A Randomized, Double-blinded, Placebo-controlled, Single Center, Phase I Study to Evaluate Pharmacokinetics, Pharmacodynamics and Safety of Emapalumab After a Single Intravenous Dose in Japanese Healthy Volunteers.
Phase: PHASE1
Conditions: Rare Diseases
Sponsor: Swedish Orphan Biovitrum



 
 
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Investigator statement 
I have read the protocol entitled “A randomized, double-blinded, placebo-controlled, single 
center, phase I study to evaluate pharmacokinetics, pharmacodynamics and safety of 
emapalumab after a single intravenous dose in Japanese healthy volunteers” and the 
accompanying current IB. I agree to conduct the clinical investigation in compliance with the 
Final Protocol, Version 1.0  4 Sep ICH harmonized guideline E6(R2): GCP [1], applicable 
regulatory/government regulations, and in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki [2]. I will not implement any changes to study procedures or 
conduct without prior approval from the sponsor and, when applicable, the IRB and Regulatory 
Authority. I will supervise any individual or party to whom I delegate study-related duties and 
functions conducted at the study site and ensure qualification of individuals or parties who 
perform delegated tasks.  
I agree to maintain the confidentiality of this study protocol, as described on the title page. 
Further, I will not publish results of the study without authorization from Swedish Orphan 
Biovitrum AB (publ). 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
 

 
 
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Table of contents 
1 
Synopsis..................................................................................................................... 6 
2 
Abbreviations and definition of terms.......................................................................... 7 
2.1 
List of Abbreviations and definitions ...................................................................... 7 
3 
Ethics ......................................................................................................................... 8 
3.1 
Institutional review board ....................................................................................... 8 
3.2 
Ethical conduct of the study.................................................................................... 8 
3.3 
Subject information and consent ............................................................................. 8 
4 
Introduction................................................................................................................ 9 
4.1 
Background ........................................................................................................... 9 
4.1.1 
Hemophagocytic lymphohistiocytosis ................................................................ 9 
4.1.2 
Emapalumab ................................................................................................... 10 
4.1.2.1 Description and Mode of Action .................................................................. 10 
4.1.2.2 Preclinical data............................................................................................ 11 
4.1.2.3 Clinical Data ............................................................................................... 12 
4.2 
Study rationale ..................................................................................................... 14 
4.3 
Potential risks and benefits ................................................................................... 14 
5 
Study objectives and endpoints ................................................................................. 15 
5.1 
Primary objective ................................................................................................. 15 
5.1.1 
Primary endpoint ............................................................................................. 15 
5.2 
Secondary objectives............................................................................................ 16 
5.2.1 
Secondary endpoints supporting the secondary objective(s)............................... 16 
6 
Investigational plan .................................................................................................. 16 
6.1 
Overall study design and plan ............................................................................... 16 
6.2 
Dosing Strategy ................................................................................................... 17 
6.3 
Stopping Rules..................................................................................................... 17 
6.3.1 
Stopping Rules for individual subject ............................................................... 18 
6.3.2 
Stopping Rules for continues dosing within the cohort ...................................... 18 
6.3.3 
Emergency Treatment...................................................................................... 18 
6.4 
Discussion of study design, including the choice of control groups ........................ 19 
6.5 
Selection of study population................................................................................ 19 
6.5.1 
Inclusion criteria.............................................................................................. 19 
6.5.2 
Exclusion criteria............................................................................................. 20 
6.5.3 
Withdrawal of subjects from treatment or study ................................................ 22 
6.5.3.1 Withdrawal from treatment .......................................................................... 22 

 
 
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6.5.3.2 Withdrawal from study ................................................................................ 22 
6.5.4 
Replacement of withdrawn subjects ................................................................. 22 
6.5.5 
Specific restrictions/requirements..................................................................... 22 
6.6 
Treatments ........................................................................................................... 23 
6.6.1 
Treatments administered .................................................................................. 23 
6.6.2 
Identity of investigational medicinal products ................................................... 23 
6.6.2.1 Emapalumab ............................................................................................... 23 
6.6.2.2 Placebo ....................................................................................................... 24 
6.6.3 
Method of assigning subjects to treatment groups ............................................. 24 
6.6.4 
Selection of doses ............................................................................................ 24 
6.6.5 
Selection and timing of doses for each subject .................................................. 25 
6.6.6 
Blinding and unblinding .................................................................................. 25 
6.6.7 
Prior and concomitant therapy.......................................................................... 26 
6.6.8 
Treatment compliance ..................................................................................... 26 
6.7 
Pharmacokinetic, pharmacodynamic and safety assessments.................................. 26 
6.7.1 
Study schedule ................................................................................................ 26 
6.7.1.1 Visit 1 screening ......................................................................................... 30 
6.7.1.2 Study Day -1 ............................................................................................... 30 
6.7.1.3 Treatment – Study Day 1  Assessments ........................................................ 30 
6.7.1.4 Follow-Up visits (Study Day2, 3,5, and 8, W2, W4, W6) .............................. 31 
6.7.1.5 Study completion visit (W8) or withdrawal .................................................. 31 
6.7.1.6 Unscheduled Visits...................................................................................... 31 
6.7.2 
Medical history ............................................................................................... 31 
6.7.3 
Prior Medication.............................................................................................. 31 
6.7.4 
Demography.................................................................................................... 32 
6.7.5 
Pharmacokinetics ............................................................................................ 32 
6.7.5.1 Bioanalytical method. .................................................................................. 32 
6.7.5.2 Pharmacokinetic calculations ....................................................................... 33 
6.7.6 
Pharmacodynamics .......................................................................................... 33 
6.7.6.1 Bioanalytical methods ................................................................................. 33 
6.7.6.2 Calculations ................................................................................................ 33 
6.7.7 
Immunogenicity .............................................................................................. 34 
6.7.8 
Safety assessments .......................................................................................... 34 
6.7.8.1 Adverse events ............................................................................................ 34 
6.7.8.2 Laboratory safety assessments ..................................................................... 39 
6.7.8.3 Vital signs................................................................................................... 40 

 
 
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6.7.8.4 Physical examination................................................................................... 41 
6.7.8.5 Electrocardiograms...................................................................................... 41 
6.7.8.6 Pregnancy Test............................................................................................ 41 
6.7.8.7 Safety Review Committee ........................................................................... 41 
7 
Quality control and quality assurance ........................................................................ 41 
8 
Statistical plan .......................................................................................................... 42 
8.1 
Determination of sample size................................................................................ 42 
8.2 
Definition of study populations............................................................................. 42 
8.3 
Overall statistical and analytical plan .................................................................... 42 
8.3.1 
General statistical issues .................................................................................. 42 
8.3.2 
Demographics and baseline characteristics ....................................................... 43 
8.3.3 
Analysis related to primary objective................................................................ 43 
8.3.3.1 Analysis of pharmacokinetic parameters ...................................................... 43 
8.3.3.2 Analysis of pharmacodynamic parameters.................................................... 43 
8.3.4 
Analysis related to secondary objective ............................................................ 43 
8.3.4.1 Adverse events ............................................................................................ 43 
8.3.4.2 Laboratory Parameters................................................................................. 43 
8.3.4.3 Anti-drug antibodies.................................................................................... 43 
8.3.5 
Analysis of safety and tolerability data ............................................................. 43 
8.3.5.1 Vital signs and physical Examination ........................................................... 43 
8.3.5.2 Infusion reactions ........................................................................................ 44 
8.3.6 
Interim analysis ............................................................................................... 44 
8.3.7 
Multiple comparison/multiplicity ..................................................................... 44 
8.3.8 
Handling of missing data ................................................................................. 44 
9 
Data collection, handling and record keeping............................................................. 44 
9.1 
Data standards ..................................................................................................... 44 
9.2 
Case report form .................................................................................................. 44 
9.3 
Source data .......................................................................................................... 45 
9.4 
Protocol Deviations.............................................................................................. 45 
9.5 
Database closure .................................................................................................. 46 
9.6 
Record retention................................................................................................... 46 
10 
End of study ............................................................................................................. 46 
11 
Sponsor’s discontinuation criteria.............................................................................. 46 
12 
Dissemination and publication of results.................................................................... 47 
13 
Reference list ........................................................................................................... 47 
Appendix 1 
Additional Protocol Signatures......................................................................... 49 

 
 
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Appendix 2 
Study Administrative Structure ........................................................................ 50 
 
Table of tables 
 
Table 1 
Investigational medicinal products ...................................................... 25 
Table 2 
Composition of emapalumab sterile concentrate .................................. 25 
Table 3 
Prophylaxis to be provided ................................................................. 26 
Table 4 
Schedule of Events ............................................................................. 30 
Table 5 
Laboratory Assessments ..................................................................... 41 
 
Table of figures 
Figure 1 
Study Design...................................................................................... 19 
 
 

 
 
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1 
Synopsis 
 
STUDY IDENTIFIERS 
 
Title of study: 
A randomized, double-blinded, placebo-controlled, single center, phase I study to 
evaluate pharmacokinetics, pharmacodynamics and safety of emapalumab after a 
single intravenous dose in Japanese healthy volunteers. 
 
