, 11, 15 and 
30 from baseline. 
 
Oxygenation 
o 
oxygenation free days in the first 30 days (to day 29). 
o 
incidence and duration of new oxygen use during the trial.  
 
Mechanical Ventilation 
o 
the proportion of patients requiring invasive mechanical ventilation 
o 
ventilator free days alive in the first 30 days (to day 29). 
o 
incidence and duration of new mechanical ventilation use during the trial. 
 
 
Hospitalization 
o 
duration of hospitalization (days).  
 
Mortality  
o 
15-day mortality 
o 
30-day mortality  
o 
90-day mortality 
 

 
 
 
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Evaluate the safety of the interventions through 30 days of follow-up as compared to the control 
arm as assessed by 
o 
transfusion-related adverse reaction 
o 
discontinuation or temporary suspension of drug administration (for any reason).  
o 
cumulative incidence of serious adverse events (SAEs) and adverse events (AEs) graded as 
severe. 
 
 
3.2 Trial outcomes 
The study outcomes are based on the WHO master protocol. 
 
3.2.1 
Primary outcome 
 
Primary outcome of the study is the number of patients alive without mechanical ventilation at day 15 
after hospitalization. 
 
Rationale: the primary objective of the study is to avoid further clinical decline by administering 
convalescent plasma to hospitalized patients early after symptom onset to provide immediate (passive) 
immunity. The hypothesis is that early administration of plasma will help to counter the clinical 
deterioration when pathology is mainly driven by viral replication, and hence will prevent the need for 
mechanical ventilation or death in the first 15 days after randomization. The null hypothesis is that 
convalescent plasma will not be effective to prevent the need for mechanical ventilation or death. It is of 
utmost importance to find treatment that reduces ICU demand as current strategies of prolonged 
distancing likely to have negative social and economic impact (PMID 32291278). 
 
 
 
3.2.2 
Secondary outcome  
 
 
1) outcomes as per WHO criteria: 
 
Clinical status of subject at day 15 and day 30 (on a 10-point “WHO progression” ordinal 
scale):  
0. Uninfected. Non viral RNA detected 
1. Ambulatory, Asymptomatic, viral RNA detected 
2. Ambulatory, Symptomatic, Independent 
3. Ambulatory, Symptomatic, Assistance needed  
4. Hospitalized, mild disease, No oxygen therapy needed 
5. Hospitalized, mild disease, Oxygen by mask of nasal prongs 
6. Hospitalized, severe disease, Oxygen by NIV or High flow 
7. Hospitalized, severe disease, Intubation and mechanical ventilation (pO2/FiO2>=150 OR 
SpO2/FIO2>=200) 
8. Hospitalized, severe disease, Mechanical ventilation (pO2/FiO2<150 OR SpO2/FIO2<200) OR 
vasopressors (norepinephrine >0.3 microg/kg/min) 
9. Hospitalized, severe disease, Mechanical ventilation pO2/FiO2<150 AND vasopressors 
(norepinephrine >0.3 microg/kg/min), OR Dialysis OR ECMO 
10. Death, Dead 
 
  
 
 

 
 
 
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2) secondary outcomes (listing): 
 
• 
proportion of patients on mechanical ventilation or death within 30 days and 90 days after 
randomisation. 
• 
Clinical Status on days 15 and 30. 
• 
time from Day 0 to sustained clinical improvement or life discharge, whichever comes first, 
whereby a sustained clinical improvement is defined as an improvement of > 2 points vs the 
highest value of Day 0 and 1 and sustained for at least 3 days. 
• 
duration of hospitalization 
• 
duration of supplemental oxygen 
• 
duration of mechanical ventilation. 
• 
need for and duration of intensive care stay. 
• 
need for and duration of ECMO. 
• 
date and cause of death (if applicable). 
• 
adverse events graded as severe or SAEs 
• 
venous thromboembolism: deep vein thrombosis and pulmonary embolism 
• 
transfusion related side effects like transfusion related acute lung injury, serious allergic 
transfusion reactions and transfusion associated circulatory overload. 
• 
correlation between clinical outcome and titer of anti-SARS-Cov-2 neutralizing antibodies in 
transfused plasma units 
• 
safety of convalescent plasma therapy 
• 
effect of plasma therapy on quality of life 30 days after randomization 
• 
Vital signs:  
o 
daily highest temperature measured during hospitalization with a maximum of 14 days 
after hospitalization 
o 
Highest amount of oxygen given (in L/min) daily during hospitalization with a maximum 
of 14 days after hospitalization 
 
 
 
3.2.3 
Exploratory outcomes  
 
• 
qualitative and quantitative PCR for SARS-CoV-2 in (naopharyngeal) swab on day 6 (when 
feasible)  
• 
NT50 values measured at baseline Day 6 
• 
Comparing clinical efficacy of convalescent plasma in patients that already had anti-COVID19 
antibody specificities with patients that did not have antibodies before the administration of 
plasma. These results will not be available real-time but are subject to a post-hoc analysis. 
 
 
 
 
3.3 Trial Design 
 
This DAWN-plasma study is a randomized, open-label clinical trial to evaluate the safety and 
efficacy of convalescent plasma in hospitalized adult patients diagnosed with COVID-19.  
 
The outcomes of the study protocol are in part based on the draft master protocol of the WHO for 
trials that evaluate safety and efficacy of investigational therapeutics for the treatment of COVID-19 in 
hospitalized patients.  
 
The study is a  phase 2 proof-of-concept multicenter trial.  
 

 
 
 
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The DAWN study will compare standard of care vs. standard of care with convalescent plasma. Since there 
are no current approved treatment options for COVID-19, the standard of care is mostly supportive. 
However, the standard of care will reflect the guidance by (inter)national guidelines and hence may change 
during the course of the study. The clinical outcomes of this study have been choosen based on the 
outcomes of the WHO master template for clinical studies to allow pooling of the data with other ongoing 
studies.  
 
The DAWN-PLASMA will randomize with a 2:1 allocation to SOC combined with convalescent plasma 
versus SOC.  
 
If judged necessary, the trial can be extended to add a third arm to allow the participation of centers 
participating to other clinical trials. This will be based on appropriate statistical considerations; 
randomization to this third arm and analysis of this third arm data will then be described in the SAP. 
A third arm can be included provided that no selection bias is introduced. This means that sites should not 
decide up front which patients are eligible for either study as this may introduce bias in allowing patients 
to enter one study or the other. 
 
3.4 Expected Duration of the Trial 
 
The DAWN PLASMA is expected to start April 2020, with a duration of 18 months. 
 
 
4 
Trial Population / Eligibility Criteria 
4.1 Inclusion criteria 
Participants eligible for inclusion in this Trial must meet all of the following criteria: 
 
1. Subject (≥18 years old) or legally authorized representative provides informed consent prior to 
initiation of any study procedures. When signed informed consent is not possible (e.g. due to 
restrictions to prevent viral transmission), verbal informed consent in the presence of a witness 
will be obtained and documented in the medical files. Signed informed consent will be obtained as 
soon as the safety concerns are mitigated. 
2. Subject (or legally authorized representative) understands and agrees to comply with planned study 
procedures.  
3. Male or non-pregnant female adult ≥18 years of age at time of enrolment.  
4. Patient should be hospitalized 
5. Has a confirmed diagnosis of SARS-CoV-2 infection, defined as either:  
a. laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or other commercial 
or public health assay in any specimen as diagnosed within 60 hours prior to randomization 
or 
b. The combination of upper or lower respiratory infection symptoms (fever, cough, 
dyspnea, desaturation) and typical findings on chest CT scan and absence of other 
plausible diagnoses  
6. Illness of any duration, and at least one of the following: 
a. Radiographic infiltrates by imaging (chest x-ray, CT scan, etc.), or  
b. Clinical assessment (evidence of rales/crackles on exam) AND SpO2 ≤ 94% on room air, 
or  
c. Requiring supplemental oxygen.  

 
 
 
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7. ABO D typing of the patient should be done at least once and the result should be known. 
 
 
 
All participants that are considered for Trial participation, per the above criteria will be documented on 
the Screening Log, including Screen Failures.  
 
4.2 Exclusion criteria 
 
Participants eligible for this Trial must not meet any of the following criteria: 
1. Receiving invasive (any mode where a patient has been intubated endotracheally, or via 
tracheostomy) or non-invasive (for instance, but not restricted to CPAP, PSV, PCV, SiMV) 
mechanical ventilation before or upon randomization. 
2. Pregnancy or breast feeding.  
3. Any medical condition which would impose an unacceptable safety hazard by participation to the 
study. 
4. Patients with a documented grade 3 allergic reaction after the administration of fresh frozen 
plasma (i.e. systemic reaction with cardiovascular and/or respiratory involvement) 
5. Patients that have treatment restriction that excludes mechanical ventilation and/or endotracheal 
intubation 
6. Rituximab or another anti-CD20 monoclonal antibody (f.ex. obinutuzumab) has been 
administered during the year prior of the date of admission. 
 
Participants who meet one or more of the above exclusion criteria must not proceed to be 
enrolled/randomized in the Trial and will be identified on the Screening Log as Screen Failure. 
 
