A Pilot, Open-label, Single Arm, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics and Efficacy of Intravenous Administrations of Emapalumab, an Anti-interferon Gamma (Anti-IFNγ) Monoclonal Antibody, in Patients With Systemic Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still's Disease (AOSD) Developing Macrophage Activation Syndrome/Secondary HLH (MAS/sHLH)
Phase: PHASE2
Conditions: Macrophage Activation Syndrome, Lymphohistiocytosis, Hemophagocytic, Arthritis, Juvenile, Adult Onset Still Disease
Sponsor: Swedish Orphan Biovitrum

Sobi AG
NI-0501-06
Emapalumab
Protocol and protocol amendments
Confidential 
Study title: A pilot, open-label, single arm, multicenter study to 
evaluate safety, tolerability, pharmacokinetics and efficacy of 
intravenous administrations of emapalumab, an anti-interferon 
gamma (anti- IFNγ) monoclonal antibody, in patients with systemic 
Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still’s Disease 
(AOSD) developing Macrophage Activation Syndrome/secondary 
HLH (MAS/sHLH)
ClinicalTrials.gov ID: NCT03311854
Protocol and protocol amendments 
Final protocol, version 2.0 US, dated 07 January 2020 
Final protocol, version 1.0 US, dated 19 October 2017 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
INVESTIGATOR AGREEMENT 
 
Protocol Number: NI-0501-06  
 
Protocol date and version: 7 January 2020 – VERSION 2.0 US 
 
Study drug: emapalumab,  also referred to as NI-0501  
 
Study title: A pilot, open-label, single arm, multicenter study to evaluate safety, tolerability, 
pharmacokinetics and efficacy of intravenous administrations of emapalumab, an anti-interferon 
gamma (anti-IFNγ) monoclonal antibody, in patients with systemic Juvenile Idiopathic Arthritis 
(sJIA) 
or 
Adult-onset 
Still’s 
Disease 
(AOSD) 
developing 
Macrophage 
Activation 
Syndrome/secondary HLH (MAS/sHLH). 
 
Investigator endorsement: 
I, the undersigned, am responsible for the conduct of this study at this site and agree to conduct the 
study according to the protocol and any approved protocol amendments, ICH GCP and all applicable 
regulatory authority requirements. 
I will not deviate from the protocol without prior permission from the Sponsor and prior review and 
written approval from the Institutional Review Board/Independent Ethics Committee, and where 
applicable, from the Competent Authorities, except where necessary to prevent any immediate danger 
to a patient. 
I have read and understand fully the Investigator Brochure for emapalumab and I am familiar with the 
investigational product and its use according to this protocol. 
 
 
 
 
 
 
 
_______________________________________  
 
 
____________________ 
Site Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
_______________________________________ 
Site Investigator’s Name 
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Study NI-0501-06         
    Emapalumab in MAS/sHLH in sJIA/AOSD patients
 Page 3 of 76 
Protocol NI-0501-06 
 Version 2.0 US – 7 January 2020 
 CONFIDENTIAL 
CONTACT LIST 
Study Location: 
Study Principal Investigator: 
Sponsor: 
Chief Medical Officer 
Immunology: 
Drug Safety Physician 
Sr. Clinical Science Leader: 
Clinical Operations Manager: 
Clinical Pharmacologist: 
Data Protection Officer 
Multicenter in North America 
Sobi AG  
12 Chemin des Aulx 
1228 Plan les Ouates 
Switzerland 
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Study NI-0501-06         
    Emapalumab in MAS/sHLH in sJIA/AOSD patients
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Protocol NI-0501-06 
 Version 2.0 US – 7 January 2020 
 CONFIDENTIAL 
NI-0501-06 SYNOPSIS 
Title: 
A pilot, open-label, single arm, multicenter study to evaluate safety, 
tolerability, 
pharmacokinetics 
and 
efficacy 
of 
intravenous 
administrations of emapalumab, an anti-interferon gamma (anti-IFNγ) 
monoclonal antibody, in patients with systemic Juvenile Idiopathic 
Arthritis (sJIA) or Adult-onset Still’s Disease (AOSD) developing 
Macrophage Activation Syndrome/ secondary HLH (MAS/sHLH)  
Sponsor: 
Sobi AG, Switzerland 
Study Type, Phase and 
Design: 

Interventional Phase 2 study

Open-label, single arm, international, multicenter study.
Please note: any reference made to MAS in this protocol should be 
intended as referring to the secondary form of HLH occurring in 
patients with sJIA/AOSD. 
Study Objectives: 
The main objectives of the study are: 

To describe the pharmacokinetics (PK) profile of emapalumab

To confirm the proposed dosing regimen of emapalumab.

To evaluate the safety and tolerability profile of intravenous (i.v.)
administrations of emapalumab

To assess the efficacy of emapalumabTo assess the levels of
relevant pharmacodynamic markers, such as IFN and main IFN-
induced chemokines (CXCL9, CXCL10).

To assess other potential disease markers (e.g. sCD25, sCD163,
IL-10, IL-6, IL-18, TNF).

To assess the immunogenicity of emapalumab
Study Population: 

sJIA and AOSD patients with MAS having shown inadequate
response to high dose glucocorticoid treatment.
Inclusion Criteria: 

Patients of both genders

sJIA patients: confirmed sJIA diagnosis. For patients presenting
with MAS in the context of the onset of sJIA, high presumption of
sJIA (as per Appendix A) will suffice for eligibility

AOSD patients: confirmed AOSD diagnosis as per Yamaguchi
criteria (Appendix E)

Diagnosis of active MAS confirmed by the treating rheumatologist,
having ascertained the followings:
Febrile patient presenting with: 
- Ferritin > 684 ng/mL 
and any two of: 
-
Platelet count  181 x109/L
-
AST levels > 48 U/L
-
Triglycerides > 156 mg/dL
-
Fibrinogen levels ≤ 360 mg/dL.
(see Appendix B) 

Patient presenting an inadequate response to high dose i.v.
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
glucocorticoid treatment administered for at least 3 days as per 
local standard of care (including but not limited to pulses of 30 
mg/kg methylprednisolone (mPDN) on 3 consecutive days).  
High i.v. glucocorticoid dose should not be lower than 2 mg/kg/ 
day of PDN equivalent in 2 divided doses (or at least 60 mg/day in 
patients of 30 kg or more). In case of rapid worsening of the 
patient’s condition and/or lab parameters, inclusion may occur 
within less than 3 days from starting high dose i.v. glucocorticoids. 
 
Tocilizumab, TNF inhibitors and canakinumab, if administered, 
have to be discontinued before emapalumab initiation.  
 
Informed consent provided by the patient (as required by local 
law), or by the patient’s legally authorized representative(s) with 
the assent of patients who are legally capable of providing it, as 
applicable. 
 
Having received guidance on contraception for both male and 
female patients sexually active and having reached puberty: 
Females of child-bearing potential require use of highly effective 
contraceptive measures (failure rate of less than 1% per year) from 
screening until 6 months after receiving last dose of the study drug. 
Highly effective contraceptive measures include: 
o Sexual abstinence 
o Hormonal contraceptives: combination or progesterone 
only 
o Intrauterine methods: intrauterine devices or systems 
o Bilateral tubal occlusion 
o Vasectomised partner 
Males with partners(s) of child-bearing potential must agree to take 
appropriate precautions (such as sexual abstinence, barrier 
contraception, vasectomy) to avoid fathering a child from 
screening until 6 months after receiving last dose of the study drug. 
Exclusion Criteria: 
 
 
Diagnosis of suspected or confirmed primary HLH or HLH 
consequent to a neoplastic disease. 
 
Active 
mycobacteria 
(typical 
and 
atypical), 
Histoplasma 
Capsulatum, Shigella, Salmonella, Campylobacter and Leishmania 
infections.  
 
Clinical suspicion of latent tuberculosis.  
 
Positive serology for HIV antibodies. 
 
Presence of malignancy. 
 
Patients who have another concomitant disease or malformation 
severely affecting the cardiovascular, pulmonary, CNS, liver or 
renal function that in the opinion of the Investigator may 
significantly affect likelihood to respond to treatment and/or 
assessment of emapalumab safety.  
 
History of hypersensitivity or allergy to any component of the 
study drug. 
 
Receipt of a BCG vaccine within 12 weeks prior to screening. 
 
Receipt of live or attenuated live vaccines (other than BCG) within 
6 weeks prior to screening. 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
 
Pregnant or lactating female patients. 
Study Drug: 
 
Emapalumab, previously referred to as NI-0501, is a fully human 
IgG1 monoclonal antibody (mAb) directed against human IFNγ. 
Dosing Regimen, Frequency 
of Administration & 
Treatment Duration: 
 
 
Emapalumab will be administered at the initial dose of 6 mg/kg by 
infusion. 
 
Emapalumab treatment will be continued at the dose of 3 mg/kg, 
every 3 days until SD15, and then twice-a-week for additional 2 
weeks, i.e. until SD28.  
 
Treatment may be shortened upon achievement of complete 
clinical response (i.e. MAS remission), however at least two 
infusions of emapalumab at the dose of 3 mg/kg have to be 
administered (i.e. after SD6).  
 
In the absence of a trend of improvement in key MAS parameters 
(including, but not limited to ferritin, LDH, AST/ALT and PLT 
count) suggestive of lack of response, the emapalumab regimen 
may be adapted (the frequency between infusions shortened, the 
dose increased or the treatment prolonged beyond 4 weeks) upon 
assessment of a favorable benefit/risk profile. 
Background Therapy & 
Concomitant Medication: 
 
Emapalumab will be administered on a background of at least 2 
mg/kg/day of PDN equivalent ( or at least 60 mg/day in patients of 
30 kg or more), which can be tapered during the treatment 
depending on patient conditions. Cyclosporine A (CsA) may be 
continued if started at least 3 days prior to initiation of 
emapalumab treatment. CsA dose adjustments are allowed in order 
to maintain therapeutic levels. CsA can be withdrawn at any time 
during the study, upon judgment of the Investigator. CsA should 
not be introduced once emapalumab treatment has started. 
 
Patients must receive prophylactic treatment for Herpes Zoster 
infections starting preferably the day before (and in any case prior 
to initiation of emapalumab treatment), and treatment must 
continue until serum emapalumab levels are no longer detectable. 
 
If being administered and if started (at any dose) at least 3 days 
before initiation of emapalumab treatment, anakinra may be 
continued at a maximum dose of 4mg/kg. 
 
Tocilizumab, canakinumab or TNF inhibitors as sJIA/AOSD 
treatment must be discontinued at the latest before the first 
emapalumab infusion.  
 
Methotrexate may be continued if ongoing as treatment for the 
underlying disease.   
 
In the case of an acute inflammatory flare of the underlying 
sJIA/AOSD during treatment with emapalumab, anakinra may be 
introduced at a dose of 1 to 4 mg/kg (max. daily dose 100 mg). 
Such episodes shall be adjudicated by at least two members of the 
SSC (excluding the treating physician, if applicable), in order to 
ascertain their nature (i.e. sJIA/AOSD versus MAS flare). 
 
If the patient is receiving intrathecal therapy (e.g. methotrexate and 
glucocorticoids) at the time of emapalumab treatment initiation, 
this treatment will be continued until clinically indicated.  
 
Vaccination with a live or attenuated-live (including BCG) vaccine 
must be avoided during the whole study until serum emapalumab 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
levels are no longer detectable.  
 
Analgesic treatment, transfusion of blood products, electrolyte and 
glucose infusions, i.v. parenteral nutrition, inotropic support, 
antibiotics, anti-fungal and anti-viral treatments, ultrafiltration or 
hemodialysis, as well as general supportive care are permitted. 
Sample Size: 
 
 Approximately 12 patients (and a minimum of 10 sJIA patients) 
will be enrolled in North America and Europe in total. 
 
Number of Sites and 
Recruitment Duration: 
 
International, multi-center. 
 
The recruitment period, in this rare population, is estimated to be 
approximately 2 years. A twin protocol NI-0501-06 EUDRACT 
2016-004223-23 is running in Europe. 
 
Patients enrolled under these two protocols  will be analyzed 
jointly and data reported in a single CSR.  
Study Duration and Study 
End Definition:   
 
The duration of the study will be at least 8 weeks for each patient 
(plus up to 1 week screening period). A short-term follow-up of 4 
weeks  follows SD28 or the last emapalumab infusion whichever 
occurs  later 
Note: If emapalumab treatment is prolonged beyond 4 weeks in a 
given patient, additional visits will be performed weekly until 
completion of a 4-week follow-up after the last emapalumab 
infusion, short-term follow-up that should occur under the present 
protocol. 
 
End of the study is defined as last patient last visit. 
 
All patients who have received at least one dose of emapalumab 
will be asked to enter a long-term follow-up study.  
Study Scientific Oversight/ 
Study Safety Monitoring : 
 
A Scientific Steering Committee (SSC) composed of international 
experts in pediatric rheumatology as well as in HLH has been 
involved in the preparation of study design and will continue to 
play an advisory role throughout the course of the study, to support 
the iDMC in the study oversight, and the Sponsor in the 
interpretation of the study results. 
 
An independent Data Monitoring Committee (iDMC) composed of 
relevant experts (pediatric rheumatologist, hemato-oncologist with 
experience in HLH, pediatric immune deficiency/infectious disease 
specialist, bio-statistician and a specialist in ethics) will oversee the 
safety management of the study, reviewing all data generated on an 
ongoing basis with the aim to ensure that patients are not exposed 
to unnecessary risks. 
Study Endpoints: 
Pharmacokinetics and Pharmacodynamics  
 
PK profile of emapalumab.  
 
Levels of circulating free IFN at pre-dose, and total IFNγ (free 
IFNγ+bound to emapalumab) after initiation of emapalumab. 
 
Levels of the main IFNγ-induced chemokines (CXCL9, CXCL10). 
 
Correlation between chemokine levels (CXCL9, CXCL10) and 
levels of free emapalumab, free IFNγ (pre-dose) and total IFNγ 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
(exploratory analysis). 
 
Correlation of chemokine and total IFNγ levels, and laboratory 
parameters of MAS severity, e.g. ferritin, platelet count, LFTs 
(exploratory analysis). 
 
Levels of other potential disease markers (e.g. sCD25, sCD163, IL-
10, IL-6, IL-18, TNF).  
 
Levels (if any) of circulating antibodies against emapalumab to 
determine immunogenicity (ADA). 
In particular, based on: 
 
levels of circulating emapalumab  
 
levels of total IFNγ  
 
levels of IFNγ–induced chemokines (namely CXCL9 and 
CXCL10) 
a PK/PD modelling will be used to confirm that the proposed dose 
regimen is adequate in relation to the IFNγ production in this patient 
population. 
 
Safety 
The tolerability and safety of emapalumab treatment will be assessed 
as follows: 
 
Incidence, severity, causality and outcomes of AEs (serious and 
non-serious), with particular attention being paid to infections. 
 
Evolution of laboratory parameters, in particular CBC, LFTs, 
inflammatory markers (ferritin and CRP) and coagulation 
parameters. 
 
Number of patients withdrawn from the study due to safety 
reasons. 
 
Efficacy  
An assessment of emapalumab efficacy in this patient population will 
be based on the following variables: 
 
Number of patients achieving MAS remission by Week 8 after 
initiation of emapalumab treatment. 
 
Time to MAS remission. 
 
Number of patients for whom at any time during the study 
glucocorticoids can be tapered i) to the same (or lower) dose being 
administered before the occurrence of MAS (in those patients who 
are already treated for the underlying condition) or ii) by 50% (or 
less) of the dose administered at emapalumab treatment start (in 
those patients who present with MAS at disease onset).  
 
Time to glucocorticoids tapering (as above described). 
 
Survival time. 
 
Number of patients withdrawn from the study due to lack of 
efficacy. 
Statistical Analysis: 
 
All study variables are considered to be exploratory in this study, 
and no hierarchy of endpoints has been specified, as the objective 
of this pilot study is to collect and analyze data to confirm that the 
proposed dose regimen is adequate in this patient population. 
Statistical methods will therefore focus on summarizing the data 
collected using descriptive statistics and on appropriate graphical 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
presentations.  
 
For binary endpoints (MAS remission by Week 8, number of 
patients who taper glucocorticoids, number of patients who 
discontinue due to lack of efficacy), 95% confidence intervals will 
be calculated for proportions. 
 
For time to event endpoints (time to MAS remission, time to 
achievement of glucocorticoids tapering and time to death), 
Kaplan-Meier curves will be calculated and summary statistics, 
such as medians, proportions event-free at various time points will 
be calculated and presented, and 95% confidence intervals 
calculated where possible.   
 
Data relating to safety will be listed and summarised using 
descriptive statistics. 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ADA 
Anti-drug-antibodies 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
AOSD 
aPTT 
Adult-onset Still’s Disease 
Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
BCG 
Bacillus Calmette-Guérin 
BSA 
Body Surface Area 
CBC 
Complete blood cell count 
CDC 
Complement Dependent Cytotoxicity 
CL 
Systemic drug clearance 
Cmax 
Peak drug plasma concentration  
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CpG 
Cytosine-phosphate-guanine 
CRF 
Case report form 
CRP 
C-reactive protein 
CsA 
Cyclosporin A 
CSF 
Cerebrospinal fluid 
Ctrough 
Plasma drug concentration immediately prior next dosing 
CU 
Compassionate use 
CXCL9 
Chemokine (C-X-C Motif) Ligand 9 
CXCL10 
Chemokine (C-X-C Motif) Ligand 10 
CXCL11 
Chemokine (C-X-C Motif) Ligand 11 
EBV 
Epstein-Barr virus 
EoT 
End of treatment 
EoS 
End of study 
γGT 
Gamma Glutamyl Transferase 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HLH 
Hemophagocytic lymphohistiocytosis 
HSCT 
Hematopoietic stem cell transplantation 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
HSV 
Herpes simplex virus 
HZ 
Herpes Zoster 
HZV 
Herpes Zoster virus 
ICMJE 
International Committee of Medical Journal Editors  
iDMC 
Independent Data Monitoring Committee 
IFNγ 
Interferon gamma 
IFNγ-R1 
Interferon gamma receptor chain 1 
IFPMA 
International Federation of Pharmaceutical Manufacturers & Associations 
IgG1 
Immunoglobulin G1 
IL 
Interleukin 
ILAR 
International League of Associations for Rheumathology  
IMP 
Investigational medicinal product 
ITT 
Intention-to-treat 
i.v. 
Intravenous 
KD 
Dissociation constant 
KM 
Michaelis-Menten constant 
KO 
Knock Out  
LCMV 
Lymphocytic choriomeningitis virus 
LDH 
Lactate dehydrogenase 
LFTs 
Liver function tests 
LLN 
Lower limit of normal 
mAb 
Monoclonal antibody 
MAS 
Macrophage activation syndrome 
mPDN 
Methylprednisolone 
MRI 
Magnetic resonance imaging 
NK 
Natural killer 
NaCl 
Sodium chloride 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PDG 
Preliminary diagnostic guidelines (Ravelli et al., 2005) 
PDN 
pHLH 
Prednisone 
Primary HLH 
PK 
Pharmacokinetic 
PLT 
Platelets 
PPD 
Purified protein derivative 
PT 
Prothrombin Time 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
SAD 
Single ascending dose 
sCD25 
soluble CD25 (i.e. soluble IL-2 receptor) 
SD(n) 
Study Day number (e.g. Study day 1 = SD1) 
sJIA 
Systemic Juvenile Idiopathic Arthritis 
SoA 
Schedule of assessments 
SSC 
Scientific steering committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
t1/2  
Elimination half-life 
Tmax 
Time when plasma concentration is at peak 
TMDD 
Target mediated drug disposition 
TMF 
Trial Master File 
TNFα 
Tumor necrosis factor alpha 
ULN 
Upper limit of normal 
US 
Ultrasonography 
Vss 
Volume of distribution at steady state 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT ...................................................................................................... 2 
CONTACT LIST .................................................................................................................................. 3 
NI-0501-06 SYNOPSIS ......................................................................................................................... 4 
LIST OF ABBREVIATIONS ............................................................................................................ 10 
1 
BACKGROUND INFORMATION .......................................................................................... 17 
1.1 
EMAPALUMAB .......................................................................................................................... 17 
1.1.1 
Description and mode of action ...................................................................................... 17 
1.1.2 
Preclinical Data .............................................................................................................. 17 
1.1.3 
Clinical Data ................................................................................................................... 18 
1.2 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) ............................................................... 19 
1.2.1 
Macrophage Activation Syndrome (MAS) ....................................................................... 19 
1.3 STUDY RATIONALE .................................................................................................................. 22 
1.3.1 
Rationale for developing emapalumab in MAS ............................................................... 22 
1.3.2 
Rationale for conducting a Clinical Study in MAS in sJIA/AOSD  patients receiving 
emapalumab treatment ................................................................................................................. 23 
2 
OBJECTIVES ............................................................................................................................ 24 
3 
STUDY DESIGN ........................................................................................................................ 25 
3.1 OVERALL DESIGN .................................................................................................................... 25 
3.2 SCREENING PERIOD .................................................................................................................. 25 
3.3 TREATMENT PERIOD ................................................................................................................ 26 
3.4 FOLLOW-UP PERIOD ................................................................................................................ 26 
3.5 STUDY END ............................................................................................................................... 26 
3.6 LONG-TERM FOLLOW-UP  STUDY ............................................................................................. 27 
4 
TARGET POPULATION ......................................................................................................... 27 
4.1 ELIGIBILITY CRITERIA ............................................................................................................. 27 
4.1.1 
Inclusion Criteria ............................................................................................................ 27 
4.1.2 
Exclusion Criteria ........................................................................................................... 28 
5 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ....................................................... 28 
5.1 DESCRIPTION OF IMP ............................................................................................................... 28 
5.2 DOSING REGIMEN ..................................................................................................................... 29 
5.3 RATIONALE FOR DOSE SELECTION ........................................................................................... 29 
5.4 IMP HANDLING ........................................................................................................................ 32 
5.4.1 
Packaging and Labeling.................................................................................................. 32 
5.4.2 
IMP Supply ...................................................................................................................... 32 
5.4.3 
IMP Receipt and Storage ................................................................................................ 32 
5.4.4 
IMP Preparation, Administration, Accountability and Destruction ............................... 32 
6 
PATIENT BACKGROUND TREATMENT AND CARE ..................................................... 33 
6.1 GLUCOCORTICOIDS .................................................................................................................. 33 
6.2 PROPHYLACTIC TREATMENT .................................................................................................... 34 
6.3 CONCOMITANT THERAPY......................................................................................................... 34 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
6.3.1 
Cyclosporine A, methotrexate and anakinra ................................................................... 34 
6.3.2 
Intrathecal Therapy ......................................................................................................... 35 
6.3.3 
Other possible concomitant therapies ............................................................................. 35 
6.3.4 
Not allowed concomitant therapies ................................................................................. 35 
6.4 EMERGENCY TREATMENT ........................................................................................................ 35 
6.5 RESCUE THERAPY .................................................................................................................... 35 
7 
ENDPOINTS .............................................................................................................................. 36 
7.1 PHARMACOKINETICS ENDPOINTS ............................................................................................ 36 
7.2 
PHARMACODYNAMICS ENDPOINTS .......................................................................................... 36 
7.3 SAFETY ENDPOINTS ................................................................................................................. 36 
7.4 EFFICACY ENDPOINTS .............................................................................................................. 37 
8 
OUTLINE OF STUDY PROCEDURES .................................................................................. 37 
8.1 STUDY VISITS ........................................................................................................................... 37 
8.2 INFORMED CONSENT AND SCREENING PROCEDURES ............................................................... 38 
8.3 CLINICAL ASSESSMENTS .......................................................................................................... 43 
8.3.1 
Vital signs ........................................................................................................................ 43 
8.3.2 
Physical examination ...................................................................................................... 43 
8.3.3 
MAS clinical signs and symptoms ................................................................................... 43 
8.4 LABORATORY ASSESSMENTS ................................................................................................... 44 
8.5 SEARCH FOR INFECTIONS ......................................................................................................... 44 
8.6 IMAGING ................................................................................................................................... 45 
8.6.1 
Abdominal ultrasound ..................................................................................................... 45 
8.6.2 
Chest X-ray ...................................................................................................................... 45 
8.6.3 
Brain MRI........................................................................................................................ 45 
8.7 OTHER PROCEDURES ................................................................................................................ 45 
8.7.1 
ECG ................................................................................................................................. 45 
8.7.2 
Cerebrospinal fluid assessment ....................................................................................... 46 
8.8 PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ....................................................... 46 
8.8.1 
Pharmacokinetics ............................................................................................................ 46 
8.8.2 
Pharmacodynamics ......................................................................................................... 46 
8.8.3 
Immunogenicity ............................................................................................................... 47 
8.9 WITHDRAWAL VISIT ................................................................................................................ 47 
8.10 
UNPLANNED (UNSCHEDULED) VISITS ................................................................................. 47 
8.10.1 
Unplanned Assessments .............................................................................................. 47 
9 
STUDY SCIENTIFIC OVERSIGHT ....................................................................................... 47 
10 
SAFETY MONITORING .......................................................................................................... 47 
10.1 
INDEPENDENT DATA MONITORING COMMITTEE .................................................................. 47 
10.2 
DESCRIPTION OF SAFETY PARAMETERS .............................................................................. 48 
10.3 
RECORDING AND REPORTING SAFETY PARAMETERS .......................................................... 48 
10.3.1 
Adverse events ............................................................................................................. 48 
10.3.2 
Serious Adverse Events ............................................................................................... 49 
10.3.3 
SUSAR reporting ......................................................................................................... 50 
10.4 
FOLLOW-UP OF SAFETY PARAMETERS ................................................................................ 51 
10.4.1 
Treatment and Follow-up of Adverse Events .............................................................. 51 
10.4.2 
Pregnancy ................................................................................................................... 51 
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10.5 
BENEFIT/RISK MANAGEMENT ............................................................................................. 51 
10.5.1 
Safety Surveillance Management - iDMC ................................................................... 51 
10.5.2 
General Benefit/Risk Considerations .......................................................................... 51 
11 
STOPPING RULES ................................................................................................................... 55 
11.1 
AT PATIENT LEVEL .............................................................................................................. 55 
11.1.1 
Investigator’s or Patient’s Decision to Discontinue ................................................... 55 
11.1.2 
Decision to Discontinue Treatment due to Safety Reason or Lack of Efficacy ........... 55 
11.1.3 
Systemic and local reaction to emapalumab infusion ................................................. 56 
11.2 
AT STUDY LEVEL................................................................................................................. 56 
11.2.1 
Suspension of Recruitment .......................................................................................... 56 
11.2.2 
Study Termination ....................................................................................................... 56 
12 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .................................... 57 
12.1 
SAMPLE SIZE ........................................................................................................................ 57 
12.2 
ANALYSIS SETS .................................................................................................................... 57 
12.2.1 
Safety Analysis Set ...................................................................................................... 57 
12.2.2 
Intent-to-Treat Analysis Set ........................................................................................ 57 
12.2.3 
Per-Protocol Analysis Set ........................................................................................... 57 
12.3 
STATISTICAL AND ANALYTICAL METHODS......................................................................... 57 
12.3.1 
Efficacy Data .............................................................................................................. 58 
12.3.2 
Safety Data .................................................................................................................. 58 
12.3.3 
Pharmacodynamic Data ............................................................................................. 58 
12.3.4 
Immunogenicity Data .................................................................................................. 58 
12.3.5 
Missing Data ............................................................................................................... 58 
12.4 
INTERIM ANALYSIS .............................................................................................................. 59 
12.5 
WITHDRAWAL AND REPLACEMENT ..................................................................................... 59 
12.5.1 
Patients ....................................................................................................................... 59 
12.5.2 
For Centers ................................................................................................................. 59 
13 
ETHICAL AND LEGAL ASPECTS ........................................................................................ 60 
13.1 
GOOD CLINICAL PRACTICE .................................................................................................. 60 
13.2 
INVESTIGATOR’S RESPONSIBILITIES .................................................................................... 60 
13.3 
CONSENT.............................................................................................................................. 60 
13.4 
CONFIDENTIALITY AND DATA PRIVACY ............................................................................. 61 
13.5 
PROTOCOL AMENDMENTS ................................................................................................... 61 
13.6 
APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS ................................ 62 
13.7 
ONGOING INFORMATION FOR IRB/IEC ............................................................................... 62 
13.8 
CLOSURE OF THE STUDY ..................................................................................................... 62 
13.9 
RECORD RETENTION ............................................................................................................ 63 
13.10 LIABILITY AND INSURANCE ................................................................................................. 63 
13.11 FINANCIAL DISCLOSURE ...................................................................................................... 63 
13.12 DISCLOSURE OF PROTOCOL AND STUDY RESULTS AND PUBLICATION POLICY .................. 63 
14 
MONITORING AND AUDITING ........................................................................................... 64 
14.1 
STUDY MONITORING AND SOURCE DATA VERIFICATION ................................................... 64 
14.2 
ON-SITE AUDITS .................................................................................................................. 64 
14.3 
SERIOUS GCP BREACHES .................................................................................................... 64 
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15 
DOCUMENTATION AND USE OF STUDY FINDINGS ..................................................... 65 
15.1 
DOCUMENTATION OF STUDY RESULTS ............................................................................... 65 
15.2 
USE OF COMPUTERIZED SYSTEMS AT THE CLINICAL TRIAL CENTER ................................. 65 
16 
REFERENCES ........................................................................................................................... 66 
17 
APPENDICES ............................................................................................................................ 71 
APPENDIX A: OPERATIONAL CASE DEFINITION OF NEW ONSET SJIA USED IN 
DEVELOPMENT OF TREATMENT PLANS (DESIGNED BY CHILDHOOD ARTHRITIS 
AND RHEUMATOLOGY RESEARCH ALLIANCE) ................................................................... 72 
APPENDIX B: 2016 CLASSIFICATION CRITERIA FOR MACROPHAGE ACTIVATION 
SYNDROME COMPLICATING SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS: A 
EUROPEAN LEAGUE AGAINST RHEUMATISM/AMERICAN COLLEGE OF 
RHEUMATOLOGY/PAEDIATRIC RHEUMATOLOGY INTERNATIONAL TRIALS 
ORGANISATION COLLABORATIVE INITIATIVE................................................................... 73 
APPENDIX C: MEMBERSHIP OF THE SCIENTIFIC STEERING COMMITTEE (SSC)..... 74 
APPENDIX D: ESTIMATED BLOOD VOLUMES TO BE DRAWN DURING THE STUDY. 75 
APPENDIX E: PRELIMINARY CRITERIA FOR CLASSIFICATION OF ADULT STILL’S 
DISEASE ............................................................................................................................................. 76 
  
