Cohort Multiple Randomized Controlled Trials Open-label of Immune Modulatory Drugs and Other Treatments in COVID-19 Patients - Tocilizumab Trial - CORIMUNO-19 - TOCI (CORIMUNO-TOCI)
Phase: PHASE2
Conditions: Corona Virus Infection
Sponsor: Assistance Publique - Hôpitaux de Paris

Version 6.0 protocole CORIMUNO 04/05/2020 1 
 
Cohort Multiple randomized controlled trials open-
label of immune modulatory drugs and other 
treatments in COVID-19 patients 
CORIMUNO-19 
  
INTERVENTIONAL RESEARCH PROTOCOL INVOLVING 
HUMAN PARTICIPANTS CONCERNING MULTIPLE 
IMMUNE REGULATORY MEDICATIONS FOR HUMAN 
USE 
  
Version N°6.0 of 04/05/2020 
  
Project code number:APHP200375 
 
 
 
The medication substance consists in multiple Immune regulatory product 
Medication number1 : Anti IL-6 Receptor (Tocizilumab) 
Medication number2 : Anti IL6 Receptor (Sarilumab) 
 
  
The IMP or drug product consists in an antibody 
 
 
 
 
 

Version 6.0 protocole CORIMUNO 04/05/2020 2 
 
  
 
Coordinating Investigator: 
  
  
  
  
  
Co-coordinating Investigator 
Pr Olivier Hermine, 
Service Hématologie Adulte 
Necker Hospital, Paris, France 
Tel: +33 144495282 +33603707920 
Email: olivier.hermine@aphp.fr 
  
Pr Xavier Mariette, 
Service Rhumatologie 
Hôpital du Kremlin Bicêtre 
Tel: +33145213758 +33623268104 
Email: xavier.mariette@aphp.fr 
  
 Immune COVID 19 group 
Scientific Director:     
  
  
  
  
  
Methodologist and statisticians: 
Dr Pierre Louis Tharaux 
INSERM U970, PARCC 
HEGP 
Tel +33689502948 
Email: pierre-louis.tharaux@inserm.fr 
  
Pr Philippe Ravaud 
Centre d’Epidémiologie Clinique. 
Hôpital Hôtel Dieu 
1 Place du Parvis Notre Dame 
75004 Paris 
EMail : philippe.ravaud@aphp.fr 
Statistician: 
Dr Raphael Porcher 
Centre d’Epidémiologie Clinique. 
Hôpital Hôtel Dieu 
1 Place du Parvis Notre Dame 
75004 Paris 
Mail : raphael.porcher@aphp.fr 
Clinical Trial Unit : 
Pr Matthieu Resche-Rigon 
Hôpital Saint-Louis 
1 av Claude vellefaux 

Version 6.0 protocole CORIMUNO 04/05/2020 3 
75010 Paris 
EMail : matthieu.resche-rigon@u-paris.fr 
 
  
Sponsor : AP-HP and by delegation: 
                                 
Délégation à la Recherche Clinique et à 
l’Innovation (DRCI) 
Saint-Louis Hospital 
1, avenue Claude Vellefaux, Paris, France 
DRCD-Siège : 
Cécile Kedzia -  
cecile.kedzia@aphp.fr 
Damien Vanhoye - 
damien.vanhoye@aphp.fr 
 
 
Monitoring and data Management: 
URC  Lariboisière Saint-Louis 
Site Saint - Louis 
Hôpital Saint-Louis, 1 av Claude Vellefaux, 
75010 PARIS 
Pr Matthieu Resche-Rigon 
EMail : matthieu.resche-rigon@u-paris.fr 
 
Nabil Raked 
EMail : nabil.raked@univ-paris-diderot.fr 
 
  
 

Version 6.0 protocole CORIMUNO 04/05/2020 4 
  
 
 

Version 6.0 protocole CORIMUNO 04/05/2020 5 
 
INTERVENTIONAL RESEARCH PROTOCOL 
RELATING TO A MEDICINAL PRODUCT FOR HUMAN USE 
 
PROTOCOL SIGNATURE PAGE 
  
APHP200375 
  
Title:  Cohort multiple Randomized open-label control trial of Immunomodulatory 
drugs and other treatments in COVID-19 patients (CORIMUNO-19 trial) 
  
Version N°6.0 of 04/05/2020 
  
The study will be carried out in accordance with the protocol, with current good practices and 
with statutory and regulatory requirements. 
  
Principal Investigator 
  
Pr. Olivier Hermine 
Hospital Necker Enfants Malades 
149, Rue de Sèvres - 75743 Paris Cedex 15            
  
Date: ……………/………/……….. 
Signature: 
  
  
Sponsor 
  
Assistance Publique – Hôpitaux de Paris 
Département de la Recherche Clinique et du 
Développement 
Hospital Saint Louis 
1 avenue Claude Vellefaux - 75010 Paris 
Date: ……………/………/……….. 
Signature: 
  

Version 6.0 protocole CORIMUNO 04/05/2020 6 
  
  
  
The study was approved by the Ethic committee (CPP) of ………. on ……… and authorised 
by the ANSM on ……... 
 
 
 
ABBREVIATIONS LIST 
  
  
 
  
 
 

Version 6.0 protocole CORIMUNO 04/05/2020 7 
 
SUMMARY 
11 
SCIENTIFIC JUSTIFICATION FOR THE STUDY 
30 
Overview of COVID-19 
30 
Rationale for using immune regulatory drug 
31 
Immune pathology of COVID infection 
31 
Sarilumab: Rationale for the use and mechanism of action 
33 
Summary of relevant pre-clinical and clinical trials on IL-6R Inhibition 
34 
OBJECTIVES 
35 
Primary objective 
35 
Secondary objectives 
35 
DESCRIPTION OF THE COHORT STUDY 
35 
Cohort multiple Randomized Controlled Trials (cmRCT) design 
35 
Settings 
37 
Study population 
37 
Inclusion and exclusion criteria in the cohort 
38 
Endpoints 
40 
Other data collected in the cohort 
40 
Biobanking (cf Annexe 3) 
43 
Standard of care provided for all patients in the cohort 
43 
Flowchart 
44 
TRIALS WITHIN THE COHORT 
47 
Adding new trials in the cohort 
47 
Clinical trial process 
47 
Methodological elements of trials nested in the cohort 
48 
Termination and exit rules for trials nested in the cohort 
48 
Monitoring subjects after the premature termination of treatment 
49 
Decision of a new trial nested in the cohort 
49 
Full or partial cancellation of a trial nested in the cohort 
49 
FIRST NESTED TRIAL : EFFICACY OF TOCILIZUMAB FOR PATIENTS WITH 
COVID-19 
51 
Investigational medicinal product(s) 
51 
Authorised and prohibited treatments (medicinal, non-medicinal, surgical), including 
rescue medications 
52 
Supply of the investigational centers 
53 
Posology and drugs administration 
53 
Traceability in investigational centers 
54 
Methods for monitoring compliance with the treatment 
54 
Control 
54 

Version 6.0 protocole CORIMUNO 04/05/2020 8 
Inclusion/Exclusion criteria for the nested trial 
54 
Endpoints for the trial 
55 
Efficacy endpoints 
55 
Safety endpoints 
58 
Specific data to be collected for this trial 
59 
Expected benefits and risks 
59 
Sketch of statistical methods 
60 
SECOND NESTED TRIAL : EFFICACY OF SARILUMAB FOR PATIENTS WITH 
COVID-19 
61 
Investigational medicinal product(s) 
61 
Authorised and prohibited treatments (medicinal, non-medicinal, surgical), including 
rescue medications 
61 
Supply of the investigational centers 
62 
Posology and drugs administration 
62 
Traceability in investigational centers 
62 
Methods for monitoring compliance with the treatment 
63 
Control 
63 
Inclusion/Exclusion criteria for the nested trial 
63 
Endpoints for the trial 
64 
Efficacy endpoints 
64 
Safety endpoints 
67 
Specific data to be collected for this trial 
68 
Expected benefits and risks 
68 
Sketch of statistical methods 
69 
RECORDING AND REPORTING ADVERSE EVENTS 
70 
Definitions 
70 
The role of the investigator 
72 
Serious adverse events that require a notification without delay by the investigator to 
the sponsor 
74 
Serious adverse events that do not require the investigator to notify the sponsor 
without delay 
74 
Special circumstances 
75 
Period during which the investigator must send notification of SAEs to the sponsor 
without delay DRCI 
76 
Procedures and deadlines for notifying the sponsor 
76 
Role of the sponsor 
77 
Analysis and declaration of serious adverse events 
78 
Analysis and declaration of other safety data 
79 
Annual safety report 
80 
SPECIFIC COMMITTEES FOR THE STUDY 
80 
Data Safety Monitoring Board (DSMB) 
80 

Version 6.0 protocole CORIMUNO 04/05/2020 9 
Steering Committee 
81 
DATA MANAGEMENT 
81 
Access to data 
81 
Source documents 
81 
Data confidentiality 
81 
Data processing and storage of documents and data 
82 
Identification of the person responsible and the location of the data processing 
management 
82 
Data Entry 
82 
Ownership of the data 
82 
STATISTICAL ASPECTS 
82 
Planned statistical methods, including the timetable for any planned interim analyses 
82 
Statistical criteria for termination of the study 
84 
Number of participants and justification 
88 
Anticipated level of statistical significance 
89 
Subject replacement strategy 
89 
Method for taking into account missing, unused or invalid 
89 
Management of modifications made to the analysis plan for the initial strategy 
89 
Choice of individuals to be included in the analyses 
89 
QUALITY CONTROL AND ASSURANCE 
89 
General organisation 
90 
Quality control 
90 
Case Report Form 
91 
Management of non-compliances 
91 
Audits/inspections 
91 
Principal Investigator's declaration of responsibility 
92 
Pharmacist's declaration of responsibility 
92 
ETHICAL AND LEGAL CONSIDERATIONS 
92 
Methods for informing and obtaining consent from the research participants 
93 
Authorisation for the research location 
94 
Legal obligations 
94 
The sponsor's role 
94 
Request for approval from the CPP (Research Ethics Committee) 
95 
Request for authorisation from ANSM 
95 
Amendments to the research 
95 
Final study report 
95 
Archiving 
96 
FUNDING AND INSURANCE 
96 
Sources of funding for the trial 
96 

Version 6.0 protocole CORIMUNO 04/05/2020 10 
Insurance 
96 
PUBLICATION RULES 
97 
BIBLIOGRAPHY 
98 
LIST OF ADDENDA 
104 
 
 
 
 
 
 

Version 6.0 protocole CORIMUNO 04/05/2020 11 
1. 
SUMMARY 
AP-HP 
  
STUDY CODE: 
  
Trial Title 
Cohort Multiple randomized controlled trials open-label of immune modulatory 
drugs and other treatments in COVID-19 patients 
CORIMUNO-19 
Coordinating 
Investigator 
COVID-19 group 
Trial site(s) 
Hospitals involved in COVID care 
Clinical Phase 
NA 
Objectives 
The overall objective of the study is to determine which treatments (e.g. immune 
modulator drugs) have the most favourable benefit-risk in adult patients 
hospitalized with COVID-19. 
The specific aims of this Covid19 cohort are to collect observational data at regular 
intervals on an ongoing basis in order to embed a series of randomized controlled 
trials evaluating a various set of interventions. 

Version 6.0 protocole CORIMUNO 04/05/2020 12 
Methodology 
The key features of the cohort multiple Randomized Controlled Trials (cmRCT) 
design are: 
(I) Recruitment of a large observational cohort of patients with the condition of 
interest 
(II) Regular measurement of outcomes for the whole cohort 
(III) Capacity for multiple randomised controlled trials over time 
Patients enrolled in the cohort agree to allow their longitudinal data to be used in the 
aggregate. They also allow their data to be used to identify them to be invited to 
participate in research interventions or for comparison purposes for intervention trials 
that may be conducted with other patients while they are participating in the cohort. 
In the cmRCT design, only eligible patients randomly selected to be offered an 
intervention, are contacted and offered treatment. Eligible patients not 
selected to be offered an intervention are not notified about this trial and will be in 
the control group. Consent for specific trials will be obtained from those eligible 
patients who are invited and accepted the offer to participate. In the cmRCT design, 
as described to patients when they consent to participate in the cohort, only eligible 
patients randomly selected to be offered an intervention, but not eligible non-selected 
patients, are contacted and offered treatment. Eligible patients not selected are not 
notified about the trial. Consent for specific trials will be obtained from those eligible 
patients who are invited and accept the offer to participate. Post-intervention 
outcomes among eligible patients who accept the offer to receive the intervention will 
be compared with outcomes among patients from the cohort who were identified as 
eligible for the intervention, but were not randomly selected to be offered the 
intervention and not contacted about the intervention. 
In the context of the COVID crisis, the advantage of the cmRCT design to conduct 
multiple trials that draw participants from the same patient cohort is important given 
the imperative that we have to answer multiple research questions (some identified 
and others not yet identified) in a very short time (a few weeks). 
The cmRCT design will enable the implementation of multiple trials over time with 
different inclusion and exclusion criteria (e.g. based on severity or comorbidities), 
testing different interventions that can be compared in the same overall population 
with similar trial methods, thus increasing the ability to compare and contrast 
different trial results. This design allows to perform a series of randomized, controlled 
adaptive trials, with frequent interim monitoring to facilitate the following: dropping 
of poorly performing arms, introduction of new candidate therapies and modification 
of current optimized standard-of-care (oSOC). 
In its simplest iteration, the study can be viewed as a series of 2-arm comparisons 
whereby the superior treatment, if identified, from each pairwise comparison 
becomes the basis of the new supportive care backbone (hence the term “optimized 
SOC”, or oSOC, to describe this potentially evolving backbone) common to each 
future arm of the study and against which additional investigational interventions 
may then be added to the protocol, tested and compared: Arm A: optimized SOC 
alone Arm B: Investigational treatment X + optimized SOC. 
If this pairwise comparison shows the superiority of Arm B over Arm A, then 
investigational treatment X featured in Arm B will be incorporated into the new 
oSOC common to each future arm of the study (assuming adequate drug supply exists 
to permit this). 
Conversely, if a given pairwise comparison of Arm A versus Arm B fails to yield a 
clear statistical winner in terms of the primary endpoint, then subsequent pairwise 
comparisons will not incorporate the “failed” intervention featured in current Arm B 
into the new oSOC backbone. 

Version 6.0 protocole CORIMUNO 04/05/2020 13 
The cmRCT design also offers advantages in that the patient consent process more 
closely replicates what occurs in actual healthcare settings compared with the consent 
procedures typically used in traditional RCT designs. In traditional RCTs, patients 
are usually told that they will be randomised to obtain the trial intervention or an 
alternative which is generally usual care. In the cmRCT design, patients are told about 
treatments that they will be able to access if they so choose. As part of the initial 
consent process, patients are made aware that a number of trials may occur via the 
cohort, and that they will not likely be offered to participate in all of them and may 
not be offered to participate in any. It is explained that patients will only be notified 
about trials for which they will be offered the intervention, but that their data may be 
used for comparison purposes in the context of some interventions not offered to 
them. 

Version 6.0 protocole CORIMUNO 04/05/2020 14 
Randomisation 
The study will include potentially all patients with COVID-19 infection and moderate 
or severe NCP. Among such large two groups of patients, subgroups of patients with 
specific characteristics will be randomized and proposed to receive treatments. 
The goal of the CORIMUNO-19 trial is to uncover large therapeutic effects. By 
default, the sample size will be 30 for the treated arms, but more than 30 subjects will 
be used as controls. Larger sample sizes can also be specified in trial protocols. 
For each trial, a random sample of eligible patients (e.g. n=30) will be selected. This 
number may be increased or decreased as a result of the efficacy and safety reviewed 
by the DSMB and sponsor by group of patients. Randomisation will be centralized 
and thus will be completely independent from patients and physicians participating 
in the study ensuring allocation concealment. 
Other trials may be conducted where patients are directly randomised with a fixed 
allocation ratio to treatment or control, with interim monitoring of the trial.. 
DSMB 
A review of efficacy and safety data by DSMB will be performed every week. DSMB 
will review in priority: safety, hospitalization and discharge, organ functions, death, 
viral load, and decide whether any arm should be stopped prematurely or be the 
preferred arm to which other arm should be switched for any predefined group of 
patients (Age, comorbidities, severity assessed by clinical and biological parameters, 
antiviral therapy). The DSMB will submit its advice to the scientific and clinical 
committee. 
At the end of each trial, DSMB will recommend the treatment with the most favorable 
benefit-risk in the most appropriate endpoint for future studies. 
Number of patients 
We expect to recruit 1 000 patients in the cohort. 
The number of patients for each subtrial within the cohort is predefined for each trial 
and can be adjusted for each sub-trial following DMSB and scientific committee 
advices in real time analysis 

Version 6.0 protocole CORIMUNO 04/05/2020 15 
Diagnosis 
and 
inclusion 
and 
Exclusion criteria 
for the cohort 
Inclusion Criteria for the cohort: 
1. Laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or 
other commercial or public health assay in any specimen and/or CT Scan 
prior to randomization (Following typical radiological findings (ground glass 
abnormalities, and absence of lymphadenopathy, pleural effusion, pulmonary 
nodules, lung cavitation) 
2. Hospitalized patients 
3. Illness of any duration and severity (mild, moderate, severe, critical, see 
annexe 1), with symptoms (fever, cough, respiratory difficulties, shortness of 
breath), and at least one of the following: 
a. 
Radiographic infiltrates by imaging (CT scan) 
b. Clinical assessment (evidence of rales/crackles 
on exam or respiratory rate >25/min) AND 
SpO2≤94% on room air 
c. 
SpO2≤97 % with O2 > 5L/min or Respiratory rate>=30/min 
d. Requiring mechanical ventilation 
e. 
With any comorbidities (TBD such as acute kidney injury, 
cardiovascular condition, pulmonary disease, obesity, high blood 
pressure, diabetes, chronic kidney diseases, haematological 
diseases, sickle cell diseases, autoimmune and auto-inflammatory, 
pregnant women, HIV infected, etc)  
4. Male or female adult ≥ 18 years of age at time of 
enrolment 
5. Patients must be able and willing to comply with study visits and procedures. 
6. Patient agrees to the collection of oropharyngeal and nasal swabs and venous 
blood per protocol 
7. Written informed consent provided by the patient or alternatively by next-of-
kin prior to any protocol-specific procedures. 
 
Exclusion Criteria for the cohort: 
Participation in another clinical trial is not an exclusion criterion depending on the 
medication. Patients included in the antiviral REACTING trial are not excluded as 
well as patients from COVIDICUS trial. 
Severe cardiovascular disease including acute myocardial 
infarction, 
unstable 
angina 
pectoris, 
coronary 
revascularization procedure, congestive heart failure of 
NYHA Class III or IV, stroke, including a transient ischemic 
attack, edema of cardiac origin and left ventricular ejection 
fraction ≤ 50% are not excluded and should be discussed in 
each therapeutic arm.  
● 
Patients with any condition that the physician judges could be detrimental to 
the patient participating in this study; including any clinically important 
deviations from normal clinical laboratory values or concurrent medical 
conditions (active infection diseases such as severe bacterial infections, 
aspergillosis, tuberculosis, depending on the tested medication). 
● 
Absence of Health Insurance 
● 
Subject protected by law under guardianship or curatorship 

Version 6.0 protocole CORIMUNO 04/05/2020 16 
Measures routinely 
collected 
during 
patient follow-up 
A core set of clinical measures will be recorded daily the first 2 weeks and then every 
week. The core measures include measures of OMS progression scale, oxygenation, 
mechanical ventilation. These measures will allow us to classify the patients state 
according to the WHO Clinical Progression Scale. All-cause mortality at hospital 
discharge or 60 days and time to hospital discharge will be also recorded. 
In addition, biological measures routinely prescribed for care will be collected 
For patients who are eligible for an intervention trial (in both the intervention and 
control arms), this 3-days measurement may also include trial-specific measures 
related to the trial outcomes of interest taking into account the WHO core outcome 
set for clinical research. 
 
CORIMUNO-19 - TOCI 
Rationale for using 
Tocilizumab 
in 
severe 
patients 
infected 
with 
COVID-19 
CORIMUNO-19 - TOCI 
The SRAS-CoV-S protein induces direct up-regulation of IL-6, IL-1 and TNFα, some 
of the most potent pro-inflammatory cytokines 
Tocilizumab (TCZ) is an anti-human IL-6 receptor monoclonal antibody that inhibits 
signal transduction by binding sIL-6R and mIL-6R. The main approved indication is 
for rheumatoid arthritis, in association or not with methotrexate. The IV the approved 
dose in RA is 8 mg/kg every month. TCZ is also approved in the treatment of juvenile 
inflammatory arthritis and in the treatment of refractory giant cell arteritis. 
Interestingly, this later indication concerns aged patients and, in this population, the 
safety profile was the same as in younger patients. In 2017, the U.S. Food and Drug 
Administration approved TCZ for the treatment of cytokine release syndrome (CRS) 
consisting in a systemic inflammatory response caused by the massive release of pro-
inflammatory cytokines in response to iatrogenic (e.g. CAR-t therapies) or infective 
stimuli. 
Despite the lack of clinical trials on TCZ efficacy and safety for COVID-19 
treatment, in China TCZ was recently approved for patients affected by severe SARS-
CoV-2 pulmonary complications by the National Health Commission of the People’s 
Republic of China. Preliminary data from an observational study conducted in China 
on 21 severe cases receiving TCZ, showed an improvement of the clinical and 
radiological outcome. 

