A Phase 2/3, Randomized, Open-label, Parallel Group, 3-arm, Multicenter Study Investigating the Efficacy and Safety of Intravenous Administrations of Emapalumab, an Anti-interferon Gamma (Anti-IFNγ) Monoclonal Antibody, and Anakinra, an Interleukin-1(IL-1) Receptor Antagonist, Versus Standard of Care, in Reducing Hyper-inflammation and Respiratory Distress in Patients With SARS-CoV-2 Infection.
Phase: PHASE2
Conditions: SARS-CoV-2
Sponsor: Swedish Orphan Biovitrum



Sobi 
 
Emapalumab/Anakinra 
Clinical Study No: Sobi.IMMUNO-101 
Confidential 
Page 2 of 62 
Version 7.0 Final Protocol, Date 24 June 2020 
 
 
purposes. In the event of actual or suspected breach of this obligation, Swedish Orphan Biovitrum should be 
promptly notified. 
 
Investigator statement 
I have read the protocol entitled “A phase 2/3, randomized, open-label, parallel group, 3-arm, 
multicenter study investigating the efficacy and safety of intravenous administrations of 
emapalumab, an anti-interferon gamma (anti-IFNγ) monoclonal antibody, and anakinra, an 
interleukin-1(IL-1) receptor antagonist, versus standard of care, in reducing hyper-inflammation 
and respiratory distress in patients with SARS-CoV-2 infection.” and the accompanying current 
Investigator´s Brochure for emapalumab and Summary of Product Characteristics for anakinra. I 
agree to conduct the clinical investigation in compliance with the Final Protocol Version 7.0,  24 
June  2020, the International Council for Harmonisation (ICH) harmonised guideline E6(R2): 
Guideline for Good Clinical Practice (GCP) [1], applicable regulatory/government regulations, 
and in accordance with the ethical principles that have their origin in the Declaration of Helsinki 
[2]. It should be noted that due to the urgency of the situation, the Sponsor has for this protocol 
requested exemptions to what is required for a Clinical Trial Application and when conducting a 
clinical trial. 
I will not implement any changes to study procedures or conduct without prior approval from the 
Sponsor and, when applicable, the Independent Ethics Committee and Regulatory Authority. I 
will supervise any individual or party to whom I delegate study-related duties and functions 
conducted at the study site and ensure qualification of individuals or parties who perform 
delegated tasks.  
I agree to maintain the confidentiality of this study protocol, as described on the title page. 
Further, I will not publish results of the study without authorization from Swedish Orphan 
Biovitrum AB. 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
 

Sobi 
 
Emapalumab/Anakinra 
Clinical Study No: Sobi.IMMUNO-101 
Confidential 
Page 3 of 62 
Version 7.0 Final Protocol, Date 24 June 2020 
 
 
Table of contents 
Synopsis .......................................................................................................................................... 7 
1 
Abbreviations and definition of terms............................................................................. 15 
1.1 
List of abbreviations and definitions .......................................................................... 15 
2 
Ethics ............................................................................................................................... 18 
2.1 
Independent ethics committee and institutional review board ................................... 18 
2.2 
Ethical conduct of the study ....................................................................................... 18 
2.3 
Patient information and consent ................................................................................. 18 
3 
Introduction ..................................................................................................................... 19 
3.1 
Background ................................................................................................................ 19 
3.2 
Study rationale ............................................................................................................ 19 
3.3 
Potential risks and benefits ......................................................................................... 20 
4 
Study objectives and endpoints ....................................................................................... 21 
4.1 
Primary objective ....................................................................................................... 21 
4.1.1 
Primary endpoint ................................................................................................... 21 
4.1.2 
Secondary endpoints supporting the primary objective......................................... 21 
4.2 
Secondary objective ................................................................................................... 22 
4.2.1 
Secondary endpoints supporting the secondary objective ..................................... 22 
4.3 
Exploratory objective ................................................................................................. 23 
4.3.1 
Exploratory endpoints ............................................................................................ 23 
5 
Investigational plan ......................................................................................................... 23 
5.1 
Overall study design and plan .................................................................................... 23 
5.2 
Discussion of study design, including the choice of control groups .......................... 25 
5.3 
Selection of study population ..................................................................................... 25 
5.3.1 
Inclusion criteria .................................................................................................... 25 
5.3.2 
Exclusion criteria ................................................................................................... 25 
5.3.3 
Withdrawal of patients from treatment or study .................................................... 26 
5.3.3.1 Withdrawal from treatment ............................................................................... 26 
5.3.3.2 Withdrawal from study ..................................................................................... 27 
5.3.4 
Replacement of withdrawn patients....................................................................... 27 
5.3.5 
Screening failures .................................................................................................. 27 
5.4 
Treatments .................................................................................................................. 27 
5.4.1 
Treatments administered ........................................................................................ 27 
5.4.2 
Identity of investigational medicinal products ...................................................... 27 
5.4.2.1 Emapalumab ..................................................................................................... 28 

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Emapalumab/Anakinra 
Clinical Study No: Sobi.IMMUNO-101 
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5.4.2.2 Anakinra ............................................................................................................ 28 
5.4.3 
Method of assigning patients to treatment groups ................................................. 28 
5.4.4 
Selection of doses .................................................................................................. 29 
5.4.4.1 Dose selection rationale for anakinra ................................................................ 29 
5.4.4.2 Dose selection rationale for emapalumab ......................................................... 29 
5.4.4.3 Rationale for stratifying the use of glucocorticoids .......................................... 30 
5.4.5 
Selection and timing of doses for each patient ...................................................... 30 
5.4.5.1 Emapalumab ..................................................................................................... 30 
5.4.5.2 Anakinra ............................................................................................................ 31 
5.4.6 
Blinding and unblinding ........................................................................................ 31 
5.4.7 
Concomitant therapy .............................................................................................. 31 
5.4.7.1 Prophylactic therapy ......................................................................................... 31 
5.4.7.2 Concomitant therapy ......................................................................................... 32 
5.4.8 
Treatment compliance ........................................................................................... 32 
5.5 
Efficacy and safety assessments ................................................................................. 32 
5.5.1 
Study schedule ....................................................................................................... 32 
5.5.1.1 Schedule of events ............................................................................................ 32 
5.5.1.2 Screening ........................................................................................................... 36 
5.5.1.3 Visit 1, Baseline (Day 1) ................................................................................... 36 
5.5.1.4 Visits 2 to 5 (Days 4, 7, 10 and 13) .................................................................. 36 
5.5.1.5 Visit 6 (Day 15) ................................................................................................ 36 
5.5.1.6 Visit 7 (Day 28) ................................................................................................ 36 
5.5.1.7 Visits 8 and 9, Follow-up (Weeks 6 and 10) .................................................... 37 
5.5.2 
Patient information and physical examination ...................................................... 37 
5.5.2.1 Demographics ................................................................................................... 37 
5.5.2.2 Medical and surgical history ............................................................................. 37 
5.5.2.3 Prior medication ................................................................................................ 37 
5.5.2.4 Physical examination ........................................................................................ 37 
5.5.2.5 Symptom onset information .............................................................................. 37 
5.5.3 
Efficacy assessments ............................................................................................. 37 
5.5.3.1 Pulmonary function (primary efficacy assessment) .......................................... 37 
5.5.3.2 MEWS score ..................................................................................................... 38 
5.5.3.3 SpO2, PaO2 and FiO2 ......................................................................................... 38 
5.5.3.4 Hemogasanalysis ............................................................................................... 38 
5.5.3.5 Oxygen supplementation .................................................................................. 38 
5.5.3.6 High-resolution computed tomography ............................................................ 38 

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Emapalumab/Anakinra 
Clinical Study No: Sobi.IMMUNO-101 
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5.5.3.7 Laboraratory assessments ................................................................................. 38 
5.5.3.8 Survival and hospital discharge ........................................................................ 39 
5.5.4 
Safety assessments ................................................................................................. 40 
5.5.4.1 Adverse events .................................................................................................. 40 
5.5.4.2 Serious adverse events ...................................................................................... 41 
5.5.4.3 Reporting requirement of adverse events ......................................................... 42 
5.5.4.4 Pregnancy .......................................................................................................... 43 
5.5.4.5 Laboratory safety assessments .......................................................................... 44 
5.5.4.6 Vital signs ......................................................................................................... 44 
5.5.4.7 Electrocardiograms ........................................................................................... 44 
5.5.4.8 Pregnancy Test .................................................................................................. 44 
5.5.4.9 Immunogenicity ................................................................................................ 44 
5.5.4.10 Viral shedding ................................................................................................... 44 
5.5.4.11 Data Review Committee ................................................................................... 44 
5.5.4.12 Safety Review Committee ................................................................................ 45 
5.5.4.13 Specific safety monitoring and management during the study ......................... 45 
5.5.5 
Exploratory assessments ........................................................................................ 45 
5.5.5.1 Clinical Status ................................................................................................... 45 
5.5.5.2 Pharmacokinetics .............................................................................................. 46 
5.5.5.3 Pharmacodynamics ........................................................................................... 46 
6 
Quality control and quality assurance ............................................................................. 46 
7 
Statistical plan ................................................................................................................. 47 
7.1 
Determination of sample size ..................................................................................... 47 
7.2 
Definition of study populations .................................................................................. 48 
7.3 
Overall statistical and analytical plan ......................................................................... 48 
7.3.1 
General statistical issues ........................................................................................ 48 
7.3.2 
Demographics and baseline characteristics ........................................................... 49 
7.3.3 
Analysis related to primary objective .................................................................... 49 
7.3.3.1 Primary endpoint ............................................................................................... 49 
7.3.3.2 Secondary endpoints supporting the primary objective .................................... 49 
7.3.4 
Analysis related to secondary objective ................................................................ 51 
7.3.4.1 Adverse events .................................................................................................. 51 
7.3.4.2 Anti-drug antibodies ......................................................................................... 51 
7.3.5 
Analysis related to the exploratory objective ........................................................ 51 
7.3.6 
Interim analysis ...................................................................................................... 51 
7.3.7 
Multiple comparison/multiplicity .......................................................................... 51 

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Emapalumab/Anakinra 
Clinical Study No: Sobi.IMMUNO-101 
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7.3.8 
Handling of missing data ....................................................................................... 52 
8 
Data collection, handling and record keeping ................................................................. 52 
8.1 
Data standards ............................................................................................................ 52 
8.2 
Case report form ......................................................................................................... 52 
8.3 
Source data ................................................................................................................. 52 
8.4 
Protocol deviations ..................................................................................................... 53 
8.5 
Database closure ......................................................................................................... 53 
8.6 
Record retention ......................................................................................................... 53 
9 
End of study .................................................................................................................... 54 
10 
Sponsor’s discontinuation criteria ................................................................................... 54 
11 
Dissemination and publication of results ........................................................................ 54 
12 
Reference list ................................................................................................................... 55 
Appendix 1 
Additional Protocol Signatures .............................................................................. 57 
Appendix 2 
Study Administrative Structure ............................................................................. 58 
Appendix 3 
Exemption Letter Italy ........................................................................................... 59 
 

Sobi 
 
Emapalumab/Anakinra 
Clinical Study No: Sobi.IMMUNO-101 
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Synopsis 
STUDY IDENTIFIERS 
 
Title of study: 
A phase 2/3,  randomized, open-label, parallel group, 3-arm, multicenter study 
investigating the efficacy and safety of intravenous administrations of 
emapalumab, an anti-interferon gamma (anti-IFNγ) monoclonal antibody, and 
anakinra, an interleukin-1(IL-1) receptor antagonist, versus standard of care, in 
reducing hyper-inflammation and respiratory distress in patients with SARS-
CoV-2 infection. 
Clinical study number: 
Sobi.IMMUNO-101 
Sponsor 
Swedish Orphan Biovitrum AB, Stockholm, Sweden 
Study sites 
International multi-center study, 12 to 20 sites in Italy and US are planned to 
participate in the study. 
Type of study: 
Phase 2/3 
STUDY RATIONALE 
As shown by the data available in the most recent literature generated from the 
Chinese experience, and by the most recent data made available by the different 
Italian hospitals responsible for the management of these patients, hyper-
inflammation, caused by a cytokine storm resulting from an exaggerated response 
of the immune system to the presence of the virus, is considered to represent one 
of the most important negative prognostic factor in patients infected with SARS-
CoV-2. The inclusion criteria for hyperinflammation used in this protocol is 
based on the analysis of routine blood chemistry data obtained from patients with 
SARS-CoV-2 infection. This criterion has been designed with high sensitivity 
(>90%) for patients who require ICU admission. This constitute the rationale for 
testing drugs specifically targeted to reduce the cytokine storm. 
This protocol has been prepared on the basis to address the current medical 
emergency, given the severity of the disease and the extremely high number of 
individuals affected. The objective of this study is to investigate new possibilities 
to reduce the number of patients requiring mechanical ventilation. This is 
intended to address the most urgent need to preserve the access to intense care 
unit support to the lower possible number of patients and may potentially reduce 
mortality. 
STUDY OBJECTIVES 
 
Primary objective: 
The primary objective of this study is to assess the effect of emapalumab and 
anakinra on hyperinflammation and pulmonary function in patients with SARS-
CoV-2 infection. 
Secondary objective(s): 
The secondary objective of this study is to evaluate the safety and tolerability 
profile, including evaluation of the immunogenicity of emapalumab and anakinra,  
of intravenous (i.v.) administrations of emapalumab and anakinra in patients with 
SARS-CoV-2 infection. 
Exploratory objective(s): 
An exploratory objective of this study is to evaluate the clinical status based on a 
7-point ordinal scale. 
An exploratory objective of this study is to evaluate the PK of emapalumab and 
anakinra. 
An exploratory objective of this study is to assess the effect of anakinra and 
emapalumab on CXCL9, IFNγ, IL-1, IL-6, sIL-2R and selected biomarkers 
relevant for hyperinflammation. 