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PART I 
1 
BACKGROUND INFORMATION 
1.1 
EMAPALUMAB 
1.1.1 
Description and mode of action 
Emapalumab is a fully human IgG1 anti-interferon gamma (IFNγ) monoclonal antibody (mAb) which 
binds and neutralizes IFNγ. emapalumab binds to soluble and receptor (IFNγR1)-bound forms of 
IFNγ.  
Since emapalumab is a human IgG1, it retains the characteristics of this immunoglobulin isotype.  
After binding to its receptor, IFNγ acts to produce a variety of physiological and cellular responses. 
Numerous studies over the last 20 years have associated IFN with the pathogenesis and the 
maintenance of inflammatory diseases (Billiau A 1996, Schoenborn JR 2007, Zhang SY 2008), and 
most recently, in the pathogenesis of HLH. 
1.1.2 
 Preclinical Data  
1.1.2.1 
Non-clinical Pharmacology 
Emapalumab has shown similar binding affinity and blocking activity for IFNγ from non-human 
species, including Rhesus and Cynomolgus monkeys, but not from dogs, cats, pigs, rabbits, rats or 
mice.  
Due to emapalumab capacity to bind free and IFNγR1-bound IFNγ, studies were performed to 
investigate the potential of emapalumab to mediate antibody dependent cellular cytotoxicity (ADCC) 
and complement dependent cytotoxicity (CDC) activities, in the presence of target. A lack of ADCC 
activity was demonstrated and no induction of CDC activity was observed.  
1.1.2.2 
Toxicology 
Binding and functional data demonstrated Rhesus or Cynomolgus monkeys to be relevant species to 
evaluate the safety of emapalumab. No off-target toxicity was attributed to the drug when 
administered to Cynomolgus monkeys in 13 weekly doses of up to 200 mg/kg. An enhanced 
susceptibility to infections due to the pharmacological effect of the drug was observed at all dose 
levels (10 to 200 mg/kg/week) in animals originally harboring gastrointestinal pathogens (Shigella, 
Salmonella, Campylobacter) prior to emapalumab administration. In a study where Cynomolgus 
monkeys were not initially found to be harboring gastrointestinal pathogens, weekly administrations 
of emapalumab for 8 consecutive weeks at doses up to 30 mg/kg were well tolerated, without the need 
for antibiotic prophylaxis.  
Results from a human tissue cross-reactivity study, involving a panel of 35 different human tissues, 
demonstrated that emapalumab did not cross-react with any of the human samples tested. 
1.1.2.3 
Safety pharmacology 
There were no abnormal findings in ECGs taken periodically during treatment and recovery periods in 
the 8 week and 13 week repeated dose toxicology studies in Cynomolgus monkeys, where animals 
were exposed to doses up to 200 mg/kg of emapalumab weekly. No abnormal findings were observed 
in the histopathological investigations of the hearts and lungs in these animals compared to untreated 
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animals. Histopathological analysis of kidneys from these animals revealed no abnormal findings and 
the periodic urinalysis readings were also normal, indicating no abnormal effects on renal function. 
There were no histopathological findings in brains in both studies. Furthermore, no abnormal behavior 
of the animals was observed throughout the study periods, suggesting no effects on CNS.  
1.1.3 
 Clinical Data 
Note to the reader: in order to reflect the information available at the time the study was initiated this 
section is not being updated. Please refer to the most current Investigator`s Brochure to ensure 
awareness of the data that served as basis for the approval of  emapalumab in the US for the 
treatment of adult and pediatric (newborn and older) patients with pHLH with refractory, recurrent 
or progressive disease or intolerance with conventional HLH therapy and to ensure awareness of all 
available clinical data. 
A Phase 1 randomized double-blinded placebo-controlled single ascending dose study in 20 healthy 
adult volunteers investigating the safety, tolerability and pharmacokinetic profiles of single 
intravenous (i.v.) administrations of emapalumab was conducted between September 2011 and April 
2012. During this study a total of 14 subjects received increasing doses of 0.01, 0.1, 1, and 3 mg/kg 
emapalumab (3, 3, 4, and 4 subjects, respectively), while 6 subjects received placebo. 
The pharmacokinetics (PK) analysis of emapalumab revealed the expected profile for an IgG1 with a 
half-life of approx. 22 days, a slow clearance (≤ 0.007 L/h) and a low volume of distribution (< 6 L on 
average). 
All emapalumab infusions were uneventful.  
A similar incidence of commonly reported infections (e.g., upper respiratory tract infections) was 
observed after administration of emapalumab and in subjects who had received placebo.  
A Herpes Zoster (HZ) infection was reported in one subject (
), 14 days after his infusion 
of 3 mg/kg of emapalumab. This event was assessed as related to the emapalumab infusion and 
considered as serious (medically significant) in the context of a Phase 1 study in healthy volunteers 
(HVs). Its intensity was moderate and its course normal under antiviral therapy. The subject recovered 
with no sequelae.  
An increased susceptibility to HZ infections in patients having developed auto-antibodies against 
IFNγ (Browne SK 2012) or having received ustekinumab (a mAb which decreases IFNγ production by 
inhibiting the p40 subunit of IL-12) has been described in the literature (Failla V 2011).  
In conclusion, the infusion of emapalumab was well tolerated and the effects observed during the 8 
week monitoring after drug infusion did not reveal any serious or unexpected off-target safety or 
immunogenicity concerns.  
A study to evaluate the efficacy and safety of emapalumab treatment in patients with primary HLH 
(protocol NI-0501-04) has been completed. The protocol allows for inclusion of patients either 
treatment-naïve (first line patients) or reactivating after initial response to conventional therapy or not 
achieving a satisfactory response or showing intolerance to conventional therapy (second line 
patients). Based on preliminary efficacy and safety evidence, and on the positive benefit/risk profile 
observed so far, the study, which originated as Phase 2 trial, has been recently amended to continue as 
Phase 2/3 study with the inclusion of the same study population (i.e., first and second line pHLH 
patients). Thirty-one patients have been enrolled as of September 15th 2016, of whom 18 received 
transplantation. Five patients received emapalumab as 1st line therapy. More than 500 emapalumab 
infusions have been performed in the study patients who have received a median of 7 weeks of 
therapy (range 4 days-31 weeks; continuation of emapalumab treatment beyond 8 weeks can occur 
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under the long-term follow-up protocol NI-0501-05). Infusions have been well tolerated with no 
premedication needed, and no safety concerns after emapalumab administration have emerged to date. 
Based on data gathered so far, emapalumab treatment has shown the potential to improve relevant 
clinical and laboratory features of HLH such as fever, splenomegaly, cytopenia, hyperferritinemia, 
hypofibrinogenemia, and also CNS signs and symptoms. Early tapering of glucocorticoids has been 
possible in the majority of patients. 
For updated information about the above, please refer to the most recent Investigator`s Brochure. 
1.2 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) 
HLH is a rare, serious and life threatening disease of pathologic immune activation, characterized by 
clinical signs and symptoms of extreme inflammation (fever, splenomegaly, cytopenias, 
coagulopathy), leading to the development of abnormal immune-mediated pathologies which, through 
tissue damage, ultimately may cause multi-organ failure and death (Henter JI(a) 1991). 
HLH comprises primary (genetic/familial) HLH and secondary HLH. 
Primary HLH is a heterogeneous autosomal recessive disorder, mostly seen in infancy and early 
childhood with an estimated prevalence in Europe of 1/50,000 live births (Henter JI(b) 1991). The 
disease is invariably fatal with a median survival of less than 2 months after onset of symptoms, if 
untreated (Janka GE(a) 1983).  
The genetic defects in primary HLH affect genes involved in cytotoxic pathway of NK-cells and/or 
cytotoxic lymphocytes required to eliminate activated macrophages, encoding proteins for perforin 
synthesis, cytolytic granule maturation, granule exocytosis and release (Filipovich A 2010). In 
addition, some immunodeficiency syndromes, e.g. Griscelli syndrome type 2 (GS-2) and Chediak-
Higashi syndrome (CHS), present frequently with HLH (Janka GE(b) 2013). 
Secondary forms of HLH can occur during the course of an infection, an autoimmune/rheumatic 
disease or in association to a malignancy. Secondary forms present with the same signs and symptoms 
of primary HLH and can be equally severe.  
The presence of signs and symptoms of HLH in patients suffering from a rheumatic disease, such as 
systemic Juvenile Idiopathic Arthritis (sJIA) and Systemic Lupus Erythematosus (SLE), is often 
referred to by rheumatologists as Macrophage Activation Syndrome (MAS), as more specifically 
described in the following section.   
Adult-onset Still’s disease is a rare autoinflammatory disorder sharing the same clinical manifestations 
and laboratory findings of sJIA (Jamilloux Y 2015). Although traditionally they have been viewed as 
separate disease entities, there is growing recognition that sJIA and AOSD represent a disease 
continuum with different ages of onset, based on a number of shared clinical, genetic and laboratory 
features, as well as a strikingly similar response to IL-1 and IL-6 inhibitors (Giampietro C 2012, Feist 
E 2018, Nirmala N 2015). 
Importantly, clinical similarities include a clear predisposition to develop MAS in both sJIA and 
AOSD (Ruscitti P 2017).  
In the present protocol, any reference made to MAS should be intended as referring to the secondary 
form of HLH occurring in patients with sJIA/AOSD. 
1.2.1 
Macrophage Activation Syndrome (MAS)  
MAS is a severe, potentially life-threatening complication of rheumatic diseases which is caused by 
excessive activation and expansion of T lymphocytes and macrophages. The uncontrolled expansion 
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of these immune cells results in a marked hypercytokinemia and a hyperinflammatory state associated 
with fever, cytopenias, hepatosplenomegaly, liver dysfunction, coagulation abnormalities and 
hyperferritinemia, and may progress to multiple organ failure and death (Schulert GS 2015). 
Because of its strong clinical and pathological similarity to HLH, MAS is classified among the 
secondary or acquired forms of HLH. In fact, it has been recently demonstrated that the majority of 
patients with MAS have impaired NK and perforin functional tests and that a significant number of 
MAS patients show polymorphisms or heterozygous mutations in PRF1 and UNC13D (Zhang M 
2014). 
MAS occurs most frequently in patients with sJIA and AOSD, less often with systemic lupus 
erythematosus (SLE), but is also described, though more rarely, in patients with vasculitis, particularly 
with Kawasaki disease. Approximately 7–17% of patients with sJIA develop overt MAS 
(Moradinejad MH 2011, Sawhney S 2001), some evidence suggests that subclinical MAS may be seen 
in as many as one third of patients with active systemic disease (Behrens EM(b) 2007). 
Because MAS is potentially fatal, a timely diagnosis and immediate therapeutic intervention are 
essential for appropriate management of the disease. The reported mortality rates in MAS reach 20-
30%, and it remains the major source of mortality in pediatric rheumatology (Grom AA(b) 2016). 
Different sets of criteria have been proposed for the diagnosis of MAS in patients with sJIA. The 
HLH-2004 diagnostic guidelines (Henter JI(c) 2007), primarily developed for primary (genetic) forms 
of HLH, have sometimes been recommended. However, they present  several limitations when applied 
to patients with sJIA. For example, criteria such as cytopenias and hypofibrinogenemia below the 
thresholds required by HLH-2004 become evident only in the later stages of MAS, as these patients 
often have increased white blood cell and platelet counts as well as elevated serum levels of 
fibrinogen as a part of the sJIA inflammatory response (Schulert GS 2015). As for primary HLH, 
hemophagocytosis may not be present in a significant proportion of patients with MAS at presentation 
(Minoia F 2014). Moreover, hemophagocytosis, NK cell activity and sCD25 are not routinely assessed 
in the context of MAS.  
An alternative approach has been proposed based on the application of preliminary diagnostic 
guidelines (PDG) for MAS complicating sJIA, which were created through the analysis of a cohort of 
patients with MAS compared with a group of patients with a flare of sJIA (Ravelli A(a) 2005).  
The HLH-2004 diagnostic guidelines and the preliminary diagnostic guidelines for sJIA-associated 
MAS were compared for their capacity to discriminate sJIA/MAS from sJIA (in the absence of MAS) 
and systemic infection in a large patient population (Davì S 2014). Although with some limitations 
due to its retrospective nature, this study suggested that the preliminary MAS diagnostic guidelines 
may achieve a satisfactory balance between sensitivity and specificity, as well as concordance with the 
diagnosis made by the treating physician when differentiating patients with sJIA/MAS from sJIA, 
while their specificity in discriminating vs. systemic infections was < 30%. Moreover, it has been 
reported that the proportion of patients fulfilling each single criterion of the PDG is highly variable, 
and some clinical features (e.g. CNS dysfunction and hemorrhages) may manifest at a late stage of 
MAS, rendering their sensitivity low in incipient MAS (Lehmberg K 2013). The sensitivity of the 
adapted HLH-2004 set of 4 of 5 criteria was poor (35%), mainly explained by the low frequency of 
cytopenia and hypofibrinogenemia. 
Very recently, an EULAR/ACR-approved set of classification criteria sets have been proposed 
through a multistep process combining expert consensus and retrospective analysis of patient data 
(Ravelli A(b) 2016). These classification criteria did not unequivocally prove to be useful for 
diagnosis in clinical practice (about 30% of patients diagnosed by the treating physician were 
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classified as not having MAS), and showed important limitations to identify patients who developed 
MAS while receiving IL-1 and IL-6 inhibitors (De Benedetti F(b) 2015, Grom AA(a) 2016).     
The limitations of the thus far proposed criteria for MAS diagnosis render the clinical diagnosis by 
expert rheumatologists still key in the challenge to distinguish MAS from clinical conditions 
presenting with overlapping features such as flares of sJIA or sepsis-like syndromes. 
There are currently no approved drugs for the treatment of MAS. Likewise, no prospective studies 
have been conducted to evaluate the safety and efficacy of the drugs currently used for the treatment 
of MAS, and data is only available as limited case reports or as retrospective surveys.  
Usually, high-dose glucocorticoids are the first-line treatment for MAS. In patients failing to respond 
to glucocorticoids, Cyclosporine A (CsA) has been proposed as additional treatment (Stéphan JL 
2001).  
Being part of the HLH-94 treatment protocol developed for treating pHLH, the administration of 
etoposide is also considered in patients failing high dose glucocorticoids. However, the potential 
toxicity of the drug remains a major concern. 
The utility of biologics inhibiting the IL-1, IL-6R or TNFα pathways in the treatment of MAS still 
remains unclear. Although biologics inhibiting these pathways have been reported to be effective in 
isolated cases, there have been a few reports of sJIA patients developing MAS while receiving these 
treatments (Ramanan AV 2003, Stern A 2001, De Benedetti F(a) 2012, Ruperto N 2012), as well as of 
patients who do not respond to these treatments, indicating that inhibition of IL-1, IL-6R or TNFα 
does not provide full protection against MAS development nor an efficacious treatment of the full 
blown syndrome. 
A large retrospective, multicenter survey has investigated the clinical, laboratory, and 
histopathological characteristics as well as current practice treatment and outcome of MAS in a total 
of 362 patients (Minoia F 2014).  
In approximately half of the patients, MAS occurred in the context of active sJIA in the absence of a 
specific trigger, with a median time interval between the onset of sJIA and MAS of approximately 4 
months. However, in about 25% of patients MAS occurred at sJIA onset with the diagnosis of MAS 
and sJIA being done simultaneously. In about one third of the patients, an infectious trigger was 
identified, most commonly EBV. Nearly all patients were given glucocorticoids, given the well-
established role of this treatment approach in MAS and HLH. Cyclosporine was the other most 
commonly prescribed drug (61% of patients), while intravenous immunoglobulins, biologic 
medications (in particular anakinra) and etoposide were given to 36%, 15% and 12% of the patients, 
respectively.  
The identification of effective therapeutic regimens for MAS represents an area of unmet high medical 
need. Approximately  30% of patients with sJIA and MAS do not respond to systemic glucocorticoids 
alone, or may require prolonged treatment at high doses with associated significant morbidity. When 
patients fail to respond to glucocorticoids, no good evidence-based data is available on the 
effectiveness and safety of additional treatments such as CsA or etoposide. The course of MAS may 
become rapidly irreversible leading to a fatal outcome, with about one third of the patients requiring 
ICU admission. Furthermore, no clinical and/or laboratory features have thus far been identified to be 
predictive of poor response to the current standard of care, hence leaving the treating physicians with 
scarce possibility to identify those patients who would rapidly progress into an unfavorable clinical 
course.    
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1.3 
STUDY RATIONALE 
1.3.1 
 Rationale for developing emapalumab in MAS 
MAS and HLH are characterized by sustained immune cell activation and an associated cytokine 
storm of proinflammatory cytokines with overproduction of IFNγ, TNFα, IL-1 and IL-6 (Henter JI(a) 
1991, Imashuku S 1996, Put K 2015, Xu XJ 2012). During the last years, evidence has been 
accumulating in support of the pivotal role of IFNγ in the development of both HLH (Jordan MB(a) 
2004, Pachlopnik Schmid J 2009, Zoller EE 2011) and MAS (Prencipe G(b) 2018, Behrens EM(a) 
2011). 
For primary HLH, perforin knock-out mice are considered a relevant model as these mice, once 
infected with LCMV, develop all the diagnostic and many of the clinical and laboratory characteristic 
features of the human disease. The HLH-like disease that they develop is dependent on CD8+ T cells 
and IFNγ produced in response to antigen stimulation (Jordan MB(a) 2004). It was demonstrated that 
when the high circulating levels of IFNγ are neutralized with the administration of an anti-IFNγ 
antibody, not only are the clinical and laboratory abnormalities reverted, but also survival rate is 
dramatically improved. On the contrary, the ablation of many other cytokines had no impact on 
survival (Jordan MB(a) 2004, Pachlopnik Schmid J 2009). Further strengthening the importance of 
IFNγ in HLH are the high concentrations of circulating IFNγ levels found in these patients (Henter 
JI(a) 1991, Xu XJ 2012).  In a series of 71 patients monitored from HLH diagnosis to treatment and 
follow-up, IFNγ levels were above the upper limit of normal (17.3 pg/mL) in all patients, and in 
particular 53.5% had levels above 1000 pg/mL. It was also reported that IFNγ levels rise early and 
quickly, and can fall from > 5000 pg/mL to normal in 48 hours upon effective treatment of HLH. 
Two animal models of secondary HLH have been investigated in the context of the emapalumab 
development program to elucidate the potential pathogenetic role of IFNγ: 
- 
In a murine model that mimics an infection-driven HLH, repeated administrations of CpG via 
activation of TLR9 triggered a hypercytokinemia that led to clinical (e.g. body weight loss, 
splenomegaly) and laboratory (e.g. cytopenia, hyperferritinemia)  features of HLH (Behrens 
EM(a) 2011). When IFNγ was neutralized by the administration of an anti-IFNγ antibody, 
clinical and laboratory features of the disease were reverted. The neutralization of IFNγ was 
shown to be complete also in relevant target tissues, such as the liver and the spleen. 
Interestingly, the administration of the anti-IFNγ antibody unveiled an amount of IFNγ 500- 
to 2,000-fold higher than that measured in blood, likely to better reflect the IFNγ production 
in tissues. The two IFNγ-inducible chemokines (CXCL9 and CXCL10) were upregulated after 
TLR9 stimulation both in blood and in liver, and a significantly correlation was observed 
between serum levels of IFNγ with CXCL9 and CXCL10 serum concentrations. The 
neutralization of IFNγ induced a significant decrease of serum CXCL9 and CXCL10, and of 
their mRNA levels in the liver (Buatois V 2017). 
- 
An animal model of IL-6 transgenic mice expressing high levels of IL-6 has been studied, 
since it mimics the condition of patients with sJIA, the rheumatic disease most frequently 
associated with secondary forms of HLH. When triggered with Toll-Like Receptor (TLR) 
ligands, increased lethality, increased inflammatory cytokine production and hyperactivation 
of inflammatory signaling pathways was observed. Moreover, these mice showed a drop in 
platelet and neutrophil counts, increased sCD25, ferritin and LDH levels, resembling many of 
the features typically present in patients with MAS (Strippoli R 2012). In these mice, when 
IFNγ is neutralized with the administration of an anti-IFNγ antibody, survival is markedly 
improved and laboratory parameters reverted (Prencipe G(a) 2015).  
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1.3.2 
Rationale for conducting a Clinical Study in MAS in sJIA/AOSD  patients receiving 
emapalumab treatment 
Evidence of high levels of IFNγ and of IFNγ-inducible chemokines has been  gathered in an 
observational study conducted in patients with secondary forms of HLH, either consequent to 
infections, or of unknown origin (pHLH having been excluded by normal cytotoxic activity, absence 
of mutation in known genes causing pHLH and absence of family history) or with MAS occurring in 
the context of sJIA.  
In 14 patients with secondary HLH (in 7 of whom an underlying infection was identifiable), serum 
samples were analyzed during active full blown disease and during disease remission. Levels of IFNγ, 
CXCL9 and CXCL10 were markedly higher in the active phase compared to disease remission (IFNγ: 
34.7 vs. <3.5 pg/ml; CXCL9: 33598 vs. 745 pg/ml; CXCL10: 4420 vs. 132 pg/ml; median values). 
IFNγ levels significantly correlated with the levels of CXCL9 (p=0.0018) and, to a lesser extent, of 
CXCL10 (p=0.014). The levels of IFNγ and chemokines (in particular CXCL9) correlated 
significantly with parameters of disease severity, such as neutrophil and platelet counts, ferritin and 
ALT, further supporting the pathogenic role of IFNγ in secondary HLH and the potential use of 
chemokines as relevant biomarkers of the disease (Buatois V 2017). 
Similar findings have been shown in patients with MAS occurring in patients with sJIA. Serum 
concentrations of IFNγ, IFNγ-inducible chemokines (CXCL9, CXCL10, CXCL11) and IL-6 were 
measured in 54 patients with sJIA, of whom 20 had MAS. The levels of IL-6 were comparable in 
patients with full-blown MAS and those with active sJIA but without MAS at the time of sampling. 
On the contrary, circulating IFNγ and chemokine levels were significantly higher in MAS, particularly 
for CXCL9, whose median levels were approximately 15-fold higher compared to patients with active 
sJIA without MAS (13392 vs. 837 pg/mL; p=0.005). Noteworthy, a significant correlation was 
demonstrated only in patients with MAS between CXCL9 levels and parameters typically abnormal 
such as ferritin (p=0.041), neutrophil (p=0.010) and platelet (p=0.022) counts, ALT (p=0.044) and 
LDH (p=0.013). Levels of IFNγ also correlated with laboratory parameters of disease severity, with 
the exception of LDH for which statistical significance was not achieved (Bracaglia C 2017). 
Increased levels of CXCL9 and CXCL10 have also been reported in patients with AOSD (Han JH 
2017).  
This pilot phase 2 study, as well as the twin study in Europe, is intended to assess the 
pharmacokinetics/pharmacodynamics profile, the safety and tolerability, and the efficacy of 
emapalumab as treatment of MAS in sJIA/AOSD patients.  
Based on the evidence above described, there is a solid rationale for the neutralization of IFNγ as 
targeted therapy for MAS/sHLH occurring in sJIA/AOSD patient, and for investigating the benefit of 
emapalumab treatment in this patient population. 
Additionally, preliminary clinical data previously gathered in a study conducted in patients with 
primary HLH receiving emapalumab treatment either as first and second line (NI-0501-04 study), 
indicated:  
1. a favorable tolerability profile of emapalumab and absence of relevant safety concerns:  
- 
all infusions administered were well tolerated, confirming the observations made in 
healthy volunteers 
- 
emerging infections reported in the study generally resolved upon proper treatment 
and HLH control   
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
- 
among the reported infections, only one (histoplasmosis) may have been favored by 
emapalumab mode of action, whereas all other infections have been related to 
patients’ impaired immune status due to HLH and to previous or concomitant 
treatments. Of note, histoplasmosis resolved upon proper treatment 
- 
no death has been attributed to emapalumab administration. 
2. a favorable impact on disease parameters, with appreciable onset of effects within the first 
days of treatment: 
- 
typical clinical signs and symptoms of HLH started to improve rapidly after the first 
administration of emapalumab (fever within hours, spleno/hepatomegaly within days)  
- 
of the 30 patients that have received at least 4 weeks of treatment at the cut-off date of 
September 15th 2016, 18 patients have proceeded to HSCT and 4 are awaiting for 
transplant.  
3. a predictable pharmacokinetic profile of emapalumab from the PK modeling and simulation 
approach, and evidence that neutralization of IFNγ is achieved and maintained 
In conclusion, there is a strong rationale for neutralizing IFNγ in MAS secondary to rheumatic 
diseases based on pre-clinical and clinical evidence, and the preliminary data in pHLH patients 
indicates a favorable benefit/risk profile of emapalumab with a significant improvement to 
normalization of HLH features.  
It is therefore anticipated that emapalumab can represent an innovative and effective therapeutic 
approach in the management of this severe, life-threatening complication of rheumatic diseases, 
potentially limiting side effects from long-term high dose glucocorticoid treatment.  
Please refer to the most recent Investigator Brochure to review clinical data available to date. 
The study population will be represented by patients with a diagnosis of sJIA or AOSD who develop 
MAS. No diagnostic criteria are available of sJIA. The classification criteria proposed by ILAR 
require the presence of arthritis persisting for at least 6 weeks. While they appear to be used to classify 
patients, they cannot be used at disease presentation. In order to allow inclusion of patients presenting 
with MAS as a feature of onset of sJIA, the operational criteria designed by CARRA (childhood 
arthritis and rheumatology research alliance) to identify patients with sJIA early in their disease course 
(DeWitt EM et al. Arthritis Care Res 2012, Appendix A) have been also considered to assess patient 
eligibility.  
The number of patients meeting the ILAR classification criteria will be in any case included in the 
description of the NI-0501-06 study results. 
Patients enrolled under these twin protocols will be analyzed jointly and data reported in a single 
CSR. 
2 
OBJECTIVES 
The objectives of this pilot phase 2 study are as follows: 
 
To describe the PK profile of emapalumab. 
 
To confirm the proposed dosing regimen of emapalumab. 
 
To evaluate the safety and tolerability profile of intravenous (i.v.) administrations of 
emapalumab. 
 
To assess the efficacy of emapalumab. 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
 
To assess the levels of relevant pharmacodynamic markers, such as IFN and main IFN-
induced chemokines CXCL9, CXCL10.    
 
To assess other potential disease markers (e.g., sCD25, sCD163, IL-10, IL-6, IL-18, TNF).  
 
To assess the immunogenicity of emapalumab. 
3 
STUDY DESIGN 
3.1 
OVERALL DESIGN 
This is an open-label, single arm, international, multicenter pilot phase 2.  
After signature of informed consent, patients will be screened and assessed for eligibility (Section 
3.2). 
The study will be conducted in hospitalized patients since, at minimum, the day before the first 
administration of the study drug (study day minus one, SD-1) until SD15 at the earliest.   
Discharge from the hospital can occur from SD15 onwards, at the Investigator’s discretion if the 
patient’s condition allows, provided that no active infections requiring i.v. antimicrobial therapy are 
present.  
For a detailed description of the study procedures, see Section 8. 
The study flow-chart is summarized in Figure 1. 
Figure 1: 
NI-0501-06 Study Flow-chart  
 
 
 
3.2 
SCREENING PERIOD 
Screening will be carried out within up to 1 week prior to first administration of emapalumab (SD0) to 
enable confirmation of patient eligibility and following the signature of the Informed Consent Form. 
In the event that a patient’s medical condition warrants rapid treatment initiation, and to avoid 
unnecessary repetition of recent interventions, results of tests which have been performed as part of 
the normal patient’s care at the site (or at the referring hospital) not more than 2 weeks prior to first 
Start of 
NI-0S0l 
6mg/kg 
SDO 
Nl-0501- 3 mg/kg1,2 
every 3 days 
twice a week 
5D3 
5D15 
5D28 
Evaluation period/Short-term fol low-up after last Nl-0501 dose. 
Efficacy/safety visits to be performed weekly 
SD28A 
5D35 
5D42 
5D49 
End of 
Study' 
5D56 
----------------------------------------
I Screen 
I Treatment Period 
Evaluation Period 
A± 2-daywindow is al lowed 
" Will coincide with the day of last Nl-0501 infusion 
if treatment is continued for 4 weeks. 
1 Treatment may be shortened upon achievement of complete cl inical response 
2 Nl-0501 dose may be increased or treatment prolonged in the event of very high IFNy production 
3 If Nl-0501 treatment is prolonged beyond4 weeks, additional follow-up visits are to be performed in order to 
complete 4 weeks of fol low-up after the last Nl-0501 infusion under the current protocol. 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
emapalumab infusion, can be considered for screening purposes (inclusion/exclusion criteria checks), 
with the agreement of both the Sponsor and the Investigator. 
Detailed information regarding the inadequate response to high dose i.v. glucocorticoids (as required 
for patient eligibility) and to any other initial MAS treatments administered prior to emapalumab, will 
be collected and recorded in the CRF. 
Samples for infection screening need to be collected for analysis according to the protocol 
requirements; however availability of the results is not required prior to emapalumab initiation if the 
patient’s medical condition warrants rapid treatment, provided that there are no clinical findings 
suggestive for the presence of any of the infections which represent exclusion criteria. 
In the case of a patient having received BCG vaccination, a PPD test must be performed and 
combined with an IFNγ-release assay. 
A negative serum pregnancy test has to be documented in female patients who are post-pubescent. 
For a detailed description of the study procedures during the screening period see Section 8.  
3.3 
TREATMENT PERIOD 
Emapalumab will be administered i.v. at the initial dose of 6 mg/kg, and continued at the dose of 3 
mg/kg, every 3 days until SD15, and then twice-a-week for additional 2 weeks, i.e. until SD28.  
Treatment may be shortened upon achievement of complete clinical response (i.e. MAS remission), 
however at least two infusions of emapalumab at the dose of 3 mg/kg have to be administered (i.e. 
after SD6). In such circumstances, efficacy/safety visits have to be in any case performed every 3 days 
until SD15 and then twice-a-week until SD28.  
In the absence of a trend of improvement in key MAS parameters (including but not limited to ferritin, 
LDH, AST/ALT and PLT count) suggestive of lack of response, the emapalumab regimen may be 
adapted (the frequency between infusions shortened, the dose increased or the  treatment prolonged 
beyond 4 weeks) upon confirmation of a favorable benefit/risk profile in that individual patient.  
3.4 
FOLLOW-UP PERIOD 
All patients who have received at least one dose of emapalumab will be monitored after the last 
administration of emapalumab. A short-term follow-up of at least 4 weeks has to be performed under 
the current protocol, therefore should emapalumab treatment in a given patient need to be prolonged 
beyond 4 weeks, additional visits will be performed weekly until completion of the 4-week short-term 
follow-up.  
The last visit for a given patient under the NI-0501-06 study will normally be on SD56 (except in case 
of prolongation of emapalumab treatment beyond 4 weeks, as above described). 
Afterwards all patients will be asked to enter a long-term follow-up study, NI0501-05, to allow long-
term outcome and safety surveillance, and to monitor emapalumab elimination profile.  
In the event that additional monitoring of emapalumab concentrations is required (e.g., emapalumab  
serum levels still measurable at EoS) and cannot be performed in the context of the long-term follow-
up study, unscheduled visits will have to be performed beyond SD56, until serum emapalumab levels 
are no longer detectable. These measurements should occur not less than every two weeks. 
3.5 
STUDY END 
The end of the study is defined as the last visit of the last patient. 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
In case of an ongoing serious adverse event (SAE), the patient will continue to be monitored until 
resolution or until the outcome of the event is known and stable, beyond the defined study end, as 
necessary.  
3.6 
LONG-TERM FOLLOW-UP STUDY 
All patients having received at least one dose of emapalumab in the study will be asked to participate 
in a long-term follow-up study, to monitor long-term outcome and safety after emapalumab treatment, 
and, when relevant, to complete the assessment of the emapalumab elimination profile. 
4 
TARGET POPULATION 
The study population comprises patients of both genders, with confirmed sJIA/AOSD or high 
presumption of sJIA, presenting with MAS (as per Appendix A) and having shown inadequate 
response to high dose i.v. glucocorticoid treatment, see Section 4.1.1. 
4.1 
ELIGIBILITY CRITERIA 
To be eligible for the study, patients must meet all inclusion criteria and not meet any of the exclusion 
criteria: 
4.1.1 
 Inclusion Criteria 
1. Patients of both genders,  
2. For sJIA patients: Confirmed sJIA diagnosis. For patients presenting with MAS in the context of 
the onset of sJIA, high presumption of sJIA (as per Appendix A) will suffice for eligibility. For 
AOSD patients: confirmed AOSD diagnosis as per Yamaguchi criteria (Appendix E) 
3. A diagnosis of active MAS confirmed by the treating rheumatologist, having ascertained the 
following: 
Febrile patient presenting with: 
- Ferritin > 684 ng/mL 
and any two of: 
- Platelet count  181 x109/L 
- AST levels > 48 U/L 
- Triglycerides > 156 mg/dL 
- Fibrinogen levels ≤ 360 mg/dL 
(see Appendix B). 
4. An inadequate response to high dose i.v. glucocorticoid treatment administered for at least 3 days 
as per local standard of care (including but not limited to pulses of 30 mg/kg PDN on 3 
consecutive days). 
High dose i.v. glucocorticoid should not be lower than 2 mg/kg/day of PDN equivalent in 2 
divided doses ( or at least 60 mg/day in patients of 30 kg or more). In case of rapid worsening of 
the patient’s condition and/or lab parameters, inclusion may occur within less than 3 days from 
starting high dose i.v. glucocorticoids. 
5. Tocilizumab, TNF inhibitors and canakinumab, if administered, have to be discontinued before 
emapalumab initiation. 
6. Informed consent provided by the patient (as required by local law), or by the patient’s legally 
authorized representative(s) with the assent of patients who are legally capable of providing it, as 
applicable.    
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
7. Having received guidance on contraception for both male and female patients sexually active and 
having reached puberty: 
Females of child-bearing potential require use of highly effective contraceptive measures (failure 
rate of less than 1% per year) from screening until 6 months after receiving last dose of the study 
drug. 
Highly effective contraceptive measures include: 
o Sexual abstinence 
o Hormonal contraceptives: combination or progesterone only 
o Intrauterine methods: intrauterine devices or systems 
o Bilateral tubal occlusion 
o Vasectomised partner 
Males with partners(s) of child-bearing potential must agree to take appropriate precautions (such 
as sexual abstinence, barrier contraception, vasectomy) to avoid fathering a child from screening 
until 6 months after receiving last dose of the study drug. 
4.1.2 
Exclusion Criteria 
1. 
Diagnosis of suspected or confirmed primary HLH or HLH consequent to a neoplastic disease. 
2. 
Active mycobacteria (typical and atypical), Histoplasma Capsulatum, Shigella, Salmonella, 
Campylobacter and Leishmania infections.  
3. 
Clinical suspicion of latent tuberculosis. 
4. 
Positive serology for HIV antibodies. 
5. 
Presence of malignancy. 
6. 
Patients who have another concomitant disease or malformation severely affecting 
cardiovascular, pulmonary, CNS, liver or renal function, that in the opinion of the Investigator 
may significantly affect likelihood to respond to treatment and/or assessment of emapalumab 
safety. 
7. 
History of hypersensitivity or allergy to any component of the study regimen. 
8. 
Receipt of BCG vaccine within 12 weeks prior to screening. 
9. 
Receipt of live or attenuated live vaccine within 6 weeks prior to screening. 
10. Pregnant or lactating female patients. 
5 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
5.1 
DESCRIPTION OF IMP 
Emapalumab, previously referred to as NI-0501, is a fully human anti-IFNγ monoclonal antibody 
which binds and neutralizes IFNγ. 
Emapalumab is manufactured by a third party manufacturing facility duly qualified by Sobi AG. It 
will be supplied to study sites in single-use 2 and/or 10 mL filled single-use glass vials at a 
concentration of 5 mg/mL, for dilution prior to administration. 
The nominal composition of the emapalumab sterile concentrate for infusion (per mL) is as follows: 
 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
Ingredient 
Quantity (per mL) 
emapalumab 
5 mg 
L-Histidine 
1.55 mg 
L-Histidine monohydrochloride, monohydrate 
3.14 mg 
Sodium chloride (NaCl) 
7.31 mg 
Polysorbate 80  
0.05 mg 
pH 
6.0 ± 0.2 
The solution contains no antimicrobial preservative, and therefore each vial must be used only once. 
5.2 
DOSING REGIMEN 
Emapalumab will be administered at the initial dose of 6 mg/kg by infusion over a period of one to 
two hours depending on the volume to infuse. Treatment will be continued at the dose of 3 mg/kg 
every 3 days until SD15, and twice-a-week thereafter for a total of 4 weeks (i.e. up to SD28).  
Treatment may be shortened upon achievement of complete clinical response (i.e. MAS remission), 
however at least two infusions of emapalumab at the dose of 3 mg/kg have to be administered (i.e. 
after SD6). 
In the absence of a trend of improvement in key MAS parameters (including, but not limited to 
ferritin, LDH, AST/ALT and PLT count) suggestive of lack of response, the emapalumab regimen 
may be adapted (the frequency between infusions shortened, the dose increased or the treatment  
prolonged beyond 4 weeks) upon assessment of a favorable benefit/risk profile in that individual 
patient. 
5.3 
RATIONALE FOR DOSE SELECTION  
 The rationale for the dosing strategy foreseen for this study is based on: 
‐ 
Data from in vitro experiments investigating the binding kinetics of emapalumab to human IFNγ 
and the functional inhibition of human IFNγ by emapalumab; 
‐ 
PK information from recombinant IFNγ in human; 
‐ 
Data from the Phase 1 NI-0501-03 study in which emapalumab was administered to healthy 
volunteers; 
‐ 
Data gathered from the NI-0501-04 study in pediatric primary HLH patients receiving 
emapalumab in first or second line; 
‐ 
Data from an observational study in patients with MAS developing on a background of sJIA 
(Bracaglia C 2017); 
‐ 
Data from an observational study in pediatric patients with secondary HLH (having excluded a 
rheumatic or neoplastic origin) (Buatois V 2017).  
The analysis of data generated from the ongoing study in which primary HLH patients have been 
treated with emapalumab has allowed to estimate the production rate of IFNγ through the assessment 
of the “total IFNγ” (i.e. IFNγ bound to emapalumab and free IFNγ), and consequently the 
concentration of emapalumab required to neutralize the variably high IFNγ concentrations. It has also 
been possible to determine that when there is a high production of IFNγ, target mediated drug 
disposition occurs. Importantly, the relationship between IFNγ and the IFNγ-inducible chemokines 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
CXCL9 and CXCL10 has been investigated establishing the tight correlation between those 
chemokines measured prior to the administration of emapalumab and “Total IFNγ” at 48 hours after 
emapalumab administration, indicating that these chemokines can be used as exploratory markers of 
IFNγ production.  
The key observations that have constituted the foundation of the dosing rationale for this protocol and 
led to the selection of the emapalumab doses to be administered to patients with MAS not responding 
to high dose glucocorticoid therapy are the followings:    
‐ 
there is a tight correlation between IFNγ and the IFNγ-related chemokines CXCL9 and CXCL10, 
as well as between disease parameters and levels of IFNγ and IFNγ-related chemokines in patients 
suffering from HLH (Buatois V 2017, Bracaglia C 2017); 
‐ 
the higher the circulating levels of the IFN-related chemokines, the higher is the concentration of 
emapalumab (and therefore the dose of emapalumab) required to neutralize the corresponding 
levels of IFNγ (data from the NI-0501-04 study on file at Sobi AG); 
‐ 
the neutralization of IFNγ has been shown to have a therapeutic role in primary HLH patients 
(Jordan MB(b) 2015); 
‐ 
a trend towards higher levels of circulating IFNγ-related chemokines has been observed in 
patients with secondary forms of HLH compared to primary HLH patients (Buatois V 2017, 
Bracaglia C 2017) during or soon after HLH conventional therapy (see Figure 2; data from the NI-
0501-04 study on file at Sobi AG); 
‐ 
the onset of MAS is usually acute and the disease worsens rapidly therefore requiring prompt and 
complete neutralization of IFN from the very beginning of treatment; 
‐ 
in MAS patients, differently from patients with primary HLH, the risk of reactivation is extremely 
low once HLH remission is achieved, and HSCT is not required. Therefore in patients with MAS, 
shorter treatment duration is anticipated compared to primary HLH patients, not requiring a 
maintenance phase while awaiting for HSCT. 
 
Figure 2: 
CXCL9 levels in patients with pHLH, sHLH and MAS 
 
 
 
 
 
 
 
 
Note:  
pHLH: CXCL9 levels from the patients with primary HLH treated with emapalumab in second line in the NI-
0501-04 study prior to receiving emapalumab (measured by Affymetrix) 
sHLH and MAS: CXCL9 levels in patients with active disease (values extrapolated from Millipore to Affymetrix) 
  
Simulations performed considering different IFNproduction rates that are anticipated to potentially 
occur in MAS patients are presented in Figure 3. The simulations clearly show that the risk of 
emapalumab accumulation, as well as the risk of exceeding the highest emapalumab concentration 
p H L H
s H L H
M AS
1 0 0
1 0 0 0
1 0 0 0 0
1 0 0 0 0 0
C X C L 9  (p g /m l)
•• ··i 
.... 
•• 
• • 
•• 
••• 
•••• 
• 
•• 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
observed so far in pHLH patients is negligible. Therefore, the expected highest peak and trough 
concentrations will remain within the ones already achieved in primary HLH patients treated in the 
ongoing study. 
The PK model used to produce these simulations is a two compartment model with linear elimination 
assuming allometric scaling based on body weight (BW) to which an additional non-linear (TMDD) 
elimination pathway characterized by a VMAX and a KM has been added. Parameters used in the 
simulations are from a population pharmacokinetic analysis of study NI-0501-03 and assuming 
allometric scaling. VMAX is the IFNγ concentration (0.1 nM) multiplied by the recombinant IFNγ 
clearance (1.2 L/h/kg) divided by the number of binding sites per antibody. KM is assumed to be 
equal to KD. 
Figure 3: 
Predicted concentration-time profiles after administration of emapalumab at the 
initial dose of 6 mg/kg followed by 9 doses of 3 mg/kg every 3 days  
 
Note:  
Simulations are shown for sJIA MAS patients of an approximate body weight of 23 kg with different levels of 
total IFNγ. The blue area corresponds to the mean of the 3 highest peak and trough concentrations observed in 
HLH patients from study NI-0501-04/05 (data cut-off date of June 24, 2016). 
The proposed dosing strategy is further supported by the following evidence: 
‐ 
primary HLH patients treated with emapalumab in the context of the ongoing study who were 
characterized by levels of CXCL9 comparable to the ones expected in MAS all required a rapid 
and significant emapalumab dose increase;  
‐ 
primary HLH patients having a high production of IFNγ, required a high dose of emapalumab, 
demonstrating the presence of target mediated drug disposition (TMDD), i.e. a pronounced 
increased clearance of emapalumab due to the high production of IFNγ. The presence of TMDD, 
while requiring to administer emapalumab at high doses and sometimes more frequently, prevents 
emapalumab accumulation to occur; 
‐ 
to date emapalumab has shown a good safety profile when administered to primary HLH patients 
up to the dose of 10 mg/kg, achieving similar or even higher emapalumab exposures compared to 
the ones expected to occur in MAS patients. More than 850 infusions have been performed in all 
patients treated (including CU) and around 20% have been performed at a dose of  6mg/kg. 
"' 
0 i 
:g 
--' I 
C 
2 
" 
TIFNG=200 pM 
8 
TIFNG=1000 pM 
iii 
TIFNG=5000 pM 
'? z 
"' '? 
0 
0 
10 
20 
30 
40 
50 
60 
Time (days) 
Page 32 of 150

Study NI-0501-06         
    Emapalumab in MAS/sHLH in sJIA/AOSD patients
 Page 32 of 76 
Protocol NI-0501-06 
 Version 2.0 US – 7 January 2020 
 CONFIDENTIAL 
In conclusion, based on a production rate of IFNγ expected to be high in sJIA/AOSD patients with 
overt MAS (Bracaglia C 2017), an initial dose of 6 mg/kg followed by repeated administrations of 3 
mg/kg is deemed appropriate to achieve rapidly and maintain the concentrations of emapalumab 
estimated to ensure a fast neutralization of IFNγ activity. 
5.4 
IMP HANDLING 
5.4.1 
 Packaging and Labeling 
Emapalumab will be supplied to study sites in single-use glass vials containing a 2 or a 10 ml solution 
at a concentration of 5 mg/ml. Labeling and packaging will be prepared to meet local regulatory 
requirements. 
5.4.2 
 IMP Supply 
Emapalumab will be supplied to the study sites as open-label supplies. 
5.4.3 
 IMP Receipt and Storage 
The emapalumab vials will be transported with temperature monitoring device, in order to ensure 
consistent temperatures during transit. When the study drug is received at the site, the Investigator or 
Pharmacist will check for accurate delivery and absence of temperature deviation alarms. 
The study drug should be stored between 2 - 8°C (36 - 46°F). All vials must be stored in a secure 
locked location in a temperature-controlled refrigerator or cold room. Any deviations from the 
recommended storage conditions should be immediately reported to the Sponsor and responsible study 
clinical research associate (CRA). Affected vials should not be used and should be quarantined until 
the Sponsor has authorized their use, return or destruction. 
Documentation of the storage conditions of the study drug must be maintained over the timeframe the 
study drug is stored at the site, until such time as it is used, disposed of, or returned to Sobi AG or 
designee. 
Regular inspections of the emapalumab vials are required, as detailed in the IMP manual indications 
for the Preparation and Administration of Individual Doses of Study Drug emapalumab. 
5.4.4 
 IMP Preparation, Administration, Accountability and Destruction 
5.4.4.1 
Preparation  
The study drug must be prepared only 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 is determined as detailed in Section 
5.2.  
Full instructions for the preparation, including dilution steps, and method for administration of 
emapalumab are available in the IMP Manual that will be provided to all the investigational sites. 
5.4.4.2 
Administration 
The patient should receive the designated volume of the infusate through an infusion pump over a 
period of 1 to 2 hours depending on the volume to infuse. IMP must be administered using either a 
syringe that has been sterilized by gamma irradiation or using any appropriate sized non-PVC 
polyolefin infusion bag and a 0.2 μm filter, which must be added to all infusion lines. (See the IMP 
manual for details.) 
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Protocol NI-0501-06                           Version 2.0 US – 7 January 2020                                     CONFIDENTIAL 
It is recommended that a  central venous access is maintained during the treatment period. This will 
improve patient’s comfort and ensure a reliable drug administration. However, as per previous 
experience in HLH patients in whom central venous access was not possible or not maintained, 
emapalumab infusions have been performed safely via peripheral venous access. Since no data is 
available on the compatibility of emapalumab with other intravenous substances or additives, other 
medications/substances should not be added to the infusion material or infused simultaneously 
through the same intravenous line. If the same intravenous line is used for subsequent infusions of 
other drugs, the line should be flushed with saline before and after infusion of emapalumab. 
The infusion of emapalumab will be administered under the direct supervision of the Investigator (or 
delegate). It should be preferably performed in the morning, and at the same time of the day during the 
study whenever possible.  
Details of the infusion administered must be recorded, including: 
 
The date of administration 
 
The time (start and end) of infusion 
 
The volume administered 
 
Any adverse effects or general illness experienced by the patient. 
 
Any other event(s) judged relevant by the site personnel. 
5.4.4.3 
Accountability 
When the study drug is received at the site, the Investigator or Pharmacist (or appropriate designee) 
should acknowledge its receipt by signing (or initialing) and dating the documentation. 
Documentation should be returned to Sobi AG (or its designee) and a copy retained in the 
Investigator’s file. 
The dispensing of the study drug shall be carefully recorded on Drug Accountability Forms and an 
accurate accounting must be available for verification by the CRA at each monitoring visit. 
Drug accountability records shall include: 
 
Confirmation of the study drug’s delivery to the study site 
 
The inventory at the study site 
 
The use of study drug by each patient  
 
Proper storage conditions at the study site 
 
The return to the Sponsor or alternative disposition of unused products. 
The records should include dates, quantities, expiration dates, batch number, and patient number.  
Unused study drug must not be discarded or used for any purpose not authorized by Sobi AG.  
5.4.4.4 
Destruction, Return and Disposal  
Periodically during the study and at the conclusion of participation of the study by the site, the CRA 
will monitor and collect the Drug Accountability Forms, before making arrangements for study drug 
return or authorization of destruction by the study site. 
6 
PATIENT BACKGROUND TREATMENT AND CARE 
6.1 
GLUCOCORTICOIDS  
For a patient to be eligible for the study, an inadequate response to high dose i.v. glucocorticoids 
administered for at least 3 days as per local standard of care (including but not limited to pulses of 30 
mg/kg PDN on 3 consecutive days) must be documented. Inclusion can however occur within less 
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than 3 days from starting high dose i.v. glucocorticoids, in case the patient’s condition and/or lab 
parameters are rapidly worsening. 
High dose i.v. glucocorticoids should not be lower than 2 mg/kg/day of PDN equivalent in 2 divided 
doses (or  at least 60 mg/day in patients of 30 kg or more).   
During the study, emapalumab will be initially administered on a background of at least 2 mg/kg/day 
of PDN equivalent ( or at least 60 mg/day in patients of 30 kg or more). 
Glucocorticoid tapering may be initiated as soon as the patient’s conditions allow, according to the 
Investigator’s assessment. The tapering scheme can be selected by the Investigator, with the objective 
of reaching the same (or lower) dose being administered before the occurrence of MAS (in patients 
already on treatment for sJIA/AOSD) or decreasing by 50% (or more) the glucocorticoid dose 
administered at initiation of emapalumab treatment (in patients presenting with MAS as first 
manifestation of sJIA/AOSD).   
In the event of disease worsening after glucocorticoid tapering, a higher dose can be re-introduced and 
maintained until a satisfactory response is achieved according to the Investigator.  
6.2 
PROPHYLACTIC TREATMENT  
Prophylaxis for Herpes Zoster (HZ) virus infection will be administered to mitigate the potential risk 
associated to emapalumab administration (see Benefit/Risk Management, Section 10.5). 
Patients will therefore receive the prophylactic treatment starting preferably the day before (i.e. SD-1), 
and in any case prior to, initiation of emapalumab treatment on SD0, and continued until serum 
emapalumab levels are no longer detectable, as follows: 
 
For HZ virus prevention, according to Institution/Country Guidelines/Recommendations 
(e.g. Acyclovir 200 mg four times daily for children over two years, for children under 
two years 100 mg four times daily). 
In the unlikely event that a patient, previously vaccinated for TB, shows a Purified Protein Derivative 
(PPD) test result ≥ 5mm and a negative IFNγ-release assay, the patients will receive TB prophylaxis 
according to Institution/Country Guidelines/Recommendations (e.g. Isoniazid).  
In case emapalumab concentrations are still measurable after the end of the study, it is required that 
the above mentioned prophylaxis be maintained, until serum emapalumab levels are no longer 
detectable. 
6.3 
CONCOMITANT THERAPY 
6.3.1 
 Cyclosporine A, methotrexate and anakinra 
Cyclosporine A (CsA) may be continued, if already started at least 3 days prior to initiation of 
emapalumab treatment. CsA dose adjustments will be performed if required based on results of 
therapeutic drug monitoring, in order to maintain therapeutic levels. CsA can be withdrawn at any 
time during the study, upon judgment of the Investigator. CsA should not be introduced once 
emapalumab administration has started.  
Methotrexate may be continued if ongoing as treatment for the underlying disease.  
If ongoing and if started (at any dose) at least 3 days before initiation of emapalumab treatment, 
anakinra may be continued at a maximum daily dose of 4 mg/kg.  In the case of an acute inflammatory 
flare of the underlying sJIA/AOSD during treatment with emapalumab, anakinra may be introduced at 
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a dose of 1 to 4 mg/kg (max. daily dose of 100 mg). Such episodes shall be adjudicated by at least two 
members of the SSC (excluding the treating physician, if applicable), in order to ascertain their nature 
(i.e. sJIA/AOSD versus MAS flare). 
6.3.2 
 Intrathecal Therapy 
For patients receiving intrathecal therapy (e.g. methotrexate and glucocorticoids) at the time of 
emapalumab treatment initiation, this treatment will be continued until clinically indicated.  
6.3.3 
 Other possible concomitant therapies 
Analgesic treatment, transfusion of blood products, electrolyte and glucose infusions, i.v. parenteral 
nutrition, inotropic support, antibiotics, anti-fungal and anti-viral treatment, ultrafiltration or 
hemodialysis, as well as general supportive care (e.g. gastro-protective agents, anti-hypertensive etc.) 
are permitted during the study.  
The use of any prescription or over-the-counter medication, including herbal and homeopathic 
preparations with the exception of multi-vitamins, needs to be notified to the Investigator. 
6.3.4 
Not allowed concomitant therapies 
Tocilizumab, canakinumab or TNF inhibitors have to be discontinued before initiation of emapalumab 
treatment. 
As long as emapalumab is being administered, no concomitant use of etoposide, T-cell depleting 
agents, or any other biologic drug is allowed with the exception of: 
 G-CSF, in case of prolonged neutropenia  
 Rituximab, in case of documented EBV infection 
 Anakinra, if administered as described in section 6.3.1 
 
Vaccination with a live or attenuated-live (including BCG) vaccine must be avoided during the whole 
study. In the event that emapalumab concentrations are still measurable after the end of the study, the 
period with no vaccinations should be extended until serum emapalumab levels are no longer 
detectable.  
6.4 
EMERGENCY TREATMENT 
As none of the emapalumab infusions administered to healthy volunteers or patients has triggered any 
medically significant reaction, this is considered an unlikely event during the study. However, should 
severe allergic reactions (such as anaphylactic shock) occur, they would require prompt i.v. treatment 
with adrenaline and antihistamines. Oxygen shall be supplied through a face mask. Patients must have 
an appropriately sized i.v. line that allows rapid infusion of colloid volume substitution. Transfer to 
the intensive care unit of the hospital should be possible.  
Following the first administration of emapalumab and before leaving the study site, each patient 
(and/or patient’s legal representative) will be given a card to carry at all times in case of any 
emergency. The card gives details of the name of the drug, name of the responsible physician, and the 
address and telephone number of the study site. 
6.5 
RESCUE THERAPY 
Patients who are withdrawn from the study due to a safety issue or for lack of efficacy (i.e. worsening 
of MAS/no response to emapalumab) will be treated according to the standard of care at the site.  
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7 
ENDPOINTS 
The main objective of the study is to confirm that the proposed dosing regimen is adequate in relation 
to the IFNγ production in patients with MAS secondary to sJIA/AOSD.  
For this purpose, a PK-PD analysis will be performed based on:  
 levels of circulating emapalumab 
 levels of total IFNγ 
 levels of main IFNγ–induced chemokines (namely CXCL9 and CXCL10). 
7.1 
PHARMACOKINETICS ENDPOINTS 
Free emapalumab concentrations will be measured in serum to determine the PK profile of 
emapalumab in this patient population, and to confirm the adequacy of the proposed dosing regimen. 
All PK data will be summarised using appropriate graphical and tabular presentations. Descriptive 
non-compartmental pharmacokinetic analysis (NCA) will be applied: Cmax (concentration 
corresponding to Tmax), Tmax (time of maximum observed concentration), CEOI (concentration at the 
end of infusion), Ctrough (concentration just before administration), AUC (area under curve of a dosing 
interval), AUClast (area under curve from the time of dosing to the last measurable concentration), t½ 
(plasma half-life), Individual and mean PK parameters will be tabulated. Exploratory compartmental 
PK analysis and population PK analysis will be undertaken to investigate linear and non-linear 
(TMDD) kinetics. 
In addition, PK analysis will be done when a total of 5 patients have been recruited in Europe and 
North America inclusive, to assess the appropriateness of the dose selection. 
7.2 
PHARMACODYNAMICS ENDPOINTS 
Assessment of PD parameters will include, but will not be limited to, the followings: 
 
Levels of circulating free IFN at pre-dose, and of total IFNγ (free IFNγ+bound to 
emapalumab) after initiation of emapalumab treatment.  
 