 
5 
Trial Procedures 
5.1 Participant Consent and withdrawal of consent 
The Trial will be conducted only on the basis of prior informed consent by the Trial participants and/or 
their legally authorized representative(s). As such, no Trial-related procedures will be conducted prior to 
obtaining written informed consent from potential Trial participants. 
When signed informed consent is not permitted because of safety regulations related to the prevention of 
the transmission of SARS-CoV-2, verbal informed consent shall be documented in the medical records. 
Signed informed consent shall then be obtained as soon as permitted based on safety regulations to prevent 
the transmission of SARS-CoV-2. 
The process for obtaining and documenting initial and continued informed consent from potential Trial 
participants will be conducted in accordance with ICH-GCP E6(R2), applicable regulatory requirements 
and internal Standard Operating Procedures (SOPs). 
All originally signed obtained Informed Consent Forms (ICFs) must be retained/archived in the Investigator 
Site File (ISF) at the Participating Site and must not be destroyed (even when a scanned copy is available) 
before expiration of the legal archiving term as defined in the protocol section entitled “Archiving”.  
Participants may voluntarily withdraw consent to participate in the Trial for any reason at any time. The 
participant’s request to withdraw from the Trial must always be respected without prejudice or 
consequence to further treatment. Consent withdrawal will be documented in the participant’s medical 
record. The PI must take into account the consequences of such withdrawal: (1) further use of personal 

 
 
 
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data/Trial data, (2) use of human biological materials already collected, (3) safe transition to alternative 
treatment options, etc. as applicable 
 
5.2 Selection of Participants / Recruitment 
Only adult hospitalized patients diagnosed with COVID-19 will be included. 
 
 
5.3 Randomization Procedure  
To ensure the integrity of the Trial, a randomization procedure through a computerized system has been 
established, generated by the data management unit of the clinical trial center leuven.  For the multicentre 
DAWN-PLASMA study a randomization ratio of 2 convalescent plasma to 1 usual care will be allocated. 
 
5.4 Trial Procedures 
 
5.4.1 
By visit 
 
Screening:  
Patients with documented COVID-19 who require hospitalization will be screened for eligibility. Informed 
consent will be obtained. Availability of plasma will be checked before the informed consent procedure. 
When written informed consent is not possible due to restrictions to prevent the transmission of SARS-
CoV-2, oral informed consent will be documented in the medical files, and completed with written 
informed consent as soon as the restrictions do no longer apply. 
Demographic parameters will be obtained. Medical history will be obtained as part or routine clinical care. 
When study-related procedures impose an additional burden on the clinical care of patients, they can be 
waived.  
A first blood grouping should be done upon hospitalization of the patient to facilitate fast plasma 
administration following randomization. 
 
Baseline / Randomization: 
Parameters should be obtained as part of routine clinical care. 
When study related procedures impose an additional burden on the clinical care of patients, they can be 
waived. Study blood product will be administered when randomized to the investigational blood product 
arm. Medication will be reviewed using the electronic medical files. Serious adverse events and adverse 
events grade IV will be collected when these are not outcomes of the study.  
 
Administration of Blood product 
Convalescent plasma (2 units of approximately 250mL) will be administered within 12 hours after 
randomization, with a second administration (2 units of approximately 250mL) 24 to 36 hours after the 
first administration.  
In the situation of non-feasibility to transfuse the plasma units overnight, the two first plasma units will be 
administered at the latest the next morning after randomization 
 
Plasma should not be transfused with the usal speed of 30 to 45 minutes but should be administered at a 
maximal speed of 50-100 millilitres per hour. This will reduce the risk of volume overload significantly. 
 
Daily assessments until discharge: 
- 
Vital signs including SpO2 
- 
Clinical data collection for assessment of study outcomes 

 
 
 
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- 
Adverse event evaluation 
- 
VAS Score: daily until discharge 
Serious adverse events and adverse events grade IV will be collected when these are not outcomes of the 
study. When study-related procedures impose an additional burden on the clinical care of patients, they 
can be waived.  
 
Visit at Day 6 (+/-2) 
If feasible: Viral qPCR (Nasopharyngeal swab) 
Blood for COVID-19 antibody titer testing and immunoparesis (optional) 
 
Visit at Day 15 (+/-2), 30(+/-3) and 90 (+/-5) 
These visits can be phone visits when patients are no longer hospitalized. 
 
 
5.4.2 
Laboratory tests 
To avoid burden on clinical care in a time of a strained health care system, laboratory tests are part or 
routine clinical care and are not mandatory, but when available, a targeted set will be collected for 
exploratory purposes  (including but not limited to CRP, total white cell and lymphocyte count, 
haemoglobin, platelets, creatinine, hsTroponinT, LDH, ferritin, glucose, total bilirubin, ALT, and AST, D-
dimers).  
 
If feasible, a blood sample from baseline before plasma transfusion should be stored locally and shipped to 
the central lab to allow to see whether anti-COVID 19 antibodies are already present and to allow for 
extra analyses after the outbreak when resourrces are more available. 
 
 
5.4.3 
Other investigations 
 
The study includes two optional samples: 
- 
at baseline: on Day 0 (+/- 2):  blood samples for the assessment of immunoparesis against SARS-
CoV-2 and antibody clearance. This blood samples should be collected before the first infusion 
of convalescent plasma. Samples will be stored locally and shipped in batches to the central 
reference lab. The practical details of local storage and shipment can be found in the lab manual. 
 
- 
on Day 6 (+/- 2): blood samples for the assessment of immunoparesis against SARS-CoV-2 and 
antibody clearance. Samples will be stored locally and shipped in batches to the central reference 
lab. The practical details of local storage and shipment can be found in the lab manual. 
 
The study includes a sample to be taken, when feasible: 
- 
viral qPCR (nasopharyngeal swab) at Day 6 (+/- 2) 
 
(the viral qPCR (nasopharyngeal swab) at baseline, on day 0 (+/- 2), is mandatory) 
 
5.4.4 
Exploratory investigations 
 
A telephone call on D90 (+/-5days) will check for hospital admission or survival status. 
 
 

 
 
 
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5.5 Premature discontinuation of Trial treatment 
Participants may voluntarily discontinue Trial treatment and/or prematurely end their participation in the 
Trial for any reason at any time. In such case the Investigator must make a reasonable effort to contact the 
participant (e.g. via telephone, e-mail, letter) in order to document the primary reason for this decision. 
The Investigator may also decide at any time during the course of the Trial, to temporarily interrupt or 
permanently discontinue the Trial treatment if it is deemed that continuation would be detrimental to, or 
not in the best interest of the participant.  
Similarly, the Sponsor, Ethics Committee or authorized regulatory authority can decide to halt or 
prematurely terminate the Trial when new information becomes available whereby the rights, safety and 
well-being of Trial participants can no longer be assured, when the integrity of the Trial has been 
compromised, or when the scientific value of the Trial has become obsolete and/or unjustifiable.  
Circumstances requiring premature treatment interruption or discontinuation of the Trial, include but 
are not limited to:  
• 
Safety concerns related to Blood product or unacceptable intolerability (potentially life-threatening 
transfusin reaction during plasma infusion)/  
• 
Trial participation while in violation of the inclusion and/or exclusion criteria  
• 
Pregnancy  
• 
Intention of becoming pregnant  
• 
… 
 
In any such case of early Trial termination and/or treatment interruption/discontinuation, the Investigator 
will continue to closely monitor the participant’s condition and ensure adequate medical care and follow-
up.  
For participants whose status is unclear because they fail to appear for Trial visits without stating an 
intention to discontinue or withdraw, the Investigator must make every effort to demonstrate “due 
diligence" by documenting in the source documents which steps have been taken to contact the 
participant to clarify their willingness and ability to continue their participation in the Trial (e.g. s of 
telephone calls, registered letters, etc.). 
A participant should not be considered lost to follow-up until due diligence has been completed. 
 
 

 
 
 
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6 
Trial Intervention 
DAWN PLASMA 
Generic Drug Name 
(& company brand name) 
 
Used within Indication? (Y or N) 
Convalescent plasma 
Plasma
N
 
 
6.1 Collection of convalescent plasma 
 
Donor eligibility 
Convalescent plasma donors should be recruited in a population of patients that were infected with 
COVID-19 and recovered. Potential donors must at least fulfill national legal requirements for eligibility 
of donors to donate blood or plasma. 
The collection of blood products is defined by the Belgian Blood legislation (Law July 5 th 1994, and R.D. 
April 4 th 1996). The plasma used within this trial is collected according to the Belgian legislation. 
Potential donors can be identified through collaboration with treating hospitals or practitioners or via 
direct search for patients cured from COVID-19. 
Personal data sharing strategies must comply with national and EU data protection rules. 
 
The following criteria for donor eligibility should be applied additional to national legal requirements: 
1. an asymptomatic donor with prior diagnosis of COVID-19 documented by a laboratory test, a 
clinical picture with radiological confirmation of COVID-19 disease. 
2. at least17 days should have passed since full recovery and disappearance of the symptoms. Blood 
establishments might modify the timing of plasma collection when findings regarding the timing of 
optimal and maximal antibody production in those who have recovered from COVID-19 
become available and is confirmed acceptable by AFMPS/FAGG. 
3. Donors without a history of blood transfusion or without history of tissue or organ 
transplantation. 
4. Donors without positive screening for irregular antibodies. 
5. Female donors can only be recruited if either no history of pregnancy or if tested and found 
negative for anti-HLA/HPA/HNA antibodies using a validated assay. Standard donor criteria for 
blood or plasma donation must be met. 
6. Informed consent in accordance with the Belgian Blood Legislation and national and EU data 
protection rules. 
 
