A Phase 2/3, Open-label, Single Arm, Multicenter Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Emapalumab in Adult Patients With Hemophagocytic Lymphohistiocytosis
Phase: PHASE2
Conditions: Hemophagocytic Lymphohistiocytoses
Sponsor: Swedish Orphan Biovitrum



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Protocol NI-0501-10 
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CONFIDENTIAL 
INVESTIGATOR AGREEMENT 
 
Protocol Number:  
 
NI-0501-10 
Protocol Date and Version:  
09 March 2020, Version 3.0 
Study Drug: 
 
 
emapalumab 
Study Title: 
A Phase 2/3, Open-label, Single Arm, Multicenter Study to Evaluate the 
Efficacy, Safety, and Pharmacokinetics of Emapalumab in Adult Patients 
with Hemophagocytic Lymphohistiocytosis 
Investigator Endorsement: 
I, the undersigned, have agreed to serve as a Principal Investigator for this study and to be responsible for 
the conduct of this study at this site, and I agree to conduct the study according to the protocol and any 
approved protocol amendments, ICH GCP and all applicable regulatory authority requirements. 
I will not deviate from the protocol without prior permission from Sobi AG and prior review and written 
approval from the Institutional Review Board/Independent Ethics Committee, and where applicable, from 
Competent Health Authorities, except where necessary to prevent any immediate danger to a patient. 
I have read and understand fully the Investigator’s Brochure for emapalumab and I am familiar with the 
investigational product and its use according to this protocol. 
 
_______________________________________ 
____________________ 
Principal Investigator’s Signature 
Date 
 
_______________________________________ 
Principal Investigator’s Name 
 
_________________________________________________ 
Site number and address 
Please sign this form and make a copy of the form for your site files. The original of the form, reflecting 
the original signature, will be collected by your monitor and returned to Sobi AG.   
 
 

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CONTACT LIST 
Sponsor: 
Swedish Orphan Biovitrum AG 
12 Chemin des Aulx 
1228 Plan-les-Ouates 
Switzerland 
Phone: +41 22 839 71 41 
Chief Medical Officer Sobi 
Immunology: 
Cristina de Min, MD 
Phone: +41 61 201 13 22 
Mobile phone: +41 79 525 14 59 
Email: Cristina.DeMin@sobi.com 
Clinical Science Leader: 
 
 
 
Veronica Asnaghi, MD 
Phone: +41 61 201 13 31 
Mobile phone: +41 79 572 24 14 
Email: Veronica.Asnaghi@sobi.com 
Drug Safety Physician: 
Yuanyuan Lu, MD  
Phone: +41 61 201 13 82 
Mobile phone: +41 79 352 06 82 
Email: Yuanyuan.Lu@sobi.com 
Clinical Operations Manager: 
Marianna Baikousi 
Mobile phone: +41 (0)79 362 97 99 
Phone: +41 (0)61 201 13 26 
Email: Marianna.Baikousi@sobi.com 
Clinical Pharmacologist: 
 
Gunilla Huledal, MSc Pharm 
Phone: +46 8 697 2156 
Mobile phone : +46 73 518 6037 
Email: Gunilla.Huledal@sobi.com 
Senior Clinical Data Manager: 
Ricardo Azedo, PharmD 
Phone: +41 61 201 1397 
Email: Ricardo.Azedo@sobi.com 
Data Protection Officer: 
DataPrivacy@sobi.com 
 
 

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NI-0501-10 SYNOPSIS 
Title: 
A Phase 2/3, Open-label, Single Arm, Multicenter Study to Evaluate the 
Efficacy, Safety, and Pharmacokinetics of Emapalumab in Adult 
Patients with Hemophagocytic Lymphohistiocytosis  
Sponsor: 
Sobi AG, Switzerland 
Study Type and Design: 
Study NI-0501-10 is an open-label, single arm, multicenter, Phase 2/3 
interventional study 
The 
study 
enrolls 
adult 
patients 
with 
hemophagocytic 
lymphohistiocytosis (HLH), specifically newly diagnosed patients with 
malignancy-associated HLH (M-HLH), and newly diagnosed or 
previously treated patients with non-malignancy-associated HLH 
The study includes an initial phase enrolling 10 patients. If no untoward 
significant safety signal attributable to emapalumab treatment (as 
judged by an iDMC) is identified, enrolment will be broadened and will 
continue until the target number of patients is reached 
The patient’s participation in the study comprises three parts: 
screening, treatment period, and follow-up 
Study Objectives: 
Primary efficacy objective: 
• 
To assess the efficacy of emapalumab in adult patients with 
HLH, as measured by Overall Response Rate  
Secondary efficacy objectives: 
• 
To assess the efficacy of emapalumab as measured by overall 
survival, time to response, best response on treatment, 
duration of response 
• 
To evaluate the safety and tolerability of emapalumab 
• 
To determine the pharmacokinetic (PK) profile of emapalumab 
• 
To determine the pharmacodynamic (PD) profile of 
emapalumab  
Study Population: 
Eligible patients include male and female patients aged 18 and older at 
the time of HLH diagnosis, who meet HLH-2004 clinical criteria for the 
diagnosis of HLH (with or without malignancy), and who have no 
primary HLH. Patients with M-HLH must be newly diagnosed (i.e. must 
have received no previous HLH treatments, with the exception of 
glucocorticoids), while patients with non-malignancy-associated HLH 
may have previously received HLH therapies (therefore they can be 
either treatment naïve or treatment experienced) 

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Inclusion Criteria: 
 
 
 
 
 
 
 
1. Male and female patients aged 18 and older at the time of HLH 
diagnosis 
2. Fulfilment of HLH-2004 clinical criteria, i.e. five of the eight criteria 
below: 
- 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 (fibrinogen ≤1.5 
g/L) 
- Hemophagocytosis in bone marrow, spleen or lymph nodes 
- Low or absent natural killer (NK)-cell activity 
- Ferritin ≥500 µg/L 
- Soluble 
CD25 (sCD25, 
i.e., 
soluble 
IL-2 
receptor) 
≥2400 U/mL (or equivalent, in case the local lab uses 
different units) 
3. Patients diagnosed with M-HLH must be treatment naïve; patients 
diagnosed with HLH driven by any other etiology or idiopathic can 
be either treatment naïve or treatment experienced 
4. Patients with non-malignancy-associated HLH who have already 
received conventional therapy for HLH must have failed prior 
treatment as per the treating physician`s judgement. At the time of 
enrolment, eligible treatment experienced patients may or may not 
be receiving conventional therapy  
5.  JAK inhibitors, if administered, must be discontinued before 
emapalumab initiation 
6. Informed consent signed by the patient or by the patient’s legally 
authorized representative(s) (as required by local law) 
7. 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 
Exclusion Criteria: 
 
1. Primary HLH (documented by the presence of known causative 
genetic mutations or by the presence of family history) 
2. Current (within 60 days from SD0) or scheduled administration of 
therapies known to trigger the cytokine release syndrome (e.g. 
chimeric antigen receptor (CAR)-modified T cells, bispecific T cell-
engaging antibodies) 
3. Current (within 60 days from SD0) or scheduled administration of 
PD-1/PD-L1/CTLA-4 inhibitors 

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4. Life-expectancy associated with the underlying disease (triggering 
HLH) < 3 months 
5. Ongoing participation in an investigational trial, or administration 
of any investigational treatment within 30 days from Screening 
6. History of hypersensitivity or allergy to any components of 
emapalumab  
7. Active mycobacteria, Histoplasma capsulatum, or Leishmania 
infections 
8. Evidence of latent tuberculosis 
9. Infection with HIV (HIV ELISA or PCR positive), hepatitis B (HBsAg 
positive), Hepatitis C (anti-HCV positive) unless the viral load by PCR 
is negative 
10. Concomitant diseases that in the opinion of the Investigator may 
significantly affect the likelihood of a response to treatment and/or 
the assessment of emapalumab safety and/or efficacy 
11. Receipt of a bacille Calmette-Guerin (BCG) vaccine within 12 weeks 
prior to Screening 
12. Receipt of a live or attenuated live (other than BCG) vaccine within 
6 weeks prior to Screening 
13. Pregnancy or lactation (female patients) 
Study Drug: 
Emapalumab (previously referred to as NI-0501) is a fully human high-
affinity monoclonal antibody that binds to and neutralizes IFNγ 
Dosing Regimen & Frequency 
of Administration: 
Emapalumab will be administered by intravenous (IV) infusion over a 
period of 1 to 2 hours depending on the volume to be infused, at an 
initial dose of 6 mg/kg  
Emapalumab treatment will be continued at the dose of 3 mg/kg, every 
3 days until SD15, and then twice-a-week  
If the treating physician deems appropriate, the dose of emapalumab 
may be increased (back to 6 mg/kg, and up to 10 mg/kg), guided by 
clinical and laboratory response. During the initial phase of the study, 
PK/PD data may also be considered 
Treatment Duration: 
It is not expected that treatment duration will be the same across the 
study population 
Treatment shall continue until a clinically satisfactory response is 
achieved. Shall the duration of treatment exceed 12 weeks, an 
assessment of a favorable benefit/risk profile must be provided and 
confirmed by the iDMC 
If HSCT is planned, treatment can be administered until HSCT 
In all cases, treatment can be stopped upon achievement of complete 
clinical response, if at least two infusions of emapalumab at the dose 
of 3 mg/kg have been administered  

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Patients will undergo a Week 4 Assessment Visit 3 days after the last 
emapalumab infusion administered in Week 4  
Treatment may be shorter, and in such instance an End of Treatment 
(EoT) visit shall be performed 3 days after the last administration of 
emapalumab 
Whenever a patient receives treatment beyond Week 4, both a Week 
4 Assessment Visit and an End of Treatment (EoT) visit shall be 
performed 
After treatment discontinuation (for any reason), patients will continue 
in the study for long-term follow-up until 1 year after last emapalumab 
administration (or after HSCT, if performed) 
If HLH recurs or reactivates during the off-drug follow-up, treatment 
with emapalumab can be reinstated 
Background Therapy & 
Concomitant Medications: 
In all patients, emapalumab will be initiated on a background of 
glucocorticoids. Therapy with dexamethasone at a dose of 10 mg/m2 
daily will be initiated in any patient not receiving glucocorticoids at the 
time of emapalumab start. If a patient is already receiving 
glucocorticoids, he/she will continue at their current dose, as long as it 
corresponds to at least 5 mg/m2 daily dexamethasone (unless 
intolerance is documented) 
In case of M-HLH, emapalumab can be administered with standard 
malignancy-directed therapy, as deemed appropriate by the 
Investigator, with the exception of the therapies listed as exclusion 
criteria 
Administration of advanced therapies known to trigger the cytokine 
release syndrome (e.g., chimeric antigen receptor (CAR)-modified T 
cells, bispecific T cell-engaging antibodies, PD-1 inhibitors) and the 
administration of JAK inhibitors are prohibited 
Calcineurin inhibitors can be continued if they are being administered 
at the time of screening. Calcineurin inhibitors can be withdrawn at any 
time at the discretion of the Investigator  
IV immunoglobulins are only allowed as replacement treatment 
During emapalumab treatment, intrathecal (IT) therapy (e.g. 
methotrexate and glucocorticoids) can be continued or started de 
novo, if clinically indicated 
The administration of additional HLH therapies, concomitantly with 
emapalumab, will be allowed in the case of documented unsatisfactory 
HLH control after at least 3 doses of emapalumab. Unless a patient has 
been previously vaccinated, prophylaxis for herpes zoster must be in 
place on study day minus 1 (or, at the latest, before initiation of 
emapalumab treatment) and must be maintained for 2 half-lives 
(approximately 44 days) after last emapalumab administration 

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Patients may receive additional prophylactic antimicrobial treatments 
according to local standards of care 
Analgesic therapies, blood product transfusions, electrolyte and 
glucose infusions, antibiotics, anti-fungal treatments, anti-viral 
treatments, and general supportive care are allowed 
Vaccination with a live or live-attenuated (including BCG) vaccine must 
be avoided for 2 half-lives after last emapalumab administration 
 Sample Size: 
According to the adaptive design of this study, the initial sample size 
planned for each etiology (i.e. M-HLH and non-malignancy-associated 
HLH) is 10 patients. The sample size for each of the two etiologies (i.e. 
M-HLH and non-malignancy-associated HLH) will be reviewed in an 
ongoing way. Recruitment to particular etiologies may be stopped for 
futility while recruitment to other etiologies may be expanded up to a 
sample size of 25 patients for a particular etiology 
Number of Sites: 
Initially approximately 5. The number may be increased depending on 
the observed recruitment rate 
Study Duration and Study 
End Definition: 
After emapalumab discontinuation (for any reason), patients will 
continue in the study for long-term follow-up until 1 year after last 
emapalumab administration (or after HSCT, if performed) 
The analysis of the primary efficacy endpoint will be performed once 
the last enrolled patient underwent the Week 4 Assessment Visit (or 
EoT Visit in case of earlier treatment discontinuation) 
The end of the study is defined as last patient last visit (LPLV) at 1 year 
after last emapalumab infusion or HSCT (as applicable)  
Study Surveillance, Safety 
Reporting and Stopping 
Rules: 
The study includes an initial phase enrolling 10 patients. If no untoward 
significant safety signal attributable to emapalumab treatment (as 
judged by an iDMC) is identified, enrolment will be broadened; 
subsequently, the iDMC will meet every time data for an additional 10 
patients in total are available (or earlier, should any untoward event 
occur), to confirm that the safety profile of emapalumab remains 
favorable. In addition, the Sponsor will review the data on an ongoing 
basis, to monitor for the emergence of any safety signals 
Emapalumab infusions should be performed under medical 
supervision, in an environment with access to emergency equipment 
and trained medical personnel, and monitored as per local standard of 
care based on the patient’s clinical condition 
Adverse events (AEs) will be recorded from the date of the ICF signature 
until the end of the study, as follows:  
- Signs and symptoms of HLH will not be reported as adverse events; 
however, sustained worsening or reactivation of HLH during or after 
emapalumab treatment will be reported as an AE 

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- SAEs must be communicated by the Investigator to Sobi AG by fax 
or e-mail within 24 hours of awareness 
- After the Day+60 Visit (i.e. once at least 2 half-lives of the drug have 
elapsed), only serious adverse events (SAEs) related to emapalumab 
will be collected  
In case of pregnancy, study treatment must be discontinued 
permanently 
Efficacy Endpoints: 
Primary efficacy endpoint: 
• 
Overall Response, i.e. achievement of either a Complete or Partial 
Response, at Week 4 (or EoT if earlier) 
Secondary efficacy endpoints: 
• 
Best response on treatment 
• 
Overall Response at EoT  
• 
Overall survival  
• 
Time to Complete or Partial Response 
• 
Duration of response 
• 
HLH Relapse 
Safety Endpoints:  
 
• Incidence, severity, causality and outcomes of AEs (serious and non-
serious) 
• Clinically significant changes in blood tests, physical examinations, 
vital signs, ECGs 
PK/PD Endpoints: 
• Serum concentrations of emapalumab at specified time points 
• Serum concentrations of total IFNγ and CXCL9, at specified time 
points 
• Serum concentrations of other relevant markers, including but not 
limited to sCD25 and IL-6,  at specified time points 
• Incidence of anti-drug antibodies (ADAs) against emapalumab 
Statistical Analysis: 
The primary analysis for each etiology (i.e. M-HLH and non-malignancy-
associated HLH) will evaluate the Overall Response (OR) rate at 4 weeks 
and use a binomial test with a one-sided significance level of 5% to 
calculate the p-value. The null hypothesis is that the OR rate is at most 
40%, which is the assumed value historically. An improvement in the 
OR rate up to 60% is being targeted 
In this adaptive design, it is proposed to review the data periodically in 
order to assess each of the 2 etiologies (i.e. M-HLH and non-
malignancy-associated HLH) for futility and efficacy. The first analyses 
for each etiology would be after 10 patients recruited with that 
etiology, and further analyses for each etiology would take place after 

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every subsequent 5 patients. The decision rule for stopping for futility 
shall be based on a one-sided p-value looking to see whether the OR 
rate was significantly below 60%, while the decision rule for 
consideration for efficacy shall be based on a one-sided p-value looking 
to see whether the OR rate was significantly above 40% 
Descriptive statistics and graphical methods will be used for the 
evaluation of the secondary efficacy endpoints 
Safety data will be listed and summarized using descriptive statistics 
To support regulatory interactions on the confirmatory strategy, a 
descriptive evaluation of the efficacy and safety results will be made 
after a small number of patients, i.e. no more than 10 patients overall 
(irrespectively of etiology), have completed 4 weeks of treatment 

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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT .............................................................................................................. 2 
CONTACT LIST .................................................................................................................................... 3 
NI-0501-10 SYNOPSIS ......................................................................................................................... 4 
TABLE OF CONTENTS ........................................................................................................................ 11 
TABLE OF TABLES ............................................................................................................................. 15 
TABLE OF FIGURES ........................................................................................................................... 15 
LIST OF ABBREVIATIONS .................................................................................................................. 16 
TABLE 1: SCHEDULE OF ASSESSMENTS – SCREENING AND TREATMENT PERIOD ................................. 19 
TABLE 2: SCHEDULE OF ASSESSMENTS - FOLLOW-UP PERIOD ............................................................ 23 
1 
BACKGROUND INFORMATION ............................................................................. 25 
1.1 
ADULT HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ................................................................. 25 
1.2 
EMAPALUMAB ................................................................................................................. 27 
1.2.1 
Description and Mode of Action .......................................................................................... 27 
1.2.2 
Preclinical Data .................................................................................................................... 27 
1.2.3 
Clinical Data ......................................................................................................................... 28 
2 
OBJECTIVES ......................................................................................................... 30 
3 
STUDY DESIGN .................................................................................................... 30 
3.1 
OVERALL DESIGN .............................................................................................................. 30 
3.2 
SCREENING PERIOD ........................................................................................................... 31 
3.3 
TREATMENT PERIOD .......................................................................................................... 32 
3.4 
FOLLOW-UP PERIOD ......................................................................................................... 32 
3.5 
STUDY END ...................................................................................................................... 32 
4 
TARGET POPULATION .......................................................................................... 32 
4.1 
ELIGIBILITY CRITERIA ......................................................................................................... 32 
4.1.1 
Inclusion Criteria .................................................................................................................. 33 
4.1.2 
Exclusion Criteria .................................................................................................................. 33 
5 
INVESTIGATIONAL MEDICINAL PRODUCT ............................................................. 34 
5.1 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT ....................................................... 34 
5.2 
RATIONALE FOR DOSING SCHEMA ....................................................................................... 34 
5.3 
DOSING SCHEMA .............................................................................................................. 37 

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5.4 
INVESTIGATIONAL MEDICINAL PRODUCT HANDLING ............................................................... 38 
5.4.1 
Packaging and Labelling ...................................................................................................... 38 
5.4.2 
Investigational Medicinal Product Supply ............................................................................ 39 
5.4.3 
Investigational Medicinal Product Receipt and Storage ...................................................... 39 
5.4.4 
Investigational Medicinal Product Preparation, Administration, Accountability, and 
Destruction ........................................................................................................................... 39 
6 
PROTOCOL TREATMENT PLAN ............................................................................. 41 
6.1 
CONCOMITANT THERAPY ................................................................................................... 41 
6.1.1 
Malignancy-related treatments ........................................................................................... 41 
6.1.2 
Dexamethasone ................................................................................................................... 42 
6.1.3 
Infection prophylaxis ............................................................................................................ 42 
6.1.4 
Calcineurin inhibitors ........................................................................................................... 42 
6.1.5 
Intrathecal Therapy.............................................................................................................. 42 
6.1.6 
Other Concomitant Therapies .............................................................................................. 42 
6.1.7 
Contraception guidance ....................................................................................................... 43 
6.2 
PROHIBITED THERAPIES ..................................................................................................... 43 
6.2.1 
Advanced therapies and JAK inhibitors ................................................................................ 43 
6.2.2 
Vaccines ............................................................................................................................... 43 
6.3 
ADDITIONAL HLH TREATMENTS .................................................................................... 43 
6.4 
EMERGENCY TREATMENT ................................................................................................... 44 
7 
ENDPOINTS ......................................................................................................... 44 
7.1 
EFFICACY ENDPOINTS ........................................................................................................ 44 
7.2 
SAFETY ENDPOINTS ........................................................................................................... 45 
7.3 
PHARMACOKINETIC ENDPOINTS .......................................................................................... 45 
7.4 
PHARMACODYNAMIC ENDPOINTS ........................................................................................ 45 
8 
OUTLINE OF STUDY PROCEDURES ........................................................................ 46 
8.1 
SCREENING ...................................................................................................................... 47 
8.2 
VISIT 1 AND ONWARDS (INFUSION 1 OF EMAPALUMAB, SD0 AND ONWARDS) ............................ 48 
8.3 
WEEK 4 ASSESSMENT (3 1 DAYS AFTER LAST WEEK 4 INFUSION) AND END OF TREATMENT 
VISIT (3 1 DAYS AFTER LAST INFUSION) ............................................................................ 49 
8.4 
FOLLOW-UP PERIOD ..................................................................................................... 51 
8.4.1 
Follow-Up Pre-HSCT: Pre-Conditioning Visit ........................................................................ 51 