Version 6.0 protocole CORIMUNO 04/05/2020 17 
Diagnosis 
and 
inclusion 
and 
Exclusion criteria 
for 
the 
Tocilizumab trial 
Inclusion Criteria for the Tocilizumab trial: 
1. Patients included in the CORIMUNO-19 cohort 
2. Patients belonging to one of the 2 following groups: 
- Group 1: patients not requiring ICU at admission with moderate and severe 
pneumopathy according to the WHO Criteria of severity of COVID pneumopathy. 
Moderate cases 
Cases meeting all of the following criteria: 
● 
Showing fever and respiratory symptoms with radiological 
findings of pneumonia. 
● 
Requiring between 3L/min and  5L/min of oxygen to maintain 
SpO2 >97% 
Severe cases  
Cases meeting any of the following criteria: 
● 
Respiratory distress (≧30 breaths/ min); 
● 
Oxygen saturation ≤93% at rest in ambient air; 
or Oxygen saturation ≤97 % with O2 > 5L/min. 
● 
PaO2/FiO2≦300mmHg  
 
- Group 2: patients requiring ICU based on Criteria of severity of COVID 
pneumopathy. 
● 
Respiratory failure and requiring mechanical ventilation 
● 
No do-not-resuscitate order (DNR order) 
 
Exclusion Criteria for the Tocilizumab trial: 
● 
Patients with exclusion criteria to the CORIMUNO-19 cohort. 
● 
Known hypersensitivity to Tocilizumab or to any of their excipients. 
● 
Pregnancy 
● 
Current documented bacterial infection 
● 
Patient with any of following laboratory results out of the ranges detailed 
below at screening should be discussed depending of the medication: 
○ 
Absolute neutrophil count (ANC) ≤ 1.0 x 109/L 
○ 
Haemoglobin level: no limitation 
○ 
Platelets (PLT) < 50 G /L 
○ 
SGOT or SGPT > 5N 

Version 6.0 protocole CORIMUNO 04/05/2020 18 
Randomisation 
and 
Treatment 
procedures 
Group defined by requiring ICU vs. not requiring ICU. 
All consecutive patients meeting the inclusion criteria will be randomised 1:1 either 
in the Tocilizumab arm or control arm in a set of 120 patients in total  (60 in each 
arm), stratified on the group. Trials within each groups are analyzed separately, but 
are conducted simultaneously (with stratification of the randomisation) for logistical 
reasons. If other subtrials are available, the inclusions will stop to allow inclusions in 
these other subtrials of the protocol and interim analysis. If the interim analysis 
indicates to continue the subtrial, a new set of 120 patients will be included on the 
same basis.  If no other subtrial is available the inclusions will not be stopped in 
waiting for the interim analysis, given tocilizumab is already a drug with known 
safety. 
Inclusions of new sets will stop when statistical analyses conclude on futility or 
efficacy or by DSMB decision. 
 
● 
Group 1: patients not requiring ICU  
○ 
Patients will be randomized to be offered Tocilizumab 8mg/kg D1 
and if no response (no decrease of oxygen requirement) a second 
injection with fixed dose of 400mg at D3. 
○ 
Patients from the cohorts and with the same baseline characteristics 
will be used as controls (best standard of care) 
  
● 
Group 2: patients requiring ICU  
○ 
Patients will be randomized to receive Tocilizumab 8mg/kg at D1 
and if no response a second injection with fixed dose of 400 mg at 
D3. These patients may receive or not steroids depending of the local 
procedures.  
○ 
Patients from the cohorts with the same baseline characteristics will 
be used as controls 
  
Duration of follow-
up 
90 days 

Version 6.0 protocole CORIMUNO 04/05/2020 19 
Criteria 
for 
efficacy 
Measures 
A core set of clinical measures will be recorded daily the first 2 weeks and then every 
week. The core measures include measures of OMS progression scale, oxygenation, 
mechanical ventilation. For patients who are eligible for an intervention trial (in both 
the intervention and control arms), this days measurement will include trial-specific 
measures related to the trial outcomes of interest. 
Primary and secondary endpoints: 
The primary endpoint and secondary endpoints will depend on the group of 
patients and tested medication. 
 
Groups will be redefined as follow : 
- Group 1: Cases meeting all of the following criteria 
 
    Requiring more than 3L/min of oxygen 
 
    OMS/WHO progression scale = 5 
 
    No NIV or High flow 
 
- Group 2: Cases meeting all of the following criteria 
 
 
    Respiratory failure AND (requiring mechanical ventilation OR NIV OR 
High flow) 
 
    WHO progression scale >=6 
 
    No do-not-resuscitate order (DNR order) 
 
  
For the group 1 of patients not requiring ICU: 
  
Co Primary Endpoints  
 
1. Survival without needs of ventilator utilization (including non invasive 
ventilation and high flow) at day 14. Thus, events considered are needing 
ventilator utilization (including Non Invasive Ventilation, NIV or high flow), 
or death. New DNR order (if given after the inclusion of the patient) will be 
considered as an event at the date of the DNR. 
2. Early endpoint : proportion of patients alive without non-invasive ventilation 
of high low at day 4 (WHO progression scale ≤ 5). A patient with new DNR 
order at day 4 will be considered as with a score > 5. 
 
OMS 
Progression 
scale 
Descriptor 
Score 
Uninfected 
Uninfected; non viral RNA detected 
0 
Ambulatory 
Asymptomatic; viral RNA detected 
1 
Ambulatory 
Symptomatic; Independent 
2 
Ambulatory 
Symptomatic; Assistance needed 
3 
Hospitalized : mild 
Hospitalized; No oxygen therapy 
4 

Version 6.0 protocole CORIMUNO 04/05/2020 20 
disease 
Hospitalized : mild 
disease 
Hospitalized; oxygen by mask or nasal 
prongs 
5 
Hospitalized : severe 
disease 
Hospitalized; oxygen by NIV or High 
flow 
6 
Hospitalized : severe 
disease 
Intubation and Mechanical ventilation, 
pO2/FIO2>=150 OR SpO2/FIO2>=200  
7 
Hospitalized : severe 
disease 
Mechanical ventilation, (pO2/FIO2<150 
OR SpO2/FIO2<200) OR vasopressors 
(norepinephrine >0.3 microg/kg/min) 
8 
Hospitalized : severe 
disease 
Mechanical ventilation, pO2/FIO2<150 
AND vasopressors (norepinephrine >0.3 
microg/kg/min), OR Dialysis OR ECMO 
9 
Death 
Dead 
10 
 
Secondary end-points will be OMS progression scale at 4, 7 and 14 days, 
overall survival at 14, 28 and 90 days, time to discharge, time to oxygen supply 
independency, time to negative viral excretion. 
Biological parameters improvement: 
Estimated GFR, CRP, myoglobin, CPK, cardiac troponin, ferritin, lactate, cell 
blood count, liver enzymes, LDH, D-Dimer, albumin, fibrinogen, triglycerides, 
coagulation tests, urine electrolyte, creatinuria, proteinuria, uricemia, IL6, 
procalcitonin, immunophenotype (Annexe 2), and exploratory tests (Annexe 
3). 
  
For the group 2 of patients requiring ICU: 
  
Co Primary Endpoints 
 
1. Cumulative incidence of successful tracheal extubation (defined as duration 
extubation > 48h) at day 14 if patients have been intubated before day 14 ; or 
removal of NIV or high flow (for > 48h) if they were included under oxygen 
by NIV or High flow (score 6) and remained without intubation. Death or new 
DNR order (if given after the inclusion of the patient) will be considered as a 
competing event. 
2. Early end point : proportion of patients with a decrease of WHO score of at 
least 1 point at day 4. 
 
Secondary end points will be OMS progression scale at 4, 7 and 14 
days, overall survival at 14, 28 and 90 days, the 28-day 
ventilator free-days, respiratory acidosis at day 4 (arterial 
blood pH of <7.25 with a partial pressure of arterial carbon 
dioxide [Paco2] of ≥60 mm Hg for >6 hours), the evolution of 
PaO2/FiO2 ratio, time to oxygen supply independency, 
duration 
of 
hospitalization, 
time 
to 
negative 
viral 
excretion, time to ICU and hospital discharge. 

Version 6.0 protocole CORIMUNO 04/05/2020 21 
 
Biological parameters improvement (estimated GFR, CRP, cardiac troponin, 
urine electrolyte and creatinine, proteinuria, uricemia, IL6, myoglobin, KIM-
1, NGAL, CPK, ferritin, lactate, cell blood count, liver enzymes, LDH, D-
Dimer, albumin, fibrinogen, triglycerides, coagulation tests (including 
activated partial thromboplastin time), procalcitonin, immunophenotype 
(Annexe 2), and exploratory tests (Frozen samples Annexe 3). Rate of renal 
replacement therapy, ventilation parameters. 
  
For each comorbidities group secondary criteria will be specifically 
addressed: 
  
For each tested medication, specific markers of efficacy and safety may be used 
and will be defined. 
Criteria of safety 
● 
Number of serious adverse events 
● 
Cumulative incidence of serious adverse events (SAEs) 
● 
Cumulative incidence of Grade 3 and 4 AEs. 
● 
Investigational medication discontinuation (for any reason) 

Version 6.0 protocole CORIMUNO 04/05/2020 22 
Statistical Method 
 
To maximize information from limited data generated, while allowing rapid decision, 
a Bayesian monitoring of the trial based on tco-primary outcomes will be used. The 
overall strategy has been determined so as to control for a frequentist one sided 5% 
type I error rate. The following methods pertain to the conduct and analysis of the 
subtrial in a given group of patients (group I or group II), that are analyzed separately 
with different primary outcomes, but conducted simultaneously (with stratified 
randomization) for logistical reasons. The total sample size will be 120 (60 in each 
arm) at the interim analysis, and 240 (120 per arm) at the second analysis. 
 
Since it is not possible to determine in advance how many patients will be recruited 
in each stratum, the sample sizes used for the following calculations are indicative, 
considering equally sized strata (groups). At the interim analysis, two posterior 
probabilities will be calculated: 1) the posterior probability of a lower event rate in 
the experimental than in the control arm (posterior probability of efficacy) and 2) the 
posterior probability of achieving at least a predefined effect corresponding to a 
hazard ratio of 0.85 (for time-to-event primary outcomes)  or a risk difference of 5.5% 
(for binary co-primary outcomes) (posterior probability of sufficient efficacy). If the 
posterior probability of sufficient efficacy is less than 0.20, the trial can be stopped 
for futility. If the posterior probability of efficacy is higher than 0.99, the trial can be 
stopped for efficacy. Otherwise, the trial will continue with inclusion of additional 
patients, as predefined, and a final analysis is conducted with decision boundary at a 
posterior probability of efficacy > 0.95. Decision boundaries are non-binding, and 
the DSMB can recommend continuing recruitment, in the whole population or a 
subgroup. Final decision boundaries are then readapted to control for a one-sided type 
I error rate close to 5%.  If the strata (groups I or II) are equally sized, the interim 
analysis should occur after 60 patients, and the second one with 120. This design 
(with only two stages) has then type I error rate 0.047 if event rates are 50% in each 
arm, and power 0.972 to detect a decrease from 0.50 to 0.20 and 0.739 to detect a 
decrease from 0.50 to 0.30. 
 
In the cmRCT design, randomisation occurs prior to offering the intervention, and 
some number of eligible patients who are randomly selected to be offered an 
intervention will not accept the offer. An intention to treat analysis could therefore 
dilute any treatment effects. Relton et al. suggested to use a complier average causal 
effect (CACE) analysis which provides unbiased estimates of the treatment effect for 
patients who comply with the protocol. Thus, all final primary analyses will be 
performed in both Intention To Treat (ITT) and CACE basis. For this purpose, it will 
be assumed that a patient's decision not to accept the intervention will not affect the 
outcome. For the ITT analysis, patients will be analysed according to the treatment 
arm they were randomized to (i.e. offer or no offer group), even if the participant did 
not accept the intervention.  
 
 
 
 
 
 
 
 
CORIMUNO-19 - SARI 

Version 6.0 protocole CORIMUNO 04/05/2020 23 
Rationale for using 
Sarilumab 
in 
severe 
patients 
infected 
with 
COVID-19 
CORIMUNO-19 - SARI 
The SRAS-CoV-S protein induces direct up-regulation of IL-6, IL-1 and TNFα, some 
of the most potent pro-inflammatory cytokines 
Sarilumab is a human IgG1 monoclonal antibody that binds specifically to both 
soluble and membrane-bound IL-6Rs (sIL-6Rα and mIL-6Rα) and has been shown 
to inhibit IL-6-mediated signalling through these receptors. Sarilumab is formulated 
for subcutaneous (SC) injection and was approved for the treatment of rheumatoid 
arthritis in the US, EU and Japan in 2017 at a dose of 200 mg Q2W. 
In this protocol involving critically ill patients, it is preferable to use an IV injection. 
While there is limited experience in the use of sarilumab by IV infusion, the choice 
of the dose the use of sarilumab to be given by the IV route in this setting is supported 
by the high degree of bio-similarity of sarilumab to tocilizumab including a number 
of similarities in clinically observed pharmacokinetics, pharmacodynamics (to 
include safety, and PD endpoints). Based on available data, on a per mg basis, 
tocilizumab and sarilumab behave comparably in vivo with respect to potency, PK, 
PD, efficacy, and safety. Thus, the safety of sarilumab at doses as high as 400 mg IV 
can be extrapolated from the experience with similar and even higher doses of 
tocilizumab. Thus, it will be an IV dose of 400 mg of sarilumab in a 1 hour-infusion 
that will be given in this study 
Diagnosis 
and 
inclusion 
and 
Exclusion criteria 
for the Sarilumab 
trial 
Inclusion Criteria for the Sarilumab trial: 
1. Patients included in the  CORIMUNO-19 cohort 
2. Patients belonging to one of the 2 following groups: 
- Group 1: patients not requiring ICU at admission with moderate and severe 
pneumopathy according to the OMS  Criteria of severity of COVID pneumopathy. 
Moderate cases 
Cases meeting all of the following criteria: 
● 
Showing fever and respiratory symptoms with radiological findings 
of pneumonia. 
● 
Requiring between 3L/min and 5L/min of oxygen to maintain SpO2 
>97% 
Severe cases  
Cases meeting any of the following criteria: 
● 
Respiratory distress (≧30 breaths/ min); 
● 
Oxygen saturation≤93% at rest in ambient air; or 
Oxygen saturation ≤97 % with O2 > 5L/min. 
● 
PaO2/FiO2≦300mmHg  
 
- Group 2: patients requiring ICU based on Criteria of severity of COVID 
pneumopathy. 
● 
Respiratory failure and requiring mechanical ventilation 
● 
No do-not-resuscitate order (DNR order) 
 
Exclusion Criteria for the Sarilumab trial: 

Version 6.0 protocole CORIMUNO 04/05/2020 24 
1. Patients with exclusion criteria to the CORIMUNO-19 cohort. 
2. Known hypersensitivity to Sarilumab or to any of their excipients. 
3. Pregnancy 
4. Current documented bacterial infection 
5. Patient with any of following laboratory results out of the ranges detailed 
below at screening should be discussed depending of the medication: 
a. 
Absolute neutrophil count (ANC) ≤ 1.0 x 109/L 
b. Haemoglobin level: no limitation 
c. 
Platelets (PLT) < 50 G /L 
d. SGOT or SGPT > 5N 
Randomisation 
and 
Treatment 
procedures 
Group defined by requiring ICU vs. not requiring ICU. 
All consecutive patients meeting the inclusion criteria will be randomised 1:1 either 
in the Sarilumab arm or control arm in a set of 120 patients in total  (60 in the each 
arm), stratified on the group. Trials within each groups are analyzed separately, but 
are conducted simultaneously (with stratification of the randomisation) for logistical 
reasons. If other subtrials are available, the inclusions will stop to allow inclusions in 
these other subtrials of the protocol and interim analysis. If the interim analysis 
indicates to continue the subtrial, a new set of 120 patients will be included on the 
same basis.  If no other subtrial is available the inclusions will not be stopped in 
waiting for the interim analysis, given tocilizumab is already a drug with known 
safety. 
Inclusions of new sets will stop when statistical analyses conclude on futility or 
efficacy or by DSMB decision. 
 
  
● 
Group 1: patients not requiring ICU  
○ 
Patients will be randomized to be offered Sarilumab (an IV dose 
of 400 mg of sarilumab in a 1 hour-infusion  at D1). In the absence 
of a clinical response, a second dose of Sarilumab will be 
administered on day 3 (D3). 
○ 
Patients from the cohorts and with the same baseline characteristics 
will be used as controls (best standard of care) 
  

Version 6.0 protocole CORIMUNO 04/05/2020 25 
● 
Group 2: patients requiring ICU  
○ 
Patients will be randomized to receive Sarilumab (an IV dose of 
400 mg of sarilumab in a 1 hour-infusion  at D1). In the absence of 
a clinical response, a second dose of Sarilumab will be 
administered on day 3 (D3). These patients may receive or not 
steroids depending on the local procedures.  
○ 
Patients from the cohorts with the same baseline characteristics will 
be used as controls 
  
Duration of follow-
up 
90 days 

Version 6.0 protocole CORIMUNO 04/05/2020 26 
Criteria 
for 
efficacy 
Measures 
A core set of clinical measures will be recorded daily the first 2 weeks and then every 
week. The core measures include measures of OMS progression scale, oxygenation, 
mechanical ventilation. For patients who are eligible for an intervention trial (in both 
the intervention and control arms), this days measurement will include trial-specific 
measures related to the trial outcomes of interest. 
Primary and secondary endpoints: 
The primary endpoint and secondary endpoints will depend on the group of 
patients and tested medication. 
  
Groups will be redefined as follow : 
- Group 1: Cases meeting all of the following criteria 
 
    Requiring more than 3L/min of oxygen 
 
    OMS/WHO progression scale = 5 
 
    No NIV or High flow 
 
- Group 2: Cases meeting all of the following criteria 
 
 
    Respiratory failure AND (requiring mechanical ventilation OR NIV OR 
High flow) 
 
    WHO progression scale >=6 
 
    No do-not-resuscitate order (DNR order) 
 
For the group 1 of patients not requiring ICU: 
  
Co Primary Endpoints  
 
1. Survival without needs of ventilator utilization (including non invasive 
ventilation and high flow) at day 14. Thus, events considered are needing 
ventilator utilization (including Non Invasive Ventilation, NIV or high flow), 
or death. New DNR order (if given after the inclusion of the patient) will be 
considered as an event at the date of the DNR. 
2. Early endpoint : proportion of patients alive without non-invasive ventilation 
of high low at day 4 (WHO progression scale ≤ 5). A patient with new DNR 
order at day 4 will be considered as with a score > 5. 
: 
OMS 
Progression 
scale 
Descriptor 
Score 
Uninfected 
Uninfected; non viral RNA detected 
0 
Ambulatory 
Asymptomatic; viral RNA detected 
1 
Ambulatory 
Symptomatic; Independent 
2 
Ambulatory 
Symptomatic; Assistance needed 
3 
Hospitalized : mild 
disease 
Hospitalized; No oxygen therapy 
4 

Version 6.0 protocole CORIMUNO 04/05/2020 27 
Hospitalized : mild 
disease 
Hospitalized; oxygen by mask or nasal 
prongs 
5 
Hospitalized : severe 
disease 
Hospitalized; oxygen by NIV or High 
flow 
6 
Hospitalized : severe 
disease 
Intubation and Mechanical ventilation, 
pO2/FIO2>=150 OR SpO2/FIO2>=200  
7 
Hospitalized : severe 
disease 
Mechanical ventilation, (pO2/FIO2<150 
OR SpO2/FIO2<200) OR vasopressor 
(norepinephrine >0.3 microg/kg/min) 
8 
Hospitalized : severe 
disease 
Mechanical ventilation, pO2/FIO2<150 
AND vasopressors (norepinephrine >0.3 
microg/kg/min), OR Dialysis OR ECMO 
9 
Death 
Dead 
10 
 
Secondary end-points will be OMS progression scale at 4, 7 and 14 days, 
overall survival at 14, 28 and 90 days, time to discharge, time to oxygen supply 
independency, time to negative viral excretion. 
Biological parameters improvement: 
Estimated GFR, CRP, myoglobin, CPK, cardiac troponin, ferritin, lactate, cell 
blood count, liver enzymes, LDH, D-Dimer, albumin, fibrinogen, triglycerides, 
coagulation tests, urine electrolyte, creatinuria, proteinuria, uricemia, IL6, 
procalcitonin, immunophenotype (Annexe 2), and exploratory tests (Annexe 
3). 
  
