Clinical trial NCT03311854
Conditions: Macrophage Activation Syndrome Lymphohistiocytosis, Hemophagocytic Arthritis, Juvenile Adult Onset Still Disease
Keywords: Emapalumab Gamifant Macrophage activation syndrome Secondary hemophagocytic lymphohistiocytosis Interferon-gamma Systemic juvenile idiopathic arthritis Adult-onset Still's disease MAS HLH sHLH IFN-gamma IFNγ sJIA AOSD NI-0501-06 NI-0501
Sponsor: Swedish Orphan Biovitrum
Start date: 2018-02-20; Completion date: 2020-05-19
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Macrophage Activation Syndrome (MAS) is a rare, life-threatening condition characterized by uncontrolled hyperinflammation which may develop on the background of systemic Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still's Disease (AOSD). Emapalumab is a monoclonal antibody neutralizing interferon-gamma (IFN-gamma), a key cytokine which contributes to the inflammation and tissue damage seen in MAS. The purpose of this study is to assess the safety, tolerability and efficacy of emapalumab in sJIA or AOSD participants developing MAS, presenting an inadequate response to high dose glucocorticoid treatment.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Emapalumab
Intervention descriptions: intervention 1: Emapalumab was administered at an initial dose of 6 mg/kg by intravenous infusion. Emapalumab treatment continued at a dose of 3 mg/kg, every 3 days until study day 15, and then twice-a-week for an additional 2 weeks, i.e., until study day 28. The emapalumab regimen could be adapted (the frequency between infusions shortened, the dose increased, or the treatment prolonged beyond 4 weeks) upon assessment of a favourable benefit-risk profile. There was a 4-week off-drug follow-up period (up to Week 8).

Protocol documents:
Prot_000.pdf: 
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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Study NI-0501-06                   Emapalumab in MAS/sHLH in sJIA/AOSD patients                          Page 2 of 76 
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
 Page 4 of 76 
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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Study NI-0501-06                   Emapalumab in MAS/sHLH in sJIA/AOSD patients                          Page 24 of 76 
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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Study NI-0501-06                   Emapalumab in MAS/sHLH in sJIA/AOSD patients                          Page 28 of 76 
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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Jordan MB(b), Locatelli F, Allen C, De Benedetti F, Grom AA, Ballabio M, Ferlin WG, De Min C. “A 
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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 
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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. 
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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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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 
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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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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., Elinder, G., Söder, O. & Ost, A. Incidence in Sweden and clinical features of familial 
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Janka, G. E. Familial hemophagocytic lymphohistiocytosis. Eur. J. Pediatr. 140, 221–230 (1983). 
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Filipovich, A., McClain, K. & Grom, A. Histiocytic disorders: recent insights into 
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Janka, G. E. & Lehmberg, K. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. 
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Schulert, G. S. & Grom, A. A. Pathogenesis of macrophage activation syndrome and potential for 
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Zhang, M. et al. Genetic defects in cytolysis in macrophage activation syndrome. Curr. 
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Moradinejad, M. H. & Ziaee, V. The incidence of macrophage activation syndrome in children 
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Sawhney, S., Woo, P. & Murray, K. J. Macrophage activation syndrome: a potentially fatal 
complication of rheumatic disorders. Arch. Dis. Child. 85, 421–426 (2001). 
15. 
Behrens, E. M., Beukelman, T., Paessler, M. & Cron, R. Q. Occult macrophage activation 
syndrome in patients with systemic juvenile idiopathic arthritis. J. Rheumatol. 34, 1133–1138 
(2007). 
16. 
Grom, A. A., Horne, A. & De Benedetti, F. Macrophage activation syndrome in the era of 
biologic therapy. Nat. Rev. Rheumatol. 12, 259–68 (2016). 
17. 
Henter, J.-I. et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic 
lymphohistiocytosis. Pediatr. Blood Cancer 48, 124–131 (2007). 
18. 
Minoia, F. et al. Clinical features, treatment, and outcome of macrophage activation syndrome 
complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 
patients. Arthritis Rheumatol. 66, 3160–3169 (2014). 
19. 
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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Page 67 of 73 
Protocol NI-0501-06                              Version 1.0 US – October 19, 2017 
       CONFIDENTIAL 
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. 
N. Engl. J. Med. 367, 2396–2406 (2012). 
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). 
35. 
Zoller, E. E. et al. Hemophagocytosis causes a consumptive anemia of inflammation. J. Exp. Med. 
208, 1203–1214 (2011). 
36. 
Prencipe, G. et al. Neutralization of interferon gamma reverts clinical and laboratory features in a 
mouse model of macrophage activation syndrome. Submitted 
37. 
Behrens, E. M. et al. Repeated TLR9 stimulation results in macrophage activation syndrome-like 
disease in mice. J. Clin. Invest. 121, 2264–2277 (2011). 
38. 
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). 
doi:10.1016/j.trsl.2016.07.023 
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). 
40. 
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). 
Pediatr. Rheumatol. 13, S1 (O29) (2015). 
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. 
Kang, S. P. & Saif, M. W. Infusion-related and hypersensitivity reactions of monoclonal 
antibodies used to treat colorectal cancer--identification, prevention, and management. J. Support. 
Oncol. 5, 451–7 (2007). 
44. 
Maggi, E., Vultaggio, A. & Matucci, A. Acute infusion reactions induced by monoclonal antibody 
therapy. Expert Rev. Clin. Immunol. 7, 55–63 (2011). 
45. 
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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Protocol NI-0501-06                              Version 1.0 US – October 19, 2017 
       CONFIDENTIAL 
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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Study NI-0501-06 
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Page 69 of 73 
Protocol NI-0501-06                              Version 1.0 US – October 19, 2017 
       CONFIDENTIAL 
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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Page 70 of 73 
Protocol NI-0501-06                              Version 1.0 US – October 19, 2017 
       CONFIDENTIAL 
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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Page 71 of 73 
Protocol NI-0501-06                              Version 1.0 US – October 19, 2017 
       CONFIDENTIAL 
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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Study NI-0501-06 
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Page 72 of 73 
Protocol NI-0501-06                              Version 1.0 US – October 19, 2017 
       CONFIDENTIAL 
APPENDIX C: Membership Of The Scientific Steering Committee (SSC) 
 
 
 
 
 
 
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Study NI-0501-06                                                                  NI-0501 in MAS/sHLH in sJIA patients                                                                               Page 73 of 73 
 
Protocol NI-0501-06 
                            Version 1.0 US– October 19, 2017                                                                                    
CONFIDENTIAL 
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.  
 
Page 150 of 150

SAP_001.pdf: 
Sobi AG 
NI-0501-06 
Confidential 
Page 1 of 77
Emapalumab
Documentation of statistical methods
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
Documentation of statistical methods 
Final statistical analysis plan, version 2.0, dated 29 October 2020 
Final errata of statistical analysis plan, version 2.0, dated 22 July 2021 
Final post-hoc analysis plan, version 1.0, dated 22 April 2021 


AD-ST-33.04 Effective date: 30-Jun-2017 
Draft Version 2.0    |    Date 29-Oct-2020 
 |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 1 of 51 
   Statistical Analysis Plan 
Sponsor 
Sobi AG 
Protocol 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) 
Protocol Number: 
NI-0501-06 
Premier Research PCN: 
NOVI 176557 
Document Version: 
Final Version 2.0 
Document Date: 
29-Oct-2020
Approvals 
Role 
Signatures 
Date (dd-Mmm-yyyy) 
Biostatistician 
Principal Biostatistician, Premier Research 
Sign Name: 
Sobi AG 
Representative 
Head Clinical Science Immunology,  Sobi 
Sign Name: 
Page 2 of 77
SIGN


Statistical Analysis Plan,  
Sponsor Sobi AG 
Protocol Number NI-0501-06 
PCN Number NOVI 176557
AD-ST-33.04 Effective date: 30-Jun-2017 
Draft Version 2.0    |    Date 29-Oct-2020 
 |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 2 of 51 
Document History 
Version 
Date 
Reason for Amendment 
1.0 
08-Jun-2019
- 
2.0 
29-Oct-2020
Updated accordingly to protocol version 2.0. 
Moreover: 

Two sections have been added to
describe the impact of COVID-19
(Section 6.1.9) and the safety patient
profile analysis (Section 12.1).

A descriptive analysis for
presentation at health authority
meetings (FDA) has been added
(Section 4.2).
The following definitions have been added in 
Section 6.1.7: 

Equivalent dose of prednisone.

Glucocorticoids tapering when it is
not possible to establish if a patient
has been treated for sJIA/AOSD
before the study start.

Daily total dose of anakinra,
canakinumab, ciclosporin, etoposide,
methotrexate, and tocilizumab has
been added.

Patients who tapered steroids to ≤1
mg/kg/day of the equivalent dose of
prednisone.
The following definitions have been 
amended in Section 6.1.7: 

Infection.

MAS remission is defined
accordingly to symptoms score <=1.

Suspected and confirmed IRR have
Page 3 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG 
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Draft Version 2.0    |    Date 29-Oct-2020      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 3 of 51 
 
Version 
Date 
Reason for Amendment 
been combined into IRR. 
The following definitions have been 
clarified: 
 Study day (Section 6.1.7). 
 TEAE in case of missing or partial 
dates has been clarified (Section 
6.1.8). 
The following analyses have been added: 
 Neutralizing antibodies for positive  
ADA patients (Section 9.5.3). 
 
Minor changes not included. 
 
 
 
 
Page 4 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG 
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Draft Version 2.0    |    Date 29-Oct-2020      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 4 of 51 
 
Table of Contents 
Approvals ........................................................................................................................................ 1 
Document History ........................................................................................................................... 2 
Table of Contents ............................................................................................................................ 4 
List of Tables .................................................................................................................................. 6 
List of Figures ................................................................................................................................. 6 
1. 
Overview ............................................................................................................................. 7 
2. 
Study Objectives and Endpoints ......................................................................................... 7 
2.1. 
Study Objectives ........................................................................................................... 7 
2.2. 
Study Endpoints ............................................................................................................ 8 
2.2.1. Safety Endpoints ........................................................................................................... 8 
2.2.2. Efficacy Endpoints ........................................................................................................ 8 
2.2.3. Pharmacokinetic Endpoints .......................................................................................... 8 
2.2.4. Pharmacodynamic Endpoints ........................................................................................ 9 
3. 
Overall Study Design and Plan ........................................................................................... 9 
3.1. 
Overall Design .............................................................................................................. 9 
3.2. 
Sample Size ................................................................................................................. 10 
3.3. 
Study Population ......................................................................................................... 10 
3.4. 
Treatments Administered ............................................................................................ 10 
3.5. 
Method of Assigning Patients to Treatment Groups................................................... 10 
3.6. 
Blinding and Unblinding............................................................................................. 10 
3.7. 
Schedule of Events ...................................................................................................... 10 
4. 
Statistical Analysis and Reporting .................................................................................... 18 
4.1. 
Introduction ................................................................................................................. 18 
4.2. 
Interim Analysis and Data Monitoring ....................................................................... 18 
5. 
Analysis Populations ......................................................................................................... 19 
6. 
General Issues for Statistical Analysis .............................................................................. 19 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 19 
6.1.1. Baseline ....................................................................................................................... 19 
6.1.2. Adjustments for Covariates......................................................................................... 19 
6.1.3. Multiple Comparisons ................................................................................................. 19 
6.1.4. Handling of Dropouts or Missing Data ....................................................................... 20 
6.1.5. Analysis Visit Windows ............................................................................................. 20 
6.1.6. Pooling of Sites ........................................................................................................... 20 
Page 5 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG 
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
 
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Draft Version 2.0    |    Date 29-Oct-2020      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 5 of 51 
 