Sobi 
 
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Clinical Study No: Sobi.IMMUNO-101 
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STUDY ENDPOINTS 
 
Primary endpoint: 
The primary endpoint is treatment success, defined as not requiring any of the 
following by Day 15: 
1. 
Invasive mechanical ventilation or 
2. 
Extracorporeal membrane oxygenation (ECMO). 
Secondary endpoints 
supporting the primary 
objective: 
1. 
Time to mechanical ventilation. 
2. 
Change from baseline in MEWs score. 
3. 
Change from baseline in resting SpO2. 
4. 
Change from baseline in PaO2/FiO2. 
5. 
Change from baseline in hemogasanalysis. 
6. 
Change from baseline in oxygen supplementation. 
7. 
Amelioration of the findings of high-resolution CT scan or X-ray of 
the chest. 
8. 
Change from baseline in hyperinflammatory parameters during 
treatment until Day 15 with measurements performed every 3 days: 
• 
Ferritin  
• 
LDH  
• 
D-dimers  
9.              Change from baseline in other relevant laboratory parameters during 
treatment until Day 15 with measurements performed every 3 days: 
• 
WBC with differential counts 
• 
RBC 
• 
Hb 
• 
Platelet count 
• 
Fibrinogen 
• 
Complement C3/C4 
• 
Prothrombin time 
• 
Cardiac troponin 
• 
Liver tests (AST, ALT, total bilirubin levels) 
• 
CRP 
• 
Creatinine 
• 
Electrolytes (Sodium, Potassium and Calcium) 
• 
Glucose 
10. 
Overall survival. 
11. 
Time to hospital discharge. 

Sobi 
 
Emapalumab/Anakinra 
Clinical Study No: Sobi.IMMUNO-101 
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Secondary endpoint 
Safety endpoints of this study are: 
1. 
Treatment-emergent serious adverse events (SAEs). 
2. 
Adverse events leading to premature discontinuation of study 
treatment. 
3. 
Infusion related reactions including anaphylactic/anaphylactoid 
reactions. 
4. 
Treatment emergent adverse events of special interest. 
5. 
Emapalumab treatment group: All new infections.Anakinra treatment 
group: Severe neutropenia. Treatment-emergent laboratory 
abnormalities. 
6. 
Presence of anti-drug antibodies (ADAs) and neutralizing antibodies 
(Nabs) against emapalumab and anakinra. 
 
Exploratory endpoint(s): 
Clinical status based on a 7-point ordinal scale. 
 
The scale consists of the the following categories: 
1. 
Death 
2. 
Hospitalized, requiring invasive mechanical ventilation or extracorporeal  
              membrane oxygenation (ECMO) 
3. 
Hospitalized, requiring non-invasive ventilation or high flow oxygen  
              devices 
4. 
Hospitalized, requiring supplemental oxygen 
5. 
Hospitalized, not requiring supplemental oxygen - requiring ongoing  
              medical care  
6. 
Hospitalized, not requiring supplemental oxygen - no longer requires     
               ongoing medical care 
7. 
Not hospitalized 
 
 
PK parameters will be calculated for emapalumab and anakinra by non-
compartmental analysis and population analysis, as applicable. 
 
PD biomarkers: Change from baseline in CXCL9, IFNγ, IL-1, IL-6, sIL-2R and 
selected biomarkers relevant for hyperinflammation. 

Sobi 
 
Emapalumab/Anakinra 
Clinical Study No: Sobi.IMMUNO-101 
Confidential 
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STUDY DESIGN AND METHODS 
 
Study design: 
This is a randomized, open-label, parallel group, 3-arm multicenter study to 
investigate the efficacy and safety of emapalumab and anakinra in reducing 
hyper-inflammation and respiratory distress in adult patients with a documented 
SARS-CoV-2 infection. 
The study consists of screening, a 2-week treatment period and an 8-week follow-
up period.  
The 2-week treatment period is open, and the patients will be randomized to 
treatment with emapalumab, anakinra or standard of care in a 1:1:1 ratio. 
Emapalumab will be administered as i.v. infusions every 3rd day for a total of 5 
infusions (Days 1, 4, 7, 10, 13). Anakinra will be administered as 4-times daily 
i.v. infustions for 15 days (Days 1 to 15). The primary endpoint will be evaluated 
at Day 15. 
An early follow-up visit will be performed at Day 28. A follow-up by visit or 
phone call will be performed 4 and 8 weeks after the end of the treatment period 
(Weeks 6 and 10).  
The study duration for an individual patient will not exceed 10 weeks. The end of 
the study is defined as last patient last follow-up visit/phone call. 
The study design has a total sample size of 54 patients and consists of two stages. 
At the end of Stage 1, the success rates are compared between each of the two 
treatment arms and standard of care and there is the potential to stop for futility.A 
data review committee composed of independent experts in intensive care, 
inflammation, infection diseases will be involved in study oversight, safety 
monitoring and interpretation of the study results. 
A safety review committee consisting of internal Sobi members (voting) and 
coordinating investigators (non-voting) members is established to monitor study 
participant safety in the study. Clinical safety information will be monitored and 
reviewed on a continuous basis by the SRC from study start to database lock. 
Should two patients develop a life threatening or fatal adverse event suspected to 
be study drug related then an ad hoc SRC meeting will be held within 24 hours 
after the Sponsor awareness of the event. The SRC has the possibility to take a 
decision to halt the enrolment of a specific study arm or continue the study with 
or without changes. Details are described in separate written operating procedures 
for the SRC.  
In patients showing worsening of clinical condition, independently of the 
treatment arm, the Investigator is completely free to decide to introduce any drug 
considered necessary for a given patient as rescue treatment. 
Number of subjects 
planned: 
The study will enroll a total of 54 patients, 18 per arm according to the 1:1:1 
randomization. 
Diagnosis and main 
criteria for inclusion: 
Patients with documented SARS-CoV-2 infection, age > 18 to < 85 years with 
respiratory distress and hyperinflammation. 
 
 

Sobi 
 
Emapalumab/Anakinra 
Clinical Study No: Sobi.IMMUNO-101 
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Assessments: 
The clinical and laboratory parameters to be collected at given time points are 
indicated in the simplified Schedule of Events presented in the end of the 
synopsis. This schedule also includes information on the patient´s demographics, 
medical history and prior medication.  
Test product; dose and 
mode and duration of 
administration: 
The patients will receive investigational medicinal products (IMP) according to 
the randomization schedule and table below. 
Arm 
IMP 
Route 
Daily dose 
Dosage 
regimen 
A 
Ema-
palumab 
i.v. 
infusion 
Day 1: 6 mg/kg 
Days 4, 7, 10, 13: 3 mg/kg 
Every 3rd day 
for in total 5 
infusions 
B 
Ana-
kinra 
i.v. 
infusion 
Days 1-15: 400 mg/day in 
total, divided into 4 doses 
given every 6 hours 
4 times daily for 
15 days 
C 
None  
N/A 
N/A 
N/A 
 
 
Prophylactic Therapy: 
For patients randomized to emapalumab, prophylaxis for Herpes Zoster virus 
infection has to be in place from the day before initiation of emapalumab 
treatment until end of study 
Concomitant Therapy: 
Concomitant use of IL-6 inhibitors (e.g., tocilizumab), non-anakinra IL-1 
inhibitors (e.g, canakinumab), TNF inhibitors and JAK inhibitors is not allowed. 
If any of these therapies are initiated at the discretion of the Investigator e.g., as 
rescue therapy due to worsening of the patient’s condition, then the patient should 
be withdrawn from study. 
Hydroxychloroquine, chloroquine, glucocorticoid treatment, antimicrobial 
therapy and prophylaxis are not limited. 
Analgesic treatment, transfusion of blood products, electrolyte and glucose 
infusions, i.v. parenteral nutrition, positive inotropic support, antibiotics, anti-
fungal and anti-viral treatments (e.g, remdesivir), ultrafiltration or hemodialysis, 
as well as general supportive care are permitted. 
Determination of sample 
size: 
The study will enroll a total of 54 patients, 18 per arm according to the 1:1:1 
randomization. Patients will be stratified based on glucocorticoid treatment at 
randomization to ensure an equal distribution between treatment arms.  
The sample size has been estimated based on the following assumptions: 
1. 
An overall one-sided significance level for efficacy of 0.097 (9.7%) 
and a power of 74% for each comparison under the assumption that 
the true success rates are 50% in the SoC group increasing to 80% in 
the emapalumab or anakinra groups. 
2. 
The study will consist of two stages, with equal numbers of patients 
randomised into Stage 1 and into Stage 2 per treatment arm. 
3. 
There is the potential to stop for futility of emapalumab or anakinra 
(or both) at the end of Stage 1. 
4. 
The futility rule for stopping at the end of Stage 1 is binding. 

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Clinical Study No: Sobi.IMMUNO-101 
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More specifically: 
1. 
The emapalumab or anakinra arm (or both) will be stopped at the end 
of Stage 1 for futility if the one-sided p-value in favour of 
emapalumab/anakinra is > 0.690. 
2. 
The emapalumab or anakinra arm (or both) will be stopped for 
efficacy at the end of Stage 1 if the one-sided p-value in favour of 
emapalumab/anakinra is < 0.025. 
If the trial continues to Stage 2, efficacy will be declared at the end of Stage 2 if 
the one-sided p-value in favour of emapalumab/anakinra is < 0.159. 
Statistical methods: 
 
For the analysis of the primary endpoint, each of the pairwise comparisons, 
emapalumab/anakinra versus standard of care, at both the end of Stage 1 and at 
the end of Stage 2, will be undertaken using Fishers Exact test comparing the 
proportion of patients with treatment success. The p-value calculations will be 
supplemented by the presentation of one-sided exact confidence intervals. A 
sensitivity analysis of the primary endpoint will also be conducted, using exact 
logistic regression adjusting for the stratification factor concurrent glucocorticoid 
treatment. 
Analysis of the time to mechanical ventilation, overall survival, and time to 
hospital discharge, respectively, will be undertaken by plotting Kaplan-Meier 
curves for each of the 3 treatment groups and by pairwise comparisons 
(emapalumab/anakinra versus standard of care) using the logrank test. Hazard 
ratios will be estimated using the Cox proportional hazards model and these will 
be presented together with 90% two-sided confidence intervals. 
Change from baseline in MEWs score at Day 15 will be analysed using analysis 
of covariance (ANCOVA) including treatment arm as a fixed factor and baseline 
MEWs score as a covariate. Least square mean change per group, associated 90% 
two-sided CI, and p-values for the comparison vs. standard of care, will be 
presented. 
All efficacy analyses will be conducted on the modified intention-to-treat (mITT) 
population which will comprise all randomized patients except patients who did 
not receive study treatment or patients who tested negative to SARS-CoV-2 
diagnosis by PCR testing.  
 

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Emapalumab/Anakinra 
 
Clinical Study No: Sobi.IMMUNO-101 
Confidential 
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Schedule of Event (for a detailed version, please refer to Section 5.5.1.1) 
ASSESSMENT 
SCREENING 
TREATMENT PERIOD 
Early 
follow-up 
FOLLOW-UP PERIOD  
Up to 72h 
prior to  
Visit 1 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8/TC  
Visit 9/TC 
Day 1 
(Baseline) 
Day 4 
Day 7 
Day 10 
Day 13 
Day 15  
(± 1 day) 
Day 28  
(± 3 day) 
Week 6  
(± 5 days) 
Week 10 
(± 5 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
TB screening 
X 
 
 
 
 
 
 
 
 
 
PCR SARS-CoV-2 
X 
 
 
 
 
 
 
 
 
 
Patient information 
X 
 
 
 
 
 
 
 
 
 
Symptom onset information 
X 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
Vital signs assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECG assessment 
X 
 
 
 
 
 
X 
X 
 
 
HRCT scan or X-ray of chest 
X 
 
 
 
 
 
X 
X 
 
 
Laboratory assessments (local) 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urine pregnancy test 
X 
 
 
 
 
 
X 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
IMP administration 
 
X------------------------------------------------------------------------X 
 
 
 
Concomitant medication incl 
background therapy 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Pulmonary function 
 
X 
X 
X 
X 
X 
X 
X 
 
 
PaO2/FiO2 
X 
 
 
 
 
 
X 
X 
 
 
Resting SpO2 (3 times per day) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Hemogasanalysis 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Oxygen supplementation 
 
X 
X 
X 
X 
X 
X 
X 
 
 
MEWS score 
 
X 
 
 
 
 
X 
X 
 
 
Survival 
 
 
 
 
 
 
 
X 
X 
X 
Time to hospital discharge 
 
 
 
 
 
 
 
X 
X 
X 
Clinical status 7 point ordinal 
scale 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarkers 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Emapalumab/Anakinra 
 
Clinical Study No: Sobi.IMMUNO-101 
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Version 7.0 Final Protocol, Date 24 Jun 2020 
 
 
Schedule of Event (for a detailed version, please refer to Section 5.5.1.1) 
ASSESSMENT 
SCREENING 
TREATMENT PERIOD 
Early 
follow-up 
FOLLOW-UP PERIOD  
Up to 72h 
prior to  
Visit 1 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8/TC  
Visit 9/TC 
Day 1 
(Baseline) 
Day 4 
Day 7 
Day 10 
Day 13 
Day 15  
(± 1 day) 
Day 28  
(± 3 day) 
Week 6  
(± 5 days) 
Week 10 
(± 5 days) 
PK: emapalumab/anakinra serum 
concentration  
 
X 
X 
X 
X 
X 
X 
X 
X  
X  
Immunogenicity  
 
X 
 
 
 
 
X 
X 
X 
X 
Viral shedding 
 
X 
 
 
X 
 
X 
X 
X 
X 
Abbreviations: CPAP, continuous positive airway pressure; ECMO, extracorporeal membrane oxygenation; FiO2, fraction of inspired oxygen; HRCT, high resolution computed tomography; IMP, 
Investigational Medicinal Product; MEWS, modified early warning system; PaO2, partial pressure of oxygen; SpO2, peripheral capillary oxygen saturation 
 

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1 
Abbreviations and definition of terms 
1.1 
List of abbreviations and definitions 
Term 
Definition 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
AIFA 
The Italian national competent authority 
AOSD 
Adult onset Still’s disease 
AST 
aspartate aminotransferase  
ALT 
Alanine aminotransferase 
Baseline 
Before study drug administration at Visit 1 (Day 1) 
CAPS 
Cryopyrin-associated periodic syndrome 
CDASH 
Clinical data acquisition standards harmonization 
CDISC 
Clinical data interchange standards consortium 
CPAP 
Continuous positive airway pressure 
CRO 
Contract research organization 
CRF 
Case report form 
CRP 
C-reactive protein 
CT 
Computed tomography 
CXCL9 
Chemokine (C-X-C Motif) ligand 9 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
FiO2 
Fraction of inspired oxygen 
GCP 
Good clinical practice 
Hb 
Hemoglobin 
HLH 
hemophagocytic lymphohistiocytosis 
pHLH 
Primary hemophagocytic lymphohistiocytosis 
sHLH 
Secondary hemophagocytic lymphohistiocytosis 
ICH 
International council for harmonisation 