Levels of the main IFNγ-induced chemokines (CXCL9, CXCL10). 
 
Correlation between chemokine levels (CXCL9, CXCL10) and levels of free emapalumab, 
free IFNγ (pre-dose) and total IFNγ (exploratory analysis). 
 
Correlation between chemokine and total IFNγ levels, and laboratory parameters of MAS 
severity, e.g. ferritin, platelet counts, LFTs (exploratory analysis). 
 
Levels of other potential disease markers (e.g. sCD25, sCD163, IL-18, IL-10, IL-6, TNF,). 
 
Levels (if any) of circulating antibodies against emapalumab to determine immunogenicity, 
i.e. the development of anti-drug antibodies (ADAs). 
7.3 
SAFETY ENDPOINTS 
The tolerability and safety of emapalumab treatment will be assessed as follows:  
 
Incidence, severity, causality and outcomes of AEs (serious and non-serious), with particular 
attention being paid to infections. 
 
Evolution of laboratory parameters, in particular CBC, LFTs, inflammatory markers (ferritin and 
CRP) and coagulation parameters. 
 
Number of patients withdrawn due to safety reasons. 
 
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7.4 
EFFICACY ENDPOINTS 
The efficacy of emapalumab in this patient population will be evaluated based on the evolution of the 
MAS distinct features of cytopenias, liver function and coagulopathy. 
In particular the following variables will be assessed: 
 Number of patients achieving MAS remission by Week 8 after initiation of emapalumab 
treatment.  
 Time to MAS remission. 
 Number of patients for whom at any time during the study glucocorticoids can be tapered i) to 
the same (or lower) dose being administered before the occurrence of MAS (in those patients 
who are already treated for sJIA/AOSD) or ii) by 50% (or less) of the dose administered at 
emapalumab treatment start (in those patients who present with MAS at sJIA/AOSD onset).  
 Time to achievement of glucocorticoids tapering (as defined above). 
 Survival time. 
 Number of patients withdrawn from the study due to lack of efficacy. 
 
MAS remission is defined as 
 Resolution of clinical signs and symptoms according to the Investigator 
and 
 Normalization of laboratory parameters relevant to MAS, as follows:  
- 
WBC and platelet count above LLN  
- 
LDH below 1.5 ULN 
- 
ALT/AST below 1.5 ULN 
- 
fibrinogen higher than 100 mg/dL 
- 
ferritin levels decreased by at least 80% from values at screening or baseline (whichever 
is higher) or below 2000 ng/ml, whichever is lower.  
8 
OUTLINE OF STUDY PROCEDURES 
8.1 
STUDY VISITS 
For a detailed description of the visit schedule and assessments, please refer to Table 1 (Schedule of 
Assessment – Screening and emapalumab Treatment Period) and Table 2 (Schedule of Assessment –
Evaluation Period). 
Patients will be recruited from specialized study centers in North America, in which an intensive care 
unit is available. If not already hospitalized, the patient will enter the hospital on SD-1. 
During the emapalumab Treatment Period, Infusion Visits will occur every 3 days until SD15, and 
twice-a-week thereafter until SD28, and will also serve as Efficacy/Safety visits. In case emapalumab 
treatment is shortened after SD6, Efficacy/Safety visits have to be in any case performed with the 
same schedule until SD28, in order to assess the evolution of MAS clinical and laboratory features, 
and to closely monitor safety.     
From SD28 and during the Evaluation Period, visits will occur on a weekly schedule (a  2-day 
window is allowed) for efficacy and safety evaluation, and follow-up after emapalumab last infusion. 
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Discharge from the hospital cannot occur before SD15. After SD15, in case the patient condition 
allows, the patient can be discharged, at the Investigator’s discretion, provided that no active 
infections requiring i.v. antimicrobial therapy are present.  
Some procedures are not mandatory or do not need to be done systematically but only when 
applicable according to the following specifications:  
 ECG is mandatory at screening, after first infusion, and at the end of the study, however it 
should also be performed whenever required based on clinical judgment. 
 Broad search for pathogens during the study (beside the ones required per protocol) should be 
done if there is any suspicion of infection.  
 Chest X-ray during the study (beside the ones required per protocol) should be done more 
frequently in case of clinical suspicion of a pulmonary infection. 
 
Functional tests relevant to HLH diagnosis should be performed whenever possible; however 
availability of results is not required for patient inclusion in the study. 
The following situations will not be considered as protocol deviations: 
 Missing data if not occurring at 2 consecutive time-points.  
 
8.2 
INFORMED CONSENT AND SCREENING PROCEDURES 
The informed consent form must be signed by the patient (as required by local law) or by the patient’s 
legally authorized representative prior to any study-related procedures, with the assent of patients who 
are deemed suitable to provide it, as applicable.  
Patients will be screened for eligibility prior to enrolment into the study. The Investigator must keep a 
log of the patients screened for the study and reasons for non-eligibility, if applicable. 
Screening evaluations should be completed within up to 1 week prior to the first administration of the 
study drug (SD0). Clinical and laboratory assessments should be performed as close as possible to 
initiation of emapalumab treatment, preferably on SD-1, as described in Table 1. 
In the event that a patient’s medical condition warrants rapid treatment initiation, and to avoid 
unnecessary repetition of recent interventions, results of tests which have been performed as part of 
the normal patient’s care at the site (or at the referring hospital) not more than 2 weeks prior to first 
emapalumab infusion, may be considered for screening purposes (inclusion/exclusion criteria checks) 
with the agreement of both the Sponsor and Investigator. 
The following patient information must be collected: 
 Demographic and medical history 
 Detailed information on inadequate response to high dose i.v. glucocorticoids and to other 
MAS treatments, including VAS of MAS activity and MAS laboratory parameters including, 
but not limited to: blood cell counts, ferritin, AST/ALT/LDH, fibrinogen, d-dimer, 
triglycerides, 
 Concomitant medication at screening.  
 Date of sJIA diagnosis/high presumption of sJIA or AOSD diagnosis. 
 sJIA/AOSD treatment previously received and ongoing at the time of screening. 
 Date and criteria of eligibility.  
 Relevant clinical and laboratory data in order to characterize a posteriori the study population 
according to HLH-2004 criteria. 
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Samples for the molecular characterization with respect to the known HLH causative genes have to be 
collected and send to a centralized laboratory only if the patient has given consent for genetic testing. 
A panel of genes already known to be involved in primary HLH (PRF1, UNC13D, STX11, STXBP2, 
LYST, RAB27A, SH2D1A, XIAP) will be tested.  
Given the evolving knowledge and new findings within the scientific community with regard to 
potential modifying genes for HLH e.g. AP3B1, HPS1, IRF5, ITK, KIR2DL1, MyD88, SLC7A7, 
TNFRSF7/ CD27, IL2RG, ARHGAP21, CADPS2, CCDC141 (CAMD1), EXPH5 (SLAC2B), 
FAM160A2, FKBPL, GDI1, LRGUK, MICAL2, TNFRSF10B, XIRP2, the panel may be extended, 
if relevant.  
Functional tests relevant to the diagnosis of HLH should be performed whenever possible; however 
availability of these results is not required for inclusion of the patient in the study. 
Prophylactic treatments for HZ virus and for TB (when applicable, as described in Section 6.2), have 
to be started.
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                               CONFIDENTIAL 
Table 1 – Schedule of assessment: Screening and emapalumab treatment period (from SD-1 to SD28) 
Assessments 
 
Protocol 
Section 
Screening (up to 
one week prior to 
1st infusion)  
SD0 
 Infusion #11 
SD1 
SD2 
SD3 
 Infusion #22 
SD5 
SD6 to SD283 
Infusion/Efficacy/ 
Safety visits  
 
SD-1 
pre 
post 
 
 
pre 
post 
 
 
Hospitalization4 
 
8.1 
From SD-1 
 
 
 
 
 
 
 
 
Patient information and Informed Consent 
8.2 
X 
 
 
 
 
 
 
 
 
Medical history including MAS laboratory parameters 
and MAS treatments  
8.2 
X 
 
 
 
 
 
 
 
 
Concomitant medication (including recording on 
glucocorticoid tapering when relevant) 
8.2 
X 
X 
 
X 
X 
X 
 
X 
X 
MAS diagnosis and Eligibility Criteria5  
8.2 
X 
 
 
 
 
 
 
 
 
Prophylactic treatments 
8.2 
From SD-1 
 
 
 
 
 
 
 
 
Clinical 
assessments 
- Vital signs 
8.3.1 
X 
X 
X6 
X 
X 
X 
X6 
X 
X7 
- Physical examination8 
8.3.2 
X 
X 
 
X 
X 
X 
 
X 
X 
- MAS clinical signs and symptoms15 
8.3.3 
x 
 
 
 
 
 
 
 
X 
Laboratory 
assessments 
- CBC 
8.4 
X 
X 
 
X 
X 
X 
 
X 
X 
- Lymphocyte subset  
8.4 
X 
 
 
 
 
 
 
 
 
- Coagulation (aPTT, PT, D-Dimers, 
Fibrinogen)  
8.4 
X 
X 
 
X 
X 
X 
 
X 
X 
- Biochemistry 
8.4 
X 
X 
 
X 
X 
X 
 
X 
X 
- Serum pregnancy test (if applicable) 
8.4 
X 
 
 
 
 
 
 
 
 
- Urinalysis 
8.4 
X 
X9 
 
 
 
 
 
 
 
Search for 
infections 
- Mycobacterium Tuberculosis 
8.5 
X 
 
 
 
 
 
 
 
X10 
- Atypical mycobacteria, Shigella, 
Salmonella, Campylobacter, 
Leishmania, Histoplasma Capsulatum 
8.5 
X 
 
 
 
 
 
 
 
 
- EBV, CMV, Adenoviruses 
8.5 
X 
 
 
 
 
 
 
 
X10 
- HSV, HZV, HIV, HBV, HCV 
8.5 
X 
 
 
 
 
 
 
 
 
Procedure 
- ECG 
8.7.1 
X11 
 
X 
 
 
 
 
 
 
Imaging 
- Abdominal Ultrasound 
8.6.1 
X 
 
 
 
 
 
 
 
X10 
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                               CONFIDENTIAL 
Assessments 
 
Protocol 
Section 
Screening (up to 
one week prior to 
1st infusion)  
SD0 
 Infusion #11 
SD1 
SD2 
SD3 
 Infusion #22 
SD5 
SD6 to SD283 
Infusion/Efficacy/ 
Safety visits  
 
SD-1 
pre 
post 
 
 
pre 
post 
 
 
 
- Chest X-ray 
8.6.2 
X 
 
 
 
 
 
 
 
X10 
 
- Brain MRI12 
8.6.3 
X 
 
 
 
 
 
 
 
 
Histopathology 
- CSF analysis (if coagulation allows) 12 
8.7.2 
X 
 
 
 
 
 
 
 
 
PK  
- emapalumab serum concentration 
8.8.1 
 
X 
X 
X 
X 
X 
X 
X 
X13 
PD 1 
- IFN, CXCL9, CXCL10, sCD25 
8.8.2 
 
X 
X14 
X 
X 
X 
 
X 
X 
PD 2 
- Other markers 
8.8.2 
 
X 
 
 
 
 
 
 
X 
Immunogenicity (ADA) 
8.8.3 
 
X 
 
 
 
 
 
 
 
1 Start of emapalumab treatment: loading dose of 6 mg/kg. 
2 Continuation of emapalumab treatment: 3 mg/kg every 3 days from SD3 onwards until SD15, and twice-a-week thereafter. 
3 After a minimum of two infusions at the dose of 3 mg/kg (i.e. after SD6), emapalumab treatment may be shortened as per Investigator’s decision upon achievement of a complete clinical response  
  (i.e. MAS remission).  In this circumstance, efficacy/safety visits have to be in any case performed according to the same schedule until (and including) SD28.  
4 Hospitalization: please note that the patients can be discharged from SD15 if their conditions allow, provided that there is no active infections requiring i.v. antimicrobial therapy. 
5 Include molecular and functional tests relevant to the diagnosis of primary HLH. Include detailed documentation of inadequate response to high dose i.v. glucocorticoids and MAS treatments   
6 Continuous monitoring of HR and SpO2 as well as body temperature and BP recording at regular time points (see Section 8.3.1) 
7 If emapalumab infusions are performed, HR, BP, SpO2, body temperature are to be measured pre-, during, and post-dose (see Section 8.3.1).  
8 Body weight to be recorded prior to infusion and every 2 weeks during the evaluation period for patients weighing less than 10 kg, and every 2 weeks throughout the study for patients weighing  
   more than 10 kg. 
9 If not performed at screening. 
10 Abdominal US and Search for infection to be performed on SD15 and SD28; chest X-ray on SD28 only. 
11 At screening, three consecutive recordings are required in order to obtain a stable baseline.  
12 Brain MRI & CSF analysis: to be performed in case of neurological involvement prior to emapalumab initiation (or at the latest by SD6 for brain MRI), whenever possible. 
13 When emapalumab is administered, PK samples have to be taken before and after the infusion. 
14 Total IFNonly. 
15 MAS activity on VAS at all indicated visits. Assessment of clinical parameters as per section 8.3.3 at the following visits: SD-1, SD14, SD21, SD28. In addition for cases where emapalumab treatment may be 
shortened (after SD6 and prior to SD28) due to a complete clinical response, the assessment is also to be made at this corresponding time-point.  
 
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                               CONFIDENTIAL 
Table 2 – Schedule of assessment: Evaluation period - from SD28 to SD56 (End of Study) 
Assessments 
 
SD35 
1st Week 
Follow-up 
SD42 
2nd Week 
Follow-up 
SD49 
3rd Week 
Follow-up 
SD561 
4th  Week 
Follow-up – 
EoS2 
Unscheduled 
Visit (UV)3 
Hospitalization4 
8.1 
 
 
 
 
 
Concomitant medication (including information on glucocorticoid tapering) 
8.2 
X 
X 
X 
X 
 
Clinical 
assessments 
- Vital signs 
8.3.1 
X 
X 
X 
X 
X 
- Physical examination 
8.3.2 
X 
X 
X 
X 
X 
 
- MAS clinical signs and symptoms6 
8.3.3 
X 
X 
X 
X 
 
Laboratory 
assessments 
- CBC 
8.4 
X 
X 
X 
X 
 
- Lymphocyte subset  
8.4 
 
 
 
X 
 
- Coagulation (aPTT, PT, D-Dimers, Fibrinogen)  
8.4 
X 
X 
X 
X 
 
- Biochemistry 
8.4 
X 
X 
X 
X 
 
- Serum pregnancy test 
8.4 
 
 
 
X 
 
- Urinalysis 
8.4 
 
 
 
X 
 
Search for 
infections 
- Mycobacterium Tuberculosis 
8.5 
 
X 
 
X 
 
- EBV, CMV, Adenoviruses 
8.5 
 
X 
 
X 
 
Procedure 
- ECG 
8.7.1 
 
 
 
X 
 
Imaging 
- Abdominal US 
8.6.1 
 
X 
 
X 
 
 
- Chest X-ray 
8.6.2 
 
 
 
X 
 
 
- Brain MRI5 
8.6.3 
 
 
 
X 
 
Histopathology 
- CSF analysis (if coagulation allows)5 
8.7.2 
 
 
 
X 
 
PK  
- emapalumab serum concentration 
8.8.1 
X 
X 
X 
X 
 
PD 1 
- IFN, CXCL9, CXCL10, sCD25 
8.8.2 
X 
X 
X 
X 
 
PD 2 
- Other markers 
8.8.2 
 
X 
 
X 
 
Immunogenicity (ADA) 
8.8.3 
 
 
 
X 
 
1 If Emapalumab treatment needs to be prolonged beyond 4 weeks, additional weekly visits must be scheduled as appropriate in order to complete the required short-term 4-week follow-up. 
2 The same procedures described for End of Study Visit should be followed for any patient who is withdrawn prematurely from the study (see protocol Section 8.9) 
3 Unscheduled Visit: depending on the reason for UV, additional assessments may be added according to the Investigator’s clinical judgment (see protocol Section 8.10).  
4 Hospitalization: please note that the patients can be discharged from SD15 if their conditions allow, provided that there is no active infections requiring i.v. antimicrobial therapy.  
5 Brain MRI & CSF analysis: to be performed in case of neurological symptoms occurrence, whenever possible. If brain MRI and CSF analysis were done at screening, an End of Study exam should be  
 performed, whenever possible. 
6 MAS activity on VAS at all indicated visits. In addition an assessment of clinical parameters as per section 8.3.3 at the following visits: SD42 and SD56. For cases where emapalumab treatment may be 
prolonged beyond SD28, the assessment of the specified clinical parameters is to be made at the time of last infusion and at the follow-up visits corresponding to 2 weeks and 4 weeks after the last 
emapalumab infusion.  
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       CONFIDENTIAL 
8.3 
CLINICAL ASSESSMENTS 
8.3.1 
Vital signs  
Vital signs include measurement of body temperature, heart rate, blood pressure and oxygen saturation. 
Body temperature will be recorded in the morning of visit days as indicated in the SoA. 
On the day of emapalumab infusion, heart rate and oxygen saturation will be recorded before and 
continuously monitored after the infusion for 4 hours. 
Body temperature and blood pressure will be recorded before and at regular intervals after emapalumab 
infusion as follows: 
- 
at the first infusion, every hour  10-min during the first 4 hours post-dose, at all other infusions, 
every hour  10-min during the first 4 hours post-dose (if no safety concerns have emerged after 
the first infusion).  
Blood pressure, heart rate and oxygen saturation will be measured every 15 minutes ( 5-min) during 
emapalumab infusion. 
8.3.2 
Physical examination 
A complete physical examination will be performed at screening and at each study visit (before the 
infusion when emapalumab is administered).  
Physical examination prior to each infusion may be performed in the late afternoon of the previous day 
instead of the morning of the infusion (the data will be captured on the infusion day of the CRF). 
At screening height (in cm), weight (in kg) and Body Surface Area (BSA) as calculated by the site will be 
recorded. 
Subsequent physical examinations will include i) recording of body weight prior to infusion and every 
2 weeks during the evaluation period for patients weighing less than 10 kg for patients weighing more 
than 10 kg, weight will be measured every 2 weeks throughout the study; ii) abdominal palpation for 
assessment of liver and spleen size (in cm from costal grill); iii) follow-up of any abnormalities 
previously recorded as well as occurrence of new signs and symptoms. 
8.3.3 
MAS clinical signs and symptoms  
The Investigator will be asked to provide his assessment of improvement/resolution of MAS signs and 
symptoms at the study timepoints indicated in the SoA. In addition, the Investigator will assess and 
document the clinical parameters as listed below at the visits on SD-1, SD14, SD21, SD28, SD42 and 
SD56 (and additional time-points as indicated in the SoA in case emapalumab treatment is shortened after 
SD6 due to a complete response or if study treatment is prolonged beyond SD28):  
 
‐ 
Fever (greater than 38.0 C°) 
‐ 
Skin Rash 
‐ 
Hemorragic manifestations 
o Skin bleeding (petecchiae, ecchymosis, purpura) (choose among  “stable”, “worsened”, 
“improved” or “resolved”) 
o Mucosal bleeding (gut, respiratory) (choose among  “present” or “absent”) 
‐ 
Evidence of CNS involvement 
o Clinical (headache, irritability, seizures, confusion, lethargy, coma) (choose among  
“stable”, “worsened”, “improved” or “resolved”) 
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o CSF abnormalities (cell count) (if lumbar puncture performed based on clinical 
indication) 
‐ 
Respiratory function 
o Oxygen support (choose among  “present” or “absent”; if present, indicate how many 
liters of O2 required to maintain O2 saturation) 
o Mechanical ventilation (choose among “present” or “absent”) 
‐ 
Cardiac 
o Pericarditis (if echocardiography is performed, results should be reported) 
o Inotropic support 
‐ 
Kidney 
o  Ultrafiltration/dialysis 
 
8.4 
LABORATORY ASSESSMENTS 
Blood and urine laboratory analyses are part of the routine monitoring of MAS patients, thus samples will 
be analyzed locally. Analyses done on blood samples will favor as much as possible the use of micro-
sampling techniques. 
If additional safety laboratory samples are required for safety reasons, the number of samples will take 
into account the weight and health status of the patient. 
Laboratory assessments will be performed at each study visit and will include: 
 
Hematology:  complete blood cell count (CBC) with differential count, a dedicated lymphocyte 
subsets count (at screening and EoS visit), and platelets. 
 
Biochemistry: Ferritin, Triglycerides, C-Reactive Protein (CRP), Aspartate Aminotransferase 
(AST), Alanine Aminotransferase (ALT), gamma Glutamyl Transferase (γGT), Alkaline 
Phosphatase (ALP), Lactate Dehydrogenase (LDH), total bilirubin, glucose, electrolytes, 
albumin, creatinine, Blood Urea Nitrogen (BUN).  
 
Coagulation tests: activated partial thromboplastin (aPTT), prothrombin time (PT), D-dimers and 
fibrinogen. 
 
Urinalysis: glucose, blood, protein, leucocytes, ketones, pH and specific gravity. On SD0, 
urinalysis will be performed before emapalumab infusion (only if not already performed at 
screening). Urinalysis will be repeated at EoS.  
 
Serum pregnancy test (if applicable) at screening and EoS. Additional pregnancy tests will be 
performed upon suspicion of pregnancy or as mandated by local regulations, as long as 
emapalumab serum concentrations are detectable. 
8.5 
SEARCH FOR INFECTIONS 
Search for infections that represent exclusion criteria include the following pathogens: 
‐ 
Mycobacterium Tuberculosis  
At screening, it will be performed via IFNγ-release assay or PPD test. In addition, a baseline via 
polymerase chain reaction [PCR] in a relevant specimen (e.g., urine or blood, if sputum is not 
easily obtained) has to be obtained, as this test will be used during the course of the study to 
perform regular TB monitoring.    
After initiation of emapalumab treatment, search for TB via PCR has to be performed every 2 
weeks as long as emapalumab is detectable in serum.  
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In the case of a patient having received BCG vaccination, a PPD test must be performed and 
combined with an IFNγ-release assay. 
‐ 
Atypical mycobacteria, Shigella, Salmonella, Campylobacter, Histoplasma Capsulatum and 
Leishmania  
Search for all these pathogens have to be performed at screening. During the study, search for 
these pathogens has to be performed if there is any suspicion of infection. 
A first screening for Histoplasma Capsulatum may be performed using galactomannan assay, 
however if the test is positive, confirmation should be obtained by using a Histoplasma 
Capsulatum specific test. The presence of Leishmania can be ascertained by direct bone marrow 
observation. 
In addition, search for the following infections is required:  
 
Herpes Simplex Virus (HSV), Herpes Zoster Virus (HZV), Hepatitis B Virus (HBV), Hepatitis C 
Virus (HCV), Human Immune Deficiency Virus (HIV) by PCR monitoring or serology, at 
screening and whenever there is a suspicion of infection. 
 
EBV, CMV, Adenoviruses by quantitative PCR, at screening and every 2 weeks as long as 
emapalumab is detectable in serum. 
A patient with a clinical assessment (including chest X-ray) not indicative of the presence of an active 
infection, provided that a usable specimen has been taken and the microbiological analysis is ongoing, 
can be enrolled prior to the availability of the results, if the patient’s clinical conditions require a rapid 
initiation of emapalumab treatment. 
8.6 
IMAGING 
8.6.1 
Abdominal ultrasound 
Abdominal ultrasounds, including spleen (longitudinal) measurements and assessment of hepatomegaly 
presence, will be performed at screening and every 2 weeks during the study. 
8.6.2 
Chest X-ray 
Chest X-ray will be performed as a measure for detection of pulmonary infections at screening and every 
4 weeks during the study. Chest X-ray should be done more frequently in case of clinical suspicion of a 
pulmonary infection. 
8.6.3 
Brain MRI 
Brain MRI should be performed in case of neurological symptoms occurrence, prior to emapalumab 
initiation (or at latest by SD6), and repeated at the end of the study, whenever possible. 
8.7 
OTHER PROCEDURES 
8.7.1 
ECG 
12-lead ECG will be performed and interpreted locally by the Investigator or delegate for immediate 
clinical assessment.  
At screening, triplicate ECG (three consecutive recordings) is required in order to obtain a stable 
baseline. 
ECG is mandatory at screening, after the first emapalumab infusion, and at the end of the study, however 
it should also be performed whenever required based on clinical judgment. 
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8.7.2 
 Cerebrospinal fluid assessment 
Lumbar puncture for CSF analysis should be done in case of neurological symptoms occurrence, 
whenever possible and if coagulation parameters allow, prior to emapalumab initiation, during the course 
of the study and at the end of the study, as clinically indicated.  
8.8 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS  
8.8.1 
Pharmacokinetics 
Serum samples for PK analysis will be collected at the visits indicated in the SoA (Table 1 and Table 2). 
In case of need for prioritization of blood analysis (considering weight and health status of the patient), 
laboratory safety parameters (which would be done as normal disease monitoring) may need to be 
prioritized over samples for PK assessments, that in turn will be prioritized over biomarkers exploratory 
parameters. 
On the days of infusion, PK samples should be collected before and after (between 15 and 30 minutes 
after) the infusion.   
After the first emapalumab infusion, PK samples will be also collected on SD1 (around 24 hrs. post- 
infusion) and SD2 (around 48 hrs. post-infusion). Additionally, PK samples will be collected on SD5 
(around 48 hrs. after the second emapalumab infusion). 
After completion of emapalumab infusions, samples for PK assessment will be collected until serum 
emapalumab concentration are no longer detectable (or until consent is withdrawn), as indicated in the 
SoA until the EoS visitIn case of CNS involvement, if lumbar puncture is performed for diagnostic and/or 
therapeutic purposes, PK analysis in CSF samples may be performed. 
Details on sample preparation and handling will be described in a separate laboratory manual. 
8.8.2 
Pharmacodynamics 
Serum samples for PD analysis will be collected at the visits indicated in the SoA (Table 1 and Table 2).  
In case of need for prioritization of blood analysis (considering weight and health status of the patient), 
laboratory safety parameters and PK assessments will be prioritized over biomarkers exploratory 
parameters. 
Pharmacodynamics assessments include the measurement of: 
 
Free IFN levels prior to emapalumab treatment start, and total IFNγ (free IFNγ+bound to 
emapalumab) during emapalumab treatment. Samples for total IFNγ measurements will be taken 
pre-dose on infusion visits, except for the first infusion when free IFN will be measured pre-
dose and total IFNγ post-dose.  
 
Chemokines known to be induced by IFNγ (CXCL9, CXCL10) and sCD25. On infusion visits, 
serum samples will be collected pre-dose only. 
 
Other potential disease markers (e.g., sCD163, IL-18, IL-10, IL-6, TNF). Serum samples will 
be collected on SD0 and every 2 weeks during the course of the study.   
In case of CNS involvement, if lumbar puncture is performed for diagnostic and/or therapeutic purposes, 
biomarker analysis in CSF samples may be performed. 
Details on sample preparation and handling will be described in a separate laboratory manual. 
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8.8.3 
Immunogenicity  
Serum samples for the assessment of ADAs will be collected on SD0 (prior to emapalumab infusion) and 
at the End of Study visit, and in case of PK Clearance of emapalumab is faster than expected during the 
study. Details on sample preparation and handling will be described in a separate laboratory manual. 
8.9 
WITHDRAWAL VISIT 
The same procedures described for the EoS Visit should be followed by the Investigator for any patient 
who is withdrawn prematurely from the study, as soon as possible after the decision to withdraw is made.  
For patients who withdraw from the study as a result of their own decision or the decision of their 
parent/guardian, the Investigator should contact the patient (or parent/guardian) and ask them to attend a 
withdrawal visit as soon as possible and in any case within 30 days from termination. 
Patients who are withdrawn due to a serious adverse event (SAE) should be followed-up until the 
resolution of the event or until the outcome of the event is known and stable. 
8.10 UNPLANNED (UNSCHEDULED) VISITS 
Unplanned visits may occur, should the patient need to be assessed or treated for any clinical condition 
that arises during the study. This may include the evaluation and follow-up of AEs, SAEs or laboratory 
tests. The assessments (as detailed in the SoA) should always be performed at minimum, but additional 
evaluations may be added according to the clinical judgment of the Investigator. 
8.10.1 Unplanned Assessments 
Additional samples to assess laboratory parameters and PK/PD may be required for safety reasons and/or 
for a better characterization of the PK/PD profile.  
The number of additional samples taken will depend on the body weight and health status of the patient. 
Sampling schedule will be proposed by the Sponsor and discussed with the Investigator. 
9 
STUDY SCIENTIFIC OVERSIGHT  
A Scientific Steering Committee (SSC) composed of international experts in pediatric rheumatology as 
well as in HLH has been involved in the preparation of study design and protocol writing. 
The SSC is also to be consulted for the composition of the independent Data Monitoring Committee 
(iDMC).  
The SSC will continue to play an advisory role throughout the course of the study, including the support 
to the iDMC oversight, and will perform evaluations of the data to support the Sponsor in the 
interpretation of the results of the study.  
Please refer to Appendix C for full details of membership of the SSC. 
10 
SAFETY MONITORING 
10.1 INDEPENDENT DATA MONITORING COMMITTEE 
The iDMC, composed of relevant experts (pediatric rheumatologist, pediatric onco-hematologist with 
experience in HLH, pediatric immunodeficiency/infectious disease specialist, bio-statistician and a 
specialist in ethics), will oversee the study, with particular regard to the evaluation of safety parameters 
and benefit/risk profile of emapalumab, reviewing all data generated on an ongoing basis with the aim to 
ensure that patients are not exposed to unnecessary risks.  Some of the iDMC members have been already 
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involved in the oversight of the ongoing emapalumab studies.  Please refer to Section 10.5.1 for further 
details on the iDMC. 
10.2 DESCRIPTION OF SAFETY PARAMETERS 
Evaluation of emapalumab tolerability and safety will be based on the following parameters: 
 
Adverse events (AEs), with special attention being paid to potential infusion related reactions 
(IRRs), (i.e events occurring during or within 24 hours post infusion) and to the occurrence of 
infections, particularly with pathogens associated with lack of IFNγ biological activity (due to 
emapalumab mode of action). 
 
Laboratory parameters, as described in Section 8.4   
 
Vital signs, as described in Section 8.3.1 
 
Physical examination with particular attention paid to evolution of signs and symptoms present at 
baseline, and to any emergent new signs or symptoms (see Section 8.3.2 for more details).  
10.3 RECORDING AND REPORTING SAFETY PARAMETERS  
10.3.1  Adverse events 
Adverse events (AEs) are defined as any undesirable experience occurring to a subject during the study, 
whether or not considered related to the IMP. All AEs reported by the patients or his/her relatives or 
observed by the Investigator or his staff during the clinical study from the signature of the ICF up to and 
including the EoS visit will be reported on the AE data collection form.   
Medical conditions present at screening (before ICF signature) should be recorded in the medical history 
section of the CRF. 
All AEs will be reported in the appropriate section of the CRF. 
An AE which occurs between start of screening visit (after ICF signature) and start of first IMP 
administration will be considered as a pre-treatment AE.  
Any AE that occurs after the start of the first IMP administration will be considered in the study as 
Treatment Emergent Adverse Event (TEAE). 
However, if a pre-existing medical condition recorded in the medical history worsens (clinically 
significant change in intensity or frequency), it must be recorded as an AE in the CRF and, depending on 
the time of its occurrence, will be considered as a pre-treatment AE or a TEAE. If a medical condition, 
recorded as a pre-treatment AE, worsens it will be recorded in the CRF as a separate TEAE. 
For each AE, the following will be assessed and recorded: intensity, relationship to the IMP, action taken 
regarding the IMP, any treatment received for the event and outcome of AE to date.  
Intensity of AEs will be graded on a three-points scale (mild, moderate, severe) using the modified WHO 
(World Health Organization) toxicity scale (Grade 3 and 4 are considered to be the severe grade). If AE 
severity cannot be assessed by this scale, assessment by the Investigator should be made using the 
following definitions: 
• 
Mild: discomfort noticed but no disruption of normal activity, 
• 
Moderate: discomfort sufficient to reduce or affect normal daily activity, 
• 
Severe: inability to work or perform normal daily activity. 
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For a given AE, the assessment of its intensity should reflect the highest grade (on the 3 points scale 
mentioned above) reported during its course (except when the intensity of a pre-treatment AE increases 
after treatment initiation, as indicated above).  
The relationship of the AE to the IMP will be assessed by the Investigator using a “Yes/No” 
classification. A “Yes” relationship infers that there is a reasonable possibility of causal relationship 
between the AE and IMP. The expression “reasonable possibility” is meant to convey that there are facts, 
evidence or arguments to suggest a causal relationship. Conversely, a “No” relationship infers that there 
is no reasonable possibility of causal relationship between the AE and IMP. Usually it implies that other 
possible causes have been identified.  
In this study emapalumab is the only IMP. 
 
Abnormal laboratory findings should be reported as AEs if requiring specific treatment. Exception to this  
is the onset of any new or worsened abnormal laboratory findings [e.g. cytopenias (all three lines), 
abnormalities denoting liver dysfunction, coagulopathy, abnormal ferritin, fibrinogen and triglyceride 
levels] indicative of an HLH/MAS reactivation or worsening: in this specific instance, the reactivation or 
worsening of HLH/MAS must be reported as the AE and not the abnormal laboratory findings, even if 
requiring intervention.  
 
If an abnormal laboratory finding leads to a new diagnosis, this diagnosis should be reported as AE (e.g. 
hyperglycaemia leading to diagnosis of diabetes mellitus). 
 
10.3.2 Serious Adverse Events 
An adverse event is considered serious if it: 
 
results in death (note: death is an outcome, not an event); 
 
is life-threatening; (note: the term "life-threatening" refers to an event in which the patient 
was at immediate risk of death at the time of the event; it does not refer to an event which 
could hypothetically have caused a death had it been more severe); 
 
requires in-patient hospitalization or prolongs an existing hospitalization; 
 
results in persistent or significant disability/incapacity; 
 
is a congenital anomaly/birth defect; 
 
is an important medical event that may not result in death, be life-threatening, or require 
hospitalization but may be considered serious 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 above. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
For the purposes of this study, the following will not be considered as serious adverse events: 
 
Elective hospitalizations or surgical procedures that are a result of a patient’s pre-existing 
condition(s) which has (have) not worsened since receiving IMP. Such events should still be 
recorded as adverse events in the CRF; 
 
Hospitalization as requested per protocol for emapalumab infusion and study visits. 
Any serious adverse event (SAE) that occurs during the course of the study, irrespective of the treatment 
received by the subject and regardless of causality to the study drug, must be communicated by the 
Investigator to Sobi AG, by fax or electronic transmission, within 24 hours of awareness. 
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For the initial SAE report, the Investigator should report all available case details concerning the patient 
and the event, using the Sobi AG SAE reporting standard form provided to the Investigators.  
Sobi AG contact information for SAE reporting: 
- 
E-mail: 
Relevant follow-up information on SAEs should be forwarded to Sobi AG as soon as it becomes 
available. In addition, the Investigator should answer without delay any request for follow-up information 
or questions Sobi AG team may have regarding the reported SAE. 
All SAEs must be recorded as an AE in the CRF. They should be reviewed, evaluated and followed 
through to resolution (or stabilization) by the Investigator. 
For any new SAE, the following minimum information is required in the initial report: 

Clear identification of the Investigator, with full contact information or site number

Subject’s identification details (study number, site number, subject’s unique study identification
number and date of birth),

IMP administration details (dose and dates)

Diagnosis of the event (or a brief description of signs/symptoms/clinical course, if the diagnosis
is not available) and the date of onset,

Seriousness criteria.
In addition causal relationship (Investigator’s opinion) of the event with the IMP or with the study 
procedure (e.g. the causality according to the Investigator during screening) should be provided whenever 
possible in this initial report, otherwise it must be included in a follow-up report.  
The Sponsor will also conduct its own assessment on seriousness and causality of all recorded AEs 
during the study. If the Sponsor becomes aware of an AE, which has not been reported by the 
Investigator as serious, but is assessed by the Sponsor as serious (e.g. medically important), the 
Investigator  will be asked to report such AEs to the Sponsor as  an SAE, according to the timelines and 
rules described above.  
10.3.3  SUSAR reporting 
Suspected unexpected serious adverse reactions (SUSARs) are adverse events that are both serious and 
unexpected (i.e. as per the Investigator’s Brochure), and are considered, by the Investigator or the 
Sponsor, to have a reasonable possibility of causal relationship between the administered IMP and the 
adverse event.  
Some of the SAEs reported by the Investigator may qualify as SUSARs, and such need to be reported in 
an expedited manner by the Sponsor to Health Authorities and Central Ethics Committees/Independent 
Ethics Committees/ Research Ethics Boards.  
Under 21 Code of Federal Regulation (CFR) 312.32(c), the Sponsor (directly or through a delegated third 
party) is required to notify the Food and Drug Administration (FDA) and all participating Investigators in 
an IND safety report (i.e., 7- or 15-day expedited report) of potentially serious risks from clinical trials or 
any other source as soon as possible, but no later than 15 calendar days after the Sponsor receives the 
safety information and determines that the information qualifies for reporting. 
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Investigators in the US are required to promptly report to the IRB all unanticipated problems involving 
risk to human subjects or others, including AEs that should be considered unanticipated problems (21 
CFR 312.66), such as IND safety reports. 
For Canada, the sponsor is required to inform Health Canada of any serious, unexpected adverse drug 
reaction that has occurred inside or outside Canada. An adverse drug report must be filed in the cases 
where the adverse drug reaction is neither fatal nor life-threatening, within 15 days after becoming aware 
of the information, within 7 days where it is fatal or life-threatening, immediately where possible and, in 
any event, after becoming aware of the information. 
10.4  FOLLOW-UP OF SAFETY PARAMETERS 
10.4.1  Treatment and Follow-up of Adverse Events 
Adverse events, especially those for which the relationship to the study drug has been assessed as ‘Yes’, 
should be followed-up until the event has returned to baseline status or has stabilised. If a clear 
explanation is established, it should be recorded on the CRF. 
All SAEs must be followed-up until the event has either resolved or reached a stable clinical outcome. 
10.4.2  Pregnancy 
In the event that a pregnancy occurs during the trial course, it must be reported to Sobi AG within 24 
hours of awareness. This includes pregnancies occurring in partners of male enrolled patients. All 
information pertaining to the pregnancy should be reported using the Sobi AG Pregnancy form provided 
to the investigators. Pregnancies should be followed until conclusion to obtain outcome information. 
Occurrence of a pregnancy in a study participant will preclude any further IMP administration.  
If the patient is withdrawn from the study, the assessments presented in the Schedule of Assessments for 
EoS are to be performed (see Section 8.9). 
10.5 BENEFIT/RISK MANAGEMENT 
10.5.1 Safety Surveillance Management - iDMC 
The main responsibility of the iDMC is to review all safety and efficacy data as they are generated to 
ensure that no patient is exposed to unnecessary risk and to continuously assess the benefit/risk profile of 
emapalumab. 
The iDMC can recommend treatment discontinuation for individual patients as well as to halt the entire 
study temporarily or permanently. Predefined stopping rules will guide the iDMC review process. For 
more details, see stopping rules in Section 11. 
10.5.2  General Benefit/Risk Considerations  
10.5.2.1 Potential benefits 
Patients presenting MAS secondary to sJIA may not respond to systemic glucocorticoids and have 
limited alternative therapeutic options. These options are represented by prolonged treatment with high 
doses glucocorticoids, and administration of CsA or chemotherapy such as etoposide, all options carrying 
an increased risk of morbidity and mortality. For those non-responders patients, an alternate therapy 
should aim to obtain remission of MAS with none or limited safety issues.   
Three elements strongly suggest that the use of emapalumab would enable MAS remission: 
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- In animal model mimicking MAS, administration of an anti-IFNγ enables the recovery/remission of 
the signs and symptoms associated with hypercytokinemia  
- Observational studies have shown a strong correlation between biomarkers (IFNγ as well as IFNγ- 
induced chemokines) and disease parameters at MAS onset and during disease evolution. 
According to the data collected to date in pHLH patients (ongoing NI-0501-04 study), emapalumab 
administration has shown the potential to improve or resolve relevant clinical and laboratory 
abnormalities of HLH, including CNS signs and symptoms when present, allowing patients to proceed to 
HSCT.  
For more details refer to the latest Investigator’s Brochure. 
Based on these considerations, sJIA patients with MAS having inadequately responded to systemic high 
dose glucocorticoids are expected to benefit from a targeted therapy with emapalumab aiming at 
neutralizing IFNγ and achieving MAS remission.  
10.5.2.2 Risks analysis 
 
Risks related to emapalumab  
emapalumab is a fully human IgG1monoclonal antibody (mAb). 
Upon the administration of mAbs, which are proteins, acute infusion reactions can occur. These may 
happen during the infusion or in the subsequent hours (usually within the first 24 hours) (Kang SP 2007, 
Maggi E 2011).  
These reactions are either IgE-mediated type I hypersensitivity reactions (anaphylactic reactions), or 
anaphylactoid reactions not mediated by IgE. True anaphylactic reactions usually do not occur upon 
initial infusion and require a certain sensitization. In contrast, the pathophysiology of anaphylactoid 
reactions appears to be secondary to the release of cytokines consequent to a mAb binding to circulating 
antigen-expressing cells. However, the clinical manifestations of anaphylactic and anaphylactoid 
reactions overlap, and both may lead to life-threatening conditions, involving cardiovascular, respiratory, 
central nervous, gastro-intestinal, and cutaneous systems. The management of anaphylactic and 
anaphylactoid reactions involves immediate administration of oxygen, epinephrine, vasopressors, 
bronchodilators, corticosteroids, and/or antihistamines.  
More than 850 infusions have been administered to HLH patients (either in the context of the NI-0501-04 
and NI-0501-05 studies or in patients who have received emapalumab in compassionate use) up to and 
including the dose of 10 mg/kg, without any serious or severe infusion related reaction reported. In less 
than 2% of infusions, mild or moderate transient erythematous rashes localized to the extremities (feet 
and/or hands) have been reported in a few patients. They occurred in most of the cases during the first 
infusions of emapalumab and resolved spontaneously. When administration of emapalumab has been 
performed occasionally through a peripheral venous access, infusions were all uneventful.  
In the population intended to be enrolled in the study, the risk of developing infusion related reactions 
compared to previously exposed HLH patients is not expected to be higher. All patients enrolled in this 
study will continue to receive glucocorticoids concomitantly, and will be monitored during and after the 
infusion. 
When administered to humans, most mAb therapeutics elicit some level of antibody response (anti-drug 
antibodies or ADAs) against the therapeutic product, as early as after the first exposure. No sign of 
immunogenicity has been reported in the emapalumab study in healthy volunteers. The presence of 
ADAs will be measured during this study as per regulatory recommendations, and the analysis is planned 
to be performed at the end of the NI-0501-06 study, unless PK or safety concerns possibly related to 
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immunogenicity would justify an interim analysis.  Data accumulated so far (in particular PK profiles and 
a negative ADA search performed in the first pHLH patient treated with emapalumab) have not led to 
suspect the presence of ADA. 
 