 
Plasma collection: 
Collection, processing and storage 
Donors will ideally donate plasma by plasmapheresis, but where apheresis is not sufficient to supply enough 
plasma, whole blood can also be collected, with plasma separation in the blood establishment. Eligible 
plasmapheresis donors are allowed, according to Belgian Blood legislation, to donate a total volume per 
year of 650 ml per session, 2 liter per month and 15 liter per year. The interdonation interval is at least 
one week. Plasma obtained by plasmapheresis and processed should be split before freezing into 2-3 
separate units (e.g. 3x200 ml). Final products should be specifically labelled as COVID-19 Convalescent 

 
 
 
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Plasma and stored in a dedicated location. The processing that is routinely used for pathogen reduction by 
Methylene Blue will be applied according to standard practice in the blood establishment. 
 
The production process and product characteristics will comply with current Belgian Blood legislation. For 
this trial, volumes will be between 200 and 250 ml. The product can be stored for 36 months at a 
temperature below- 25°C or for 3 months at a temperature between -18°C and -25°C. 
 
 
Data collected from donors 
The following data should be collected: 
- date of nasopharyngeal swab that subsequently proved COVID-19-positive by PCR (or alternative date 
of radiological confirmation) 
- Time from diagnosis until resolution of symptoms 
 
 
Testing of donated plasma 
Defined SARS-CoV-2 neutralizing antibody titers will be measured in the donated plasma. A Blood or 
Plasma sample from all donors will be stored in tube with gel for that purpose and for testing of antibody 
specificities. 
Blood establishments will determine SARS-CoV-2 neutralizing antibody titers at or prior to the first 
donation to allow the selection of donors with high titers. The neutralizing antibody titers will be 
repeated with a maximal interval of one month. Samples of donations done in-between will be stored for 
later testing. 
The Blood Establishment will qualify donations from donors with neutralizing antibody titers greater or 
equal to 1/320 as appropriate for this study.  
Only in the exceptional situation of scarcity of convalescent plasma of a specific blood group, convalescent 
plasma containing 1/160 neutralizing antibody titers can be released to treat study patients. 
Convalescent plasma with less than 1/160 neutralizing antibody titers is not allowed in the study.  
 
If an adequate correlation between neutralizing activity and Elisa antibody testing for SARS-CoV2 were to 
be demonstrated, this assay could replac e the test for neutralizing antibodies. Additional archive samples 
of the donated plasma will be saved for reference studies e.g. frozen aliquots from plasma samples taken 
at the time of donation. In emergency cases, plasma from convalescent donors might be released for 
transfusion without any antibody testing, then archived samples should be tested at a later date once 
testing is available.  
When the measured neutralizing activity in the collected plasma is considered to be too low, the plasma 
should be made available for other use. 
 
6.2 Convalescent Plasma and Dosing Regimen 
 
The study design is adaptive, to allow the adjustment of a treatment arm/stratum, the addition of a 
new treatment arm/stratum or the removal of a treatment arm/stratum based on the most updated 
information in a rapidly evolving field, based on the continuous assessment of the existing evidence 
available for the Blood Product and other potential drug candidates. 
 

 
 
 
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The DAWN-PLASMA will randomize participants 2:1 to standard of care in combination with the 
convalescent plasma to standard of care alone. Convalescent plasma will be administered to 
hospitalized patients. 
 
• 
Patients will get a total of 800 -1000 mL plasma divided in 4 doses. A single unit has a volume 
that ranges from 200mL to 250mL.The first dose will be administered within 12 hours of 
randomization, with the absolute goal to have the first infusion of 2 units of convalescent plasma 
as early as practically possible after randomization.. The administration of the second dose of 2 
units convalescent plasma will occur between 24h and 36h after the end of the infusion of the 2 
first units convalescent plasma. Only in the exceptional situation of scarcity of convalescent plasma 
of a specific blood group, convalescent plasma containing 1/160 neutralizing antibody titers can be 
released to treat study patients. 
Convalescent plasma with less than 1/160 neutralizing antibody titers is not allowed in the study.  
 
Importantly, not the usual 30 to 45 minutes infusion time of plasma will be used but convalescent plasma 
should be given at the maximal speed of 50 – 100 millilitres per hour. This will reduce the risk of volume 
overload significantly. Determination of ABO compatibility, duration of administration should follow local 
SOP and plasma should be transfused within six hour after thawing. Plasma will be provided by the local 
blood bank. Convalescent plasma is stored in a limited number of places. Products can only be shipped to 
the local site only when the patient is randomized. 
 
 
6.3 Concomitant / Prohibited Medication / Treatment 
 
There are currently no approved treatments for COVID-19. Patients will receive the standard of care as 
continuously updated by national and international guidance. 
 
 
 

 
 
 
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7 Safety  
7.1 Specification, timing and recording of safety parameters 
 
o 
Grade 4 adverse events (life-threathening or urgent intervenstion required) 
o 
SAEs. 
o 
Transfusion related reactions. Transfusion of plasma is procedure with a long-standing 
experience. The only safety concern with convalescent plasma during acute hospital are 
transfusion related side effects like transfusion related acute lung injury, serious allergic 
transfusion reactions and transfusion associated circulatory overload.   
Patients with a documented grade 3 allergic reaction to fresh frozen plasma will be excluded from 
this trial.  
 
 
7.1.1 
Definitions 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or subject during an experiment, and which does 
not necessarily have a causal relationship with this treatment. 
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 product, whether or not considered related 
to the product. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of 
a pre-existing condition) should be considered an AE. 
 
 
Adverse Reaction (AR) or Adverse Drug Reaction (ADR) 
An AR is any untoward and unintended responses to an investigational medicinal product or to an 
experiment and, when an investigational product is concerned, related to any dose administered. 
 
Serious Adverse Event (SAE) 
An SAE is untoward medical occurrence that results in any of the following: 
• 
Death 
• 
A life-threateninga experience 
• 
In-patient hospitalisation or prolongation of existing hospitalisation 
• 
A persistent or significant disability or incapacity 
• 
A congenital anomaly or birth defect 
• 
Important medical events that may be considered an SAE when - based on appropriate medical 
judgement - they may jeopardise the subject and may require medical or surgical intervention to 
prevent one of the above outcomes 
 
a The term “life threatening” in the definition of SAE 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 was more severe. 
 
 
 
7.1.2 
Adverse Events that do not require reporting 
In general, the following should not be reported as AEs: 
• 
Pre-existing conditions, including those found as a result of screening (these should be reported 
as medical history or concomitant illness). 
• 
Pre-planned procedures, unless the condition for which the procedure was planned has worsened 
from the first trial-related activity after the subject has signed the informed consent. 
The following events not to be considered as SAEs are: 

 
 
 
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• 
Pre-planned hospitalisations unless the condition for which the hospitalisation was planned has 
worsened from the first trial-related activity after the subject has signed the informed consent.  
• 
Hospitalisation as part of a standard procedure for protocol therapy administration. However, 
hospitalisation or prolonged hospitalisation for a complication of therapy administration will be 
reported as an SAE. 
• 
Hospitalisation or prolongation of hospitalisation for technical, practical, or social reasons, in 
absence of an AE. 
For this trial, only Adverse Events graded as severe shall be collected, i.e. adverse events that are life-
threatening and/or require an urgent intervention.  
 
7.1.3 
Recording and reporting of Adverse Events 
Investigators will seek information on AEs during each patient contact. All events, whether reported by the 
patient or noted by trial staff, will be recorded in the patient’s medical record and in the (e)CRF within a 
reasonable time after becoming aware. If available, the diagnosis should be reported on the AE form, rather 
than the individual signs or symptoms. If no diagnosis is available, the Investigator should record each sign 
and symptom as individual AEs. 
The following minimum information should be recorded for each AE: 
- AE description 
- start and stop date of the AE 
- severity 
- seriousness 
- causality assessment to the Blood product and/or study procedures 
- outcome 
 
As stated, selected (S)AEs will be reported. In a large outbreak like the COVID-19 pandemic the 
registration of all AEs is not feasible.  
 
7.1.4 
Assessment  
All AEs must be evaluated by an Investigator as to: 
• 
Seriousness: whether the AE is an SAE. See above for the seriousness criteria. 
• 
Severity:  
o 
Severity must be evaluated by an Investigator according to the following definitions: 
 
Mild – no or transient symptoms, no interference with the subject’s daily activities 
 
Moderate – marked symptoms, moderate interference with the subject’s daily 
activities 
 
Severe – considerable interference with the subject’s daily activities, unacceptable 
• 
Causality: 
 
None – An AE which is not related to the Blood product or experiment 
 
Unlikely – An AE for which an alternative explanation is more likely (e.g. concomitant 
medication(s), concomitant disease(s)), and/or the relationship in time suggests that a 
causal relationship is unlikely 
 
Possible – An AE which might be due to the use of the Blood Product or the experiment. 
An alternative explanation is inconclusive. The relationship in time is reasonable; therefore 
the causal relationship cannot be ruled out. 
 
Probable - An AE which might be due to the use of the Blood Product or the experiment. 
The relationship in time is suggestive (e.g. confirmed by dechallenge). An alternative 
explanation is less likely. 
 