Clinical study number: 
Sobi.emapalumab-102 
 
 
 
 
Type of study: 
Phase I; Human pharmacology  
STUDY OBJECTIVES 
 
Primary objective: 
To evaluate the pharmacokinetics and pharmacodynamics of emapalumab in 
healthy Japanese subjects following a single intravenous dose of emapalumab 
 
Secondary objective(s): 
To assess safety in healthy Japanese subjects following a single intravenous dose 
of emapalumab 
To investigate immunogenicity of emapalumab 
 
 
STUDY ENDPOINTS 
 
Primary endpoint: 
PK parameters: Cmax, tmax, CEOI, AUClast, AUCinf, %AUCextr, λz, t½, CL, 
Vss, MRTlast and MRTinf 
PD biomarkers:  
Pre-dose circulating IFNγ concentration 
Total IFNγ concentrations  
CXCL9 concentration  
sIL2R concentration 
 
Secondary endpoint(s): 
Adverse Events  
Laboratory parameters 
The presence of anti-drug antibodies (ADAs) and neutralizing antibodies (nAbs) 
 
STUDY DESIGN AND METHODS 
 
Study design: 
This is a randomized, placebo controlled and double-blinded study to evaluate the 
PK, PD and safety of a single dose (1 mg/kg) of emapalumab in adult healthy 
Japanese subjects. 
Number of subjects 
planned: 
8  

 
 
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Diagnosis and main 
criteria for inclusion: 
Healthy volunteers, age between 20 to 50 (inclusive) 
Assessments for 
pharmacokinetic (PK) and 
pharmacodynamics (PD) 
evaluation: 
Serum concentration vs time profiles are obtained for determination of 
emapalumab PK/PD variables at Study Days 1, 2, 3, 5, 8 and Weeks 2, 4, 6, 10 
and 14.  
 
Assessment for safety 
evaluation: 
Adverse events are collected from the time of investigational product 
administration until last study visit (Week 14) 
Heart rate, blood pressure, body temperature are assessed at Screening, Study 
Day -1 prior to the infusion, every 30 minutes after infusion up to 2 hours post 
infusion, every hour from 4 hours post infusion up to 8 hours post infusion, 10 
and 12 hours post infusion, Study Days 2, 3, 5, 8, Weeks 2, 4, 6 and 14. 
Blood and urine samples for local laboratory analyses of hematology, clinical 
chemistry and coagulation are collected at Screening, Study Days -1, 1, 2 ,3 ,5 ,8, 
Weeks 2, 4, 6, 10 and 14 
12-lead ECGs are obtained at Screening, prior to the infusion on Study Day 1, 
after the infusion, and at last study visit (Week 14)  
A physical examination will be performed at Screening, Study Day -1 and at last 
study visit (Week 14) 
Blood samples for central laboratory analyses of ADAs are collected at Study 
Day -1 pre-infusion and at Week 14. 
Test product; dose and 
mode of administration: 
Emapalumab 5 mg/mL for i.v. infusion 
Reference product; dose 
and mode of 
administration: 
Saline 0.9% for i.v. infusion 
Duration of treatment(s): 
Single dose 
Determination of sample 
size: 
No formal sample size calculation. 6 subjects receiving emapalumab are 
considered sufficient, considering the inter-subject variability in the PK results 
from earlier studies. 
Statistical methods: 
No formal statistical hypothesis testing will be performed. All endpoints will be 
summarized with descriptive statistics and presented individually in listings. 
 

 
 
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2 
Abbreviations and definition of terms 
2.1 
List of Abbreviations and definitions 
Term 
Definition 
AE 
Adverse event 
ADA 
Anti-Drug Antibodies 
BLA 
biologics license application 
CDASH 
Clinical data acquisition standards harmonization 
CDISC 
Clinical data interchange standards consortium 
CEOI 
Concentration at end of infusion 
CRO 
Contract research organization 
CRF 
Case report form 
EOT 
End of Treatment 
GCP 
Good clinical practice 
HED 
HLH  
Human Equivalent Dose 
Hemaphagocytic Lymphohistiocytosis 
HSCT 
Hematopoietic stem cell transplantation 
HZ 
Herpes Zoster 
ICH 
International Council for Harmonisation 
IRB 
Independent review board 
IRR 
Infusion Related Reaction 
IMP 
Investigational medicinal product 
LOQ 
Limit of Quantification 
MAA 
Market Authorization Application 
MAS 
Macrophagic  
NOAEL 
ORR 
No Observed Adverse Effect Level 
Overall Response Rate 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
SAE 
Serious adverse event 

 
 
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sIL2R 
Soluble IL2 receptor 
SJIA 
Systemic Juvenile Idiopathic Arthritis 
Sobi 
Swedish Orphan Biovitrum AB (publ) 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
3 
Ethics 
3.1 
Institutional review board  
It is the responsibility of the investigator to obtain approval of the study protocol, possible 
amendments and the written subject information and informed consent form from the IRB. The 
investigator should file all correspondence with the IRB. Copies of IRB correspondence and 
approvals should be forwarded to the CRO.  
3.2 
Ethical conduct of the study 
This study will be conducted in compliance with this protocol, the ICH GCP (1), applicable 
regulatory requirements, and in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki (2). 
3.3 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant records 
or datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data to 
be used as described in the informed consent  
・The participant must be informed that his/her medical records may be examined by Clinical Quality Assurance 
auditors or other authorized personnel appointed by the sponsor, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities. 
 
3.4 
Subject information and consent 
It is the responsibility of the investigator to, prior to any study-related activities, give each 
subject , full and adequate verbal and written information regarding the objective and procedures 

 
 
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of the study and the possible risks involved. The subjects must be informed about their right to 
withdraw from the study at any time. The written subject information and/or informed consent 
form must not be changed without prior discussion with Sobi. Before any revisions are 
implemented, the revised written subject information and/or informed consent form must be 
approved by the IRB.  
It is the responsibility of the investigator to obtain signed informed from all subjects prior to any 
study-related activities. The subjects should receive a copy of the written information and the 
signed informed consent form. 
4 
Introduction 
4.1 
Background 
4.1.1 
Hemophagocytic lymphohistiocytosis 
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome of pathologic 
immune activation. HLH comprises primary (genetic/familial) HLH and secondary HLH 
(sHLH), both clinically described as dysregulations of the immune system leading to a profound 
hypercytokinemia with deleterious consequences on various tissues and organs (3).  
Primary HLH (pHLH) is a heterogeneous autosomal recessive disorder characterized by a severe 
impairment or absence of cytotoxic function by natural killer (NK) and CD8+ T cells with 
striking activation of the immune system. Primary HLH is mostly seen in infancy and early 
childhood with an estimated prevalence in Europe of 1/50,000 live births (4). In Japan, as well as 
ex-Japan, primary HLH is an extremely rare disease with an annual incidence of approximately 
0.342/100,000 live births (5) The disease is invariably fatal if untreated, with a median survival 
of less than 2 months after diagnosis (6, 7). 
Typical features of HLH are (8): 
• Prolonged fever 
• Organomegaly 
• Cytopenia 
• Hyperferritinemia 
• Hypertriglyceridemia 
• Hypofibrinogenemia 
• Lymphohistiocytic infiltrate, bone marrow hypoplasia, meningeal infiltrate 
• Hypercytokinemia. 
There is mounting evidence supporting the pivotal pathogenic role of interferon gamma (IFNγ) 
in the development of both primary (9, 10) and secondary forms of HLH (11-14). 
 
No drugs had been specifically developed and approved for the treatment of HLH until 

 
 
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emapalumab was approved in the United States for the treatment of refractory, recurrent or 
progressive pHLH in November 2018. Nonetheless during the last decades, experts in the field 
have established guidelines for the management of HLH patients (8, 15, 16) 
 
 Despite adoption of the above guidelines, no significant improvement in mortality rates has 
been seen for primary HLH during the last 20 years. The overall mortality rate for pHLH 
remains high, around 40%, as shown by the results of the HLH-1994 and of the HLH-2004 
studies and as reported for the HIT study (16, 17) . The known short- and long-term toxicities, in 
particular myelosuppression and immunosuppression, of the current treatment of HLH further 
contributes to the already high mortality (18, 19). 
 
There is a high unmet need to develop a targeted treatment for HLH that ensures efficacy and 
less toxicity than available compounds. 
4.1.2 
Emapalumab 
4.1.2.1 
Description and Mode of Action  
Emapalumab (previously referred to as NI-0501) is a fully human immunoglobulin G1 (IgG1) 
anti-interferon gamma (IFNγ) monoclonal antibody which binds and neutralizes IFNγ. 
Emapalumab binds to both free and receptor (IFNγR1)-bound forms of IFNγ. 
Since emapalumab is a human IgG1, it retains the characteristics of this immunoglobulin isotype, 
including the capacity to engage Fcγ receptors and to bind complement. 
IFNγ is produced predominantly by NK and NK T cells, as part of the innate immune response, 
and by CD4 Th1 and CD8 cytotoxic T lymphocyte effector T cells, once antigen-specific 
immunity develops. IFNγ is one of the most potent and pleiotropic cytokines of the immune 
system. 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 IFNγ with the pathogenesis 
and the maintenance of inflammatory diseases (20-22). 
 
4.1.2.2 
Preclinical data 
4.1.2.2.1 
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 cell-mediated 
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.  

 
 
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As to safety pharmacology, no abnormalities in electrocardiograms (ECGs), histopathology of 
organs and behavior of the animals were observed throughout the pre-clinical emapalumab 
program. 
4.1.2.2.2 
Toxicology 
Binding and functional data demonstrated Rhesus and 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. Shigella 
and Campylobacter infections were observed at all dose levels (10 to 200 mg/kg/week) in 
animals originally harboring gastrointestinal pathogens (Shigella, Salmonella, Campylobacter) 
prior to emapalumab administration. These findings were assessed to be in line with 
emapalumab pharmacological effect (i.e., neutralization of IFNγ), given the role played by IFNγ 
in controlling these pathogens. Subsequently, in a study where cynomolgus monkeys were free 
from gastrointestinal pathogens at Screening, weekly administrations of emapalumab for 8 
consecutive weeks at doses up to 30 mg/kg were well tolerated with no toxicity or 
gastrointestinal disturbances observed, and no 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. 
 
Embryo-fetal development, fertility and early embryonic development as well as peri- and post-
natal development studies were performed in mice. No effects on embryo-fetal development, 
mating or fertility were observed. No effects on sexual maturation, organ weights, learning and 
memory, reproductive or immunological functions evaluated in the F1 generation mice were 
observed. 
 