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8.4.2 
Follow-Up After Last Emapalumab Infusion (or Post-HSCT) ................................................ 52 
8.4.3 
1-Year Visit After Last Emapalumab Infusion or After HSCT/ Withdrawal Visit .................. 53 
8.5 
UNPLANNED/UNSCHEDULED VISITS ............................................................................ 53 
8.6 
UNPLANNED ASSESSMENTS ......................................................................................... 54 
9 
SAFETY MONITORING .......................................................................................... 54 
9.1 
STUDY SCIENTIFIC OVERSIGHT ............................................................................................. 54 
9.2 
DESCRIPTION AND DEFINITIONS OF SAFETY PARAMETERS......................................................... 54 
9.2.1 
Adverse Events ..................................................................................................................... 54 
9.2.2 
Serious Adverse Events ........................................................................................................ 54 
9.3 
RECORDING AND REPORTING SAFETY PARAMETERS ................................................................ 55 
9.3.1 
Adverse Events ..................................................................................................................... 55 
9.3.2 
Serious Adverse Events ........................................................................................................ 56 
9.4 
PROCEDURES FOR RECORDING ADVERSE EVENTS ....................................................... 57 
9.4.1 
Diagnosis versus Signs and Symptoms ................................................................................ 57 
9.4.2 
Persistent and recurrent adverse events ............................................................................. 57 
9.4.3 
Managing Abnormal Laboratory Test Values ...................................................................... 57 
9.4.4 
Deaths .................................................................................................................................. 57 
9.4.5 
Worsening of preexisting medical conditions ...................................................................... 57 
9.4.6 
Pregnancy ............................................................................................................................ 57 
9.5 
FOLLOW-UP OF SAFETY PARAMETERS .................................................................................. 58 
9.5.1 
Investigator Follow-up of Adverse Events ............................................................................ 58 
9.5.2 
Sponsor Follow-up................................................................................................................ 58 
9.6 
POST-STUDY ADVERSE EVENTS ............................................................................................. 58 
9.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES .................................................................................................. 58 
9.8 
BENEFIT/RISK MANAGEMENT ............................................................................................. 59 
9.8.1 
Safety Surveillance Management ........................................................................................ 59 
9.8.2 
General Benefit/Risk Considerations ................................................................................... 59 
10 
STUDY, AND SITE DISCONTINUATION ................................................................... 61 
10.1 
PATIENT DISCONTINUATION ................................................................................................ 61 
10.2 
STUDY TREATMENT DISCONTINUATION ................................................................................ 62 
10.3 
STUDY DISCONTINUATION ................................................................................................... 62 

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10.4 
MANAGEMENT OF TREATMENT DISCONTINUATION ................................................................ 62 
11 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN........................................ 62 
11.1 
SAMPLE SIZE .................................................................................................................... 62 
11.2 
ANALYSIS SETS ................................................................................................................. 62 
11.2.1 
All Treated Analysis Set ........................................................................................................ 63 
11.2.2 
Per Protocol Analysis Set ...................................................................................................... 63 
11.3 
STATISTICAL AND ANALYTICAL METHODS .............................................................................. 63 
11.3.1 
Efficacy Data ........................................................................................................................ 63 
11.3.2 
Adaptive Evaluation of the Overall Response Rate .............................................................. 63 
11.3.3 
Safety Data .......................................................................................................................... 64 
11.3.4 
Pharmacokinetic Data ......................................................................................................... 64 
11.3.5 
Pharmacodynamic Data ...................................................................................................... 64 
11.3.6 
Missing Data ........................................................................................................................ 65 
11.4 
REPLACEMENT POLICY ....................................................................................................... 65 
11.4.1 
For Patients .......................................................................................................................... 65 
11.4.2 
For Centers ........................................................................................................................... 65 
12 
ETHICAL AND LEGAL ASPECTS .............................................................................. 65 
12.1 
GOOD CLINICAL PRACTICE .................................................................................................. 65 
12.2 
INVESTIGATOR RESPONSIBILITIES ..................................................................................... 65 
12.3 
INFORMED CONSENT ......................................................................................................... 66 
12.4 
CONFIDENTIALITY AND DATA PRIVACY .................................................................................. 66 
12.5 
PROTOCOL AMENDMENTS ................................................................................................. 67 
12.6 
APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS .......................................... 67 
12.7 
ONGOING INFORMATION FOR IRB/IEC ................................................................................ 67 
12.8 
CLOSURE OF THE STUDY ..................................................................................................... 67 
12.9 
RECORD RETENTION .......................................................................................................... 68 
12.10 
LIABILITY AND INSURANCE .................................................................................................. 68 
12.11 
FINANCIAL DISCLOSURE ..................................................................................................... 69 
12.12 
DISCLOSURE OF PROTOCOL AND STUDY RESULTS AND PUBLICATION POLICY ............................... 69 
13 
MONITORING AND AUDITING .............................................................................. 69 
13.1 
STUDY MONITORING AND SOURCE DATA VERIFICATION .......................................................... 69 

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13.2 
ON-SITE AUDITS ............................................................................................................... 70 
13.3 
SERIOUS GCP BREACHES ................................................................................................... 70 
14 
DOCUMENTATION AND USE OF STUDY FINDINGS ................................................ 70 
14.1 
DOCUMENTATION OF STUDY RESULTS .................................................................................. 70 
14.2 
USE OF COMPUTERIZED SYSTEMS AT THE CLINICAL TRIAL CENTRE ............................................ 70 
15 
REFERENCES ........................................................................................................ 71 
16 
APPENDIX 1 ......................................................................................................... 74 
 
TABLE OF TABLES 
Table 1: Schedule of Assessments – Screening and Treatment Period ...................................................... 19 
Table 2: Schedule of Assessments - Follow-up Period ................................................................................ 23 
Table 3: Clinical and Laboratory Criteria to Guide Dose Increases ............................................................. 38 
Table 4: Definition of Response .................................................................................................................. 45 
 
TABLE OF FIGURES 
Figure 1: NI-0501-10 Study Design ............................................................................................................. 31 
Figure 2: Total IFNγ Concentrations up to the Last Dose in HLH Patients Treated with Emapalumab in 
Studies NI-0501-04 and NI-0501-05 (HLH) and in Compassionate Use (CU) Patients ............. 35 
Figure 3: Emapalumab and CXCL9 Concentrations at the Initial Dose of 6 mg/kg Followed by 3 mg/kg/3d 
and then 3 mg/kg Maintained Twice a Week During the Treatment Course .......................... 36 
Figure 4: Emapalumab and CXCL9 Concentrations at the Initial Dose of 6 mg/kg Reduced to 3 mg/kg on 
Day 3 Followed by 6 mg/kg/3d and then 6 mg/kg Maintained Twice a Week During the 
Treatment Course ..................................................................................................................... 36 
Figure 5: Emapalumab and CXCL9 Concentrations at the Initial Dose of 6 mg/kg Followed by 3 mg/kg on 
Day 3, 6 mg/kg on Day 6, 10 mg/kg/3d and then 10 mg/kg Maintained Twice a Week During 
the Treatment Course .............................................................................................................. 37 

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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
ATG 
Anti-thymocyte globulin 
AUC 
Area Under the Curve 
BAL 
Bronchoalveolar lavage 
BCG 
Bacillus Calmette-Guérin 
CBC 
Complete blood cell count 
CFR 
Code of Federal Regulation 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CR 
Complete response 
CRA 
Clinical research associate 
CRF 
Case report form 
CRP 
C-reactive protein 
CSF 
Cerebrospinal fluid 
CU 
Compassionate Use 
eCRF 
Electronic case report form 
DMC 
Data Monitoring Committee 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
EOT 
End of treatment 
FDA 
Food and Drug Administration 

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FHL 
Familial hemophagocytic lymphohistiocytosis 
G-CSF 
Granulocyte-colony-stimulating factor 
HIV 
Human immunodeficiency virus 
HLH 
Hemophagocytic lymphohistiocytosis 
HSCT 
Hematopoietic stem cell transplantation 
HV 
Healthy volunteer 
HZ 
Herpes Zoster 
ICF 
Informed Consent Form 
ICMJE 
International Committee of Medical Journal Editors  
IDMC 
Independent Data Monitoring Committee 
IFNγ 
Interferon gamma 
IFPMA 
International Federation of Pharmaceutical Manufacturers & Associations 
IgG1 
Immunoglobulin G1 
IMP 
Investigational medicinal product 
IRR 
Infusion-related reaction 
IT 
Intrathecal 
IVIG 
Intravenous immunoglobulin 
LCMV 
Lymphocytic choriomeningitis virus 
LDH 
Lactate dehydrogenase 
LPLV 
Last patient last visit 
mAb 
Monoclonal antibody 
MAS 
Macrophage Activation Syndrome 
M-HLH 
MRI 
Malignancy associated HLH 
Magnetic resonance imaging 
NK 
Natural killer 
NaCl 
Sodium Chloride 
NOAEL 
No Observed Adverse Effect Level 
NOEL 
No Observed Effect Level 

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ORR 
Overall response rate 
OS 
Overall Survival 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
pHLH 
Primary hemophagocytic lymphohistiocytosis 
PPD 
Purified protein derivative 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Prothrombin Time 
ROC 
Receiver Operating Characteristic 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
sCD25 
soluble CD25 (i.e., soluble IL-2 receptor) 
SD(n) 
Study Day number (e.g., Study day 1 = SD1) 
sHLH 
Secondary hemophagocytic lymphohistiocytosis 
sJIA 
systemic Juvenile Idiopathic Arthritis 
SUSARs 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment Emergent Adverse Event 
TB 
Tuberculosis 
TMF 
Trial Master File 
 
 

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Table 1: Schedule of Assessments – Screening and Treatment Period 
Assessment 
Screening Visit 
(up to 2 Weeks 
prior to Visit 1) 
Week 1 
Week x  
Week 4 Assessment 
Visit b  
(3 ± 1 day) 
EoT (3±1 day after 
last infusion) 
Visit 1 / SD0 
Visit 2 / SD3  
Visit 3 / SD6 
Visit 4 onwards a  
Visit `Wk4 
Assessment` 
Visit `EoT` 
Informed Consent 
X 
 
 
 
 
 
 
Review of Inclusion/Exclusion Criteria 
X 
X (pre-infusion) 
 
 
 
 
 
Patient Information c 
X 
 
 
 
 
 
 
Background Dexamethasone/Glucocorticoids d 
X 
 X 
X  
X  
X  
 X 
X 
Anti-viral Prophylaxis e 
X 
 X 
X 
X 
X  
X  
X 
Emapalumab infusion f 
  
X 
X 
X 
X 
X (if applicable) 
 
Clinical 
Assessment  
Vital Signs g 
X 
X (Pre/post-inf.) 
X (Pre/post-inf.) 
X (Pre/post-inf.) 
X (Pre/post-inf.) 
X (Pre/post-inf., if 
applicable) 
X  
Body weight  
X 
X (pre-inf) 
X (pre-inf) 
X (pre-inf) 
X (pre-inf) 
X (pre-inf, if 
applicable) 
X 
Height 
X 
 
 
 
 
 
 
ECOG Performance Status 
X 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (pre-inf, if 
applicable) 
X 
Physical Examination  
X 
X (Pre-inf.) p 
X (Pre-inf.) p 
X (Pre-inf.) p 
X (Pre-inf.) p 
X (pre-inf, if 
applicable) p 
X p  
Procedure 
ECG 
X 
 
 
 
 
 
X  
Evaluation for 
Infection q 
TB h 
X 
Every 4 weeks 
Adenovirus, EBV, CMV (viral load) 
X 
If infection suspected 
HIV, Hep B, Hep C 
X 
 
Atypical mycobacteria, Histoplasma 
capsulatum, Leishmania  
X 
If infection suspected 

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Assessment 
Screening Visit 
(up to 2 Weeks 
prior to Visit 1) 
Week 1 
Week x  
Week 4 Assessment 
Visit b  
(3 ± 1 day) 
EoT (3±1 day after 
last infusion) 
Visit 1 / SD0 
Visit 2 / SD3  
Visit 3 / SD6 
Visit 4 onwards a  
Visit `Wk4 
Assessment` 
Visit `EoT` 
Laboratory 
CBC 
X 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (pre-inf, if 
applicable) 
 X 
Biochemistry  
X 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (pre-inf, if 
applicable) 
 X  
Coagulation 
X 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (pre-inf, if 
applicable) 
 X  
Pregnancy test (if applicable)  
X 
Every 4 weeks 
 X  
Urinalysis i  
 
X 
 
 
 
 
 X 
Imaging 
Abdominal Ultrasound j 
X 
X o 
Every 2 weeks 
X 
X 
Chest X-ray 
X 
If clinically indicated 
X 
Brain MRI  
X k 
If clinically indicated  
Histopathology 
CSF Analysis (only if CNS disease and 
if coagulation allows) l 
X l 
 If clinically indicated l 
Investigator assessment of clinical response 
 
X  
X 
X 
X 
X 
X 
AE recording 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications recording 
X 
X 
X 
X 
X 
X 
X 
PK m 
  
X (Pre - post 
inf.)  
X (Pre - post 
inf.)  
X (Pre - post inf.) 
X (Pre - post inf.) 
X (Pre - post inf., if 
applicable) 
X 
PDn  
  
X (Pre inf.)  
X (Pre inf.) 
X (Pre inf.) 
X (Pre inf.) 
X (pre-inf, if 
applicable) 
X 
Immunogenicity (ADA) 
 
X (Pre inf.) 
 
 
  
X s (pre-inf, if 
applicable) 
 X r 
 

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Abbreviations: ADA, anti-drug antibodies; 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; ECG, electrocardiogram; EOT, end of treatment; EBV, Epstein-Barr virus; HLH, hemophagocytic 
lymphohistiocytosis; IGRA, interferon-gamma release assays; SD, study day; IFNγ, interferon gamma; inf, infusion; IMP, investigational medicinal product; MRI, magnetic resonance imaging; PCR, polymerase chain 
reaction; PD, pharmacodynamic; PK, pharmacokinetic; PPD, purified protein derivative; PT, prothrombin time; TB, tuberculosis; US, ultrasound 
CBC: complete blood count (white blood cells and subsets, red blood cells including hemoglobin, hematocrit, platelets). Coagulation: aPTT and/or aPTT ratio; PT and/or PT/INR, D-dimer, fibrinogen. Biochemistry: 
glucose, CRP, ferritin, triglyceride (fasting whenever possible), liver (AST, ALT, LDH, ALP, total bilirubin) and renal function (albumin, creatinine and urea) 
From SD0 on, clinical assessments and procedures, evaluation for infections, laboratory and imaging assessments, Investigator assessment of clinical response shall be performed pre-infusion, ideally on the day of 
the infusion, and in any case no more than 1 day prior to the infusion 
a Visit X: Sequential visit numbers will be used. Visit X lists all assessments required at any infusion visit, occurring either before or after the Week 4 Assessment Visit 
b Week 4 Assessment Visit: The primary endpoint will be evaluated 3 days after the last emapalumab infusion administered in Week 4 (or at the EoT visit, for patients who discontinued treatment earlier) 
c Patient Information: includes demographics (including race and ethnicity where allowed), medical history, medications at Screening, prior HLH therapy received (when applicable), date of HLH diagnosis, molecular 
diagnosis and relevant functional tests performed for the diagnosis of HLH (if available); for treatment experienced patients with non M-HLH, recording of reasons to determine failure of conventional therapy, as per 
Investigator`s assessment; for patients diagnosed with idiopathic HLH, recording of outcome of investigations performed to exclude an underlying malignancy 
d Background Dexamethasone/Glucocorticoids: starting from SD minus1 (at latest). For details, see Section 6.1.2 
e Anti-viral prophylaxis: for patients not vaccinated against Herpes Zoster, starting from SD minus 1 (or, at the latest, before the first emapalumab infusion) and until 2 half-lives after the last administration of 
emapalumab. Patients will receive any additional prophylactic antimicrobial treatment according to local guidelines for HLH. 
f Infusion: to be performed over 1-2 hours, every 3 days until SD15, and then twice-a-week, not more than 4 days apart; the second infusion must be administered on SD3   
g Vital Signs: includes body temperature, blood pressure, heart rate, respiratory rate. To be measured pre-infusion, at the end of the infusion, and 1 and 2 hours after the end of the infusion, except for body 
temperature, to be taken only pre-infusion 
h TB: search for tuberculosis mycobacteria: at Screening: IGRA/PPD and PCR; after Screening by PCR if infection is suspected 
i Urinalysis: glucose, blood, protein, leukocytes, ketones 
j Abdominal ultrasound: must include longitudinal measure of spleen 
k Brain MRI: only in cases of CNS disease and/or as clinically indicated 
l CSF analysis: if lumbar puncture is performed for monitoring/therapy of CNS disease, spared sample (if any) may be analyzed for PK and PD parameters, if clinically indicated 
m PK: emapalumab concentration 
n PD: CXCL9,  sCD25, total IFNγ, and other exploratory biomarkers 
o Abdominal ultrasound: required at SD0 only if 2 weeks or longer elapsed between the Screening visit and SD0 
p Physical examination: includes as a minimum: spleen and liver size (by abdominal palpation), neurological examination 
q Evaluation for infection: if a patient’s medical condition warrants rapid treatment initiation, availability of the results for infection screening is not required prior to initiation of emapalumab, provided that there 
are no clinical findings suggestive of any of the infections which represent exclusion criteria. However, samples for infection screening need to be collected for analysis prior to first administration of emapalumab 
according to the protocol requirements. As Leishmania is not endemic in North America, only patients who have been in endemic regions (e.g., South America) during the 6 months prior to screening, are required 
to be actively screened for Leishmania 

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r ADA: for patients who received the last emapalumab dose at Week 4, no ADA sampling is required at EoT 
s ADA: for patients who remain on study drug beyond the Week 4 Assessment Visit, ADA sampling is required every 3 months after the Week 4 Assessment Visit. 
 