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IEC 
Independent ethics committee 
IL 
Interleukin 
IL-1Ra 
Interleukin 1 receptor antagonist 
IMP 
Investigational medicinal product 
IFNγ 
Inteferon gamma  
IRB 
Institutional review board 
IRS 
Interactive response system  
i.v. 
Intravenous 
LDH 
Lactate dehydrogenase 
MAS 
Macrophage activation syndrome 
MedDRA 
Medical dictionary for regulatory activities 
MEW score 
The modified early warning score 
Nab 
Neutralizing antibodies  
NOMID 
Neonatal-onset multisystem inflammatory disease 
NYHA 
New York heart association 
PaO2 
Partial pressure of oxygen 
PLT 
Platelets 
RA 
PCR 
Rheumatoid arthritis 
Polymerase chain reaction 
PK 
Pharmacokinetic 
RBC 
Red blood cells 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
s.c. 
Subcutaneous 
SJIA 
Systemic juvenile idiopathic arthritis 
Sobi 
Swedish Orphan Biovitrum AB (publ) 
SoC 
Standard of care 
SOP 
Standard operating procedure 
SpO2 
Peripheral capillary oxygen saturation 

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SRC 
Safety review committee 
SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Tuberculosis 
TNF 
Tumor necrosis factor 
WBC 
White blood cells 
 
 

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2 
Ethics 
2.1 
Independent ethics committee and institutional review board 
It is the responsibility of the investigator to obtain approval of the study protocol, possible 
amendments and the written subject information and informed consent form from the 
IEC/IRB.The investigator should file all correspondence with the IEC/IRB. Copies of IEC/IRB 
correspondence and approvals should be forwarded to Swedish Orphan Biovitrum (Sobi) or to 
the CRO as applicable.  
2.2 
Ethical conduct of the study 
This study will be conducted in compliance with this protocol, the ICH GCP [1], applicable 
regulatory requirements, and in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki) [2]. 
It should be noted that due to the urgency of the situation the Sponsor has for this protocol 
requested and been granted certain exemptions in connection to the approval in Italy to what is 
required for a Clinical Trial Application, certain ICH GCP requirements and when conducting a 
clinical trial (see Appendix 3). A study exemption to AE reporting is included in the study 
protocol in order to minimize clinical burden during the SARS-CoV-2 pandemic, limiting 
reporting to SAEs, AEs leading to premature discontinuation of study treatment, and AEs of 
special interest as described in the protocol (Section 5.5.4.3.1).  
2.3 
Patient information and consent 
It is the responsibility of the investigator to give each patient (or the patient’s acceptable 
representative) prior to any study-related activities, full and adequate verbal and written 
information regarding the objective and procedures of the study and the possible risks involved. 
The patients must be informed about their right to withdraw from the study at any time. The 
written patient information and/or informed consent form must not be changed without prior 
discussion with Sobi. Before any revisions are implemented, the revised written patient 
information and/or informed consent form must be approved by the IEC/IRB. 
It is the responsibility of the investigator to obtain signed informed consent (or witnessed verbal 
consent according to applicable regulations) from all patients prior to any study-related activities. 
The patients should receive a copy of the written information and the signed informed consent 
form. 

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3 
Introduction 
3.1 
Background 
This protocol has been prepared in response to the request formulated by Prof. Franco Locatelli 
(current President of the Italian Consiglio Superiore di Sanità and member of the Scientific 
Committee of the Italian Civil Protection, previously serving as Principal Investigator for the 
European development of emapalumab in children with primary HLH), and the Scientific 
Director of the National Institute for Infectious Diseases (INMI) Lazzaro Spallanzani, Prof. 
Giuseppe Ippolito. INMI is the only IRCCS (national institute for research and care of the Italian 
Ministry of Health) fully devoted to Infectious disease and as WHO-CC for diagnosis, research, 
care and training against highly infectious diseases. Both are members of the Scientific 
Committee of the Italian Civil Protection and are working in strict collaboration with the Italian 
national competent authority (AIFA) and are committed to investigate, among others, the use of 
emapalumab and anakinra, in patients suffering from the SARS-CoV-2 infection and 
experiencing respiratory distress. 
For the preparation of this protocol, expertize in hyperinflammation, in the treatment of cytokine 
release syndromes, and in the treatment of infection diseases, has been provided by Franco 
Locatelli, Fabrizio De Benedetti and Giuseppe Ippolito, together with contribution of the many 
physicians currently involved in the treatment of patients infected with SARS-CoV-2 in Italy.  
Following discussions with the FDA and given the global urgency to develop treatment for 
patients with SARS-CoV-2 infection and experiencing respiratory distress, the study protocol 
has been amended to include US study sites and patients. The current study is intended to 
provide proof of concept for the treatment of anakinra and/or emapalumab as add-on to standard 
of care, and to guide the plan for further development.  
The objective of this study is to investigate new possibilities to reduce the number of patients 
requiring mechanical ventilation. This is intended to address the most urgent need to preserve the 
access to intense care unit support to the lower possible number of patients and may potentially 
reduce mortality. 
3.2 
Study rationale 
As shown by the data available in the most recent literature generated from the Chinese 
experience [4, 5, and 6], and by the most recent data made available by the different Italian 
hospitals responsible for the management of these patients (unpublished data generated in the 
laboratory of Immunology of the National Institute for Infectious Diseases and the Laboratory of 
ImmunoRheumatology of the Ospedale Pediatrico Bambino Gesù), hyper-inflammation, caused 
by a cytokine storm resulting from an exaggerated response of the immune system to the 
presence of the virus, is considered to represent one of the most important negative prognostic 
factor in patients infected with SARS-CoV-2. The inclusion criteria for hyperinflammation used 
in this protocol is based on the analysis of routine blood chemistry data obtained from patients 
with SARS-CoV-2 infection. This criterion has been designed with high sensitivity (>90%) for 

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patients who require ICU admission. This constitute the rationale for testing drugs specifically 
targeted to reduce the cytokine storm. 
3.3 
Potential risks and benefits 
Anakinra is a recombinant form of the human IL-Ra, r-metHuIL-1Ra, which is produced by 
recombinant DNA technology in an E. coli expression system. Therapeutically, anakinra 
neutralizes the biological activity of IL-1 (IL-1α and IL-1β) by competitively inhibiting its 
binding to the IL-1RI. 
Kineret (anakinra) was first approved for treatment of RA in the US in 2001 and subsequently in 
the EU/EEA in 2002. More than 3000 patients were included in this development program.  
In 2012, an sBLA on anakinra for treatment of NOMID was approved in the US. Kineret is also 
approved for treatment of CAPS (in EU/EEA, Israel and Australia), Still’s disease, including 
SJIA and AOSD (in EU/EEA), FMF (in EU/EEA), and SJIA (in Australia). 
The initial IND for anakinra was granted in 1991. The estimated cumulative exposure to 
anakinra in completed company sponsored clinical studies up to 1 May 2018 is 6404 subject-
years in 8518 subjects with various indications. 
Anakinra is administered s.c. at doses of 100 mg/day (RA) or in weight-based doses of up to 8 
mg/kg/day (NOMID). In clinical studies in sepsis, doses up to 2 mg/kg/hour i.v. over 72 hours 
were administered to >500 patients and were well tolerated. For additional information of i.v. 
administration of anakinra, see Section 5.4.4.1. 
Based on the most recent PSUR (with data from May 1994 through to May 2019) the estimated 
exposure to anakinra in completed company sponsored clinical studies is 6404 subject-years in 
8518 subjects. The cumulative post-marketing exposure is estimated to 113 414 patient years.  
The safety profile of anakinra has been consistent across indications, age groups, and doses 
studied; this includes data that have been reported in the literature for off-label indications. The 
safety profile has remained stable also when anakinra has been studied in long-term safety 
studies and in patients with various co-morbidities. There are no indications of increasing AE 
rates over time. The most common AEs are non-serious, mostly mild to moderate injection site 
reaction that usually occur early and resolve during continued anakinra treatment. No dose-
limiting toxicities have been observed in clinical studies or during post-marketing use and the 
maximum tolerated dose has not been established. There are no indications of changes to the 
safety profile even when very high doses are administered. 
For the most recent information about anakinra, please refer to the current Summary of Product 
Characteristics (SPC). 
Emapalumab (previously referred to as NI-0501, trade name Gamifant®) is a fully human 
Immunoglobulin G1 (IgG1) Anti-Interferon gamma (IFNγ) monoclonal antibody that binds to 
and neutralizes IFNγ.  
Emapalumab binds to both soluble and receptor (IFNγR1)-bound forms of IFNγ. 

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Emapalumab is in development for the treatment of primary and secondary forms of HLH. The 
benefit expected from the targeted neutralization of IFNγ by emapalumab has been validated by 
the FDA approval in November 2018 of emapalumab for the treatment of patients with primary 
HLH who have refractory, recurrent or progressive disease or intolerance with conventional 
HLH therapy. The safety profile of emapalumab has been assessed as acceptable, and no post-
marketing commitments have been requested by the FDA with regard to safety. 
Since the start of the clinical development program for emapalumab, 103 patients have received 
emapalumab in clinical trials and through compassionate use. Furthermore, 70 patients have 
been treated to date in the US following FDA approval, and post-marketing surveillance has not 
revealed any additional safety concerns with the use of emapalumab. 
Based on the analyses conducted to date, no sign of any off-target effect of emapalumab has 
been detected. 
Multiple medications have been administered concomitantly with emapalumab and no evidence 
of significant drug-drug interactions has been reported so far. 
For the most recent information about emapalumab, please refer to the current Investigator´s 
Brochure (version 10.0, dated 24 JAN 2020). 
The overall assessment is that the benefit of using anakinra and emapalumab as add-on to 
standard of care in patients diagnosed with SARS-CoV-2 infection outweighs the risks. 
4 
Study objectives and endpoints 
4.1 
Primary objective  
The primary objective of this study is to assess the effect of emapalumab and anakinra on 
hyperinflammation and pulmonary function in patients with SARS-CoV-2 infection. 
4.1.1 
Primary endpoint 
The primary endpoint is treatment success, defined as not requiring any of the following by Day 
15: 
• Invasive mechanical ventilation or 
• Extracorporeal membrane oxygenation (ECMO). 
4.1.2 
Secondary endpoints supporting the primary objective 
• Time to mechanical ventilation. 
• Change from baseline in MEWs score. 
• Change from baseline in resting SpO2. 
• Change from baseline in PaO2/FiO2. 

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• Change from baseline in hemogasanalysis. 
• Change from baseline in oxygen supplementation. 
• Amelioration of the findings of high-resolution CT scan or X-ray of the chest. 
• Change from baseline in hyperinflammatory parameters during treatment until Day 15 
with measurements performed every 3 days: 
o Ferritin  
o LDH  
o D-dimers  
• Change from baseline in other relevant laboratory parameters during treatment until Day 
15 with measurements performed every 3 days: 
o WBC with differential counts 
o RBC 
o Hb 
o Platelet count 
o Fibrinogen 
o Complement C3/C4 
o Prothrombin time 
o Cardiac troponin 
o Liver tests (AST, ALT, total bilirubin levels) 
o CRP  
o Creatinine  
o Electrolytes (Sodium, Potassium and Calcium) 
o Glucose 
• Overall survival. 
• Time to hospital discharge. 
4.2 
Secondary objective  
The secondary objective of this study is to evaluate the safety and tolerability profile, including 
evaluation of the immunogenicity of emapalumab and anakinra, of intravenous (i.v.) 
administrations of emapalumab and anakinra in patients with SARS-CoV-2 infection. 
4.2.1 
Secondary endpoints supporting the secondary objective  
Safety endpoints of this study are: 
• Treatment-emergent serious adverse events (SAEs). 
• Adverse events leading to premature discontinuation of study treatment. 
• Infusion related reactions including anaphylactic/anaphylactoid reactions. 
• Treatment emergent adverse events of special interest: 
o Emapalumab treatment group: All new infections. 
o Anakinra treatment group: Severe neutropenia.  
• Treatment-emergent laboratory abnormalities. 

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• Presence of anti-drug antibodies (ADAs) and neutralizing antibodies (Nabs) against 
emapalumab and anakinra. 
•  
4.3 
Exploratory objective 
An exploratory objective of this study is to evaluate the clinical status based on a 7-point ordinal 
scale. 
An exploratory objective of this study is to evaluate the PK of emapalumab and anakinra.   
An exploratory objective of this study is to assess the effect of anakinra and emapalumab on 
CXCL9, IFNγ, IL-1, IL-6, sIL-2R and selected biomarkers relevant for hyperinflammation.  
4.3.1 
Exploratory endpoints  
Clinical status based on a 7-point ordinal scale.  
The scale consists of the the following categories:   
1. Death 
2. Hospitalized, requiring invasive mechanical ventilation or extracorporeal  
       membrane oxygenation (ECMO) 
3. Hospitalized, requiring non-invasive ventilation or high flow oxygen devices 
4. Hospitalized, requiring supplemental oxygen 
5. Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care  
6. Hospitalized, not requiring supplemental oxygen - no longer requires ongoing  
      medical care 
7. Not hospitalized 
 
PK parameters will be calculated for emapalumab and anakinra by non-compartmental analysis 
and population analysis, as applicable. 
 
PD biomarkers: Change from baseline in CXCL9, IFNγ, IL-1, IL-6, sIL-2R and selected 
biomarkers relevant for hyperinflammation. 
5 
Investigational plan 
5.1 
Overall study design and plan 
This is a randomized, open-label, parallel group, 3-arm multicenter study to investigate the 
efficacy and safety of emapalumab and anakinra in reducing hyper-inflammation and respiratory 
distress in adult patients with a documented SARS-CoV-2 infection. 

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The study consists of screening, a 2-week treatment period and an 8-week follow-up period.  
The 2-week treatment period is open, and the patients will be randomized to treatment with 
emapalumab, anakinra or standard of care in a 1:1:1 ratio. Emapalumab will be administered as 
i.v. infusions every 3rd day for a total of 5 infusions (Days 1, 4, 7, 10, 13). Anakinra will be 
administered as 4-times daily i.v. infusions for 15 days (Days 1 to 15). The primary endpoint will 
be evaluated at Day 15. 
An early on-site follow-up visit will be performed at Day 28. A follow-up by visit or phone call 
will be performed 4 and 8 weeks after the end of the treatment period (Weeks 6 and 10).  
The study duration for an individual patient will not exceed 10 weeks. The end of the study is 
defined as last patient last follow-up visit/phone call. 
 
