Conditions: Primary Hemophagocytic Lymphohistiocytosis
Keywords: Interferon-gamma NI-0501 primary HLH emapalumab
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 35
Healthy volunteers: no

Brief summary:
The purpose of this study is to expand the knowledge on the efficacy and safety of emapalumab (previously known as NI-0501) as a treatment for primary haemophagocytic lymphohistiocytosis (HLH) patients, including on long-term outcomes and quality of life assessments. Emapalumab can be administered as the first-line therapy to patients not previously treated with the current standard of care, or can be given to patients who have either failed or were unable to tolerate the available standard of care.

Emapalumab is to be administered until the start of conditioning for hematopoietic stem cell transplantation (HSCT), with an anticipated duration ranging from a minimum of 4 weeks to approximately 12 weeks and not exceeding 6 months.

After treatment completion, patients will continue in the study for long-term follow-up until 1 year after either HSCT or last emapalumab infusion (if HSCT is not performed).

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Emapalumab
Intervention descriptions: intervention 1: Emapalumab will be administered by intravenous infusion, twice weekly.

Protocol document:
Prot_000.pdf: 
PROTOCOL TITLE:  An Open-label, Single Arm, Multicenter Study to Broaden Access to 
Emapalumab, an Anti Interferon Gamma (Anti-IFNγ) Monoclonal 
Antibody, and to Assess its Efficacy, Safety, Impact on Quality of Life, 
and Long-term Outcome in Pediatric Patients with Primary 
Hemophagocytic Lymphohistiocytosis 
PROTOCOL DATE:  Final protocol, version 4.0 Global, dated 31 March 2020 
NCT Number: 
NCT03312751 
Summary of changes for protocol versions prior to version 4.0 
Final protocol, version 4.0 Global, dated 31 March 2020 
Page 1 of 98


Summary of changes for protocol versions prior to version 4.0 
No samples for exploratory biomarkers were analyzed. 
The following changes to the global protocol V1.0 (dated 19 September 2017) were included by 
amendments due to requests from the authorities: 
The Protocol V1.1 for the EU (dated 12 December 2017) introduced the following changes: 
•
Inconsistencies between the body of the protocol, synopsis, and schedule of assessments
were harmonized to ensure an optimal study conduct.
•
The timing of chest X-ray assessment was moved to the Pre-conditioning visit to better
reflect standard clinical practice.
•
References to the new IB and updated information on ADA were added.
The protocol V2.0 for Germany (dated 24 May 2018) introduced the following changes: 
•
The study contact list was updated.
•
It was added that the primary objective is to gather additional efficacy data on
emapalumab in pHLH patients, and efficacy was removed from the first the secondary
objective.
•
The timeframe for the medical supervision of the infusions was extended from 1 hour to
2 hours, and it was added that active infections, as per patient’s clinical presentation,
have to be carefully followed over time.
•
Viral load positivity, in particular for EBV, CMV and adenovirus, and evolution, was
removed from the exceptions for AE recording requirements. Quantitative monitoring
(e.g., viral loads, antigenemia, and antigenuria) as relevant according to the patient’s
clinical presentation, requiring EBV and CMV quantitative PCR at a minimum at
screening, was added.
•
It was added that any emergent safety concern will be timely assessed and appropriate
measure will be taken for the patients, if relevant, by an iDMC.
•
Another timepoint for vital signs measurement at 2 hours after the infusion was added.
•
The estimate of the blood volume to be collected throughout the study was updated.
The Protocol V1.2 for the United Kingdom (dated 04 September 2018) introduced the following 
changes: 
•
In response to comments from the British authority, the protocol section on contraception
was expanded.
•
As an administrative change, contact details for 2 Sponsor team members were updated.
Protocol V2.0 for North America (dated 18 July 2018) introduced the following changes: 
•
The study contact list was updated.
•
Vital signs assessments were made more frequently during each infusion when a dose
increase was applied and during the subsequent infusions in any patient who had
Page 2 of 98


experienced an IRR. The duration of monitoring after infusion was extended to up to 
2 hours for all patients. Clinically appropriate windows were applied to these 
measurements. 
• 
The required duration of TB search testing was added as a footnote to the schedule of 
assessments. 
• 
In the rationale for dosing schema, simulations were updated to present the “worst-case” 
scenario in the dose escalation schema, based on the updated, larger dataset accumulated 
in emapalumab development program that was previously submitted to FDA. 
• 
The considerations that could prompt the Investigator to increase the emapalumab dose 
were further clarified. A dedicated dose notification form was implemented to capture the 
specificities and reasoning around the Investigator decision. 
• 
A higher flexibility around the possibility to add other HLH treatments in the first week 
of treatment, i.e., the use of etoposide (or other drugs), could be considered on SD6 in a 
patient in whom an HLH worsening or no initial response was observed after the first 
emapalumab dose increase on SD3. With regard to the addition of other HLH treatments 
later during the study, definition of “unsatisfactory HLH control” had replaced 
“unsatisfactory HLH improvement”, in order to better reflect the clinical conditions in 
which the Investigator could decide so. For completeness in the guidance to the 
Investigator, a reference to section on decision to discontinue treatment was added. 
• 
A window of 1 day was introduced in the circumstances of weekly emapalumab 
infusions, to decrease study burden for these patients who were expected to be clinically 
stable and likely outpatients. 
• 
An iDMC was appointed in place of the safety management team to regularly assess the 
benefit/risk profile of emapalumab treatment. 
• 
The requirement to particularly monitor signs of fluid retention and purpura was lifted, as 
these pathological elements were not judged to be specifically indicative of HLH. These 
signs and symptoms were collected in accordance with general principles of AE 
recording. 
• 
To ensure correct questionnaire completion, the patient name field was removed from the 
questionnaire and replaced by patient ID. 
The country-specific Protocols V3.0 for the USA/Canada and Germany and Protocols V2.0 for 
the United Kingdom and the EU (version for Italy, Spain, and Switzerland) (all versions dated 
31 October 2019) introduced the following changes: 
• 
The Sponsor name was changed from NovImmune to Swedish Orphan Biovitrum AG. 
An Administrative Letter (dated 29 January 2019) provided the following clarification for the 
USA sites: 
Following the approval of emapalumab in the USA and its commercialization as Gamifant® for 
the “treatment of adult and pediatric (newborn and older) patients with primary HLH with 
refractory, recurrent or progressive disease or intolerance with conventional HLH therapy”, the 
enrollment in USA was limited to those patients who were naïve to conventional HLH therapy. 
Page 3 of 98


The global Protocol V4.0 (dated 31 March 2020) introduced the following changes: 
•
The study contact list was updated.
•
Some clinical and laboratory parameters were defined broader in accordance with the
observed median age at presentation and standard laboratory practices for routine tests.
•
Suggestions from FDA for special circumstances in vital signs monitoring were
implemented, blood pressure monitoring was homogenized across the countries using a
conservative approach, and clinically appropriate windows were applied to the vital sign
monitoring timepoints.
•
Further changes were introduced to minimize the study burden on these severely ill and
young patients and to simplify study conduct from logistical standpoint while still
collecting sufficient data.
•
Based on accumulated data, infection search was adapted to be more flexible and
considerate of an individual patient while still being rigorous.
•
To make the Schedule of Assessments a more complete tool for sites’ convenience, a
reminder about AE collection timelines was inserted, and an IRR was defined in the
footnote. Definition of IRRs that required increased monitoring during subsequent
infusions was expanded to include relatedness to ensure meaningful and risk-based
monitoring.
•
Additional measurements of height/length were introduced to accommodate calculation
of creatinine clearance throughout the study duration.
•
The approval of emapalumab in the USA was reflected, and updated information on other
HLH treatment modalities and latest data accumulated in emapalumab development
program were added.
•
A provision for retreatment of patients who experience HLH reactivation in the follow-up
period was made.
•
The 2-year and 3-year survival data collection timepoints were removed from the body of
the protocol, with the intention to collect those data in a separate study to provide a
comprehensive long-term follow-up across the emapalumab development program. As
per the note to file (dated 23 February 2023) to protocol version 4.0, an inconsistency
within the protocol was addressed, as removal of collection of survival data at the 2-year
and 3-year timepoints had been omitted in the synopsis. It was clarified that survival data
collection would only be performed at 1 year after either HSCT or the last emapalumab
infusion (as applicable).
•
A separate section was added to list study committees to improve readability and easier
search for this information.
•
Clarifications on testing methods used for diagnosis of pHLH and assessment of
eligibility criteria were made to reflect current global practices: NK-cell degranulation
test was emerged as a more readily available alternative to NK-cell activity testing, and
reference to sites’ laboratories units for sCD25 was made.
Page 4 of 98


• 
The wording on sexual abstinence was expanded based on suggestions from the British 
authority. 
• 
Simulations were updated to present the “worst-case” scenario in the dose escalation 
schema, based on the updated, larger dataset accumulated in the emapalumab 
development program. 
• 
The considerations that could prompt the Investigator to increase the emapalumab dose 
were further clarified. Also, additional instructions were included for lowering the dose 
of emapalumab to provide complete guidance to the Investigator. 
• 
Language on the drug accountability was amended to include the reference to IRT. 
• 
It was clarified that biologic drugs were not allowed for indications other than additional 
HLH treatments. 
• 
Janus kinase inhibitors were added to the list of not allowed concomitant therapies due to 
their mechanism of action, possibly interfering with emapalumab efficacy and safety 
assessment. 
• 
More explicit guidance was provided to the Investigator on introduction of additional 
HLH treatments in the beginning of the study. Also, “unsatisfactory HLH improvement” 
was replaced with “unsatisfactory HLH control”, a definition that better reflects the 
clinical conditions in which the Investigator could require additional HLH treatments. 
• 
A window of 1 day was added to allow for more flexible scheduling of emapalumab 
infusions in the circumstances of weekly administration. 
• 
The screening process was further detailed in the protocol. It was clarified that standard 
of care procedures performed before consent were accepted for screening. 
Two documents were made available and appended to the protocol in order to facilitate 
expeditious assessment of the patients (eligibility review form and pre-screening 
checklist). 
• 
Blood sampling assessment was expanded in accordance with a German authority 
request. 
• 
It was explicitly stated that race, ethnicity, and country of origin were only to be collected 
if allowed per local regulations. 
• 
The safety monitoring section language was amended for clarity and to avoid any 
ambiguity. 
• 
Specific references to signs of fluid retention and purpura were removed (since these data 
were already collected in physical examination). 
• 
The risks and benefits considerations were updated with the latest available information, 
and the current IB version was referenced. References to the development risk 
management plan are removed. 
• 
A minor rewording was performed in the stopping rules section to clarify the role of 
Sponsor in the process. 
• 
A maximum number of dropouts was specified considering the ongoing pandemic. 
Page 5 of 98


• 
Regarding the disclosure of protocol and study results and publication policy, references 
to the Coordinating Investigator were removed. No Coordinating Investigator was 
appointed on the study-wide level. 
• 
A serious GCP breach definition was provided for clarity, and the terminology was 
updated from violation to deviation. 
• 
The PedsQL questionnaires were added to Appendix A. 
An Addendum, V4.0 – V1.0 for Sweden, dated 26 August 2020, was generated to introduce 
measures to ensure patient safety and counteract potential study conduct disruption during a 
COVID-19 outbreak. 
 
Page 6 of 98


Study Nl-0501-09 
Nl-0501 in Primary HLH 
Page 1 of 92 
SObl 
Clinical Study Protocol 
An Open-label, Single Arm, Multicenter Study to Broaden Access to Emapalumab, an Anti-
Interferon Gamma (Anti-lFNy) Monoclonal Antibody, and to Assess its Efficacy, Safety, Impact on 
Quality of Life, and Long-term Outoome in Pediatric Patients with Primary Hemophagocytic 
Lymphohistiocytosis 
Study Number: 
Protocol Number: 
Version: 
Date: 
P-IND Number: 
EudraCT 
Sponsor: 
Clinical Scientist 
Nl-0501-09 
Nl-0501-09 
4.0 Global 
31 March 2020 
111015 
2017-003114-10 
Swedish Orphan Biovitrum AG 
Corporate address: 
12 Chemin des Aulx 
1228 Plan-les-Ouates 
Switzerland 
Address for all study-related correspondence: 
10 Messeplatz 
4058 Basel 
Switzerland 
This document is a confidential communication of Swedish Orphan Biovitrum AG. Acceptance of th is document constitutes the agreement by 
the recipient that no unpublished information contained within will be published or disclosed without prior written approval, except as 
required to permit review by responsible Institutional Review Board/Independent Ethics Committee and Health Authorities or to obtain 
informed consent from potential patients. 
Protocol Nl-0501-09 
Version 4.0 Global - 31 March 2020 
CONFIDENTIAL 
Page 7 of 98


Study NI-0501-09 
NI-0501 in Primary HLH 
Page 2 of 92 
Protocol NI-0501-09  
 Version 4.0 Global – 31 March 2020 
 CONFIDENTIAL 
INVESTIGATOR AGREEMENT 
Protocol Number: NI-0501-09 
Protocol Date and Version: 31 March 2020 – Version 4.0 Global 
Study Drug:  Emapalumab 
Study Title: An Open-label, Single Arm, Multicenter Study to Broaden Access to Emapalumab, an Anti-
Interferon Gamma (Anti-IFNγ) Monoclonal Antibody, and to Assess its Efficacy, Safety, Impact on Quality 
of Life, and Long-term Outcome in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis. 
Investigator Endorsement: 
I, the undersigned, am responsible for the conduct of this study at this site and agree to conduct the study 
according to the protocol and any approved protocol amendments, ICH GCP and all applicable regulatory 
authority requirements. 
I will not deviate from the protocol without prior permission from Swedish Orphan Biovitrum 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 Brochure for emapalumab and I am familiar with the 
investigational product and its use according to this protocol. 
_______________________________________ 
____________________ 
Site Investigator’s Signature 
Date 
_______________________________________ 
Site Investigator’s Name 
Page 8 of 98


Study NI-0501-09 
NI-0501 in Primary HLH 
Page 3 of 92 
Protocol NI-0501-09  
 Version 4.0 Global – 31 March 2020 
 CONFIDENTIAL 
CONTACT LIST 
Study Location: 
Sponsor: 
Chief Medical Officer, Swedish 
Orphan Biovitrum 
Immunology: 
Clinical Scientist: 
Drug Safety Physician: 
Clinical Operations Manager: 
Clinical Pharmacologist: 
Data Protection Officer: 
Multicenter 
Swedish Orphan Biovitrum AG 
Corporate address:  
12 Chemin des Aulx 
1228 Plan les Ouates 
Switzerland 
Phone: +41 22 839 71 41 
Fax: +41 22 839 71 42 
Address for all study-related correspondence: 
10 Messeplatz 
4058 Basel 
Switzerland 
Phone: 
Mobile phone: 
Email: 
Phone: 
Mobile phone: 
Email: 
Phone: 
Mobile phone: 
Email: 
Phone : 
Mobile phone: 
Email: 
Phone: 
Email: 
DataPrivacy@sobi.com 
Medical Monitors: 
Email: medmonitor.NI-0501-09@premier-research.com 
Phone numbers (24/7): 
 Europe: +44 118 936 4096 
 US: +1 512 686 1256 
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Study NI-0501-09 
 NI-0501 in Primary HLH 
Page 4 of 92 
 
Protocol NI-0501-09                           Version 4.0 Global – 31 March 2020  
 CONFIDENTIAL 
NI-0501-09 SYNOPSIS 
Title: 
An Open-label, Single Arm, Multicenter Study to Broaden Access to 
Emapalumab, an Anti-Interferon Gamma (Anti-IFNγ) Monoclonal 
Antibody, and to Assess its Efficacy, Safety, Impact on Quality of Life, 
and Long-term Outcome in Pediatric Patients with Primary 
Hemophagocytic Lymphohistiocytosis  
Sponsor: 
Swedish Orphan Biovitrum AG, Switzerland 
Study Type and Design: 
Study NI-0501-09 is an open-label, single arm, multicenter, 
interventional study performed both in North America and in Europe. 
The study is open to enrolment to pediatric patients with confirmed or 
suspected primary HLH (pHLH) who are either treatment-naïve, or 
failed conventional HLH therapy or showed intolerance to it.  
The study is divided into three parts: screening, treatment period, and 
follow-up.  
Patients will be in the treating unit the day before the first 
administration of emapalumab (Study Day minus one, SD-1). 
Study Objectives: 
‐ 
To gather additional safety and efficacy data on emapalumab 
in pHLH patients  
‐ 
To assess a starting dose of emapalumab of 3 mg/kg 
‐ 
To assess the impact of emapalumab on Quality of Life (QOL) 
‐ 
To gather additional evidence on the long-term outcome of 
pHLH patients treated with emapalumab 
‐ 
To further evaluate the pharmacokinetics (PK) profile of 
emapalumab in pHLH patients  
‐ 
To further evaluate the pharmacodynamic (PD) effects (levels of 
circulating total Interferon Gamma (IFNγ) and biomarkers of its 
neutralization, namely CXCL9 and CXCL10) 
‐ 
To assess the profile of other relevant HLH biomarkers, e.g., 
sCD25 and other exploratory biomarkers 
‐ 
To monitor for potential occurrence of anti-drug antibodies 
(ADAs). 
Study Population: 
Male and female pHLH patients, from birth up to and including 18 years 
at diagnosis of HLH. 
Patients can be naïve to HLH treatment or may have received 
conventional HLH therapy without having obtained a satisfactory 
response according to the treating physician,  or having shown signs of 
intolerance to previous HLH therapy. 
Inclusion Criteria: 
 
1. Of note, the enrolment of patients will continue until emapalumab 
is commercially available for a given indication, or until sample size 
is reached, whichever comes first; thus, US enrolment will be 
limited to treatment-naïve patients.Male and female pHLH 
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Study NI-0501-09 
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Protocol NI-0501-09                           Version 4.0 Global – 31 March 2020  
 CONFIDENTIAL 
 
 
 
 
 
 
patients, from birth up to and including 18 years at diagnosis of 
HLH.  
2. A molecular diagnosis or familial history consistent with pHLH or 
fulfilment of HLH-2004 diagnostic 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 (≤1.5 g/L) 
- Hemophagocytosis in bone marrow, spleen or lymph nodes, 
with no evidence of malignancy 
- Low or absent natural killer (NK)-cell activity 
- Ferritin ≥500 µg/L 
- Soluble 
CD25 (sCD25, 
i.e., 
soluble 
IL-2 
receptor) 
≥2400 U/mL 
3. Presence of active HLH disease as assessed by the treating 
physician.  
4. Patients having already received conventional HLH therapy must 
fulfil one of the following criteria as assessed by the treating 
physician:  
- 
Having not responded 
- 
Having not achieved a satisfactory response or 
worsened  
- 
Having reactivated 
- 
Showing 
intolerance 
to 
previous 
conventional 
treatment of HLH. 
At the time of enrolment, eligible patients might still be receiving 
treatment (induction or maintenance) or might have already 
discontinued it. 
5. Informed consent signed by the patient (as required by local law), 
or by the patient’s legally authorized representative(s) with the 
assent of patients who are legally capable of providing it, as 
applicable. 
6. Having received guidance on contraception for both male and 
female patients sexually active and having reached puberty. 
Females of child-bearing potential require use of highly effective 
contraceptive measures (failure rate of less than 1% per year) from 
Screening until 6 months after receiving last dose of the study drug. 
Highly effective contraceptive measures include: 
o Sexual abstinence 
o Hormonal contraceptives: combination or progesterone 
only 
o Intrauterine methods: intrauterine devices or systems 
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Protocol NI-0501-09                           Version 4.0 Global – 31 March 2020  
 CONFIDENTIAL 
o Bilateral tubal occlusion 
o Vasectomised partner. 
Males with partner(s) of child-bearing potential must agree to take 
appropriate precautions (such as sexual abstinence, barrier 
contraception, vasectomy) to avoid fathering a child from 
Screening until 6 months after receiving last dose of study drug. 
Exclusion Criteria: 
 
1. 
Diagnosis of secondary HLH consequent to a proven rheumatic, 
metabolic or neoplastic disease. 
2. 
Active 
mycobacteria, 
Histoplasma 
capsulatum, 
Shigella, 
Salmonella, Campylobacter or Leishmania infections.  
3. 
Evidence of latent tuberculosis. 
4. 
Presence of malignancy. 
5. 
Patients who have another concomitant disease or malformation 
severely affecting cardiovascular, pulmonary, central nervous 
system (CNS), liver, or renal function that in the opinion of the 
Investigator may significantly affect the likelihood to respond to 
treatment and/or the assessment of emapalumab safety and/or 
efficacy. 
6. 
History of hypersensitivity or allergy to any component of the 
study regimen (e.g., polysorbate). 
7. 
Receipt of a bacille Calmette-Guerin (BCG) vaccine within 12 
weeks prior to Screening. 
8. 
Receipt of a live or attenuated live (other than BCG) vaccine within 
6 weeks prior to Screening. 
9. 
Pregnant or lactating female patients. 
Study Drug: 
 
Emapalumab (previously referred to as NI-0501) is a fully human high 
affinity anti-IFNγ monoclonal antibody that binds to and neutralizes 
human IFNγ. 
Dosing Regimen & Frequency 
of Administration: 
 
Emapalumab will be administered by IV infusion over a period of 1 to 2 
hours depending on the volume to infuse, at a dose of 3 mg/kg.  
Infusions will be performed twice weekly (not more than 4 days apart), 
except for the second infusion which must be administered on Study 
Day 3 (SD3). 
The 3 mg/kg dose will be maintained 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 (see parameters to be 
satisfied for dose increase in Section 5.3).  
The dose of emapalumab may be further increased to 10 mg/kg per 
Investigator’s decision based on the patient’s clinical and laboratory 
response (as per Section 5.3). 
Upon achievement of Complete Response (i.e., normalization of all 
clinical and laboratory HLH parameters), the dose of emapalumab 
should be lowered to achieve 1 mg/kg twice a week and maintained 
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Protocol NI-0501-09                           Version 4.0 Global – 31 March 2020  
 CONFIDENTIAL 
until conditioning for transplant, as long as the patient’s clinical 
conditions are satisfactory. Decrease of emapalumab dose will occur in 
a stepwise fashion (e.g. if patient was on 6 mg/kg, emapalumab will be 
administered in 3 mg/kg for at least one infusion before achieving 1 
mg/kg). 
Given the unpredictable course of the disease, in case of reactivation 
(e.g. triggered by intercurrent infections), subsequent dose increases 
to 3 mg/kg (and up to 6 or 10 mg/kg, as appropriate) may need to be 
considered and will be guided by the same clinical and laboratory 
parameters described in Section 5.3. 
Upon regaining a Complete Response, the dose of emapalumab will be 
lowered again to achieve 1 mg/kg twice a week. 
Should hematopoietic stem cell transplantation (HSCT) be scheduled 
beyond 12 weeks from emapalumab initiation for reasons unrelated to 
the administration of emapalumab (e.g., lack of donor availability) and 
provided Complete Response is maintained, the treatment  with 
emapalumab may continue at the dose of 1 mg/kg once a week. 
Treatment Duration: 
The duration of treatment is foreseen until the start of conditioning for 
HSCT, but must not exceed 6 months.  
The minimum treatment duration is 4 weeks, if the patient’s condition 
and donor availability allow the performance of HSCT.  
No wash-out period is required between the last administration of 
emapalumab and the start of conditioning. 
After treatment completion or treatment discontinuation (for any 
reason), patients will continue in the study for long-term follow-up until 
1 year after either HSCT or last emapalumab infusion (in case HSCT is 
not performed). This will represent the last visit in the study. 
A patient who experiences HLH reactivation during the follow-up 
period, may be re-treated with emapalumab upon discussion with 
Sponsor. Re-treated patients will follow the same schedule of 
assessments as applicable during initial treatment (i.e., starting from 
Visit 1), and will enter the follow-up period after completion of re-
treatment. 
Attempts to gather additional information on survival only will be made 
at 2 and 3 years after either HSCT or last emapalumab infusion (as 
applicable) to extend the assessment of long-term survival. 
Background Therapy & 
Concomitant Medication: 
Emapalumab will be administered initially on a background of 
dexamethasone. Patients are required to receive dexamethasone from 
not later than SD-1. 
In treatment-naïve patients, an initial background therapy of 10 mg/m2 
dexamethasone will be required. 
In patients who failed previous HLH therapy, dexamethasone is to be 
administered at a dose of at least 5 mg/m2 or at the dose administered 
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Protocol NI-0501-09  
 Version 4.0 Global – 31 March 2020 
 CONFIDENTIAL 
prior to Screening if higher. Lower dexamethasone doses at study entry 
are allowed in case of documented intolerance to glucocorticoids.  
During the study, dexamethasone can be tapered depending on the 
patient’s condition, according to the judgment of the treating 
physician. 
Prophylaxis for Herpes Zoster virus infection has to be in place from the 
day before initiation of emapalumab treatment until serum levels of 
emapalumab are no longer detectable. 
Patients will receive any required prophylactic antimicrobial 
treatments according to local recommendations for the management 
of pHLH. 
Cyclosporin A (CsA) can be continued if already being administered to 
the patient prior to Screening. CsA can be withdrawn at any time, upon 
judgment of the Investigator. CsA is not to be introduced (or re-
introduced) during the course of the study once emapalumab 
administration has started. 
If the patient is receiving intrathecal (IT) therapy (e.g., methotrexate 
and glucocorticoids) at the time of emapalumab treatment initiation, 
this therapy will be continued until clinically indicated. The introduction 
of IT therapy during emapalumab treatment is allowed should CNS 
signs and symptoms occur. 
IV immunoglobulins are only allowed as replacement treatment. 
Analgesic treatment, transfusion of blood products, electrolyte and 
glucose infusions, IV parenteral nutrition, inotropic support, antibiotics, 
anti-fungal and anti-viral treatment, hemofiltration or hemodialysis, as 
well as general supportive care are allowed. Vaccination with a live or 
attenuated (including BCG) vaccine must be avoided until serum levels 
of emapalumab are no longer detectable. 
The administration of additional HLH treatments will be allowed in  a 
patient in whom an HLH worsening or no initial response has been 
observed after an increase of emapalumab dose to 6 mg/kg on SD3, as 
well as later during the course of emapalumab treatment in case of 
unsatisfactory HLH control, provided that emapalumab has been 
administered at a dose of 6 mg/kg (or 10 mg/kg, if the Investigator 
decided to do so) for at least 2 infusions. 
Unsatisfactory HLH control is defined as follows: 
‐ patients who have not achieved or maintained a disease control 
and general conditions that would allow to proceed to transplant 
‐ patients who present a clinically relevant HLH worsening. 
If an additional HLH treatment is needed, etoposide is the drug of 
choice, unless there is evidence indicating that an alternative agent 
should be selected.  
 Sample Size: 
The sample size calculation is based on the primary efficacy endpoint 
of `Overall Response`. Assuming an Overall Response Rate of 65%, a 
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Protocol NI-0501-09                           Version 4.0 Global – 31 March 2020  
 CONFIDENTIAL 
minimum of 34 patients is required to show a significant improvement 
above 40% with 85% power using an exact binomial test at a one-sided 
significance level of 2.5%. A drop-out rate of 20% may be expected, 
hence a total maximum of 41 patients may be enrolled. 
 
Number of Sites: 
It is estimated that approximately 13 sites in North America and 
approximately 15 sites in Europe will participate in this study.  
Study Duration and Study 
End Definition: 
After treatment completion or treatment discontinuation (for any 
reason), patients will continue in the study for a long-term follow-up. 
End of the study is defined as last patient last visit at 1 year after either 
HSCT or last emapalumab infusion (as applicable). Survival data 
obtained at 2 year and 3 year follow-up will be analyzed separately. 
Study Surveillance, Safety 
Reporting and Stopping 
Rules: 
Infusions should be performed under medical supervision and 
monitored as per local standard of care based on patient’s conditions, 
with a minimum requirement of monitoring blood pressure, body 
temperature, heart rate and oxygen saturation during the 
administration of emapalumab, and up to 2 hours after the end of the 
infusion. 
Adverse events (AEs) will be recorded from the date of the informed 
consent form (ICF) signature until serum levels of emapalumab are no 
longer detectable, except for the following:  
- Common HLH signs and symptoms (e.g. anemia, neutropenia, 
thrombocytopenia, hepatosplenomegaly) will not be reported as 
separate events unless clearly attributed to a cause different from 
HLH; however, reactivation  or worsening of HLH from start of 
treatment with emapalumab will be reported as AE; 
- fever will only be reported when not linked to an identified cause 
(fever of unknown origin). If fever is considered as a sign of a 
confirmed infection or of HLH worsening or reactivation, it will not 
be reported as `fever`, but the cause will be reported as an AE; 
- viral load positivity, in particular for Epstein-Barr virus (EBV), 
cytomegalovirus (CMV) and adenovirus, and evolution will be 
collected on a dedicated electronic Case Report Form (eCRF) 
module.  
- Active infections will be reported as AEs, indicating whether 
constituting a primary infection or a reactivation (whenever 
possible). Pathogen positivity and evolution will be collected in a 
dedicated eCRF module. 
- expected effects of conditioning (i.e., pancytopenia during 
conditioning and until engraftment) will not be reported as AEs 
Any serious adverse event (SAE) that occurs during the course of the 
study, and regardless of causality to the study drug, must be notified by 
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the Investigator to Swedish Orphan Biovitrum AG, by fax or electronic 
transmission, within 24 hours of awareness, with the exception of:  
- elective hospitalizations for surgical procedures that are a result of  
patient’s pre-existing condition(s) which have not worsened during 
the study; 
- hospitalizations required for emapalumab infusion and study visits 
(including a possible hospital stay overnight, if due to logistic 
convenience); 
- hospitalizations post-HSCT lasting less than 72 hours and not leading 
to a new diagnosis, but triggered by a sign which will be reported as 
an AE. If a new diagnosis is found, it will be reported as an SAE.  
After elimination of emapalumab only SAEs will be reported. 
There are no predefined rules for permanent study drug 
discontinuation based on the current safety profile of the drug. An 
independent Data Monitoring Committee (iDMC) will be formed to 
ensure that any emergent safety concern will be timely assessed  and 
appropriate measure taken for the patients, if relevant. Moreover, 
iDMC will be specifically tasked with regular assessment of extent of 
benefit and fatal events prior to transplant in treatment-naïve 
subgroup of patients. 
A patient, his/her representative or the Investigator can decide at any 
time to prematurely discontinue treatment or to withdraw a patient 
from the study. This decision will have no impact on the patient’s care. 
A patient who prematurely discontinues treatment will receive 
alternative HLH therapy, according to the standard of care at the site. 
Efficacy Endpoints: 
Primary efficacy endpoint: 
• Overall Response, i.e., achievement of either Complete or Partial 
Response or HLH Improvement, at End of Treatment (EOT) or Week 
8 (whichever occurs earlier).  
Secondary efficacy endpoints: 
• Overall Survival, including survival to HSCT and survival after either 
HSCT or last emapalumab infusion (if HSCT is not performed) 
• Event-free Survival  
• Overall Response, i.e., achievement of either Complete or Partial 
Response or HLH Improvement, at start of conditioning (or at last 
emapalumab infusion if HSCT is not performed) 
• Duration of Response, i.e., maintenance of response achieved any 
time during the study (with censoring time at start of conditioning 
for patients with no events) 
• Time to Response at any time during the study 
• Number of patients able to reduce glucocorticoids by 50% or more 
of baseline dose during emapalumab treatment 
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• Number of patients able to proceed to HSCT, when deemed 
indicated 
• QOL indices. 
Safety Endpoints:  
 
 
• Incidence, severity, causality and outcomes of AEs (serious and non-
serious). 
• Evolutions of relevant laboratory parameters, e.g., complete blood 
cell (CBC) count, liver and renal function tests, and coagulation 
parameters. 
• Number of patients who discontinued emapalumab treatment for 
safety reasons. 
PK/PD Endpoints: 
• Serum concentrations of emapalumab to further evaluate 
emapalumab PK profile. 
• Determination of PD parameters (levels of circulating total IFNγ and 
markers of its neutralization, namely CXCL9 and CXCL10). 
• Determination of other relevant disease biomarkers, e.g., sCD25 
and other exploratory biomarkers. 
• Measurement of emapalumab concentrations and PD parameters in 
other matrices, e.g., cerebrospinal fluid (CSF), bronchoalveolar 
lavage (BAL), if clinically appropriate (exploratory). 
• Level (if any) of circulating antibodies against emapalumab (ADAs). 
Statistical Analysis: 
The primary endpoint Overall Response Rate will be evaluated using 
the exact binomial test at the one-sided 0.025 level.  
Time to Response, Duration of Response, and Survival time will be 
presented using Kaplan-Meier curves with medians calculated where 
available. Associated two-sided 95% confidence intervals will be 
calculated for the median for each of these endpoints.  
Additional endpoints based on binary outcomes including number of 
patients who reduce glucocorticoids by 50% or more and number of 
patients able to proceed to HSCT will be converted to proportions and 
associated 95% confidence intervals calculated.  
Statistical significance in terms of p-values will only be obtained for the 
primary endpoint. All other endpoints will be viewed as supportive for 
the primary endpoint and as a consequence no formal hierarchy of 
endpoints will be declared. 
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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT .................................................................................................................................. 2 
CONTACT LIST ........................................................................................................................................................ 3 
NI-0501-09 SYNOPSIS ............................................................................................................................................. 4 
LIST OF ABBREVIATIONS ...................................................................................................................................... 16 
1 
BACKGROUND INFORMATION ............................................................................................. 24 
1.1 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS ........................................................................... 24 
1.2 
EMAPALUMAB ................................................................................................................. 26 
1.2.1 
Description and Mode of Action .......................................................................................... 26 
1.2.2 
Preclinical Data .................................................................................................................... 26 
1.2.3 
Clinical Data ......................................................................................................................... 27 
2 
OBJECTIVES .......................................................................................................................... 29 
3 
STUDY DESIGN ..................................................................................................................... 29 
3.1 
OVERALL DESIGN .............................................................................................................. 29 
3.2 
SCREENING PERIOD ........................................................................................................... 30 
3.3 
TREATMENT PERIOD .......................................................................................................... 30 
3.4 
FOLLOW-UP PERIOD ......................................................................................................... 30 
3.5 
STUDY END ...................................................................................................................... 31 
3.6 
STUDY COMMITTEES .......................................................................................................... 31 
4 
TARGET POPULATION .......................................................................................................... 31 
4.1 
ELIGIBILITY CRITERIA ......................................................................................................... 31 
4.1.1 
Inclusion Criteria .................................................................................................................. 31 
4.1.2 
Exclusion Criteria .................................................................................................................. 33 
5 
INVESTIGATIONAL MEDICINAL PRODUCT ............................................................................ 33 
5.1 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT ....................................................... 33 
5.2 
RATIONALE FOR DOSING SCHEMA ....................................................................................... 34 
5.3 
DOSING SCHEMA .............................................................................................................. 38 
5.4 
INVESTIGATIONAL MEDICINAL PRODUCT HANDLING ............................................................... 39 
5.4.1 
Packaging and Labelling ...................................................................................................... 39 
5.4.2 
Investigational Medicinal Product Supply ............................................................................ 40 
5.4.3 
Investigational Medicinal Product Receipt and Storage ...................................................... 40 
5.4.4 
Investigational Medicinal Product Preparation, Administration, Accountability, and 
Destruction ........................................................................................................................... 40 
6 
PATIENT BACKGROUND TREATMENT AND CARE ................................................................. 42 
6.1 
BACKGROUND THERAPY WITH DEXAMETHASONE ................................................................... 42 
6.2 
PROPHYLACTIC TREATMENT................................................................................................ 42 
6.3 
CONCOMITANT THERAPY ................................................................................................... 42 
6.3.1 
Cyclosporin A ........................................................................................................................ 42 
6.3.2 
Intrathecal Therapy.............................................................................................................. 43 
6.3.3 
Other Concomitant Therapies .............................................................................................. 43 
6.3.4 
Not Allowed Concomitant Therapies ................................................................................... 43 
6.3.5 
Additional HLH treatments .................................................................................................. 43 
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6.4 
CONTRACEPTION .............................................................................................................. 44 
6.5 
EMERGENCY TREATMENT ................................................................................................... 44 
7 
ENDPOINTS .......................................................................................................................... 45 
7.1 
EFFICACY ENDPOINTS ........................................................................................................ 45 
7.2 
SAFETY ENDPOINTS ........................................................................................................... 46 
7.3 
PHARMACOKINETIC ENDPOINTS .......................................................................................... 46 
7.4 
PHARMACODYNAMIC ENDPOINTS ........................................................................................ 46 
8 
OUTLINE OF STUDY PROCEDURES ........................................................................................ 47 
8.1 
SCREENING ...................................................................................................................... 48 
8.2 
VISIT 1 (INFUSION 1 OF EMAPALUMAB; SD0) ....................................................................... 50 
8.3 
VISIT 2 (INFUSION 2 OF EMAPALUMAB; SD3) ....................................................................... 51 
8.4 
VISIT 3 AND ONWARDS (INFUSION 3 OF EMAPALUMAB AND ONWARDS) ................................... 52 
WEEK 8 ASSESSMENT VISIT (3 DAYS AFTER WEEK 8 INFUSION) AND ................................... 53 
8.5 
END OF TREATMENT VISIT (3 DAYS AFTER LAST EMAPALUMAB INFUSION) ........................... 53 
8.6 
FOLLOW-UP PERIOD ..................................................................................................... 54 
8.6.1 
Follow-Up Pre-HSCT: Pre-Conditioning Visit ........................................................................ 54 
8.6.2 
Follow-Up Post-HSCT (or After Last Emapalumab Infusion) ................................................ 55 
8.6.3 
End of Study: 1-Year Visit Post-HSCT (or After Last Emapalumab Infusion)/Withdrawal Visit
 ............................................................................................................................................. 56 
8.7 
ASSESSMENTS IN CASE OF UNPLANNED/UNSCHEDULED VISITS .................................. 57 
8.8 
UNPLANNED ASSESSMENTS ......................................................................................... 57 
9 
SAFETY MONITORING .......................................................................................................... 57 
9.1 
DESCRIPTION OF SAFETY PARAMETERS ................................................................................. 57 
9.2 
RECORDING AND REPORTING SAFETY PARAMETERS ................................................................ 58 
9.2.1 
Adverse Events ..................................................................................................................... 58 
9.2.2 
Serious Adverse Events ........................................................................................................ 59 
9.2.3 
SUSAR reporting ................................................................................................................... 60 
9.2.4 
Managing Abnormal Laboratory Test Values ...................................................................... 61 
9.3 
FOLLOW-UP OF SAFETY PARAMETERS .................................................................................. 61 
9.3.1 
Follow-up of Adverse Events ................................................................................................ 61 
9.3.2 
Follow-up of Abnormal Laboratory Test Values .................................................................. 61 
9.3.3 
Pregnancy ............................................................................................................................ 61 
9.4 
BENEFIT/RISK MANAGEMENT ............................................................................................. 62 
9.4.1 
Safety Surveillance Management ........................................................................................ 62 
9.4.2 
General Benefit/Risk Considerations ................................................................................... 62 
10 
STOPPING RULES ................................................................................................................. 65 
10.1 
AT PATIENT LEVEL ............................................................................................................ 65 
10.1.1 
Decision to Slow Down or Stop Emapalumab Infusion due to Systemic Reaction ............... 65 
10.1.2 
Local Issues During Emapalumab Infusion .......................................................................... 65 
10.1.3 
Decision to Discontinue Treatment or to Withdraw from the Study ................................... 65 
10.2 
AT STUDY LEVEL ............................................................................................................... 66 
10.3 
MANAGEMENT OF TREATMENT DISCONTINUATION ................................................................ 66 
11 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN ...................................................... 66 
11.1 
SAMPLE SIZE .................................................................................................................... 66 
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11.2 
ANALYSIS SETS ................................................................................................................. 67 
11.2.1 
All Treated Analysis Set ........................................................................................................ 67 
11.2.2 
Evaluable Analysis Set .......................................................................................................... 67 
11.2.3 
Enrolled Population Analysis Set .......................................................................................... 67 
11.3 
STATISTICAL AND ANALYTICAL METHODS .............................................................................. 67 
11.3.1 
Efficacy Data ........................................................................................................................ 67 
11.3.2 
Safety Data .......................................................................................................................... 68 
11.3.3 
Pharmacodynamic Data ...................................................................................................... 68 
11.3.4 
Immunogenicity Data .......................................................................................................... 68 
11.3.5 
Missing Data ........................................................................................................................ 68 
11.4 
REPLACEMENT POLICY ....................................................................................................... 68 
11.4.1 
For Patients .......................................................................................................................... 68 
11.4.2 
For Centers ........................................................................................................................... 68 
12 
ETHICAL AND LEGAL ASPECTS .............................................................................................. 69 
12.1 
GOOD CLINICAL PRACTICE .................................................................................................. 69 
12.2 
INVESTIGATOR RESPONSIBILITIES ..................................................................................... 69 
12.3 
CONSENT ........................................................................................................................ 69 
12.4 
CONFIDENTIALITY AND DATA PRIVACY .................................................................................. 70 
12.5 
PROTOCOL AMENDMENTS ................................................................................................. 70 
12.6 
APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS .......................................... 70 
12.7 
ONGOING INFORMATION FOR IRB/IEC/REB ........................................................................ 71 
12.8 
CLOSURE OF THE STUDY ..................................................................................................... 71 
12.9 
RECORD RETENTION .......................................................................................................... 72 
12.10 
LIABILITY AND INSURANCE .................................................................................................. 72 
12.11 
FINANCIAL DISCLOSURE ..................................................................................................... 72 
12.12 
DISCLOSURE OF PROTOCOL AND STUDY RESULTS AND PUBLICATION POLICY ............................... 72 
13 
MONITORING AND AUDITING ............................................................................................. 73 
13.1 
STUDY MONITORING AND SOURCE DATA VERIFICATION .......................................................... 73 
13.2 
ON-SITE AUDITS ............................................................................................................... 73 
13.3 
SERIOUS GCP BREACHES ................................................................................................... 74 
14 
DOCUMENTATION AND USE OF STUDY FINDINGS ............................................................... 74 
14.1 
DOCUMENTATION OF STUDY RESULTS .................................................................................. 74 
14.2 
USE OF COMPUTERIZED SYSTEMS AT THE CLINICAL TRIAL CENTRE ............................................ 74 
15 
REFERENCES ........................................................................................................................ 76 
APPENDICES ......................................................................................................................................................... 78 
 