Risks related to the target 
The impact on the immune defense caused by the neutralization of IFNγ is known from patients with 
inborn errors of the IL-12/23-IFN-γ circuit, particularly patients with complete or partial IFNγ receptor 
(R) deficiency, and subjects developing neutralizing auto anti-IFNγ antibodies. 
Patients with IFNγ R deficiency are prone to developing mycobacterial infections and, although to a 
lesser extent, Salmonella infections (Dorman SE 2000, Jouanguy E 1997). The mean age of the first 
environmental mycobacterial infection is 3.1 and 13.4 years in patients with complete and partial 
deficiency, respectively (Remus N 2001). No systematic prophylaxis has been recommended in these 
patients. 
If an infection occurs, appropriate antibiotherapy based on sensitivity of isolated species is prescribed. 
Individuals with anti-IFNγ auto-antibodies are also susceptible to develop mycobacterial infections (for 
the vast majority atypical mycobacterial infections), but also opportunistic infections (e.g. by 
Histoplasma Capsulatum, Salmonella, Herpes Zoster virus infections) (Browne SK 2012).   
Toxicological studies carried out with emapalumab have shown an increased susceptibility of the 
monkeys having received emapalumab to enteral pathogen infections when the pathogen is present into 
the intestinal tract prior to emapalumab administration. Presence of infections due to Shigella, Salmonella 
and Campylobacter is part of the exclusion criteria. 
A reactivation of Herpes Zoster virus after the single emapalumab infusion at 3 mg/kg, was observed in 
one healthy volunteer in the NI-0510-03 study with a non-uneventful course and full recovery.   
Preliminary data on infections collected in patients treated with emapalumab to date allow the following 
conclusions to be drawn:   
- Active infections, in particular bacterial and viral infections (among them EBV or CMV infections, 
which are often the trigger of the HLH), were present at the first administration of emapalumabin 
some of them. During emapalumab administration these infections resolved with appropriate 
antimicrobial treatment and while achieving control of HLH. 
‐ Some HLH patients treated in second line after immune-chemotherapy developed infections during 
the course of emapalumab treatment. A long and profound generalized immune suppression caused by 
HLH treatments administered prior to the initiation of emapalumab constitutes a higher risk for 
infection development. However in the presence of a satisfactory control of HLH, and upon 
appropriate anti-microbial treatment, infections have usually resolved. 
‐ Patients treated in first line or after a limited exposure to glucocorticoids or chemotherapy seem to 
develop less infections during the course of emapalumab.  
‐ Systematic search for tuberculosis was negative and no atypical mycobacteria were detected in any of 
the patients. Stool/blood cultures were negative for Salmonella, Shigella or Campylobacter in all 
patients. No Herpes Zoster infection has been reported. 
‐ Only one infection reported (disseminated histoplasmosis in a patient with a severely compromised 
immune status and suspected to carry the pathogen prior to the administration of emapalumab) was 
reported as a serious adverse reaction as it is one of the few pathogens known to be favored by IFNγ 
neutralization. However the patient recovered from it rapidly after the administration of an effective 
antifungal treatment. 
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‐ The severity and duration of neutropenia, a hallmark of HLH as well as a potential consequence of 
previous HLH treatments, seemed to contribute significantly to the development of infections. 
For more details refer to the latest Investigator’s Brochure.  
 
Risk related to the study population 
Most of the patients are expected to have already received at least glucocorticoid treatments as well as 
having possibly been previously treated by sJIA specific therapies, some of them for a relatively long 
time depending on the duration of their underlying rheumatic disease; therefore they may carry variable 
degree of toxicities caused by those treatments. The data collected to date in pHLH patients who have 
been heavily pretreated by immune-chemotherapy show that administration of emapalumab does not 
aggravate toxicities of previous therapies while showing, in general, a favorable impact on HLH activity.  
All information collected on disease severity and previous treatments will be taken into account for the 
analysis of adverse events.  
Toxicities of concomitant treatments, authorized or recommended during the administration of 
emapalumab, may also potentially expose the patients to adverse events; however their benefits may 
outweigh their risks. No safety concern related to the concomitant administration of emapalumab with 
other treatments (e.g., antimicrobial agents, anti-hypertensive drugs) has been reported so far. 
Corticosteroids have already been administered with anti-IFNγ therapy in Crohn’s Disease without any 
particular safety concerns (Reinisch W 2010). Of interest, tapering of glucocorticoids had no impact on 
safety and tolerability of emapalumab infusions and has shown benefit for patients with steroids-related 
hypertension and generalized immunosuppression. 
Although the risk that the emapalumab treatment will not be able to control the disease may exist, the 
close monitoring and the stopping rules of the study ensure that, in this event, emapalumab treatment will 
be discontinued and the patients will rapidly receive rescue treatments according to the standard clinical 
practice at the participating sites. The risks of administering alternate therapy after having received 
emapalumab seems to be low, since no particular safety concerns were observed during treatment with 
emapalumab. 
10.5.2.3 Risk minimization measures 
In view of the expected benefits and previous experience gathered with patients exposed to emapalumab 
the above listed risks are considered to be manageable in this patient population, if adequate 
minimization measures are put in place. An overview of specific measures to minimize the subject’s risk 
is provided below: 
 
Study designed with rheumatologists experienced in the treatment of sJIA and MAS, forming 
the SSC. 
 
Patients are hospitalized in specialized centers for the treatment of MAS, and therefore with 
all necessary emergency assistance equipment. 
 
Inclusion/exclusion criteria: patients with malformations or severely altered functions (either 
due to the disease stage or to a concomitant disease), as well as patients with evidence of 
patent or latent TB infections or active mycobacteria, Shigella, Salmonella, Campylobacter,  
Histoplasma Capsulatum or Leishmania infections, will not be included in the study (for 
details see Section 4.1).  
 
Although unlikely to be observed based on preliminary results gathered from patients treated 
with emapalumab up to 10mg/kg, Infusion Related Reactions (IRRs) will be detected and 
managed in due time through patients’ monitoring during and after drug infusions. Each of 
the specialized centers will have physicians adequately trained in IRR management. 
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 
Recommendations on prophylaxis for Herpes Zoster virus for all patients and Tuberculosis 
for a defined subpopulation (see Section 6.2) in the protocol to avoid occurrence of these 
infections. 
 
The monitoring for specific infections, known to be favored by IFNɣ neutralization, will 
continue after emapalumab discontinuation as long as serum emapalumab levels are 
detectable. 
 
Close monitoring of potential infections through careful physical examination, laboratory 
parameters, active search for EBV, CMV, Adenoviruses, detection of tuberculosis  
 
Study safety surveillance by an independent Data Monitoring Committee 
The Development Risk Management Plan addresses risks, identify signals for early detection of safety 
concerns and propose mitigating actions. It will be part of the study documentation shared with 
Investigators and any relevant third party involved in the study.Stopping rules have been also developed 
to ensure individual patient safety and determine whether the study should be put on hold or terminated 
prematurely. 
11 
STOPPING RULES 
11.1 AT PATIENT LEVEL 
11.1.1 Investigator’s or Patient’s Decision to Discontinue 
An Investigator can decide at any time during the study to discontinue the treatment for an individual 
patient based on his/her own medical judgment, taking into account the individual benefit risk ratio for 
his/her patient. In addition, the patient (or their legal representative) can decide at any time to withdraw 
from the study.  
In any case the decision to withdraw or be withdrawn will have no impact on the patient’s care and 
further treatments administered to him/her after withdrawal.  
Patients who are withdrawn from the study will receive alternative treatments according to the standard 
of care at the site. 
 
11.1.2 Decision to Discontinue Treatment due to Safety Reason or Lack of Efficacy 
11.1.2.1 Treatment Discontinuation for a Safety Reason 
A patient must be discontinued from study treatment if a SAE occurring after emapalumab administration 
is: 
1. considered by the Investigator to be related to emapalumab (with guidance from the iDMC if 
needed)  
AND 
2. is a life-threatening event. 
11.1.2.2 All other related SAEs will be judged by the iDMC on a case-by-case basis taking 
into account the disease evolution (such as signs of improvement in HLH) and the 
possibility of managing the SAE and ensuring that no patient is exposed to 
unnecessary risks. Treatment Discontinuation for Lack of Efficacy 
A patient should be discontinued from study treatment for lack of efficacy in the event of any of the 
followings: 
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- Rapid worsening of MAS representing immediate risk for the patient and requiring the use 
of a salvage therapy.   
- No Response to emapalumab, provided that there is evidence of IFNg neutralization. 
However, upon request by the Investigator to continue emapalumab treatment in the absence of 
therapeutic alternatives, the iDMC can authorize it after a thorough review of the patient’s data and 
confirmation of lack of risks for the patient.  
11.1.3 Systemic and local reaction to emapalumab infusion 
In case of clinical relevant changes in vital signs compared to pre-infusion values, the rate of 
emapalumab infusion may be decreased or the infusion temporarily interrupted, if deemed necessary by 
the Investigator.  
A decision to definitely stop the infusion should only be taken in case of very severe systemic reactions 
and be based on the evolution of patient status after appropriate symptomatic measures, e.g. oxygenation, 
and upon physician’s own medical judgment.  
All changes in the infusion rate should be recorded on the Infusion Worksheet: each time with the rate 
modification.  
Unless related to a hypersensitivity reaction, the occurrence of local issues related to the infusion (such as 
catheter displacement, obstruction or product extravasation) should be managed through the identification 
of a new venous access as soon as possible to complete the infusion. All relevant information needs to be 
recorded in the Infusion Worksheet, including the volume of IMP potentially lost (in order to calculate 
the quantity of drug infused), and the time at which the infusion was stopped and restarted.  
11.2 AT STUDY LEVEL 
11.2.1 Suspension of Recruitment 
Recruitment may be suspended in the following situations: 
 
Any occurrence of death or life-threatening SAE related to the drug  
 
At the iDMC’s own request as an outcome of their regular study review. 
Patients already enrolled in the study should continue receiving emapalumab as per protocol unless 
decided otherwise by the Investigator. 
The suspension will allow the iDMC to analyse the data already generated and consider a 
recommendation. 
After re-evaluation of benefit/risk profile, the iDMC may recommend any of the following:  
 
To resume recruitment without any change 
 
To implement minimisation measures that may require protocol amendment 
 
To implement conditions for study termination, e.g. next occurrence of a particular serious drug 
reaction or at the next patient worsening or reactivation 
11.2.2 Study Termination 
11.2.2.1  Study Termination for Safety Reason 
Occurrence of two deaths suggesting a reasonably possible relationship with continuous exposure to 
emapalumab and occurring in similar conditions will trigger the decision to terminate the study. 
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This process will involve both the iDMC and the Investigator. The management of patients already 
enrolled in the study will also be part of the iDMC recommendations. 
11.2.2.2 Study Termination for Absence of a Demonstrated Benefit  
The decision to terminate the study due to absence of a demonstrated benefit will be one of the 
responsibilities of the iDMC, based on the ongoing review of the individual patient data and benefit/risk 
analysis. 
In case of study termination, the management of the patients already enrolled in the study will also be 
part of the iDMC recommendations. 
12 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
Full details of all planned analyses will be specified in separate documents describing PK/PD and 
Statistical Analyses, which will be finalized prior to the locking of the study database. This section 
contains an overview of the planned methods of analysis with regard to safety and efficacy variables. 
12.1 SAMPLE SIZE   
Approximately 12 patients (a minimum of 10 sJIA patients) will be enrolled across North America and 
Europe. The sample size is based on pragmatic considerations, and on the experience acquired from 
primary HLH patients treated with emapalumab. 
12.2 ANALYSIS SETS   
All analysis sets will be defined prior to final database closure. In addition to the analysis sets listed 
below, further exploratory analyses may be performed using other subgroups of patients. 
12.2.1 Safety Analysis Set 
The safety analysis set will include all patients who receive any part of an infusion of study drug. 
12.2.2 Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will coincide with the Safety Analysis Set. 
12.2.3 Per-Protocol Analysis Set 
The per-protocol analysis set will consist of all ITT patients who complete the study without major 
violations of the study protocol. Detailed listing of major protocol deviations will be defined in the SAP 
prior to locking of the final database.  
12.3 STATISTICAL AND ANALYTICAL METHODS  
For measurements of continuous endpoints, summary statistics will include n, mean, median, standard 
deviation, minimum and maximum values. For binary data (proportions of patients showing a defined 
variable) the numbers and percentages will be tabulated.  
All study variables are considered to be exploratory in this study, and no hierarchy of endpoints has been 
specified, as the objective of this pilot study is to confirm that the proposed dose regimen is adequate in 
this patient population. 
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Analysis will focus on descriptive statistics and confidence intervals. As this is a pilot study, statistical 
methods will focus on summarizing the data collected using descriptive statistics and on appropriate 
graphical presentations. 
12.3.1 Efficacy Data 
Graphical and tabular summaries will be prepared for each of the MAS distinct features, e.g. fever; 
splenomegaly; WBC; platelet counts; liver function test (in particular ALT/AST); fibrinogen; ferritin; 
LDH.  
For binary endpoints (MAS remission by Week 8, number of patients who taper glucocorticoids, number 
of patients who discontinue due to lack of efficacy), 95% confidence intervals will be calculated for 
proportions. 
For time to event endpoints (time to MAS remission, time to achievement of glucocorticoids tapering and 
time to death), Kaplan-Meier curves will be calculated and summary statistics, such as medians, 
proportions event-free at various time points will be calculated and presented, and 95% confidence 
intervals calculated where possible.  
12.3.2 Safety Data 
All data relating to safety will be listed and summarized using descriptive statistics.  
AEs will be coded and tabulated by body system, and by individual events within each body system. AEs 
will also be tabulated by severity and relationship to the study medication. Summaries will also be 
produced of SAEs and AEs leading to withdrawal from the study. 
For each clinical laboratory test, individual patient values will be listed and summarized and change from 
pre-treatment baseline values calculated and summarized. Summaries of marked abnormalities and shift 
tables will be tabulated for each laboratory test. 
In addition, other exploratory analyses of safety data, including summaries for different subsets of 
patients, may be conducted. 
12.3.3 Pharmacodynamic Data 
All PD data will be summarized using appropriate graphical and tabular presentations. 
Exploratory statistical models will be fitted, and correlation analyses undertaken, to investigate the 
relationships between PD data and clinical measures of response. ROC curves may be used to summarize 
any relationships that are found. 
In addition, other exploratory analyses of pharmacodynamic endpoints, including summaries for different 
subsets of patients, may be conducted. 
12.3.4 Immunogenicity Data 
The numbers of patients with anti-drug antibodies present at each assessment point will be summarized. 
12.3.5 Missing Data 
No imputations of missing data will be performed. However, the following rules will be applied to ensure 
that all patients can be included in the final analysis:  
- 
patients who are withdrawn from the study prior to Week 8 because of safety concerns or 
poor efficacy will be classified as non-responders from the time of their withdrawal in all 
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analyses of response status, and their data will be censored at time of withdrawal in all time-
to-event analyses. For continuous endpoints in such patients, all analyses for time points 
beyond the point of withdrawal will exclude missing data for these patients. 
12.4 INTERIM ANALYSIS 
No interim analysis is planned. 
12.5 WITHDRAWAL AND REPLACEMENT  
12.5.1 Patients 
Additional patients will be recruited into the study if patients are withdrawn from the study for reasons 
other than safety or lack of efficacy to ensure a sample size of approximately12 patients across North 
America and Europe. 
12.5.2 For Centers 
Centers may be closed down for the following administrative reasons: excessively slow recruitment, poor 
protocol adherence.  
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PART II 
13 
ETHICAL AND LEGAL ASPECTS 
13.1 GOOD CLINICAL PRACTICE 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and documentation of 
this study are designed to ensure that Sobi AG, its authorized representative, and Investigator abide by 
Good Clinical Practice (GCP), as described in International Conference on Harmonization (ICH) 
Guideline E6 and in accordance with the general ethical principles grounded in the Declaration of 
Helsinki. The study will receive approval from an IRB/IEC prior to commencement and where applicable 
by law also from National Competent Authorities. The Investigator will conduct all aspects of this study 
in accordance with applicable national, state, and local laws of the pertinent regulatory authorities. 
13.2 INVESTIGATOR’S RESPONSIBILITIES 
The Investigator must ensure that all persons assisting with the trial are appropriately qualified and 
adequately informed about the protocol, amendments, study treatments, as well as study-related duties 
and functions and should ensure this is appropriately documented in the site file. The Investigator should 
maintain a list of sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties. 
The Investigator is responsible for keeping a record of all patients (or their legally authorised 
representative) who sign an informed consent document and are screened for entry into the study. 
Patients who fail screening must have the reason(s) recorded in their source documents and the study-
screening log. 
The Investigator, or a designated member of the Investigators’ staff, must be available during monitoring 
visits, audits and inspections to review data, resolve queries and allow direct access to patients’ records 
(e.g. medical/hospital records, office charts, hospital charts, and study related charts) for source data and 
other type of verification. The Investigator must ensure timely and accurate completion of CRFs and 
queries. The Investigator must make himself/herself personally available during at least one monitoring 
visit per month, in order to address questions and to generally demonstrate his/her direct oversight of the 
conduct of the study. 
The Investigator must allow regular visits at the site when patients are enrolled, to be not less than one 2 
day visit every 14 days. In addition, the Investigator must ensure that all source data, including but not 
limited to medical records and hospital charts are available for review by the monitor for at least 30 days 
after a study day. 
13.3 CONSENT 
Before being admitted to the clinical study, the patient or the patient’s legally authorized representative 
must consent to participate after the nature, scope, and possible consequences of the clinical study have 
been explained in a manner understandable to him or her. An informed consent document that includes 
both information about the study and the consent form will be prepared and given to the patient. This 
document will contain all ICH, GCP, and locally required regulatory elements (whichever is more 
stringent). The informed consent will be translated in a language understandable to the patient, as 
required by local regulations and customs, and must specify who informed the patient, and when the 
informed consent was obtained.  
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Information to patients will be split into a Patient Information Sheet that provides detailed information 
about the trial and its benefits and risks, and the Informed Consent Form that summarises the content of 
the Patient Information Sheet and is used to obtain the dated signature from the patient as evidence of the 
patient’s agreement to partake in the study. 
If applicable, since minors are involved in the trial, assent must be obtained from the minor and informed 
consent from at least one of the parents or as mandated by local rules (individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective patient to the patient’s participation 
in the procedures involved in the research). The language used in the Assent Form is adapted to the 
maturity level of the minor involved in the trial. Since minors of different age groups are likely to be 
entered into the trial different versions of the Assent Form will be provided. The modalities for obtaining 
informed consent from the parents and Assent from the minor will be defined at the site initiation visit 
and documented at the clinical trial center. 
The Investigator, or designee, will obtain consent for participation in the study in writing. The written 
informed consent will be obtained prior to conducting any study-related procedures or tests, although 
procedures or tests that are done as a part of routine medical care and conducted before consent can be 
used for the purposes of screening. The patient’s consent (or the consent of the patient’s legally 
authorized representative) must be confirmed at the time of consent by the personally dated signature of 
the person conducting the informed consent discussions. A copy of the signed consent document must be 
given to the patient or their legally authorized representative. The Investigator will retain the original 
signed consent document.  
If an amended protocol impacts the content of the informed consent document, the consent document 
must be revised. Patients already participating in the study when the amended protocol is implemented 
must be re-consented with the revised version of the informed consent document, if the changes impact 
the continued participation of that patient. A copy of the revised informed consent document must be 
given to the patient or their legally authorised representative. The Investigator will retain the original 
signed updated consent document in the study files. 
13.4 CONFIDENTIALITY AND DATA PRIVACY 
Sobi AG affirms the patient's right to protection against invasion of privacy and to be in compliance with 
ICH and other local regulations (whichever is more stringent). Sobi AG requires the Investigator to 
permit Sobi AG representatives and when necessary, representatives from regulatory authorities, to 
review and/or copy any medical records relevant to the study in accordance with local laws (any copies of 
patients’ records must be duly anonymized to protect patients’ confidentiality). 
Should direct access to medical records require a waiver or authorisation separate from the patient’s 
statement of informed consent, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual. 
13.5 PROTOCOL AMENDMENTS 
Substantial amendments will be submitted to the IRB/IEC for written approval and where applicable to 
National Competent Authorities. Written approval must be obtained before implementation of the 
amended version occurs unless the amendment is implemented to increase safety measures for the 
patients in the study. The written signed approval from the IRB/IEC should specifically reference the 
Principal Investigator’s name, protocol number, study title and amendment number(s) that is/are 
applicable. 
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13.6 APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS 
Before the start of the study, the study protocol, informed consent document, and any other appropriate 
documents will be submitted to the IRB/IEC with a cover letter or a form listing the documents 
submitted, their dates of issue, and the site (or region or area of jurisdiction, as applicable) for which 
approval is sought. If applicable, the documents will also be submitted to the authorities in accordance 
with local legal requirements. 
Sobi AG can only supply study drug to an Investigator after Sobi AG or their authorised representative 
has received documentation on all ethical and legal requirements for starting the study. This 
documentation must also include a list of the members of the IRB/IEC and their occupation and 
qualifications. If the IRB/IEC will not disclose the names of the committee members, it should be asked 
to issue a statement confirming that the composition of the committee is in accordance with GCP. Formal 
approval by the IRB/IEC should preferably mention the study title, study code, study site, and any other 
documents reviewed. It must mention the date on which the decision was made and must be officially 
signed by a committee member (chairman or secretary of the IRB/IEC). Before the first patient is 
enrolled at a given study site, all ethical and legal requirements must be met. 
The IRB/IEC and, if applicable, the authorities, must be informed of all subsequent protocol amendments 
in accordance with local legal requirements. Amendments must be evaluated to determine whether formal 
approval must be sought and whether the informed consent document should also be revised. 
The Investigator must keep a record of all communication with the IRB/IEC and, if applicable, between a 
coordinating Investigator and the IRB/IEC. This statement also applies to any communication between 
the Investigator (or coordinating Investigator, if applicable) and regulatory authorities. 
All documents handed over to patients or their legal representative will be reviewed by Sobi AG prior to 
submission to the competent Regulatory Authorities and to IRB/IEC. This includes but is not limited to 
the informed consent form, patient information sheet, assent form, advertisements, training materials, etc. 
13.7 ONGOING INFORMATION FOR IRB/IEC 
If required by legislation or the IRB/IEC, the investigator must submit to the IRB/IEC: 
 
Information on SAEs or SUSARs as per local applicable rules and timelines;  
 
Periodic reports on the progress of the study; 
 
Deviations from the protocol or anything that may involve added risk to patients. 
13.8 CLOSURE OF THE STUDY 
Sobi AG reserves the right to terminate this study at any time for reasonable medical or administrative 
reasons. Any premature discontinuation will be appropriately documented according to local 
requirements (e.g., IRB/IEC, Regulatory Authorities). 
In addition, the Investigator or Sobi AG has the right to discontinue a single site at any time during the 
study for medical or administrative reasons such as: 
 
Lack of screening or recruiting activities  
 
Significant non-compliance with contractual enrolment timelines and targets 
 
Persistent GCP non-compliance 
 
Inaccurate, incomplete or delayed data collection 
 
Persistent failure to adhere to the study protocol 
 
Persistent failure to provide requested follow-up information for data queries 
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13.9 RECORD RETENTION 
The investigator will ensure that essential records are kept in a secure archiving facility for the retention 
period stipulated in the study contract. Essential documents include, but are not limited to, the following: 
 
Signed informed consent documents for all patients 
 
Patient identification code list, screening log (if applicable), and enrolment log 
 
Record of all communications between the investigator and the IRB/IEC 
 
Composition of the IRB/IEC 
 
Record of all communications between the investigator, Sobi AG and their authorized 
representative 
 
List of sub-investigators and other appropriately qualified persons to whom the investigator has 
delegated significant trial-related duties, together with their roles in the study, curricula vitae and 
their signatures 
 
Copies of CRFs and of documentation of corrections for all patients 
 
Drug accountability records 
 
Record of any body fluids or tissue samples retained 
 
All other source documents (patient records, hospital records, laboratory records, etc.) 
 
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP (Essential 
Documents for the Conduct of a Clinical Trial) 
Normally, these records will be held in the Investigator’s archives. If the Investigator is unable to meet 
this obligation, the Investigator must ask Sobi AG for permission to make alternative arrangements. 
Details of these arrangements should be documented in the clinical trial center TMF. 
13.10 LIABILITY AND INSURANCE 
Liability and insurance provisions for this study are provided in the investigator contract. 
13.11 FINANCIAL DISCLOSURE 
Investigators are required to provide financial disclosure information to allow Sobi AG to submit 
complete and accurate certification or disclosure statements in accordance with applicable national and 
local regulations. In addition, investigators must provide Sobi AG with a commitment to promptly update 
this information if any relevant changes occur during the course of the study and for 1 year following the 
completion of the study. 
13.12 DISCLOSURE OF PROTOCOL AND STUDY RESULTS AND PUBLICATION POLICY 
Information about this trial will be posted following the principles of the International Committee of 
Medical Journal Editors (ICMJE), the International Federation of Pharmaceutical Manufacturers & 
Associations (IFPMA) Industry Position Paper and applicable national or regional regulations and laws.  
The results of this study may be published or presented at scientific meetings. If this is foreseen, the 
Investigator agrees to submit all manuscripts or abstracts to Sobi AG prior to submission. This allows 
Sobi AG to protect proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
Sobi AG will comply with the requirements for publication of study results. In accordance with standard 
editorial and ethical practice, Sobi AG will support publication of multicenter trials only in their entirety 
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and not as individual center data. In this case, a coordinating investigator will be designated by mutual 
agreement prior to the start of the trial. 
Authorship will be determined by mutual agreement and in line with ICMJE authorship requirements. 
Any formal publication of the study in which contribution of Sobi AG personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and the appropriate 
Sobi AG personnel. 
All contributors who do not meet the criteria for authorship should be listed in an acknowledgments 
section. Examples of those who might be acknowledged include a person who provided purely technical 
help, writing assistance, or a department chairperson who provided only general support. 
Any inventions and resulting patents, improvements, and/or know-how originating from the use of data 
from this study will become and remain the exclusive and unburdened property of Sobi AG, except where 
agreed otherwise. 
14 
MONITORING AND AUDITING 
All aspects of the study will be monitored by Sobi AG or its representative for this study (Sobi AG 
authorised representative), for compliance with applicable government regulations with respect to current 
GCP and standard operating procedures. Direct access to the on-site study documentation and medical 
records must be ensured. 
14.1 STUDY MONITORING AND SOURCE DATA VERIFICATION 
As part of the responsibilities commensurate with participating in the study, the investigator agrees to 
maintain and have available for monitoring, adequate case records (accurate source documents and 
CRFs) for the patients treated under this protocol. In addition, the investigator agrees to maintain all 
administrative documents (e.g. IEC correspondence, investigational product and supplies shipment 
manifests, monitoring logs, or correspondence with Sobi AG and with any of its representative for this 
study). 
14.2 ON-SITE AUDITS 
Investigators and institutions involved in the study will permit trial-related monitoring, audits, IRB/IEC 
review, and domestic or foreign regulatory inspection(s) by providing direct access to source documents, 
CRFs, and all other study documentation. 
The Investigator should promptly notify Sobi AG of any inspections scheduled by any regulatory 
authorities and promptly forward to Sobi AG copies of any audit reports received. 
14.3 SERIOUS GCP BREACHES 
Sobi AG is required to report a serious GCP Breach within 7 days to applicable health authorities. 
Therefore, should an Investigator become aware of a possible serious GCP breach, e.g. a protocol 
violation, or non-reporting of critical safety information that has the potential of jeopardizing patients’ 
safety, Sobi AG must be notified within 24 hours. 
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15 
DOCUMENTATION AND USE OF STUDY FINDINGS 
15.1 DOCUMENTATION OF STUDY RESULTS 
A CRF (including electronic data capture) is used in this study and a specific CRF will correspond to 
each patient.  
All required information must be entered on the CRFs. If an item is not available or is not applicable, this 
fact should be indicated and no blank spaces must be left. The data collected on the CRF will be entered 
into the study database. If the investigator authorises other personnel to enter data into the CRF, the 
names, positions, signatures, and initials of these persons must be supplied to Sobi AG or their authorised 
representative before these individuals start completing CRF information.  
The CRF must be reviewed by the Investigator named in the study protocol or by a designated sub-
investigator, and final signature will be required.  
15.2 USE OF COMPUTERIZED SYSTEMS AT THE CLINICAL TRIAL CENTER 
When clinical observations are entered directly into an investigational site’s computerized medical record 
system (i.e. in lieu of original hardcopy records), the electronic record can serve as the source document 
if the system has been validated in accordance with health authority requirements pertaining to 
computerized systems used in clinical research. An acceptable computerized data collection system 
allows preservation of the original entry of data. If original data are modified, the system should maintain 
a viewable audit trail that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
The system must allow the clinical research associate, auditors or inspectors to verify source data without 
infringing privacy rights of other patients, e.g. access must be restricted to records pertaining to the study 
patients and access to other patients must not be possible. 
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16 
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APPENDICES 
Appendix A – Literature reference for sJIA diagnosis: “Operational case definition of new onset sJIA 
used in development of treatment plans” 
Appendix B – Literature reference for MAS diagnosis: “2016 Classification Criteria for Macrophage 
Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis”  
Appendix C – Membership of the Scientific Steering Committee (SSC) 
Appendix D – Estimated blood volumes to be drawn during the study 
Appendix E – Literature reference for Yamaguchi AOSD Criteria: “Preliminary Criteria for 
Classification of Adult Still’s Disease”   
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APPENDIX A: OPERATIONAL CASE DEFINITION OF NEW ONSET SJIA USED IN 
DEVELOPMENT 
OF 
TREATMENT 
PLANS 
(DESIGNED 
BY 
CHILDHOOD 
ARTHRITIS AND RHEUMATOLOGY RESEARCH ALLIANCE) 
 (DeWitt EM 2012) 
Patient should have: 
 
1. Age 6 months to 18 years 
 
2. Fever1 for at least 2 weeks 
 
3. Arthritis2 in one or more joints (6 weeks duration not required) 
 
4. At least one of the following: 
      a. Evanescent erythematous rash 
      b. Generalized lymphadenopathy 
      c. Hepatomegaly or splenomegaly 
      d. Pericarditis, pleuritis and/or peritonitis 
Patient should not have any of the following:  
 
1. Infection:  including concomitant active or recurrent chronic bacterial, fungal 
or viral infection at presentation; nor underlying infection which may mimic 
initial presentation of sJIA3 
 
2.  Malignancy3   
 
3. Positive screening test for TB without documented past treatment 
 
4. Prior treatment for SJIA other than NSAIDs or short term steroids4 
 
5. Immunization with live virus vaccines within the 4 weeks prior to enrollment 
1Daily fever is not required, but must at some point exhibit a quotidian fever pattern, defined as fever 
that rises to ≥39°C at least once a day and returns to ≤37°C between fever peaks.  
2Swelling within a joint, or limitation in the range of joint movement with joint pain or tenderness, is 
observed by a physician, and which is not due to primarily mechanical disorders or to other identifiable 
causes.  
3 Infections, malignancy and other diagnoses which can present with similar symptoms as sJIA should be 
excluded before initiating treatment plans for new onset sJIA in order to avoid unintended adverse 
effects of the treatment plans if used for other diagnoses. 
4 Prior treatment with steroids should not exceed 2 weeks of oral steroids, and/or 3 pulses of 
methylprednisolone. Prior treatment with IVIG for possible Kawasaki Disease is allowed. Duration of 
NSAIDs is without restriction. 
 
NOTE: The above is not meant to represent diagnostic nor classification criteria for sJIA. The 
differences between this operational case definition and the ILAR criteria are: 
‐ 
ILAR specifies that the duration of quotidian fever has to be 3 days (the total duration of fever is 
two weeks in both). 
‐ 
ILAR specifies six weeks’ duration of arthritis. 
‐ 
Psoriasis, positive RF, arthritis in HLA B27 positive male after 6 years of age, family history of 
AS, IBD with sacroiliitis, acute anterior uveitis and reactive arthritis are listed as exclusions in 
the ILAR definition. 
 
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APPENDIX 
B: 
2016 
CLASSIFICATION 
CRITERIA 
FOR 
MACROPHAGE 
ACTIVATION SYNDROME COMPLICATING SYSTEMIC JUVENILE IDIOPATHIC 
ARTHRITIS: A EUROPEAN LEAGUE AGAINST RHEUMATISM/AMERICAN 
COLLEGE 
OF 
RHEUMATOLOGY/PAEDIATRIC 
RHEUMATOLOGY 
INTERNATIONAL TRIALS ORGANISATION COLLABORATIVE INITIATIVE 
(Ravelli A(b) 2016) 
Classification of macrophage activation syndrome 
in systemic juvenile idiopathic arthritis 
A febrile patient with known or suspected systemic juvenile idiopathic arthritis is classified 
as having macrophage activation syndrome if the following criteria are met:  
- Ferritin > 684 ng/mL 
and any two of the following: 
- Platelet count  181 x109/L 
- AST levels > 48 U/L 
- Triglycerides > 156 mg/dL 
- Fibrinogen levels ≤ 360 mg/dL. 
 
 
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APPENDIX C: MEMBERSHIP OF THE SCIENTIFIC STEERING COMMITTEE (SSC) 
 
 
 
 
 
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APPENDIX D: ESTIMATED BLOOD VOLUMES TO BE DRAWN DURING THE STUDY 
 
 
Assessments 
 
Screening  
 Emapalumab Treatment period  
Evaluation period 
EoS 
SD-1 
SD0 
SD1 
SD2 
SD3 
SD5 
Infusion Visits1  
SD6 to SD28 
SD35 – SD42 – SD49 
SD 56 
Week 8 
Laboratory 
assessments 
- CBC (including Lymphocyte subset) 
1 
1 
1 
1 
1 
1 
1 
1 
1 
- Coagulation, Fibrinogen  
1 
1 
1 
1 
1 
1 
1 
1 
1 
- Biochemistry 
2 
2 
2 
2 
2 
2 
2 
2 
2 
- Serum pregnancy test (if applicable) 
0.5 
 
 
 
 
 
 
 
0.5 
- Search for EBV, CMV, Adenoviruses, 
Mycobacteria 
0.5 
 
 
 
 
 
0.52 
0.53 
0.5 
- Search for HSV, HZV, HIV, HBV, HCV 
0.5 
 
 
 
 
 
 
 
 
- Search for other pathogens (if needed) 
1 
 
 
 
 
 
 
 
 
Subtotal per visit 
6.5 
4 
4 
4 
4 
4 
4/4.52 
4/4.53 
5 
Subtotal per month 
 
 
 
 
 
 
59.5 
 
17.5 
PK  
- Emapalumab serum concentration 
 
1 
0.5 
0.5 
1 
0.5 
1 
0.5 
0.5 
PD 1 
- IFN, CXCL9, CXCL10, sCD25 
 
1 
1 
1 
1 
1 
1 
1 
1 
PD 2 
- Other biomarkers 
 
1 
 
 
 
 
12 
13 
1 
Immunogenicity (ADA) 
 
0.5 
 
 
 
 
 
 
0.5 
Molecular diagnosis (if consent for genetic testing is given) 
(3) 
 
 
 
 
 
 
 
 
Subtotal per visit 
(3) 
3.5 
1.5 
1.5 
2 
1.5 
2/32 
1.5/2.53 
3.0 
Total per month (maximum) 
 
 
 
 
 
 
90.5 
 
26.0 
TOTAL OVERALL STUDY (maximum) 
 
 
 
 
 
 
 
 
116.5 
1 Assumes worst case scenario in terms of blood volumes, i.e. emapalumab treatment is continued until SD28 (total of 10 infusions). If treatment is shortened, the amount of blood to be drawn would be less. 
2 At SD15 and SD28. 
3 At SD42.  
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APPENDIX E: PRELIMINARY CRITERIA FOR CLASSIFICATION OF ADULT 
STILL’S DISEASE  
(Yamaguchi M 1992) 
 
Classification of adult Still's disease requires 5 or more criteria including 2 or more major 
criteria1.  
Any disease listed under "Exclusions" should be excluded. 
 
Major criteria 
 
Fever of 39°C or higher, lasting 1 week or longer 
 
Arthralgia lasting 2 weeks or longer 
 
Typical rash2 
 
Leukocytosis (10.000/mm3 or greater) including 80% more of granulocytes 
 
Minor criteria 
 
Sore throat 
 
Lymphadenopathy and/or splenomegaly3 
 
Liver dysfunction4 
 
Negative RF and negative ANA5 
 
Exclusions 
 
Infections (especially, sepsis and infectious mononucleosis)  
 
Malignancies (especially, malignant lymphoma) 
 
Rheumatic diseases (especially, polyarteritis nodosa and rheumatoid vasculitis with 
extraarticular features) 
 
1. All criteria are applicable only in absence of other clinical explanations.  
2. Macular or maculopapular nonpruritic salmon-pink eruption usually appearing during fever. 
3. Lymphadenopathy is defined as recent development of significant lymph node swelling, and splenomegaly 
is confirmed on palpation or by an echogram. 
4. Liver dysfunction is defined as an abnormally elevated level of transaminases and/or lactate 
dehydrogenase, which is attributed to liver damage associated with this disease but not with drug 
allergy/toxicity or other causes. For the differentiation, it is recommended to see if liver function returns to 
normal upon discontinuation of hepatotoxic drug or not, before applying this criterion. 
5. RF in serum must be negative by routine test for the detection of IgM RF, and serum ANA must be 
negative by routine immunofluorescence test. 
RF: rheumatoid factor, ANA: antinuclear antibody. 
 