6.1.7. Derived Variables ....................................................................................................... 20 
6.1.8. Data Adjustments/Handling/Conventions .................................................................. 25 
6.1.9. COVID-19................................................................................................................... 26 
7. 
Study Patients and Demographics .................................................................................... 26 
7.1. 
Disposition of Patients and Withdrawals from the study ........................................... 26 
7.2. 
Protocol Deviations ..................................................................................................... 27 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 27 
7.4. 
Exposure and Drug Administration ............................................................................ 28 
8. 
Efficacy Analysis .............................................................................................................. 28 
8.1. 
Efficacy Analysis ........................................................................................................ 28 
8.2. 
MAS Clinical Signs and Symptoms ........................................................................... 28 
9. 
Safety and Tolerability Analysis ....................................................................................... 29 
9.1. 
Adverse Events ........................................................................................................... 29 
9.1.1. Treatment-Emergent Adverse Events Leading to Study Treatment 
Discontinuation ........................................................................................................... 30 
9.1.2. Deaths and Serious Adverse Events ........................................................................... 30 
9.1.3. Infusion-related Reactions .......................................................................................... 30 
9.1.4. Infections..................................................................................................................... 30 
9.2. 
Clinical Laboratory Evaluations ................................................................................. 31 
9.3. 
Vital Signs ................................................................................................................... 31 
9.4. 
Electrocardiograms ..................................................................................................... 31 
9.5. 
Further Safety Evaluations .......................................................................................... 32 
9.5.1. Physical Examination.................................................................................................. 32 
9.5.2. Pregnancy Outcome .................................................................................................... 32 
9.5.3. Immunogenicity – anti-drug antibodies (ADAs) ........................................................ 32 
9.5.4. Other Exploratory Analyses ........................................................................................ 32 
9.6. 
Concomitant Medication ............................................................................................. 33 
10. 
Pharmacokinetic/Pharmacodynamic Analysis .................................................................. 33 
11. 
Changes from Planned Analysis ....................................................................................... 33 
12. 
Other Planned Analysis..................................................................................................... 34 
12.1. Patient Profile Report .................................................................................................. 34 
13. 
References ......................................................................................................................... 35 
14. 
Tables, Listings, and Figures ............................................................................................ 36 
14.1. Planned Table Descriptions ........................................................................................ 36 
14.2. Planned Listing Descriptions ...................................................................................... 41 
Page 6 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG 
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Draft Version 2.0    |    Date 29-Oct-2020      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 6 of 51 
 
14.3. Planned Figure Descriptions ....................................................................................... 44 
15. 
Tables, Listings, and Listing Shells .................................................................................. 45 
15.1. Standard Layout for all Tables, Listings, and Figures ................................................ 45 
15.2. Planned Patient Profile Shells ..................................................................................... 45 
Appendix 1: Premier Research Library of Abbreviations ............................................................ 49 
 
List of Tables 
Table 1: Schedule of assessments: screening and treatment period (from SD-1 to SD28) .......... 11 
Table 2: Schedule of assessments: evaluation period (from SD28 to SD56) ............................... 15 
Table 3: Demographic Data Summary Tables and Figures .......................................................... 37 
Table 4 Efficacy Data ................................................................................................................... 38 
Table 5 Safety Data ....................................................................................................................... 39 
Table 6 Pharmacokinetic/Pharmacodynamic Data ....................................................................... 41 
Table 7 Planned Figures................................................................................................................ 44 
 
List of Figures 
Figure 1: Patient Profile Shells ..................................................................................................... 46 
 
 
Page 7 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG 
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Draft Version 2.0    |    Date 29-Oct-2020      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 7 of 51 
 
1. 
Overview 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Sobi AG 
protocol number NI-0501-06 (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)). 
The study was being conducted in North America and Europe according to 2 original twin 
protocols (Version 1.0 dated 19 Oct 2017 for North America and Version 1.1. dated 7 Apr 2017 
for Europe) and country-specific versions (to take into account requirements from the national 
ethics committees).  The versions previously in use have been recently amended, in January 
2020, and the study is currently being conducted according to protocol version 2.0 (with country 
specific requirements for France and Italy as previously). 
This SAP describes the planned analysis for the combined data of the twin protocols, and a 
single clinical study report (CSR) will present the results from the protocols. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the Food and Drug Administration, European Medicines Agency, and International 
Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals 
for Human Use: Guidance on Statistical Principles in Clinical Trials1. All work planned and 
reported for this SAP will follow internationally accepted guidelines, published by the American 
Statistical Association2 and the Royal Statistical Society3, for statistical practice. 
The planned analyses identified in this SAP will be included in CSRs, and they may be included 
in regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-hoc 
or unplanned, exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be submitted to file prior to the 
database lock pertaining to study NI-0501-06. 
2. 
Study Objectives and Endpoints 
2.1. 
Study 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 administrations of 
emapalumab. 
 To assess the efficacy of emapalumab. 
Page 8 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG 
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
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 To assess the levels of relevant pharmacodynamic markers, such as IFNγ and main IFNγ-
induced chemokines CXCL9, CXCL10. 
 To assess other potential disease markers (e.g. sCD25, sCD163, IL-10, IL-6, IL-18, 
TNFα). 
 To assess the immunogenicity of emapalumab. 
2.2. 
Study Endpoints 
2.2.1. Safety Endpoints 
The safety endpoints of this study include the following: 
 Incidence, severity, causality and outcomes of adverse events (AEs) (serious and 
non-serious), with particular attention being paid to infections. 
 Evolution of laboratory parameters, in particular complete blood count (CBC), liver 
function tests (LFTs), inflammatory markers (ferritin and C-reactive protein [CRP]), and 
coagulation parameters. 
 Number of patients withdrawn due to safety reasons. 
2.2.2. Efficacy Endpoints 
The efficacy of emapalumab will be evaluated 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:  
- 
To the same (or lower) dose being administered before the occurrence of MAS (in 
those patients who are already treated for sJIA/AOSD) or 
- 
By at least 50% 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 previously). 
 Survival time. 
 Number of patients withdrawn from the study due to lack of efficacy. 
2.2.3. Pharmacokinetic Endpoints 
Non-compartmental pharmacokinetic analysis (NCA) will be applied to calculate the following 
parameters, as applicable: 
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 Cmax (concentration corresponding to Tmax) 
 Tmax (time of maximum observed concentration) 
 CEOI (concentration at the end of infusion)  
 Ctrough (concentration just before administration)  
 AUCτ (area under curve of a dosing interval)  
 AUClast (area under curve from the time of dosing to the last measurable concentration) 
 t½ (serum half-life) 
Population PK modelling will also be performed to determine the PK properties of emapalumab, 
but will be described in a separate PK analysis plan and will be reported separately. NCA and 
population PK analysis will be undertaken to investigate linear and non-linear (TMDD) kinetics.  
2.2.4. Pharmacodynamic Endpoints 
PK/PD analysis will be performed to describe the relationship between emapalumab and IFNγ 
and CXCL9, which will be described in a separate PK/PD analysis plan and the outcome of the 
analyses will be reported separately. 
Assessment of PD parameters will include, but will not be limited to the following:  
 Levels of circulating free IFNγ 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, 
TNFα). 
 Levels (if any) of circulating antibodies against emapalumab to determine 
immunogenicity, i.e. the development of anti-drug antibodies (ADAs). 
3. 
Overall Study Design and Plan 
3.1. 
Overall Design 
This is an open-label, single arm, international, multicenter pilot study conducted in Europe and 
North America. 
Emapalumab will be administered intravenously at the initial dose of 6 mg/kg at study day 0 
(SD0: initiation of emapalumab treatment), 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. 
All patients who have received at least 1 dose of emapalumab will be monitored after the last 
administration of emapalumab. A short-term follow-up of 4 weeks has to be performed; 
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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.  
If treatment is shortened (as allowed by the protocol upon achievement of MAS remission), the 
schedule of visits has to be in any case followed until SD56. Therefore, the last visit for a given 
patient in the NI-0501-06 study will normally be on SD56 (except in case of prolongation of 
emapalumab treatment beyond 4 weeks). 
3.2. 
Sample Size  
The sample size was not formally calculated. The sample size of approximately 12 evaluable 
patients (a minimum of 10 sJIA patients) is based on pragmatic considerations, and on the 
experience acquired from patients with primary HLH treated with emapalumab. 
3.3. 
Study Population 
The study population comprises patients of both genders, with sJIA or AOSD, presenting with 
MAS and having shown inadequate response to high dose intravenous glucocorticoid treatment.  
3.4. 
Treatments Administered 
This is an open-label, single-arm study and no randomization is being performed. Emapalumab 
is administered at the initial dose of 6 mg/kg by infusion over a period of 1 to 2 hours, depending 
on the volume to infuse. Treatment is 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) before a patient can be considered to achieve MAS remission. 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. 
3.5. 
Method of Assigning Patients to Treatment Groups 
This is an open-label, single-arm study. Screening is carried out to enable confirmation of patient 
eligibility. Eligible patients are administered emapalumab. 
3.6. 
Blinding and Unblinding 
There is no need of a blinding and unblinding scheme since this is an open-label, single-arm 
study.  
3.7. 
Schedule of Events 
A detailed schedule of events for the study is provided in Table 1 and Table 2. 
 
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Table 1: Schedule of assessments: screening and 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 
 
 
 
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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 
Laboratory 
assessments 
 
 
CBC 
8.4 
X 
X 
 
X 
X 
X 
 
X 
X 
Lymphocyte subset 
8.4 
X 
 
 
 
 
 
 
 
 
Coagulation (aPTTT, 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 
 
 
 
 
 
 
 
X (SD28 only) 
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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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 
 
 
 
 
 
 
 
 
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 
IFNγ, 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 Protocol 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 Protocol 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. 
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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 IFNγ only. 
15 MAS activity on VAS at all indicated visits. Assessment of clinical parameters as per Protocol 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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Table 2: Schedule of assessments: evaluation period (from SD28 to SD56) 
 Assessments 
Protocol 
Section 
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 
 
 
 
 
X 
 
Urinalysis 
 
 
 
 
X 
 
Search for infections 
Mycobacterium Tuberculosis 
8.5 
 
X 
 
X 
 
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 Assessments 
Protocol 
Section 
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 
 
EBV, CMV, Adenoviruses 
8.5 
 
X 
 
X 
 
Procedure 
ECG 
8.7.1 
 
 
 
X 
 
Imaging 
Abdominal Ultrasound 
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 
IFNγ, CXCL9, CXCL10, sCD25 
8.8.2 
X 
X 
X 
X 
 
PD 2 
Other markers 
8.8.2 
 
X 
 
X 
 
Immunogenicity 
(ADA)6 
 
88.3 
 
 
 
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 the 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 needed 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 condition 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 
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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 Protocol 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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4. 
Statistical Analysis and Reporting 
4.1. 
Introduction 
All study variables in this study are considered to be exploratory, and no hierarchy of 
endpoints has been specified. The analysis focuses on descriptive statistics and 
confidence intervals (CIs). 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, 
and graphical representations will be performed primarily using SAS (release 9.4 or 
higher).  
Continuous (quantitative) variable summaries will include the number of patients (n) with 
non-missing values, mean, standard deviation, median, minimum, and maximum.  
Categorical (qualitative) variable summaries will include the frequency and percentage of 
patients who are in the particular category or each possible value. In general, the 
denominator for the percentage calculation will be based upon the total number of 
patients in the study population, unless otherwise specified.  
The minimum and maximum will be reported with the same degree of precision (i.e., the 
same number of decimal places) as the observed data. Measures of location (mean and 
median) will be reported to 1 degree of precision more than the observed data and 
measures of spread (standard deviation) will be reported to 2 degrees of precision more 
than the observed data. 
Percentages will be presented to 1 decimal place, unless otherwise specified. 
Unless otherwise indicated, all CIs will be calculated at the 95% CI. 
4.2. 
Interim Analysis and Data Monitoring 
An independent iDMC has monitored patient safety during the NI-0501-06 study. The 
iDMC is composed of relevant experts: pediatric rheumatologist, pediatric onco-
hematologists, pediatric immune deficiency/infectious disease specialists, a 
biostatistician, and a specialist in ethics. 
The main iDMC responsibility has been to review safety and relevant efficacy data as 
they were generated, with the objective of determining the benefit/risk profile of 
emapalumab treatment in the patients enrolled in the study, thus ensuring that no patient 
was exposed to unnecessary risks. 
The iDMC could recommend treatment discontinuation for individual patients as well as 
temporary study suspension or study termination. 
A PK analysis has been conducted when a total of 5 patients were recruited to assess the 
appropriateness of the proposed dose regimen. 
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No formal interim analyses were planned. However, a descriptive summary of the 
efficacy and safety results from this open label study has been prepared for presentation 
at health authority meetings (FDA). Some of these preliminary results have been 
presented at congresses.  
5. 
Analysis Populations 
The following analysis populations are planned for this study: 
 All Treated Population (All Treated): The All Treated Population includes all 
patients who receive any part of an infusion of study drug. In this study, this 
population corresponds to the Safety population. 
 Evaluable Population (EVAL): The EVAL Population includes all patients in 
All Treated Population who have received a minimum of 3 consecutive infusions 
of emapalumab, and for whom the diagnosis of background disease sJIA is 
confirmed (e.g., no evidence for malignancy-related HLH or primary HLH has 
emerged after enrollment).  Should any deviations be considered to significantly 
impact on efficacy, the impacted patient(s) should be excluded from the EVAL 
Population. 
 