TABLE OF TABLES 
Table 1: Schedule of Assessments – Screening and Treatment Period ...................................................... 19 
Table 2: Schedule of Assessments - Follow-up Period ................................................................................ 22 
Table 3: Clinical and Laboratory Criteria to Guide Dose Increase .............................................................. 39 
Table 4: Definition of Response .................................................................................................................. 45 
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TABLE OF FIGURES 
Figure 1: NI-0501-09 Study Design ............................................................................................................. 30 
Figure 2: Total IFNγ Concentrations up to the Last Dose or HSCT 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 3 mg/kg (Maintained TWICE A 
WEEK During the Treatment Course) ....................................................................................... 36 
Figure 4: Emapalumab and CXCL9 Concentrations at the Initial Dose of 3 mg/kg, Increased to 6 mg/kg 
ON DAY 6 and Maintained TWICE A WEEK During the Treatment Course .............................. 37 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ADA 
Anti-drug antibodies 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse event 
ALC 
Absolute lymphocyte count 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATG 
Anti-thymocyte globulin 
BAL 
Bronchoalveolar lavage  
BCG 
Bacillus Calmette-Guérin 
BLA 
Biologics license application 
CBC 
Complete blood cell (count) 
CDC 
Complement dependent cytotoxicity 
CFR 
Code of Federal Regulation 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CRA 
Clinical Research Associate 
CRF 
Case report form 
CRP 
C-reactive protein
CRO 
Contract Research Organization 
CsA 
Cyclosporin A 
CSF 
Cerebrospinal fluid 
CT 
Computerized tomography 
CU 
Compassionate use 
CYP 
Cytochrome P450 enzyme 
eCRF 
Electronic case report form 
EBV 
Epstein-Barr virus 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
EOT 
End of treatment 
FDA 
Food and Drug Administration 
γGT 
Gamma glutamyl transferase 
G-CSF
Granulocyte-colony-stimulating factor 
HGB 
Hemoglobin 
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HLH 
Hemophagocytic lymphohistiocytosis 
HSCT 
Hematopoietic stem cell transplantation 
HZ[V] 
Herpes zoster [virus] 
HZV 
Herpes zoster virus 
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 
IGRA 
Interferon gamma release assays 
IL 
Interleukin 
IMP 
Investigational medicinal product 
IND 
Investigational New Drug 
Inf 
Infusion 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
IRT 
Interactive response technology 
IT 
Intrathecal 
IV 
Intravenous 
IVIG 
IV immunoglobulin 
JAK 
Janus kinase 
LCMV 
Lymphocytic choriomeningitis virus 
LDH 
Lactate dehydrogenase 
LPLV 
Last patient last visit 
LUC 
Large unstained cells 
MAA 
Market authorization application 
MAS 
Macrophage activating syndrome 
MRI 
Magnetic resonance imaging 
NA 
North America 
NEU 
Neutrophils 
NaCl 
Sodium chloride 
NK 
Natural killer 
ORR 
Overall response rate 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
pHLH 
Primary hemophagocytic lymphohistiocytosis 
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PLT 
Platelets 
PK 
Pharmacokinetic 
PPD 
Purified protein derivative 
PT 
Prothrombin time 
QOL 
Quality of life 
REB 
Research ethics boards 
ROC 
Receiver operating characteristic 
RSI 
Reference safety information 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
sCD25 
Soluble CD25 (i.e., soluble IL-2 receptor) 
SD 
Study day 
SD(n) 
Study day number (e.g., Study day 1 = SD1) 
sHLH 
Secondary hemophagocytic lymphohistiocytosis 
sJIA 
Systemic juvenile idiopathic arthritis 
SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Tuberculosis 
TEAE 
treatment-emergent adverse event 
TG 
Triglycerides 
TLR9 
Toll-like receptor-9 
TMF 
Trial master file 
TP-DI 
Therapeutic protein-drug interactions 
US 
Ultrasound 
USA 
United States of America 
Wk 
Week 
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Table 1: Schedule of Assessments – Screening and Treatment Period 
Assessments 
Screening Visit 
(up to 2 Weeks 
prior to Visit 1) 
Week 1 
Week 2  
Week 8 
Assessment Visit 
b
EOT (3±1 days 
after last inf.) 
UV c 
Visit 1 / SD0 
Visit 2 / SD3  
Visit 3 onwards  
Visit X a 
Visit X b 
Dexamethasone d 
X 
Anti-viral Prophylaxis d 
X 
Informed Consent/Assent  
X 
Infusion e 
X 
X 
X 
X 
Patient Information f 
X 
Clinical 
Assessments  
Vital Signs g 
X 
X (Pre/post-inf.) 
X (Pre/post-inf.) 
X (Pre/post-inf.) 
X (Pre/post-inf.) 
X  
Physical Examination h 
X 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X  
QOL - PedsQL™, Pediatric Quality of Life Inventory™ 
X 
X o  
X 
X 
QOL – BASES p 
X 
Procedure 
ECG 
X 
X  
Search for 
Infections 
TB i 
X 
X (every 4 weeks) 
Infection search & monitoring  
X (at minimum EBV 
& CMV viral loads) 
n case of suspicion of infection or if there is an active infection at screening/baseline to monitor 
evolution of viral load and positivity for an identified pathogen 
Atypical mycobacteria, Histoplasma capsulatum, 
Shigella, Salmonella, Campylobacter, Leishmania  
X 
In case of suspicion of infection  
Laboratory 
CBC t 
X 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X  (Pre-inf.) 
X 
Coagulation t 
X 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X  (Pre-inf.) 
X 
Biochemistry t 
X 
X (Pre-inf.) 
X (Pre-inf.) 
X (Pre-inf.) 
X  (Pre-inf.) 
X 
Pregnancy Test (if applicable)  
X 
X 
Urinalysis j  
X 
X 
Imaging 
Abdominal Ultrasound k,t 
X 
X  (every 2 weeks) 
X 
X 
Chest X-ray u,t 
X 
If clinically indicated (e.g. in case of clinical suspicion of pulmonary infection or to follow-up a pre-
existing infection at screening/baseline) 
Brain MRI l,t 
X l 
If clinically indicated (to monitor evolution or to confirm occurrence of new CNS symptoms) 
Histopathology 
CSF Analysis (if coagulation allows) m 
X 
If clinically indicated (to monitor evolution of CSF abnormalities or in case of occurrence of new CNS 
symptoms) 
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Assessments 
Screening Visit 
(up to 2 Weeks 
prior to Visit 1) 
Week 1 
Week 2  
Week 8 
Assessment Visit 
b
EOT (3±1 days 
after last inf.) 
UV c 
Visit 1 / SD0 
Visit 2 / SD3  
Visit 3 onwards  
Visit X a 
Visit X b 
Assessment of clinical response 
X (every 2 weeks) 
X 
X 
AE Recordings 
X 
X 
X 
X 
X 
X 
IMP Handling (Preparation, Dispensing, Accountability)  
X 
X 
X 
X 
PK (Emapalumab Concentration)  
X (Pre - post inf.)  
X (Pre - post inf.)  
X (Pre - post inf.) n 
X (Pre - post inf.) 
X 
PD (CXCL9, CXCL10, sCD25), total IFNγ, and other exploratory 
biomarkers 
X (Pre - inf)  
X (Pre-inf.) 
X (Pre-inf.) n 
X (Pre-inf.) 
X 
Immunogenicity (ADAs) 
X 
Xq 
 X 
 X 
Abbreviations: ADAs, 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; EBV, Epstein-Barr virus; ECG, electrocardiogram; EOT, end of treatment; γGT, gamma glutamyl transferase; 
HLH, hemophagocytic lymphohistiocytosis; HSCT, hematopoietic stem cell transplantation; ICF, informed consent form; IGRA, interferon-gamma release assays; IFNγ, interferon gamma; IMP, investigational medicinal 
product; inf, infusion; INR, International normalized ratio; IRR, infusion related reaction; LDH, lactate dehydrogenase; LUC, large unstained cells; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; 
PD, pharmacodynamic; PK, pharmacokinetic; PPD, purified protein derivative; PT, prothrombin time; QOL, quality of life; SD, study day; TB, tuberculosis; US, ultrasound 
CBC: complete blood count (white blood cells and differential, red blood cells , hemoglobin, hematocrit, platelets, LUC (if performed as routine). Coagulation: aPTT (time and/or ratio), PT and/or INR, d-Dimers, 
fibrinogen. Biochemistry: glucose, CRP, ferritin, triglycerides, liver (AST, ALT, γGT, LDH, ALP, bilirubin) and renal function (albumin, creatinine and urea) 
a Visit X: sequential visit number to be attributed 
b Week 8 Assessment Visit: indicates a full patient assessment performed 3 days after the last emapalumab infusion performed during week 8.  If emapalumab treatment continues and the visit is performed on the 
same day of next infusion, all indicated assessments are to be performed pre- or post- infusion, as appropriate. If treatment with emapalumab is completed before Week 8, only an EOT visit will be performed 3 (1) 
days after the last infusion. EOT: indicates a full patient assessment performed 3 days after last emapalumab infusion 
c UV: assessments to be performed as clinically indicated 
d Dexamethasone and anti-viralprophylaxis: starting from SD-1 (at latest). A prophylaxis for herpes zoster virus infection has to be in place from the day before initiation of emapalumab treatment until serum levels 
of emapalumab are no longer detectable. Patients will receive any required prophylactic antimicrobial treatment according to local recommendations in pHLH 
e Infusion: to be performed over a period of 1 to 2 hours, twice weekly, not more than 4 days apart, except for the second infusion which must be administered on SD3 
f Patient Information:  Includes demographic and medical history, medications at Screening, HLH induction treatment received when applicable, date of HLH diagnosis, molecular diagnosis and relevant functional 
tests performed for the diagnosis of HLH if available, date and assessment of eligibility criteria 
g Vital Signs: include body temperature, heart rate, blood pressure, oxygen saturation. Temperature is to be measured pre-infusion, at the end of the infusion, 1 hour and 2 hours after the end of each infusion. For 
the first infusion for each patient (SD0), for the first infusion at an increased dose and/or for any infusions in a patient who has experienced an IRR (defined as signs or symptoms with a temporal relationship to the 
administration of an infusion and assessed as related, occurring typically soon following the start of the infusion, although symptoms may be delayed for up to 24h; they might be limited (skin reaction), or systemic), 
blood pressure, heart rate and oxygen saturation are to be collected every 15 minutes during and until the end of the infusion, 1 hour and 2 hours after the end of the infusion. After the first infusion in all other cases, 
blood pressure, heart rate and oxygen saturation can be collected pre-infusion, at 30 minutes after the beginning of the infusion, at the end of the infusion, 1 hour and 2 hours after the end of the infusion 
h Physical Examination includes as a minimum: weight, height/length (at screening only), spleen and liver size (by abdominal palpation), neurological examination 
i TB: search for tuberculosis mycobacteria: at screening: IGRA/PPD and PCR; after screening by PCR. 
j Urinalysis: glucose, blood, protein and/or albumin, leukocytes, ketones, pH, gravity 
k Abdominal ultrasound: must include longitudinal measure of spleen. At SD0 only if 2 weeks elapsed between the screening visit and SD0.  
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l Brain MRI: to be performed in case of CNS disease and/or onset of neurological signs and/or symptoms. Brain CT or cranial ultrasound will be accepted as a replacement of brain MRI.
m CSF analysis: if lumbar puncture is performed at the site for monitoring/therapy of CNS disease, spare sample (if any) may be analyzed for emapalumab and biomarkers levels
n PK & PD samplings: from Visit 3 onwards, every other infusion
o QOL, PedsQL: to be performed post-infusion at Visit 3
p QOL, BASES: if HSCT is planned 
q Immunogenicity (ADAs): only at Week 4, to be collected together with a PK sample
sAE recording: all AEs are collected after signing of ICF up to Study Completion or  until serum levels of emapalumab are no longer detectable (whichever occurs first)
t CBC, coagulation, biochemistry and imaging assessments: If cannot be performed on the day of the scheduled visit,  assessments within 1 day window from scheduled visit date will be accepted.
u Chest X-ray: Chest CT will be accepted as a replacement for Chest X-ray.
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Table 2: Schedule of Assessments - Follow-up Period 
Assessments 
Follow-up pre-HSCT a 
Follow-up post-HSCT (or after last emapalumab infusion, as applicable) 
UV f 
EOT b 
Pre 
Conditioning 
visit c 
Weekly visits 
wk 1 – 2 – 3 d 
D+30 
visit d 
D+60 
visit d 
D+100 
visit d 
6 month 
visit d 
1 year 
visit d/ WD e 
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  
Post-HSCT outcome h 
X 
X 
X 
X 
X 
X  
QOL - PedsQL™, Pediatric 
Quality of Life 
Inventory™  
X 
X 
X 
X 
QOL – BASES (if HSCT 
done) 
X 
X 
X 
X 
Survival 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
CBC 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
Search for 
infections  
TBm 
X 
X 
X 
X 
X 
Infection search & 
monitoring  
In case of suspicion of infection - according to the patient’s clinical presentation 
Imaging  
Chest X ray i 
 X i 
In case of suspicion of infection 
Abdominal US j 
X 
X 
X 
AE recordingn 
X 
X 
X 
X 
X 
X 
X 
X 
PK/PD (emapalumab concentrations / 
total IFNγ and other biomarkers) 
X 
X k 
X 
X l 
X l 
X l 
X l 
Immunogenicity (ADAs) 
X  
X  
Abbreviations: ADAs, anti-drug antibodies; AE, adverse event; ALP, alkaline phosphatase; ALT, alanine transaminase, aPTT, activated partial thromboplastin time; AST, aspartate transaminase; CBC, complete 
blood count; cm, centimeter; CMV, cytomegalovirus; CRP, C-reactive protein; D, day; EBV, Epstein-Barr virus; EOT, end of treatment; γGT, gamma glutamyl transferase; HSCT, hematopoietic stem cell 
transplantation; ICF, informed consent form; IFNγ, interferon gamma; INR, International normalized ratio; LDH, lactate dehydrogenase; LUC, large unstained cells; mo, month; PD, pharmacodynamic; PK, 
pharmacokinetic; PT, prothrombin time; QOL, quality of life; SAE, serious adverse event; TB, tuberculosis; US, ultrasound; UV, unscheduled visit; WD, withdrawal visit; wk, week; yr, year 
CBC: white blood cells and differential, red blood cells, hemoglobin, hematocrit, platelets, LUC (as available). Coagulation: aPTT (time and/or ratio), PT and/or INR, d-Dimers, fibrinogen. Biochemistry: glucose, 
CRP, ferritin, triglycerides, liver (AST, ALT, γGT, LDH, ALP, bilirubin) and renal function (albumin, creatinine and urea).  Urinalysis: glucose, blood, protein and/or albumin, leukocytes, ketones, pH, gravity 
a Follow-up pre-HSCT:  if HSCT is not planned, patient will directly follow the Schedule of Assessment indicated for Follow-up after last emapalumab infusion  
b EOT: indicated as reference only, refer to Table 1  
c Pre Conditioning visit: may be combined with EOT visit (if not more than 2 days apart). The EOT schedule of assessments has to be applied 
d Allowed time-windows:  a ±2 day window is allowed until D+30 visit. A ±1 week window is allowed for D+60 and D+100 visits. A ±4 week window is allowed for 6-mo and 1-yr visits 
e WD (Withdrawal visit): assessments as indicated for last study 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), height/length (at Pre-Conditioning and 6 month visit only) and neurological examination 
h Post-HSCT outcome: applies to patients who undergo HSCT. Includes engraftment rate, donor chimerism achieved (as available), incidence of acute and chronic graft versus host disease 
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i Chest X-ray: to be performed at pre-conditioning and then only if clinically indicated. Other imaging modalities (e.g. CT) performed as part of pre-transplant work-up are also acceptable. 
j Abdominal ultrasound: must include longitudinal measure of spleen 
k PK/PD: in patients who receive HSCT, assessment of PK/PD to be also performed at D+3 after HSCT 
l PK: if serum levels of emapalumab were detectable at the previous visit; PD: if serum levels of emapalumab were detectable at the previous visit; thereafter only if clinically indicated
mTB: as clinically indicated, at minimum at D+30, D+60, D+100, 6 month and 1 year/WD visits; until serum levels of emapalumab are no longer detectable
nAE recording: all AEs are collected after signing of ICF up to Study Completion or  until serum levels of emapalumab are no longer detectable (whichever occurs first). After elimination of emapalumab only SAEs will 
be reported.
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 CONFIDENTIAL 
1 BACKGROUND INFORMATION 
1.1 
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS 
Hemophagocytic lymphohistiocytosis (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. 
HLH comprises primary (genetic/familial) and secondary forms, both clinically characterized by a 
dysregulation of the immune system leading to a profound hypercytokinemia with deleterious 
consequences on various tissues and organs (Henter 1991). 
Primary HLH (pHLH) is a heterogeneous autosomal recessive disorder. Primary HLH is mostly seen in 
infancy and early childhood with an estimated prevalence in Europe of 1/50,000 live births (Henter 1991). 
The disease is invariably fatal with a median survival of less than 2 months after onset of symptoms, if 
untreated (Janka 1983, Arico 1996).  
The impaired cytotoxic function present in HLH leads to hypercytokinemia and hemophagocytosis. These, 
in turn, cause all of the typical signs and symptoms of HLH (Dhote 2003, Risdall 1979, Risdall 1984): 
•
Prolonged fever
•
Splenomegaly
•
Cytopenia
•
Hyperferritinemia
•
Hypertriglyceridemia
•
Hypofibrinogenemia
•
Lymphohistiocytic infiltrate, bone marrow hypoplasia, meningeal infiltrate.
Secondary forms of HLH (sHLH) are reported to occur during the course of an infection, of an autoimmune 
or auto-inflammatory disease, or of a malignancy. While pHLH is a predominantly childhood disease, sHLH 
is a condition that can also be diagnosed in adults, and increased awareness indicates this may occur more 
often than recognized in the past.  
Secondary HLH presents with the same signs and symptoms of primary forms and can be equally severe. 
Of note, the presence of certain infections, in particular viral infections such as those due to 
cytomegalovirus (CMV) or Epstein-Barr virus (EBV), is very often the trigger for the manifestation of 
primary forms of HLH.  
During the last years, evidence has been accumulating in support of the pivotal role of interferon gamma 
(IFNγ) in the development of both primary (Jordan 2004; Pachlopnik 2009) and secondary (Behrens 2011, 
Bracaglia 2017, Buatois 2017) forms of HLH. 
Perforin knock-out mice represent a relevant model for pHLH since, once infected with Lymphocytic 
choriomeningitis virus (LCMV), they develop an HLH-like disease dependent on activation and 
proliferation of CD8+ T cells and increased IFNγ production, with many of the clinical and laboratory 
characteristic features of the human disease. When the high circulating levels of IFNγ are neutralized with 
the administration of an anti-IFNγ antibody, not only are the clinical and laboratory abnormalities 
reverted, but also survival rate is dramatically improved. On the contrary, the ablation of many other 
cytokines had no impact on survival (Jordan 2004).  
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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 
oligodeoxynucleotides and activation of toll-like receptor-9 (TLR9) (Strippoli 2012), and a model of 
interleukin-6 (IL-6) transgenic mice expressing high levels of IL-6 that mimics the condition of patients 
with systemic juvenile idiopathic arthritis (sJIA), the rheumatic disease most frequently associated with 
secondary forms of HLH (Prencipe 2017). 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 2012), and survival  markedly improved (Prencipe 2017). 
Further strengthening the importance of IFNγ in HLH are the high concentrations of circulating IFNγ levels 
found in pHLH patients (Browne 2012, Remus 2001), with IFNγ levels above the upper limit of normal 
(17.3 pg/mL) in all patients, and above 1000 pg/mL in 53.5% of cases.  
With regard to sHLH, evidence has been recently gathered in two observational studies conducted in 
patients with secondary forms of HLH: one study in sHLH consequent to infections or of unknown origin 
(Buatois 2017), and another one in macrophage activating syndrome (MAS) occurring in the context of 
sJIA (Bracaglia 2017). Levels of IFNγ and IFNγ-induced chemokines (CXCL9 and CXCL10) were markedly 
higher in the active phase compared to disease remission and significantly correlated significantly with 
parameters of disease severity, such as neutrophil and platelet counts, ferritin and alanine transaminase 
(ALT) (Bracaglia 2017, Buatois 2017). 
At present, no drug, other than emapalumab (in the USA), is approved for the treatment of pHLH. Most 
commonly used conventional therapy for the initial treatment of pHLH and severe forms of sHLH is 
immunochemotherapy. Hematopoietic stem cell transplantation (HSCT) is required to cure pHLH and is 
indicated in forms (independently of the trigger, if known) of HLH which appear recurrent or progressive 
despite intensive therapy, or which present central nervous system (CNS) involvement (Jordan 2004). It 
has been shown that a reduction or abrogation of signs of HLH activity prior to HSCT is an important step 
in order to improve HSCT outcome and survival. 
The most commonly used immunochemotherapy is the so called HLH-94 regimen which includes the use 
of high doses of dexamethasone and etoposide.  The results of prospective study of this regimen, initially 
published by (Henter 2002) and subsequently by (Trottestam 2011) showed a 5-year cumulative 
probability of survival of 54%.  
In an attempt to improve survival, two alternative treatment regimens have been proposed and assessed: 
the HLH-2004 one based on addition of cyclosporine A to the HLH-94 treatment protocol (Henter 2007), 
and the treatment investigated in the ‘HIT-HLH’ study (Hybrid Immunotherapy for HLH) combining 
treatment with anti-thymocyte globulin (ATG), etoposide and dexamethasone.  
Despite these more aggressive immunochemotherapies, no significant improvement in mortality was 
obtained with either of the two regimens, as reported at the latest Histiocyte Society meeting in October 
2016 (Henter for the HLH-2004 study oral presentation, Jordan 2016 for the HIT-HLH study). 
A significant number of patients with HLH either fail to respond to current therapies or relapse prior to 
HSCT. Furthermore, withdrawal of the drugs commonly used for the treatment of HLH may be required 
due to their toxicities (e.g., severe infections, myelosuppression, malignant hypertension), thus leaving 
HLH patients without alternative treatment options and significantly increasing the risk of death. No 
conventional salvage therapy is available at present, although the use of rescue alemtuzumab has been 
reported in a retrospective series of 22 patients (Marsh 2013). 
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 CONFIDENTIAL 
With mortality and morbidity remaining high, the scientific community concurs that new therapeutic 
approaches are needed. 
The possibility to treat HLH by means of the targeted neutralization of the most relevant recognized 
pathogenic player, namely IFNγ, offers an innovative approach towards the management of this disease, 
aimed at ensuring efficacy with minor toxicity. The USA approval of emapalumab in pHLH in patients with 
refractory, recurrent or progressive disease or intolerance with conventional HLH therapy confirms the 
strength of this rationale. 
1.2 
EMAPALUMAB 
1.2.1
Description and Mode of Action 
Emapalumab (previously referred to as NI-0501) is a fully human immunoglobulin G1 (IgG1) anti-
interferon gamma (IFNγ) monoclonal antibody which binds and neutralizes IFNγ. Emapalumab binds to 
both free and receptor (IFNγR1)-bound forms of IFNγ.  
Since emapalumab is a human IgG1, it retains the characteristics of this immunoglobulin isotype, including 
the capacity to engage Fcγ receptors and to bind complement.  
IFNγ is produced predominantly by NK and NK T cells, as part of the innate immune response, and by CD4 
Th1 and CD8 cytotoxic T lymphocyte effector T cells, once antigen-specific immunity develops. IFNγ is one 
of the most potent and pleiotropic cytokines of the immune system. After binding to its receptor, IFNγ 
acts to produce a variety of physiological and cellular responses. Numerous studies over the last 20 years 
have associated IFN with the pathogenesis and the maintenance of inflammatory diseases (Billiau 1996, 
Schoenborn 2007, Zhang 2008). 
. 
1.2.2 
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.  
Due to emapalumab capacity to bind free and IFNγR1-bound IFNγ, studies were performed to investigate 
the potential of emapalumab to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) and 
complement dependent cytotoxicity (CDC) activities, in the presence of target. A lack of ADCC activity was 
demonstrated and no induction of CDC activity was observed.  
As to safety pharmacology, no abnormalities in electrocardiograms (ECGs), histopathology of organs and 
behavior of the animals were observed throughout the pre-clinical emapalumab program. 
1.2.2.2 Toxicology 
Binding and functional data demonstrated Rhesus or Cynomolgus monkeys to be relevant species to 
evaluate the safety of emapalumab. No off-target toxicity was attributed to the drug when administered 
to Cynomolgus monkeys in 13 weekly doses of up to 200 mg/kg. Shigella and Campylobacter infections 
were observed at all dose levels (10 to 200 mg/kg/week) in animals originally harboring gastrointestinal 
pathogens (Shigella, Salmonella, Campylobacter) prior to emapalumab administration. These findings 
were assessed to be in line with emapalumab pharmacological effect (i.e., neutralization of IFNγ), given 
the role played by IFNγ in controlling these pathogens. Subsequently, in a study where cynomolgus 
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 CONFIDENTIAL 
monkeys were free from gastrointestinal pathogens at Screening, weekly administrations of emapalumab 
for 8 consecutive weeks at doses up to 30 mg/kg were well tolerated with no toxicity or gastrointestinal 
disturbances observed, and no need for antibiotic prophylaxis.  
Results from a human tissue cross-reactivity study, involving a panel of 35 different human tissues, 
demonstrated that emapalumab did not cross-react with any of the human samples tested. 
Embryo-fetal development, fertility and early embryonic development as well as peri- and post-natal 
development studies were performed in mice. No effects on embryo-fetal development, mating or 
fertility were observed. No effects on sexual maturation, organ weights, learning and memory, 
reproductive or immunological functions evaluated in the F1 generation mice were observed. 
More details are available in the current Investigator Brochure (version 10.0, dated 24 January 2020). 
1.2.3 
Clinical Data 
A Phase 1 randomized double-blinded placebo-controlled single ascending dose study, Study NI-0501-03, 
in 20 healthy adult volunteers investigating the safety, tolerability and pharmacokinetic (PK) profiles of 
single intravenous (IV) administrations of emapalumab took place between September 2011 and January 
2013. During this study, 6 subjects received placebo, while 3, 3, 4, and 4 subjects (in total 14 subjects) 
received emapalumab doses of 0.01, 0.1, 1, and 3 mg/kg, respectively. 
The PK analysis of emapalumab revealed 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). 
All emapalumab infusions were uneventful. 
A similar incidence of commonly reported infections (e.g., upper respiratory tract infections) was 
observed after administration of emapalumab and in subjects who had received placebo. 
A Herpes Zoster (HZ) infection was reported in one subject (male, aged 26), 14 days after infusion of 
3 mg/kg of emapalumab. This event was assessed as related to the emapalumab infusion and considered 
as serious (medically significant) in the context of a Phase I study in healthy volunteers. Its intensity was 
moderate and its course normal under antiviral therapy. The subject recovered with no sequelae.  
An increased susceptibility to HZ infections in patients having developed auto-antibodies against IFNγ 
(Browne 2012) or having received ustekinumab (a monoclonal antibody which decreases IFNγ production 
by inhibiting the p40 subunit of IL-12) has been described in the literature (Failla 2011).  
In conclusion, the infusion of emapalumab was well tolerated and the effects observed during the 8-week 
monitoring after drug infusion did not reveal any serious or unexpected off-target safety or 
immunogenicity concerns.  
An open-label, single arm, international, multicenter Phase 2/3 study is ongoing to evaluate the efficacy 
and safety of emapalumab treatment in patients with pHLH (protocol NI-0501-04). The protocol allows 
for inclusion of patients either treatment-naïve or reactivating after initial response to conventional 
therapy or not achieving a satisfactory response or showing intolerance to conventional therapy. 
Upon completion of study NI-0501-04, patients were invited to enter a long-term safety follow-up (study 
NI-0501-05) of 1 year after HSCT or after last emapalumab infusion. NI-0501-05 study protocol made 
provision for continuation of emapalumab treatment if required by the treating physician as a bridge to 
transplantation. 
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 CONFIDENTIAL 
An interim analysis of the data gathered in both NI-0501-04 and NI-0501-05 studies (cut-off date of 20 July 
2017) has been conducted and these data have been the basis of the biologics license application (BLA) 
and the market authorization application (MAA) submissions.    
At  the  BLA/MAA  cut-off  date,  34  patients  have  been  treated  in  Study  NI-0501-04.  The  primary 
efficacy endpoint of the study, overall response rate (ORR) at End of Treatment (EOT) was met. ORR 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.  
During  pre-conditioning,  the  most  frequently  reported  adverse  events  (AEs)  were  those  related  to 
HLH reactivation, flare or worsening. The most frequently reported AEs in post-conditioning were pyrexia 
and hypertension.    
At the BLA/MAA cut-off date, a total of 34 patients were treated and 10 patients died in studies NI-0501-
04/05. None of the deaths were assessed to be related to emapalumab by Investigator, Sponsor and 
independent data monitoring committee (iDMC). 
In line with the risks due to the immune deficiency status in pHLH patients, 19 out of 34 patients (56 %) 
reported at least 1 infection from start of emapalumab treatment until start of HSCT conditioning. 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 with appropriate antibiotic therapy.   
In second-line patients who were intolerant to previous  conventional HLH therapies due to their 
toxicities, the administration  of emapalumab did not aggravate these toxicities, while showing, in 
general, a favorable impact on disease activity.  
Likewise, no safety concern related to the concomitant administration of emapalumab with other 
treatments (e.g., antimicrobial agents, anti-hypertensive drugs) has been reported so far. Of interest, 
tapering of glucocorticoids had no impact on the safety and tolerability of emapalumab infusions and has 
shown benefit for patients with steroid-related hypertension and generalized immunosuppression. 
Study NI-0501-04 has currently completed enrolment, with a total of 45 patients recruited. 
Study NI-0501-06 is a phase 2 study in sJIA patients with MAS/sHLH who have shown an inadequate 
response to high-dose glucocorticoid treatment. As of 24 August 2019,  a  total  of  8  patients  have  been  
treated.  In  all  6  patients,  complete response was achieved. Systemic glucocorticoids were weaned in 
all patients. Emapalumab infusions were  well  tolerated  and  none  of  the  patients  discontinued  
emapalumab  prematurely.  A CMV reactivation was reported by Investigator as a serious event possibly 
related to emapalumab, but resolved completely with treatment (De Benedetti F, 2019).  
Overall,  6  out  of  the  8  patients  experienced  at  least  1  treatment-emergent  AE (TEAE).  No  AEs  with  
fatal outcome or leading to study treatment discontinuation were reported.   
For more details on the clinical experience, refer to the latest Investigator’s Brochure (currently version 
10.0, dated 24 January 2020). 
Refer to Section 9.4.2 for the current benefit/risk assessment on the use of emapalumab in pHLH patients. 
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 CONFIDENTIAL 
2 OBJECTIVES 
-
To gather additional safety and efficacy data on emapalumab in pHLH patients.
-
To assess a starting dose of emapalumab of 3 mg/kg.
‐
To assess the impact of emapalumab on Quality of Life (QOL). 
‐
To gather additional evidence on the long-term outcome of pHLH patients treated with 
emapalumab. 
‐
To further evaluate the PK profile of emapalumab in pHLH patients. 
‐
To further evaluate the pharmacodynamic (PD) effects (levels of circulating total IFNγ and 
biomarkers of its neutralization; namely CXCL9 and CXCL10). 
‐ 
To assess the profile of other relevant HLH biomarkers, e.g., soluble IL-2 receptor (sCD25) and other 
exploratory biomarkers. 
‐ 
To monitor for potential occurrence of anti-drug antibodies (ADAs). 
3 STUDY DESIGN 
3.1 
OVERALL DESIGN 
Study NI-0501-09 is an open-label, single arm, multicenter, interventional study performed both in North 
America (NA) and in Europe. 
The study enrolls pediatric patients with confirmed or suspected pHLH who are treatment-naïve, or have 
failed conventional HLH therapy, or showed intolerance to it.  
The study is divided into three parts: screening, treatment, and follow-up. 
Patients will be in the treating unit the day before the first administration of emapalumab (Study Day 
minus one; SD-1). 
Patients are required to receive dexamethasone from SD-1. 
In treatment-naïve patients, a background therapy of 10 mg/m2 dexamethasone will be required. 
In patients who failed previous HLH therapy, dexamethasone is to be administered at a dose of at least 5 
mg/m2 or at the dose administered prior to Screening if higher.  
Lower dexamethasone doses are allowed in case of documented intolerance to glucocorticoids. 
During the study, dexamethasone can be tapered depending on the patient’s condition, according to the 
judgment of the treating physician. 
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 CONFIDENTIAL 
Figure 1: NI-0501-09 Study Design 
SCREENING 
Up to 2 weeks  
prior to Visit 1 
TREATMENT PERIOD UNTIL END OF TREATMENT 
(EOT: 31 days after last infusion) 
FOLLOW-UP 
 Initial dose  
   Subsequent doses * 
   3 mg/kg  
Pre- HSCT 
Post-HSCT 
 
V1 
V2 (SD3) and Onwards 
Pre-Cond 
Visit 
W1/W2/W3 
D30 
D60 
D100 
M6 
Y1 
Abbreviations: D, day; EOT, end of treatment; HSCT, hematopoietic stem cell transplant; M, month; Pre-Cond Visit, pre-conditioning 
visit; SD, study day; V, visit; W, week; Y, year. 
Additional HLH treatments allowed in case of documented 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. Upon achievement of Complete Response (i.e., normalization
of all clinical and laboratory HLH parameters), the dose of emapalumab will be lowered to achieve 1 mg/kg twice a week and
maintained until conditioning for transplant, as long as the patient’s clinical condition is satisfactory. See Section 5.3 for full dosing
schema.
3.2 
SCREENING PERIOD 
Screening will be carried out within 2 weeks prior to first administration of emapalumab (SD0) to enable 
confirmation of patient eligibility, and following the signature of the Informed Consent Form (ICF). 
Samples for infection screening need to be collected for analysis prior to first administration of 
emapalumab according to the protocol requirements. However, if a patient’s medical condition warrants 
rapid treatment initiation, availability of the results 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.  
3.3 
TREATMENT PERIOD 
The duration of treatment is foreseen until the start of conditioning for HSCT, but must not exceed 
6 months.   
The minimum treatment duration is 4 weeks, if the patient’s conditions and donor availability allow for 
HSCT. 
No wash-out period is required between the last administration of emapalumab and the start of 
conditioning. 
3.4 
FOLLOW-UP PERIOD 
After treatment completion or treatment discontinuation (for any reason), patients will continue in the 
study for long-term follow-up until 1 year after either HSCT or last emapalumab infusion (if HSCT is not 
performed). 
I 
I 
I 
I 
I 
I 
11 
1' 1' 
1' 1' 
1' 
1' 
1' 
1' 
1' 
1' 
I 
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Protocol NI-0501-09 Version 4.0 Global – Final 31 March 2020 
 CONFIDENTIAL 
 