More details are available in the current version, 10.0 dated 24Jan2020, of the Investigator 
Brochure. 
4.1.2.3 
Clinical Data  
Since the start of the clinical development program for emapalumab, more than 100 patients 
have received emapalumab in clinical trials and through compassionate use. Furthermore, more 
than 70 patients have been treated to date in the US following FDA approval, and post-marketing 
surveillance has not revealed any additional safety concerns with the use of emapalumab 
Emapalumab has been granted Orphan Drug Designation in the United States (US) on 26 March 
2010 and in Europe (EU) on 09 June 2010. Emapalumab has obtained Breakthrough designation 
in US on 11 March 2016 and PRIME designation in EU on 26 May 2016. 
On 20 November 2018 the FDA approved emapalumab 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. 
The FDA approval was based on data from study NI-0501-03, interim data from the pivotal 
study NI-0501-04 and interim data from the long-term follow-up study NI-0501-05. 

 
 
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Study NI-0501-03 was a phase 1 randomized double-blinded placebo-controlled single 
ascending dose study, in 20 healthy adult volunteers investigating the safety, tolerability and 
pharmacokinetic (PK) profiles of single intravenous (IV) administrations of emapalumab took 
place between September 2011 and January 2013. During this study, 6 subjects received placebo, 
while 3, 3, 4, and 4 subjects (in total 14 subjects) received emapalumab doses of 0.01, 0.1, 1, and 
3 mg/kg, respectively.  
 
Emapalumab PK data from healthy volunteers were evaluated using a population modeling 
approach. The PK of emapalumab was best described by a two-compartment model (NI-0501-03 
- Modelling and Simulation support to NI-0501 PK analysis of study NI-0501-03). In healthy 
volunteers, emapalumab has the typical PK profile expected for a mAb, with low central and 
peripheral volumes of distribution (3.02 L and 2.83 L), slow clearance (0.007 L/h) and long 
distribution and terminal half-lives (1.55 and 25.4 days).  
 
In placebo-treated subjects, mean total IFNγ levels (which represents free IFNγ in the absence of 
emapalumab) ranged from 60.09 pg/mL to 125.2 pg/mL, showing no visible trend over time. In 
contrast, in subjects on emapalumab, total IFNγ levels (which to the majority represents IFNγ 
bound to emapalumab due to the marked emapalumab molar excees of IFNγ) started to increase 
within 24 hours post-dosing. The maximal mean level of total IFNγ of 1013.6 pg/mL was 
reached at Week 8 post-dosing for the subjects who received a dose of 1 mg/kg and maximal 
mean level of 1011.2 pg/mL was reached at Week 4 post-dosing for the subjects who received a 
dose of 3 mg/kg.  
The infusions of emapalumab were 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 Herpes Zoster was reported as a serious adverse reaction in the 
highest dose group (3 mg/kg). Its intensity was moderate and healed with antiviral therapy. The 
subject recovered with no sequelae. An increased susceptibility to HZ infections in patients 
having developed auto-antibodies against IFNγ (23) or having received ustekinumab (a 
monoclonal antibody which decreases IFNγ production by inhibiting the p40 subunit of IL-12) 
has been described in the literature (24).  
In conclusion, no safety signal emerged from the safety parameters (AEs, clinical laboratory 
evaluations, vital signs and ECG analysis) collected during the follow-up period extended up to 
week 44 after emapalumab infusion. The tolerability/safety profile, as well as the PK 
characteristics observed after administration of emapalumab in healthy volunteers supported the 
continuation of the development program for emapalumab for the treatment of HLH. 
Study NI-0501-04 was designed to investigate the safety and tolerability profile of multiple 
intravenous (IV) administrations of emapalumab and its efficacy in primary hemophagocytic 
lymphohistiocytosis (pHLH) patients. The evaluation of the pharmacokinetic (PK) profile and 
the pharmacodynamic (PD) effects of emapalumab is also an important objective of the study to 
define the appropriate therapeutic dose regimen for the treatment of pHLH patients. The study 
has been conducted according to twin protocols in EU and in the US. 
 

 
 
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Study NI-0501-05 is a long-term, follow-up study that includes patients treated in Study NI-
0501-04. Of note, HLH patients who received emapalumab treatment in the pilot NI-0501-06 
study (patients with systemic Juvenile-onset Idiopathic Arthritis developing Macrophage 
Activation Syndrome) and in compassionate use (CU) were also followed-up long-term in this 
study. The objectives of the long-term follow-up NI-0501-05 study are the long-term monitoring 
of the safety profile in patients treated with emapalumab, the assessment of survival after 
emapalumab treatment, the assessment of emapalumab immunogenicity and the evaluation of its 
elimination profile. 
Study NI-0501-04 was completed on 04 January 2019 (last patient last visit, LPLV). Study NI-
0501-05 is ongoing; data provided in this CSR are based on a database cut-off date of 31 January 
2019, at which date 7 patients originally enrolled in the NI-0501-04 are still ongoing. 
Therefore, overall, 45 patients were treated whereof 11 (24.4%) were treated as first-line patients 
and 34 (75.6%) as second-line patients. A total of 35 (77.8%) patients completed Study NI-0501-
04, i.e.,  
• completed emapalumab treatment, i.e., received a minimum of 4 weeks of treatment 
(from SD0 to EOT) unless discontinued subsequently due to lack of efficacy or safety 
reason, and 
• completed the 4-week short-term follow-up or continued treatment in the NI-0501-05 
study. 
The safety profile of emapalumab is favorable in this fragile, immunocompromised patient 
population, requiring high number of co-medications and procedures. Infusions were in general 
well tolerated, no anaphylaxis or severe hypersensitivity reaction have been associated with any 
emapalumab infusion, the IRRs being mild, self-limiting and not requiring any treatment at any 
of the doses administered. 
Infections caused by pathogens reported to be potentially favored by neutralization of IFNγ 
occurred in 1 patient with Histoplasmosis disseminated during the course of emapalumab 
treatment and in 1 patient with Salmonella gastroenteritis during the long-term follow-up after 
HSCT; both infections resolved.  
No patient reported Varicella or Herpes Zoster, including patients who could not receive the 
recommended anti-viral prophylaxis due to the presence of contraindications.  
Emapalumab administration did not appear to be associated with any organ/function toxicity and 
emapalumab treatment was not discontinued as a result of any cardiac, respiratory, liver or renal 
events 
Study NI-0501-06 is a phase 2 study in sJIA patients with MAS/sHLH who have shown an 
inadequate response to high-dose glucocorticoid treatment. As of  01 of July 2020, a total of 9 
patients have been completed the study. In all 9 patients, complete response was achieved. 
Systemic glucocorticoids were weaned in all patients. Emapalumab infusions were well tolerated 
and none of the patients discontinued emapalumab prematurely. A CMV reactivation was 
reported by investigator as a serious event possibly related to emapalumab, but resolved 
completely with treatment (25). 

 
 
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For more details on the clinical experience, see Investigator’s Brochure version 10.0, 24 Jan 
2020. 
 
4.2 
Study rationale  
The primary objective of the study is to evaluate PK and PD in Japanese Healthy subjects, and 
the results of this study will be compared with the results of the non-Japanese phase I single-dose 
study (NI-0501-03). As there is no experience using emapalumab in Japanese subjects it is 
important to compare the PK and PD of emapalumab data between Japanese and non-Japanese 
subjects to confirm comparable PK and PD properties.  
4.3 
Rationale for Herpes Zoster prophylaxis.  
One Healthy Volunteer reported Herpes zoster infection of moderate intensity after a single 
emapalumab infusion of 3 mg/kg during the NI-0501-03 study. The event resolved upon 
treatment and was considered related to emapalumab (IFNγ neutralization suspected to favor 
emergence of the infection).  
Patients treated with emapalumab are recommended prophylactic treatment with valaciclovir to 
prevent reactivation of Herpes zoster. Studies with valaciclovir as Herpes zoster prophylaxis 
have been performed in Japan with prophylactic treatment up to one yea (26). The benefit of 
valaciclovir prophylaxis is judged to exceed the risks with Herpes zoster reactivation. 
4.4 
Potential risks and benefits 
The healthy volunteers will not derive any therapeutic benefit from participating in the study. 
However, every effort will be made to minimize potential risk(s) to subjects participating. 
Emapalumab is approved by FDA since November 2018, for the treatment of patients with 
primary HLH who have refractory, recurrent or progressive disease or intolerance with 
conventional HLH therapy.  
Since the start of the clinical development program for emapalumab, more than 100 patients 
have received emapalumab in clinical trials and through compassionate use. Furthermore, more 
than 70 patients have been treated to date in the US following FDA approval, and post-marketing 
surveillance has not revealed any additional safety concerns with the use of emapalumab. Based 
on the analyses conducted to date, no sign of any off-target effect of emapalumab has been 
detected. 
Subjects in the proposed phase I study will receive a single dose of 1 mg/kg, as compared with 
dose up to 10mg/kg used in other studies with no safety concerns.  
Potential risks based on emapalumab’s mechanism of action are presented below. 
 