Definitely – An AE which is listed as a possible adverse reaction and cannot be reasonably 
explained by an alternative explanation. The relationship in time is very suggestive (e.g. it 
is confirmed by dechallenge and rechallenge). 

 
 
 
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7.1.5 
Timelines for reporting 
For this trial, only Adverse Events grade 4 shall be collected, i.e. adverse event that are life-threatening 
and/or require an urgent intervention. Adverse events that are also collected as outcomes will not be 
separately reported. 
All SAEs must be reported to the Sponsor within 24 hours of the trial staff becoming aware of the event. 
The immediate report shall be followed by detailed, written reports. The immediate and follow-up reports 
shall identify subjects by Trial identification. 
 
SAE details will be reported by the Investigator to the Sponsor:  
• 
By completing the SAE form in the (e)CRF 
 
7.1.6 
Follow-up  
The Investigator must record follow-up information by updating the patient’s medical records and the 
appropriate forms in the (e)CRF. The worst-case severity and seriousness of an event must be kept 
throughout the trial. 
SAE follow-up information should only include new (e.g. corrections or additional) information and must 
be reported within 24 hours of the Investigator’s first knowledge of the information. This is also the case 
for previously non-serious AEs which subsequently become SAEs. 
• 
All SAEs must be followed up until the outcome of the event is ‘recovered’, ‘recovered with 
sequelae’, ‘not recovered’ (in case of death due to another cause) or ‘death’ (due to the SAE) and 
until all related queries have been resolved, or until end of trial (whichever occurs first). 
• 
Non-serious AEs must be followed up until the patient’s last study visit, and until all related queries 
have been resolved. 
 
SAEs after the end of the trial: If the Investigator becomes aware of an SAE with suspected causal 
relationship to the Blood Product or experiment after the subject has ended the trial, the Investigator 
should report this SAE within the same timelines as for SAEs during the trial. 
 
7.1.7 
Death 
All deaths will be reported without delay to the sponsor (irrespective of whether the death is related to 
disease progression, the Blood Product, study procedure or is an unrelated event). The sponsor will notify 
all deaths, as soon as possible after becoming aware, to the Central EC and the EC of the concerned site 
and provide additional information if requested. 
 
7.1.8 
Reporting requirements to Ethics Committee’s (EC’s) and Competent Authorities 
(CA’s) 
The Investigator is responsible for ensuring that all safety events are recorded in the (e)CRF and reported 
to the Sponsor in accordance with instructions provided below. 
The Sponsor will promptly evaluate all SAEs against medical experience to identify and expeditiously 
communicate possible new safety findings to Investigators, EC’s and applicable CA’s based on applicable 
legislation. 
 
7.1.9 
Hemovigilance 
 
Any transfusion-related reactions in the study, must be reported to the Compentent Authorities according 
to the hemovigilance guidelines and local hospital procedures. 
 

 
 
 
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7.1.10 Annual reporting 
The Sponsor has the obligation to, once a year throughout the clinical trial (or on request), submit a 
progress report to the EC’s and CA’s containing an overview of all SARs occurred during the reporting 
period and taking into account all new available safety information received during the reporting period.  
 
 
7.1.11 Data and safety monitoring committee (DSMB) and treatment stopping rules 
Data monitoring committee will composed of specialists in transfusion medicine, immunology, infectiology 
and a statistician. The members are independent from the Sponsor. 
Given the severity of illness in COVID-19, there are no pre-specified study stopping rules for safety. The 
protocol team will review AE / SAE data on an ongoing basis. If there are a concerning number of 
unexpected AEs, the DSMB will be asked to review safety data in an ad hoc meeting.  
 
The DSMB will review safety data after 50 of the subjects are entered into the trial, a DSMB review will be 
done every 3 months and ad hoc reviews will be undertaken if there are other specific safety concerns. 
The study will not stop enrolment awaiting these DSMB reviews, though the DSMB may recommend 
temporary or permanent cessation of enrolment based on their safety reviews. There are no pre-specified 
statistical stopping rules. 
 
 
 
 

 
 
 
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8 
Statistics and Data Analysis. 
Statistical analysis will be performed in accordance with ICH E9; a detailed description of the analysis is 
provided in the separate Trial-specific Statistical Analysis Plan (SAP). ICH E3 and E8 will guide the structure 
and content of the clinical trial report. A brief summary is provided here. Details will be described in the 
SAP.  
Primary outcome 
The primary outcome is the number of patients alive without mechanical ventilation.  
The plan is to evaluate the primary outcome on Day 15, in line with the WHO master protocol.  
Secondary outcomes 
The WHO outcome is based on an ordinal severity scale with 11 categories. This scale has been proposed 
by the WHO for COVID-19 related research and has been previously used in trials of patients with 
influenza. Previously reported studies and ongoing studies record the same primary outcome, which allows 
cross-study data pooling.  
 
8.1 Sample Size Determination 
Despite rapid dissemination of data from clinical case series and some early stage clinical trials, detailed 
information about the course of the disease is limited in this stage of the COVID-19 pandemia. The samples 
sizes presented here are only illustrative. 
Furthermore, in the absence of treatments with a known benefit, rapid changes in standard of care are to 
be expected and important signs of a benefit or a harm of a treatment under investigations will require 
rapid reporting. Safety issues will be continuously monitored by a Data and Safety Monitoring Committee, 
and if at any stage evidence emerges that any one treatment arm/stratum is definitely inferior then it can 
be decided that the study will be discontinued. Conversely, if good evidence emerges while the trial is 
continuing that some other treatment(s) should also be being evaluated then it can be decided that one or 
more extra arms or strata will be added while the trial is in progress. 
Around 20% of patients hospitalized for a SARS-CoV-2 infection are admitted to the ICU with respiratory 
failure. When admitted to the ICU, 80% of these patients need mechanical ventilation. With the 
administration of convalescent plasma as early as possible, we hope to decrease the proportion of patients 
who have a clinical decline and need ICU support. We assume by providing passive immunity with 
convalescent plasma, we are able to reduce the proportion of patients admitted to the ICU from 20% to 
15%. Furthermore, we assume that when admitted to ICU the need for mechanical ventilation is reduced 
from 80% to 50%.  With a power of 0.8, a delta of 8.5% (16% in the control group and 7.5% in the invention 
group), a randomization ratio of 2:1 and an alpha of 0.05, sample size estimates to detect a difference 
between both groups, is 483 patients with 322 patients and 161 patients in the invervention and standard 
of care group, respectively (using a Pearson Chi-square test for proportion difference). 
We propose a pragmatic initial sample size of 483 patients (161 control patients, 322 in the plasma 
intervention group).  

 
 
 
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Outcomes are in line with other studies with convalescent plasma that are being set up or just started 
recruitment in other countries. A huge effort is now made on European scale to combine all results of 
other studies studying the added value of convalescent plasma. All results will be made real-time available 
in an European database. This allows to make sound scientific conclusions in limited time frame. When this 
European database is available, an amendment will be made to the institutional review board. 
8.2 Statistical Analysis 
8.2.1 Population for analysis 
The following analysis sets will be defined: 
Full Analysis Set (FAS): The FAS will include all randomised patients according to their randomised 
treatment.  However, the following patients will be excluded from the FAS: 
a) Covid-negative patients: violation of inclusion criterion 5; 
b) Patients randomised to receive plasma, but plasma could not be administered because none was 
available at the site.  
The FAS will be used for the evaluation of all efficacy and safety endpoints. 
 
Safety Set (SS): No separate Safety Set will be defined. 
Per Protocol Set (PPS): if warranted, patients from the FAS with major protocol deviations will be 
excluded from the Per Protocol Set.  The PPS will be reviewed and finalized in a blinded fashion prior to 
database lock at a Blind Review Meeting, attended by the Principal Investigator, Study Statistician and other 
relevant study personnel. 
8.2.2 Statistical Analyses 
8.2.2.1 General Approach  
This is an open label controlled randomized trial testing a superiority hypothesis with a two-sided type I 
error rate of 0.05. In this explorarory study, secondary hypotheses will be tested in a non-hierachical way 
and without adjustment to the significance level for multiple testing.  Hence, care should be taken with 
the interpretation of the significant results, since the probability of a false-positive result for any of the 
secondary endpoints will be considerably higher than 5%. 
Due to the dynamic and changing nature of the disease, patient population and Standard of Care,  time 
will be accounted for by adjusting all analyses for a period factor.  At the Blind Review Meeting (see 
section 8.2.1 – Per Protocol Set), the periods will be defined and finalized in a blinded manner.  
 
All data will be summarized using appropriate summary statistics by treatment group.  Continuous data 
will be described by their mean value and standard deviation, or median and interquartile range if serious 
deviations from the normal distribution are observed.  Categorical data will be summarized by observed 
counts and percentages.  Time-to-event data will be summarized by event rates, obtained using Kaplan-
Meier methodology or Cumulative Incidence Functions (CIF) when competing risks are present. 