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Table 2: Schedule of Assessments - Follow-up Period 
Assessments 
Follow-up pre-HSCT a 
Follow-up after last emapalumab infusion or after HSCT 
 
UV f 
EOT b 
Pre Conditioning 
visit c 
Weekly visits 
wk 1 – 2 – 3 d 
(± 2 days) 
D+30  
visit d 
(± 2 days) 
D+60  
visit d 
(± 2 weeks) 
D+100  
visit d 
(± 2 weeks) 
6 month  
visit d 
(± 4 weeks) 
1 year 
visit d/ WD e 
(± 4 weeks) 
 
Clinical 
Assessments 
Vital signs  
As 
indicated 
in  
Table 1 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical Examination g  
X 
X 
X 
X 
X 
X 
X  
 
 
ECOG Performance Status 
X 
 
X 
X 
X 
X 
X 
 
 
Post-HSCT outcome h 
 
X 
X 
X 
X 
X 
X  
 
 
Survival 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory 
CBC 
X 
X 
X 
X 
X 
X 
X 
 
 
Biochemistry 
X 
X 
X 
X 
X 
X 
X 
 
 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy test (if 
applicable) 
X 
 
X 
X 
X 
X 
X 
 
 
Urinalysis 
 
 
 
 
 
 
X 
 
 
Search for 
infection  
TB i 
Every 4 weeks until D+60; then at D+100, 6 month and 1 year visits 
Adenovirus, EBV, CMV  
If infection suspected 
 
 
Imaging  
Chest X-ray i 
If infection suspected 
X 
 
 
Abdominal US j 
X 
 
 
 
X 
 
X 
 
 
Investigator assessment of clinical response 
X 
X 
X 
X 
X 
X 
X 
 
 
AE recording 
X 
X 
X 
X 
Only SAEs related to IMP  
 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
 
PK/PD k  
X 
X  
X 
X  
X  
X  
X  
 
 
Immunogenicity (ADA) 
 
 
X 
 
X  
 
X  
 
 

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Abbreviations: ADA, anti-drug antibodies; AE, adverse event; ALP, alkaline phosphatase; ALT, alanine transaminase, AST, aspartate transaminase; CBC, complete blood count; CMV, cytomegalovirus; CRP, C-
reactive protein; D, day; EOT, end of treatment; EBV, Epstein-Barr virus; HSCT, hematopoietic stem cell transplantation; IFNγ, interferon gamma; mo, month; PD, pharmacodynamic; PK, pharmacokinetic; TB, 
tuberculosis; US, ultrasound; UV, unscheduled visit; WD, withdrawal visit; wk, week; yr, year 
CBC: white blood cells and subsets, red blood cells including hemoglobin, hematocrit, platelets. Coagulation: aPTT and/or aPTT ratio; PT and/or PT/INR, D-dimer, fibrinogen. Biochemistry: glucose, CRP, ferritin, 
triglycerides (fasting whenever possible), liver (AST, ALT, LDH, ALP, total bilirubin) and renal function (albumin, creatinine and urea)  
During the follow-up after last emapalumab infusion or after HSCT, all assessments shall be performed ideally on the day of the visit, and in any case no more than 1 day prior to the visit 
a Follow-up pre-HSCT:  if HSCT is not planned, patient will directly follow the Schedule of Assessments indicated for Follow-up after last emapalumab infusion  
b EOT: indicated as reference only, please refer to Table 1  
c Pre Conditioning visit: may be combined with EOT visit (if not more than 2 days apart). In such case, the EOT schedule of assessments has to be applied 
d Allowed time-windows:  a ±2 day window is allowed until D+30 visit. A ±2 weeks window is allowed for D+60 and D+100 visits. A ±4 week window is allowed for 6-mo and 1-year visits 
e WD (Withdrawal Visit): assessments as indicated for the 1-year visit are to be performed in case of premature study discontinuation 
f UV (Unscheduled Visit): assessments to be performed as clinically indicated  
g Physical examination: includes as a minimum: spleen and liver size (by abdominal palpation), neurological examination 
h Post-HSCT outcome: applies to patients who undergo HSCT. Includes engraftment rate, donor chimerism (as available), acute and chronic GvHD 
i TB search and chest X-ray: to be performed as long as emapalumab serum concentrations are detectable, thereafter only if clinically indicated (except for one chest X-ray required at 1 year visit) 
j Abdominal ultrasound: must include longitudinal measurement of the spleen 
k PK/PD: to be collected if serum levels of emapalumab were still measurable at the previous visit; if serum levels of emapalumab were not measurable at the previous visit, PD can be collected if clinically indicated. 
 

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1 BACKGROUND INFORMATION 
1.1 
ADULT HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS 
Adult-onset hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome that has 
historically been diagnosed using criteria extrapolated from pediatric-onset HLH. These criteria include 
fever, splenomegaly, peripheral blood cytopenias (at least two lineages), hypertriglyceridemia and/or 
hypofibrinogenemia, hemophagocytosis in the bone marrow, spleen, or lymph nodes, hyperferritinemia, 
high levels of soluble IL2 receptor (i.e. sCD25), and low or absent NK-cell activity. The diagnosis relies on 
fulfilling 5 of the 8 criteria (Henter JI(c) 2007). Importantly, although the original criteria posit the absence 
of malignancy in pediatric HLH (Henter JI(b) 2002), a similar syndrome occurs in adults with specific types 
of cancer, especially NK/T-cell lymphomas and leukemia. In addition, HLH can complicate certain types of 
infection and specific rheumatologic diseases or be idiopathic. Therefore, while pediatric HLH is largely 
genetically defined by mutations affecting cytotoxic lymphocyte function, adult HLH is more 
heterogeneous in its etiology. 
Despite the multiple triggers for adult-onset HLH and its less clearly defined genetic basis compared to 
pediatric HLH, the underlying pathophysiology is conserved: HLH is a syndrome characterized by a severe 
impairment or absence of cytotoxic function by natural killer (NK) and CD8+ T cells leading to striking 
activation of the immune system, manifested by hypercytokinemia and hemophagocytosis. These, in turn, 
cause all of the typical signs and symptoms of HLH (Dhote R 2003, Risdall RJ(b) 1984), leading to organ 
failure, and often to death.  
The incidence of adult-onset HLH is unclear but is probably higher than generally realized. At the Mayo 
Clinic, the incidence has been estimated at 1 in every 2000 inpatient admissions (Parikh SA 2014) . For 
comparison, the incidence in the pediatric population has been estimated at 1 in every 3000 inpatient 
admissions (Jordan MB 2011) . The incidence of malignancy-associated HLH in adults has been reported 
as 0.36/100,000 individuals/year (Machaczka M 2011). Adult patients who respond to therapy can 
relapse, but the incidence of relapse has not been documented. Many patients do not have the 
opportunity to relapse because of initial difficulty in achieving disease control.  
Clinically, adult patients with HLH do notoriously poorly. In one of the largest case series reported to date, 
67 adult patients meeting strict criteria for HLH were found to have a median overall survival of only 4 
months. Patients with malignancy-associated HLH had the worst prognosis, with a median overall survival 
of 2.8 months and only 0.9 months in the setting of myeloid malignancies. Patients with HLH but without 
malignancy had a median overall survival of 10.7 months (Schram AM 2016). Other studies have reported 
similarly dismal outcomes, especially in patients with concomitant hematologic malignancies (Li J 2014, 
Parikh SA 2014, Rivière S 2014, Takahashi N 2001). In all causes of HLH in adults, the overall mortality is 
significant at 41%, ranging from 5 to 39% in autoimmune disease-associated HLH, and between 42% and 
88% in malignancy-associated HLH (Carter SJ 2019). 
The scientific literature suggests a correlation between clinical response and probability of survival. 
However, there are no standardized criteria or time points to define clinical response in the few published 
studies. Published overall response rates range from 32% (Assi R 2018) to 76% (Wang Y 2015, Shin HJ 
2008), where the latter study uses a definition of partial response of at least a 25% improvement in 2 or 
more quantifiable symptoms and laboratory markers. 
There are no validated treatment protocols for HLH in adults. Treatment regimens have been informed 
by experience in pediatric HLH and by retrospective case series and case reports. One single prospective 

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study has been conducted in adults, investigating the efficacy of DEP regimen in patients with refractory 
HLH (Wang Y 2015).  
In general, adult patients with HLH receive therapy directed at the underlying etiology such as infection 
or malignancy (Rivière S 2014, Schram AM 2016). Many also receive therapy more specifically directed at 
HLH, for instance glucocorticoids and/or etoposide with or without cyclosporine (La Rosée P 2015, Rivière 
S 2014, Schram AM 2016). These treatments are extrapolated from experience in pediatric HLH (Henter 
JI(b) 2002). In certain cases, intravenous immunoglobulin (IVIG) and other therapies have been used 
(Larroche C 2000, Li J 2014, Parikh SA 2014, Rivière S 2014, Schram AM 2016, Takahashi N 2001). Although 
the inclusion of etoposide in the treatment of adult-onset HLH has not been shown to confer a statistically 
significant survival benefit, there is a trend toward improved survival (Arca M 2015, Schram AM 2016). 
Many physicians treating adults with HLH are hesitant to use etoposide, a chemotherapeutic agent, unless 
the HLH is related to malignancy. This is due primarily to concerns regarding toxicity in very sick patients, 
often with multi-system organ failure (elevated creatinine and bilirubin), as well as to more long-term 
risks, such as secondary leukemia. The relative benefits of the other therapies in the adult population 
have not been conclusively demonstrated. Because of the high mortality rates associated with adult-onset 
HLH, stem cell transplantation is often considered. This can be curative but carries its own unique set of 
risks and cannot be contemplated unless the HLH is controlled. The overall median survival for patients 
who undergo stem cell transplantation has been reported as 21.5 months (Schram AM 2016) and may be 
better than this (Nikiforow S 2015).  
Emapalumab (previously referred to as NI-0501, trade name Gamifant®) is an anti-interferon gamma 
(IFNγ) monoclonal antibody that binds to and neutralizes IFNγ. It is approved by FDA for the treatment of 
patients with primary HLH who have refractory, recurrent or progressive disease or intolerance with 
conventional HLH therapy. 
The central role of IFNγ in the pathogenesis of secondary HLH (sHLH) is supported by pre-clinical data: 
two animal models of sHLH have been investigated to elucidate the pathogenetic role of IFNγ,  a murine 
model that mimics an infection-driven HLH through repeated administrations of CpG and activation of 
TLR9 (Strippoli R 2012), and a model of IL-6 transgenic mice expressing high levels of IL-6 that mimics the 
condition of patients with sJIA, the rheumatic disease most frequently associated with secondary forms 
of HLH (Prencipe G 2018). In both models, when IFNγ was neutralized by the administration of an anti-
IFNγ antibody, clinical and laboratory features of the disease were reverted (Strippoli R 2012), and survival  
markedly improved (Prencipe G 2018). 
Consistent with a central role for IFNγ in human HLH, elevated levels of this cytokine are found in 
paediatric as well as adult patients with HLH (Akashi K 1994, Ohga S 1993, Maruoka H 2014, Henter JI(a) 
1991). 
Further evidence has been gathered in an observational study conducted in patients with secondary 
forms of HLH, either consequent to infections, or of unknown origin or with MAS occurring in the context 
of sJIA. In 14 patients with secondary HLH (in 7 of whom an underlying infection was identifiable), serum 
samples were analyzed during active full-blown disease and during disease remission. Levels of IFNγ and 
CXCL9 and CXCL10 (two IFNγ-induced chemokines) were markedly higher in the active phase compared 
to disease remission. The levels of IFNγ and chemokines (in particular CXCL9) correlated significantly with 
parameters of disease severity, such as neutrophil and platelet counts, ferritin and ALT, further supporting 
the pathogenic role of IFNγ in sHLH (Buatois V 2017). 
Similar findings have been shown in patients with MAS occurring in patients with sJIA. Serum 
concentrations of IFNγ, IFNγ-inducible chemokines (CXCL9, CXCL10, CXCL11) and IL-6 were measured in 
54 patients with sJIA, of whom 20 had MAS. The levels of IL-6 were comparable in patients with full-blown 

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MAS and those with active sJIA but without MAS at the time of sampling. On the contrary, circulating IFNγ 
and chemokine levels were significantly higher in MAS, particularly for CXCL9. Levels of IFNγ also 
correlated with laboratory parameters of disease severity, with the exception of LDH for which statistical 
significance was not achieved (Bracaglia C 2017). 
Observational studies have been initiated by the Sponsor (in malignancy-associated HLH in study NI-0501-
07, in adult HLH in study NI-0501-08; data on file) to characterize the levels of IFNγ and the IFNγ-inducible 
chemokines CXCL9 and CXCL10 in adult HLH, using in-house validated assays. The majority of the patients 
had elevated levels of IFNγ, CXCL9 and CXCL10, confirming the presence of an IFNγ-signature in adult HLH. 
The range of IFNγ, CXCL9 and CXCL10 levels at disease onset in the adult HLH patient sera was similar to 
the range observed in the paediatric HLH population (NI-0501-04 study and CU patients). 
Given the central role of IFNγ in mediating the immune dysregulation and severe inflammation in all forms 
of HLH, it is hypothesized that neutralization of IFNγ will improve outcomes in patients with adult-onset 
HLH. The anti-IFNγ antibody emapalumab has been developed for this purpose, and has demonstrated 
efficacy in primary HLH.  
The need for such a therapy in adult-onset HLH is clear based on the poor early outcomes obtained with 
existing treatment options and the fact that these must often be dose-reduced or withheld due to kidney 
and/or liver impairment.  
1.2 
EMAPALUMAB 
 
Description and Mode of Action 
Emapalumab (previously referred to as NI-0501, trade name Gamifant®) is a fully human immunoglobulin 
G1 (IgG1) anti-interferon gamma (IFNγ) monoclonal antibody that binds to and neutralizes IFNγ. 
Emapalumab binds to both soluble and receptor (IFNγR1)-bound forms of IFNγ.  
 
Preclinical Data 
1.2.2.1 Non-clinical Pharmacology 
Emapalumab has shown similar binding affinity and blocking activity for IFNγ from non-human species, 
including Rhesus and Cynomolgus monkeys, but not from dogs, cats, pigs, rabbits, rats, or mice.  
As to safety pharmacology, no abnormalities in ECGs, histopathology of organs and behavior of the 
animals were observed throughout the pre-clinical emapalumab program. 
1.2.2.2 Toxicology 
Binding and functional data demonstrated that Rhesus and Cynomolgus monkeys were relevant species 
for evaluating the safety of emapalumab. No off-target toxicity was attributed to emapalumab when it 
was administered to Cynomolgus monkeys in 13 weekly doses of up to 200 mg/kg. Shigella and 
Campylobacter infections were observed at all dose levels (10 to 200 mg/kg/week) in animals originally 
harboring gastrointestinal pathogens (Shigella, Salmonella, Campylobacter) prior to emapalumab 
administration. These findings were assessed to be in line with the expected pharmacologic effect of 
emapalumab (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.  

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While it was not possible to establish the No Observed Adverse Effect Level (NOAEL) in the 13-week 
toxicity study, the NOAEL in the 8-week study was assumed to be the highest dose tested, i.e. 30 
mg/kg/week.  
Embryo-fetal development as well as fertility and early embryonic development studies were performed 
in mice testing therapeutic and multiple doses of the rat anti-mouse IFNy surrogate antibody XMG 1.2. 
No effects on embryo-fetal development (i.e., embryo-fetal survival, fetal weight, sex ratio or 
morphology) were observed. No effects were observed on estrous cycling in treated females, mating or 
fertility in treated male or treated female mice, male reproductive organ weights, or any ovarian, uterine, 
or litter parameter related to treatment of male or female mice. The NOAEL in these studies was therefore 
determined to be the highest dose-level tested of 150 mg/kg. 
More details are available in the Investigator`s Brochure. Please refer to the most recent version of the 
Investigator`s Brochure. 
 
Clinical Data 
1.2.3.1 Phase 1 experience 
A randomized, double-blinded, placebo-controlled, single ascending dose Phase 1 study (protocol NI-
0501-03) has been performed in 20 healthy adult subjects, of which 14 received emapalumab IV at doses 
up to 3 mg/kg. 
The pharmacokinetic (PK) analysis of emapalumab confirmed the expected profile for an IgG1 with a long 
half-life (around 22 days), a slow clearance (approximately 0.007 L/h) and a low volume of distribution (< 
6 L on average).  
The infusion of emapalumab was well tolerated and 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. A Herpes Zoster infection was reported as a serious adverse reaction in the highest dose group 
(3 mg/kg), and resolved. 
More details are available in the Investigator`s Brochure. Please refer to the most recent version of the 
Investigator`s Brochure. 
1.2.3.2 Phase 2/3 experience 
An open-label, single arm, international, multicenter Phase 2/3 study is ongoing to evaluate the efficacy 
and safety of emapalumab in pediatric patients with primary HLH (pHLH) (protocol NI-0501-04). The 
protocol enrols both treatment-naïve and second-line patients.  
At the BLA/MAA cut-off date of 20 July 2017, 34 patients (16 M, 18 F) have been treated, of whom 7 
patients have received emapalumab as front-line therapy.  
The patients’ median age was 12 months (range: 1 month-13 years), and 27 patients (79%) had a 
documented mutation in known HLH causative genes. 
The primary efficacy endpoint of the study was met. Overall Response Rate (ORR) at EoT was 64.7% (95% 
CI: 44%, 78%) in all patients, and 63% (95% CI: 42%, 81%) in second-line patients. In both groups, the 
lower limit of the 95% CI was higher than the pre-defined null hypothesis of 40% (p=0.0031 and p=0.0134, 
respectively).  
Response occurred early during treatment and was generally sustained. 

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The majority of patients proceeded to HSCT (65% of all treated patients and 70% of second-line patients), 
with a survival benefit that persisted after HSCT. Three patients completed emapalumab treatment 
achieving and maintaining control of HLH disease, without proceeding to HSCT upon decision of the 
treating physician in the patient’s best interest. 
Overall, 70.6% of all treated patients and 74.1% of second-line patients were alive at last observation, 
with a median follow-up time of 13.6 months (interquartile range: 4.5 to 15.3 months). Among the 
patients who underwent HSCT, 91% of all treated patients and 89.5% of second-line patients were alive 
at last observation (up to 1-year post-HSCT). 
The median duration of treatment was 8.4 weeks (range from 4 days to 30 weeks). Doses of 1-10 mg/kg 
have been administered. The great majority of infusions have been well tolerated.  
In line with the risks due to the immune deficiency status of pHLH patients, the most commonly reported 
adverse events (AEs) were infections, which were reported in 19 patients. In 11 patients, infections were 
reported as a serious adverse event (SAE). Only 2 SAEs (both infections) were assessed as possibly related 
to emapalumab, one disseminated histoplasmosis (leading to treatment discontinuation) and one 
necrotizing fasciitis (assessed by the Investigator as possibly related based on the temporal relationship). 
Both events resolved upon administration of appropriate antibiotics. At study entry, 13 patients had 
ongoing infections, which did not preclude initiation of emapalumab.  
At the BLA/MAA cut-off date, ten patients had died; none of the deaths was assessed to be related to 
emapalumab by Investigator, Sponsor and iDMC.  
Study NI-0501-04 completed enrolment on the 25th Jan 2019: a total of 45 patients have been recruited. 
In addition to the patients enrolled in the NI-0501-04 study, 26 patients with HLH have received 
emapalumab treatment in compassionate use (CU). Approximately 450 infusions up to 10 mg/kg have 
been administered and were well tolerated. No SAEs related to emapalumab administration have been 
reported. 
An open-label, single arm, multicenter Phase 2 study is ongoing to evaluate the efficacy and safety of 
emapalumab in sJIA patients developing active MAS/sHLH. The dosing regimen foresees emapalumab 
administration at the initial dose of 6 mg/kg and continuation at the dose of 3 mg/kg every 3 days (until 
SD15) and twice-a-week afterwards.  
As of 14 November 2018, 6 patients with MAS have been enrolled and treated: in all of them, a 
complete response (as per protocol defined criteria) has been achieved, and all patients are continuing 
in study NI-0501-05 for long-term follow-up. The tolerability and safety profile of emapalumab appears 
to be favorable, with all infusions completed. Three SAEs have been reported in two patients, of which 
one (CMV reactivation, of moderate intensity) was assessed to be related to emapalumab by the 
Investigator.  
A safety long-term follow-up study is ongoing (protocol NI-0501-05) to enable the long-term surveillance 
of patients who have received at least one infusion of emapalumab. The protocol includes a follow-up 
period of one year after HSCT or after last emapalumab infusion, if no HSCT is performed. 
No safety concern has emerged from the long-term safety surveillance. 
For more details on the clinical experience, please refer to the most recent version of the Investigator`s 
Brochure. 

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1.2.3.3 Conclusion 
Emapalumab is in development for the treatment of primary and secondary forms of HLH. The benefit 
expected from the targeted neutralization of IFNγ by emapalumab has been validated by the recent FDA 
approval of emapalumab for the treatment of patients with pHLH who have refractory, recurrent or 
progressive disease or intolerance with conventional HLH therapy. The safety profile of emapalumab has 
been assessed as acceptable, and no post-marketing commitments have been requested by the FDA with 
regard to safety. 
Based on the analyses conducted to date, no sign of any off-target effect of emapalumab has been 
detected. 
Multiple medications have been administered concomitantly with emapalumab and no evidence of 
significant drug-drug interactions has been reported to date. 
For more details, please refer to the most recent version of the Investigator`s Brochure. 
2 OBJECTIVES 
• 
Primary efficacy objective: to assess the efficacy of emapalumab in adult patients with HLH, as 
measured by Overall Response Rate. 
• 
Secondary efficacy objectives: 
- 
to assess the efficacy of emapalumab as measured by overall survival, time to response, best 
response on treatment, duration of response, and other efficacy parameters. 
- 
To evaluate the safety and tolerability of emapalumab. 
- 
To determine the pharmacokinetic (PK) profile of emapalumab. 
- 
To determine the pharmacodynamic (PD) profile of emapalumab. 
3 STUDY DESIGN 
3.1 
OVERALL DESIGN 
Study NI-0501-10 is an open-label, single arm, multicenter, Phase 2/3 interventional study. 
The study enrols adult patients with hemophagocytic lymphohistiocytosis (HLH), specifically newly 
diagnosed patients with malignancy-associated HLH (M-HLH), and newly diagnosed or previously treated 
patients with non-malignancy-associated HLH. 
The study includes an initial phase enrolling 10 patients. If no untoward significant safety signal 
attributable to emapalumab treatment (as judged by an iDMC) is identified, enrolment will be broadened; 
subsequently, the iDMC will meet (at a minimum) every time data for an additional 10 patients in total 
are available, to confirm that the safety profile of emapalumab remains favorable and the benefit/risk of 
treating remains positive. The details of the iDMC are provided in the iDMC Charter.  
The patient’s participation in the study comprises three parts: screening, treatment period, and follow-
up, as shown in Figure 1. 
 