 
 
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• Infusion related reactions and hypersensitivity 
Up to the 24-Aug-2019, cumulatively, a total of 1290 emapalumab infusion have been 
administered in clinical trials and 13 of the 62 study subjects (21.0 %) treated had 
experienced at least 1 IRR. No serious hypersensitivity reactions such as anaphylactic or 
anaphylactoid reactions have been reported. Patients should, however, not be re-exposed 
to the investigational treatment in case of hypersensitivity to emapalumab or any of the 
excipients. 
The most frequently reported IRRs were cutaneous reactions coded drug eruption, rash or 
erythema or erythematous rash, hyperhidrosis or pyrexia. 
• Majority of IRRs were of mild or moderate intensity. IRRs did not prevent administration 
of the full dose of emapalumab. All IRRs resolved. No specific premedication is required 
prior to emapalumab administration. 
• Infections 
As emapalumab neutralizes IFNγ activity, emapalumab may increase the risk of 
infections caused by some specific pathogens potentially favored by IFNγ neutralization 
including mycobacteria (typical and atypical), salmonella, herpes zoster, and Histoplasma 
capsulatum. Among the 103 subjects treated with emapalumab up to 24-Aug-2019, 1 
patient had developed disseminated histoplasmosis which resulted in treatment 
discontinuation. The infection resolved with adequate antifungal therapy while 
emapalumab was still at measurable concentrations in blood. One case of Herpes Zoster 
infection was reported in the phase 1 study in healthy volunteers (study NI-0501-03), as 
described above. Study specific requirements should be followed for infections 
screening, prophylaxis and monitoring.  
• Immunogenicity 
The development of ADAs can impact both safety and PK properties of a drug. 
Antibodies against emapalumab have been detected in 1 out of 14 healthy subjects (7.1%) 
after administration of a single dose of emapalumab. The analyses performed up to the 
24-Aug-2019 on HLH subjects treated in the NI-0501-04/05/06 studies have detected the 
presence of ADAs in 3 of 49 subjects (6.1 %). In none of the subjects was the presence of 
ADA associated with any AEs or significant changes in the PK profile, and ADA titers 
were generally low.  
 
For the most recent information about emapalumab, please refer to the current 
Investigator´s Brochure. The current risk benefit analysis supports this clinical trial to 
evaluate PK, PD and safety of emapalumab in Japanese healthy subjects. 

 
 
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5 
Study objectives and endpoints 
5.1 
Primary objective  
• To evaluate the pharmacokinetics and pharmacodynamics of emapalumab in healthy 
Japanese subjects following a single intravenous dose of emapalumab 
 
5.1.1 
Primary endpoint 
• PK parameters: Cmax, tmax, CEOI, AUClast, AUCinf, %AUCextr, λz, t½, CL, Vss, 
MRTlast and MRTinf. 
• PD biomarkers:  
o Pre-dose circulating IFNγ concentration 
o Total IFNγ concentrations  
o CXCL9 concentration  
o sIL2R concentration 
5.2 
Secondary objectives  
• To assess safety in healthy Japanese subjects following a single intravenous dose of 
emapalumab 
• To investigate immunogenicity of emapalumab. 
5.2.1 
Secondary endpoints supporting the secondary objective(s) 
• Adverse Events  
• Laboratory parameters 
• The presence of anti-drug antibodies (ADAs) and neutralizing antibodies (nAbs) 
 
6 
Investigational plan 
6.1 
Overall study design and plan 
This is a randomized, placebo-controlled and double-blinded study to evaluate the PK, PD and 
safety of a single dose (1 mg/kg) of emapalumab in adult healthy Japanese subjects, performed 
in Japan. The subjects, 8 in total, will be randomized to receive either emapalumab or matching 
placebo in a 3:1 ratio (emapalumab: placebo). 
 

 
 
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• Two or more subjects report a severe treatment emergent AE or a severe laboratory 
safety test result  
• One or more subjects develop a treatment emergent serious (life-threatening or fatal) AE 
at any time during the study  
• The investigator considers the AE profile or the laboratory safety assessment to indicate 
an unacceptable risk to the well-being of trial subjects 
 
The study may be terminated by the sponsor at any time for any reason. This may include 
reasons related to benefit-risk, practical, regulatory or medical reasons. 
6.3.1 
Stopping Rules for individual subject 
As per the judgement of the investigator:  
• In the event of any severe events, administration of IMP to the individual 
subject must be discontinued. 
o If an event, considered to be mild or moderate, occurs during the infusion, the 
subject 
shall be treated as the investigator deems appropriate and may continue receiving 
the single infusion. 
o In the event of appearance of mild or moderate local infusion site reactions during 
the infusion, the infusion rate may be lowered. However, infusion time should not 
exceed two hours. 
Subjects for whom IMP administration has stopped will be followed-up as per protocol. 
6.3.2 
Emergency Treatment 
This study will be conducted at a single center (Phase I Unit) under the supervision of the 
principal investigator. The Phase I Unit is equipped with emergency care facilities to provide a 
safe environment for the study. Subjects in this study will be hospitalized from the day before 
treatment until 8 days after and immediate access to medical staff and equipment necessary for 
emergency treatments are available. 
 
In case of hypersensitivity reaction, immediate treatment is given at the discretion of the 
investigator. Depending on symptoms, this may e.g., be antipyretics such as acetaminophen 
(paracetamol), corticosteroids or additional antihistamines, epinephrine and bronchodilators in 
case of severe hypersensitivity reactions (e.g. anaphylaxis) Necessary equipment for 
resuscitation must be available during study drug infusion. 
6.4 
Discussion of study design, including the choice of control groups 
The study is designed to investigate safety, PK/PD in Japanese healthy subjects. The 
investigator, study subjects and sponsor will be blinded to treatment allocation (placebo vs. 
active) to avoid reporting, assessment and allocation biases.  

 
 
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6 subjects are considered sufficient, considering the inter-subject variability in the PK results in 
the NI-0501-03 study and 2 placebo is considered a reasonable number of subjects.  
 
6.5 
Selection of study population 
6.5.1 
Inclusion criteria 
A subject must fulfill the following criteria in order to be included in the study: 
1. Healthy Japanese (male and female) subjects between 20 and 50 years (inclusive). 
2. Body weight greater than 45 kg (female) or 50 kg (male) and a body mass index (BMI) 
>18 kg/m2 and < 30 kg/m2 (BMI= weight (kg) / height (m)²) 
3. Vital signs in the following range:  
• Axillary body temperature: 35.2 – 37,5 
• Heart rate (after at least 3 minutes of rest, measured in the supine position): 40-
100 bpm 
• BP < 140/80, mean of 3 readings after 15 minutes rest 
4. Haemoglobin level equal or above 11 g/dL in females and 13 g/dL in males. 
5. Subject having C-reactive protein (CRP) levels within the normal range (local laboratory 
range). 
6. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant having agreed to use highly effective methods of contraception 
during dosing and for 6 months after receiving IMP.  
Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment. 
• Male sterilization (at least 6 months prior to screening). For female patients on the study, 
the vasectomized male partner should be the sole partner for that patient, otherwise 
highly effective methods to be applied. 
• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), 

 
 
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or other forms of hormonal contraception that have comparable efficacy (failure rate 
<1%). 
• In case of use of oral contraception women should have been stable on the same brand 
(or generic equivalent) for a minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. 
7. Signed informed consent.  
6.5.2 
Exclusion criteria 
The presence of any of the following will exclude a subject from inclusion in the study: 
1. Any clinically significant abnormality in the results of the safety laboratory tests. 
Subjects presenting a minor deviation from laboratory ranges could be enrolled if the 
investigator judge it to be non-clinically significant 
2. Any clinically significant abnormality on the screening electrocardiogram (ECG), as 
judged by the investigator 
3. History or clinical evidence of any disease and/or existence of any surgical or medical 
condition that might interfere with the absorption, distribution, metabolism or excretion 
of the study drugs 
4. Actual presence or occurrence of any bacterial, viral, parasitic or fungal infection within 
the 4 weeks preceding IMP infusion 
5. Positive results from serology examination for Hepatitis B surface antigen (HBsAg), 
Hepatitis C Virus (HCV), Human Immunodeficiency Virus (HIV), syphilis (TP-antigen 
and RPR) or pregnancy 
6. Positive stool test for Shigella or salmonella infection. 
7. Positive results from Sars-CoV-19 screening within 96 hours prior to randomization 
8. History or clinical evidence suggestive of active or latent tuberculosis at screening. (i.e. 
test positive to the IFNγ-release assay) 
9. History or presence of any severe allergic reactions 
10. Suspected hypersensitivity to any component of the drug formulation. 
11. History or presence of any malignancy 
12. History or presence of drug or alcohol abuse 
13. Subject with a smoking history within the last 6 months prior to the time of screening 
14. Immunization with a live vaccine within 6 weeks prior to receiving IMP and 12 weeks 
after IMP infusion 

 
 
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15. Experience of collected blood corresponding to any of the following 
 Component blood donation within 2 weeks before the screening test and within 2 
weeks before the first study drug administration 
 Collection of 200 mL or more of blood (blood donation, etc.) from 4 weeks before 
the screening test until admission 
 Collection of 400 mL or more of blood (blood donation, etc.) from 12 weeks before 
the screening test until admission 
16. Usage of any prescription drugs within 2 weeks or over-the-counter medication including 
herbal supplements (with the exception of multi-vitamins) within 1 week before IMP 
administration without prior approval from the investigator 
17. Positive pregnancy test at screening or Day -1 
18. Any circumstances or conditions, which, in the opinion of the investigator, may affect the 
subject’s full participation in the study or compliance with the protocol 
19. Enrollment in another concurrent clinical interventional study, or intake of another IMP, 
within four months or 5 half-lives (of the other IMP) prior to inclusion in this study  
6.5.3 
Withdrawal of subjects from treatment or study  
6.5.3.1 
Withdrawal from treatment 
As this is a single dose study withdrawal from treatment is not applicable. 
The IMP administration of a subject should be prematurely stopped if, in the opinion of the 
investigator, it is medically necessary, or if it is the wish of the subject. These subjects will 
continue to participate in the study and will not be considered as treatment withdrawals.  
If the IMP administration of a subject is prematurely stopped the reason should be clearly 
described in the relevant sections of the CRF. If the dosing is prematurely stopped because of an 
AE, the reason should always be stated as ‘adverse event’ irrespective of whether this was the 
investigator’s or the subject’s decision. 
6.5.3.2 
Withdrawal from study 
Whenever possible and irrespective of the reason for withdrawal, a subject that has received a 
partial or full dose of IMP should be examined as soon as possible. Relevant samples should be 
obtained, and all relevant assessments should be completed, preferably according to the schedule 
for the week 14 visit (Table 3). The CRF should be completed as far as possible. Date and reason 
for the study withdrawal should be clearly described in the CRF. If a subject is removed from the 
study because of an AE, the reason for study withdrawal should always be stated as ‘adverse 
event’ irrespective of whether this was the investigator’s or the subject’s decision. 
A subject for whom the treatment blind is broken at the request of the investigator should not by 
default be withdrawn from the study.  