 
 
 
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All treatment comparisons will be adjusted for study site and period, both included as fixed factors in the 
model.  An appropriate measure of the treatment effect (e.g. mean difference, odds ratio, hazard ratio) 
will be estimated for all primary and secondary endpoints and presented along with its associated 95% 
confidence interval. 
A statistical analysis plan (SAP) will be developed and filed with the study sponsor prior to database lock. 
Missing Clinical Status data during hospital stay and at Day 15 and 30 will be accounted for by multiple 
imputation, whereby a total of 100 imputations will be done.  The imputation methodology will be fully 
described in the Statistical Analyis Plan. 
8.2.2.2 Analysis of the Primary Efficacy Endpoint  
The primary endpoint is defined as the number of patients alive without mechanical ventilation at day 15 
after randomization.  Treatment groups will be compared using a logistic regression analysis adjusted for 
study site and study period , both included as fixed factors in the model (see Section 8.2.2.1 – second 
paragraph).  The treatment effect will be estimated as an odds ratio from this model. 
The analysis of the primary endpoint will be performed for the FAS and PPS (if defined). 
 
8.2.2.3 Analysis of the Secondary Endpoints  
 
All efficacy endpoints will be assessed for both the FAS and PSS (if defined).  Secondary endpoints 
evaluating the safety of convalescent plasma will be assessed for the FAS only.  The following statistical 
methods will be used: 
1. All-Cause mortality rates will be estimated by treatment group using the Kaplan-Meier method.  
The resulting Kaplan-Meier curves will be compared using a log-rank test.  The treatment effect 
will be estimated by the hazard ratio using a Cox regression, adjusted for study site and period. 
2. Time-to-event parameters with competing risk (time to clinical improvement, incidence of 
supplemental oxygen, mechanical ventilation, ECMO and ICU admission): event rates will be 
estimated using cumulative incidence functions (CIF), the resulting CIF curves will be compared 
using Gray’s test.  The treatment effect will be estimated by the subdistribution hazard ratio 
using a Gray’s regression analysis, adjusted for study site and period.   
3. Duration of hospital and ICU stay, supplemental oxygen, mechanical ventilation and ECMO: 
these will be analysed as time-to-event parameters with competing risk, whereby the event of 
interest is life discharge from hospital/ICU and the competing risk is hospital/ICU death. 
4. Continuous variables (e.g. QTc, NT50, QoL) will be analysed using a general linear model 
including study site and period as factors and, if applicable, the baseline value as covafxriate.  
Treatment effects will be estimated by the difference in mean values between the groups.  If 
applicable, changes from baseline will be calculated.   
 
8.2.2.4 Safety Analyses  
Safety endpoints are described above. These events will be analysed univariately and as a composite 
endpoint. Time-to-event methods will be used for death and the composite endpoint. Each AE will be 

 
 
 
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counted once for a given participant and graded by severity and relationship to COVID-19 or study 
intervention.  
Adverse events leading to premature discontinuation from the study intervention and serious treatment-
emergent AEs will be described as part of the primary publication of the study results.  
8.2.2.5 Baseline Descriptive Statistics  
Baseline characteristics will be summarized by treatment arm. For continuous measures the mean and 
standard deviation will be summarized. Categorical variables will be described by the proportion in each 
category (with the corresponding sample size numbers).  
8.2.2.6 Planned Interim and Early Analyses  
Early analysis  
Early analyses include monitoring enrolment, baseline characteristics, and follow-up rates throughout the 
course of the study by the study team.. 
In case the study is terminated early either due to safety concerns or clear evidence of 
efficacy/futility/safety from external studies, the following analyses will be performed for the primary 
outcome: 
1) A Bayesian logistic regression analysis will be performed on the primary efficacy endpoint in 
order to obtain a posterior probability of a positive treatment effect.  Full details will be 
provided in the SAP. 
2) Conditional power will be calculated for the originally planned sample size (n=483) based on data 
collected up to time of termination.  Full details will be provided in the SAP. 
Interim analyses  
No formal interim analysis will be planned. A data and safety monitoring committee (DSMB) will monitor 
ongoing results to ensure patient well-being and safety as well as study integrity. The DSMB, containing 
one statistician, will have the opportunity to ask for data, to require analyses or to compare Belgian trial 
results with results available from other countries. The DSMB will be asked to recommend early 
termination or modification only when there is clear and substantial evidence of a safety issue. 
8.2.2.7 Sub-Group Analyses 
Subgroup analyses for the primary outcome will evaluate the treatment effect across the following 
subgroups:  
1. Duration of symptoms prior to enrolment; 
2. Age groups;  
3. Study period; 
4. Blood group (A, B, AB, O); 
5. Size of study site (according to median); 
6. Admission to ICU at hospital admission (yes vs no) 
7. Virus neutralization titer (at least one dose of at least 1/320 versus only 1/160 titer plasma 
administered) 
 

 
 
 
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A forest plot will display confidence intervals across subgroups. Interaction tests will be conducted to 
determine whether the effect of treatment varies by subgroup. 
 
 
8.3 Data & Safety Monitoring Board (DSMB) 
 
 
The DSMB, composed of different members compared to the steering committee of the trial, will review 
safety data after 50 of the subjects are entered into the trial, a DSMB review will be done every 3 months 
and ad hoc reviews will be undertaken if there are other specific safety concerns. The study will not stop 
enrolment awaiting these DSMB reviews, though the DSMB may recommend temporary or permanent 
cessation of enrolment based on their safety reviews. There are no pre-specified statistical stopping rules. 
 
 
Given the severity of illness in COVID-19, there are no pre-specified study stopping rules for safety. The 
protocol team will review AE / SAE data on an ongoing basis. If there are a concerning number of 
unexpected AEs, the DSMB will be asked to review safety data in an ad hoc meeting. 
 
 
9 
Data handling  
9.1 Data Collection Tools and Source Document Identification 
Data collection, handling, processing and transfer for the purpose of this Trial will be performed in 
compliance with applicable regulations, guidelines for clinical trials and internal procedures, as follows: 
9.1.1.1 
Data collection  
Source Data will be collected and recorded in the Trial participant’s files/medical records. 
Worksheets may be used for capturing some specific data in order to facilitate completion of the eCRF. 
Any such worksheets will become part of the Trial participant's source documentation and will be filed 
together with or as part of the medical records (during but also following completion of the Trial). 
It remains the responsibility of the Investigator to check that all data relating to the Trial, as specified in 
the Trial protocol, are entered into the eCRF in accordance with the instructions provided and that the 
forms are filled out accurately, completely and in a timely manner. 
eCRFs are provided by the Sponsor for each participant. The Trial data will be transcribed from the source 
records (i.e. participant’s medical file or Trial-specific source data worksheets) into an eCRF by Trial Staff. 
Transcription to the eCRF will be done as soon as possible after a participant visit and in a pseudonymized 
manner using a unique identifier assigned by the Sponsor.  
The eCRFs will be available for review at the next scheduled monitoring visit (as applicable).  
9.1.1.2 
Data Validation  
All data relating to the Trial must be prepared and validated by the Investigator. Any eCRF entries, 
corrections and alterations must be made by the Investigator or other authorized Trial staff.  
Proper audit trails are available in REDCap to demonstrate the validity of the Trial data collected. This 
includes historical records of original data entries, by whom and when the data was entered, as well as 
detailed records of any corrections or additions made to the original data entry (i.e. who made the 
correction/addition, when and why), without obliterating the original data entry information. 

 
 
 
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9.1.1.3 
Data Management 
The Trial Data Manager will perform extensive consistency checks on the received data. Queries will be 
issued in case of inconsistencies in accordance with internal procedures. A Data Management Plan will be 
developed to map data flows, data validation measures that will be taken, how (interim) database lock(s) 
will be managed and, as applicable, the role and responsibilities of the Data Safety Monitoring Committee 
(DSMB) 
9.1.1.4 
Data Transfer 
Any participant records or datasets that are transferred to the Sponsor or any partners of the Sponsor 
will contain the Trial-specific participant identifier only; participant names or any information which would 
make the participant identifiable will not be transferred. All pseudonymized data relating to the Trial must 
be transmitted in a secure manner to the Sponsor (see 9.1.2. legal requirements). 
9.1.2 
Legal requirements 
All source data will be kept at a secured location with restricted access at all times. These data must be 
collected and processed with adequate precautions to ensure confidentiality and compliance with applicable 
data protection laws and regulations and more in particular the EU General Data Protection Regulation 
2016/679 (GDPR) and relevant national laws implementing the GDPR. Appropriate technical and 
organizational measures to protect the data against unauthorized disclosure or access, accidental or 
unlawful destruction, or accidental loss or alteration must be established. Trial staff whose responsibilities 
require access to personal data agree to keep the data confidential. 
The Investigator and the Participating Site(s) (as applicable) shall treat all information and data relating to 
the Trial disclosed to them as confidential and shall not disclose such information to any third parties or 
use such information for any purpose other than the objectives of the Trial as described in this protocol. 
The collection, processing and disclosure of personal data, such as participant health and medical 
information is subject to compliance with applicable laws and regulations regarding personal data protection 
and the processing of personal data. 
The Investigator will maintain all source documents and completed eCRF that support the data collected 
from each Trial participant, and will maintain a Trial Master File (TMF) containing all Trial documents as 
specified in ICH-GCP E6(R2) Chapter 8 entitled “Essential Documents for the Conduct of a Clinical 
Trial”, and as specified by applicable regulatory requirement(s). 
The Investigator will take appropriate measures to prevent accidental or premature destruction of these 
documents. 
Transfer of the pseudonymized data will be performed via a secured method of transfer taking into 
account all applicable security arrangements and regulations (such as the European General Data 
Protection Regulation). The receiving party will be bound to keep the transferred data confidential at all 
times and to only process the data for the purpose of the Trial. To this end, Appendix 1 will apply.  
9.2 Audits and Inspections 
The Investigator will permit direct access to Trial data and documents for the purpose of monitoring, audits 
and/or inspections by authorized entities such as but not limited to: the Sponsor or its designees and 
competent regulatory or health authorities. As such eCRFs, source records and other Trial related 
documentation (e.g. the Trial Master File, pharmacy records, etc.) must be kept current, complete and 
accurate at all times.  
9.3 Monitoring 
In accordance with ICH-GCP E6(R2) the Sponsor is responsible for monitoring the Trial to ensure 
compliance with GCP and current legislation, and to verify, among other requirements, that proper written 
informed consent has been obtained and documented, that the Trial procedures have been followed as 
shown in the approved protocol, and that relevant Trial data have been collected and reported in a manner 
that assures data integrity. To this end Source Data will be compared with the data recorded in the eCRF. 
Monitoring of the Trial will be performed by qualified individuals (independent from the site Trial staff) 
according to the monitoring plan.  The Sponsor and Investigator/Participating Site will permit direct access 
to the Trial data and corresponding Source Data and to any other Trial related documents or materials to 