 

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Figure 1: NI-0501-10 Study Design 
 
SCREENING 
Up to 2 weeks  
prior to V1 
 
TREATMENT PERIOD  
 
 
FOLLOW-UP 
                     Initial dose         Subsequent doses  
                      6 mg/kg                 3 mg/kg* 
Pre-HSCT** 
 Post-last dose of emapalumab (or post-HSCT) 
 
 
 
V1 
(SD0) 
 
V2 (SD3) and Onwards 
Pre-Cond 
Visit 
W1/W2/W3 
D30 
D60 
D100 
M6 
Y1 
Abbreviations: SD, study day; EoT, End of Treatment; HSCT, hematopoietic stem cell transplant; M, month; Pre-Cond Visit, pre-
conditioning visit; V, visit; W, week; Y, year. 
Additional HLH treatments allowed in case of unsatisfactory HLH control. 
* The 3 mg/kg dose is continued unless the Investigator, guided by the clinical and laboratory response in each patient, deems that 
a dose increase is appropriate: at any time during the study, it will be possible to increase the emapalumab dose to 6 mg/kg. If 
needed, a further dose increase to 10 mg/kg may also be considered. 
** If applicable. 
 
3.2 
SCREENING PERIOD 
Written informed consent for participation in the study must be obtained before performing any study-
specific screening tests. Informed Consent Forms for enrolled patients and for patients who are not 
subsequently enrolled will be maintained at the study site. 
After giving written informed consent, patients who are willing to participate in the study will undergo 
screening assessments within 2 weeks prior to the baseline visit (SD0), as detailed in the Schedule of 
Assessments (Table 1).  
Patients must fulfill all the entry criteria for participation in the study and the results must be available 
prior to the baseline visit. However, if a patient’s medical condition warrants rapid treatment initiation, 
availability of the results for infection screening is not required prior to initiation of emapalumab, 
provided that there are no clinical findings suggestive of any of the infections which represent exclusion 
criteria. However, samples for infection screening need to be collected for analysis prior to first 
administration of emapalumab according to the protocol requirements.  
In rare cases of unexpected delay due to logistical or technical reasons, it may be necessary to extend the 
screening period by a few days. Extending the screening period beyond 2 weeks must be prospectively 
approved by the Sponsor and should be in exceptional circumstances only; careful scheduling should 
remain a priority.  
Patients may be rescreened if there is a substantial change in the patient’s condition (e.g., a prohibited 
medication was stopped) and if recruitment for the study is still ongoing; all inclusion criteria and none 
of the exclusion criteria have to be met at the re-screening.  
Patients may be rescreened if the protocol is amended and, as a result of this, the patients satisfy the 
amended criteria, and if recruitment for the study is still ongoing.  
A patient eligibility checklist that documents the investigator’s assessment of each screened patient with 
regard to the study’s inclusion and exclusion criteria is to be completed by the Investigator. A screening 

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log must be maintained by the Investigator. In addition, an Eligibility Review Form (please see Appendix 
1) must be completed and shared with the Sponsor upon identification and consent of any potentially 
eligible patient. The Sponsor will review the form and be available to answer any potential questions.  
3.3 
TREATMENT PERIOD 
It is not expected that treatment duration will be the same across the study population. 
Treatment shall continue until a clinically satisfactory response is achieved. Shall the duration of 
treatment exceed 12 weeks, an assessment of a favorable benefit/risk profile must be provided and 
confirmed by the iDMC.  
If HSCT is planned, treatment can be administered until HSCT. 
In all cases, treatment can be discontinued upon achievement of complete clinical response, if at least 
two infusions of emapalumab at the dose of 3 mg/kg have been administered.  
Patients will undergo a Week 4 Assessment Visit 3 days after the last emapalumab infusion administered 
in Week 4.  
Treatment may be shorter, and in such instance an End of Treatment (EoT) visit shall be performed 3 days 
after the last administration of emapalumab. 
Whenever a patient receives treatment beyond Week 4, both a Week 4 Assessment Visit and an End of 
Treatment (EoT) visit shall be performed. 
If HLH recurs or reactivates during the off-drug follow-up period, treatment with emapalumab can be 
reinstated, upon discussion with the Sponsor. While receiving emapalumab, patients will undergo the 
same assessments planned during the initial treatment phase, as described in the Schedule of 
Assessments – Screening and Treatment Period (Table 1) for the “Week x” visits. They will enter the 
follow-up period after completion of the re-treatment. 
3.4 
FOLLOW-UP PERIOD 
After treatment discontinuation (for any reason), patients will continue in the study for long-term follow-
up until 1 year after last emapalumab administration (or after HSCT, if performed).  
3.5 
STUDY END 
The end of the study is defined as last patient last visit (LPLV) at 1 year after either last emapalumab 
infusion or HSCT (as applicable).   
4 TARGET POPULATION 
Male and female patients aged 18 and older at the time of diagnosis, who meet HLH-2004 clinical criteria 
for the diagnosis of HLH (with or without malignancy) and who have no primary HLH are eligible. Patients 
with M-HLH must be newly diagnosed (i.e. must have received no previous HLH treatments, with the 
exception of initial glucocorticoids), while patients with non-malignancy-associated or idiopathic HLH may 
have previously received HLH therapies (therefore they can be either treatment naïve or treatment 
experienced). 
4.1 
ELIGIBILITY CRITERIA 
Patients will be included in the study if they meet all the inclusion criteria and none of the exclusion 
criteria. 

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Inclusion Criteria 
1. Male and female patients of age 18 and older at the time of HLH diagnosis 
2. Fulfilment of HLH-2004 clinical criteria, i.e., five of the eight criteria below: 
a. Fever  
b. Splenomegaly 
c. Cytopenias affecting 2 of 3 lineages in the peripheral blood (hemoglobin <90 g/L; 
platelets <100 x 109/L; neutrophils <1 x 109/L) 
d. Hypertriglyceridemia (fasting triglycerides ≥3 mmol/L or ≥265 mg/dL) and/or 
hypofibrinogenemia (fibrinogen ≤1.5 g/L) 
e. Hemophagocytosis in bone marrow, spleen or lymph nodes 
f. Low or absent natural killer (NK)-cell activity 
g. Ferritin ≥500 µg/L 
h. Soluble CD25 (sCD25, i.e., soluble IL-2 receptor) ≥2400 U/mL (or equivalent, in case the 
local lab uses different units) 
3. Patients diagnosed with M-HLH must be treatment naïve; patients diagnosed with HLH driven by 
any other etiology or idiopathic can be either treatment naïve or treatment experienced 
4. Patients with non-malignancy-associated or idiopathic HLH who have already received 
conventional therapy for HLH must have failed prior treatment as per the treating physician`s 
judgement. At the time of enrolment, eligible treatment experienced patients may or may not be 
receiving conventional therapy  
5. JAK inhibitors, if administered, must be discontinued before emapalumab initiation  
6. Informed consent signed by the patient or by the patient’s legally authorized representative(s) 
(as required by local law) 
7. 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. 
 
Exclusion Criteria 
1. Primary HLH (documented by the presence of known causative genetic mutations or by the 
presence of family history) 
2. Current (within 60 days from SD0) or scheduled administration of therapies known to trigger the 
cytokine release syndrome (e.g. chimeric antigen receptor (CAR)-modified T cells, bispecific T cell-
engaging antibodies) 
3. Current (within 60 days from SD0) or scheduled administration of PD-1/PD-L1/ CTLA-4  inhibitors 
4. Life-expectancy associated with the underlying disease (triggering HLH) < 3 months 
5. Ongoing participation in an investigational trial, or administration of any investigational 
treatment within 30 days 
6. History of hypersensitivity or allergy to any components of emapalumab  
7. Active mycobacteria, Histoplasma capsulatum, or Leishmania infections 

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8. Evidence of latent tuberculosis 
9. Infection with HIV (HIV ELISA or PCR positive), hepatitis B (HBsAg positive), Hepatitis C (anti-HCV 
positive) unless the viral load is negative 
10. Concomitant diseases that in the opinion of the Investigator may significantly affect the likelihood 
of a response to treatment and/or the assessment of emapalumab safety and/or efficacy 
11. Receipt of a bacille Calmette-Guerin (BCG) vaccine within 12 weeks prior to Screening 
12. Receipt of a live or attenuated live (other than BCG) vaccine within 6 weeks prior to Screening 
13. Pregnancy or lactation (female patients). 
5 INVESTIGATIONAL MEDICINAL PRODUCT 
5.1 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT 
Emapalumab (previously referred to as NI-0501) is a fully human anti-IFNγ monoclonal antibody that 
binds to and neutralizes human IFNγ. 
Emapalumab is manufactured by a third-party manufacturing facility duly qualified by Sobi AG and is 
supplied as described in the IMP Manual. Concentrated product is filled in single-use glass vials. A dilution 
is required 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 or 25 mg 
L-Histidine 
1.55 mg 
L-Histidine monohydrochloride, monohydrate 
3.14 mg 
Sodium chloride (NaCl) 
7.31 mg 
Polysorbate 80  
0.05 mg 
pH 
6.0 ± 0.2 
 
The solution contains no antimicrobial preservative, and therefore each vial must be used only once. 
5.2 
RATIONALE FOR DOSING SCHEMA 
PK-PD-efficacy data from studies NI-0501-04 and NI-0501-05 in primary HLH patients and from the CU 
experience in both primary and secondary HLH patients receiving emapalumab have previously been 
analyzed in order to explore the structural and quantitative relationships between emapalumab, total 
IFNγ (free + complex with emapalumab), and CXCL9, a chemokine specifically induced by IFNγ. The results 
revealed that: 
• 
the PK and PD of emapalumab were significantly influenced by the level of IFNγ, which varied 
significantly between patients and within patients as a function of time, as shown in Figure 2.  

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• 
CXCL9 appeared to be the biomarker of choice of the biological and pharmacological effects of 
IFNγ (key player in the disease) and emapalumab, and was an indicator of the probability of 
overall clinical response in HLH patients treated with emapalumab. 
• 
 
Figure 2: Total IFNγ Concentrations up to the Last Dose in HLH Patients Treated with Emapalumab in 
Studies NI-0501-04 and NI-0501-05 (HLH) and in Compassionate Use (CU) Patients 
 
Primary HLH and adult-onset HLH share numerous clinical and pathophysiological features, including the 
presence of elevated serum levels of IFNγ and IFNγ-inducible chemokines (Marukoa et al., 2013; data on 
file).  
Secondary forms of HLH in adults are associated with significant mortality rates and, particularly in the 
setting of M-HLH, overall survivals that dismal. 
To achieve rapid IFNγ neutralization, an initial dose of 6 mg/kg emapalumab will be administered. To 
maintain further IFNγ neutralization, emapalumab treatment will be continued at the dose of 3 mg/kg, 
every 3 days until SD15, and then twice-a-week until a clinically satisfactory response is achieved. A similar 
dosing regimen is currently under investigation in the NI-0501-06 study (i.e. emapalumab in sJIA patients 
developing MAS).  
Simulations using the most current emapalumab model for this dosing scheme are shown in Figure 3. 
Simulations representing a dose increase to 6 mg/kg from SD6 onwards and a dose increase to 10 mg/kg 
from SD9 onwards (i.e. worst-case scenario) are shown in Figures 4 and 5 respectively. 
In these Figures, the concentration of emapalumab (graphs on the left) and CXCL9 (graphs on the right) 
are represented at three different production rates of IFNγ (represented by total IFNγ levels), namely a 
“relatively low” production of 10,000 pg/mL (orange line), a “medium” production of 50,000 pg/mL (blue 
line), and a “high” production of 250,000 pg/mL (green line). As reference on these graphs: the grey area 
on the left graph indicates the mean of the individual three highest peak and trough concentrations 
observed in Studies NI-0501-04 and NI-0501-05 and in CU patients (cut-off date 20 July 2017). The black 
line (mean) and grey shadowed area (90% CI) on the right graph indicate CXCL9 levels at week 2 and end 
of treatment that appear to be associated with the probability of clinical response at end of treatment in 

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the HLH paediatric population as indicated by exploratory Receiver Operating Characteristic (ROC) 
analyses. 
Figure 3: Emapalumab and CXCL9 Concentrations at the Initial Dose of 6 mg/kg Followed by 3 mg/kg/3d 
and then 3 mg/kg Maintained Twice a Week During the Treatment Course 
 
Figure 4: Emapalumab and CXCL9 Concentrations at the Initial Dose of 6 mg/kg Reduced to 3 mg/kg 
on Day 3 Followed by 6 mg/kg/3d and then 6 mg/kg Maintained Twice a Week During the Treatment 
Course 
 

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Figure 5: Emapalumab and CXCL9 Concentrations at the Initial Dose of 6 mg/kg Followed by 3 mg/kg 
on Day 3, 6 mg/kg on Day 6, 10 mg/kg/3d and then 10 mg/kg Maintained Twice a Week During the 
Treatment Course 
 
The simulation with the dose increase to 10 mg/kg from the fourth infusion onwards (Figure 5) shows 
that patients with a low production of IFNγ (TIFNG=10,000 pg/mL) reach emapalumab concentrations 
similar to the highest ones already observed in studies NI-0501-04 and NI-0501-05 and in CU patients. 
However, this condition is unlikely to occur as these patients are expected to respond primarily at the 
dose of 3 mg/kg. As shown in Figure 2, none of the patients with maximal total IFNγ levels remaining 
below 10,000 pg/mL required a dose increase up to 10 mg/kg. 
5.3 
DOSING SCHEMA  
If not already hospitalized, patients will be in the treating unit from the day before the first administration 
of emapalumab. 
Emapalumab will be administered by intravenous (IV) infusion over a period of 1 to 2 hours depending 
on the volume to be infused, at an initial dose of 6 mg/kg. 
Emapalumab treatment will be continued at the dose of 3 mg/kg, every 3 days until SD15, and then twice-
a-week.  
If the treating physician deems appropriate, the dose of emapalumab may be increased (back to 6 mg/kg, 
and up to 10 mg/kg), guided by clinical and laboratory response. During the initial phase of the study, 
PK/PD data may also be considered.  
Treatment can be discontinued upon achievement of complete clinical response; however, at least two 
infusions of emapalumab at the dose of 3 mg/kg have to be administered.  
Patients will be discharged whenever deemed clinically appropriate by the Investigator. 
 
 

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Table 3: Clinical and Laboratory Criteria to Guide Dose Increases 
On  Visit / 
Study Day (SD) 
Emapalumab Dose 
 
On Visit 1/SD0 
6 mg/kg 
 
On Visit 2/SD3 
3 mg/kg 
 
On Any Visit, 
from Visit 3/SD6 
onwards  
Increase to 6 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 counts*  
→ lack of normalization1 or  
     Worsening 
 
 
ANC* 
→ lack of normalization2 or  
     Worsening 
 
 
Ferritin 
→ less than 30% decrease or  
     Worsening 
 
 
Splenomegaly 
→  worsening (at clinical exam or 
     US examination) 
 
 
Coagulopathy (either 
D-dimer or fibrinogen) 
→ lack of normalization3 or  
     Worsening 
On Any Visit, 
from Visit 4 
onwards 
Increase up to 10 mg/kg  
Upon assessment by the Investigator that a further increase 
of emapalumab dose may provide additional benefit 
 and presence of 1 of the criteria listed above  
Abbreviations:  ANC = absolute neutrophil count; SD = study day; US = ultrasound 
*To be considered carefully if not HLH-related, e.g. in patients receiving chemotherapy to treat the underlying disease 
1 Normalization of platelet counts is defined as values >100 x 103/mcl, as per HLH diagnostic criteria 
2 Normalization of ANC is defined as values >1000 count/mcl, as per HLH diagnostic criteria   
3 Normalization of D-dimer is defined as values <1.0 g/mL; normalization of fibrinogen is defined as values >150 mg/dL 
 
5.4 
INVESTIGATIONAL MEDICINAL PRODUCT HANDLING 
 
Packaging and Labelling 
Emapalumab will be supplied to study sites in glass vials containing 10 ml or 20 ml solution at a 
concentration of 5 mg/ml or 25mg/ml. Labelling and packaging will be prepared to meet local regulatory 
requirements. The Investigational Medicinal Product (IMP) Manual provides further details. 

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Investigational Medicinal Product Supply 
Emapalumab will be supplied to the study sites as open-label supplies. 
 
Investigational Medicinal Product Receipt and Storage 
Emapalumab vials will be transported with temperature deviation alarms (TempTale 4 or equivalent 
device), to confirm consistent temperatures during transit. When the study drug is received at the site, 
the Investigator or Pharmacist will check for accurate delivery and absence of temperature deviation 
alarms. 
Emapalumab should be stored between 2 - 8°C (36 - 46°F). All vials must be stored in a secure locked 
location in a temperature-controlled refrigerator or cold room. Any deviations from the recommended 
storage conditions must be immediately reported to the Sponsor and responsible study monitor or 
contract research organization (CRO). Affected vials must not be used and must be quarantined until the 
Sponsor has authorized their use, return or destruction. 
Documentation of the storage conditions of the study drug must be maintained for the duration of the 
time the study drug is stored at the site, until the time it is used, disposed of, or returned to Sobi AG or 
designee. 
Emapalumab vials must be visually inspected before preparing the infusion, as described in the IMP 
Manual. 
 
Investigational Medicinal Product Preparation, Administration, Accountability, and 
Destruction 
5.4.4.1 Preparation  
The study drug must be prepared only by a Pharmacist or other appropriately qualified staff member, 
specifically authorized by the Investigator/Pharmacist and appropriately licensed to perform the task. 
The specific dose to be administered for an individual infusion is determined as detailed in Section 5.3. 
As emapalumab is dosed in mg/kg, the weight of the patient must be taken within 24 hours of the 
preparation of the study drug for administration.  
Full instructions for the preparation of emapalumab, including dilution steps and method for 
administration, are available in the IMP manual’s directions for the Preparation and Administration of 
Individual Doses of Study Drug Emapalumab. 
5.4.4.2 Administration 
The patient should receive the designated volume of the infusion material through an infusion pump over 
1 to 2 hours depending on the volume to infuse. A 0.2 μm filter must be included in all infusion lines.  
It is recommended that an IV central line remains in place to ensure venous access during the treatment 
period. This will improve patient’s comfort and ensure a reliable drug administration. However, peripheral 
infusions have been successfully performed in some patients. 
Since no data are available on the compatibility of emapalumab with other IV substances or additives, 
other medications/substances should not be added to the infusion material or infused simultaneously 
through the same IV line. If the same IV line is used for subsequent infusions of other drugs, the line 
should be flushed appropriately with saline before and after infusion of emapalumab. 

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The infusion of emapalumab will be performed under the direct supervision of the Investigator (or 
delegate), preferably in the morning and preferably at the same time for each infusion, in an environment 
with access to emergency equipment and trained medical personnel.   
Details of the infusion must be recorded in the patient’s Medical Notes or other source documents and 
have to include: 
• 
Dose prescribed (in mg/kg) 
• 
Date of administration 
• 
If flushing was performed 
• 
Start time & End time 
• 
Rate of administration 
• 
Total volume infused (ml) 
• 
Total dose infused (mg) 
• 
In case infusion was interrupted:  
▪ 
reason for interruption 
▪ 
the stop time of the infusion 
▪ 
the new start time of the infusion 
▪ 
the new rate of administration 
• 
Any untoward signs and/or symptoms, event or illness experienced by the patient during the 
infusion 
• 
Any other event(s) judged relevant by the site personnel. 
In the event that a patient experiences an infusion-related reaction (IRR), the infusion may be halted (as 
per Investigator’s judgment) and symptomatic treatment may be administered. 
The decision to restart the infusion will be based on the evolution of the patient’s status and on the 
physician’s own medical judgment. The infusion will be restarted at half of the rate being used at the time 
of onset of the IRR. 
All changes in infusion rate will be recorded in the patient’s medical chart and the electronic Case Report 
Form (eCRF): each time at which there is a rate modification, as well as end time of the premature or 
delayed termination of the 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, time of infusion stop, time at which the infusion was resumed and time of end of the 
infusion.  