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Study Nl-0501-06 
NI-0501 in MAS/sHLH in sJIA patients 
Page 1 of73 
novimmu,e fS' 
Clinical Study Protocol 
A pilot, open-label, single arm, multicenter study to evaluate safety, tolerability, 
pharmacokinetics and efficacy of intravenous administrations of NI-0501, an anti-
interferon gamma (anti-IFNy) monoclonal antibody, in patients with systemic Juvenile 
Idiopathic Arthritis (sJIA) developing Macrophage Activation Syndrome/secondary HLH 
(MAS/sHLH) 
Protocol number: 
Version: 
Date: 
P-IND Number: 
Sponsor: 
Study Principal Investigator 
Clinical Science Leader NI-0501 
Chief Medical Officer 
NI-0501-06 
1.0 US - Final 
October 19, 2017 
111015 
Novimmune SA 
14 Chemin des AuJx 
1228 Plan-les-Ouates 
Sw
This document is a confidential communication ofNovimmune SA Acceptance of this document constitutes the agreement by the recipient U1at 
no unpublished information contained within will be published or disclosed without prior writlen approval, except as required to permit review 
by responsible Institutional Review Board/Independent Ethics Committee and Health Authorities, 
or to obtain informed consent from potential patients. 
Protocol NI-0501-06 
Versionl.0 US- October 19, 2017 
CONFIDENTIAL 
Page 78 of 150

Study NI-0501-06 
NI-0501 in MAS/sHLH in sJIA patients 
Page 2 of 73 
Protocol NI-0501-06                           Version1.0 US – October 19, 2017 
CONFIDENTIAL 
INVESTIGATOR AGREEMENT 
 
Protocol Number: NI-0501-06  
 
Protocol date and version: October 19, 2017 – VERSION 1.0 US 
 
Study drug:  NI-0501   
 
Study title: A pilot, open-label, single arm, multicenter study to evaluate safety, tolerability, 
pharmacokinetics and efficacy of intravenous administrations of NI-0501, an anti-interferon gamma 
(anti-IFNγ) monoclonal antibody, in patients with systemic Juvenile Idiopathic Arthritis (sJIA) 
developing Macrophage Activation Syndrome/secondary HLH (MAS/sHLH). 
 
Investigator endorsement: 
I, the undersigned, am responsible for the conduct of this study at this site and agree to conduct the study 
according to the protocol and any approved protocol amendments, ICH GCP and all applicable regulatory 
authority requirements. 
I will not deviate from the protocol without prior permission from the Sponsor and prior review and 
written approval from the Institutional Review Board/Independent Ethics Committee, and where 
applicable, from the Competent Authorities, except where necessary to prevent any immediate danger to 
a patient. 
I have read and understand fully the Investigator Brochure for NI-0501 and I am familiar with the 
investigational product and its use according to this protocol. 
 
 
 
 
 
 
 
_______________________________________  
 
 
____________________ 
Site Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
_______________________________________ 
Site Investigator’s Name 
Page 79 of 150

Study NI-0501-06 
NI-0501 in MAS/sHLH in sJIA patients 
Page 3 of 73 
Protocol NI-0501-06 
 Version1.0 US – October 19, 2017 
CONFIDENTIAL 
CONTACT LIST 
Study Location: 
Study Principal Investigator: 
Sponsor: 
Chief Medical Officer: 
Safety Officer: 
Clinical Science Leader NI-0501: 
Head Clinical Operations: 
Clinical Pharmacologist: 
Multicenter in North America 
Novimmune SA 
14 Chemin des Aulx 
1228 Plan les Ouates 
Switzerland 
Page 80 of 150

Study NI-0501-06 
NI-0501 in MAS/sHLH in sJIA patients 
Page 4 of 73 
Protocol NI-0501-06                           Version1.0 US – October 19, 2017 
CONFIDENTIAL 
NI-0501-06 SYNOPSIS 
Title: 
A pilot, open-label, single arm, multicenter study to evaluate safety, 
tolerability, 
pharmacokinetics 
and 
efficacy 
of 
intravenous 
administrations of NI-0501, an anti-interferon gamma (anti-IFNγ) 
monoclonal antibody, in patients with systemic Juvenile Idiopathic 
Arthritis (sJIA) developing Macrophage Activation Syndrome/ 
secondary HLH (MAS/sHLH)  
Sponsor: 
Novimmune SA, Switzerland 
Study Type, Phase and 
Design: 
 
Interventional Phase 2 study  
 
Open-label, single arm, international, multicenter study.  
Please note: any reference made to MAS in this protocol should be 
intended as referring to the secondary form of HLH occurring in 
patients with sJIA. 
Study Objectives: 
The main objectives of the study are: 
 
To describe the pharmacokinetics (PK) profile of NI-0501 in sJIA 
patients with MAS. 
 
To confirm the proposed dosing regimen of NI-0501 in sJIA 
patients with MAS. 
 
To evaluate the safety and tolerability profile of intravenous (i.v.) 
administrations of NI-0501 in sJIA patients with MAS. 
 
To preliminary assess the efficacy of NI-0501 in sJIA patients with 
MAS. 
 
To assess the levels of relevant biomarkers, such as IFN and main 
IFN-induced chemokines (CXCL9, CXCL10).    
 
To assess other potential disease biomarkers (e.g. sCD25, sCD163, 
IL-10, IL-6, IL-18, TNFCXCL11).  
 
To assess the immunogenicity of NI-0501 in sJIA patients with 
MAS. 
Study Population: 
 
sJIA patients with MAS having shown inadequate response to high 
dose glucocorticoid treatment. 
Inclusion Criteria: 
 
Patients of both genders, aged <18 years  
 
Confirmed sJIA diagnosis. For patients presenting with MAS in 
the context of the onset of sJIA , high presumption of sJIA (as per 
Appendix A) will suffice for eligibility. 
 
Diagnosis of active MAS confirmed by the treating rheumatologist, 
having ascertained the followings: 
Febrile patient presenting with: 
- Ferritin > 684 ng/mL 
and any two of: 
- Platelet count  181 x109/L 
- AST levels > 48 U/L 
- Triglycerides > 156 mg/dL 
- Fibrinogen levels ≤ 360 mg/dL. 
Page 81 of 150

Study NI-0501-06 
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Page 5 of 73 
Protocol NI-0501-06                           Version1.0 US – October 19, 2017 
CONFIDENTIAL 
(see Appendix B) 
 
Patient presenting an inadequate response to high dose i.v. 
glucocorticoid treatment administered for at least 3 days as per 
local standard of care (including but not limited to pulses of 30 
mg/kg methylprednisolone (mPDN) on 3 consecutive days).  
High i.v. glucocorticoid dose should not be lower than 2 mg/kg/ 
day of mPDN equivalent in 2 divided doses (to a maximum of 60 
mg/day in patients of 30 kg or more). In case of rapid worsening of 
the patient’s condition and/or lab parameters, inclusion may occur 
within less than 3 days from starting high dose i.v. glucocorticoids. 
 
Informed consent provided by the patient (as required by local 
law), or by the patient’s legally authorized representative(s) with 
the assent of patients who are legally capable of providing it, as 
applicable. 
 
Having received guidance on contraception for both male and 
female patients sexually active and having reached puberty: 
Females of child-bearing potential require use of highly effective 
contraceptive measures (failure rate of less than 1% per year) from 
screening until 6 months after receiving last dose of the study drug. 
Highly effective contraceptive measures include: 
o Sexual abstinence 
o Hormonal contraceptives: combination or progesterone 
only 
o Intrauterine methods: intrauterine devices or systems 
o Bilateral tubal occlusion 
o Vasectomised partner 
Males with partners(s) of child-bearing potential must agree to take 
appropriate precautions (such as sexual abstinence, barrier 
contraception, vasectomy) to avoid fathering a child from 
screening until 6 months after receiving last dose of the study drug. 
Exclusion Criteria: 
 
 
Diagnosis of suspected or confirmed primary HLH or HLH 
consequent to a neoplastic disease. 
 
Patients treated with Tocilizumab, Canakinumab or TNF inhibitors 
within 5 times of their defined half-life. 
 
Active 
mycobacteria 
(typical 
and 
atypical), 
Histoplasma 
Capsulatum, Shigella, Salmonella, Campylobacter and Leishmania 
infections.  
 
Clinical suspicion of latent tuberculosis.  
 
Positive serology for HIV antibodies. 
 
Presence of malignancy. 
 
Patients who have another concomitant disease or malformation 
severely affecting the cardiovascular, pulmonary, CNS, liver or 
renal function that in the opinion of the Investigator may 
significantly affect likelihood to respond to treatment and/or 
assessment of NI-0501 safety.  
 
History of hypersensitivity or allergy to any component of the 
study drug. 
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Page 6 of 73 
Protocol NI-0501-06                           Version1.0 US – October 19, 2017 
CONFIDENTIAL 
 
Receipt of a BCG vaccine within 12 weeks prior to screening. 
 
Receipt of live or attenuated live vaccines (other than BCG) within 
6 weeks prior to screening. 
 
Pregnant or lactating female patients. 
Study Drug: 
 
NI-0501 is a fully human IgG1 monoclonal antibody (mAb) 
directed against human IFNγ. 
Dosing Regimen, Frequency 
of Administration & 
Treatment Duration: 
 
 
NI-0501 will be administered at the initial dose of 6 mg/kg by 
infusion. 
 
NI-0501 treatment will be continued at the dose of 3 mg/kg, every 
3 days until SD15, and then twice-a-week for additional 2 weeks, 
i.e. until SD28.  
 
Treatment may be shortened upon achievement of complete 
clinical response (i.e. MAS remission), however at least two 
infusions of NI-0501 at the dose of 3 mg/kg have to be 
administered (i.e. after SD6).  
 
In the event that the PK profile of NI-0501 in a given patient 
indicates a Target Mediated Drug Disposition (TMDD) suggestive 
for very high IFN production, the dose of NI-0501 may be 
increased upon assessment of a favorable benefit/risk profile in that 
individual patient.  
 
NI-0501 treatment may be prolonged beyond 4 weeks guided by 
clinical and PK/PD evidence in an individual patient, upon 
assessment of a favorable benefit/risk profile. 
Background Therapy & 
Concomitant Medication: 
 
NI-0501 will be administered on a background of at least 2 
mg/kg/day of mPDN equivalent (to a maximum of 60 mg/day in 
patients of 30 kg or more), which can be tapered during the 
treatment depending on patient conditions.  
 
Patients must receive prophylactic treatment for Herpes Zoster 
infections starting preferably the day before (and in any case prior 
to initiation of NI-0501 treatment), and treatment must continue 
until serum NI-0501 levels are no longer detectable.  
 
Anakinra must be discontinued at latest before the first NI-0501 
infusion; no wash-out period is required given its short half-life. 
 
A wash-out period of 5 times of respective half-lives is required in 
patients who have received Tocilizumab, Canakinumab or TNF 
inhibitors as sJIA treatment. 
 
It is recommended background treatment of sJIA not to be re-
introduced during the 8 weeks of the study, unless the patient’s 
clinical condition requires it. 
 
Cyclosporine A (CsA) may be continued if started at least 3 days 
prior to initiation of NI-0501 treatment. CsA dose adjustments are 
allowed in order to maintain therapeutic levels.  CsA can be 
withdrawn at any time during the study, upon judgment of the 
Investigator. CsA cannot be introduced once NI-0501 treatment 
has started. 
 
If the patient is receiving intrathecal therapy (e.g. methotrexate and 
glucocorticoids) at the time of NI-0501 treatment initiation, this 
treatment will be continued until clinically indicated.  
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Study NI-0501-06 
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Page 7 of 73 
Protocol NI-0501-06                           Version1.0 US – October 19, 2017 
CONFIDENTIAL 
 
Vaccination with a live or attenuated-live (including BCG) vaccine 
must be avoided during the whole study until serum NI-0501 levels 
are no longer detectable.  
 
Analgesic treatment, transfusion of blood products, electrolyte and 
glucose infusions, i.v. parenteral nutrition, inotropic support, 
antibiotics, anti-fungal and anti-viral treatments, ultrafiltration or 
hemodialysis, as well as general supportive care are permitted. 
Sample Size: 
 
A minimum of 5 evaluable patients will be enrolled in North 
America.  
 
The sample size of 5 patients is based on pragmatic considerations, 
and on the experience acquired from primary HLH patients treated 
with NI-0501. 
Number of Sites and 
Recruitment Duration: 
 
International, multi-center. 
 
The recruitment period, in this rare population, is estimated to be 
approximately 2 years in North America. A twin protocol NI-0501-
06 EUDRACT 2016-004223-23is running in Europe.  
 
Patients enrolled under these two protocols (for a total of 10 
patients) will be analyzed jointly and data reported in a single 
CSR. 
Study Duration and Study 
End Definition:   
 
The duration of the study will be 8 weeks for each patient (plus up 
to 1 week screening period). The study duration of 8 weeks allows 
performing a short-term follow-up of 4 weeks after the last NI-
0501 infusion on SD28. 
Note: If NI-0501 treatment is prolonged beyond 4 weeks in a 
given patient, additional visits will be performed weekly until 
completion of a 4-week follow-up after the last NI-0501 infusion,   
follow-up that should occur under the present protocol. 
 
End of the study is defined as last patient last visit. 
 
All patients who have received at least one dose of NI-0501 will be 
asked to enter a long-term follow-up study.  
Study Scientific Oversight/ 
Study Safety Monitoring : 
 
A Scientific Steering Committee (SSC) composed of international 
experts in pediatric rheumatology as well as in HLH, has been 
involved in the preparation of study design and will continue to 
play an advisory role throughout the course of the study, to support 
the iDMC in the study oversight, and the Sponsor in the 
interpretation of the study results. 
 
An independent Data Monitoring Committee (iDMC) composed of 
relevant experts (pediatric rheumatologist, hemato-oncologist with 
experience in HLH, pediatric immune deficiency/infectious disease 
specialist, bio-statistician and a specialist in ethics) will oversee the 
safety management of the study, reviewing all data generated on an 
ongoing basis with the aim to ensure that patients are not exposed 
to unnecessary risks. 
Study Endpoints: 
Pharmacokinetics and Pharmacodynamics  
 
PK profile of NI-0501.  
 
Levels of circulating free IFN at predose, and total IFNγ (free 
Page 84 of 150

Study NI-0501-06 
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Page 8 of 73 
Protocol NI-0501-06                           Version1.0 US – October 19, 2017 
CONFIDENTIAL 
IFNγ+bound to NI-0501) after initiation of NI-0501. 
 
Levels of the main IFNγ-induced chemokines (CXCL9, CXCL10). 
 
Correlation between chemokine levels (CXCL9, CXCL10) and 
levels of free NI-0501, free IFNγ (pre-dose) and total IFNγ 
(exploratory analysis). 
 
Correlation of chemokine and total IFNγ levels, and laboratory 
parameters of MAS severity, e.g. ferritin, platelet count, LFTs 
(exploratory analysis). 
 
Levels of other potential disease biomarkers (e.g. sCD25, sCD163, 
IL-10, IL-6, IL-18, TNFCXCL11).  
 
Levels (if any) of circulating antibodies against NI-0501 to 
determine immunogenicity (ADA). 
In particular, based on: 
 
levels of circulating NI-0501  
 
levels of total IFNγ  
 
levels of main IFNγ–induced chemokines (namely CXCL9 and 
CXCL10) 
a PK/PD modelling will be used to confirm that the proposed dose 
regimen is adequate in relation to the IFNγ production in this patient 
population. 
 
Safety 
The tolerability and safety of NI-0501 treatment will be assessed as 
follows: 
 
Incidence, severity, causality and outcomes of AEs (serious and 
non-serious), with particular attention being paid to infections. 
 
Evolution of laboratory parameters, in particular CBC, LFTs, 
inflammatory markers (ferritin and CRP) and coagulation 
parameters. 
 
Number of patients withdrawn from the study due to safety 
reasons. 
 
Efficacy  
A preliminary assessment of NI-0501 efficacy in this patient 
population will be based on the following variables: 
 
Number of patients achieving MAS remission by Week 8 after 
initiation of NI-0501 treatment. 
 
Time to MAS remission. 
 
Number of patients for whom at any time during the study 
glucocorticoids can be tapered i) to the same (or lower) dose being 
administered before the occurrence of MAS ((in those patients who 
are already treated for sJIA) or ii) by 50% (or less) of the dose 
administered at NI-0501 treatment start (in those patients who 
present with MAS at sJIA onset).  
 
Time to glucocorticoids tapering (as above described). 
 
Survival time. 
 
Number of patients withdrawn from the study due to lack of 
efficacy. 
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Study NI-0501-06 
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Page 9 of 73 
Protocol NI-0501-06                           Version1.0 US – October 19, 2017 
CONFIDENTIAL 
Statistical Analysis: 
 
All study variables are considered to be exploratory in this study, 
and no hierarchy of endpoints has been specified, as the objective 
of this pilot study is to collect and analyze data to confirm that the 
proposed dose regimen is adequate in this patient population. 
Statistical methods will therefore focus on summarizing the data 
collected using descriptive statistics and on appropriate graphical 
presentations.  
 
For binary endpoints (MAS remission by Week 8, number of 
patients who taper glucocorticoids, number of patients who 
discontinue due to lack of efficacy), 95% confidence intervals will 
be calculated for proportions. 
 
For time to event endpoints (time to MAS remission, time to 
achievement of glucocorticoids tapering and time to death), 
Kaplan-Meier curves will be calculated and summary statistics, 
such as medians, proportions event-free at various time points will 
be calculated and presented, and 95% confidence intervals 
calculated where possible.   
 
Data relating to safety will be listed and summarised using 
descriptive statistics. 
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Study NI-0501-06 
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Page 10 of 73 
Protocol NI-0501-06                           Version1.0 US – October 19, 2017 
CONFIDENTIAL 
 LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ADA 
Anti-drug-antibodies 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
BCG 
Bacillus Calmette-Guérin 
BSA 
Body Surface Area 
CBC 
Complete blood cell count 
CDC 
Complement Dependent Cytotoxicity 
CL 
Systemic drug clearance 
Cmax 
Peak drug plasma concentration  
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CpG 
Cytosine-phosphate-guanine 
CRF 
Case report form 
CRP 
C-reactive protein 
CsA 
Cyclosporin A 
CSF 
Cerebrospinal fluid 
Ctrough 
Plasma drug concentration immediately prior next dosing 
CU 
Compassionate use 
CXCL9 
Chemokine (C-X-C Motif) Ligand 9 
CXCL10 
Chemokine (C-X-C Motif) Ligand 10 
CXCL11 
Chemokine (C-X-C Motif) Ligand 11 
EBV 
Epstein-Barr virus 
EoT 
End of treatment 
EoS 
End of study 
γGT 
Gamma Glutamyl Transferase 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HLH 
Hemophagocytic lymphohistiocytosis 
HSCT 
Hematopoietic stem cell transplantation 
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Page 11 of 73 
Protocol NI-0501-06                           Version1.0 US – October 19, 2017 
CONFIDENTIAL 
HSV 
Herpes simplex virus 
HZ 
Herpes Zoster 
HZV 
Herpes Zoster virus 
ICMJE 
International Committee of Medical Journal Editors  
iDMC 
Independent Data Monitoring Committee 
IFNγ 
Interferon gamma 
IFNγ-R1 
Interferon gamma receptor chain 1 
IFPMA 
International Federation of Pharmaceutical Manufacturers & Associations 
IgG1 
Immunoglobulin G1 
IL 
Interleukin 
ILAR 
International League of Associations for Rheumathology  
IMP 
Investigational medicinal product 
ITT 
Intention-to-treat 
i.v. 
Intravenous 
KD 
Dissociation constant 
KM 
Michaelis-Menten constant 
KO 
Knock Out  
LCMV 
Lymphocytic choriomeningitis virus 
LDH 
Lactate dehydrogenase 
LFTs 
Liver function tests 
LLN 
Lower limit of normal 
mAb 
Monoclonal antibody 
MAS 
Macrophage activation syndrome 
mPDN 
Methylprednisolone 
MRI 
Magnetic resonance imaging 
NK 
Natural killer 
NaCl 
Sodium chloride 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PDG 
Preliminary diagnostic guidelines (Ravelli et al., 2005) 
pHLH 
Primary HLH 
PK 
Pharmacokinetic 
PPD 
Purified protein derivative 
PT 
Prothrombin Time 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAD 
Single ascending dose 
sCD25 
soluble CD25 (i.e. soluble IL-2 receptor) 
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Page 12 of 73 
Protocol NI-0501-06                           Version1.0 US – October 19, 2017 
CONFIDENTIAL 
SD(n) 
Study Day number (e.g. Study day 1 = SD1) 
sJIA 
Systemic Juvenile Idiopathic Arthritis 
SoA 
Schedule of assessments 
SSC 
Scientific steering committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
t1/2  
Elimination half-life 
Tmax 
Time when plasma concentration is at peak 
TMDD 
Target mediated drug disposition 
TMF 
Trial Master File 
TNFα 
Tumor necrosis factor alpha 
ULN 
Upper limit of normal 
US 
Ultrasonography 
Vss 
Volume of distribution at steady state 
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Page 13 of 73 
Protocol NI-0501-06 
 Version1.0 US – October 19, 2017 
CONFIDENTIAL 
TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT ................................................................................................................................. 2 
CONTACT LIST ....................................................................................................................................................... 3 
NI-0501-06 SYNOPSIS ............................................................................................................................................ 4 
LIST OF ABBREVIATIONS ......................................................................................................................................10 
1 
BACKGROUND INFORMATION ....................................................................................................................17 
1.1 
NI-0501 ......................................................................................................................................................... 17 
1.1.1 
Description and mode of action .......................................................................................................... 17 
1.1.2 
Preclinical Data ................................................................................................................................... 17 
1.1.3 
Clinical Data ........................................................................................................................................ 18 
1.2 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) ................................................................................................... 18 
1.2.1 
Macrophage Activation Syndrome (MAS) ........................................................................................... 19 
1.3 
STUDY RATIONALE ............................................................................................................................................. 21 
1.3.1 
Rationale for developing NI-0501 in MAS ........................................................................................... 21 
1.3.2 
Rationale for conducting a Clinical Study in MAS/sJIA patients receiving NI-0501 treatment ........... 22 
2 
OBJECTIVES .................................................................................................................................................23 
3 
STUDY DESIGN ............................................................................................................................................24 
3.1 
OVERALL DESIGN .............................................................................................................................................. 24 
3.2 
SCREENING PERIOD ............................................................................................................................................ 25 
3.3 
TREATMENT PERIOD .......................................................................................................................................... 25 
3.4 
FOLLOW-UP PERIOD .......................................................................................................................................... 25 
3.5 
STUDY END ...................................................................................................................................................... 26 
3.6 
LONG-TERM FOLLOW-UP STUDY ........................................................................................................................... 26 
4 
TARGET POPULATION .................................................................................................................................26 
4.1 
ELIGIBILITY CRITERIA .......................................................................................................................................... 26 
4.1.1 
Inclusion Criteria ................................................................................................................................. 26 
4.1.2 
Exclusion Criteria ................................................................................................................................. 27 
5 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) ..........................................................................................27 
5.1 
DESCRIPTION OF IMP ........................................................................................................................................ 27 
5.2 
DOSING REGIMEN .............................................................................................................................................. 28 
5.3 
RATIONALE FOR DOSE SELECTION .......................................................................................................................... 28 
5.4 
IMP HANDLING ................................................................................................................................................ 32 
5.4.1 
Packaging and Labeling ...................................................................................................................... 32 
5.4.2 
IMP Supply .......................................................................................................................................... 32 
5.4.3 
IMP Receipt and Storage..................................................................................................................... 32 
5.4.4 
IMP Preparation, Administration, Accountability and Destruction..................................................... 32 
6 
PATIENT BACKGROUND TREATMENT AND CARE ........................................................................................33 
6.1 
GLUCOCORTICOIDS ............................................................................................................................................ 33 
6.2 
PROPHYLACTIC TREATMENT ................................................................................................................................. 34 
6.3 
CONCOMITANT THERAPY .................................................................................................................................... 34 
6.3.1 
Cyclosporine A ..................................................................................................................................... 34 
6.3.2 
Intrathecal Therapy............................................................................................................................. 34 
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Page 14 of 73 
Protocol NI-0501-06                           Version1.0 US – October 19, 2017 
CONFIDENTIAL 
6.3.3 
Other possible concomitant therapies ................................................................................................ 34 
6.3.4 
Not allowed concomitant therapies .................................................................................................... 35 
6.4 
EMERGENCY TREATMENT .................................................................................................................................... 35 
6.5 
RESCUE THERAPY .............................................................................................................................................. 35 
7 
ENDPOINTS .................................................................................................................................................35 
7.1 
PHARMACOKINETICS ENDPOINTS .......................................................................................................................... 36 
7.2 
PHARMACODYNAMICS ENDPOINTS ........................................................................................................................ 36 
7.3 
SAFETY ENDPOINTS ............................................................................................................................................ 36 
7.4 
EFFICACY ENDPOINTS ......................................................................................................................................... 36 
8 
OUTLINE OF STUDY PROCEDURES ...............................................................................................................37 
8.1 
STUDY VISITS .................................................................................................................................................... 37 
8.2 
INFORMED CONSENT AND SCREENING PROCEDURES .................................................................................................. 38 
8.3 
CLINICAL ASSESSMENTS ...................................................................................................................................... 43 
8.3.1 
Vital signs ............................................................................................................................................ 43 
8.3.2 
Physical examination .......................................................................................................................... 43 
8.3.3 
MAS clinical signs and symptoms ....................................................................................................... 43 
8.4 
LABORATORY ASSESSMENTS ................................................................................................................................. 43 
8.5 
SEARCH FOR INFECTIONS ..................................................................................................................................... 44 
8.6 
IMAGING ......................................................................................................................................................... 45 
8.6.1 
Abdominal ultrasound ........................................................................................................................ 45 
8.6.2 
Chest X-ray .......................................................................................................................................... 45 
8.6.3 
Brain MRI ............................................................................................................................................ 45 
8.7 
OTHER PROCEDURES .......................................................................................................................................... 45 
8.7.1 
ECG ...................................................................................................................................................... 45 
8.7.2 
Cerebrospinal fluid assessment ........................................................................................................... 45 
8.8 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ........................................................................................... 45 
8.8.1 
Pharmacokinetics ................................................................................................................................ 45 
8.8.2 
Pharmacodynamics ............................................................................................................................. 46 
8.8.3 
Immunogenicity .................................................................................................................................. 46 
8.9 
WITHDRAWAL VISIT ........................................................................................................................................... 46 
8.10 
UNPLANNED (UNSCHEDULED) VISITS ................................................................................................................ 47 
8.10.1 
Unplanned Assessments ................................................................................................................. 47 
9 
STUDY SCIENTIFIC OVERSIGHT ....................................................................................................................47 
10 
SAFETY MONITORING .................................................................................................................................47 
10.1 
INDEPENDENT DATA MONITORING COMMITTEE ................................................................................................... 47 
10.2 
DESCRIPTION OF SAFETY PARAMETERS .............................................................................................................. 47 
10.3 
RECORDING AND REPORTING SAFETY PARAMETERS ............................................................................................. 48 
10.3.1 
Adverse events ............................................................................................................................... 48 
10.3.2 
Serious Adverse Events ................................................................................................................... 49 
10.3.3 
SUSAR reporting ............................................................................................................................. 50 
10.3.4 
Managing Abnormal Laboratory Test Values ................................................................................ 50 
10.4 
FOLLOW-UP OF SAFETY PARAMETERS ............................................................................................................... 51 
10.4.1 
Treatment and Follow-up of Adverse Events ................................................................................. 51 
10.4.2 
Follow-up of Abnormal Laboratory Test Values ............................................................................. 51 
10.4.3 
Pregnancy ...................................................................................................................................... 51 
10.5 
BENEFIT/RISK MANAGEMENT ......................................................................................................................... 51 
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10.5.1 
Safety Surveillance Management .................................................................................................. 51 
10.5.2 
General Benefit/Risk Considerations .............................................................................................. 51 
11 
STOPPING RULES ........................................................................................................................................55 
11.1 
AT PATIENT LEVEL ........................................................................................................................................ 55 
11.1.1 
Investigator’s or Patient’s Decision to Discontinue ........................................................................ 55 
11.1.2 
Decision to Discontinue Treatment due to Safety Reason or Lack of Efficacy ................................ 55 
11.1.3 
Systemic and local reaction to NI-0501 infusion ............................................................................ 56 
11.2 
AT STUDY LEVEL ........................................................................................................................................... 56 
11.2.1 
Suspension of Recruitment ............................................................................................................. 56 
11.2.2 
Study Termination .......................................................................................................................... 56 
12 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .............................................................................57 
12.1 
SAMPLE SIZE ................................................................................................................................................ 57 
12.2 
ANALYSIS SETS ............................................................................................................................................. 57 
12.2.1 
Safety Analysis Set ......................................................................................................................... 57 
12.2.2 
Intent-to-Treat Analysis Set............................................................................................................ 57 
12.2.3 
Per-Protocol Analysis Set ................................................................................................................ 57 
12.3 
STATISTICAL AND ANALYTICAL METHODS .......................................................................................................... 57 
12.3.1 
Efficacy Data .................................................................................................................................. 58 
12.3.2 
Safety Data ..................................................................................................................................... 58 
12.3.3 
Pharmacodynamic Data ................................................................................................................. 58 
12.3.4 
Immunogenicity Data ..................................................................................................................... 58 
12.3.5 
Missing Data .................................................................................................................................. 58 
12.4 
INTERIM ANALYSIS ........................................................................................................................................ 59 
12.5 
WITHDRAWAL AND REPLACEMENT ................................................................................................................... 59 
12.5.1 
Patients .......................................................................................................................................... 59 
12.5.2 
For Centers ..................................................................................................................................... 59 
13 
ETHICAL AND LEGAL ASPECTS .....................................................................................................................60 
13.1 
GOOD CLINICAL PRACTICE .............................................................................................................................. 60 
13.2 
INVESTIGATOR’S RESPONSIBILITIES.................................................................................................................... 60 
13.3 
CONSENT .................................................................................................................................................... 60 
13.4 
CONFIDENTIALITY AND DATA PRIVACY .............................................................................................................. 61 
13.5 
PROTOCOL AMENDMENTS .............................................................................................................................. 61 
13.6 
APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS ........................................................................ 62 
13.7 
ONGOING INFORMATION FOR IRB/IEC ............................................................................................................. 62 
13.8 
CLOSURE OF THE STUDY ................................................................................................................................. 62 
13.9 
RECORD RETENTION ...................................................................................................................................... 63 
13.10 
LIABILITY AND INSURANCE .............................................................................................................................. 63 
13.11 
FINANCIAL DISCLOSURE ................................................................................................................................. 63 
13.12 
DISCLOSURE OF PROTOCOL AND STUDY RESULTS AND PUBLICATION POLICY ............................................................. 63 
14 
MONITORING AND AUDITING ....................................................................................................................64 
14.1 
STUDY MONITORING AND SOURCE DATA VERIFICATION ....................................................................................... 64 
14.2 
ON-SITE AUDITS ........................................................................................................................................... 64 
14.3 
SERIOUS GCP BREACHES ............................................................................................................................... 64 
15 
DOCUMENTATION AND USE OF STUDY FINDINGS ......................................................................................65 
15.1 
DOCUMENTATION OF STUDY RESULTS .............................................................................................................. 65 
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15.2 
USE OF COMPUTERIZED SYSTEMS AT THE CLINICAL TRIAL CENTER .......................................................................... 65 
16 
REFERENCES ...............................................................................................................................................66 
17 
APPENDICES ...............................................................................................................................................69 
APPENDIX A: OPERATIONAL CASE DEFINITION OF NEW ONSET SJIA USED IN DEVELOPMENT OF TREATMENT 
PLANS (DESIGNED BY CHILDHOOD ARTHRITIS AND RHEUMATOLOGY RESEARCH ALLIANCE) ...............................70 
APPENDIX B: 2016 CLASSIFICATION CRITERIA FOR MACROPHAGE ACTIVATION SYNDROME COMPLICATING 
SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS: A EUROPEAN LEAGUE AGAINST RHEUMATISM/AMERICAN COLLEGE 
OF RHEUMATOLOGY/PAEDIATRIC RHEUMATOLOGY INTERNATIONAL TRIALS ORGANISATION COLLABORATIVE 
INITIATIVE ............................................................................................................................................................71 
APPENDIX C: MEMBERSHIP OF THE SCIENTIFIC STEERING COMMITTEE (SSC) ......................................................72 
APPENDIX D: ESTIMATED BLOOD VOLUMES TO BE DRAWN DURING THE STUDY ................................................73 
  