 
 
 
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verify the accuracy and completeness of the data collected. More details about the monitoring strategy are 
described in the Trial specific Monitoring Plan (MP). 
9.4 Archiving  
As specified in ICH-GCP E6(R2) section 8.1 Addendum the Sponsor and Investigator/Participating Site will 
maintain a record of the location(s) of all respective Essential Trial Documents (including but not limited 
to Source Documents, completed and final eCRF and ISF(s)/TMF). The Sponsor should ensure that the 
Investigator has control of and continuous access to the eCRF data reported to the Sponsor during the 
Trial.  
The Investigator/Participating Site should have control of all Essential Documents and records generated 
by the Investigator/Participating Site before, during and following termination of the Trial. 
The Sponsor is responsible for archiving Trial specific documentation (such as but not limited to the Trial 
protocol, any amendments thereto, the final Clinical Study Report (CSR) and the Trial database) according 
to ICH-GCP E6(R2). Source data and site-specific Trial documents (such as but not limited to the original 
signed ICFs) will be archived by the participating site(s) according to local practice, and for at least 25 years 
following termination of the Trial. Archived data may be held on electronic record, provided that media 
back-up exists, hard copies can be obtained, if required and measures are taken to prevent accidental or 
premature loss or destruction of data. Destruction of Essential Documents will require written 
authorisation from the Sponsor. 
10 Ethical and Regulatory Considerations 
10.1 Ethics Committee (EC) review & reports  
Before the start of the Trial, this protocol and other related documents (e.g. ICF, advertisements, IB, etc.) 
will be submitted for review to the EC and to the relevant CA for Trial authorization. The Trial shall not 
commence until such approvals have been obtained. 
It is the responsibility of the CI to produce the Annual Progress Report (APR) and submit to the EC/CA 
within 30 days of the anniversary date on which favourable opinion to start the Trial was given, and annually 
until the Trial is declared ended. 
The CI shall notify the EC/CA of the end of the Trial. Should the Trial be ended prematurely, the CI will 
notify the EC/CA and include the reasons for premature termination within 15 days of the decision. The 
CI will submit a final report with the results, including any publications/abstracts, to the EC/CA within 1 
year or within 6 months for paediatric Trials. 
10.2 Regulatory Compliance 
The Trial will be conducted in compliance with the principles outlined in the requirements for the conduct 
of clinical Trials in the EU as provided for in Directive 2001/20/EC or EU Regulation 536/2014, as applicable, 
and any subsequent amendments, as well as in compliance with ICH-GCP E6(R2) guidelines, other GxP 
guidelines, the most recent version of the Declaration of Helsinki,  the Belgian law of May 7th 2004 
regarding experiments on the human person (as amended) or the Belgian law of May 7th 2017 on clinical 
Trials with medicinal products for human use, as applicable, and with the EU General Data Protection 
Regulation 2016/679 (GDPR), the relevant Belgian laws implementing the GDPR, the Belgian Law of August 
22nd 2002 on patient rights and all other applicable legal and regulatory requirements. 
10.3 Protocol / GCP compliance 
The Trial must be performed in accordance with the protocol, current ICH-GCP guidelines, and applicable 
regulatory and country-specific requirements. GCP is an international ethical and scientific quality standard 
for designing, conducting, recording, and reporting studies that involve the participation of human 
participants. Compliance with this standard provides public assurance that the rights, safety, and well-being 
of Trial participants are protected, consistent with the principles that originated in the most recent version 
of the Declaration of Helsinki, and that the Trial data are credible, reliable and reproducible. 
The Investigator and Trial team acknowledge and agree that prospective, planned deviations or waivers to 
the protocol are not permitted under applicable regulations on clinical studies. However, should there be 

 
 
 
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an accidental protocol deviation, such deviation shall be adequately documented in the source documents 
and on the relevant forms and reported to the CI and Sponsor. Deviations should also be reported to the 
EC as part of the EC’s continued review of the Trial (e.g. through the ASR, APR, etc.). Protocol deviations 
which are found to frequently recur, will require (immediate) action. Investigator acknowledges that such 
recurring protocol deviations could potentially be classified as a serious violation. 
It is understood that “a serious violation” is likely to affect to a significant degree: 
- 
the safety or physical or mental integrity of the Trial participants; or 
- 
the scientific validity of the Trial 
The Investigator is expected to take any immediate action required to protect the safety of any 
participant included in the Trial, even if this action represents a deviation from the protocol. In such 
cases, the Sponsor should be notified of this action and the EC at the Trial site should be informed 
according to local procedures and regulations. 
10.4 Data protection and participant confidentiality 
The Trial will be conducted in compliance with the requirements of the EU General Data Protection 
Regulation 2016/679 (GDPR), the relevant Belgian laws implementing the GDPR including the Belgian 
Privacy Act of 30 July 2018 on the protection of privacy in relation to the processing of personal data. 
Any collection, processing and disclosure of personal data, such as participant health and medical 
information is subject to compliance with the aforementioned personal data protection laws (cfr. Data 
Processing Annex (DPA) in Appendix I). In case personal data is transferred outside the European 
Economic Area, safeguards will be taken to ensure that appropriate protection travels with the data in 
accordance with the GDPR. (https://ec.europa.eu/info/law/law-topic/data-protection/international-
dimension-data-protection/rules-international-data-transfers_en#documents) 
Any personal data shall be treated as confidential at all times including during collection, handling and use 
or processing, and the personal data (including in any electronic format) shall be stored securely at all times 
and with all technical and organizational security measures that would be necessary for compliance with 
EU and national data protection legislation (whichever is more stringent). The Sponsor shall take 
appropriate measures to ensure the security of all personal data and guard against unauthorized access 
thereto or disclosure thereof or loss or destruction while in its custody. 
10.5 Insurance 
The Participating Site, the Investigator and Sponsor shall have and maintain in full force and effect during 
the term of this Trial, and for a reasonable period following termination of the Trial, adequate insurance 
coverage for: (i) medical professional and/or medical malpractice liability, and (ii) general liability. 
For Belgian Participating Sites 
Art 29 of the Belgian Law relating to experiments on human persons dated May 7th, 2004 applies. 
Prior to the start of the Trial, the Sponsor shall enter into an insurance contract in order to adequately 
cover Trial participants from Belgian sites in accordance with art. 29 of the said law. 
For non-Belgian Participating Sites 
The Participating Site shall have and maintain in full force and effect during the term of this Trial (and for 
a reasonable period following termination of the Trial, adequate insurance coverage for other possible 
damages resulting from the Trial at the Participating Site, as required by local law. Each such insurance 
coverage shall be in amounts appropriate to the conduct of the services of the Participating Site under 
this Trial. The Participating Site and Sponsor shall be solely responsible for any deductible or self-insured 
retention under any such policies. 
 
10.6 Access to the Study Data by KCE and similar institutes in the EU 
This section should be read in conjunction with the research agreement for funding, which supersedes 
the protocol in case of contradictory statements.  

 
 
 
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After the completion of the study the Sponsor will transfer the pseudonymized study data set to KCE. KCE 
will request approval from the competent chamber of the Information Security Committee to have the 
relevant study data linked with IMA data by a trusted third party (TTP, eHealth platform) using the patient 
national number. 
 
The patient information and consent includes wording that the national number will be recorded on site 
by the investigator for later data linkage. The patient information and consent will also include that in case 
the patient is randomized, it is planned that a trusted third party (TTP, eHealth platform) will receive and 
use the national number to link with IMA administrative data. This data linkage is planned to obtain a more 
complete data set that will be used for the analysis of effectiveness and cost-effectiveness of the intervention 
by KCE. 
 
KCE and Sponsor have entered into a research agreement detailing the roles and responsibilities of each 
party, as well as other legal aspects of this collaboration, including the right to use and access of KCE to 
the Study Data. 
  
“Background” means any intellectual property (IP), data, materials, information owned or controlled by the 
Sponsor or a Site, and required to run this Study. Sponsor will identify such Background including the legal 
restrictions of which Sponsor or Sites are aware that may affect the use of the Background for the purpose 
of the Study or the rights granted to KCE under this Agreement. 
  