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5.4.4.3 Accountability 
When the study drug is received at the site, the Investigator or Pharmacist (or appropriate designee) 
should acknowledge its receipt by signing (or initialing) and dating the documentation. Documentation 
should be returned to Sobi AG (or its designee) and a copy retained in the Investigator’s file. 
The dispensing of the study drug shall be carefully recorded on drug accountability forms and an accurate 
accounting must be available for verification by the Monitor at monitoring visits. 
Drug accountability records shall include: 
• 
Confirmation of the study drug’s delivery to the study site 
• 
The inventory at the study site 
• 
The use of study drug by each patient 
• 
The return to the Sponsor or alternative disposition of unused products. 
The records should include dates, quantities, expiration dates, batch number, and if applicable patient 
number.  
Unused study drug vials must not be used for any purpose other than the present study without Sponsor’s 
approval. Study drug vials that have been allocated to a patient and remain unused must not be re-
allocated to a different patient without Sponsor’s approval. 
Unused study drug vials must not be discarded prior to verification by the Monitor. 
5.4.4.4 Destruction, Return, and Disposal  
Periodically during the study and at the conclusion of participation of the study by the site, the clinical 
research associate (CRA) will monitor and collect the Drug Accountability Forms, before making 
arrangements for study drug return or authorizing certified destruction by the study site. 
6 PROTOCOL TREATMENT PLAN 
Patients will receive emapalumab as outlined in section 5. Patients are permitted to have a treatment 
delayed for up to 1 day for a major life event or weather-related issues (e.g., serious illness in a family 
member, infusion center closed due to snow) without this being considered a protocol violation. 
Justification for the delay should be provided to the Sponsor. 
6.1 
CONCOMITANT THERAPY 
 
Malignancy-related treatments 
Patients with malignancy-associated HLH will undergo concomitant treatment directed at the underlying 
malignancy. In general, the malignancies are expected to be hematologic malignancies such as 
lymphomas 
and 
leukemias. 
Any 
standard 
chemotherapy-based 
therapy, 
such 
as 
CHOP 
(cyclophosphamide, hydroxydaunorubicin, Oncovin, prednisone), will be permitted, except for the 
treatments listed as exclusion criteria. 
 
 

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Dexamethasone 
All patients are required to receive glucocorticoids starting no later than SD-1: 
• 
Therapy with dexamethasone at a dose of 10 mg/m2 daily will be initiated in any patient not 
receiving glucocorticoids at the time of emapalumab start.  
• 
If a patient is already receiving glucocorticoids, he/she will continue at their current dose, as long 
as it corresponds to at least 5 mg/m2 daily dexamethasone. 
• 
Lower doses at study entry are allowed in the case of documented intolerance to glucocorticoids 
(e.g., psychosis). 
• 
Glucocorticoids tapering may be initiated as soon as the patient’s conditions allow, according to 
the Investigator’s assessment. The tapering scheme can be selected by the Investigator.   
• 
In the event of disease worsening after glucocorticoids tapering, a higher dose can be re-
introduced and maintained until a satisfactory response is achieved according to the Investigator. 
For patients with M-HLH, glucocorticoids are often administered with malignancy-directed therapy; 
dexamethasone can be used at the discretion of the Investigator.  
 
Infection prophylaxis 
Unless a patient has been previously vaccinated, prophylaxis against Herpes Zoster virus infection must 
be in place on study day minus 1 (or, at the latest, before initiation of emapalumab treatment) and must 
be maintained for 2 half-lives (approximately 44 days) after the last administration of emapalumab.  
Patients will receive any additional required prophylactic antimicrobial treatment according to local 
practice. 
 
Calcineurin inhibitors 
Calcineurin inhibitors can be continued, if administered at screening. Calcineurin inhibitors can be 
withdrawn at any time, upon the judgment of the Investigator.  
 
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 is allowed should CNS signs and symptoms occur during the study, as 
clinically indicated. 
 
Other Concomitant Therapies 
Intravenous immunoglobulin (IVIG) is only allowed as replacement treatment (i.e., not at doses expected 
to produce an immunomodulatory effect) according to the clinical judgment of the Investigator. Any IVIG 
infusion within the 4 weeks prior to Screening, as well as any infusion during emapalumab treatment, 
should be documented in the CRF (dose, date of administration).  
Granulocyte-colony-stimulating factor (G-CSF) is permitted in case of prolonged neutropenia or if 
required for treatment of malignancy-associated HLH as part of a standard protocol. 

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As long as emapalumab is being administered, concomitant use of other biologic drugs shall not occur, 
except for rituximab in the setting of documented EBV infection. The use of any biologic drugs other than 
rituximab shall be prospectively discussed with the Sponsor. 
Analgesic treatment, transfusion of blood products, electrolyte and glucose infusions, IV parenteral 
nutrition, inotropic support, antibiotics, anti-fungal and anti-viral treatment, ultrafiltration or 
hemodialysis, as well as general supportive care (e.g., gastro-protective agents, anti-hypertensive etc.) 
are permitted during the study.  
Guidance on concomitant medications recording will be provided in a separate document. 
 
Contraception guidance 
Females of childbearing potential require the use of highly effective contraceptive measures (failure rate 
of less than 1% per year) from study drug initiation to 6 months after last dose of emapalumab. 
Highly effective contraceptive measures include: 
• 
Sexual abstinence: refraining from heterosexual intercourse during the entire period 
defined above.  The reliability of sexual abstinence needs to be evaluated in relation to 
its duration and compatibility with the preferred and usual lifestyle of the subject. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not an 
acceptable method of contraception 
• 
Hormonal contraceptives: combination or progesterone only 
• 
Intrauterine methods: intrauterine devices or systems 
• 
Bilateral tubal occlusion 
• 
Vasectomised partner. 
6.2 
PROHIBITED THERAPIES 
 
Advanced therapies and JAK inhibitors 
Administration of advanced therapies known to trigger the cytokine release syndrome (e.g., chimeric 
antigen receptor (CAR)-modified T cells, bispecific T cell-engaging antibodies, PD-1 inhibitors) and the 
administration of JAK inhibitors are prohibited.  
 
Vaccines 
Vaccination with a live or attenuated-live (including BCG) vaccine must be avoided for 2 half-lives 
(approximately 44 days) after last emapalumab administration. 
6.3 
ADDITIONAL HLH TREATMENTS 
The administration of additional HLH treatments (e.g., etoposide, T-cell depleting agents) will be allowed 
in case of documented unsatisfactory HLH control, provided that at least 3 doses of emapalumab have 
been administered. 
Unsatisfactory HLH control is defined as follows: 
- 
patients who present a clinically relevant worsening 
- 
patients who have not achieved or maintained a disease control and general conditions that 
would allow to proceed to transplant (if applicable) and/or to receive required concomitant 
treatments for the underlying disease. 

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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. 
6.4 
EMERGENCY TREATMENT 
Emapalumab will be administered to patients under close medical supervision in a setting with access to 
emergency equipment and staff who are trained to monitor and respond to medical emergencies. 
7 ENDPOINTS 
7.1 
EFFICACY ENDPOINTS 
Criteria for the definitions of response are reported in Table 4. 
Given the absence of validated endpoints, the experience gathered in the registrational trial of 
emapalumab in pHLH, input from recognized experts in the field of adult HLH and data in the scientific 
literature have been used to compile the response criteria. 
Week 4 has been chosen as the time point to evaluate the primary endpoint taking into consideration the 
heterogeneity of the enrolled population and the clinical course of the different medical conditions 
triggering HLH, and acknowledging the absence of experience with emapalumab in these diseases: while 
an initial response to emapalumab is expected early during treatment, based on the mechanism of action 
of the molecule and the experience accumulated to date in pHLH and MAS in sJIA, the data collected in 
the initial phase of this study will provide support to the hypothesis. The secondary endpoints (i.e. best 
response on treatment, time to response) will aid in the overall interpretation of the potential efficacy of 
emapalumab in this study.  
Primary efficacy endpoint 
• 
Overall Response, i.e. achievement of either a Complete or Partial Response at Week 4 (or EoT if 
earlier)  
Secondary efficacy endpoints: 
• 
Best response on treatment 
• 
Overall Response at EoT  
• 
Overall survival 
• 
Time to complete or partial response 
• 
Duration of response 
• 
HLH Relapse. 
Treatment response may be analysed using other sets of clinical criteria (to be described in the 
Statistical Analysis Plan), if supported by evolving medical knowledge and/or scientific literature.  
 
 
 
 

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Table 4: Definition of Response 
Overall Response  
Complete Response 
Complete Response is adjudicated if: 
- 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: 
- Improvement (>50% change from baseline or normalization) of at least 3 
HLH clinical and laboratory abnormalities (including CNS abnormalities)  
*Not to be assessed if not HLH-related, such as cytopenia induced by drugs administered to treat the underlying disease (e.g. 
chemotherapy) 
7.2 
SAFETY ENDPOINTS 
Safety and tolerability of emapalumab will be assessed as follows: 
• 
Incidence, severity, causality and outcomes of AEs (serious and non-serious) 
• 
Clinically significant changes in blood tests, physical examinations, vital signs, ECGs. 
7.3 
PHARMACOKINETIC ENDPOINTS 
The serum concentration of emapalumab will be measured as a function of time to determine the 
emapalumab PK profile in this patient population and to confirm adequacy of the proposed dosing 
regimen. 
All PK data will be summarised using appropriate graphical and tabular presentations and the following 
PK parameters will be reported: Cmax (peak serum concentration), Ctrough (concentration just before 
administration), Cmeantau (mean concentration over a dosing interval) and AUCtau (area under curve of a 
dosing interval). 
In addition, individual emapalumab concentration-time profiles will be subject to population PK analysis 
using non-linear mixed effects modelling. The anticipated covariate effects of body weight and time-
varying total IFNγ will be included in the model. Additional covariate effects might be investigated.  
Measurement of emapalumab concentrations may be performed in an exploratory manner, if clinically 
indicated, in other matrices, e.g., cerebrospinal fluid (CSF), bronchoalveolar lavage (BAL). 
7.4 
PHARMACODYNAMIC ENDPOINTS 
Determination of PD parameters as a function of time will include the following: 
• 
Levels of circulating total IFNγ (free + bound)  

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• 
Markers of IFNγ neutralization, i.e. CXCL9  
• 
Other relevant markers, including but not limited to sCD25 and IL-6  
• 
Incidence of anti-drug antibodies (ADAs) against emapalumab. 
Population PK/PD analysis using non-linear mixed effects modelling will be undertaken.   
The main PD marker investigated will be CXCL9. Additional PD markers will also be evaluated (e.g., sCD25 
and other exploratory biomarkers). The anticipated covariate effect of time-varying total IFNγ will be 
included in the CXCL9 model. Additional covariate effects might be investigated. 
Individual and mean PD parameters will be tabulated. 
Measurement of PD parameters may be performed in an exploratory manner, if clinically indicated, in 
other matrices, e.g., cerebrospinal fluid (CSF), bronchoalveolar lavage (BAL). 
PD samples may be used to investigate potential drug-drug interactions. 
8 OUTLINE OF STUDY PROCEDURES 
If not already hospitalized, the patient will be in the treating unit from the day before the first 
administration of emapalumab (SD-1). 
Following the first administration of emapalumab and before leaving their reference center, each patient 
(and/or patient’s legal representative) will be given a card to carry at all times in case of any emergency. 
The card will include details of the name of the drug, name of the responsible physician, and the address 
and telephone number of the study site. 
For a detailed description of the schedule of visits and assessments, please refer to Table 1 (Screening 
and Treatment Period) and Table 2 (Follow-up Period). 
The Informed Consent Form must be signed by the patient or his/her legally authorized representative 
prior to any study-related procedures.  
During treatment with emapalumab, visits for infusion will occur on SD0 (i.e. enrolment time point), SD3, 
every 3 days until SD15, and twice-a-week thereafter (not more than 4 days apart). A Week 4 Assessment 
Visit shall be performed 31 days after the last emapalumab infusion administered in Week 4. If 
emapalumab treatment is shortened, an EoT Visit has to be performed 31 days after the last 
emapalumab infusion. If emapalumab treatment continues beyond the Week 4 Assessment Visit, an 
additional EoT Visit has to be performed 31 days after the last emapalumab infusion. 
During the follow-up period, the following time-windows are allowed around visits: 
- Pre-conditioning:  
 
it can be combined with EOT visit provided the two visits are 
not more than 2 days apart 
- Wk 1-2-3, D+30 post-HSCT:  
2 days 
- D+60, D+100 post-HSCT:  
2 weeks 
- 6-mo, 1-yr post-HSCT:   
4 weeks 
If HSCT is not performed, the above schedule describes the time points after the last emapalumab 
infusion, rather than after HSCT. 
During treatment, emapalumab and biomarker concentrations may be measured in matrices other than 
blood, such as CSF or BAL, if samples obtained in procedures which are performed for 

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diagnostic/therapeutic purposes can also be available for these exploratory investigations, and if clinically 
indicated. 
8.1 
SCREENING 
Patients will be screened for eligibility prior to enrollment into the study. A screening log will be 
maintained by the Investigator with specification of reasons for non-eligibility. 
Screening evaluations should be completed within 2 weeks prior to the first administration of study drug 
(Visit 1/SD0).  
The following information must be collected and the following procedures must be performed: 
Patient information: 
 
▪ Informed consent 
▪ Demographics (including race and ethnicity where allowed) 
▪ Medical history 
▪ Medications at Screening  
▪ Any HLH therapy previously received 
▪ Date of HLH diagnosis and HLH history  
▪ Molecular diagnosis of HLH, if available 
▪ Perforin expression and other functional tests performed for the 
diagnosis of HLH, if available 
▪ Review of Inclusion/Exclusion Criteria 
▪ For treatment experienced patients with non M-HLH, recording of 
reasons to determine failure of conventional therapy, as per 
Investigator`s assessment 
▪ For patients diagnosed with idiopathic HLH, recording of outcome of 
investigations performed to exclude an underlying malignancy 
Clinical Assessment: 
 
▪ Vital signs including body temperature, blood pressure, heart rate, 
respiratory rate 
▪ Height and body weight 
▪ Eastern Cooperative Oncology Group (ECOG) performance status 
▪ Complete physical examination 
Procedure: 
▪ Single, standard 12-lead ECG  
Search for infectionsi: 
 
▪ HIV, hepatitis B (including surface antigen), and hepatitis C testing 
(the latter with reflex to PCR if serologies are positive)  
▪ Tuberculosis mycobacteria via IGRA/PPD test and polymerase chain 
reaction (PCR). In a patient having received BCG vaccination, a PPD 
test must be performed and combined with IFNγ-release assay if the 
PPD result is ≥5 mm. In addition, search for Tuberculosis via PCR in 
any relevant specimen should be performed to have a baseline, as 
                                                          
i A patient with a clinical assessment (including chest X-ray) not indicative of the presence of the above mentioned 
infections, provided that a usable specimen has been taken and the microbiological analysis is ongoing, can be 
enrolled prior to the availability of the results, if a patient’s medical condition warrants rapid treatment initiation. 

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this test will be used during the course of the study to perform 
regular TB monitoring.  
▪ Adenovirus, EBV, CMV (viral load) 
▪ 
Atypical 
mycobacteria, 
Histoplasma 
Capsulatum 
and 
Leishmaniaii, as appropriate. The presence of Leishmania can also 
be ascertained by direct bone marrow observation. A first 
screening for Histoplasma Capsulatum may be performed using 
galactomannan assay; however, if the test is positive, 
confirmation should be obtained by using a Histoplasma 
Capsulatum specific test. 
Laboratory: 
• 
CBC with differential count  
▪ 
Coagulation tests: activated partial thromboplastin time and/or 
aPTT ratio (if both available, both to be recorded), prothrombin 
time and/or PT INR (if both available, both to be recorded), D-
dimer and fibrinogen 
▪ 
Biochemistry: ferritin, C-reactive protein (CRP), glucose, 
aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), 
total bilirubin, albumin, creatinine, urea, triglycerides (fasting 
whenever possible) 
▪ 
Pregnancy test, if applicable 
Imaging: 
▪ 
Abdominal ultrasound (spleen longitudinal measure) 
▪ 
Chest X-ray 
▪ 
Brain MRI (only in cases of CNS disease and/or as clinically 
indicated) 
Histopathology: 
 
▪ 
CSF Analysis (only in cases of CNS disease and only if coagulation 
parameters allow) 
Safety: 
▪ 
Recording of any AEs that have occurred since signature of the 
ICF 
8.2 
VISIT 1 AND ONWARDS (Infusion 1 of Emapalumab, SD0 and onwards) 
The following assessments are to be performed pre-infusion (i.e. ideally on the day of the infusion, and 
in any case no more than 1 day prior to the infusion) at all visits from Visit 1 (SD0, enrolment time point) 
onwards, unless specified differently: 
Patient information: 
Clinical Assessment: 
 
▪ Review of Inclusion/Exclusion Criteria (only at SD0) 
▪ Vital signs including body temperature, blood pressure, heart rate, 
respiratory rate 
▪ Body weight 
                                                          
ii As Leishmania is not endemic in North America, only patients who have been in endemic regions (e.g., South 
America) during the 6 months prior to screening, are required to be actively screened for Leishmania.  

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Search for infections: 
 
▪ Eastern Cooperative Oncology Group (ECOG) performance status 
▪ Physical examination, including liver and spleen size (by palpation), 
and neurological examination 
▪ Investigator assessment of clinical response 
▪ TB by PCR (every 4 weeks) 
▪ Adenovirus, EBV, CMV (viral load) - in case of suspicion of infection  
▪ Atypical mycobacteria, Histoplasma Capsulatum, Leishmania - if an 
infection is suspected 
Laboratory: 
▪ CBC with differential count  
▪ Coagulation tests: activated partial thromboplastin time and/or aPTT 
ratio (if both available, both to be recorded), prothrombin time 
and/or PT INR (if both available, both to be recorded), D-dimer, and 
fibrinogen 
▪ Biochemistry: ferritin, C-reactive protein (CRP), glucose, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), lactate dehydrogenase (LDH), total bilirubin, 
albumin, creatinine, urea, triglycerides (fasting) 
▪ Pregnancy test, if applicable 
▪ Urinalysis: glucose, blood, protein, leukocytes, ketones (only at SD0) 
Imaging: 
▪ Abdominal ultrasound (spleen longitudinal measure), at SD0 if 2 
weeks or more elapsed between the screening visit and SD0, then 
every 2 weeks during emapalumab treatment 
▪ Chest X-ray - in case of clinical suspicion of pulmonary infection 
Safety: 
▪ Recording of any AEs that have occurred since the last visit  
PK: 
▪ Emapalumab serum concentrations 
PD: 
▪ CXCL9, sCD25, total IFNγ 
Immunogenicity: 
▪ ADAs (at SD0) 
IMP Handling: 
▪ Preparation, dispensing, and accountability 
Medications: 
▪ Concomitant medications recording. 
 
The following assessments are to be performed post-infusion: 
Clinical assessment: 
▪ Vital signs including blood pressure, heart rate and respiratory rate, 
at the end of the infusion and at 1 and 2 hours after the end of the 
infusion 
PK: 
▪ Emapalumab serum concentration. 
8.3 
WEEK 4 ASSESSMENT (3 1 Days After last Week 4 Infusion) AND END OF TREATMENT VISIT (3 
1 Days After Last Infusion)  
These visits will include a full patient’s assessment. 

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The Week 4 Assessment Visit will be performed 3 (1) days after the last emapalumab infusion 
administered in Week 4. If treatment with emapalumab is completed before Week 4, only an EoT visit 
will be performed 3 (1) days after the last infusion. 
For patients continuing treatment beyond Week 4, an EoT visit will be conducted 3 (1) days after the 
last emapalumab infusion. 
The following assessments are to be performed (i.e. ideally on the day of the visit, and in any case no 
more than 1 day prior to the visit), pre-infusion in case emapalumab treatment continues beyond Week 
4: 
Clinical Assessment: 
 
▪ Vital signs, including body temperature, heart rate, blood pressure, 
and respiratory rate 
▪ Weight 
▪ Eastern Cooperative Oncology Group (ECOG) performance status 
▪ Physical examination, including as a minimum spleen and liver size 
(by abdominal palpation), and neurological examination 
▪ Investigator assessment of clinical response 
Procedure: 
▪ ECG (only at EOT) 
Search for infections: 
▪ TB by PCR (if not performed within the last 4 weeks) 
▪ Adenovirus, EBV, CMV (viral load) – only in case of suspicion of 
infection  
▪ Atypical mycobacteria, Histoplasma Capsulatum, Leishmania – only 
if an infection is suspected 
Laboratory: 
▪ CBC with differential count  
▪ Coagulation tests: activated partial thromboplastin time and/or aPTT 
ratio (if both available, both to be recorded), prothrombin time 
and/or PT/INR (if both available, both to be recorded), D-dimers, and 
fibrinogen 
▪ Biochemistry: ferritin, C-reactive protein (CRP), glucose, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), lactate dehydrogenase (LDH), total bilirubin, 
albumin, creatinine, urea, triglycerides (fasting) 
▪ Pregnancy test, if applicable  
▪ Urinalysis: glucose, blood, protein, leukocytes, ketones (only EOT) 
Imaging: 
Safety: 
▪ Abdominal ultrasound with spleen longitudinal measure 
▪ Recording of any AEs that have occurred since the last visit 
Medications: 
▪ Concomitant medications recording 
PK: 
▪ Emapalumab serum concentration  
PD: 
▪ CXCL9, sCD25, total IFNγ 
Immunogenicity: 
▪ ADAs. 
If emapalumab treatment is continued, and Week 4 Assessment Visit is performed on the same day of 
the subsequent infusion, the infusion will be administered, and the following assessments will be 
performed post-infusion: 

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Vital sign assessment: 
▪ Vital signs including blood pressure, heart rate and respiratory rate, 
at the end of the infusion and at 1 and 2 hours after the end of the 
infusion 
PK: 
▪ Emapalumab serum concentration 
 
For patients who remain on study drug beyond the Week 4 Assessment Visit, ADA sampling is required 
every 3 months after the Week 4 Assessment Visit. 
8.4 
FOLLOW-UP PERIOD 
Long-term follow up will be conducted after the discontinuation of emapalumab treatment, until 1 year 
after last administration of emapalumab or HSCT.  
If HLH recurs or reactivates during the off-drug follow-up period, treatment with emapalumab can be 
reinstated, upon discussion with the Sponsor While receiving emapalumab, patients will undergo the 
same assessments planned during the initial treatment phase, as described in the Schedule of 
Assessments (Table 1), for the “Week x” visits. They will enter the follow-up period after completion of 
the re-treatment. 
 