For the group 2 of patients requiring ICU: 
  
Co Primary Endpoints 
 
1. Cumulative incidence of successful tracheal extubation (defined as duration 
extubation > 48h) at day 14 if patients have been intubated before day 14 ; or 
removal of NIV or high flow (for > 48h) if they were included under oxygen 
by NIV or High flow (score 6) and remained without intubation. Death or new 
DNR order (if given after the inclusion of the patient) will be considered as a 
competing event. 
2. Early end point : proportion of patients with a decrease of WHO score of at 
least 1 point at day 4. 
 
Secondary end points will be OMS progression scale at 4, 7 and 14 
days, overall survival at 14, 28 and 90 days, the 28-day 
ventilator free-days, respiratory acidosis at day 4 (arterial 
blood pH of <7.25 with a partial pressure of arterial carbon 
dioxide [Paco2] of ≥60 mm Hg for >6 hours), the evolution of 
PaO2/FiO2 ratio, time to oxygen supply independency, 
duration 
of 
hospitalization, 
time 
to 
negative 
viral 
excretion, time to ICU and hospital discharge. 
 

Version 6.0 protocole CORIMUNO 04/05/2020 28 
Biological parameters improvement (estimated GFR, CRP, cardiac troponin, 
urine electrolyte and creatinine, proteinuria, uricemia, IL6, myoglobin, KIM-
1, NGAL, CPK, ferritin, lactate, cell blood count, liver enzymes, LDH, D-
Dimer, albumin, fibrinogen, triglycerides, coagulation tests (including 
activated partial thromboplastin time), procalcitonin, immunophenotype 
(Annexe 2), and exploratory tests (Frozen samples Annexe 3). Rate of renal 
replacement therapy, ventilation parameters. 
  
For each comorbidities group secondary criteria will be specifically 
addressed: 
  
For each tested medication, specific markers of efficacy and safety may be used 
and will be defined. 
Criteria of safety 
● 
Number of serious adverse events 
● 
Cumulative incidence of serious adverse events (SAEs) 
● 
Cumulative incidence of Grade 3 and 4 AEs. 
● 
Investigational medication discontinuation (for any reason) 

Version 6.0 protocole CORIMUNO 04/05/2020 29 
Statistical Method 
To maximize information from limited data generated, while allowing rapid decision, 
a Bayesian monitoring of the trial based on tco-primary outcomes will be used. The 
overall strategy has been determined so as to control for a frequentist one sided 5% 
type I error rate. The following methods pertain to the conduct and analysis of the 
subtrial in a given group of patients (group I or group II), that are analyzed separately 
with different primary outcomes, but conducted simultaneously (with stratified 
randomization) for logistical reasons. The total sample size will be 120 (60 in each 
arm) at the interim analysis, and 240 (120 per arm) at the second analysis. 
 
Since it is not possible to determine in advance how many patients will be recruited 
in each stratum, the sample sizes used for the following calculations are indicative, 
considering equally sized strata (groups). At the interim analysis, two posterior 
probabilities will be calculated: 1) the posterior probability of a lower event rate in 
the experimental than in the control arm (posterior probability of efficacy) and 2) the 
posterior probability of achieving at least a predefined effect corresponding to a 
hazard ratio of 0.85 (for time-to-event primary outcomes)  or a risk difference of 5.5% 
(for binary co-primary outcomes) (posterior probability of sufficient efficacy). If the 
posterior probability of sufficient efficacy is less than 0.20, the trial can be stopped 
for futility. If the posterior probability of efficacy is higher than 0.99, the trial can be 
stopped for efficacy. Otherwise, the trial will continue with inclusion of additional 
patients, as predefined, and a final analysis is conducted with decision boundary at a 
posterior probability of efficacy > 0.95. Decision boundaries are non-binding, and 
the DSMB can recommend continuing recruitment, in the whole population or a 
subgroup. Final decision boundaries are then readapted to control for a one-sided type 
I error rate close to 5%.  If the strata (groups I or II) are equally sized, the interim 
analysis should occur after 60 patients, and the second one with 120. This design 
(with only two stages) has then type I error rate 0.047 if event rates are 50% in each 
arm, and power 0.972 to detect a decrease from 0.50 to 0.20 and 0.739 to detect a 
decrease from 0.50 to 0.30. 
 
 
In the cmRCT design, randomisation occurs prior to offering the intervention, and 
some number of eligible patients who are randomly selected to be offered an 
intervention will not accept the offer. An intention to treat analysis could therefore 
dilute any treatment effects. Relton et al. suggested to use a complier average causal 
effect (CACE) analysis which provides unbiased estimates of the treatment effect for 
patients who comply with the protocol. Thus, all final primary analyses will be 
performed in both Intention To Treat (ITT) and CACE basis. For this purpose, it will 
be assumed that a patient's decision not to accept the intervention will not affect the 
outcome. For the ITT analysis, patients will be analysed according to the treatment 
arm they were randomized to (i.e. offer or no offer group), even if the participant did 
not accept the intervention.  
  
 

Version 6.0 protocole CORIMUNO 04/05/2020 30 
 
2. 
SCIENTIFIC JUSTIFICATION FOR THE STUDY 
2.1. 
Overview of COVID-19   
COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2) and causes 
substantial morbidity and mortality (1-4). There is currently no vaccine to prevent Covid-19 or 
infection with SARS-CoV-2 or therapeutic agent to treat COVID-19. This clinical trial is 
designed to evaluate the efficacy and tolerance of various immune modulators of adult patients 
hospitalized with COVID-19. 
Coronavirus (CoVs) are positive-sense single stranded enveloped RNA viruses, many of which 
are commonly found in humans and cause mild symptoms. Over the past two decades, 
emerging pathogenic CoVs capable of causing life-threatening disease in humans and animals 
have been identified, namely severe acute respiratory syndrome coronavirus (SARS-CoV) and 
Middle Eastern respiratory syndrome coronavirus (MERS- CoV) (5). 
In December 2019, the Wuhan Municipal Health Committee (Wuhan, China) 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 abbreviated as SARS- COV-2 and 
has 89% nucleotide identity with bat SARS-like-CoVZXC21 and 82% with that of human 
SARS-CoV (6). Most of the infections outside China have been travel- associated cases in 
those who had recently visited Wuhan City and are thought to have acquired the virus through 
contact with infected animals or contact with infected people. This novel coronavirus has been 
designated SARS-CoV-2, and the disease caused by this virus has been designated COVID-
19. Outbreak forecasting and mathematical modelling suggest that these numbers will continue 
to rise (7, 8). Global efforts to evaluate novel antivirals and therapeutic strategies to treat 
COVID-19 have intensified. Due to the recent increase in the number of overflow patients in 
ICU and dying adult patients, previously healthy or with comorbidities at all ages, there is an 
urgent public health need for rapid development of novel interventions. 
There is currently no treatment approved in the treatment of patients with COVID-19. 
Remdesivir, which failed against Ebola Virus, is being tested in China as an emergency 
countermeasure. Other antiviral agents including hydroxychloroquine and azithromycine, 
protease inhibtors (lopinavir/ritonavir) alone or in combination, interferon are currently tested. 
However, the severe and critically ill patients display high inflammatory state. While most 
people with COVID-19 develop only mild or uncomplicated illness, approximately 14% 

Version 6.0 protocole CORIMUNO 04/05/2020 31 
develop severe disease that requires hospitalization and oxygen support, and 5% require 
admission to an intensive care unit. In severe cases, COVID-19 can be complicated by the acute 
respiratory distress syndrome (ARDS), sepsis and septic shock, multiorgan failure, including 
acute kidney injury and cardiac injury (9, 10). Older age and co-morbid disease have been 
reported as risk factors for death, and recent multivariable analysis confirmed older age, higher 
Sequential Organ Failure Assessment (SOFA) score (11) and d-dimer > 1 μg/L on admission 
were associated with higher mortality. 
COVID-19 infection causes clusters of severe respiratory illness similar to severe acute 
respiratory syndrome coronavirus (SARS-CoV) and MERS-CoV and is associated with 
intensive care unit admission and high mortality (1). COVID-19 pneumonia manifests with 
chest computed Tomography (CT) imaging abnormalities, even in asymptomatic patients (12-
15). On hospital admission, abnormalities in chest CT images were detected among all patients. 
Complications included acute respiratory distress syndrome (29% cases), RNAaemia (15%), 
acute cardiac injury (12%) and secondary infection (10%). 
 
2.2. 
Rationale for using immune regulatory drug 
2.2.1. 
Immune pathology of COVID infection 
 
Histopathological observations and imaging features of pulmonary lesions in COVID-19 
patients overlap with those of SARS-CoV and MERS-CoV. COVID-2019 patients present non-
specific inflammatory responses, including edema and inflammatory cell infiltration, and 
exhibit severe exfoliation of alveolar epithelial cells, alveolar septal widening, damage to 
alveolar septa, and alveolar space infiltration in a distinctly organized manner. This 
pathological inflammation includes tissue necrosis, infiltration, and hyperplasia. Thus, damage 
to the pulmonary interstitial arteriolar walls indicates that inflammatory response plays an 
important role throughout the course of disease in spite of the pathogenic effect of CoVs . These 
deleterious excessive and aberrant non-effective host immune responses are related to a 
“cytokine storm” reported in most Cov-infected patients (COVID-19, SARS-CoV and MERS-
CoV). They present a hypercytokenia displaying an increased plasma concentration of a 
number of pro-inflammatory cytokines and chemokines such as IL-1β, IL-1α, IL-2, IL-6, IL-
7, IL-8, IL-9, IL-10, IL-37, IL-17, bFGF, GCSF, GMCSF, IFNγ, IP10, MCP1, MIP1A, MIP1B, 
PDGF, TNFα, or VEGF, Endothelin-1, Complement C5a…and this list is far to be exhaustive 
(16-31). 

Version 6.0 protocole CORIMUNO 04/05/2020 32 
  
Host-directed therapy could constitute a strategy of choice to efficiently treat COVID-19 
patients by controlling inflammation in order to promote tolerance to disease (31, 32). Existing 
safe therapies could potentially be repurposed to treat COVID-19 infection, including 
metformin, glitazones, fibrates, sartans, and atorvastatin as well as nutrients (Zinc and others 
metal formulation) or biologics such as Anakinra an IL-1 trap, Canakinumab an antibody 
targeting IL-1beta, antikinases compounds such as Abl or JAK inhibitors, or Tocilizumab and 
Sarilumab, two monoclonal antibodies targeting IL6R. All these compounds could be used in 
adjunct therapy or in combination with antiviral therapies including Remdesivir, Lopinavir–
Ritonavir, interferon beta‑1β, or ribavirin (33)(doi: 10.1038/d41587-020-00003-1). 
  
Some others class of drugs, presenting potent anti-inflammatory or antiviral properties, such as 
the tyrosine kinase inhibitors which target the JAK/STAT pathway (Ruxolitinib, Tofacitinib, 
Bafecitinib)(34), or these that block the SARS-CoV/MERS-CoV early entry and/or post entry 
events (Imatinib (35)) have been proposed to be of interest for the treatment of severe cases of 
COVID-19, when the host inflammatory response becomes a major cause of lung damage and 
subsequent mortality (36, 37). 
  
Recently, Kritas et al., have proposed to use anti-inflammatory cytokines belonging to the IL-
1 family members, such as IL-37, to treat coronavirus pathogenic inflammation based on the 
fact that Coronavirus infection activate the early release of inflammatory compounds (IL-6, 
TNFα) by mast cells (MCs), while late MCs activation provokes the generation of pro-
inflammatory IL-1 family members including IL-1 and IL-33 (38). 
 
IL-6 is a pleotropic cytokine promptly and transiently produced by multiple cell types 
including fibroblasts, keratinocytes, mesangial cells, vascular endothelial cells, mast cells, 
macrophages, dendritic cells, and T and B cells in response to tissue damage and infections. 
IL-6 stimulates diverse cellular responses such as proliferation, differentiation, survival, and 
apoptosis and can activate hepatocytes to release acute-phase proteins, including C-reactive 
protein (CRP) and serum amyloid A. IL-6 is also involved in diverse physiological processes 
such as migration and activation of T-cells, B-cells, monocytes, macrophages and osteoclasts 
leading to systemic and local inflammation. IL-6 facilitates the transition from the innate to 
adaptive immune response by driving down neutrophil activity while concurrently promoting 
the recruitment, differentiation, and activity of monocytes and T cells (19).  

Version 6.0 protocole CORIMUNO 04/05/2020 33 
It is well recognized that dysregulated continual synthesis of IL-6 plays a pathological 
effect on chronic inflammation and autoimmunity (39-41). IL-6 contributes to many of the key 
symptoms of cytokine release syndromes (CRS). Via trans-signaling IL-6 leads to 
characteristic symptoms of severe (CRS), i.e. vascular leakage, and activation of the 
complement and coagulation cascade inducing disseminated intravascular coagulation 
(DIC)(42). In addition, IL-6 likely contributes to cardiomyopathy that is often observed in 
patients with CRS, and COVID-19 (41, 42), promoting myocardial dysfunction (43). 
The SRAS-CoV-S protein induces direct up-regulation of IL-6 and TNFα, SARS-CoV 
infection also induces up-regulation of TLR4 and TLR9 which correlate with the induction of 
inflammatory response. Elevated levels of IL-6 are found in the plasma of patients with 
COVID-19 
pneumonia 
(doi.org/10.1101/2020.02.25.20025643, 
doi.org/10.1101/2020.02.16.20023903)(44-46). These data suggest that high levels of IL-6 
play a key role in the coronavirus-induced pathogenic inflammation. 
 
2.2.2. 
Tocilizumab : Rationale for the use and mechanism of 
action 
 
Tocilizumab (TCZ)(Actemra) is an anti-human IL-6 receptor monoclonal antibody that 
inhibits signal transduction by binding sIL-6R and mIL-6R (47). The main approved indication 
is for rheumatoid arthritis, in association or not with methotrexate (48). Tocilizumab has been 
approved for the treatment of rheumatoid arthritis, idiopathic multicentric Castleman’s disease 
(iMCD) and in 2017, the U.S. Food and Drug Administration approved TCZ for the treatment 
of cytokine release syndrome (CRS) consisting in a systemic inflammatory response caused by 
the massive release of pro-inflammatory cytokines in response to iatrogenic (e.g. CAR-t 
therapies) or infective stimuli (49-54), including with high production in the lungs (55). 
2.2.3. 
Sarilumab: Rationale for the use and mechanism of action 
Sarilumab (Kevzara) is a human monoclonal antibody (IgG1 subtype) that specifically binds 
to both soluble and membrane-bound IL-6 receptors (IL-6Ra), and inhibits IL-6-mediated 
signalling which involves ubiquitous signal-transducing glycoprotein 130 (gp130) and the 
Signal Transducer and Activator of Transcription-3 (STAT-3). Sarilumab is FDA- and EMA-
approved for rheumatoid arthritis and is being investigated in clinical trials in other 
rheumatologic conditions (56-58). 

Version 6.0 protocole CORIMUNO 04/05/2020 34 
Based on available data, on a per mg basis, tocilizumab and sarilumab behave comparably in 
vivo with respect to potency, PK, PD, efficacy, and safety. 
2.3. 
Summary of relevant pre-clinical and clinical trials on IL-6R 
Inhibition 
 
Although the lack of data on SARS-CoV-2 pathogenesis, studies in China showed a possible 
correlation of massive inflammation and severe lung damage on the rapid evolution of fatal 
pneumonia. Indeed, in COVID-19 patients, significant differences in IL-6 plasmatic levels 
were observed at different stages of disease with a higher expression in severe cases than mild 
ones. Moreover, in the biopsy samples at autopsy from a severe COVID-19 patient, histological 
examination showed diffuse alveolar damage with cellular fibromyxoid exudates and 
interstitial mononuclear inflammatory infiltrates suggesting severe immune injury (59). 
Despite the lack of clinical trials on TCZ efficacy and safety for COVID-19 treatment, in China 
TCZ was recently approved for patients affected by severe SARS-CoV-2 pulmonary 
complications by the National Health Commission of the People’s Republic of China. 
Preliminary data from an observational study conducted in China on 21 severe cases receiving 
TCZ, 
showed 
an 
improvement 
of 
the 
clinical 
and 
radiological 
outcome 
(www.chinaxiv.org/user/download.htm?id=30387&filetype=pdf ). 
  
2.4. 
Description of the population of the cohort and justification for the 
choice of subjects 
 
The novel coronavirus pneumonia (NCP) is a fast-emerging disease with a severe health and 
economic burden. The kinetics of the epidemics provokes an overflow of patients to hospitals 
and critically, to Intensive Care units because a number of patients experience acute respiratory 
distress syndrome (ARDS) with poor prognosis. For instance, a recent study of 99 patients with 
2019-nCoV pneumonia reported that 17% patients developed acute respiratory distress 
syndrome and, among them, 11% patients worsened in a short period of time and died of 
multiple organ failure (3). In another single-center case series of 138 hospitalized patients with 
confirmed NCIP in Wuhan, China, 26% of patients received ICU care, and mortality was 4.3% 
(10). A large range of age is affected. The case studies of Li et al., encapsulates the first 425 
cases recorded in Wuhan indicate that the patients' median age was 59 years, with a range of 

Version 6.0 protocole CORIMUNO 04/05/2020 35 
15 to 89 years (60) with no significant gender differences. They reported no clinical cases in 
children below 15 years of age. 
3. 
OBJECTIVES 
The overall objective of the study is to determine which treatments (e.g. immune modulator 
drugs) have the most favourable benefit-risk in adult patients hospitalized with COVID-19.  
The specific aims of this Covid-19 cohort are to collect observational data at regular intervals 
on an ongoing basis in order to embed a series of randomized controlled trials evaluating a 
various set of interventions. 
3.1. 
Primary objective 
The primary objectives of this study are to decrease the rate of transfer to ICU and mechanical 
ventilation for the group of no ICU patients and to decrease the time of mechanical ventilation 
for the ICU group   
3.2. 
Secondary objectives 
Secondary objectives are improvement of clinical and biological  parameters and overall 
survival at 90 days 
4. 
DESCRIPTION OF THE COHORT STUDY 
This study is a prospective cohort of patients with confirmed Covid (infection by SARS-CoV-
2). The cohort will be split in different groups, 1) patients requiring or not ICU, and 2) groups 
based on comorbidities and tested medications. 
 
This cohort is specifically designed to nest trials using a cohort multiple Randomized 
Controlled Trials (cmRCT) design. 
4.1. 
Cohort multiple Randomized Controlled Trials (cmRCT) 
design 
The key features of the cohort multiple Randomized Controlled Trials (cmRCT) design (61-
63) are: 
(I) Recruitment of a large observational cohort of patients with the condition of interest 
(II) Regular measurement of outcomes for the whole cohort 
(III) Capacity for multiple randomised controlled trials over time 
 

Version 6.0 protocole CORIMUNO 04/05/2020 36 
Patients enrolled in the cohort agree to allow their longitudinal data to be used in the aggregate. 
They also allow their data to be used to identify them to be invited to participate in research 
interventions or for comparison purposes for intervention trials that may be conducted with 
other patients while they are participating in the cohort. 
In the cmRCT design, only eligible patients randomly selected to be offered an 
intervention, are contacted and offered treatment. Eligible patients not selected to be offered 
an intervention are not notified about this trial and will be in the control group. Consent for 
specific trials will be obtained from those eligible patients who are invited and accepted the 
offer to participate.  
In the cmRCT design, as described to patients when they consent to participate in the 
cohort, only eligible patients randomly selected to be offered an intervention, but not eligible 
non-selected patients, are contacted and offered treatment. Eligible patients not selected are not 
notified about the trial. Consent for specific trials will be obtained from those eligible patients 
who are invited and accept the offer to participate. Post-intervention outcomes among eligible 
patients who accept the offer to receive the intervention will be compared with outcomes 
among patients from the cohort who were identified as eligible for the intervention, but were 
not randomly selected to be offered the intervention and not contacted about the intervention. 
In the context of the COVID crisis, the advantage of the cmRCT design to conduct 
multiple trials that draw participants from the same patient cohort is important given the 
imperative that we have to answer multiple research questions (some identified and others not 
yet identified) in a very short time (a few weeks). 
The cmRCT design will enable the implementation of multiple trials over time with 
different inclusion and exclusion criteria (e.g based on severity or comorbidities), testing 
different interventions that can be compared in the same overall population with similar trial 
methods, thus increasing the ability to compare and contrast different trial results. 
 
The cmRCT design also offers advantages in that the patient consent process more closely 
replicates what occurs in actual healthcare settings compared with the consent procedures 
typically used in traditional RCT designs. In traditional RCTs, patients are usually told that 
they will be randomised to obtain the trial intervention or an alternative, which is generally 
usual care. In the cmRCT design, patients are told about treatments that they will be able to 
access if they so choose. As part of the initial consent process, patients are made aware that a 
number of trials may occur via the cohort, and that they will not likely be offered to participate 
in all of them and may not be offered to participate in any. It is explained that patients will only 

Version 6.0 protocole CORIMUNO 04/05/2020 37 
be notified about trials for which they will be offered the intervention, but that their data may 
be used for comparison purposes in the context of some interventions not offered to them. 
 