 
 
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6.5.4 
Replacement of withdrawn subjects 
Subjects who withdrawn from the study after IMP administration will not be replaced. Subjects 
who withdraw from the study prior to IMP administration will be replaced to ensure that 8 
subjects, i.e. 6 who receive emapalumab and 2 who receive placebo.  
6.5.5 
Specific restrictions/requirements  
The subjects will need to comply with the following restrictions: 
• The subjects should follow local guidance to minimize risk of Covid-19 infection , 
between the PCR test for SARS-CoV-19 and the admission to the phase I unit, to avoid 
getting infected  
• The subjects need to fast 8 hours (water allowed) prior to each visit as food may affect 
the results of some of the laboratory tests that are being performed 
• The subjects should avoid eating poppy seeds or food containing poppy seeds (for 
example poppy seed bread) in the 24 hours before any urine testing 
• The subjects need to avoid alcohol intake 48 hours prior to admission to the clinical unit 
on Study Day -1 
• Subjects should refrain from donating plasma for at least 12 weeks after study 
completion 
• Subjects should refrain from smoking during the course of the study  
 
6.6 
Treatments 
The different treatment groups are; 
 
Arm A: Emapalumab  
Arm B: Placebo (saline) 
 
One randomization list will be prepared by CRO. The ratio between the treatment groups is 3:1, 
i.e., the 6 subjects will be randomized to emapalumab, and 2 subjects will be randomized to 
placebo/saline.  
 
6.6.1 
Treatments administered  
Table 1 describes the investigational medicinal products.  
 

 
 
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Table 1 
Investigational medicinal products 
Treatment 
Investigational 
product 
Dosage form 
Route 
Daily dose 
Dosage regimen 
A 
Emapalumab 
Solution 
i.v. infusion 
1 mg/kg 
Single dose 
B (placebo) 
Saline 
Solution  
i.v. infusion 
NA 
Single dose 
6.6.2 
Identity of investigational medicinal products 
Emapalumab and placebo (saline) will be supplied to the study site as open label supplies. 
Possible deficiencies related to the handling and quality of the IMP(s) should be reported to the 
study monitor and also directly to complaints@sobi.com. 
6.6.2.1 
Emapalumab 
The IMP emapalumab is delivered as a sterile concentrate for infusion, prefilled in single use 
glass vials which require a dilution prior to administration. The concentrate of emapalumab in 
the solution is 5 mg/mL. The solution contains no antimicrobial preservative, and therefore each 
vial must be used only once. 
 
The nominal composition of the emapalumab sterile concentrate for infusion (per mL) is as 
presented in Table 2.: 
Table 2 
Composition of emapalumab sterile concentrate 
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  
 
 
Emapalumab should be stored between 2 and 8°C in a secure area at the study 
site. Further instructions on handling and storage of emapalumab are available in the Pharmacy 
manual. 
 
Labeling will comply with national regulatory requirements. 
 
6.6.2.2 
Placebo 
For emapalumab there is no matching placebo available, instead saline will be used. Once 
diluted, there is no visual differences between emapalumab and saline solution. However, visual 

 
 
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changes can be detected between emapalumab and saline prior to dilution. Therefore, a carefully 
monitored process with an unblinded site pharmacist will be developed and described in detail in 
the Pharmacy Manual. The unblinded pharmacist will prepare emapalumab, or saline, for 
infusion. 
 
Saline should be stored between 2 and 8°C in a secure area at the study 
sites. Further instructions on handling and storage of saline are available in the Pharmacy 
manual. 
 
Labeling will comply with national regulatory requirements. 
 
6.6.2.3 
Herpes Zoster prophylaxis  
Prophylaxis for Herpes Zoster will start at Study Day -1 and be taken up to the visit at week 14. 
The prophylaxis will be provided by Sobi. Table 3 shows information of prophylaxis. 
 
Table 3 
Prophylaxis to be provided 
Investigational product 
Dosage form 
Route 
Daily dose 
Dosage regimen 
Valaciclovir 
tablet 
oral 
1000 mg 
500 mg twice daily 
 
6.6.3 
Methods of assigning subjects to treatment groups 
A single intravenous dose of 1 mg/kg is considered relevant for this Phase 1 study in Japanese 
healthy subject to bridge to the global Phase 1 study NI-0501-03 where single dose 
administration of 0.01, 0.1, 1 and 3 mg/kg were administered.   
Because the PK of emapalumab in healthy adults is linear, one dose level is sufficient for a 
comparison between Japanese and non-Japanese. Also, a single dose is sufficient to compare PK 
between Japanese and non-Japanese, since the PK of emapalumab does not show any time-
dependency upon repeated-dose since administration. 
The global Phase 1 study (NI-0501-03) in 20 healthy adult volunteers investigated the safety, 
tolerability and PK profiles of single IV administrations of emapalumab. During this study 6 
subjects received placebo, while 3, 3, 4, and 4 subjects (in total 14 subjects) received 
emapalumab doses of 0.01, 0.1, 1, and 3 mg/kg, respectively. All IMP infusions were uneventful, 
and most AEs were singular occurrences and no trend in relation to increasing emapalumab 
dosage was observed.  
The PK analysis of emapalumab in the NI-0501-03 study revealed the expected profile for an 
IgG1 with a long half-life (around 22 days), a slow clearance (≤ 0.1 mL/kg/hr) and a low volume 
of distribution (< 65 mL/kg on average). The serum concentrations following 1 mg/kg were 

 
 
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pharmacologically relevant since Cmax (32 200 ng/mL) was approximately 50 times the IC50 
(603 ng/mL) for significant neutralization of IFNγ.  
Considering the scaling factor from the Non-human primate to human (x0.32). 30 mg/kg (NO 
AEL) which was very well tolerated in monkeys, with no adverse clinical signs or organ toxicity 
reported, correspond to a HED of 10 mg/kg, therefore the 30 mg/kg in monkey is 10-fold higher 
than the starting dose in human of 1 mg/kg  
Taken these aspects into account, a single intravenous dose of 1 mg/kg emapalumab has been 
selected for the Phase 2-3 study in pHLH thus this dose is selected also for this study in Japanese 
healthy subjects.  
6.6.4 
Selection and timing of dose for each subject 
IMP will be administered by i.v. infusion over a period of 1 hour, as a single dose of 1 mg/kg. 
 
The following information will be recorded in the CRF for each IMP administration: date, start 
and end time, total volume infused, and, if infusion was interrupted, reason for interruption. 
 
The subject should receive the designated volume of the infusion material through an infusion 
pump over 1 hour (could be extended to up to 2 hours in case of high volume or mild to 
moderate reactions as per 6.3.1). A 0.2 μm filter must be included in all infusion lines. 
 
Full instructions for the preparation of IMP, including dilution steps and method for 
administration, are available in the pharmacy manual. 
6.6.5 
Blinding and unblinding 
6.6.5.1 
Blinding 
This study will be performed in a double-blind fashion. The investigator and study staff, the 
subjects, the monitors, Sobi staff, and the contract research organization (CRO), involved in the 
conduct of the study will remain blinded to the study treatment until database closure. However, 
as saline will be used as placebo, emapalumab/saline must be prepared by an unblinded 
Pharmacist or other appropriately qualified staff member, specifically authorized by the 
investigator/pharmacist and appropriately licensed to perform the task. A carefully monitored 
process with an unblinded site pharmacist will be applied to ensure the blinding of the study. The 
unblinded pharmacist will prepare emapalumab, or saline only, for infusion. The pharmacist 
must be independent and not involved in any other study activities. 
 
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential, and accessible only to authorized persons. 
 

 
 
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6.6.5.2 
Unblinding 
6.6.5.2.1 
Unblinding for finally analyses 
Full randomization information will be made available for data analysis only after database 
closure in accordance with Sobi SOPs. 
6.6.5.2.2 
Unblinding for SUSARs 
When a SUSAR occurs for a subject participating in the study, Sobi Global Pharmacovigilance 
& Patient Safety will request the unblinding of the treatment assignment. The randomization 
code will not be communicated to the site staff, or to the Sobi study team; unblinded SUSAR 
information will be provided to respective Health Authorities only. SUSARs will be reported to 
investigators and independent ethics committees (IECs) or institutional review boards (IRBs) in 
a blinded fashion. 
Emergency unblinding 
The investigator, study staff, sponsor staff and CRO must remain blinded to the subject’s study 
treatment assignment. The identity of the study treatment may be revealed only if the subject 
experiences a medical event, the management of which would require knowledge of the blinded 
treatment assignment. The decision to break the code must be made by the investigator. 
Whenever it is possible and if it does not interfere with (or does not delay) any decision in the 
best interest of the subject, the investigator is invited to discuss the intended code-break with the 
sponsor. If the treatment blind is broken, the reason and the date should be recorded on the code 
envelope and signed by the investigator.  
6.6.6 
Prior and concomitant therapy 
Prophylaxis for HZ virus infection has to be in place from the day before emapalumab infusion 
until W14 (i.e. after at least 2 times the terminal half-life of emapalumab levels in serum).   
Each healthy volunteer will be supplied with commercially available Valaciclovir by the study 
site. Site will be provided with this, either locally purchased/supplied by pharmacy or by sponsor 
as per local regulations. 
Valaciclovir will be labeled in local language and comply with legal requirements.  
Other therapy considered necessary for the subject’s welfare may be given at the discretion of 
the investigator. All such therapy must be recorded in the CRF. No other concomitant 
medication can be used concomitantly with the IMP in this study.  
6.6.7 
Documentation of IMP handling 
Product accountability records will be kept. The pharmacy and investigator must maintain 
accurate records demonstrating date and amount of IMP(s) received, to whom and by whom 
administered or dispensed (subject-by-subject accounting), and accounts of returned IMP(s) and 
any IMP accidentally or deliberately destroyed. All unused IMP will be counted. At the end of 

 
 
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the study, any remaining IMP(s) will be returned to Sobi for destruction or destroyed locally. In 
either case, a certificate of destruction must be issued. 
6.7 
Pharmacokinetic, pharmacodynamic and safety assessments 
6.7.1 
Study schedule 
Table 4 describes the study schedule. 
 