Follow-Up Pre-HSCT: Pre-Conditioning Visit 
The following assessments have to be performed before starting the administration of conditioning 
agents for HSCT. This visit can be combined with the EoT visit, if the visits are not more than 2 days apart. 
In this case, the assessments required at EoT visit have to be performed. 
If the pre-conditioning and EoT visits are not combined, the following assessments are to be performed: 
Clinical Assessment: 
 
▪ Vital signs, including body temperature, heart rate, blood pressure, 
and respiratory rate 
▪ Eastern Cooperative Oncology Group (ECOG) performance status  
▪ Physical examination, including as a minimum spleen and liver size 
(by abdominal palpation), and neurological examination 
▪ Survival 
▪ Investigator assessment of clinical response 
Laboratory: 
▪ CBC with differential count  
▪ Coagulation tests: activated partial thromboplastin time and/or aPTT 
ratio (if both available, both to be recorded), prothrombin time 
and/or PT/INR (if both available, both to be recorded), D-dimers, and 
fibrinogen 
▪ Biochemistry: ferritin, C-reactive protein (CRP), glucose, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), lactate dehydrogenase (LDH), total bilirubin, 
albumin, creatinine, urea, triglycerides (fasting) 
▪ Pregnancy test, if applicable  
Imaging: 
▪ Abdominal ultrasound with spleen longitudinal measure 
Safety: 
▪ Recording of any AEs occurred since last visit 
Medications: 
▪ Concomitant medications recording 

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PK: 
▪ Emapalumab serum concentration  
PD: 
▪ CXCL9, sCD25, total IFNγ. 
 
Follow-Up After Last Emapalumab Infusion (or Post-HSCT) 
The following assessments will be performed at the time points specified in the Schedule of Assessments 
- Follow-up Period (Table 2). Ideally all assessments shall be performed on the day of the visit, and in any 
case no more than 1 day prior to the visit. 
Clinical Assessment: 
 
▪ Vital signs, including body temperature, heart rate, blood pressure, 
and respiratory rate 
▪ Physical examination, including as a minimum spleen and liver size 
(by abdominal palpation), and neurological examination 
▪ Eastern Cooperative Oncology Group (ECOG) performance status 
(only at D+30, D+60, D+100, 6 month visits) 
▪ Post HSCT outcome, if applicable and as per available information 
▪ Survival 
▪ Investigator assessment of clinical response 
Laboratory: 
▪ CBC with differential count 
▪ Coagulation tests: activated partial thromboplastin time and/or aPTT 
ratio (if both available, both to be recorded), prothrombin time 
and/or PT/INR (if both available, both to be recorded), D-dimers, and 
fibrinogen 
▪ Biochemistry: ferritin, C-reactive protein (CRP), glucose, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), lactate dehydrogenase (LDH), total bilirubin, 
albumin, creatinine, urea, triglycerides (fasting) 
▪ Pregnancy test, if applicable  
Search for infections: 
 
▪ TB by PCR in any relevant specimen, every 4 weeks until D+60; then 
at D+100, 6 month and 1 year visits as long as serum levels of 
emapalumab are detectable 
▪ Adenovirus, EBV, CMV – in case of suspicion of infection 
Imaging: 
▪ Chest X-ray – in case of suspicion of infection  
▪ Abdominal ultrasound with spleen longitudinal measure (at Day 100 
visit only) 
Safety: 
▪ Recording of any AEs occurred since last visit until D+60. Afterwards, 
recording of SAEs related to study drug 
Medications: 
▪ Concomitant medications recording 
PK: 
▪ Emapalumab concentrations (if serum levels of emapalumab were 
still measurable at the previous visit) 
PD: 
▪ CXCL9, sCD25, total IFNγ (if serum levels of emapalumab were still 
measurable at the previous visit; then only if clinically indicated) 
Immunogenicity: 
▪ Assessment for ADAs (at Day +30 and Day +100 visits only). 

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1-Year Visit After Last Emapalumab Infusion or After HSCT/ Withdrawal Visit  
The 1-Year visit represents the last visit of the study. The assessments indicated for the 1-year visit are to 
be performed also in case of premature withdrawal/discontinuation from the study, i.e. at the end of the 
study. 
The following assessments will be performed for the 1-Year visit: 
Clinical Assessment: 
 
▪ Vital signs, including body temperature, heart rate, blood pressure, 
and respiratory rate  
▪ Eastern Cooperative Oncology Group (ECOG) performance status 
▪ Physical examination, including as a minimum spleen and liver size 
(by abdominal palpation), and neurological examination 
▪ Post HSCT outcome, if applicable and as per available information 
▪ Survival 
▪ Investigator assessment of clinical response 
Laboratory: 
▪ CBC with differential  
▪ Coagulation tests: activated partial thromboplastin time and/or aPTT 
ratio (if both available, both to be recorded), prothrombin time 
and/or PT/INR (if both available, both to be recorded), D-dimers, and 
fibrinogen 
▪ Biochemistry: ferritin, C-reactive protein (CRP), glucose, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase (ALP), lactate dehydrogenase (LDH), total bilirubin, 
albumin, creatinine, urea, triglycerides (fasting) 
▪ Pregnancy test, if applicable  
▪ Urinalysis: glucose, blood, protein, leukocytes, ketones 
Search for infections: 
▪ TB by PCR in any relevant specimen (if serum levels of emapalumab 
were still measurable at the previous visit) 
▪ Adenovirus, EBV, CMV – in case of suspicion of infection 
Imaging: 
▪ Chest X-ray 
▪ Abdominal ultrasound with spleen longitudinal measure 
Safety: 
▪ Recording of  SAEs related to study drug occurred since last visit 
Medications: 
▪ Concomitant medications recording 
PK: 
▪ Emapalumab concentrations (if serum levels of emapalumab were 
still measurable at the previous visit) 
PD: 
▪ CXCL9, sCD25, total IFNγ (if serum levels of emapalumab were still 
measurable at the previous visit, or if clinically indicated) 
Immunogenicity: 
▪ Assessment for ADAs. 
8.5 
UNPLANNED/UNSCHEDULED VISITS 
Unplanned visits may occur should the patient need to be assessed or treated for any clinical condition 
that arises during the study. This includes the evaluation and follow-up of AEs. 

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8.6 
UNPLANNED ASSESSMENTS 
Additional PK/PD samples may be required to better characterize the PK/PD profile and/or for safety 
reasons.  The number of additional samples taken will depend on the weight and health status of the 
patient. 
9 SAFETY MONITORING 
9.1 
STUDY SCIENTIFIC OVERSIGHT 
A review of the data at regular intervals will be conducted by the iDMC, to ensure that the safety profile 
of emapalumab remains favorable and the benefit/risk of treating remains positive: initially, data will be 
reviewed after the first 10 patients are enrolled, subsequently (and at a minimum) every time data for an 
additional 10 patients in total are available. In addition, the iDMC will monitor the efficacy results, as 
described in Section 11.3.2. 
The details of the iDMC are provided in the iDMC Charter. 
9.2 
DESCRIPTION AND DEFINITIONS OF SAFETY PARAMETERS 
Safety assessments will consist of monitoring and recording adverse events, performing protocol-
specified safety laboratory assessments, measuring protocol-specified vital signs, and conducting other 
protocol-specified tests that are deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in Section 9.3.2. 
 
 Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any untoward medical 
occurrence in a clinical investigation subject administered a pharmaceutical product, regardless of causal 
attribution. An adverse event can therefore be any of the following: 
• Any unfavorable and unintended sign or symptom temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product 
• Any new disease or exacerbation of an existing disease (a worsening in the character, frequency, or 
severity of a known condition). 
 
Serious Adverse Events  
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death); 
• 
is life-threatening (note: the term "life-threatening" refers to an event in which the patient 
was at immediate risk of death at the time of the event; it does not refer to an event which 
could hypothetically have caused a death had it been more severe); 
• 
requires in-patient hospitalization or prolongs an existing hospitalization; 
• 
results in persistent or significant disability/incapacity; 
• 
is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study 
drug; 
• 
is a significant medical event in the Investigator’s judgment (e.g. may jeopardize the patient 
or may require medical/surgical intervention to prevent one of the outcomes listed above). 

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The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an adverse event 
(e.g., rated as mild, moderate, or severe); the event itself may be of relatively minor medical significance 
(such as severe headache without any further findings).  
Severity and seriousness need to be independently assessed for each adverse event recorded on the 
eCRF. 
Serious adverse events are required to be reported by the Investigator to the Sponsor immediately (i.e. 
no more than 24 hours after learning of the event; see Section 9.3.2 for reporting instructions). 
For the purposes of this study, the following will not be considered as SAEs: 
• 
elective hospitalizations for surgical procedures that are a result of a patient’s pre-existing 
condition(s) which have not worsened since receiving IMP; 
• 
hospitalization requested for emapalumab infusion and study visits (including a possible 
hospital stay overnight, if due to logistic convenience). 
9.3 
RECORDING AND REPORTING SAFETY PARAMETERS 
 
Adverse Events 
All AEs reported spontaneously by the patients or observed by study personnel will be recorded in the 
patient’s medical record and on the Adverse Event eCRF. 
An AE which occurs between the Screening visit and the start of first IMP administration will be 
considered as a pre-treatment AE.  
Any AE that occurs after the start of first IMP administration will be considered as a Treatment Emergent 
Adverse Event (TEAE). 
After initiation of study drug, all adverse events (serious and not serious) will be reported until the Day+60 
Visit (i.e. once at least 2 half-lives of the drug have elapsed). After this period, the Investigator should 
report serious adverse events deemed as related to emapalumab (see Section 9.2.2).  
For each AE, the Investigator will make an assessment of seriousness (see Section 9.3.2), severity, and 
causality.  
Severity of AEs will be graded on a three-points scale (mild, moderate, severe), using the following 
definitions: 
• 
Mild: Discomfort noticed but no disruption of normal activity 
• 
Moderate: Discomfort sufficient to reduce or affect normal daily activity 
• 
Severe: Incapacitating with inability to work or perform normal daily activity. 
Regardless of the severity, some events may also meet seriousness criteria. Refer to the definition of 
serious adverse event in Section 9.2.2. 
The relationship of AEs to the IMP will be assessed by the Investigator using a “Yes/No” classification. In 
this study, emapalumab is the only IMP.  
Investigators should use their knowledge of the patient, the circumstances surrounding the event, and 
an evaluation of any potential alternative causes to determine whether or not an adverse event is 
considered to be related to the study drug. The following guidance should be taken into consideration: 

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• Temporal relationship of event onset to the initiation of study drug 
• Course of the event, considering especially the effects of dose reduction, discontinuation of study drug, 
or reintroduction of study drug (as applicable) 
• Known association of the event with the study drug or with similar treatments 
• Known association of the event with the disease under study. 
Specific situations: 
- 
HLH signs and symptoms are not to be reported as AEs 
- 
If changes in HLH signs and symptoms indicate HLH worsening or reactivation, HLH worsening or 
reactivation shall be reported as an AE 
- 
Infections characterized by clinically significant manifestations and identification of their etiology will 
be monitored by means of collection of viral load positivity over time. 
 
Serious Adverse Events 
The Investigator must report SAEs to the Sponsor immediately; under no circumstances should reporting 
take place more than 24 hours after the investigator learns of the event. 
For the purposes of this study, the following will not be considered as SAEs: 
• 
elective hospitalizations for surgical procedures that are a result of a patient’s pre-existing 
condition(s) which have not worsened since receiving IMP; 
• 
hospitalization requested for emapalumab infusion and study visits (including a possible 
hospital stay overnight, if due to logistic convenience). 
For the initial SAE report, the Investigator should report all available details, using the Sobi AG SAE 
reporting form. 
Sobi AG contact information for SAE reporting: 
 E-mail: NI-0501drugsafety@sobi.com  
The Investigator must report new significant follow-up information for these events to the Sponsor 
immediately (i.e., no more than 24 hours after becoming aware of the information). New significant 
information includes the following: 
• New signs or symptoms or a change in the diagnosis 
• Significant new diagnostic test results 
• Change in causality based on new information 
• Change in the event’s outcome, including recovery 
• Additional narrative information on the clinical course of the event. 
Investigators must also comply with local requirements for reporting serious adverse events to the local 
health authority and IRB/EC. 
All SAEs will also be recorded on the appropriate page of the eCRF.  

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9.4 
PROCEDURES FOR RECORDING ADVERSE EVENTS 
 
Diagnosis versus Signs and Symptoms 
For any adverse event, a diagnosis should be recorded on the Adverse Event eCRF rather than individual 
signs and symptoms. However, if a constellation of signs and/or symptoms cannot be characterized as a 
single diagnosis or syndrome at the time of reporting, each individual event should be recorded on the 
Adverse Event eCRF. If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event report based on the 
single diagnosis, with a starting date that corresponds to the starting date of the first symptom of the 
eventual diagnosis. 
 
Persistent and recurrent adverse events 
A persistent adverse event is one that extends without resolution between patient evaluation timepoints. 
Such events should only be recorded once on the Adverse Event eCRF.  
A recurrent adverse event is one that resolves between patient evaluation timepoints and subsequently 
recurs. Each recurrence of an adverse event should be recorded as a separate event on the Adverse Event 
eCRF. 
 
Managing Abnormal Laboratory Test Values  
All laboratory tests performed locally will be captured in the database and should not be reported as AEs 
even if qualified as ‘clinically significant’ at site, unless requiring a specific intervention for correction, or 
leading to a modification of the dose/regimen of study drug. If a laboratory abnormality leads to a new 
clinical diagnosis (e.g., high white cell count is found to be due to incidental leukemia), the new clinical 
diagnosis should be reported as an AE rather than the laboratory abnormality. If reported as AEs, 
abnormal laboratory values will follow the AE/ SAE reporting process described in this section. 
Laboratory abnormalities which are common HLH signs and symptoms will not be reported as AEs. If 
laboratory abnormalities are indicative of an HLH reactivation or worsening, the reactivation or worsening 
of HLH will be reported as the AE, and not the laboratory abnormalities themselves 
 
Deaths 
Death should be considered an outcome and not an adverse event term. The event or condition that 
caused or contributed to the fatal outcome should be recorded as Adverse Event. Generally, only one 
such event should be reported.  
 
Worsening of preexisting medical conditions 
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the Medical History eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the frequency, severity, 
or character of the condition worsens during the study. 
 
Pregnancy 
In the event that a pregnancy occurs during the study, it must be reported to Sobi AG within 24 hours of 
awareness. This includes pregnancies occurring in partners of male patients. All information pertaining to 
pregnancy should be reported using the Sobi AG Pregnancy form. Pregnancy is not to be reported as an 
AE.  

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Occurrence of pregnancy in a study participant will require discontinuation of the IMP and entry into the 
study follow-up period. 
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious adverse events 
associated with the pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the Adverse Event 
eCRF. In addition, the investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available. 
9.5 
FOLLOW-UP OF SAFETY PARAMETERS 
 
Investigator Follow-up of Adverse Events 
The Investigator should follow each adverse event until the event has resolved (returned to baseline 
grade or better), the event is assessed as stable by the Investigator, the patient is lost to follow-up, or the 
patient withdraws consent. Every effort should be made to follow all serious AEs considered related to 
study drug or trial-related procedures until a final outcome can be reported. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
 
Sponsor Follow-up 
For serious adverse events and pregnancies, the Sponsor or a designee may follow up by telephone, fax, 
electronic mail, and/or a monitoring visit to obtain additional case details and outcome information (e.g., 
from hospital discharge summaries, consultant reports, autopsy reports) in order to perform an 
independent medical assessment of the reported case. 
9.6 
POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the Investigator becomes aware of any serious adverse event that occurs 
after the end of the adverse event reporting period, if the event is believed to be related to prior study 
drug. 
The Investigator should report these events directly to the Sponsor, by scanning and emailing the Serious 
Adverse Event Form using the email address provided to Investigators. 
9.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, INVESTIGATORS, INSTITUTIONAL REVIEW 
BOARDS, AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events against cumulative experience with study 
drug to identify and expeditiously communicate possible new safety findings to Investigators, IRBs, ECs, 
and applicable health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will assess the 
expectedness of these events using the emapalumab Investigator’s Brochure. 
The Sponsor will compare the severity of each event and the cumulative event frequency reported for 
the study with the severity and frequency reported in the applicable reference document. 
Reporting requirements will also be based on the Investigator's assessment of causality and seriousness, 
with allowance for upgrading by the Sponsor as needed. 

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9.8 
BENEFIT/RISK MANAGEMENT 
 
Safety Surveillance Management 
The safety of patients who participate in this trial will be ensured through the use of stringent inclusion 
and exclusion criteria, and close monitoring of patients. Investigators will assess the occurrence of 
adverse events and serious adverse events at all patient evaluation timepoints during the study. All 
adverse events and serious adverse events, whether volunteered by the patient, discovered by study 
personnel during questioning, or detected through physical examination, laboratory test, or other means, 
will be recorded in the patient’s medical record and on the appropriate adverse event eCRF. Patients will 
be carefully followed for adverse events during the study, including a long-term follow-up period off study 
drug. 
An iDMC will review safety and efficacy data at regular intervals.  
The iDMC can recommend treatment discontinuation for individual patients as well as to halt the entire 
study temporarily or permanently.  
 