4.2. 
Settings 
Ten Hospitals have already accepted to participate (Bichat, Saint Louis-Lariboisière, HEGP, 
Cochin-Hotel Dieu, Necker, Pitié, Bicêtre, CHU Strasbourg, CHU Lille, Institut Gustave 
Roussy (IGR) 
4.3. 
Study population 
The study will include potentially all patients with confirmed COVID-19 infection and 
moderate or severe NCP.  
● Illness of any duration and severity, with symptoms (fever, cough, respiratory 
difficulties, shortness of breath), and at least one of the following: 
○ Radiographic infiltrates by imaging (CT scan), and 
○ Clinical assessment (evidence of rales/crackles on 
exam) OR SpO2 ≤ 94% on room air, or oxygen 
saturation ≤97 % with O2 > 5L/min. 
○ Requiring mechanical ventilation and/or supplemental oxygen 
○ With any comorbidities (TBD such as acute kidney injury, 
cardiovascular condition, pulmonary disease, obesity, high blood 
pressure, diabetes, chronic kidney diseases, haematological diseases, 
Solid cancer, sickle cell diseases, autoimmune and auto-inflammatory, 
pregnant women, HIV infected). 
● Male or female adult ≥ 18 years of age at time of 
enrolment 
● Any Weight 
● Written informed consent provided by the patient or alternatively by next-of-
kin prior to any protocol-specific procedures. 
 
Three populations will be identified at baseline.  
Moderate cases according the CDC classification: 
● Showing fever and respiratory symptoms with radiological findings of pneumonia. 
● Requiring between 3L/min>Oxygen <5L/min 

Version 6.0 protocole CORIMUNO 04/05/2020 38 
 
Severe cases, meeting any of the following criteria: 
● Respiratory distress (≧30 breaths/ min); 
● Oxygen saturation≤93% at rest in ambient air; or Oxygen 
saturation ≤97 % with O2 > 5L/min. 
● PaO2/FiO2≦300mmHg (l mmHg=0.133kPa). 
● PaO2/ FiO2 in high-altitude areas (at an altitude of over 1,000 meters above the sea 
level) shall be corrected by the following formula:  PaO2/ FiO2 x[Atmospheric pressure 
(mmHg)/760] 
● Cases with chest imaging that showed obvious lesion progression within 24-48 hours 
>50% shall be managed as severe cases. 
  
Critical cases, meeting any of the following criteria: 
● Respiratory failure and requiring mechanical ventilation; 
● Shock; 
● With other organ failure that requires ICU care 
 
 
After inclusion, participants in this research will be identified as follows by a unique identifier 
corresponding to the Site number (3 digits) - Sequential enrolment number for the site (4 digits) 
- surname initial - first name initial 
This reference number is unique and will be used for the entire duration of the study. 
 
4.4. 
Inclusion and exclusion criteria in the cohort  
Inclusion Criteria for the cohort: 
● Laboratory-confirmed SARS-CoV-2 infection as determined by PCR, or other 
commercial or public health assay in any specimen and/or CT Scan prior to 
randomization (Following typical radiological findings (ground glass abnormalities, 
and absence of lymphadenopathy, pleural effusion, pulmonary nodules, lung 
cavitation) 
● Hospitalized patients 

Version 6.0 protocole CORIMUNO 04/05/2020 39 
● Illness of any duration and severity (mild, moderate, severe, critical, see annexe 1), 
with symptoms (fever, cough, respiratory difficulties, shortness of breath), and at least 
one of the following: 
○ Radiographic infiltrates by imaging (CT scan) 
○ Clinical assessment (evidence of rales/crackles on exam) 
AND SpO2≤94% on room air 
○ SpO2≤97 % with O2 > 5L/min. 
○ Requiring mechanical ventilation 
○ With any comorbidities (TBD such as acute kidney injury, cardiovascular 
condition, pulmonary disease, obesity, high blood pressure, diabetes, chronic 
kidney diseases, haematological diseases, solid cancer, sickle cell diseases, 
autoimmune and auto-inflammatory, pregnant women, HIV infected, etc)  
● Male or female adult ≥ 18 years of age at time of enrolment 
● Patients must be able and willing to comply with study visits and procedures. 
● Patient agrees to the collection of oropharyngeal and nasal swabs and venous blood 
per protocol 
● Written informed consent provided by the patient or alternatively by next-of-kin prior 
to any protocol-specific procedures. 
 
Exclusion Criteria for the cohort: 
Participation in another clinical trial is not an exclusion criteria depending on the medication. 
Patients included in the antiviral REACTING trial are not excluded as well as patients from 
COVIDICUS trial. 
Severe 
cardiovascular 
disease 
including 
acute 
myocardial 
infarction, unstable angina pectoris, coronary revascularization 
procedure, congestive heart failure of NYHA Class III or IV, stroke, 
including a transient ischemic attack, edema of cardiac origin and 
left ventricular ejection fraction ≤ 50% are not excluded and 
should be discussed in each therapeutic arm.  
● Patients with any condition that the physician judges could be detrimental to the patient 
participating in this study; including any clinically important deviations from normal 

Version 6.0 protocole CORIMUNO 04/05/2020 40 
clinical laboratory values or concurrent medical conditions (active infection diseases 
such as severe bacterial infections, aspergillosis, tuberculosis, depending on the tested 
medication). 
● Absence of Health Insurance 
● Subject protected by law under guardianship or curatorship 
4.5. 
Endpoints 
A core set of clinical measures will be recorded daily the first 2 weeks and then every week. 
● The core measures include measures of OMS progression scale, oxygenation, 
mechanical ventilation. These measures will allow us to classify the patient's state 
according to the WHO Clinical Progression Scale.  
● All-cause mortality at hospital discharge or 60 days and time to hospital discharge will 
be also recorded. 
These core set of clinical measures are aimed to be used as outcomes in trials nested within the 
cohort 
4.6. 
Other data collected in the cohort 
For the inclusion of women of childbearing age, a pregnancy test is done at baseline before the 
administration of the investigational medicinal product. 
 
Data collected in the cohort are part of routine care (standard care for patients with COVID-
19) will be recorded. Among these parameters we could cite:     
 
Baseline 
● Complete medical history and physical examination with record of vital signs (within 
one month) including O2 saturation by finger oximeter 
● Viral load 
● Concomitant medications 
● CBC with differential (including lymphocytes and neutrophils, platelets) 
● Blood group phenotype 
● Clinical chemistry (to include sodium, potassium, chloride, CO2, glucose, calcium, 
BUN, creatinine, Vitamine D) 
● AST, ALT, total bilirubin, alkaline phosphatase, total protein and albumin, ferritin 
● CRP, high sensitivity troponin, CPK, Myoglobin, PCT (procalcitonin) 
● Coagulation panel including D-Dimers, fibrinogen , IL-6 
● CH50, C3, C4 

Version 6.0 protocole CORIMUNO 04/05/2020 41 
● Urine analysis (pH, glucose, erythrocytes, leukocytes, protein, albumin, nitrite, 
creatinine) 
● Electrocardiogram  
● Blood gas 
● Cardiac ultrasound (optional) 
● CT scan of thorax 
● Collection of frozen blood samples performed for care 
● Biobanking according to the local facilities (Annexe 3) 
 
Everyday, Every week 
Physical examination with record of vital signs (until discharge) including O2 saturation by 
finger oximeter 
● Medications taken by the patient 
Biological tests 
● CBC with differential (including lymphocytes and neutrophils, platelets) 
 
● Clinical chemistry (to include sodium, potassium, chloride, CO2, glucose, calcium, 
BUN, creatinine) 
● AST, ALT, total bilirubin, alkaline phosphatase, total protein and albumin, ferritin 
● CRP, high sensitivity troponin, CPK, Myoglobin, PCT (procalcitonin) 
● Coagulation panel including D-Dimers, fibrinogen , IL-6 
● CH50, C3, C4 (every weeks) 
● Urine analysis (pH, glucose, erythrocytes, leukocytes, protein, albumin, nitrite, 
creatinine) 
● Electrocardiogram (ECG) 
● Blood gas 
● Cardiac ultrasound (optional) 
● CT scan of thorax (at least once a week and on demand) 
 
Every weeks or in case of significant clinical change 
● Viral load 
● Biobanking according to the local facilities (Annexe 3)  
  
At hospital discharge 

Version 6.0 protocole CORIMUNO 04/05/2020 42 
● Medications taken by the patient 
● Viral load 
● CBC with differential (including lymphocytes and neutrophils, platelets) 
● Clinical chemistry (to include sodium, potassium, chloride, CO2, glucose, calcium, 
BUN, creatinine) 
● AST, ALT, total bilirubin, alkaline phosphatase, total protein and albumin, ferritin 
● CRP, high sensitivity troponin, CPK, Myoglobin, PCT (procalcitonin) 
● Coagulation panel including D-Dimers, fibrinogen , IL-6 
● Urine analysis (pH, glucose, erythrocytes, leukocytes, protein, albumin, nitrite, 
creatinine) 
● Electrocardiogram (ECG) 
● Blood gas 
● Cardiac ultrasound (optional) 
● CT scan of thorax 
● Biobanking according to the local facilities (Annexe 3) 
  
At day 90 after inclusion in the cohort 
·   Physical examination with record of vital signs including O2 saturation by finger 
oximeter 
·   Medications taken by the patient 
·   CBC with differential (including lymphocytes and neutrophils, platelets) 
·   Clinical chemistry (to include sodium, potassium, chloride, CO2, glucose, calcium, 
BUN, creatinine) 
·   AST, ALT, total bilirubin, alkaline phosphatase, total protein and albumin, ferritin 
·   CRP 
·   Coagulation panel including D-Dimers, fibrinogen , IL-6 
·   Urine analysis (pH, glucose, erythrocytes, leukocytes, protein, nitrite, creatinine) 
·   Electrocardiogram (ECG) 
·   Blood gas and pulmonary function tests 
·   Cardiac ultrasound (optional) 
·   CT scan of thorax  
- 
 Biobanking according to the local facilities (Annexe 3)  
 

Version 6.0 protocole CORIMUNO 04/05/2020 43 
4.7. 
Biobanking (cf Annexe 3) 
During the study, the samples (plasma, serum, DNA, RNA, cells and urine) taken will be stored 
in a biological sample collection at the local laboratory of each centre. Use of samples will be 
coordinated by a scientific advisory board chaired by Dr Pierre-Louis Tharaux, in order to be 
centrally analysed. 
At the end of the study, the samples may be used for further analysis useful for investigation 
of the condition, in light of advances in scientific knowledge, provided the participant is 
informed and does not oppose this, as stated in the information note/consent form. The sample 
collection will be declared to the ministry of research and to the director of the competent 
regional healthcare authority (Article L. 1243-3 of the Code de la Santé Publique [French 
Public Health Code]). 
4.8. 
Standard of care provided for all patients in the cohort 
 
All patients in the cohort will receive standard care. This care may evolve over time. At the 
beginning of the study, the standard care consists of supportive therapy, oral or IV 
rehydratation, antimicrobial therapy, O2 therapy. In severe and critically ill patients, although 
its benefit is not yet fully demonstrated, corticosteroids may be used (methylprednisolone 1 
mg/kg daily intravenously for 5 days, followed by 40 mg daily for 3 days and, lastly, 10 mg 
daily for 2 days, or dexamethasone 20 mg daily intravenously for 5 days, followed by 10 mg 
daily for 3 days and lastly 5 mg daily for 2 days). In this group of patients in case of hypoxia 
refractory to mechanical ventilation ECMO might be considered. 
 

Version 6.0 protocole CORIMUNO 04/05/2020 44 
4.9. 
Flowchart 

Version 6.0 protocole CORIMUNO 04/05/2020 45 

Version 6.0 protocole CORIMUNO 04/05/2020 46 
 

Version 6.0 protocole CORIMUNO 04/05/2020 47 
5. 
TRIALS WITHIN THE COHORT 
The cohort is specifically designed to conduct trials within cohorts.  
These trials are randomized, controlled adaptive trials, with frequent interim monitoring to 
facilitate the following: dropping of poorly performing arms, introduction of new candidate 
therapies and modification of current optimized standard-of-care (oSOC). 
In its simplest iteration, the study can be viewed as a series of 2-arm comparisons whereby the 
superior treatment, if identified, from each pairwise comparison becomes the basis of the new 
supportive care backbone (hence the term “optimized SOC”, or oSOC, to describe this 
potentially evolving backbone) common to each future arm of the study and against which 
additional investigational interventions may then be added to the protocol, tested and 
compared: Arm A: optimized SOC alone Arm B: Investigational treatment X + optimized SOC. 
- 
If this pairwise comparison shows the superiority of Arm B over Arm A, then 
investigational treatment X featured in Arm B will be incorporated into the new oSOC 
common to each future arm of the study (assuming adequate drug supply exists to 
permit this). 
- 
Conversely, if a given pairwise comparison of Arm A versus Arm B fails to yield a 
clear statistical winner in terms of the primary endpoint, then subsequent pairwise 
comparisons will not incorporate the “failed” intervention featured in current Arm B 
into the new oSOC backbone. 
 
5.1. 
Adding new trials in the cohort 
The choice of which experimental treatments may be studied in trials nested in the cohort and 
the order in which they are to be studied will be made by the scientific committee of the cohort, 
which is composed of a panel of physicians with expertise in the care and management of 
patients with Covid-19 infection. 
 
5.2. 
Clinical trial process 
● Trials with non overlap of the targeted population i.e. with inclusion and exclusion 
criteria leading to distinct groups will be driven in parallel. Thus, patients of the cohort 
will be randomized in the trial corresponding to their characteristics. 
● Trials with overlap of the targeted population will be driven sequentially. A first set of 
patients will be included in the first trial (A). After inclusion of the predefined number 

Version 6.0 protocole CORIMUNO 04/05/2020 48 
of patients in the ith set, the set (i+1)th set of patients will be included in one (B) of the 
other trials with the overlapped targeted population. This allows to run the interim 
analyses of trial A on the i-th set and to continue to include patients in trials B. After 
the results of the interim analysis it will be decided to continue or not the trial A and 
potentially to come back to trial A or not for the (i+2)th set of patients 
The sample of the sets will depend of each trial. 
Inclusions of new sets will stop when statistical analyses conclude on futility or efficacy 
or by DSMB decision. 
5.3. 
Methodological elements of trials nested in the cohort 
Trials nested in the cohorts may involve: 
- 
All patients of the cohort  
- 
OR a subpopulation of patients with specific eligibility criteria (e.g., patients in ICU, 
patients with a specific biomarker, etc.) 
 
Endpoints of the trials may involve: 
- 
The endpoints regularly collected in the cohort (see section 4.4) 
- 
OR specific endpoints collected for the given trial 
 
Interventions may be of any type (e.g.,  medications, non pharmacological treatments, 
organisation of care…). According to the cmRCT design, a random sample of patients is 
selected among all patients eligible for the trial and is proposed the intervention. Their outcome 
is compared to patients who did not receive the intervention.    
 
All elements of trials will be defined in specific dedicated protocols. 
Patients who will be proposed for the intervention will provide a new consent, specific for the 
trial. Patients who serve as controls will not provide a new consent, according to the cmRCT 
design. 
5.4. 
Termination and exit rules for trials nested in the cohort 
The patient can prematurely terminate the research any time. If consent is withdrawn, none of 
the participant's data may be used unless the participant states in writing that he/she does not 
object to the said use of the data. In practice, the participant is excluded from the research. 
 
The investigator can temporarily or permanently end a participant's participation in the study 
for any reason that affects the participant's safety or would be in the participant's best interests. 
 

Version 6.0 protocole CORIMUNO 04/05/2020 49 
The case report form (CRF) must list the various reasons for ending participation in the 
research: 
•       
Ineffective treatment 
•       
Adverse reaction 
•       
Other medical problem 
•       
Participant's personal reasons 
•       
Explicit withdrawal of consent 
5.5. 
Monitoring subjects after the premature termination of 
treatment 
Ending a participant's inclusion does not affect the normal management of the participant's 
illness in any way. 
The Data and Safety Monitoring Board (DSMB) may specify and/or validate the study 
monitoring procedures. 
In case of serious adverse events, the investigator must notify the sponsor and monitor the 
subject until complete resolution of any clinical symptoms or until the final treatment phase in 
the case of life threatening conditions. 
5.6. 
Decision of a new trial nested in the cohort 
Any decision of performing a new trial within the cohort would be approved by the scientific 
committee and  the sponsor. The project would be then submitted to the CPP and ANSM.  
5.7. 
Full or partial cancellation of a trial nested in the cohort 
The sponsor (AP-HP) or the competent authority (ANSM) can prematurely terminate all or part 
of the research (whether temporarily or permanently) when recommended by the DSMB in the 
following situations: 
If suspected unexpected serious adverse reactions (SUSARs) are observed in patients being 
treated which prompt reassessment of the study's benefit-risk ratio 
Excessive toxicity observed in an interim analysis 
Unexpected facts or new information about the product in the light of which the study's 
objectives are unlikely to be achieved may prompt the sponsor (AP-HP) or the competent 
authority (ANSM) to terminate the research prematurely 
The sponsor (AP-HP) reserves the right to permanently suspend inclusions at any time if it 
appears that the inclusion objectives are not being met. 
If the research is terminated prematurely, the decision and accompanying justification will be 
transmitted by the sponsor to the competent authority and the CPP within two weeks, along 
with recommendations from the DSMB. 

Version 6.0 protocole CORIMUNO 04/05/2020 50 
 
 

Version 6.0 protocole CORIMUNO 04/05/2020 51 
6. 
FIRST 
NESTED 
TRIAL 
: 
EFFICACY 
OF 
TOCILIZUMAB FOR PATIENTS WITH COVID-19 
6.1. 
Investigational medicinal product(s) 
6.1.1. 
ROACTEMRA® 20mg/mL, 20mL (400mg) 
Tocilizumab (TCZ), ROACTEMRA® is an anti-human IL-6 receptor monoclonal antibody 
that inhibits signal transduction by binding sIL-6R and mIL-6R. The main approved indication 
is for rheumatoid arthritis, in association or not with methotrexate. TCZ is also approved in the 
treatment of juvenile inflammatory arthritis and in the treatment of refractory giant cell arteritis. 
Interestingly, this later indication concerns aged patients and, in this population, the safety 
profile was the same as in younger patients. In 2017, the U.S. Food and Drug Administration 
approved TCZ for the treatment of cytokine release syndrome (CRS) consisting in a systemic 
inflammatory response caused by the massive release of pro-inflammatory cytokines in 
response to iatrogenic (e.g. CAR-t therapies) or infective stimuli. 
Clinical trials on TCZ efficacy and safety for COVID-19 treatment 
are underway in China (A multicenter, randomized controlled trial 
for the efficacy and safety of tocilizumab in the treatment of new 
coronavirus 
pneumonia 
(COVID-19) 
[Registration 
number：
ChiCTR2000029765 / date of Registration: 2020-02-13) and about to 
start in Italy]. In China TCZ was recently approved for patients 
affected by severe SARS-CoV-2 pulmonary complications by the 
National Health Commission of the People’s Republic of China. 
Preliminary data from an observational study conducted in China on 
21 severe cases receiving TCZ, showed an improvement of the 
clinical and radiological outcome. 
Although the optimal dose and schedule of TCZ for treatment of CRS is not known, the 
intended posology is 8 mg/kg intravenously infused over an hour. In the case of patients 
weighing 100 kg or more, taking into account the PK / PD elements given in the SmPC, the 
dosage is limited to 800 mg max.  
Additional administration(s) (one additional infusion at day 3 (D3)) are evaluated on the basis 
of patient’s response to TCZ 8-12 hours apart, in case of:  

Version 6.0 protocole CORIMUNO 04/05/2020 52 
- Absence/poor clinical improvement (decrease in oxygen supply by 50%) or clinical 
worsening and/or  
- Failure in reduction of 50% baseline C-reactive protein (a reliable surrogate marker of IL-6) 
or failure in normalization and/or  
- Failure in reduction in D-dimer, fibrinogen or ferritin levels. 
Dosage adjustment is required in relation to blood parameters of liver function and blood count 
according to the indications specified in the patient package insert.  It is advisable monitoring 
of the following blood parameters (full blood count including platelet count, ALT/AST, LDH, 
fibrinogen, D-dimer, ferritin, C-reactive protein and IL-6) at different time points: immediately 
before 1st infusion, immediately before 2nd infusion, 24h after 2nd infusion, 36h after 2nd 
infusion. 
In case of absence of response after 48 hours, a second infusion of TCZ could be realized at 
day 3 (D3). This second dose is fixed at 400mg. 
6.1.2. 
Authorised and prohibited treatments (medicinal, non-
medicinal, surgical), including rescue medications 
 
The medical staff is expected to monitor patients and administer any drug required for the 
treatment and/or prevention of all the usual complications that can develop in this setting. For 
all additional treatments, the SCP must have been obtained from the EMA website 
(http://www.ema.europa.eu/ema/), 
or 
from 
the 
ANSM 
website 
(http://agence-
prd.ansm.sante.fr/php/ecodex/index.php), 
or 
http://base-donnees-
publique.medicaments.gouv.fr 
 
Interactions with CYP450 Substrates Cytochrome P450s in the liver are down-regulated by 
infection and inflammation stimuli including cytokines such as IL-6 : 
Inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 
activities to higher levels than those in the absence of tocilizumab leading to increased 
metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has 
the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, 
CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effects on CYP2C8 or transporters is 
unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and 
simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one 
week following a single dose of ROACTEMRA®, respectively. The effect of tocilizumab on 
CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, 

Version 6.0 protocole CORIMUNO 04/05/2020 53 
where the dose is individually adjusted. Upon initiation or discontinuation of 
ROACTEMRA®, in patients being treated with these types of medicinal products, perform 
therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or 
theophylline) and the individual dose of the medicinal product adjusted as needed. Exercise 
caution when coadministering ROACTEMRA® with CYP3A4 substrate drugs where 
decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. 
The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after 
stopping therapy. 
 