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PART I 
1 
BACKGROUND INFORMATION 
1.1 
NI-0501 
1.1.1 Description and mode of action 
NI-0501 is a fully human IgG1 anti-interferon gamma (IFNγ) monoclonal antibody (mAb) which binds 
and neutralizes IFNγ. NI-0501 binds to soluble and receptor (IFNγR1)-bound forms of IFNγ.  
Since NI-0501 is a human IgG1, it retains the characteristics of this immunoglobulin isotype.  
After binding to its receptor, IFNγ acts to produce a variety of physiological and cellular responses. 
Numerous studies over the last 20 years have associated IFN with the pathogenesis and the maintenance 
of inflammatory diseases1–3, and most recently, in the pathogenesis of HLH. 
1.1.2  Preclinical Data  
1.1.2.1 Non-clinical Pharmacology 
NI-0501 has shown similar binding affinity and blocking activity for IFNγ from non-human species, 
including Rhesus and Cynomolgus monkeys, but not from dogs, cats, pigs, rabbits, rats or mice.  
Due to NI-0501 capacity to bind free and IFNγR1-bound IFNγ, studies were performed to investigate the 
potential of NI-0501 to mediate antibody dependent cellular cytotoxicity (ADCC) and complement 
dependent cytotoxicity (CDC) activities, in the presence of target. A lack of ADCC activity was 
demonstrated and no induction of CDC activity was observed.  
1.1.2.2 Toxicology 
Binding and functional data demonstrated Rhesus or Cynomolgus monkeys to be relevant species to 
evaluate the safety of NI-0501. No off-target toxicity was attributed to the drug when administered to 
Cynomolgus monkeys in 13 weekly doses of up to 200 mg/kg. An enhanced susceptibility to infections 
due to the pharmacological effect of the drug was observed at all dose levels (10 to 200 mg/kg/week) in 
animals originally harboring gastrointestinal pathogens (Shigella, Salmonella, Campylobacter) prior to 
NI-0501 administration. In a study where Cynomolgus monkeys were not initially found to be harboring 
gastrointestinal pathogens, weekly administrations of NI-0501 for 8 consecutive weeks at doses up to 30 
mg/kg were well tolerated, without the need for antibiotic prophylaxis.  
Results from a human tissue cross-reactivity study, involving a panel of 35 different human tissues, 
demonstrated that NI-0501 did not cross-react with any of the human samples tested. 
1.1.2.3 Safety pharmacology 
There were no abnormal findings in ECGs taken periodically during treatment and recovery periods in 
the 8 week and 13 week repeated dose toxicology studies in Cynomolgus monkeys, where animals were 
exposed to doses up to 200 mg/kg of NI-0501 weekly. No abnormal findings were observed in the 
histopathological investigations of the hearts and lungs in these animals compared to untreated animals. 
Histopathological analysis of kidneys from these animals revealed no abnormal findings and the periodic 
urinalysis readings were also normal, indicating no abnormal effects on renal function. There were no 
histopathological findings in brains in both studies. Furthermore, no abnormal behavior of the animals 
was observed throughout the study periods, suggesting no effects on CNS.  
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1.1.3  Clinical Data 
A Phase 1 randomized double-blinded placebo-controlled single ascending dose study in 20 healthy adult 
volunteers investigating the safety, tolerability and pharmacokinetic profiles of single intravenous (i.v.) 
administrations of NI-0501 was conducted between September 2011 and April 2012. During this study a 
total of 14 subjects received increasing doses of 0.01, 0.1, 1, and 3 mg/kg NI-0501 (3, 3, 4, and 4 
subjects, respectively), while 6 subjects received placebo. 
The pharmacokinetics (PK) analysis of NI-0501 revealed the expected profile for an IgG1 with a half-life 
of approx. 22 days, a slow clearance (≤ 0.007 L/h) and a low volume of distribution (< 6 L on average). 
All NI-0501 infusions were uneventful.  
A similar incidence of commonly reported infections (e.g., upper respiratory tract infections) was 
observed after administration of NI-0501 and in subjects who had received placebo.  
A Herpes Zoster (HZ) infection was reported in one subject (
), 14 days after his infusion of 
3 mg/kg of NI-0501. This event was assessed as related to the NI-0501 infusion and considered as serious 
(medically significant) in the context of a Phase 1 study in healthy volunteers (HVs). Its intensity was 
moderate and its course normal under antiviral therapy. The subject recovered with no sequelae.  
An increased susceptibility to HZ infections in patients having developed auto-antibodies against IFNγ4 
or having received ustekinumab (a mAb which decreases IFNγ production by inhibiting the p40 subunit 
of IL-12) has been described in the literature5.  
In conclusion, the infusion of NI-0501 was well tolerated and the effects observed during the 8 week 
monitoring after drug infusion did not reveal any serious or unexpected off-target safety or 
immunogenicity concerns.  
A study is presently ongoing to evaluate the efficacy and safety of NI-0501 treatment in patients with 
primary HLH (protocol NI-0501-04). The protocol allows for inclusion of patients either treatment-naïve 
(first line patients) or reactivating after initial response to conventional therapy or not achieving a 
satisfactory response or showing intolerance to conventional therapy (second line patients). Based on 
preliminary efficacy and safety evidence, and on the positive benefit/risk profile observed so far, the 
study, which originated as Phase 2 trial, has been recently amended to continue as Phase 2/3 study with 
the inclusion of the same study population (i.e., first and second line pHLH patients). Thirty-one patients 
have been enrolled as of September 15th 2016, of whom 18 received transplantation. Five patients 
received NI-0501 as 1st line therapy. More than 500 NI-0501 infusions have been performed in the study 
patients who have received a median of 7 weeks of therapy (range 4 days-31 weeks; continuation of NI-
0501 treatment beyond 8 weeks can occur under the long-term follow-up protocol NI-0501-05). Infusions 
have been well tolerated with no premedication needed, and no safety concerns after NI-0501 
administration have emerged to date. Based on data gathered so far, NI-0501 treatment has shown the 
potential to improve relevant clinical and laboratory features of HLH such as fever, splenomegaly, 
cytopenia, hyperferritinemia, hypofibrinogenemia, and also CNS signs and symptoms. Early tapering of 
glucocorticoids has been possible in the majority of patients. 
1.2 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) 
HLH is a rare, serious and life threatening disease of pathologic immune activation, characterized by 
clinical signs and symptoms of extreme inflammation (fever, splenomegaly, cytopenias, coagulopathy), 
leading to the development of abnormal immune-mediated pathologies which, through tissue damage, 
ultimately may cause multi-organ failure and death6. 
HLH comprises primary (genetic/familial) HLH and secondary HLH. 
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Primary HLH is a heterogeneous autosomal recessive disorder, mostly seen in infancy and early 
childhood with an estimated prevalence in Europe of 1/50,000 live births7. The disease is invariably fatal 
with a median survival of less than 2 months after onset of symptoms, if untreated8.  
The genetic defects in primary HLH affect genes involved in cytotoxic pathway of NK-cells and/or 
cytotoxic lymphocytes required to eliminate activated macrophages, encoding proteins for perforin 
synthesis, cytolytic granule maturation, granule exocytosis and release9. In addition, some 
immunodeficiency syndromes, e.g. Griscelli syndrome type 2 (GS-2) and Chediak-Higashi syndrome 
(CHS), present frequently with HLH10. 
Secondary forms of HLH can occur during the course of an infection, an autoimmune/rheumatic disease 
or in association to a malignancy. Secondary forms present with the same signs and symptoms of primary 
HLH and can be equally severe.  
The presence of signs and symptoms of HLH in patients suffering from a rheumatic disease, such as 
systemic Juvenile Idiopathic Arthritis (sJIA) and Systemic Lupus Erythematosus (SLE), is often referred 
to by rheumatologists as Macrophage Activation Syndrome (MAS), as more specifically described in the 
following section.   
In the present protocol, any reference made to MAS should be intended as referring to the secondary 
form of HLH occurring in patients with sJIA. 
1.2.1 Macrophage Activation Syndrome (MAS)  
MAS is a severe, potentially life-threatening complication of rheumatic diseases which is caused by 
excessive activation and expansion of T lymphocytes and macrophages. The uncontrolled expansion of 
these immune cells results in a marked hypercytokinemia and a hyperinflammatory state associated with 
fever, 
cytopenias, 
hepatosplenomegaly, 
liver 
dysfunction, 
coagulation 
abnormalities 
and 
hyperferritinemia, and may progress to multiple organ failure and death11. 
Because of its strong clinical and pathological similarity to HLH, MAS is classified among the secondary 
or acquired forms of HLH. In fact, it has been recently demonstrated that the majority of patients with 
MAS have impaired NK and perforin functional tests and that a significant number of MAS patients 
show polymorphisms or heterozygous mutations in PRF1 and UNC13D12. 
MAS occurs most frequently in patients with sJIA and, less often with systemic lupus erythematosus 
(SLE), but is also described, though more rarely, in patients with vasculitis, particularly with Kawasaki 
disease. Approximately 7–17% of patients with sJIA develop overt MAS13,14, some evidence suggests 
that subclinical MAS may be seen in as many as one third of patients with active systemic disease15. 
Because MAS is potentially fatal, a timely diagnosis and immediate therapeutic intervention are essential 
for appropriate management of the disease. The reported mortality rates in MAS reach 20-30%, and it 
remains the major source of mortality in pediatric rheumatology16. 
Different sets of criteria have been proposed for the diagnosis of MAS in patients with sJIA. The HLH-
2004 diagnostic guidelines17, primarily developed for primary (genetic) forms of HLH, have sometimes 
been recommended. However, they present   several limitations when applied to patients with sJIA. For 
example, criteria such as cytopenias and hypofibrinogenemia below the thresholds required by HLH-
2004 become evident only in the later stages of MAS, as these patients often have increased white blood 
cell and platelet counts as well as elevated serum levels of fibrinogen as a part of the sJIA inflammatory 
response11. As for primary HLH, hemophagocytosis may not be present in a significant proportion of 
patients with MAS at presentation18. Moreover, hemophagocytosis, NK cell activity and sCD25 are not 
routinely assessed in the context of MAS.  
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An alternative approach has been proposed based on the application of preliminary diagnostic guidelines 
(PDG) for MAS complicating sJIA, which were created through the analysis of a cohort of patients with 
MAS compared with a group of patients with a flare of sJIA19.  
The HLH-2004 diagnostic guidelines and the preliminary diagnostic guidelines for sJIA-associated MAS 
were compared for their capacity to discriminate sJIA/MAS from sJIA (in the absence of MAS) and 
systemic infection in a large patient population20. Although with some limitations due to its retrospective 
nature, this study suggested that the preliminary MAS diagnostic guidelines may achieve a satisfactory 
balance between sensitivity and specificity, as well as concordance with the diagnosis made by the 
treating physician when differentiating patients with sJIA/MAS from sJIA, while their specificity in 
discriminating vs. systemic infections was < 30%. Moreover, it has been reported that the proportion of 
patients fulfilling each single criterion of the PDG is highly variable, and some clinical features (e.g. CNS 
dysfunction and hemorrhages) may manifest at a late stage of MAS, rendering their sensitivity low in 
incipient MAS21. The sensitivity of the adapted HLH-2004 set of 4 of 5 criteria was poor (35%), mainly 
explained by the low frequency of cytopenia and hypofibrinogenemia. 
Very recently, an EULAR/ACR-approved set of classification criteria sets have been proposed through a 
multistep process combining expert consensus and retrospective analysis of patient data22. These 
classification criteria did not unequivocally prove to be useful for diagnosis in clinical practice (about 
30% of patients diagnosed by the treating physician were classified as not having MAS), and showed 
important limitations to identify patients who developed MAS while receiving IL-1 and IL-6 
inhibitors23,24.     
The limitations of the thus far proposed criteria for MAS diagnosis render the clinical diagnosis by expert 
rheumatologists still key in the challenge to distinguish MAS from clinical conditions presenting with 
overlapping features such as flares of sJIA or sepsis-like syndromes. 
There are currently no approved drugs for the treatment of MAS. Likewise, no prospective studies have 
been conducted to evaluate the safety and efficacy of the drugs currently used for the treatment of MAS, 
and data is only available as limited case reports or as retrospective surveys.  
Usually, high-dose glucocorticoids are the first-line treatment for MAS. In patients failing to respond to 
glucocorticoids, Cyclosporine A (CsA) has been proposed as additional treatment25.  
Being part of the HLH-94 treatment protocol developed for treating pHLH, the administration of 
etoposide is also considered in patients failing high dose glucocorticoids. However, the potential toxicity 
of the drug remains a major concern. 
The utility of biologics inhibiting the IL-1, IL-6R or TNFα pathways in the treatment of MAS still 
remains unclear. Although biologics inhibiting these pathways have been reported to be effective in 
isolated cases, there have been a few reports of sJIA patients developing MAS while receiving these 
treatments26–29, as well as of patients who do not respond to these treatments, indicating that inhibition of 
IL-1, IL-6R or TNFα does not provide full protection against MAS development nor an efficacious 
treatment of the full blown syndrome. 
A large retrospective, multicenter survey has investigated the clinical, laboratory, and histopathological 
characteristics as well as current practice treatment and outcome of MAS in a total of 362 patients18.  
In approximately half of the patients, MAS occurred in the context of active sJIA in the absence of a 
specific trigger, with a median time interval between the onset of sJIA and MAS of approximately 4 
months. However, in about 25% of patients MAS occurred at sJIA onset with the diagnosis of MAS and 
sJIA being done simultaneously. In about one third of the patients, an infectious trigger was identified, 
most commonly EBV. Nearly all patients were given glucocorticoids, given the well-established role of 
this treatment approach in MAS and HLH. Cyclosporine was the other most commonly prescribed drug 
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(61% of patients), while intravenous immunoglobulins, biologic medications (in particular anakinra) and 
etoposide were given to 36%, 15% and 12% of the patients, respectively.  
The identification of effective therapeutic regimens for MAS represents an area of unmet high medical 
need. More than 50% of patients with sJIA and MAS do not respond to systemic glucocorticoids alone, or 
may require prolonged treatment at high doses with associated significant morbidity. When patients fail 
to respond to glucocorticoids, no good evidence-based data is available on the effectiveness and safety of 
additional treatments such as CsA or etoposide. The course of MAS may become rapidly irreversible 
leading to a fatal outcome, with about one third of the patients requiring ICU admission. Furthermore, no 
clinical and/or laboratory features have thus far been identified to be predictive of poor response to the 
current standard of care, hence leaving the treating physicians with scarce possibility to identify those 
patients who would rapidly progress into an unfavorable clinical course.    
1.3 
STUDY RATIONALE 
1.3.1  Rationale for developing NI-0501 in MAS 
MAS and HLH are characterized by sustained immune cell activation and an associated cytokine storm of 
proinflammatory cytokines with overproduction of IFNγ, TNFα, IL-1 and IL-66,30–32. During the last 
years, evidence has been accumulating in support of the pivotal role of IFNγ in the development of both 
HLH33–35 and MAS36,37. 
For primary HLH, perforin knock-out mice are considered a relevant model as these mice, once infected 
with LCMV, develop all the diagnostic and many of the clinical and laboratory characteristic features of 
the human disease. The HLH-like disease that they develop is dependent on CD8+ T cells and IFNγ 
produced in response to antigen stimulation33. It was demonstrated that when the high circulating levels 
of IFNγ are neutralized with the administration of an anti-IFNγ antibody, not only are the clinical and 
laboratory abnormalities reverted, but also survival rate is dramatically improved. On the contrary, the 
ablation of many other cytokines had no impact on survival33,34. Further strengthening the importance of 
IFNγ in HLH are the high concentrations of circulating IFNγ levels found in these patients6,32.  In a series 
of 71 patients monitored from HLH diagnosis to treatment and follow-up, IFNγ levels were above the 
upper limit of normal (17.3 pg/mL) in all patients, and in particular 53.5% had levels above 1000 pg/mL. 
It was also reported that IFNγ levels rise early and quickly, and can fall from > 5000 pg/mL to normal in 
48 hours upon effective treatment of HLH. 
Two animal models of secondary HLH have been investigated in the context of the NI-0501 development 
program to elucidate the potential pathogenetic role of IFNγ: 
- 
In a murine model that mimics an infection-driven HLH, repeated administrations of CpG via 
activation of TLR9 triggered a hypercytokinemia that led to clinical (e.g. body weight loss, 
splenomegaly) and laboratory (e.g. cytopenia, hyperferritinemia)  features of HLH37. When IFNγ 
was neutralized by the administration of an anti-IFNγ antibody, clinical and laboratory features 
of the disease were reverted. The neutralization of IFNγ was shown to be complete also in 
relevant target tissues, such as the liver and the spleen. Interestingly, the administration of the 
anti-IFNγ antibody unveiled an amount of IFNγ 500- to 2,000-fold higher than that measured in 
blood, likely to better reflect the IFNγ production in tissues. The two IFNγ-inducible chemokines 
(CXCL9 and CXCL10) were upregulated after TLR9 stimulation both in blood and in liver, and a 
significantly correlation was observed between serum levels of IFNγ with CXCL9 and CXCL10 
serum concentrations. The neutralization of IFNγ induced a significant decrease of serum 
CXCL9 and CXCL10, and of their mRNA levels in the liver38. 
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- 
An animal model of IL-6 transgenic mice expressing high levels of IL-6 has been studied, since it 
mimics the condition of patients with sJIA, the rheumatic disease most frequently associated with 
secondary forms of HLH. When triggered with Toll-Like Receptor (TLR) ligands, increased 
lethality, increased inflammatory cytokine production and hyperactivation of inflammatory 
signaling pathways was observed. Moreover, these mice showed a drop in platelet and neutrophil 
counts, increased sCD25, ferritin and LDH levels, resembling many of the features typically 
present in patients with MAS39. In these mice, when IFNγ is neutralized with the administration 
of an anti-IFNγ antibody, survival is markedly improved and laboratory parameters reverted40.  
1.3.2 Rationale for conducting a Clinical Study in MAS/sJIA patients receiving NI-0501 
treatment 
Evidence has been recently gathered in an observational study conducted in patients with secondary 
forms of HLH, either consequent to infections, or of unknown origin (pHLH having been excluded by 
normal cytotoxic activity, absence of mutation in known genes causing pHLH and absence of family 
history) or with MAS occurring in the context of sJIA.  
In 14 patients with secondary HLH (in 7 of whom an underlying infection was identifiable), serum 
samples were analyzed during active full blown disease and during disease remission. Levels of IFNγ, 
CXCL9 and CXCL10 were markedly higher in the active phase compared to disease remission (IFNγ: 
34.7 vs. <3.5 pg/ml; CXCL9: 33598 vs. 745 pg/ml; CXCL10: 4420 vs. 132 pg/ml; median values). IFNγ 
levels significantly correlated with the levels of CXCL9 (p=0.0018) and, to a lesser extent, of CXCL10 
(p=0.014). The levels of IFNγ and chemokines (in particular CXCL9) correlated significantly with 
parameters of disease severity, such as neutrophil and platelet counts, ferritin and ALT, further 
supporting the pathogenic role of IFNγ in secondary HLH and the potential use of chemokines as relevant 
biomarkers of the disease38. 
Similar findings have been shown in patients with MAS occurring in patients with sJIA. Serum 
concentrations of IFNγ, IFNγ-inducible chemokines (CXCL9, CXCL10, CXCL11) and IL-6 were 
measured in 54 patients with sJIA, of whom 20 had MAS. The levels of IL-6 were comparable in patients 
with full-blown MAS and those with active sJIA but without MAS at the time of sampling. On the 
contrary, circulating IFNγ and chemokine levels were significantly higher in MAS, particularly for 
CXCL9, whose median levels were approximately 15-fold higher compared to patients with active sJIA 
without MAS (13392 vs. 837 pg/mL; p=0.005). Noteworthy, a significant correlation was demonstrated 
only in patients with MAS between CXCL9 levels and parameters typically abnormal such as ferritin 
(p=0.041), neutrophil (p=0.010) and platelet (p=0.022) counts, ALT (p=0.044) and LDH (p=0.013). 
Levels of IFNγ also correlated with laboratory parameters of disease severity, with the exception of LDH 
for which statistical significance was not achieved41. 
This pilot phase 2 study, as well as the twin study in Europe, is intended to assess the 
pharmacokinetics/pharmacodynamics profile, the safety and tolerability, and the preliminary efficacy of 
NI-0501 as treatment of MAS in sJIA patients.  
Based on the evidence above described, there is a solid rationale for the neutralization of IFNγ as targeted 
therapy for MAS/sHLH occurring in sJIA patient, and for investigating the benefit of NI-0501 treatment 
in this patient population. 
Additionally, clinical data gathered in an ongoing study conducted in patients with primary HLH 
receiving NI-0501 treatment either as first and second line (NI-0501-04 study), to date indicate:  
1. a favorable tolerability profile of NI-0501 and absence of relevant safety concerns:  
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- 
all infusions administered were well tolerated, confirming the observations made in 
healthy volunteers 
- 
emerging infections reported in the study generally resolved upon proper treatment and 
HLH control   
- 
among the reported infections, only one (histoplasmosis) may have been favored by NI-
0501 mode of action, whereas all other infections have been related to patients’ impaired 
immune status due to HLH and to previous or concomitant treatments. Of note, 
histoplasmosis resolved upon proper treatment 
- 
no death has been attributed to NI-0501 administration. 
2. a favorable impact on disease parameters, with appreciable onset of effects within the first days 
of treatment: 
- 
typical clinical signs and symptoms of HLH started to improve rapidly after the first 
administration of NI-0501 (fever within hours, spleno/hepatomegaly within days)  
- 
of the 30 patients that have received at least 4 weeks of treatment at the cut-off date of 
September 15th 2016, 18 patients have proceeded to HSCT and 4 are awaiting for 
transplant.  
3. a predictable pharmacokinetic profile of NI-0501 from the PK modeling and simulation 
approach, and evidence that neutralization of IFNγ is achieved and maintained 
In conclusion, there is a strong rationale for neutralizing IFNγ in MAS secondary to rheumatic diseases 
based on pre-clinical and clinical evidence, and the preliminary data in pHLH patients indicates a 
favorable benefit/risk profile of NI-0501 with a significant improvement to normalization of HLH 
features.  
It is therefore anticipated that NI-0501 can represent an innovative and effective therapeutic approach in 
the management of this severe, life-threatening complication of rheumatic diseases, potentially limiting 
side effects from long-term high dose glucocorticoid treatment. 
The study population will be  represented by children with a diagnosis of sJIA who develop 
MAS. No diagnostic criteria are available of sJIA. The classification criteria proposed by ILAR  
require the presence of arthritis persisting for at least 6 weeks. While they appear to be used to 
classify patients, they cannot be used at disease presentation. In order to allow inclusion of 
patients presenting with MAS as a feature of onset of sJIA a, the operational criteria  designed 
by CARRA (childhood arthritis and rheumatology research alliance) to identify patients with 
sJIA early in their disease course (DeWitt EM et al. Arthritis Care Res 2012 , Appendix A) have been 
also considered to assess patient eligibility.  
The number of patients meeting the ILAR classification criteria will be in any case included in 
the description of the NI-0501-06 study results. 
Patients enrolled under these twin protocols (for a total of 10 patients, 5 in Europe and 5 in North 
America) will be analyzed jointly and data reported in a single CSR. 
 
2 
OBJECTIVES 
The objectives of this pilot phase 2 study are as follows: 
 
To describe the PK profile of NI-0501 in sJIA patients with MAS. 
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 
To confirm the proposed dosing regimen of NI-0501 in sJIA patients with MAS. 
 
To evaluate the safety and tolerability profile of intravenous (i.v.) administrations of NI-0501 in 
sJIA patients with MAS. 
 
To preliminary assess the efficacy of NI-0501 in sJIA patients with MAS. 
 
To assess the levels of relevant biomarkers, such as IFN and main IFN-induced chemokines 
(CXCL9, CXCL10).    
 
To assess other potential disease biomarkers (e.g., sCD25, sCD163, IL-10, IL-6, IL-18, 
TNFCXCL11).  
 
To assess the immunogenicity of NI-0501 in sJIA patients with MAS. 
3 
STUDY DESIGN 
3.1 
OVERALL DESIGN 
This is an open-label, single arm, international, multicenter pilot phase 2.  
After signature of informed consent, patients will be screened and assessed for eligibility (Section 3.2). 
The study will be conducted in hospitalized patients since, at minimum, the day before the first 
administration of the study drug (study day minus one, SD-1) until SD15 at the earliest.   
Discharge from the hospital can occur from SD15 onwards, at the Investigator’s discretion if the patient’s 
condition allows, provided that no active infections requiring i.v. antimicrobial therapy are present.  
For a detailed description of the study procedures, see Section 8. 
The study flow-chart is summarized in Figure 1. 
 
Figure 1: 
NI-0501-06 Study Flow-chart  
 
 
 
Start of 
Nl-0501 
6mg/kg 
SDO 
Nl-0501 - 3 mg/kg1,2 
every 3 days 
twice a week 
5D3 
5D15 
5D28 
Evaluation period/Short-term fo llow-up after last Nl-0501 dose. 
Efficacy/safety visits to be performed weekly 
SD28A 
5D35 
5D42 
5D49 
End of 
Study' 
5D56 
----------------------------------------
I Screen 
I Treatment Period 
Evaluation Period 
A± 2-daywindow is al lowed 
11 Wil l coincide with the day of last Nl-0501 infusion 
if treatment is continued for 4 weeks. 
1 Treatment may be shortened upon achievement of complete cl inical response 
2 Nl-0501 dose may be increased or treatment prolonged in the event of very high IFNy production 
3 If Nl-0501 treatment is prolonged beyond4 weeks, additional fo llow-up visits are to be performed in orderto 
complete4 weeks of follow-up after the last Nl-0501 infusion under the current protocol. 
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3.2 
SCREENING PERIOD 
Screening will be carried out within up to 1 week prior to first administration of NI-0501 (SD0) to enable 
confirmation of patient eligibility and following the signature of the Informed Consent Form. 
In the event that a patient’s medical condition warrants rapid treatment initiation, and to avoid 
unnecessary repetition of recent interventions, results of tests which have been performed as part of the 
normal patient’s care at the site (or at the referring hospital) not more than 2 weeks prior to first NI-0501 
infusion, can be considered for screening purposes (inclusion/exclusion criteria checks), with the 
agreement of both the Sponsor and the Investigator. 
Information regarding the inadequate response to high dose i.v. glucocorticoids (as required for patient 
eligibility), will be collected and recorded in the CRF. 
Samples for infection screening need to be collected for analysis according to the protocol requirements; 
however availability of the results is not required prior to NI-0501 initiation if the patient’s medical 
condition warrants rapid treatment, provided that there are no clinical findings suggestive for the presence 
of any of the infections which represent exclusion criteria. 
In the case of a patient having received BCG vaccination, a PPD test must be performed and combined 
with an IFNγ-release assay. 
A negative serum pregnancy test has to be documented in female patients who are post-pubescent. 
For a detailed description of the study procedures during the screening period see Section 8.  
3.3 
TREATMENT PERIOD 
NI-0501 will be administered i.v. at the initial dose of 6 mg/kg, and continued at the dose of 3 mg/kg, 
every 3 days until SD15, and then twice-a-week for additional 2 weeks, i.e. until SD28.  
Treatment may be shortened upon achievement of complete clinical response (i.e. MAS remission), 
however at least two infusions of NI-0501 at the dose of 3 mg/kg have to be administered (i.e. after SD6). 
In such circumstances, efficacy/safety visits have to be in any case performed every 3 days until SD15 
and then twice-a-week until SD28.  
In the event that the PK profile of NI-0501 in a given patient indicates a Target Mediated Drug 
Disposition (TMDD) suggestive for very high IFN production, the planned NI-0501 regimen may be 
adapted (e.g. the dose of NI-0501 may be increased or the NI-0501 treatment may be prolonged beyond 4 
weeks) guided by clinical and PK evidence, upon confirmation of a favorable benefit/risk profile in that 
individual patient.  
3.4 
FOLLOW-UP PERIOD 
All patients who have received at least one dose of NI-0501 will be monitored after the last 
administration of NI-0501. A short-term follow-up of 4 weeks has to be performed under the current 
protocol, therefore should NI-0501 treatment in a given patient need to be prolonged beyond 4 weeks, 
additional visits will be performed weekly until completion of the 4-week short-term follow-up.  
The last visit for a given patient under the NI-0501-06 study will normally be on SD56 (except in case of 
prolongation of NI-0501 treatment beyond 4 weeks, as above described). 
Afterwards all patients will be asked to enter a long-term follow-up study, NI0501-05, to allow long-term 
outcome and safety surveillance, and to monitor NI-0501 elimination profile.  
In the event that additional monitoring of NI-0501 concentrations is required (e.g., NI-0501 serum levels 
still measurable at EoS) and cannot be performed in the context of the long-term follow-up study, 
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unscheduled visits will have to be performed beyond SD56, until serum NI-0501 levels are no longer 
detectable. These measurements should occur not less than every two weeks. 
3.5 
STUDY END 
The end of the study is defined as the last visit of the last patient. 
In case of an ongoing serious adverse event (SAE), the patient will continue to be monitored until 
resolution or until the outcome of the event is known and stable, beyond the defined study end, as 
necessary.  
 
3.6 
LONG-TERM FOLLOW-UP STUDY 
All patients having received at least one dose of NI-0501 in the study will be asked to participate in a 
long-term follow-up study, to monitor long-term outcome and safety after NI-0501 treatment, and, when 
relevant, to complete the assessment of the NI-0501 elimination profile. 
4 
TARGET POPULATION 
The study population comprises patients of both genders, , aged < 18 years, with confirmed sJIA or high 
presumption of sJIA, presenting with MAS (as per appendix A) and having shown inadequate response to 
high dose i.v. glucocorticoid treatment, see Section 4.1.1. 
4.1 
ELIGIBILITY CRITERIA 
To be eligible for the study, patients must meet all inclusion criteria and not meet any of the exclusion 
criteria: 
4.1.1  Inclusion Criteria 
1. Patients of both genders, aged < 18 years  
2. Confirmed sJIA diagnosis. For patients presenting with MAS in the context of the onset of sJIA, high 
presumption of sJIA (as per Appendix A) will suffice for eligibility. 
3. A diagnosis of active MAS confirmed by the treating rheumatologist, having ascertained the 
following: 
Febrile patient presenting with: 
- Ferritin > 684 ng/mL 
and any two of: 
- Platelet count  181 x109/L 
- AST levels > 48 U/L 
- Triglycerides > 156 mg/dL 
- Fibrinogen levels ≤ 360 mg/dL 
(see Appendix B22). 
4. An inadequate response to high dose i.v. glucocorticoid treatment administered for at least 3 days as 
per local standard of care (including but not limited to pulses of 30 mg/kg mPDN on 3 consecutive 
days). 
High dose i.v. glucocorticoid should not be lower than 2 mg/kg/day of mPDN equivalent in 2 divided 
doses (to a maximum of 60 mg/day in patients of 30 kg or more). In case of rapid worsening of the 
patient’s condition and/or lab parameters, inclusion may occur within less than 3 days from starting 
high dose i.v. glucocorticoids. 
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5. Informed consent provided by the patient (as required by local law), or by the patient’s legally 
authorized representative(s) with the assent of patients who are legally capable of providing it, as 
applicable.    
6. Having received guidance on contraception for both male and female patients sexually active and 
having reached puberty: 
Females of child-bearing potential require use of highly effective contraceptive measures (failure rate 
of less than 1% per year) from screening until 6 months after receiving last dose of the study drug. 
Highly effective contraceptive measures include: 
o Sexual abstinence 
o Hormonal contraceptives: combination or progesterone only 
o Intrauterine methods: intrauterine devices or systems 
o Bilateral tubal occlusion 
o Vasectomised partner 
Males with partners(s) of child-bearing potential must agree to take appropriate precautions (such as 
sexual abstinence, barrier contraception, vasectomy) to avoid fathering a child from screening until 6 
months after receiving last dose of the study drug. 
4.1.2 Exclusion Criteria 
1. 
Diagnosis of suspected or confirmed primary HLH or HLH consequent to a neoplastic disease. 
2. 
Patients treated with Tocilizumab, Canakinumab or TNF inhibitors within 5 times of their defined 
half-life. 
3. 
Active mycobacteria (typical and atypical), Histoplasma Capsulatum, Shigella, Salmonella, 
Campylobacter and Leishmania infections.  
4. 
Clinical suspicion of latent tuberculosis. 
5. 
Positive serology for HIV antibodies. 
6. 
Presence of malignancy. 
7. 
Patients who have another concomitant disease or malformation severely affecting cardiovascular, 
pulmonary, CNS, liver or renal function, that in the opinion of the Investigator may significantly 
affect likelihood to respond to treatment and/or assessment of NI-0501 safety. 
8. 
History of hypersensitivity or allergy to any component of the study regimen. 
9. 
Receipt of BCG vaccine within 12 weeks prior to screening. 
10. Receipt of live or attenuated live vaccine within 6 weeks prior to screening. 
11. Pregnant or lactating female patients. 
5 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
5.1 
DESCRIPTION OF IMP 
NI-0501 is a fully human anti-IFNγ monoclonal antibody which binds and neutralizes IFNγ. 
NI-0501 is manufactured by a third party manufacturing facility duly qualified by Novimmune. It will be 
supplied to study sites in single-use 2 and/or 10 mL filled single-use glass vials at a concentration of 
5 mg/mL, for dilution prior to administration. 
The nominal composition of the NI-0501 sterile concentrate for infusion (per mL) is as follows: 
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Ingredient 
Quantity (per mL) 
NI-0501 
5 mg 
L-Histidine 
1.55 mg 
L-Histidine monohydrochloride, monohydrate 
3.14 mg 
Sodium chloride (NaCl) 
7.31 mg 
Polysorbate 80  
0.05 mg 
pH 
6.0 ± 0.2 
The solution contains no antimicrobial preservative, and therefore each vial must be used only once. 
 
5.2 
DOSING REGIMEN 
NI-0501 will be administered at the initial dose of 6 mg/kg by infusion over a period of one to two hours 
depending on the volume to infuse. Treatment will be continued at the dose of 3 mg/kg every 3 days until 
SD15, and twice-a-week thereafter for a total of 4 weeks (i.e. up to SD28).  
Treatment may be shortened upon achievement of complete clinical response (i.e. MAS remission), 
however at least two infusions of NI-0501 at the dose of 3 mg/kg have to be administered (i.e. after SD6). 
In the event that the PK profile of NI-0501 in a given patient indicates a Target Mediated Drug 
Disposition (TMDD) suggestive for very high IFN production, the planned NI-0501 regimen may be 
adapted by increasing the dose of NI-0501 upon assessment of a favorable benefit/risk profile in that 
individual patient. NI-0501 treatment may be prolonged beyond 4 weeks guided by clinical and PK/PD 
evidence, upon confirmation of a favorable benefit/risk profile in that individual patient. 
5.3 
RATIONALE FOR DOSE SELECTION  
 The rationale for the dosing strategy foreseen for this study is based on: 
‐ 
Data from in vitro experiments investigating the binding kinetics of NI-0501 to human IFNγ and the 
functional inhibition of human IFNγ by NI-0501; 
‐ 
PK information from recombinant IFNγ in human; 
‐ 
Data from the Phase 1 NI-0501-03 study in which NI-0501 was administered to healthy volunteers; 
‐ 
Data gathered so far from the ongoing NI-0501-04 study in pediatric primary HLH patients receiving 
NI-0501 in first or second line; 
‐ 
Data from an observational study in patients with MAS developing on a background of sJIA41; 
‐ 
Data from an observational study in pediatric patients with secondary HLH (having excluded a 
rheumatic or neoplastic origin)38.  
The analysis of data generated from the ongoing study in which primary HLH patients have been treated 
with NI-0501 has allowed to estimate the production rate of IFNγ through the assessment of the “total 
IFNγ” (i.e. IFNγ bound to NI-0501 and free IFNγ), and consequently the concentration of NI-0501 
required to neutralize the variably high IFNγ concentrations. It has also been possible to determine that 
when there is a high production of IFNγ, target mediated drug disposition occurs. Importantly, the 
relationship between IFNγ and the IFNγ-inducible chemokines CXCL9 and CXCL10 has been 
investigated establishing the tight correlation between those chemokines measured prior to the 
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administration of NI-0501 and “Total IFNγ” at 48 hours after NI-0501 administration, indicating that 
these chemokines can be used as exploratory markers of IFNγ production.  
The key observations that have constituted the foundation of the dosing rationale for this protocol and led 
to the selection of the NI-0501 doses to be administered to patients with MAS not responding to high 
dose glucocorticoid therapy are the followings:    
‐ 
there is a tight correlation between IFNγ and the IFNγ-related chemokines CXCL9 and CXCL10, as 
well as between disease parameters and levels of IFNγ and IFNγ-related chemokines in patients 
suffering from HLH38,41; 
‐ 
the higher the circulating levels of the IFN-related chemokines, the higher is the concentration of 
NI-0501 (and therefore the dose of NI-0501) required to neutralize the corresponding levels of IFNγ 
(data from the NI-0501-04 study on file at Novimmune); 
‐ 
the neutralization of IFNγ has been shown to have a therapeutic role in primary HLH patients42; 
‐ 
a trend towards higher levels of circulating IFNγ-related chemokines has been observed in patients 
with secondary forms of HLH compared to primary HLH patients38,41 during or soon after HLH 
conventional therapy (see Figure 2; data from the NI-0501-04 study on file at Novimmune); 
‐ 
the onset of MAS is usually acute and the disease worsens rapidly therefore requiring prompt and 
complete neutralization of IFN from the very beginning of treatment; 
‐ 
in MAS patients, differently from patients with primary HLH, the risk of reactivation is extremely 
low once HLH remission is achieved, and HSCT is not required. Therefore in patients with MAS, 
shorter treatment duration is anticipated compared to primary HLH patients, not requiring a 
maintenance phase while awaiting for HSCT. 
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Figure 2: 
CXCL9 levels in patients with pHLH, sHLH and MAS 
 
 
 
 
 
 
 
 
Note:  
pHLH: CXCL9 levels from the patients with primary HLH treated with NI-0501 in second line in the NI-0501-04 
study prior to receiving NI-0501 (measured by Affymetrix) 
sHLH and MAS: CXCL9 levels in patients with active disease (values extrapolated from Millipore to Affymetrix) 
 
  
Simulations performed considering different IFNproduction rates that are anticipated to potentially 
occur in MAS patients are presented in Figure 3. The simulations clearly show that the risk of NI-0501 
accumulation, as well as the risk of exceeding the highest NI-0501 concentration observed so far in 
pHLH patients is negligible. Therefore, the expected highest peak and trough concentrations will remain 
within the ones already achieved in primary HLH patients treated in the ongoing study. 
The PK model used to produce these simulations is a two compartment model with linear elimination 
assuming allometric scaling based on body weight (BW) to which an additional non-linear (TMDD) 
elimination pathway characterized by a VMAX and a KM has been added. Parameters used in the 
simulations are from a population pharmacokinetic analysis of study NI-0501-03 and assuming allometric 
scaling. VMAX is the IFNγ concentration (0.1 nM) multiplied by the recombinant IFNγ clearance 
(1.2 L/h/kg) divided by the number of binding sites per antibody. KM is assumed to be equal to KD. 
 
p H L H
s H L H
M AS
1 0 0
1 0 0 0
1 0 0 0 0
1 0 0 0 0 0
C X C L 9  (p g /m l)
• 
•• 
•• ·j· 
}: 
••• 
•••• 
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Figure 3: 
Predicted concentration-time profiles after administration of NI-0501 at the initial dose 
of 6 mg/kg followed by 9 doses of 3 mg/kg every 3 days  
 
Note:  
Simulations are shown for sJIA MAS patients of an approximate body weight of 23 kg with different levels of total 
IFNγ. The blue area corresponds to the mean of the 3 highest peak and trough concentrations observed in HLH 
patients from study NI-0501-04/05 (data cut-off date of June 24, 2016). 
The proposed dosing strategy is further supported by the following evidence: 
‐ 
primary HLH patients treated with NI-0501 in the context of the ongoing study who were 
characterized by levels of CXCL9 comparable to the ones expected in MAS all required a rapid and 
significant NI-0501 dose increase;  
‐ 
primary HLH patients having a high production of IFNγ, required a high dose of NI-0501, 
demonstrating the presence of target mediated drug disposition (TMDD), i.e. a pronounced increased 
clearance of NI-0501 due to the high production of IFNγ. The presence of TMDD, while requiring to 
administer NI-0501 at high doses and sometimes more frequently, prevents NI-0501 accumulation to 
occur; 
‐ 
to date NI-0501 has shown a good safety profile when administered to primary HLH patients up to 
the dose of 10 mg/kg, achieving similar or even higher NI-0501 exposures compared to the ones 
expected to occur in MAS patients. More than 850 infusions have been performed in all patients 
treated (including CU) and around 20% have been performed at a dose of  6mg/kg. 
In conclusion, based on a production rate of IFNγ expected to be high in sJIA patients with overt MAS41, 
an initial dose of 6 mg/kg followed by repeated administrations of 3 mg/kg is deemed appropriate to 
achieve rapidly and maintain the concentrations of NI-0501 estimated to ensure a fast neutralization of 
IFNγ activity. 
 
 
"' 
;' 
:g 
I 
C 
2 
TIFNG=200 pM 
8 
TIFNG=1000 pM 
ij 
TIFNG=5000 pM 
z 
"' 
;' 
.!! 
0 
0 
10 
20 
30 
40 
50 
60 
Time (days) 
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5.4 
IMP HANDLING 
5.4.1  Packaging and Labeling 
NI-0501 will be supplied to study sites in single-use glass vials containing a 2 or a 10 ml solution at a 
concentration of 5 mg/ml. Labeling and packaging will be prepared to meet local regulatory 
requirements. 
5.4.2  IMP Supply 
NI-0501 will be supplied to the study sites as open-label supplies. 
5.4.3  IMP Receipt and Storage 
The NI-0501 vials will be transported with temperature monitoring device, in order to ensure consistent 
temperatures during transit. When the study drug is received at the site, the Investigator or Pharmacist 
will check for accurate delivery and absence of temperature deviation alarms. 
The study drug should be stored between 2 - 8°C (36 - 46°F). All vials must be stored in a secure locked 
location in a temperature-controlled refrigerator or cold room. Any deviations from the recommended 
storage conditions should be immediately reported to the Sponsor and responsible study clinical research 
associate (CRA). Affected vials should not be used and should be quarantined until the Sponsor has 
authorized their use, return or destruction. 
Documentation of the storage conditions of the study drug must be maintained over the timeframe the 
study drug is stored at the site, until such time as it is used, disposed of, or returned to Novimmune or 
designee. 
Regular inspections of the NI-0501 vials are required, as detailed in the IMP manual indications for the 
Preparation and Administration of Individual Doses of Study Drug NI-0501. 
5.4.4  IMP Preparation, Administration, Accountability and Destruction 
5.4.4.1 Preparation  
The study drug must be prepared only 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 is determined as detailed in Section 5.2.  
Full instructions for the preparation, including dilution steps, and method for administration of NI-0501 
are available in the IMP Manual that will be provided to all the investigational sites. 
5.4.4.2 Administration 
The patient should receive the designated volume of the infusate through an infusion pump over a period 
of 1 to 2 hours depending on the volume to infuse. IMP must be administered using either a syringe that 
has been sterilized by gamma irradiation or using any appropriate sized non-PVC polyolefin infusion bag 
and a 0.2 μm filter, which must be added to all infusion lines. (See the IMP manual for details.) 
A central venous access is to be maintained during the treatment period. However, as per previous 
experience in HLH patients in whom central venous access was not possible or not maintained, NI-0501 
infusions have been performed safely via peripheral venous access. Since no data is available on the 
compatibility of NI-0501 with other intravenous substances or additives, other medications/substances 
should not be added to the infusion material or infused simultaneously through the same intravenous line. 
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If the same intravenous line is used for subsequent infusions of other drugs, the line should be flushed 
with saline before and after infusion of NI-0501. 
The infusion of NI-0501 will be administered under the direct supervision of the Investigator (or 
delegate). It should be preferably performed in the morning, and at the same time of the day during the 
study whenever possible.  
Details of the infusion administered must be recorded, including: 
 
The date of administration 
 
The time (start and end) of infusion 
 
The volume administered 
 
Any adverse effects or general illness experienced by the patient. 
 
Any other event(s) judged relevant by the site personnel. 
5.4.4.3 Accountability 
When the study drug is received at the site, the Investigator or Pharmacist (or appropriate designee) 
should acknowledge its receipt by signing (or initialing) and dating the documentation. Documentation 
should be returned to Novimmune (or its designee) and a copy retained in the Investigator’s file. 
The dispensing of the study drug shall be carefully recorded on Drug Accountability Forms and an 
accurate accounting must be available for verification by the CRA at each monitoring visit. 
Drug accountability records shall include: 
 
Confirmation of the study drug’s delivery to the study site 
 
The inventory at the study site 
 
The use of study drug by each patient  
 
Proper storage conditions at the study site 
 
The return to the Sponsor or alternative disposition of unused products. 
The records should include dates, quantities, expiration dates, batch number, and patient number.  
Unused study drug must not be discarded or used for any purpose not authorized by Novimmune.  
5.4.4.4 Destruction, Return and Disposal  
Periodically during the study and at the conclusion of participation of the study by the site, the CRA will 
monitor and collect the Drug Accountability Forms, before making arrangements for study drug return or 
authorization of destruction by the study site. 
6 
PATIENT BACKGROUND TREATMENT AND CARE 
6.1 
GLUCOCORTICOIDS  
For a patient to be eligible for the study, an inadequate response to high dose i.v. glucocorticoids 
administered for at least 3 days as per local standard of care (including but not limited to pulses of 30 
mg/kg mPDN on 3 consecutive days) must be documented. Inclusion can however occur within less than 
3 days from starting high dose i.v. glucocorticoids, in case the patient’s condition and/or lab parameters 
are rapidly worsening. 
High dose i.v. glucocorticoids should not be lower than 2 mg/kg/day of mPDN equivalent in 2 divided 
doses (to a maximum of 60 mg/day in patients of 30 kg or more).   
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During the study, NI-0501 will be initially administered on a background of at least 2 mg/kg/day of 
mPDN equivalent (to a maximum of 60 mg/day in patients of 30 kg or more). 
Glucocorticoid tapering may be initiated as soon as the patient’s conditions allow, according to the 
Investigator’s assessment. The tapering scheme can be selected by the Investigator, with the objective of 
reaching the same (or lower) dose being administered before the occurrence of MAS (in patients already 
on treatment for sJIA) or decreasing by 50% (or more) the glucocorticoid dose administered at initiation 
of NI-0501 treatment (in patients presenting with MAS as first manifestation of sJIA).   
In the event of disease worsening after glucocorticoid tapering, a higher dose can be re-introduced and 
maintained until a satisfactory response is achieved according to the Investigator.  
6.2 
PROPHYLACTIC TREATMENT  
Prophylaxis for Herpes Zoster (HZ) virus infection will be administered to mitigate the potential risk 
associated to NI-0501 administration (see Benefit/Risk Management, Section 10.5). 
Patients will therefore receive the prophylactic treatment starting preferably the day before (i.e. SD-1), 
and in any case prior to, initiation of NI-0501 treatment on SD0, and continued until serum NI-0501 
levels are no longer detectable, as follows: 
 
For HZ virus prevention, according to Institution/Country Guidelines/Recommendations (e.g. 
Acyclovir 200 mg four times daily for children over two years, for children under two years 
100 mg four times daily). 
In the unlikely event that a patient, previously vaccinated for TB, shows a Purified Protein Derivative 
(PPD) test result ≥ 5mm and a negative IFNγ-release assay, the patients will receive TB prophylaxis 
according to Institution/Country Guidelines/Recommendations (e.g. Isoniazid).  
In case NI-0501 concentrations are still measurable after the end of the study, it is required that the above 
mentioned prophylaxis be maintained, until serum NI-0501 levels are no longer detectable. 
6.3 
CONCOMITANT THERAPY 
6.3.1  Cyclosporine A 
CsA may be continued, if already started at least 3 days prior to initiation of NI-0501 treatment. CsA 
dose adjustments will be performed if required based on results of therapeutic drug monitoring, in order 
to maintain therapeutic levels. CsA can be withdrawn at any time during the study, upon judgment of the 
Investigator. CsA cannot be introduced once NI-0501 administration has started. 
6.3.2  Intrathecal Therapy 
For patients receiving intrathecal therapy (e.g. methotrexate and glucocorticoids) at the time of NI-0501 
treatment initiation, this treatment will be continued until clinically indicated.  
6.3.3  Other possible concomitant therapies 
Analgesic treatment, transfusion of blood products, electrolyte and glucose infusions, i.v. parenteral 
nutrition, inotropic support, antibiotics, anti-fungal and anti-viral treatment, ultrafiltration or 
hemodialysis, as well as general supportive care (e.g. gastro-protective agents, anti-hypertensive etc.) are 
permitted during the study.  
The use of any prescription or over-the-counter medication, including herbal and homeopathic 
preparations with the exception of multi-vitamins, needs to be notified to the Investigator. 
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6.3.4 Not allowed concomitant therapies 
Any background treatment of sJIA has to be discontinued before initiation of NI-0501 treatment as 
follows: 
- Anakinra must be discontinued at latest before the first NI-0501 infusion; however no wash-out period 
is required due to the short half-life of the drug. 
- A wash-out period of 5 times of respective half-lives is required in patients who have been treated 
with Tocilizumab, Canakinumab or TNF inhibitors. 
It is recommended background treatment of sJIA not to be re-introduced during the 8 weeks of the study, 
unless the patient’s clinical conditions require it. 
As long as NI-0501 is being administered, no concomitant use of etoposide, T-cell depleting agents, or 
any other biologic drug is allowed, with the exception of: 
 G-CSF, in case of prolonged neutropenia  
 Rituximab, in case of documented EBV infection. 
Vaccination with a live or attenuated-live (including BCG) vaccine must be avoided during the whole 
study. In the event that NI-0501 concentrations are still measurable after the end of the study, the period 
with no vaccinations should be extended until serum NI-0501 levels are no longer detectable.  
 
6.4 
EMERGENCY TREATMENT 
As none of the NI-0501 infusions administered to healthy volunteers or patients has triggered any 
medically significant reaction, this is considered an unlikely event during the study. However, should 
severe allergic reactions (such as anaphylactic shock) occur, they would require prompt i.v. treatment 
with adrenaline and antihistamines. Oxygen shall be supplied through a face mask. Patients must have an 
appropriately sized i.v. line that allows rapid infusion of colloid volume substitution. Transfer to the 
intensive care unit of the hospital should be possible.  
Following the first administration of NI-0501 and before leaving the study site, each patient (and/or 
patient’s legal representative) will be given a card to carry at all times in case of any emergency. The card 
gives details of the name of the drug, name of the responsible physician, and the address and telephone 
number of the study site. 
 
6.5 
RESCUE THERAPY 
Patients who are withdrawn from the study due to a safety issue or for lack of efficacy (i.e. worsening of 
MAS/no response to NI-0501) will be treated according to the standard of care at the site.  
7 
ENDPOINTS 
The main objective of the study is to confirm that the proposed dosing regimen is adequate in relation to 
the IFNγ production in patients with MAS secondary to sJIA.  
For this purpose, a PK-PD analysis will be performed based on:  
 levels of circulating NI-0501 
 levels of total IFNγ 
 levels of main IFNγ–induced chemokines (namely CXCL9 and CXCL10). 
 