General Benefit/Risk Considerations  
9.8.2.1 Potential benefits 
Therapies specifically directed at HLH in adult patients are extrapolated from experience in pediatric HLH. 
These treatments are either with high toxicity (i.e. etoposide) or without conclusively demonstrated 
benefit to the condition.  
Given the central role of IFNγ in mediating the immune dysregulation and severe inflammation in all forms 
of HLH, it is hypothesized that neutralization of IFNγ will improve outcomes in patients with adult-onset 
HLH. 
The expected benefit of a partial or complete resolution of clinical and laboratory signs of HLH activity in 
pHLH patients receiving treatment with emapalumab has been demonstrated in the NI-0501-04 and NI-
0501-05 studies, with the majority of patients being able to receive HSCT and experiencing a survival 
benefit which persisted after HSCT. The results of the study have confirmed that emapalumab, as a 
targeted treatment, could control HLH activity while being safe and well tolerated in a very fragile 
pediatric population. Furthermore, emapalumab treatment could be continued safely and effectively 
beyond 8 weeks in patients for whom the search for a donor was longer than expected. Since non-active 
or minimally active disease at the time of HSCT has been reported to correlate with overall survival in 
HLH, this has represented a major benefit for pHLH patients. 
On the basis of the data available so far, the FDA has approved emapalumab as the first specific treatment 
for pHLH patients who have refractory, recurrent or progressive disease or intolerance with conventional 
HLH therapy.  
Based on these considerations, adult onset HLH patients are expected to benefit from a targeted therapy 
with emapalumab.  
For more details, refer to the latest Investigator’s Brochure.  
9.8.2.2 Risks analysis 
Based on the available pre-clinical and clinical data, the nature and mechanism of action of 
emapalumab, the acquired experience from fontolizumab (a humanized anti-IFNγ monoclonal 
antibody) and other immunomodulatory antibodies, attention should be paid to: 

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▪ Risks related to the neutralization of the target (IFNγ): 
As to the development of infections caused by pathogens reported to be potentially favored by 
the absence of IFNγ biological activity, among the 73 patients treated with emapalumab at the 
cut-off date of 14 November 2018, 1 patient developed disseminated histoplasmosis which 
resulted in treatment discontinuation. The infection resolved with adequate antifungal therapy 
while emapalumab was still at measurable concentrations in blood. One case of Herpes Zoster 
infection was reported in the Phase 1 study in healthy volunteers, and recovered. 
As to the development of other infections (bacterial, viral, fungal), which are expected and 
commonly reported in immunocompromised patients, based on the experience gained so far, the 
following considerations can be made: 
− 
the presence of an active infection (not being an exclusion criteria of the pHLH protocols) did 
not prevent initiation of emapalumab treatment 
− 
infections occurring during emapalumab treatment, when in the presence of satisfactory 
HLH control and with appropriate anti-microbial treatment, generally resolved  
− 
the severity and duration of neutropenia, a hallmark of HLH, as well as a potential 
consequence of previous HLH treatments or HSCT conditioning, seemed to significantly 
contribute to the development of infections. 
▪ Hypersensitivity and infusion related reactions: 
Infusion related reactions (IRRs) are reported with monoclonal antibodies (mAbs) and have 
been reported as anaphylaxis, anaphylactoid reactions and cytokine release syndrome, among 
other terms used. They are defined as signs or symptoms timely related to the administration 
of an infusion, occurring typically between 30 minutes to 2 hours following the start, although 
symptoms may be delayed for up to 24 hours. Anaphylactic and anaphylactoid reactions are the 
most severe forms of acute allergic reactions.  
With regard to emapalumab, no signal has been identified in the pre-clinical studies and in the 
Phase 1 study in HV. 
During emapalumab treatment in the NI-0501-04 and -05 studies, 11 of 45 (24%) treated 
patients experienced at least 1 IRR. The most frequently reported IRRs were hyperhidrosis (4 
patients), cutaneous reactions coded drug eruption, rash or erythema or erythematous rash (7 
patients) or pyrexia (3 patients).  
All IRRs were of mild intensity, except for 1 event of moderate pyrexia. No IRR was reported as 
a serious adverse event and no IRR required a permanent discontinuation of emapalumab or 
prevented administration of the full dose of emapalumab.  
No IRR has been reported to date in the NI-0501-06 study (6 patients having completed 
treatment). 
No anaphylactic/anaphylactoid reactions or delayed hypersensitivity reactions have been 
observed.  
▪ Immunogenicity:  
Immunogenic responses to antibody therapeutics can impact both safety and pharmacokinetic 
properties of a drug. The analyses performed so far on HLH patients treated in the NI-0501-04/05/06 
studies have detected the presence of ADAs in 3 of 38 patients (7.9%). In none of the patients was 

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the presence of ADA associated with any adverse event or significant changes in the 
pharmacokinetics profile, and ADA titers were generally low. 
More details on the safety profile of emapalumab as currently known are available in the latest 
Investigator`s Brochure. 
9.8.2.3 Risk minimization measures 
The above listed risks are considered to be fully manageable in HLH patients, with adequate minimization 
measures as follows: 
• 
The ongoing study has been designed with HLH experts; 
• 
Inclusion/exclusion criteria: patients with malformations or severely altered organ functions 
(due to a concomitant disease), as well as patients with active or latent (in case of TB) 
infection by Mycobacteria, Histoplasma, Leishmania, known to be potentially favored by IFNγ 
neutralization, are not to be included in emapalumab studies; 
• 
Patients are managed in specialized centers for the treatment of HLH, and therefore 
equipped with all necessary emergency assistance devices; 
• 
Prophylaxis for Herpes Zoster virus is mandatory to avoid occurrence of this infection which 
might be favoured by IFNγ neutralisation; 
• 
Close monitoring for potential infections through careful physical examination, laboratory 
parameters, active search for EBV, CMV, Adenoviruses, and M. Tuberculosis at Screening and 
when clinically indicated, are required per protocol; 
• 
The ongoing study is performed under the surveillance of an iDMC. 
10 STUDY, AND SITE DISCONTINUATION 
10.1 PATIENT DISCONTINUATION 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  In addition, 
the Investigator has the right to withdraw a patient from the study at any time. 
Reasons for withdrawal from the study may include, but are not limited to, the following: 
• Patient withdrawal of consent at any time 
• Any medical condition that the investigator or Sponsor determines may jeopardize the patient’s safety 
if he or she continues in the study 
• Investigator or Sponsor determines it is in the best interest of the patient. 
Patients should be informed of circumstances under which their participation may be terminated by the 
Investigator without the patient’s consent. Any administrative or other reasons for withdrawal must be 
explained to the patient.  
Every effort should be made to obtain information on patients who withdraw from the study. The primary 
reason for withdrawal from the study should be documented on the appropriate eCRF. Patients will not 
be followed for any reason after consent has been withdrawn. 

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10.2 STUDY TREATMENT DISCONTINUATION  
Patients must discontinue study treatment permanently if they experience the following: 
- 
Pregnancy 
The primary reason for study treatment discontinuation should be documented on the appropriate eCRF.  
All patients who discontinue from the study treatment shall return for all scheduled visits until the end of 
the study. 
10.3 STUDY DISCONTINUATION 
Recruitment may be temporarily suspended in case of occurrence of unexpected fatal adverse reactions. 
Patients already enrolled in the study should continue receiving emapalumab per protocol unless decided 
otherwise by the Investigator. 
The suspension will allow the Sponsor and/or the iDMC to analyze the data already generated and to 
formulate recommendations (e.g. resuming recruitment with no changes to the protocol, implementing 
risk minimization measures). 
10.4 MANAGEMENT OF TREATMENT DISCONTINUATION 
All patients who discontinue emapalumab treatment will be treated according to the standard care at the 
site and they will continue in the study for long-term follow-up. 
11 STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
Full details of all statistical issues and planned statistical analyses will be specified in a separate Statistical 
Analysis Plan (SAP), which will be finalized before 10 patients with a specific HLH etiology completed 
treatment (i.e. before the first analyses of data for a specific etiology, please see Section 11.3.2). This 
section contains an overview of the planned methods of analysis. 
11.1 SAMPLE SIZE  
Initial Planned Sample Size 
The primary analysis will evaluate the Overall Response (OR) rate at 4 weeks and use a binomial test with 
a one-sided significance level of 5% to calculate the p-value. The initial sample size planned for each 
etiology is 10. 
Final Sample Size 
The sample size for each of the two etiologies (i.e. M-HLH and non-malignancy-associated HLH) will be 
reviewed in an ongoing way. Recruitment to particular etiologies may be stopped for futility while 
recruitment to other etiologies may be expanded up to a sample size of 25 patients for a particular 
etiology. 
11.2 ANALYSIS SETS   
Analysis sets will be defined in the SAP. In conjunction with the analysis set listed below, further 
exploratory analyses may be performed using certain subgroups of patients. In particular, there will be 
separate consideration of the different etiologies. 

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All Treated Analysis Set 
The All Treated Analysis Set will include all patients entering the study who receive any part of an infusion 
of study drug. 
 
Per Protocol Analysis Set 
The Per Protocol Analysis Set will be the subset of the All Treated Analysis Set excluding major protocol 
violators. The criteria for identifying ‘major violations’ will be set down in detail in the SAP. 
The All Treated Analysis Set will be the primary analysis set for all efficacy evaluations. Each of the efficacy 
endpoints will also be analysed in the Per Protocol Analysis Set. 
11.3 STATISTICAL AND ANALYTICAL METHODS 
 
Efficacy Data 
The primary analysis of the primary endpoint will evaluate the null and alternative hypotheses defined as 
follows: 
𝐻0: 𝑂𝑅𝑅≤40%           𝐻1:𝑂𝑅𝑅> 40% 
 The analysis will be based on a binomial test with a one-sided significance level of 5%. Descriptive 
statistics and graphical methods will be used for the evaluation of the secondary efficacy endpoints. 
Overall Survival (OS), time to response and duration of response will be summarised in Kaplan-Meier 
curves. For OS, patients still alive at the end of the study or lost-to-follow-up will be censored at the last 
known time alive. For time to response, patients without a response at the end of the study or lost-to-
follow-up will be censored at the last known time known to not have had a response. The Kaplan-Meier 
curve for duration of response will be constructed only for those patients who are responders. Summary 
statistics (namely estimated value, standard error with 95% confidence interval) will be obtained at key 
time points for OS and time to response. Best response on treatment and HLH response will be 
summarized with counts and associated 95% confidence intervals. The secondary endpoints are 
considered to be exploratory and no statistical testing has been planned. 
 
Adaptive Evaluation of the Overall Response Rate 
This study recruits patients with different HLH etiologies, namely M-HLH and non malignancy-associated 
HLH. Emapalumab may not be equally effective across these etiologies, therefore it is proposed to analyse 
the accumulating data periodically, in order to assess each of the 2 etiologies for futility and efficacy. In 
this adaptive design, the first analysis for each etiology will occur after 10 patients with that etiology 
reached the primary endpoint time point, and further reviews for each etiology will take place after every 
subsequent 5 patients. The decision rule for stopping for futility shall be based on a one-sided p-value 
looking to see whether the OR rate was significantly below 60%, while the decision rule for considerations 
for efficacy shall be based on a one-sided p-value looking to see whether the OR rate was significantly 
above 40%. 
For example, with 10 patients, the probability of seeing 2 or fewer ORs is 0.0123 if the true OR rate is 60% 
and such evidence may result in a decision to stop recruitment for that etiology. In contrast, the 
probability of seeing 8 or more ORs is 0.0123 if the true OR rate is 40% and this may result in a decision 
to consider interacting with regulators to discuss the potential for an indication in that etiology. These 
decision rules are based on the one-sided p-values being below 0.05. 
The table below provides the cut-offs for both futility and efficacy based on these same considerations 
for various sample sizes in multiples of 5 from n=10 through to n=25. 

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Thresholds for Futility and Efficacy as a Function of Sample Size 
Sample size 
(by etiology) 
Threshold for consideration of 
futility 
#ORs ≤ this value 
Threshold for consideration of 
efficacy 
#ORs ≥ this value 
10 
2 (20%) 
8 (80%) 
15 
5 (33%) 
10 (67%) 
20 
7 (35%) 
13 (65%) 
25 
10 (40%) 
15 (60%) 
 
These thresholds provide a guide for the decision making for futility and efficacy. 
To support regulatory interactions on the confirmatory strategy, a descriptive evaluation of the efficacy 
and safety results will be made after a small number of patients, i.e. no more than 10 patients overall 
(irrespectively of etiology), have completed 4 weeks of treatment.  
 
Safety Data 
All data relating to safety will be listed and summarized using descriptive statistics.  
AEs will be coded and tabulated by body system, and by individual events within each body system. AEs 
will also be tabulated by severity and relationship to the study medication. Summaries will also be 
produced of SAEs and AEs leading to withdrawal of treatment. 
For each clinical laboratory test, individual patient values will be listed and summarized, and change from 
pre-treatment baseline values calculated and summarized. Any values outside the standard reference 
range will be flagged. Summaries of marked abnormalities and shift tables or boxplots will be tabulated 
for each laboratory test. 
In addition, other exploratory analyses of safety data, including summaries for different subsets of 
patients, may be conducted. 
 
Pharmacokinetic Data 
Population PK and PKPD analyses using non-linear mixed effects modelling will be performed and 
reported separately.  A specific PK and PKPD modelling analysis plan will be prepared. 
 
Pharmacodynamic Data 
All PD data will be summarized using appropriate graphical and tabular presentations. 
Exploratory statistical models will be fitted, and correlation analyses undertaken, to investigate the 
relationships between PD data and other markers and the clinical measures of response. ROC curves may 
be used to summarize any relationships that are found. 
In addition, other exploratory analyses of PD endpoints, including summaries for different subsets of 
patients, may be conducted. 

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Missing Data 
Imputation rules will be pre-defined in the SAP prior to final database close, in order to keep to a minimum 
the number of patients not being evaluable for the primary and key secondary endpoints. 
11.4 REPLACEMENT POLICY 
 
For Patients 
Additional patients may be recruited into the study if patients are withdrawn from the study for reasons 
other than safety or lack of efficacy. 
 
For Centers 
A center may be replaced for the following administrative reasons: excessively slow recruitment, poor 
protocol adherence.  
12 ETHICAL AND LEGAL ASPECTS 
12.1 GOOD CLINICAL PRACTICE 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and documentation 
of this study are designed to ensure that Sobi AG, its authorized representatives, and Investigator abide 
by Good Clinical Practice (GCP), as described in International Conference on Harmonization (ICH) 
Guideline E6 and in accordance with the general ethical principles rooted in the Declaration of Helsinki. 
The study will receive approval from an Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) prior to commencement and where applicable by law also from National Competent Authorities. 
The Investigator will conduct all aspects of this study in accordance with applicable national, state, and 
local laws of the pertinent regulatory authorities. 
12.2 INVESTIGATOR RESPONSIBILITIES 
The Investigator should ensure they maintain documentation to demonstrate that all persons assisting 
with the trial are appropriately qualified and adequately informed about the protocol, amendments, 
study treatments, as well as study-related duties and functions. The Investigator should maintain a list of 
sub-investigators and other appropriately qualified persons to whom he or she has delegated significant 
study-related duties, including the dates they begin and end working on the study. 
The Investigator is responsible for keeping a record of all patients (or their legally authorized 
representative) that sign an informed consent document and are screened for entry into the study. 
Patients who fail screening must have the reason(s) recorded in their source documents and the study-
screening log. The investigator should maintain source documents and trial records that include all 
pertinent observations on each of the site’s trial subjects. Source data should be attributable, legible, 
contemporaneous, original, accurate and complete. 
The Investigator, or a designated member of the Investigator’s staff, must be available during monitoring 
visits, audits and inspections to review data, resolve queries and allow direct access to subjects’ records 
(e.g., medical/hospital records, office charts, hospital charts, and study related charts) for source data 
and other type of verification. The Investigator must ensure timely and accurate completion of CRFs and 
queries. 

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12.3 INFORMED CONSENT 
Before being enrolled in this clinical study, the patient (or the patient’s legally authorized representative) 
must consent to participate, after the nature, scope, and possible consequences of the study have been 
explained in a form understandable to him or her. An informed consent document that includes both 
information about the study and the consent form will be prepared and given to the patient. This 
document will contain all ICH GCP, and locally required regulatory elements (whichever is more stringent). 
The document will be in a language understandable to the patient and will specify who obtained informed 
consent from the patient (or the patient’s legally authorized representative), and when the informed 
consent was obtained.  
Information for patients will be split into a Patient Information Sheet that provides detailed information 
about the trial and its benefits and risks, and the Informed Consent Form that summarizes the content of 
the Patient Information Sheet and is used to obtain the dated signature from the patient as evidence of 
the patient’s agreement to participate in the study. The Investigator acknowledges that consent is a 
process that begins with explaining the study and obtaining signature on the consent document, and 
continues throughout the patient’s participation in the study. The Investigator will remain responsible for 
ensuring adequate consent is obtained and documented. 
After reading and understanding the informed consent document, the patient (or their legally authorized 
representative) must give consent in writing. The written informed consent will be obtained prior to 
conducting any study-related procedures or tests. The patient’s consent (or the consent of the patient’s 
legally authorized representative) must be confirmed at the time of consent by the personally dated 
signature of the person conducting the informed consent discussion. A copy of the signed consent 
document must be given to the patient or their legally authorized representative. The Investigator will 
retain the original signed consent document. The Investigator will not undertake any measures 
specifically required only for the clinical study until valid consent has been obtained. In the event that the 
patient’s legally authorized representative signed the ICF due to the patient’s condition at the time of 
consent, the subject’s personal consent should be pursued, should his/her condition allow to personally 
consent. If the patient is not capable to personally consent, this should be clearly documented in the 
patient’s medical file. 
If an amended protocol impacts the content of the informed consent document, the consent document 
must be revised. Patients already participating in the study when the amended protocol is implemented 
must be re-consented with the revised version of the informed consent document. A copy of the revised 
informed consent document must be given to the patient or their legally authorized representative. The 
Investigator will retain the original signed updated consent document in the study files. 
12.4 CONFIDENTIALITY AND DATA PRIVACY 
Sobi AG shall respect patients’ rights to protect their personal data in compliance with ICH, relevant 
national legislation, and international data protection regulations (whichever is the most stringent). All 
medical records and copies thereof used for conducting the study or regulatory purposes shall be 
anonymized in accordance with relevant national legislation and international data protection laws.  
Should direct access to medical records require a waiver or authorization separate from the patient’s 
statement contained in the informed consent form, it is the responsibility of the Investigator to obtain 
such permission in writing from the appropriate individual. 

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12.5 PROTOCOL AMENDMENTS 
Substantial amendments will be submitted to the IRB/IEC for approval, and where applicable to National 
Competent Authorities. Approval must be obtained before implementation of the amended version 
occurs.  
12.6 APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS 
Before the start of the study, the study protocol, informed consent document, any subject-facing 
documents (e.g. patient card) and any other documents (as appropriate) will be submitted to the IRB/IEC 
with a cover letter or a form listing the documents submitted, their version and date of issue, and the site 
(or region or area of jurisdiction, as applicable) for which approval is sought. If applicable, the documents 
will also be submitted to the authorities in accordance with local legal requirements. 
Sobi AG can only supply study drug to an Investigator after Sobi AG or their authorized representative has 
received documentation on all ethical and legal requirements for starting the study. This documentation 
must also include a list of the members of the IRB/IEC and their occupation and qualifications. If the 
IRB/IEC will not disclose the names of the committee members, it should be asked to issue a statement 
confirming that the composition of the committee is in accordance with ICH GCP. Formal approval by the 
IRB/IEC should mention the study title, study code, study site, and any other documents reviewed. It must 
mention the date on which the decision was made and must be officially signed by an IRB/IEC committee 
member. Before the first patient is enrolled in the study, all ethical and legal requirements must be met. 
The IRB/IEC and, if applicable, the competent authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to determine 
whether formal approval must be sought and whether the informed consent document and/or any other 
documents (as appropriate) should also be revised. 
The Investigator must keep a record of all communication with the IRB/IEC and, if applicable, between a 
coordinating Investigator and the IRB/IEC. This statement also applies to any communication between 
the Investigator (or coordinating Investigator, if applicable) and regulatory authorities. 
All documents handed over to patients or their legally authorized representative prior to use must first 
be reviewed and approved by Sobi AG, and upon approval by Sobi AG submitted to and reviewed and 
approved by the IRB/IEC and in accordance with local legal requirements by the regulatory authorities. 
This includes but is not limited to the Informed Consent Form, Patient Information Sheet, assent form, 
advertisements, training materials. 
12.7 ONGOING INFORMATION FOR IRB/IEC 
If required by legislation or by the IRB/IEC, the Investigator must submit to the IRB/IEC: 
• 
Information on SAEs, SUSARs, periodic safety reports or any other safety measure, as per local 
applicable rules and timelines 
• 
Periodic reports on the progress of the study 
• 
Deviations from the protocol or anything that may involve added risk to subjects. 
12.8 CLOSURE OF THE STUDY 
Sobi AG reserves the right to terminate this study at any time for reasonable medical or administrative 
reasons. Any premature discontinuation will be appropriately documented according to local 
requirements (e.g., IRB/IEC, regulatory authorities). 

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In addition, Sobi AG reserves the right to discontinue a single site at any time during the study for medical 
or administrative reasons such as: 
• 
Significant non-compliance with contractual enrolment timelines and targets 
• 
Serious or continued ICH GCP non-compliance 
• 
Inaccurate, incomplete or delayed data collection 
• 
Failure to adhere to the study protocol 
• 
Failure to provide requested follow-up information for data queries. 
12.9 RECORD RETENTION 
The Investigator will ensure that essential records are kept in a secure archiving facility for the retention 
period stipulated in the study contract and as per ICH GCP and legal requirements and should maintain a 
record of the location(s) of the essential documents.  Essential documents include, but are not limited to, 
the following: 
• 
Signed informed consent documents for all subjects 
• 
Subject identification code list, screening log and enrolment log (if applicable) 
• 
Record of all communications between the Investigator and the IRB/IEC and/or regulatory 
authorities 
• 
Composition of the IRB/IEC 
• 
Record of all communications between the Investigator, Sobi AG and their authorized 
representatives 
• 
List of sub-investigators and other appropriately qualified persons to whom the Investigator has 
delegated significant trial-related duties, together with their roles in the study, curricula vitae and 
their signatures 
• 
Copies of CRFs and of documentation of corrections for all subjects 
• 
IMP shipments, returns, destruction and accountability records 
• 
Record of any body fluids or tissue samples retained 
• 
All other source documents (subject records, hospital records, laboratory records, etc.) 
• 
All other documents, as listed in Section 8 of the ICH consolidated guideline on GCP (Essential 
Documents for the Conduct of a Clinical Trial). 
Normally, these records will be held in the Investigator’s archives. If the Investigator is unable to meet 
this obligation, the Investigator must ask Sobi AG for permission to make alternative arrangements. 
Details of these arrangements should be documented and archived both at the clinical trial center and in 
the Trial Master File (TMF). These may include but are not limited to notifications to the IRB/IEC and/or 
regulatory authorities (as applicable). 
12.10 LIABILITY AND INSURANCE 
Liability and insurance provisions for this study are provided in the Investigator/Investigational site/Other 
site personnel or facility contract as applicable. 