Thus the following treatment are prohibited : 
● AVK 
● cyclosporin 
● theophylline 
● Oral contraception 
● lovastatin 
● atorvastatin 
6.1.3. 
Supply of the investigational centers 
 
ROACTEMRA® will be specifically supplied by the sponsor to hospital pharmacies. 
ROACTEMRA® vials are subject to regulatory counter-labeling with research mentions. 
Hospital pharmacies will provide care units on the basis of a specific research prescription. 
 
Origin : Specialty with marketing authorization in UE/France, marketed in France. 
 
Storage :  
Store the bottle in the refrigerator (2 ° C to 8 ° C). Do not freeze. 
Keep the bottle in the outer carton in order to protect from light. 
For the storage conditions of the diluted medicinal product, please refer to the SmPC. 
 
6.1.4. 
Posology and drugs administration 
 
Treatment includes the administration on day 1 (D1) of an infusion of ROACTEMRA® 8 mg 
/ kg with a maximum dose of 800 mg for all patients weighing 100 kg or more. 
In the absence of a clinical response, a second fixed dose of 400 mg of ROACTEMRA® will 
be administered on day 3 (D3).  
For the terms of dilution and reconstitution, please refer to the SmPC. 
 

Version 6.0 protocole CORIMUNO 04/05/2020 54 
6.1.5. 
Traceability in investigational centers 
In accordance with the rules of Good Practices and to track the treatment given to each patient, 
all the information related to the treatment will be collected on a traceability sheet (Preparation, 
Dispensation, Date of administration, Time of administration, Batch number and expiry date, 
and Dose administered). 
6.1.6. 
Methods for monitoring compliance with the treatment 
To track the treatment given to each patient, all the information related to the treatment will be 
collected on a traceability sheet. This sheet will be prospectively and exhaustively monitored 
by clinical research assistants during the study. In case of deviations from the protocol there 
will be reminders to the centers and regular checks. 
6.2. 
Control 
Control patients will receive the best standard of care.  
6.3. 
Inclusion/Exclusion criteria for the nested trial 
Inclusion Criteria: 
1. Patients included in the CORIMUNO-19 cohort 
2. Patients belonging to one of the 2 following groups: 
- Group 1: patients not requiring ICU at admission with moderate and severe pneumopathy 
according to the WHO  Criteria of severity of COVID pneumopathy. 
Moderate cases 
Cases meeting all of the following criteria: 
● Showing fever and respiratory symptoms with radiological findings of 
pneumonia. 
● Requiring between 3L/min and  5L/min of of oxygen to maintain SpO2 >97% 
Severe cases  
Cases meeting any of the following criteria: 
● Respiratory distress (≧30 breaths/ min); 
● Oxygen saturation≤93% at rest in ambient air; or Oxygen 
saturation ≤97 % with O2 > 5L/min. 
● PaO2/FiO2≦300mmHg  
 
- Group 2: patients requiring ICU based on Criteria of severity of COVID pneumopathy. 
● Respiratory failure and requiring mechanical ventilation 
● No do-not-resuscitate order (DNR order) 

Version 6.0 protocole CORIMUNO 04/05/2020 55 
 
Exclusion Criteria: 
● Patients with exclusion criteria to the CORIMUNO-19 cohort. 
● Known hypersensitivity to Tocilizumab or to any of their excipients. 
● Pregnancy 
● Current documented bacterial infection. 
● Patient with any of following laboratory results out of the ranges detailed below at 
screening should be discussed depending of the medication: 
○ Absolute neutrophil count (ANC) ≤ 1.0 x 109/L 
○ Haemoglobin level: no limitation 
○ Platelets (PLT) < 50 G /L 
○ SGOT or SGPT > 5N 
The primary endpoint and secondary endpoints will depend on the group of patients and tested 
medication. 
6.4. 
Endpoints for the trial 
6.4.1. 
Efficacy endpoints 
Measures 
A core set of clinical measures will be recorded daily the first 2 weeks and then every week. 
The core measures include measures of OMS progression scale, oxygenation, mechanical 
ventilation. For patients who are eligible for an intervention trial (in both the intervention 
and control arms), this days measurement will include trial-specific measures related to the 
trial outcomes of interest. 
Primary and secondary endpoints: 
The primary endpoint and secondary endpoints will depend on the group of patients and 
tested medication. 
 
Groups will be redefined as follow : 
- Group 1: Cases meeting all of the following criteria 
 
    Requiring more than 3L/min of oxygen 
 
    OMS/WHO progression scale = 5 
 
    No NIV or High flow 
 
- Group 2: Cases meeting all of the following criteria 
 
 
    Respiratory failure AND (requiring mechanical ventilation OR NIV OR High flow) 
 
    WHO progression scale >=6 
 
    No do-not-resuscitate order (DNR order) 
 
  

Version 6.0 protocole CORIMUNO 04/05/2020 56 
For the group 1 of patients not requiring ICU: 
  
Co Primary Endpoints  
 
1. Survival without needs of ventilator utilization (including non invasive ventilation and high flow) at 
day 14. Thus, events considered are needing ventilator utilization (including Non Invasive Ventilation, 
NIV or high flow), or death. New DNR order (if given after the inclusion of the patient) will be 
considered as an event at the date of the DNR. 
2. Early endpoint : proportion of patients alive without non-invasive ventilation of high low at day 4 
(WHO progression scale ≤ 5). A patient with new DNR order at day 4 will be considered as with a score 
> 5. 
 
OMS Progression 
scale 
Descriptor 
Scor
e 
Uninfected 
Uninfected; non viral RNA 
detected 
0 
Ambulatory 
Asymptomatic; viral RNA 
detected 
1 
Ambulatory 
Symptomatic; Independent 
2 
Ambulatory 
Symptomatic; Assistance needed 
3 
Hospitalized : 
mild disease 
Hospitalized; No oxygen therapy 
4 
Hospitalized : 
mild disease 
Hospitalized; oxygen by mask or 
nasal prongs 
5 
Hospitalized : 
severe disease 
Hospitalized; oxygen by NIV or 
High flow 
6 
Hospitalized : 
severe disease 
Intubation and Mechanical 
ventilation, pO2/FIO2>=150 OR 
SpO2/FIO2>=200  
7 
Hospitalized : 
severe disease 
Mechanical ventilation, 
(pO2/FIO2<150 OR 
SpO2/FIO2<200) OR 
vasopressors (norepinephrine 
>0.3 microg/kg/min)  
8 
Hospitalized : 
severe disease 
Mechanical ventilation, 
pO2/FIO2<150 AND 
vasopressors (norepinephrine 
>0.3 microg/kg/min), OR 
9 

Version 6.0 protocole CORIMUNO 04/05/2020 57 
Dialysis OR ECMO 
Death 
Dead 
10 
 
Secondary end-points will be OMS progression scale at 4, 7 and 14 days, overall 
survival at 14, 28 and 90 days, time to discharge, time to oxygen supply independency, 
time to negative viral excretion. 
Biological parameters improvement: 
Estimated GFR, CRP, myoglobin, CPK, cardiac troponin, ferritin, lactate, cell blood 
count, liver enzymes, LDH, D-Dimer, albumin, fibrinogen, triglycerides, coagulation 
tests, urine electrolyte, creatinuria, proteinuria, uricemia, IL6, procalcitonin, 
immunophenotype (Annexe 2), and exploratory tests (Annexe 3). 
  
For the group 2 of patients requiring ICU: 
  
Co Primary Endpoints 
1. Cumulative incidence of successful tracheal extubation (defined as duration extubation 
> 48h) at day 14 if patients have been intubated before day 14 ; or removal of NIV or 
high flow (for > 48h) if they were included under oxygen by NIV or High flow (score 
6) and remained without intubation. Death or new DNR order (if given after the 
inclusion of the patient) will be considered as a competing event. 
2. Early end point : proportion of patients with a decrease of WHO score of at least 1 point 
at day 4. 
 
Secondary end points will be OMS progression scale at 4, 7 and 14 days, overall survival at 
14, 28 and 90 days, the 28-day ventilator free-days, the evolution of PaO2/FiO2 ratio, 
respiratory acidosis at day 4 (arterial blood pH of <7.25 with a partial pressure of arterial 
carbon dioxide [Paco2] of ≥60 mm Hg for >6 hours), time to oxygen supply 
independency, duration of hospitalization, time to negative viral 
excretion, time to ICU and hospital discharge. 
 
Biological parameters improvement (estimated GFR, CRP, cardiac troponin, urine 
electrolyte and creatinine, proteinuria, uricemia, IL6, myoglobin, KIM-1, NGAL, CPK, 
ferritin, lactate, cell blood count, liver enzymes, LDH, D-Dimer, albumin, fibrinogen, 
triglycerides, coagulation tests (including activated partial thromboplastin time), 
procalcitonin, immunophenotype (Annexe 2), and exploratory tests (Frozen samples 
Annexe 3). Rate of renal replacement therapy, ventilation parameters. 
  
For each comorbidities group secondary criteria will be specifically addressed: 
  
For each tested medication, specific markers of efficacy and safety may be used and 
will be defined. 

Version 6.0 protocole CORIMUNO 04/05/2020 58 
 
6.4.2. 
Safety endpoints 
 
In the setting of COVID-19 NCP and short term immunomodulatory therapy, we will monitor 
major safety endpoints: blood cells and platelets counts and liver transaminases, frequently, 
every three days systematically. 
● Neutrophil count 
Treatment with Tocilizumab (Actemra) or Sarilumab (Kevzara) was associated with a 
higher incidence of decrease in ANC. Decrease in ANC was not associated with higher 
incidence of infections, including serious infections. 
○ In patients who develop an ANC less than 0.5 x 109/L, treatment with 
Tocilizumab or Sarilumab should be discontinued. 
○ Neutrophil count should be monitored 4 to 8 weeks after start of therapy and 
according to clinical judgment thereafter. For recommended dose modifications 
based on ANC results. 
● Platelet count 
Treatment with Tocilizumab or Sarilumab was associated with a reduction in platelet 
counts in clinical studies. 
○ In patients who develop a platelet count less than 50 x 103/ μL, treatment with 
Tocilizumab or Sarilumab should be discontinued. 
○ Platelet count should be monitored 4 to 8 weeks after start of therapy and 
according to clinical judgment thereafter. 
● Liver enzymes 
Treatment with Tocilizumab was associated with a higher incidence of transaminase 
elevations. 
○ Initiating treatment with Tocilizumab is not recommended in patients with 
elevated transaminases, ALT or AST greater than 1.5 x ULN for chronic 
therapies. However, given the emergency situation due to COVID-19, we still 
propose the use of these treatments. 

Version 6.0 protocole CORIMUNO 04/05/2020 59 
○ In patients who develop elevated ALT greater than 5 x ULN, treatment with 
Tocilizumab should be discontinued 
● Hypersensitivity reactions: monitoring of occurrence of skin rashes, drop of blood 
pressure, ventilatory asynchronization. At the time of treatment injection. 
 
6.5. 
Specific data to be collected for this trial 
None 
6.6. 
Expected benefits and risks 
The clinical benefit is globally to prevent death in all patient groups. 
Other benefits are to: 
- 
blunt not only the pneumopathy-induced damage but also other COVID-19-associated 
injuries such as acute kidney injury (AKI), myocarditis, secondary bacterial infections. 
- 
shorten the duration of hospital stay with minimization of physical (hospital acquired 
pressure ulcers, increased morbidity and mortality associated with nosocomial 
infections), psychological and economic complications related with prolonged stay.  
- 
Shortening the hospital stay fosters not only individual clinical benefit but also 
collective clinical benefit through facilitation of collective access to caregivers. 
- 
limit long term sequelae, in particular lung fibrosis and chronic kidney disease 
secondary to acute kidney injury (markedly prevalent in about 20% of individuals with 
ARDS). 
 
The risks pertain to potential adverse effects of Tocilizumab 
There are currently no known published reports of IL-6R antagonists for infectious sepsis or 
pneumonia. Because IL-6 contributes to host defense against bacterial and viral pathogens, 
there is a concern that IL-6 inhibition may exacerbate infections thus delaying recovery from 
sepsis. 
For Tocilizumab: The most common adverse events (at least 5%) seen in TCZ/ 
ROACTEMRA-IV treated patients in a 12-week controlled portion of a study were: upper 
respiratory tract infection, headache, nasopharyngitis and diarrhea. 
Risks exist of rare but severe hepatotoxicity, reactivation of latent tuberculosis, gastrointestinal 
perforations, neutropenia, with special risk In patients who develop an ANC less than 500 per 

Version 6.0 protocole CORIMUNO 04/05/2020 60 
mm3. Treatment with TCZ/ACTEMRA was associated with a reduction in platelet counts. 
Hypersensitivity reactions, including anaphylaxis. 
 
6.7. 
Sketch of statistical methods 
The detailed statistical methods are identical for both subtrials, and presented in paragraph 11. 
A sketch of methods is given here.  
To maximize information from limited data generated, while allowing rapid decision, a 
Bayesian monitoring of the trial based on tco-primary outcomes will be used. The overall 
strategy has been determined so as to control for a frequentist one sided 5% type I error rate. 
The following methods pertain to the conduct and analysis of the subtrial in a given group of 
patients (group I or group II), that are analyzed separately with different primary outcomes, but 
conducted simultaneously (with stratified randomization) for logistical reasons. The total 
sample size will be 120 (60 in each arm) at the interim analysis, and 240 (120 per arm) at the 
second analysis. 
Since it is not possible to determine in advance how many patients will be recruited in each 
stratum, the sample sizes used for the following calculations are indicative, considering equally 
sized strata (groups). At the interim analysis, two posterior probabilities will be calculated: 1) 
the posterior probability of a lower event rate in the experimental than in the control arm 
(posterior probability of efficacy) and 2) the posterior probability of achieving at least a 
predefined effect corresponding to a hazard ratio of 0.85 (for time-to-event primary outcomes)  
or a risk difference of 5.5% (for binary co-primary outcomes) (posterior probability of 
sufficient efficacy). If the posterior probability of sufficient efficacy is less than 0.20, the trial 
can be stopped for futility. If the posterior probability of efficacy is higher than 0.99, the trial 
can be stopped for efficacy. Otherwise, the trial will continue with inclusion of additional 
patients, as predefined, and a final analysis is conducted with decision boundary at a posterior 
probability of efficacy > 0.95. Decision boundaries are non-binding, and the DSMB can 
recommend continuing recruitment, in the whole population or a subgroup. Final decision 
boundaries are then readapted to control for a one-sided type I error rate close to 5%.  If the 
strata (groups I or II) are equally sized, the interim analysis should occur after 60 patients, and 
the second one with 120. This design (with only two stages) has then type I error rate 0.047 if 
event rates are 50% in each arm, and power 0.972 to detect a decrease from 0.50 to 0.20 and 
0.739 to detect a decrease from 0.50 to 0.30. 
 
 

Version 6.0 protocole CORIMUNO 04/05/2020 61 
 
7. 
SECOND 
NESTED 
TRIAL 
: 
EFFICACY 
OF 
SARILUMAB FOR PATIENTS WITH COVID-19 
7.1. 
Investigational medicinal product(s) 
7.1.1. 
KEVZARAⓇ 200mg, Pre-filled syringe 
 
Sarilumab (KEVZARAⓇ) is a human monoclonal antibody (IgG1 subtype) that specifically 
binds to both soluble and membrane-bound IL-6 receptors (IL-6Ra). Sarilumab is currently 
approved for treatment in patients with RA at 200 mg Q2W (SC) [with down dosing to 150 mg 
Q2W (SC) for certain laboratory changes]. Sarilumab is highly similar to tocilizumab and there 
is reported evidence that IV treatment with 400 mg of tocilizumab (Actemra®), an anti-IL-6R 
monoclonal antibody (mAb), provides a clinically meaningful improvement in clinical 
symptoms that are thought to be mediated by cytokine release in patients with severe or critical 
COVID-19 infection. 
Sarilumab is currently approved at 200 mg Q2W (SC) for the treatment of rheumatoid arthritis 
in multiple countries. In this protocol involving critically ill patients, it is preferable to use an 
IV injection. While there is limited experience in the use of sarilumab by IV infusion, the choice 
of the dose the use of sarilumab to be given by the IV route in this setting is supported by the 
high degree of bio-similarity of sarilumab to tocilizumab including a number of similarities in 
clinically observed pharmacokinetics, pharmacodynamics (to include safety, and PD 
endpoints). Based on available data, on a per mg basis, tocilizumab and sarilumab behave 
comparably in vivo with respect to potency, PK, PD, efficacy, and safety. Thus, the safety of 
sarilumab at doses as high as 400 mg IV can be extrapolated from the experience with similar 
and even higher doses of tocilizumab. Thus, it will be an IV dose of 400 mg of sarilumab in a 
1 hour-infusion that will be given in this study.  
Regarding the methods of administration of KEVZARAⓇ, we rely on the recommendations 
made by the SANOFI-AVENTIS laboratory in the particular context of the COVID-19 
epidemic (cf. Corona Virus (COVID-19) Sarilumab IV ** Information for Research purposes 
only **). 
7.1.2. 
Authorised and prohibited treatments (medicinal, non-
medicinal, surgical), including rescue medications 

Version 6.0 protocole CORIMUNO 04/05/2020 62 
There are no prohibited treatments. The medical staff is expected to monitor patients and 
administer any drug required for the treatment and/or prevention of all the usual complications 
that can develop in this setting. For all additional treatments, the SCP must have been obtained 
from the EMA website (http://www.ema.europa.eu/ema/), or from the ANSM website 
(http://agence-prd.ansm.sante.fr/php/ecodex/index.php), 
or 
http://base-donnees-
publique.medicaments.gouv.fr 
7.1.3. 
Supply of the investigational centers 
 
KEVZARAⓇ will not be specifically provided by the sponsor in the context of the COVID 19 
pandemic. The drugs will be provided by the hospital pharmacies to the care units on the basis 
of a specific research prescription. 
 
Origin : Origin : Specialty with marketing authorization in UE/France, marketed in France. 
 
Storage : 
Store in the refrigerator (between 2 ° C and 8 ° C). Do not freeze. 
The pre-filled syringe should be stored in the original package in order to protect from light. 
After reconstitution, administer immediately. 
 
7.1.4. 
Posology and drugs administration 
Treatment consists of the administration of a single 400 mg dose of Sarilumab IV. 
The treatment will be administered as a slow IV infusion over a period of one hour, as 
indicated on the brochure provided by SANOFI GENZYME (Corona Virus COVID-19 
Sarilumab (KEVZARA®) IV Information for research purpose only). 
The solution should not be used if it is cloudy, discolored or contains particles, or if any part 
of the injection device appears damaged. 
The contents of the 2 syringes of KEVZARA® 200mg must be diluted in a bag without 
DEHP of 100 mL of 0.9% NaCl. 
In the absence of a clinical response, a second dose of KEVZARA® will be administered on 
day 3 (D3). 
Administration should be performed using a DEHP-free infusion kit equipped with a 0.2µm 
PES filter. 
 
7.1.5. 
Traceability in investigational centers 
In accordance with the rules of Good Practices and to track the treatment given to each patient, 
all the information related to the treatment will be collected on a traceability sheet (Preparation, 
Dispensation, Date of administration, Time of administration, Batch number and expiry date, 
and Dose administered). 

Version 6.0 protocole CORIMUNO 04/05/2020 63 
7.1.6. 
Methods for monitoring compliance with the treatment 
To track the treatment given to each patient, all the information related to the treatment will be 
collected on a traceability sheet. This sheet will be prospectively and exhaustively monitored 
by clinical research assistants during the study. In case of deviations from the protocol there 
will be reminders to the centers and regular checks. 
7.2. 
Control 
Control patients will receive the best standard of care.  
7.3. 
Inclusion/Exclusion criteria for the nested trial 
 
Inclusion Criteria: 
1. Patients included in the CORIMUNO-19 cohort 
2. Patients belonging to one of the 2 following groups: 
- Group 1: patients not requiring ICU at admission with moderate and severe pneumopathy 
according to the WHO  Criteria of severity of COVID pneumopathy. 
Moderate cases 
Cases meeting all of the following criteria: 
● Showing fever and respiratory symptoms with radiological findings of 
pneumonia. 
● Requiring between 3L/min and 5L/min of oxygen to maintain SpO2 >97% 
Severe cases  
Cases meeting any of the following criteria: 
● Respiratory distress (≧30 breaths/ min); 
● Oxygen saturation≤93% at rest in ambient air; or Oxygen 
saturation ≤97 % with O2 > 5L/min. 
● PaO2/FiO2≦300mmHg  
 
- Group 2: patients requiring ICU based on Criteria of severity of COVID pneumopathy. 
● Respiratory failure and requiring mechanical ventilation 
● No do-not-resuscitate order (DNR order) 
 
Exclusion Criteria: 
● Patients with exclusion criteria to the CORIMUNO-19 cohort. 
● Known hypersensitivity to Sarilumab or to any of their excipients. 