If patient experiences HLH reactivation during the follow-up period, patient may be re-treated with 
emapalumab, upon discussion with Sponsor. Re-treated patient will follow the same schedule of 
assessments as applicable during initial treatment (i.e., starting from Visit 1), and will enter follow-up 
period after completion of re-treatment.  
If the patient is unable to return to the site for all follow-up visits, every effort should be made to schedule 
visits until emapalumab is no longer detectable in the blood. 
3.5 
STUDY END 
The end of the study is defined as last patient last visit (LPLV) at 1 year after either HSCT or last 
emapalumab infusion (as applicable).  
In case of an ongoing SAE, the patient will continue to be monitored until resolution or until the outcome 
of the event is known and stable, beyond the defined study end as necessary.  
3.6 
STUDY COMMITTEES 
An Independent Data Monitoring Committee (iDMC) has overall responsibility for safeguarding the 
interests of subjects by monitoring relevant data obtained in the study and making appropriate 
recommendations based on the reported data, thus ensuring that the study is being conducted with the 
highest scientific and ethical standards. Moreover, the iDMC will be specifically tasked with regular 
assessment of extent of benefit and fatal events prior to transplant in the treatment-naïve subgroup of 
patients.  
iDMC operations will be described in the iDMC charter. 
4 TARGET POPULATION 
The criteria for study eligibility are provided below.  Patients in this study can be naïve to HLH treatment 
or may have already received conventional HLH therapy without having obtained a satisfactory response 
according to the treating physician or having shown signs of intolerance to HLH therapy. Of note, 
enrolment of patients who have failed previous conventional HLH therapy will continue until emapalumab 
is commercially available for a given indication, or until sample size is reached, whichever comes first; 
thus, US enrolment will be limited to treatment-naïve patients.  
Conventional HLH therapy is defined as per site standard-of-care, e.g., any of the following, alone or in 
combination (etoposide, ATG, alemtuzumab and cyclosporine A) or glucocorticoids, namely 
dexamethasone at 10 mg/m2 for at least 7 days or methylprednisolone pulses for 3 consecutive days. 
4.1 
ELIGIBILITY CRITERIA 
Patients will be included in the study if they meet all the inclusion criteria and none of the exclusion 
criteria. 
4.1.1 
Inclusion Criteria 
1. Male and female pHLH patients, from birth up to and including 18 years at diagnosis of HLH.  
2. A molecular diagnosis or familial history consistent with pHLH or fulfilment of HLH-2004 diagnostic 
criteria, i.e., five out of eight of the criteria below: 
- Fever 
- Splenomegaly 
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-
Cytopenias affecting 2 of 3 lineages in the peripheral blood (hemoglobin <90 g/L; platelets
<100 x 109/L; neutrophils <1 x 109/L)
-
Hypertriglyceridemia (fasting triglycerides ≥3 mmol/L or ≥265 mg/dL) and/or
hypofibrinogenemia (≤1.5 g/L)
-
Hemophagocytosis in bone marrow, spleen or lymph nodes, with no evidence of malignancy.
-
Low or absent NK-cell activityi
-
Ferritin ≥500 µg/L
-
Soluble CD25 (sCD25; i.e., soluble IL-2 receptor) ≥2400 U/mLii
3.
Presence of active HLH disease as assessed by the treating physician.
4.
Patients having already received conventional HLH therapy must fulfil one of the following criteria as
assessed by the treating physician:
-
Having not responded
-
Having not achieved a satisfactory response or worsened
-
Having reactivatediii
-
Showing intolerance to previous conventional treatment of HLH
At the time of enrolment, eligible patients might still be receiving treatment (induction or 
maintenance) or might have already discontinued it. 
5.
Informed consent signed by the patient (as required by local law), or by the patient’s legally
authorized representative(s) with the assent of patients who are legally capable of providing it, as
applicable.
6.
Having received guidance on contraception for both male and female patients sexually active and
having reached puberty.
Females of child-bearing potential require use of highly effective contraceptive measures (failure rate
of less than 1% per year) from Screening until 6 months after receiving last dose of the study drug.
Highly effective contraceptive measures include:
o
Sexual abstinence: refraining from heterosexual intercourse during the entire period defined
above.  The reliability of sexual abstinence needs to be evaluated in relation to its duration
i NK-cell degranulation testing is considered to be acceptable 
ii Or equivalent as measured by the site’s laboratory 
iii Reactivation is defined as: 
-
Deterioration of two or more HLH clinical and laboratory criteria (following an initial response) with the following 
specifications:
1.
numerical laboratory values* must become abnormal and worsen by more than 30% compared to the previous 
evaluation, on two sequential assessments performed with an interval of minimum 1 day and maximum 1 week
2.
deterioration of clinical criteria must be confirmed by consistent observations of worsening over three consecutive days
-
The development of new or recurrent CNS symptoms counts as a single criterion for reactivation.
* The following laboratory parameters are specifically considered for determination of reactivation: platelets, neutrophils, 
fibrinogen, ferritin, sCD25 (i.e., soluble IL-2 receptor). 
The assessment of NK function, red blood cells/hemoglobin and triglyceride levels cannot be considered for the determination of
reactivation.
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Protocol NI-0501-09 Version 4.0 Global – Final 31 March 2020 
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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) 
o
Hormonal contraceptives: combination or progesterone only
o
Intrauterine methods: intrauterine devices or systems
o
Bilateral tubal occlusion
o
Vasectomised partner
Males with partner(s) of child-bearing potential must agree to take appropriate precautions (such as 
sexual abstinence, barrier contraception, vasectomy) to avoid fathering a child from Screening until 
6 months after receiving last dose of the study drug. 
4.1.2
Exclusion Criteria 
1.
Diagnosis of secondary HLH consequent to a proven rheumatic, metabolic or neoplastic disease.
2.
Active mycobacteria, Histoplasma capsulatum, Shigella, Salmonella, Campylobacter or Leishmania 
infections.
3.
Evidence of latent tuberculosis.
4.
Presence of malignancy.
5.
Patients who have another concomitant disease or malformation severely affecting cardiovascular,
pulmonary, CNS, liver, or renal function that in the opinion of the Investigator may significantly affect
the likelihood to respond to treatment and/or the assessment of emapalumab safety and/or efficacy.
6.
History of hypersensitivity or allergy to any component of the study regimen (e.g., polysorbate).
7.
Receipt of a Bacillus Calmette-Guérin (BCG) vaccine within 12 weeks prior to Screening.
8.
Receipt of a live or attenuated live (other than BCG) vaccine within 6 weeks prior to Screening.
9.
Pregnant or lactating female patients.
5 INVESTIGATIONAL MEDICINAL PRODUCT 
5.1 
DESCRIPTION OF INVESTIGATIONAL MEDICINAL PRODUCT 
Emapalumab (previously referred to as NI-0501) is a fully human high affinity anti-IFNγ monoclonal 
antibody that binds to and neutralizes human IFNγ. 
Emapalumab is manufactured by a third-party manufacturing facility duly qualified by Swedish Orphan 
Biovitrum AG and is supplied to study sites in 2 mL and/or 10 mL filled single-use glass vials at a 
concentration of 5 mg/mL, for dilution prior to administration. 
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Protocol NI-0501-09 Version 4.0 Global – Final 31 March 2020 
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The nominal composition of the emapalumab sterile concentrate for infusion (per mL) is as follows: 
Ingredient 
Quantity (per mL) 
Emapalumab 
5 mg 
L-Histidine
1.55 mg 
L-Histidine monohydrochloride, monohydrate
3.14 mg 
Sodium chloride (NaCl) 
7.31 mg 
Polysorbate 80 
0.05 mg 
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 
The dosing regimen for emapalumab is determined based on patient outcomes and PK/PD data collected 
in the ongoing NI-0501-04 and NI-0501-05 studies. Preliminary analyses indicate that the administered 
dose needs to be adapted to the IFNγ production, which varies significantly between subjects but can also 
significantly change over time within a subject, e.g. in case of infection (Figure 2). 
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Protocol NI-0501-09 Version 4.0 Global – Final 31 March 2020 
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Figure 2: Total IFNγ Concentrations up to the Last Dose or HSCT in HLH Patients Treated with 
Emapalumab in Studies NI-0501-04 and NI-0501-05 (HLH) and in Compassionate Use (CU) Patients  
 
 
Results of preliminary PK/PD analyses demonstrate that: 1) the higher the total IFNγ production, the 
higher the clearance of emapalumab due to target mediated drug disposition and 2) the higher the IFNγ 
concentration, the higher the required emapalumab concentration to reach neutralization.  
In the 34 pHLH patients enrolled in the NI-0501-04 study as of 15 May 2017, emapalumab has been 
administered at a dose ranging from 1 to 10 mg/kg. Out of these 34 patients, 14 remained at the dose of 
1 mg/kg and 20 required a dose increase at any time during the course of treatment, with 12 patients 
requiring a dose increase by Day 9. These dose adaptations were based on PK observations and on 
clinical/laboratory parameters (in the initial pilot phase of the study) and on clinical criteria only 
thereafter. Specifically, in this later phase, in which 8 patients were enrolled, dose increase occurred in 7 
patients and only 1 remained at 1 mg/kg. These dose increases did not lead to any safety concerns. 
Based on these learnings from the NI-0501-04 study, a starting dose of 3 mg/kg is applied in this study, 
with a simplified schema for dose escalation up to 10 mg/kg (refer to Section 5.3). 
The impact on the PK and PD of the proposed dosing schema is shown by the simulations reported in 
Figure 3, Figure 4 and Figure 5. 
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) that exemplify the variability 
of IFNγ: 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: 
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Page 41 of 98


Study NI-0501-09 
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Protocol NI-0501-09 Version 4.0 Global – Final 31 March 2020 
 CONFIDENTIAL 
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 compassionate use patients (cut-
off date 20 July 2017). 
The black line (mean) and grey shadowed area on the right graph indicates CXCL9 levels at week 2 and 
end of treatment  that appear to be associated with the probability of clinical response at end of 
treatment as indicated by preliminary Receiver Operating Characteristic (ROC) analyses (data on file). The 
right y-axis gives the probability of overall response at the end of treatment as estimated by logistic 
regression analysis. 
The simulation with the dose increase up to 10 mg/kg (Figure 5) shows that patients with a low production 
of IFNγ (TIFNγ=10,000 pg/mL) reach emapalumab concentrations close to the highest ones already 
observed in studies NI-0501-04 and NI-0501-05 and in compassionate use 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 NI-0501-04 study patients with maximal total IFNγ levels remaining 
below 10,000 pg/mL required a dose increase up to 10 mg/kg. 
Figure 3: Emapalumab and CXCL9 Concentrations at the Initial Dose of 3 mg/kg (Maintained TWICE A 
WEEK During the Treatment Course) 
Dose=3 mg/kg twice a week 
Dose=3 mg/kg twice a week 
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Page 42 of 98


Study NI-0501-09 
NI-0501 in Primary HLH 
Page 37 of 92 
Protocol NI-0501-09 Version 4.0 Global – Final 31 March 2020 
 CONFIDENTIAL 
Figure 4: Emapalumab and CXCL9 Concentrations at the Initial Dose of 3 mg/kg, Increased to 6 mg/kg 
ON DAY 6 and Maintained TWICE A WEEK During the Treatment Course 
Figure 5: Emapalumab and CXCL9 Concentrations at the Initial Dose of 3 mg/kg, increased to 6 mg/kg 
on day 3, to 10 mg/kg on day 7 and Maintained TWICE A WEEK During the Treatment Course 
Dose=3 + 6 mg/kg twice a week 
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Protocol NI-0501-09 Version 4.0 Global – Final 31 March 2020 
 CONFIDENTIAL 
5.3 
DOSING SCHEMA 
Emapalumab will be administered by IV infusion over a period of 1 to 2 hours depending on the volume 
to infuse, at a dose of 3 mg/kg.  Infusions will be performed twice weekly (not more than 4 days apart), 
except for the second infusion which must be administered on SD3. 
The 3 mg/kg dose will be maintained 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 emapalumab dose to 6 mg/kg (Table 3).  A further dose increase to 10 mg/kg can 
be considered per Investigator’s decision based on the patient’s condition and appreciation of some 
benefit from the administration of emapalumab.  
Upon achievement of Complete Response (i.e., normalization of all clinical and laboratory HLH 
parameters), the dose of emapalumab should be lowered to achieve 1 mg/kg twice a week and 
maintained until conditioning for transplant, as long as the patient’s clinical conditions is satisfactory. 
Decrease of emapalumab dose will occur in a stepwise fashion (e.g. if patient was on 6 mg/kg, 
emapalumab will be administered in 3 mg/kg for at least one infusion before achieving 1 mg/kg). 
Given the unpredictable course of the disease, in case of reactivation (e.g. triggered by intercurrent 
infections), subsequent dose increases to 3 mg/kg (and up to 6 or 10 mg/kg, as appropriate) may need to 
be considered and will be guided by the same clinical and laboratory parameters described above (Table 
3). 
The Investigators’ assessments for emapalumab dose increase will be documented in the Dose 
Notification form (Appendix E) to be completed for each infusion and provided to Sponsor in a timely 
manner. 
Upon regaining a Complete Response, the dose of emapalumab should be lowered again to achieve 
1 mg/kg twice a week. Should HSCT be scheduled beyond 12 weeks from emapalumab initiation, for 
reasons unrelated to the administration of emapalumab (e.g., lack of donor availability), and provided 
Complete Response is maintained, the treatment  with emapalumab may continue at the dose of 1 mg/kg 
once a week. 
The duration of treatment is foreseen until the start of conditioning for HSCT, but must not exceed 
6 months. The minimum treatment duration is 4 weeks, if the patient’s conditions and donor availability 
allow the performance of HSCT.  
No wash-out period is required between the last administration of emapalumab and the start of 
conditioning.  
If patient experiences HLH reactivation during the follow-up period, patient may be re-treated with 
emapalumab, upon discussion with Sponsor. Re-treated patients will follow the same schedule of 
assessments as applicable during initial treatment (i.e., starting from Visit 1), and will enter the follow-up 
period after completion of re-treatment. 
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Protocol NI-0501-09 Version 4.0 Global – Final 31 March 2020 
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Table 3: Clinical and Laboratory Criteria to Guide Dose Increase 
On  Visit / 
Study Day (SD) 
Emapalumab Dose 
 
On Visit 1/SD0 
Starting dose of 3 mg/kg 
 
On Any Visit, 
from Visit 2/SD3 
onwards  
Increase to 6 mg/kg5 
Upon an overall assessment by the Investigator that  
improvement in clinical conditions1 is unsatisfactory 
and 
presence of at least 1 of the following: 
 
 
Fever  
→ persistence or reoccurrence 
 
 
Platelet counts  
→ lack of normalization2 or  
     Worsening 
 
 
ANC  
→ lack of normalization3 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 normalization4 or  
     Worsening 
On Any Visit, 
from Visit 3 
onwards 
Increase up to 10 mg/kg 
(if deemed necessary) 
Upon assessment by the Investigator that a further 
increase of emapalumab dose may provide a better 
benefit/risk ratio than administration of alternative 
HLH treatments (see Section 6.3.5) and presence of 1 
of the criteria listed above  
Abbreviations:  ALC = absolute lymphocyte count; ANC = absolute neutrophil count; SD = study day; US = ultrasound 
Note: the table is based on an initial dose of emapalumab of 3 mg/kg. 
1 Features to be assessed may include patient’s overall performance and well-being, as well as evolution of clinical and 
laboratory signs that significantly contribute to or indicate overall severity of the patient’s disease, e.g. signs of CNS 
involvement or liver impairment, dynamics of ALC, sIL2Ra 
2 Normalization of platelet counts is defined as values >100 x 103/mcl, as per HLH diagnostic criteria 
3 Normalization of ANC is defined as values >1000 count/mcl, as per HLH diagnostic criteria   
4 Normalization of D-dimer is defined as values <1.0 g/mL; normalization of fibrinogen is defined as values >150 mg/dL 
5 The dose of 6 mg/kg may be maintained as long as deemed appropriate by the Investigator to obtain a satisfactory 
improvement.  
 
 
5.4 
INVESTIGATIONAL MEDICINAL PRODUCT HANDLING 
5.4.1 
Packaging and Labelling 
Emapalumab will be supplied to study sites in glass vials containing either 2 or 10 mL solution at a 
concentration of 5 mg/mL. Labelling and packaging will be prepared to meet local regulatory 
requirements. 
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Protocol NI-0501-09 Version 4.0 Global – Final 31 March 2020 
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5.4.2 
Investigational Medicinal Product Supply 
Emapalumab will be supplied to the study sites as open-label supplies. 
5.4.3
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 should be immediately reported to the Sponsor and responsible study monitor or 
contract research organization (CRO). Affected vials should not be used and should be quarantined until 
the Sponsor has authorized their use, return or destruction. 
Documentation of the storage conditions of the study drug must be maintained 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 Swedish 
Orphan Biovitrum AG or designee. 
Regular inspections of the emapalumab vials are required, as detailed in the Investigational medicinal 
product (IMP) manual’s directions for the Preparation and Administration of Individual Doses of Study 
Drug Emapalumab. 
5.4.4
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 before 
preparation of the study drug for administration.  
Full instructions for the preparation, including dilution steps, and method for administration of 
emapalumab 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 added to all infusion lines.  
It is recommended that an IV central line remain in place to ensure venous access during the treatment 
period. This will improve patient’s comfort and ensure a reliable drug administration, in particular in 
infants and toddlers, or in case of foreseen difficulties with peripheral venous access. 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 
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Protocol NI-0501-09 Version 4.0 Global – Final 31 March 2020 
 CONFIDENTIAL 
 
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. 
The infusion of emapalumab will be performed under the direct supervision of the Investigator (or 
delegate), preferably in the morning at the same time for each infusion. 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 
▪ 
What was the stop time of the infusion 
▪ 
What was the new start time of the infusion 
▪ 
What was 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. 
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, and updating the 
Interactive response technology (IRT) system. Documentation should be returned to Swedish Orphan 
Biovitrum 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. 
The used (or unused) infusion material should be sent back to the Pharmacist at the end of the infusion, 
if possible, for later inventory.  
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. 
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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 perform drug accountability via the IRT system, before making 
arrangements for study drug return or authorizing destruction by the study site. 
6 PATIENT BACKGROUND TREATMENT AND CARE 
6.1 
BACKGROUND THERAPY WITH DEXAMETHASONE 
Initially, emapalumab will be administered on a background of dexamethasone. 
Patients are required to receive dexamethasone from not later than SD-1. 
In treatment-naïve patients, a background therapy of 10 mg/m2 of dexamethasone will be required. In 
patients receiving emapalumab after having failed previous HLH therapy, dexamethasone is to be 
administered at a dose of at least 5 mg/m2, or at the dose administered prior to Screening if higher. Lower 
dexamethasone doses at study entry are allowed in case of documented intolerance to glucocorticoids. 
During the study, dexamethasone can be tapered depending on patient`s condition. The tapering scheme 
can be selected by the treating physician, and should take into account the potential risk of disease (HLH) 
reactivation. 
In the event of disease reactivation/worsening after tapering of dexamethasone, the dose of 
dexamethasone can be increased and maintained until a satisfactory response is achieved according to 
the treating physician.  
6.2 
PROPHYLACTIC TREATMENT 
Prophylaxis for HZ virus (HZV) infection will be performed to mitigate the potential risk associated to 
emapalumab administration (see Section 9.4) and has to be in place from the day before initiation of 
emapalumab treatment until serum levels of emapalumab are no longer detectable.  
Patients will receive any additional required prophylactic antimicrobial treatment according to local 
recommendations in pHLH. 
Consider the following: 
•
For HZV prevention, according to Institution Guidelines/Recommendations (e.g., Acyclovir
200 mg four times daily for children over two years, for children under two years 100 mg four
times daily).
•
For tuberculosis (TB) prophylaxis (if required as indicated above) according to Institution
Guidelines/ Recommendations (e.g., Isoniazid).
These treatments will be given orally, whenever possible, otherwise intravenously. 
6.3 
CONCOMITANT THERAPY 
6.3.1 
Cyclosporin A 
Cyclosporin A (CsA) can be continued, if already administered prior to Screening. CsA can be withdrawn 
at any time, upon the judgment of the Investigator. CsA is not to be introduced (or re-introduced) during 
the course of the study once emapalumab administration has started. 
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6.3.2
Intrathecal Therapy 
For patients receiving intrathecal (IT) therapy (e.g., methotrexate and glucocorticoids) at the time of 
emapalumab treatment initiation, this therapy will be continued until clinically indicated. The 
introduction of IT therapy during emapalumab treatment is allowed should CNS signs and symptoms 
occur during the study, as clinically indicated. 
6.3.3
Other Concomitant Therapies 
Intravenous immunoglobulin (IVIG) are only allowed as replacement treatment (i.e., not at doses 
expected to produce an immunomodulatory effect) according to the clinical judgement of the 
Investigator. Any IVIG infusion within the previous 4 weeks prior to Screening, as well as any infusion 
during emapalumab treatment, should be documented in the Case Report Form (CRF; dose, date of 
administration). 
Analgesic treatment, transfusion of blood products, electrolyte and glucose infusions, IV parenteral 
nutrition, inotropic support, antibiotics, anti-fungal and anti-viral treatment, hemofiltration or 
hemodialysis, as well as general supportive care (e.g., gastro-protective agents, anti-hypertensive etc.) 
are permitted within the study.  
The use of any prescription or over-the-counter medication, including herbal and homeopathic 
preparations with the exception of multi-vitamins, needs to be notified to the Investigator. 
Contraception guidance: see Section 6.4. 
6.3.4
Not Allowed Concomitant Therapies 
As long as emapalumab is being administered, the concomitant use of other biologic drugs (for indications 
other than additional HLH treatments) is generally not allowed, except for the following: 
-
Granulocyte-colony-stimulating factor (G-CSF), in case of prolonged neutropenia
-
Rituximab, in case of documented EBV infection.
Administration of Janus kinase (JAK) inhibitors concomitantly with emapalumab is not allowed. 
Vaccination with a live or attenuated-live (including BCG) vaccine must be avoided until serum levels of 
emapalumab are no longer detectable, unless the investigator has a specific reason for overcoming this 
recommendation, and upon discussion with the Sponsor.  
6.3.5
Additional HLH treatments 
The administration of additional HLH treatments (e.g., etoposide, T-cell depleting agents) will be allowed 
concomitantly with emapalumab.  
In a patient in whom an HLH worsening or no initial response has been observed after an increase of 
emapalumab dose to 6 mg/kg on SD3, at SD6 the Investigator may consider the therapeutic option of 
adding an alternative HLH treatment while continuing emapalumab.  
Benefit/risk of administering an additional HLH treatment (with or without emapalumab dose increase) 
must be assessed, taking into consideration e.g. possible drug toxicities, trends of relevant clinical/ 
laboratory parameters in that individual patient, extent of past response to conventional HLH therapy (if 
a second-line patient).  
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The administration of an additional HLH treatment is also allowed later during the course of emapalumab 
treatment  in case of unsatisfactory HLH control, provided that emapalumab has been administered at a 
dose of 6 (or 10 mg/kg if the Investigator decided to do so) for at least 2 infusions.  
Unsatisfactory HLH control is defined as follows: 
-
patients who have not achieved or maintained a disease control and general conditions that
would allow to proceed to transplant
-
patients who present a clinically relevant worsening.
If an additional HLH treatment is needed, etoposide is the drug of choice, unless there is evidence 
indicating that an alternative agent should be selected. The rationale for administration of additional HLH 
treatments (including the choice of an agent alternative to etoposide, if applicable) has to be documented 
in the patient’s medical file and in the Dose Notification Form (Appendix E). 
At any time, the Investigator can decide to discontinue emapalumab treatment and opt for a different 
HLH regimen in the patient’s best interest, as described in the Section 10.1.3. 
6.4 
CONTRACEPTION 
Females of child-bearing potential require the use of highly effective contraceptive measures (failure rate 
of less than 1% per year) from Screening until 6 months after receiving last dose of the study drug. 
Highly effective contraceptive measures include: 
•
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.
Males with partner(s) of child-bearing potential must agree to take appropriate precautions (such as 
sexual abstinence, barrier contraception, vasectomy) to avoid fathering a child from Screening until 
6 months after receiving last dose of study drug. 
6.5 
EMERGENCY TREATMENT 
Severe allergic reactions such as anaphylactic shock require prompt IV treatment with adrenaline and 
antihistamines. Oxygen shall be supplied through a face mask. Patients must have an appropriately sized 
IV line that allows rapid infusion of colloid volume substitution. In case of an anaphylactic reaction 
patients shall be transferred as soon as possible to the intensive care unit of the hospital.  
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 gives details of the name of the drug, name of the responsible physician, and the address and 
telephone number of the study site. 
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7 ENDPOINTS 
7.1 
EFFICACY ENDPOINTS 
Criteria for the definitions of response are reported in Table 4. 
Primary efficacy endpoint 
•
Overall Response, i.e., achievement of either Complete or Partial Response or HLH Improvement, at
EOT or Week 8 (whichever occurs earlier).
Secondary efficacy endpoints: 
•
Overall Survival, including survival to HSCT and survival after either HSCT or last emapalumab infusion
(if HSCT is not performed)
•
Event-free survival
•
Overall Response, i.e., achievement of either Complete or Partial Response or HLH Improvement, at
start of conditioning (or at last emapalumab infusion if HSCT is not performed)
•
Duration of Response, i.e., maintenance of the response achieved any time during the study (with
censoring time at start of conditioning for patients with no event)
•
Time to Response at any time during the study
•
Number of patients able to reduce glucocorticoids by 50% or more of the baseline dose  during
emapalumab treatment
•
Number of patients able to proceed to HSCT, when deemed indicated
•
Quality of Life assessed through PedsQL™, Pediatric Quality of Life Inventory™ (link to examples of
questionnaires are placed in (Appendix A) and BASES questionnaires (Appendix B).  While PedsQL
(Varni JW, 1999) is a validated tool, BASES (Phipps S, 1994; Phipps S, 2002) is not, but it is of potentially
great interest given the fact it focuses on HSCT; BASES will be used in an exploratory fashion.
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: 
-
At least 3 of the HLH clinical and laboratory abnormalities (including CNS abnormalities)
meet the above mentioned criteria for “Complete Response”
-
In the case of “reactivated patients” who enter the study with 3 abnormal HLH features,
Partial Response is adjudicated if at least 2 parameters normalize
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-
In case of reactivated patients who enter the study with 2 abnormal HLH clinical and 
laboratory parameters only, Partial Response is adjudicated if one of the 2 parameters 
normalizes
-
There is no progression of other aspects of HLH disease pathology
HLH improvement 
-
Improvement (>50% change from baseline or normalization) of at least 3 HLH clinical and 
laboratory abnormalities (including CNS abnormalities).
-
In the case of “reactivated patients” who enter the study with only 2 abnormal HLH 
features, a change from baseline greater than 50% for both will define HLH as improved.
Abbreviations:  CNS, central nervous system; CSF, cerebrospinal fluid; G-CSF, granulocyte-colony-stimulating factor; HLH, 
hemophagocytic lymphohistiocytosis  
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)
•
Evolution of relevant laboratory parameters, e.g., complete blood cell (CBC) count, liver and renal
function tests, and coagulation parameters
•
Number of patients who discontinued emapalumab treatment for safety reasons
7.3 
PHARMACOKINETIC ENDPOINTS 
The serum concentration of emapalumab will be measured as a function of time to determine the 
emapalumab PK profile.  
Pharmacokinetic data will be visually examined using appropriate graphical analysis. 
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. Individual and mean 
PK parameters will be tabulated. 
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 followings: 
•
Levels of circulating total IFNγ (free + bound) at any time-point
•
Markers of IFNγ neutralization, namely CXCL9 and CXCL10
•
Other relevant HLH biomarkers, e.g., sCD25 and other exploratory biomarkers
•
Level (if any) of circulating antibodies against emapalumab (ADAs)
Population PK/PD analysis using non-linear mixed effects modelling will be undertaken.  The main PD 
biomarker investigated will be CXCL9.  
Additional PD biomarkers 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. 
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Measurement of PD parameters may be performed in an exploratory manner, if clinically indicated, in 
other matrices, e.g., cerebrospinal fluid CSF, BAL. 
PD samples may be used to investigate potential drug-drug interactions. 
8 OUTLINE OF STUDY PROCEDURES 
Patients will be recruited from specialized study sites, equipped with an intensive care unit and access to 
a bone marrow transplant unit. 
Patients will be in the treating unit the day before the first administration of emapalumab (Study Day 
minus one, SD-1). 
For a detailed description of the schedule of visits and assessments, refer to the Schedule of Assessment 
Table 1 (Screening and Treatment Period) and Table 2 (Follow-up Period). 
Informed consent form must be signed by the patient or his/her legally authorized representative prior 
to any study-related procedures, with the assent of patients who are deemed suitable to provide it.  
During the emapalumab treatment period, visits for infusion and efficacy/safety assessments will occur 
on SD0, SD3 and twice-a-week thereafter (not more than 4 days apart). In the circumstances when HSCT 
is scheduled beyond 12 weeks from emapalumab initiation and Complete Response is maintained (see 
Section 5.3), the treatment with emapalumab may continue once a week; acceptable time-window for 
visits in this case will be 1 day. An EOT visit has to be performed 31 days after last emapalumab infusion. 
Furthermore, during the follow-up period, the following time-windows are allowed around visits: 
- Pre-conditioning:  
can be combined with EOT visit provided the two visits are 
not more than 2 days apart 
-
Week (Wk) 1-2-3, D+30 post-HSCT:  2 days
-
D+60, D+100 post-HSCT:
1 week 
-
6-mo, 1-yr post-HSCT:
4 weeks 
If HSCT is not performed, the described schedule applies to the follow-up visits required to occur after 
the last emapalumab infusion. 
Following windows can be applied to the vital signs measurement: 
-
When measured every 15 minutes:
   5 minutes 
-
When measured every 30 minutes:
10 minutes 
-
When measured at 1 hour and 2 hours after infusion:  15 minutes
Some procedures are not to be done systematically but only if clinically relevant. For example: 
•
ECG is mandatory at Screening and at EOT visits, however it should be done at any other time-
point during the study, if deemed appropriate.
•
Brain magnetic resonance imaging (MRI) is mandatory at Screening only in case of CNS disease,
but should be done at any other time-points during the study to monitor evolution or to confirm
onset of CNS involvement, as clinically indicated.
•
Lumbar puncture for CSF analysis is to be performed at Screening providing that coagulation
function allows, but should be done at any other time-points during the study to monitor
evolution (if the initial analysis was abnormal), or to confirm new onset of CNS involvement.
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•
Search for pathogens (other than TB) at Screening and during the study should be done if there is
any suspicion of infection, and should be performed at relevant time intervals to follow the
evolution of infections, either pre-existing or emerging during the study.
•
Chest X-ray should be performed at Screening and during the study in case of clinical suspicion of
a pulmonary infection or to follow-up a pre-existing infection at Screening/baseline.
If planned as standard of care, alternative imaging methods will be accepted as a replacement for per 
protocol imaging (with exception of abdominal ultrasound): namely, brain computerized tomography (CT) 
or cranial ultrasound will be accepted as a replacement of brain MRI, and chest CT will be accepted as a 
replacement of chest X-Ray. 
If CBC, coagulation, biochemistry and imaging assessments cannot be performed on the day of the 
scheduled visit,  assessments within 1 day window from scheduled visit date will be accepted as a 
replacement. 
Analysis done on blood samples will favor as much as possible the use of micro-sampling techniques. 
When blood drawing needs to be limited, laboratory safety parameters (which would have been done as 
normal disease monitoring) will be prioritized.  
Volumes of blood are calculated assuming a maximum 2-week screening, 6-month treatment period with 
infusions twice a week, 1-year follow-up with emapalumab detectable at all timepoints, pregnancy test 
performed (total study duration of 18.5 months), and amount to 98 mL for study-specific assessments 
(PK, PD, ADA); 253 mL for CBC, biochemistry, coagulation and pregnancy test; 31.5 mL for search for 
infections. Amount of blood drawn per 8 weeks of study (41.4 mL) is therefore within acceptableiv 5-10% 
total blood volume draw for patients of the first year of life, and under 5% of total blood volume for older 
children. 
8.1 
SCREENING 
Patients will be screened for eligibility prior to enrolment into the study. An Eligibility Review Form 
(Appendix C) will be completed and shared with the Sponsor after the patient is consented, to guide the 
joint review of patient’s eligibility.  
A pre-screening checklist (Appendix D) is an additional tool to assist the Investigator to make decisions 
such as patient transfer,. This checklist enables rapid preliminary assessment of patient’s eligibility based 
strictly on the information available from routine patient care. The pre-screening checklist does not need 
to be shared with the Sponsor 
A screening log will be maintained by the Investigator with specification of reasons for non-eligibility. 
Screening evaluations should be completed within the 2 weeks prior to the first administration of study 
drug (Visit 1). Evaluations performed before ICF signature, but within this window and as per routine care, 
will be accepted for screening purposes. Patient’s medical record should clearly denote these evaluations 
as standard of care. 
The following information must be collected and the following procedures must be performed: 
iv WHO | Blood Sample Volumes in Child Health Research: Review of Safe Limits.” n.d. WHO. 
https://doi.org//entity/bulletin/volumes/89/1/10-080010/en/index.html.  
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Patient information: 
▪
Demographic and medical history, including race, ethnicity and
country of origin, if allowed per local Regulations
▪
Medications at Screening
▪
Any conventional HLH therapy previously received
▪
Date of HLH diagnosis and HLH history
▪
Molecular diagnosis of HLH, as available
▪
Perforin expression and other functional tests performed for the
diagnosis of HLH, as available
▪
Date and criteria of eligibility
Clinical Assessment: 
▪
Vital signs, including body temperature, heart rate, blood pressure,
and oxygen saturation
▪
Physical examination, including at a minimum, weight, height/length,
spleen and liver size (by abdominal palpation), and neurological
examination
▪
Quality of Life questionnaire: PedsQL™, Pediatric Quality of Life
Inventory™
Procedure: 
▪
ECG
Search for infectionsv: 
▪
Tuberculosis mycobacteria via interferon-gamma release assays
(IGRA)/ purified protein derivative (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 this test will be used during the
course of the study to perform regular TB monitoring.
▪
Infection search at Screening should be performed according to the
patient’s clinical presentation. At a minimum EBV and CMV viral loads
should be assessed.
▪
Atypical 
mycobacteria, 
Histoplasma 
capsulatum, 
Shigella,
Salmonella, Campylobacter and Leishmaniavi, 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
v 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. 
vi 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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is positive- confirmation should be obtained by using a Histoplasma 
capsulatum specific test. 
Laboratory: 
▪
CBC with differential count (including large unstained cells count,
whenever performed as routine)
▪
Coagulation tests: activated partial thromboplastin time and/or ratio,
prothrombin time and/or International Normalized Ratio (INR), D-
dimers and fibrinogen
▪
Biochemistry: glucose, ferritin, C-reactive protein (CRP), liver
function (aspartate amino transferase [AST], ALT, gamma glutamy
transferase 
[γGT], 
lactate 
dehydrogenase 
[LDH], 
alkaline
phosphatase [ALP], bilirubin), renal function (albumin, creatinine and
urea) and triglycerides (fasting whenever possible)
▪
Pregnancy test (blood or urine), if applicable
Imaging: 
▪
Abdominal ultrasound (spleen longitudinal measure)
▪
Chest X-ray (or chest CT as an alternative)
▪
Brain MRI to be performed in case of CNS disease (brain CT or cranial
ultrasound as an alternative)
Histopathology: 
Safety:  
▪
CSF Analysis (if coagulation allows)
▪
Recording of any AEs occurred since signature of the ICF
8.2 
VISIT 1 (INFUSION 1 OF EMAPALUMAB; SD0) 
The following assessments are to be performed pre-infusion at Visit 1 (SD0): 
Clinical Assessment: 
▪
Vital signs, including body temperature, heart rate, blood pressure,
and oxygen saturation 
▪
Physical examination, including as a minimum, weight, spleen and
liver size (by abdominal palpation), and neurological examination
Laboratory: 
▪
CBC with differential count (including large unstained cells count,
whenever performed as routine)
▪
Coagulation tests: activated partial thromboplastin time and/or ratio,
prothrombin time and/or INR, D-dimers and fibrinogen
▪
Biochemistry: glucose, ferritin, CRP, liver function (AST, ALT, γGT,
LDH, ALP, bilirubin), renal function (albumin, creatinine and urea) and
triglycerides (fasting whenever possible)
▪
Urinalysis: glucose, blood, protein and/or albumin, leucocytes,
ketones, pH and specific gravity
Imaging 
▪
Abdominal ultrasound (spleen longitudinal measure), if 2 weeks or
longer elapsed between the screening visit and SD0
Safety: 
▪
Recording of any AEs occurred since last screening visit or prior to
infusion
PK: 
▪
Emapalumab serum concentrations
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PD: 
▪ CXCL9, CXCL10, sCD25, total IFNγ  
Immunogenicity: 
▪ ADAs 
IMP Handling: 
▪ Preparation, dispensing, and accountability 
The infusion will be administered over a period of 1 to 2 hours depending on the volume to be infused. 
Blood pressure, heart rate and oxygen saturation (pulse oximetry) will be collected every 15 minutes 
during and until the end of the infusion. 
The following assessments are to be performed post-infusion: 
Vital sign assessment:
▪
Heart rate, oxygen saturation, blood pressure and temperature at
the end of the infusion, 1 hour and 2 hours after completion of 
emapalumab infusion  
PK: 
▪
Emapalumab serum concentration.
8.3 
VISIT 2 (INFUSION 2 OF EMAPALUMAB; SD3) 
The following assessments are to be performed pre-infusion at Visit 2 (SD3): 
Clinical Assessment: 
▪
Vital signs, including body temperature, heart rate, blood pressure,
and oxygen saturation 
▪
Physical examination, including as a minimum, weight, spleen and
liver size (by abdominal palpation), and neurological examination
Laboratory: 
▪
CBC with differential count (including large unstained cells count,
whenever performed as routine)
▪
Coagulation tests: activated partial thromboplastin time and/or ratio,
prothrombin time and/or INR, D-dimers, and fibrinogen
▪
Biochemistry: glucose, ferritin, CRP, liver function (AST, ALT, γGT,
LDH, ALP, bilirubin), renal function (albumin, creatinine and urea) and
triglycerides (fasting whenever possible)
Safety: 
▪ Recording of any AEs occurred since start of first infusion 
PK: 
▪ Emapalumab serum concentrations 
PD: 
▪ CXCL9, CXCL10, sCD25, total IFNγ 
IMP Handling: 
▪ Preparation, dispensing, and accountability 
The infusion will be administered over a period of 1 to 2 hours depending on the volume to be infused. 
The second infusion must be administered on SD3.  
During the infusion, monitoring of heart rate and oxygen saturation will be performed, with recording of 
values at 30 minutes after the beginning of the infusion. If this is the first infusion at an increased dose of 
emapalumab, and/or patient has experienced an infusion-related reaction, blood pressure, heart rate and 
oxygen saturation are to be collected every 15 minutes during and until the end of the infusion.  
The following assessments are to be performed post-infusion: 
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Vital sign assessment: 
▪
Heart rate, oxygen saturation, blood pressure and temperature at
the end of the infusion, 1 hour and 2 hours after completion of
emapalumab infusion
PK: 
▪
Emapalumab serum concentration.
8.4 
VISIT 3 AND ONWARDS (INFUSION 3 OF EMAPALUMAB AND ONWARDS) 
The following assessments are to be performed pre-infusion at all visits from Visit 3 onwards, unless 
specified differently: 
Clinical Assessment: 
▪
Vital signs, including body temperature, heart rate, blood pressure,
and oxygen saturation
▪
Physical examination, including as a minimum, weight, spleen and
liver size (by abdominal palpation), and neurological examination
▪
Assessment of clinical response every 2 weeks
Search for infections: 
▪
TB by PCR (every 4 weeks)
▪
Infection search & monitoring in case of suspicion of infection or if
there is an active infection at screening/baseline to monitor
evolution of viral load and positivity for an identified pathogen
▪
Atypical 
mycobacteria, 
Histoplasma 
capsulatum, 
Shigella,
Salmonella, Campylobacter, Leishmania - if an infection is suspected
Laboratory: 
▪
CBC with differential count (including large unstained cells count,
whenever performed as routine)
▪
Coagulation tests: activated partial thromboplastin time and/or ratio,
prothrombin time and/or INR, D-dimers and fibrinogen
▪
Biochemistry: glucose, ferritin, CRP, liver function (AST, ALT, γGT,
LDH, ALP, bilirubin), renal function (albumin, creatinine and urea) and
triglycerides (fasting whenever possible)
Imaging: 
▪
Abdominal ultrasound with spleen longitudinal measure (every 2
weeks during emapalumab treatment)
▪
Chest X-ray - in case of clinical suspicion of pulmonary infection or to
monitor existing abnormalities
Safety: 
▪
Recording of any AEs occurred since last visit
PK: 
▪
Emapalumab serum concentration (every other infusion starting
from Visit 3)
PD: 
▪
CXCL9, CXCL10, sCD25, total IFNγ (every other infusion starting from
Visit 3)
Immunogenicity: 
▪
ADAs (only at Week 4, together with a PK sample)
IMP Handling: 
▪
Preparation, dispensing, and accountability
The infusion will be administered over a period of 1 to 2 hours twice a week (not more than 4 days apart). 
Monitoring of heart rate and oxygen saturation will be performed, with recording of values at 30 minutes 
after the beginning of the infusion. If this is the first infusion at an increased dose of emapalumab, and/or 
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patient has experienced an infusion-related reaction, blood pressure, heart rate and oxygen saturation 
are to be collected every 15 minutes during and until the end of the infusion. 
The following assessments are to be performed post-infusion at Visit 3 and onwards: 
Vital sign assessment: 
▪
Heart rate, oxygen saturation, blood pressure and temperature at the
end of the infusion, 1 hour and 2 hours after completion of 
emapalumab infusion 
PK: 
Clinical Assessment: 
▪
Emapalumab serum concentration (every other infusion starting from
Visit 3)
▪
QOL questionnaire - PedsQL™, Pediatric Quality of Life Inventory™ (at
Visit 3 only)
During treatment, emapalumab and biomarker concentrations may be measured in other matrices, such 
as CSF or BAL, if samples obtained in procedures which are performed for diagnostic/therapeutic 
purposes can also be available for these exploratory investigations, and if clinically indicated. 
8.5 
WEEK 8 ASSESSMENT VISIT (3 DAYS AFTER WEEK 8 INFUSION) AND END OF TREATMENT VISIT 
(3 DAYS AFTER LAST EMAPALUMAB INFUSION) 
These visits will include a full patient`s assessment. 
The Week 8 Assessment Visit will be performed 3 (1) days after the last Week 8 emapalumab infusion. 
If treatment with emapalumab is completed before Week 8, only an EOT visit will be performed 3 (1) 
days after the last infusion. 
For patients continuing treatment beyond Week 8, an EOT visit will be conducted 3 (1) days after the 
last emapalumab infusion. 
The following assessments are to be performed at the Week 8 Assessment Visit and at the EOT Visit: 
Clinical Assessment: 
▪
Vital signs, including body temperature, heart rate, blood pressure,
and oxygen saturation 
▪
Physical examination, including as a minimum, weight, spleen and
liver size (by abdominal palpation), and neurological examination
▪
Assessment of clinical response
▪
QOL questionnaires - PedsQL™, Pediatric Quality of Life Inventory™,
BASES (BASES only at EoT and if HSCT is planned)
Procedure: 
▪
ECG (only at EOT)
Search for infections: 
▪
TB by PCR (if not performed within the last 4 weeks)
▪
Infection search & monitoring in case of suspicion of infection or if
there is an active infection at screening/baseline to monitor
evolution of viral 
load 
and 
positivity 
for an 
identified
pathogenAtypical mycobacteria, Histoplasma Capsulatum, Shigella,
Salmonella, Campylobacter, Leishmania – only if an infection is
suspected
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Laboratory: 
▪
CBC with differential count (including large unstained cells count,
whenever performed as routine)
▪
Coagulation tests: activated partial thromboplastin time and/or ratio,
prothrombin time and/or INR, D-dimers, and fibrinogen
▪
Biochemistry: glucose, ferritin, CRP, liver function (AST, ALT, γGT,
LDH, ALP, bilirubin), renal function (albumin, creatinine and urea) and
triglycerides (fasting whenever possible)
▪
Pregnancy test, if applicable (only EOT)
▪
Urinalysis: glucose, blood, protein and/or albumin, leucocytes,
ketones, pH (only EOT), gravity
Imaging: 
▪
Abdominal ultrasound with spleen longitudinal measure
Safety: 
▪
Recording of any AEs occurred since last visit
PK: 
▪
Emapalumab serum concentration
PD: 
▪
CXCL9, CXCL10, sCD25, total IFNγ
Immunogenicity: 
▪
ADAs
IMP Handling: 
▪
Preparation, dispensing, and accountability (week 8 only)
If emapalumab treatment is continued, and Week 8 Assessment Visit is performed on the same day of 
the subsequent infusion, the infusion will be administered over a period of 1 to 2 hours. Monitoring of 
heart rate and oxygen saturation will be performed, with recording of values at 30 minutes after the 
beginning of the infusion. If this is the first infusion at an increased dose of emapalumab, and/or patient 
has experienced an infusion-related reaction, blood pressure, heart rate and oxygen saturation are to be 
collected every 15 minutes during and until the end of the infusion. 
The following assessments will be performed post-infusion: 
Vital sign assessment: 
▪
Heart rate, oxygen saturation, blood pressure and temperature at
the end of the infusion, 1 hour and 2 hours after completion of 
emapalumab infusion 
PK: 
▪
Emapalumab serum concentration
8.6 
FOLLOW-UP PERIOD 
A long-term follow-up will be conducted after the completion (or premature discontinuation) of 
emapalumab treatment, until 1 year after either HSCT or last emapalumab infusion (if HSCT is not 
performed). For patients not planned to receive HSCT, the long-term follow-up period will be conducted 
according to the same schedule of post-HSCT follow-up. 
8.6.1
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.  
If the pre-conditioning and EOT visits are not combined, the following assessments are to be performed: 
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Clinical Assessment: 
 