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7.1 
PHARMACOKINETICS ENDPOINTS 
Free NI-0501 concentrations will be measured in serum to determine the PK profile of NI-0501 in this 
patient population, and to confirm the adequacy of the proposed dosing regimen. 
All PK data will be summarised using appropriate graphical and tabular presentations. Descriptive non-
compartmental pharmacokinetic analysis (NCA) will be applied: Cmax (concentration corresponding to 
Tmax), Tmax (time of maximum observed concentration), CEOI (concentration at the end of infusion), Ctrough 
(concentration just before administration), AUC (area under curve of a dosing interval), AUClast (area 
under curve from the time of dosing to the last measurable concentration), λz (first order rate constant 
associated with the terminal (log-linear) portion of the curve, estimated via linear regression of time 
versus log concentration), t½ (plasma half-life), CL (systemic drug clearance), Vss (volume of distribution 
at steady state). Individual and mean PK parameters will be tabulated. Exploratory compartmental PK 
analysis and population PK analysis will be undertaken to investigate linear and non-linear (TMDD) 
kinetics. 
In addition, PK analysis will be done when a total of 5 patients have been recruited in Europe and North 
America inclusive, to assess the appropriateness of the dose selection. 
 
7.2 
PHARMACODYNAMICS ENDPOINTS 
Assessment of PD parameters will include, but will not be limited to, the followings: 
 
Levels of circulating free IFN at pre-dose, and of total IFNγ (free IFNγ+bound to NI-0501) after 
initiation of NI-0501 treatment.  
 
Levels of the main IFNγ-induced chemokines (CXCL9, CXCL10). 
 
Correlation between chemokine levels (CXCL9, CXCL10) and levels of free NI-0501, free IFNγ 
(pre-dose) and total IFNγ (exploratory analysis). 
 
Correlation between chemokine and total IFNγ levels, and laboratory parameters of MAS 
severity, e.g. ferritin, platelet counts, LFTs (exploratory analysis). 
 
Levels of other potential disease biomarkers (e.g. sCD25, sCD163, IL-18, IL-10, IL-6, TNF, 
CXCL11). 
 
Levels (if any) of circulating antibodies against NI-0501 to determine immunogenicity, i.e. the 
development of anti-drug antibodies (ADAs). 
 
7.3 
SAFETY ENDPOINTS 
The tolerability and safety of NI-0501 treatment will be assessed as follows:  
 
Incidence, severity, causality and outcomes of AEs (serious and non-serious), with particular 
attention being paid to infections. 
 
Evolution of laboratory parameters, in particular CBC, LFTs, inflammatory markers (ferritin and 
CRP) and coagulation parameters. 
 
Number of patients withdrawn due to safety reasons. 
 
7.4 
EFFICACY ENDPOINTS 
The efficacy of NI-0501 in this patient population will be evaluated based on the evolution of the MAS 
distinct features of cytopenias, liver function and coagulopathy. 
In particular the following variables will be preliminarily assessed: 
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 Number of patients achieving MAS remission by Week 8 after initiation of NI-0501 treatment.  
 Time to MAS remission. 
 Number of patients for whom at any time during the study glucocorticoids can be tapered i) to the 
same (or lower) dose being administered before the occurrence of MAS (in those patients who are 
already treated for sJIA) or ii) by 50% (or less) of the dose administered at NI-0501 treatment 
start (in those patients who present with MAS at sJIA onset).  
 Time to achievement of glucocorticoids tapering (as defined above). 
 Survival time. 
 Number of patients withdrawn from the study due to lack of efficacy. 
 
MAS remission is defined as 
 Resolution of clinical signs and symptoms according to the Investigator  
and 
 Normalization of laboratory parameters relevant to MAS, as follows:  
- 
WBC and platelet count above LLN  
- 
LDH below 1.5 ULN 
- 
ALT/AST below 1.5 ULN 
- 
fibrinogen higher than 100 mg/dL 
- 
ferritin levels decreased by at least 80% from values at screening or baseline (whichever is 
higher) or below 2000 ng/ml, whichever is lower.  
8 
OUTLINE OF STUDY PROCEDURES 
8.1 
STUDY VISITS 
For a detailed description of the visit schedule and assessments, please refer to Table 1 (Schedule of 
Assessment – Screening and NI-0501 Treatment Period) and Table 2 (Schedule of Assessment –
Evaluation Period). 
Patients will be recruited from specialized study centers in North America, in which an intensive care unit 
is available. If not already hospitalized, the patient will enter the hospital on SD-1. 
During the NI-0501 Treatment Period, Infusion Visits will occur every 3 days until SD15, and twice-a-
week thereafter until SD28, and will also serve as Efficacy/Safety visits. In case NI-0501 treatment is 
shortened after SD6, Efficacy/Safety visits have to be in any case performed with the same schedule until 
SD28, in order to assess the evolution of MAS clinical and laboratory features, and to closely monitor 
safety.     
From SD28 and during the Evaluation Period, visits will occur on a weekly schedule (a  2-day window 
is allowed) for efficacy and safety evaluation, and follow-up after NI-0501 last infusion. 
Discharge from the hospital cannot occur before SD15. After SD15, in case the patient condition allows, 
the patient can be discharged, at the Investigator’s discretion, provided that no active infections requiring 
i.v. antimicrobial therapy are present.  
Some procedures are not mandatory or do not need to be done systematically but only when applicable 
according to the following specifications:  
 ECG is mandatory at screening, after first infusion, and at the end of the study, however it should 
also be performed whenever required based on clinical judgment. 
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 Broad search for pathogens during the study (beside the ones required per protocol) should be 
done if there is any suspicion of infection.  
 Chest X-ray during the study (beside the ones required per protocol) should be done more 
frequently in case of clinical suspicion of a pulmonary infection. 
 Functional tests relevant to HLH diagnosis should be performed whenever possible; however 
availability of results is not required for patient inclusion in the study. 
The following situations will not be considered as protocol deviations: 
 Missing data if not occurring at 2 consecutive time-points.  
 A  5-min difference in the timing of vital sign measurements during NI-0501 infusion. 
 A  10-min difference in the timing of vital sign measurements after NI-0501 infusion. 
 
 
8.2 
INFORMED CONSENT AND SCREENING PROCEDURES 
The informed consent form must be signed by the patient (as required by local law) or by the patient’s 
legally authorized representative prior to any study-related procedures, with the assent of patients who are 
deemed suitable to provide it, as applicable.  
Patients will be screened for eligibility prior to enrolment into the study. The Investigator must keep a log 
of the patients screened for the study and reasons for non-eligibility, if applicable. 
Screening evaluations should be completed within up to 1 week prior to the first administration of the 
study drug (SD0). Clinical and laboratory assessments should be performed as close as possible to 
initiation of NI-0501 treatment, preferably on SD-1, as described in Table 1.  
In the event that a patient’s medical condition warrants rapid treatment initiation, and to avoid 
unnecessary repetition of recent interventions, results of tests which have been performed as part of the 
normal patient’s care at the site (or at the referring hospital) not more than 2 weeks prior to first NI-0501 
infusion, may be considered for screening purposes (inclusion/exclusion criteria checks) with the 
agreement of both the Sponsor and Investigator. 
The following patient information must be collected: 
 Demographic and medical history 
 Detailed information on inadequate response to high dose i.v. glucocorticoids. 
 Concomitant medication at screening.  
 Date of sJIA diagnosis. 
 sJIA treatment previously received and ongoing at the time of screening. 
 Date and criteria of eligibility.  
 Relevant clinical and laboratory data in order to characterize a posteriori the study population 
according to HLH-2004 criteria. 
Samples for the molecular characterization with respect to the known HLH causative genes have to be 
collected and send to a centralized laboratory only if the patient has given consent for genetic testing. 
A panel of genes already known to be involved in primary HLH (PRF1, UNC13D, STX11, STXBP2, 
LYST, RAB27A, SH2D1A, XIAP) will be tested.  
Given the evolving knowledge and new findings within the scientific community with regard to potential 
modifying genes for HLH e.g. AP3B1, HPS1, IRF5, ITK, KIR2DL1, MyD88, SLC7A7, TNFRSF7/ 
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CD27, IL2RG, ARHGAP21, CADPS2, CCDC141 (CAMD1), EXPH5 (SLAC2B), FAM160A2, FKBPL, 
GDI1, LRGUK, MICAL2, TNFRSF10B, XIRP2, the panel may be extended, if relevant.  
Functional tests relevant to the diagnosis of HLH should be performed whenever possible; however 
availability of these results is not required for inclusion of the patient in the study. 
Prophylactic treatments for HZ virus and for TB (when applicable, as described in Section 6.2), have to 
be started. 
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Table 1 – Schedule of assessment: Screening and NI-0501 treatment period (from SD-1 to SD28) 
 
Assessments 
 
Protocol 
Section 
Screening (up to 
one week prior to 
1st infusion)  
SD0 
 Infusion #11 
SD1 
SD2 
SD3 
 Infusion #22 
SD5 
SD6 to SD283 
Infusion/Efficacy/ 
Safety visits  
 
SD-1 
pre 
post 
 
 
pre 
post 
 
 
Hospitalization4 
 
8.1 
From SD-1 
 
 
 
 
 
 
 
 
Patient information and Informed Consent 
8.2 
X 
 
 
 
 
 
 
 
 
Medical history 
8.2 
X 
 
 
 
 
 
 
 
 
Concomitant medication (including recording on 
glucocorticoid tapering when relevant) 
8.2 
X 
X 
 
X 
X 
X 
 
X 
X 
MAS diagnosis and Eligibility Criteria5  
8.2 
X 
 
 
 
 
 
 
 
 
Prophylactic treatments 
8.2 
From SD-1 
 
 
 
 
 
 
 
 
Clinical 
assessments 
- Vital signs 
8.3.1 
X 
X 
X6 
X 
X 
X 
X6 
X 
X7 
- Physical examination8 
8.3.2 
X 
X 
 
X 
X 
X 
 
X 
X 
- MAS clinical signs and symptoms 
8.3.3 
 
 
 
 
 
 
 
 
X 
Laboratory 
assessments 
- CBC 
8.4 
X 
X 
 
X 
X 
X 
 
X 
X 
- Lymphocyte subset  
8.4 
X 
 
 
 
 
 
 
 
 
- Coagulation (aPTT, PT, D-Dimers, 
Fibrinogen)  
8.4 
X 
X 
 
X 
X 
X 
 
X 
X 
- Biochemistry 
8.4 
X 
X 
 
X 
X 
X 
 
X 
X 
- Serum pregnancy test (if applicable) 
8.4 
X 
 
 
 
 
 
 
 
 
- Urinalysis 
8.4 
X 
X9 
 
 
 
 
 
 
 
Search for 
infections 
- Mycobacterium Tuberculosis 
8.5 
X 
 
 
 
 
 
 
 
X10 
- Atypical mycobacteria, Shigella, 
Salmonella, Campylobacter, 
Leishmania, Histoplasma Capsulatum 
8.5 
X 
 
 
 
 
 
 
 
 
- EBV, CMV, Adenoviruses 
8.5 
X 
 
 
 
 
 
 
 
X10 
- HSV, HZV, HIV, HBV, HCV 
8.5 
X 
 
 
 
 
 
 
 
 
Procedure 
- ECG 
8.7.1 
X11 
 
X 
 
 
 
 
 
 
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CONFIDENTIAL 
Assessments 
 
Protocol 
Section 
Screening (up to 
one week prior to 
1st infusion)  
SD0 
 Infusion #11 
SD1 
SD2 
SD3 
 Infusion #22 
SD5 
SD6 to SD283 
Infusion/Efficacy/ 
Safety visits  
 
SD-1 
pre 
post 
 
 
pre 
post 
 
 
Imaging 
- Abdominal Ultrasound 
8.6.1 
X 
 
 
 
 
 
 
 
X10 
 
- Chest X-ray 
8.6.2 
X 
 
 
 
 
 
 
 
X10 
 
- Brain MRI12 
8.6.3 
X 
 
 
 
 
 
 
 
 
Histopathology 
- CSF analysis (if coagulation allows) 12 
8.7.2 
X 
 
 
 
 
 
 
 
 
PK  
- NI-0501 serum concentration 
8.8.1 
 
X 
X 
X 
X 
X 
X 
X 
X13 
PD 1 
- IFN, CXCL9, CXCL10, sCD25 
8.8.2 
 
X 
X14 
X 
X 
X 
 
X 
X 
PD 2 
- Other biomarkers 
8.8.2 
 
X 
 
 
 
 
 
 
X 
Immunogenicity (ADA) 
8.8.3 
 
X 
 
 
 
 
 
 
 
1 Start of NI-0501 treatment: loading dose of 6 mg/kg. 
2 Continuation of NI-0501 treatment: 3 mg/kg every 3 days from SD3 onwards until SD15, and twice-a-week thereafter. 
3 After a minimum of two infusions at the dose of 3 mg/kg (i.e. after SD6), NI-0501 treatment may be shortened as per Investigator’s decision upon achievement of a complete clinical response  
  (i.e. MAS remission).  In this circumstance, efficacy/safety visits have to be in any case performed according to the same schedule until (and including) SD28.  
4 Hospitalization: please note that the patients can be discharged from SD15 if their conditions allow, provided that there is no active infections requiring i.v. antimicrobial therapy. 
5 Include molecular and functional tests relevant to the diagnosis of primary HLH.  
6 Continuous monitoring of HR and SpO2 as well as body temperature and BP recording at regular time points (see Section 8.3.1) 
7 If NI-0501 infusions are performed, HR, BP, SpO2, body temperature are to be measured pre-, during, and post-dose (see Section 8.3.1).  
8 Body weight to be recorded prior to infusion and every 2 weeks during the evaluation period for patients weighing less than 10 kg, and every 2 weeks throughout the study for patients weighing  
   more than 10 kg. 
9 If not performed at screening. 
10 Abdominal US and Search for infection to be performed on SD15 and SD28; chest X-ray on SD28 only. 
11 At screening, three consecutive recordings are required in order to obtain a stable baseline.  
12 Brain MRI & CSF analysis: to be performed in case of neurological involvement prior to NI-0501 initiation (or at the latest by SD6 for brain MRI), whenever possible. 
13 When NI-0501 is administered, PK samples have to be taken before and after the infusion. 
14 Total IFNonly.  
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Table 2 – Schedule of assessment: Evaluation period - from SD28 to SD56 (End of Study) 
Assessments 
 
SD35 
1st Week 
Follow-up 
SD42 
2nd Week 
Follow-up 
SD49 
3rd Week 
Follow-up 
SD561 
4th  Week 
Follow-up – 
EoS2 
Unscheduled 
Visit (UV)3 
Hospitalization4 
8.1 
 
 
 
 
 
Concomitant medication (including information on glucocorticoid tapering) 
8.2 
X 
X 
X 
X 
 
Clinical 
assessments 
- Vital signs 
8.3.1 
X 
X 
X 
X 
X 
- Physical examination 
8.3.2 
X 
X 
X 
X 
X 
 
- MAS clinical signs and symptoms 
8.3.3 
X 
X 
X 
X 
 
Laboratory 
assessments 
- CBC 
8.4 
X 
X 
X 
X 
 
- Lymphocyte subset  
8.4 
 
 
 
X 
 
- Coagulation (aPTT, PT, D-Dimers, Fibrinogen)  
8.4 
X 
X 
X 
X 
 
- Biochemistry 
8.4 
X 
X 
X 
X 
 
- Serum pregnancy test 
8.4 
 
 
 
X 
 
- Urinalysis 
8.4 
 
 
 
X 
 
Search for 
infections 
- Mycobacterium Tuberculosis 
8.5 
 
X 
 
X 
 
- EBV, CMV, Adenoviruses 
8.5 
 
X 
 
X 
 
Procedure 
- ECG 
8.7.1 
 
 
 
X 
 
Imaging 
- Abdominal US 
8.6.1 
 
X 
 
X 
 
 
- Chest X-ray 
8.6.2 
 
 
 
X 
 
 
- Brain MRI5 
8.6.3 
 
 
 
X 
 
Histopathology 
- CSF analysis (if coagulation allows)5 
8.7.2 
 
 
 
X 
 
PK  
- NI-0501 serum concentration 
8.8.1 
X 
X 
X 
X 
 
PD 1 
- IFN, CXCL9, CXCL10, sCD25 
8.8.2 
X 
X 
X 
X 
 
PD 2 
- Other biomarkers 
8.8.2 
 
X 
 
X 
 
Immunogenicity (ADA) 
8.8.3 
 
 
 
X 
 
1 If NI-0501 treatment needs to be prolonged beyond 4 weeks, additional weekly visits must be scheduled as appropriate in order to complete the required short-term 4-week follow-up. 
2 The same procedures described for End of Study Visit should be followed for any patient who is withdrawn prematurely from the study (see protocol Section 8.9) 
3 Unscheduled Visit: depending on the reason for UV, additional assessments may be added according to the Investigator’s clinical judgment (see protocol Section 8.10).  
4 Hospitalization: please note that the patients can be discharged from SD15 if their conditions allow, provided that there is no active infections requiring i.v. antimicrobial therapy.   
5 Brain MRI & CSF analysis: to be performed in case of neurological symptoms occurrence, whenever possible. If brain MRI and CSF analysis were done at screening, an End of Study exam should be  
  performed, whenever possible. 
 
 
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8.3 
CLINICAL ASSESSMENTS 
8.3.1 Vital signs  
Vital signs include measurement of body temperature, heart rate, blood pressure and oxygen saturation. 
Body temperature will be recorded in the morning of visit days as indicated in the SoA. 
On the day of NI-0501 infusion, heart rate and oxygen saturation will be recorded before and 
continuously monitored after the infusion (for 24 hours if the patient is hospitalized, and for 4 hours if 
patient is an outpatient).  
Body temperature and blood pressure will be recorded before and at regular intervals after NI-0501 
infusion as follows: 
- 
at the first infusion, every hour during the first 4 hours post-dose, and every 4 hours thereafter to 
cover a 24-hour monitoring period 
- 
at all other infusions, every hour during the first 4 hours post-dose (if no safety concerns have 
emerged after the first infusion).  
Blood pressure, heart rate and oxygen saturation will be measured every 15 minutes during NI-0501 
infusion. 
8.3.2 Physical examination 
A complete physical examination will be performed at screening and at each study visit (before the 
infusion when NI-0501 is administered).  
Physical examination prior to each infusion may be performed in the late afternoon of the previous day 
instead of the morning of the infusion (the data will be captured on the infusion day of the CRF). 
At screening height (in cm), weight (in kg) and Body Surface Area (BSA) as calculated by the site will be 
recorded. 
Subsequent physical examinations will include i) recording of body weight prior to infusion and every 
2 weeks during the evaluation period for patients weighing less than 10 kg for patients weighing more 
than 10 kg, weight will be measured every 2 weeks throughout the study; ii) abdominal palpation for 
assessment of liver and spleen size (in cm from costal grill); iii) follow-up of any abnormalities 
previously recorded as well as occurrence of new signs and symptoms. 
8.3.3 MAS clinical signs and symptoms  
The Investigator will be asked to provide his assessment of improvement/resolution of MAS signs and 
symptoms at the study timepoints indicated in the SoA. 
 
8.4 
LABORATORY ASSESSMENTS 
Blood and urine laboratory analyses are part of the routine monitoring of MAS patients, thus samples will 
be analyzed locally. Analyses done on blood samples will favor as much as possible the use of micro-
sampling techniques. 
If additional safety laboratory samples are required for safety reasons, the number of samples will take 
into account the weight and health status of the patient. 
Laboratory assessments will be performed at each study visit and will include: 
 
Hematology:  complete blood cell count (CBC) with differential count, a dedicated lymphocyte 
subsets count (at screening and EoS visit), and platelets. 
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 
Biochemistry: Ferritin, Triglycerides, C-Reactive Protein (CRP), Aspartate Aminotransferase 
(AST), Alanine Aminotransferase (ALT), gamma Glutamyl Transferase (γGT), Alkaline 
Phosphatase (ALP), Lactate Dehydrogenase (LDH), total bilirubin, glucose, electrolytes, 
albumin, creatinine, Blood Urea Nitrogen (BUN).  
 
Coagulation tests: activated partial thromboplastin (aPTT), prothrombin time (PT), D-dimers and 
fibrinogen. 
 
Urinalysis: glucose, blood, protein, leucocytes, ketones, pH and specific gravity. On SD0, 
urinalysis will be performed before NI-0501 infusion (only if not already performed at 
screening). Urinalysis will be repeated at EoS.  
 
Serum pregnancy test (if applicable) at screening and EoS. Additional pregnancy tests will be 
performed upon suspicion of pregnancy or as mandated by local regulations, as long as NI-0501 
serum concentrations are detectable. 
8.5 
SEARCH FOR INFECTIONS 
Search for infections that represent exclusion criteria include the following pathogens: 
 Mycobacterium Tuberculosis  
At screening, it will be performed via IFNγ-release assay or PPD test. In addition, a baseline via 
polymerase chain reaction [PCR] in a relevant specimen (e.g., urine or blood, if sputum is not 
easily obtained) has to be obtained, as this test will be used during the course of the study to 
perform regular TB monitoring.    
After initiation of NI-0501 treatment, search for TB via PCR has to be performed every 2 weeks 
as long as NI-0501 is detectable in serum.  
In the case of a patient having received BCG vaccination, a PPD test must be performed and 
combined with an IFNγ-release assay. 
 Atypical mycobacteria, Shigella, Salmonella, Campylobacter, Histoplasma Capsulatum and 
Leishmania  
Search for all these pathogens have to be performed at screening. During the study, search for 
these pathogens has to be performed if there is any suspicion of infection. 
A first screening for Histoplasma Capsulatum may be performed using galactomannan assay, 
however if the test is positive, confirmation should be obtained by using a Histoplasma 
Capsulatum specific test. The presence of Leishmania can be ascertained by direct bone marrow 
observation. 
In addition, search for the following infections is required:  
 Herpes Simplex Virus (HSV), Herpes Zoster Virus (HZV), Hepatitis B Virus (HBV), Hepatitis C 
Virus (HCV), Human Immune Deficiency Virus (HIV) by PCR monitoring or serology, at 
screening and whenever there is a suspicion of infection. 
 EBV, CMV, Adenoviruses by quantitative PCR, at screening and every 2 weeks as long as NI-
0501 is detectable in serum. 
A patient with a clinical assessment (including chest X-ray) not indicative of the presence of an active 
infection, provided that a usable specimen has been taken and the microbiological analysis is ongoing, 
can be enrolled prior to the availability of the results, if the patient’s clinical conditions require a rapid 
initiation of NI-0501 treatment. 
 
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8.6 
IMAGING 
8.6.1 Abdominal ultrasound 
Abdominal ultrasounds, including liver and spleen (longitudinal) measurements, will be performed at 
screening and every 2 weeks during the study. 
8.6.2 Chest X-ray 
Chest X-ray will be performed as a measure for detection of pulmonary infections at screening and every 
4 weeks during the study. Chest X-ray should be done more frequently in case of clinical suspicion of a 
pulmonary infection. 
8.6.3 Brain MRI 
Brain MRI should be performed in case of neurological symptoms occurrence, prior to NI-0501 initiation 
(or at latest by SD6), and repeated at the end of the study, whenever possible. 
 
8.7 
OTHER PROCEDURES 
8.7.1 ECG 
12-lead ECG will be performed and interpreted locally by the Investigator or delegate for immediate 
clinical assessment.  
At screening, triplicate ECG (three consecutive recordings) is required in order to obtain a stable 
baseline. 
ECG is mandatory at screening, after the first NI-0501 infusion, and at the end of the study, however it 
should also be performed whenever required based on clinical judgment. 
As part of the regulatory requirements for the overall assessment of NI-0501 safety profile, ECGs will be 
sent for evaluation to a central laboratory designated by Novimmune, and results fully described in the 
Clinical Study Report. 
8.7.2 Cerebrospinal fluid assessment 
Lumbar puncture for CSF analysis should be done in case of neurological symptoms occurrence, 
whenever possible and if coagulation parameters allow, prior to NI-0501 initiation, during the course of 
the study and at the end of the study, as clinically indicated.  
 
8.8 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS  
8.8.1 Pharmacokinetics 
Serum samples for PK analysis will be collected at the visits indicated in the SoA (Table 1 and Table 2). 
In case of need for prioritization of blood analysis (considering weight and health status of the patient), 
laboratory safety parameters (which would be done as normal disease monitoring) may need to be 
prioritized over samples for PK assessments, that in turn will be prioritized over biomarkers exploratory 
parameters. 
On the days of infusion, PK samples should be collected before and after (between 15 and 30 minutes 
after) the infusion.   
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After the first NI-0501 infusion, PK samples will be also collected on SD1 (around 24 hrs. post- infusion) 
and SD2 (around 48 hrs. post-infusion). Additionally, PK samples will be collected on SD5 (around 48 
hrs. after the second NI-0501 infusion). 
After completion of NI-0501 infusions, samples for PK assessment will be collected until serum NI-0501 
concentration are no longer detectable (or until consent is withdrawn), as indicated in the SoA until the 
EoS visit, and subsequently as described in Section 3.4. 
In case of CNS involvement, if lumbar puncture is performed for diagnostic and/or therapeutic purposes, 
PK analysis in CSF samples may be performed. 
Details on sample preparation and handling will be described in a separate laboratory manual. 
8.8.2 Pharmacodynamics 
Serum samples for PD analysis will be collected at the visits indicated in the SoA (Table 1 and Table 2).  
In case of need for prioritization of blood analysis (considering weight and health status of the patient), 
laboratory safety parameters and PK assessments will be prioritized over biomarkers exploratory 
parameters. 
Pharmacodynamics assessments include the measurement of: 
 Free IFN levels prior to NI-0501 treatment start, and total IFNγ (free IFNγ+bound to NI-0501) 
during NI-0501 treatment. Samples for total IFNγ measurements will be taken pre-dose on 
infusion visits, except for the first infusion when free IFN will be measured pre-dose and total 
IFNγ post-dose.  
 Chemokines known to be induced by IFNγ (CXCL9, CXCL10). On infusion visits, serum 
samples will be collected pre-dose only. 
 Other potential disease biomarkers (e.g. sCD25, sCD163, IL-18, IL-10, IL-6, TNFCXCL11). 
Serum samples will be collected on SD0 and every 2 weeks during the course of the study.   
In case of CNS involvement, if lumbar puncture is performed for diagnostic and/or therapeutic purposes, 
biomarker analysis in CSF samples may be performed. 
Details on sample preparation and handling will be described in a separate laboratory manual. 
8.8.3 Immunogenicity  
Serum samples for the assessment of ADAs will be collected on SD0 (prior to NI-0501 infusion) and at 
the End of Study visit, and in case of suspected loss of activity of NI-0501 during the study. Details on 
sample preparation and handling will be described in a separate laboratory manual. 
 
 
8.9 
WITHDRAWAL VISIT 
The same procedures described for the EoS Visit should be followed by the Investigator for any patient 
who is withdrawn prematurely from the study, as soon as possible after the decision to withdraw is made.  
For patients who withdraw from the study as a result of their own decision or the decision of their 
parent/guardian, the Investigator should contact the patient (or parent/guardian) and ask them to attend a 
withdrawal visit as soon as possible and in any case within 30 days from termination. 
Patients who are withdrawn due to a serious adverse event (SAE) should be followed-up until the 
resolution of the event or until the outcome of the event is known and stable. 
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8.10 UNPLANNED (UNSCHEDULED) VISITS 
Unplanned visits may occur, should the patient need to be assessed or treated for any clinical condition 
that arises during the study. This may include the evaluation and follow-up of AEs, SAEs or laboratory 
tests. The assessments (as detailed in the SoA) should always be performed at minimum, but additional 
evaluations may be added according to the clinical judgment of the Investigator. 
8.10.1 Unplanned Assessments 
Additional samples to assess laboratory parameters and PK/PD may be required for safety reasons and/or 
for a better characterization of the PK/PD profile.  
The number of additional samples taken will depend on the body weight and health status of the patient. 
Sampling schedule will be proposed by the Sponsor and discussed with the Investigator. 
9 
STUDY SCIENTIFIC OVERSIGHT 
A Scientific Steering Committee (SSC) composed of international experts in pediatric rheumatology as 
well as in HLH has been involved in the preparation of study design and protocol writing. 
The SSC is also to be consulted for the composition of the independent Data Monitoring Committee 
(iDMC).  
The SSC will continue to play an advisory role throughout the course of the study, including the support 
to the iDMC oversight, and will perform evaluations of the data to support the Sponsor in the 
interpretation of the results of the study.  
Please refer to Appendix C for full details of membership of the SSC. 
10 SAFETY MONITORING 
10.1 INDEPENDENT DATA MONITORING COMMITTEE 
The iDMC, composed of relevant experts (pediatric rheumatologist, pediatric onco-hematologist with 
experience in HLH, pediatric immunodeficiency/infectious disease specialist, bio-statistician and a 
specialist in ethics), will oversee the study, with particular regard to the evaluation of safety parameters 
and benefit/risk profile of NI-0501, reviewing all data generated on an ongoing basis with the aim to 
ensure that patients are not exposed to unnecessary risks.  Some of the iDMC members have been already 
involved in the oversight of the ongoing NI-0501 studies.  Please refer to Section 10.5.1 for further 
details on the iDMC. 
10.2 DESCRIPTION OF SAFETY PARAMETERS 
Evaluation of NI-0501 tolerability and safety will be based on the following parameters: 

Adverse events (AEs), with special attention being paid to events temporally related to the
infusion of NI-0501 (occurring during the infusions and within 24 hours post infusion) and to the
occurrence of infections

Laboratory parameters, as described in Section 8.4

Vital signs, as described in Section 8.3.1
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 
Physical examination with particular attention paid to evolution of signs and symptoms present at 
baseline, and to any emergent new signs or symptoms (see Section 8.3.2 for more details).  
 
10.3 RECORDING AND REPORTING SAFETY PARAMETERS  
10.3.1  Adverse events 
Adverse events (AEs) are defined as any undesirable experience occurring to a subject during the study, 
whether or not considered related to the IMP. All AEs reported spontaneously by the patients or his/her 
relatives or observed by the Investigator or his staff during the clinical study from the signature of the 
ICF up to and including the EoS visit will be reported on the AE data collection form.   
Medical conditions present at screening (before ICF signature) should be recorded in the medical history 
section of the CRF. 
All AEs will be reported in the appropriate section of the CRF. 
An AE which occurs between start of screening visit (after ICF signature) and start of first IMP 
administration will be considered as a pre-treatment AE.  
Any AE that occurs after the start of the first IMP administration will be considered in the study as 
Treatment Emergent Adverse Event (TEAE). 
However, if a pre-existing medical condition recorded in the medical history worsens (clinically 
significant change in intensity or frequency), it must be recorded as an AE in the CRF and, depending on 
the time of its occurrence, will be considered as a pre-treatment AE or a TEAE. If a medical condition, 
recorded as a pre-treatment AE, worsens it will be recorded in the CRF as a separate TEAE. 
For each AE, the following will be assessed and recorded: intensity, relationship to the IMP, action taken 
regarding the IMP, any treatment received for the event and outcome of AE to date.  
Intensity of AEs will be graded on a three-points scale (mild, moderate, severe) using the modified WHO 
(World Health Organization) toxicity scale (Grade 3 and 4 are considered to be the severe grade). If AE 
severity cannot be assessed by this scale, assessment by the Investigator should be made using the 
following definitions: 
• 
Mild: discomfort noticed but no disruption of normal activity, 
• 
Moderate: discomfort sufficient to reduce or affect normal daily activity, 
• 
Severe: inability to work or perform normal daily activity. 
For a given AE, the assessment of its intensity should reflect the highest grade (on the 3 points scale 
mentioned above) reported during its course (except when the intensity of a pre-treatment AE increases 
after treatment initiation, as indicated above).  
The relationship of the AE to the IMP will be assessed by the Investigator using a “Yes/No” 
classification. A “Yes” relationship infers that there is a reasonable possibility of causal relationship 
between the AE and IMP. The expression “reasonable possibility” is meant to convey that there are facts, 
evidence or arguments to suggest a causal relationship. Conversely, a “No” relationship infers that there 
is no reasonable possibility of causal relationship between the AE and IMP. Usually it implies that other 
possible causes have been identified.  
In this study NI-0501 is the only IMP. 
 
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10.3.2 Serious Adverse Events 
An adverse event is considered serious if it: 

results in death (note: death is an outcome, not an event);

is life-threatening; (note: the term "life-threatening" refers to an event in which the patient
was at immediate risk of death at the time of the event; it does not refer to an event which
could hypothetically have caused a death had it been more severe);

requires in-patient hospitalization or prolongs an existing hospitalization;

results in persistent or significant disability/incapacity;

is a congenital anomaly/birth defect;

is an important medical event that may not result in death, be life-threatening, or require
hospitalization but may be considered serious 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 above. Examples of such medical events include
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of
drug dependency or drug abuse.
For the purposes of this study, the following will not be considered as serious adverse events: 

Elective hospitalizations or surgical procedures that are a result of a patient’s pre-existing
condition(s) which has (have) not worsened since receiving IMP. Such events should still be
recorded as adverse events in the eCRF;

Hospitalization as requested per protocol for NI-0501infusion and study visits.
Any serious adverse event (SAE) that occurs during the course of the study, irrespective of the treatment 
received by the subject and regardless of causality to the study drug, must be communicated by the 
Investigator to NovImmune, by fax or electronic transmission, within 24 hours of awareness. 
For the initial SAE report, the Investigator should report all available case details concerning the patient 
and the event, using the Novimmune SAE reporting standard form provided to the Investigators.  
Novimmune contact information for SAE reporting: 
Fax: 
 
E-mail:
Relevant follow-up information on SAEs should be forwarded to Novimmune as soon as it becomes 
available. In addition, the Investigator should answer without delay any request for follow-up information 
or questions Novimmune team may have regarding the reported SAE. 
All SAEs must be recorded as an AE in the CRF. They should be reviewed, evaluated and followed 
through to resolution (or stabilization) by the Investigator. 
For any new SAE, the following minimum information is required in the initial report: 

Clear identification of the Investigator, with full contact information or site number

Subject’s identification details (study number, site number, subject’s unique study identification
number and date of birth),

IMP administration details (dose and dates)
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 
Diagnosis of the event (or a brief description of signs/symptoms/clinical course, if the diagnosis 
is not available) and the date of onset,  
 
Seriousness criteria. 
In addition causal relationship (Investigator’s opinion) of the event with the IMP or with the study 
procedure (e.g. the causality according to the Investigator during screening) should be provided whenever 
possible in this initial report, otherwise it must be included in a follow-up report.  
The Sponsor will also conduct its own assessment on seriousness and causality of all recorded AEs 
during the study. If the Sponsor becomes aware of an AE, which has not been reported by the 
Investigator as serious, but is assessed by the Sponsor as serious (e.g. medically important), the 
Investigator  will be asked to report such AEs to the Sponsor as  an SAE, according to the timelines and 
rules described above.  
10.3.3  SUSAR reporting 
Suspected unexpected serious adverse reactions (SUSARs) are adverse events that are both serious and 
unexpected (i.e. as per the Investigator’s Brochure), and are considered, by the Investigator or the 
Sponsor, to have a reasonable possibility of causal relationship between the administered IMP and the 
adverse event.  
Some of the SAEs reported by the Investigator may qualify as SUSARs, and such need to be reported in 
an expedited manner by the Sponsor to Health Authorities and Central Ethics Committees/Independent 
Ethics Committees/ Research Ethics Boards.  
Under 21 Code of Federal Regulation (CFR) 312.32(c), the Sponsor (directly or through a delegated third 
party) is required to notify the Food and Drug Administration (FDA) and all participating Investigators in 
an IND safety report (i.e., 7- or 15-day expedited report) of potentially serious risks from clinical trials or 
any other source as soon as possible, but no later than 15 calendar days after the Sponsor receives the 
safety information and determines that the information qualifies for reporting. 
Investigators in the US are required to promptly report to the IRB all unanticipated problems involving 
risk to human subjects or others, including AEs that should be considered unanticipated problems (21 
CFR 312.66), such as IND safety reports. 
For Canada, the sponsor is required to inform Health Canada of any serious, unexpected adverse drug 
reaction that has occurred inside or outside Canada. An adverse drug report must be filed in the cases 
where the adverse drug reaction is neither fatal nor life-threatening, within 15 days after becoming aware 
of the information, within 7 days where it is fatal or life-threatening, immediately where possible and, in 
any event, after becoming aware of the information. 
 
10.3.4  Managing Abnormal Laboratory Test Values  
Abnormal safety test values should not be reported as AEs unless specific treatment is given for the 
abnormality (e.g. a blood transfusion is given for a low haemoglobin) or a laboratory abnormality leads to 
further investigation and the diagnosis of a new clinical event (e.g. a high white blood cell count is found 
to be due to incidental leukaemia). In this latter event, the clinical diagnosis should be reported on the AE 
form, not the laboratory abnormality leading to the diagnosis. Clinically significant abnormal laboratory 
test value can be qualified as important medical events (see Section 10.3.2) and should then follow the 
process described in this section. 
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10.4 FOLLOW-UP OF SAFETY PARAMETERS 
10.4.1  Treatment and Follow-up of Adverse Events 
Adverse events, especially those for which the relationship to the study drug has been assessed as ‘Yes’, 
should be followed-up until the event has returned to baseline status or has stabilised. If a clear 
explanation is established, it should be recorded on the CRF. 
All SAEs must be followed-up until the event has either resolved or reached a stable clinical outcome. 
10.4.2  Follow-up of Abnormal Laboratory Test Values 
In the event of unexplained clinically relevant abnormal laboratory test values, the tests should be 
repeated immediately and followed-up until the values have returned to within normal range and/or an 
adequate explanation of the abnormality is found. If a clear explanation is established, it should be 
recorded on the eCRF. 
10.4.3  Pregnancy 
In the event that a pregnancy occurs during the trial course, it must be reported to Novimmune within 24 
hours of awareness. This includes pregnancies occurring in partners of male enrolled patients. All 
information pertaining to the pregnancy should be reported using the Novimmune Pregnancy form 
provided to the investigators. Pregnancies should be followed until conclusion to obtain outcome 
information. 
Occurrence of a pregnancy in a study participant will preclude any further IMP administration.  
If the patient is withdrawn from the study, the assessments presented in the Schedule of Assessments for 
EoS are to be performed (see Section 8.9). 
10.5 BENEFIT/RISK MANAGEMENT 
10.5.1 Safety Surveillance Management 
The main responsibility of the DMC is to review all safety and efficacy data as they are generated to 
ensure that no patient is exposed to unnecessary risk and to continuously assess the benefit/risk profile of 
NI-0501. 
The DMC can recommend treatment discontinuation for individual patients as well as to halt the entire 
study temporarily or permanently. Predefined stopping rules will guide the DMC review process. For 
more details, see stopping rules in Section 11. 
10.5.2  General Benefit/Risk Considerations  
10.5.2.1 Potential benefits 
Patients presenting MAS secondary to sJIA may not respond to systemic glucocorticoids and have 
limited alternative therapeutic options. These options are represented by prolonged treatment with high 
doses glucocorticoids, and administration of CsA or chemotherapy such as etoposide, all options carrying 
an increased risk of morbidity and mortality. For those non-responders patients, an alternate therapy 
should aim to obtain remission of MAS with none or limited safety issues.   
Three elements strongly suggest that the use of NI-0501 would enable MAS remission: 
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- In animal model mimicking MAS, administration of an anti-IFNγ enables the recovery/remission of 
the signs and symptoms associated with hypercytokinemia  
- Observational studies have shown a strong correlation between biomarkers (IFNγ as well as IFNγ- 
induced chemokines) and disease parameters at MAS onset and during disease evolution. 
According to the data collected to date in pHLH patients (ongoing NI-0501-04 study), NI-0501 
administration has shown the potential to improve or resolve relevant clinical and laboratory 
abnormalities of HLH, including CNS signs and symptoms when present, allowing patients to proceed to 
HSCT.  
For more details refer to the latest Investigator’s Brochure. 
Based on these considerations, sJIA patients with MAS having inadequately responded to systemic high 
dose glucocorticoids are expected to benefit from a targeted therapy with NI-0501 aiming at neutralizing 
IFNγ and achieving MAS remission.  
10.5.2.2 Risks analysis 
 
Risks related to NI-0501  
NI-0501 is a fully human IgG1monoclonal antibody (mAb). 
Upon the administration of mAbs, which are proteins, acute infusion reactions can occur. These may 
happen during the infusion or in the subsequent hours (usually within the first 24 hours)43,44.  
These reactions are either IgE-mediated type I hypersensitivity reactions (anaphylactic reactions), or 
anaphylactoid reactions not mediated by IgE. True anaphylactic reactions usually do not occur upon 
initial infusion and require a certain sensitization. In contrast, the pathophysiology of anaphylactoid 
reactions appears to be secondary to the release of cytokines consequent to a mAb binding to circulating 
antigen-expressing cells. However, the clinical manifestations of anaphylactic and anaphylactoid 
reactions overlap, and both may lead to life-threatening conditions, involving cardiovascular, respiratory, 
central nervous, gastro-intestinal, and cutaneous systems. The management of anaphylactic and 
anaphylactoid reactions involves immediate administration of oxygen, epinephrine, vasopressors, 
bronchodilators, corticosteroids, and/or antihistamines.  
More than 850 infusions have been administered to HLH patients (either in the context of the NI-0501-04 
and NI-0501-05 studies or in patients who have received NI-0501 in compassionate use) up to and 
including the dose of 10 mg/kg, without any serious or severe infusion related reaction reported. In less 
than 2% of infusions, mild or moderate transient erythematous rashes localized to the extremities (feet 
and/or hands) have been reported in a few patients. They occurred in most of the cases during the first 
infusions of NI-0501 and resolved spontaneously. When administration of NI-0501 has been performed 
occasionally through a peripheral venous access, infusions were all uneventful.  
In the population intended to be enrolled in the study, the risk of developing infusion related reactions 
compared to previously exposed HLH patients is not expected to be higher. All patients enrolled in this 
study will continue to receive glucocorticoids concomitantly, and will be monitored during and after the 
infusion. 
When administered to humans, most mAb therapeutics elicit some level of antibody response (anti-drug 
antibodies or ADAs) against the therapeutic product, as early as after the first exposure. No sign of 
immunogenicity has been reported in the NI-0501 study in healthy volunteers. The presence of ADAs 
will be measured during this study as per regulatory recommendations, and the analysis is planned to be 
performed at the end of the NI-0501-06 study, unless PK or safety concerns possibly related to 
immunogenicity would justify an interim analysis.  Data accumulated so far (in particular PK profiles and 
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a negative ADA search performed in the first pHLH patient treated with NI-0501) have not led to suspect 
the presence of ADA. 
 