Version 6.0 protocole CORIMUNO 04/05/2020 64 
● Pregnancy 
● Current documented bacterial infection 
● Patient with any of following laboratory results out of the ranges detailed below at 
screening should be discussed depending of the medication: 
○ Absolute neutrophil count (ANC) ≤ 1.0 x 109/L 
○ Haemoglobin level: no limitation 
○ Platelets (PLT) < 50 G /L 
○ SGOT or SGPT > 5N 
The primary endpoint and secondary endpoints will depend on the group of patients and tested 
medication. 
 
7.4. 
Endpoints for the trial 
7.4.1. 
Efficacy endpoints 
 
Measures 
A core set of clinical measures will be recorded daily the first 2 weeks and then every week. 
The core measures include measures of OMS progression scale, oxygenation, mechanical 
ventilation. For patients who are eligible for an intervention trial (in both the intervention 
and control arms), this day measurement will include trial-specific measures related to the 
trial outcomes of interest. 
Primary and secondary endpoints: 
The primary endpoint and secondary endpoints will depend on the group of patients and 
tested medication. 
  
Groups will be redefined as follow : 
- Group 1: Cases meeting all of the following criteria 
 
    Requiring more than 3L/min of oxygen 
 
    OMS/WHO progression scale = 5 
 
    No NIV or High flow 
 
- Group 2: Cases meeting all of the following criteria 
 
 
    Respiratory failure AND (requiring mechanical ventilation OR NIV OR High flow) 
 
    WHO progression scale >=6 
 
    No do-not-resuscitate order (DNR order) 
 
For the group 1 of patients not requiring ICU: 
  
Co Primary Endpoints  

Version 6.0 protocole CORIMUNO 04/05/2020 65 
 
1. Survival without needs of ventilator utilization (including non invasive ventilation and high flow) at 
day 14. Thus, events considered are needing ventilator utilization (including Non Invasive Ventilation, 
NIV or high flow), or death. New DNR order (if given after the inclusion of the patient) will be 
considered as an event at the date of the DNR. 
2. Early endpoint : proportion of patients alive without non-invasive ventilation of high low at day 4 
(WHO progression scale ≤ 5). A patient with new DNR order at day 4 will be considered as with a score 
> 5. 
 
OMS Progression 
scale 
Descriptor 
Scor
e 
Uninfected 
Uninfected; non viral RNA 
detected 
0 
Ambulatory 
Asymptomatic; viral RNA 
detected 
1 
Ambulatory 
Symptomatic; Independent 
2 
Ambulatory 
Symptomatic; Assistance needed 
3 
Hospitalized : 
mild disease 
Hospitalized; No oxygen therapy 
4 
Hospitalized : 
mild disease 
Hospitalized; oxygen by mask or 
nasal prongs 
5 
Hospitalized : 
severe disease 
Hospitalized; oxygen by NIV or 
High flow 
6 
Hospitalized : 
severe disease 
Intubation and Mechanical 
ventilation, pO2/FIO2>=150 OR 
SpO2/FIO2>=200  
7 
Hospitalized : 
severe disease 
Mechanical ventilation, 
(pO2/FIO2<150 OR 
SpO2/FIO2<200) OR vasopressor 
8 
Hospitalized : 
severe disease 
Mechanical ventilation, 
pO2/FIO2<150 AND 
vasopressors, OR Dialysis OR 
ECMO 
9 
Death 
Dead 
10 
 

Version 6.0 protocole CORIMUNO 04/05/2020 66 
Secondary end-points will be OMS progression scale at 4, 7 and 14 days, overall 
survival at 14, 28 and 90 days, time to discharge, time to oxygen supply independency, 
time to negative viral excretion. 
Biological parameters improvement: 
Estimated GFR, CRP, myoglobin, CPK, cardiac hs troponin, ferritin, lactate, cell blood 
count, liver enzymes, LDH, D-Dimer, albumin, fibrinogen, triglycerides, coagulation 
tests, urine electrolyte, creatinuria, proteinuria, uricemia, IL-6, procalcitonin, 
immunophenotype (Annexe 2), and exploratory tests (Annexe 3). 
  
For the group 2 of patients requiring ICU: 
  
Co Primary Endpoints 
 
1. Cumulative incidence of successful tracheal extubation (defined as duration extubation 
> 48h) at day 14 if patients have been intubated before day 14 ; or removal of NIV or 
high flow (for > 48h) if they were included under oxygen by NIV or High flow (score 
6) and remained without intubation. Death or new DNR order (if given after the 
inclusion of the patient) will be considered as a competing event. 
2. Early end point : proportion of patients with a decrease of WHO score of at least 1 point 
at day 4. 
 
Secondary end points will be OMS progression scale at 4, 7 and 14 days, overall survival at 
14, 28 and 90 days, the 28-day ventilator free-days, respiratory acidosis at day 4 (arterial 
blood pH of <7.25 with a partial pressure of arterial carbon dioxide [Paco2] of ≥60 mm 
Hg for >6 hours), the evolution of PaO2/FiO2 ratio, time to oxygen 
supply independency, duration of hospitalization, time to negative 
viral excretion, time to ICU and hospital discharge. 
 
Biological parameters improvement (estimated GFR, CRP, cardiac troponin, urine 
electrolyte and creatinine, proteinuria, uricemia, IL6, myoglobin, KIM-1, NGAL, CPK, 
ferritin, lactate, cell blood count, liver enzymes, LDH, D-Dimer, albumin, fibrinogen, 
triglycerides, coagulation tests (including activated partial thromboplastin time), 
procalcitonin, immunophenotype (Annexe 2), and exploratory tests (Frozen samples 
Annexe 3). Rate of renal replacement therapy, ventilation parameters. 
  
For each comorbidities group secondary criteria will be specifically addressed: 
  
For each tested medication, specific markers of efficacy and safety may be used and 
will be defined. 
 

Version 6.0 protocole CORIMUNO 04/05/2020 67 
7.4.2. 
Safety endpoints 
In the setting of COVID-19 NCP and short term immunomodulatory therapy, we will monitor 
major safety endpoints: blood cells and platelets counts and liver transaminases, frequently, 
every three days systematically. 
● Neutrophil count 
Treatment with Sarilumab (Kevzara) was associated with a higher incidence of decrease 
in ANC. Decrease in ANC was not associated with higher incidence of infections, 
including serious infections. 
○ In patients who develop an ANC less than 0.5 x 109/L, treatment with 
Tocilizumab or Sarilumab should be discontinued. 
○ Neutrophil count should be monitored 4 to 8 weeks after start of therapy and 
according to clinical judgment thereafter. For recommended dose modifications 
based on ANC results. 
● Platelet count 
Treatment with Sarilumab was associated with a reduction in platelet counts in clinical 
studies. 
○ In patients who develop a platelet count less than 50 x 103/ μL, treatment with 
Sarilumab should be discontinued. 
○ Platelet count should be monitored 4 to 8 weeks after start of therapy and 
according to clinical judgment thereafter. 
● Liver enzymes 
Treatment with Sarilumab was associated with a higher incidence of transaminase 
elevations. 
Initiating treatment with Sarilumab is not recommended in patients with elevated 
transaminases, ALT or AST greater than 1.5 x ULN for chronic therapies. However, given the 
emergency situation due to COVID-19, we still propose the use of these treatments. 
In patients who develop elevated ALT greater than 5 x ULN, treatment with Sarilumab should 
be discontinued 
 

Version 6.0 protocole CORIMUNO 04/05/2020 68 
● Hypersensitivity reactions: monitoring of occurrence of skin rashes, drop of blood 
pressure, ventilatory asynchronization. At the time of treatment injection. 
 
7.5. 
Specific data to be collected for this trial 
None 
7.6. 
Expected benefits and risks 
The clinical benefit is globally to prevent death. 
Other benefits are to: 
- 
blunt not only the pneumopathy-induced damage but also other COVID-19-associated 
injuries such as acute kidney injury (AKI), myocarditis, secondary bacterial infections. 
- 
shorten the duration of hospital stay with minimization of physical (hospital acquired 
pressure ulcers, increased morbidity and mortality associated with nosocomial 
infections), psychological and economic complications related with prolonged stay.  
- 
Shortening the hospital stay fosters not only individual clinical benefit but also 
collective clinical benefit through facilitation of collective access to caregivers. 
- 
limit long term sequelae, in particular lung fibrosis and chronic kidney disease 
secondary to acute kidney injury (markedly prevalent in about 20% of individuals with 
ARDS). 
 
The risks pertain to potential adverse effects of Sarilumab. 
There are currently no known published reports of IL-6R antagonists for infectious sepsis or 
pneumonia. Because IL-6 contributes to host defense against bacterial and viral pathogens, 
there is a concern that IL-6 inhibition may exacerbate infections thus delaying recovery from 
sepsis. 
 
Common adverse drug reactions seen in the clinical trials for Sarilumab/ Kevzara include 
infections (such as nasopharyngitis, upper respiratory tract infections, and urinary tract 
infections), neutropenia, injection-site erythema, increased low-density lipoprotein (LDL) 
cholesterol, and increased liver enzymes. 
Severe adverse effects were hypersensitivity reactions, including anaphylaxis, upper 
respiratory  and urinary tract infection. Patients chronically treated with sarilumab are at 
increased risk for developing serious and opportunistic infections. Most developed infections 

Version 6.0 protocole CORIMUNO 04/05/2020 69 
while taking other immunosuppressants or disease modifying anti-rheumatic arthritis 
(DMARDs) with sarilumab. 
The safety profile of Sarilumab is well known. While decreases in absolute neutrophil count 
(ANC) is seen in patients treated with sarilumab, they are reported not to be associated with 
increased incidence of infection or serious infections in patients with rheumatoid arthritis 
(Fleischmann, 2017). A clinical study of neutrophil trafficking suggested that this decrease is 
due to an redistribution into the marginating pool, rather than a net decrease in the neutrophil 
population (Lok, 2017). 
Treatment with Sarilumab was associated with a higher incidence of decrease in ANC (absolute 
neutrophil count); a reduction in platelet counts; and transaminase elevations. In addition, 
gastrointestinal perforation has been reported in clinical studies, including in patients receiving 
corticosteroids. 
7.7. 
Sketch of statistical methods 
The detailed statistical methods are identical for both subtrials, and presented in paragraph 11. 
A sketch of methods is given here.  
To maximize information from limited data generated, while allowing rapid decision, a 
Bayesian monitoring of the trial based on tco-primary outcomes will be used. The overall 
strategy has been determined so as to control for a frequentist one sided 5% type I error rate. 
The following methods pertain to the conduct and analysis of the subtrial in a given group of 
patients (group I or group II), that are analyzed separately with different primary outcomes, but 
conducted simultaneously (with stratified randomization) for logistical reasons. The total 
sample size will be 120 (60 in each arm) at the interim analysis, and 240 (120 per arm) at the 
second analysis. 
Since it is not possible to determine in advance how many patients will be recruited in each 
stratum, the sample sizes used for the following calculations are indicative, considering equally 
sized strata (groups). At the interim analysis, two posterior probabilities will be calculated: 1) 
the posterior probability of a lower event rate in the experimental than in the control arm 
(posterior probability of efficacy) and 2) the posterior probability of achieving at least a 
predefined effect corresponding to a hazard ratio of 0.85 (for time-to-event primary outcomes)  
or a risk difference of 5.5% (for binary co-primary outcomes) (posterior probability of 
sufficient efficacy). If the posterior probability of sufficient efficacy is less than 0.20, the trial 
can be stopped for futility. If the posterior probability of efficacy is higher than 0.99, the trial 
can be stopped for efficacy. Otherwise, the trial will continue with inclusion of additional 

Version 6.0 protocole CORIMUNO 04/05/2020 70 
patients, as predefined, and a final analysis is conducted with decision boundary at a posterior 
probability of efficacy > 0.95. Decision boundaries are non-binding, and the DSMB can 
recommend continuing recruitment, in the whole population or a subgroup. Final decision 
boundaries are then readapted to control for a one-sided type I error rate close to 5%.  If the 
strata (groups I or II) are equally sized, the interim analysis should occur after 60 patients, and 
the second one with 120. This design (with only two stages) has then type I error rate 0.047 if 
event rates are 50% in each arm, and power 0.972 to detect a decrease from 0.50 to 0.20 and 
0.739 to detect a decrease from 0.50 to 0.30. 
 
 
 
8. 
RECORDING 
AND 
REPORTING 
ADVERSE 
EVENTS 
8.1. 
Definitions 
According to Article R1123-46 of the French Public Health Code: 
  
· Adverse event 
Any untoward medical occurrence in a trial subject, which does not necessarily have a causal 
relationship with the clinical trial or with the investigational product. 
  
· Adverse reaction to an investigational medicinal product 
Any adverse event occurred in a trial subject, which has at least a possible  causal relationship 
with the clinical trial or with the investigational medicinal product 
  
· Serious adverse event or reaction 
Any adverse event or reaction that at any dose of medication, results in death, threatens the life 
of the research subject, requires hospitalisation or prolongs hospitalisation, causes a severe or 
long-term disability or handicap, or results in a congenital abnormality or deformity. 
  
· Unexpected adverse reaction to an investigational medicinal product 
Any adverse reaction to the product, whose nature, severity, frequency or outcome is 
inconsistent with the safety information described in the Reference Safety Information 

Version 6.0 protocole CORIMUNO 04/05/2020 71 
(summary of product characteristics, or the investigator's brochure if the product is not 
authorised). 
  
According to Article R.1123-46 of the Code de la Santé Publique and the guidelines for clinical 
trial sponsors (ANSM):  
  
· Emerging safety issue 
Any new safety information that may lead to a reassessment of the risk/benefit ratio of the trial 
or the investigational medicinal product, modifications in the investigational medicinal product 
use, the conduct of the clinical trial, or the clinical trial documents, or a suspension, interruption 
or modification of the protocol of the clinical trial or other similar trials. 
For the clinical trials involving the first administration or use of an investigational medicinal 
product in healthy volunteers, any serious adverse reaction. 
  
Examples: 
a) Any clinically significant increase in the frequency of an expected serious adverse reaction 
b) Suspected unexpected serious adverse reactions in patients who have terminated their 
participation in the clinical trial that are notified by the investigator to the sponsor together with  
follow-up reports 
c) Any new safety issue relating to the conduct of the clinical trial or the development of the 
investigational medicinal product that may impact the safety of the trial subjects.  
Examples: 
- A serious adverse event likely to be related to the interventions and the trial’s 
diagnostic procedures and which may impact the conduct of the clinical trial, 
- A significant risk on the trial subjects such as ineffectiveness of the investigational 
medicinal product in treating a life-threatening illness under investigation, 
- Significant safety results from a recently completed non-clinical study (such as a 
carcinogenicity study), 
- The premature termination, or temporary suspension, of a trial conducted on the same 
investigational medicinal product in another country, for safety reasons, 
- An unexpected serious adverse reaction associated with a non-experimental 
medication required for the conduct of the clinical trial, (e.g. challenge agents, rescue 
treatment) 

Version 6.0 protocole CORIMUNO 04/05/2020 72 
d) Recommendations from the Data Safety Monitoring Board (DSMB), if applicable, that may 
affect the safety of the trial subjects 
e) Any suspected unexpected serious adverse reaction (SUSAR) reported to the sponsor by 
another sponsor of a trial carried out in a different country but relating to the same medication. 
 
8.2. 
The role of the investigator 
The investigator must assess the seriousness criteria of each adverse event and record all 
serious and non-serious adverse events in the case report form (CRF). The investigator must 
document serious adverse events as thorough as possible and provide a definitive medical 
diagnosis, if possible. 
  
The investigator must assess the severity of the adverse events by using: 
- either general terms: 
o   Mild: tolerated by the patient, does not interfere with daily activities 
o   Moderate: sufficiently uncomfortable to affect daily activities 
o   Severe: preventing daily activities 
- or a severity grading scale for adverse events, attached to the protocol: by using an adverse 
events rating scale developed by the International Bone Marrow Transplant Registry (IBMTR) 
in 1997 and as described by Cahn and coll. and assess the causal relationship between the 
experimental procedure and the SAE. 
- or using the NCI CTCAE v5.0. 
The investigator must assess the causal relationship between the serious adverse events and 
the investigational medicinal product(s) or the study procedure(s). 
  
The method used by the investigator is based on the WHO Uppsala Monitoring Centre method 
and uses the following causality terms: 
● Certain 
● Probable/likely 
● Possible 
● Unlikely (not ruled out). 
 
These terms are defined as follows (extracted from the WHO-UMC causality categories, 
version dated 17/04/2012). 

Version 6.0 protocole CORIMUNO 04/05/2020 73 
  
Table: WHO-UMC causality categories (extract) 
Causality term 
Assessment criteria* 
Certain 
·  Event or laboratory test abnormality, with plausible time 
relationship to drug intake ** 
·  Cannot be explained by disease or other drugs 
·  Response 
to 
withdrawal 
plausible 
(pharmacologically, 
pathologically) 
·  Event definitive pharmacologically or phenomenologically (i.e. an 
objective and specific medical disorder or a recognized 
pharmacological phenomenon) 
·  Rechallenge satisfactory, if necessary 
Probable / Likely 
  
·  Event or laboratory test abnormality, with reasonable time 
relationship to drug intake** 
·  Unlikely to be attributed to disease or other drugs 
·  Response to withdrawal clinically reasonable 
·  Rechallenge not required 
Possible 
·  Event or laboratory test abnormality, with reasonable time 
relationship to drug intake ** 
·  Could also be explained by disease or other drugs 
·  Information on drug withdrawal may be lacking or unclear 
Unlikely 
·  Event or laboratory test abnormality, with a time to drug intake ** 
·  That makes a relationship improbable (but not impossible) 
·  Disease or other drugs provide plausible explanations 
*All points should be reasonably complied with 
** Or study procedures 
 

Version 6.0 protocole CORIMUNO 04/05/2020 74 
8.2.1. 
Serious adverse events that require a notification without 
delay by the investigator to the sponsor 
As per article R.1123-49 of the French Public Health Code (CSP), the investigator must notify 
the sponsor without delay on the day when the investigator becomes aware of any serious 
adverse event which occurs during a trial and at the latest within 24 hours  as described in 
Article L.1121-1(1) CSP, except those which are listed in the protocol and, if applicable, in the 
investigator's brochure as not requiring a notification without delay. 
  
A serious adverse event is any untoward medical occurrence that: 
● Results in death 
● Is life-threatening 
● Requires inpatient hospitalisation or prolongation of existing hospitalisation 
● Results in persistent or significant disability/incapacity 
● Is a congenital anomaly/birth defect 
 
Any other grade III or higher severe or toxic manifestations (defined accordingly to the 
Common Terminology Criteria for Adverse Events v5.0 (CTCAE). 
The sponsor will particularly monitor haematological abnormalities (grade > or = 3), serious 
liver damage, serious infections and hypersensitivity reactions. 
 
  
The investigator must notify the sponsor without delay on the day when the investigator 
becomes aware of these adverse events and at the latest within 24 hours, , according to the same 
modalities and within the same timeline as for serious adverse events (see above). 
 
8.2.2. 
Serious adverse events that do not require the investigator to 
notify the sponsor without delay 
 These serious adverse events are simply recorded in the case report form. 
 
Normal and natural course of the condition 
● Scheduled inpatient hospitalisation for monitoring the condition under investigation 
(with no deterioration in the subject's medical condition compared to baseline) 

Version 6.0 protocole CORIMUNO 04/05/2020 75 
● Inpatient hospitalisation for routine treatment or monitoring the condition under 
investigation, not associated with a deterioration in the subject's medical condition 
● Any routine complications occurring in patients in ICU and or infected by COVID 19 
(except death), especially: 
         Acute cardiac injury: acute heart failure, type 1 or 2 myocardial infarction, 
myocarditis 
-       
Acute kidney injury, need for renal replacement therapy except grade 4 and 5 
according CTCAE scale 
-       
Acute respiratory distress syndrome, requirement of mechanical ventilation 
(invasive or not) or an ECMO 
-        Multiple organ failure except grade 5 according CTCAE scale. 
- 
Pulmonary embolism 
 
 
 
 
 
8.2.3. 
Special circumstances  
In utero exposure 
The investigator must notify the sponsor without delay on the day the investigator becomes 
aware of any pregnancy that occurs during the study and at the latest within 24 hours, even if 
it is not associated with an adverse event. 
If the investigational medicinal product is genotoxic, every case of maternal or paternal 
exposure must be notified. 
  
  
Adverse events during the trial possibly related with the treatments prescribed as part of 
the patient's standard care 
The investigator must report these adverse events to the relevant regional pharmacovigilance 
centre, Centre Régional de Pharmacovigilance (CRPV). 
 