▪ Vital signs, including body temperature, heart rate, blood pressure, 
and oxygen saturation 
▪ Physical examination, including as a minimum, spleen and liver size 
(by 
abdominal 
palpation), 
height/length 
and 
neurological 
examination 
▪ Survival 
Laboratory: 
▪ CBC with differential count (including large unstained cells count,  
whenever performed as routine)   
▪ Coagulation tests: activated partial thromboplastin time and/or ratio, 
prothrombin time and/or INR, D-dimers, and fibrinogen 
▪ Biochemistry: glucose, ferritin, CRP, liver function (AST, ALT, γGT, 
LDH, ALP, bilirubin), renal function (albumin, creatinine and urea) and 
triglycerides (fasting whenever possible)  
▪ Urinalysis: glucose, blood, protein, leucocytes, ketones, pH, gravity 
Imaging: 
▪ Abdominal ultrasound with spleen longitudinal measure 
▪ Chest X-ray. Other imaging modalities (e.g. CT) performed as part of 
pre-transplant work-up are also acceptable. 
Safety: 
▪ Recording of any AEs occurred since last visit 
PK: 
▪ Emapalumab serum concentration  
PD: 
▪ CXCL9, CXCL10, sCD25, total IFNγ. 
8.6.2 
Follow-Up Post-HSCT (or After Last Emapalumab Infusion) 
The following assessments will be performed at weekly visits after either HSCT or last emapalumab 
infusion (as applicable) until Day 30, and subsequently at Day 60, Day 100, and Month 6: 
(In addition to the below, in patients undergoing HSCT, PK/PD samples will be collected at Day 3 post-
transplant). 
Clinical Assessment: 
 
▪ Vital signs, including body temperature, heart rate, blood pressure, 
and oxygen saturation 
▪ Physical examination, including as a minimum, spleen and liver size 
(by abdominal palpation), height/length (at 6 month visit only) and 
neurological examination 
▪ Post HSCT outcome, if applicable 
▪ Survival 
▪ QOL questionnaires - PedsQL™, Pediatric Quality of Life Inventory™ 
and BASES if HSCT is performed (at Day 30, Day 100 and Month 6 
visits)   
Laboratory: 
▪ CBC with differential count (including large unstained cells count,  
whenever performed as routine)   
▪ Coagulation tests: activated partial thromboplastin time and/or ratio, 
prothrombin time and/or INR, D-dimers, and fibrinogen 
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▪
Biochemistry: glucose, ferritin, CRP, liver function (AST, ALT, γGT,
LDH, ALP, bilirubin), renal function (albumin, creatinine and urea) and
triglycerides (fasting whenever possible)
▪
Urinalysis: glucose, blood, protein and/or albumin, leucocytes,
ketones, pH, gravity
Search for infections: 
▪
TB by PCR in any relevant specimen, as clinically indicated, at
minimum at D+30, D+60, D+100, 6 month and 1 year/WD visits;  until
serum levels of emapalumab are no longer detectable
▪
Infection search & monitoring according to the patient’s clinical
presentation – in case of suspicion of infection
Imaging: 
▪
Chest X-ray – in case of clinical suspicion of pulmonary infection or to
monitor existing abnormalities
▪
Abdominal ultrasound with spleen longitudinal measure (at Day 100
visit only)
Safety: 
▪
Recording of any AEs occurred since last visit until serum levels of
emapalumab are no longer detectable. After elimination of
emapalumab only SAEs will be reported.
PK: 
▪
Emapalumab concentrations (if serum levels of emapalumab were
still measurable at the previous visit). Also at D+3 after HSCT, if
performed
PD: 
▪
CXCL9, CXCL10, sCD25, total IFNγ (if serum levels of emapalumab
were still measurable at the previous visit; then only if clinically
indicated). Also at D+3  after HSCT, if performed
Immunogenicity: 
▪
Assessment for ADAs (at Day 100 visit only)
8.6.3
End of Study: 1-Year Visit Post-HSCT (or After Last Emapalumab Infusion)/Withdrawal 
Visit 
This visit represents the last visit of the study. The following assessments will be performed: 
Clinical Assessment: 
▪
Vital signs, including body temperature, heart rate, blood pressure,
and oxygen saturation 
▪
Physical examination, including as a minimum, spleen and liver size
(by abdominal palpation), and neurological examination
▪
Post HSCT outcome, if applicable
▪
Survival
▪
QOL questionnaires - PedsQL™, Pediatric Quality of Life Inventory™ 
and BASES if HSCT is performed
Laboratory: 
▪
CBC with differential (including large unstained cells count,
whenever performed as routine)
▪
Coagulation tests: activated partial thromboplastin time and/or
ratio, prothrombin time and/or INR, D-dimers, and fibrinogen
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▪ Biochemistry: glucose, ferritin, CRP, liver function (AST, ALT, γGT, 
LDH, ALP, bilirubin), renal function (albumin, creatinine and urea) 
and triglycerides (fasting whenever possible)  
▪ Urinalysis: glucose, blood, protein, leucocytes, ketones, pH, gravity 
Search for infections: 
▪ TB by PCR in any relevant specimen (if serum levels of emapalumab 
were still measurable at the previous visit) 
▪ Infection search & monitoring according to the patient’s clinical 
presentation – in case of suspicion of infection 
Imaging: 
▪ Abdominal ultrasound with spleen longitudinal measure 
Safety: 
▪ Recording of any AEs occurred since last visit until serum levels of 
emapalumab are no longer detectable. After elimination of 
emapalumab only SAEs will be reported. 
PK: 
▪ Emapalumab concentrations (if serum levels of emapalumab were 
still measurable at the previous visit) 
PD: 
▪ CXCL9, CXCL10, sCD25, total IFNγ (if serum levels of emapalumab 
were still measurable at the previous visit, or if clinically indicated) 
Immunogenicity: 
▪ Assessment for ADAs 
 
8.7 
ASSESSMENTS IN CASE OF 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 and SAEs. 
8.8 
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, and will be taken only if the amount of blood required is acceptable in the context of the EMA 
guideline and USA pediatric recommendations (see Section 8).  
9 SAFETY MONITORING 
9.1 
DESCRIPTION OF SAFETY PARAMETERS 
Evaluation of emapalumab tolerability and safety will be based on the following parameters: 
• 
AEs (serious and non-serious) 
• 
Laboratory parameters, including:  
- 
CBC with differential counts 
- 
Coagulation tests (activated partial thromboplastin time and/or ratio, prothrombin time 
and/or INR), d-Dimer, and fibrinogen 
- 
Biochemistry: glucose, ferritin, CRP, liver function (AST, ALT, γGT, LDH, ALP, bilirubin), 
renal function (albumin, creatinine and urea) and triglycerides (fasting whenever 
possible) 
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-
TB PCR results
•
Vital signs: body temperature, heart rate, blood pressure, oxygen saturation
•
If present at baseline or emerging during treatment, the following parameters will be collected
until resolution:
-
evolution of viral load and positivity for an identified pathogen(frequency of collection
driven by site local practices).
9.2 
RECORDING AND REPORTING SAFETY PARAMETERS 
9.2.1 
Adverse Events 
Adverse events (AEs) are defined as any undesirable experience occurring to a patient during the study, 
whether or not considered related to the IMP. All  AEs occurring during the study, i.e.,  from the date of 
ICF signature up to and including the end-of-study visit must be recorded on the AE page of the electronic 
CRF (eCRF). Once emapalumab serum levels are no longer detectable, only serious AEs (SAEs) will be 
recorded on the AE page of the eCRF. 
Medical conditions present at Screening or diagnosed at the Screening visit will be recorded in the medical 
history section of the 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), including the specific situations described below. AEs are collected after signing of 
ICF up to Study Completion or  until serum levels of emapalumab are no longer detectable (whichever 
occurs first). After elimination of emapalumab only SAEs will be reported. 
Should a pre-existing medical condition worsen (clinically significant change in intensity or frequency), it 
must be recorded as an AE in the eCRF and, depending on the time of its occurrence, will be considered 
as a pre-treatment AE or a TEAE. Should a medical condition recorded as a pre-treatment AE worsen after 
start of IMP administration, it will be recorded in the eCRF as a separate TEAE, specifying `Worsening of 
xxx`.  
For all AEs, the following will be assessed and recorded: onset and end dates (and -when relevant- time), 
intensity, seriousness, relationship to IMP, action taken regarding IMP, any treatment received, and 
outcome.  
Intensity of AEs will be graded on a three-points scale (mild, moderate, severe) using the modified World 
Health Organization (WHO) toxicity scale (Grade 3 and 4 are considered to be the severe grade). If AE 
severity is not mentioned in the scale, assessment will be made using the following definitions: 
•
Mild: Discomfort noticed but no disruption of normal activity
•
Moderate: Discomfort sufficient to reduce or affect normal daily activity
•
Severe: Inability to work or perform normal daily activity
For a given AE, the assessment of its intensity should reflect the highest grade (on the three-point scale 
mentioned above) reported during its course (except when the intensity of a pre-treatment AE increases 
after treatment initiation, as indicated above).  
The relationship of AEs to the IMP will be assessed by the Investigator using a “Yes/No” classification. A 
“Yes” relationship infers that there is a reasonable suspected causal relationship to the IMP. The 
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expression “reasonable causal relationship” is meant to convey that there are facts, evidence or 
arguments to suggest a causal relationship. In this study, emapalumab is the only IMP.  
Specific situations: 
-
Common HLH signs and symptoms (e.g., anemia, neutropenia, thrombocytopenia, pancytopenia,
splenomegaly, hepatomegaly) will not be reported as separate AEs unless clearly attributed to a cause
different from HLH, and the verbatim term should indicate the cause.
-
If changes in the above mentioned HLH signs and symptoms indicate HLH worsening or reactivation,
worsening or reactivation will be reported as an AE.
-
Fever will only be reported when not linked to an identified cause with the highest temperature
considered during the period. If it is a recurrent fever it can be entered as intermittent fever with no
need to specify the temperature (the intensity should be a reflection of the highest temperature
observed). If fever is considered as a sign of a confirmed infection or of HLH worsening or reactivation,
only the diagnosis should be reported as an AE, and not `fever`.
-
Viral load positivity, in particular for EBV, CMV and adenovirus, and evolution will be collected on a
dedicated eCRF module.
-
Active infections will be reported as AEs, indicating whether constituting a primary infection or a
reactivation (whenever possible). Pathogen positivity and evolution will be collected in a dedicated
eCRF module.
-
Expected effects of conditioning (i.e., pancytopenia during conditioning and until engraftment) will
not be reported.
9.2.2
Serious Adverse Events 
 Any AE is considered “serious” if it: 
•
results in death (note: death is an outcome, not an event);
•
is life-threatening; (note: the term "life-threatening" refers to an event in which the patient was
at immediate risk of death at the time of the event; it does not refer to an event which could
hypothetically have caused a death had it been more severe);
•
requires in-patient hospitalization or prolongs an existing hospitalization;
•
results in persistent or significant disability/incapacity;
•
is a congenital anomaly/birth defect;
•
is an important medical event, i.e., refers to an event  that may not result in death, be life-
threatening, or require hospitalization but  may be considered as serious when, based upon
appropriate medical judgment, may jeopardize the patient, and may require medical or surgical
intervention to prevent one of the outcomes listed in this definition above.
The following reasons for hospitalization are exempted from being reported: 
•
elective hospitalizations for surgical procedures that are a result of a patient’s pre-existing
condition(s) which have not worsened during the study;
•
hospitalization requested for emapalumab infusion and study visits (including a possible hospital
stay overnight, if due to logistic convenience);
•
post-HSCT hospitalization as a measure of caution in this fragile population, to investigate a
clinical sign or symptom (e.g. fever), provided that the hospital stay has a duration of less than 72
hours and does not result in any confirmed new diagnosis (e.g., negative search of infection in
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presence of fever which resolves with symptomatic measures); in this case the sign will be 
recorded as an AE.  
For the initial SAE report, the Investigator should report all available case details concerning the patient 
and the event, using the Swedish Orphan Biovitrum AG SAE reporting form within 24 hours of awareness. 
Swedish Orphan Biovitrum AG contact information for SAE reporting: 
E-mail: NI-0501drugsafety@sobi.com
Relevant follow-up information on SAEs should be forwarded to Swedish Orphan Biovitrum AG as soon 
as it becomes available. In addition, the Investigator must be available to answer without delay any 
request for follow-up information or questions that Swedish Orphan Biovitrum AG may have regarding 
the SAE. 
All SAEs will be recorded on the appropriate page of the eCRF. They will be reviewed, evaluated and 
followed up until the event resolves or is considered stable by a study physician. 
If either the Sponsor or Investigator believes that the event is serious, the event must be considered 
serious and evaluated by the Sponsor for expedited reporting. 
9.2.3 
SUSAR reporting 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are SAEs that are both: 
•
related, i.e., there must be a certain degree of probability that the event is a harmful and
undesirable reaction to the IMP under investigation, regardless of the administered dose
•
unexpected, i.e., the event is not listed as an expected serious adverse reaction in the Reference
Safety Information (RSI) of the Investigator’s Brochure
All SUSARs will reported by the sponsor to relevant Health Authorities, Ethics Committees 
(ECs)/Institutional Review Boards (IRBs)/Research Ethics Boards (REB) and investigators as per 
applicable regulations. 
Under the USA 21 Code of Federal Regulation (CFR) 312.32(c), the Sponsor (directly or through a 
delegated third party) is required to notify the Food and Drug Administration (FDA) and all participating 
Investigators in an Investigational New Drug (IND) safety report (i.e., 7- or 15-day expedited report) of 
potentially serious risks from clinical trials or any other source as soon as possible, but no later than 
15 calendar days after the Sponsor receives the safety information and determines that the information 
qualifies for reporting. 
Investigators in the USA are required to promptly report to the IRB all unanticipated problems involving 
risk to human subjects or others, including AEs that should be considered unanticipated problems (21 CFR 
312.66), such as IND safety reports. 
In countries other than the USA, the Sponsor will promptly evaluate all SAEs and against cumulative 
product experience to identify and expeditiously communicate possible new safety findings to 
investigators, IRBs, ECs, REBs and applicable health authorities based on applicable legislation. 
Swedish Orphan Biovitrum AG will also report all SUSARs to the EMA's EudraVigilance database within 15 
days, as well as to the relevant National Competent Authorities when required. Fatal and life-threatening 
SUSARs will be reported within 7 calendar days, with another 8 days for completion of the report.  
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9.2.4
Managing Abnormal Laboratory Test Values 
All  laboratory tests (hematology, coagulation, blood chemistry) will be captured in the database from the 
local laboratory.  
Laboratory test abnormalities must be considered as AEs and recorded on specific AE pages of the CRF 
only if they:  
•
require specific intervention for correction, or
•
lead to a change in study medication (e.g., dose modification, interruption or permanent
discontinuation), or
•
qualify as grade 4 severity as per modified WHO toxicity scale
If a laboratory test abnormality leads to a new clinical diagnosis, the new clinical diagnosis should be 
reported as an AE rather than the laboratory abnormality.  
Laboratory test abnormality that qualifies as an AE as per the definition above,  will follow the AE/SAE 
reporting process described in this section.  
Laboratory abnormalities which are considered to be part of HLH signs and symptoms (see Section 9.2.1) 
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.   
9.3 
FOLLOW-UP OF SAFETY PARAMETERS 
9.3.1 
Follow-up of Adverse Events 
Adverse events should be followed up to resolution or stabilization or until they return to baseline status 
(in the event of an exacerbation of a pre-existing condition).  
For AEs still ongoing at study completion or withdrawal, where return to baseline status or stabilization 
cannot be established, an explanation should be recorded. 
9.3.2 
Follow-up of Abnormal Laboratory Test Values 
Abnormal laboratory findings that qualify as AEs should be followed-up as per Section 9.3.1. 
9.3.3 
Pregnancy 
Occurrence of pregnancy in a study participant will require discontinuation of the IMP and entry into the 
study follow-up period. 
Pregnancies, including pregnancies of female partners of male study participants must be reported to 
Swedish Orphan Biovitrum AG within 24 hours of awareness on the Swedish Orphan Biovitrum AG 
Pregnancy form.  
A pregnancy must be followed until its conclusion. Any AE associated with the pregnancy occurring during 
the follow-up period after study treatment discontinuation must be reported in the eCRF. Any SAE 
occurring during the pregnancy must be reported on an SAE form as described in Section 9.2.2. 
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9.4 
BENEFIT/RISK MANAGEMENT 
9.4.1
Safety Surveillance Management 
HLH is a rare disease, and experience gathered from previous exposure of patients to emapalumab is still 
limited. It is therefore required that patients are monitored during and for 2 hours after each infusion of 
emapalumab, and that infusions are administered under medical supervision within a unit having 
emergency equipment.   
The iDMC will ensure that any emergent safety concern will be assessed in a timely manner and 
appropriate measure taken for the patients, if relevant. Moreover, iDMC will be specifically tasked with 
regular assessment of the extent of benefit and fatal events prior to transplant in the treatment-naïve 
subgroup of patients. 
9.4.2
General Benefit/Risk Considerations 
9.4.2.1 Potential benefits 
Based on evidence available from comprehensive analysis of the NI-0501-04 and NI-0501-05 studies that 
formed the basis of the BLA and MAA submissions, emapalumab administration has shown the potential 
to improve or resolve relevant clinical and laboratory abnormalities of HLH. Emapalumab demonstrated 
a statistically significant and clinically relevant reduction in HLH disease activity, assessed through 
objective clinical and laboratory parameters, in 64.7% of patients. Response occurred early during 
treatment and was generally sustained. The reduction in HLH disease activity was sustained and was 
associated with an overall survival benefit that persisted following HSCT. The observed treatment effect 
was consistent across all efficacy endpoints. Emapalumab was well tolerated in doses up to 10 mg/kg and 
no off-target toxicity has been identified. Emapalumab treatment could be continued safely and 
effectively beyond 8 weeks in patients for whom the search for a donor was longer than expected. 
The response to emapalumab seems independent of: 
•
the presence and type of causative mutations
•
the presence and type of an infectious trigger
On 20 November 2018, emapalumab was approved by the FDA "for the treatment of adult and  pediatric  
(newborn and  older)  patients  with  primary  hemophagocytic lymphohistiocytosis (HLH) with refractory, 
recurrent or progressive disease or intolerance with conventional HLH therapy".   
For more details, refer to the latest Investigator’s Brochure (currently version 10.0, dated 24 January 
2020).  
9.4.2.2 Risks 
•
Infusion-related reactions
Infusion-related reactions (IRRs) are commonly associated with monoclonal antibody infusions and are 
defined as signs or symptoms with a temporal relationship to the administration of an infusion and 
assessed as related, typically occurring soon after the start of the infusion, although symptoms may be 
delayed for up to 24h. They might be limited (skin reaction) or systemic. 
After more than 1000 infusions administered to HLH patients up to the dose of 10 mg/kg, no 
anaphylactic/anaphylactoid or other significant reactions were observed with emapalumab. IRRs were 
mainly transient skin reactions observed during and shortly after emapalumab infusions (corresponding 
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to less than 2% of the infusions performed). They resolved spontaneously and did not lead to 
emapalumab permanent discontinuation.  
From the clinical experience to date, the risk of IRRs associated with emapalumab treatment seems to be 
very low. However, the infusion should be performed under medical supervision with monitoring of vital 
signs during and for 2 hours after emapalumab infusion as outline in Section 8.  
•
Immunogenicity
Occurrence of ADAs inactivating therapeutic effects of the treatment and, in rare cases, inducing adverse 
reactions, is a potential risk associated with the administration of monoclonal antibodies (mAbs). As of 
24 August 2019, treatment-emergent ADAs were detected in: 
•
1 out of 14 healthy subjects participating in study NI-0501-03; a low titer of ADAs was
measured at the last follow-up visit (at week 44 post-emapalumab administration
•
3 out of 45 patients treated in the context of NI-0501-04/05 studies
•
1 patient treated in compassionate use developed transient ADAs
No AEs, including decreased efficacy, attributable to antibodies have occurred in these patients. In 
addition, in ongoing studies in patients with sJIA/MAS (NI-0501-06, N=8) and in patients with pHLH 
(NI-0501-09, N=9), no ADA were detected. 
•
Drug-drug interactions
High IFNγ production and subsequent hyper production of other cytokines during active pHLH might 
downregulate cytochrome P450 enzymes (CYPs), resulting in suppression of CYP isoenzymes activity 
during active disease. Anti-cytokine mAbs have the potential to restore CYP activity back to normal, 
through neutralization of the pro-inflammatory cytokine which is targeted by the antibody and the 
ensuing reduction in inflammation (Morgan, 2009). The restoration of CYP activity may therefore alter 
the elimination of concomitant medications metabolized by these CYPs. During the clinical trials with 
emapalumab, no events of Therapeutic Protein-Drug Interactions (TP-DI) were reported in pHLH patients. 
•
Infections
The impact on the immune defense caused by the neutralization of IFNγ is known from patients with 
inborn errors of the IL-12/23-IFN-γ circuit, particularly patients with complete or partial IFNγ receptor (R) 
deficiency, and patients developing neutralizing auto anti-IFNγ antibodies. Patients with IFNγ R deficiency 
are prone to develop mycobacterial infections and, although to a lesser extent, Salmonella infections 
(Dorman 2000, Jouanguy 1997). The mean age of the first environmental mycobacterial infection is 3.1 
and 13.4 years in patients with complete and partial deficiency, respectively (Remus 2001).  
No systematic prophylaxis is recommended in these patients. If an infection occurs, appropriate antibiotic 
therapy based on sensitivity of isolated species is prescribed. 
Individuals with anti-IFNγ auto-antibodies are also susceptible to develop mycobacterial infections (for 
the vast majority atypical mycobacterial infections), but also opportunistic infections (e.g., caused by 
Histoplasma capsulatum, Salmonella, HZV) (Browne 2012). 
Toxicological studies carried out with emapalumab have shown an increased susceptibility to enteral 
pathogen infections in monkeys having received emapalumab, when the enteral pathogen was present 
in the intestinal tract prior to emapalumab administration. Therefore, presence of infections due to 
Shigella, Salmonella and Campylobacter pathogens is part of the exclusion criteria. 
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As to the development of infections caused by pathogens known to be favored by the absence of IFNγ 
biological activity, a reactivation of HZV (which resolved after a normal course with no sequelae) was 
observed in one healthy volunteer, at a dose of 3 mg/kg; and one HLH patient enrolled in the NI-0501-04 
study developed a disseminated histoplasmosis which resulted in treatment discontinuation. This 
infection resolved with adequate antifungal therapy, even though emapalumab was still at detectable 
concentrations in blood.  
Other infections reported during or after administration of emapalumab are the same ones commonly 
observed in immunocompromised patients or are the same ones described in pediatric populations 
(seasonal viral infections). Patients with active infections (except for the exclusionary ones) were enrolled 
and treated in the study. The presence of active infections did not lead to the discontinuation or dose 
decrease of emapalumab treatment, and infections resolved on study drug when treated appropriately 
and not associated with a refractory disease status.  Severe or serious infections were generally reported 
in patients with previous recent significant exposure to immunosuppressive treatments as they added an 
additional risk factor for infection development. Importantly, emapalumab treatment has not been 
associated with myelosuppression. 
Active infections, as per patient’s clinical presentation, must be carefully followed over time, including 
quantitative monitoring (e.g. viral loads, antigenemia, antigenuria), when relevant. 
For more details refer to the latest Investigator’s Brochure (currently version 10.0, dated 24 January 
2020).  
9.4.2.3 Risk minimization measures 
In view of the above reported considerations, the benefit/risk profile of emapalumab in children 
diagnosed with pHLH is considered to be favorable.  
Specific measures are implemented to minimize the potential risks described above  as follows: 
•
As per eligibility criteria, patients with evidence of active Mycobacteria, Histoplasma,
Shigella, Salmonella, Campylobacter or Leishmania infections, or latent tuberculosis will not
be included in the study (for details see Section 4.1.2). Patients who received live or
attenuated live vaccine within 6 weeks prior to screening are excluded from the studies with
emapalumab.
•
Monitoring of IRRs: infusions will be performed under medical supervision to immediately
identify the occurrence of any IRRs. Each of the specialized centers will have personnel
adequately trained in IRR management.
•
Prophylaxis for HZV for all patients, and tuberculosis for a defined subpopulation (see Section
6.2), is required per protocol.
•
Occurrence of emerging infections and evolution of pre-existing infections are monitored
through regular physical examination and laboratory testing, including detection of
tuberculosis. Ad hoc search for infections will be performed based on signs and symptoms
indicating a suspicion of infection. Empirical antibiotherapy will be introduced when deemed
appropriate, and proper monitoring of active pre-existing infections or emerging infections
will be conducted.
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10 STOPPING RULES 
10.1 AT PATIENT LEVEL 
10.1.1 
Decision to Slow Down or Stop Emapalumab Infusion due to Systemic Reaction 
During the infusion of emapalumab, any significant change compared to pre-infusion values in vital signs, 
such as those listed below, should trigger appropriate immediate care:  
•
Sudden and sustained increase or paradoxical decrease of heart rate (duration of more than
5 minutes) compared to pre-infusion value and not linked to child’s anxiety or fear;
•
Sustained (an episode of more than 5 minutes duration or more than 3 episodes of shorter
duration, i.e., 3 minute) oxygen desaturation (below 90%);
•
Any clinical sign or complaint indicative of patient distress
The decision to interrupt the infusion might be taken by the physician in the event of any of the above 
mentioned occurrences. 
The decision to restart the infusion will be based on the evolution of the patient`s status (i.e., resolution 
of symptoms after appropriate symptomatic measures, e.g., oxygenation or administration of anti-
histamine treatment), and upon physician’s own medical judgment. The infusion will generally be 
restarted at a lower rate. 
All changes in infusion rate will be recorded in the patient’s medical chart and the eCRF each time there 
is a rate modification, as well as at the end time of premature or delayed termination of the infusion.  
10.1.2 
Local Issues During Emapalumab Infusion 
Unless related to a hypersensitivity reaction, a local infusion issue such as catheter displacement, 
obstruction or product extravasation, will trigger the infusion of the remaining quantity through a new 
venous access as soon as possible. All information related to the incident will be recorded accurately in 
the patient’s medical chart prior to being entered in the eCRF. This includes reasons, volume of IMP 
potentially lost (to calculate the quantity of drug infused), time at which the infusion stopped, time at 
which the infusion was resumed and time of end of the infusion.  
To avoid this type of incident, it is preferable that a central venous access is used: this will improve 
patient’s comfort and ensure a reliable drug administration in particular in infants and toddlers or in case 
of foreseen difficulties with peripheral venous access.  
10.1.3 
Decision to Discontinue Treatment or to Withdraw from the Study 
The Investigator can decide at any time during the study to discontinue the treatment for an individual 
patient based on his/her own medical judgment, taking into account the individual benefit/risk ratio for 
his/her patient. After treatment discontinuation (for any reason), the patient will continue in the study 
for a long-term follow-up. 
In addition, the patient (or their legal representative) can decide at any time to withdraw from the study. 
The reason for premature treatment discontinuation or study withdrawal should be documented in the 
patient’s chart and shared with the Sponsor. 
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The Investigator may request expert advice or a discussion with the Sponsor to receive additional 
information, if relevant prior to taking a decision; however, the ultimate decision remains the 
Investigator`s responsibility.  
In any case, the decision to withdraw or be withdrawn from the study and/or treatment will have no 
impact on the patient’s care and on further treatments administered to him/her after withdrawal. The 
management of these patients is described in Section 10.3. 
10.2 AT STUDY LEVEL 
Recruitment may be temporarily suspended in the following situations: 
•
occurrence of unexpected fatal or life-threatening  adverse reactions;
•
emergence of severe drug reactions linked to a common cause/ risk factor at different sites
Patients already enrolled in the study should continue receiving emapalumab per protocol unless decided 
otherwise by the Investigator. 
The suspension will allow for the analysis of  the available data by the Sponsor and  the iDMC. 
After re-evaluation of benefit/risk, the sponsor and iDMC may recommend any of the following: 
•
to resume recruitment without any change;
•
to implement risk minimization measures that may require protocol amendment;
•
to implement conditions for study termination, e.g., next occurrence of a particular serious drug
reaction
The management of patients already enrolled in the study will also be part of the iDMC recommendations. 
10.3 MANAGEMENT OF TREATMENT DISCONTINUATION 
All patients who discontinue emapalumab treatment will be treated according to the standard care at the 
site. However, it is recommended they continue in the study for long-term follow-up monitoring. 
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 prior to the locking of the study database. This section contains 
an overview of the planned methods of analysis. 
11.1 SAMPLE SIZE  
The sample size calculation is based on the primary efficacy endpoint of “Overall Response”. 
Assuming an Overall Response Rate of 65%, a minimum of 34 treated patients is required to show a 
significant improvement above 40% with 85% power using an exact binomial test at a one-sided 
significance level of 2.5%.   A drop-out rate of 20% may be expected, hence a total maximum of 41 patients 
may be enrolled. 
Due to the rarity of pHLH, recruitment is competitive across all European and NA sites in order to gather 
data in a reasonable timeframe. 
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11.2 ANALYSIS SETS  
All analysis sets will be defined prior to final database closure. In addition to the analysis sets listed below, 
further exploratory analyses may be performed using other subgroups of patients. 
11.2.1 
All Treated Analysis Set 
The All Treated Analysis Set will include all patients who receive any part of an infusion of study drug, and 
will be as the Primary Efficacy and Safety Analysis Set. 
11.2.2 
Evaluable Analysis Set 
The Evaluable Analysis Set will consist of patients in the All Treated Analysis Set who are evaluable for 
efficacy, i.e.: 
•
Have received a minimum of 3 consecutive infusions of emapalumab
•
Have not had a diagnosis of secondary HLH subsequent to the initiation of emapalumab
treatment
11.2.3 
Enrolled Population Analysis Set 
The Enrolled Population Analysis Set will include all subjects who sign the inform consent. This population 
will be used for disposition and major protocol deviations summaries only. 
11.3 STATISTICAL AND ANALYTICAL METHODS 
For measurements of continuous endpoints, summary statistics will include n, mean, median, standard 
deviation, minimum and maximum values. For binary data (proportions of patients showing a defined 
response for example) numbers and percentages will be tabulated. For time to event data, Kaplan-Meier 
plots will be provided together with the median should this be available. Finally, 95% confidence intervals 
will be calculated for suitable summary statistics associated with endpoints of interest. 
Efficacy analyses will be conducted on both the All Treated and Evaluable Analysis Sets. Safety analyses 
will be conducted on the safety set. 
11.3.1 
Efficacy Data 
The analysis of the primary endpoint, Overall Response Rate, will utilize an exact binomial test to evaluate 
the null hypothesis that the response rate is at most 40%. This test will be undertaken at the one-sided 
0.025 level.  
Time to Response, Duration of Response, and Survival time will be presented using Kaplan-Meier curves 
with medians calculated if available. Ninety-five percent confidence intervals will be calculated for the 
median for each of these endpoints.  
For maintenance of response achieved any time during the study, event of interest will be the loss of 
response, with patients in response being censored on the day starting conditioning. 
Additional endpoints based on binary outcomes including number of patients who reduce glucocorticoids 
by 50% or more, and number of patients able to proceed to HSCT will be converted to proportions and 
associated 95% confidence intervals calculated. 
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Statistical significance in terms of p-values will only be obtained for the primary endpoint in both the All 
Treated and the Evaluable analysis sets. All other endpoints will be viewed as supportive for the primary 
endpoint and as a consequence no formal hierarchy of endpoints will be declared. 
11.3.2 
Safety Data 
All data relating to safety will be listed and summarized using descriptive statistics. 
AEs will be coded and tabulated by body system, and by individual events within each body system. AEs 
will also be tabulated by severity and relationship to the study medication. Summaries will also be 
produced for 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. 
11.3.3 
Pharmacodynamic Data 
All PD data will be summarized using appropriate graphical and tabular presentations. 
Exploratory statistical models will be fitted, and correlation analyses undertaken, to investigate the 
relationships between PD data and other biomarkers 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. 
11.3.4 
Immunogenicity Data 
The numbers of patients with anti-drug antibodies present at each assessment point will be summarized. 
11.3.5 
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 evaluated for the primary and key secondary endpoints. 
11.4 REPLACEMENT POLICY 
11.4.1 
For Patients 
Additional patients will be recruited into the study if patients are withdrawn from the study for reasons 
other than safety or lack of efficacy to ensure a sample size of a minimum of 34 patients. 
11.4.2 
For Centers 
A center may be replaced for the following administrative reasons: excessively slow recruitment, poor 
protocol adherence.  
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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 Swedish Orphan Biovitrum AG, its authorized representative, 
and Investigators abide by Good Clinical Practice (GCP), as described in International Conference on 
Harmonization (ICH) Guideline E6 and in accordance with the general ethical principles outlined in the 
Declaration of Helsinki. The study will receive approval from an IRB/IEC/REB 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 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. 
The Investigator is responsible for keeping a record of all patients (or their legally authorized 
representative) who sign an informed consent document and are screened for entry into the study. 
Patients who fail screening must have the reason(s) recorded in their source documents and the study-
screening log. The Investigator 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 Investigators’ 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 types of verification. The Investigator must ensure timely and accurate completion of eCRFs 
and queries. 
12.3 CONSENT 
Before being admitted to the clinical study, the patient must consent to participate after the nature, 
scope, and possible consequences of the clinical 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 must be in a language 
understandable to the patient and must specify who informed the patient, and when the informed 
consent was obtained.  
Information to patients will be split into a Patient Information Sheet that provides detailed information 
about the trial and its benefits and risks, and the Informed Consent Form that 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 partake in the study. 
If applicable, since minors are involved in the trial, assent must be obtained from the minor and informed 
consent from at least one of the parents or as mandated by local rules (individual or judicial or other body 
authorized under applicable law to consent on behalf of a prospective patient to the patient’s 
participation in the procedures involved in the research). The language used in the Assent Form is adapted 
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to the maturity level of the minor involved in the trial. Since minors of different age groups are likely to 
be entered into the trial different versions of the Assent Form will be provided. The modalities for 
obtaining informed consent from the parents and Assent from the minor will be defined at the site 
initiation visit and documented in the clinical trial center Trial Master File (TMF). 
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 discussions. A copy of the signed consent 
document must be given to the patient or their legally authorized representative. The Investigator will 
retain the original signed consent document. The Investigator will not undertake any measures 
specifically required only for the clinical study until valid consent has been obtained. 
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 
Swedish Orphan Biovitrum AG affirms the patient's right to protection against invasion of privacy and to 
be in compliance with ICH-GCP and other local regulations (whichever is more stringent). Swedish Orphan 
Biovitrum AG requires the Investigator to permit Swedish Orphan Biovitrum AG representatives and when 
necessary, representatives from regulatory authorities, to review and/or copy any medical records 
relevant to the study in accordance with local laws (any copies of patients’ records must be duly 
anonymized to protect patients’ confidentiality). 
Should direct access to medical records require a waiver or authorization separate from the patient’s 
statement of informed consent, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual. 
12.5 PROTOCOL AMENDMENTS 
Substantial amendments will be submitted to the IRB/IEC/REB for written approval and where applicable 
to National Competent Authorities. Written approval must be obtained before implementation of the 
amended version occurs. The written signed approval from the IRB/EC/REB should specifically reference 
the Principal Investigator’s name, protocol number, study title and amendment number(s) that is/are 
applicable. 
12.6 APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS 
Before the start of the study, the study protocol, informed consent document, and any other appropriate 
documents will be submitted to the IRB/IEC/REB with a cover letter or a form listing the documents 
submitted, their dates of issue, and the site (or region or area of jurisdiction, as applicable) for which 
approval is sought. If applicable, the documents will also be submitted to the authorities in accordance 
with local legal requirements. 
Swedish Orphan Biovitrum AG can only supply study drug to an Investigator after Swedish Orphan 
Biovitrum 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 
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IRB/IEC/REB and their occupation and qualifications. If the IRB/IEC/REB will not disclose the names of the 
committee members, it should be asked to issue a statement confirming that the composition of the 
committee is in accordance with GCP. Formal approval by the IRB/IEC/REB 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 a committee member (chairman or secretary of the 
IRB/IEC/REB. Before the first patient is enrolled in the study, all ethical and legal requirements must be 
met. 
The IRB/IEC/REB and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to determine 
whether formal approval must be sought and whether the informed consent document should also be 
revised. 
The Investigator must keep a record of all communication with the IRB/IEC/REB. This statement also 
applies to any communication between the Investigator and regulatory authorities. 
All documents handed over to patients or their legal representative prior to use must first be reviewed 
and approved by Swedish Orphan Biovitrum AG, and upon approval by Swedish Orphan Biovitrum AG 
submitted to and reviewed and approved by, the competent IRB/IEC/REB. This includes but is not limited 
to the informed consent form, patient information sheet, assent form, advertisements, training materials, 
etc. 
12.7 ONGOING INFORMATION FOR IRB/IEC/REB 
If required by legislation or the IRB/IEC/REB, the Investigator must submit to the IRB/IEC/REB: 
•
Information on SAEs, SUSARs, 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 
Swedish Orphan Biovitrum 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/REB, regulatory authorities). 
In addition, Swedish Orphan Biovitrum 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 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
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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 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 (if applicable), and enrolment log
•
Record of all communications between the Investigator and the IRB/IEC/REB
•
Composition of the IRB/IEC/REB
•
Record of all communications between the Investigator, Swedish Orphan Biovitrum AG and their
authorized representative
•
List of sub-investigators and other appropriately qualified persons to whom the Investigator has
delegated significant trial-related duties, together with their roles in the study, curricula vitae and
their signatures
•
Copies of CRFs and of documentation of corrections for all subjects
•
“Drug 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 Swedish Orphan Biovitrum AG for permission to make 
alternative arrangements. Details of these arrangements should be documented in the clinical trial 
center’s TMF. 
12.10 LIABILITY AND INSURANCE 
Liability and insurance provisions for this study are provided in the Investigator contract. 
12.11 FINANCIAL DISCLOSURE 
Investigators are required to provide financial disclosure information to allow Swedish Orphan Biovitrum 
AG to submit complete and accurate certification or disclosure statements in accordance with applicable 
national and local regulations, including FDA CFR21 requirements. In addition, Investigators must provide 
Swedish Orphan Biovitrum 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.  
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Swedish Orphan Biovitrum AG will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, Swedish Orphan Biovitrum AG will support 
publication of multicenter trials only in their entirety and not as individual center data.  
Authorship will be determined by mutual agreement and in line with ICMJE authorship requirements. Any 
formal publication of the study in which contribution of Swedish Orphan Biovitrum AG personnel 
exceeded that of conventional monitoring will be considered as a joint publication by the Investigator and 
the appropriate Swedish Orphan Biovitrum 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 Swedish Orphan Biovitrum AG prior to submission. This allows Swedish Orphan 
Biovitrum 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 Swedish Orphan 
Biovitrum AG, except where agreed otherwise. 
13 MONITORING AND AUDITING 
All aspects of the study will be monitored by Swedish Orphan Biovitrum AG or its representative for this 
study (Swedish Orphan Biovitrum AG authorized representative), for compliance with applicable 
government regulations with respect to current GCP and standard operating procedures. Direct access to 
the on-site study documentation and medical records must be ensured. 
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/REB correspondence, investigational product and supplies 
shipment manifests, monitoring logs, or correspondence with Swedish Orphan Biovitrum AG and with 
any of its representative for this study). When a copy is used to replace an original document, the copy 
should fulfil 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/REB review, and domestic or foreign regulatory inspection(s) by providing direct access to source 
documents, CRFs, and all other study documentation. 
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The Investigator should promptly notify Swedish Orphan Biovitrum AG of any inspections scheduled by 
any regulatory authorities and promptly forward to Swedish Orphan Biovitrum AG copies of any audit 
reports received. 
13.3 SERIOUS GCP BREACHES 
Swedish Orphan Biovitrum AG is required to report a serious GCP Breach within 7 days of awareness of 
the breach to applicable health authorities.  
A serious GCP breach is a breach likely to affect to a significant degree the safety (both physical and 
mental) 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, Swedish Orphan Biovitrum AG must be notified within 24 hours. 
14 DOCUMENTATION AND USE OF STUDY FINDINGS 
14.1 DOCUMENTATION OF STUDY RESULTS 
An 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 CRF, the 
names, positions, signatures, and initials of these persons must be supplied to Swedish Orphan Biovitrum 
AG or their authorized representative before these individuals start completing CRF information.  
Swedish Orphan Biovitrum AG will ensure that the Investigator has control of and continuous access to 
the eCRF data reported to the Sponsor. Swedish Orphan Biovitrum AG will not have exclusive control of 
those data. 
The eCRF pages must be reviewed and signed by the Investigator named in the study protocol or by a 
designated sub-Investigator. Swedish Orphan Biovitrum AG will ensure that the CRF copies left with the 
Investigator (print-outs and/or CD-ROM) 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 
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, 
the name of the person making the change, the date and the hour 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 associates, 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 
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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.  
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15 REFERENCES 
A'Hern RP. Sample size tables for exact single-stage phase II designs. Stat Med. 2001;20(6):859-866. 
Arico M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the 
International Registry. FHL Study Group of the Histiocyte Society. Leukemia. 1996;10(2):197-203. 
Behrens EM, Canna SW, Slade K, et al. Repeated TLR9 stimulation results in macrophage activation 
syndrome-like disease in mice. J Clin Invest. 2011;121(6):2264-2277. 
Billiau A. Interferon-gamma: biology and role in pathogenesis. Adv Immunol. 1996;62:61-130. 
Bracaglia C, de Graaf K, Pires Marafon D, et al. Elevated circulating levels of interferon-gamma and 
interferon-gamma-induced chemokines characterise patients with macrophage activation syndrome 
complicating systemic juvenile idiopathic arthritis. Ann Rheum Dis. 2017;76(1):166-172. 
Browne SK, Burbelo PD, Chetchotisakd P, et al. Adult-onset immunodeficiency in Thailand and Taiwan. N 
Engl J Med. 2012;367(8):725-734. 
Buatois V, Chatel L, Cons L, et al. Use of a mouse model to identify a blood biomarker for IFNgamma 
activity in pediatric secondary hemophagocytic lymphohistiocytosis. Translational research : the journal 
of laboratory and clinical medicine. 2017;180:37-52 e32. 
De Benedetti F, Brogan P, Grom A, Quartier P, Schneider R, De Graaf K, Jacqmin P, Ballabio M, Cristina de 
Min C. “OP0204 emapalumab, an interferon gamma (INF-Y)-blocking monoclonal antibody, in patients 
with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA).” 
Annual European Congress of Rheumatology, EULAR 2019, 12–15 June 2019. Madrid: Annuals of the 
Rheumatic Diseases, 2019. 78:S2. 
Dhote R, Simon J, Papo T, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of 
twenty-six cases and literature review. Arthritis Rheum. 2003;49(5):633-639. 
Dorman SE, Holland SM. Interferon-gamma and interleukin-12 pathway defects and human disease. 
Cytokine Growth Factor Rev. 2000;11(4):321-333. 
Failla V, Nikkels AF. Ustekinumab and herpes zoster. Dermatology. 2011;222(2):119-122. 
Henter JI, Elinder G, Soder O, Hansson M, Andersson B, Andersson U. Hypercytokinemia in familial 
hemophagocytic lymphohistiocytosis. Blood. 1991;78(11):2918-2922. 
Henter JI, Elinder G, Soder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic 
lymphohistiocytosis. Acta Paediatr Scand. 1991;80(4):428-435. 
Henter JI, Horne A, Arico M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic 
lymphohistiocytosis. Pediatric blood & cancer. 2007;48(2):124-131. 
Henter JI, Samuelsson-Horne A, Arico M, et al. Treatment of hemophagocytic lymphohistiocytosis with 
HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100(7):2367-2373.Janka 
GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr. 1983;140(3):221-230. 
Jordan M, Locatelli F, Allen C. A novel targeted approach to the treatment of Hemophagocytic 
Lymphohistiocytosis (HLH) with an anti-Interferon Gamma (IFNγ) monoclonal Antibody (mAb), NI-0501: 
First results from a pilot phase 2 study in children with primary HLH. Blood. 2015;LBA-3:126. 
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Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic 
lymphohistiocytosis. Blood. 2011;118(15):4041-4052. 
Jordan MB, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis 
(HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood. 2004;104(3):735-743. 
Jordan MB, Henry M, Allen C, McClain K, Greenberg J, Ladisch S, Hermiston M, Jeng M, Degar B, Kanter J, 
Naqvi A, Joyce M, Nichols K, Teachey D, Marsh R, Grimley M, and Davies S; A Combination of ATG and 
Etoposide for theTreatment of HLH: Results of The HIT-HLH Trial, Abstracts from the 32nd Annual Meeting 
of the Histiocyte Society, Dublin, Ireland, October 17–19, 2016 
Jouanguy E, Altare F, Lamhamedi-Cherradi S, Casanova JL. Infections in IFNGR-1-deficient children. J 
Interferon Cytokine Res. 1997;17(10):583-587. 
Kogl T, Muller J, Jessen B, et al. Hemophagocytic lymphohistiocytosis in syntaxin-11-deficient mice: T-cell 
exhaustion limits fatal disease. Blood. 2013;121(4):604-613. 
Marsh RA, Allen CE, McClain KL, Weinstein JL, Kanter J, Skiles J, Lee ND, Khan SP, Lawrence J, Mo JQ, 
Bleesing JJ, Filipovich AH, Jordan MB.  Salvage therapy of refractory hemophagocytic lymphohistiocytosis 
with alemtuzumab. Pediatr Blood Cancer. 2013 Jan;60(1):101-9. 
Morgan E. Impact of Infectious and Inflammatory Disease on Cytochrome P450–Mediated Drug 
Metabolism and Pharmacokinetics. Clin Pharmacol Ther 2009 85, 434–438.  
Pachlopnik Schmid J, Ho CH, Chretien F, et al. Neutralization of IFNgamma defeats haemophagocytosis in 
LCMV-infected perforin- and Rab27a-deficient mice. EMBO molecular medicine. 2009;1(2):112-124. 
Phipps S., Hinds P:S., Channell S., Bell G. L., Measurement of Behavioral, Affective, and Somatic Responses 
to Pediatric Bone Marrow Transplantation: Development of the BASES Scale. Journal of Pediatric 
Oncology Nursing, 1994; 11(3): 109-117 
Phipps S, Dunavant M & Garvie PA et al. Acute health-related quality of life in children undergoing stem-
cell transplants. I-Descriptive outcomes. II Medical and demographic determinants. Bone Marrow 
Transplant 2002; 29: 425−442. 
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. J Allergy Clin Immunol. 2017 Aug 12 
Remus N, Reichenbach J, Picard C, et al. Impaired interferon gamma-mediated immunity and 
susceptibility to mycobacterial infection in childhood. Pediatr Res. 2001;50(1):8-13. 
Risdall RJ, Brunning RD, Hernandez JI, Gordon DH. Bacteria-associated hemophagocytic syndrome. 
Cancer. 1984;54(12):2968-2972. 
Risdall RJ, McKenna RW, Nesbit ME, et al. Virus-associated hemophagocytic syndrome: a benign 
histiocytic proliferation distinct from malignant histiocytosis. Cancer. 1979;44(3):993-1002. 
Schoenborn JR, Wilson CB. Regulation of interferon-gamma during innate and adaptive immune 
responses. Adv Immunol. 2007;96:41-101. 
Sepulveda FE, Debeurme F, Menasche G, et al. Distinct severity of HLH in both human and murine mutants 
with complete loss of cytotoxic effector PRF1, RAB27A, and STX11. Blood. 2013;121(4):595-603. 
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Strippoli R, Carvello F, Scianaro R, et al. Amplification of the response to Toll-like receptor ligands by 
prolonged exposure to interleukin-6 in mice: implication for the pathogenesis of macrophage activation 
syndrome. Arthritis Rheum. 2012;64(5):1680-1688. 
Trottestam H, Horne A, Arico M, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: 
long-term results of the HLH-94 treatment protocol. Blood. 2011;118(17):4577-4584. 
Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life inventory. 
Med Care. 1999 Feb;37(2):126-39 
Zhang SY, Boisson-Dupuis S, Chapgier A, et al. Inborn errors of interferon (IFN)-mediated immunity in 
humans: insights into the respective roles of IFN-alpha/beta, IFN-gamma, and IFN-lambda in host defense. 
Immunol Rev. 2008;226:29-40. 
16 APPENDICES 
Appendix A – QOL questionnaires: PedsQL™, Pediatric Quality of Life Inventory™ (link to examples of 
questionnaires) 
Appendix B – QOL questionnaires: BASES 
Appendix C – Eligibility Review Form 
Appendix D – Pre-Screening Checklist 
Appendix E – Dose Notification Form 
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APPENDIX A 
QOL QUESTIONNAIRES 
PedsQL™, Pediatric Quality of Life Inventory™: 
•
Infant, version 1.0, Parent Report for Infants (ages 1-12 months)
•
Infant, version 1.0, Parent Report for Infants (ages 13-24 months)
•
Core, version 4.0, Parent Report for Toddlers (ages 2-4)
•
Core, version 4.0, Young Child Report (ages 5-7)
•
Core, version 4.0, Parent Report for Young Children (ages 5-7)
•
Core, version 4.0, Child Report (ages 8-12)
•
Core, version 4.0, Parent Report for Children (ages 8-12)
•
Core, version 4.0, Teenager Report (ages 13-18)
•
Core, version 4.0, Parent Report for Teenagers (ages 13-18)
•
Core, version 4.0, Young Adult Report (ages 18-25)
•
Core, version 4.0, Parent Report for Young Adults (ages 18-25)
http://www.pedsql.org 
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APPENDIX B 
QOL QUESTIONNAIRES 
BASES (Behavioral, Affective and Somatic responses to pediatric BMT) 
Bases-R: Parent Report 
Subject ID:  
 