 

 
 
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Table 4 
Schedule of Events 

 
 
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6.7.1.1 
Visit 1 screening 
After the informed consent has been signed, the subjects will be assigned a screening-ID, the 
screening-IDs will be assigned in consecutive order. The investigator should keep a log of the 
subjects screened for the study and the reasons for non-eligibility. 
 
Subjects should be screened according to study eligibility criterias. 
 
Screening evaluations should be completed within 21 days prior to IMP administration 
as per the schedule of events (Table 3). Within 96 hours of the IMP administration, a PCR test 
for SAR-CoV-19 should be performed, the test result must be available prior to the IMP 
administration.  
 
Should any of the tests be out of the range specified for this study, subject(s) may eventually 
be asked to return to the Phase I Unit to provide an additional sample for repeat testing. 
 
Some subjects may be asked to be “reserved participants” as additional participants may be 
needed to replace screened subjects (e.g. non-attendance, subject exclusion or last minute 
withdrawal). 
6.7.1.2 
Study Day -1   
Once all screening results are available and the subject meets all inclusion criteria, and none 
of the exclusion criteria, subjects will be admitted to the Phase I Unit on the morning of Study 
Day -1 and will undergo study specific procedures as per the schedule of events (Table 3). 
Prophylaxis treatment against Herpes Zoster should be initiated.  
 
6.7.1.3 
Treatment – Study Day 1  Assessments 
Pre-infusion 
Prior to the administration of IMP on the morning of Study Day1, the subjects will be assigned a 
randomization number and undergo study specific procedures as per the schedule of events 
(Table 4)  
Post-infusion 
Once the assessments and procedures listed above have been performed and the eligibility if the 
subjects is once again confirmed, the subject will be randomized, be assigned a randomization 
ID  and thereafter receive an i.v. infusion of emapalumab or placebo/saline according to the IMP 
administration instructions (Pharmacy manual). Subsequent to the start of IMP administration, 
the subjects will undergo study specific procedures as per the schedule of events (Table 4) 

 
 
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All subjects will be discharged on Study Day8 post-infusion provided that no safety issues have 
emerged. 
6.7.1.4 
Follow-Up visits (Study W2, W4, W6, W8, W10, W12) 
All assessments and procedures will be performed according to the schedule of events (Table 4). 
The time window for the visits on week 2, 4, 6, 8, 10, and 12 is ± 2 days.  
6.7.1.5 
Study completion visit (W14) or withdrawal  
At the last visit (Study completion visit) the subjects will undergo assessment and procedures 
according to the schedule of events (Table 4). The time window for this visit is ± 2 days. 
 
The same assessment and procedures should be conducted at a withdrawal visit for any subject 
who withdraws prematurely or is withdrawn by the investigator. The withdrawal visit should be 
scheduled within 30 days of termination. 
 
Subjects withdrawn due to a SAE should be followed-up until resolution of the event or until 
the outcome is known and stable. 
 
In order to measure the emapalumab serum levels during at least 3 times the terminal half-life (a 
total of approximately 3 months) PK samples will be taken up to week 14. 
 
6.7.1.6 
Unscheduled Visits 
In the event of unscheduled visits, a non-exhaustive list of assessments and procedures which 
may be performed can be found in the schedule of events (Table 4).   
6.7.2 
Medical history 
A relevant medical and surgical history, including current medical status and allergies should be 
collected at the screening visit and recorded in the CRF.  
6.7.3 
Prior and Concomitant Medication  
Details on the subject’s prior medications (including over-the-counter and herbal medications) 
within 3 months of the screening visit, should be collected at the screening visit. As no 
concomitant medication is allowed, adequate time (depending of half-life and mechanism of 
action) should have elapsed since the use of previous medication to ensure no residues of the 
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6.7.4 
Demography 
The subject’s age at screening, gender, race, body weight and body length will be collected at 
screening and recorded in the CRF. The body weight recording will be repeated at Study Day -1.  
6.7.5 
Pharmacokinetics  
PK blood samples, to measure serum levels of emapalumab, will be collected for all subjects 
receiving study treatment.  
At Study Day 1 sampling should be done pre-dose and at end of infusion, 2, 4, 8, and 10h post 
dose. PK samples will thereafter be collected on all study visits. It should be noted that a separate 
i.v. line will have to be used when collecting the PK samples, i.e. not the same i.v. line as used 
for the i.v. infusion of study treatment.  
The date and time of blood sampling will be recorded in the CRF.  
Samples will be sent to central laboratory for analysis. The procedures for blood collection, 
processing into serum, storing and transporting to the central laboratory as well as the 
laboratories responsible for the analysis are fully described in the laboratory manual. 
6.7.5.1 
Bioanalytical method 
The PK measurements will be performed at 
 
  
  
  
  
  
  
 
The quantification of emapalumab (NI-0501) in human serum samples will be performed using a 
validated Sandwich sequential immunoassay on Gyrolab platform, with a quantification range of 
62.50 ng/mL (LLOQ) – 8’000.00 ng/mL (ULOQ). All the samples are to be dispatched under 
frozen conditions to the bioanalytical Laboratory and will be analysed within established 
timeframe stability. 
Further details regarding the PK serum samples analysis will be described in a bioanalytical plan 
which will be agreed and signed between the Sobi Clinical Representative and the bioanalytical 
Laboratory before any biological sample is dispatched to the bioanalytical Laboratory. 
 

 
 
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6.7.5.2 
Pharmacokinetic calculations 
Emapalumab serum concentration-time data, based on actual administered dose and actual relative 
time-points, will be evaluated by Non compartmental analysis. The following PK parameters will be 
calculated as applicable: Cmax, tmax, CEOI, AUClast, AUCinf, %AUCextr, λz, t½, CL, Vss, 
MRTlast and MRTinf. PK modelling may also be conducted using compartmental analysis and/or 
non-linear mixed effects modelling as appropriate, based on the PK results from this study only 
alternatively based on these results pooled with other PK data e.g. From study NI-0501-03. 
6.7.6 
Pharmacodynamics 
Blood samples for determination of CXCL9, IFNγ and sIL-2R will be collected according to 
Table 4. It should be noted that a separate i.v. line will have to be used when collecting the PD 
samples, i.e. not the same i.v. line as used for the i.v. infusion of study treatment. 
The date and time of sampling will be recorded in the CRF.  
Samples will be sent to central laboratory for analysis. The procedures for blood collection, 
processing into serum, storing and transporting to the central laboratory as well as the 
laboratories responsible for the analysis are fully described in the laboratory manual. 
6.7.6.1 
Bioanalytical methods 
The PD measurements will be performed at 
 
 
  
  
  
  
  
The measurements of the biomarkers in human serum samples will be performed using a 
validated Sandwich sequential ECLIA on Meso Scale Discovery (MSD) Platform. All the 
samples are to be dispatched under frozen conditions to the bioanalytical Laboratory and will be 
analyzed within established timeframe stability. 
All the details regarding the PD serum samples analysis will be described in a bioanalytical plan 
which will be agreed and signed between the Clinical Representative and the bioanalytical 
Laboratory before any biological sample is dispatched to the bioanalytical Laboratory. 
6.7.6.2 
Calculations 
The PD biomarkers (Total IFNγ, CXCL9 and sIL2R serum levels) will be described 
descriptively, and the change from base-line levels will be derived.  

 
 
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6.7.7 
Immunogenicity  
Immunogenicity samples will be collected for all subjects Study Day 1 – pre-infusion, and at the 
study completion visit. The date and time of blood sampling will be recorded in the CRF. 
Samples will be sent to central laboratory for analysis. The procedures for blood collection, 
processing into serum, storing and transporting to the central laboratory as well as the 
laboratories responsible for the analysis are fully described in the laboratory manual. 
All the ADA and any Nab analyses will be performed at  
  
  
  
 
using validated methods. All the details regarding these analyses will be described in a sample 
analysis plan which will be agreed and signed before any biological serum sample is dispatched 
to LGC. 
Safety assessments 
6.7.7.1 
Adverse events 
6.7.7.1.1 
Definitions 
An Adverse Event (AE) is any adverse change i.e. any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom or disease that occurs in a subject during the 
course of the study, whether or not considered by the investigator as related to the use of IMP.  
AEs include: 
• Exacerbation of a pre-existing disease. 
• Increase in frequency or intensity of a pre-existing episodic disease or medical condition. 
• Disease or medical condition detected or diagnosed during the course of the study even 
though it may have been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at study start that worsen following the 
start of the study.  
• Abnormal assessments, e.g., change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at study start or worsened 
during the course of the study. 
 