 

Version 6.0 protocole CORIMUNO 04/05/2020 76 
8.3. 
Period during which the investigator must send notification of 
SAEs to the sponsor without delay 
The investigator notifies the sponsor without delay and at the latest within 24 hours of all the 
serious adverse events listed in the corresponding section: 
-  Starting from the date on which the subject signs the consent form 
-  Throughout the whole follow-up period intended by the trial (90 days) 
-, After the end of the clinical trial, if the SAE is likely to be due to the investigational 
medicinal product (IMP) or to the study interventions (e.g. serious reactions that could 
appear at long term after exposure to the medication, such as cancers or congenital 
abnormalities). In that case, the investigator does not have to systematically and indefinitely 
collect all SAEs possibly related to the IMP, but must transmit all possible SAEs related to 
the IMP of which he has knowledge. 
 
8.4. 
Procedures and deadlines for notifying the sponsor 
The investigator should initially complete a SAE reporting form (contained in the case report 
form). This report must be signed by the investigator. 
  
The investigator must complete every section of the SAE form so that the sponsor can carry 
out the appropriate assessment. 
  
The initial report sent to the sponsor must be rapidly followed up by one or more additional 
written reports describing the course of the event and any complementary information. 
  
Whenever possible, the investigator will provide the sponsor with any documents that may be 
useful for medical assessment of the case (medical reports, laboratory test results, results of 
additional exams, etc.). These documents must be anonymized. In addition, the investigator 
must state the study acronym and the number and initials of the study participant on each paper. 
  
Any adverse event will be monitored until fully resolved (stabilisation at a level considered 
acceptable by the investigator, or return to the previous state) even if the subject has terminated 
his participation in the trial. 
  

Version 6.0 protocole CORIMUNO 04/05/2020 77 
The initial report, the SAE follow-up reports and all other documents must be sent to the 
sponsor's safety Department bye-mail (eig-vigilance.drc@aphp.fr) to the sponsor’s safety 
department. It is possible to send the SAE to the Safety department by fax to the sponsor’s 
safety department, fax No. +33 (0)1 44 84 17 99 only in case of unsuccessful attempt to send 
the SAE by e-mail and in order to avoid duplicates. 
  
For trials which use e-CRF 
-  The investigator completes the SAE report form in the e-CRF, then validates, prints and 
signs the form before sending it by e-mail; 
-  In case of failure to connect to the e-CRF, the investigator should complete, sign and send 
the SAE report form to the safety Department. As soon as the connection is restored, the 
investigator must complete the SAE report form in the e-CRF. 
  
The investigator must comply with all requests for additional information from the sponsor. 
For all questions relating to an adverse event report, the safety Department can be contacted 
via email at vigilance.drc@aphp.fr. 
For cases of in utero exposure, the investigator will complete the Notification and Follow-up 
form for a pregnancy occurring during participation in a study". 
The investigator must monitor the pregnant woman throughout her pregnancy or until the 
pregnancy is terminated, and must notify the sponsor of the outcome of the pregnancy using 
this form. 
If the outcome of the pregnancy falls within the definition of a serious adverse event 
(miscarriage, pregnancy termination, foetal death, congenital abnormality, etc.), the 
investigator must follow the procedure for reporting SAEs. 
The initial pregnancy notification, the SAE follow-up reports, and any other documents will be 
sent to the sponsor according to the same procedures specified herein. 
If it was the father who was exposed, the investigator must obtain the pregnant woman's 
permission before collecting information about the pregnancy. 
 
 
8.5. 
Role of the sponsor 
The sponsor, represented by its safety Department, shall continuously assess the safety of each 
investigational medicinal product throughout the trial. 

Version 6.0 protocole CORIMUNO 04/05/2020 78 
8.5.1. 
Analysis and declaration of serious adverse events 
The sponsor assesses: 
-    The seriousness of all reported adverse events, 
-    The causal relationship between these adverse events and investigational medicinal 
product and any other treatments, 
All serious adverse events for which the investigator and/or the sponsor suspect a causal 
relationship with the investigational medicinal product are classed as suspected serious 
adverse reactions. 
-    The expectedness assessment of the serious adverse reactions 
Any serious adverse reaction whose nature, severity, frequency or outcome is 
inconsistent with the safety information described in the summary of product 
characteristics, or in the investigator's brochure if the product is not authorised, is 
considered unexpected. 
The sponsor, acting through its safety Department, assesses the expectedness of the 
serious adverse reaction based on the information described below. 
  
For serious adverse events likely to be related to the investigational medicinal product(s): 
·  Refer to the SPC in Appendix for each drugs. 
● For sarilumab: 
The most frequent adverse reactions observed with sarilumab in clinical studies were 
neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary 
tract infections. The most common serious adverse reactions were infections. Refer to the 
SmPC of Kevzara® for more details. 
  
● For tocilizumab 
The most commonly reported adverse reactions observed with were upper respiratory tract 
infections, nasopharyngitis, headache, hypertension and increased ALT. The most serious 
adverse reactions were serious infections, complications of diverticulitis, and hypersensitivity 
reactions. Refer to the SmPC of RoActemra® for more details. 
 
  

Version 6.0 protocole CORIMUNO 04/05/2020 79 
The serious adverse events associated with the study procedures are: 
Blood samples for the analyses are carried out at the same time as those necessary for 
the usual follow-up. 
  
The sponsor will report all suspected unexpected serious adverse reactions (SUSARs),) and all 
expected serious adverse reactions of fatal outcome (as requested by ANSM), within the 
regulatory time frame, to the ANSM (French Health Products Safety Agency). 
-  The sponsor must send the initial report without delay upon receipt of the unexpected serious 
adverse reaction if it is fatal or life-threatening, or otherwise within 15 days from receipt of 
any other type of unexpected serious adverse reaction; 
-  The sponsor must provide all relevant additional information by sending follow-up reports, 
within 8 calendar days following receipt. 
Any suspected unexpected serious adverse reaction must also be declared electronically using 
the Eudravigilance European adverse drug reactions database managed by the European 
Medicines Agency (EMA). 
The sponsor must notify all the investigators about any information that could adversely affect 
the safety of the trial subjects. 
  
8.5.2. 
Analysis and declaration of other safety data 
This relates to any new safety data that may lead to a reassessment of the risk/benefit ratio of 
the trial or the investigational medicinal product, modifications in the investigational medicinal 
product use, the conduct of the clinical trial, or the clinical trial documents, or a suspension, 
interruption or modification of the protocol of the clinical trial or other similar trials. 
  
The sponsor will inform the competent authority and the Ethics committee without delay after 
becoming aware of the emerging safety issue and, if applicable, describe which measures have 
been taken. 
  
Following the initial declaration of emerging safety issues, the sponsor will declare to ANSM 
any additional relevant information about the new safety issues in the form of a follow-up 
report, which must be sent no later than 8 days after becoming aware of the information. 

Version 6.0 protocole CORIMUNO 04/05/2020 80 
 
8.5.3. 
Annual safety report 
The sponsor must prepare once yearly throughout the trial duration an annual safety report 
(Development Safety Update Report - DSUR) which includes, in particular: 
- An analysis of safety data concerning trial subjects 
- A description of the patients included in the trial (demographic profile etc.) 
- A list of all the suspected serious adverse reactions that occurred during the period covered 
by the report, 
- Cumulative summary tabulation of all the serious adverse events that have occurred since the 
beginning of the clinical trial 
  
The report must be transmitted to ANSM no later than 60 days after the anniversary date 
corresponding to the date of authorization of the clinical trial by ANSM. 
  
9. 
SPECIFIC COMMITTEES FOR THE STUDY 
9.1. 
Data Safety Monitoring Board (DSMB) 
A Data Safety Monitoring Board (DSMB) can be set up by the sponsor. Its primary mission is 
to monitor safety data. It can have other missions, such as monitoring efficacy data (especially 
if the protocol includes interim analyses). 
The sponsor is responsible for justifying the creation or absence of a DSMB to the Competent 
Authority (ANSM) and to the Ethics committee. 
A DSMB will be set up for this trial. The DSMB must hold its first meeting before the first 
subject is enrolled. 
  
The members of the DSMB are: 
Cristina Mussini, University of Modena, Modena, IT;  
 
Patrick Yeni, Maladies Infectieuses, Paris, FR 
 
Sandro Galea, School of Public Health, Boston University, Boston, MA, USA; 
 
Kevin Winthrop, Oregon Health and Science University, Portland, OR, USA; 
 
Deepak L Bhatt, Harvard Medical School, Boston, MA, USA; 

Version 6.0 protocole CORIMUNO 04/05/2020 81 
 
Frank Harrell, Department of Biostatistics, Vanderbilt University School of Medicine, Nashville TN, 
USA. 
 
The DSMB’s principal missions and their operating procedures are described in the DSMB 
chart of the study. The DSMB has a consultative role. The decision concerning the conduct of 
the clinical trial relies on the sponsor. 
The DSMB will meet at least once a week or upon request. 
9.2. 
Steering Committee 
The steering will be constituted of : Pierre-Louis Tharaux, Olivier Hermine, Xavier Mariette, 
Philippe Ravaud, Matthieu Resche-Rigon, Xavier Lescure, Alexandre Demoule,  David 
Montani, Lila Boudama, Jean François Timsit, Antoine Dossier, Frédéric Pène, Damien Sène, 
Bruno Megarbane, Julien Poissy, (to be extended)   
 
10. 
DATA MANAGEMENT 
10.1. 
Access to data 
In accordance with GCP: 
- The sponsor is responsible for ensuring all parties involved in the study agree to guarantee 
direct access to all locations where the study will be carried out, the source data, the source 
documents and the reports, for the purposes of the sponsor's quality control and audit 
procedures. 
- The investigators will ensure the persons in charge of monitoring and auditing the clinical 
trial and of quality control have access to the documents and personal data strictly necessary 
for these tasks, in accordance with the statutory and regulatory provisions in force (Articles 
L.1121-3 and R.5121-13 of the French Public Health Code) 
10.2. 
Source documents 
The source documents are any original document or item that proves the existence or accuracy 
of a data-point or fact recorded during the trial. Source documents will be kept by the 
investigator, or by the hospital in the case of hospital medical records, for the statutory period. 
10.3. 
Data confidentiality 
The persons responsible for the quality control of clinical studies (Article L.1121-3 of the 
French Public Health Code) will take all necessary precautions to ensure the confidentiality of 

Version 6.0 protocole CORIMUNO 04/05/2020 82 
information relating to the investigational medicinal products, the study, the study participants 
and in particular the identity of the participants and the results obtained. 
These persons, as well as the investigators themselves, are bound by professional secrecy (in 
accordance with the conditions set out in Articles 226-13 and 226-14 of the French Criminal 
Code). 
During and after the clinical study, all data collected about the study participants and sent to 
the sponsor by the investigators (or any other specialised collaborators) will be anonymised. 
Under no circumstances will the names and addresses of the subjects be shown. 
The sponsor will ensure that each subject has agreed in writing for any personal information 
about him or her which is strictly necessary for the quality control of the study to be accessed. 
10.4. 
Data processing and storage of documents and data 
10.4.1. 
Identification of the person responsible and the location of 
the data processing management 
Pr. Matthieu RESCHE-RIGON from Service BioStatistique et Information Médicale (SBIM) 
Hôpital Saint Louis, AP-HP, Paris will be responsible for data entry and the relevant 
procedures. The same goes for conducting the statistical analysis. 
10.4.2. 
Data Entry 
Data entry for data made non-identifying will be carried out on electronic media via a web 
browser (Cleanweb) linked to a database stored on the sponsor server. 
10.4.3. 
Ownership of the data 
Data entry for data made non-identifying will be carried out on electronic media via a web 
browser (Cleanweb) linked to a database stored on the sponsor server. 
 
11. 
STATISTICAL ASPECTS 
11.1. 
Planned statistical methods, including the timetable for any 
planned interim analyses 
The CORIMUNO-19 trial is planned according to a cohort multiple Randomized Controlled 
Trials design. The basic idea is that individuals in the cohort eligible to a specific trial are 
randomised 1:1 to the first trial until a predefined sample size is reached. Then, they are 

Version 6.0 protocole CORIMUNO 04/05/2020 83 
randomized to a second trial while inclusions in the first trial are frozen, waiting for the 
evaluation of the primary outcome and an interim analysis. Then inclusions in the first trial can 
be resumed, whereas inclusions in the second trial are frozen, and so on. If no other trial is 
available for this specific population of patients and the drug is already known (for instance if 
it is already marketed for another indication, and has a known safety profile), then inclusions 
may not stop to wait for the interim analysis results. 
The methods outlined thereafter describe the principles for analysing one specific trial in one 
specific population (i.e. patients not requiring ICU). The trials are analysed separately in each 
population—or group—of patients, but are conducted simultaneously for logistical reasons. 
Information from previous trials or populations can be incorporated in the prior distribution 
(see below a description of Bayesian methods). 
One crucial feature of the CORIMUNO-19 trial is to remain as flexible as possible, in an 
urgency context, when information may change quickly. The study therefore attempts to 
maximize information from limited data generated, while allowing rapid decision. This will be 
achieved by the use of Bayesian monitoring of the trial. While using a Bayesian approach, 
where standard definition of type I and II error rate do not apply, the trial is also planned to 
control for frequentist (i.e. non-Bayesian) error rates. In particular, the overall strategy will be 
to control for a frequentist one sided type I error rate close to 5% over one specific trial. 
The analysis will therefore rely on computing the posterior distribution of the hazard ratio 
between the experimental and control arms for time-to-event co-primary outcomes and the 
posterior distributions of event rates in each arm for binary co-primary outcomes. From the 
latter, the posterior distribution of the difference in event rate will be derived. These posterior 
distributions will be graphically displayed, and summarized by their medians and 95% 
credibility intervals (the Bayesian counterparts of confidence intervals). 
In a Bayesian analysis, the specification of the prior distribution is crucial. For the first trials 
conducted in the cmRCT, we want the conclusions to depend primarily on data from the trial, 
not on prior opinion. An uninformative prior for the hazard ratio will therefore be used. More 
precisely, the prior distribution for the log hazard ratio will be a Gaussian distribution with 
mean 0 and variance 10^6. For binary outcomes, let p denote the probability of outcome in a 
given arm; the prior distribution of p is set as a beta prior distribution with parameters 1 and 1, 
equivalent to a uniform distribution on the interval (0,1). This corresponds to a hypothetical 
situation where we would have data on two individuals treated with the corresponding arm 
strategy, and observing that exactly 1 of the 2 experiencing the outcome. These prior 
distributions ensure very little influence of our prior opinion on conclusions. For subsequent 

Version 6.0 protocole CORIMUNO 04/05/2020 84 
trials where a tested agent would become oSOC, then an informative prior could be used, based 
on the results observed on previous trials. This prior information may translate into a different 
prior distribution for the baseline cumulative hazard (cumulative hazard under control 
strategy). This procedure will be described in future trial-specific protocols. 
For now the calculations in this base protocol have been performed for a sample size of 60 
individuals per arm, with interim analyses after 30. However, this may be adapted to allow 
continuing the trial if results are promising, though not formally achieving the predefined 
efficacy boundary. Additional calculations have thus been performed with the additional 
recruitment of 30 individuals per arm after the sample size of 60 has been reached (see below). 
This may also be modified in future protocols. Moreover, it is practically unfeasible in the 
urgency context of COVID-19 to conduct a trial with the same experimental drug 
independently in the two groups of patients. Accordingly, the trial is conducted as a single 
trial, with randomisation stratified on the patients group. The total sample size is therefore 
fixed for the whole trial at 120 (60 per arm) for the first formal interim analysis, and 240 (120 
per arm) for the final analysis, but with an option to accrue 120 patients more (60 per am) 
depending of the recommendations of the DSMB (see below). The share of each stratum (group 
of patients) may not be equal, but calculations presented in the paragraph 11.2 below have been 
performed assuming an equal number per stratum. This will be adapted to show the properties 
of the design according to the observed proportion of patients in each stratum.  
Baseline characteristics will be described with summary statistics, namely frequencies and 
percentages, or medians and interquartile ranges (IQR). Secondary and safety outcomes will 
be analysed in a frequentist framework. Final analysis will account for randomization 
stratification factors. All the analyses will be described in a statistical analysis plan (SAP) that 
will be written and signed before freezing of the database. 
At the end of the study subgroup analyses will be performed according to antiviral therapies. 
Moreover interactions between experimental treatments and  antiviral therapies will explored 
and tested.  
Statistical analyses will be performed using the R statistical package version 3.6.1 or later (The 
R Foundation for Statistical Computing, https://www.R-project.org/). 
 
11.2. 
Statistical criteria for termination of the study 
This section describes the Bayesian monitoring of the trial in the base protocol. The strategy is 
planned similarly for all trials in the cmRCT, but control event rates and therefore the number 

Version 6.0 protocole CORIMUNO 04/05/2020 85 
of interim analyses, decision boundaries and the sample sizes will be adapted for each trial. In 
each trial, we defined two co-primary outcomes, one time-to-event outcome evaluated up to 
day 14, and an early success outcome evaluated on day 4. Methods for trial monitoring have 
been developed for the early outcome because (1) short-term outcomes are obtained more 
quickly so are easier for early interim decision and (2) calculations of all possible outcomes are 
more tractable for binary outcomes. For analyses based on the hazard ratio, which allow to 
account for all information gathered in the trial (even for patients who do not have the entire 
follow-up necessary to evaluate a binary outcome), the same decision boundaries will be used. 
It is not expected that the properties of the boundaries would be significantly different when 
using the posterior distribution of the hazard ratio (identically to the use of O’Brien Fleming 
boundaries in frequentist trials for continuous, binary or survival outcomes). The main 
adaptation is to convert the timing of the interim analysis in terms of fraction of information, 
i.e. fraction of the total expected number of events instead of fraction of the total number of 
patients). More comprehensive simulation studies will be performed to describe the properties 
of the design in an appendix to the protocol. Also, in all what follows, we assume the “event” 
corresponding to the outcome being detrimental to patients, so that an effective treatment would 
lower the event rate, or achieve a hazard ratio q < 1. When the clinical definition of the outcome 
is opposite, then analysis will be performed on the inverse (e.g. failure instead or success, or 
inverse of the hazard ratio 1/q). 
Let us denote pE and pC the event rates in the experimental and control arms, respectively. At 
the interim analysis, the posterior probability of a lower event rate in the experimental than in 
the control arm is calculated, i.e. P(pE < pC | data), which we term the posterior probability of 
efficacy. The posterior probability P(pE < pC - d | data) is also computed, corresponding to the 
probability to achieve at least a d treatment effect, termed the posterior probability of sufficient 
efficacy. At each interim analysis, if the posterior probability of sufficient efficacy is less than 
0.20, the trial could be stopped for futility upon decision of the DSMB (indicative and not 
binding futility boundary). If the posterior probability of efficacy is higher than 0.99, then the 
trial may be stopped for efficacy (again this boundary is not binding and the DSMB may 
propose to continue the accrual based on other information, such as secondary outcomes or 
safety). The choice of interim monitoring for futility based on the posterior probability of 
sufficient efficacy and not the posterior probability of efficacy is justified by the need to 
increase the chance of early stopping for futility when information increases, if the 
experimental treatment is no better than the control. Conversely, keeping a constant futility 
boundary on the posterior probability of efficacy would decrease the chances of early stopping 

Version 6.0 protocole CORIMUNO 04/05/2020 86 
if additional analyses are performed, because under the null, as information increases, the 
posterior distribution of efficacy would converge to 0.5. This boundary is stricter than using a 
boundary on the posterior probability of efficacy (grey line on the figure 1, left panel), but this 
choice is justified by the need to quickly identify treatments with a large effect. The futility 
threshold (0.20) may be revised in future trials, if expected effects are lower. 
When no stopping for futility or efficacy is decided,  additional patients are recruited in each 
arm. At the interim analyses, the predictive probability of achieving a success after inclusion 
of a total of 60 patients per arm (posterior probability of efficacy > 0.95) will also be computed, 
and the trial can be stopped for futility if it is less than 10%. The final analysis will occur after 
final recruitment, and a posterior probability of efficacy higher than 0.95 will be considered as 
indicating efficacy.  
To compute the probability of sufficient efficacy, we assumed that the hazard ratio for time-to-
event outcomes should be at least 0.85, which translates to an event rate of 45.5% in the 
experimental arm when it is 50% in the control arm. Accordingly, d was set to 0.055 for 
calculations with binary outcomes. The table 1 presents the properties of the design under 
different scenarios, assuming 30 patients per arm have been recruited at the interim analysis, 
and 30 additional per arm have been recruited to reach the final analysis. The figure 1 displays 
the decision boundaries for the early outcome. 
 
Table 1. Operational characteristics of the design under different scenarios. 
  
Failure rate p in each group 
Scenario 
No effect 
Very large effect 
Large effect 
Mild effect 
Parameterizations 
pC=0.5, pE=0.5 
pC=0.5, pE=0.2 
pC=0.5, pE=0.3 
pC=0.5, pE=0.35 
Corresponding hazard ratio 
1 
0.32 
0.51 
0.62 
Probability of early stopping for 
futility 
0.349 
0.0017 
0.023 
0.057 
Probability of early stopping for 
efficacy 
0.0087 
0.558 
0.228 
0.121 

Version 6.0 protocole CORIMUNO 04/05/2020 87 
Probability of efficacy at 2nd stage 
0.038 
0.413 
0.510 
0.393 
Overall probability of rejection 
0.047 
0.972 
0.739 
0.514 
 
 
 
 
 
 
 
Figure 1. Decision boundaries for the interim and final analysis. Red lines indicate efficacy boundaries, and 
black lines futility boundaries. On the left plot, the interim analysis is performed after inclusion of 30 patients per 
arm, and the gray line indicate what the boundary would be if the posterior probability of efficacy was used to 
define futility instead of the posterior probability of sufficient efficacy. On the right plot, the final analysis after 
accrual of 30 more patients per arm is presented. Gloden stars indicate regions that should not occur if the decision 
boundaries are respected, because the trial would have been stopped for efficacy at the interim analysis. Gray 
points indicate regions that should not occur if the decision boundaries are respected, because the trial would have 
been stopped for futility at the interim analysis. 
 