Figure 1 
 
The study design has a total sample size of 54 patients and consists of two stages. At the end of 
Stage 1, the success rates are compared between each of the two treatment arms and standard of 
care and there is the potential to stop for futility. 
A data review committee composed of independent experts in intensive care, inflammation, 
infection diseases will be involved in study oversight, safety monitoring and interpretation of the 
study results. 
A safety review committee consisting of internal Sobi members (voting) and coordinating 
investigators (non-voting) members is established to monitor study participant safety in the 
study. Clinical safety information will be monitored and reviewed on a continuous basis by the 
SRC from study start to database lock. Details are described in a separate written operating 
procedures for the SRC.  
In patients showing worsening of clinical condition, independently of the treatment arm, the 
Investigator is completely free to decide to introduce any drug considered necessary for a given 
patient as rescue treatment. 

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5.2 
Discussion of study design, including the choice of control groups 
5.3 
Selection of study population 
5.3.1 
Inclusion criteria 
A patient must fulfill the following criteria in order to be included in the study: 
1. Signed informed consent provided by the patient, or by the patient’s legally authorized 
representative(s), as applicable. 
2. Documented presence of SARS-CoV-2 infection as per hospital routine.  
3. Age > 18 to < 85 years at the time of screening. 
4. Presence of respiratory distress, defined as: 
a. PaO2/FiO2 < 300 mm Hg and >200 mm Hg or 
b. RR ≥30 breaths/min or 
c. SpO2 <93% in air at rest. 
Note: Patients given CPAP ventilator support are eligible for inclusion. 
5. Presence of hyperinflammation defined as: 
a. Lymphocyte counts: 
- < 1000 cells/µL, in patients who have not received systemic glucocorticoids for 
at least 2 days prior to the assessment of the lymphocyte count  
- < 1200 cells/µL, in patients who have received systemic glucocorticoids for at 
least 2 days prior to the assessment of the lymphocyte count  
and 
b. One of the following three criteria: 
i. Ferritin > 500ng/mL 
ii. LDH > 300 U/L 
iii. D-Dimers > 1000 ng/mL 
5.3.2 
Exclusion criteria 
The presence of any of the following will exclude a patient from inclusion in the study: 
1. Patients in mechanical ventilation or with MEWS score >4 with evidence of moderate or 
above ARDS (Berlin definition) or severe respiratory insufficiency or evidence of rapid 
worsening (respiratory distress requiring mechanical ventilation or presence of shock or 
presence of concomitant organ failure requiring ICU admission). 

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Note: For the evaluation of patient eligibility, temperature will not be considered in the 
calculation of the total MEWS score since presence of fever is a hallmark of SARS-CoV-2 
infection. 
2. Impairment of cardiac function defined as poorly controlled heart diseases, such as 
NYHA class II (mild) and above, cardiac insufficiency, unstable angina pectoris, 
myocardial infarction within 1 year before enrollment, supraventricular or ventricular 
arrhythmia need treatment or intervention. 
3. Severe renal dysfunction (estimated glomerular filtration rate ≤ 30mL/min/1.73 m2) or 
receive continuous renal replacement therapy, hemodialysis, or peritoneal dialysis. 
4. Uncontrolled hypertension (seated systolic blood pressure >180mmHg, or diastolic blood 
pressure >110mmHg) . 
5. Administration of plasma from convalescent patients who recovered from SARS-CoV-2 
infection. 
6. Clinical suspicion of active or latent tuberculosis. 
7. History of hypersensitivity or allergy to any component of the study drug. 
8. Pregnant women. 
9. Existence of any life-threatening co-morbidity or any other medical condition which, in 
the opinion of the investigator, makes the patient unsuitable for inclusion. 
10. Enrollment in another concurrent clinical interventional study, or intake of an 
investigational drug within three months or 5 half-lives prior to inclusion in this study, if 
considered interfering with this study objectives as assessed by the Investigator. 
11. Foreseeable inability to cooperate with given instructions or study procedures. 
12. Clinical suspicion of active mycobacteria histoplasma capsulatum, herpes zoster, 
salmonella and shigella Infections.  
13. Patients with liver dysfunction defined as AST or ALT > 5 × ULN  
5.3.3 
Withdrawal of patients from treatment or study 
5.3.3.1 
Withdrawal from treatment 
A patient should be withdrawn from the study treatment if, in the opinion of the Investigator, it is 
medically necessary, or if it is the wish of the patient.  
When a patient is withdrawn, the date of last IMP administration and the date and reason for 
treatment withdrawal should be clearly described in the relevant sections of the CRF. If a patient 
is removed from treatment because of an AE, the reason for treatment withdrawal should always 
be stated as ‘adverse event’ irrespective of whether this was the investigator’s or the patient’s 
decision. 
The patient will continue to participate in the study without taking study treatment. 

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5.3.3.2 
Withdrawal from study 
Whenever possible and irrespective of the reason for withdrawal, the patient should be examined 
as soon as possible. Relevant samples should be obtained and all relevant assessments should be 
completed, preferably according to the schedule for Visit 6 (Day 15). The CRF should be 
completed as far as possible. Date and reason for the study withdrawal should be clearly 
described in the CRF. 
5.3.4 
Replacement of withdrawn patients 
Patients withdrawn from the study will not be replaced.  
5.3.5 
Screening failures 
Screening failures are defined as patients who consent to participate in the study but are not 
subsequently randomized into the study. A minimal set of screening failure information is 
required which includes demographics, reason for screen failure and failed eligibility criteria. 
Patients who do not meet the criteria for participation in this study (screening failure) may not be 
rescreened.  
5.4 
Treatments 
5.4.1 
Treatments administered  
The patients will receive investigational medicinal products (IMP) according to the 
randomization schedule, see Table 1.  
Table 1 
Investigational medicinal products 
Arm 
Investigational 
product 
Dosage 
form 
Route 
Daily dose 
Dosage regimen 
A 
Emapalumab 
Solution 
i.v. 
infusion 
Day 1: 6 mg/kg 
Days 4, 7, 10, 13: 3 mg/kg 
Every 3rd day for in 
total 5 infusions 
B 
Anakinra 
Solution 
i.v. 
infusion 
Days 1-15: 400 mg/day in 
total, divided into 4 doses 
given every 6 hours 
4 times daily for 15 
days 
C 
None  
N/A 
N/A 
N/A 
N/A 
 
5.4.2 
Identity of investigational medicinal products 
Emapalumab and anakinra will be supplied to the study sites as open-label supplies. 

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Possible deficiencies related to the handling and quality of the IMPs should be reported to the 
study monitor and also directly to complaints@sobi.com. 
5.4.2.1 
Emapalumab 
The IMP emapalumab is delivered as a sterile concentrate for infusion, prefilled in single-use 
glass vials which require a dilution prior to administration. The concentrate of emapalumab in 
the solution is 5 mg/mL. The solution contains no antimicrobial preservative, and therefore each 
vial must be used only once. 
Emapalumab should be stored between 2 and 8°C (36 and 46°F) in a secure area at the study 
sites. Further instructions on handling and storage of emapalumab are available in the IMP 
manual.  
Emapalumab is manufactured by a third-party manufacturing facility duly qualified by Sobi AG 
and is supplied as described in the IMP Manual.  
Labeling will comply with national regulatory requirements. 
5.4.2.2 
Anakinra 
The IMP anakinra is delivered as a sterile solution for injection, prefilled in a single-use syringe 
with the strength 100 mg. The total volume of injection is 0.67 mL and the concentration of 
anakinra in the solution is 150 mg/mL.  
Anakinra must be stored at refrigerated conditions at 2-8 °C (36°-46°F) in a secure area at the 
study sites. Further instructions for handling and storage of the IMP anakinra are available in the 
IMP manual.  
The anakinra drug substance is manufactured by Boehringer Ingelheim (Vienna, Austria) or by 
Pfizer (Strängnäs, Sweden) and anakinra drug product is manufactured by Patheon Italia SpA 
(Monza, Italy).  
Labeling will comply with national regulatory requirements. 
5.4.3 
Method of assigning patients to treatment groups 
The different treatment groups are; 
Arm A: Emapalumab as add on to standard of care 
Arm B: Anakinra as add on to standard of care  
Arm C: Standard of care only 
The ratio between the treatment groups is 1:1:1, i.e., the same number of patients will be 
randomized to emapalumab, anakinra, or standard of care. Patients will be stratified based on 
glucocorticoid treatment at randomization to ensure an equal distribution between treatment 
arms.The randomization numbers are generated in blocks. Each block includes the three 
treatment groups per the ratio described above. An IWRS will be used for the randomization. 

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5.4.4 
Selection of doses 
5.4.4.1 
Dose selection rationale for anakinra 
Anakinra is approved for the chronic treatment of a number of inflammatory diseases as a 
subcutaneous treatment (at doses of 100 mg/day or in weight-based doses of up to 8 mg/kg/day). 
The i.v. administration of anakinra has been studied in clinical trials in healthy volunteers and in 
critically ill patients with sepsis and hyper-inflammation at variable i.v. doses up to 3500 mg/day 
over 72 hours: e.g., 2 mg/kg/hour, 20 mg/kg/day (<40 kg) and 916 mg/day (> 40kg), bolus of 
100 mg followed by infusion of 2 mg/kg/hour. No safety concerns emerged in these studies [7, 8, 
9, 10, and 11]. 
A study in children with systemic onset juvenile arthritis complicated by refractory macrophage 
activation syndrome is currently ongoing (NCT02780583) in which anakinra is administered at 
dose of 10 mg/kg/day to a maximum of dose of 200 mg/day divided every 12 hours (for children 
≤40 kg) or 5 mg/kg/day up to a maximum dose of 400 mg/day divided every 6 hours (children > 
40 kg and adults). This dosing schema reflects the dose at which anakinra is administered, 
although off label, in children affected by this severe disease, as reported in a number of case 
studies. 
Since the start of the current clinical study, there is emerging data based on anakinra given by i.v 
infusions in treament of cytokine storm syndromes (21), and emerging data of anakinra i.v 
administration studied in the SARS-CoV-2 setting (22). 
Based on the above, in this study anakinra is administered at a total dose of 400 mg per day, 
divided in 4 i.v. doses of 100 mg every 6 hours. 
5.4.4.2 
Dose selection rationale for emapalumab 
Preliminary data on inflammatory makers in blood, e.g., D-dimer, LDH and ferritin [4, and 
unpublished data generated in the laboratory of Immunology of the National Institute for 
Infectious Diseases and the Laboratory of ImmunoRheumatology of the Ospedale Pediatrico 
Bambino Gesù] indicate that patients with SARS-CoV-2 infection have longer and more marked  
inflammatory response. This seems to be more evident in patients with severe disease. These 
markers, though elevated, appear to be less elevated than what is generally observed in systemic 
onset Juvenile Idiopathic Arthritis (sJIA) patients who develop Macrophage Activation 
Syndrome (MAS), a form of secondary HLH. Furthermore, their evolution over time seem to be 
also less rapid. Of note, it must be mentioned that these observations in blood may not fully 
reflect the amount of IFN released in the inflamed lungs. 
The emapalumab dosing scheme used in the ongoing NI-0501-06 study in sJIA/MAS patients 
(NCT03311854) foresees an initial dose of 6 mg/kg followed by 3 mg/kg every 3 days. The 
available data in the 9 patients who have completed treatment to date indicate the achievement of 
complete response in all the patients with no relevant safety or tolerability concern [12]. In the 
trial in primary HLH, doses up to 10 mg/Kg/infusion have been used again with no relevant 
safety or tolerability concern [16]. 

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Based on the above, an initial emapalumab dose of 6 mg/kg followed by 3 mg/kg every 3 days 
has been selected for the present study in SARS-CoV-2 infected patients.  
This dose is considered appropriate to give the best chance to demonstrate efficacy in the 
specific patient population of this study, taking into account (I) the favourable safety profile of 
emapalumab not only in secondary, but also in primary HLH, (II) the life-threatening condition 
to be treated, (III) the low number of patients to be enrolled in the study (n=18), (IV) and the 
extremely challenging situation which the epidemic of SARS-CoV-2 infection represents.   
5.4.4.3 
Rationale for stratifying the use of glucocorticoids  
As glucocorticoids are one of the main first line anti-inflammatory treatments in secondary HLH, 
they have been suggested as one of the potential treatments for patients with severe SARS-CoV-
2 infection [14]. Further to the relevance of the hyper-production of inflammatory cytokines in 
this infection, initial promising data have been reported with the use of IL-6 targeted therapies, 
namely tocilizumab, in the treatment of patients with SARS-CoV-2 infection [15]. Noteworthy, 
in this report all patients treated with tocilizumab also received glucocorticoids.  
The use of glucocorticoids in patients with SARS-CoV-2 differs between regions and countries. 
Based on the experience accumulated so far in Europe, glucocorticoids have become part of 
standard of care for SARS-CoV-2 patients with hyperinflammation. Meanwhile, in US 
glucocorticoids currently seem not to be widely used in the treatment of patients with SARS-
CoV-2 and hyperinflammation. 
Interim WHO guidance argues against the use of glucocorticoids in the treatment of patients with 
SARS-CoV-2 infection [19]. This view is supported by the Infectious Diseases Society of 
America Guidelines on the Treatment and Management of Patients with COVID-19 [20].  
Glucocorticoids are anti-inflammatory and the potential use of glucocorticoids could have an 
impact on biomarkers of hyper-inflammation and potentially also on the clinical outcome.  
Since the use of glucocorticoids will differ between regions study patients will be stratified based 
on glucocorticoid treatment at randomization to ensure an equal distribution between treatment 
arms. 
5.4.5 
Selection and timing of doses for each patient 
5.4.5.1 
Emapalumab 
Emapalumab will be administered by intravenous (i.v.) infusion over a period of 1 to 2 hours 
depending on the volume to be infused, at an initial dose of 6 mg/kg.  
Emapalumab treatment will be continued at the dose of 3 mg/kg, every 3rd day until Day 13 i.e., 
Days 4, 7, 10 and 13. The following information will be recorded in the CRF for each 
emapalumab administration: date, start and end time, total dose infused, and, if infusion was 
interrupted, reason for interruption. 