The Study Data consist of this protocol, including amendments, the electronic forms for data capture, 
including the annotations and guidance for use, the electronic database of the pseudonymized clinical and 
non-clinical data collected using data capture, including the log of changes from data entry to database lock, 
study reports based on these pseudonymized data, and any data or reports generated at a later stage, eg 
based on exploratory analyses or stored samples. 
  
“Foreground” means any Study Data, and any tangible biological, chemical and physical material and 
inventions, that are generated, acquired, discovered, conceived, developed, created, exemplified or derived 
as a result of carrying out the Clinical Study, whatever its form or nature, whether it can be protected or 
not, as well as any Foreground IP. Sponsor acknowledges that the main purpose of the research performed 
under this Agreement is to generate results that will serve the general public interests, and specifically the 
interests of the patients and public healthcare decision making bodies, and, therefore, undertakes not to 
exploit the Foreground in any way that is or could be detrimental to such interests. 
 
The Sponsor owns the Study Data, but provides KCE with a copy of the pseudonymized database after 
database lock as well as a royalty-free unrestricted license to use the Study Data for non-commercial public 
health related purposes as detailed in the Agreement between KCE and UZ Gent. If judged appropriate, 
KCE will introduce the request to the competent chamber of the Information Security Committee and 
arrange for the data linkage. For the sake of clarity, the linked data are not part of the Study Data. However, 
KCE will discuss with the Sponsor the results of the analyses and the reporting of the linked data. 
 
Access to Study Data by KCE and similar institutes in the EU is fully defined in the contract between KCE 
and the Sponsor. The research agreement template is publicly available on the KCE website. Link: 
https://kce.fgov.be/en/resources-for-investigators 
 
 
10.7 Amendments 
Unless for urgent reasons as specified in ICH-GCP E6(R2) section 4.5.4, amendments must not be 
implemented prior to EC and/or CA review and/or approval, as applicable. 
In accordance with the Belgian law of May 7th 2004 regarding experiments on humans, the Sponsor may 

 
 
 
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develop a non-substantial amendment at any time during the Trial. If a substantial amendment to the 
clinical Trial agreement or the documents that supported the original application for the clinical Trial 
authorisation is needed, the Sponsor must submit a valid substantial amendment to the Competent 
Authority (CA) for consideration, and to the EC for review and approval. The CA and/or EC will provide 
a response in accordance with timelines defined by applicable regulations. It is the Sponsor’s 
responsibility to assess whether an amendment is substantial or non-substantial for the purpose of 
submission to the CA and/or EC. 
Amendments to the Trial are regarded as ‘substantial’ when they are likely to have a significant impact on 
the safety or physical or mental integrity of the clinical Trial participants, or the scientific value of the 
Trial. 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2010_c82_01/2010_c82_01_en.pdf  
 
10.8 Post-Trial activities 
Not applicable. 
 
 
11 Research Registration, Dissemination of Results and 
Publication Policy 
The Declaration of Helsinki (latest version) and European and Belgian regulations require that every 
research Trial involving human participants be registered in a publicly accessible database before 
recruitment of the first participant. The CI is responsible for registering the Trial.  
In addition, the CI will fulfil their ethical obligation to disseminate and make the research results publicly 
available. As such the CI is accountable for the timeliness, completeness and accuracy of the reports. 
Researchers, authors, Sponsors, editors and publishers must adhere to accepted guidelines for ethical 
reporting. Negative and inconclusive, as well as positive results must be published or otherwise made 
publicly available. Sources of funding, institutional affiliations and conflicts of interest must be declared in 
publication.  
Publications will be coordinated by the CI. Authorship to publications will be determined in accordance 
with the requirements published by the International Committee of Medical Journal Editors and in 
accordance with the requirements of the respective medical journal.  
For multi-centric Trials, it is anticipated that the primary results of the overall Trial shall be published in a 
multi-centre publication. 
Participating Sites are not allowed to publish any subset data or results from the Trial prior to such 
multicentre publication.  
Any publication by a Participating Site must be submitted to the Sponsor for review at least thirty (30) 
calendar days prior to submission or disclosure. Sponsor shall have the right to delay the projected 
publication for a period of up to three (3) months from the date of first submission to the Sponsor in order 
to enable the Sponsor to take steps to protect its intellectual property rights and know-how.  
12 Intellectual Property 
Any know-how, inventions, methods, developments, innovations, discoveries and therapies, whether 
patentable or not, arising from the Trial or made in the performance of the Trial protocol (“Inventions”) 
shall vest in the Sponsor. The Participating Site, its employees and Investigator(s) shall promptly disclose 
to the Sponsor any such Inventions. Parties have expressly agreed that any and all Trial data as collected 
and prepared in the performance of the Trial protocol shall be the sole property of Sponsor. Publication 
policy guidelines will be created. 

 
 
 
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13 Joint Commission International (JCI) 
In order to ensure the same quality and safety standards in patient care for clinical research as commonly 
applied by the Sponsor in its regular activities, and in accordance with JCI standards, the Sponsor shall 
comply with the following obligations: (a) the Sponsor will use trained and qualified employees or 
contractors to manage and coordinate the Trial; (b) the Sponsor will ensure that multi-center Trial 
reporting is reliable and valid, statistically accurate, ethical, and unbiased. (c) the Sponsor will not grant 
incentives, other than standard compensations and reimbursement of costs, to Trial participants or to 
participating site’s staff that would compromise the integrity of the research; (d) the Sponsor is 
responsible for monitoring and evaluating the quality, safety, and ethics of the Trial and will respect the 
participating site’s policies and processes when performing such monitoring and evaluation activities; (e) 
the Sponsor will protect the privacy and confidentiality of the Trial participants in accordance with all 
applicable laws. 
 
 

 
 
 
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References   
1.  
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with 
COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. 
doi:10.1016/s0140-6736(20)30566-3 
2.  
Keyaerts E, Vijgen L, Maes P, Neyts J, Ranst M Van. In vitro inhibition of severe acute respiratory 
syndrome coronavirus by chloroquine. Biochem Biophys Res Commun. 2004;323(1):264-268. 
doi:10.1016/j.bbrc.2004.08.085 
3.  
Mehta P, Mcauley DF, Brown M, et al. Correspondence COVID-19 : consider cytokine storm 
syndromes and. Lancet. 2020;6736(20):19-20. doi:10.1016/S0140-6736(20)30628-0 
4.  
Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in 
patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;(February):844-847. 
doi:10.1111/jth.14768 
5.  
Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased 
mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020. 
doi:10.1111/jth.14817 
6.  
Wu C, Liu Y, Yang Y, et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential 
drugs by computational methods. Acta Pharm Sin B. 2020. doi:10.1016/j.apsb.2020.02.008 
7.  
Takano T, Akiyama M, Doki T, Hohdatsu T. Antiviral activity of itraconazole against type i feline 
coronavirus infection. Vet Res. 2019;50(1):1-6. doi:10.1186/s13567-019-0625-3 
8.  
Schloer S, Goretzko J, Kühnl A, Brunotte L, Ludwig S, Rescher U. The clinically licensed antifungal drug 
itraconazole inhibits influenza virus in vitro and in vivo. Emerg Microbes Infect. 2019;8(1):80-93. 
doi:10.1080/22221751.2018.1559709 
9.  
Parnham MJ, Haber VE, Giamarellos-Bourboulis EJ, Perletti G, Verleden GM, Vos R. Azithromycin: 
Mechanisms of action and their relevance for clinical applications. Pharmacol Ther. 2014;143(2):225-245. 
doi:10.1016/j.pharmthera.2014.03.003 
10.  
Albert RK, Connett J, Bailey WC, et al. Azithromycin for Prevention of Exacerbations of COPD. N 
Engl J Med. 2011;365(8):689-698. doi:10.1056/NEJMoa1104623 
11.  
Brusselle GG, VanderStichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in 
severe asthma (AZISAST): A multicentre randomised double-blind placebo-controlled trial. Thorax. 
2013;68(4):322-329. doi:10.1136/thoraxjnl-2012-202698 
12.  
Vermeersch K, Gabrivska M, Aumann J, et al. Azithromycin during Acute Chronic Obstructive 
Pulmonary Disease Exacerbations Requiring Hospitalization (BACE). A Multicenter, Randomized, 
Double-Blind, Placebo-controlled Trial. Am J Respir Crit Care Med. 2019;200(7):857-868. 
13.  
Vos R, Vanaudenaerde BM, Verleden SE, et al. A randomised controlled trial of azithromycin to 
prevent chronic rejection after lung transplantation. Eur Respir J. 2011;37(1):164-172. 
doi:10.1183/09031936.00068310 
14.  
Wong C, Jayaram L, Karalus N, et al. Azithromycin for prevention of exacerbations in non-cystic fi 
brosis bronchiectasis (EMBRACE): A randomised, double-blind, placebo-controlled trial. Lancet. 
2012;380(9842):660-667. doi:10.1016/S0140-6736(12)60953-2 
15.  
Menzel M, Akbarshahi H, Bjermer L, Uller L. Azithromycin induces anti-viral effects in cultured 
bronchial epithelial cells from COPD patients. Sci Rep. 2016;6(June):1-11. doi:10.1038/srep28698 
16.  
Gielen V, Johnston SL, Edwards MR. Azithromycin induces anti-viral responses in bronchial epithelial 
cells. Eur Respir J. 2010;36(3):646-654. doi:10.1183/09031936.00095809 
17.  
Van Herck A, Frick AE, Schaevers V, et al. Azithromycin and early allograft function after lung 
transplantation: A randomized, controlled trial. J Hear Lung Transplant. 2019;38(3):252-259. 
doi:10.1016/j.healun.2018.12.006 
18.  
Vermeersch K, Belmans A, Bogaerts K, et al. Treatment failure and hospital readmissions in severe 
COPD exacerbations treated with azithromycin versus placebo - A post-hoc analysis of the BACE 
randomized controlled trial. Respir Res. 2019;20(1):1-12. doi:10.1186/s12931-019-1208-6 
19.  
Posch M, Proschan MA. Unplanned adaptations before breaking the blind. Stat Med. 2012;31(30):4146-
4153. doi:10.1002/sim.5361 
20.  
Mulangu S, Dodd LE, Davey RT, et al. A randomized, controlled trial of Ebola virus disease 
therapeutics. N Engl J Med. 2019;381(24):2293-2303. doi:10.1056/NEJMoa1910993 
21.  
Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-
19. N Engl J Med. 2020:1-13. doi:10.1056/NEJMoa2001282 
 