Inclusion in the EVAL analysis populations will be determined at a data review meeting 
before database lock. Sobi will review patient level data and a list of subjects for whom 
the diagnosis of background disease sJIA is confirmed will be provided to the statistician. 
The All Treated Population will be the primary population for safety and efficacy 
endpoints. The EVAL Population will be secondary for the efficacy analysis.  
6. 
General Issues for Statistical Analysis 
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
The last observation recorded prior to the first dose of emapalumab will be used as the 
baseline observation for all calculations of change from baseline.  
6.1.2. Adjustments for Covariates 
Not applicable. 
6.1.3. Multiple Comparisons 
Not applicable. 
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6.1.4. Handling of Dropouts or Missing Data 
An additional patient will be recruited for any patient who withdraws from the study for 
reasons other than safety or lack of efficacy to ensure a sample size of approximately 12 
patients across North America and Europe.  
No imputation of missing data will be performed. However, for MAS remission, if one or 
more laboratory data are unavailable within the visit window, the LOCF approach will be 
used. Partial date assumptions for the definition of TEAEs are described in Section 6.1.8 
6.1.5. Analysis Visit Windows 
Statistical analyses will be based on scheduled visits as collected in the case report form 
(CRF) realigned on study days, which are defined based on the date of first emapalumab 
infusion (SD0) as follows:  
Study Day = date of interest – date of first emapalumab infusion. 
The following rules will be applied for MAS remission and glucocorticoid tapering. 
 For the assessment of MAS remission and glucocorticoid tapering at Week 8, the 
SD56±5 days analysis period will be considered. Where several such observations 
occur in this time window, the one closest to SD56 will be selected. If there are 2 
such observations that are equidistant from SD56, the observation that is after SD56 
will be selected. 
 For the assessment of time to MAS remission, see Section 6.1.7. 
6.1.6. Pooling of Sites 
As relatively few patients are expected in the study, center will not be taken into account 
in the analyses. 
6.1.7. Derived Variables 
 Change from baseline = value at current time point – value at baseline. 
 Conversion factors: The following conversion factors will be used to convert days into 
months or years:  
o 1 month = 30.4375 days  
o 1 year = 365.25 days  
 
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 Treatment-emergent AE (TEAE) = any adverse event with an onset date/time after 
the start of the first emapalumab administration. 
 Infusion-related reactions (IRRs) = any TEAE that is reported to have occurred 
within 24 hours after start of infusion and assessed as related to study treatment by 
the Investigator, excluding the following system organ classes (SOCs): “Infections 
and infestations,” “Congenital familial and genetic disorders,” “Neoplasms benign, 
malignant and unspecified (incl. cysts and polyps),” “Product issues,” “Social 
circumstances,” and “Surgical and medical procedures.”  
If the onset time of the AE or the start time of the infusion is missing, then an AE 
with an onset date equal to an infusion date or infusion date + 1 will be  considered 
for the assessment of IRRs.  
 Infection: any TEAEs part of the SOC ‘infection and infestation’.  
 Duration of exposure (days) = date last study drug intake – date first study drug 
intake + 1 
 Study Day = date of interest – date of first emapalumab infusion. 
This SAP follows the protocol assumption that the day of the first infusion is SD0. 
Starting with 0, rather than with 1, can cause trouble for SDTM programming since 
it is not compliant with the SDTM Implementation Guide4.  SDTM data set will 
include two ways in counting the study day: starting with zero as in the protocol 
and starting with 1 as reccommended by the SDTM Inplementation Guide4.   
 Cumulative administered dose of emapalumab (mg/kg) = sum of administered 
emapalumab doses (mg/kg) 
 Average administered dose of emapalumab (mg/kg) = (cumulative dose of 
emapalumab)/(number of doses) 
 Equivalent dose of prednisone 
The Systemic Glucocorticoids data are collected into two modules of the paper 
CRF:  
- 
the ‘Systemic Glucocorticoids from SD-3 until SD15”  log   
- 
the ‘Concomitant Medication’ log  
For the analysis of systemic glucocorticoid dose tapering, conversion to prednisone-
equivalent dose may be required, if different glucocorticoids have been administered. 
Furthermore, the glucocorticoid dose will be expressed as prednisone-equivalent mg/kg 
body weight/day. 
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Steps to calculate the prednisone equivalent dose (mg/kg/day):  
1) Select systemic glucocorticoids where route is IV or oral from the ‘Systemic 
glucocorticoids from SD-3 until SD15’ form. Reported doses in the ‘Systemic 
glucocorticoids from SD-3 unit SD15’ form are daily doses and the number of 
doses per day is set to 1.  
 
2) Select concomitant medications with ATC code H02B (Glucocorticoids) from the 
‘Concomitant medication’ form with IV or oral route of administration. Calculate 
the frequency per day as follows (this list should not be seen as exhaustive):  
Frequency 
Description 
Number of doses per day 
OB, QD 
Once a day 
1 
BID 
Twice a day 
2 
TIB 
Three times a day 
3 
QID 
Four times a day 
4 
QW 
Every week 
1/7 
2xW 
Twice per week 
2/7 
3xW 
Three times per week 
3/7 
NxW 
N times per week 
N/7 
EVERY 2 WEEKS 
Every 2 weeks 
1/14 
QM 
Every month 
1/30.4375 
QAD 
Every other day 
0.5 
Once 
Single intake 
1/(stop date – start date 
+1) 
PRN 
As needed 
0 
Other 
Other 
0 
UNK 
Unknown 
0 
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Statistical Analysis Plan,  
 
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CI 
Continuous infusion 
0 
Note: Administration of glucocorticoids with ’as needed’, ‘other’, or 
‘unknown’ frequency will not be included in the calculation of the equivalent 
dose.  
 
3) If the dose unit is not mg, then the following conversion will be done:  
1 g = 1000 mg, 1 mcg = 0.001 mg.  IV and oral routes of administration are 
equivalent.  
 
4) Select the weight in kg from the physical examination visit closest to the 
glucocorticoids administration date. 
 
5) Calculate the equivalent dose of prednisone using the following formula: 
𝐸𝑞𝑢𝑖𝑣𝑎𝑙𝑒𝑛𝑡 𝑑𝑜𝑠𝑒 (mg/kg/day)= 𝐶𝑜𝑛𝑣𝑒𝑟𝑠𝑖𝑜𝑛 𝐹𝑎𝑐𝑡𝑜𝑟∗𝐷𝑜𝑠𝑒(𝑚𝑔) ∗ 𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑜𝑠𝑒𝑠 𝑝𝑒𝑟 𝑑𝑎𝑦
𝑊𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
 
where the conversion factor is: 
1 for prednisone  
1.25 for methylprednisolone 
1 for prednisolone 
 
 Glucocorticoids tapering = glucocorticoids permanently tapered  
• 
to the same (or lower) dose being administered before the 
occurrence of MAS (in patients already on treatment for 
sJIA/AOSD 
 or  
• 
by at least 50% of the equivalent dose of prednisone administered 
at emapalumab treatment start (in those patients who present with 
MAS at sJIA/AOSD onset). 
The daily equivalent dose of prednisone will be compared with the daily equivalent 
dose of prednisone at SD0.  
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If it is not possible to establish if a patient has been treated for sJIA/AOSD or not 
before study start for all patients, or if it is not possible to retrieve glucocorticoids 
dose administered before the occurrence of MAS for all patients who already are 
treated for sJIA/AOSD, the glucocorticoids tapering endpoint will be changed. In 
this case the endpoint will be: “glucocorticoids permanently tapered at any time 
during the study by at least 50% of the equivalent dose of prednisone administered 
at emapalumab treatment start (SD0). 
If glucocorticoid dosing data are unavailable at a given time point, the assumption 
that dose has not been further tapered from the previous available observation will 
be made. Glucocorticoid doses will be calculated as (prednisone-equivalent) 
mg/kg/day.  
 MAS remission = resolution of clinical signs and symptoms according to the 
Investigator (MAS clinical signs and symptoms score ≤ 1)  AND normalization of 
laboratory parameter relevant to MAS as follows: 
• 
White blood cell count (WBC) and platelet count above the lower 
limit of normal (LLN) 
• 
Lactate dehydrogenase (LDH) below 1.5 upper limit of normal 
(ULN) 
• 
Alanine aminotransferase/aspartate aminotransferase (ALT/AST) 
below 1.5 ULN 
• 
Fibrogen higher than 100 mg/dL 
• 
Ferritin level decreased by at least 80% from values at screening or 
baseline (whichever is higher) or below 2000 ng/mL, whichever is 
lower 
If one or more laboratory data are unavailable within the visit window, the LOCF 
approach will be used.  
 MAS remission by week 8 = patients who meet MAS remission conditions in the 
period SD56 ± 5 days regardless the time of first MAS remission or its duration. 
 Survival:   
Time to death = date of death – date of first emapalumab infusion + 1 
Patients who survive to the end of the study will be censored at the date of last 
contact. In case in which a patient withdrew consent the censoring date will be the 
date of withdrawal of consent.  
 Time to MAS remission: 
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date of first MAS remission –  date of first emapalumab infusion  + 1 
Time to the first MAS remission will be calculated from the date of first 
emapalumab infusion until the date of first MAS remission. Patients who do not 
meet the criteria of MAS remission will be censored at the date of last contact.  
The MAS remission evaluation is based on a combination of assessments, including 
Investigator assessment and laboratory findings. The latest date of assessments, 
within the visit window of ± 3 days around the planned day of the visit, will be used 
for the calculation of the time to MAS remission. 
 Time to achievement of permanent glucocorticoids tapering:  
date of glucocorticoids tapering – date of first emapalumab infusion + 1 
Time to achievement of glucocorticoids tapering will be calculated from the date 
of first emapalumab infusion until the date in which the target level of 
glucocorticoid dose reduction is permanently achieved. Patients who do not meet 
the criteria of glucocorticoids tapering will be censored at the date of last contact. 
 The total daily dose of anakinra, canakinumab, ciclosporin, etoposide, 
methotrexate, and tocilizumab will be calculated for each subject using the same 
unit of measurement provided in the concomitant medication log.  
Total daily dose = dose * Number of doses per day 
Where the number of doses per day are derived using the same approach for the 
calculation of the equivalent dose of prednisone equivalent. 
 Glucocorticoids  tapering to ≤1 mg/kg/day of the equivalent dose of prednisone: 
 
Achievement of permanent glucocorticoids tapering and last equivalent dose of 
prednisone is ≤1 mg/kg/day. 
6.1.8. Data Adjustments/Handling/Conventions 
All collected data will be presented in listings. Data not subject to analysis according to 
this plan will not appear in any tables or graphs but rather in the data listings only. 
Adverse events will be coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA). 
For TEAEs: 
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
If an AE with partial time occurs on the same day of the first infusion then the AE will be
considered a TEAE.

If an AE has missing date then the AE will be considered a TEAE.