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Emapalumab must be prepared by a Pharmacist or other appropriately qualified staff member, 
specifically authorized by the Investigator/Pharmacist and appropriately licensed to perform the 
task. 
The specific dose to be administered for an individual infusion will be determined based on the 
patient´s body weight at screening. 
Full instructions for the preparation of emapalumab, including dilution steps and method for 
administration, are available in the IMP manual. 
The patient should receive the designated volume of the infusion material through an infusion 
pump over 1 to 2 hours depending on the volume to infuse. A 0.2 μm filter must be included in 
all infusion lines.  
It is recommended that an i.v. central line remains in place to ensure venous access during the 
treatment period.  
Since no data are available on the compatibility of emapalumab with other i.v. substances or 
additives, other medications/substances should not be added to the infusion material or infused 
simultaneously through the same i.v. line. If the same i.v. line is used for subsequent infusions of 
other drugs, the line should be flushed appropriately with saline before and after infusion of 
emapalumab. 
5.4.5.2 
Anakinra 
Anakinra will be administered by i.v. infusion at total dose of 400 mg per day, divided in 4 doses 
100 mg i.v. every 6 hours.  
Anakinra treatment will continue for 15 days i.e., Days 1 to 15. The following information will 
be recorded in the CRF for each anakinra administration: date, start and end time, total dose 
infused, and, if infusion was interrupted, reason for interruption. 
Before administration, the full content of the prefilled, single-use syringe (anakinra 100 mg) will 
be diluted in 100 mL saline. The i.v. administration of anakinra has to occur immediately after 
the preparation over an infusion period of 60 minutes. A particle reduction inline filter will be 
assembled with the infusion set. 
Full instructions for the preparation of anakinra are available in the IMP manual. 
5.4.6 
Blinding and unblinding 
This is an open study with no level of blinding. 
5.4.7 
Concomitant therapy 
5.4.7.1 
Prophylactic therapy 
For patients randomized to emapalumab, prophylaxis for Herpes Zoster virus infection has to be 
in place from the day before initiation of emapalumab treatment until end of study.  

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The prophylactic therapy will be recorded in the CRF.  
5.4.7.2 
Concomitant therapy 
Concomitant use of IL-6 inhibitors (e.g., tocilizumab), non-anakinra IL-1 inhibitors (e.g, 
canakinumab), TNF inhibitors and JAK inhibitors is not allowed. If any of these therapies are 
initiated at the discretion of the Investigator e.g., as rescue therapy due to worsening of the 
patient’s condition, then the patient should be withdrawn from study (see Section 5.3.3.2). 
Hydroxychloroquine, chloroquine, glucocorticoid treatment, antimicrobial therapy and 
prophylaxis are not limited. 
Analgesic treatment, transfusion of blood products, electrolyte and glucose infusions, i.v. 
parenteral nutrition, positive inotropic support, antibiotics, anti-fungal and anti-viral treatments 
(e.g, remdesivir), ultrafiltration or hemodialysis, as well as general supportive care are permitted. 
Other therapy considered necessary for the patient’s welfare may be given at the discretion of the 
Investigator.  
For patients taking other treatments that are substrates for CYP450 with a narrow therapeutic 
index (e.g. warfarin and phenytoin), the treating physician should make appropriate treatment 
adjustments and monitor the patient as deemed necessary.   
All relevant concomitant therapy, as defined by the Investigator, will be recorded in the CRF.  
5.4.8 
Treatment compliance 
The IMP administrations will be recorded in the CRF as described in Section 5.4.5. 
Product accountability records will be kept. The pharmacy and Investigator must maintain 
accurate records demonstrating date and amount of study drug(s) received, to whom and by 
whom administered or dispensed (patient-by-patient accounting), and accounts of returned study 
drug (s) and any study drug accidentally or deliberately destroyed. All unused study drug will be 
counted.  
At the end of the study, any remaining study drug (s) will be destroyed locally or returned to the 
depot for destruction. In either case, a certificate of destruction must be issued. 
5.5 
Efficacy and safety assessments 
5.5.1 
Study schedule 
5.5.1.1 
Schedule of events 

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Table 2 Schedule of Events 
ASSESSMENT 
SCREENING 
TREATMENT PERIOD 
Early FU 
FOLLOW-UP PERIOD  
Up to 72h 
prior to  
Visit 1 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8/TC  
Visit 9/TC 
Day 1 
(Baseline) 
Day 4 
Day 7 
Day 10 
Day 13 
Day 15  
(± 1 day) 
Day 28  
(± 3 days) 
Week 6  
(± 5 days) 
Week 10 
(± 5 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X1  
 
 
 
 
 
 
 
 
TB screening13 
X 
 
 
 
 
 
 
 
 
 
PCR SARS-CoV-214 
X 
 
 
 
 
 
 
 
 
 
Patient information2 
X 
 
 
 
 
 
 
 
 
 
Symptom onset information 
X 
 
 
 
 
 
 
 
 
 
Physical examination3 
X 
 
 
 
 
 
 
 
 
 
Vital signs assessment4 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECG assessment 
X 
 
 
 
 
 
X 
X 
 
 
HRCT scan or X-ray of chest 
X5 
 
 
 
 
 
X 
X 
 
 
Laboratory assessments (local)6 
X5 
X 
X 
X 
X 
X 
X 
X 
 
 
Urine pregnancy test7 
X 
 
 
 
 
 
X 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
IMP administration8 
 
X-------------------------------------------------------------------------X 
 
 
 
Concomitant medication incl 
background therapy9 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Pulmonary function10 
 
X 
X 
X 
X 
X 
X 
X 
 
 
PaO2/FiO2 
X 
 
 
 
 
 
X 
X 
 
 
Resting SpO2 (3 times per day) 
 
X 
X 
X 
X 
X 
X 
X18 
 
 
Hemogasanalysis 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Oxygen supplementation 
 
X 
X 
X 
X 
X 
X 
X 
 
 
MEWS score 
 
X 
 
 
 
 
X 
X 
 
 
Clinical status 7 point ordinal 
scale 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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ASSESSMENT 
SCREENING 
TREATMENT PERIOD 
Early FU 
FOLLOW-UP PERIOD  
Up to 72h 
prior to  
Visit 1 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8/TC  
Visit 9/TC 
Day 1 
(Baseline) 
Day 4 
Day 7 
Day 10 
Day 13 
Day 15  
(± 1 day) 
Day 28  
(± 3 days) 
Week 6  
(± 5 days) 
Week 10 
(± 5 days) 
Survival 
 
 
 
 
 
 
 
X 
X 
X 
Time to hospital discharge 
 
 
 
 
 
 
 
X 
X 
X 
Adverse events11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarkers12 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK: emapalumab/anakinra serum 
concentration15  
 
X 
X 
X 
X 
X 
X 
X 
X  
X  
Immunogenicity16 
 
X 
 
 
 
 
X 
X 
X 
X 
Viral shedding17 
 
X 
 
 
X 
 
X 
X 
X 
X 
Abbreviations: CPAP, continuous positive airway pressure; ECMO, extracorporeal membrane oxygenation; FiO2, fraction of inspired oxygen; HRCT, high resolution computed 
tomography; IMP, Investigational Medicinal Product; MEWS, modified early warning system; PaO2, partial pressure of oxygen; SpO2, peripheral capillary oxygen saturation 
During the treatment period (Days 1 to 15), clinical and laboratory assessments and procedures should preferably be performed before IMP administration. 
1Before study drug administration. 
2Includes demographics, medical and surgical history and prior medication. 
3Including recording of body weight and length. 
4Body temperature, blood pressure, heart rate, respiratory rate and oxygen saturation. 
5HRCT scan results and laboratory results already available in medical records at the time of informed consent can be used to confirm eligibility, if collected within 72 hours.   
6Ferritin, LDH, D-dimers. WBC with differential counts, RBC, Hb, Platelet count, Fibrinogen, Complement C3/C4, Prothrombin Time, Cardiac troponin, AST, ALT, total bilirubin levels, CRP 
and Creatinine. 
7Only applicable for females of childbearing potential. 
8Emapalumab will be administered once daily Days 1, 4, 7, 10 and 13 (Section 5.4.5.1). Anakinra will be administered 4 times daily for 15 days i.e., Day 1 to 15 (Section 5.4.5.2). 
9For details, see Section 5.4.7. 
10Requirement for invasive mechanical ventilation or ECMO. 
11Incidence, severity, causality and outcomes of treatment-emergent serious AEs, adverse events leading to premature discontinuation of study treatment and adverse events of 
special interest.  
12 PD biomarkers: CXCL9, IFNγ, IL-1, IL-6, sIL-2R. Samples to be collected Visit 1:pre-dose and thereafter at Visits 2, 3, 4, 5 and 6: end of infusion. (for anakinra treated patients; samples 
will only be collected in connection with  the first infusion per day) In addition, at Visits 8 and 9,  a PD biomarker sample will be collected in case the patient is coming to the clinic for 
these visits.   
13Local TB testing to confirm patient status. Test result are accepted post randomization not to delay treatment.  

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14Local PCR testing to confirm patient SARS-CoV-2 diagnosis. For sites where PCR is not part of hospital routine for confirming diagnosis/eligibility, test results are accepted post 
randomization not to delay treatment. 
15  PK blood samples will be collected at Visit 1: pre-dose and at end-of infusion (for anakinra after the first infusion per day), and thereafter at Visits 2, 3, 4, 5 and 6: at end-of infusion 
(for anakinra treated patients; samples will only be collected in connection with  the first infusion). In addition, for emapalumab treated patients at Visits 7. For Visit, 8 and Visit 9, a PK 
sample will be collected in case the patient is coming to the clinic for these visits.   
16     Immunogenicity samples  will be collected at Visit 1: Pre-dose and  at Visit 6 at end-of infusion (for anakinra after the first infusion per day), and at Visit 7.  For Visit 8 and Visit 9 
immunogenicity samples will be collected in case the patient is coming to the clinic for these visits.  
 
17   Viral shedding samples will be collected and stored for subsequent analysis.  
  18  If the patient is discharged before Visit 7, the resting SpO2  is only required 1 time per day. 

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5.5.1.2 
Screening 
Screening will occur up to 72 hours prior to Visit 1 (Baseline). The aim of the screening is to 
collect necessary data to confirm the patient’s eligibility and can be ongoing up the 
randomization of the patient at Visit 1. A signed informed consent form must be obtained from 
the patient prior to any study-related activities. However, HRCT scan results and laboratory 
results already available in medical records at the time of informed consent can be used to 
confirm eligibility, if collected within 72 hours. Please refer to Table 3 for the clinical and 
laboratory parameters to be collected during screening.  
Patients who do not meet the criteria for participation in this study (screening failure) may not be 
rescreened.  
5.5.1.3 
Visit 1, Baseline (Day 1) 
Once all inclusion and exclusion criteria have been reviewed and recorded, and the patient has 
been found eligible, the patient will be randomized into one of the treatment groups and the first 
dose of study drug will be administered accordingly (see Section 5.4.5). Please refer to Table 2 
for other clinical and laboratory parameters to be collected during the visit.  
During the treatment period (Days 1 to 15), clinical and laboratory assessments and procedures 
should preferably be performed before IMP administration. 
5.5.1.4 
Visits 2 to 5 (Days 4, 7, 10 and 13) 
Please refer to Table 2 for the clinical and laboratory parameters to be collected during these 
visits. For study drug administration schedule, see Section 5.4.5. 
Effort should be made to adhere to the schedule of assessment. However, a window of ±1 day 
will be allowed for all assessments scheduled for Visits 2 to 5. This does not include IMP 
administration. 
During the treatment period (Days 1 to 15), clinical and laboratory assessments and procedures 
should preferably be performed before IMP administration. 
5.5.1.5 
Visit 6 (Day 15) 
Please refer to Table 2 for the clinical and laboratory parameters to be collected during these 
visits. For study drug administration schedule, see Section5.4.5. 
Effort should be made to adhere to the schedule of assessment. However, a visit window of ±1 
day will be allowed for Visit 6 (Day 15). 
During the treatment period (Days 1 to 15), clinical and laboratory assessments and procedures 
should preferably be performed before IMP administration 
The primary endpoint will be evaluated at Visit 6 (Day 15). 
5.5.1.6 
Visit 7 (Day 28) 
An early follow-up visit will be performed at Day 28. 

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Please refer to Table 2 Schedule of EventsTable 2 for the clinical and laboratory parameters to 
be collected during this visit. If the patient is discharged from the hospital before this visit, 
efforts should be made to adhere to the visit window of ±3 days.  
5.5.1.7 
Visits 8 and 9, Follow-up (Weeks 6 and 10) 
These visits can be conducted either as a follow-up telephone call or in-person visit, if the patient 
is still hospitalized. Please refer to Table 2 for the clinical parameters to be collected during the 
visits.  
A window of ±5 days will be allowed for Visits 8 and 9. 
5.5.2 
Patient information and physical examination 
5.5.2.1 
Demographics 
The patient´s date of birth, gender, race and ethnicity will be collected at screening, and recorded 
in the CRF. 
5.5.2.2 
Medical and surgical history 
Details of the patient’s relevant medical and surgical history as judged by the Investigator will be 
collected at screening, and recorded in the CRF. 
5.5.2.3 
Prior medication 
Details of the patient’s relevant prior medication as judged by the Investigator will be collected 
at screening, and recorded in the CRF. 
5.5.2.4 
Physical examination 
A general physical examination will be performed at screening and recorded in the CRF. The 
assessment will be reported as “normal” or “abnormal”. Any abnormalities should be specified 
and recorded as medical history.  
Body weight and height will be recorded as a part of the physical examination. 
5.5.2.5 
Symptom onset information 
Date of symptom onset will be collected at screening, and recorded in the CRF. This data is 
collected to explore the time between symptom onset and start of treatment.  
5.5.3 
Efficacy assessments 
5.5.3.1 
Pulmonary function (primary efficacy assessment) 
The date and time of the requirement for invasive mechanical ventilation and extracorporeal 
membrane oxygenation (ECMO) will be assessed at Visits 1 to 7, and recorded in the CRF.  

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5.5.3.2 
MEWS score 
Modified early warning system score (MEWS) will be assessed at Visit 1 (Day 1), Visit 6 (Day 
15) and Visit 7 (Day 28)and recorded in the CRF. 
5.5.3.3 
SpO2, PaO2 and FiO2 
Resting peripheral capillary oxygen saturation (SpO2) will be measured 3 times per day at Visits 
1 to 7, and recorded in the CRF. For Visit 7, if the patient is discharged from the hospital prior to 
this visit, the SpO2 will be performed only once at this visit. 
The partial pressure of oxygen (PaO2) and the fraction of inspired oxygen (FiO2) will be 
measured at screening, at Visit 6 and Visit 7, and recorded in the CRF. 
5.5.3.4 
Hemogasanalysis 
Hemogasanalysis will be assessed at Visits 1 to 7, and recorded in the CRF.  
Analysis may for example include pH, carbon dioxide tension (pCO2), oxygen tension (pO2), 
electrolytes, lactate and hemoglobin. 
5.5.3.5 
Oxygen supplementation 
Oxygen supplementation will be assessed at Visits 1 to 7. The date, time and amount of 
supplementation will be recorded in the CRF.  
5.5.3.6 
High-resolution computed tomography 
A high-resolution computed tomography scan (HR-CT) of the chest or a chest X-ray will be 
performed at screening, Visit 6 (Day 15) and Visit 7 (Day 28). The HR-CT scan or the X-ray of 
the chest will be recorded in the CRF and reported as “normal” or “abnormal”.  
Any abnormalities reported at screening should be specified and recorded as medical history. 
5.5.3.7 
Laboratory assessments 
Blood samples for determination of the laboratory assessments described in Table 3 will be 
drawn at screening, and at Visits 1 to 7. The date and time of blood sampling will be recorded in 
the CRF. 