In the case the DSMB would deem results promising but not yet conclusive after inclusion of 
60 individuals per arm (that we consider for illustration as a posterior probability of sufficient 
efficacy of 0.40 or more but a posterior probability of efficacy is of 0.97 or less), 30 additional 
patients per arm could be recruited, the final decision boundary could be adapted to a posterior 
probability of efficacy > 0.963 to control the type I error rate. The table 2 summarizes the 

Version 6.0 protocole CORIMUNO 04/05/2020 88 
properties of such extension under the four previous scenarios, and illustrates that this could 
have an important effect on the power in scenarios where the efficacy is less than anticipated. 
 
Table 2. Operational characteristics of the design with extension to a third stage, under different 
scenarios. In this example, it is assumed that the DSMB would consider results to be promising if the 
posterior probability of sufficient efficacy of 0.40 or more but a posterior probability of efficacy is of 0.97 
or less, and the final decision boundary is set to a posterior probability of efficacy > 0.963 to control the type 
I error rate. 
  
Failure rate p in each group 
Scenario 
No effect 
Very large effect 
Large effect 
Mild effect 
Parameterizations 
pC=0.5, pE=0.5 
pC=0.5, pE=0.2 
pC=0.5, pE=0.3 
pC=0.5, pE=0.35 
Probability of occurrence 
0.307 
0.046 
0.313 
0.460 
Probability of efficacy at 3rd stage 
0.018 
0.043 
0.209 
0.221 
Overall probability of rejection 
0.050 
0.994 
0.848 
0.631 
 
In terms of trial monitoring, it is also planned that more interim analyses would be performed, 
primary safety reviews, but the posterior distribution of key efficacy parameters should then 
also be presented to the DSMB, without formal stopping rules. This may be performed on a 
weekly basis, depending on the speed of inclusions, to monitor the progress of the trial. 
11.3. 
Number of participants and justification 
The total sample size is therefore fixed for the whole trial at 240 (120 per arm) for the final 
analysis, with interim analysis after 120 (60 per arm), and an option to accrue 120 patients 
more (60 per am) depending of the recommendations of the DSMB. 
The calculations shown in the table 1 show that the type I error rate of the design would be 
4.7% if the event rate is 0.50 in each arm, and the power to detect a decrease from 0.50 to 0.20 
would be 97.2%. This trial would also have power 73.9% to detect a decrease from 0.50 to 
0.30. 

Version 6.0 protocole CORIMUNO 04/05/2020 89 
11.4. 
Anticipated level of statistical significance 
The trial is not designed for frequentist statistical testing at a predefined level of statistical 
significance. Nevertheless, as explained above, the current decision boundaries allow to control 
for a frequentist type I error rate of 0.047. 
 
11.5. 
Subject replacement strategy 
No subject replacement is planned. 
11.6. 
Method for taking into account missing, unused or invalid  
We do not expect missing data for the primary outcome. However, were data to be missing, 
they will be imputed as failures for the trial monitoring. No imputation will be used for 
secondary efficacy and safety outcomes. 
 
11.7. 
Management of modifications made to the analysis plan for the 
initial strategy 
All the analyses will be described in a statistical analysis plan (SAP) that will be written and 
signed before freezing of the database), in order to accommodate any event or protocol 
modification that may have occurred and that would affect the way the analysis should be 
conducted.. 
We do not expect modifications of the initial analysis strategy. However, should such 
modifications occur after the SAP has been validated, a modified SAP would be issued. The 
original SAP as well as the modified SAP will be kept in the study files, with the justification 
for any modification. 
11.8. 
Choice of individuals to be included in the analyses 
In the classical cmRCT design, randomisation occurs prior to offering an intervention, and 
some number of eligible patients who are randomly selected to be offered an intervention will 
not accept the offer. An intention to treat analysis could therefore dilute any treatment effects. 
Relton et al. suggested using a complier average causal effect (CACE) analysis which provides 
unbiased estimates of the treatment effect for patients who comply with the protocol. Thus, for 
al trials where only patients in the intervention arm are offered the intervention, all primary 
analyses will be performed in both Intention To Treat (ITT) and CACE basis. For CACE 
analyses, an instrumental variable approach to the analysis, which assumes that a patient's 
decision not to accept the intervention will not affect the outcome (except through the 
intervention actually received). For the ITT analysis, patients will be analysed according to the 
treatment arm they were randomized to (i.e. offer or no offer group), even if the participant did 
not accept the intervention.  
 
12. 
QUALITY CONTROL AND ASSURANCE 

Version 6.0 protocole CORIMUNO 04/05/2020 90 
Every clinical study managed by AP-HP is ranked according to the projected risk incurred by 
the study participants using a classification system specific to AP-HP-sponsored clinical trials. 
12.1. 
General organisation 
The sponsor must ensure the safety and respect of individuals who have agreed to participate 
in the trial. The sponsor must have a quality assurance system for monitoring the 
implementation of the study at the research centres. 
  
For this purpose, the sponsor shall appoint Clinical Research Associates (CRA) whose primary 
role is to carry out regular follow-up visits at the study sites, after completing their initial visits. 
The purpose of monitoring the study, as defined in the Good Clinical Practices, is to verify that: 
•     The research subjects are safe, protected and their rights are being met 
•     The data being recorded is accurate, complete and consistent with the source documents 
•     The study is carried out in accordance with the current version of the protocol, with GCP 
and with all statutory and regulatory requirements. 
Strategy for site opening 
The strategy for opening the sites is determined using the tailored monitoring plan. 
Scope of site monitoring 
In the case of this risk study the appropriate monitoring level has been determined based on the 
complexity, the impact and the budget for the study. Therefore, in agreement with the 
coordinating investigator, the sponsor has determined the logistical score and impact, resulting 
in a study monitoring level to be implemented: level B 
  
12.2. 
Quality control 
A Clinical Research Associate (CRA) appointed by the sponsor will be responsible for the good 
completion of the study, for collecting, documenting, recording and reporting all handwritten 
data, in accordance with the Standard Operating Procedures applied within the DRCI (Clinical 
Research and Innovation Department) and in accordance with Good Clinical Practices as well 
as the statutory and regulatory requirements. 
  
The investigator and the members of the investigator’s team agree to make themselves 
available during regular Quality Control visits carried out by the Clinical Research Associate. 
During these visits, the following elements will be reviewed depending on the monitoring level: 

Version 6.0 protocole CORIMUNO 04/05/2020 91 
-    written consent 
-    compliance with the study protocol and with the procedures defined therein 
-    quality of the data collected in the case report form: accuracy, missing data, 
consistency of the data with the “source” documents (medical files, appointment 
books, original copies of laboratory results, etc.) 
-    management of the treatments used 
  
12.3. 
Case Report Form 
Electronic CRF: 
All information required by the protocol must be entered in the case report forms. The data 
must be collected as and when it is obtained, and clearly recorded in these case report forms. 
Any missing data must be coded. 
Every site will have access to the electronic case report forms via a web-based data collection 
system. Investigators will be given instructions for using this tool. 
Using on-line case report forms means the CRA can view the data quickly and remotely. The 
investigator is responsible for the accuracy, quality and relevance of all the data entered. In 
addition, there are consistency checks to ensure the data are verified immediately upon being 
entered. The investigator must validate any changes to the values in the case report form. An 
audit trail will be kept of all changes. A justification can be added when applicable, as a 
comment. A print-out, authenticated (signed and dated) by the investigator, will be requested 
at the end of the study. The investigator must archive a copy of the authenticated document 
that was delivered to the sponsor. 
 
12.4. 
Management of non-compliances 
Any events that occur as a result of the investigator or any other individual involved in 
conducting the study failing to comply with the protocol, standard operating procedures, good 
clinical practice or statutory and regulatory requirements must be recorded in a declaration of 
non-compliance and sent to the sponsor. 
  
The sponsor has its own procedures for managing these non-compliances. 
12.5. 
Audits/inspections 

Version 6.0 protocole CORIMUNO 04/05/2020 92 
The investigators agree to accept the quality assurance audits carried out by the sponsor as well 
as the inspections carried out by the competent authorities. All data, documents and reports 
may be subject to regulatory audits and inspections. These audits and inspections cannot be 
refused on the basis of medical secrecy. 
An audit can be carried out at any time by independent individuals appointed by the sponsor. 
The aim of the audits is to ensure the quality of the study, the validity of the results and 
compliance with the legislation and regulations in force. 
  
The persons who manage and monitor the trial agree to comply with the sponsor's requirements 
and with the competent authority regarding study audits or inspections. 
  
The audit may encompass all stages of the study, from the development of the protocol to the 
publication of the results and the storage of the data used or produced as part of the study. 
12.6. 
Principal Investigator's declaration of responsibility 
Before starting the trial, each investigator will give the sponsor’s representative a signed and 
dated copy of his/her curriculum vitæ and RPPS number (Répertoire Partagé des Professionnels 
de Santé, Collective Database of Health Professionals). 
  
Each investigator will agree to comply with legislation and to conduct the trial in line with 
GCP, in accordance with the Declaration of Helsinki. 
  
The Principal Investigator at each participating site will sign a declaration of responsibility 
(standard DRCD document), which will be sent to the sponsor's representative. 
The investigators and their co-workers will sign a delegation form specifying each person's 
role. 
12.7. 
Pharmacist's declaration of responsibility 
Production problems must be recorded according to the Manufacturing unit (LTCG) 
procedures. 
 
 
13. 
ETHICAL AND LEGAL CONSIDERATIONS 

Version 6.0 protocole CORIMUNO 04/05/2020 93 
13.1. 
Methods for informing and obtaining consent from the 
research participants 
The study will be conducted in compliance with the principles of the Declaration of Helsinki 
(2008) and other major ethical guidelines. 
Information and consent process specific to cmRCT design 
The process for informing patients and obtaining their consent in a cmRCT is conducted in 2 
steps: 
a. Participants are invited to participate in a cohort study.  
In the cmRCT design, individuals first consent to participate in a cohort. The local recruiting 
physician will explain the nature and purpose of the COVID Cohort and provide the 
participants with a copy of the consent and information sheet. Participants will be informed 
that agreeing to participate in the COVID Cohort will involve (1) giving permission to the 
research staff to use their medical record to complete the COVID baseline Medical Data form; 
(2) giving permission for COVID investigators to propose them an intervention that is being 
evaluated in any COVID intervention trials embedded in the cohort; (3) giving permission for 
their data to be used for comparison purposes in any COVID intervention trials embedded in 
the cohort. 
Patients will be informed that participation in the COVID Cohort will not affect their usual 
care in any way. They will also be informed that only patients who are randomly selected to be 
offered an intervention will be contacted about the intervention. Finally, it is explained that 
patients’ current consent is only for participation in the COVID Cohort, and that separate 
consent will be sought for participation in a particular COVID intervention. 
 
b. Participants are invited to receive the intervention / treatment tested in a COVID 
trial 
When patients are eligible to participate in a COVID embedded trial, they will be contacted by 
the local recruiting physician who will describe the intervention/treatment evaluated with its 
risk and benefit and provide the participants with a copy of the consent and information sheet. 
Patients will be informed that their participation will not affect their usual care in any way. 
 

Version 6.0 protocole CORIMUNO 04/05/2020 94 
Other general aspect of the consent process 
In accordance with Article L1122-1-1 of the French Code of Public Health, biomedical research 
may only be initiated after the participant has been provided with comprehensive study 
information (as set out in Article L.1122-1) and has given his/her prior, written, informed 
consent. 
The participant's written, informed consent shall be obtained by the investigator (or a physician 
representing the investigator) during the selection visit, before inclusion of the participant in 
the research. After the receipt of study information, the participant will be given time if needed 
to consider his/her participation before being asked to sign the consent form. Copies of the 
study information sheet and the consent form (signed and dated by the research participant and 
by the investigator or the physician representing the investigator) will be given to the individual 
prior to his/her participation in the study. Furthermore, the methods used for obtaining the 
participant's consent and the methods used to provide information with the goal of obtaining 
consent will be specified in the participant's medical records. The investigator will keep the 
original signed and dated copy of the participant's consent form. 
If the person is unable to give his or her written consent, consent may be obtained, in 
descending order of priority, from a legal representative, family member or a close relative. 
These persons must have no connection whatsoever to the investigator or the sponsor. 
Whilst participating in this study, subjects may not take part in any other clinical study without 
first speaking to the doctor in charge of this trial. 
 
13.2. 
Authorisation for the research location 
Units participating in the study will have specific authorisation for the location if requested. 
13.3. 
Legal obligations 
13.3.1. 
The sponsor's role 
Assistance Publique - Hôpitaux de Paris (AP-HP) is the sponsor of this study and, by 
delegation, the DRCI (Clinical Research and Innovation Department) carries out the study's 
missions in accordance with Article L.1121-1 of the Code de la Santé Publique (French Public 
Health Code). Assistance Publique - Hôpitaux de Paris reserves the right to halt the study at 
any time for medical or administrative reasons. In this case, notification will be sent to the 
investigator. 

Version 6.0 protocole CORIMUNO 04/05/2020 95 
13.3.2. 
Request for approval from the CPP (Research Ethics 
Committee) 
Prior to starting the study, AP-HP, as sponsor, must obtain for this interventional study 
involving human participants concerning a medicinal product for human use, approval from 
the appropriate CPP (Research Ethics Committee), within the scope of its authority and in 
accordance with in force legislation and regulatory requirements. 
13.3.3. 
Request for authorisation from ANSM 
Prior to starting the study, AP-HP, as sponsor, must obtains authorisation from the ANSM 
(French Health Products Safety Agency) for the interventional study involving human 
participants concerning a medicinal products for human use, within the scope of the ANSM's 
authority and in accordance with in force legislation and regulatory requirements. 
13.3.4. 
Procedures relating to data protection regulations 
The computer file used for this research is implemented in accordance with French (amended 
“Informatique et Libertés” law governing data protection) and European (General Data 
Protection Regulation – GDPR) regulations. 
This research is not governed by the CNIL (French Data Protection Agency) “Reference 
Methodology for processing personal data used within the scope of health research” (amended 
MR-001). AP-HP, as sponsor of the research, must obtain approval of CNIL. 
13.3.5. 
Amendments to the research 
Any substantial modification to the protocol by the coordinating investigator must be sent to 
the sponsor for approval. After approval is given, the sponsor must obtain approval from the 
CPP (Research Ethics Committee) and authorisation from the ANSM within the scope of their 
respective authorities, before the amendment can be implemented. 
The information note and the consent form can be revised if necessary, in particular in case of 
a substantial amendment to the study or if adverse reactions occur. 
13.3.6. 
Final study report 
The final report for the research involving human participants referred to in Article R1123-67 
of the Code de la Santé Publique (French Public Health Code) is written and signed by the 
sponsor and the investigator. A report summary drafted according to the reference plan of the 
competent authority must be sent to the competent authority within a period of one year 

Version 6.0 protocole CORIMUNO 04/05/2020 96 
following the end of the study, i.e., the end of the participation of the last participant in the 
study. 
13.3.7. 
Archiving 
Specific documents for an interventional study involving human participants concerning a 
medicinal product for human use will be archived by the investigator and the sponsor for 15 
years  after the end of the research. 
This indexed archiving includes, in particular:  
-   A sealed envelope for the investigator containing a copy of all the information notes and 
consent forms signed by all individuals at the centre who participated in the study; 
-   A sealed envelope for the sponsor, containing a copy of all the information notes and 
consent forms signed by all individuals at the centre who participated in the study; 
-   "Study" binders for the Investigator and the sponsor, including (non-exhaustive list) : 
·   the successive versions of the protocol (identified by the version number and its 
date), and any appendices 
·   the ANSM authorisations and CPP (Research Ethics Committee) decisions 
·   any correspondence 
·   the enrolment list or register 
·   the appendices specific to the research 
·   final study report 
-   The data collection documents 
 
14. 
FUNDING AND INSURANCE 
14.1. 
Sources of funding for the trial 
National PHRC (Ministry of Health) 
14.2. 
Insurance 
For the duration of the study, the Sponsor will take out an insurance policy covering the 
sponsor’s own third party liability as well as the third party liability of all the doctors involved 
in the study. The sponsor will also provide full compensation for any damages caused by the 
study to the study participant and their beneficiaries, unless the sponsor can prove that the harm 
is not the fault of the sponsor or any collaborator. Compensation cannot be refused on the 

Version 6.0 protocole CORIMUNO 04/05/2020 97 
grounds of a third party act or the voluntary withdrawal of the person who initially consented 
to participate in the study. 
  
Assistance Publique-Hôpitaux de Paris (AP-HP) has taken out insurance with HDI-GERLING 
through BIOMEDIC-INSURE, covering its own third party liability and that of any 
collaborator (doctor or research staff), in accordance with Article L.1121-10 of CSP. 
 
15. 
PUBLICATION RULES 
Mention of AP-HP affiliation for projects sponsored by AP-HP 
- If an author has several affiliations, the order in which the institutions are mentioned (AP-
HP, University, INSERM, etc.) is unimportant 
- However, if the study is funded in the context of an internal AP-HP call for tender, the first 
affiliation must be “AP-HP”  
- Each of these affiliations must be identified by an address and separated by a semicolon (;) 
- The AP-HP institution must feature under the acronym “AP-HP” first in the address, 
specifically followed by: AP-HP, hospital, department, city, postcode, France  
  
Mention of the sponsor AP-HP (DRCI) in the acknowledgements of the text 
-  “The sponsor was Assistance Publique – Hôpitaux de Paris (Délégation à la Recherche 
Clinique et à l’Innovation)” 
  
Mention of the financial backer in the acknowledgements of the text 
-  If PHRC: “The study was funded by a grant from Programme Hospitalier de Recherche 
Clinique - PHRC 20XX (French Ministry of Health)” 
-  If an AP-HP internal call for tenders, specify: “The study was funded by a grant from 
Assistance Publique – Hôpitaux de Paris” 
  
  
This study has been registered on the website http://clinicaltrials.gov/ under number (add 
the registration number when the study is registered). 
 

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17. 
LIST OF ADDENDA 
 
Every addendum and the log of addenda versions are attached, independently of the protocol. 
Every addendum can be modified (change of addendum version) without modifying the version 
of the protocol. 
-List of the team 
-Serious Adverse Events report form 
-Pregnancy report form 
-Adverse events rating scale developed by the International Bone Marrow Transplant Registry 
(IBMTR) in 1997 and as described by Cahn and coll.  
-The NCI CTCAE v5.0. (https://evs.nci.nih.gov/ftp1/CTCAE/About.html) 
-SCP and Investigator's Brochure 
The SCP must have been obtained from the EMA website (http://www.ema.europa.eu/ema/), 
or from the ANSM website (http://agence-prd.ansm.sante.fr/php/ecodex/index.php) 
 
-Addendum 1: CORIMUNO19-ANA protocol: Nested trial N°3: Efficacity of anakinra in COVID19  
patients 
 
-Addendum 2: CORIMUNO19-VIRO protocol: Nested trial N°4: TRIAL EVALUATING 
EFFICACY OF SARILUMAB + AZITHROMYCIN + HYDROXYCHLOROQUINE, AND 
SARILUMAB alone, FOR ADULT PATIENTS HOSPITALIZED WITH MODERATE TO 
SEVERE COVID-19 
 
-Addendum 3: CORIMUNO19-ECU protocol: Nested trial N°5: TRIAL EVALUATING 
EFFICACY OF ECULIZUMAB IN PATIENTS WITH COVID-19 INFECTION 
 
-Addendum 4: CORIMUNO19-CORIPLASM: Nested trial N°6: EFFICACY OF 
CONVALESCENT PLASMA TO TREAT SARS-COV2 INFECTED PATIENTS , A NESTED 
TRIAL IN THE CORIMUNO-19 COHORT 
 
-Addendum 5: CORIMUNO19-BARI protocol: Nested trial N°7: TRIAL EVALUATING 
EFFICACY OF BARICITINIB FOR PATIENTS WITH COVID-19 (JAKOVID) 
 
-Addendum 6: CORIMUNO19-SECU protocol: Nested trial N°8: TRIAL EVALUATING 
EFFICACY OF SECUKINUMAB FOR PATIENTS WITH COVID-19  
 
-Addendum 7: CORIMUNO19-BEVA protocol: Nested trial N°9 : TRIAL EVALUATING 
EFFICACY and SAFETY OF BEVACIZUMAB (AVASTIN®) IN PATIENTS WITH SEVERE 
HYPOXEMIC COVID-19, NESTED IN THE CORIMUNO-19 COHORT