Abnormal laboratory values or test results should be reported as adverse events only if they fulfill 
at least one of the following criteria: 
• they induce clinical signs or symptoms, 

 
 
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• they are considered clinically significant, 
• they require therapy or 
• they result in dose reduction, interruption or permanent discontinuation of IMP 
administration. 
Overdose, misuse, and abuse of the IMP should be reported as an AE and, in addition, IMP errors 
must be documented in the IMP log of the eCRF. 
6.7.7.1.2 
Intensity of adverse events  
The intensity of clinical AEs is graded on a three-point scale (mild, moderate and severe) as 
follows: 
• Mild  
The event may be noticeable to the subject. It does not influence daily activities, and usually 
does not require intervention 
• Moderate  
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
• Severe  
The event may cause noticeable discomfort, and usually interferes with daily activities. The 
subject may not be able to continue in the study, and treatment or intervention is usually 
needed. 
If the intensity of an AE worsens during the study, only the worst intensity should be reported on 
the AE page. If the AE lessens in intensity, no change in the severity is required. 
If an AE occurs during the screening period (i.e. after signature of informed consent up to IMP 
initiation) and worsens after IMP initiation or during the follow-up period, a new AE form must 
be entered with the appropriated intensity. 
A mild, moderate, or severe AE may or may not be serious (see Section 6.7.7.2.1 for definition of 
SAE).  Medical judgment should be used on a case-by-case basis.  
6.7.7.1.3 
Relationship to investigational medicinal product  
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the IMP administration and reported as either related or 
unrelated. The determination of the likelihood that the IMP caused the AE will be provided by an 
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6.7.7.1.4 
Adverse event reporting 
All AEs occurring after IMP initiation and up to end-of study (EOS) must be recorded on specific 
AE forms of the eCRF. 
6.7.7.1.5 
Follow-up of adverse events 
All AEs should be followed until they are resolved, or the investigator assesses them as stable, or 
the subject’s participation in the study ends, i.e., last scheduled visit (Study Completion).  
All AEs assessed by the investigator as related to the IMP should continue to be followed until 
they resolve or until the investigator assesses them as “stable”, including after EOS. In the latter 
case, no changes to eCRF are made.  
6.7.7.2 
Serious Adverse Events 
6.7.7.2.1 
Definitions of SAE 
An AE that meets one or more of the following criteria/outcomes is classified as serious if: 
• Results in death. 
• Is life-threatening (i.e., at immediate risk of death). 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 
• Is a congenital anomaly/birth defect (i.e., in an offspring to the study subject). 
• Is a medically important AE. 
 
Medically important AEs are events that may not result in death, be life threatening, or require 
hospitalization but may be considered serious when, based upon appropriate medical judgment, 
may jeopardize the patient or subject or may require medical or surgical intervention to prevent 
one of the outcomes listed above. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization or development of dependency or abuse. 
The following reasons for hospitalization are exempt from being reported: 
• 
Hospitalization for social and/or convenience reasons. 
• 
Hospitalization for pre-planned (i.e., planned prior to signing informed consent) surgery 
or standard monitoring of a pre-existing disease or medical condition that did not worsen. 
However, complications that occur during hospitalization are AEs or SAEs (for example if a 
complication prolongs hospitalization or is medically significant as defined above). 
6.7.7.2.2 
Reporting of SAEs  
During screening, administration of IMP and follow-up period 

 
 
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All SAEs occurring after study start (i.e., signing of informed consent) up to EOS must be 
reported on the SAE form and recorded in the AE pages of the eCRF. 
After EOS 
New SAEs occurring after the EOS must be reported to the Sobi safety department within 24 hours 
of the investigator’s knowledge of the event, only if considered by the investigator as causally 
related to previous exposure to the IMP. 
6.7.7.2.3 
Follow-up of SAEs 
SAEs still ongoing at the EOS must be followed up until resolution or stabilization. 
6.7.7.2.4 
Reporting procedures 
All SAEs must be reported by the investigator to Sobi safety department within 24 hours of the 
investigator’s first knowledge of the event. 
All SAEs must be recorded on an SAE form, irrespective of the study treatment received by the 
subject, and whether or not this event is considered by the investigator to be related to IMP.  
SAE forms must be emailed to Sobi safety department and Sobi Study Physician (contact details 
are provided on the SAE form). The investigator must complete the SAE form in English, must 
assess the causal relationship of the event to IMP and sign the report. 
Follow-up information about a previously-reported SAE must also be reported within 24 hours of 
receiving it. The Sobi safety department may contact the investigator to obtain further information.  
If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE-relevant information and documentation. 
The reference safety document to assess expectedness of a suspect serious adverse reaction and 
for reporting by the sponsor to Health Authorities, ECs/IRBs and investigators is the reference 
safety information section of the current version of the Investigator Brochure (IB). 
6.7.7.2.5 
Pregnancy 
There are no data from the use of emapalumab in pregnant women. Animal studies do not 
indicate direct or indirect harmful effects with respect to reproductive toxicity (see IB). 
Females of childbearing potential should not get pregnant during the study and should agree to 
use appropriate contraception (see Section 6.5.1). 
6.7.7.2.6 
Reporting of pregnancy 
Any pregnancy occurring after IMP administration up to the EOS must be reported within 24 hours 
of the investigator’s knowledge of the event. 
Pregnancies must be reported on the Sobi pregnancy form and e-mailed to the Sobi safety 
department.  

 
 
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6.7.7.2.7 
Follow-up of pregnancy 
Any pregnancy must be followed to its conclusion, and its outcome must be reported to the Sobi 
safety department. 
Such follow-up information will only be entered in the sponsor’s safety database, and hence will 
not affect study closure. Table 5 presents the laboratory assessments. 
Table 5 
Laboratory Assessments 
Biochemistry 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Direct Bilirubin 
Total Bilirubin 
Uric acid 
Alkaline phosphatase 
Total Protein 
Albumin 
Prothrombin Time/International Normalized Ratio (PT-
INR) 
Fibrinogen 
Complement C3/C4 
Cardiac troponin  
Creatinine 
C-reactive protein (CRP) 
Electrolytes (Sodium, Potassium, Calcium) 
Glucose 
Lipids (fasting (except screening) triglycerides, HDL, 
LDL) 
BUN/Urea 
 
Hematology  
Hemoglobin 
Hematocrit 
Platelet count 
White blood cells 
Red blood cells 
Differential blood count 
Immunoglobulin levels 
Coagulation profile (APTT) 
 
Urinalysis (dipstick) 
Erythrocytes, Leukocytes 
Glucose 
Ketones 
pH 
Protein 
Sediment (only if positive results are obtained for 
Protein, Erythrocytes and leukocytes measurements) 
Urine pregnancy test 
 
Additional testing at screening 
TB screening (Quantiferon/T-spot) 
PCR SARS-CoV-2  
Viral serology and infections HBV, HCV, HIV and 
syphilis) 
Microbiology testing (stool) for shigella and 
salmonella bacteria 
s-HCG 
Drug screen; 
Benzodiazepines, cocaine, methamphetamines, 
marijuana, barbiturates, morphine, Phencyclidines and 
tricyclic antidepressants  
 
 
All laboratory samples will be analyzed at the local laboratory of the phase I unit according to 
their standard routines. 

 
 
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Clinically significant laboratory values should be reported as AEs (see Section 6.7.7.1.1 for 
details).  
 
6.7.7.3 
Vital signs 
Vital signs (body temperature, heart rate, and semi-supine systolic and diastolic blood pressure 
will be measured at all study visit at timepoint indicated the schedule of events (Table 3) and 
recorded in the CRF.  
Clinically significant abnormal vital signs values should be reported as AEs (see Section 
6.7.7.1.1 for details).   
6.7.7.4 
Physical examination 
A complete physical examination will be performed at screening and at the Study Completion 
Visit. At all other visits brief physical examinations will be performed, only if indicated. 
The complete physical examination will be performed by a physician and will include 
examination of the following: general appearance, eyes, ears, nose, throat, chest/respiratory, 
heart/cardiovascular, gastrointestinal/liver, musculoskeletal/extremities, dermatological/skin, 
thyroid/neck, lymph nodes, and neurological/psychiatric. Each component will be recorded as 
“normal” or “abnormal” at each visit. Abnormalities should be described. 
If any abnormalities are reported at baseline they should be recorded as medical history. New or 
worsening of abnormalities should be reported as AEs (see Section 6.7.7.1.1 for details). 
6.7.7.5 
Electrocardiograms 
A 12-lead ECG recording will be performed at screening, at Study Day1 pre-infusion and at 4h 
post-infusion, and at the study completion visit. The ECG assessments will be performed at the 
phase I unit and will be reported as “normal” or “abnormal” in the CRF. Any abnormalities 
should be specified. Abnormalities reported at screening should be recorded as medical history.  
Clinically significant abnormal ECG findings should be reported as AEs (see Section 6.7.7.1.1 
for details). 
6.7.7.6 
Pregnancy Test 
Female of childbearing potential will have a serum pregnancy test taken at screening and Study 
Day -1 and then urine pregnancy tests monthly (week 4, 8 and 12) and at study completion, week 
14. The outcome of the test will be reported as “positive” or “negative” in the CRF. 
7 
Quality control and quality assurance 
This study will be conducted in compliance with this protocol, study specific procedures, Sobi’s 
and the CRO’s SOPs, the ICH Guideline for GCP (1), and applicable regulatory requirements. 