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Table 3 Laboratory assessments 
Biochemistry 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Total bilirubin (if >upper limit of normal also 
conjugated and non-conjugated bilirubin) 
Prothrombin Time/International Normalized Ratio 
(PT-INR) 
Fibrinogen 
Complement C3/C4 
Cardiac troponin  
Creatinine 
C-reactive protein (CRP) 
Electrolytes (Sodium, Potassium, Calcium) 
Glucose 
 
Hematology  
Hemoglobin 
Platelet count 
White blood cells 
RBC 
Differential blood count 
 
Hyperinflammatory parameters 
Ferritin 
LDH  
D-dimers 
 
Additional testing at screening 
TB screening 
PCR SARS-CoV-2  
 
 
All laboratory samples will be analysed at the respective local hospital laboratory according to 
their standard routines. 
The laboratory results will be entered by the respective hospital into the study eCRF.  
 
 
Additional testing at screening 
Patients randomized to study with no clinical suspicion of active or latent tuberculosis as per 
study exclusion criteria (see 5.3.2) may on rare occasions test positive for TB based on lab 
screening. Should such situation occur, the principal investigator will decide based on the 
assessed benefit/risk for the patient whether or not it is in the best interest of the patient to 
continue in the study.  
For study sites where PCR is not part of hospital routine for confirming SARS-CoV-2 
diagnosis/eligibility as per study inclusion criteria (see 5.3.1), PCR test results are accepted post 
randomization not to delay treatment. The test can be done in specimens of different origins as 
decided by principal investigator. Should an enrolled patient show a negative PCR test result for 
SARS-CoV-2, the principal investigator will decide based on the assessed benefit/risk for the 
patient whether or not it is in the best interest of the patient to continue in the study. Such patient 
is to be excluded from the study efficacy analysis but included in the safety analysis.   
5.5.3.8 
Survival and hospital discharge 
Data on survival and hospital discharge will be collected at Visits 7 (Day 28), Visit 8 and 9 
(Weeks 6 and 10) and recorded in the CRF. 

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5.5.4 
Safety assessments 
5.5.4.1 
Adverse events 
 
Definitions 
Adverse event (AE) 
An AE is any adverse change, i.e., any unfavorable and unintended sign, including an abnormal 
laboratory finding, symptom, or disease that occurs in a patient during the course of the study, 
whether or not considered by the investigator as related to study treatment. 
A treatment-emergent AE is any AE temporally associated with the use of study treatment 
whether or not considered by the investigator as related to study treatment. 
Adverse events include: 
• Exacerbation of a pre-existing disease. 
• Increase in frequency or intensity of a pre-existing episodic disease or medical condition. 
• Disease or medical condition detected or diagnosed during the course of the study even 
though it may have been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at study start that worsen following 
the start of the study (i.e., signing of informed consent). 
• Abnormal assessments, e.g., change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at study start or worsened 
during the course of the study. 
• Laboratory test abnormalities are considered as AEs if they represent a clinically 
significant finding, symptomatic or not, which was not present at study start or worsened 
during the course of the study or led to dose reduction, interruption or permanent 
discontinuation of study treatment.An AE is any untoward medical occurrence in a 
patient administered a pharmaceutical product; the event does not necessarily have a 
causal relationship with the treatment or usage. 
 
Intensity of adverse events 
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – and is 
reported on specific AE pages of the CRF. 
If the intensity of an AE worsens during study treatment administration, only the worst intensity 
should be reported on the AE page. If the AE lessens in intensity, no change in the severity is 
required. 
If the intensity of an AE with an onset date between informed consent signature and start of 
study treatment and which is ongoing at the start of treatment worsens after the start of study 
treatment, a new AE page must be completed. The onset date of this new AE corresponds to the 
date of worsening in intensity. 
The three categories of intensity are defined as follows: 

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Mild 
The event may be noticeable to the patient. It does not influence daily activities, and usually does 
not require intervention. 
 
Moderate 
The event may make the patient uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
 
Severe 
The event may cause noticeable discomfort, and usually interferes with daily activities. The 
patient may not be able to continue in the study, and treatment or intervention is usually needed. 
A mild, moderate, or severe AE may or may not be serious, see Section 5.5.4.2. These terms are 
used to describe the intensity of a specific event. Medical judgment should be used on a case-by-
case basis. 
Seriousness, rather than severity assessment, determines the regulatory reporting obligations. 
 
Relationship to study treatment 
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study treatment, and reported as either related or 
unrelated. The determination of the likelihood that the study treatment caused the AE will be 
provided by an investigator who is a qualified physician. 
5.5.4.2 
Serious adverse events 
 
Definitions of serious adverse events 
An SAE is defined by the International Conference on Harmonisation (ICH) guidelines as any 
AE fulfilling at least one of the following criteria: 
• Fatal. 
• Life-threatening: refers to an event in which the patient was at risk of death at the time of 
the event. It does not refer to an event that hypothetically might have caused death had it 
been more severe. 
• Requiring inpatient hospitalization, or prolongation of existing hospitalization. 
• Resulting in persistent or significant disability or incapacity. 
• Congenital anomaly or birth defect. 
• Medically significant: refers to important medical events that may not immediately result 
in death, be life-threatening, or require hospitalization but may be considered to be SAEs 
when, based upon appropriate medical judgment, they may jeopardize the patient, and 
may require medical or surgical intervention to prevent one of the outcomes listed in the 
definitions above. 
The following reasons for hospitalization are exempted from being reported: 
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 

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• Hospitalization for pre-planned (i.e., planned prior to signing informed consent) surgery 
or standard monitoring of a pre-existing disease or medical condition that did not worsen, 
e.g., hospitalization for coronary angiography in a patient with stable angina pectoris. 
However, complications that occur during hospitalization are AEs or SAEs (for example if a 
complication prolongs hospitalization). 
5.5.4.3 
Reporting requirement of adverse events 
 
Reporting of adverse events 
Irrespective of seriousness, the following adverse events are considered as adverse events of 
special interest and must be reported on AE page of the CRF. 
In all patients: 
• AEs leading to discontinuation of study treatment 
Infusion related reactions including anaphylactic/anaphylactoid reactions. In patients treated with 
emapalumab, the following AEs will be considered of special interest: 
• All new infections. 
In patients treated with anakinra, the following AEs will be considered of special interest: 
• Severe neutropenia defined as neutrophil count < 0.5x109/l. 
No other AEs are required to be reported on the AE page of the CRF 
 
Reporting of serious adverse events 
All SAEs occurring after study drug initiation and up to the end of study visit (Visit 9, Week 10) 
must be reported on AE pages in the CRF and on an SAE form, regardless of the investigator-
attributed causal relationship with study treatment. 
Abnormal laboratory findings 
Abnormal laboratory findings, if serious, must be reported on specific AE pages of the CRF. 
Following laboratory variables are collected for the assessment of efficacy (see Section 6.5.3.2) 
at screening and during the treatment period, and are not required to be reported as SAEs as 
described above: WBC including differential counts, RBC, Hgb, platelet count, fibrinogen,  
complement C3/C4, PT-INR, and cardiac troponin; ALT, AST, total bilirubin, creatinine, 
ferritin, LDH, D-dimer, CRP, electrolytes (sodium, potassium, calcium), and glucose. 
 
Follow-up of serious adverse events 
Serious adverse events still ongoing at the end of study visit (Visit 9, Week 10) must be followed 
up until resolution or stabilization, or until a definite event outcome is provided, e.g., resolved 
with sequelae or death. 

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Reporting procedures 
All SAEs must be reported by the investigator to the Sobi drug safety department within 24 
hours of the investigator’s first knowledge of the event. 
All SAEs must be recorded on an SAE form, irrespective of the study treatment received by the 
patient, and whether or not this event is considered by the investigator to be related to study 
treatment. 
The SAE forms must be e-mailed to the Sobi drug safety department: 
• 
NI-0501drugsafety@sobi.com  
The investigator must complete the SAE form in English, and must assess the causal relationship 
of the event to study treatment. 
Follow-up information about a previously reported SAE must also be reported within 24 hours of 
receiving it. The Sobi drug safety department may contact the investigator to obtain further 
information. 
If the patient is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE relevant information and documentation. 
The reference safety document to assess expectedness of a suspected serious adverse reaction 
and for reporting by the Sponsor to Health Authorities, IRBs/IECs, and investigators is: 
• For emapalumab - the reference safety information section of the Investigator’s Brochure 
[Emapalumab IB]. 
• For anakinra -  Section 4.8. of anakinra SmPC (Kineret SmPC) + i.v. data 
5.5.4.4 
Pregnancy 
 
Reporting of pregnancy 
Irrespective of the treatment received by the patient, any pregnancy occurring after study drug 
initiation up to the end of study visit (Visit 9, Week 10) must be reported within 24 hours of the 
investigator’s knowledge of the event. Pregnancies of female patients will be followed until final 
outcome of pregnancy. For emapalumab treated patients; Pregnancies of a female partner of 
male patients in the study need to be similarly reported and to be followed until the final 
outcome of the pregnancy 
Pregnancies must be reported on the pregnancy form which is e-mailed to the Sobi drug safety 
department (NI-0501drugsafety@sobi.com), and on an AE page in the CRF. 
 
Follow-up of pregnancy 
Any pregnancy must be followed to its conclusion and its outcome must be reported to the Sobi 
drug safety department. This information will be only entered in the drug safety database. 

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Any AE associated with the pregnancy occurring during the study must be reported on separate 
AE pages in the CRF. Any SAE occurring during the pregnancy must be reported on an SAE 
form as described in Section 5.5.4.3. 
5.5.4.5 
Laboratory safety assessments 
For details on laboratory assessments, see Section 5.5.3.7. 
5.5.4.6 
Vital signs 
Vital signs (body temperature, blood pressure, heart rate. respiratory rate and oxygen saturation) 
will be measured at screening, and Visit 1 to 7, and recorded in the CRF.  
For AE reporting of abnormalities, see Section 5.5.4.3.   
5.5.4.7 
Electrocardiograms 
A 12-lead ECG recording will be performed at screening, Visit 6 (Day 15) and Visit 7 (Day 28), 
and recorded in the CRF. The ECG assessments will be peformed at site and will be reported as 
“normal” or “abnormal”. Any abnormalities should be specified. Abnormalities reported at 
screening should be recorded as medical history.  
For AE reporting of abnormalities, see Section 5.5.4.3. 
5.5.4.8 
Pregnancy Test 
Female of childbearing potential will have a urine pregnancy test taken at screening and at Visit 
6 (Day 15). The outcome of the test will be reported as “positive” or “negative” in the CRF. 
5.5.4.9 
Immunogenicity 
Immunogenicity samples will be collected for all patients receiving active study treatment at 
Visit 1 Pre-dose, at Visit 6 at end-of infusion (for anakinra a sample should be taken after the 
first infusion per day) at Visit 7. If the patient is coming to the clinic at the follow-up visits, 
immunogenicity samples will also be collected at Visit 8 and Visit 9. The date and time of blood 
sampling will be recorded in the CRF. Samples will be sent to central laboratory for analysis.  
5.5.4.10 
Viral shedding 
Samples for viral shedding will be collected for all patients at Visits 1, 4, 6 (Day 15) and 7 (Day 
28). For patients coming to the clinic for the follow-up visit, samples will also be collected at 
Visit 8 and Visit 9. The date of the sampling will be recorded in the CRF. Samples will be sent to 
a central laboratory for analysis. 
5.5.4.11 
Data Review Committee 
The Data Review Committee members are to be independent from any of the sponsors and 
without any conflicts of interest, providing their expertise in intensive care, inflammation, 
infectious diseases and will be involved in study oversight, safety monitoring and interpretation 
of the emerging study results. 

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5.5.4.12 
Safety Review Committee 
An SRC consisting of internal Sobi members (voting) and coordinating investigators (non-
voting) members is established to monitor study participant safety in the study. Clinical study 
safety information (eg AEs, SAEs, laboratory values, ECGs, vital signs, and additional safety 
related study assessments, as required) is monitored and reviewed on a continuous basis by SRC 
from study start to database lock.  
If two patients develops a life threatening or fatal adverse event suspected to be study drug 
related then an ad hoc SRC meeting will be held within 24 hours after the Sponsor awareness of 
the Event. At this meeting the decision on continuation of the study with or without changes or 
to halt the enrollment of the specific study arm will be taken. Details are described in a separate 
written operating procedures for the SRC. 
5.5.4.13 
Specific safety monitoring and management during the study 
Infusion related reactions for all treatment arms:  
The infusion related reactions will be closely monitored by the treating physician. Should severe 
allergic reactions (such as anaphylactic shock) occur, the patient would be managed according to 
the local standard treatment guidelines. 
Anakinra treatment:  
• 
Neutrophil counts should be assessed prior to initiating and during anakinra treatment. 
Should neutropenia (neutrophil count < 1.0 ×109/L) occur in a patient treated with anakinra, dose 
reduction or discontinuation of the treatment may be considered as judged by the investigator. 
Should neutropenia (neutrophil count < 0.5 ×109/L) occur in a patient treated with anakinra, the 
treatment should be discontinued.    
• 
Anakinra is mainly eliminated by the kidney. Should severe renal impairment (CLcr < 30 
ml/min) or end stage renal disease occur, the reduction of anakinra dose (100mg IV 2 times 
daily) should be considered as judged by the investigator. 
Emapalumab treatment: 
• Monitoring of new infections is requested throughout the study. Type of investigation, 
specimen, result and pathogen identified will be captured in the CRF. Such data will be 
captured for all new infection. Should serious infection caused by pathogens potentially 
favored by IFNγ neutralization, i.e. mycobacteria, histoplasma capsulatum, herpes zoster, 
salmonella and shigella occur in a patient treated with emapalumab, the treatment should 
be stopped, and appropriate anti-infective treatment should be initiated.   
5.5.5 
Exploratory assessments 
5.5.5.1 
Clinical Status 
Data on clinical status based on a 7-point ordinal scale will be collected at Visits 1 to 9 and 
recorded in the CRF. 