If partial dates of AE occur, the convention for replacing missing dates for the purpose of
discriminate TEAE is as follows:
•
If just day is missing then the AE will be considered a TEAE when the mm/year
of AE is the same of after the mm/year of the first infusion;
•
If just month is missing then the AE will be considered a TEAE when the year of
AE is the same or after the year of the first infusion.
6.1.9. COVID-19 
A Coronavirus Disease 2019 (COVID-19) Continuity Plan has been written to mitigate 
the negative effects of the COVID-19 pandemic on the conduct of this clinical trial.  
The impact of COVID-19 on this clinical trials and trial participants will be extensively 
described both in tables and listings and in the CSR.  
The following aspects will be summarized when due to COVID-19: 

Changes to treatment dispensation

Changes to treatment administration

Changes to visit windows to accommodate delays for some assessments

Protocol deviations

Missing efficacy endpoints Missing visits
7.
Study Patients and Demographics
7.1. 
Disposition of Patients and Withdrawals from the study 
The number of patients for each of the following categories will be presented in a table: 

All Treated Population

Evaluable Population

Completed patients

Withdrawn from the study after start of treatment
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Statistical Analysis Plan,  
 
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 Reason of early study termination 
Percentages will be calculated using the number of patients in the All Treated Population.  
The total number of screening failures and the reasons for screen failure will be presented 
in a separate table. 
In addition, assignment to analysis populations, the study completion status, and the 
reason of withdrawal from the study, and the screening failures will be listed.  
7.2. 
Protocol Deviations 
Protocol deviations will be identified and classified at the data review meeting. 
Protocol deviations will be medically reviewed. Protocol deviations, especially related to 
occasional lack of adherence to the schedule of assessments or visit timings (primarily 
attributable to optimization in the clinical management of this fragile children 
population), will not be presented.  
In particular, the following situations will not be considered as protocol deviations: 
 Missing data if not occurring at 2 consecutive time points.  
 A  5-minute difference in the timing of vital sign measurements during 
emapalumab infusion. 
 A  10-minute difference in the timing of vital sign measurements after 
emapalumab infusion. 
Relevant protocol deviations categorized as major and minor will be tabulated in a 
summary table. Individual major and minor protocol deviations will be listed by patient.  
7.3. 
Demographics and Other Baseline Characteristics 
Summary statistics for age, sex, race, country of origin, height, weight, and body surface 
area (BSA) will be presented.  
The MAS features present at the time of diagnosis of the current episode, the overall level 
of MAS activity, the functional testing related to HLH if available, and the optional 
genetic testing results, if available will be tabulated. 
This analysis will be conducted for the All Treated Population and for the EVAL 
Population.  
The number and percent of patients reporting various medical histories, grouped by 
MedDRA SOC and preferred term (PT) will be tabulated for the All Treated Population. 
All demographics and baseline characteristics will be displayed in the data listings.  
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Statistical Analysis Plan,  
 
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7.4. 
Exposure and Drug Administration 
Investigational product administration will be summarized in terms of the number of 
doses received, average dose and cumulative dose per kg, and duration of exposure, from 
the first dose to the last dose of treatment.  
This analysis will be conducted for the All Treated Population. 
Drug administration and infusion details will be listed by patient and presented for the All 
Treated Population.  
8. 
Efficacy Analysis 
8.1. 
Efficacy Analysis 
The following binary efficacy endpoints will be described using counts, proportions, and 
exact Clopper-Person 95% CI: 
 Patients achieving MAS remission by Week 8 after initiation of emapalumab 
treatment 
 Patients for whom at any time during the study glucocorticoids can be tapered 
 Patients who tapered steroids to ≤1 mg/kg/day of prednisone equivalent dose 
 Patients withdrawn from the study due to lack of efficacy 
The following time-to-event efficacy endpoints will be analyzed descriptively: 
 Time to first MAS remission 
 Time to achievement of permanent glucocorticoids tapering  
 Survival time 
Summaries will include for each observed time, the survival estimate, failure rate, 
number of events and the number of patients remaining, also called population at risk. 
The median, lower quartile and upper quartile estimates of time-to-event and their 95% 
CI will be tabulated in a separate table. A Kaplan–Meier graph will be presented for each 
time-to-event endpoint. 
The efficacy analysis will be based on the All Treated Population. Efficacy analyses will 
be repeated for the EVAL Population.   
8.2. 
MAS Clinical Signs and Symptoms 
Descriptive summaries of the overall level of disease activity, clinical signs and 
symptoms by visit will be tabulated and patient-level data will be displayed in listing. 
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Statistical Analysis Plan,  
 
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9. 
Safety and Tolerability Analysis 
Safety will be evaluated from reported AEs, changes from baseline in clinical laboratory 
values, changes in vital signs, electrocardiogram (ECG), physical examination results, 
pregnancies, and emergence of anti-drug antibodies. 
All safety analyses will be performed on the All Treated Population.  
9.1. 
Adverse Events 
A summary table will present the number and percent of patients reporting:  
 Any AEs 
 Treatment-emergent AEs (TEAEs) 
 Non-TEAEs 
 Serious AEs (SAEs) 
 TEAEs leading to study treatment withdrawal  
 TEAEs resulting in death 
The table will show the number of events for each category.  
All AEs, TEAEs, and SAEs will be coded using the latest version of MedDRA. 
Summaries of the incidence (number and percentage of patients reporting the TEAE and 
the number of the TEAE) of TEAEs will be displayed by: 
 PT 
 SOC and PT 
 SOC, PT and maximum severity 
 SOC, PT and relationship to study drug  
TEAEs related to study drug will be displayed by SOC and PT in a separate table for 
readability.  
Summaries of the incidence of non-TEAEs will be displayed by PT. 
In the case of multiple occurrences of the same TEAE in the same patient, each patient will 
only be counted once for each PT. However, all multiple occurrences will be included in 
the number of events. In the summaries showing severity and relationship to the study drug, 
the event with the maximum severity or strongest relationship will be reported. If a 
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Statistical Analysis Plan,  
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particular event is missing the severity and/or relationship, then the strongest possible 
severity or relationship will be assumed for analysis (severity = severe, relationship =  
related). 
By-patient AE data listings with all AEs will be displayed. Adverse events that are not 
treatment emergent will be flagged. 
9.1.1. Treatment-Emergent Adverse Events Leading to Study Treatment 
Discontinuation 
The number and percentage of patients reporting the TEAE and the number of the TEAE 
leading to study treatment discontinuation, by SOC and PT will be tabulated for the All 
Treated Population.  
By-patient data listing of TEAEs leading to study treatment discontinuation will also be 
provided, displaying details of the event(s) captured on the CRF. 
9.1.2. Deaths and Serious Adverse Events 
Serious adverse events will be tabulated by: 

PT

SOC and PT.
By-patient data listing of AEs with a fatal outcome will be displayed. Serious adverse 
events will be described in a separate listing.  
9.1.3. Infusion-related Reactions 
The number and percentage of patients reporting IRRs and number of the events by PT 
will be tabulated in total and by maximum severity.  
In the case of multiple occurrences of the same TEAE in the same patient, each patient 
will only be counted once for each PT. In the case of different severities of the multiple 
occurrences of the same IRR in the same patient, the worse severity will be used for 
analysis. 
A by-patient listing of all IRR will be displayed. 
9.1.4. Infections 
The number and percentages of patients reporting infections and number of events, 
displayed by MedDRA PT, and will be tabulated in total and by maximum severity. 
A by-patient listing of all infections will be displayed with date of sampling, pathogen, 
source, type of investigation, result (positive, negative, numerical value and units), and 
the AE it was linked to.  
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Statistical Analysis Plan,  
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9.2. 
Clinical Laboratory Evaluations 
The number of patients with clinical laboratory values below, within, or above the normal 
range by time point and in relation to baseline will be tabulated for each clinical laboratory 
analyte (shift table). Denominator of the percentages will be the number of patients in the 
All Treated Population. 
Clinical chemistry and hematology results will be presented in separate tables. 
Urinalysis results will not be tabulated. Abnormalities in urinalysis results assessed 
as medically relevant will be recorded as AEs and analyzed as described in Section 9.1. 
Pregnancy test results will be tabulated by visit. 
All laboratory values will be displayed in the data listings and those that are outside the 
normal range will be flagged, along with corresponding normal ranges. 
9.3. 
Vital Signs 
Descriptive summaries of actual values by study day and time point will be calculated for 
systolic blood pressure (mmHg), diastolic blood pressure (mmHg), heart rate (bpm), 
oxygen saturation (%), and highest daily body temperature (Celsius).     
During an infusion, day time points include: 

pre-dose assessment

assessments during infusion at 15 minutes, 30 minutes, 45 minutes, 1 hour
15 minutes, 1 hour 30 minutes, 1 hour 45 minutes, and at the end of infusion and

post-dose assessments at 1 hour, 2 hours, 3 hours, 4 hours, and 24 hours
For each infusion day, the post-infusion changes from pre-dose will be calculated and 
displayed in summary tables for systolic blood pressure (mmHg), diastolic blood pressure 
(mmHg), heart rate (bpm), oxygen saturation (%), and highest daily body temperature 
(Celsius). From infusion #2 onwards the table will show the following time points: pre-
dose, end of infusion, and post-dose assessments at 1 hour, 4 hours, and 24 hours, if 
applicable. 
All vital signs will be provided in data listings. For systolic blood pressure, any reduction 
of ≥30% from baseline will be flagged.  
9.4. 
Electrocardiograms 
By-patient listing of all abnormal ECG results will be displayed. 
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9.5. 
Further Safety Evaluations 
9.5.1. Physical Examination 
By-patient listing of all abnormal findings will be displayed in each body system: general 
appearance, skin and mucous, ears/nose/throat, pulmonary, cardiac, gastro-intestinal, 
neurological, and other. 
Abnormalities related to physical examination assessed as medically relevant will be 
recorded as AEs and analyzed as described in Section 9.1. 
9.5.2. Pregnancy Outcome 
Abnormalities related to pregnancy outcome assessed as medically relevant will be 
recorded as AEs and analyzed as described in Section 9.1. 
9.5.3. Immunogenicity – anti-drug antibodies (ADAs) 
A list of patients who developed ADAs and neutralizing antibodies will be presented, 
including information about the findings and timing of occurrence.  
Descriptive summaries of ADA findings (neutralizing antibodies) will be tabulated when 
available. 
9.5.4. Other Exploratory Analyses 
Other exploratory analyses of safety data, including summaries for different subsets of 
patients, may be conducted. Any unplanned exploratory analysis performed will be 
clearly identified as such in the final CSR. 
Data in the following CRF forms will be included in listings only: 

Imaging

Brain magnetic resonance imaging (MRI)

Cerebrospinal fluid (CSF) analysis

Hospitalization

Concomitant procedures

Transfusion
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9.6. 
Concomitant Medication 
Concomitant medications by ATC level 2 will be summarized descriptively using counts 
and percentages. Concomitant medication administered for the treatment of sJIA will be 
also summarized and presented separately. 
Concomitant use of biologics will be also summarized and presented separately. 
Glucocorticoids administered since the date of MAS diagnosis will be summarized and 
presented separately as prednisone-equivalent mg/kg/day.   
Medications that start prior to initiation of study drug will be considered prior 
medications, whether or not they were stopped prior to treatment. Any medications that 
are continuing or start post-dose will be considered to be concomitant. Medications that 
start prior to initiation of study drug and continue post-dose will be considered both prior 
and concomitant. If the start/stop dates of a medication are partially or completely missing, 
then the medication will be assumed to be concomitant if it cannot be definitely shown that it 
was not administered during the treatment period. Missing dates will not be replaced. 
Concomitant medications and systemic glucocorticoids use from SD-3 until SD15 will be 
presented in separate listings.  
Medications will be coded using anatomical therapeutic chemical (ATC) classification 
level 2 (World Health Organization Drug Dictionary [WHO-DD] Version 2019). 
10.
Pharmacokinetic/Pharmacodynamic Analysis
PK and PK/PD analyses will be conducted separately and are not included in this SAP. 
However, descriptive summaries of circulating emapalumab and PD parameter, including 
marker levels, will be tabulated and included in this SAP. By-patient listing of circulating 
emapalumab, PD parameters, and marker levels will be displayed. 
11.
Changes from Planned Analysis
The Safety analysis set coincides with the All Treated Population and it is not listed in the 
analysis populations section. The EVAL Population has been added to check the 
robustness of the efficacy results. The Per-Protocol analysis set has been removed due to 
the small sample size and the introduction of the EVAL population.  
Infusion-related reaction has been added in the safety endpoints (Section 2.2.1). 
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Statistical Analysis Plan,  
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The glucocorticoids tapering endpoint has been modified when it is not possible to 
establish whether a patient have been treated for sJIA/AOSD or not before study start for 
all patients or when it is not possible to retrieve glucocorticoids dose administered before 
the occurrence of MAS for all patients who already are treated for sJIA/AOSD. In this 
case the endpoint is “Number of patients for whom, at any time during the study, 
glucocorticoids can be tapered by 50% (or more) of the dose administered at emapalumab 
treatment start. 
IL-10, sCD163, TNFa and IL-18 may be analysed and/or reported separately. 
The following have been added: 
•
safety patient profile reports (Section 12.1)
•
descriptive summaries of neutralizing antibody in case of positive ADA results 
(Section 9.5.3)
•
Number and percentage of patients who tapered steroids to ≤1mg/kg/day of the 
equivalent dose of prednisone (Section 6.1.7)
No other changes from the analyses specified in the protocol are planned. 
12.
Other Planned Analysis
12.1. Patient Profile Report 
A graphical display of the evolution of laboratory parameters and medications 
administered, collected for an individual patient and also known as patient profile report, 
will be presented. 
For each individual patient a PDF document will include the following data: 
o
Header: subject identification number, sex, study site, date of birth, age at
screening.
o
Administered dose (mg) of emapalumab by study day.
o
Equivalent dose of prednisone (mg/kg/day) by study day.
o
CXCL9 by study day.
o
Laboratory test results by study day:
o
C-Reactive protein (mg/dL)
o
Ferritin (ng/dL)
o
Triglycerides (mg/dL)
o
ALT/GPT (IU/L)
o
AST/GOT (IU/L)
o
LHD (IU/L)
o
White  blood cell (x1000/mcL)
o
Platelets (x1000/mcL)
o
D-Dimer (mcg/mL)
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Statistical Analysis Plan,  
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Protocol Number NI-0501-06  
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A niddle plot, i.e., a plot in which data points are connected by a vertical line that 
connects to a horizontal baseline, will be used for the prescribed dose of emapalumab.    
A connected scatterplot, i.e., a plot in which data points are represented by a dot and 
connected by straight line segments, will be used for the equivalent dose of prednisone  
and potentially other sJIA/MAS treatments and relevant laboratory test results. The 
header and the plots for the prescribed dose and the equivalent dose of prednisone will be 
repeated at the beginning of each page.  
The first page will include the CXCL9 data and in order the plots of the following 
laboratory test results:  ALT/GPT (IU/L), AST/GOT (IU/L), and LHD (IU/L). 
The second page will include in order the plots of the following laboratory test results:  
Ferritin (mcg/L), WBC (x10^9/L), platelets (x10^9/L), and D-Dimer (mcg/mL). 
The third page will include in order the  plots of the following laboratory test results:  
triglycerides (mmol/L) and C-Reactive protein (mg/dL). 
The X-axis of all plots will show the study day ranging from -14 to 70 for all patients. 
Laboratory normal ranges will be included in the plots when available.  
An example of patient profile report document is presented in Section 15.2. 
The same plots will be produced in RTF format with the header, the prescribed dose of 
emapalumab, and the equivalent dose of prednisone available only on the first page. 
Additional data, i.e. laboratory test results or concomitant medications,   may be added to 
the patient profile report.  
13.
References
1. US Federal Register. (1998) International Conference on Harmonization; Guidance 
on Statistical Principles for Clinical Trials. Department of Health and Human 
Services: Food and Drug Administration [Docket No. 97D-0174]. Federal Register 
Volume 63, Number 179, pages 49583-49598. September 16, 1998.
2. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee 
on Professional Ethics, April 2016.
http://www.amstat.org/about/ethicalguidelines.cfm
3. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014.
http://www.rss.org.uk/Images/PDF/join-us/RSS-Code-of-Conduct-2014.pdf
4. CDISC. SDTM Implementation Guide: Human Clinical Trials, Version 3.2, 2013. 
https://www.cdisc.org/standards/foundational/sdtmig
Page 36 of 77


 
Statistical Analysis Plan,  
 
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Protocol Number NI-0501-06  
 
PCN Number NOVI.6557 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
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14. 
Tables, Listings, and Figures 
All tables, listings, and graphs will have a header showing the sponsor company name 
and protocol and a footer showing the version of SAS, the file name and path, and the 
source of the data (CRF page or listing number). 
14.1. Planned Table Descriptions 
The following are planned summary tables for protocol number NI-0501-06. The table 
numbers and page numbers are placeholders only and will be determined when the tables 
are produced. 
 
 
Page 37 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI.6557 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
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 Page 37 of 51 
 
Table 3: Demographic Data Summary Tables and Figures 
Table/Figure 
Number 
Population(s) 
Table/Figure Title / Summary 
Supporting 
Listing 
14.1 Demographics and Baseline Characteristics 
Table 14.1.1 
All Treated 
Study Populations and Patient Disposition 
16.2.1.1 
16.2.1.2 
Table 14.1.2 
Screen Failures 
Reason of Screening Failure 
16.2.1.3 
Table 14.1.3.1 
All Treated, EVAL 
Summary of Demographics and Baseline Characteristics  
16.2.4.1 
Table 14.1.3.2 
All Treated, EVAL 
MAS Features Present at the Time of Diagnosis of the 
Current Episode 
16.2.4.5 
Table 14.1.3.3 
All Treated, EVAL 
Overall Level of MAS Activity 
16.2.4.6 
Table 14.1.3.4 
All Treated, EVAL 
Functional Testing Related to HLH 
16.2.4.7 
Table 14.1.3.5 
All Treated, EVAL 
Genetic Testing 
16.2.4.8 
Table 14.1.3.6 
All Treated 
Medical History by System Organ Class and Preferred Term 
16.2.4.2 
Table 14.1.4 
All Treated 
Protocol Deviations 
16.2.2.1 
 
 
 
Page 38 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI.6557 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
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 Page 38 of 51 
 
Table 4 Efficacy Data   
 
Table Number 
Population(s) 
Table Title / Summary 
Supporting 
Listing 
14.2 Efficacy Data 
Table 14.2.1 
All Treated, EVAL 
MAS Remission, Glucocorticoid Tapering,  and Lack of 
Efficacy 
16.2.6.1 
16.2.1.2 
Table 14.2.2.1 
All Treated, EVAL 
Statistical Analysis of Time to MAS Remission: Event-free 
Estimates by Day  
16.2.6.1 
Table 14.2.2.2 
All Treated, EVAL 
Statistical Analysis of Time to MAS Remission: Median and 
Quartile Estimates of Time to MAS Remission 
16.2.6.1 
Table 14.2.3.1 
All Treated, EVAL 
Statistical analysis of Time to Glucocorticoid Tapering: 
Event-free Estimates by Day  
16.2.6.1 
Table 14.2.3.2 
All Treated, EVAL 
Statistical Analysis of Time to Glucocorticoid Tapering: 
Median and Quartile Estimates of Time to Glucocorticoid 
Tapering 
16.2.6.1 
Table 14.2.4.1 
All Treated, EVAL 
Statistical Analysis of Time to Death: Survival Estimates by 
Day  
16.2.6.1 
Table 14.2.4.2 
All Treated, EVAL 
Statistical Analysis of Time to Death: Median and Quartile 
Estimates of the Survival  Time 
16.2.6.1 
Table 14.2.5 
All Treated, EVAL 
MAS Clinical Signs and Symptoms 
16.2.4.6 
 
 
 
Page 39 of 77


 
Statistical Analysis Plan,  
 
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Protocol Number NI-0501-06  
 
PCN Number NOVI.6557 
 
 
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 Page 39 of 51 
 
Table 5 Safety Data 
Table Number 
Population(s) 
Table Title / Summary 
Supporting 
Listing 
14.3 Safety Data 
14.3.1 Displays of Adverse Events 
Table 14.3.1.1 
All Treated 
Summary of All Adverse Events 
16.2.7.1 
Table 14.3.1.2.1 
All Treated 
Treatment-Emergent  Adverse Events by Preferred Term 
16.2.7.1 
Table 14.3.1.2.2 
All Treated 
Treatment-Emergent  Adverse Events by System Organ Class 
and Preferred Term 
16.2.7.1 
Table 14.3.1.3 
All Treated 
Treatment-Emergent Adverse Events by Maximum Severity, 
System Organ Class, and Preferred Term 
16.2.7.1 
Table 14.3.1.4 
All Treated 
Treatment-Emergent Adverse Events by Relationship to 
Study Drug, System Organ Class, and Preferred Term 
16.2.7.1 
Table 14.3.1.5 
All Treated 
Treatment-Emergent Adverse Events Related to the Study 
Drug by System Organ Class and Preferred Term 
16.2.7.1 
Table 14.3.1.6 
All Treated 
Non-Treatment-Emergent Adverse Events by Preferred Term 16.2.7.1 
14.3.2 Other Serious and Significant Adverse Events 
Table 14.3.2.1.1 
All Treated 
Serious Treatment-Emergent Adverse Events by Preferred 
Term 
16.2.7.2 
Table 14.3.2.1.2 
All Treated 
Serious Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
16.2.7.2 
Table 14.3.2.2 
All Treated 
Treatment-Emergent Adverse Events Leading to Study 
Treatment Discontinuation by System Organ Class and 
Preferred Term 
16.2.7.3 
Table 14.3.2.3 
All Treated 
Infusion-related Reaction by Preferred Term 
16.2.7.1 
Table 14.3.2.4 
All Treated 
Infections by Maximum Severity and Preferred Term. 
16.2.9.14 
 
 
 
Page 40 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI.6557 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 2.0   |    Date 29-Oct-2020      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 40 of 51 
 
Table Number 
Population(s) 
Table Title / Summary 
Supporting 
Listing 
14.3.5  Laboratory Data Summary Tables 
Table 14.3.5.1 
All Treated 
Shift Table of Clinical Chemistry Results  
16.2.8.1 
Table 14.3.5.2 
All Treated 
Shift Table of Hematology Results 
16.2.8.2 
Table 14.3.5.3 
All Treated (women) Pregnancy Test Results 
16.2.8.4 
14.3.6 Other Safety Data Summary Tables 
Table 14.3.6.1 
All Treated 
Vital Sign Results 
16.2.9.1 
Table 14.3.6.2.1 
All Treated 
Concomitant Medications by ATC Level 2 and Preferred 
Term 
16.2.9.3 
Table 14.3.6.2.2 
All Treated 
Concomitant Medications Administered for the Treatment of 
sJIA by ATC Level 2 and Preferred Term 
16.2.9.3 
Table 14.3.6.2.3 
All Treated 
Concomitant use of Biologics by ATC Level 2 and Preferred 
Term 
16.2.9.3 
Table 14.3.6.2.4 
All Treated 
Glucocorticoids Administered Since the Date of MAS 
Diagnosis 
16.2.9.3 
Table 14.3.6.3 
All Treated 
Summary of Exposure 
16.2.5.1 
 
 
 
Page 41 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI.6557 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 2.0   |    Date 29-Oct-2020      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 41 of 51 
 
Table 6 Pharmacokinetic/Pharmacodynamic Data 
Table Number 
Population(s) 
Table Title / Summary 
Supporting 
Listing 
14.4 Pharmacokinetic and Pharmacodynamic Data Summary Tables 
Table 14.4.1 
All Treated 
Summary of Pharmacodynamic Parameters 
16.2.10.1 
Table 14.4.2 
All Treated 
Summary of  Circulating Emapalumab 
16.2.10.1 
Table 14.4.3 
All Treated 
Summary of ADA Parameters 
16.2.10.1 
 
14.2. Planned Listing Descriptions 
The following are planned data and patient data listings for protocol number NI-0501-06.  
In general, one listing will be produced per CRF domain. 
All listings will be sorted by site and patient number. 
All calculated variables will be included in the listings. 
In all listings, a blank line will be placed between each patient. Within a data listing, if an 
item appears repetitively (e.g., patient number), then only the first occurrence will be 
displayed. 
In data listings, the information for a patient will be kept on a single page if possible, 
rather than splitting it across multiple pages. 
 
 
Page 42 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI.6557 
 
 
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Version 2.0   |    Date 29-Oct-2020      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 42 of 51 
 
Table 6: Planned Data Listings 
Data Listing Number 
Population 
Data Listing Title / Summary 
16.2 Patient Data Listings 
16.2.1 Patient Disposition 
Data listing 16.2.1.1 
All Treated 
Assignment to Analysis Populations 
Data listing 16.2.1.2 
All Treated 
Study Completion Status 
Data listing 16.2.1.3 
Screen Failures 
List of Reasons for Screening Failure 
16.2.2. Protocol Deviations 
Data listing 16.2.2.1 
All Treated 
Protocol Deviations 
16.2.3 Patients Excluded from the Evaluable Set 
Data listing 16.2.3.1 
All Treated 
List of Patients Excluded from EVAL 
Population 
16.2.4 Demographics and Other  Characteristics 
Data listing 16.2.4.1 
All Treated 
Demographic Data 
Data listing 16.2.4.2 
All Treated 
Medical History 
Data listing 16.2.4.3 
All Treated 
Prior Medications 
Data listing 16.2.4.4 
All Treated 
sJIA and MAS History 
Data listing 16.2.4.5 
All Treated 
MAS Diagnosis (Current Episode) 
Data listing 16.2.4.6 
All Treated 
MAS Clinical Signs and Symptoms 
Data listing 16.2.4.7 
All Treated 
Functional Testing Related to HLH 
Data listing 16.2.4.8 
All Treated 
Genetic Testing 
16.2.5 Drug Exposure 
Data Listing 16.2.5.1 
All Treated 
Drug Administration 
Data Listing 16.2.5.2 
All Treated 
Infusion 
16.2.6 Efficacy Listings 
Data listing 16.2.6.1  
All Treated 
MAS Remission, Glucocorticoid Tapering, 
and Mortality 
16.2.7 Adverse Event Listings 
Data listing 16.2.7.1 
All Treated 
Adverse Events 
Data listing 16.2.7.2 
All Treated 
Serious Adverse Events  
Page 43 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI.6557 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 2.0   |    Date 29-Oct-2020      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 43 of 51 
 
Data Listing Number 
Population 
Data Listing Title / Summary 
Data listing 16.2.7.3 
All Treated 
Treatment-Emergent Adverse Events Leading 
to Study Treatment Discontinuation  
Data listing 16.2.7.4 
All Treated 
Adverse Events Leading to Death 
16.2.8 Laboratory Data Listings 
Data listing 16.2.8.1 
All Treated 
Clinical Chemistry Results 
Data listing 16.2.8.2 
All Treated 
Hematology Results 
Data listing 16.2.8.3 
All Treated 
Urinalysis Results 
Data listing 16.2.8.4 
All Treated (Women) 
Pregnancy Test Results 
Data listing 16.2.8.5 
All Treated 
Other Laboratory Measurement Results 
16.2.9 Other Clinical Observations and Measurements  
Data listing 16.2.9.1 
All Treated 
Vital Signs  
Data listing 16.2.9.2 
All Treated 
Physical Examination Results 
Data listing 16.2.9.3 
All Treated 
Concomitant Medications 
Data listing 16.2.9.4 
All Treated 
Concomitant Procedure 
Data listing 16.2.9.5 
All Treated 
Systemic Glucocorticoids from SD-3 until 
SD15 
Data listing 16.2.9.6 
All Treated 
ECG Results 
Data listing 16.2.9.7 
All Treated 
Imaging: Abdominal Ultrasound 
Data listing 16.2.9.8 
All Treated 
Imaging: X-Ray 
Data listing 16.2.9.9 
All Treated 
Brain MRI 
Data listing 16.2.9.10 
All Treated 
CSF Analysis 
Data listing 16.2.9.11 
All Treated 
Hospitalization 
Data listing 16.2.9.12 
All Treated 
Serum PK/PD/ADA 
Data listing 16.2.9.13 
All Treated 
Transfusion 
Data listing 16.2.9.14 
All Treated 
Infections 
Data listing 16.2.9.15 
All Treated 
Infusion-related Reactions 
Data listing 16.2.9.16 
All Treated 
ADA Findings 
16.2.10 Pharmacokinetic and Pharmacodynamic Measurements 
Data listing 16.2.10.1 
All Treated 
Pharmacodynamic Measurements 
Data listing 16.2.10.2 
All Treated 
Pharmacokinetic Measurements 
Page 44 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI.6557 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 2.0   |    Date 29-Oct-2020      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 44 of 51 
 
 
14.3. Planned Figure Descriptions 
The following are planned summary figures for protocol number NI-0501-06. The figure 
numbers and page numbers are placeholders only and will be determined when the 
figures are produced. 
Table 7 Planned Figures 
Figure Number 
Population 
Figure Title / Summary 
Supporting Listing 
Figure 14.2.1 
All Treated 
Vital Sign Profiles: Systolic Blood Pressure 
16.2.9.1 
Figure 14.2.2 
All Treated 
Vital Sign Profiles: Diastolic Blood Pressure 
16.2.9.1 
Figure 14.2.3 
All Treated 
Vital Sign Profiles: Heart Rate 
16.2.9.1 
Figure 14.2.4 
All Treated 
Vital Sign Profiles: Temperature 
16.2.9.1 
Figure 14.2.5 
All Treated 
Vital Sign Profiles: Oxygen Saturation 
16.2.9.1 
Figure 14.2.6 
All Treated 
Statistical Analysis of Time to MAS Remission: 
Kaplan-Meier Curve 
16.2.6.2 
Figure 14.2.7 
All Treated 
Statistical Analysis of Time to Glucocorticoid 
Tapering: Kaplan-Meier Curve 
16.2.6.2 
Figure 14.2.8 
All Treated 
Statistical Analysis of Time to Death: Kaplan-
Meier curve 
16.2.6.2 
 
Moreover, a patient profile report will be produced for each individual. The PDF 
document including the patient profile will be named pp_<subjectid>.pdf. . 
Page 45 of 77


Statistical Analysis Plan,  
Sponsor Sobi AG  
Protocol Number NI-0501-06  
PCN Number NOVI.6557
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 2.0   |    Date 29-Oct-2020      |    AD-PR-109.01  Effective date: 26-Jun-2017 
 Page 45 of 51 
15.
Tables, Listings, and Listing Shells
15.1. 
Standard Layout for all Tables, Listings, and Figures
Table and listing shells are provided as a separate document.  
Note that programming notes may be added if appropriate after each TLF shell. 
The final statistical tables will be produced in the format of the shells and will 
additionally include “double” page numbering in the format “page xx of yy.” The first 
page numbering will count all pages of the document continuously and the second 
numbering will count the pages for each table separately.  
The standardized layout of tables and listing will include information about source data, 
program path and name, date and time of program execution, and date of database. 
The final statistical output will be provided as fully bookmarked pdf file, including a 
table of contents. 
No shells are provided for figures. However, an example of a patient profile report is 
provided in Section 15.2.  
15.2. 
Planned Patient Profile Shells 
The planned patient profile shells are presented in Figure 1. 
Page 46 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI.6557 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
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 Page 46 of 51 
 
Figure 1: Patient Profile Shells 
 
 
 
I 
premier' 
research) 
Page 47 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI.6557 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 2.0   |    Date 29-Oct-2020      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 47 of 51 
 
 
 
 
 
I 
premier' 
research) 
Page 48 of 77


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI.6557 
 
 
AD-ST-33.04 Effective date: 30-Jun-2017 
Version 2.0   |    Date 29-Oct-2020      |    AD-PR-109.01  Effective date: 26-Jun-2017  
 Page 48 of 51 
 
 
 
I 
premier' 
research) 
Page 49 of 77


 
Statistical  Analysis Plan,  
 
Sponsor Sobi AG 
 
Protocol Number NI-0501-06  
 
PCN Number NOVI.6557 
 
 
Version 2.0    |    Date 29-Oct-2020     |    AD-PR-109.01  Effective date: 26-Jun-2017  
  
 
Appendix 1: Premier Research Library of Abbreviations 
Abbreviation 
Definition 
ADA 
anti-drug antibodies 
AE 
adverse event 
AOSD 
adult-onset Still’s disease 
ATC 
anatomical therapeutic chemical 
ALT 
alanine aminotransferase 
ASA 
American statistical association 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BSA 
body surface area 
CBC 
complete blood count 
CEOI 
concentration at the end of infusion 
CI 
confidence intervals 
Cmax 
concentration corresponding to Tmax 
CRF 
case report form 
CRP 
C-reactive protein 
CSF 
cerebrospinal fluid  
CSR 
clinical study report 
Ctrough 
concentration just before administration 
CXCL9 
Chemokine (C-X-C Motif) Ligand 9 
Page 50 of 77


 
Statistical  Analysis Plan,  
 
Sponsor Sobi AG 
 
Protocol Number NI-0501-06  
 
PCN Number NOVI.6557 
 
 
Version 2.0    |    Date 29-Oct-2020     |    AD-PR-109.01  Effective date: 26-Jun-2017  
  
 
Abbreviation 
Definition 
CXCL10 
Chemokine (C-X-C Motif) Ligand 10 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
EVAL 
evaluable 
HLH 
Hemophagocytic lymphohistiocytosis 
IL 
interleukin 
INFγ 
Interferon gamma 
IMP 
Investigational medicine product 
LDH 
lactate dehydrogenase 
LFT 
liver function tests 
LLN 
lower limit of normal 
LOCF 
last observation carried forward 
MAS 
macrophage activation syndrome 
MedDRA 
medical dictionary for regulatory activities 
MRI 
magnetic resonance imaging 
NCA 
non-compartmental pharmacokinetic analysis 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PT 
preferred term 
SAE 
serious adverse event 
Page 51 of 77


 
Statistical  Analysis Plan,  
 
Sponsor Sobi AG 
 
Protocol Number NI-0501-06  
 
PCN Number NOVI.6557 
 
 
Version 2.0    |    Date 29-Oct-2020     |    AD-PR-109.01  Effective date: 26-Jun-2017  
  
 
Abbreviation 
Definition 
SAP 
statistical analysis plan 
SAS®  
a software system used for data analysis 
sCD25 
soluble CD25 (i.e soluble IL-2 receptor) 
sCD163 
soluble CD163 
SD 
study day 
sHLH 
secondary HLH 
sJIA 
juvenile idiopathic arthritis 
SOC 
system organ class 
t1/2 
serum half-life 
TEAE 
treatment-emergent adverse event 
TLF 
table listing figure 
Tmax 
time of maximum observed concentration 
TMDD 
target-mediated drug disposition 
TNFα 
tumor necrosis factor alpha 
US 
ultrasound  
ULN 
upper limit of normal 
WBC 
white blood cell 
WHO-DD 
world health organization drug dictionary 
 
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AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 1 of 18 
   Errata of Statistical Analysis Plan 
Sponsor 
Sobi AG 
Protocol 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)  
Protocol Number: 
NI-0501-06 
Premier Research PCN: 
NOVI 176557 
Document Version: 
Final Version 2.0 
Document Date: 
22-Jul-2021
Approvals 
Role 
Signatures 
Biostatistician 
Print Name: 
Senior Biostatistician, Premier Research 
Sign Name: 
Page 53 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 2 of 18 
 
 
Role 
Signatures 
Sobi AG 
Representative 
Print Name: 
Statistical Science Director, Sobi 
Sign Name: 
 
 
 
 
 
 
 
 
Page 54 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 3 of 18 
 
 
Document History 
The errata of the statistical analysis plan (SAP) describes the last changes compared to signed 
statistical analysis plan version 2.0 (dated on 29-OCT-2020) reported for Sobi AG protocol 
number NI-0501-06 (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)). 
The changes identified in this document will be included in the clinical study report (CSR), in 
regulatory submissions, or future manuscripts. Post-hoc exploratory analyses are not part of this 
document and should be specified in a separate document, if any. Any post-hoc or unplanned, 
exploratory analysis performed will be clearly identified as such in the final CSR. 
The changes described hereafter will be submitted to file prior to the database lock pertaining to 
study NI-0501-06. 
Version 1.0 (Dated 19 April 2021): 
 Not applicable – first version. 
Version 2.0 (Dated: 22 July 2021): 
Section 6.1.5 – Analysis Visit Windows/ Assessment selection: New rules added for 
selection of assessments used in outputs where multiple records exist within a visit 
window. 
Section 6.1.7 - Derived variables/ MAS remission: Updated visit windowing rules for 
MAS remission and time to MAS remission to be in line with assessment selection rules. 
Section 6.1.7 – Derived variables/ Definition of Biologics: Updated from L03AC to 
L04AC due to typo when defining medications. 
Section 6.1.7 – Derived variables/ Steps to calculate the prednisone equivalent dose 
(mg/kg/day) and total daily doses of anakinra, canakinumab, ciclosporin, etoposide, 
methotrexate, and tocilizumab: Wording added to clarify prednisone equivalent dose and 
total daily doses should be calculated from study day -180 and until the end of the study. 
Section 6.1.8 - Data Adjustments/Handling/Conventions/ Handling partial or missing 
start/stop dates for equivalent daily dose of prednisone, and daily total doses of anakinra, 
canakinumab, ciclosporin, etoposide, methotrexate, and tocilizumab: Clarified derivation 
of medication imputed dates and when to calculate equivalent dose of prednisone and 
total daily dose when start date is missing and end date is not missing. 
Section 7.2 – Protocol Deviations: Implemented new terminology used in categorization 
of deviations referenced in the ICH E3 Q&A R1 and ICH GCP E6 R2 and update to 
terminology in output displays to align.  
Page 55 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 4 of 18 
 
 
Section 6.1.8 - Data Adjustments/Handling/Conventions and Section 9.1 – Adverse 
Events: Correction to MedDRA version used in coding. 
 
 
Page 56 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 5 of 18 
 
 
Summary of Amended Sections 
SAP Section(s)/ 
Purpose 
Initial text from SAP version 2.0 
Rationale 
/ 
Updated text 
Section 6.1.5 – 
Analysis Visit 
Windows / 
Assessment 
selection 
No rules specified for the selection of 
assessments where multiple assessments may be 
eligible for tables except for Week 8 assessment. 
Rules for selection of assessments 
used in Week 8 assessment of 
MAS 
remission 
provided 
in 
section 
6.1.5, 
however 
no 
information provided for other 
safety and efficacy analysis and 
timepoint. 
/ 
“In case there are two (or more) 
assessments from a subject within 
the visit window, the assessment 
with the date closest to the 
expected visit date will be used for 
the efficacy and safety analysis. In 
the event that two assessments are 
available and equidistant from the 
expected visit date, the result from 
earliest assessment will be used. If 
there are still two or more 
assessments recorded during the 
same 
day, 
the 
earliest 
measurement 
before 
the 
emapalumab infusion will be used 
(not applicable for the assessment 
of MAS remission at Week 8). If 
there is no treatment on the 
selected 
day, 
the 
earliest 
assessment of the selected day will 
be selected (not applicable for the 
assessment of MAS remission at 
Week 8). If there is no possibility to 
identify the earliest assessment, 
the assessment with the earliest 
sequence number will be used.” 
Page 57 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 6 of 18 
 
 
SAP Section(s)/ 
Purpose 
Initial text from SAP version 2.0 
Rationale 
/ 
Updated text 
Section 6.1.7 -  
Derived 
variables/ 
New Age group 
variable 
No age group was defined in the SAP version 
2.0. 
Results 
will 
be 
posted 
and 
published in Eudra CT and 
predefined age group should be 
displayed 
as 
per 
template, 
therefore age group variable will 
be created and presented in the 
demographic table. 
/ 
The new age group variable will be 
defined as follows 
Age Group 
Definition 
Newborns (0-
27 days) 
0 
≤ 
(Date 
of 
informed consent 
– Date of Birth) ≤ 
27 
Infant 
and 
toddlers (28 
days 
- 23 
months) 
28 
≤ 
(Date 
of 
informed consent – 
Date of Birth) and 
age in years = 1 
Children (2-
11 years) 
2 <= age in years <= 
11 
Adolescents 
(12-17 
years) 
12 <= age in years 
<= 17 
From 18-64 
years 
18<= age in years 
<= 64 
From 65-84 
years 
65 <= age in years 
<= 84 
Over 
85 
years 
85 <= age in years 
 
 
 
Page 58 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 7 of 18 
 
 
Section 6.1.7 -  
Derived 
variables/ 
IRR with missing 
start date 
“If the onset time of the AE or the start time of 
the infusion is missing, then an AE with an onset 
date equal to an infusion date or infusion date + 
1 will be considered for the assessment of 
IRRs.” 
Describe how completely missing 
AE start date will be imputed for 
an IRR assessment. 
/ 
Corrected to “If the onset time of 
the AE or the start time of the 
infusion is missing, then an AE 
with an onset date equal to an 
infusion date or infusion date + 1 
will 
be 
considered 
for 
the 
assessment of IRRs. If the onset 
date of the AE is completely 
missing, the AE will be considered 
as 
IRR 
(most 
conservative 
approach).” 
Section 6.1.7 - 
Derived 
variables/ 
Infection 
definition 
“Infection = any TEAEs part of the SOC 
'infection and infestation'” 
Infection definition updated to a 
broader search strategy for all 
potential 
infections 
with 
emapalumab use. 
/ 
Updated to Infection = All AEs in 
the 
SOC 
“Infections 
and 
infestations” or in the HLGT 
“Microbiology 
and 
serology 
investigations”. 
Section 6.1.7 - 
Derived 
variables/ 
Selection of 
systemic 
glucocorticoid 
dose 
“Select concomitant medications with ATC 
code H02B” 
Selection should be applied on 
ATC code H02AB. The ATC level 
4 
H02AB 
correctly 
and 
specifically 
corresponds 
to 
GLUCOCORTICOIDS, whereas 
in the SAP version 2.0, selection 
by code H02B is an error, as this 
code does not include plain 
glucocorticoid products, but only 
combinations 
(CORTICOSTEROIDS 
FOR 
SYSTEMIC 
USE, 
COMBINATIONS).  
Page 59 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 8 of 18 
 
 
/ 
Corrected to “Select medications 
with ATC Level 4 code H02AB” 
Section 6.1.7 – 
Derived 
variables/  
Steps to calculate 
the prednisone 
equivalent dose 
(mg/kg/day) 
“4) Select the weight in kg from the physical 
examination visit closest to the glucocorticoids 
administration date.” 
Further clarification on which 
assessment should be selected if 
observations are equidistant and 
prior 
to 
first 
treatment 
administration. 
/ 
Under the Steps to calculate the 
prednisone 
equivalent 
dose 
(mg/kg/day), corrected to: 
“4) Select the weight in kg from the 
physical examination visit closest 
to 
the 
glucocorticoids 
administration date. If there are 2 
such 
observations 
that 
are 
equidistant 
from 
the 
glucocorticoids 
administration 
date, the first observation will be 
selected. Prior to first treatment 
administration, the weight at 
screening will be selected.” 
Section 6.1.7 – 
Derived 
variables/  
Steps to calculate 
the prednisone 
equivalent dose 
(mg/kg/day) and 
total daily doses 
of anakinra, 
canakinumab, 
ciclosporin, 
etoposide, 
methotrexate, and 
tocilizumab 
No specification of time frame for calculation of 
equivalent prednisone dose or total daily doses 
of 
anakinra, 
canakinumab, 
ciclosporin, 
etoposide, methotrexate, and tocilizumab. 
To add detail on when equivalent 
daily dose of prednisone, and daily 
total 
doses 
of 
anakinra, 
canakinumab, 
ciclosporin, 
etoposide, 
methotrexate, 
and 
tocilizumab will be derived. 
/ 
Specifications added: “Equivalent 
daily dose of prednisone, and daily 
total 
doses 
of 
anakinra, 
canakinumab, 
ciclosporin, 
etoposide, 
methotrexate, 
and 
tocilizumab will be derived from 
study day -180 until the end of the 
study.” 
Page 60 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 9 of 18 
 
 
Section 6.1.7 - 
Derived 
variables/ 
Conversion factor 
for derivation of 
equivalent dose of 
prednisone 
“where the conversion factor is: 
1 for prednisone  
1.25 for methylprednisolone 
1 for prednisolone” 
 
The use of dexamethasone was 
not considered initially and should 
be added as administered to some 
patients. 
/ 
Corrected to “where the 
conversion factor is: 
1 for prednisone  
1.25 for methylprednisolone 
1 for prednisolone 
6 for dexamethasone” 
Section 6.1.7 - 
Derived 
variables/  
MAS remission 
“The MAS remission evaluation is based on a 
combination 
of 
assessments, 
including 
Investigator assessment and laboratory findings. 
The latest date of assessments, within the visit 
window of ± 3 days around the planned day of 
the visit, will be used for the calculation of the 
time to MAS remission.” 
To clarify assessment handling for 
the MAS remission. Currently in 
the SAP, it specifies “If one or 
more 
laboratory 
data 
are 
unavailable 
within 
the 
visit 
window” but no details on the visit 
windows. 
/ 
Updated to: “The MAS remission 
evaluation 
is 
based 
on 
a 
combination 
of 
assessments, 
including Investigator assessment 
and laboratory findings, and will 
only 
be 
calculated 
if 
the 
Investigator assessment has been 
performed. The earliest date of 
assessments, within a visit window 
of ± 3 days, will be used in the 
calculation 
of 
the 
individual 
assessments feeding into MAS 
remission. See Section 6.1.5 for 
further details on assessment 
selection. The latest date of the 
combination of assessments within 
a visit window will be used for the 
calculation of time to MAS 
remission and MAS remission." 
Page 61 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 10 of 18 
 
 
Section 6.1.7 – 
Derived 
variables/ 
Definition of 
Biologics  
No specification of biologics concomitant used 
is specified in the SAP version 2.0. 
Concomitant 
use 
of 
relevant 
biologics will be also summarized 
per section 9.6 however no 
specification was provided under 
section 6.1.7. 
/ 
Specifications added: “Relevant 
concomitant biologics medications 
will be defined as medications 
from 
ATC 
4 
levels 
L04AB, 
L04AC.” 
Section 6.1.8 - 
Data 
Adjustments/Han
dling/Convention
s/ 
Handling partial 
or missing 
start/stop dates 
for equivalent 
daily dose of 
prednisone, and 
daily total doses 
of anakinra, 
canakinumab, 
ciclosporin, 
etoposide, 
methotrexate, and 
tocilizumab 
 
No details regarding how to handle partial or 
missing start/stop dates for equivalent daily dose 
of prednisone, and daily total doses of anakinra, 
canakinumab, 
ciclosporin, 
etoposide, 
methotrexate, and tocilizumab 
To add detail on how to handle 
partial or missing start/stop dates 
for equivalent daily dose of 
prednisone, and daily total doses of 
anakinra, 
canakinumab, 
ciclosporin, 
etoposide, 
methotrexate, and tocilizumab. 
/ 
Imputation 
of 
partial/missing 
medication start or stop dates for 
equivalent 
daily 
dose 
of 
prednisone and daily total doses of 
anakinra, 
canakinumab, 
ciclosporin, 
etoposide, 
methotrexate, and tocilizumab: 
-Partial medication end date 
 If only month and year are 
available, medication end 
date will be imputed to the 
last 
day 
of 
the 
corresponding month 
 If only year is available, 
medication end date will be 
imputed to the 31st of 
December of 
the 
corresponding year 
-Partial medication start date 
 If only month and year are 
available, medication start 
Page 62 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 11 of 18 
 
 
date will be imputed to the 
1st 
day 
of 
the 
corresponding month 
 If only year is available, 
medication start date will 
be imputed to the 1st of 
January 
of 
the 
corresponding year. 
-Medication start and end dates are 
both missing, then the record of the 
medication will not be considered 
(i.e. no derivation of equivalent 
dose of prednisone or daily dose of 
anakinra, ….). 
-Medication end date is missing 
(and medication start date not 
missing) 
 When medication end date 
is missing and “Ongoing” 
is not ticked 
 If medication start 
date < Study day -
180, 
then 
this 
record will not be 
considered (i.e. no 
derivation 
of 
equivalent dose of 
prednisone or daily 
dose of anakinra, 
….). 
 If Study day -180 ≤ 
medication 
start 
date < Study day 0, 
then 
medication 
end date is set to 
medication 
start 
date. 
 If medication start 
date ≥ Study day 0, 
then 
medication 
end date is set to 
end of study date of 
Page 63 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 12 of 18 
 
 
the corresponding 
patient.  
 When “Ongoing” is ticked, 
then medication end date is 
set to end of study date of 
the corresponding patient 
unless 
medication 
start 
date > end of study date 
then set to medication start 
date of the corresponding 
patient. 
-Medication start date is missing 
(and Medication end date is not 
missing) 
 If medication end date < 
Study day -180, then this 
record 
will 
not 
be 
considered 
(i.e. 
no 
derivation of equivalent 
dose of prednisone or daily 
dose of anakinra, ….).  
 If medication end date ≥ 
Study day -180, then the 
medication start date will 
be set to the medication 
end date. 
Note: medication end date if 
available should have priority over 
the ongoing flag. 
Section 6.1.8 - 
Data 
Adjustments/ 
Handling/ 
Conventions/ 
Handling < 
LLOQ, > ULOQ 
 
No details regarding how the laboratory data 
below or above the limit of quantification will 
be handled. 
Imputation rules to be applied to 
shift table when laboratory data 
below or above the limit of 
quantification. Laboratory listings 
will present data as collected. 
/ 
Imputation rules added: “Values 
below 
the 
lower 
limit 
of 
quantitation (i.e. < LLOQ) for 
individual values will be imputed 
to zeros when summarizing for 
Page 64 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 13 of 18 
 
 
descriptive statistics. Values above 
the upper limit of quantitation (i.e. 
> ULOQ) for individual values 
will be imputed to ULOQ values 
when summarizing for descriptive 
statistics.” 
Section 7.2 – 
Protocol 
Deviations / 
Correction 
“Relevant protocol deviations categorized as 
major and minor will be tabulated in a summary 
table. Individual major and minor protocol 
deviations will be listed by patient.” 
Change in category terminology 
(applicable to the classification of 
deviations from a study conduct 
perspective) 
to 
align 
with 
references in regulations ICH E3 
Q&A R1 and ICH GCP E6 R2. 
/ 
Corrected to: “Relevant protocol 
deviations categorized as important 
and non important will be tabulated 
in a summary table. Individual 
important 
and 
non 
important 
protocol deviations will be listed by 
patient.” 
Section 7.3 - 
Demographics 
and Other 
Baseline 
Characteristics / 
New Age group 
variable 
“Summary statistics for age, sex, race, country 
of origin, height, weight, and body surface area 
(BSA) will be presented.”  
Pre-defined age group, as defined 
per Eudra CT publishing template, 
was added (see Section 6.1.7) and 
will 
be 
summarized 
in 
the 
demographic table. 
/ 
Updated to: “Summary statistics 
for age (as continuous and 
categorical variables), sex, race, 
country of origin, height, weight, 
and body surface area (BSA) will 
be presented.” 
Section 9.1.2 – 
Deaths and 
Serious Adverse 
Events/ 
Correction 
“Serious adverse events will be tabulated by:” 
 
Corrected to:  
“Serious TEAEs will be tabulated 
by:” 
Section 6.1.8 – 
Data 
Section 6.1.8 states “Adverse events will be coded 
using the latest version of the Medical Dictionary 
Correction 
of 
the 
MedDRA 
version. 
Page 65 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 14 of 18 
 
 
Adjustments/ 
Handling/ 
Conventions 
and 
Section 9.1 – 
Adverse Events / 
Correction 
for Regulatory Activities (MedDRA).” 
 