Risks related to the target 
The impact on the immune defense caused by the neutralization of IFNγ is known from patients with 
inborn errors of the IL-12/23-IFN-γ circuit, particularly patients with complete or partial IFNγ receptor 
(R) deficiency, and subjects developing neutralizing auto anti-IFNγ antibodies. 
Patients with IFNγ R deficiency are prone to developing mycobacterial infections and, although to a 
lesser extent, Salmonella infections45,46. The mean age of the first environmental mycobacterial infection 
is 3.1 and 13.4 years in patients with complete and partial deficiency, respectively47. No systematic 
prophylaxis has been recommended in these patients. 
If an infection occurs, appropriate antibiotherapy based on sensitivity of isolated species is prescribed. 
Individuals with anti-IFNγ auto-antibodies are also susceptible to develop mycobacterial infections (for 
the vast majority atypical mycobacterial infections), but also opportunistic infections (e.g. by 
Histoplasma Capsulatum, Salmonella, Herpes Zoster virus infections)4.   
Toxicological studies carried out with NI-0501 have shown an increased susceptibility of the monkeys 
having received NI-0501 to enteral pathogen infections when the pathogen is present into the intestinal 
tract prior to NI-0501 administration. Presence of infections due to Shigella, Salmonella and 
Campylobacter is part of the exclusion criteria. 
A reactivation of Herpes Zoster virus after the single NI-0501 infusion at 3 mg/kg, was observed in one 
healthy volunteer in the NI-0510-03 study with a non-uneventful course and full recovery.   
Preliminary data on infections collected in patients treated with NI-0501 to date allow the following 
conclusions to be drawn:   
- Active infections, in particular bacterial and viral infections (among them EBV or CMV infections, 
which are often the trigger of the HLH), were present at the first administration of NI-0501in some of 
them. During NI-0501 administration these infections resolved with appropriate antimicrobial 
treatment and while achieving control of HLH. 
- Some HLH patients treated in second line after immune-chemotherapy developed infections during 
the course of NI-0501 treatment. A long and profound generalized immune suppression caused by 
HLH treatments administered prior to the initiation of NI-0501 constitutes a higher risk for infection 
development. However in the presence of a satisfactory control of HLH, and upon appropriate anti-
microbial treatment, infections have usually resolved. 
- Patients treated in first line or after a limited exposure to glucocorticoids or chemotherapy seem to 
develop less infections during the course of NI-0501.  
- Systematic search for tuberculosis was negative and no atypical mycobacteria were detected in any of 
the patients. Stool/blood cultures were negative for Salmonella, Shigella or Campylobacter in all 
patients. No Herpes Zoster infection has been reported. 
- Only one infection reported (disseminated histoplasmosis in a patient with a severely compromised 
immune status and suspected to carry the pathogen prior to the administration of NI-0501) was 
reported as a serious adverse reaction as it is one of the few pathogens known to be favored by IFNγ 
neutralization. However the patient recovered from it rapidly after the administration of an effective 
antifungal treatment. 
- The severity and duration of neutropenia, a hallmark of HLH as well as a potential consequence of 
previous HLH treatments, seemed to contribute significantly to the development of infections. 
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For more details refer to the latest Investigator’s Brochure.  
 
Risk related to the study population 
Most of the patients are expected to have already received at least glucocorticoid treatments as well as 
having possibly been previously treated by sJIA specific therapies, some of them for a relatively long 
time depending on the duration of their underlying rheumatic disease; therefore they may carry variable 
degree of toxicities caused by those treatments. The data collected to date in pHLH patients who have 
been heavily pretreated by immune-chemotherapy show that administration of NI-0501 does not 
aggravate toxicities of previous therapies while showing, in general, a favorable impact on HLH activity.  
All information collected on disease severity and previous treatments will be taken into account for the 
analysis of adverse events.  
Toxicities of concomitant treatments, authorized or recommended during the administration of NI-0501, 
may also potentially expose the patients to adverse events; however their benefits may outweigh their 
risks. No safety concern related to the concomitant administration of NI-0501 with other treatments (e.g., 
antimicrobial agents, anti-hypertensive drugs) has been reported so far. Corticosteroids have already been 
administered with anti-IFNγ therapy in Crohn’s Disease without any particular safety concerns48. Of 
interest, tapering of glucocorticoids had no impact on safety and tolerability of NI-0501 infusions and has 
shown benefit for patients with steroids-related hypertension and generalized immunosuppression. 
Although the risk that the NI-0501 treatment will not be able to control the disease may exist, the close 
monitoring and the stopping rules of the study ensure that, in this event, NI-0501 treatment will be 
discontinued and the patients will rapidly receive rescue treatments according to the standard clinical 
practice at the participating sites. The risks of administering alternate therapy after having received NI-
0501 seems to be low, since no particular safety concerns were observed during treatment with NI-0501. 
10.5.2.3 Risk minimization measures 
In view of the expected benefits and previous experience gathered with patients exposed to NI-0501 the 
above listed risks are considered to be manageable in this patient population, if adequate minimization 
measures are put in place. An overview of specific measures to minimize the subject’s risk is provided 
below: 
 
Study designed with rheumatologists experienced in the treatment of sJIA and MAS, forming 
the SSC. 
 
Patients are hospitalized in specialized centers for the treatment of MAS, and therefore with 
all necessary emergency assistance equipment. 
 
Inclusion/exclusion criteria: patients with malformations or severely altered functions (either 
due to the disease stage or to a concomitant disease), as well as patients with evidence of 
patent or latent TB infections or active mycobacteria, Shigella, Salmonella, Campylobacter,  
Histoplasma Capsulatum or Leishmania infections, will not be included in the study (for 
details see Section 4.1).  
 
Although unlikely to be observed based on preliminary results gathered from patients treated 
with NI-0501 up to 10mg/kg, Infusion Related Reactions (IRRs) will be detected and 
managed in due time through patients’ monitoring during and after drug infusions. Each of 
the specialized centers will have physicians adequately trained in IRR management. 
 
Recommendations on prophylaxis for Herpes Zoster virus for all patients and Tuberculosis 
for a defined subpopulation (see Section 6.2) in the protocol to avoid occurrence of these 
infections. 
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 
The monitoring for specific infections, known to be favored by IFNɣ neutralization, will 
continue after NI-0501 discontinuation as long as serum NI-0501 levels are detectable. 
 
Close monitoring of potential infections through careful physical examination, laboratory 
parameters, active search for EBV, CMV, Adenoviruses, detection of tuberculosis  
 
Study safety surveillance by an independent Data Monitoring Committee 
The Development Risk Management Plan addresses risks, identify signals for early detection of safety 
concerns and propose mitigating actions. It will be part of the study documentation shared with 
Investigators and any relevant third party involved in the study. 
Stopping rules have been also developed to ensure individual patient safety and determine whether the 
study should be put on hold or terminated prematurely. 
11 STOPPING RULES 
11.1 AT PATIENT LEVEL 
11.1.1 Investigator’s or Patient’s Decision to Discontinue 
An Investigator can decide at any time during the study to discontinue the treatment for an individual 
patient based on his/her own medical judgment, taking into account the individual benefit risk ratio for 
his/her patient. In addition, the patient (or their legal representative) can decide at any time to withdraw 
from the study.  
In any case the decision to withdraw or be withdrawn will have no impact on the patient’s care and 
further treatments administered to him/her after withdrawal.  
Patients who are withdrawn from the study will receive alternative treatments according to the standard 
of care at the site. 
 
11.1.2 Decision to Discontinue Treatment due to Safety Reason or Lack of Efficacy 
11.1.2.1 Treatment Discontinuation for a Safety Reason 
A patient must be discontinued from study treatment if a SAE occurring after NI-0501 administration is: 
1. considered by the Investigator to be related to NI-0501 (with guidance from the iDMC if needed)  
AND 
2. is a life-threatening event. 
All other AEs will be judged by the DMC on a case-by-case basis taking into account the disease 
evolution (such as signs of improvement in HLH) and the possibility of managing the AE and ensuring 
that no patient is exposed to unnecessary risks. 
11.1.2.2  Treatment Discontinuation for Lack of Efficacy 
A patient should be discontinued from study treatment for lack of efficacy in the event of any of the 
followings: 
- Rapid worsening of MAS representing immediate risk for the patient and requiring the use 
of a salvage therapy.   
- No Response to NI-0501, provided that there is evidence of IFNg neutralization. 
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However, upon request by the Investigator to continue NI-0501 treatment in the absence of therapeutic 
alternatives, the iDMC can authorize it after a thorough review of the patient’s data and confirmation of 
lack of risks for the patient.  
 
11.1.3 Systemic and local reaction to NI-0501 infusion 
In case of clinical relevant changes in vital signs compared to pre-infusion values, the rate of NI-0501 
infusion may be decreased or the infusion temporarily interrupted, if deemed necessary by the 
Investigator.  
A decision to definitely stop the infusion should only be taken in case of very severe systemic reactions 
and be based on the evolution of patient status after appropriate symptomatic measures, e.g. oxygenation, 
and upon physician’s own medical judgment.  
All changes in the infusion rate should be recorded on the Infusion Worksheet: each time with the rate 
modification.  
Unless related to a hypersensitivity reaction, the occurrence of local issues related to the infusion (such as 
catheter displacement, obstruction or product extravasation) should be managed through the identification 
of a new venous access as soon as possible to complete the infusion. All relevant information needs to be 
recorded in the Infusion Worksheet, including the volume of IMP potentially lost (in order to calculate 
the quantity of drug infused), and the time at which the infusion was stopped and restarted.  
 
11.2 AT STUDY LEVEL 
11.2.1 Suspension of Recruitment 
Recruitment may be suspended in the following situations: 
 
Any occurrence of death or life-threatening SAE related to the drug  
 
At the iDMC’s own request as an outcome of their regular study review. 
Patients already enrolled in the study should continue receiving NI-0501 as per protocol unless decided 
otherwise by the Investigator. 
The suspension will allow the iDMC to analyse the data already generated and consider a 
recommendation. 
After re-evaluation of benefit/risk profile, the iDMC may recommend any of the following:  
 
To resume recruitment without any change 
 
To implement minimisation measures that may require protocol amendment 
 
To implement conditions for study termination, e.g. next occurrence of a particular serious drug 
reaction or at the next patient worsening or reactivation 
11.2.2 Study Termination 
11.2.2.1  Study Termination for Safety Reason 
Occurrence of two deaths suggesting a reasonably possible relationship with continuous exposure to NI-
0501 and occurring in similar conditions will trigger the decision to terminate the study. 
This process will involve both the DMC and the Investigator. The management of patients already 
enrolled in the study will also be part of the DMC recommendations. 
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11.2.2.2 Study Termination for Absence of a Demonstrated Benefit  
The decision to terminate the study due to absence of a demonstrated benefit will be one of the 
responsibilities of the iDMC, based on the ongoing review of the individual patient data and benefit/risk 
analysis. 
In case of study termination, the management of the patients already enrolled in the study will also be 
part of the iDMC recommendations. 
12 STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
Full details of all planned analyses will be specified in separate documents describing PK/PD and 
Statistical Analyses, which will be finalized prior to the locking of the study database. This section 
contains an overview of the planned methods of analysis with regard to safety and efficacy variables. 
12.1 SAMPLE SIZE   
The sample size of 5 patients is based on pragmatic considerations, and on the experience acquired from 
primary HLH patients treated with NI-0501. 
12.2 ANALYSIS SETS   
All analysis sets will be defined prior to final database closure. In addition to the analysis sets listed 
below, further exploratory analyses may be performed using other subgroups of patients. 
12.2.1 Safety Analysis Set 
The safety analysis set will include all patients who receive any part of an infusion of study drug. 
12.2.2 Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will coincide with the Safety Analysis Set. 
12.2.3 Per-Protocol Analysis Set 
The per-protocol analysis set will consist of all ITT patients who complete the study without major 
violations of the study protocol. Detailed listing of major protocol deviations will be defined in the SAP 
prior to locking of the final database.  
12.3 STATISTICAL AND ANALYTICAL METHODS  
For measurements of continuous endpoints, summary statistics will include n, mean, median, standard 
deviation, minimum and maximum values. For binary data (proportions of patients showing a defined 
variable) the numbers and percentages will be tabulated.  
All study variables are considered to be exploratory in this study, and no hierarchy of endpoints has been 
specified, as the objective of this pilot study is to confirm that the proposed dose regimen is adequate in 
this patient population. 
Analysis will focus on descriptive statistics and confidence intervals. As this is a pilot study, statistical 
methods will focus on summarizing the data collected using descriptive statistics and on appropriate 
graphical presentations. 
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12.3.1 Efficacy Data 
Graphical and tabular summaries will be prepared for each of the MAS distinct features, e.g. fever; 
splenomegaly; WBC; platelet counts; liver function test (in particular ALT/AST); fibrinogen; ferritin; 
LDH.  
For binary endpoints (MAS remission by Week 8, number of patients who taper glucocorticoids, number 
of patients who discontinue due to lack of efficacy), 95% confidence intervals will be calculated for 
proportions. 
For time to event endpoints (time to MAS remission, time to achievement of glucocorticoids tapering and 
time to death), Kaplan-Meier curves will be calculated and summary statistics, such as medians, 
proportions event-free at various time points will be calculated and presented, and 95% confidence 
intervals calculated where possible.  
12.3.2 Safety Data 
All data relating to safety will be listed and summarized using descriptive statistics.  
AEs will be coded and tabulated by body system, and by individual events within each body system. AEs 
will also be tabulated by severity and relationship to the study medication. Summaries will also be 
produced of SAEs and AEs leading to withdrawal from the study. 
For each clinical laboratory test, individual patient values will be listed and summarized and change from 
pre-treatment baseline values calculated and summarized. Summaries of marked abnormalities and shift 
tables will be tabulated for each laboratory test. 
In addition, other exploratory analyses of safety data, including summaries for different subsets of 
patients, may be conducted. 
12.3.3 Pharmacodynamic Data 
All PD data will be summarized using appropriate graphical and tabular presentations. 
Exploratory statistical models will be fitted, and correlation analyses undertaken, to investigate the 
relationships between PD data and clinical measures of response. ROC curves may be used to summarize 
any relationships that are found. 
In addition, other exploratory analyses of pharmacodynamic endpoints, including summaries for different 
subsets of patients, may be conducted. 
12.3.4 Immunogenicity Data 
The numbers of patients with anti-drug antibodies present at each assessment point will be summarized. 
12.3.5 Missing Data 
No imputations of missing data will be performed. However, the following rules will be applied to ensure 
that all patients can be included in the final analysis:  
- 
patients who are withdrawn from the study prior to Week 8 because of safety concerns or 
poor efficacy will be classified as non-responders from the time of their withdrawal in all 
analyses of response status, and their data will be censored at time of withdrawal in all time-
to-event analyses. For continuous endpoints in such patients, all analyses for time points 
beyond the point of withdrawal will exclude missing data for these patients. 
 
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12.4 INTERIM ANALYSIS 
No interim analysis is planned. 
 
12.5 WITHDRAWAL AND REPLACEMENT  
12.5.1 Patients 
Additional patients will be recruited into the study if patients are withdrawn from the study for reasons 
other than safety or lack of efficacy to ensure a sample size of a minimum of 5 evaluable patients in 
North America. 
12.5.2 For Centers 
Centers may be closed down for the following administrative reasons: excessively slow recruitment, poor 
protocol adherence.  
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PART II 
13 ETHICAL AND LEGAL ASPECTS 
13.1 GOOD CLINICAL PRACTICE 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and documentation of 
this study are designed to ensure that Novimmune, its authorized representative, and Investigator abide 
by Good Clinical Practice (GCP), as described in International Conference on Harmonization (ICH) 
Guideline E6 and in accordance with the general ethical principles grounded in the Declaration of 
Helsinki. The study will receive approval from an IRB/IEC prior to commencement and where applicable 
by law also from National Competent Authorities. The Investigator will conduct all aspects of this study 
in accordance with applicable national, state, and local laws of the pertinent regulatory authorities. 
13.2 INVESTIGATOR’S RESPONSIBILITIES 
The Investigator must ensure that all persons assisting with the trial are appropriately qualified and 
adequately informed about the protocol, amendments, study treatments, as well as study-related duties 
and functions and should ensure this is appropriately documented in the site file. The Investigator should 
maintain a list of sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties. 
The Investigator is responsible for keeping a record of all patients (or their legally authorised 
representative) who sign an informed consent document and are screened for entry into the study. 
Patients who fail screening must have the reason(s) recorded in their source documents and the study-
screening log. 
The Investigator, or a designated member of the Investigators’ staff, must be available during monitoring 
visits, audits and inspections to review data, resolve queries and allow direct access to patients’ records 
(e.g. medical/hospital records, office charts, hospital charts, and study related charts) for source data and 
other type of verification. The Investigator must ensure timely and accurate completion of CRFs and 
queries. The Investigator must make himself/herself personally available during at least one monitoring 
visit per month, in order to address questions and to generally demonstrate his/her direct oversight of the 
conduct of the study. 
The Investigator must allow regular visits at the site when patients are enrolled, to be not less than one 2 
day visit every 14 days. In addition, the Investigator must ensure that all source data, including but not 
limited to medical records and hospital charts are available for review by the monitor for at least 30 days 
after a study day. 
13.3 CONSENT 
Before being admitted to the clinical study, the patient or the patient’s legally authorized representative 
must consent to participate after the nature, scope, and possible consequences of the clinical study have 
been explained in a manner understandable to him or her. An informed consent document that includes 
both information about the study and the consent form will be prepared and given to the patient. This 
document will contain all ICH, GCP, and locally required regulatory elements (whichever is more 
stringent). The informed consent will be translated in a language understandable to the patient, as 
required by local regulations and customs, and must specify who informed the patient, and when the 
informed consent was obtained.  
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Information to patients will be split into a Patient Information Sheet that provides detailed information 
about the trial and its benefits and risks, and the Informed Consent Form that summarises the content of 
the Patient Information Sheet and is used to obtain the dated signature from the patient as evidence of the 
patient’s agreement to partake in the study. 
If applicable, since minors are involved in the trial, assent must be obtained from the minor and informed 
consent from at least one of the parents or as mandated by local rules (individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective patient to the patient’s participation 
in the procedures involved in the research). The language used in the Assent Form is adapted to the 
maturity level of the minor involved in the trial. Since minors of different age groups are likely to be 
entered into the trial different versions of the Assent Form will be provided. The modalities for obtaining 
informed consent from the parents and Assent from the minor will be defined at the site initiation visit 
and documented at the clinical trial center. 
The Investigator, or designee, will obtain consent for participation in the study in writing. The written 
informed consent will be obtained prior to conducting any study-related procedures or tests, although 
procedures or tests that are done as a part of routine medical care and conducted before consent can be 
used for the purposes of screening. The patient’s consent (or the consent of the patient’s legally 
authorized representative) must be confirmed at the time of consent by the personally dated signature of 
the person conducting the informed consent discussions. A copy of the signed consent document must be 
given to the patient or their legally authorized representative. The Investigator will retain the original 
signed consent document.  
If an amended protocol impacts the content of the informed consent document, the consent document 
must be revised. Patients already participating in the study when the amended protocol is implemented 
must be re-consented with the revised version of the informed consent document, if the changes impact 
the continued participation of that patient. A copy of the revised informed consent document must be 
given to the patient or their legally authorised representative. The Investigator will retain the original 
signed updated consent document in the study files. 
13.4 CONFIDENTIALITY AND DATA PRIVACY 
Novimmune affirms the patient's right to protection against invasion of privacy and to be in compliance 
with ICH and other local regulations (whichever is more stringent). Novimmune requires the Investigator 
to permit Novimmune representatives and when necessary, representatives from regulatory authorities, to 
review and/or copy any medical records relevant to the study in accordance with local laws (any copies of 
patients’ records must be duly anonymized to protect patients’ confidentiality). 
Should direct access to medical records require a waiver or authorisation separate from the patient’s 
statement of informed consent, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual. 
13.5 PROTOCOL AMENDMENTS 
Substantial amendments will be submitted to the IRB/IEC for written approval and where applicable to 
National Competent Authorities. Written approval must be obtained before implementation of the 
amended version occurs unless the amendment is implemented to increase safety measures for the 
patients in the study. The written signed approval from the IRB/IEC should specifically reference the 
Principal Investigator’s name, protocol number, study title and amendment number(s) that is/are 
applicable. 
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13.6 APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS 
Before the start of the study, the study protocol, informed consent document, and any other appropriate 
documents will be submitted to the IRB/IEC with a cover letter or a form listing the documents 
submitted, their dates of issue, and the site (or region or area of jurisdiction, as applicable) for which 
approval is sought. If applicable, the documents will also be submitted to the authorities in accordance 
with local legal requirements. 
Novimmune can only supply study drug to an Investigator after Novimmune or their authorised 
representative has received documentation on all ethical and legal requirements for starting the study. 
This documentation must also include a list of the members of the IRB/IEC and their occupation and 
qualifications. If the IRB/IEC will not disclose the names of the committee members, it should be asked 
to issue a statement confirming that the composition of the committee is in accordance with GCP. Formal 
approval by the IRB/IEC should preferably mention the study title, study code, study site, and any other 
documents reviewed. It must mention the date on which the decision was made and must be officially 
signed by a committee member (chairman or secretary of the IRB/IEC). Before the first patient is 
enrolled at a given study site, all ethical and legal requirements must be met. 
The IRB/IEC and, if applicable, the authorities, must be informed of all subsequent protocol amendments 
in accordance with local legal requirements. Amendments must be evaluated to determine whether formal 
approval must be sought and whether the informed consent document should also be revised. 
The Investigator must keep a record of all communication with the IRB/IEC and, if applicable, between a 
coordinating Investigator and the IRB/IEC. This statement also applies to any communication between 
the Investigator (or coordinating Investigator, if applicable) and regulatory authorities. 
All documents handed over to patients or their legal representative will be reviewed by Novimmune prior 
to submission to the competent Regulatory Authorities and to IRB/IEC. This includes but is not limited to 
the informed consent form, patient information sheet, assent form, advertisements, training materials, etc. 
13.7 ONGOING INFORMATION FOR IRB/IEC 
If required by legislation or the IRB/IEC, the investigator must submit to the IRB/IEC: 
 
Information on SAEs or SUSARs as per local applicable rules and timelines;  
 
Periodic reports on the progress of the study; 
 
Deviations from the protocol or anything that may involve added risk to patients. 
13.8 CLOSURE OF THE STUDY 
Novimmune reserves the right to terminate this study at any time for reasonable medical or administrative 
reasons. Any premature discontinuation will be appropriately documented according to local 
requirements (e.g., IRB/IEC, Regulatory Authorities). 
In addition, the Investigator or Novimmune has the right to discontinue a single site at any time during 
the study for medical or administrative reasons such as: 
 
Lack of screening or recruiting activities  
 
Significant non-compliance with contractual enrolment timelines and targets 
 
Persistent GCP non-compliance 
 
Inaccurate, incomplete or delayed data collection 
 
Persistent failure to adhere to the study protocol 
 
Persistent failure to provide requested follow-up information for data queries 
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13.9 RECORD RETENTION 
The investigator will ensure that essential records are kept in a secure archiving facility for the retention 
period stipulated in the study contract. Essential documents include, but are not limited to, the following: 
 
Signed informed consent documents for all patients 
 
Patient identification code list, screening log (if applicable), and enrolment log 
 
Record of all communications between the investigator and the IRB/IEC 
 
Composition of the IRB/IEC 
 
Record of all communications between the investigator, Novimmune and their authorized 
representative 
 
List of sub-investigators and other appropriately qualified persons to whom the investigator has 
delegated significant trial-related duties, together with their roles in the study, curricula vitae and 
their signatures 
 
Copies of CRFs and of documentation of corrections for all patients 
 
Drug accountability records 
 
Record of any body fluids or tissue samples retained 
 
All other source documents (patient records, hospital records, laboratory records, etc.) 
 
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP (Essential 
Documents for the Conduct of a Clinical Trial) 
Normally, these records will be held in the Investigator’s archives. If the Investigator is unable to meet 
this obligation, the Investigator must ask Novimmune for permission to make alternative arrangements. 
Details of these arrangements should be documented in the clinical trial center TMF. 
13.10 LIABILITY AND INSURANCE 
Liability and insurance provisions for this study are provided in the investigator contract. 
13.11 FINANCIAL DISCLOSURE 
Investigators are required to provide financial disclosure information to allow Novimmune to submit 
complete and accurate certification or disclosure statements in accordance with applicable national and 
local regulations. In addition, investigators must provide Novimmune with a commitment to promptly 
update this information if any relevant changes occur during the course of the study and for 1 year 
following the completion of the study. 
13.12 DISCLOSURE OF PROTOCOL AND STUDY RESULTS AND PUBLICATION POLICY 
Information about this trial will be posted following the principles of the International Committee of 
Medical Journal Editors (ICMJE), the International Federation of Pharmaceutical Manufacturers & 
Associations (IFPMA) Industry Position Paper and applicable national or regional regulations and laws.  
The results of this study may be published or presented at scientific meetings. If this is foreseen, the 
Investigator agrees to submit all manuscripts or abstracts to Novimmune prior to submission. This allows 
Novimmune to protect proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
Novimmune will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, Novimmune will support publication of multicenter trials only in 
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their entirety and not as individual center data. In this case, a coordinating investigator will be designated 
by mutual agreement prior to the start of the trial. 
Authorship will be determined by mutual agreement and in line with ICMJE authorship requirements. 
Any formal publication of the study in which contribution of Novimmune personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and the appropriate 
Novimmune personnel. 
All contributors who do not meet the criteria for authorship should be listed in an acknowledgments 
section. Examples of those who might be acknowledged include a person who provided purely technical 
help, writing assistance, or a department chairperson who provided only general support. 
Any inventions and resulting patents, improvements, and/or know-how originating from the use of data 
from this study will become and remain the exclusive and unburdened property of Novimmune, except 
where agreed otherwise. 
14 MONITORING AND AUDITING 
All aspects of the study will be monitored by Novimmune or its representative for this study 
(Novimmune authorised representative), for compliance with applicable government regulations with 
respect to current GCP and standard operating procedures. Direct access to the on-site study 
documentation and medical records must be ensured. 
14.1 STUDY MONITORING AND SOURCE DATA VERIFICATION 
As part of the responsibilities commensurate with participating in the study, the investigator agrees to 
maintain and have available for monitoring, adequate case records (accurate source documents and 
CRFs) for the patients treated under this protocol. In addition, the investigator agrees to maintain all 
administrative documents (e.g. IEC correspondence, investigational product and supplies shipment 
manifests, monitoring logs, or correspondence with Novimmune and with any of its representative for 
this study). 
14.2 ON-SITE AUDITS 
Investigators and institutions involved in the study will permit trial-related monitoring, audits, IRB/IEC 
review, and domestic or foreign regulatory inspection(s) by providing direct access to source documents, 
CRFs, and all other study documentation. 
The Investigator should promptly notify Novimmune of any inspections scheduled by any regulatory 
authorities and promptly forward to Novimmune copies of any audit reports received. 
14.3 SERIOUS GCP BREACHES 
Novimmune is required to report a serious GCP Breach within 7 days to applicable health authorities. 
Therefore, should an Investigator become aware of a possible serious GCP breach, e.g. a protocol 
violation, or non-reporting of critical safety information that has the potential of jeopardizing patients’ 
safety, Novimmune must be notified within 24 hours. 
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15 DOCUMENTATION AND USE OF STUDY FINDINGS 
15.1 DOCUMENTATION OF STUDY RESULTS 
A CRF (including electronic data capture) is used in this study and a specific CRF will correspond to 
each patient.  
All required information must be entered on the CRFs. If an item is not available or is not applicable, this 
fact should be indicated and no blank spaces must be left. The data collected on the CRF will be entered 
into the study database. If the investigator authorises other personnel to enter data into the CRF, the 
names, positions, signatures, and initials of these persons must be supplied to Novimmune or their 
authorised representative before these individuals start completing CRF information.  
The CRF must be reviewed by the Investigator named in the study protocol or by a designated sub-
investigator, and final signature will be required.  
15.2 USE OF COMPUTERIZED SYSTEMS AT THE CLINICAL TRIAL CENTER 
When clinical observations are entered directly into an investigational site’s computerized medical record 
system (i.e. in lieu of original hardcopy records), the electronic record can serve as the source document 
if the system has been validated in accordance with health authority requirements pertaining to 
computerized systems used in clinical research. An acceptable computerized data collection system 
allows preservation of the original entry of data. If original data are modified, the system should maintain 
a viewable audit trail that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
The system must allow the clinical research associate, auditors or inspectors to verify source data without 
infringing privacy rights of other patients, e.g. access must be restricted to records pertaining to the study 
patients and access to other patients must not be possible. 
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16 REFERENCES 
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Henter, J.-I. et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic 
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Minoia, F. et al. Clinical features, treatment, and outcome of macrophage activation syndrome 
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Ravelli, A. et al. Preliminary diagnostic guidelines for macrophage activation syndrome 
complicating systemic juvenile idiopathic arthritis. J. Pediatr. 146, 598–604 (2005). 
20. 
Davì, S. et al. Performance of current guidelines for diagnosis of macrophage activation syndrome 
complicating systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 66, 2871–2880 (2014). 
21. 
Lehmberg, K. et al. Differentiating macrophage activation syndrome in systemic juvenile 
idiopathic arthritis from other forms of hemophagocytic~lymphohistiocytosis. J. Pediatr. 162, 
1245–1251 (2013). 
22. 
Ravelli, A. et al. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating 
Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American 
College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborat. 
Ann. Rheum. Dis. 75, 481–9 (2016). 
23. 
De Benedetti, F. et al. Macrophage activation syndrome in patients with systemic juvenile 
idiopathic arthritis treated with tocilizumab (abstract). Pediatr. Blood Cancer 62, S1 (2015). 
24. 
Grom, A. A. et al. Rate and Clinical Presentation of Macrophage Activation Syndrome in Patients 
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With Systemic Juvenile Idiopathic Arthritis Treated With Canakinumab. Arthritis Rheumatol. 68, 
218–28 (2016). 
25. 
Stéphan, J. L. et al. Reactive haemophagocytic syndrome in children with inflammatory disorders. 
A retrospective study of 24 patients. Rheumatology 40, 1285–1292 (2001). 
26. 
Ramanan, A. V & Schneider, R. Macrophage activation syndrome following initiation of 
etanercept in a child with systemic onset juvenile rheumatoid arthritis. J. Rheumatol. 30, 401–403 
(2003). 
27. 
Stern, A., Riley, R. & Buckley, L. Worsening of macrophage activation syndrome in a patient 
with adult onset Still’s disease after initiation of etanercept therapy. J. Clin. Rheumatol. 7, 252–
256 (2001). 
28. 
De Benedetti, F. et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N. 
Engl. J. Med. 367, 2385–2395 (2012). 
29. 
Ruperto, N. et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. 
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30. 
Imashuku, S., Hibi, S., Fujiwara, F. & Todo, S. Hyper-interleukin (IL)-6-naemia in 
haemophagocytic lymphohistiocytosis. Br. J. Haematol. 93, 803–807 (1996). 
31. 
Put, K. et al. Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic 
lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-gamma. 
Rheumatology 54, 1507–1517 (2015). 
32. 
Xu, X.-J. et al. Diagnostic accuracy of a specific cytokine pattern in hemophagocytic 
lymphohistiocytosis in children. J. Pediatr. 160, 984–90.e1 (2012). 
33. 
Jordan, M. B., Hildeman, D., Kappler, J. & Marrack, P. An animal model of hemophagocytic 
lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. 
Blood 104, 735–743 (2004). 
34. 
Pachlopnik Schmid, J. et al. Neutralization of IFN gamma defeats haemophagocytosis in LCMV-
infected perforin- and Rab27a-deficient mice. EMBO Mol. Med. 1, 112–124 (2009). 
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Zoller, E. E. et al. Hemophagocytosis causes a consumptive anemia of inflammation. J. Exp. Med. 
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Prencipe, G. et al. Neutralization of interferon gamma reverts clinical and laboratory features in a 
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Behrens, E. M. et al. Repeated TLR9 stimulation results in macrophage activation syndrome-like 
disease in mice. J. Clin. Invest. 121, 2264–2277 (2011). 
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Buatois, V. et al. Use of a mouse model to identify a blood biomarker for IFNγ activity in 
pediatric secondary hemophagocytic lymphohistiocytosis. Transl. Res. (2016). 
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39. 
Strippoli, R. et al. Amplification of the response to Toll-like receptor ligands by prolonged 
exposure to interleukin-6 in mice: implication for the pathogenesis of macrophage activation 
syndrome. Arthritis Rheum. 64, 1680–1688 (2012). 
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Prencipe, G., Caiello, I., Bracaglia, C., de Min, C. & De Benedetti, F. Neutralization of interferon-
gamma is efficacious in a mouse model of HLH secondary to chronic inflammation (abstract). 
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41. 
Bracaglia, C. et al. Elevated circulating levels of interferon-γ and interferon-γ-induced 
chemokines characterise patients with macrophage activation syndrome complicating systemic 
juvenile idiopathic arthritis. Ann. Rheum. Dis. (2016). doi:10.1136/annrheumdis-2015-209020 
42. 
Jordan, M. B. et al. A Novel Targeted Approach to the Treatment of Hemophagocytic 
Lymphohistiocytosis (HLH) with an Anti-Interferon Gamma (IFNg) Monoclonal Antibody 
(mAb), NI-0501: First Results from a Pilot Phase 2 Study in Children with Primary HLH 
(abstract). Blood 126, (2015). 
43. 
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antibodies used to treat colorectal cancer--identification, prevention, and management. J. Support. 
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Maggi, E., Vultaggio, A. & Matucci, A. Acute infusion reactions induced by monoclonal antibody 
therapy. Expert Rev. Clin. Immunol. 7, 55–63 (2011). 
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Dorman, S. E. & Holland, S. M. Interferon-gamma and interleukin-12 pathway defects and human 
disease. Cytokine growth factor Rev. 11, 321–333 (2000). 
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46. 
Jouanguy, E., Altare, F., Lamhamedi-Cherradi, S. & Casanova, J. L. Infections in IFNGR-1-
deficient children. J. Interf. Cytokine Res. 17, 583–587 (1997). 
47. 
Remus, N. et al. Impaired interferon gamma-mediated immunity and susceptibility to 
mycobacterial infection in childhood. Pediatr. Res. 50, 8–13 (2001). 
48. 
Reinisch, W. et al. Fontolizumab in moderate to severe Crohn’s disease: a phase 2, randomized, 
double-blind, placebo-controlled, multiple-dose study. Inflamm. Bowel Dis. 16, 233–242 (2010). 
49. 
DeWitt, E. M. et al. Consensus treatment plans for new-onset systemic juvenile idiopathic 
arthritis. Arthritis Care Res. (Hoboken). 64, 1001–10 (2012). 
 
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17 APPENDICES 
 
Appendix A – Literature reference for sJIA diagnosis: “Operational case definition of new onset sJIA 
used in development of treatment plans” 
Appendix B – Literature reference for MAS diagnosis: “2016 Classification Criteria for Macrophage 
Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis”  
Appendix C – Membership of the Scientific Steering Committee (SSC) 
Appendix D – Estimated blood volumes to be drawn during the study 
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APPENDIX A: Operational Case Definition Of New Onset sJIA Used In Development Of 
Treatment Plans (designed by Childhood arthritis and rheumatology research alliance) 
(DeWitt EM et al. Arthritis Care Res 2012)49 
Patient should have: 
 
1. Age 6 months to 18 years 
 
2. Fever1 for at least 2 weeks 
 
3. Arthritis2 in one or more joints (6 weeks duration not required) 
 
4. At least one of the following: 
      a. Evanescent erythematous rash 
      b. Generalized lymphadenopathy 
      c. Hepatomegaly or splenomegaly 
      d. Pericarditis, pleuritis and/or peritonitis 
Patient should not have any of the following:  
 
1. Infection:  including concomitant active or recurrent chronic bacterial, fungal 
or viral infection at presentation; nor underlying infection which may mimic 
initial presentation of sJIA3 
 
2.  Malignancy3   
 
3. Positive screening test for TB without documented past treatment 
 
4. Prior treatment for SJIA other than NSAIDs or short term steroids4 
 
5. Immunization with live virus vaccines within the 4 weeks prior to enrollment 
1Daily fever is not required, but must at some point exhibit a quotidian fever pattern, defined as fever 
that rises to ≥39°C at least once a day and returns to ≤37°C between fever peaks.  
2Swelling within a joint, or limitation in the range of joint movement with joint pain or tenderness, is 
observed by a physician, and which is not due to primarily mechanical disorders or to other identifiable 
causes.  
3 Infections, malignancy and other diagnoses which can present with similar symptoms as sJIA should be 
excluded before initiating treatment plans for new onset sJIA in order to avoid unintended adverse 
effects of the treatment plans if used for other diagnoses. 
4 Prior treatment with steroids should not exceed 2 weeks of oral steroids, and/or 3 pulses of 
methylprednisolone. Prior treatment with IVIG for possible Kawasaki Disease is allowed. Duration of 
NSAIDs is without restriction. 
 
NOTE: The above is not meant to represent diagnostic nor classification criteria for sJIA. The 
differences between this operational case definition and the ILAR criteria are: 
1. ILAR specifies that the duration of quotidian fever has to be 3 days (the total duration of fever is 
two weeks in both). 
2. ILAR specifies six weeks’ duration of arthritis. 
3. Psoriasis, positive RF, arthritis in HLA B27 positive male after 6 years of age, family history of 
AS, IBD with sacroiliitis, acute anterior uveitis and reactive arthritis are listed as exclusions in 
the ILAR definition. 
 
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APPENDIX B: 2016 Classification Criteria For Macrophage Activation Syndrome 
Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against 
Rheumatism/American College Of Rheumatology/Paediatric Rheumatology International 
Trials Organisation Collaborative Initiative 
(Ravelli A et al. Ann Rheum Dis 2016)22 
Classification of macrophage activation syndrome 
in systemic juvenile idiopathic arthritis 
A febrile patient with known or suspected systemic juvenile idiopathic arthritis is classified 
as having macrophage activation syndrome if the following criteria are met:  
- Ferritin > 684 ng/mL 
and any two of the following: 
- Platelet count  181 x109/L 
- AST levels > 48 U/L 
- Triglycerides > 156 mg/dL 
- Fibrinogen levels ≤ 360 mg/dL. 
 
 
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APPENDIX C: Membership Of The Scientific Steering Committee (SSC) 
 
 
 
 
 
 
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APPENDIX D: Estimated Blood Volumes To Be Drawn During The Study 
 
 
Assessments 
 
Screening  
NI-0501 Treatment period  
Evaluation period 
EoS 
SD-1 
SD0 
SD1 
SD2 
SD3 
SD5 
Infusion Visits1  
SD6 to SD28 
SD35 – SD42 – SD49 
SD 56 
Week 8 
Laboratory 
assessments 
- CBC (including Lymphocyte subset) 
1 
1 
1 
1 
1 
1 
1 
1 
1 
- Coagulation, Fibrinogen  
1 
1 
1 
1 
1 
1 
1 
1 
1 
- Biochemistry 
2 
2 
2 
2 
2 
2 
2 
2 
2 
- Serum pregnancy test (if applicable) 
0.5 
 
 
 
 
 
 
 
0.5 
- Search for EBV, CMV, Adenoviruses, 
Mycobacteria 
0.5 
 
 
 
 
 
0.52 
0.53 
0.5 
- Search for HSV, HZV, HIV, HBV, HCV 
0.5 
 
 
 
 
 
 
 
 
- Search for other pathogens (if needed) 
1 
 
 
 
 
 
 
 
 
Subtotal per visit 
6.5 
4 
4 
4 
4 
4 
4/4.52 
4/4.53 
5 
Subtotal per month 
 
 
 
 
 
 
59.5 
 
17.5 
PK  
- NI-0501 serum concentration 
 
1 
0.5 
0.5 
1 
0.5 
1 
0.5 
0.5 
PD 1 
- IFN, CXCL9, CXCL10, sCD25 
 
1 
1 
1 
1 
1 
1 
1 
1 
PD 2 
- Other biomarkers 
 
1 
 
 
 
 
12 
13 
1 
Immunogenicity (ADA) 
 
0.5 
 
 
 
 
 
 
0.5 
Molecular diagnosis (if consent for genetic testing is given) 
(3) 
 
 
 
 
 
 
 
 
Subtotal per visit 
(3) 
3.5 
1.5 
1.5 
2 
1.5 
2/32 
1.5/2.53 
3.0 
Total per month (maximum) 
 
 
 
 
 
 
90.5 
 
26.0 
TOTAL OVERALL STUDY (maximum) 
 
 
 
 
 
 
 
 
116.5 
1 Assumes worst case scenario in terms of blood volumes, i.e. NI-0501 treatment is continued until SD28 (total of 10 infusions). If treatment is shortened, the amount of blood to be drawn    
  would be less. 
2 At SD15 and SD28. 
3 At SD42.  
 
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