 
 
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The sponsor will systematically review the study quality management to identify, evaluate and 
control risks to study critical processes and data which would affect subject safety and reliability 
of study data. 
The Sponsor will establish a systematic, prioritized, risk-based approach to monitoring and has 
chosen a combination of on-site and centralized monitoring.  
Monitoring visits to the study site will be performed periodically during the study, to help ensure 
compliance with the protocol, study specific procedures and applicable regulatory requirements. 
Source documents will be reviewed for verification of agreement with data in CRFs. All subject 
informed consent forms will be reviewed. The investigator or institution guarantees access to 
source documents by Sobi, its representatives, and appropriate regulatory agencies. 
The study site may be subject to a quality assurance audit by Sobi or its representatives, as well 
as inspection by appropriate regulatory agencies. 
It is important that the investigator(s) and the(ir) relevant personnel are available during the 
monitoring visits and possible audits and that sufficient time is devoted to the process. 
8 
Statistical plan 
8.1 
Determination of sample size 
This is a phase I study to evaluate the pharmacokinetics and pharmacodynamics of emapalumab 
in healthy Japanese subjects following single dose administration of emapalumab.  
No formal sample size calculation was made but the sample size was chosen based on previous 
experience in phase I studies. Also, 6 subjects receiving emapalumab are considered sufficient, 
considering the inter-subject variability in the PK results in the NI-0501-03 study and 2 placebo 
is considered a reasonable number of subjects. In study NI-0501-03 CV for inter-subject 
variability was within 30% for PK parameters such as Cmax and AUC % based on 4 subjects at 
a dose level of 1 mg/kg emapalumab.    
8.2 
Definition of study populations 
All analyses will be conducted on the modified intention-to-treat (mITT) population which will 
comprise all randomized subjects who received an infusion of IMP and have at least one blood 
draw to determine PK and PD. 
The Safety population will comprise of all patients who received an infusion of IMP.  
 

 
 
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8.3 
Overall statistical and analytical plan 
8.3.1 
General statistical issues 
A study specific statistical analysis plan (SAP) containing a detailed description of all analyses 
to be conducted will be developed and finalized prior to database lock. Suitable tabular and 
graphical summaries will be prepared for individual data and for appropriate summary statistics, 
and all data will be listed. No formal statistical hypothesis testing will be performed. All 
endpoints will be summarized with descriptive statistics and presented individually in listings. 
8.3.2 
Demographics and baseline characteristics 
Demographics and baseline characteristics will be summarized using descriptive statistics.  
8.3.3 
Analysis related to primary objective 
8.3.3.1 
Analysis of pharmacokinetic parameters 
The pharmacokinetic analysis will primarily be conducted using non-compartmental procedures 
and results of PK parameter will be presented by descriptive statistical methods.  
 
PK modelling may also be used based on naïve pooled compartmental modeling and/or non-
linear mixed effects modeling compartmental analysis may be used as deemed appropriate.  
 
PK results may be compared with other studies e.g. study NI-0501-03, but will not be presented 
in the report for this study.  
8.3.3.2 
Analysis of pharmacodynamic parameters 
All PD data will be summarized using appropriate graphical and tabular presentations. 
8.3.4 
Analysis related to secondary objective  
8.3.4.1 
Adverse events 
Reported AEs during the study will be coded using MedDRA. The incidence of AEs will be 
summarized in frequency tables by IMP, system organ class, preferred term, relationship to IMP 
and maximum severity. Separate tabulations will be performed for serious and non-serious AEs.  
8.3.4.2 
Laboratory Parameters 
Abnormal laboratory values will be listed and their incidence, severity and relationship to the 
IMP will be tabulated for the IMP groups. Change from baseline will be summarized by IMP 
group. Individual changes (shift tables), individual clinically significant abnormalities and 
severity grading (mild, moderate, severe) will also be presented. 

 
 
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8.3.4.3 
Anti-drug antibodies 
The number and percentage of patients with ADA at baseline and at the post-baseline assessment 
will be summarized.  
8.3.5 
Analysis of safety and tolerability data 
8.3.5.1 
Vital signs and physical Examination  
Abnormal values from physical examination findings and vital signs will be summarized 
descriptively over time. 
8.3.5.2 
Infusion reactions 
The incidence and severity of infusion related reactions will be analyzed (including the need for 
medication) 
8.3.6 
Interim analysis 
No interim analysis will be performed. 
8.3.7 
Multiple comparison/multiplicity 
As no formal hypothesis testing will be performed adjustment for multiple comparisons will not 
be applicable in this study. 
8.3.8 
Handling of missing data 
No imputations of missing data will be performed. 
9 
Data collection, handling and record keeping 
9.1 
Data standards 
Collection of data should be performed in the CDASH format, according to the CDISC.  The 
standards should be used to the extent possible and/or required for the specific study/project. The 
minimum requirement of the CDISC standard is to collect all core variables specified as 
‘Required’ in the Study Data Tabulation Model format.  

 
 
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9.2 
Case report form 
A CRF is required and should be completed for each included subject. In this study an electronic 
CRF will be used. The completed original CRFs are the sole property of Sobi and should not be 
made available in any form to third parties, except for authorized representatives of appropriate 
Regulatory Authorities, without written permission from Sobi. 
It is the responsibility of the investigator to ensure completion and to review and approve all 
CRFs. CRFs must be signed electronically by the investigator. These signatures serve to attest 
that the information contained on these CRFs is correct. At all times, the investigator has final 
responsibility for the accuracy and authenticity of all clinical and laboratory data entered on the 
CRFs.  
9.3 
Source data 
Subject source documents are the physician’s subject records maintained at the study site. In 
most cases, the source documents will be the hospital’s or the physician’s chart. In those cases, 
the information collected on the CRFs must match those charts. In some cases, a portion of the 
source documents for a given subject may be the CRF.  
A separate source document location agreement will be completed and signed by the principle 
investigator and the monitor before study start. 
Source data should be attributable, legible, contemporaneous, original, accurate, and complete. 
Changes to source data should be traceable, should not obscure the original entry, and should be 
explained if necessary (e.g. via an audit trial). 
9.4 
Protocol Deviations 
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The investigator is responsible for ensuring the 
study is conducted in accordance with the procedures and evaluations described in this protocol 
and must protect the rights, safety, and welfare of subjects. The investigator should not 
implement any deviation from, or changes of, the protocol, unless it is necessary to eliminate an 
immediate hazard to study subjects. 
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.  
For the purpose of this protocol, deviations requiring notification to the CRO are defined as any 
subjects who: 
• Entered into the study even though they did not satisfy entry criteria; 
• Developed withdrawal criteria during the study and not withdrawn; 
• Received wrong treatment or incorrect dose; 
• Received excluded concomitant treatment. 

 
 
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When a deviation from the protocol is identified, the investigator or designee must ensure the 
CRO is notified. The CRO will follow up with the investigator, as applicable, to assess the 
deviation and the possible impact to the safety and / or efficacy of the subject to determine 
subject continuation in the study. 
The investigator and CRO must contact Sobi immediately if a deviation is discovered that 
significantly affects or has the potential to significantly affect human subject protection or the 
reliability of study results. 
The investigator will also assure that deviations are reported and documented in accordance with 
IRB and applicable regulatory requirements.  
9.5 
Database closure 
Prior to database closure, all tasks or criteria defined in the data management plan must be 
completed and documented. The study database must be locked before breaking of the blind and 
before generation of any results. The database lock will be approved by relevant study personnel 
and all edit accesses will be removed. The study database can only be unlocked in case critical 
errors, affecting the main conclusions of the study, are discovered.  
9.6 
Record retention 
The investigator should maintain a record of the location(s) of investigator’s essential documents 
as defined in the ICH GCP Guideline (1) including source documents and should have control of 
and continuous access to all essential documents and records generated by the 
investigator/institution before, during, and after the study.  
All documents and data relating to the study will be kept securely by the investigator in a 
secure file and/or electronically. The storage system used during the study and for archiving 
(irrespective of the type of media used) should provide for document identification, version 
history, search and retrieval. The data will be available for evaluation and/or audits from Health 
Authorities, Sobi or Sobi’s representatives. 
When a copy is used to replace an original document (e.g. source documents, EDC), the copy 
should fulfill the requirements for certified copy as defined in ICH GCP Guideline (1).  
The records should be retained by the Investigator as specified in the Clinical Trial Agreement 
and in accordance with local regulations.  
   
10 
End of study 
The end of this study is defined as the date of last subject out, i.e., the last subject’s last visit. 

 
 
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11 
Sponsor’s discontinuation criteria 
Sobi reserves the right to discontinue the study prior to inclusion of the intended number of 
subjects but intends only to exercise this right for valid scientific or administrative reasons. After 
such a decision, the investigator must contact all participating subjects within 10 days. All study 
materials must be collected and all the CRFs completed to the greatest extent possible. 
12 
Dissemination and publication of results 
Sobi will register the study by posting study information and post study results regardless of 
outcome on a publicly accessible website in accordance with applicable laws and regulations, 
e.g., on www.clinicaltrials.gov.  
Sobi is committed to publishing study results in a complete, accurate, balanced, transparent and 
timely manner. Sobi follows the principles of the International Committee of Medical Journal 
Editors (ICMJE) recommendations for the conduct, reporting, editing, and publication of 
scholarly work in medical journals including criteria for authorship (27). 
The data from this study will be considered for reporting at a scientific meeting or for 
publication in a scientific journal. The sponsor will be responsible for these activities and will 
work with the investigators to determine how the publication is written, the number and order of 
authors, the journal or scientific meeting to which it will be submitted, and other related issues. 
The results of the study, or any part thereof, shall not be published without the prior written 
consent and approval of Sobi, such consent and approval not to be unreasonably withheld. 
13 
Reference list 
1. 
ICH Harmonised Guideline: Integrated addendum to ICH E6 (R1) GfGCERCSvdNAf, 
http://www.ich.org/products/guidelines/efficacy/article/efficacy-guidelines.html. 
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Appendix 1 
Additional Protocol Signatures 
 
 
Sponsor’s Clinical Program Leader  
 
 
 
Signature
 
 
Date 
 
 
Sponsor’s Statistician 
  
 
 
Signature
 
 
Date 
 

 
 
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Appendix 2 
Study Administrative Structure  
  
Study center: 
 
Monitoring: 
 
SAE reporting: 
 
Data management:  
 
Statistics: 
 
Pharmacokinetics: 
 
Investigational products 
(production): 
 
Investigational products 
(packaging and labeling): 
 
Clinical laboratory: 
 
PK/PD analyses: 
 
Bioanalysis: