An Open Label, Single Arm, Multi-Centre, Post-authorization Study to Describe the Safety and Efficacy of Emapalumab for the Treatment of Primary Hemophagocytic Lymphohistiocytosis in Treatment Experienced Chinese Patients
Phase: PHASE4
Conditions: Primary Hemophagocytic Lymphohistiocytosis
Sponsor: Swedish Orphan Biovitrum

 
emapalumab/Gamifant®  
Clinical Study No: Sobi.EMAPALUMAB-104 
Confidential 
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An Open Label, Single Arm, Multi-Centre, Post-authorization Study to 
describe the safety and efficacy of Emapalumab for the Treatment of Primary 
Hemophagocytic Lymphohistiocytosis in Treatment Experienced Chinese 
Patients 
 
Protocol Number: Sobi.EMAPALUMAB-104 
Version 2.0, 01 Jun 2022 
Sponsor: Swedish Orphan Biovitrum AB  
Type of Study: Therapeutic Use, Phase 4  
 
 
Sponsor’s Medical Director  
Principal Coordinating Investigator  
    
 
 
 
 
 
 
Signature 
Date 
Signature 
Date 
 
 
 
 
 
 
 
 
 
Confidential 
This protocol contains confidential information belonging to Swedish Orphan Biovitrum. Except as may be 
otherwise agreed to in writing, by accepting or reviewing these materials, you agree to hold such information in 
confidence and not to disclose it to others (except where required by applicable law) nor use it for unauthorized 
purposes. In the event of actual or suspected breach of this obligation, Swedish Orphan Biovitrum should be 
promptly notified. 

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Investigator statement 
I have read the protocol entitled “An Open Label, Single Arm, Multi-Centre, Post-authorization 
Study to describe the safety and efficacy of Emapalumab for the Treatment of Primary 
Hemophagocytic Lymphohistiocytosis in Treatment Experienced Chinese Patients” and the 
accompanying current investigator’s brochure. I agree to conduct the clinical investigation in 
compliance with the Final Protocol, Version version 2.0, 01 Jun 2022, the International Council 
for Harmonisation (ICH) harmonised guideline E6(R2): Guideline for Good Clinical Practice 
(GCP) [1], applicable regulatory/government regulations, and in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki [2]. I will not implement any 
changes to study procedures or conduct without prior approval from the sponsor and, when 
applicable, the Independent Ethics Committee/Institutional Review Board 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. 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
 

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Table of contents 
1 
Synopsis ............................................................................................................................ 7 
2 
Abbreviations and definition of terms............................................................................... 9 
2.1 
List of Abbreviations and definitions ........................................................................... 9 
3 
Ethics ............................................................................................................................... 11 
3.1 
Independent ethics committee and/or institutional review board ............................... 11 
3.2 
Ethical conduct of the study ....................................................................................... 11 
3.3 
Patient information and consent ................................................................................. 11 
4 
Introduction ..................................................................................................................... 12 
4.1 
Background ................................................................................................................ 12 
4.1.1 
Emapalumab .......................................................................................................... 14 
4.1.1.1 Description and Mode of Action ....................................................................... 14 
4.1.1.2 Pre-Clinical data ................................................................................................ 14 
4.1.1.3 Clinical Data ..................................................................................................... 15 
4.2 
Study rationale ............................................................................................................ 18 
4.3 
Potential risks and benefits ......................................................................................... 18 
4.3.1 
Potential benefits ................................................................................................... 19 
4.3.2 
Potential risks based on emapalumab’s mechanism of action ............................... 19 
4.3.2.1 Risk minimization measures and safety monitoring ......................................... 21 
4.3.3 
Confidentiality of personal data............................................................................. 22 
5 
Study objectives and endpoints ....................................................................................... 23 
5.1 
Primary objective ....................................................................................................... 23 
5.1.1 
Primary endpoint ................................................................................................... 23 
5.1.2 
Secondary endpoints supporting the primary objective......................................... 23 
5.2 
Secondary objective ................................................................................................... 23 
5.2.1 
Secondary endpoints supporting secondary objective ........................................... 23 
5.2.2 
Exploratory endpoint supporting the secondary objective .................................... 24 
6 
Investigational plan ......................................................................................................... 24 
6.1 
Overall study design and plan .................................................................................... 24 
6.1.1 
Number of patients planned ................................................................................... 25 
6.2 
Discussion of study design, including the choice of control groups .......................... 26 
6.3 
Selection of study population ..................................................................................... 26 
6.3.1 
Inclusion criteria .................................................................................................... 26 
6.3.2 
Exclusion criteria ................................................................................................... 28 
6.3.3 
Withdrawal of patients from treatment or study .................................................... 29 

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6.3.3.1 Withdrawal from treatment or study ................................................................. 29 
6.3.4 
Replacement of withdrawn patients....................................................................... 29 
6.3.5 
Specific restrictions/requirements ......................................................................... 29 
6.4 
Treatments .................................................................................................................. 30 
6.4.1 
Investigational medicinal product.......................................................................... 30 
6.4.2 
Handling of investigational medicinal products .................................................... 30 
6.4.3 
Selection of doses .................................................................................................. 31 
6.4.4 
Selection and timing of doses for each patient ...................................................... 31 
6.4.5 
Prior and concomitant therapy ............................................................................... 34 
6.4.5.1 Background therapy .......................................................................................... 34 
6.4.5.2 Concomitant therapy ......................................................................................... 34 
6.4.5.3 Prohibited treatments and treatments with specific restrictions ....................... 35 
6.4.5.4 Prophylactic treatments ..................................................................................... 36 
6.4.6 
Treatment compliance ........................................................................................... 36 
6.5 
Safety and efficacy assessments ................................................................................. 36 
6.5.1 
Study schedule ....................................................................................................... 36 
6.5.1.1 Schedule of events ............................................................................................ 37 
6.5.1.2 Screening ........................................................................................................... 43 
6.5.1.3 Treatment period ............................................................................................... 43 
6.5.1.4 Follow-up period ............................................................................................... 43 
6.5.1.5 Unscheduled visits ............................................................................................ 44 
6.5.2 
Medical history ...................................................................................................... 44 
6.5.3 
Demography .......................................................................................................... 44 
6.5.4 
Efficacy endpoints assessments ............................................................................. 44 
6.5.4.1 Overall Response .............................................................................................. 44 
6.5.4.2 Time to first Overall Response ......................................................................... 45 
6.5.4.3 Duration of response ......................................................................................... 45 
6.5.4.4 Glucocorticoids tapering ................................................................................... 45 
6.5.4.5 HSCT ................................................................................................................ 45 
6.5.4.6 Investigator’s assessment of clinical response .................................................. 46 
6.5.5 
Safety assessments ................................................................................................. 46 
6.5.5.1 Adverse events .................................................................................................. 46 
6.5.5.2 Safety endpoint assessment ............................................................................... 51 
6.5.6 
Clinical safety assessments .................................................................................... 52 
6.5.6.1 Vital signs ......................................................................................................... 52 
6.5.6.2 Height and weight ............................................................................................. 52 

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6.5.6.3 Physical examination ........................................................................................ 52 
6.5.6.4 Electrocardiogram ............................................................................................. 53 
6.5.7 
Laboratory safety assessments ............................................................................... 53 
6.5.7.1 Pregnancy test ................................................................................................... 54 
6.5.7.2 Hematology ....................................................................................................... 54 
6.5.7.3 Chemistry .......................................................................................................... 54 
6.5.7.4 Coagulation ....................................................................................................... 54 
6.5.7.5 sCD25 ............................................................................................................... 54 
6.5.7.6 Urinalysis .......................................................................................................... 54 
6.5.7.7 Genetic confirmation ........................................................................................ 54 
6.5.7.8 CSF ................................................................................................................... 54 
6.5.7.9 Tuberculosis (TB) ............................................................................................. 54 
6.5.7.10 Infections, other ................................................................................................ 55 
6.5.8 
Imaging .................................................................................................................. 55 
6.5.8.1 Abdominal ultrasound ....................................................................................... 55 
6.5.8.2 Chest X-ray ....................................................................................................... 55 
6.5.8.3 Brain Magnetic Resonance Imaging (MRI) ...................................................... 55 
6.5.9 
Post HSCT outcome .............................................................................................. 55 
7 
Quality control and quality assurance ............................................................................. 55 
8 
Statistical plan ................................................................................................................. 56 
8.1 
Determination of sample size ..................................................................................... 56 
8.2 
Definition of study populations .................................................................................. 56 
8.3 
Overall statistical and analytical plan ......................................................................... 57 
8.3.1 
General statistical issues ........................................................................................ 57 
8.3.2 
Demographics and baseline characteristics ........................................................... 57 
8.3.3 
Analysis related to the primary objective .............................................................. 57 
8.3.3.1 Secondary endpoints supporting the primary objective .................................... 57 
8.3.4 
Analysis related to the secondary objective........................................................... 58 
8.3.4.1 Clinical response ............................................................................................... 58 
8.3.4.2 Reduced glucocorticoids compared to baseline ................................................ 59 
8.3.4.3 Survival ............................................................................................................. 59 
8.3.5 
Exploratory endpoint supporting the secondary objective .................................... 59 
8.3.6 
Analysis of safety and tolerability data ................................................................. 59 
8.3.6.1 Adverse events .................................................................................................. 59 
8.3.7 
Interim analysis ...................................................................................................... 59 
8.3.8 
Multiple comparison/multiplicity .......................................................................... 60 

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8.3.9 
Handling of missing data ....................................................................................... 60 
9 
Data collection, handling and record keeping ................................................................. 60 
9.1 
Data standards ............................................................................................................ 60 
9.2 
Case report form ......................................................................................................... 60 
9.3 
Source data ................................................................................................................. 61 
9.4 
Protocol Deviations .................................................................................................... 61 
9.5 
Database closure ......................................................................................................... 62 
9.6 
Record retention ......................................................................................................... 62 
10 
End of study .................................................................................................................... 62 
11 
Sponsor’s discontinuation criteria ................................................................................... 63 
11.1 
At patient level ........................................................................................................... 63 
11.1.1 
Decision to Slow Down or Stop Emapalumab Infusion due to Systemic Reaction
 ............................................................................................................................... 63 
11.1.2 
Local Issues During Emapalumab Infusion ........................................................... 63 
11.1.3 
Decision to Discontinue Treatment ....................................................................... 64 
11.2 
At site level ................................................................................................................. 64 
11.3 
At the study level ........................................................................................................ 64 
12 
Dissemination and publication of results ........................................................................ 65 
13 
Reference list ................................................................................................................... 66 
Appendix 1 
Additional Protocol Signatures .............................................................................. 69 
Appendix 2 
Study Administrative Structure ............................................................................. 70 
 
Table of figures 
Figure 1 
Overview of the study design .................................................................. 24 
Figure 2 
Overview of non-serious AE and SAE reporting period ......................... 49 
Table of tables 
Table 1 
Investigational medicinal products .......................................................... 30 
Table 2 
Clinical and Laboratory Criteria to Guide Dose Increase ....................... 32 
Table 3 
Schedule of events – Treatment period ................................................... 38 
Table 4 
Schedule of events – Follow-up period ................................................... 41 
Table 5 
Definition of response ............................................................................. 44 
1 

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Synopsis 
STUDY IDENTIFIERS 
 
Title of study: 
An Open Label, Single Arm, Multi-Center, Post-authorization Study to describe 
the safety and efficacy of Emapalumab for the Treatment of Primary 
Hemophagocytic Lymphohistiocytosis in Treatment Experienced Chinese 
Patients 
Clinical study number: 
Sobi.EMAPALUMAB-104 
 
 
Type of study: 
Therapeutic use, Phase 4 
STUDY OBJECTIVES 
 
Primary objective: 
To collect safety data on emapalumab in treatment-experienced Chinese pHLH 
patients 
 
Secondary Objective:  
To collect efficacy data on emapalumab in treatment-experienced Chinese pHLH 
patients 
STUDY ENDPOINTS 
 
Primary endpoint: 
• Permanent discontinuation of study drug due to emapalumab-related adverse 
events as judged by the investigator 
 
Secondary endpoints 
supporting the primary 
objective: 
• Treatment-emergent adverse events (AEs)  
• Treatment-emergent serious adverse events (SAEs) 
• Treatment emergent laboratory abnormalities,  
• Treatment-emergent vital sign abnormalities. 
 
Secondary endpoints 
supporting the secondary 
objective: 
• Overall Response, i.e., achievement of either Complete or Partial Response or 
HLH Improvement, at EOT or Week 8 (whichever occurs earlier). 
• Time to first Overall Response, i.e., time from the date of first dose of 
emapalumab to the first achievement of response (Complete or Partial 
Response or HLH Improvement) 
• Cumulative duration of response, i.e., total time in response from the first 
achievement of an Overall Response until EOT 
• Ability to reduce glucocorticoids by 50% or more of the baseline dose during 
emapalumab treatment 
• Investigator assessed response  
• Survival:  
o To start of HSCT conditioning, i.e., time from the date of first dose of 
Emapalumab to date of death, with censoring at conditioning for HSCT or 
at last date of contact for patients who did not undergo conditioning for 
HSCT 
o After HSCT, i.e., time from HSCT to death, with censoring time at last date 
of contact for patients with no event. Only patients undergoing HSCT will 
be included in the analysis 
Exploratory endpoint 
supporting the secondary 
objective: 
•   

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STUDY DESIGN AND METHODS 
 
Study design: 
This will be an open-label, single-arm, multi-center study to collect safety and 
efficacy data on emapalumab in treatment-experienced male and female patients 
diagnosed with pHLH. 
Number of patients 
planned: 
At least 10 and up to 18 patients 
 
Diagnosis and main 
criteria for inclusion: 
Male and female HLH patients of any age. 
Patients diagnosed with confirmed or suspected pHLH defined by; a molecular 
diagnosis or familial history consistent with pHLH or fulfilment of at least five 
out of eight HLH-2004 diagnostic criteria 
Presence of active disease  
Presence of at least one of the following criteria, as assessed by the Investigator: 
• Unsatisfactory or no response to conventional therapy 
• Worsening on conventional therapy 
• Reactivation after initial response to conventional therapy  
• Intolerance to conventional therapy 
Expectation of survival beyond 1 week as judged by the investigator 
Patient has expectation of proceeding to HSCT 
 
Main criteria for 
exclusion:  
Diagnosis of secondary HLH consequent to a proven rheumatic, metabolic or 
neoplastic disease.  
Active mycobacteria, Histoplasma capsulatum, Salmonella, or Leishmania 
infections. 
Evidence of latent tuberculosis.  
Presence of malignancy. 
Existence of any severe co-morbidity or any other medical condition which, in 
the opinion of the investigator, makes the patient unsuitable for the treatment  
Receipt of a Bacillus Calmette-Guérin (BCG) vaccine within 12 weeks prior to 
Screening. 
Receipt of a live or attenuated live (other than BCG) vaccine within 4 weeks prior 
to Screening.  
Pregnant or lactating female patients. 
 
Assessments: 
See schedule of events in Table 3 and Table 4 
Test product; dose and 
mode of administration: 
 Emapalumab 5 mg/mL solution for intravenous infusion to be administered over 
a period of 1-2 hours in doses of 1, 3, 6 or 10 mg/ kg body weight twice weekly. 
Starting dose is 1mg/kg.  
Reference product; dose 
and mode of 
administration: 
Not applicable  
Duration of treatment(s): 
The duration of treatment is expected to last until HSCT. 
Determination of sample 
size: 
Sample size is not based on statistical considerations but the data from 10 up to 
18 Chinese patients will add sufficient information to the safety and efficacy 
profile established during the global clinical development program for 
emapalumab in pHLH patients. 
Statistical methods: 
Safety and efficacy analyses will be conducted on the “All treated analysis set” 
which will comprise all patients who received at least one infusion of IMP. 
 

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2 
Abbreviations and definition of terms 
2.1 
List of Abbreviations and definitions 
Term 
Definition 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse event 
BP 
Blood pressure 
CBC 
Complete blood count 
CDASH 
Clinical data acquisition standards harmonization 
CDC 
Complement dependent cytotoxicity 
CDISC 
Clinical data interchange standards consortium 
CMV 
Cytomegalovirus 
CRO 
Contract research organization 
CRF 
Case report form 
CsA 
Cyclosporine A 
CSR 
Clinical study report 
EBV  
Epstein-Barr virus 
EDC 
Electronic data capture 
EOS 
End of study 
EOT 
End of treatment 
FDA 
US Food and Drug Administration  
GCP 
Good clinical practice 
GDPR 
General data protection regulation 
GPV 
Global Pharmacovigilance & Patient Safety 
HLH  
Hemophagocytic lymphohistiocytosis 
HSCT 
Hematopoietic stem cell transplantation 
ICH 
International Council for Harmonisation 
IEC 
Independent ethics committee 
IFNγ 
Interferon gamma 
IgG 
Immunoglobulin G 
IGRA 
Interferon gamma release assays 
IMP 
Investigational medicinal product 
IRR 
Infusion related reactions 

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IRS 
Interactive response system  
IT 
Intrathecal 
IV 
Intravenous 
JAK 
Janus kinase  
LCMV 
Lymphocytic choriomeningitis virus  
LPLV 
Last patient last visit 
ORR 
Overall response rate 
PD 
Pharmacodynamic 
pHLH 
Primary hemophagocytic lymphohistiocytosis 
PK 
Pharmacokinetic 
PRIME 
Priority medicines 
SAE 
Serious adverse event 
SD 
Study day 
SDTM 
Study data tabulation model 
Sobi 
Swedish Orphan Biovitrum  
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
TMDD 
Target-mediated drug disposition 
US 
Ultrasound 
VZV 
Varicella zoster virus 
 
 
 

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3 
Ethics 
3.1 
Independent ethics committee and/or institutional review board  
It is the responsibility of the investigator to obtain approval of the study protocol, possible 
amendments and the written patient information and informed consent form from the IEC. The 
investigator should file all correspondence with the IEC. Copies of IEC correspondence and 
approvals should be forwarded to the CRO/Swedish Orphan Biovitrum (Sobi).  
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 
Patient information and consent 
It is the responsibility of the investigator to give each patient and/or the patient’s legally 
acceptable representative prior to any study-related activities, full and adequate verbal and 
written information regarding the objective and procedures of the study and the possible risks 
involved. The patients and/or the patient’s legally acceptable representative must be informed 
about their right to withdraw from the study at any time without prejudice. The written patient 
information and/or informed consent form must not be changed without prior approval from 
Sobi. Before any revisions are implemented, the revised written patient information and/or 
informed consent form must also be approved by the IEC and assent form for patients not being 
able to provide full consent (i.e., minors).  
It is the responsibility of the investigator to obtain signed informed consent/assent from all 
patients prior to any study-related activities. The patients should receive a copy of the written 
information and the signed informed consent form. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. 
If approved by the IEC the task of obtaining informed consent can be delegated to an 
appropriately qualified site staff although the responsibility and the oversight of the procedure 
remains with the Investigator.  
If approved by the IEC the consent process can be conducted remotely, outside of the study site 
without physical presence of the site personnel, for example by sending the patient information 
and informed consent form to the patient’s home and answering questions via phone. 
If remote consenting is used the Investigator should have methods in place to ensure that the 
informed consent process allows patients to ask questions and to prevent fraudulent use of 
remote/electronic signatures. Irrespective of where the consent process takes place, on-site or 

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remotely, the responsibility for obtaining informed consent remains with the Investigator and the 
study personnel to which responsibility has been appropriately delegated. 
If a female study participant or a female partner of a male participant becomes pregnant during 
the study period a separate consent form should be collected before collecting any details on the 
pregnancy, its outcome and the birth and health of the baby, if required per local regulations. 
4 
Introduction 
4.1 
Background 
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome of pathologic 
immune activation. HLH comprises primary (genetic/familial) HLH and secondary HLH 
(sHLH), both clinically described by a dysregulation of the immune system leading to a 
profound hypercytokinemia with deleterious consequences on various tissues and organs [3]. 
Primary HLH (pHLH) is a heterogeneous 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. While pHLH is mostly seen in infancy and early 
childhood with an estimated prevalence in Europe of 1/50,000 live births [4], adult cases are 
described [5-7]. The incidence of HLH in China has not been reported in literature. The disease 
is invariably fatal if untreated, with a median survival of less than 2 months after diagnosis [8, 
9]. 
Typical features of HLH are [10]: 
• Prolonged fever 
• Splenomegaly and hepatomegaly 
• Cytopenia 
• Hyperferritinemia 
• Hypertriglyceridemia 
• Hypofibrinogenemia 
• Lymphohistiocytic infiltrate 
• Hypercytokinemia. 
There is mounting evidence supporting the pivotal pathogenic role of interferon gamma (IFNγ) 
in the development of both primary [11, 12] and secondary forms of HLH [13-16]. 
Perforin knock-out mice represent a relevant model for pHLH since, once infected with 
lymphocytic choriomeningitis virus (LCMV), they develop an HLH-like disease dependent on 
CD8+ T cells and IFNγ production, with many of the clinical and laboratory features of the 
human disease. When the high circulating levels of IFNγ are neutralized by the administration of 
an anti-IFNγ antibody, not only are the clinical and laboratory abnormalities reverted, but also 

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survival rate is dramatically improved. On the contrary, the inhibition of many other cytokines 
had no impact on survival [11].  
Further strengthening the importance of IFNγ in pHLH are the high concentrations of circulating 
IFNγ levels found in pHLH patients[3, 17, 18], with IFNγ levels above the upper limit of normal 
in all patients, and above 1000 pg/mL in 53.5% of the cases.  
No drugs had been specifically developed and approved for the treatment of HLH until 
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 [10, 19, 20].  
The management of pHLH patients currently comprises the following steps [19, 21]: 
• 8-weeks induction therapy based on a combination of glucocorticoids and etoposide, 
administered with or without cyclosporine A. 
• Patients with central nervous system involvement receive intrathecal injection of 
methotrexate and glucocorticoids. 
• Hematopoietic stem cell transplantation (HSCT). 
The main goal of the induction therapy is to suppress the life-threatening inflammatory process 
that characterizes pHLH, enabling HSCT in those patients who require it [22]. HSCT is the only 
curative treatment for HLH associated with high penetrance genetic mutations [20]. 
Despite the adoption of the above guidelines, no significant improvement in mortality rates have 
been seen for pHLH 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 [20, 23, 24]. 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 [24, 25]. 
Currently, there is limited literature concerning the salvage therapy of patients with resistant or 
refractory disease, and there are no consensus guidelines regarding treatment options. [26] 
Overall, there is a lack of adequate literature upon which to confidently base decisions regarding 
salvage therapy of HLH or predict outcomes of patients with refractory HLH. Prospective 
clinical trials of salvage and/or alternative therapies are urgently needed. [26] 
The 2018 Expert Consensus on the Diagnosis and Treatment of Hemophagocytic Syndrome in 
China describes the DEP or L-DEP treatment protocol for salvage therapy. In this protocol, 
patients’ response to the HLH-94 protocol should be evaluated after 2-3 weeks of initiating 
induction therapy, with salvage therapy begun if suboptimal response to first-line therapy. While 
there is no standardized recommendation for salvage therapy, a protocol combining liposomal 
doxorubicin, etoposide and methylprednisolone is described. 
The efficacy of emapalumab administered with dexamethasone was assessed in an open-label, 
single-group, phase 2/3 study, involving European and North American patients who had 
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naïve patients who were 18 years of age or younger and had pHLH. The primary analysis of the 
study (cut off July 2017) included a total of 34 patients (27 treatment experienced patients and 7 
treatment naïve patients). 63.0 % (95 % confidence interval 42 to 81 %) of the treatment 
experienced patients and 64.7 % (95 % confidence interval 46 to 80 %) of all treated patients 
(treatment experienced and treatment naïve) had a response; these percentages were significantly 
higher than the prespecified null hypothesis of 40% (P=0.02 and P=0.005, respectively). [27].  
4.1.1 
Emapalumab 
4.1.1.1 
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 [28-30]  
4.1.1.2 
Pre-Clinical data 
 
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.  
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. 
 
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 

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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 of the Investigator Brochure (IB). 
4.1.1.3 
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 130 patients have been treated to date in the US following Federal Food and Drug 
Administration (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. 
 
Study NI-0501-03  
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 

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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).  
The infusions of emapalumab were well tolerated and the effects observed during the 8-week 
monitoring after drug infusion did not reveal any unexpected off target safety or immunogenicity 
concerns. One case of Herpes Zoster was reported as a serious adverse reaction in the highest 
dose group (3 mg/kg). This is considered a consequence of the expected pharmacological effect 
of emapalumab. Its intensity was moderate and healed with antiviral therapy. The subject 
recovered with no sequelae. An increased susceptibility to Herpes Zoster infections in patients 
having developed auto-antibodies against IFNγ [31] 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 [32]. 
In conclusion, the infusion of emapalumab was well tolerated and the effects observed during the 
8-week monitoring after drug infusion, then extended up to week 44, did not reveal any serious 
or unexpected off-target safety or immunogenicity concerns. 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 and NI0501-05 
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 
was conducted according to twin protocols in EU and in the US. 
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. 
The primary analysis for Study NI-0501-04 was completed on 20 July 2017 (last patient last 
visit, LPLV). A supplemental analysis for Study NI-0501-04 including 11 additional patients 
was completed on 04 January 2019. Study NI-0501-05 is ongoing. 
In the primary analysis population, 34 patients were treated whereof 27 (79.4%) were treated as 
second-line (treatment-experienced) patients and 7 (20.6%) as first-line (treatment-naïve i.e., 
prior to starting emapalumab the sole medication received is dexamethasone at doses of 10 
mg/m2/day for not more than 7 days) patients. A total of 26 (76.5%) patients completed Study 
NI-0501-04, i.e., 

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• completed emapalumab treatment, i.e., received a minimum of 4 weeks of treatment 
[from SD0 to end of treatment (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. 
In the primary analysis population 63.0 % (95 % confidence interval 42 to 81 %) of the treatment 
experienced patients and 64.7 % (95 % confidence interval 46 to 80 %) of all treated patients 
(treatment experienced and treatment naïve) had a response; these percentages were significantly 
higher than the prespecified null hypothesis of 40% (P=0.02 and P=0.005, respectively). In the 
treatment experienced group, 70% of the patients were able to proceed to transplantation, as 
were 65% of the all treated group. At the last observation, 74% of the treatment experienced 
patients and 71% of the patients who received emapalumab were alive.  
The supplemental analysis efficacy endpoint in Study NI-0501-04, the Overall Response was 
60.0% (27/45 patients) with exact 95% CI of 44.3%, 74.3% at EOT in the “All treated analysis 
set”. The lower 95% CI is confirmed to be significantly higher than the pre-specified null 
hypothesis of 40%. These results were also supported by the investigator-assessed Overall 
Response, which was consistent with the primary efficacy analysis, to some extent more 
favorable. In the “All treated analysis set”, the response was assessed in 30 (66.7%) patients 
compared to the 27 patients according to the protocol-defined algorithm.  
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 infusion-related reactions (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-0501-09 
Study NI-0501-09 is an ongoing phase 3 study in pediatric patients with confirmed or suspected 
pHLH who are either treatment-naïve, have failed conventional HLH therapy, or are intolerant to 
it. This study was initiated to gather additional safety and efficacy data on emapalumab, to assess 
the impact of emapalumab on quality of life indicators, and to evaluate a starting dose of 
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As of 26 Feb 2021, 32 patients had been treated with emapalumab in the study. A total of 2 
SAEs (acute respiratory failure and BCG adenitis) were assessed by the Investigator as possibly 
related to emapalumab, and one of which led to permanent emapalumab discontinuation (acute 
respiratory failure). Both events resolved. The reported SAEs generally reflected mortality 
and morbidity of the underlying pHLH and known complications, including events typically 
associated with HSCT. Based on the data collected so far, the tolerability and safety profile of 
emapalumab is consistent with previous observations in pHLH patients receiving emapalumab. 
For more details on the clinical experience, see current IB. 
4.2 
Study rationale 
Currently the diagnosis and first-line treatment of pHLH in China follows the HLH-2004 
diagnostic criteria and the HLH-94 treatment protocol recommended by the Histiocyte Society 
and endorsed in the 2018 Expert Consensus on the Diagnosis and Treatment of Hemophagocytic 
Syndrome in China [21, 25]. Early assessment and salvage therapy is recommended in patients 
who do not respond. In a Chinese review paper, treatment suggestions and future research 
directions are described, and it is proposed that more attention should be paid to the treatment of 
refractory HLH. Refractory HLH accounts for 25% ~ 50% of all HLH patients [33]. These 
patients are in critical condition, with poor prognosis and high fatality rate, and treatment options 
are limited in clinical practice [33].  
Given the reported high mortality rate in pHLH and the known toxicities of conventional 
therapies, the development of targeted therapies was warranted. Moreover, morbidity and 
mortality of patients with HLH remained significant in the HLH-94 and HLH-04 studies. 
Alternative treatment approaches are urgently needed and increasingly explored [34]. 
As there is limited experience of emapalumab in Chinese patients it is of interest to describe the 
safety and efficacy of emapalumab in Chinese patients diagnosed with pHLH and that have 
already received conventional HLH therapy (treatment experienced patients), without obtaining a 
satisfactory response according to the investigator or having shown signs of intolerance to it. 
4.3 
Potential risks and benefits 
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 130 patients 
have received emapalumab in clinical trials and through compassionate use. Furthermore, it is 
estimated that more than 255 patients have received Gamifant® through commercial (market) 
distribution worldwide since the launch of the product, 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. 

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4.3.1 
Potential benefits 
Based on evidence available from comprehensive analysis of the NI-0501-04 and NI-0501-05 
studies, emapalumab administration has shown the overall potential to improve or resolve 
relevant clinical and laboratory abnormalities of pHLH.  
Also, in the cohort of the treatment experienced patients which corresponds to the patient 
population of the current study, emapalumab demonstrated a statistically significant and 
clinically relevant reduction in pHLH disease activity, the Overall Response Rate (ORR) was 
assessed through objective clinical and laboratory parameters as being 58.8% (20/34 patients). 
Response occurred early during treatment (the median time to response was 7.0 days) and was 
generally sustained. The median cumulative time at which the patients remained “in response” 
was 31.5 days and in 75% of patients the first response was maintained for at least 22 days. The 
reduction in HLH disease activity was sustained and was associated with an overall survival 
benefit that persisted following HSCT. 27 of 34 patients (79.4%) survived to HSCT and the post-
HSCT survival probability estimates were 91% (95% CI: 68.3%, 97.6%) at 3 months and 89% 
(95% CI: 64%, 97%) at 1 year post-HSCT. The observed treatment effect was consistent across 
all efficacy endpoints.  
Emapalumab was well tolerated in doses up to 10 mg/kg and no off-target toxicity has been 
identified.  
4.3.2 
Potential risks based on emapalumab’s mechanism of action 
Infusion related reactions and hypersensitivity: 
IRRs are commonly associated with monoclonal antibody infusions and are defined as signs or 
symptoms with a temporal relationship to the administration of an infusion and assessed as 
related, typically occurring soon after the start of the infusion, although symptoms may be 
delayed for up to 24h. They might be limited (skin reaction) or systemic.  
Cumulatively, among 108 subjects receiving emapalumab in clinical trials up to safety data cut-
off point of 24-Aug-2020, no patient experienced anaphylactic or anaphylactoid reaction, 
including: 
• Study NI-0501-03: Of 20 healthy volunteers participating in the study, 6 emapalumab and 2 
placebo-treated subjects experienced IRRs. IRRs in subjects receiving emapalumab included 
ventricular tachycardia, paraesthesia, feeling cold, pyrexia, myalgia, and headache  
• Study NI-0501-04: Of 45 patients participating in the study, a total of 12 patients (26.7 %) 
experienced at least one IRR. All were non-serious and, except for one which was moderate, 
all were mild and none of them led to emapalumab discontinuation. The majority were skin 
reactions (drug eruption 8.9 %; rash, 4.4 %; erythema, 4.4 % rash erythematous 2.2 %), 
hyperhidrosis (8.9 %), pyrexia (6.7 %), tachycardia (2.2 %) and lymphadenopathy (2.2 %).  
• Study NI-0501-09: Of 26 patients participating in the study, one IRR (acute respiratory 
failure) was reported as serious, occurring during 8th emapalumab infusion, leading to 
permanent emapalumab discontinuation; it resolved with appropriate treatment. Two (2) 

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additional, non-serious IRRs of sinus tachycardia, one mild and one moderate were reported, 
both of which recovered within 24 hours.  
From the clinical experience to date, the risk of IRRs associated with emapalumab treatment 
seems to be very low. Nevertheless, the infusion should be performed under medical supervision 
with monitoring of vital signs during and for 2 hours after emapalumab infusion as outlined in 
Section 6.5.6.1 
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, varicella zoster virus (VZV), and Histoplasma 
capsulatum. Study specific requirements should be followed for infections screening, 
prophylaxis, and monitoring.  
The impact on the immune defense caused by the neutralization of IFNγ is known from patients 
with inborn errors of the IL-12/23-IFN-γ circuit, particularly patients with complete or partial 
IFNγ receptor (R) deficiency, and patients developing neutralizing auto anti-IFNγ antibodies. 
Patients with IFNγ R deficiency are prone to develop mycobacterial infections and, although to a 
lesser extent, Salmonella infections [35, 36]. The mean age of the first environmental 
mycobacterial infection is 3.1 and 13.4 years in patients with complete and partial deficiency, 
respectively [37]. 
If an infection occurs, appropriate antibiotic therapy based on sensitivity of isolated species is 
prescribed.  
Individuals with anti-IFNγ auto-antibodies are also susceptible to develop mycobacterial 
infections (for the vast majority atypical mycobacterial infections), but also opportunistic 
infections (e.g., caused by Histoplasma capsulatum, Salmonella, VZV) [31]. 
Toxicological studies carried out with emapalumab have shown an increased susceptibility to 
enteral pathogen infections in monkeys having received emapalumab, when the enteral pathogen 
was present in the intestinal tract prior to emapalumab administration. Therefore, presence of 
active infections due to Salmonella is part of the exclusion criteria. 
As to the development of infections caused by pathogens known to be favored by the absence of 
IFNγ biological activity, cumulatively, among the 108 subjects receiving emapalumab in clinical 
trials up to the safety data cut-off point of 24-Aug-2020: 
• Study NI-0501-03: One case of herpes zoster infection was reported in a healthy volunteer and 
recovered with antiviral treatment. 
• Study NI-0501-04: One patient developed disseminated histoplasmosis which resulted in 
treatment discontinuation. The infection resolved with adequate antifungal therapy while 
emapalumab was still at measurable concentrations in the blood.  
• Study NI-0501-09: One previously vaccinated patient developed BCG adenitis during the 
study, which resolved with appropriate therapy. 
Other infections reported during or after administration of emapalumab are the same ones 
commonly observed in immunocompromised patients or are the same ones described in pediatric 

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populations (seasonal viral infections). Patients with active infections (except for the 
exclusionary ones) were enrolled and treated in the study. The presence of active infections did 
not lead to the discontinuation or dose decrease of emapalumab treatment, and infections 
resolved on study drug when treated appropriately and not associated with a refractory disease 
status. Severe or serious infections were generally reported in patients with previous recent 
significant exposure to immunosuppressive treatments as they added an additional risk factor for 
infection development. Importantly, emapalumab treatment has not been associated with 
myelosuppression.  
Active infections, as per patient’s clinical presentation, must be carefully followed over time, 
including quantitative monitoring (e.g., viral loads, antigenemia, antigenuria), when relevant.  
For more details refer to the latest Investigator’s Brochure 
Therapeutic Protein-Drug Interactions (TP-DI): 
The expression of CYP450 enzymes may be suppressed by increased levels of cytokines (such as 
IFNγ) during inflammation. By neutralizing IFNγ, the use of emapalumab may normalize 
CYP450 activities which may change the metabolism of drugs that are CYP450 substrates. The 
restoration of CYP activity may therefore alter the elimination of concomitant medications 
metabolized by these CYPs.  
During the clinical trial program with emapalumab, no events of TP-DI were reported in pHLH 
patients treated with emapalumab. 
Immunogenicity: 
The immunogenicity of emapalumab has been evaluated in all prior clinical studies.  
In the emapalumab development program in the studies completed up to safety data cut-off point 
of 24-Aug-2020 anti-drug antibodies (ADAs) against emapalumab have been detected in 4 
subjects with no impact on safety or efficacy parameters: 
• one out of 14 (or 7.1%) of healthy subjects participating in study NI-0501-03 after 
administration of a single dose of emapalumab 
• three out of 43 (or 7%) patients with post-baseline test participating in study NI-0501-04 
with 2 patients tested positive for neutralizing antibodies 
Antibodies against emapalumab may potentially cause decreased efficacy, allergic reactions, or 
infusion related reactions. However, no adverse events, including decreased efficacy, attributable 
to antibodies have occurred. For the most recent information about emapalumab, please refer to 
the current IB. The current risk benefit analysis supports this clinical trial to assess Safety and 
tolerability of Emapalumab in Chinese Patients with pHLH 
4.3.2.1 
Risk minimization measures and safety monitoring 
In view of the above reported considerations, the benefit/risk profile of emapalumab in children 
and adults diagnosed with pHLH, is considered to be favorable. 
Specific measures are implemented to minimize the potential risks described above as follows: 

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• As per eligibility criteria, patients with evidence of active Mycobacteria, Histoplasma, 
Salmonella, or Leishmania infections, or latent tuberculosis will not be included in the study 
(for details see Section 6.3.2). Patients who received live or attenuated vaccine within 4 
weeks prior to screening are excluded from the studies with emapalumab. 
• Monitoring of IRRs: The infusion related reactions will be closely monitored by the 
investigator. Infusions will be performed under medical supervision to immediately identify 
the occurrence of any IRRs. Each of the specialized centers will have personnel adequately 
trained in IRR management. Should severe allergic reactions (such as anaphylactic shock) 
occur, the patient would be managed according to the local standard treatment guidelines. 
• Monitoring of infections is requested throughout the study. Type of investigation, specimen, 
result, and pathogen identified will be captured in the eCRF. Details see section 6.5.5.1.2  
• Prophylaxis for Pneumocystis jirovecii, and for fungal infections for all patients according to 
local practice. Prophylaxis for Herpes Zoster for all patient required per protocol. 
• Occurrence of emerging infections and evolution of pre-existing infections are monitored 
through regular physical examination and laboratory testing, including detection of 
tuberculosis. Ad hoc search for infections will be performed based on signs and symptoms 
indicating a suspicion of infection. Empirical or prophylactic antimicrobial therapy will be 
introduced when deemed appropriate according to local practice, and proper monitoring of 
active pre-existing infections or emerging infections will be conducted. 
• It’s not recommended to treat patients with emapalumab beyond 6 months as safety data to 
support treatment beyond 6 months is limited. 
4.3.3 
Confidentiality of personal data 
The following risk mitigations are in place to maintain confidentiality of personal data collected 
within the study. 
Personal data collected and processed in the study will be coded. (The coded personal data can 
only be directly traced back to a specific patient by using the code key. The code key will never 
leave the study site and only authorized personnel will have access to it.)  
 
Any reports, publications or presentations resulting from the study will never contain personal 
data that directly identifies a patient. 
As Sobi has it’s headquarter in Europe, personal data will be handled in accordance with the 
European data protection regulation, GDPR. It may be necessary that coded personal data are 
transferred to, or processed in, countries outside the EU/EEA, where the laws may not protect 
personal data to the same extent as the laws in the EU/EEA. When personal data are transferred 
to, or processed in such countries outside the EU/EEA, Sobi is responsible to take all reasonable 
steps to ensure that the level of protection and confidentiality of personal data is the same as 
required in the EU/EEA.  

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5 
Study objectives and endpoints 
5.1 
Primary objective  
• To collect safety data on emapalumab in treatment-experienced Chinese pHLH patients 
5.1.1 
Primary endpoint 
• Permanent discontinuation of study drug due to emapalumab-related adverse events as 
judged by the investigator  
5.1.2 
Secondary endpoints supporting the primary objective 
• Treatment-emergent adverse events (AEs) 
• Treatment-emergent serious adverse events (SAEs) 
• Treatment emergent laboratory abnormalities,  
• Treatment-emergent vital sign abnormalities. 
5.2 
Secondary objective 
• To collect efficacy data on emapalumab in treatment-experienced Chinese pHLH patients 
5.2.1 
Secondary endpoints supporting secondary objective  
• Overall Response, i.e., achievement of either Complete or Partial Response or HLH 
Improvement, at EOT or Week 8 (whichever occurs earlier). 
• Time to first Overall Response, i.e., time from the date of first dose of emapalumab to the 
first achievement of response (Complete or Partial Response or HLH Improvement) 
• Cumulative duration of response, i.e., total time in response from the first achievement of an 
Overall Response until EOT 
• Ability to reduce glucocorticoids by 50% or more of the baseline dose during emapalumab 
treatment 
• Investigator assessed response  
• Survival:  
o To start of HSCT conditioning, i.e., time from the date of first dose of Emapalumab to 
date of death, with censoring at conditioning for HSCT or at last date of contact for 
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o After HSCT, i.e., time from HSCT to death, with censoring time at last date of contact for 
patients with no event. Only patients undergoing HSCT will be included in the analysis 
5.2.2 
Exploratory endpoint supporting the secondary objective 
•   
6 
Investigational plan 
6.1 
Overall study design and plan 
This is an open-label, single-arm, multi-centre study to collect safety and efficacy data on 
emapalumab in treatment experienced male and female patients diagnosed with pHLH. The 
study will be performed in China.  
The study will recruit at least 10 patients, and up to 18 patients if enrolled within the recruitment 
period. 
Patients should already have received conventional HLH therapy (treatment experienced 
patients), without obtaining a satisfactory response according to the investigator or having shown 
signs of intolerance to it.  
Figure 1 summarizes the study design.  
The study is divided into three parts: screening, treatment period, and follow-up. Patients will be 
admitted to the unit the day before the first administration of the study drug (study day minus 
one, SD-1). 
Figure 1 
Overview of the study design 
 
 

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SCREENING 
TREATMENT 
FOLLOW-UP 
Day -14 to  
Visit 1 
Visit 1 
(SD 0) 
Visit 2  
(SD 3-4 
and 
onwards) 
every 3-4 
days 
W8 
 
Primary 
assessment 
timepoint if 
treatment 
continues  
W9-onwards  
until start of 
conditioning 
for HSCT 
EOT 
(3±1 day after 
last infusion) 
 
Primary 
assessment 
timepoint if 
treatment  
stopped before 
 week 8 
Pre-HSCT 
Post HSCT 
Initial 
dose 
Subsequent doses 
Pre-
conditioning 
W 
1/2/3 
D 
30 
D 
60 
D 
100 
M6 
M 12 
(EOS) 
Abbreviations SD, study day; EOT, end of treatment; HSCT, hematopoietic stem cell transplant; W, week; D, day after HSCT; 
M, month; EOS, end of study 
 
The patient will enter screening after informed consent is obtained and will undergo screening 
assessments to confirm eligibility. Duration of the screening period will be kept as short as 
possible and should not exceed 2 weeks.  
First emapalumab infusion, at a dose of 1 mg/kg, marks the start of the treatment period. The 
treatment period is foreseen to continue until start of conditioning for HSCT, if deemed indicated 
for this patient. Infusions will take place twice weekly, at a dose determined by the Investigator 
for each infusion, as described in Section 6.4.4. Emapalumab will be administered on the 
background of dexamethasone, which can be tapered or increased as needed. No wash-out is 
required prior to conditioning for HSCT. 
Last visit of the treatment period is the end of treatment, which occurs 3 days after the last 
infusion of emapalumab. Assessment of efficacy objectives occurs at end of treatment.  
After the start of conditioning for HSCT (or treatment completion, if HSCT is not deemed 
indicated), the patient proceeds to follow-up period. Follow-up visits are planned in relation to 
the date of the HSCT, or last emapalumab infusion (if HSCT is not deemed indicated). Duration 
of the follow-up is one year after HSCT, or after the last emapalumab infusion. 
The end of study visit (EOS) for each patient will occur at the latest 18 months from first dose of 
emapalumab. 
Patient will be considered screened after informed consent is obtained.  
6.1.1 
Number of patients planned 
The goal is to recruit at least 10 patients and up to 18 patients, if enrolled within the recruitment 
period, receiving at least one dose of emapalumab. 

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6.2 
Discussion of study design, including the choice of control groups 
Open-label, single arm design of this prospective study is chosen, considering extreme rarity of 
the disease under study, its life-threatening nature, and lack of licensed alternative therapeutic 
approaches for the patients who have already received conventional HLH therapy without 
satisfactory response, or developed intolerance to it. For the same reasons, sample size is not 
driven by the statistical calculations, but rather by pragmatic considerations. 
HLH is a challenging condition to manage, and disease control is known to be impacted by 
intercurrent conditions, such as infections. This is reflected in the flexible dosing schedule, 
which is the basis of the current established emapalumab dosing regimen for pHLH. Background 
treatment with dexamethasone with at least 5 mg/m2/day, or at the same dose administered prior 
to screening if higher, will be put in place. Additional HLH treatments (etoposide as a drug of 
choice) will be allowed, provided specific conditions, outlined in Section 6.4.5.2.3 are fulfilled.  
It is expected that most patients with pHLH will proceed to HSCT whenever possible 
Treatment duration, which is expected to last until start of conditioning for HSCT, has been 
defined based on previous experience and observed time required to proceed to HSCT; logistical 
considerations (e.g., donor unavailability) that may at times delay HSCT, were also considered. 
Treatment is thus allowed to be flexible but is not recommended to exceed 6 months.  
Schedule of Assessments takes into consideration the limitations imposed by the expected young 
age of the patients, and a significant number of standard of care assessments and interventions 
that may be needed for HLH management. Windows are implemented to minimize the study 
burden.  
6.3 
Selection of study population 
The study population comprises male and female treatment experienced Chinese patients of any 
age diagnosed with primary Hemophagocytic Lymphohistiocytosis (pHLH).  
Patients should have already received conventional HLH therapy (treatment experienced 
patients), without obtaining a satisfactory response according to the investigator or having shown 
signs of intolerance to it. 
Patients will be included in the study if they meet all the inclusion criteria and none of the 
exclusion criteria.  
6.3.1 
Inclusion criteria 
A patient must fulfill the following criteria in order to be included in the study: 
1. Male and female HLH patients of any age. 
2. Patients diagnosed with confirmed or suspected pHLH, based on; a molecular diagnosis 
or familial history consistent with pHLH or fulfilment of HLH-2004 diagnostic criteria, 
i.e., five out of eight of the criteria below: 

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• Fever 
• Splenomegaly 
• Cytopenias affecting 2 of 3 lineages in the peripheral blood (hemoglobin <90 g/L; 
platelets <100 x 109/L; neutrophils <1 x 109/L) 
• Hypertriglyceridemia (fasting triglycerides ≥3 mmol/L or ≥265 mg/dL) and/or 
hypofibrinogenemia (≤1.5 g/L) 
• Hemophagocytosis in bone marrow, spleen, or lymph nodes, with no evidence of 
malignancy. 
• Low or absent NK-cell activity i 
• Ferritin ≥500 μg/L 
• Soluble CD25 (sCD25; i.e., soluble IL-2 receptor) ≥2400 U/mL ii 
3. Presence of active HLH disease as assessed by the investigator. 
4. Patients must fulfil one of the following criteria as assessed by the investigator:  
• Having not responded to previous conventional treatment of HLH 
• Having not achieved a satisfactory response to previous conventional treatment of 
HLH or worsened  
• Having reactivated iii 
• Showing intolerance to previous conventional treatment of HLH 
At the time of enrollment, eligible patients might still be receiving treatment (induction 
or maintenance) or might have already discontinued it. 
5. Expectation of survival beyond 1 week as judged by the investigator. 
6. Patient has expectation of proceeding to HSCT 
7. Informed consent signed by the patient (as required by local law), or by the patient’s 
legally authorized representative(s) with the assent of patients who are legally capable of 
providing it, as applicable. 
8. Willing to use highly effective methods of contraception from study drug initiation to 6 
months after the last dose of study drug, if female and of childbearing potential. 
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 childbearing 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. 

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i NK-cell degranulation testing is considered to be acceptable 
ii Or equivalent as measured by the site’s laboratory 
iii Reactivation is defined as: 
- Deterioration of two or more HLH clinical and laboratory criteria (following an initial response) with the following 
specifications: 
1. numerical laboratory values* must become abnormal and worsen by more than 30% compared to the previous 
evaluation, on two sequential assessments performed with an interval of minimum 1 day and maximum 1 week 
2. deterioration of clinical criteria must be confirmed by consistent observations of worsening over three consecutive 
days 
- The development of new or recurrent CNS symptoms counts as a single criterion for reactivation. 
* The following laboratory parameters are specifically considered for determination of reactivation: platelets, 
neutrophils, fibrinogen, ferritin, sCD25 (i.e., soluble IL-2 receptor). 
The assessment of NK function, red blood cells/hemoglobin and triglyceride levels cannot be considered for the 
determination of reactivation. 
6.3.2 
Exclusion criteria 
The presence of any of the following will exclude a patient from inclusion in the study: 
1. Diagnosis of secondary HLH consequent to a proven rheumatic, metabolic or neoplastic 
disease.  
2. Active mycobacteria, Histoplasma capsulatum, Salmonella, or Leishmania infections. 
3. Evidence of latent tuberculosis. 
4. Presence of malignancy. 
5. Existence of any severe co-morbidity or any other medical condition which, in the 
opinion of the investigator, makes the patient unsuitable for the treatment  
6. History of hypersensitivity or allergy to any component of the study regimen (e.g., 
polysorbate). 
7. Receipt of a Bacillus Calmette-Guérin (BCG) vaccine within 12 weeks prior to 
Screening. 
8. Receipt of a live or attenuated live (other than BCG) vaccine within 4 weeks prior to 
Screening.  
9. Pregnant or lactating female patients. 
10. Enrollment in another concurrent clinical interventional study, or intake of an IMP, 
within three months prior to inclusion in this study 
11. Any condition or circumstance that in the opinion of the Investigator may make the 
patient unlikely to complete the study or comply with study procedures or requirements. 

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6.3.3 
Withdrawal of patients from treatment or study  
6.3.3.1 
Withdrawal from treatment or study 
A patient should be withdrawn from the study for any one of the following reasons: 
• if, in the opinion of the investigator, it is medically necessary 
• if the patient or their legally authorized representative(s) withdraws consent 
• if the patient enrolls into an interventional clinical study in which an investigational 
treatment or approved therapy for investigational use is administered 
There are no predefined rules for permanent study drug discontinuation based on the current 
safety profile of the drug. The Investigator can decide to interrupt or discontinue the treatment 
for his/her patient at any time during the study, based on his/her medical judgment taking into 
account the individual benefit/risk ratio for the patient. The Investigator may request a discussion 
with the Sponsor, if relevant prior to taking a decision; however, the ultimate decision remains 
the Investigator`s responsibility. 
Pregnancy in a patient will lead to permanent discontinuation of study treatment. 
The date of last IMP dose and the date and reason for treatment and/or study withdrawal should 
be clearly described in the relevant sections of the eCRF. If a patient is withdrawn because of an 
AE, the reason for withdrawal should always be stated as ‘adverse event’ irrespective of whether 
this was the investigator’s or the patient’s decision. All serious and non-serious 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 “chronic” or “stable”, even after the patient's participation in 
the study is over, but without further recordings into the eCRF. 
After treatment discontinuation for any reason, patient should be invited to continue the follow-
up period in the study, and every effort should be made to obtain the data collected at the End of 
Treatment and the follow-up visits as complete as possible.  
In any case, withdrawal from the treatment and/or study will have no impact on the patient’s care 
and on further standard of care treatments administered to him/her after withdrawal.  
6.3.4 
Replacement of withdrawn patients 
Patients withdrawn before first dose will be replaced. Withdrawn patients who received at least 
one dose of emaplaumab will not be replaced. 
6.3.5 
Specific restrictions/requirements  
Females of child-bearing potential require use of highly effective contraceptive measures (failure 
rate of less than 1% per year) from Screening until 6 months after the last emapalumab treatment 
have elapsed. 
All women who are physiologically capable of becoming pregnant, will have a ß-hCG test 
(serum pregnancy test) performed at screening, baseline and at EOT. Urine pregnancy tests will 

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be performed monthly during the treatment period and at the scheduled visits day 30, 60, 100, 
and 6 months after HSCT (or last emapalumab treatment if HSCT is not performed) in the 
follow-up period.  
6.4 
Treatments 
6.4.1 
Investigational medicinal product 
Emapalumab is a fully human high affinity anti-IFNγ monoclonal antibody that binds to and 
neutralizes human IFNγ. 
Emapalumab is manufactured by a third-party manufacturing facility duly qualified by the 
Sponsor and is supplied to study sites in 10 mL filled single-use glass vials at a concentration of 
5 mg/mL, for dilution prior to administration. 
The nominal composition of the emapalumab sterile concentrate for infusion (per mL) is as 
follows: 
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  
 
 
 
The solution contains no antimicrobial preservative, and therefore each vial must be used only 
once. Further instructions on handling and storage of emapalumab are available in the 
Investigational Product Management Manual. 
Table 1 
Investigational medicinal products 
Treatment 
Dosage form 
Route 
Dose 
Dosage regimen 
emapalumab 
Solution for infusion 
i.v. 
1, 3, 6, or 10 mg/kg 
Every 3-4 days 
6.4.2 
Handling of investigational medicinal products 
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. 
Product accountability records will be kept. The pharmacy and investigator/head of site must 
maintain accurate records demonstrating date and amount of IMP received, to whom and by 

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whom administered or dispensed (patient-by-patient accounting), and accounts of used IMP and 
any IMP accidentally or deliberately destroyed. All unused IMP will be counted. At the end of 
the study, any remaining IMP will be returned to the depot for destruction. After destruction the 
depot will issue a certificate of destruction. 
6.4.3 
Selection of doses 
Data from in vitro experiments investigating the binding kinetics of emapalumab to human IFNγ 
and the functional inhibition of human IFNγ by emapalumab have been used for predicting the 
concentrations of emapalumab expected to inhibit (e.g. 99%) the effect of circulating IFNγ 
concentrations.  
These predictions were based on: 
• 
the calculated neutralizing concentrations of emapalumab 
• 
the PK parameters of emapalumab in healthy volunteers  
• 
the PK information from recombinant IFNγ in humans.  
Simulations were performed regarding the dose that would inhibit the effect of circulating and 
newly formed IFNγ by up to 99% over a period of 3 days in HLH patients.  
Based on these simulations, the starting dose in HLH patients is 1 mg/kg. This dose is predicted 
to inhibit for 3 days at least 99% of IFNγ effect in patients with baseline IFNγ concentrations 
lower or equal to 3400 pg/mL. This dose is mainly driven by the estimated production of IFNγ 
which is expected to impact the clearance of emapalumab (due to target-mediated drug 
disposition) and varies considerably between patients. 
These assumptions were confirmed in the clinical study NI-0501-04, which showed a wide range 
of baseline IFNγ concentrations observed in these patients. 13 (28.9 %) of 45 patients received 
the dose of 1 mg/kg every 3 to 4 days during the entire duration of the study; in some patients, 
the interval between infusions was elongated to 6-7 days. The dose of emapalumab was 
increased to 3-4 mg/kg in 11 patients (24.4 %) and 21 patients (46.7 %) received a dose of ≥6 
mg/kg (up to 10 mg/kg). Among those 21 patients receiving a dose of ≥6 mg/kg, 10 patients 
(22.2 %) received a dose of 10 mg/kg on at least one occasion.  
Due to the expected target-mediated drug disposition (TMDD) effect and to the high inter-
individual variability of IFNγ concentrations in HLH patients, doses subsequent to the initial one 
can be increased in a step-wise fashion if required, as outlined in Table 2. This decision should 
be based on clinical and laboratory criteria, which are further outlined in Section 6.4.4 and Table 
5. 
6.4.4 
Selection and timing of doses for each patient 
Initial dose of emapalumab (Gamifant®) is 1 mg/kg and it will be administered by intravenous 
infusion over a period of 1 hour. Depending on the volume to infuse and the individual patient’s 
condition, duration of infusion can be extended to maximum of 2 hours. Infusions will be 

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performed twice per week (not more than 4 days apart, e.g. every Monday / Thursday, or every 
Tuesday / Friday). 
Dose increase may occur any time during the study, if the clinical and laboratory criteria listed in 
the Table 5 are met. Dose increase will occur in a stepwise manner, from 1 mg/kg to 3 mg/kg, 
from 3 mg/kg to 6 mg/kg, and from 6 mg/kg to 10 mg/kg.  
After the patient’s clinical condition is stabilized, decrease the dose to the previous level to 
maintain clinical response.  
The duration of treatment is expected to last until start of conditioning for HSCT (if HSCT 
deemed necessary) or unacceptable toxicity, but is not recommended to exceed 6 months.  
No wash-out period is required between the last administration of emapalumab and the start of 
conditioning for HSCT. 
Table 2 
Clinical and Laboratory Criteria to Guide Dose Increase 
Study Visit 
Emapalumab 
Dose 
Criteria for Dose Increase 
Day 1 
1 mg/kg 
N/A 

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Study Visit 
Emapalumab 
Dose 
Criteria for Dose Increase 
Any visit from 
V2 onwards 
Increase to 3 
mg/kg 
Upon an overall assessment by the Investigator that 
improvement in clinical conditions is unsatisfactory 
and 
presence of at least 1 of the following: 
• Fever – persistence or reoccurrence 
• Platelet count 
o If baseline <50,000/mm3 and no improvement 
to >50,000/mm3 
o If baseline >50,000/mm3 and less than 30% 
improvement 
o If baseline >100,000/mm3 and decrease to 
<100,000/mm3 
• Neutrophil count 
o If baseline <500/mm3 and no improvement to 
>500/mm3  
o If baseline >500 -1000/mm3 and decrease to < 
500/mm3 
o If baseline 1000-1500/mm3 and decrease to 
<1000/mm3 
• Ferritin (ng/mL) 
o If baseline ≥3000 ng/mL and <20% decrease 
o If baseline <3000 ng/mL and any increase to 
>3000 ng/mL 
• Splenomegaly – any worsening 
• Coagulopathy (both D-dimer and Fibrinogen must 
apply) 
o D-Dimer – if abnormal at baseline and no 
improvement 
o Fibrinogen (mg/dL) 
▪ If baseline levels ≤100 mg/dL and no 
improvement  
▪ If baseline levels >100 mg/dL and any 
decrease to <100 mg/dL 
Any visit from 
V3 onwards 
Increase to 6 
mg/kg 
Previous dose was 3 mg/kg + same as above 
Any visit from 
V4 onwards 
Increase to 10 
mg/kg 
Previous dose was 6 mg/kg + Investigator assesses that 
based of initial signs of response, a further increase of 
emapalumab dose can be of benefit 

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6.4.5 
Prior and concomitant therapy 
A prior and concomitant therapy is any drug or substance administered from the screening visit 
until the EOS visit. The investigator must instruct patients and/or legal representatives to notify 
the study site about any new medications taken after the patient has been screened for the study. 
All medications, non-drug therapies (including physical therapy and blood transfusions) 
administered after the patient was enrolled must be recorded in the eCRF. Information about 
medication name, indication, dose, unit, frequency, route date and time is to be recorded for each 
medication. 
Any conventional treatment for pHLH (including but not limited to plasmapheresis, HSCT) must 
be recorded, regardless of when it has been received. 
No other medicinal product under investigation may be used concomitantly with the IMP in this 
study.  
6.4.5.1 
Background therapy 
Emapalumab will be administered on a background of dexamethasone. At least 5 mg/m2/day of 
dexamethasone should be administered from not later than the day before SD initiation, unless 
there is a known intolerance to glucocorticoids, which must be documented in the patient’s 
medical chart and eCRF. Lower dexamethasone doses at study entry are allowed in case of 
documented intolerance to glucocorticoids. 
For patients who were receiving baseline dexamethasone, they may continue their regular dose 
provided the dose is at least 5 mg/m2.  
During the study, dexamethasone can be tapered depending on patient`s condition. The tapering 
scheme can be selected by the investigator and should take into account the potential risk of 
disease (HLH) reactivation. 
In the event of disease reactivation/worsening after tapering of dexamethasone, the dose of 
dexamethasone can be increased and maintained until a satisfactory response is achieved 
according to the investigator.  
Dexamethasone may be substituted for another glucocorticoid at an equivalent dose according to 
clinical judgement or local availability. Equivalent dosage should be converted using a steroid 
conversion calculator 
6.4.5.2 
Concomitant therapy 
 
Cyclosporine A 
Cyclosporine A (CsA) can be continued if already being administered to the patient prior to 
screening. CsA can be withdrawn at any time, upon the judgement of the Investigator. CsA is not 
to be introduced de novo during the course of the study once emapalumab administration has 
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Intrathecal therapy 
For patients receiving intrathecal (IT) therapy (e.g., methotrexate and glucocorticoids) at the time 
of emapalumab treatment initiation, this therapy will be continued until clinically indicated. The 
introduction of IT therapy during emapalumab treatment is allowed should CNS signs and 
symptoms occur during the study, as clinically indicated. 
 
Additional HLH therapies 
Administration of additional HLH treatments can be considered in a patient in whom an HLH 
worsening, or no initial response has been observed after an increase of emapalumab dose to 6 
mg/kg, as well as later during the course of emapalumab treatment in case of unsatisfactory HLH 
control.  
Unsatisfactory HLH control is defined as follows: 
• patients who have not achieved or maintained a disease control and general 
conditions that would allow to proceed to transplant 
• patients who present a clinically relevant worsening. 
If an additional HLH treatment is needed, etoposide is the drug of choice, unless there is 
evidence indicating that an alternative agent should be selected. In this circumstance, the 
Investigator has to fully document the rationale for an alternative choice in the patient’s medical 
file and in the eCRF. 
 
Other treatments 
Analgesic treatment, transfusion of blood products, electrolyte and glucose infusions, antibiotics, 
antifungal and anti-viral treatment, and general supportive care (e.g. gastro-protective agents) are 
allowed. The use of any prescription or over-the-counter medication, including herbal and 
homeopathic preparations with the exception of multi-vitamins, needs to be notified to the 
Investigator. 
6.4.5.3 
Prohibited treatments and treatments with specific restrictions 
 
 Intravenous immunoglobulin (IVIG) 
IVIG is only allowed as replacement treatment (i.e., not at doses expected to produce an 
immunomodulatory effect) according to the clinical judgement of the Investigator. 
 
JAK inhibitors 
Administration of JAK inhibitors concomitantly with emapalumab is not allowed. 
 
Vaccinations 
Vaccination with a live or attenuated (including BCG) vaccine must be avoided for 44 days 
(corresponding to 2 half-lives) after last emapalumab administration. 

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Other treatments 
Concomitant use of other biologic drugs for indications other than additional HLH treatments is 
generally not allowed. Rituximab for documented EBV infection, colony stimulating factor in 
case of prolong neutropenia and blood products are allowed.  
The use of traditional Chinese medicine treatments must be avoided during the treatment period 
until 44 days (corresponding to 2 half-lives) after last emapalumab administration, if used for 
treatment of HLH. 
6.4.5.4 
Prophylactic treatments 
 
Herpes Zoster 
Patients will receive prophylactic treatment for Herpes Zoster from the day before initiation of 
emapalumab treatment and must be maintained for 44 days (corresponding to 2 half-lives) after 
the last emapalumab treatment according to local practice.  
 
Antimicrobial and antifungal prophylaxis 
Patients will receive any other required prophylactic antimicrobial and antifungal treatments 
according to local recommendations for the management of pHLH. 
6.4.6 
Treatment compliance 
Compliance with IMP and mandatory prophylaxis will be assessed by the study investigator 
and/or study personnel at each visit. IMP will be administered intravenously by hospital staff 
twice per week. The amount, date and time of the IMP administrations will be recorded in the 
eCRF. 
6.5 
Safety and efficacy assessments 
6.5.1 
Study schedule 
All visits should take place as close to planned dates as possible. Infusions should not take place 
more than 4 days apart. Detailed information on assessments and timing could be found in 
Sections 6.5.2 - 6.5.8 and Table 3 and Table 4 
 
In the follow-up period, the following time-windows are allowed: 
Pre-conditioning: can be combined with EOT visit provided the two visits are not more than 5 
days apart 
• Week (W) 1-2-3, Day+30 post-HSCT: 2 days 
• Day+60, Day+100 post-HSCT: 1 week 

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• 6-months, 1-year post-HSCT: 4 weeks 
 
6.5.1.1 
Schedule of events

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Table 3 
Schedule of events – Treatment period 
Assessments 
Screening Visit 
(up to 2 Weeks 
prior to Visit 1) 
Week 1 
Week 2  
Week 8 
Week 9 – start 
of conditioning 
for HSCT 
EOT (3±1 days after 
last inf.)b 
Visit 1 / SD0 
Visit 2  
Visit 3 onwards a  
Primary assessment 
timepoint if 
treatment continues a 
if treatment 
continues a 
Visit X a 
Primary assessment 
timepoint if 
treatment stopped 
before week 8 a 
Dexamethasone or other glucocorticoid c 
X 
X 
X 
X 
X 
X 
X 
Prophylactic treatment c 
X 
X 
X 
X 
X 
X 
X 
Informed Consent/Assent  
X 
 
 
 
 
 
 
Study Drug Infusion d 
 
X 
X 
X 
X 
X 
 
Medical history e 
X 
 
 
 
 
 
 
Prior and concomitant medications e 
X 
X 
X 
X 
X 
X 
X 
Eligibility criteria 
X 
 
 
 
 
 
 
Clinical 
Assessments  
Vital Signs f 
X 
X (Pre/post-inf.) 
X (Pre/post-inf.) 
X (Pre/post-inf.) 
X 
X (Pre/post-inf.) 
X 
Physical Examination g 
X 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X 
X (Pre-inf.) 
X 
Height 
X 
 
 
 
X 
 
X 
Weight 
X 
X (Pre-inf.) 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
X 
 
X 
Assessment of clinical response 
 
X 
X 
X 
X 
X 
X 
Procedure 
HSCT 
 
 
 
 
X 
 
X 
Search for 
Infections 
TB h 
X 
X monitoring clinical signs and symptoms of TB (every two weeks) h. 
Adenovirus, EBV & CMV viral 
loads 
X  
X monitoring clinical signs and symptoms of viral infection (every two weeks) In case of suspicion of infection, viral load test should be 
performed 
Atypical mycobacteria, Histoplasma 
capsulatum, Salmonella, Leishmania,  
X 
In case of suspicion of infection 
Brucella 
In case of suspicion 
of infection 
In case of suspicion of infection 
Laboratory k 
Genetic confirmation i 
X 
 
 
 
 
 
 
Hematology  
X 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X 
Biochemistry  
X 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X 
Coagulation 
X 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X 

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Assessments 
Screening Visit 
(up to 2 Weeks 
prior to Visit 1) 
Week 1 
Week 2  
Week 8 
Week 9 – start 
of conditioning 
for HSCT 
EOT (3±1 days after 
last inf.)b 
Visit 1 / SD0 
Visit 2  
Visit 3 onwards a  
Primary assessment 
timepoint if 
treatment continues a 
if treatment 
continues a 
Visit X a 
Primary assessment 
timepoint if 
treatment stopped 
before week 8 a 
sCD25  
X 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X 
Pregnancy test (if applicable) s 
X 
X (Pre-inf.) 
 
X s 
X s 
X s 
X 
CSF analysis (if coagulation allows) l 
X l 
If clinically indicated (to monitor evolution of CSF abnormalities or in case of occurrence of new CNS symptoms) 
Urinalysis m 
 
X 
 
 
X 
 
X 
Imaging k 
Abdominal Ultrasound n 
X 
X (every 2 weeks) 
X 
Chest X-ray o 
X 
If clinically indicated (e.g. in case of clinical suspicion of pulmonary infection or to follow-up a pre-existing infection at 
screening/baseline) 
Brain MRI p 
(X) p 
If clinically indicated (to monitor evolution or to confirm occurrence of new CNS symptoms) 
AE recording q 
 
X 
X 
X 
X 
X 
X 
SAE recording r 
X (from signing 
ICF) 
X 
X 
X 
X 
X 
X 
IMP Handling (Preparation, Dispensing, 
Accountability)  
 
X 
X 
X 
X 
X 
X (accountability) 
 
 
Abbreviations AE, adverse event; ALP, alkaline phosphatase; ALT, alanine transaminase, aPTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete blood count; 
CMV, cytomegalovirus; CNS, central nervous system; CRP, C-reactive protein; CSF, cerebrospinal fluid; EBV, Epstein-Barr virus; ECG, electrocardiogram; EOT, end of treatment; γGT, gamma 
glutamyl transferase; HLH, hemophagocytic lymphohistiocytosis; HSCT, hematopoietic stem cell transplantation; ICF, informed consent form; IGRA, interferon-gamma release assays; IFNγ, 
interferon gamma; IMP, investigational medicinal product; inf, infusion; INR, International normalized ratio; IRR, infusion related reaction; LDH, lactate dehydrogenase; LUC, large unstained 
cells; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PPD, purified protein derivative; PT, prothrombin time; SD, study day; TB, tuberculosis; US, ultrasound 
Hematology: complete blood count (white blood cells and differential, red blood cells, hemoglobin, hematocrit, platelets, LUC (if performed as routine). Coagulation: aPTT (time and/or ratio), 
PT and/or INR, d-Dimers, fibrinogen. Biochemistry: glucose, CRP, ferritin, triglycerides, liver (AST, ALT, γGT, LDH, ALP, bilirubin) and renal function (albumin, creatinine, and urea).  
a Visit X: sequential visit number to be attributed 
b EOT: indicates a full patient assessment performed 3 days after last emapalumab infusion 
c Dexamethasone and prophylactic treatment: starting from SD-1 (at latest). A prophylaxis for herpes zoster virus infection must be in place from the day before initiation of emapalumab 
treatment until 44 days (corresponding to 2 half-lives) after last emapalumab administration. Prophylaxis for Pneumocystis jirovecii, and for fungal infections for all patients according to local 
practice. Patients will receive any other required prophylactic antimicrobial treatment according to local recommendations in pHLH. Dexamethasone may be substituted for another glucocorticoid 
at an equivalent dose according to clinical judgement or local availability. Equivalent dosage should be converted using a steroid conversion calculator 

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d Infusion: to be performed over a period of 1 to 2 hours, twice weekly, not more than 4 days apart 
e Medical history and concomitant medications: Includes demographic and medical history, medications at Screening, HLH induction treatment received when applicable, date of HLH diagnosis, 
molecular diagnosis and relevant functional tests performed for the diagnosis of HLH if available. 
f Vital Signs: include body temperature, heart rate, blood pressure, oxygen saturation. Temperature is to be measured pre-infusion, at the end of the infusion, 1 hour and 2 hours after the end of 
each infusion.  
g Physical Examination includes as a minimum: spleen and liver size (by abdominal palpation), neurological examination 
h TB: search for tuberculosis mycobacteria: at screening: IGRA/PPD and PCR; after screening, if clinically indicated (e.g. any clinical signs and symptoms suggestive of TB infection as per 
investigator discretion), a PCR testing should be performed. 
I Genetic Confirmation: sample to be collected if this is not available in the medical records 
k Laboratory and imaging assessments: If cannot be performed on the day of the scheduled visit, assessments within 1 day window from scheduled visit date will be accepted.  
l CSF sample: to be performed in case of CNS disease and/or onset of neurological signs and/or symptoms. 
m Urinalysis: glucose, blood, protein and/or albumin, leukocytes, ketones, pH, gravity 
n Abdominal ultrasound: must include longitudinal measure of spleen. At SD0 only if 2 weeks elapsed between the screening visit and SD0.  
o Chest X-ray: Chest CT will be accepted as a replacement for Chest X-ray. 
p Brain MRI: to be performed in case of CNS disease and/or onset of neurological signs and/or symptoms. Brain CT or cranial ultrasound will be accepted as a replacement of brain MRI. 
q AE recording: All AEs are collected from start of the first infusion of study drug, until study completion 
r SAE recording: SAEs are collected after signing of ICF until study completion. Thereafter only related SAEs will be reported 
s Pregnancy test: Female of childbearing potential will have a serum pregnancy test taken at Screening and Baseline and at EOT and then local urine pregnancy test will be taken monthly (week 
4, 8, 12 etc.) until 44 days (corresponding to 2 half-lives) after last emapalumab administration 
 
 

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Table 4 
Schedule of events – Follow-up period 
Assessments 
 
Follow-up 
pre-HSCT a 
Follow-up post-HSCT (or after last emapalumab infusion, as applicable) b 
EOT n 
 
 
Pre-
conditioning 
visit 
Weekly visits 
wk 1 – 2 – 3 c 
D+30  
visit c 
D+60  
visit c 
D+100 visit c 
6 months visit c 
EOS 
1 year  
visitc/ WD d 
Clinical 
Assessments 
Vital signs  
As 
indicated 
in  
Table 1 
X 
X 
X 
X 
X 
X 
X 
Physical Examination e  
X 
X 
X 
X 
X 
X 
X  
Height 
 
 
 
 
 
 
X 
Post-HSCT outcome f 
 
X 
X 
X 
X 
X 
X  
Survival 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
Hematology 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
X 
X 
X 
X 
X 
X 
X 
sCD25 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
Search for 
infections  
TB g 
 
 
X 
X 
X 
X 
X 
Infection search & 
monitoring  
In case of suspicion of infection – according to the patient’s clinical presentation 
Imaging  
Chest X ray  
In case of suspicion of infection 
Abdominal US j 
X 
 
 
 
X 
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Prophylactic treatment m 
X 
X 
X m 
 
 
 
 
AE recording k 
X 
X 
X 
X 
X 
X 
X 
SAE recording l 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE, adverse event; ALP, alkaline phosphatase; ALT, alanine transaminase, aPTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete blood 
count; cm, centimeter; CMV, cytomegalovirus; CRP, C-reactive protein; D, day; EBV, Epstein-Barr virus; EOS, end of study; EOT, end of treatment; γGT, gamma glutamyl transferase; HSCT, 
hematopoietic stem cell transplantation; ICF, informed consent form; IFNγ, interferon gamma; INR, International normalized ratio; LDH, lactate dehydrogenase; LUC, large unstained cells; 
mo, month; PT, prothrombin time; QOL, quality of life; SAE, serious adverse event; TB, tuberculosis; US, ultrasound; UV, unscheduled visit; WD, withdrawal visit; wk, week; yr, year 
Hematology: complete blood count (white blood cells and differential, red blood cells, hemoglobin, hematocrit, platelets, LUC (if performed as routine). Coagulation: aPTT (time and/or 
ratio), PT and/or INR, d-Dimers, fibrinogen. Biochemistry: glucose, CRP, ferritin, triglycerides, liver (AST, ALT, γGT, LDH, ALP, bilirubin) and renal function (albumin, creatinine, and 
urea). Urinalysis: glucose, blood, protein and/or albumin, leukocytes, ketones, pH, gravity. 