 

 
 
 
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Some references have been documented by PubMed ID number. The corresponding article can be easily 
found on https://www.ncbi.nlm.nih.gov/pubmed/ . 
 
 

 
 
 
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APPENDICES 
14 Appendix 1: Data Processing Annex (DPA)  
Definitions: 
• 
“Protocol” means the document entitled “A randomized, open-label, adaptive, proof-of-concept 
clinical trial of convalescent plasma against SARS-CoV-2” containing the details of the academic 
Trial as developed by the Sponsor and approved by the relevant Ethics Committee. 
• 
“Sponsor” means University Hospitals Leuven (UZ Leuven). 
• 
Participating site acts as a data processor as defined under article 4, 8) of the Regulation (EU) 
2016/679 (“Data Processor”) for the Sponsor who acts as data controller as defined under article 
4, 7) of the Regulation (EU) 2016/679 (“Data Controller”). 
• 
“Applicable Law” means any applicable data protection or privacy laws, including:  
a) the Regulation (EU) 2016/679 also referred as the General Data Protection Regulation 
("GDPR");  
b) other applicable laws that are similar or equivalent to or that are intended to or implement 
the laws that are identified in (a) of this definition;  
• 
"Personal Data" means any information relating to an identified or identifiable natural person 
(”Data Participant”), including without limitation pseudonymized information, as defined in 
Applicable Law and described in the Protocol. 
Rights and obligations: 
1. The Data Processor is instructed to process the Personal Data for the term of the Trial and only 
for the purposes of providing the data processing tasks set out in the Protocol. The Data Processor 
may not process or use Personal Data for any purpose other than a Data Participant’s medical 
records, or other than provided in the instructions of the Trial protocol, including with regard to 
transfers of personal data to a third country or an international organization, unless the Data 
Processor is required to do so according to Union or Member State law.  
2. Data Processor shall at all times maintain a record of processing of Personal Data in accordance 
with Applicable Law and if the Data Processor considers an instruction from the Data Controller 
to be in violation of the Applicable Law, the Data Processor shall promptly inform the Data 
Controller in writing about this. 
3. The Data Processor must ensure that persons authorized to process the Personal Data have 
committed themselves to confidentiality or are under an appropriate statutory obligation of 
confidentiality. 
4. The Data Processor shall implement appropriate technical and organizational measures to prevent 
that the Personal Data processed is: 
(i) accidentally or unlawfully destroyed, lost or altered, 
(ii) disclosed or made available without authorization, or 
(iii) otherwise processed in violation of Applicable Law.  
5. The appropriate technical and organizational security measures must be determined with due 
regard for: 
(i) the current state of the art, 
(ii) the cost of their implementation, and 
(iii) the nature, scope, context and purposes of processing as well as the risk of varying likelihood 
and severity for the rights and freedoms of natural persons. 

 
 
 
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6. Taking into account the nature of the processing, the Data Processor shall assist the Data 
Controller, by means of appropriate technical and organizational measures, insofar as this is 
possible, in fulfilling its obligation to respond to requests from Data Participants pursuant to laws 
and regulations in the area of privacy and data protection (such as, the right of access, the right to 
rectification, the right to erasure, the right to restrict the processing, the right to data portability 
and the right to object) 
7. The Data Processor shall upon request provide the Data Controller with sufficient information to 
enable the Data Controller to ensure that the Data Processor's obligations under this DPA are 
complied with, including ensuring that the appropriate technical and organizational security 
measures have been implemented. 
8. The Data Controller is entitled to appoint at its own cost an independent expert, reasonably 
acceptable to the Data Processor, who shall have access to the Data Processor's data processing 
facilities and receive the necessary information for the sole purpose of auditing whether the Data 
Processor has implemented and maintained said technical and organizational security measures. 
The expert shall upon the Data Processor's request sign a non-disclosure agreement provided by 
the Data Processor, and treat all information obtained or received from the Data Processor 
confidentially, and may only pass on, after conferral with the Data Processor, the findings as 
described under 10) (ii) below to the Data Controller. 
9. The Data Processor must give authorities who by Union or Member State law have a right to 
enter the Data Controller's or the Data Controller's processors’ facilities, or representatives of 
the authorities, access to the Data Processor's physical facilities against proper proof of identity 
and mandate, during normal business hours and upon reasonable prior written notice. 
10. The Data Processor must without undue delay in writing notify the Data Controller about: 
(i) any request for disclosure of Personal Data processed under the Protocol by authorities, 
unless expressly prohibited under Union or Member State law, 
(ii) any  finding of (a) breach of security that results in accidental or unlawful destruction, loss, 
alteration, unauthorized disclosure of, or access to, Personal Data transmitted, stored or 
otherwise processed by the Data Processor under the Protocol, or (b) other failure to comply 
with the Data Processor's obligations, or 
(iii) any request for access to the Personal Data (with the exception of medical records for which 
the Data Processor is considered data controller) received directly from the Data Participants 
or from third parties. 
11. Such a notification from the Data Processor to the Data Controller with regard to a breach of 
security as meant in 10) (ii)(a) above will contain at least the following information: 
(i) the nature of the Personal Data breach, stating the categories and (by approximation) the 
number of Data Participants concerned, and stating the categories and (by approximation) the 
number of the personal data registers affected (datasets); 
(ii) the likely consequences of the Personal Data breach; 
(iii) a proposal for measures to be taken to address the Personal Data breach, including (where 
appropriate) measures to mitigate any possible adverse effects of such breach. 
12. The Data Processor shall document (and shall keep such documentation available for the Data 
Controller) any Personal Data breaches, including the facts related to the Personal Data breach, 
its effects and the corrective measures taken. After consulting with the Data Controller, the Data 
Processor shall take any measures needed to limit the (possible) adverse effects of Personal Data 
breaches (unless such consultation cannot be awaited due to the nature of the Personal Data 
breach). 
13. The Data Processor must promptly and reasonably assist the Data Controller (with the handling 
of (a) responses to any breach of security as described in 10) (ii) above and (b) any requests from 
Data Participants under Chapter III of the GDPR, including requests for access, rectification, 
blocking or deletion. The Data Processor must also reasonably assist the Data Controller by 

 
 
 
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implementing appropriate technical and organizational measures for the fulfilment of the Data 
Controller's obligation to respond to such requests.  
14. The Data Processor must reasonably assist the Data Controller with meeting the other obligations 
that may be incumbent on the Data Controller according to Union or Member State law where 
the assistance of the Data Processor is implied, and where the assistance of the Data Processor is 
necessary for the Data Controller to comply with its obligations. This includes, but is not limited 
to, at the request to provide the Data Controller with all necessary information about an incident 
under 10) (ii), and all necessary information for an impact assessment in accordance with Article 
35 and Article 36 of the GDPR.  
Subprocessor: 
15. The Data Processor may only engage a subprocessor, with prior specific or general written 
consent from the Data Controller. The Data Processor undertakes to inform the Data Controller 
of any intended changes concerning the addition or replacement of a subprocessor by providing a 
reasonable prior written notice to the Data Controller. The Data Controller may reasonably and 
in a duly substantiated manner object to the use of a subprocessor. The Data Processor must 
inform the Data Controller in writing of the discontinued use of a subprocessor. 
16. Prior to the engagement of a subprocessor, the Data Processor shall conclude a written agreement 
with the subprocessor, in which at least the same data protection obligations as set out in this 
DPA shall be imposed on the subprocessor, including obligations to implement appropriate 
technical and organizational measures and to ensure that the transfer of Personal Data is done in 
such a manner that the processing will meet the requirements of the Applicable Law. 
17. The Data Controller has the right to receive a copy of the relevant provisions of Data Processor's 
agreement with the subprocessor related to data protection obligations. The Data Processor shall 
remain fully liable to the Data Controller for the performance of the subprocessor obligations 
under this DPA. The fact that the Data Controller has given consent to the Data Processor's use 
of a subprocessor is without prejudice for the Data Processor's duty to comply with this DPA.