Section 9.1 states “All AEs, TEAEs, and SAEs 
will be coded using the latest version of 
MedDRA.” 
/ 
Corrected to: 
Section 6.1.8: “Adverse events will 
be coded using Medical Dictionary 
for Regulatory Activities (MedDRA) 
version 23.0.” 
Section 9.1: “All AEs, TEAEs, and 
SAEs will be coded using MedDRA 
version 23.0.” 
Section 9.3 – 
Vital signs/  
Temperature 
presented per 
route 
No details regarding how the temperature will 
be presented. 
As temperature could be measured 
at different location, summary 
statistics and change from baseline 
should consider the location/route. 
/ 
Sentence added: “Highest daily 
body 
temperature 
will 
be 
presented by route; shift tables will 
display baseline and post-baseline 
body temperatures from the same 
route.” 
Sections 9.6 – 
Concomitant 
Medication / 
Remove of 
Concomitant 
Medications 
Administered for 
the Treatment of 
sJIA analysis 
“Concomitant Medications Administered for the 
Treatment of sJIA will be also summarized and 
presented separately.” 
A number of medications can be 
administered to treat both sJIA and 
MAS. The investigators may 
record either sJIA or MAS (or 
both) as indication for their use. A 
summary table presenting only 
medications administered to treat 
sJIA may provide partial and 
potentially 
misleading 
information. 
All 
concomitant 
medications with their reported 
indications will be presented in 
listings. It was decided that the 
following 
sentence 
will 
be 
removed: 
“Concomitant 
medication 
administered for the treatment of 
sJIA will be also summarized and 
presented separately.” 
Page 66 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 15 of 18 
 
 
Section 9.6 – 
Concomitant 
Medication/ 
WHO-DD 
version correction 
“Medications will be coded using anatomical 
therapeutic 
chemical 
(ATC) 
classification 
level 2 (World Health Organization Drug 
Dictionary [WHO-DD] Version 2019).” 
Correction 
of 
the 
WHO-DD 
version 
/ 
Corrected to:  
“Medications will be coded using 
anatomical therapeutic chemical 
(ATC) classification level 2 (World 
Health 
Organization 
Drug 
Dictionary [WHO-DD] Version 
March 2020).” 
Section 12.1 – 
Patient profile 
report/ 
Removal of DOB 
“Header: subject identification number, sex, 
study site, date of birth, age at screening.” 
 
As described for Section 15.2, 
Date of birth (DOB) is protected 
information under the GDPR, 
therefore the DOB was removed 
from the patient profile. 
/ 
Corrected to: “Header: subject 
identification number, sex, study 
site, age at screening (years).” 
Section 14.1, 
Table 5 – Safety 
Data/ 
Remove of 
Concomitant 
Medications 
Administered for 
the Treatment of 
sJIA table 
Concomitant Medications Administered for the 
Treatment of sJIA by ATC Level 2 and 
Preferred Term 
 
As detailed for Section 9.6, the 
table on Concomitant Medications 
Administered for the Treatment of 
sJIA by ATC Level 2 and 
Preferred Term will be removed. 
/ 
Remove Table 14.3.6.2.2 from the 
list of Tables. 
Section 14.1, 
Table 5 – Safety 
Data/ 
Update 
Concomitant use 
of Biologics 
“Concomitant use of Biologics by ATC Level 2 
and Preferred Term” 
Display by ATC level 4 instead on 
ATC level 2 as selection of 
medications are based on ATC 
Level 4. 
/ 
Corrected to: “Concomitant use of 
Biologics by ATC Level 4 and 
Preferred Term” 
Section 14.3 – 
Figures 14.2.6, 14.2.7, 14.2.8, described as Per section 8.1, “The efficacy 
Page 67 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 16 of 18 
 
 
Planned Figure 
Descriptions/ 
Update 
populations 
Kaplan Meier curves, will be produced on the 
All Treated Population per the Population 
column. 
analysis will be based on the All 
Treated 
Population. 
Efficacy 
analyses will be repeated for the 
EVAL 
Population.”; 
figures 
should also be produced on the 
Evaluable Population 
/ 
Corrected 
to: 
“All 
Treated 
Population, 
All 
Evaluable 
Population” 
Section 15.2 – 
Figure 1: Patient 
Profile Shells/ 
Remove DOB 
from the Patient 
Profile 
Date of birth (DOB) is protected 
information under the GDPR. The 
age in years is sufficient and there 
is no need to present the DOB.   
/ 
Removal of Date of Birth in the 
header of Patient Profile as age in 
years is sufficient. 
 
 
 
Page 68 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 17 of 18 
 
 
List of Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AOSD 
adult onset Still’s disease 
ATC 
anatomical therapeutic chemical 
BSA 
body surface area 
CSR 
clinical study report 
DOB 
date of birth 
Eudra CT 
European Union Drug Regulating Authorities Clinical Trials Database 
GCP 
Good Clinical Practice 
GDPR 
general data protection regulation 
HLGT 
high level group term 
HLH 
hemophagocytic lymphohistiocytosis  
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IRR 
infusion related reactions 
LLOQ 
lower limit of quantification 
MAS 
macrophage activation syndrome 
MedDRA 
medical dictionary for regulatory activities 
SAP 
statistical analysis plan 
SD 
study day 
Page 69 of 77


 
Errata v2.0 of Statistical Analysis Plan v2.0,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 22-Jul-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 18 of 18 
 
 
Abbreviation 
Definition 
SOC 
system organ class 
sJIA 
systemic juvenile idiopathic arthritis 
TEAE 
treatment-emergent adverse event 
ULOQ 
upper limit of quantification 
WHO-DD 
world health organization drug dictionary 
 
Page 70 of 77


AD-ST-33.06 Effective date: 12-Nov-2020 
Version 1.0    |    Date 22-Apr-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 1 of 7 
   Post-hoc Analysis Plan 
Sponsor 
Sobi AG 
Protocol 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) 
Protocol Number: 
NI-0501-06 
Premier Research PCN: 
NOVI 176557 
Document Version: 
Final Version 1.0 
Document Date: 
22-Apr-2021
Approvals 
Role 
Signatures 
Biostatistician 
Print Name: 
Senior Biostatistician, Premier Research 
Sign Name: 
Page 71 of 77
SIGN


Post-hoc Analysis Plan,  
Sponsor Sobi AG  
Protocol Number NI-0501-06  
PCN Number NOVI 176557
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 1.0    |    Date 22-Apr-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 2 of 7 
Role 
Signatures 
Sobi AG 
Representative 
Print Name: 
Senior Statistical Scientist, Sobi 
Sign Name: 
Page 72 of 77


Post-hoc Analysis Plan,  
Sponsor Sobi AG  
Protocol Number NI-0501-06  
PCN Number NOVI 176557
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 1.0    |    Date 22-Apr-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 3 of 7 
Document History 
The post-hoc analysis plan describes additional analyses to the signed Statistical Analysis Plan 
(SAP) version 2.0 (dated on 29-OCT-2020) considering the SAP Errata version 1.0 (dated on 19-
Apr-2021) reported for Sobi AG protocol number NI-0501-06 (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)). 
The post-hoc analyses identified in this document will be included in the clinical study report 
(CSR), in regulatory submissions, or future manuscripts. Any post-hoc or unplanned, exploratory 
analysis performed will be clearly identified as such in the final CSR. In that regards, “Post-Hoc 
Analysis” will be added on the top right header of each additional outputs described in the current 
document. 
Page 73 of 77


 
Post-hoc Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 1.0    |    Date 22-Apr-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 4 of 7 
 
 
Post-hoc analysis description  
SAP Section 
Description 
Section 6.1.7 - 
Derived 
variables 
 
The following variables will be added and derived: 
• Number of emapalumab doses = number of emapalumab doses received 
during the study regardless the dose was completed or interrupted. 
• Prescribed dose of emapalumab (mg/kg) = prescribed dose of 
emapalumab (mg) / weight (kg) 
• Cumulative prescribed dose of emapalumab (mg/kg) = sum of prescribed 
emapalumab doses (mg/kg) 
• 
Average prescribed dose of emapalumab (mg/kg) = (cumulative dose of 
emapalumab)/(number of doses) 
Section 7.4 – 
Exposure and 
drug 
administration 
The following text will be added for creation of a new variables and listing: 
Study drug exposure data (date of first dosing, date of last dosing, the number 
of doses received, prescribed dose (mg/kg), average prescribed dose (mg/kg), 
cumulative prescribed dose (mg/kg), average administered dose (mg/kg), 
cumulative administered dose (mg/kg), and duration of exposure (days)), will 
be listed for patients in the All Treated Population. 
Section 8.1 – 
Efficacy 
analysis 
The following text will be added for creation of new listing: 
Assessments to MAS remission data will be presented in data listing using the 
All Treated Population.  
Section 9.1 – 
Adverse 
events 
The following text will be added for creation of new table: 
Summary of the incidence of non-serious TEAEs will be displayed by SOC and 
PT. 
Section 12 – 
Other Planned 
Analysis 
New narrative figure per patient: 
• Overview of sJIA and/or MAS therapies prior to emapalumab initiation 
 
Presentation of MAS episodes and treatments from Study day -180 to Study 
day 0. 
 
The following medications will be presented separately:  
anakinra, canakinumab, ciclosporin, etoposide, and tocilizumab  
 
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Post-hoc Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 1.0    |    Date 22-Apr-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 5 of 7 
 
 
SAP Section 
Description 
Medications under ATC level 4 ‘H02AB’ will be presented under ‘Equivalent 
dose of Prednisone’. Pulses (i.e. equivalent dose of prednisone ≥ 20 mg/kg/day) 
will be presented using symbol. 
Anakinra daily dose (mg/kg/day) will be displayed from Study day -180 to Study 
day 0. 
Section 14.1  - 
Planned Table 
Descriptions 
New table: 
• Table 14.3.1.7- Non Serious Treatment-Emergent Adverse Events by 
SOC and Preferred Term 
Section 14.2  - 
Planned 
Listing 
Descriptions 
 
New listings: 
• Data Listing 16.2.4.9 – MAS History Comments 
• Data Listing 16.2.5.3 – Study Drug Exposure, All Treated Population 
• Data Listing 16.2.6.2 – Assessment of MAS Remission, All Treated 
Population 
• Data Listing 16.2.9.17 - Search for Infection, All Treated Population 
Page 75 of 77


 
Post-hoc Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-06  
 
PCN Number NOVI 176557 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 1.0    |    Date 22-Apr-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 6 of 7 
 
 
SAP Section 
Description 
• Data Listing 16.2.9.18 – BCG Vaccine, All Treated Population 
 
 
Page 76 of 77


Post-hoc Analysis Plan,  
Sponsor Sobi AG  
Protocol Number NI-0501-06  
PCN Number NOVI 176557
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 1.0    |    Date 22-Apr-2021      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 7 of 7 
List of Abbreviations 
Abbreviation 
Definition 
AOSD 
Adult-onset Still’s disease 
ATC 
anatomical therapeutic chemical 
BCG 
bacille Calmette Guerin 
CSR 
clinical study report 
HLH 
hemophagocytic lymphohistiocytosis  
MAS 
macrophage activation syndrome 
PT 
preferred term 
SAP 
statistical analysis plan 
SD 
study day 
SOC 
system organ class 
sJIA 
systemic juvenile idiopathic arthritis 
TEAE 
treatment-emergent adverse event 
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