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a Follow-up pre-HSCT: if HSCT is not planned, patient will directly follow the Schedule of Assessment indicated for Follow-up after last emapalumab infusion  
b Follow-up post-HSCT: If search for a donor is longer than 6 months, the follow-up period will be reduced, and the EOS will take place no later than 18 months after the first dose of 
emapalumab.  
c Allowed time-windows: a ±2 day window is allowed until D+30 visit. A ±1 week window is allowed for D+60 and D+100 visits. A ±4 week window is allowed for 6-mo and 1-yr visits 
d WD (Withdrawal visit): assessments as indicated for last study visit are to be performed in case of premature study discontinuation  
e Physical examination: includes as a minimum: spleen and liver size (by abdominal palpation), and neurological examination 
f Post-HSCT outcome: applies to patients who undergo HSCT. Includes engraftment rate, donor chimerism achieved (as available), incidence of acute and chronic graft versus host disease 
g TB: as clinically indicated, at minimum at D+30, D+60, D+100, 6 month and 1 year/WD visits; (e.g. any clinical signs and symptoms suggestive of TB infection as per investigator discretion), a 
PCR testing should be performed. 
j Abdominal ultrasound: must include longitudinal measure of spleen 
k AE recording: All AEs are collected from start of the first infusion of study drug, until study completion. 
l SAE recording: SAEs are collected after signing of ICF until study completion. Thereafter only related SAEs will be reported 
m Prophylactic treatment: Prophylaxis for herpes zoster virus infection must be in place from the day before initiation of emapalumab treatment until 44 days (corresponding to 2 half-lives) 
after last emapalumab administration. Prophylaxis for Pneumocystis jirovecii, and for fungal infections for all patients according to local practice. Patients will receive any required prophylactic 
antimicrobial treatment according to local recommendations in pHLH.  
n EOT: indicated as reference only, refer to Table 3 
 
 
 
 
 
 
 
 
 
 

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6.5.1.2 
Screening  
Patients will be screened for eligibility prior to enrollment into the study. 
A signed informed consent form must be obtained from the patient/patient’s legally authorized 
representative prior to any study specific activities. If applicable assent will be obtained in 
accordance with local requirements. Once the informed consent is signed the patient will be 
assigned a patient number.  
A pre-screening checklist is an additional tool that is made available to assist the Investigator to 
make decisions. This checklist enables rapid preliminary assessment of patient’s eligibility based 
strictly on the information available from routine patient care. The pre-screening checklist will be 
kept at site and will not be shared with Sponsor. 
A screening log will be maintained by the Investigator with specification of reasons for non-
eligibility.  
Any SAE that occurs after informed consent has been signed must be reported. 
Screening evaluations should be completed within the 2 weeks prior to the first administration of 
study drug (Visit 1). Evaluations performed before ICF signature as per routine care, will be 
accepted for study purposes. Patient’s medical record should clearly denote these evaluations as 
standard of care. 
6.5.1.3 
Treatment period 
Patients will be in the treating unit the day before the first administration of emapalumab SD-1.  
During the treatment period, visits for infusion and safety /efficacy assessments will occur on 
SD0, and twice-a-week thereafter (not more than 4 days apart). After the patient’s clinical 
condition is stabilized, decrease the dose to the previous level to maintain clinical response. 
Given the unpredictable course of the disease, in case of reactivation (e.g. triggered by 
intercurrent infections), subsequent dose increases to 3 mg/kg (and up to 6 or 10 mg/kg, as 
appropriate) may need to be considered and will be guided by the same clinical and laboratory 
parameters described above and based on the Investigator’s decision.  
Treatment period will last until pre-conditioning for HSCT.  
An end of treatment (EOT) visit has to be performed 3±1 days after last emapalumab infusion. 
6.5.1.4 
Follow-up period 
After treatment completion or treatment discontinuation (for any reason), patients will continue in 
the study for long-term follow-up until 1 year after either HSCT or last emapalumab infusion (if 
HSCT is not performed). This will represent the last visit in the study. If search for a donor is 
longer than 6 months, the follow-up period will be reduced, and the EOS will take place no later 
than 18 months after the first dose of emapalumab.  
A patient who experiences HLH reactivation during the follow-up period, may be re-treated with 
emapalumab.  

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After the patient has completed the EOS visit, they should be treated and followed-up according 
to investigator judgment and local practice. No further investigational medicinal product will be 
provided. 
In case of an ongoing SAE, the patient will continue to be monitored until resolution or until the 
outcome of the event is known and stable, beyond the defined study end as necessary. 
6.5.1.5 
Unscheduled visits 
Unplanned visits may occur anytime during the study should the patient need to be assessed or 
treated for any clinical condition that arises during the study. This includes the evaluation and 
follow-up of AEs and SAEs. Data collected during such a visit should be entered in the eCRF. An 
unscheduled visit should not affect the regular visit schedule and assessments.  
6.5.2 
Medical history 
Medical history will be collected during the screening period up until the day of the first dose.  
Relevant medical history events with onset date at any time prior to ICF signature date will be 
recorded in the eCRF. 
HLH history will be recorded to the best possible extent, including (as available): 
molecular diagnosis of HLH and perforin expression and other functional tests performed for the 
diagnosis of HLH, disease features at diagnosis, date of diagnosis, family history of HLH, 
conventional treatments received to date, including procedures (such as plasmapheresis and 
HSCT), molecular diagnosis (genetic and functional test results), EBV load at diagnosis. 
If results of genetic and/or functional tests are pending at inclusion, they shall be reported when 
they become available. 
6.5.3 
Demography 
Date of birth, gender, race, and childbearing potential will be collected at screening. 
6.5.4 
Efficacy endpoints assessments 
6.5.4.1 
Overall Response 
Overall Response is defined as achievement of either Complete or Partial Response or HLH 
Improvement, at EOT or week 8 (whichever occurs earlier). 
Complete response, partial response and HLH improvement and time to first response will be 
assessed after the database lock via a programmed algorithm, based on the Table 5 below. 
Table 5 
Definition of response 
Overall Response  
Complete Response 
Complete Response is adjudicated if: 

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- No fever = body temperature <37.5C 
- Normal spleen size  
- No cytopenia = Absolute Neutrophil Counts 1.0x109/L and platelet count 100x109/L 
absence of G-CSF and transfusion support must be documented for at least 4 days to report 
no cytopenia 
- No hyperferritinemia = serum level is <2000 g/L 
- No evidence of coagulopathy, i.e., normal D-Dimer and/or normal (>150 mg/dL) fibrinogen 
levels  
- No neurological and CSF abnormalities attributed to HLH 
- No sustained worsening of sCD25 (as indicated by at least two consecutive measurements that 
are > 2-fold higher than baseline)  
Partial Response 
Partial Response is adjudicated if: 
- At least 3 of the HLH clinical and laboratory abnormalities (including CNS abnormalities) 
meet the above-mentioned criteria for “Complete Response” 
- In the case of “reactivated patients” who enter the study with 3 abnormal HLH features, Partial 
Response is adjudicated if at least 2 parameters normalize 
- In case of reactivated patients who enter the study with 2 abnormal HLH clinical and 
laboratory parameters only, Partial Response is adjudicated if one of the 2 parameters 
normalizes  
- There is no progression of other aspects of HLH disease pathology 
HLH improvement 
- Improvement (>50% change from baseline or normalization) of at least 3 HLH clinical and 
laboratory abnormalities (including CNS abnormalities).  
- In the case of “reactivated patients” who enter the study with only 2 abnormal HLH features, 
a change from baseline greater than 50% for both will define HLH as improved. 
 
6.5.4.2 
Time to first Overall Response 
Time to first response will be assessed after the database lock via a programmed algorithm, 
based on the Table 5 
6.5.4.3 
Duration of response 
Duration of Response, i.e., maintenance of the response achieved will be assessed after the 
database lock via a programmed algorithm, based on the Table 5 
6.5.4.4 
Glucocorticoids tapering 
Reduction of glucocorticoids by 50 % or more of the baseline dose  
6.5.4.5 
HSCT 
Information about conditioning for HSCT and of the HSCT will be recorded in the eCRF. This 
information will be used to calculate the number and proportion of patients able to commence 
conditioning for HSCT 

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6.5.4.6 
Investigator’s assessment of clinical response  
Investigator’s assessment of clinical response will be collected at every visit throughout the 
treatment period and will be based on the evaluation of clinical signs and laboratory parameters 
which characterize the disease; clinical signs, e.g. fever, splenomegaly, CNS symptoms, and 
laboratory parameters, e.g. CBC, fibrinogen, ferritin, sCD25 levels. The assessment will be 
assisted by the Investigator`s clinical judgment and previous experience in treating patients with 
pHLH and will be used to assess the achievement of response. The patient’s clinical response 
will be rated as ’complete response’, ‘partial response’, or ‘no response’ as judged by the 
investigator 
6.5.5 
Safety assessments 
6.5.5.1 
Adverse events 
 
Definitions 
Adverse event (AE) 
An AE is any untoward medical occurrence in a patient or study patient administered a 
pharmaceutical product; the event does not necessarily have a causal relationship with the 
treatment or usage. 
AEs include the following: 
• Abnormal test findings, as specified below. 
• Clinically significant signs and symptoms. 
• Changes in physical examination findings. 
• Progression/worsening of underlying disease. 
In addition, signs and symptoms resulting from the following should also be handled according 
to the same principles as AEs: 
• Overdose. 
• Withdrawal of treatment. 
• Interactions. 
• Abuse. 
• Misuse. 
For pregnancies and breastfeeding, see 6.5.5.1.6 

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Abnormal test findings 
An abnormal test finding, e.g. abnormal laboratory analysis results, vital signs, or ECG, should 
be recorded as an AE in any of the following situations: 
• The investigator considers the abnormal test finding to be clinically significant. 
• The abnormal test finding is associated with accompanying symptoms. Note, that the 
symptom, not the test result, should be recorded as an AE. 
• The abnormal test finding leads to a medical/surgical intervention including withdrawal 
of IMP(s) or discontinuation from the study. Repeat/confirmatory testing is not 
considered a medical intervention. 
Preexisting conditions  
A preexisting condition (i.e., a disorder present before the AE reporting period started and noted 
on the pretreatment medical history/physical examination form) should not be reported as an AE 
unless the condition worsens, or episodes increase in frequency during the AE reporting period.  
Procedures 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE. For example, an acute appendicitis that begins 
during the AE reporting period should be reported as the AE and the resulting appendectomy 
entered in the comments section of the eCRF. 
Lack of efficacy  
“Lack of efficacy” or “expected pharmacological effect has not been reached” will not be 
reported as an AE or SAE. However, failure of pharmacologic action or therapeutic benefit shall 
be recorded as an AE when they associated with a SAE or Serious outcome. 
Serious adverse event (SAE) 
An AE that meets one or more of the following criteria/outcomes is classified as serious: 
• 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 patient). 
• Is a medically important AE. 

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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 patient 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. 
Serious also includes any other event that the investigator or company judges to be serious. Any 
suspected transmission of an infectious agent via IMP shall also be considered serious. 
Hospitalization 
Hospitalization includes transfers within a hospital (e.g. from the psychiatric unit to the intensive 
care unit) and also includes admissions less than 24 hours. The following situations are not 
considered hospitalizations (although other SAE criteria may still apply): 
• Outpatient procedures / ambulatory care. 
• Emergency department visits. 
Hospitalization in the absence of an AE occurring during the study should not be considered an 
SAE. This includes: 
• Hospitalization due to a pre-existing condition not associated with a worsening of the 
pre-existing condition. 
• Protocol specified admission. 
• Elective admission, e.g. due to cosmetic surgery. 
• Pre-planned admission for a condition specified at baseline for the patient. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A SUSAR is an unexpected serious adverse event, suspected to be related to the study drug, 
which is not consistent with the reference safety information in the Investigator’s Brochure. 
 
Adverse event reporting period 
The period for recording AEs in the eCRF, begins upon receiving the first dose of investigational 
medication until EOS. All AEs must be recorded on specific AE forms of the eCRF. AEs that are 
reported from start of infusion and over the next 24 hours will be considered infusion related, 
and they will be analyzed separately. The investigator should report the actual event, e.g. rash, 
hypotension.  
Monitoring of suspicion of infections is requested throughout the study. Type of investigation, 
specimen, result, and pathogen identified will be captured in the eCRF. Any entry of new 
infection (assessed as serious and clinical suspicion of infections caused by pathogens potentially 
favored by IFN-γ neutralizations) in the eCRF will prompt to complete "infection log" to collect 
information regarding pathogen and specimen from which a pathogen has been isolated. 

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Figure 2 
Overview of non-serious AE and SAE reporting period 
 
 
Eliciting and recording adverse event information 
The investigator is to record all directly observed AEs, and all AEs spontaneously reported by 
the patient, in the eCRF using concise medical terminology. In addition, each patient will be 
questioned about AEs at each clinic visit following initiation of treatment 
When possible and appropriate, a diagnosis rather than individual signs and symptoms shall be 
recorded. The investigator is responsible for obtaining sufficient information to determine 
seriousness, causality, and outcome of each AE. 
Severity assessment 
The investigator will use the adjectives MILD, MODERATE, or SEVERE to describe the 
maximum severity of the AE. For the purpose of consistency, these severity grades are defined 
as follows:  
MILD 
Does not interfere with patient's usual function 
MODERATE  
Interferes to some extent with patient's usual function 
SEVERE 
 
Interferes significantly with patient's usual function 
Note the distinction between the gravity (seriousness) and the severity of an AE. Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For example, a 
headache may be severe in intensity, but would not be classified as serious unless it met one of the 
criteria for serious events listed above.  
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. 
Events occurring during the screening period (i.e. after signature of informed consent up to IMP 
initiation) are considered medical history. If it worsens after IMP initiation or during the follow-
up period, an AE form must be entered with the appropriated intensity. 
Causality assessment 
For each AE, the investigator must make a causality assessment to determine if there is a 
reasonable possibility that the IMP caused the AE. The AE is assessed as related or not related to 
  
  
  
  
  
  
  
 
Recording of Non-serious AEs in eCRF 
Non-serious related AEs reported to Sobi   
  
  
 
SAEs reported to Sobi (related or not related)
  
Informed 
Consent 
Signed 
First Dose of 
IMP   
EOT – End of 
Treatment 
 
  
 
EOS – End of study 
 
 
 

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the IMP. The determination of the likelihood that the IMP caused the AE will be provided by an 
investigator who is a qualified physician. 
• Related  
An AE that follows a reasonable temporal sequence from administration of the IMP (including 
the course after withdrawal of the IMP), or for which possible involvement of the IMP cannot 
be ruled out, although factors other than the IMP, such as underlying diseases, complications, 
concomitant drugs, and concurrent treatments, may also be responsible. 
• Unrelated  
An AE that does not follow a reasonable temporal sequence from administration of the IMP 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant drugs, and concurrent treatments. 
 
Serious adverse event (SAE) and non-serious related AE reporting 
Both serious and non-serious AEs are to be reported on the AE page of the CRF in English as 
specified in the CRF instructions and the investigator must assess the causal relationship of the 
event to study treatment.  
The Sobi Global Pharmacovigilance & Patient Safety (GPV) department is to be notified by e-
mail to adverseevent@sobi.com, using the designated SAE reporting form / non-serious related 
AE reporting form, within 24 hours of the investigator’s first knowledge of the following events: 
• All SAEs (whether or not considered by the investigator to be related to study treatment) 
• All non-serious related AEs (all non-serious AEs considered by the investigator to be 
related to study treatment) 
The SAE reporting form/non-serious related AE reporting form is not always the same as the 
adverse event eCRF form. The forms must be completed in a consistent manner. For example, 
the same AE term should be used on both forms. The investigator must assess the causal 
relationship of the event to IMP and sign the report. 
If the patient is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE relevant information and documentation. 
All new information obtained, relevant to an SAE and/or a non-serious related AEreport, should 
be forwarded to Sobi within the same timeframe as the initial information. 
The investigator shall provide Sobi with sufficient information to enable a complete medical 
assessment of the reported event. Best efforts shall be made by the investigator to provide Sobi 
with additional information related to any SAE and/or a non-serious related AE as requested. 
Prompt notification by the Investigator to the Sponsor of SAEs and non-serious related AEs is 
essential so that legal obligations and ethical responsibilities towards the safety of participants 
and the safety of a study intervention under clinical investigation are met.  

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• An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor, will 
review it and will notify the IECs/IRBs, if appropriate according to local requirements.  
• Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy, and forwarded to investigators as necessary. 
• The reference safety document to assess expectedness of a suspect serious adverse reaction 
and for reporting by the sponsor to Health Authorities, IECs/IRBs and investigators is the 
reference safety information section of the current version of the IB. 
 
Follow-up of unresolved adverse events 
All serious and non-serious AEs assessed by the investigator as related to the IMP should be 
followed until they are resolved or the investigator assesses them as chronic or stable, or the 
patient’s participation in the study ends, i.e., until the EOS visit. How to report changes in an 
ongoing AE during a patient's participation in the study is described in the eCRF instructions.  
In addition, all serious and non-serious 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 
“chronic” or “stable”, even after the patient's participation in the study is over, but without 
further recordings into the eCRF.  
 
Exposure during pregnancy and breastfeeding 
All events of exposure to the IMP during pregnancy (female patient or male patient’s partner) or 
breastfeeding, shall be reported to Sobi Global Pharmacovigilance & Patient Safety by e-mail to 
adverseevent@sobi.com within 24 hours of awareness by any study personnel, whether the 
exposure is associated with an AE or not. This includes all situations where a female is or has 
been found to be pregnant after being exposed to IMP; directly, indirectly or via her partner 
(paternal exposure). 
In all reported situations of exposure during pregnancy, Sobi will provide the investigator with a 
Pregnancy report form which shall be completed and returned by the investigator. The 
investigator is responsible for monitoring the outcome of the pregnancy and to inform Sobi of 
relevant information and any information requested related to the outcome of the pregnancy.  
Any AEs and SAEs observed during and in relation to pregnancy, delivery or breastfeeding 
should be recorded in the eCRF and as applicable be reported to Sobi as described previously in 
this section. 
6.5.5.2 
Safety endpoint assessment 
Number of patients who permanently discontinued study drug due to emapalumab-related 
adverse events. Occurrence and type of emapalumab-related adverse event as assessed by the 
investigator. Management and reporting of AEs related to these functions is described in Section 
6.5.5.1. 

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The definitions of AEs related to the respective area above will be based on MedDRA System 
Organ Class (SOC) terms, High-Level Group Term (HLGT), High-Level Term (HLT), Preferred 
Terms (PT), and Standardized MedDRA Queries (SMQ). 
6.5.6 
Clinical safety assessments 
6.5.6.1 
Vital signs 
Vital signs (body temperature, heart rate, and systolic/diastolic BP and oxygen saturation) will be 
measured at every visit and recorded in the eCRF.  
BP should be measured in the same body position consistently throughout the study, if possible.  
Temperature is to be measured pre-infusion, at the end of the infusion, 1 hour and 2 hours after 
the end of each infusion.  
For the first infusion (or the first infusion after an increased dose) BP and heart rate will be 
measured every 15 minutes during the infusion, at the end of infusion and 1 and 2 hr. post-
infusion. Oxygen saturation will be measured continuously during the infusion and up to 2 hr. 
post-infusion.  
For subsequent visits, if no infusion-related reactions have occurred, BP, heart rate and oxygen 
saturation will be measured every 30 minutes, at the end of infusion and 1 and 2 hr. post-
infusion.  
Following windows can be applied to the vital signs measurement: 
• When measured every 15 minutes: 
5 minutes 
• When measured every 30 minutes: 
10 minutes 
• When measured at 1 hour and 2 hours after infusion:  15 minutes 
Clinically significant abnormal vital signs should be reported as AEs (see Section 6.5.5.1.1 for 
details). 
6.5.6.2 
Height and weight 
Body weight (in kg) will be recorded at each visit during the treatment period, at the EOT visit, 
and at the final 1-year visit during the follow-up period (EOS)/discontinuation visit. Height (in 
cm) will be recorded at screening, at the EOT visit, and at the EOS/discontinuation visit. For 
patients older than 18 years of age height is only recorded at enrollment visit.  
6.5.6.3 
Physical examination 
A complete physical examination will be performed at screening and a brief examination 
(including spleen and liver size (by abdominal palpation) general appearance of the skin and 
neurological status) at all other visits indicated in the schedule of assessments, see Table 3 and 
Table 4. Information for all physical examinations must be included in source data and will not 
be recorded in the database.  

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Each component will be recorded in eCRF as “normal” or “abnormal” at each visit. 
Abnormalities should be described, and clinical significance assessed. 
If any abnormalities are reported at baseline they should be recorded as medical history. New or 
worsening of abnormalities should be reported as AEs if clinically significant (see Section 
6.5.5.1.1 for details). 
6.5.6.4 
Electrocardiogram 
A 12-lead ECG recording will be performed at screening, at the 8 weeks visit, and EOT. The 
ECG assessments will be performed locally at site and will be reported as “normal” or 
“abnormal” in the eCRF. Any abnormalities should be specified, and clinical significance 
assessed. ECGs assessed as abnormal should be assessed by an investigator with experience of 
assessing ECGs in children at different ages. Abnormalities reported at screening should be 
recorded as medical history.  
Clinically significant abnormal ECG findings should be reported as AEs (see Section 6.5.5.1 for 
details). 
6.5.7 
Laboratory safety assessments 
Due to the low blood volume in patients foreseen to participate in this study, it will be necessary 
to reduce sampling. Therefore, WHO recommendations regarding blood sampling are to be 
followed and if patient care or normal disease monitoring requires prioritization of sampling, this 
should be adhered to.  
Samples will be analyzed at the local laboratory using the local laboratory’s standardized 
analytical procedures and local procedures for blood collection and processing will be followed. 
The local laboratory should be accredited or participate in an external quality assurance scheme, 
e.g. China National Accreditation Service for Conformity Assessment (CNAS). The results from 
the local laboratory will constitute the primary data of the study to be used for statistical analysis.  
Local lab will also be used for patient care and treatment decisions in between study visits. 
In the event a study site is unable to analyze any of the protocol required laboratory tests at the 
local hospital laboratory, such samples can be sent to an external laboratory for analysis, and the 
results will be accepted in this study. Similarly, test results of the patients performed in other 
hospitals can be accepted in this study. The test content, test time window, and test result time 
window and requirements should be consistent with the study protocol. 
Clinically significant laboratory values should be reported as AEs (see Section 6.5.5.1.1 for 
details).  
If a sample cannot be performed on the day of the scheduled visit, assessments within 1 day 
window from scheduled visit date will be accepted.  

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6.5.7.1 
Pregnancy test 
Female of childbearing potential will have a serum pregnancy test taken at screening and 
Baseline and at EOT and then local urine pregnancy test will be taken monthly (week 4, 8, 12 
etc.) until 6 months after the last emapalumab administration. 
The outcome of the test will be reported as “positive” or “negative” in the eCRF. 
6.5.7.2 
Hematology 
CBC: white blood cells and differential (including large unstained cells count, whenever 
performed as routine), red blood cells, hemoglobin, hematocrit, platelets. 
6.5.7.3 
Chemistry 
Glucose, CRP, ferritin, triglycerides, liver (AST, ALT, γGT, LDH, ALP, bilirubin) and renal 
function (albumin, creatinine, and urea). 
6.5.7.4 
Coagulation 
aPTT (time and/or ratio), PT and/or INR, d-Dimers, fibrinogen. 
6.5.7.5 
sCD25 
sCD25  
6.5.7.6 
Urinalysis 
Glucose, blood, protein and/or albumin, leukocytes, ketones, pH, specific gravity. 
6.5.7.7 
Genetic confirmation 
Sample will be collected during screening if this information is not available in the medical 
records. 
6.5.7.8 
CSF  
Lumbar puncture for CSF analysis is to be performed in case of suspicion of CNS involvement at 
Screening providing that coagulation function allows and should be done at any other time-points 
during the study to monitor evolution (if the initial analysis was abnormal), or to confirm new 
onset of CNS involvement. 
6.5.7.9 
Tuberculosis (TB) 
At screening: IGRA/PPD and PCR; after screening, if clinically indicated (e.g. any clinical signs 
and symptoms suggestive of TB infection as per investigator discretion), a PCR testing should be 
performed. 
After screening visit TB is to be performed by PCR in any relevant specimen until 44 days after 
last emapalumab infusion.  

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6.5.7.10 
Infections, other 
Infection assessment at Screening should be performed according to the patient’s clinical 
presentation. At a minimum Adenovirus, EBV and CMV viral loads should be assessed together 
with screen for Histoplasma capsulatum, Leishmania, Salmonella, and atypical mycobacteria.  
In case of suspicion of any infection, local testing and treatment guidelines should be followed. 
6.5.8 
Imaging  
6.5.8.1 
Abdominal ultrasound 
Will be performed every two weeks during the treatment period. Has to include longitudinal 
measure of the spleen. 
6.5.8.2 
Chest X-ray 
Will be performed if clinically indicated (e.g. in case of clinical suspicion of pulmonary infection 
or to follow-up a pre-existing infection at screening/baseline). If a CT is performed it will be 
accepted instead of Chest X-ray. 
6.5.8.3 
Brain Magnetic Resonance Imaging (MRI) 
Only to be performed in case of CNS disease and/or onset of neurological signs and/or 
symptoms. Brain CT or cranial ultrasound will be accepted as a replacement of brain MRI.  
6.5.9 
Post HSCT outcome 
Will be assessed in patients who undergo HSCT. Includes engraftment rate, donor chimerism 
achieved (as available), incidence of acute and chronic graft versus host disease 
7 
Quality control and quality assurance 
This study will be conducted in compliance with this protocol, study specific procedures, 
contracts, CRO SOPs, the ICH Guideline for GCP [1], and applicable regulatory requirements. 
The sponsor will systematically review the study quality management to identify, evaluate and 
control risks to study critical processes and data which would affect patient safety and reliability 
of study data. 
The data collection tool will be a validated Electronic Data Capture (EDC) system. Patient data 
necessary for analysis and reporting will be entered/transmitted into a validated database or data 
system. 
Data required according to this protocol will be recorded by data entry by the study site 
personnel. EDC enables the application of software logic to set-up data entry screens and data 

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checks to ensure the completeness and accuracy of the data entered by the site personnel. Data 
queries resulting from the application of the software logic are resolved by the site personnel. 
The sponsor will identify the data to be collected based on the protocol and prepare EDC system 
requirement specifications. 
The EDC system is a password-protected security system. All study site personnel requiring 
access must go through a training process before they are granted access. Training records will 
be maintained. 
All personnel with access to EDC system should follow Sponsors requirement for the data entry, 
the change, and the correction of existing data. 
EDC system complies with applicable regulatory requirements and ICH GCP and contains a 
system-generated audit trail that captures any changes made to a data field, including who made 
the change, why the change was made and the date and time it was made. 
The Sponsor will establish a systematic, prioritized, risk-based approach to monitoring and 
details will be outlined in the Monitoring Plan 
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 eCRFs. All patient 
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 relevant personnel are available during the 
monitoring visits and possible audits and that sufficient time is devoted to the process. 
8 
Statistical plan 
A formal statistical analysis plan (SAP) will be written and will provide details of all analyses to 
be conducted. 
8.1 
Determination of sample size 
Sample size is not based on statistical considerations but the data from up to 18 Chinese patients 
will add sufficient information to the safety and efficacy profile established during the global 
clinical development program for emapalumab in pHLH patients.  
8.2 
Definition of study populations 
Safety and efficacy analyses will be conducted on the “All treated analysis set” which will comprise 
all patients who received at least one infusion of IMP.  

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8.3 
Overall statistical and analytical plan 
8.3.1 
General statistical issues 
The statistical analysis will be described in more detail in the statistical analysis plan (SAP). 
All endpoints will be summarized with descriptive statistics. For measurements of continuous 
endpoints, summary statistics will include n, mean, median, standard deviation, minimum and 
maximum values.  
For binary data (proportions of patients showing a defined variable) the counts and percentages 
will be presented.  
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 statistical analyses will be performed with statistical analysis software (SAS) System (SAS 
Institute, Cary, NC) version 9.4 or later. 
8.3.2 
Demographics and baseline characteristics 
All demographics and baseline characteristics will be summarized with descriptive statistics. 
8.3.3 
Analysis related to the primary objective 
The primary objective is to collect safety data on emapalumab in treatment-experienced pHLH 
patients 
The primary endpoint is permanent discontinuation of study drug due to emapalumab-related 
adverse events 
The number and percentage of patients who permanently discontinue study drug due to 
emapalumab-related adverse events will be presented. 
8.3.3.1 
Secondary endpoints supporting the primary objective 
Secondary endpoints supporting the primary objective are: 
• Treatment-emergent adverse events (AEs) 
• Treatment-emergent serious adverse events (SAEs) 
• Treatment-emergent laboratory abnormalities 
• Treatment-emergent vital sign abnormalities 

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The incidence of treatment-emergent AEs, treatment-emergent SAEs, treatment emergent 
laboratory abnormalities and treatment-emergent vital sign abnormalities will be summarized in 
frequency tables by system organ class and preferred term.  
8.3.4 
Analysis related to the secondary objective 
The secondary objective is to collect efficacy data on emapalumab in treatment-experienced 
pHLH patients 
The secondary endpoints supporting the secondary objective are: 
• Overall Response, i.e., achievement of either Complete or Partial Response or HLH 
Improvement, at EOT or week 8 (whichever occurs earlier). 
o Criteria for the definition of Overall Response Rate are reported in Table 5 
• Time to first Overall Response, i.e., time from the date of first dose of emapalumab to the 
first achievement of response (Complete or Partial Response or HLH Improvement) 
• Cumulative duration of response, i.e., total time in response from the first achievement of an 
Overall Response until EOT or week 8 (whichever occurs earlier). 
• Ability to reduce glucocorticoids by 50% or more of the baseline dose during emapalumab 
treatment 
• Investigator assessed response 
• Survival:  
o To start of HSCT conditioning, i.e., time from the date of first dose of Emapalumab to 
date of death, with censoring at conditioning for HSCT or at last date of contact for 
patients who did not undergo conditioning for HSCT 
o After HSCT, i.e., time from HSCT to death, with censoring time at last date of contact for 
patients with no event. Only patients undergoing HSCT will be included in the analysis  
8.3.4.1 
Clinical response 
Achievement of response and time to first response will be assessed after the database lock via a 
programmed algorithm. The derivation of the Overall Response is detailed in Table 5. 
The number and percentage of patients achieving Overall Response at EOT or week 8 
(whichever occurs earlier), i.e., Complete Response or Partial Response or HLH improvement, 
as well as No Response will be provided. 
The number and percentage of patients achieving each component of Overall Response will also 
be provided. 
Time to first Overall Response is defined as time from the date of first dose of emapalumab to 
the first achievement of response (Complete or Partial Response or HLH Improvement). Patients 
without a response will be censored at the EOT visit date or last assessment. 

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Time to first response prior to HSCT will be presented by Kaplan-Meier curve with median 
calculated if available. Associated two-sided 95% confidence intervals will be calculated for the 
median.  
 
Cumulative duration of response is defined as total time in response from the first achievement 
of an Overall Response until EOT or week 8 (whichever occurs earlier). Cumulative duration of 
response will be analyzed descriptively using summary statistics. 
 
In addition to the programmed algorithm of response, investigator’s assessment of clinical 
response up to HSCT will be presented descriptively.  
8.3.4.2 
Reduced glucocorticoids compared to baseline 
Number and percentage of patients able to reduce glucocorticoids by 50% or more of the 
baseline dose during emapalumab treatment will be provided.  
8.3.4.3 
Survival  
Survival to start of HSCT conditioning is defined as time from first dose of IMP to date of death 
from any cause. Patients with no event will be censored at start of conditioning for HSCT or at 
the date of last contact for patients who did not undergo HSCT. 
Survival after HSCT is defined as time from HSCT to date of death from any cause, with 
censoring time at last date of contact for patients with no event. Only patients undergoing HSCT 
will be included in the analysis. 
Survival to start of HSCT conditioning and Survival after HSCT will be estimated applying 
Kaplan-Meier methodology. Survival rates and associated two-sided 95% confidence intervals 
will be obtained at key time points. Median survival time, 75th and 25th percentiles will be 
calculated where available with associated two-sided 95% confidence intervals. 
8.3.5 
Exploratory endpoint supporting the secondary objective 
       
           
  
8.3.6 
Analysis of safety and tolerability data 
8.3.6.1 
Adverse events 
Reported AEs during the study will be coded using MedDRA. 
8.3.7 
Interim analysis 
No formal interim analysis is planned. 

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8.3.8 
Multiple comparison/multiplicity 
Not applicable since no formal statistical hypothesis testing will be performed. 
8.3.9 
Handling of missing data 
Methods for handling missing data will be described in the SAP. 
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.  
9.2 
Case report form 
A CRF is required and should be completed for each enrolled patient. In this study a web based, 
validated electronic data capture (EDC) software tool will be used to collect and process the 
study data. The management of the EDC system will be based on the model of outsourcing.  
The data should be entered by site users into the EDC system on an ongoing basis. In principle, it 
is recommended to perform data entry within 5 working days from the visit date unless otherwise 
specified by the site Clinical Trial Agreement. To ensure data quality within EDC, automated 
edit checks will be built into the EDC system and triggered to correct or verify the input data. 
Any data changes or modifications within EDC will be automatically tracked by an audit trail 
detailing date, time and name of the user performing corrections.  
Clinical data management will be conducted in accordance with regulatory standards. This 
applies to data recorded directly in eCRF and to data from other sources stored at secure servers 
(e.g. IXRS). Additional details regarding data collection and validation procedures will be 
detailed in a Data Management Plan.  
Access to the EDC system is granted and revoked in accordance with regulatory requirements. 
Only authorized personnel will have access to the electronic data capture system upon 
completion of the user training. 
The investigator will review and approve the eCRF entries for each patient with an electronic 
signature. The signatures serve to attest that the information contained on the eCRFs is correct. 
At all times, the investigator has final responsibility for the accuracy and authenticity of all data 
entered on the CRFs. 

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The completed original eCRFs 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.  
At the end of the study, a final copy of the database will be stored at the Sponsor. Sobi will 
ensure that an eCRF copy of trial’s final and locked data is provided to the Investigator in a form 
of a write protected PDF files and that the eCRF copies are an exact copy of the data maintained 
in the database.  
9.3 
Source data 
Patient source documents are the physician’s patient 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 eCRFs must match those charts. In some cases, a portion of the 
source documents for a given patient may be the eCRF.  
A separate source document location agreement will be completed and signed by the principal 
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 trail). 
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 patients. The investigator should not 
implement any deviation from, or changes of, the protocol, unless it is necessary to eliminate an 
immediate hazard to study patients. 
A protocol waiver is a documented prospective approval of a request from an investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.  
When a deviation from the protocol is identified, the investigator or designee must ensure 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 patient to determine 
patient continuation in the study. 
The investigator and CRO must contact Sobi immediately if a deviation is discovered that 
significantly affects or has the potential to significantly affect human patient protection or the 
reliability of study results. 
The investigator will also assure that deviations are reported and documented in accordance with 
IEC and applicable regulatory requirements.  

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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 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 or head of the study site (medical institution) 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, eCRF), the copy 
should fulfill the requirements for certified copy as defined in ICH GCP Guideline [1].  
The records should be retained by the Investigator as specified in the Clinical Trial Agreement 
and in accordance with local regulations.  
If the investigator relocates, retires, or for any reason withdraws from the study, the study 
records may be transferred to an acceptable designee, such as another investigator or another 
institution. Archiving on behalf of the investigator can also be delegated to Sobi.  
10 
End of study 
The end of study at a patient level is either the EOS visit or the withdrawal visit. 
The end of this study at the study level is defined as date of the last patient out, i.e. the last 
patient’s last visit.  

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11 
Sponsor’s discontinuation criteria 
11.1 
At patient level 
11.1.1 
Decision to Slow Down or Stop Emapalumab Infusion due to Systemic 
Reaction  
During the infusion of emapalumab, any significant change compared to pre-infusion values in 
vital signs, such as those listed below, should trigger appropriate immediate care:  
• Sudden and sustained increase or paradoxical decrease of heart rate (duration of more 
than 5 minutes) compared to pre-infusion value and not linked to child’s anxiety or fear;  
• Sustained (an episode of more than 5 minutes duration or more than 3 episodes of shorter 
duration, i.e., 3 minute) oxygen desaturation (below 90%);  
• Any clinical sign or complaint indicative of patient distress  
 
The decision to interrupt the infusion might be taken by the investigator in the event of any of 
the above-mentioned occurrences.  
The decision to restart the infusion will be based on the evolution of the patient`s status (i.e., 
resolution of symptoms after appropriate symptomatic measures, e.g., oxygenation or 
administration of anti-histamine treatment), and upon investigator’s own medical judgment. The 
infusion will generally be restarted at a lower rate.  
All changes in infusion rate will be recorded in the patient’s medical chart and the eCRF each 
time there is a rate modification, as well as at the end time of premature or delayed termination 
of the infusion.  
11.1.2 
Local Issues During Emapalumab Infusion  
Unless related to a hypersensitivity reaction, a local infusion issue such as catheter displacement, 
obstruction, or product extravasation, will trigger the infusion of the remaining quantity through 
a new venous access as soon as possible. All information related to the incident will be recorded 
accurately in the patient’s medical chart prior to being entered in the eCRF. This includes 
reasons, volume of IMP potentially lost (to calculate the quantity of drug infused), time at which 
the infusion stopped, time at which the infusion was resumed and time of end of the infusion.  
To avoid this type of incident, it is preferable that a central venous access is used: this will 
improve patient’s comfort and ensure a reliable drug administration in particular in infants and 
toddlers or in case of foreseen difficulties with peripheral venous access.  

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11.1.3 
Decision to Discontinue Treatment  
The Investigator can decide at any time during the study to discontinue the treatment for an 
individual patient based on his/her own medical judgment, taking into account the individual 
benefit/risk ratio for his/her patient. There are no predefined rules for permanent study drug 
discontinuation based on the current safety profile of the drug. The Investigator may request 
expert advice or a discussion with the Sponsor, if relevant prior to taking a decision; however, 
the ultimate decision remains the Investigator`s responsibility. The reason for premature 
treatment discontinuation should be documented in the patient’s chart and the eCRF. After 
treatment discontinuation (for any reason), it is recommended that the patient will continue in the 
study for a long-term follow-up. 
11.2 
At site level 
Significant violation of ICH GCP and all applicable laws, regulations and protocol procedure 
that compromises the ability to achieve the primary study objectives or compromises patient 
safety may lead to the affected site to be discontinued from study participation by to Sponsor.  
11.3 
At the study level 
Sponsor reserves the right to temporarily suspend and to discontinue the study prior to inclusion 
of the intended number of patients but intends only to exercise this right for valid scientific or 
administrative reasons. After such a decision, the investigator must contact all participating 
patients as soon as possible. Patients already enrolled in the study should continue in the study as 
per protocol unless judged otherwise by Investigator.  
All study materials must be collected and all the eCRFs completed to the greatest extent 
possible. 
Recruitment may be temporarily suspended in the following situations:  
• occurrence of unexpected fatal or life-threatening adverse reactions;  
• emergence of severe drug reactions linked to a common cause/ risk factor at different 
sites  
Patients already enrolled in the study should continue receiving emapalumab per protocol unless 
decided otherwise by the Investigator.  
The suspension will allow for the analysis of the available data by the Sponsor.  
After re-evaluation of benefit/risk, the sponsor may recommend any of the following:  
• to resume recruitment without any change;  
• to implement risk minimization measures that may require protocol amendment;  
• to implement conditions for study termination, e.g., next occurrence of a particular 
serious drug reaction; 
• to discontinue the study.  

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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 http://www.chictr.org.cn/, http://www.chinadrugtrials.org.cn/ and 
www.clinicaltrials.gov. The results of this study will be published within 12 months of the end of 
study. 
Sobi is committed to publishing study results in a complete, accurate, balanced, transparent, and 
timely manner. Sobi follows the principles of the International Committee of Medical Journal 
Editors (ICMJE) recommendations for the conduct, reporting, editing, and publication of 
scholarly work in medical journals including criteria for authorship [38]. 
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.  

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13 
Reference list 
1. 
ICH, ICH Harmonised Guideline: Integrated addendum to ICH E6 (R1) 
GfGCERCSvdNAf, https://www.ich.org/page/efficacy-guidelines. 
2. 
WMA, World Medical Association Declaration of Helsinki; Ethical Principles for 
Medical Research Involving Human Patients. Available from:  
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-
research-involving-human-subjects/. 
3. 
Henter, J.I., et al., Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. 
Blood, 1991. 78(11): p. 2918-22. 
4. 
Henter, J.I., et al., Incidence in Sweden and clinical features of familial hemophagocytic 
lymphohistiocytosis. Acta Paediatr Scand, 1991. 80(4): p. 428-35. 
5. 
Sieni, E., et al., Familial hemophagocytic lymphohistiocytosis may present during 
adulthood: clinical and genetic features of a small series. PLoS One, 2012. 7(9): p. 
e44649. 
6. 
Wang, Y., et al., Genetic features of late onset primary hemophagocytic 
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Appendix 1 
Additional Protocol Signatures 
 
 
Sponsor’s Clinical Study Manager  
 
Signature 
 
Date 
 
 
Sponsor’s Statistician 
 
Signature 
 
Date 
 

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Appendix 2 
Study Administrative Structure 
All sites and investigator will be listed with names and their curricula vitae (CVs) in the TMF 
 
 
Monitoring: 
 
 
 
SAE reporting: 
Swedish Orphan Biovitrum AB (Sobi) 
SE-112 76 Stockholm, Sweden 
Data management:  
 
Statistics: 
 
Investigational products 
(production): 
 
 
Investigational products 
(packaging and labeling): 
 
Clinical laboratory: 
Local laboratories to be used 
 
Central laboratory: 
 
 
 
 
 
 
 
Commented [BP1]: Should this be redacted? I’m not too familiar 
with doing redactions but could the lab information be important to 
redact if not for the rest? 
Commented [BP2R1]: I think have Tigermed in here should be 
redacted as I think the CRO information should be kept separate? 
Commented [PH3R1]: I think you are right about this. Will be 
redacted