 
 
 
 
 
Date: 
Please complete the following ratings, based on how your child has been feeling and behaving over the 
past day (in the last 24 hours). Please circle your answer. 
Physical Discomfort 
None 
Mild 
Mild-
Moderate 
Moderate-
Severe 
Severe 
1.
Nausea/Vomiting
1 
2 
3 
4 
5 
2.
Mouth Sores
1 
2 
3 
4 
5 
3.
Loss of appetite
1 
2 
3 
4 
5 
4.
Tired/Run down
1 
2 
3 
4 
5 
5.
Overall level of discomfort
1 
2 
3 
4 
5 
Cooperation/Compliance 
Very 
cooperative 
Cooperative 
Neutral 
Uncooperative 
Very 
uncooperative 
6.
Taking medicines or doing
mouth care
1 
2 
3 
4 
5 
7.
Bath or sitz bath
1 
2 
3 
4 
5 
8.
Hickman line care
1 
2 
3 
4 
5 
9.
Vital signs/physical exam
1 
2 
3 
4 
5 
10. Overall level of cooperation
1 
2 
3 
4 
5 
Mood/Behavior 
Very much 
like this 
Somewhat 
like this 
Neutral 
Somewhat 
unlike this 
Very much 
unlike this 
11. Sad/subdued
1 
2 
3 
4 
5 
12. Withdrawn
1 
2 
3 
4 
5 
13. Fearful/Anxious
1 
2 
3 
4 
5 
14. Angry/Irritable
1 
2 
3 
4 
5 
15. Complaining/Demanding
1 
2 
3 
4 
5 
16. Restless/Fidgety
1 
2 
3 
4 
5 
Very negative 
Negative 
Neutral 
Positive 
Very positive 
17. Overall Mood
1 
2 
3 
4 
5 
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Quality of interactions 
Very positive 
Positive 
Neutral 
Negative 
Very negative 
18. How did your child get along
with staff today?
1 
2 
3 
4 
5 
19. How did you and your child get
along today?
1 
2 
3 
4 
5 
20. In general, what was the
quality of your child’s
interactions with others today?
1 
2 
3 
4 
5 
Activity/Sleep 
Not at all; 
sleeping most 
of the time, 
watching TV 
Not very 
active; mostly 
sleeping 
A little 
active; 
sitting up in 
bed 
Fairly active; 
Out of bed 
Very active; 
energetic 
21. Please circle the number which
best describes your child’s
activity level today:
1 
2 
3 
4 
5 
No problems, 
sleeping very 
well 
Some 
difficulty 
Much difficulty, 
sleeping poorly 
22. To what extent has your child
experienced difficulty sleeping
(for example, days/night
reversed, nightmares, can’t
sleep)
1 
2 
3 
4 
5 
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BASES – R, Nurse Report 
Subject ID:  
 
 
 
 
 
 
Date:  
Please rate the patients' behavior based on your observations from the past shift, as well as reports 
from earlier shifts.   Note that the meaning of the 5-point scale changes for some groups of items. 
PHYSICAL DISCOMFORT 
None 
Mild 
Mild-
Moderate 
Moderate-
Severe 
Severe 
1.
Nausea/Vomiting
1 
2 
3 
4 
5 
2.
Mucositis
1 
2 
3 
4 
5 
3.
Appetite Loss
1 
2 
3 
4 
5 
4.
Fatigue/Malaise
1 
2 
3 
4 
5 
5.
Overall level of discomfort
1 
2 
3 
4 
5 
COOPERATION/COMPLIANCE 
Very 
cooperative 
Cooperative 
Neutral 
Uncooperative 
Very 
uncooperative 
6.
Taking medicines or doing
mouth care
1 
2 
3 
4 
5 
7.
Bath/sitz bath
1 
2 
3 
4 
5 
8.
Hickman line care
1 
2 
3 
4 
5 
9.
Vital signs/physical exam
1 
2 
3 
4 
5 
10. Overall level of cooperation
1 
2 
3 
4 
5 
MOOD/BEHAVIOR 
Very much like 
this 
Somewhat 
like this 
Neutral 
Somewhat 
unlike this 
Very much 
unlike this 
11. Sad/subdued
1 
2 
3 
4 
5 
12. Withdrawn
1 
2 
3 
4 
5 
13. Fearful/Anxious
1 
2 
3 
4 
5 
14. Angry/Irritable
1 
2 
3 
4 
5 
15. Complaining/Demanding
1 
2 
3 
4 
5 
16. Restless/Agitated
1 
2 
3 
4 
5 
Very negative 
Negative 
Neutral 
Positive 
Very positive 
17. Overall Mood
1 
2 
3 
4 
5 
QUALITY OF INTERACTIONS 
Very positive 
Positive 
Neutral 
Negative 
Very negative 
18. Quality of patient-staff
interaction this shift
1 
2 
3 
4 
5 
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19.  Quality of patient-parent 
interaction this shift 
1 
2 
3 
4 
5 
20.  In general, quality of patient 
interactions with others this 
shift 
1 
2 
3 
4 
5 
ACTIVITY/SLEEP 
Very little 
activity; almost 
always asleep 
Frequent 
sleeping; 
passive activity 
(e.g. watching 
T.V.) 
Mostly awake 
but in bed; 
quiet activities 
(e.g. drawing, 
puzzles) 
Fairly active; 
interactive 
games; out of 
bed 
Very active; 
physical play; 
energetic 
21.  Please circle the number 
which best describes the 
patient’s activity level 
today: 
1 
2 
3 
4 
5 
 
No problems, 
sleeping very 
well 
 
Some 
difficulty 
 
Much 
difficulty, 
sleeping 
poorly 
22.  Rate the extent of patient’s 
problems/ difficulties 
sleeping (e.g., days/night 
reverses, nightmares, can’t 
sleep)  
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX C
ELIGIBILITY REVIEW FORM 
Institution 
Institution name and location: 
Treating physician: 
Patient information 
Patient ID:  
assigned sequentially 
Age: 
Gender 
☐Male
☐Female
If patient is a female, is she pregnant or 
lactating? 
☐Yes
☐No
☐Not applicable (patient is not a female)
Primary HLH diagnosis 
Age at diagnosis of HLH: 
Date of diagnosis of HLH: 
DD/MMM/YYYY 
HLH-2004 criteria (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)
☐Hypertriglyceridemia (fasting triglycerides ≥ 3
mmol/L or ≥ 265 mg/dL) and/or
hypofibrinogenemia (≤ 1.5 g/L)
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☐ Hemophagocytosis in bone marrow, spleen or 
lymph nodes 
      
☐ Low or absent NK-cell activity 
      
☐ Ferritin ≥ 500 µg/L 
      
☐ Soluble CD25 ≥ 2400 U/mL 
      
 
What elements led you to suspect primary HLH: 
☐ Molecular diagnosis: 
Indicate mutated gene and/or functional testing 
suggestive of pHLH 
      
☐ Family history consistent with pHLH 
Briefly describe affected relatives and their 
disease features, as available 
      
☐ Other elements 
Specify what other elements contributed to 
adjudication of primary nature of the disease, e.g. 
presentation during infancy, reactivations 
      
 
Exclusion of secondary HLH: 
☐ Rheumatic disease 
Please indicate any known or suspected 
rheumatic conditions 
      
☐ Metabolic disease 
Please indicate any known or suspected 
metabolic conditions 
      
☐ Neoplastic disease 
Please indicate any known or suspected 
neoplastic diseases 
      
 
Do you assess patient’s HLH disease as active? 
☐ Yes 
      
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Indicate which disease features contribute most 
to overall disease activity 
•
If patient reactivated following initial
response to therapy, please indicate at
least two clinical / laboratory criteria that
worsened, and/or new or recurrent CNS
symptoms
☐No
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? (e.g. adverse reactions,
intolerance, benefit/risk concerns)
☐No
☐Yes
Overall patient’s condition and infectious status 
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
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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
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 Shigella, Salmonella, 
Campylobacter infection been excluded? 
☐Yes (specify):
☐Waiting for test results. There are no clinical findings
suggestive of these infections.
☐No
☐Yes (specify):
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Has the presence of Leishmania infection 
been excluded? 
☐Waiting for test results. There are no clinical findings
suggestive of this infection.
☐No
Does the patient have history of hypersensitivity or allergy to any of the following components of the 
study regimen? 
☐Emapalumab
☐L-histidine
☐L-histidine monohydrochloride, monohydrate
☐Sodium chloride
☐Polysorbate 80
☐NONE OF THE ABOVE
By signing this document I confirm that that the above provided patient data are accurate and can be 
shared with Swedish Orphan Biovitrum AG.  
Enter date 
Investigator’s name and signature 
Date 
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APPENDIX D 
PRE-SCREENING CHECKLIST 
Date of assessment: 
_____________________ 
Patient Identifier (initials, complete or incomplete date of birth, other 
identifier as per your local regulations): 
_____________________ 
PATIENT MUST HAVE 
•
Primary HLH:
☐ 
o
Diagnosed at the age of 0-18 years
☐ 
o
Molecular diagnosis,
o
OR family history consistent with HLH,
o
OR 5/8 HLH-2004 diagnostic criteria*
☐ 
•
Active HLH disease
☐ 
•
If already received HLH conventional therapy (applicable outside of US):
o
no response,
o
OR unsatisfactory response,
o
OR worsening,
o
OR reactivation**,
o
AND/OR intolerance
☐ 
*HLH-2004 diagnostic criteria (5/8 required)
☐Fever
☐Splenomegaly
☐Cytopenias affecting 2 of 3 lineages (HGB <90 g/L;
PLT <100 x 109/L; NEU <1 x 109/L)
☐Hypertriglyceridemia (fasting TG ≥3 mmol/L or ≥265
mg/dL) and/or hypofibrinogenemia (≤1.5 g/L)
☐Hemophagocytosis in bone marrow, spleen or
lymph nodes, with no evidence of malignancy
☐Low or absent NK-cell activity
☐Ferritin ≥500 µg/L
☐Soluble CD25 (sCD25; i.e., soluble IL-2 receptor)
≥2400 U/mL
**Abbreviated definition of reactivation  (1/2 
required) 
☐Deterioration of at least two of the below
parameters over three days
• Platelets
• Neutrophils
• Fibrinogen
• Ferritin
• sCD25 (i.e., soluble IL-2 receptor)
☐Development of new or recurrent CNS symptoms
(single criterion)
PATIENT MUST NOT HAVE 
•
Secondary HLH consequent to proven
o
rheumatic,
o
metabolic,
o
neoplastic disease
☐ 
•
Active infections
o
Mycobacteria
o
Histoplasma capsulatum
o
Shigella
o
Salmonella
☐ 
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o
Campylobacter
o
Leishmania
•
Latent tuberculosis
☐ 
•
Malignancy
☐ 
•
Another disease or malformation that may impact likelihood to respond or assessment of
safety or efficacy, severely affecting
o
cardiovascular,
o
pulmonary,
o
CNS,
o
liver,
o
kidney function
☐ 
•
Hypersensitivity or allergy to any component of the study regimen:
o
emapalumab
o
polysorbate 80
o
L-histidine
o
L-histidine monohydrochloride, monohydrate
o
sodium chloride
☐ 
•
BCG vaccination within 12 weeks prior to Screening
☐ 
•
Any other live or attenuated live vaccine within 6 weeks prior to Screening
☐ 
•
Pregnancy or lactation
☐ 
To be completed after patient’s consent 
Was this patient consented? 
☐Yes
☐No
If YES, please record patient ID 
_____________________ 
If NO: 
☐Patient did not meet  eligibility criteria (above)
☐Other reason, specify:
_____________________ 
_____________________ 
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Protocol NI-0501-09 Version 4.0 Global – Final 31 March 2020 
 CONFIDENTIAL 
APPENDIX E
DOSE NOTIFICATION FORM 
PART A 
Dose of emapalumab 
☐Unchanged at
 mg/kg 
☐Decreased to
 mg/kg 
☐Increased to
 mg/kg 
Please complete the below fields 
Reasons for deciding to increase emapalumab dose 
☐Dose increase to 6 mg/kg
☐Dose increase to 10 mg/kg
The improvement in the patient’s clinical conditions is 
unsatisfactory based on the followings: 
There was an initial benefit after the previous dose 
increase, however the improvement in patient’s clinical 
conditions is unsatisfactory based on the followings: 
☐patient’s overall performance and well-being status 
has not ameliorated as expected
☐CNS signs and symptoms due to HLH remained 
unchanged or worsened
☐liver HLH involvement remained unchanged or
worsened
☐there is a clinically relevant increase of absolute 
lymphocyte count
☐there is a substantial increase of sIL2Ra levels
☐other, specify:
☐patient’s overall performance and well-being status has 
not ameliorated as expected
☐CNS signs and symptoms due to HLH remained 
unchanged or worsened
☐liver HLH involvement remained unchanged or
worsened
☐there is a clinically relevant increase of absolute 
lymphocyte count
☐there is a substantial increase of sIL2Ra levels
☐other, specify:
AND at least one of the following criteria are met: 
AND at least one of the following criteria are met: 
☐Fever: persistence or reoccurence
☐Platelet counts: lack of normalization (i.e. >100 x
103/mcl) or worsening
☐ANC: lack of normalization (i.e. >1000 count/mcl) or
worsening
☐Ferritin: less than 30% decrease or worsening
☐Splenomegaly: worsening
☐Coagulopathy (D-dimer OR fibrinogen): lack of
normalization (i.e. D-dimer <1.0 mcg/mL and fibrinogen 
>150 mg/dL) or worsening
☐Fever: persistence or reoccurence
☐Platelet counts: lack of normalization (i.e. >100 x
103/mcl) or worsening
☐ANC: lack of normalization (i.e. >1000 count/mcl) or
worsening
☐Ferritin: less than 30% decrease or worsening
☐Splenomegaly: worsening
☐Coagulopathy (D-dimer OR fibrinogen): lack of
normalization (i.e., D-dimer <1.0 mcg/mL and fibrinogen 
>150 mg/dL) or worsening
Page 97 of 98


Study NI-0501-09 
NI-0501 in Primary HLH 
Page 92 of 92 
Protocol NI-0501-09 Version 4.0 Global – Final 31 March 2020 
 CONFIDENTIAL 
PART B
  if no additional HLH treatments is considered, please tick this box ☐ 
Additional HLH treatments 
☐Etoposide*
Emapalumab treatment is 
☐Another HLH treatment*:
☐continued
☐discontinued
If other than etoposide drug was chosen, please specify the reasons: 
☐medical history records indicating poor response to etoposide
☐medical history records indicating intolerance to etoposide
☐other, specify:
* Please complete the below fields
Reasons for deciding to administer an additional HLH treatment 
Unsatisfactory HLH control 
☐patient has not achieved a disease control and general clinical conditions that would allow him/her to proceed to
transplant
☐patient has not maintained a disease control and general clinical conditions that would allow him/her to proceed to
transplant
☐patient has presented a clinically relevant worsening
☐other**, specify:
AND the following benefit/risk considerations have been made: 
☐another HLH treatment is expected to improve HLH control to rapidly move to transplant
☐applied emapalumab dose increases have not achieved the desired HLH control
☐another HLH treatment may be helpful to control disease activity since no previous chemotherapy/broad 
immunosuppression has been administered
☐side effects of the additional HLH treatment do not seriously preclude its administration
☐other**, specify:
**Please use the free text field for any additional information that can further elucidate your decision 
Page 98 of 98

SAP_001.pdf: 
PROTOCOL TITLE:  An Open-label, Single Arm, Multicenter Study to Broaden Access to 
Emapalumab, an Anti Interferon Gamma (Anti-IFNγ) Monoclonal 
Antibody, and to Assess its Efficacy, Safety, Impact on Quality of Life, 
and Long-term Outcome in Pediatric Patients with Primary 
Hemophagocytic Lymphohistiocytosis 
NCT Number: 
NCT03312751 
 
 


 
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 Statistical Analysis Plan 
Sponsor 
Sobi AG 
Protocol Title: 
An Open-label, Single Arm, Multicenter Study to Broaden Access 
to Emapalumab, an Anti-Interferon Gamma (Anti-IFNγ) 
Monoclonal Antibody, and to Assess its Efficacy, Safety, Impact on 
Quality of Life, and Long-term Outcome in Pediatric Patients with 
Primary Hemophagocytic Lymphohistiocytosis 
Protocol Number: 
NI-0501-09 
Premier Research PCN: 
176784 
Document Version: 
Final Version 2.0 
Document Date:  
24Oct2022 
Approvals 
Role 
Signatures 
Biostatistician 
Print Name:
Sign Name: 
 
 
Sobi 
Representative 
Print Name: 
 
Sign Name: 
 
 
 


 
Statistical Analysis Plan,  
 
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Protocol Number NI-0501-09  
 
PCN Number 176784 
 
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Document History 
Version 
Date 
Reason for Amendment 
1.0 
09-Apr-2021 
Not applicable. 
2.0 
24-Oct-2022 
Section 5 
Added the analysis set Evaluable Analysis Set 
Without Major Protocol Deviations so it is clear 
which analysis set is used in sensitivity analysis 5.  
Section 6.1.5 
Revision of analysis visit windows in order to 
clarify which visit should be used as the EOT/Week 
8 visit. 
Section 6.1.9.4/Section 9 
Supplementary analysis included using an updated 
definition of overall response. The number of 
abnormalities at baseline is considered along with 
the number of abnormalities which worsen from 
baseline. 
Section 6.1.9.4 
Clarification of the response definition. 
 
 


 
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Table of Contents 
Approvals ........................................................................................................................................ 1 
Document History ........................................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
List of Tables .................................................................................................................................. 5 
List of Figures ................................................................................................................................. 6 
List of Abbreviations ...................................................................................................................... 7 
1. 
Overview ............................................................................................................................. 9 
2. 
Study Objectives and Endpoints ......................................................................................... 9 
2.1. 
Study Objectives ........................................................................................................... 9 
2.2. 
Study Endpoints .......................................................................................................... 10 
2.2.1. Efficacy Endpoints ...................................................................................................... 10 
2.2.1.1. 
Primary Efficacy Endpoint ................................................................................... 10 
2.2.1.2. 
Secondary Efficacy Endpoint(s) ........................................................................... 10 
2.2.2. Safety Endpoints ......................................................................................................... 10 
2.2.3. Pharmacokinetic/Pharmacodynamic Variable(s) ........................................................ 11 
3. 
Overall Study Design and Plan ......................................................................................... 11 
3.1. 
Overall Design ............................................................................................................ 11 
3.2. 
Sample Size and Power ............................................................................................... 12 
3.3. 
Study Population ......................................................................................................... 12 
3.4. 
Treatments Administered ............................................................................................ 12 
3.5. 
Method of Assigning Subjects to Treatment Groups .................................................. 13 
3.6. 
Blinding and Unblinding............................................................................................. 13 
3.7. 
Schedule of Events ...................................................................................................... 13 
4. 
Statistical Analysis and Reporting .................................................................................... 13 
4.1. 
Introduction ................................................................................................................. 13 
4.2. 
Interim Analysis and Data Monitoring ....................................................................... 14 
5. 
Analysis Sets ..................................................................................................................... 14 
6. 
General Issues for Statistical Analysis .............................................................................. 15 
6.1. 
Statistical Definitions and Algorithms ........................................................................ 15 
6.1.1. Baseline ....................................................................................................................... 15 
6.1.2. Adjustments for Covariates......................................................................................... 15 
6.1.3. Multiple Comparisons ................................................................................................. 15 
6.1.4. Handling of Dropouts or Missing Data ....................................................................... 15 


 
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6.1.5. Analysis Visit Windows ............................................................................................. 16 
6.1.6. Treatment naïve / experienced patients ....................................................................... 19 
6.1.7. Subgroup Analyses ..................................................................................................... 20 
6.1.8. Pooling of Sites ........................................................................................................... 24 
6.1.9. Derived Variables ....................................................................................................... 24 
6.1.9.1. 
General .................................................................................................................. 24 
6.1.9.2. 
Demography and Baseline Parameters ................................................................. 24 
6.1.9.3. 
Safety Parameters.................................................................................................. 25 
6.1.9.4. 
Efficacy Parameters .............................................................................................. 27 
6.1.10. Data Adjustments/Handling/Conventions .................................................................. 42 
6.1.11. COVID-19................................................................................................................... 44 
7. 
Study Patients/Subjects and Demographics ...................................................................... 45 
7.1. 
Disposition of Patients/Subjects and Withdrawals ..................................................... 45 
7.2. 
Protocol Violations and Deviations ............................................................................ 46 
7.3. 
Demographics and Other Baseline Characteristics ..................................................... 47 
7.4. 
Exposure and Compliance .......................................................................................... 48 
8. 
Efficacy Analysis .............................................................................................................. 48 
8.1. 
Primary Efficacy Analysis .......................................................................................... 48 
8.2. 
Secondary Efficacy Analysis ...................................................................................... 49 
8.2.1. Overall Survival .......................................................................................................... 49 
8.2.2. Event-free Survival ..................................................................................................... 49 
8.2.3. Overall Response at Start of Conditioning ................................................................. 49 
8.2.4. Duration of Response .................................................................................................. 50 
8.2.5. Time to Response ........................................................................................................ 50 
8.2.6. Clinical Response........................................................................................................ 50 
8.2.7. Glucocorticoids Reduction.......................................................................................... 50 
8.2.8. Number of Patients Proceeding to HSCT ................................................................... 50 
8.2.9. Quality of Life Assessed Through PedsQL™, Pediatric Quality of Life 
Inventory ..................................................................................................................... 50 
8.2.10. Quality of Life Assessed Through BASES Questionnaires ........................................ 50 
9. 
Supplementary Analysis ................................................................................................... 51 
10. 
Safety and Tolerability Analysis ....................................................................................... 51 
10.1. Adverse Events ........................................................................................................... 51 
10.1.1. Adverse Events Leading to Study Drug Withdrawal .................................................. 53 
10.1.2. Deaths and Serious Adverse Events ........................................................................... 53 


 
Statistical Analysis Plan,  
 
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10.1.3. Treatment-Emergent Adverse Events with Infections ................................................ 53 
10.1.4. Infusion-related reactions............................................................................................ 53 
10.2. Clinical Laboratory Evaluations ................................................................................. 53 
10.2.1. Hematology, Coagulation and Clinical Chemistry ..................................................... 53 
10.2.2. Urinalysis .................................................................................................................... 54 
10.2.3. Cerebrospinal Fluid Data ............................................................................................ 54 
10.3. Vital Signs ................................................................................................................... 54 
10.4. Physical examination .................................................................................................. 54 
10.5. Electrocardiograms ..................................................................................................... 54 
10.6. Imaging Test Results................................................................................................... 54 
10.7. Systematic Search for Infections ................................................................................ 54 
10.8. Hematopoietic Stem Cell Transplantation (HSCT) .................................................... 55 
10.9. Concomitant Medications and Procedures.................................................................. 55 
11. 
Changes from Planned Analysis ....................................................................................... 55 
12. 
Other Planned Analysis..................................................................................................... 56 
12.1. Pharmacokinetic/Pharmacodynamic/Immunogenicity Analysis ................................ 56 
13. 
References ......................................................................................................................... 56 
14. 
Tables, Listings, and Figures ............................................................................................ 57 
14.1. Planned Table Descriptions ........................................................................................ 57 
14.2. Planned Listing Descriptions ...................................................................................... 63 
14.3. Planned Figure Descriptions ....................................................................................... 66 
15. 
Tables, Listings, and Listing Shells .................................................................................. 68 
15.1. Standard Layout for all Tables, Listings, and Figures ................................................ 68 
15.2. Planned TFL Shells ..................................................................................................... 69 
16. 
APPENDICES .................................................................................................................. 70 
16.1. Calculation of Dexamethasone daily dose .................................................................. 70 
16.2. Concomitant Medications for HSCT Conditioning .................................................... 71 
16.3. Disease Indicating Central Nervous System (CNS) Involvement / CSF 
abnormalities by Medical History/AE Preferred Term and Code .............................. 72 
16.4. Adverse Events Indicating Organ Failure by MedDRA Preferred Term and 
Code ............................................................................................................................ 73 
 
List of Tables 
Table 1: Treatment Visit Windows, treatment duration < 8 weeks .............................................. 17 


 
Statistical Analysis Plan,  
 
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Table 2: Treatment Visit Windows, treatment duration >= 8 weeks ............................................ 18 
Table 3: Patient Populations for Each Analysis/Summary ........................................................... 22 
Table 4: Definition of Drug Administration Variables ................................................................. 25 
Table 5: Definition of Adverse Events ......................................................................................... 25 
Table 6: Definition of Response for the Primary Endpoint .......................................................... 28 
Table 7: Definition of Response for Supplementary Analysis ..................................................... 31 
Table 8: Overall Survival .............................................................................................................. 34 
Table 9: Survival to HSCT ........................................................................................................... 34 
Table 10: Survival post HSCT ...................................................................................................... 35 
Table 11: Event-Free Survival ...................................................................................................... 36 
Table 12: Duration of Response ................................................................................................... 36 
Table 13: Time to Response ......................................................................................................... 37 
Table 14: Derivations for Medications ......................................................................................... 38 
Table 15: Planned Tables .............................................................................................................. 58 
Table 16: Planned Listings............................................................................................................ 64 
Table 17: Planned Figures ............................................................................................................ 67 
Table 18: Dexamethasone Daily Dose .......................................................................................... 70 
Table 19: Concomitant HSCT Conditioning Medication Preferred Terms .................................. 71 
Table 20: Medical History/AE Preferred Terms for CNS Involvement / CSF Abnormalities ..... 72 
Table 21: AE Preferred Terms for Organ Failure ......................................................................... 73 
 
List of Figures 
Figure 1: Standardized Layout ...................................................................................................... 68 
 
 
 


 
Statistical Analysis Plan,  
 
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PCN Number 176784 
 
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List of Abbreviations 
Abbreviation 
Definition 
ADA 
anti-drug antibody 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
BAL 
bronchoalveolar lavage 
BASES 
behavioral, affective and somatic experiences questionnaire 
CBC 
complete blood cell 
CMV 
cytomegalovirus 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
iDMC 
independent data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EBV 
Epstein-Barr virus 
EMA 
European Medicines Agency 
EOT 
end of treatment 
FDA 
food and drug administration 
HLGT 
high level group term 
HLH 
hemophagocytic lymphohistiocytosis 
HLT 
high level term 
HSCT 
hematopoietic stem cell transplantation 
ICH 
international council for harmonization  
IFNγ 
interferon gamma 
IRR 
infusion related reactions 
IV 
intravenous 
LLOQ 
lower limit of quantitation 
MedDRA 
medical dictionary for regulatory activities 
n 
number of patients 
PD 
pharmacodynamic 


 
Statistical Analysis Plan,  
 
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Abbreviation 
Definition 
PedsQL 
Pediatric quality of life inventory 
pHLH 
primary hemophagocytic lymphohistiocytosis 
PK 
pharmacokinetic 
PO 
per os – by mouth in Latin 
PT 
preferred term 
QOL 
quality of life 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS®  
a software system used for data analysis 
SD 
study day 
SOC 
system organ class 
TB 
tuberculosis  
TEAE 
treatment-emergent adverse event 
TLFs 
tables, listings, and figures 
ULOQ 
upper limit of quantitation 
US 
United States of America 
WHO-DD 
world health organization drug dictionary 


Statistical Analysis Plan,  
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Protocol Number NI-0501-09  
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1. 
Overview
This statistical analysis plan (SAP) describes the planned analysis and reporting for Sobi 
protocol number NI-0501-09 (An Open-label, Single Arm, Multicenter Study to Broaden Access 
to Emapalumab, an Anti-Interferon Gamma [Anti-IFNγ] Monoclonal Antibody, and to Assess its 
Efficacy, Safety, Impact on Quality of Life, and Long-term Outcome in Pediatric Patients with 
Primary Hemophagocytic Lymphohistiocytosis), dated 31-Mar-2020 version 4.0.  
Reference materials for this statistical plan include the protocol and the accompanying sample 
data collection documents (e.g. case report forms, guidelines for completion of CRF, etc.). 
Operational aspects related to collection and timing of planned clinical assessments are not 
repeated in this SAP unless relevant to the planned analysis. 
The structure and content of this SAP meets the requirements identified by the Food and Drug 
Administration (FDA), European Medicines Agency (EMA), and International Conference on 
Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human 
Use: Guidance on Statistical Principles in Clinical Trials1. All work planned and reported for 
this SAP will follow internationally accepted guidelines, published by the American Statistical 
Association3 and the Royal Statistical Society1, for statistical practice. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts. Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data. Any post-hoc 
or unplanned, exploratory analysis performed will be clearly identified as such in the final CSR. 
The statistical plan described hereafter is an a priori plan. It will be submitted to file prior to 
database lock of Sobi’s study NI-0501-09. 
2. 
Study Objectives and Endpoints
2.1. 
Study Objectives 
•
To gather additional safety and efficacy data on emapalumab (previously referred to as
NI-0501) in primary hemophagocytic lymphohistiocytosis (pHLH) patients.
•
To assess a starting dose of emapalumab of 3 mg/kg.
•
To assess the impact of emapalumab on Quality of Life (QOL).
•
To gather additional evidence on the long-term outcome of pHLH patients treated with
emapalumab.
•
To further evaluate the pharmacokinetic (PK) profile of emapalumab in pHLH patients.
•
To further evaluate the pharmacodynamic (PD) effects (levels of circulating total IFNγ
and biomarkers of its neutralization, namely CXCL9 and CXCL10).
•
To assess the profile of other relevant HLH biomarkers, e.g., soluble IL-2 receptor


Statistical Analysis Plan,  
Sponsor Sobi AG  
Protocol Number NI-0501-09  
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(sCD25) and other exploratory biomarkers. 
•
To monitor for potential occurrence of anti-drug antibodies (ADAs).
2.2. 
Study Endpoints 
2.2.1. Efficacy Endpoints 
2.2.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is Overall Response, i.e., achievement of either 
Complete or Partial Response or HLH Improvement, at end of treatment (EOT) or Week 8 
(whichever occurs earlier). 
2.2.1.2. 
Secondary Efficacy Endpoint(s) 
The secondary efficacy endpoints of this study include the following:  
•
Overall Survival, including survival to hematopoietic stem cell transplantation (HSCT)
and survival after either HSCT or last emapalumab infusion (if HSCT is not performed).
•
Event-free survival.
•
Overall Response, i.e., achievement of either Complete or Partial Response or HLH
Improvement, at start of conditioning (or at last emapalumab infusion if HSCT is not
performed).
•
Duration of Response, i.e., maintenance of the response achieved any time during the
study (with censoring time at start of conditioning for patients with no event).
•
Time to Response at any time during the study.
•
Number of patients able to reduce glucocorticoids by 50% or more of the baseline dose at
any time during emapalumab treatment.
•
Number of patients able to proceed to HSCT, when deemed indicated.
•
Quality of Life assessed through PedsQL™, Pediatric Quality of Life Inventory™.4
•
Quality of Life assessed through BASES, The Behavioral, Affective and Somatic
Experiences questionnaires.
2.2.2. Safety Endpoints 
Safety and tolerability of emapalumab will be assessed as follows: 
•
Incidence, severity, causality and outcomes of adverse events (AEs) (serious and non-
serious).


Statistical Analysis Plan,  
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•
Evolution of relevant laboratory parameters, e.g., complete blood cell (CBC) count, liver
and renal function tests, and coagulation parameters.
•
Number of patients who discontinued emapalumab treatment for safety reasons.
2.2.3. Pharmacokinetic/Pharmacodynamic Variable(s) 
In the present SAP, the following PK/PD parameters are considered for the purpose of 
descriptive statistics only: 
•
Serum concentration of emapalumab.
•
Levels of circulating total IFNγ (free + bound) at any time point.
•
Markers of IFNγ neutralization, namely CXCL9 and CXCL10.
•
Other relevant HLH biomarkers, e.g., sCD25 and other exploratory biomarkers.
•
Level (if any) of circulating antibodies against emapalumab (ADAs).
Measurement of emapalumab concentrations and PD parameters in other matrices, e.g., 
cerebrospinal fluid (CSF), bronchoalveolar lavage (BAL), if clinically appropriate, will be used 
in an exploratory fashion. 
3.
Overall Study Design and Plan
3.1. 
Overall Design 
This is an open-label, single arm, multicenter, interventional study conducted in Europe and 
North America. 
The study enrols pediatric patients with confirmed or suspected pHLH who are treatment-naïve, 
have failed conventional HLH therapy, or have shown intolerance to it. 
Patients will be in the treating unit the day before the first administration of emapalumab (study 
day minus 1, SD-1). 
Patients are required to receive dexamethasone from SD-1. In treatment-naïve patients, a 
background therapy of 10 mg/m2 dexamethasone will be required. In patients who failed 
previous HLH therapy, dexamethasone is to be administered at a dose of at least 5 mg/m2 or at 
the dose administered prior to Screening if higher. 
Lower dexamethasone doses are allowed in case of documented intolerance to glucocorticoids. 
During the study, dexamethasone can be tapered depending on the patient’s condition, according 
to the judgment of the treating physician. 
The study is divided into three parts: 
•
Screening period. Screening will be carried out within 2 weeks prior to first
administration of emapalumab (SD0) to enable confirmation of patient eligibility and


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following the signature of the Informed Consent Form. 
•
Treatment period. The duration of treatment is foreseen until the start of conditioning
for HSCT but must not exceed 6 months. The minimum treatment duration is 4 weeks, if
the patient’s conditions and donor availability allow for HSCT. No washout period is
required between the last administration of emapalumab and the start of conditioning.
•
Follow-up period. After treatment completion or treatment discontinuation (for any
reason), patients will continue in the study for long-term follow-up until 1 year after
either HSCT or last emapalumab infusion (if HSCT is not performed). A patient who
experiences HLH reactivation during the follow-up period, may be re-treated with
emapalumab. Re-treated patients will follow the same schedule of assessments as
applicable during the initial treatment and will enter follow-up period after completion of
re-treatment.
The end of the study is defined as last patient last visit at 1 year after either HSCT or last 
emapalumab infusion (as applicable). In case of an ongoing serious adverse event (SAE) the 
patient will continue to be monitored until resolution or until the outcome of the event is known 
and stable, beyond the defined study end as necessary. 
3.2. 
Sample Size and Power 
The sample size calculation is based on the primary efficacy endpoint of Overall Response. 
Assuming an Overall Response Rate of 65%, a minimum of 34 treated patients is required to 
show a significant improvement above 40% with 85% power using an exact binomial test at a 
one-sided significance level of 2.5%. A drop-out rate of 20% may be expected, hence a total 
maximum of 41 patients may be enrolled. Due to the rarity of pHLH, recruitment is competitive 
across all European and North American sites in order to gather data in a reasonable timeframe. 
3.3. 
Study Population 
The study population comprises pHLH patients of both genders, from birth up to and including 
18 years at diagnosis of HLH. Patients in this study can be naïve to HLH treatment or may have 
already received conventional HLH therapy without having obtained a satisfactory response 
according to the treating physician or shown signs of intolerance to HLH therapy. 
3.4. 
Treatments Administered 
This is an open-label, single-arm study and no randomization is being performed. Emapalumab 
will be administered by intravenous (IV) infusion over a period of 1 to 2 hours depending on the 
volume to infuse, at a dose of 3 mg/kg. Infusions will be performed twice weekly (not more than 
4 days apart), except for the second infusion which must be administered on SD-3. The 3 mg/kg 
dose will be maintained 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. The dose of emapalumab may be further 
increased to 10 mg/kg per Investigator’s decision based on the patient’s clinical and laboratory 
response. 


 
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Upon achievement of Complete Response (i.e., normalization of all clinical and laboratory HLH 
parameters), the dose of emapalumab will be lowered to achieve 1 mg/kg twice a week and 
maintained until conditioning for transplant, as long as the patient’s clinical conditions are 
satisfactory. Given the unpredictable course of the disease, in case of reactivation (e.g. triggered 
by intercurrent infections), subsequent dose increases to 3 mg/kg (and up to 6 or 10 mg/kg, as 
appropriate) may need to be considered and will be guided by the same clinical and laboratory 
parameters. Upon obtaining again a Complete Response, the dose of emapalumab will be 
lowered again to achieve 1 mg/kg twice a week. Should hematopoietic stem cell transplantation 
(HSCT) be scheduled beyond 12 weeks from emapalumab initiation for reasons unrelated to the 
administration of emapalumab (e.g., lack of donor availability) and provided Complete Response 
is maintained, the treatment with emapalumab may continue at the dose of 1 mg/kg once a week. 
3.5. 
Method of Assigning Subjects to Treatment Groups 
This is an open-label, single-arm study. Screening is carried out to enable confirmation of patient 
eligibility. Eligible patients are administered emapalumab. 
3.6. 
Blinding and Unblinding 
Not applicable. 
 
3.7. 
Schedule of Events 
A detailed schedule of events for the study is provided in Table 1 and Table 2 of the protocol. 
 
4. 
Statistical Analysis and Reporting 
4.1. 
Introduction 
Data processing, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher). If the 
use of other software is warranted, the final statistical methodology report will detail what 
software was used for what purposes. 
Continuous (quantitative) variable summaries will include the number of patients (n) with 
non-missing values, mean, standard deviation, median, minimum, and maximum. The minimum 
and maximum will be reported with the same degree of precision (i.e., the same number of 
decimal places) as the observed data. Mean, standard deviation and median will be reported to 1 
degree of precision more than the observed data.  
Categorical (qualitative) variable summaries will include the frequency and percentage of 
patients who are in the particular category or each possible value. In general, the denominator for 
the percentage calculation will be based upon the total number of patients in the study population 
unless otherwise specified. Percentages will be rounded to 1 decimal place, unless otherwise 


Statistical Analysis Plan,  
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specified. Therefore, there may be cases where for instance the total of the percentages does not 
exactly equal 100%. In case confidence intervals are provided, they will be shown with 1 
decimal place. 
The number of missing values will be calculated as difference of the total number of subjects in 
the study population minus the number of non-missing values. 
All p-values will be displayed to four decimals and rounded using standard scientific notation (e.g., 
0.XXXX). If a p-value less than 0.0001 occurs it will be shown in tables as <0.0001.
All collected data will be presented in listings. Data not subject to analysis according to this plan 
will not appear in any tables or graphs but will be included only in the data listings. 
4.2. 
Interim Analysis and Data Monitoring 
No interim analyses are planned. 
An Independent Data Monitoring Committee (iDMC) has overall responsibility for safeguarding 
the interests of subjects by monitoring relevant data obtained in the study and making 
appropriate recommendations based on the reported data, thus ensuring that the study is being 
conducted with the highest scientific and ethical standards.  
5.
Analysis Sets
The following analysis populations are planned for this study: 
•
Enrolled Analysis Set: The Enrolled Population Analysis Set includes all patients who
sign the informed consent form including screen failures. This population will be used
only for the purpose of describing patient disposition and for protocol deviations (note:
screen failures will be excluded in protocol deviation outputs).
•
All Treated Analysis Set: The All Treated Analysis Set includes all patients who receive
any part of an infusion of study drug. The All Treated Analysis Set will be the primary
population for efficacy endpoints, and will be used for safety and PK/PD endpoints.
•
Evaluable Analysis Set: The Evaluable Analysis Set includes all patients in the All
Treated Analysis Set who have
o
Received a minimum of 3 consecutive infusions of emapalumab, not more than 6
days between infusions,
o
Not had a diagnosis of secondary HLH subsequent to the initiation of
emapalumab treatment.
•
Evaluable Analysis Set Without Major Protocol Deviations: The Evaluable Analysis
Set Without Major Protocol Deviations includes all patients in the Evaluable analysis set
who do not have a major protocol deviation that is deemed to have an impact on the
statistical analysis.


Statistical Analysis Plan,  
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Protocol Number NI-0501-09  
PCN Number 176784
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Inclusion in the analysis sets defined above will be determined at a data review meeting before 
database lock.  
6.
General Issues for Statistical Analysis
6.1. 
Statistical Definitions and Algorithms 
6.1.1. Baseline 
The last observation recorded prior to the first dose of emapalumab will be used as the baseline 
observation for all calculations of change from baseline.  
6.1.2. Adjustments for Covariates 
Not applicable. 
6.1.3. Multiple Comparisons 
Not applicable. 
6.1.4. Handling of Dropouts or Missing Data 
While all possible efforts will be made to ensure that patients stay in the study and all data is 
collected as scheduled, the occurrence of missing data cannot be completely eliminated.  
Rules for handling missing or partial AEs or birth dates are described in Section 6.1.10 
For defining the primary efficacy endpoint (Overall Response, see Section 6.1.9.4 for definition), 
values of some parameters may be missing, thus impacting the response assessment. Imputation 
rules for assessing disease response at EOT or Week 8 (whichever occurs earlier) and throughout 
the study have been pre-defined as follows. Note: Imputed values will be flagged in the listings 
for all endpoints where applicable. 
Response at EOT or Week 8 (whichever occurs earlier): 
•
Missing data at EOT/Week 8 for the parameters relevant to assessment of Overall
Response will be imputed by the closest available value from the EOT/Week 8 target day
(as per Table 1 and Table 2) up to 8 days, provided upper window limit is before start of
conditioning. For body temperature, in the event of repeated measures recorded on the
same study day, the highest value will be selected.
•
No imputation will be applied if no value is available within the time of the EOT/Week 8
target day up to 8 days. That parameter will be viewed as missing and complete response
will not be assigned, even if all other parameters are normal.
•
Values recorded at both scheduled and unscheduled visits will be considered.


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•
If all parameters are unable to be imputed then the overall response assessment will be
recorded as missing.
Response throughout the study: 
•
For secondary time to event analyses (e.g., duration of response, time to response), both
scheduled and unscheduled visits will be used for assessment of response.
•
If a numerical parameter (i.e. Body Temperature, D-Dimer, Fibrinogen, Ferritin,
Platelets, Neutrophils) needed for the response assessment is missing, the midpoint
approach will be used to estimate the missing value – i.e., the last observed value before
the missing period will be averaged with the first value available after the missing period.
This rule will be applied to parameter values missing for a period of up to a maximum of
7 consecutive days.
If a character parameter needed for the response assessment (i.e. Spleen Assessment,
CNS) is missing, last observation carried forward method will be used to estimate the
missing value – i.e., the last observed value within a maximum of 7 consecutive days
before the missing period will be used.
In case that, after imputation, data is still missing in any of the criteria considered for the
definition of response, a Complete Response cannot be adjudicated.
•
If the maintenance of response (of at least 4 days) cannot be confirmed due to missing
data, the response will be assumed to be lost. In case of calculation of duration of
response (i.e. durability of first response) the next response period will be considered. If
none of the subject’s responses could have been confirmed to last for at least 4 days or
only one response was documented which could not have been confirmed to last for at
least 4 days, the duration of response will be set to 1 day applying a conservative
imputation strategy.
•
Since data relevant to CNS assessment has been collected at irregular time-points (based
on individual patient conditions), the investigators assessment of CNS status will be
carried-forward until the time-points of relevance for response analysis
For descriptive statistics on the evolution over time of clinical signs characterizing HLH disease, 
the time windows listed in Table 1 and Table 2 will be applied in the case that a parameter is not 
available on the specified study day.  
For any assessment, if there is more than one observation during the visit window, the closest 
value (within the visit window) to the target day will be chosen first. In the case that there are 2 
equidistant values to the study day of interest, the observation that is after the study day in 
question will be selected.  
6.1.5. Analysis Visit Windows 
Statistical analyses will be based on the windowing displayed in Table 1 (patients with a 


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treatment duration less than 8 weeks, i.e. < 56 days) and Table 2 (patients with a treatment 
duration of 8 weeks or more, i.e. >= 56 days).  
However, imputation of missing data will be applied as described in Section 6.1.4.  
Table 1: Treatment Visit Windows, treatment duration < 8 weeks  
Visit Name 
Target day 
Analysis visit window 
From SD 
To SD 
Baseline 
Last observation recorded prior to the first dose 
of emapalumab 
Study Day 0 (first infusion of 
emapalumab) 
1 
1 
1 
Study Day 3 
4 
2 
5 
Study Day x 
Study Day x 
+ 1 day
Target day 
– 1 day
Target day 
+ 1 day
a) EOT visit
available
Study Day n-1 
Study Day x 
+1 day
Target day 
– 1 day
Day of last infusion of 
emapalumab  
EOT / Week 8 
EOT visit 
Day of last infusion 
of emapalumab +1 
EOT visit 
EOT 
EOT visit 
EOT visit 
EOT visit 
b) no EOT visit
available
Study Day n-1 
Study Day x 
+1 day
Target day 
– 1 day
Day of last infusion of 
emapalumab – 1 day 
EOT / Week 8 
Start day of last 
infusion * 
Start day of  
last infusion * 
End day of  
last infusion * 
EOT 
Start day of last 
infusion * 
Start day of  
last infusion * 
End day of  
last infusion * 
* Start and End date of infusion are in most of the cases the same date. 
a) If an EOT visit was performed and treatment duration was < 8 weeks (i.e. < 56 days), the
day of EOT visit will be assigned as EOT/Week 8 analysis visit and as EOT visit prior to
start of conditioning.
b) If no EOT visit was performed and treatment duration was < 8 weeks (i.e. < 56 days), the
day of last infusion will be assigned as EOT/Week 8 analysis visit and as EOT visit prior
to start of conditioning.


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Table 2: Treatment Visit Windows, treatment duration >= 8 weeks 
Visit Name 
Target day 
Analysis visit window 
From SD 
To SD 
Baseline 
Last observation recorded prior to the first dose 
of emapalumab 
Study Day 0 (first infusion of 
emapalumab) 
1 
1 
1 
Study Day 3 
4 
2 
5 
Study Day 6 
7 
6 
8 
Study Day 9 
10 
9 
11 
Study Day 12 
13 
12 
14 
Study Day 15 
16 
15 
17 
Study Day 18 
19 
18 
20 
Study Day 21 
22 
21 
23 
Study Day 24 
25 
24 
26 
Study Day 27 
28 
27 
29 
Study Day 30 
31 
30 
32 
Study Day 33 
34 
33 
35 
Study Day 36 
37 
36 
38 
Study Day 39 
40 
39 
41 
Study Day 42 
43 
42 
44 
Study Day 45 
46 
45 
47 
Study Day 48 
49 
48 
50 
Week 8 is the last week prior to EOT visit or last infusion 
a) EOT visit
available
Study 
Day 51 
52 
51 
Day of last infusion of 
emapalumab 
EOT / 
Week 8 
EOT visit 
Day of last infusion 
of emapalumab + 1 
day 
EOT visit 
EOT 
EOT visit 
EOT visit 
EOT visit 
b) no EOT visit
available
Study 
Day 51 
52 
51 
Day of last infusion of 
emapalumab - 1 day 
EOT / 
Week 8 
57 
Day of last infusion 
of emapalumab 
Day of last infusion of 
emapalumab + 6 days 
EOT 
Start day of last 
infusion * 
Start day of  
last infusion * 
End day of  
last infusion * 


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Visit Name 
Target day 
Analysis visit window 
From SD 
To SD 
Week 8 is not the last week prior to EOT visit or last infusion (subsequent weeks (x to n)) 
a) EOT visit
available
Week x 
Week (x*7) +1 
Target day 
– 3 days
EOT visit – 1 day 
EOT / 
Week 8 
57 
54 
60 
EOT 
EOT visit 
EOT visit 
EOT visit 
b) no EOT visit
available
Week x 
Week (x*7) +1 
Target day 
– 3 days
Day of last infusion of 
emapalumab – 1 day 
EOT / 
Week 8 
57 
54 
60 
EOT 
Start day of last 
infusion * 
Start day of  
last infusion * 
End day of  
last infusion * 
* Start and End date of infusion are in most of the cases the same date. 
If treatment duration was >= 8 weeks (i.e. >= 56 days) the visit within the analysis visit window 
of 54 and 60 days and closest to the target day will be assigned as EOT/Week 8 analysis visit.  
a) If an EOT visit was performed the day of EOT visit will be assigned as EOT visit prior to
start of conditioning.
b) If no EOT visit was performed the day of last infusion will be assigned as EOT visit prior
to start of conditioning.
6.1.6. Treatment naïve / experienced patients 
Treatment naïve (First Line) patients: 
Patients who have not received any conventional treatment for pHLH. In treatment-naïve 
patients, an initial background therapy of 10 mg/m2 dexamethasone will be required. 
Dexamethasone not more than 7 days or Methylprednisolone pulses for less than 3 consecutive 
days until emapalumab treatment start (SD0). 
Treatment experienced (Second line) patients: 
Patients who have received conventional HLH therapy (as per site standard of care), e.g., any of 
the following alone or in combination (Etoposide, ATG, Alemtuzumab and Cyclosporine A) and 
Dexamethasone at 10 mg/m2 for more than 7 days or methylprednisolone pulses for 3 or more 
consecutive days before emapalumab treatment start (SD0). 


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The following derivation to identify second line patients will be done:  
•
Yes to Question: Was any HLH treatment administered at diagnosis [History of HLH
treatments]
and 
•
Medication that:
- Contains text ‘HLH 2004’.
or 
- Medication recorded in eCRF with a start date prior to emapalumab first infusion as
follows: (priorities need to be followed as below list, check first condition first if not met
then check second condition, if not met then the third and so on).
o Etoposide [ATC04ID L01CB - Preferred code 00511901001], any dose, any duration
o Antithymocyte immunoglobulin [ATC04ID L04AA - Preferred code 00575401001],
any dose, any duration
o Alemtuzumab [ATC04ID L04AA - Preferred code 01268601001], any dose, any
duration
o Cyclosporin A [ATC04ID L04AD - Preferred code 00549701001], any dose, any
duration
o Anakinra [ATC04ID L04AC - Preferred code 01345101001], any dose, any duration
o Tocilizumab [ATC04ID L04AC - Preferred code 01759101001], any dose, any
duration
o Dexamethasone [ATC04ID H02AB - Preferred code 00016001001], dose ≥ 10mg/m2
for at least 7 days
o Methylprednisolone [ATC04ID H02AB - Preferred code 00049601001], with a
verbatim indicating “pulses” or “high dose”, or any dose for more than 7 days or 30
mg/kg for 3 consecutive days
and any of the following 
-
Having not achieved a satisfactory response (Unsatisfactory response)
-
Having not responded or worsened (No response or worsening)
-
Showing intolerance to previous conventional treatment of HLH.
-
Having reactivated after satisfactory response based on investigator assessment at
screening.
6.1.7. Subgroup Analyses 
All data will be presented for the following subgroups, with the relevant analysis sets described 
in Table 3: 
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•
Treatment-naïve: Patients in the All Treated Analysis Set who are naïve to HLH treatment 
(according to section 6.1.6).
•
Treatment-experienced: Patients in the All Treated Analysis Set who have received 
conventional HLH therapy (as per site standard of care) without having obtained a 
satisfactory response according to the treating physician or having shown signs of intolerance 
to previous HLH therapy.
Conventional HLH therapy is defined as per site standard-of-care, e.g., any of the following, 
alone or in combination (etoposide, ATG, alemtuzumab and cyclosporine A) or glucocorticoids, 
namely dexamethasone at 10 mg/m2 for at least 7 days or methylprednisolone pulses for 3 
consecutive days. 


Statistical Analysis Plan,  
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Table 3: Patient Populations for Each Analysis/Summary 
Patient Populations 
Analyses 
Enrolled 
Population 
Analysis Set 
All Treated Analysis Set 
Evaluable Analysis Set 
Treatment 
naïve 
Treatment 
experienced 
Total 
Treatment 
naïve 
Treatment 
experienced 
Total 
Patient Disposition 
X 
X 
X 
X 
X 
X 
X 
Protocol Deviations 
X* 
Demographics, Baseline 
X 
X 
X 
Prior and Concomitant Therapies 
X 
X 
X 
Primary Efficacy Endpoint 
X 
X 
X 
X 
X 
X 
Secondary Efficacy Endpoints 
X 
X 
X 
X 
X 
X 
Sensitivity analysis 1: Overall Response at 
EOT or Week 8 (whichever occurs earlier) 
with deaths considered as non-responders 
X 
X 
X 
Sensitivity analysis 2: Overall Response at 
EOT or Week 8 (whichever occurs earlier) 
with early withdrawal considered as non-
responders 
X 
X 
X 
Sensitivity analysis 3: Overall Response at 
EOT or Week 8 (whichever occurs earlier) 
with patients who receive concomitant 
administration of other HLH treatments 
considered as non-responders 
X 
X 
X 


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Patient Populations 
Analyses 
Enrolled 
Population 
Analysis Set 
All Treated Analysis Set 
Evaluable Analysis Set 
Treatment 
naïve 
Treatment 
experienced 
Total 
Treatment 
naïve 
Treatment 
experienced 
Total 
Sensitivity analysis 4: Overall Response at 
EOT or Week 8 (whichever occurs earlier) 
with deaths, early withdrawals, and patients 
who receive concomitant administration of 
other HLH treatment considered as non-
responders 
X 
X 
X 
Sensitivity analysis 5: Overall Response at 
EOT or Week 8 (whichever occurs earlier) 
with patients deemed as having a major 
protocol deviation impacting statistical analysis 
removed from the Analysis Set 
X^ 
X^ 
X^ 
Supplementary analysis: Overall Response at 
EOT or Week 8 (whichever occurs earlier) - 
Modified Definition 
X 
X 
X 
Exposure 
X 
X 
X 
Quality of life: PedsQL™, BASES 
X 
X 
X 
Safety: AEs, SAEs, Lab tests 
X 
X 
X 
Safety: Vital Signs, Physical Examination, 
ECG 
X 
X 
X 
* Excluding Screening failures
^ Evaluable Analysis Set Without Major Protocol Deviations


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6.1.8. Pooling of Sites 
As relatively few patients are expected in the study, the centers will not be taken into account in 
the analyses. 
6.1.9. Derived Variables 
6.1.9.1. 
General 
•
Sponsor defined study day = date of interest – date of first emapalumab infusion
Note: This study day will be used in the analysis visit windowing and displayed on listings
if required. Study Day 0 (SD0) is the day when first emapalumab infusion is performed.
•
Change from baseline = value at current time point – value at baseline.
6.1.9.2. 
Demography and Baseline Parameters 
•
Conversion factors: The following conversion factors will be used to convert days into
months or years:
•
1 month = 30.4375 days
•
1 year = 365.25 days
•
Age at diagnosis in years = date of diagnosis – date of birth +1.
•
Age in days = date of informed consent – date of birth +1.
•
Age in years = Age in days / 365.25.
•
Age categories: The following groups will be used for categorizing age:
Age Group 
Definition 
Newborns (0-27 days) 
0 ≤ (Date of informed consent – Date of Birth +1) ≤ 27 
Infant and toddlers (28 days - 23 months) 
28 ≤ (Date of informed consent – Date of Birth +1) and age 
in years = 1 
Children (2-11 years) 
2 <= age in years <= 11 
Adolescents (12-18 years) 
12 <= age in years <= 18 


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6.1.9.3. 
Safety Parameters 
Table 4: Definition of Drug Administration Variables 
Statistics for Exposure (dosing) 
Derivation 
Duration of exposure (days) 
Date of last infusion of emapalumab – date of 
first infusion of emapalumab + 1 
Duration of exposure (weeks) 
Duration of exposure (days)/7 
Maximum dose prescribed 
Maximum of all doses prescribed (mg/kg) 
Cumulative dose (mg/kg) 
Sum of total actual dose per kg administered 
from first infusion date until last infusion date 
Average dose frequency (days) 
Duration of exposure (days)/ total number of 
infusions 
Average dose of emapalumab per day 
(mg/kg) 
Cumulative dose (mg/kg)/ duration of 
exposure (days) 
Percentage of dose increases from baseline 
dose 
(Number of dose increases from baseline dose 
/ number of total doses) multiplied by 100. 
Percentage of dose decreases from baseline 
dose 
(Number of dose decreases from baseline 
dose / number of total doses) multiplied by 
100. 
Table 5: Definition of Adverse Events 
Variable 
Definition 
Adverse Event (AE) 
All recorded AEs (collection of AEs starts after ICF 
signature). 
Treatment-Emergent Adverse 
Event (TEAE) 
Any AE (serious and non-serious) with an onset date after 
the start of the first emapalumab infusion. 
Pre-conditioning AE 
Any AE (serious and non-serious) with start date before the 
start of conditioning for HSCT*. 


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Variable 
Definition 
Post-conditioning AE 
Any AE (serious and non-serious) with start date after the 
start of conditioning for HSCT*. 
TEAEs related to the study drug 
Any AEs with an onset date after the start of the first 
emapalumab infusion with “Relationship to Study Drug” of 
“Related”. 
Serious TEAEs 
Any AEs with an onset date after the start of the first 
emapalumab infusion with “Serious” of “Yes”. 
TEAEs leading to withdrawal of 
study drug 
Any AEs with an onset date after the start of the first 
emapalumab infusion with “Action taken with study drug” 
of “Drug Withdrawn”. 
TEAEs resulting in death 
Any AEs with an onset date after the start of the first 
emapalumab infusion with “Results in death” of “Yes”. 
TEAE with infections 
Any AE with an onset date after the start of the first 
emapalumab infusion with system organ class (SOC) 
‘Infections and Infestations’ or in the HLGT ‘Microbiology 
and serology investigations’. 
TEAE with infusion-related 
reactions (IRRs) 
Any AE reported to have occurred within 24 hours after the 
start of infusion and reported as related to study treatment 
by the Investigator, excluding the following SOCs: 
“Infections and infestations,” “Congenital familial and 
genetic disorders,” “Neoplasms benign, malignant and 
unspecified (incl. cysts and polyps),” “Product issues,” 
“Social circumstances,” and “Surgical and medical 
procedures.” 
If the onset time of the AE or the start time of the infusion is 
missing, then an AE with an onset date equal to an infusion 
date or infusion date +1 will be considered for the 
assessment of IRRs, unless the available information clearly 
indicates the AE was not treatment-emergent. 
*Note: The start date of conditioning is captured in the HSCT module of the eCRF or CM module. For 
more information of HSCT medications see Appendix 16.2.


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6.1.9.4. 
Efficacy Parameters 
•
Overall Response at EOT or Week 8 = achievement (yes/no) of either Complete or Partial
Response or HLH improvement at EOT or the Week 8 assessment, whichever occurs
earlier.
•
Overall Response at start of conditioning for HSCT = achievement (yes/no) of either
Complete or Partial Response or HLH improvement at start of conditioning of HSCT (date
of start of conditioning) or last emapalumab if HSCT is not performed.
The definition of the Overall Response for the primary endpoint is detailed in Table 6 along with 
additional clarifications. 
The definition of the Overall Response used in the supplementary analysis is detailed in Table 7. 


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Table 6: Definition of Response for the Primary Endpoint 
Response for 
Primary Endpoint 
Definition 
Additional Clarifications 
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 ferritin level is
< 2000 µg/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)
- All HLH parameters that were abnormal at baseline 
must be normalized
- No AEs relating to organ failure
- All other parameters that were normal at baseline 
must still meet the definition of normalized
- Normal spleen size confirmed by abdominal 
ultrasound (US) whenever possible based on the 
splenomegaly not present; if US not performed 
physical examination will be used
- Normal D-Dimer levels are <= 500 ug/L
- No neurological abnormalities attributed to HLH = 
“normal” neurological assessment by investigator in 
the neurological examination page (without findings 
in brain imaging (Brain MRI/Brain CT/cranial 
ultrasound) or AEs indicative of “CNS 
involvement” (Appendix 15.3)
-
No CSF abnormalities = no AE indicative of 
“CSF abnormalities” (Appendix 15.3)


Statistical Analysis Plan,  
Sponsor Sobi AG  
Protocol Number NI-0501-09  
PCN Number 176784
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Response for 
Primary Endpoint 
Definition 
Additional Clarifications 
Partial Response 
Partial Response is adjudicated if: 
- At least 3 of the HLH clinical and laboratory
abnormalities (including CNS abnormalities) meet
the above mentioned criteria for “Complete
Response”
- In the case of “reactivated patients” who enter the
study with 3 abnormal HLH features, Partial
Response is adjudicated if at least 2 parameters
normalize
- In case of reactivated patients who enter the study
with 2 abnormal HLH clinical and laboratory 
parameters only, Partial Response is adjudicated if 
one of the 2 parameters normalizes  
- There is no progression of other aspects of HLH
disease pathology
If a patient is not considered as “reactivated” or a 
patient is considered “reactivated” with 4 or more 
abnormal HLH features upon entry to the study and 
at least 3 of the HLH clinical and laboratory 
abnormalities (including CNS abnormalities) meet 
the above-mentioned criteria for “Complete 
Response” Partial Response is adjudicated.  
For all patients: no progression of other aspects of 
HLH disease pathology is assessed by absence of 
AEs indicating organ failure including no worsening 
of sCD25 levels. 


Statistical Analysis Plan,  
Sponsor Sobi AG  
Protocol Number NI-0501-09  
PCN Number 176784
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Response for 
Primary Endpoint 
Definition 
Additional Clarifications 
HLH Improvement 
HLH Improvement is adjudicated if: 
- Improvement (>50% change from baseline or
normalization) of at least 3 HLH clinical and
laboratory abnormalities (including CNS
abnormalities).
- In the case of “reactivated patients” who enter the
study with only 2 abnormal HLH features, a change
from baseline greater than 50% for both will define
HLH as improved.
Definition of 50% improvement from baseline: 
- Spleen size decreased by 50%, as recorded in cm
from costal margin at physical examination.
- Absolute Neutrophil Count increased by 50%, if G-
CSF has not been administered in the previous 4 days
and Platelet count increased by 50%, if no platelet
transfusion has been administered in the previous 4
days
- Ferritin decreased by 50%
- Fibrinogen increased by 50% or D-Dimer decreased
by 50%
Normalization of CNS abnormalities = normal 
neurological assessment by investigator without 
findings in brain imaging (Brain MRI/Brain 
CT/cranial ultrasound), CSF analysis or AEs 
indicative of “CNS involvement” or “CSF 
abnormalities” 
No Response 
If a subject does not meet the criteria for at least 
HLH improvement, response is categorized as “No 
Response”  
Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; G-CSF, granulocyte-colony-stimulating factor; HLH, hemophagocytic 
lymphohistiocytosis 


Statistical Analysis Plan,  
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Table 7: Definition of Response for Supplementary Analysis 
Response for 
Supplementary 
Analysis 
Definition 
Additional Clarifications 
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 ferritin level is
< 2000 µg/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)
- All HLH parameters that were abnormal at baseline
must be normalized
- No AEs relating to organ failure
- All other parameters that were normal at baseline
must still meet the definition of normalized
- Normal spleen size confirmed by abdominal
ultrasound (US) whenever possible based on the
splenomegaly not present; if US not performed
physical examination will be used
- Normal D-Dimer levels are <= 500 ug/L
- No neurological abnormalities attributed to HLH =
“normal” neurological assessment by investigator in
the neurological examination page (without findings
in brain imaging (Brain MRI/Brain CT/cranial
ultrasound) or AEs indicative of “CNS involvement”
(Appendix 15.3)
-
No CSF abnormalities = no AE indicative of
“CSF abnormalities” (Appendix 15.3)


Statistical Analysis Plan,  
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Response for 
Supplementary 
Analysis 
Definition 
Additional Clarifications 
Partial Response 
Partial Response is adjudicated if: 
- A patient has more than 3 abnormal HLH features
at baseline and at least 3 parameters normalize. The
remaining may be the same or worse as baseline
(unless 2 or more parameters no longer meet the
definition of normality)
- In the case where a patient has only 3 abnormal
HLH features at baseline, Partial Response is
adjudicated if at least 2 parameters normalize. The
remaining may be the same or worse as baseline
(unless 2 or more parameters no longer meet the
definition of normality)
- In the case where a patient has only 2 abnormal
HLH features at baseline, Partial Response is
adjudicated if one of the 2 parameters normalizes.
The remaining may be the same or worse as
baseline (unless 2 or more parameters no longer
meet the definition of normality)
- There is no progression of other aspects of HLH
disease pathology
If a patient is not considered as “reactivated” or a 
patient is considered “reactivated” with 4 or more 
abnormal HLH features upon entry to the study and 
at least 3 of the HLH clinical and laboratory 
abnormalities (including CNS abnormalities) meet 
the above-mentioned criteria for “Complete 
Response” Partial Response is adjudicated.  
For all patients: no progression of other aspects of 
HLH disease pathology is assessed by absence of 
AEs indicating organ failure including no worsening 
of sCD25 levels. 


Statistical Analysis Plan,  
Sponsor Sobi AG  
Protocol Number NI-0501-09  
PCN Number 176784
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Response for 
Supplementary 
Analysis 
Definition 
Additional Clarifications 
HLH Improvement 
- At least 3 of the HLH parameters that were
abnormal at baseline must be normalized or
improved (i.e., >=50% change from baseline). The
remaining may be the same or worse as baseline
(unless 2 or more parameters no longer meet the
definition of normality)
- In the case where a patient has only 2 abnormal
HLH features at baseline, a change from baseline
greater than 50% for both will define HLH as
improved.
Definition of 50% improvement from baseline: 
- Spleen size decreased by 50%, as recorded in cm
from costal margin at physical examination.
- Absolute Neutrophil Count increased by 50%, if G-
CSF has not been administered in the previous 4 days
and Platelet count increased by 50%, if no platelet
transfusion has been administered in the previous 4
days
- Ferritin decreased by 50%
- Fibrinogen increased by 50% or D-Dimer decreased
by 50%
Normalization of CNS abnormalities = normal 
neurological assessment by investigator without 
findings in brain imaging (Brain MRI/Brain 
CT/cranial ultrasound), CSF analysis or AEs 
indicative of “CNS involvement” or “CSF 
abnormalities” 
No Response 
If a subject does not meet the criteria for at least 
HLH improvement, response is categorized as “No 
Response”  
Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; G-CSF, granulocyte-colony-stimulating factor; HLH, hemophagocytic 
lymphohistiocytosis 


Statistical Analysis Plan,  
Sponsor Sobi AG  
Protocol Number NI-0501-09  
PCN Number 176784
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•
Overall Survival, defined as the time from the date of first dose to the date of death. Patients
without an event will be censored at date of last contact. The analysis start and end dates
and the censoring rules are described in the following scheme:
Table 8: Overall Survival
Situation 
Outcome 
(event or 
censored) 
Analysis start 
date 
Analysis end date 
No assessments after 
first infusion 
Censored 
Start of treatment 
Start of treatment + 1 
Death for any cause 
Event 
Start of treatment 
Death 
Alive at the end of the 
observation period* 
Censored 
Start of treatment 
Last known alive 
* end of study, or premature end of study for the patient (including withdrawal of consent)
•
Survival to HSCT, defined as the time from the date of first dose to the date of death.
Patients who receive a HSCT will be censored at that date. Patients who did not receive
HSCT will be censored at date of last contact. The analysis start and end dates and the
censoring rules are described in the following scheme:
Table 9: Survival to HSCT
Situation 
Outcome 
(event or 
censored) 
Analysis start 
date 
Analysis end date 
No assessments after 
first infusion 
Censored 
Start of treatment 
Start of treatment + 1 
Death for any cause 
Event 
Start of treatment 
Death 
Alive at HSCT 
Censored 
Start of treatment 
HSCT date 
Alive without having 
received HSCT 
Censored 
Start of treatment 
Last known alive date 


Statistical Analysis Plan,  
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Protocol Number NI-0501-09  
PCN Number 176784
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•
Survival post HSCT, defined as the time from date of HSCT to the date of death. Patients
without an event will be censored at date of last contact. Patients who do not proceed to
HSCT will be excluded from this analysis. The analysis start and end dates and the
censoring rules are described in the following scheme:
Table 10: Survival post HSCT
Situation 
Outcome 
(event or 
censored) 
Analysis start 
date 
Analysis end date 
Death for any cause 
Event 
Date of HSCT 
Death 
Alive at the end of the 
observation period* 
Censored 
Date of HSCT 
Last known alive date 
* end of study, or any time during follow-up period (including withdrawal of consent)
•
HLH Reactivation = any adverse event in the following preferred term (PT) (PT code):
o
Condition Aggravated (10010264)
•
Graft failure = any adverse event in at least one of the following PTs (PT code):
o
Transplant failure (10060872)
o
Engraft failure (10068081)
o
Bone marrow transplant rejection (10048396)
o
Transplant rejection (10044439)
o
Complications of bone marrow transplant (10010162)
o
Graft loss (10048748)
•
Event-free survival = time from HSCT to date of (whichever occurs first): death from any
cause, graft failure, HLH reactivation. The analysis start and end dates and the censoring
rules are described in the following scheme:


Statistical Analysis Plan,  
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Table 11: Event-Free Survival 
Situation 
Outcome 
(event or 
censored) 
Analysis start 
date 
Analysis end 
date 
At least one event, i.e. graft 
failure, HLH reactivation, 
death for any cause 
Event 
Date of HSCT 
Date of first 
event 
None of the events at the end 
of the observation period* 
Censored 
Date of HSCT 
Last known alive 
* end of study, or any time during follow-up period (including withdrawal of consent)
•
Duration of Response (i.e. maintenance of response achieved at any time during the study
until EOT) is defined as the total elapsed time from achievement of first Overall Response
to first loss of response, pending the duration of this response is at least 4 days. If the first
observed response does not last for at least 4 days, then the next response period will be
considered. Similarly, loss of response should persist for at least 4 days, otherwise the next
loss of response period will be considered. Patients who are in response at EOT will be
censored at that date. Patients who do not achieve at least HLH improvement once between
the date of first dose and EOT will be excluded from the analysis.
The analysis start and end dates and the censoring rules for calculation of duration of
response are described in the following scheme:
Table 12: Duration of Response
Situation 
Outcome 
(event or 
censored) 
Analysis start 
date 
Analysis end date 
Maintained loss of overall 
response 
Event 
Date of first 
response 2 
Date of loss of 
overall response 2 
Death for any cause 
Event 
Date of first 
response 2 
Date of death 
In response at the end of the 
observation period1   
Censored 
Date of first 
response 2 
Last known 
response 


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1 end of treatment without conditioning, or start of conditioning for HSCT, or early 
termination (including withdrawal of consent);  
2 last for at least 4 days 
•
Cumulative Duration of Response = Total time in response from the first achievement of
an Overall Response until HSCT conditioning (or EOT if the patient did not have HSCT
performed). Considering patients who achieve a response, lost that response, and then
achieve it subsequently, the total time in response will be calculated by adding together
these separate periods in response. Patients who do not achieve response at least once
between the date of first dose and the time of conditioning start are excluded from the
analysis.
•
Percent days in response = Cumulative response duration divided by number of days from
first infusion until HSCT conditioning (or EOT if the patient did not have HSCT
performed).
•
Time to Response (i.e. time to first maintained response) is defined as elapse time from
start of treatment to first achievement of a response maintained for at least 4 days prior to
or at EOT. Patients with no post-baseline assessments (assessment after the first infusion)
will be censored at the first dose date. The analysis start and end dates and the censoring
rules are described in the following scheme:
Table 13: Time to Response
Situation 
Outcome (event 
or censored) 
Analysis start 
date 
Analysis end date 
No assessments after first 
infusion 
Censored 
Start of 
treatment 
Start of treatment + 1 
At least 1 event i.e. 
complete or partial 
response or HLH 
improvement 
Censored 
Start of 
treatment 
Date of first response 
which lasted for at 
least 4 days 
Death for any cause 
Censored 
Start of 
treatment 
Death 
Alive at the end of the 
observation period* 
Censored 
Start of 
treatment 
Last known alive 
* end of study, or premature end of study for the patient (including withdrawal of
consent)


Statistical Analysis Plan,  
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Protocol Number NI-0501-09  
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Medication Parameters 
The definition of treatment naïve and treatment experienced patients are described in detail in 
section 6.1.6.  
Table 14: Derivations for Medications 
Dexamethasone daily dose 
The dose of dexamethasone is to be expressed as mg/m2/day in order to give homogeneous 
metrics across patients. 
The ‘Systemic Steroids Administration’ module of the eCRF also collects other glucocorticoids 
that need to be converted to dexamethasone equivalent using the following assumptions: 
•
The equivalent dose will include only glucocorticoids administered IV or per os (PO)
•
IV and PO route of administration are equivalent, which means 1 mg of IV
dexamethasone is equivalent to 1 mg of PO dexamethasone, and 1 mg of IV
methylprednisolone is equivalent to 1 mg of PO methylprednisolone.
•
Conversion factor:
o
1 for dexamethasone
o
1/5.3 for methylprednisolone
o
1/6.7 for prednisolone
o
1/6.7 for prednisone
o
1/5.3 for triamcinolone
o
1/26.6 for hydrocortisone
o
1/33.3 for cortisone
•
Dose unit: If the dose unit is not mg, then the following conversion will be done:
o
1 g = 1000 mg
o
1 mcg = 0.001 mg
Given the possibility of having dexamethasone doses recorded differently in the eCRF or 
conversions from other glucocorticoids required the following calculation will be performed:  
•
Daily dose = Conversion factor* Dose of dexamethasone in mg
* number of administrations per day
•
BSA Surface Area (BSA) [VS]
•
Equivalent dose (mg/m2/day) = Daily dose / BSA


Statistical Analysis Plan,  
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Glucocorticoid tapering 
For the reduction of glucocorticoid dose by 50% or more of baseline dose, the use of 
glucocorticoid for systemic use during the study period will be obtained by the CM (ATC04ID 
H02AB) or medications captured on the SSA module of the eCRF. Drug names on the SSA page 
are standardized (Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisolone, 
Prednisone), not coded. The calculation of reduction of glucocorticoid dose by 50% or more of 
baseline dose will take into consideration the following:  
•
Dexamethasone (H02AB - PREFERRED CODE 00016001001) dose expressed as
mg/m2/day at
o
Baseline = SD-1 or closest day to SD0
o
The lowest dose received during the study and the corresponding SD,
o
The dose received at EOT
provided that:  
•
No other glucocorticoids have been received by oral or IV route on the SD of interest
with reference to:
o
Methylprednisolone (CM page: H02AB - PREFERRED CODE 00049601001)
o
Prednisolone (CM page: H02AB - PREFERRED CODE 00016201001)
o
Prednisone (CM page: H02AB - PREFERRED CODE 00044701001)
o
Hydrocortisone (CM page: H02AB – PREFERRED CODE 00028601001,
00028603001,00028602001)
o
Triamcinolone (CM page: H02AB – PREFERRED CODE 00031901001 if
single ingredient medication; in case of multiple ingredients medications or salt
derivates every entry need to be checked manually for Triamcinolone)
o
Cortisone (CM page: H02AB – PREFERRED CODE 00014601001 if single
ingredient medication; in case of multiple ingredients medications or salt
derivates every entry need to be checked manually for Cortisone)
In that case, the dose of the other glucocorticoids has to be summed up, taking into consideration 
glucocorticoid conversion.  
•
Glucocorticoids reduction until EOT
A patient will achieve a glucocorticoids reduction by 50% or more of the baseline dose if
the equivalent dose of dexamethasone at any post-baseline time until EOT is less than or
equal to (≤) ½ the equivalent dose of dexamethasone at baseline. This reduction has to be
maintained for at least one week.
•
Patients proceeding to HSCT = patient with HSCT (date of HSCT non missing in the HSCT
module of the eCRF).


Statistical Analysis Plan,  
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Quality of Life Parameters 
•
The Pediatric Quality of Life Inventory (PedsQL) is a brief measure of health-related
quality of life in children and adults. PedsQLTM 4.0 generic core scales (ages 2 to over 26)
and PedsQLTM infant scales (ages 1 to 24 months) are used in the study. The PedsQLTM
4.0 generic core scales can be completed by parents (Parent Proxy-Report from 2 years
old) as well as children and adults (Child/Adult Self-Report from 5 years old). The PedsQL
generic core scales are composed of four scales grouped together in one questionnaire:
•
Physical functioning
•
Emotional functioning
•
Social functioning
•
School functioning
The PedsQL Infant Scales, specific for healthy and ill infants ages 1-24 months, are 
completed by parents and composed of five scales grouped together in one questionnaire: 
•
Physical functioning
•
Physical symptoms
•
Emotional functioning
•
Social functioning
•
Cognitive functioning
Scales are estimated using the following 2-step process as described in the ‘Scaling and 
Scoring of the Pediatric Quality of Life Inventory PedsQL’ version 17, dated May 2017 
and available online https://www.pedsql.org/PedsQL-Scoring.pdf .  
1) Calculate reversed scored items transforming the 0-4 scale item to 0-100 as follows:
Response Choices 
Never Almost Never 
Sometimes 
Often 
Almost Always 
Raw scores 
0 
1 
2 
3 
4 
Reversed score 
100 
75 
50 
25 
0 
Notes: 
-
Higher scale scores indicate better HRQOL (Health-Related Quality of Life).
-
3-point scales: 0 (Not at all), 2 (Sometimes) and 4 (A lot) applicable for the young child (ages 5-7)
self-report.
2) Calculate the average as sum of the items divided by the number of items answered. If
more than 50% of the items in the scale are missing, the Scale Score should not be
computed.


Statistical Analysis Plan,  
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•
Functioning scale scores as average of the transformed functioning scale items
o
Physical Functioning Scale Score = average of transformed physical
functioning scale items; up to 6 items for infants (1-12 months), 9 items for
infants (13-24 months), and 8 items for toddlers, young children, children,
teens, and young adults.
o
Physical Symptoms Scale Score = average of transformed physical
symptoms scale items; up to 10 items for infants (1-12 months) and infants
(13-24 months). This scale score is not available for toddlers, young
children, children, teens, and young adults.
o
Emotional Functioning Scale Score = average of the transformed emotional
functioning scale items; up to 12 items for infants (1-12 months) and infants
(13-24 months) and 5 items for toddlers, young children, children, teens,
and young adults.
o
Social Functioning Scale Score = average of the transformed social
functioning scale items; up to 4 items for infants (1-12 months) and 5 items
for infants (13-24 months), toddlers, young children, children, teens, and
young adults.
o
Work/Study Functioning Scale Score = average of the transformed school
functioning scale items; up to 3 items for toddler and 5 items for young
children, children, teens, and young adults. This scale was not collected for
infants (1-12 months) or infants (13-24 months).
o
Cognitive Functioning Scale Score = average of the transformed cognitive
functioning scale items; up to 4 items for infants (1-12 months) and 9 items
for infants (13-24 months). This scale score is not available for toddlers,
young children, children, teens, and young adults.
•
Health summary scores
o
Physical Health Summary Score = Physical Functioning Scale Score for
toddlers, young children, children, teens, and young adults. For infants (1-
12 months) and infants (13-24 months), it is the sum of transformed items
over the number of items answered in physical functioning and physical
symptoms scales.
o
Psychosocial Health Summary Score = sum of transformed items over the
number of items answered in Emotional, Social, and Work/Study
Functioning Scales for toddlers, young children, children, teens, and young
adults. It is the sum of transformed items over the number of items answered
in Emotional, Social, and Cognitive Functioning Scales for infants (1-12
months) and infants (13-24 months).


Statistical Analysis Plan,  
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•
Total Scale Score = sum of all the transformed items over the number of items
answered on all the scales. (i.e. average as sum of the items divided by the
number of items answered).
•
The BASES questionnaire is a validated 38 item questionnaire. In this study a reduced non-
validated 22 item version is used in an exploratory nature for the secondary endpoint.
BASES subscale scores will be calculated using a 5-point Likert scale from 1 to 5 for all
items and they will be weighted equally to calculate subscale scores. for the following
domains:
o
Physical Discomfort, items 1 to 5 (5 items – where 1 is considered best response
for all items)
o
Cooperation/Compliance, items 6 to 10 (5 items – where 1 is considered best
response for all items)
o
Mood/Behavior, items 11 to 17 (7 items – where 5 is considered best response for
all items)
o
Quality of Interactions, items 18 to 20 (3 items – where 1 is considered best
response for all items)
o
Activity/Sleep, items 21 to 22 (2 items – where 5 is considered best response for
patient’s activity level and 1 is considered best response for patient’s sleeping)
6.1.10. Data Adjustments/Handling/Conventions 
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 21.0 (or later) thesaurus. 
Medications will be coded using World Health Organization Drug Dictionary (WHO-DD) B2 
Enhanced v. March 2018 (or later). 
Tables describing AEs will show SOCs by descending number of patients and preferred terms 
within SOC also by descending number of patients. Tables describing prior and concomitant 
medication will show Anatomical Therapeutic Chemical (ATC) level 1 by descending number of 
patients and ATC level 2 term also by descending number of patients. 
A treatment-related AE is any AE with a relationship to the study drug of ‘related’. If a particular 
event is missing the relationship, the strongest possible relationship will be assumed for analysis 
(relationship = related).  
Adverse events will also be described by intensity (mild, moderate, severe). If a particular event is 
missing the intensity, the strongest possible intensity will be assumed for analysis 
(intensity=severe). 


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Partially missing dates for AEs will be imputed as follows. Note, imputation of missing/partial AE 
date will be performed only to identify treatment emergent AEs. 
AE onset dates 
•
Partially missing onset dates will be imputed as follows:
o
When only day is missing:

If month and year of the onset date are the same as month and year of the
first infusion date, the imputed onset date will be imputed as the minimum
of the first infusion date and the AE resolution date (imputed if needed).

Otherwise, the missing day will be replaced as the first day of the month.
o
When day and month are missing:

If year of the onset date is the same as year of the first infusion date, the
imputed onset date will be imputed as the minimum of the first infusion date
and the AE end date (imputed if needed).

Otherwise, the missing day and month will be replaced by “01JAN”.
•
Complete missing onset dates for AEs will be imputed by the first infusion date and the
AE will be considered as treatment emergent unless, the end date of the AE (imputed if
needed) or the end year of the AE (if day and month are missing) is entered and is before
the first infusion date.
AE end dates (for non-ongoing events) 
•
If only day is missing, incomplete end dates will be replaced by the last day of the month,
if not resulting in a date later than the date of patient’s death. In the latter case the date of
death will be used to impute the incomplete end date.
•
If day and month are missing, day and month will be replaced by “31DEC”, if not resulting
in a date later than the date of patient’s death. In the latter case the date of death will be
used to impute the incomplete end date.
•
In all other cases the incomplete end date will not be imputed.
Medication dates 
Partially or missing dates for medications will be imputed as follows. Note, imputation of 
missing/partial medication dates will be performed for differentiating between prior vs 


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concomitant medications and used in the derivation of equivalent daily dose of dexamethasone. 
•
If the start date of the medication is unknown (i.e., complete missing date) and there is no
end date or any evidence to suggest the medication is ongoing, the worst-case scenario
will be assumed. The medication will be considered as both a prior and concomitant
medication.
•
If the month and the day of the start date of the medication are missing, the month and day
will be imputed as “01JAN” of the year specified.
•
If the day of the start date of the medication is missing and there is no end date, the day
will be imputed as the first day of the month specified.
•
If the month and the day of the end date of the medication are missing, the month and day
will be imputed as “31DEC” of the year specified, unless there is evidence that the
medication is not ongoing in the NI-0501-09 study (although complete end date is
unknown). In such circumstances the medication will be considered as prior to enrolment.
•
If the day of the end of the medication is missing, the day will be imputed to the last day
of the month specified, unless there is evidence that the medication is not ongoing in the
NI-0501-09 study (although complete end date is unknown). In such circumstances the
medication will be considered as prior to enrolment.
No other dates will be imputed, unless otherwise specified. In data listings, the original incomplete, 
missing or partial dates (not the imputed dates) will be presented. 
Laboratory parameters 
For laboratory results, as well as pharmacokinetic and pharmacodynamic results, with values 
below the lower limit of quantitation (i.e. < LLOQ), values will be imputed to zeros when 
summarizing for descriptive statistics and presented as “Below LLOQ” in listings. Values above 
the upper limit of quantitation (i.e. > ULOQ) for individual values will be imputed to ULOQ 
values when summarizing for descriptive statistics and presented as “Above ULOQ” in listings. 
Pharmacokinetic/Pharmacodynamic/Immunogenicity parameters 
For PK, PD and ADA the primary samples should be used in analyses, unless there is a reason 
(e.g., sample mishandling or bioanalytical reason) for the primary data to be considered invalid, 
in which case the back-up sample will be utilized. All results will be listed. 
6.1.11. COVID-19 
A Coronavirus Disease 2019 (COVID-19) Continuity Plan will be written to mitigate the 
negative effects of the COVID-19 pandemic on the conduct of this clinical trial.  


Statistical Analysis Plan,  
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Protocol Number NI-0501-09  
PCN Number 176784
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The impact of COVID-19 on this clinical trial and trial participants will be extensively described 
both in the tables, listings, figures (TLFs) and in the CSR. 
The following aspects will be summarized when due to COVID-19: 
•
Changes to treatment dispensation
•
Changes to treatment administration
•
Changes to visit windows to accommodate delays for some assessments
•
Protocol deviations
•
Missing efficacy endpoints
•
Missing visits
The situation is rapidly evolving and further updates to the COVID-19 Continuity Plan and to 
this SAP are possible and likely. 
7.
Study Patients/Subjects and Demographics
7.1. 
Disposition of Patients/Subjects and Withdrawals 
The number of patients for each of the following categories will be presented in a table: 
•
Patients screened (i.e. Enrolled Population Analysis Set)
•
Patients as screen failures and reason for screen failures
•
Treated patients
o
Treatment naïve patients
o
Treatment experienced patients
•
All Treated Analysis Set
•
Evaluable Analysis Set
•
Patients who completed the study
•
Patients who stopped treatment and reason for stopping treatment
•
Patients who prematurely terminated the study and primary reason for early study
termination
Percentages will be calculated using the number of patients in the All Treated Analysis Set as the 
denominator unless otherwise specified.  
A separate tabulation of re-treated patients will be provided, outlining the number of re-treated 
patients and number of re-treated periods per patient. 


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Protocol Number NI-0501-09  
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7.2. 
Protocol Violations and Deviations 
Protocol deviations will be identified and classified as important/non-important during the study 
in line with ICH guidelines after a medical review.  
Important protocol deviations: are a subset of protocol deviations that may significantly 
impact the completeness, accuracy, and/or reliability of key study data, or that may significantly 
affect a subject’s rights, safety or well-being.  
Major protocol deviations: are defined as protocol deviations that have an impact on efficacy. 
Classification of important and major protocol deviations will be assessed at ongoing PD review 
meetings and the blinded data review meeting prior to data base lock. 
Any major deviations will lead to an individual being excluded from the Evaluable Analysis Set 
Without Major Protocol Deviations in a sensitivity analysis as outlined in Section 8.1. 
Important deviations will be summarized by category and relationship to COVID-19 in a table 
considering at minimum the following categories:  
•
Eligibility: patients entering the study who do not meet all eligibility criteria
•
Co-medication: non-adherence to protocol with regard to administration of concomitant
medications
o
Patients are required to receive dexamethasone from not later than SD-1.
Treatment-naïve patients: 10 mg/m2 of dexamethasone will be required.
In patients who failed previous HLH therapy (second line patients): At least 5
mg/m2, or at the dose administered prior to Screening if higher. Lower
dexamethasone doses at study entry are allowed in case of documented
intolerance to glucocorticoids
o
Biologic drugs (for other indications than HLH) during emapalumab
administration. The following are allowed: Granulocyte-colony-stimulating factor
(G-CSF), in case of prolonged neutropenia and Rituximab, in case of documented
EBV infection.
o
Cyclosporin A (CsA) can be continued, if already administered prior to
Screening. CsA is not to be introduced (or re-introduced) during the course of the
study once emapalumab administration has started.
o
Janus kinase (JAK) inhibitors used concomitantly with emapalumab
o
IVIG at doses expected to produce immunomodulatory effect (IVIG is only
allowed as replacement therapy)
•
Study drug:
o
Patients receiving less than 3 consecutive infusions (i.e. an infusion will be
considered as missed If infusions are given more than 6 days apart) of
emapalumab and major deviations to treatment dose assessed as impacting
efficacy by the study team.


Statistical Analysis Plan,  
Sponsor Sobi AG  
Protocol Number NI-0501-09  
PCN Number 176784
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•
Assessments: deviations re. schedule of assessments (e.g., missing examinations assessed
as impacting the efficacy evaluation)
•
Other protocol deviations impacting on patient evaluability (e.g. GCP incompliance)
Important protocol deviations by category, statistical major and minor classification and those 
due to COVID-19 will be listed by patient.  
An assessment of the potential impact on study data analysis and subject’s well-being (e.g. 
major, minor) will also be included. 
7.3. 
Demographics and Other Baseline Characteristics 
Demographics and baseline data will be summarized as outlined in Table 3. 
•
Summary of patient demographics
Summary statistics for age at informed consent (as continuous and categorical variables), 
body weight (kg), height (cm), body surface area (m2), gender (including childbearing 
potential), race, ethnicity, and country of origin will be presented.  
Patients reporting more than 1 race will be counted in a ‘More than one race’ category for 
purposes of tabulating summary statistics race.  
•
Summary of HLH disease characteristics at diagnosis
The following will be summarized:
o
Age at HLH diagnosis (years)
o
Number of patients meeting each HLH criteria
o
Number of patients with genetic mutations identified and which mutations
•
Summary of medical history other than HLH disease
The number and percentage of patients reporting various medical histories, grouped by 
MedDRA system organ class and preferred term will be tabulated.  
•
Summary of HLH disease characteristics at Screening and Baseline
o
Number of patients meeting each HLH criteria at screening and baseline
o
Number of patients presenting with CNS involvement at screening and baseline 
(as defined in Appendix 15.4)
•
Summary of steroid use prior to first emapalumab infusion
•
Summary of previous HLH treatments
o
Number of patients who received HLH treatment including type of drug will be 
tabulated grouped by ATC level 1 and level 2.
All demographic and baseline characteristic data will be presented in patient listings. 


Statistical Analysis Plan,  
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7.4. 
Exposure and Compliance 
Investigational product administration will be listed at patient level including all dose 
adjustments over time and summarized in terms of the number of doses administered, maximum 
dose, equivalent dose of dexamethasone, duration of exposure from the first dose to the last dose 
of treatment, cumulative dose, average dose frequency and average dose per day.  
The emapalumab dose change from the baseline dose will be summarized showing the number of 
patients with a dose increase or a dose decrease at each visit. Moreover, the percentage of dose 
increases and decreases for each patient will be summarized using a descriptive table.  
A listing outlining dose increases along with dose level increased to and reasons for the increase, 
as well as dose decreases over the study will be provided. 
This analysis will be conducted as outlined in Table 3.  
8. 
Efficacy Analysis
The evolution of clinical signs (fever, liver and spleen size) characterizing HLH disease, will be 
presented per visit using descriptive statistics.  
All efficacy data will be presented in patient listings. 
8.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint is Overall Response at EOT or Week 8 (whichever occurs earlier) 
(Section 6.1.9.4) with imputation of missing values. The primary efficacy endpoint and its 
components (Complete Response, Partial Response, and HLH Improvement) will be summarized 
using descriptive statistics. The analysis of the primary endpoint will utilize an exact binomial 
test to evaluate the following hypotheses: 
H0: R ≤ 40% 
H1: R > 40% 
where R is the percentage of the number of patients that achieved Overall Response in the All 
Treated Analysis Set divided by the total number of patients in the All Treated Analysis Set. The 
test will be undertaken at the one-sided 0.025 level. The 2-sided exact 95% confidence interval 
will be provided as well as the 95% confidence interval calculated via the Wilson score method 
as supportive. 
This evaluation will be presented as described in Table 3. 
The components of the primary efficacy endpoint (Complete Response, Partial Response, HLH 
Improvement and No response) will be summarized using counts and percentages at Week 8 or 
EOT (whichever occurs first). 
Sensitivity analyses will be performed on the primary efficacy endpoint using the same test, and 
displayed as outlined in Table 3: 
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Sensitivity analysis 1: Overall Response at EOT or Week 8 (whichever occurs earlier) with 
deaths considered as non-responders. 
Sensitivity analysis 2: Overall Response at EOT or Week 8 (whichever occurs earlier) with early 
withdrawal considered as non-responders. 
Sensitivity analysis 3: Overall Response at EOT or Week 8 (whichever occurs earlier) with 
patients who receive concomitant administration of other HLH treatments considered as non-
responders. 
Sensitivity analysis 4: Overall Response at EOT or Week 8 (whichever occurs earlier) with 
deaths, early withdrawals, and patients who receive concomitant administration of other HLH 
treatment considered as non-responders. 
Sensitivity analysis 5: Overall Response at EOT or Week 8 (whichever occurs earlier) with 
patients deemed as having a major protocol deviation impacting statistical analysis removed 
from the Evaluable Analysis Set.  
8.2. 
Secondary Efficacy Analysis 
All secondary efficacy endpoints are viewed as supportive for the primary endpoint and therefore 
no formal hierarchy of endpoint will be declared.  
The evaluations will be performed as outlined in Table 3.  
The secondary efficacy endpoints of this study are included in the following sections. 
8.2.1. Overall Survival 
Overall Survival, Survival to HSCT and Survival post HSCT (Section 6.1.9.4) will be analysed 
using a descriptive time-to-event approach including Kaplan-Meier curves. 
Summaries will include the number and rates of patients experiencing the event and the number 
of censored observations; the median and 95% confidence interval, and lower quartile and upper 
quartile estimates of time-to-event; survival estimates at specified timepoints; and the median, 
minimum and maximum follow-up time in months.  
8.2.2. Event-free Survival 
Event-free survival (Section 6.1.9.4) will be analysed using the same methods described in 
Section 8.2.1. 
8.2.3. Overall Response at Start of Conditioning 
Overall Response (Section 6.1.9.4) at the start of conditioning will be analysed using the same 
methods described for the primary efficacy endpoint in Section. 
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8.2.4. Duration of Response 
The Duration of Response (Section 6.1.9.4) will be calculated only for patients showing 
confirmed overall response and will be analysed using the same methods described in Section 
8.2.1. The Cumulative Duration of Response will be analysed in absolute days and percent days 
in response using descriptive summaries.  
Swimmer plots will be presented to show response progression and duration of response by patient. 
8.2.5. Time to Response  
The Time to Response will be analysed using comparable methods described in Section 8.2.1. 
However, the survival function will be plotted based on the complement of the Kaplan-Meier 
estimates (1-KM) to provide an estimate of the cumulative incidence of response over time.  
8.2.6. Clinical Response 
Assessment of Clinical Response using the response categories seen in Table 6, will be described 
using counts and percentages at each visit.  
8.2.7. Glucocorticoids Reduction 
Number of patients able to reduce glucocorticoids by 50% or more of the baseline dose during 
emapalumab treatment (Section 6.1.9.4) will be described using counts and percentages. 
8.2.8. Number of Patients Proceeding to HSCT 
The number of patients proceeding to HSCT (Section 6.1.9.4) will be described using counts and 
percentages.  
8.2.9. Quality of Life Assessed Through PedsQL™, Pediatric Quality of Life Inventory 
Descriptive summaries of absolute score and change from baseline will be calculated for the 
PedsQL total scale score, the health summary scores, and the functioning scale scores (Section 
6.1.9.4) for all visits where the questionnaire was completed (Baseline, Visit 3 post-infusion, 
EOT and follow-up visits D+30, D+100, 6 months and 1 year). PedsQL parent and child/adult 
reports as well as parent report for infants will be presented separately as outlined in Table 3.  
PedsQL subject-data, including derived scores, will be listed. 
8.2.10. Quality of Life Assessed Through BASES Questionnaires 
The BASES questionnaire scores for the 6 domains (note: activity and sleep subscales will be 
split into two separate domains due to differing best responses and exploratory nature of 
questionnaire) at the EOT and follow-up visits D+30, D+100, 6 months and 1 year will be 
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Protocol Number NI-0501-09  
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described using descriptive summaries of absolute values. BASES nurse and parent reports will 
be presented separately. Only patients with HSCT planned and/or performed will be analysed. 
Note: HSCT planned is defined as patients captured on the HSCT module of the eCRF with a 
start of conditioning date or on the CM module with HSCT conditioning medications as 
indicated in Appendix 15.3.  
9. 
Supplementary Analysis
A supplementary analysis for Overall Response at EOT or Week 8 (whichever occurs earlier) 
using the definition of Overall Response in Table 7 will be performed. This will be evaluated 
using an exact binomial test as outlined in Section 8.1 and with the components of the overall 
response (Complete Response, Partial Response, HLH Improvement and No response) 
summarized using counts and percentages at Week 8 or EOT (whichever occurs first). 
10. 
Safety and Tolerability Analysis
All safety analyses will be performed as specified in Table 3. All data relating to safety will be 
listed and summarized using descriptive statistics. No inferential statistical tests will be performed. 
The analysis of safety assessments in this study will include summaries of the following categories 
of safety and tolerability data collected for each patient: 
•
Adverse events, treatment-emergent AEs (TEAEs), non-TEAEs, serious AEs (SAEs) and
non-serious TEAEs
•
Clinical laboratory parameters
•
Vital signs
Where applicable, analyses will be performed separately for the pre and post-conditioning time 
periods and by treatment naïve/experienced (unless otherwise specified). 
Data of patients who have not undergone HSCT will be analyzed in the pre-conditioning period. 
10.1. Adverse Events 
All AEs, non-TEAEs, TEAEs, and SAEs will be coded using the MedDRA v. 21.0 (or later). For 
definitions of AEs see Table 5. 
A summary table will present: 
•
All AEs
•
Non-TEAEs
•
TEAEs


Statistical Analysis Plan,  
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Protocol Number NI-0501-09  
PCN Number 176784
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•
TEAEs related to study drug
•
Mild TEAEs
•
Moderate TEAEs
•
Severe TEAEs
•
TEAEs leading to withdrawal of study drug
•
TEAEs resulting in death
•
Serious TEAEs
•
Treatment emergent SAEs related to study drug
•
TEAEs with IRRs
•
TEAEs with Infections
•
Mild infections
•
Moderate infections
•
Severe infections
For summary tables the incidence of the safety event of interest (i.e. AE, TEAE, non-SAE) and 
the number of patients with at least one safety event of interest will be given. A patient with more 
than one occurrence of the same safety event of interest will be counted only once in the total of 
those experiencing this safety event.  
Information grouped by severity (mild, moderate, severe) will be presented by the worst severity 
per patient. Any AEs with a missing severity will be reported in the “missing” category grade. 
The following safety events of interest will be provided in summary tables grouped by MedDRA 
system organ class and preferred term (coded using MedDRA v. 21.0 or later): 
•
AEs
•
overall
•
by severity
•
TEAEs
•
overall
•
by severity
•
by relationship to the study drug
•
Non-TEAEs
•
overall
•
Non-SAEs
•
overall
•
pre-conditioning TEAEs
•
overall
•
by severity
•
by relationship to the study drug
•
post-conditioning TEAEs


Statistical Analysis Plan,  
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•
overall
•
by severity
•
by relationship to the study drug
In the AE data listings, all AEs will be displayed. AEs that are treatment-emergent will be flagged. 
Additional listings for pre-conditioning and post-conditioning AE will be displayed.  
10.1.1. Adverse Events Leading to Study Drug Withdrawal   
A summary of incidence rates (percentages) of TEAEs leading to study drug withdrawal and 
preferred term will be displayed as specified in Table 3.  
A data listing of AEs leading to withdrawal of study drug will also be provided, displaying details 
of the event(s) captured on the CRF. 
10.1.2. Deaths and Serious Adverse Events 
TEAEs resulting in death will be listed and tabulated by preferred term. 
Serious TEAEs will be tabulated by system organ class and preferred term separately for overall, 
by pre-conditioning and post-conditioning. 
10.1.3. Treatment-Emergent Adverse Events with Infections 
The number and percentage of patients reporting infections, by SOC and preferred term, and by 
severity will be tabulated separately for pre-conditioning and post-conditioning infections. 
10.1.4. Infusion-related reactions 
Infusion-related reactions will be tabulated by system organ class and preferred term. 
10.2. Clinical Laboratory Evaluations 
10.2.1. Hematology, Coagulation and Clinical Chemistry 
The number of patients with clinical laboratory values below, within, or above the normal range 
by visit and in relation to baseline will be tabulated for each clinical laboratory analyte (shift table). 
Denominator of the percentages will be the number of patients in the All Treated Analysis Set. 
Clinical chemistry, hematology, and coagulation results will be presented in separate tables.  
Box and whisker plots for each parameter under clinical chemistry, hematology and coagulation 
will be produced to display absolute values over time.  
All laboratory data will be provided in data listings. Laboratory data will be listed by patient 
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Protocol Number NI-0501-09  
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number and visit, and flagged according to pre/post-conditioning. Laboratory values that are 
outside the normal range will be flagged in the data listings. 
10.2.2. Urinalysis 
Urinalysis results will be listed only. 
10.2.3. Cerebrospinal Fluid Data 
The following information has been collected during the study with regard to CSF analysis: 
•
Protein
•
RBC
•
WBC
•
Neopterin
All CSF data will be provided in data listings including comments on the results and reasons if 
not performed. 
10.3. Vital Signs 
Vital signs results will be presented in listings by patient number and visit. Values outside the 
normal range (+/-10%) and body temperature >= 37.5 Celsius will be flagged.  
10.4. Physical examination 
A by-patient listing will be provided for physical examination results by patient number and visit. 
10.5. Electrocardiograms 
ECG results will be presented in listings. 
10.6. Imaging Test Results 
A by-patient listing will be provided separately for abdominal ultrasound, chest examinations 
(including x-ray and CT) and brain examinations (including MRI and CT). 
10.7. Systematic Search for Infections 
Abnormal results of TB search as well as adenovirus, CMV, EBV and other specific infections 
assessed as medically relevant were to be recorded as AEs and will be presented in AE tables. 
A by-patient listing will be provided with results from each infection search. 


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Protocol Number NI-0501-09  
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10.8. Hematopoietic Stem Cell Transplantation (HSCT)  
A by-patient listing will be provided including patients undergoing HSCT with regards to: 
•
Date of start of conditioning / HSCT
•
Stem cell source
•
Graft manipulation
•
Donor type.
10.9. Concomitant Medications and Procedures 
Prior medication/therapy is defined as any medication/therapy with an end date prior to the first 
emapalumab infusion date or recorded with ongoing = ‘No’, if the end date is unknown. A 
concomitant medication is defined as a medication taken on or after the first dose of study drug 
(start date/time is on or after the first dose of study medication, end date/time is after the first dose 
of study drug), or recorded with ongoing = ‘Yes’, if the end date is unknown. If a medication starts 
prior to the date of first dose and continues after the date of first dose it will be considered both 
prior and concomitant. 
Prior and concomitant medications will be summarized descriptively using counts and 
percentages as specified in Table 3. Summary tables of concomitant steroid use and 
concomitant HLH treatment (from the time of the first emapalumab infusion) will be provided. 
Prior medications will be presented separately from concomitant medications. Prior medications 
will be split by previous HLH treatment and previous medications other than HLH treatment. 
Concomitant medications will be split by concomitant medications for HLH treatment and 
concomitant medications other than HLH treatment.  
The frequency and percentage of medications will be summarized by ATC level 2 within level 1 
by treatment groups, unless otherwise specified. 
Prior and concomitant medications will be presented in listings. Prior and concomitant procedures 
will be listed separately and defined similarly as specified for prior and concomitant medications. 
11. 
Changes from Planned Analysis
A summary of the changes with respect to analyses described in the study protocol is given 
below: 
•
Protocol Violations and Deviations – terminology of major protocol deviations is used in
the protocol. Due to an update in regulations ICH E3 Q&A R1 and ICH GCP E6 R2
terminology of important and non-important will be used when referring to protocol
deviation classification from a study conduct perspective.
•
Pharmacokinetic endpoints- population PK analysis will not be conducted as part of this


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study. However, data from this study might be used in combination with data from other 
studies to refine existing population PK models. 
•
Pharmacodynamic endpoints- Population PK/PD analysis using non-linear mixed effects
modelling will not be conducted as part of this study. However, data from this study
might be used in combination with data from other studies to refine existing population
PK/PD models. As part of the SAP, only PD parameters (i.e., concentrations) will be
reported descriptively.
•
Secondary efficacy endpoint: cumulative duration of response has been added to protocol
specified endpoints.
•
‘Evaluable Analysis Set Without Major Protocol Deviations’ added which contains
patients in the Evaluable analysis set who do not have a major protocol deviation that is
deemed to have an impact on the statistical analysis.
•
Sensitivity analysis 5 added where the overall response at EOT or Week 8 (whichever
occurs earlier) is displayed based on patients in the ‘Evaluable Analysis Set Without
Major Protocol Deviations’.
•
Supplementary analysis added where the overall response at EOT or Week 8 (whichever
occurs earlier) is derived checking the number of abnormalities at baseline and the
number of HLH criteria which worsen from baseline.
12.
Other Planned Analysis
12.1. Pharmacokinetic/Pharmacodynamic/Immunogenicity Analysis 
Descriptive summaries per timepoint of the serum concentration of emapalumab, PD parameters 
and ADAs (if any), as well as corresponding listings including CSF analysis or other matrices as 
applicable, will be provided in TLFs of this SAP. 
Descriptive summaries of the following results will be presented in appropriate graphical 
analysis and tables for the All Treated Analysis Set: 
•
Levels of circulating total IFNγ (free IFNγ + bound to emapalumab) after initiation of
emapalumab treatment.
•
Levels of the main IFNγ-induced chemokines (CXCL9, CXCL10).
•
Levels of other potential disease biomarkers.
•
Level (if any) of circulating antibodies against emapalumab (ADAs).
•
Serum concentration of emapalumab.
•
Levels of serum sCD25
13.
References
1. US Federal Register. (1998) International Conference on Harmonization; Guidance on
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food
and Drug Administration [Docket No. 97D-0174]. Federal Register Volume 63, Number 179,


Statistical Analysis Plan,  
Sponsor Sobi AG  
Protocol Number NI-0501-09  
PCN Number 176784
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 57 of 73 
pages 49583-49598. September 16, 1998. 
2. ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the Committee on
Professional Ethics, April 2016. http://www.amstat.org/about/ethicalguidelines.cfm
3. RSS. (2014) The Royal Statistical Society: Code of Conduct, 2014.
4. Varni, J.W., Seid, M., Rode, C.A (1999). The PedsQL™: Measurement Model for the
Pediatric Quality of Life Inventory. Medical Care, 37(2), 126-139.
5. Phipps, S., Hinds, P. S., Channell, S., & Bell, G. L. (1994). Measurement of Behavioral,
Affective, and Somatic Responses to Pediatric Bone Marrow Transplantation: Development
of the BASES Scale. Journal of Pediatric Oncology Nursing, 11(3), 109–117.
6. Phipps, S., Dunavant, M., Lensing, S., Rai, S.N. (2002). Acute health-related quality of life in
children undergoing stem cell transplant: II. Medical and demographic determinants. Bone
Marrow Transplantation, 29 (5) 435-442.
14.
Tables, Listings, and Figures
All listings, tables, and graphs will have a header showing the sponsor company name and 
protocol and a footer showing the version of SAS, the file name and path, and the source of the 
data (CRF page or listing number). 
14.1. Planned Table Descriptions 
The following are planned summary tables for protocol number NI-0501-09. The table numbers 
and page numbers are place holders only and will be determined when the tables are produced. 


Statistical Analysis Plan,  
Sponsor Sobi AG  
Protocol Number NI-0501-09  
PCN Number 176784
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 58 of 73 
Table 15: Planned Tables 
Table 
Number 
Table Title / Summary 
Population(s) 
Supporting listing 
14.1 Demographic Data 
14.1.1.1 
Summary of Patient Enrollment and Disposition 
Enrolled Pop 
16.2.1.1, 16.2.1.2 
14.1.1.2 
Summary of Re-Treated Patients 
All Treated Pop 
16.2.1.1, 16.2.5.1 
14.1.2 
Summary of Protocol Deviations 
Enrolled Pop 
Excluding Screen 
Failures 
16.2.2.1 
14.1.3.1 
Demographic Characteristics 
All Treated Pop 
16.2.4.1 
14.1.3.2 
Baseline Characteristics 
All Treated Pop 
16.2.4.1 
14.1.4.1 
HLH Disease Characteristics at Diagnosis 
All Treated Pop 
16.2.4.4, 16.2.4.5 
14.1.4.2 
Medical History Other Than HLH Disease by System Organ 
Class and Preferred Term 
All Treated Pop 
16.2.4.2 
14.1.4.3 
HLH Disease Characteristics at Screening/Baseline 
All Treated Pop 
16.2.4.11, 16.2.4.12 
14.1.5 
Summary of Previous HLH Treatment by ATC Level 1 and 
Level 2 
All Treated Pop 
16.2.4.3 
14.1.6 
Summary of Systemic Steroid Use Prior to First 
Emapalumab Infusion 
All Treated Pop 
16.2.4.3 
14.1. 
Summary of Prior Medications Other Than HLH Treatment 
by ATC Level 1 and Level 2 
All Treated Pop 
16.2.4.6 
14.2 Efficacy Data 
14.2.1.1.1 
Statistical Analysis of the Overall Response 
All Treated Pop, 
Evaluable Pop 
16.2.6.3 
14.2.1.1.2 
Sensitivity Analysis 1: Overall Response at EOT or Week 8 
(Whichever Occurs Earlier) With Deaths Considered as Non-
Responders 
All Treated Pop 
16.2.6.3 
14.2.1.1.3 
Sensitivity Analysis 2: Overall Response at EOT or Week 8 
(Whichever Occurs Earlier) With Early Withdrawal 
Considered as Non-Responders 
All Treated Pop 
16.2.6.3 


Statistical Analysis Plan,  
Sponsor Sobi AG  
Protocol Number NI-0501-09  
PCN Number 176784
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 59 of 73 
Table 
Number 
Table Title / Summary 
Population(s) 
Supporting listing 
14.2.1.1.4 
Sensitivity Analysis 3: Overall Response at EOT or Week 8 
(Whichever Occurs Earlier) With Patients Who Receive 
Concomitant Administration of Other HLH Treatments 
Considered as Non-Responders 
All Treated Pop 
16.2.6.3 
14.2.1.1.5 
Sensitivity Analysis 4: Overall Response at EOT or Week 8 
(Whichever Occurs Earlier) With Deaths, Early 
Withdrawals, and Patients Who Receive Concomitant 
Administration of Other HLH Treatment Considered as Non-
Responders 
All Treated Pop 
16.2.6.3 
14.2.1.1.6 
Sensitivity analysis 5: Overall Response at EOT or Week 8 
(whichever occurs earlier) with patients deemed as having a 
protocol deviation impacting statistical analysis removed  
Evaluable Pop 
Without Major 
PDs 
16.2.6.3 
14.2.1.1.7 
Supplementary Analysis: Overall Response at EOT or Week 
8 (whichever occurs earlier) – Modified Definition 
All Treated Pop 
16.2.6.3 
14.2.1.2 
Overall Response Components: Complete Response, Partial 
Response, HLH Improvement, No Response 
All Treated Pop, 
Evaluable Pop 
16.2.6.3 
14.2.1.3.1 
Evolution of Clinical Signs Characterizing HLH Disease - 
Part 1 
All Treated Pop, 
Evaluable Pop 
16.2.6.1.1, 16.2.9.3. 
14.2.1.3.2 
Evolution of Clinical Signs Characterizing HLH Disease - 
Part 2 
All Treated Pop, 
Evaluable Pop 
16.2.9.4 
14.2.2.1 
Overall Survival 
All Treated Pop, 
Evaluable Pop 
16.2.6.2 
14.2.2.2 
Survival to HSCT 
All Treated Pop, 
Evaluable Pop 
16.2.6.2 
14.2.2.3 
Survival post HSCT 
All Treated Pop, 
Evaluable Pop 
16.2.6.2 
14.2.3 
Event-free Survival post HSCT 
All Treated Pop, 
Evaluable Pop 
16.2.6.2 
14.2.4.1 
Duration of Response 
All Treated Pop, 
Evaluable Pop 
16.2.6.2 
14.2.4.2 
Cumulative Duration of Response for Patients Achieving 
Overall Response 
All Treated Pop, 
Evaluable Pop 
16.2.6.1.1, 
16.2.6.1.2, 
16.2.6.1.3, 
16.2.6.1.4. 


Statistical Analysis Plan,  
Sponsor Sobi AG  
Protocol Number NI-0501-09  
PCN Number 176784
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 60 of 73 
Table 
Number 
Table Title / Summary 
Population(s) 
Supporting listing 
14.2.5 
Time-to-Response 
All Treated Pop, 
Evaluable Pop 
16.2.6.2 
14.2.6 
Investigator Assessment of Clinical Response 
All Treated Pop, 
Evaluable Pop 
16.2.6.4 
14.2.7.1 
Summary of Dexamethasone Daily Dose (mg/m^2) Over 
Time 
All Treated Pop, 
Evaluable Pop 
16.2.5.3 
14.2.7.2 
Glucocorticoids Reduction 
All Treated Pop, 
Evaluable Pop 
16.2.6.3 
14.2.7.3 
Patients Proceeding to HSCT 
All Treated Pop, 
Evaluable Pop 
16.2.6.3 
14.2.8.1 
Summary of PedsQL Total Scale Score (Parent Reports) and 
Change from Baseline by Questionnaire Age Group 
All Treated Pop, 
Evaluable Pop  
16.2.6.8 
14.2.8.2 
Summary of PedsQL Physical Health Summary Score 
(Parent Reports) and Change from Baseline by Questionnaire 
Age Group 
All Treated Pop, 
Evaluable Pop 
16.2.6.8 
14.2.8.3 
Summary of PedsQL Psychosocial Health Summary Score 
(Parent Reports) and Change from Baseline by Questionnaire 
Age Group 
All Treated Pop, 
Evaluable Pop  
16.2.6.8 
14.2.8.4 
Summary of PedsQL Physical Functioning Scale Score 
(Parent Reports) and Change from Baseline by Questionnaire 
Age Group 
All Treated Pop, 
Evaluable Pop 
16.2.6.8 
14.2.8.5 
Summary of PedsQL Emotional Functioning Scale Score 
(Parent Reports) and Change from Baseline by Questionnaire 
Age Group 
All Treated Pop, 
Evaluable Pop 
16.2.6.8 
14.2.8.6 
Summary of PedsQL Social Functioning Scale Score (Parent 
Reports) and Change from Baseline by Questionnaire Age 
Group 
All Treated Pop, 
Evaluable Pop 
16.2.6.8 
14.2.8.7 
Summary of PedsQL Work/Study Functioning Scale Score 
(Parent Reports for Child >24 months) and Change from 
Baseline by Questionnaire Age Group 
All Treated Pop, 
Evaluable Pop 
16.2.6.8 
14.2.8.8 
Summary of PedsQL Physical Symptoms Scale Score 
(Parent Reports for Infants 1-24 months) and Change from 
Baseline by Questionnaire Age Group 
All Treated Pop, 
Evaluable Pop  
16.2.6.8 
14.2.8.9 
Summary of PedsQL Cognitive Functioning Scale Score 
(Parent Reports for Infants 1-24 months) and Change from 
Baseline by Questionnaire Age Group 
All Treated Pop, 
Evaluable Pop 
16.2.6.8 
14.2.9.1 
Summary of PedsQL Total Scale Score (Child Reports) and 
Change from Baseline by Questionnaire Age Group 
All Treated Pop, 
Evaluable Pop  
16.2.6.9 


Statistical Analysis Plan,  
Sponsor Sobi AG  
Protocol Number NI-0501-09  
PCN Number 176784
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 61 of 73 
Table 
Number 
Table Title / Summary 
Population(s) 
Supporting listing 
14.2.9.2 
Summary of PedsQL Physical Health Summary Score (Child 
Reports) and Change from Baseline by Questionnaire Age 
Group 
All Treated Pop, 
Evaluable Pop 
16.2.6.9 
14.2.9.3 
Summary of PedsQL Psychosocial Health Summary Score 
(Child Reports) and Change from Baseline by Questionnaire 
Age Group 
All Treated Pop, 
Evaluable Pop 
16.2.6.9 
14.2.9.4 
Summary of PedsQL Physical Functioning Scale Score 
(Child Reports) and Change from Baseline by Questionnaire 
Age Group 
All Treated Pop, 
Evaluable Pop 
16.2.6.9 
14.2.9.5 
Summary of PedsQL Emotional Functioning Scale Score 
(Child Reports) and Change from Baseline by Questionnaire 
Age Group 
All Treated Pop, 
Evaluable Pop 
16.2.6.9 
14.2.9.6 
Summary of PedsQL Social Functioning Scale Score (Child 
Reports) and Change from Baseline by Questionnaire Age 
Group 
All Treated Pop, 
Evaluable Pop 
16.2.6.9 
14.2.9.7 
Summary of PedsQL Work/Study Functioning Scale Score 
(Child Reports 5-25 years) and Change from Baseline by 
Questionnaire Age Group 
All Treated Pop, 
Evaluable Pop 
16.2.6.9 
14.2.10.1 
Summary of BASES Questionnaire (Parent Reports) 
All Treated Pop, 
Evaluable Pop 
16.2.6.10 
14.2.10.2 
Summary of BASES Questionnaire (Nurse Reports) 
All Treated Pop, 
Evaluable Pop 
16.2.6.11 
14.3 Safety Data 
14.3.1.1.1 
Summary of all Adverse Events 
All Treated Pop 
16.2.7.1.1 
14.3.1.1.2 
Summary of Adverse Events occurring prior to HSCT 
conditioning 
All Treated Pop 
16.2.7.1.2 
14.3.1.1.3 
Summary of Adverse Events occurring post HSCT 
conditioning 
All Treated Pop 
16.2.7.1.3 
14.3.1.2.1 
Summary of Adverse Events by System Organ Class and 
Preferred Term 
All Treated Pop 
16.2.7.1.1 
14.3.1.2.2 
Summary of non-SAEs by System Organ Class and Preferred 
Term 
All Treated Pop 
16.2.7.1.1 
14.3.1.3 
Summary of Adverse Events by Maximum Severity, System 
Organ Class and Preferred Term 
All Treated Pop 
16.2.7.1.1 
14.3.1.4.1 
Summary of Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
All Treated Pop 
16.2.7.1.1 
14.3.1.4.2 
Summary of Treatment-Emergent Adverse Events by 
Maximum Severity, System Organ Class and Preferred Term All Treated Pop 
16.2.7.1.1 
14.3.1.4.3 
Summary of Treatment-Emergent Adverse Events by 
Relationship to Study Drug, System Organ Class and 
Preferred Term 
All Treated Pop 
16.2.7.1.1 


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-09  
 
PCN Number 176784 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 62 of 73 
 
Table 
Number 
Table Title / Summary 
Population(s) 
Supporting listing 
14.3.1.5.1 
Summary of Treatment-Emergent Adverse Events occurring 
prior to HSCT conditioning by System Organ Class and 
Preferred Term 
All Treated Pop 
16.2.7.1.2 
14.3.1.5.2 
Summary of Treatment-Emergent Adverse Events occurring 
prior to HSCT conditioning by Maximum Severity, System 
Organ Class and Preferred Term 
All Treated Pop 
16.2.7.1.2 
14.3.1.5.3 
Summary of Treatment-Emergent Adverse Events occurring 
prior to HSCT conditioning by Relationship to Study Drug, 
System Organ Class and Preferred Term 
All Treated Pop 
16.2.7.1.2 
14.3.1.6.1 
Summary of Treatment-Emergent Adverse Events occurring 
post HSCT conditioning by System Organ Class and 
Preferred Term 
All Treated Pop 
16.2.7.1.3 
14.3.1.6.2 
Summary of Treatment-Emergent Adverse Events occurring 
post HSCT conditioning by Maximum Severity, System 
Organ Class and Preferred Term 
All Treated Pop 
16.2.7.1.3 
14.3.1.6.3 
Summary of Treatment-Emergent Adverse Events occurring 
post to HSCT conditioning by Relationship to Study Drug, 
System Organ Class and Preferred Term 
All Treated Pop 
16.2.7.1.3 
14.3.2.1 
Summary of Treatment-Emergent Adverse Events Leading 
to Study Drug Withdrawal by Preferred Term  
All Treated Pop 
16.2.7.3 
14.3.2.2 
Summary of Treatment-Emergent Adverse Events Resulting 
in Death by Preferred Term 
All Treated Pop 
16.2.7.4 
14.3.2.3.1 
Summary of Serious Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
All Treated Pop 
16.2.7.2 
14.3.2.3.2 
Summary of Serious Treatment-Emergent Adverse Events 
occurring prior to HSCT conditioning by System Organ 
Class and Preferred Term 
All Treated Pop 
16.2.7.1.2 
16.2.7.2 
14.3.2.3.3 
Summary of Serious Treatment-Emergent Adverse Events 
occurring post HSCT conditioning by System Organ Class 
and Preferred Term 
All Treated Pop 
16.2.7.1.3 
16.2.7.2 
14.3.2.4 
Summary of Treatment-Emergent Adverse Events with 
Infusion-related Reactions by System Organ Class and 
Preferred Term 
All Treated Pop 
16.2.7.1.1 
14.3.2.5.1 
Summary of Treatment-Emergent Adverse Events with 
Infections occurring prior to HSCT conditioning by Severity, 
System Organ Class and Preferred Term 
All Treated Pop 
16.2.7.1.2 
14.3.2.5.2 
Summary of Treatment-Emergent Adverse Events with 
Infections occurring post to HSCT conditioning by Severity, 
System Organ Class and Preferred Term 
All Treated Pop 
(only patients 
with start date of 
conditioning for 
HSCT) 
16.2.7.1.3 
14.3.5.1.1 
Shift Table of Clinical Chemistry Results 
All Treated Pop  
16.2.8.1 
14.3.5.1.2 
Shift Table of Clinical Chemistry Results by Treatment Type All Treated Pop 
16.2.8.1 


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-09  
 
PCN Number 176784 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 63 of 73 
 
Table 
Number 
Table Title / Summary 
Population(s) 
Supporting listing 
14.3.5.2.1 
Shift Table of Hematology Results 
All Treated Pop  
16.2.8.2 
14.3.5.2.2 
Shift Table of Hematology Results by Treatment Type 
All Treated Pop  
16.2.8.2 
14.3.5.3.1 
Shift Table of Coagulation Results 
All Treated Pop  
16.2.8.3 
14.3.5.3.2 
Shift Table of Coagulation Results by Treatment Type 
All Treated Pop  
16.2.8.3 
14.3.6.1 
Concomitant Medications for HLH Treatment by ATC 
Level 1 and Standardized Medication Term 
All Treated Pop, 
Evaluable Pop 
16.2.4.8 
14.3.6.2 
Concomitant Medications other than HLH Treatment by 
ATC Level 1 and Level 2 
All Treated Pop, 
Evaluable Pop 
16.2.4.9 
14.3.6.3.1 
Summary of Exposure to Emapalumab 
All Treated Pop, 
Evaluable Pop 
16.2.5.1 
16.2.5.2 
14.3.6.3.2 
Percentage of Emapalumab Dose Changes from the Baseline 
Dose 
All Treated Pop, 
Evaluable Pop 
16.2.5.1 
16.2.5.2 
14.3.6.4 
Summary of Serum Concentration of Emapalumab Levels 
All Treated Pop 
16.2.9.8.2 
14.3.6.5 
Summary of Pharmacodynamic Parameters 
All Treated Pop 
16.2.9.8.3 
14.3.6.6 
Summary of ADA Parameters 
All Treated Pop 
16.2.9.8.4 
14.2. Planned Listing Descriptions 
The following are planned data and patient data listings for protocol number NI-0501-09.  
In general, one listing will be produced per CRF domain. All listings will be sorted by treatment, 
site, and patient number. All calculated variables will be included in the listings. 
In all listings a blank line will be placed between each patient. Within a data listing, if an item 
appears line after line (e.g., repetition of patient number), then only the first occurrence will be 
displayed. 
In data listings, the information for one patient will be kept on one page if at all possible, rather 
than splitting a patient’s information across pages. 


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-09  
 
PCN Number 176784 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 64 of 73 
 
Table 16: Planned Listings 
Listing Number 
Listing Title / Summary 
Population(s) 
16.2.1.1 
Study Completion Status and Assignment to Analysis Populations 
All Treated Pop 
16.2.1.2 
List of Reasons for Screening Failure 
Screen Failures 
16.2.2.1 
Protocol Deviations 
Enrolled Pop 
Excluding Screen 
Failure 
16.2.3.1 
Analysis Populations 
All Treated Pop 
16.2.4.1 
Demographic Data 
All Treated Pop 
16.2.4.2 
Medical History 
All Treated Pop 
16.2.4.3 
History of HLH Treatments 
All Treated Pop 
16.2.4.4 
Primary HLH Diagnosis Part 1 
All Treated Pop 
16.2.4.5 
Primary HLH Diagnosis Part 2 
All Treated Pop 
16.2.4.6 
Prior Medications Other Than HLH Treatments 
All Treated Pop 
16.2.4.7 
Prior Procedures 
All Treated Pop 
16.2.4.8 
Concomitant Medications for HLH Treatment 
All Treated Pop 
16.2.4.9 
Concomitant Medications Other Than HLH Treatment 
All Treated Pop 
16.2.4.10 
Concomitant Procedures 
All Treated Pop 
16.2.4.11 
HLH Disease Characteristics at Screening / Baseline - Part 1 
All Treated Pop 
16.2.4.12 
HLH Disease Characteristics at Screening / Baseline - Part 2 
All Treated Pop  
16.2.5.1 
Study Drug Administration 
All Treated Pop 
16.2.5.2 
Study Drug Exposure 
All Treated Pop 
16.2.5.3 
Systemic Glucocorticoids Administration 
All Treated Pop 
16.2.6.1.1 
Response Criteria and Response Status by Visit – Part 1 
All Treated Pop 
16.2.6.1.2 
Response Criteria and Response Status by Visit – Part 2 
All Treated Pop 
16.2.6.1.3 
Response Criteria and Response Status by Visit – Part 3 
All Treated Pop 


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-09  
 
PCN Number 176784 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 65 of 73 
 
Listing Number 
Listing Title / Summary 
Population(s) 
16.2.6.1.4 
Response Criteria and Response Status by Visit – Part 4 
All Treated Pop 
16.2.6.2 
Time-to-Event Efficacy Endpoints 
All Treated Pop 
16.2.6.3 
Overall Response, Glucocorticoids Reduction, and Ability to Proceed to 
HSCT 
All Treated Pop 
16.2.6.4 
Investigator Assessment of Clinical Response 
All Treated Pop 
16.2.6.5 
HSCT 
All Treated Pop 
16.2.6.6 
Post-HSCT Outcome 
All Treated Pop 
16.2.6.7 
Survival Assessment 
All Treated Pop 
16.2.6.8 
PedsQL Parent Reports 
All Treated Pop 
16.2.6.9 
PedsQL Child Reports 
All Treated Pop 
16.2.6.10 
BASES Parent Reports 
All Treated Pop 
16.2.6.11 
BASES Nurse Reports 
All Treated Pop 
16.2.7.1.1 
Adverse Events 
All Treated Pop 
16.2.7.1.2 
Adverse Events occurring prior to HSCT conditioning 
All Treated Pop 
16.2.7.1.3 
Adverse Events occurring post HSCT conditioning 
All Treated Pop 
16.2.7.2 
Serious Adverse Events 
All Treated Pop 
16.2.7.3 
Adverse Events Leading to Withdrawal of Study Drug 
All Treated Pop 
16.2.7.4 
Deaths 
All Treated Pop 
16.2.7.5 
Tuberculosis 
All Treated Pop 
16.2.7.6 
Adenovirus, Epstein-Barr Virus, Cytomegalovirus 
All Treated Pop 
16.2.7.7 
Other Specific Infections 
All Treated Pop 
16.2.8.1 
Clinical Chemistry Results 
All Treated Pop 
16.2.8.2 
Hematology Results 
All Treated Pop 
16.2.8.3 
Coagulation Results 
All Treated Pop 


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-09  
 
PCN Number 176784 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 66 of 73 
 
Listing Number 
Listing Title / Summary 
Population(s) 
16.2.8.4 
Urinalysis Results 
All Treated Pop 
16.2.8.5 
Pregnancy Test Results 
All Treated Pop 
16.2.9.1 
Vital Signs 
All Treated Pop 
16.2.9.2 
ECG Results 
All Treated Pop 
16.2.9.3 
Physical Examination Results 
All Treated Pop 
16.2.9.4 
Neurological Examination Results 
All Treated Pop 
16.2.9.5 
Hospitalization 
All Treated Pop 
16.2.9.6 
Abdominal Ultrasound 
All Treated Pop 
16.2.9.7.1 
Chest Examinations 
All Treated Pop 
16.2.9.7.2 
Brain and Cranial Examinations 
All Treated Pop 
16.2.9.8.1 
CSF Analysis Results 
All Treated Pop 
16.2.9.8.2 
Serum Concentration of Emapalumab 
All Treated Pop 
16.2.9.8.3 
Pharmacodynamic Measurements 
All Treated Pop 
16.2.9.8.4 
ADA Findings 
All Treated Pop 
16.2.9.9 
Transfusion 
All Treated Pop 
16.2.9.10 
List of Patients Who Were Affected by COVID-19 
All Treated Pop 
 
14.3. Planned Figure Descriptions 
The following are planned summary figures for protocol number NI-0501-09. The figure 
numbers and page numbers are placeholders only and will be determined when the figures are 
produced. 
 


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-09  
 
PCN Number 176784 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 67 of 73 
 
Table 17: Planned Figures 
Figure Number 
Figure Title/Summary 
Population  
14.4.1.1 
Kaplan-Meier Graph of Overall Survival 
All Treated Pop 
14.4.1.2 
Kaplan-Meier Graph of Survival to HSCT 
All Treated Pop 
14.4.1.3 
Kaplan-Meier Graph of Survival post HSCT 
All Treated Pop 
14.4.2 
Kaplan-Meier Graph of Event-free Survival 
All Treated Pop 
14.4.3 
Cumulative Incidence Graph of Time to Response 
All Treated Pop 
14.4.4 
Kaplan-Meier Graph of Duration of Response 
All Treated Pop 
14.4.5.1 
Box and Whisker Plots of Clinical Biochemistry Results 
All Treated Pop 
14.4.5.2 
Box and Whisker Plots of Hematology Results 
All Treated Pop 
14.4.5.3 
Box and Whisker Plots of Coagulation Results 
All Treated Pop 
 


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-09  
 
PCN Number 176784 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 68 of 73 
 
15. 
Tables, Listings, and Listing Shells 
15.1. 
Standard Layout for all Tables, Listings, and Figures 
The following standard layout will be applied to all Tables, Listings, and Figures in support of this study. Note that programming 
notes may be added if appropriate after each TLF shell.  
Figure 1: Standardized Layout 
Sobi AG 
Page xx of xx 
Protocol: NI-0501-09 
Version xxx 
 
Table, Listing, Figure xx.x.x 
<Title of Table Listing or Figure> 
<Study Population and if applicable subgroup Description> 
____________________________________________________________________________________________________________ 
 
 
Body of Table, Listing or Figure 
 
 
___________________________________________________________________________________________________________ 
Abbreviations: XXXXX 
Note: XXXXX 
Source: XXXXX 
 
Footnote: Program path and name 
Footnote: Executed on DDMMMYYY at HH:MM on data from DDMMMYYYY 
 


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-09  
 
PCN Number 176784 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 69 of 73 
 
15.2. 
Planned TFL Shells 
Table and listing shells are provided as a separate document. Descriptions are provided for 
figures. 


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-09  
 
PCN Number 176784 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 70 of 73 
 
16. 
APPENDICES 
16.1. Calculation of Dexamethasone daily dose  
Dexamethasone daily dose will be calculated based on the recorded dose frequency as follows: 
Table 18: Dexamethasone Daily Dose 
Dose frequency 
Total daily dose = CMDOSE*factor 
QD (once a day) 
CMDOSE 
BID (twice a day) 
CMDOSE*2 
TID (three times a day) 
CMDOSE*3 
QID (four times a day) 
CMDOSE*4 
PRN (as needed) 
0 per day (not included) 
QHS (at bedtime) 
CMDOSE*1 
ONCE (once for the reporting period) 
CMDOSE/(end date – start date + 1) per day 
WEEKLY 
CMDOSE/7 per day 
OTHER – Q6HR/Q6HRS 
CMDOSE*4 
OTHER – Q8HR/Q8HRS 
CMDOSE*3 
OTHER – EVERY OTHER DAY 
CMDOSE/2 
OTHER – DAILY CUMULATIVE DOSE 
CMDOSE 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-09  
 
PCN Number 176784 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 71 of 73 
 
16.2. Concomitant Medications for HSCT Conditioning 
Table 19: Concomitant HSCT Conditioning Medication Preferred Terms 
ATC Level 4 
Preferred Code Preferred Text 
L01AA 
00021101001  
00006401001  
CYCLOPHOSPHAMIDE  
MELPHALAN  
L01AB 
00036801001  
00418901001  
BUSULFAN  
TREOSULFAN  
L01AC 
00053501001  
THIOTEPA  
 
L01BB 
02122001001  
01004601001  
01004602001  
CLOFARABINE  
FLUDARABINE  
FLUDARABINE PHOSPHATE  
L01BC 
00146201001  
 
CYTARABINE  
 
L01BC 
00511901001  
00511902001  
ETOPOSIDE  
ETOPOSIDE PHOSPHATE  
L01XC 
01402501001  
 
RITUXIMAB  
 
L04AA 
01268601001  
00575401001  
00575402001  
02082701001  
ALEMTUZUMAB  
ANTITHYMOCYTE IMMUNOGLOBULIN  
ANTITHYMOCYTE IMMUNOGLOBULIN (RABBIT)  
ANTILYMPHOCYTE IMMUNOGLOBULIN  
 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-09  
 
PCN Number 176784 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
 Page 72 of 73 
 
16.3. Disease Indicating Central Nervous System (CNS) Involvement / CSF abnormalities 
by Medical History/AE Preferred Term and Code 
Table 20: Medical History/AE Preferred Terms for CNS Involvement / CSF Abnormalities 
Preferred Term Code 
Preferred Term 
10029818 
Nuclear magnetic resonance imaging brain abnormal  
10059703 
CSF test abnormal  
10053805 
CSF white blood cell count increased  
10011522 
CSF cell count increased  
10035551 
Pleocytosis  
10012559 
Developmental delay  
10056832 
Neurological examination abnormal  
10047641 
VIth nerve paralysis  
10020745 
Hyperreflexia  
10041962 
Status epilepticus  
10039906 
Seizure  
10021118 
Hypotonia  
10002948 
Aphasia  
10029202 
Nervous system disorder  
10017577 
Gait disturbance  
10048334 
Mobility decreased  
10008096 
Cerebral atrophy  
10015037 
Epilepsy  
10071066 
Posterior reversible encephalopathy syndrome  
10022840 
Intraventricular haemorrhage  
The overall response criterion ‘No neurological and CSF abnormalities attributed to HLH’ is not 
fulfilled during the time period in which any of the above listed AEs is present or the assessment 
on neurological examination CRF is ‘abnormal’ with comment ‘CNS involvement’. 
 
 


 
Statistical Analysis Plan,  
 
Sponsor Sobi AG  
 
Protocol Number NI-0501-09  
 
PCN Number 176784 
 
AD-ST-33.06 Effective date: 12-Nov-2020 
Version 2.0    |    Date 24-Oct-2022      |    AD-PR-109.02  Effective date: 17-Aug-2020 
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16.4. Adverse Events Indicating Organ Failure by MedDRA Preferred Term and Code 
Table 21: AE Preferred Terms for Organ Failure 
Preferred Term Code 
Preferred Term 
10007554 
Cardiac failure 
10007556 
Cardiac failure acute 
10060953 
Ventricular failure 
10024119 
Left ventricular failure 
10063081 
Acute left ventricular failure 
10039163 
Right ventricular failure 
10063082 
Acute right ventricular failure 
10051093 
Cardiopulmonary failure 
10038695 
Respiratory failure 
10001053 
Acute respiratory failure 
10019663 
Hepatic failure 
10000804 
Acute hepatic failure 
10077305 
Acute on chronic liver failure 
10019845 
Hepatorenal failure 
10038435 
Renal failure 
10077361 
Multiple organ dysfunction syndrome 
10053159 
Organ failure 
10010264 
Condition aggravated 
Progression of other aspects of HLH disease pathology (i.e. worsening of disease, as assessed by 
absence of AEs indicating organ failure) is fulfilled during the time period in which any of the 
above listed AEs is present and partial response cannot be adjudicated even if other criteria were 
fulfilled.