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The scale consists of the following categories: 
1. 
Death 
2. 
Hospitalized, requiring invasive mechanical ventilation or extracorporeal membrane  
            oxygenation (ECMO) 
3. 
Hospitalized, requiring non-invasive ventilation or high flow oxygen devices 
4. 
Hospitalized, requiring supplemental oxygen 
5. 
Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care  
6. 
Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical  
            care 
7. 
Not hospitalized 
5.5.5.2 
Pharmacokinetics 
PK blood samples will be collected for all patients receiving active study treatment. At Visit 1 
sampling should be done pre-dose and at end-of infusion and during Visits 2, 3, 4, 5 and 6 a PK 
sample should be taken at end-of infusion. For anakinra treated patients; samples will only be 
collected in connection with the first infusion per day. In addition, for emapalumab treated 
patients, a PK sample will be collected also at Visit 7 (Day 28) and during follow-up on Visit 8 
and 9 in case the patient is at the clinic for these visits. It should be noted that a separate iv line 
will have to be used when collecting the PK samples, ie not the same iv line as used for the iv 
infusion of active study treatment.  
The date and time of blood sampling will be recorded in the CRF. Samples will be sent to a 
central laboratory for analysis.  
5.5.5.3 
Pharmacodynamics 
Blood samples for determination of CXCL9, IFNγ, IL-1, IL-6, sIL-2R and selected exploratory 
parameters will be collected at Visit 1 to 9 at the end of infusion (for anakinra treated patients; 
samples will only be collected in connection with the first infusion per day ). The date and time 
of blood sampling will be recorded in the CRF. It should be noted that a separate iv line will 
have to be used when collecting the PD samples, ie not the same iv line as used for the iv 
infusion of active study treatment. 
Samples will be sent to a central laboratory for analysis.   
6 
Quality control and quality assurance 
This study will be conducted in compliance with this protocol, study specific procedures, CRO 
SOPs, Sobi SOPs, the ICH Guideline for GCP [1], and applicable regulatory requirements. 

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The Sponsor/CRO will establish a systematic, prioritized, risk-based approach to monitoring 
and, considering the current situation, will need to utilize remote monitoring. The Sponsor/CRO 
will develop a risk management plan with the aim to limit the contacts with patients and site 
personnel during the emergency period, while ensuring the patients safety and integrity, 
compliance with the protocol, study specific procedures and applicable regulatory requirements.  
To ensure ongoing patient safety and well-being, and control risks to study critical processes, 
such as review of all informed consent forms and all primary efficacy variables, alternative 
mechanisms of oversight will be introduced (such as phone calls, video calls, remote monitoring 
etc). The Sponsor/CRO will also investigate if other measures for sharing data can be 
implemented, e.g. sharing de-identified source documents in shared drives/locations.  
On-site monitoring visits will be postponed until the emergency period is over. Source 
documents will then be reviewed for verification of agreement with data in CRFs.  
The investigator or institution guarantees access to source documents by Sobi, its 
representatives, and appropriate regulatory agencies. 
The study site may be subject to a quality assurance audit by Sobi or its representatives, as well 
as inspection by appropriate regulatory agencies. 
It is important that the investigator(s) and the(ir) relevant personnel are available during the 
monitoring visits and possible audits and that sufficient time is devoted to the process. 
7 
Statistical plan 
7.1 
Determination of sample size  
The study will enroll a total of 54 patients, 18 per arm according to the 1:1:1 randomization. 
The sample size has been estimated based on the following assumptions: 
• An overall one-sided significance level for efficacy of 0.097 (9.7%) and a power of 74% 
for each comparison under the assumption that the true success rates are 50% in the SoC 
group increasing to 80% in the emapalumab or anakinra groups. 
• The study will consist of two stages, with equal numbers of patients randomised into 
Stage 1 and into Stage 2 per treatment arm. 
• There is the potential to stop for futility or for efficacy of emapalumab or anakinra (or 
both) at the end of Stage 1, but only the futility rule is binding and irrespective of the 
Stage 1 results, the study will not be stopped for efficacy but continue to accrue safety 
data. 
More specifically: 
• The emapalumab or anakinra arm (or both) will be stopped at the end of Stage 1 for 
futility if the one-sided p-value in favour of emapalumab/anakinra is > 0.690. 

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• Efficacy of the emapalumab or anakinra arm (or both) will be declared at the end of 
Stage 1 if the one-sided p-value in favour of emapalumab/anakinra is < 0.025. 
• If the trial continues to Stage 2, efficacy will be declared at the end of Stage 2 if the one-
sided p-value in favour of emapalumab/anakinra is < 0.159. 
The calculations on the operating characteristics of this design have been undertaken using 
PASS, Version 14: Group-Sequential Tests for Two Proportions (Simulation). 
The value for the type I error has been chosen in recognition of the urgent unmet medical need to 
allow the identification of a signal, at least, from a statistical perspective. Having seen a 
statistical signal, it is then a matter of evaluating whether the observed treatment differences 
represent clinically relevant effects that can satisfy that unmet need.  
Assuming no untoward safety signal is observed and no futility stopping occurs at the Stage 1 
interim, the decision may be taken to increase the sample size beyond 54 patients in order to 
accrue further safety and efficacy data. Details of this would be described in a protocol 
amendment.  
In case the outcome is statistically convincing, i.e. statistically significant on a 5% level in the 
stage 2 analysis, efficacy will be considered confirmed and the results may, where warranted, be 
used to seek regulatory approvals. 
7.2 
Definition of study populations 
All efficacy analyses will be conducted on the modified intention-to-treat (mITT) population 
which will comprise all randomized patients except patients who did not receive study treatment 
or patients who tested negative to SARS-CoV-2 diagnosis confirmation by PCR testing. 
In case of exclusion due to tested negative to SARS-CoV-2 diagnosis confirmation by PCR 
testing, additional patients may be recruited to ensure an adequate number of evaluable patients 
for the efficacy analysis. 
The Safety population will comprise all patients who received at least one dose of study 
treatment or standard of care.  
Patients will be included in the groups to which they were randomized for all evaluations of 
efficacy and in the groups according to treatment received for all evaluations of safety. 
7.3 
Overall statistical and analytical plan 
Statistical analysis will be performed using SAS software Version 9.4 or later (SAS Institute, 
Inc, Cary, North Carolina, United States). 
7.3.1 
General statistical issues 
This design has acceptable properties in terms of the false positive potential, controlling the 
overall type I error at 9.7%, for each of the two treatment comparisons.  

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Secondary endpoints will be evaluated in a descriptive way. In some cases p-value comparisons 
will be undertaken, but these are to be interpreted in an exploratory way. 
7.3.2 
Demographics and baseline characteristics 
Demographic and baseline characteristics will be summarized in appropriate tabular 
presentations.  
For measurements of continuous endpoints, summary statistics will include n, mean, median, 
standard deviation, minimum and maximum values. For categorical variables, summary 
tabulations of the number and percentage within each category (with a category for missing data) 
of the parameter will be presented. 
7.3.3 
Analysis related to primary objective 
7.3.3.1 
Primary endpoint 
 
Treatment success 
For the analysis of the primary endpoint, each of the pairwise comparisons, 
emapalumab/anakinra versus standard of care, at both the end of Stage 1 and at the end of Stage 
2, will be undertaken using Fishers Exact test comparing the proportion of patients with 
treatment success. This will be supplemented by the presentation of one-sided exact confidence 
intervals of the differences in proportion between emapalumab/anakinra and standard of care, 
with confidence coefficients of 97.5% at the end of Stage 1 and 84% at the end of Stage 2. Two-
sided confidence intervals of the proportions in each group will also be presented, using the 
method of Clopper-Pearson [18]. 
The primary analysis will not adjust for the stratification factor glucocorticoid use at inclusion 
due to the small sample size at Stage 1. However, a sensitivity analysis of the primary endpoint 
using exact logistic regression will be performed at Stage 1 and 2. This will allow for conditional 
testing of the treatment effect given the stratification factor. The results of the analysis will be 
presented in terms of model-adjusted treatment success rates for each treatment group, and p-
values and confidence intervals for the odds ratio of the pairwise comparisons to the standard-of-
care arm.  
7.3.3.2 
Secondary endpoints supporting the primary objective 
 
Time to mechanical ventilation and overall survival 
Analysis of the time to mechanical ventilation from the point of randomization will be 
undertaken by plotting Kaplan-Meier curves for each of the 3 treatment groups and by pairwise 
comparisons (emapalumab/anakinra versus standard of care) using the logrank test. Hazard ratios 
will be estimated using the Cox proportional hazards model and these will be presented together 
with 90% two-sided confidence intervals. 

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Overall survival (time to death from the point of randomization) and time to hospital discharge 
(from the point of randomization) will not be analysed at the end of Stage 2, but at the end of the 
follow-up period. This endpoint will be analysed as for time to mechanical ventilation. 
 
Change from baseline in MEWs score 
Change from baseline in MEWs score at Day 15 will be analysed using analysis of covariance 
(ANCOVA) including treatment arm as a fixed factor and baseline MEWs score as a covariate. 
Least square mean change per group, associated 90% two-sided CI, and p-values for the 
comparison vs. standard of care, will be presented. 
 
Change from baseline in hyperinflammatory parameters  
Change from baseline during treatment until Day 15 with measurements performed every 3 days 
of the following parameters will be summarized using descriptive statistics: 
• Ferritin  
• LDH  
• D-dimers  
 
Change from baseline in other relevant laboratory parameters  
Change from baseline during treatment until Day 15 with measurements performed every 3 days 
of the following parameters will be summarized using descriptive statistics: 
• WBC with differential counts 
• RBC 
• Hb 
• Platelet count 
• Fibrinogen 
• Complement C3/C4 
• Prothrombin Time 
• Cardiac troponin 
• Liver tests (AST, ALT, total bilirubin levels) 
• CRP  
• Creatinine 
• Electrolytes (Sodium, Potassium, Calcium) 
• Glucose 
 
Change from baseline in resting SpO2 and oxygen supplementation 
Change from baseline during treatment until Day 15 with measurements performed every 3 days 
will be summarized using descriptive statistics for each of these parameters. 

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Change from baseline in PaO2/FiO2 
Change from baseline (screening) during treatment until Day 15 will be summarized using 
descriptive statistics. 
 
Change from baseline in hemogasanalysis 
Change from baseline during treatment until Day 15 with measurements performed every 3 days 
will be summarized using descriptive statistics for each of the collected parameters. 
7.3.4 
Analysis related to secondary objective  
7.3.4.1 
Adverse events 
Reported AEs during the study will be coded using MedDRA. The incidence of AEs will be 
summarized in frequency tables by treatment, system organ class, preferred term and maximum 
severity. Separate tabulations will performed for serious and non-serious AEs. 
7.3.4.2 
Anti-drug antibodies 
The number and percentage of patients with ADA and NAb at baseline and at each post-baseline 
assessment will be summarized. 
7.3.5 
Analysis related to the exploratory objective 
Clinical status using the 7-point ordinal scale is an exploratory endpoint and the data collected 
will be summarized to show the number and percentage of patients in each category over time. 
PK and PD data will be listed and summarized at each visit with descriptive statistics.  
7.3.6 
Interim analysis 
The study will consist of one interim analysis (Stage 1) and a final analysis (Stage 2), with 
approximately the same numbers of patients randomised into Stage 1 and into Stage 2 per 
treatment arm. The Stage 1 interim analysis will be conducted after the accrual of at least 9 
patients per treatment arm. See Section 7.1 for further details concerning the interim analysis. 
7.3.7 
Multiple comparison/multiplicity 
There will be no adjustments for multiplicity for the two pairwise treatment comparisons for the 
primary endpoint. Multiplicity for the sequential comparisons at the end of Stage 1 and at the end 
of Stage 2 are however accounted for by the design. 

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7.3.8 
Handling of missing data 
There will be no imputation of missing data for the primary endpoint (treatment success by Day 
15), but patients who discontinue study treatment (or discontinue the study if randomized to 
standard of care) prior to Day 15 and had IMV or ECMO on their last assessment by the time of 
study treatment discontinuation, will be considered not having achieved treatment success by 
Day 15. Patients discontinuing prior to Day 15 without ever having initiated IMV/ECMO, will 
be considered having achieved treatment success by Day 15. Patients discontinuing prior to Day 
15 due to having significantly improved will be considered having achieved treatment success. 
Patients who died by Day 15, have not achieved treatment success regardless of IMV/ECMO use 
by Day 15.  
For change-from-baseline efficacy endpoints at Day 15, the last observation carried forward 
(LOCF) approach will be used to impute missing data, using the last post-baseline observation 
available for each patient. 
8 
Data collection, handling and record keeping 
8.1 
Data standards 
Collection of data should be performed in the CDASH format, according to the CDISC. The 
standards should be used to the extent possible and/or required for the specific study/project. The 
minimum requirement of the CDISC standard is to collect all core variables specified as 
‘Required’ in the Study Data Tabulation Model format.  
8.2 
Case report form 
A CRF is required and should be completed for each included patient. In this study an electronic 
CRF will be used. The completed original CRFs are the sole property of Sobi and should not be 
made available in any form to third parties, except for authorized representatives of appropriate 
Regulatory Authorities, without written permission from Sobi. 
It is the responsibility of the investigator to ensure completion and to review and approve all 
CRFs. CRFs must be signed electronically by the investigator. These signatures serve to attest 
that the information contained on these CRFs is correct. At all times, the investigator has final 
responsibility for the accuracy and authenticity of all clinical and laboratory data entered on the 
CRFs.  
8.3 
Source data 
Patient source documents are the patient’s medical records maintained at the study site. In most 
cases, the source documents will be the hospital’s or the physician’s chart, including laboratory 

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test results, radiology results, ECG etc. In those cases, the information collected in the CRFs 
must match those charts.  
A separate source document location agreement will be completed and signed by the Principal 
Investigator and the site monitor. 
Source data should be attributable, legible, contemporaneous, original, accurate, and complete. 
Changes to source data should be traceable, should not obscure the original entry, and should be 
explained if necessary (e.g. via an audit trial). 
8.4 
Protocol deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring the 
study is conducted in accordance with the procedures and evaluations described in this protocol 
and must protect the rights, safety, and welfare of patients. The investigator should not 
implement any deviation from, or changes of, the protocol, unless it is necessary to eliminate an 
immediate hazard to study patients. 
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.  
When a deviation from the protocol is identified, the investigator or designee must ensure 
Sobi/CRO is notified. Sobi/CRO will follow up with the investigator, as applicable, to assess the 
deviation and the possible impact to the safety and / or efficacy of the patient to determine 
patient continuation in the study. 
The investigator and CRO must contact Sobi immediately if a deviation is discovered that 
significantly affects or has the potential to significantly affect human subject protection or the 
reliability of study results. 
The investigator will also assure that deviations are reported and documented in accordance with 
IEC and applicable regulatory requirements.  
8.5 
Database closure 
Prior to database closure, all tasks or criteria defined in the data management plan must be 
completed and documented. The study database must be locked before generation of any results. 
The database lock will be approved by relevant study personnel and all edit accesses will be 
removed. Following database closure, the study database can only be unlocked in case critical 
errors, affecting the main conclusions of the study, are discovered. 
8.6 
Record retention 
The investigator should maintain a record of the location(s) of investigator’s essential documents 
as defined in the ICH GCP Guideline [1] including source documents and should have control of 

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and continuous access to all essential documents and records generated by the 
investigator/institution before, during, and after the study.  
All documents and data relating to the study will be kept securely by the investigator in a 
secure file and/or electronically. The storage system used during the study and for archiving 
(irrespective of the type of media used) should provide for document identification, version 
history, search and retrieval. The data will be available for evaluation and/or audits from Health 
Authorities, Sobi or Sobi’s representatives. 
When a copy is used to replace an original document (e.g. source documents, CRF), the copy 
should fulfill the requirements for certified copy as defined in ICH GCP Guideline [1].  
The records should be retained by the Investigator as specified in the Clinical Trial Agreement 
and in accordance with local regulations.  
If the investigator relocates, retires, or for any reason withdraws from the study, the study 
records may be transferred to an acceptable designee, such as another investigator or another 
institution. Archiving on behalf of the investigator can also be delegated to Sobi.   
9 
End of study 
The end of this study is defined as the date of the last patient’s last visit/end of study call (Visit 
9, Week 10). 
10 
Sponsor’s discontinuation criteria 
Sobi reserves the right to discontinue the study prior to inclusion of the intended number of 
patients, but intends only to exercise this right for valid scientific or administrative reasons. After 
such a decision, the investigator must contact all participating patients within 30 days. All study 
materials must be collected and all the CRFs completed to the greatest extent possible. 
11 
Dissemination and publication of results 
Sobi will register the study by posting study information and post study results regardless of 
outcome on a publicly accessible website in accordance with applicable laws and regulations, 
e.g., on www.clinicaltrials.gov and EudraCT. The results of this study will be published within 
12 months of the end of study. 
Sobi is committed to publishing study results in a complete, accurate, balanced, transparent and 
timely manner. Sobi follows the principles of the International Committee of Medical Journal 
Editors (ICMJE) recommendations for the conduct, reporting, editing, and publication of 
scholarly work in medical journals including criteria for authorship [3]. 
The data from this study will be considered for reporting at a scientific meeting or for 
publication in a scientific journal. The Sponsor will be responsible for these activities and will 

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work with the investigators to determine how the publication is written, the number and order of 
authors, the journal or scientific meeting to which it will be submitted, and other related issues. 
The results of the study, or any part thereof, shall not be published without the prior written 
consent and approval of Sobi, such consent and approval not to be unreasonably withheld. 
12 
Reference list 
1  
ICH Harmonised Guideline: Integrated addendum to ICH E6 (R1), Guideline for Good 
ClinicalPractice E6(R2) Current Step 4 version dated 9 November 2016. Available from: 
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html   
2 
World Medical Association Declaration of Helsinki; Ethical Principles for Medical 
Research Involving Human Subjects. Available from:  
https://www.wma.net/publications/wma-doh-1964-2014/  
3 
International Committee of Medical Journal Editors. Recommendations for the conduct, 
reporting, editing, and publication of scholarly work in medical journals: updated 
December 2016 [Internet]. International Committee of Medical Journal Editors (ICMJE); 
2016. [cited 2017 Jan 12]. Available from: http://www.icmje.org/recommendations/   
4  
Zhou F et al. Clinical course and risk factors for mortality if adult inpatients with 
COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; (published 
online March 09) doi.org/10.1016/S0140-6736(20)30566-3 1  
5  
Huang C et al. Clinical features of patients infected with 2019 novel coronavirus in 
Wuhan. Lancet 2020; 395(10223):497-506 
6  
Ruan Q et al. Clinical predictors of mortality due to COVID-19 based on an analysis of 
data of 150 patients from Wuhan, China. Intensive Care Med. 2020; (published online 
Mar 03) doi: 10.1007/s00134-020-05991-x 
7  
Granowitz E et al. Pharmacokinetics, safety, and immunomodulatory effects of human 
recombinant interleukin-1 receptor antagonist in healthy humans. CYTOKINE 1992; 
4(5):353-360 
8  
Badheka A et al. Use of an interleukin-1 receptor antagonist for suspected sepsis with 
hyperinflammation in children. Crit Care Med. 2019; 48:1561 
9  
Opal S et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: A 
phase III, randomized, double-blind, placebo-controlled, multicenter study. Crit Care 
Med. 1997; 25:1115-1124 
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Fisher C et al. Initial evalutation of human recombinant interleukin-1 receptor antagonist 
in the treatment of sepsis syndrome: A randomized, open-label, placebo-controlled 
multicenter study. CRITICAL CARE MEDICINE 1994; 22(1):12-21 
11  
Galea J et al. Intravenous anakinra can achieve experimentally effective concentrations in 
the central nervous system within a therapeutic time window results of a dose-ranging 
study. JCBFM. 2011; 31:439-447 
12  
Benedetti F et al. Emapalumab, an interferon gamma (IFN-γ)-blocking monoclonal 
antibody, in patients with Macrophage Activation Syndrome (MAS) complicating 

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systemic Juvenile Idiopathic Arthritis (sJIA).  Annals of Rheumatic Diseases, 2019; 78 
(Suppl 2):178.1-178 
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Wang D et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel 
Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 (published online Feb 
7) doi: 10.1001/jama.2020.1585. 
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Mehta P et al. COVID-19: consider cytokine storm syndromes and immunosuppression. 
Lancet 2020; (published online Mar 13) doi.org/10.1016/ S0140-6736(20)30628-0 
15  
Xu X et al. Effective Treatment of Severe COVID-19 Patients with Tocilizumab 
ChinaXiv:202003.00026v1 
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Locatelli F et al. Safety and Efficacy of Emapalumab in Pediatric Patients with Primary 
Hemophagocytic Lymphohistiocytosis. Blood 2018;132: LBA-6; doi: 
https://doi.org/10.1182/blood-2018-120810 
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Eloseily EM et al. Benefit of anakinra in treating pediatric secondary hemophagocytic 
lymphohistiocytosis. Arthritis Rheumatol. 2020;72:326-334 doi: 10.1002/art.41103 
18  
Clopper C et al. The use of confidence or fiducial limits illustrated in the case of the 
Binomial. Biometrika 1934;26: 404-413 
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https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-
patients.html  
20 
Infectious Diseases Society of America Guidelines on the Treatment and Management of 
Patients with COVID-19 Published by IDSA, 4/11/2020 
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Puja M et al. COVID-19: consider cytokine storm syndromes and immunosuppression. 
The Lancet. March 2020 
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Cavalli G et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-
19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort 
study. The Lancet. May 2020 
 

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Appendix 1 
Additional Protocol Signatures 
 
 
Sponsor’s Clinical Program Leader  
Karin Becker, MSc Pharm 
Clinical Program Leader 
E-mail: karin.becker@sobi.com 
Signature
 
 
Date 
 
 
Sponsor’s Statistician 
Henrik Andersson, MSc 
Statistician 
E-mail: henrik.andersson@sobi.com 
Signature
 
 
Date 
 
DocuSign Envelope ID: F9047F81-565C-4132-8AA0-CF9EEB2F19DE
30 juni 2020 | 02:14:22 PDT
30 June 2020 | 12:11:15 CEST

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Appendix 2 
Study Administrative Structure 
Sponsor: 
Swedish Orphan Biovitrum AB (publ), SE-112 76 Stockholm, Sweden 
Phone: +46 8 697 20 00 
Study sites: 
12 to 20 study sites in Italy and US. 
Monitoring: 
Pharmaceutical Research Associates, Inc., Raleigh, North Carolina, USA (CRO) 
SAE reporting: 
Swedish Orphan Biovitrum AB (publ). 
Data management:  
Pharmaceutical Research Associates, Inc., Raleigh, North Carolina, USA (CRO) 
Statistics: 
Swedish Orphan Biovitrum AB (publ). 
Investigational products 
(production): 
See Section 5.4.2. 
Investigational products 
(packaging and labeling): 
Rechon Life Science AB (Limhamn, Sweden). 
Clinical laboratory: 
All clinical laboratory safety assessmentswill be performed at the local hospital. 
Central laboratory  
Emapalumab PK samples: Sobi AG, Plan-les-Ouates, Switzerland 
Exploratory biomarkers: Sobi AG, Plan-les-Ouates, Switzerland 
Emapalumab ADA samples: LGC, Cambridgeshire, United Kingdom 
Viral shedding: A central lab to be confirmed. 
Anakinra PK & ADA samples: York Bioanalytical Solutions Limited, York, United 
Kingdom 
Anakinra Nab samples: Wieslab AB, Malmö, Sweden 
 

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Appendix 3 
Exemption Letter Italy 
AIFA 
Italian Medicines Agency 
Via del Tritone, 181 
I-00187 Roma 
Italy 
 
 
March 16, 2020 
 
Dear Sirs, 
 
Re: Clinical trial of emapalumab and anakinra in patients with Coronavirus disease 
(COVID-19) 
 
Swedish Orphan Biovitrum AB is planning to conduct a clinical trial with emapalumab and 
Kineret (anakinra) in patients with Coronavirus disease (COVID-19) and hyperinflammation.  
 
The protocol (Sobi.IMMUNO-101, EudraCT 2020-001167-93) has been prepared in response to 
the request from the President of the Italian Consiglio Superiore di Sanità, Prof. Franco 
Locatelli, and the Scientific Director of the National Institute for Infectious Diseases (Ospedale 
Lazzaro Spallanzani, coordinating site for the COVID-19 pandemia in Italy), Prof. Giuseppe 
Ippolito. 
 
It will be a randomised open study with three parallel arms, empalumab or anakinra as add-on 
therapy to Standard of Care, to be compared to Standard of Care only.The study will comprise 
up to 54 patients and cover a treatment duration of 2 weeks. The assessment will follow a step-
wise approach which will be described in the protocol. 
 
The CTA includes: 
 
1. 
The CTA Form 
2. 
The Clinical Study Protocol 
3. 
The Patient Information and Informed Consent 
4. 
The already existing IB for emapalumab (supporting HLH indications) 
5. 
SmPC for Kineret, USPI for emapalumab 
6. 
The labelling of the IMPs 

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The clinical trial will be submitted for review by the Ethics Committee. 
 
It should be noted that due to the urgency of the situation, the Sponsor has for this protocol 
requested exemptions to what is required for a Clinical Trial Application and when 
conducting a clinical trial: 
 
1. 
An IMPD has not been established. However, Kineret is approved centrally in the 
EU/EEA since March 2002 (SmPC enclosed). Emapalumab was approved by the 
FDA for primary hemophagocytic lymphohistiocytosis (pHLH) in November 
2018 (USPI enclosed). Further, clinical trials with emapalumab to document the 
pHLH indication (Protocols NI-0501-04, -05 & -09) have previously been 
approved in Italy. The batch planned for the current study is the same which was 
used for Protocols  NI-0501-04, -05 in Italy, with the study specific labelling 
adjusted. 
 
Please note that for emapalumab, the same IMPD will be used as for study NI-0501-09 (NI-0501 IMPD 
Part 3 – November 2017). The QP certification site will be ABF Pharmaceutical Services GmbH, 
Gastgebgasse 5-13, 1230 Vienna, Austria or Swedish Orphan Biovitrum AB (publ), the latter being an 
addition in comparison to the IMPD. The packaging site will be ABF or Rechon, PO Box 60043, 
Soldattorpsvägen 5, SE-216 10 Limhamn Sweden, the latter also being an addition in comparison to the 
IMPD. 
 
2. 
Contract negotiations with hospitals is a time consuming process and it will not 
be possible to finalise this in time for start of the study. The principal 
investigators at each site will however be required to sign the Clinical Study 
Protocol. 
 
3. 
SAEs and AEs will be collected according to instructions in the protocol, in short:  
 
1. 
All fatal and life-threatening SAEs occurring after study drug 
(emapalumab, anakinra) initiation or after randomisation to Standard of 
Care must be reported on an SAE form to the company and on AE pages 
in the CRF. 
2. 
Non-serious AEs of special interest, as defined in the protocol, will be 
recorded only in the CRF. 
3. 
Abnormal laboratory findings, if serious (fatal or life-threatening), must 
be reported on an SAE form to the company and on AE pages in the 
CRF. Certain lab values are however not required to be reported as SAEs 
as defined in the protocol. 
 
We will follow Directive 2001/20/EC, Article 17 1(a) and shall ensure that all relevant 
information about suspected serious unexpected adverse reactions that are fatal or life-
threatening will be reported to competent authorities and to the concerned Ethical 

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Committees within seven days. We will not be able to comply with Article 17(b) for all other 
suspected serious unexpected adverse reactions to be reported within fifteen days since they 
will not be collected. 
 
Based on the known safety profile of emapalumab and Kineret, the sponsor is of the opinion that their 
administration in the unapproved indication of COVID-19 infection would not pose additional risk to 
subject safety compared to normal clinical practice. 
 
 
4. 
The Sponsor will establish a risk-based approach to monitoring and, considering the current 
situation, will need to utilize remote monitoring only during study conduct. 
 
To ensure ongoing subject safety and well-being, and control risks to study critical processes, such as 
review of informed consent forms and primary efficacy variables, alternative mechanisms of oversight 
will be introduced (such as phone calls, video calls etc). The Sponsor will also investigate if other 
measures for sharing data can be implemented, e.g. sharing de-identified source documents in shared 
drives/locations.  
 
 
5. 
CV:s for the prinicpal investigator at each site will be collected, but not for the 
subinvestigators. 
 
6. 
Information on experience of prior clinical trials and GCP training for the 
investigators will not be collected. 
 
7. 
Financial disclosure forms for the investigators will not be collected. 
 
8. 
Delegation log on site will not be implemented. 
 
9. 
A source data documentation log will not be established 
 
10. 
A sample handling procedure will not be provided. 
 
11. 
Laboratory accreditation will not be available at start of the study but collected 
later. 
 
 
Looking forward to any comments AIFA may have.Yours sincerely, 
 
 
 

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Christina Rickhammar 
VP Global Regulatory Affairs 
Swedish Orphan Biovitrum AB (publ)