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12.11 FINANCIAL DISCLOSURE 
Investigators and study site staff listed on the Delegation of Authority Log are required to provide financial 
disclosure information at the start of the study, every 2 years during the conduct of the study, and at the 
end of the study, in order for Sobi AG to be able to submit complete and accurate certification or 
disclosure statements in accordance with applicable national and local regulations, including FDA 21 CFR 
Part 54 requirements. In addition, Investigators must provide Sobi AG with a commitment to promptly 
update this information if any relevant changes occur during the course of the investigation and for 1 year 
following the completion of the study. 
12.12 DISCLOSURE OF PROTOCOL AND STUDY RESULTS AND PUBLICATION POLICY 
Information about this trial will be posted following the principles of the International Committee of 
Medical Journal Editors (ICMJE), the International Federation of Pharmaceutical Manufacturers & 
Associations (IFPMA) Industry Position Paper, and applicable national or regional regulations and laws.  
Sobi AG will comply with the requirements for publication of study results. In accordance with standard 
editorial and ethical practice, Sobi AG will support publication of multicenter trials only in their entirety 
and not as individual center data. In this case, a coordinating Investigator will be designated by mutual 
agreement prior to the start of the trial. 
Authorship will be determined by mutual agreement and in line with ICMJE authorship requirements. Any 
formal publication of the study in which contribution of Sobi AG personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the Investigator and the appropriate Sobi AG 
personnel. 
So-called ‘ghost writing’ is not permitted. All contributors who do not meet the criteria for authorship 
should be listed in an acknowledgments section. Examples of those who might be acknowledged include 
a person who provided purely technical help, writing assistance, or a department chairperson who 
provided only general support. 
The results of this study may be presented at scientific meetings. If this is foreseen, the Investigator agrees 
to submit abstracts to Sobi AG prior to submission. This allows Sobi AG to protect proprietary information 
and to provide comments based on information from other studies that may not yet be available to the 
Investigator. 
Any inventions and resulting patents, improvements, and/or know-how originating from the use of data 
from this study will become and remain the exclusive and unburdened property of Sobi AG, except where 
agreed otherwise. 
13 MONITORING AND AUDITING 
All aspects of the study will be monitored and audited by Sobi AG or its representative for this study (Sobi 
AG authorized representative), for compliance with applicable government regulations with respect to 
current ICH GCP and applicable standard operating procedures/working instructions. Direct access to the 
on-site study documentation and medical records must be ensured. 
13.1 STUDY MONITORING AND SOURCE DATA VERIFICATION 
As part of the responsibilities commensurate with participating in the study, the Investigator agrees to 
maintain and have available for monitoring adequate case records (accurate source documents and CRFs) 
for the patients treated under this protocol. In addition, the Investigator agrees to maintain all 
administrative documents (e.g., IRB/IEC correspondence, investigational product and supplies shipment 

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manifests, monitoring logs, or correspondence with Sobi AG and with any of its representatives for this 
study). When a copy is used to replace an original document, the copy should fulfill the requirements for 
certified copies. 
The Investigator/institution should maintain a record of the location(s) of the essential documents. The 
storage system (irrespective of the media used) should provide for document identification, search and 
retrieval. 
13.2 ON-SITE AUDITS 
Investigators and institutions involved in the study will permit trial-related monitoring, audits, IRB/IEC 
review, and domestic or foreign regulatory inspection(s) by providing direct access to source documents, 
CRFs, and all other study documentation. 
The Investigator should promptly notify Sobi AG of any inspections scheduled by any regulatory 
authorities and promptly forward to Sobi AG copies of any audit reports received. 
13.3 SERIOUS GCP BREACHES 
Sobi AG is required to report a serious ICH GCP Breach within 7 days to applicable health authorities.  
A serious GCP breach is a breach likely to affect to a significant degree the safety and rights of a subject 
or the reliability and robustness of the data generated in the clinical trial. 
Therefore, should an Investigator become aware of a possible serious GCP breach, e.g. an important 
protocol deviation, or non-reporting of critical safety information that has the potential of jeopardizing 
patients’ safety, Sobi AG must be notified within 24 hours. 
14 DOCUMENTATION AND USE OF STUDY FINDINGS 
14.1 DOCUMENTATION OF STUDY RESULTS 
An electronic CRF (eCRF) is used in this study and a specific eCRF will correspond to each subject.  
All required information must be entered on the eCRFs. If an item is not available or is not applicable, this 
fact should be indicated and no blank spaces must be left. The data collected on the eCRF will be entered 
into the study database. If the Investigator authorizes other personnel to enter data into the eCRF, the 
names, positions, signatures, and initials of these persons must be supplied to Sobi AG or their authorized 
representative before these individuals start completing eCRF information.  
Sobi AG will ensure that the Investigator has control of and continuous access to the eCRF data reported 
to the Sponsor. Sobi AG will not have exclusive control of those data. 
The eCRF pages must be reviewed and electronically signed by the Investigator named in the study 
protocol or by a designated sub-investigator. At the end of the study, Sobi AG will ensure that a readable 
image of the eCRF is provided to the Investigator, to be maintained in his/her records. Sobi AG will ensure 
that the CRF copies left with the Investigator (print-outs and/or pdf exports) are an exact copy of the data 
maintained in the database.  
14.2 USE OF COMPUTERIZED SYSTEMS AT THE CLINICAL TRIAL CENTRE 
When clinical information of patients are entered directly into an investigational site’s computerized 
medical record system (electronic Health Records System; i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in accordance with 

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health authority requirements pertaining to computerized systems used in clinical research. An 
acceptable electronic Health Records System allows preservation and integrity of the original entry of 
data by ongoing review, change control processes and audit trails. If original data are modified, the system 
should maintain a viewable audit trail that shows the original data as well as the reason for the change, 
name of the person making the change, and date of the change. The Investigator should be able to 
demonstrate medical oversight of the trial when electronic Health Records Systems are used, e.g. 
verifying entries of study nurses on ongoing basis.  
The system must allow the Sponsor, clinical research associate, auditors or inspectors to verify source 
data without infringing privacy rights of other patients, e.g., access must be restricted to records 
pertaining to the study patients and access to other patients must not be possible. This should include 
access to the audit trail. If the electronic Health System does not comply with these requirements, the 
Sponsor reserves the right to be provided with paper print outs from the System containing the same 
information as the electronic original records. 
 
15 REFERENCES 
Akashi K, Hayashi S, Gondo H, Mizuno S, Harada M, Tamura K, Yamasaki K, Shibuya T, Uike N, Okamura T 
et al. “Involvement of interferon-gamma and macrophage colony-stimulating factor in 
pathogenesis of haemophagocytic lymphohistiocytosis in adults.” British journal of 
haematology, June 1994: 87(2):243-50. 
Arca M, Fardet L, Galicier L, Rivière S, Marzac C, Aumont C, Lambotte O, Coppo P. “Prognostic factors of 
early death in a cohort of 162 adult haemophagocytic syndrome: impact of triggering disease 
and early treatment with etoposide.” British journal of haematology, January 2015: 168(1):63-8. 
Assi R, Boddu P, Kadia T, Estrov Z, Manero G, Ravandi F, Jabbour E, Takahashi K, Konopleva M, Andreeff 
M, Zahr A, DiNardo C, Borthakur G, Jain N, Pemmaraju N, Yilmaz M, Short N, Ning J, Pierce S, 
Wierda W, Cortes J, Kantarjian H and Daver N. “Characteristics and Outcomes of Patients (pts) 
with Malignancy-Associated Hemophagocytic Lymphohistiocytosis (M-HLH) in Adults: A Single-
Center, Prospective Analysis of 36 Pts.” Blood, November 2018: 132(Suppl_1):3689-3689. 
Bracaglia C, de Graaf K, Pires Marafon D, Guilhot F, Ferlin W, Prencipe G, Caiello I, Davì S, Schulert G, 
Ravelli A, Grom AA, de Min C, De Benedetti F. “Elevated circulating levels of interferon-γ and 
interferon-γ-induced chemokines characterise patients with macrophage activation syndrome 
complicating systemic juvenile idiopathic arthritis.” Annals of the rheumatic diseases, 2017: 
76(1):166-172. 
Buatois V, Chatel L, Cons L, Lory S, Richard F, Guilhot F, Johnson Z, Bracaglia C, De Benedetti F, de Min C, 
Kosco-Vilbois MH, Ferlin WG. “Use of a mouse model to identify a blood biomarker for IFNγ 
activity in pediatric secondary hemophagocytic lymphohistiocytosis.” Translational research : 
the journal of laboratory and clinical medicine, 2017: 180:37-52. 
Carter SJ, Tattersall RS, Ramanan AV. “Macrophage activation syndrome in adults: recent advances in 
pathophysiology, diagnosis and treatment.” Rheumatology (Oxford, England), January 2019: 
58(1):5-17. 
Dhote R, Simon J, Papo T, Detournay B, Sailler L, Andre MH, Dupond JL, Larroche C, Piette AM, 
Mechenstock D, Ziza JM, Arlaud J, Labussiere AS, Desvaux A, Baty V, Blanche P, Schaeffer A, 
Piette JC, Guillevin L, Boissonnas A, Christoforov B. “Reactive hemophagocytic syndrome in 

Study NI-0501-10 
Emapalumab in Adult HLH  
Page 72 of 78 
Protocol NI-0501-10 
Version 3.0 – FINAL - 09Mar2020 
CONFIDENTIAL 
adult systemic disease: report of twenty-six cases and literature review.” Arthritis and 
rheumatism, 2003: 49(5):633-9. 
Henter JI(a), Elinder G, Söder O, Hansson M, Andersson B, Andersson U. “Hypercytokinemia in familial 
hemophagocytic lymphohistiocytosis.” Blood, December 1991: 78(11):2918-22. 
Henter JI(b), Samuelsson-Horne A, Aricò M, Egeler RM, Elinder G, Filipovich AH, Gadner H, Imashuku S, 
Komp D, Ladisch S, Webb D, Janka G, Histocyte Society. “Treatment of hemophagocytic 
lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation.” 
Blood, 2002: 100(7):2367-73. 
Henter JI(c), Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, 
Winiarski J, Janka G. “HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic 
lymphohistiocytosis.” Pediatric blood & cancer, February 2007: 48(2):124-31. 
Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. “How I treat hemophagocytic 
lymphohistiocytosis.” Blood, 2011: 118(15):4041-52. 
La Rosée P. “Treatment of hemophagocytic lymphohistiocytosis in adults.” Hematology. American 
Society of Hematology. Education Program, 2015: 2015:190-6. 
Larroche C, Bruneel F, André MH, Bader-Meunier B, Baruchel A, Tribout B, Genereau T, Zunic P, Comité 
d'Evaluation et de Diffusion des Innovation Technologiques (CEDIT). “[Intravenously 
administered gamma-globulins in reactive hemaphagocytic syndrome. Multicenter study to 
assess their importance, by the immunoglobulins group of experts of CEDIT of the AP-HP] 
[Article in French].” Annales de médecine interne, November 2000: 151(7):533-539. 
Li J, Wang Q, Zheng W, Ma J, Zhang W, Wang W, Tian X. “Hemophagocytic lymphohistiocytosis: clinical 
analysis of 103 adult patients.” Medicine, March 2014: 93(2):100-5. 
Machaczka M, Vaktnäs J, Klimkowska M, Hägglund H. “Malignancy-associated hemophagocytic 
lymphohistiocytosis in adults: a retrospective population-based analysis from a single center.” 
Leukemia & lymphoma, April 2011: 52(4):613-9. 
Maruoka H, Inoue D, Takiuchi Y, Nagano S, Arima H, Tabata S, Matsushita A, Ishikawa T, Oita T, 
Takahashi T. “IP-10/CXCL10 and MIG/CXCL9 as novel markers for the diagnosis of lymphoma-
associated hemophagocytic syndrome.” Annals of hematology, March 2014: 93(3):393-401. 
Nikiforow S. “The Role of Hematopoietic Stem Cell Transplantation in Treatment of Hemophagocytic 
Lymphohistiocytosis.” Hematology/oncology clinics of North America, October 2015: 29(5):943-
59. 
Ohga S, Matsuzaki A, Nishizaki M, Nagashima T, Kai T, Suda M, Ueda K. “Inflammatory cytokines in virus-
associated hemophagocytic syndrome. Interferon-gamma as a sensitive indicator of disease 
activity.” The American journal of pediatric hematology/oncology, May 1993: 15(3):291-8. 
Parikh SA, Kapoor P, Letendre L, Kumar S, Wolanskyj AP. “Prognostic factors and outcomes of adults 
with hemophagocytic lymphohistiocytosis.” Mayo Clinic proceedings, April 2014: 89(4):484-92. 
Prencipe G, Caiello I, Pascarella A, Grom AA, Bracaglia C, Chatel L, Ferlin WG, Marasco E, Strippoli R, de 
Min C, De Benedetti F. “Neutralization of IFN-γ reverts clinical and laboratory features in a 
mouse model of macrophage activation syndrome.” 2018: 141(4):1439-1449. 
Risdall RJ(b), Brunning RD, Hernandez JI, Gordon DH. “Bacteria-associated hemophagocytic syndrome.” 
Cancer, 1984: 54(12):2968-72. 

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Rivière S, Galicier L, Coppo P, Marzac C, Aumont C, Lambotte O, Fardet L. “Reactive hemophagocytic 
syndrome in adults: a retrospective analysis of 162 patients.” The American journal of medicine, 
November 2014: 127(11):1118-25. 
Schram AM, Comstock P, Campo M, Gorovets D, Mullally A, Bodio K, Arnason J, Berliner N. 
“Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years.” British 
journal of haematology, February 2016: 172(3):412-9. 
Shin HJ, Chung JS, Lee JJ, Sohn SK, Choi YJ, Kim YK, Yang DH, Kim HJ, Kim JG, Joo YD, Lee WS, Sohn CH, 
Lee EY, Cho GJ. “Treatment outcomes with CHOP chemotherapy in adult patients with 
hemophagocytic lymphohistiocytosis.” Journal of Korean medical science, June 2008: 23(3):439-
44. 
Strippoli R, Carvello F, Scianaro R, De Pasquale L, Vivarelli M, Petrini S, Bracci-Laudiero L, De Benedetti F. 
“Amplification of the response to Toll-like receptor ligands by prolonged exposure to 
interleukin-6 in mice: implication for the pathogenesis of macrophage activation syndrome.” 
Arthritis and rheumatism, 2012: 64(5):1680-8. 
Takahashi N, Chubachi A, Kume M, Hatano Y, Komatsuda A, Kawabata Y, Yanagiya N, Ichikawa Y, Miura 
AB, Miura I. “A clinical analysis of 52 adult patients with hemophagocytic syndrome: the 
prognostic significance of the underlying diseases.” International journal of hematology, August 
2001: 74(2):209-13. 
Wang Y, Huang W, Hu L, Cen X, Li L, Wang J, Shen J, Wei N, Wang Z. “Multicenter study of combination 
DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis.” 
Blood, November 2015: 126(19):2186-92. 
 
 
 
 
 

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16 APPENDIX 1 
NI-0501-10: ELIGIBILITY REVIEW FORM 
How to use this form 
1. This form is used to guide the review of patient’s eligibility (by Site and Sponsor).  
2. It should be completed after the patient has been consented, and before the joint eligibility 
review call, if scheduled. 
3. Please send the completed form to NI-0501-10@sobi.com 
 
Institution  
Institution name and location: 
      
Treating physician: 
      
 
Patient information 
Patient ID:  
assigned sequentially 
      
Age:  
      
Gender 
☐ Male 
☐ Female 
If the patient is a female, is she pregnant or 
lactating? 
☐ Yes 
☐ No 
 
HLH initial diagnosis  
Age at diagnosis of HLH:  
      
Date of diagnosis of HLH:  
DD/MMM/YYYY 
 
HLH-2004 criteria currently met (please indicate the values) 
☐ Fever 
      
☐ Splenomegaly 
      
☐ Cytopenias affecting 2 of 3 lineages 
(hemoglobin < 90 g/L; platelets <100 x 109/L; 
neutrophils  < 1 x 109/L) 
      

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☐ 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 
      
☐ Low or absent NK-cell activity 
      
☐ Ferritin ≥ 500 µg/L 
      
☐ Soluble CD25 ≥ 2400 U/mL 
      
 
Trigger of secondary HLH: 
☐ Rheumatic disease 
Please indicate any known or suspected 
rheumatic conditions 
      
☐ Infectious disease 
Please indicate any known or suspected infections 
      
☐ Neoplastic disease 
Please indicate any known or suspected 
neoplastic diseases 
      
☐ Other 
 
      
 
Did the patient already receive any therapy for HLH? 
☐ No 
☐ Yes:  
• 
Please describe therapy that patient 
received since HLH diagnosis 
      
• 
Please describe patient’s response to this 
therapy  
      
• 
Does the patient have any 
contraindications to continuation of this 
therapy? (eg. adverse reactions, 
intolerance, benefit/risk concerns) 
☐ No 
☐ Yes (specify): 
      
 
Overall patient’s condition and infectious status 

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Patient’s general condition 
      
Cardiovascular function 
      
Pulmonary function 
      
CNS function 
      
Liver function 
      
Renal function 
      
Other important concomitant diseases 
☐ Yes (specify):       
☐ No 
• 
recently resolved and ongoing 
infections (indicate duration and 
severity) 
☐ Yes (specify):       
☐ No 
Treatments / procedures ongoing at the time of request (other than HLH treatments) 
       ☐ Biologics 
      
       ☐ Transfusions 
      
       ☐ G-CSF 
      
       ☐ Antibioticotherapy 
      
       ☐ Antifungal treatments 
      
       ☐ Antiviral treatments 
      
       ☐ Cardiorespiratory support 
      
       ☐ Renal replacement therapy 
      
       ☐ Other 
      
Current (within 60 days from SD0) or 
scheduled administration of therapies 
known to trigger the cytokine release 
syndrome 
☐ Yes (specify):       
☐ No 
Current (within 60 days from SD0) or 
scheduled administration of PD-1/PD-
L1/CTLA-4 inhibitors 
☐ Yes (specify):       
☐ No 
Current JAK-inhibitors administration 
☐ Yes (specify):       
☐ No 
Life-expectancy associated with the 
underlying disease (triggering HLH) < 3 
months 
☐ Yes (specify):       
☐ No 

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Ongoing 
participation 
in 
an 
investigational trial, or administration of 
any investigational treatment within 30 
days from Screening 
☐ Yes (specify):       
☐ No 
Vaccinations within prior 12 weeks: 
☐ Yes (specify):       
☐ No 
Has the presence of active or latent TB 
infection been excluded? 
☐ Yes (specify):       
☐ Waiting for test results. There are no clinical findings 
suggestive of this infection. 
☐ No 
Has the presence of atypical 
mycobacterial infection been excluded? 
☐ Yes (specify):       
☐ Waiting for test results. There are no clinical findings 
suggestive of this infection. 
☐ No 
Has the presence of Histoplasma 
capsulatum infection been excluded? 
☐ Yes (specify):       
☐ Waiting for test results. There are no clinical findings 
suggestive of this infection. 
☐ No 
Has the presence of Leishmania 
infection been excluded? 
☐ Yes (specify):       
☐ Waiting for test results. There are no clinical findings 
suggestive of this infection. 
☐ No 
Is infection with HIV (HIV ELISA or PCR 
positive), hepatitis B (HBsAg positive), 
hepatitis C (anti-HCV positive) present? 
☐ Yes (specify):       
☐ No 
 
Does the patient have history of hypersensitivity or allergy to any of the following? 
☐ Emapalumab 
☐ L-histidine 
☐ L-histidine monohydrochloride, monohydrate 
☐ Sodium chloride 
☐ Polysorbate 80 
☐ NONE OF THE ABOVE 

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By signing this document I confirm that that the above provided patient data are accurate and can be 
shared with Sobi AG.  
 
 
 
      
Enter date 
Investigator’s name and signature 
Date