Conditions: Hemophagocytic Lymphohistiocytosis
Keywords: Hemophagocytic lymphohistiocytosis (HLH) previously treated with NI-0501 Emapalumab
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 58
Healthy volunteers: no

Brief summary:
International, multicenter, long-term, follow-up study that will enrol HLH participants who have received emapalumab in previous clinical trials, in the context of the clinical development program for emapalumab or under compassionate use (CU).

Detailed description:
The aim of this study is to monitor the long-term safety profile of emapalumab in participants who have previously received at least one dose of emapalumab, including survival time after the administration of emapalumab.

Moreover, the elimination profile of emapalumab and the immunogenicity will also be assessed.

Furthermore, safety, tolerability, efficacy, and pharmacokinetic (PK) profile of emapalumab will be closely monitored in the event that some participants, upon request of the treating physician, will receive emapalumab treatment in the follow-up study.

Arms:
arm 1: Participants enrolled in Study NI-0501-04 (NCT01818492) will be invited to participate for long-term follow-up for 1 year either after haematopoietic stem cell transplantation (HSCT) or after the last administration of emapalumab.

In Study NI-0501-04, participants received emapalumab for 4 to 8 weeks. After the treatment period, participants could have undergone HSCT.

Participants for whom an appropriate donor was not identified by Week 8, or in a case where HSCT will be delayed for reasons unrelated to the administration of emapalumab, can continue receiving treatment with emapalumab beyond the foreseen 8 weeks in the current study (NI-0501-05, NCT02069899) at the request of the investigator, providing a favorable benefit/risk assessment of treatment is established.

The dose and timing was either carried forward from the last administered emapalumab dose as part of the parent protocol or an adjusted dose was administered, if necessary. arm 2: All participants who received at least 1 dose of emapalumab and were monitored for at least 4 weeks after the last drug administration in Study NI-0501-06 (NCT03311854) will be invited to participate for long-term follow-up for 1 year after the last administration of emapalumab.

Participants will not receive emapalumab in the current study (NI-0501-05, NCT02069899). arm 3: In exceptional cases, at the spontaneous request of a treating physician, CU treatment will be granted to the participants who had exhausted all possible treatment options and who could not be enrolled in a clinical study. All participants who receive at least 1 dose of emapalumab under CU will be invited to participate for long-term follow-up for 1 year either after HSCT or after the last administration of emapalumab.

Participants can continue treatment in the context of the current Study (NI-0501-05, NCT02069899) while stem cell donor search is ongoing, or if the investigator assesses that continuation of treatment is beneficial.

Interventions: intervention 1: Emapalumab
Intervention descriptions: intervention 1: Treatment with emapalumab is not planned for all enrolled participants. For participants who will continue receiving emapalumab in the context of this study (NI-0501-05), the dose and timing will be either carried forward from the last administered emapalumab dose as part of the parent study in which the participant was enrolled, or an adjusted dose will be administered, if necessary.

Protocol document:
Prot_000.pdf: 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 2 of 42 
 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
This document is a confidential communication of Sobi AG. Acceptance of this 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 Ethics Committees and Health Authorities or to obtain informed consent from 
potential subjects.


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 3 of 42 
 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
Investigator Agreement 
 
Protocol Number: NI-0501-05-US-P-IND#111015 
Protocol date and version: October 31, 2019 – Version 4.0 
 
Study drug:  NI-0501   
 
Study title: A Multicenter Study for the Long-term Follow-up of HLH Patients who Received 
Treatment with NI-0501, an Anti-interferon Gamma Monoclonal Antibody 
 
Investigator endorsement: 
I, the undersigned, am responsible for the conduct of this study at this site and agree to conduct 
the study according to the protocol and any approved protocol amendments, ICH GCP and all 
applicable regulatory authority requirements. 
I will not deviate from the protocol without prior permission from the Sponsor and prior review 
and written approval from the Institutional Review Board, and where applicable, from the 
Competent Authorities, except where necessary to prevent any immediate danger to the patient. 
I have read and understand fully the Investigator Brochure for NI-0501 and I am familiar with 
the investigational product(s) and its use according to this protocol. 
 
 
 
___________________________________________________ 
Site Principal Investigator’s Printed Name 
 
 
 
 
__________________________________________________ 
 
 
______________________________ 
Site Principal Investigator’ Signature  
 
 
 
Date


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 4 of 42 
 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
CONTACT LIST 
 
Study Location: 
 
Multicenter 
US Study Coordinator: 
 
 
, MD, PhD 
  
 
 
 
 
USA 
Phone: 
 
Fax: 
 
Email: 
 
 
Sponsor: 
Swedish Orphan Biovitrum AG 
12 Chemin des Aulx 
1228 Plan les Ouates 
Switzerland 
Phone: +41 22 839 71 41 
Fax: +41 22 839 71 42 
 
Chief Medical Officer Sobi 
Immunology: 
, MD 
Phone: 
 
Mobile phone: 
 
Fax: 
 
Email: 
 
Head of Emapalumab Clinical     
Development:     
, MD 
Phone: 
 
Mobile phone: 
 
Fax: 
 
Email: 
 
 
Drug Safety Physician: 
, MD 
Phone: 
 
Mobile phone: 
 
Fax: 
 
Email: 
 
 
Head of Clinical Operations: 
 
Phone: 
 
Mobile phone : 
 
Fax: 
 
Email: 
 
 
Clinical Pharmacologist: 
 
Phone: 
 
Mobile phone : 
 
Email:
 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 5 of 42 
 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
NI-0501-05 SYNOPSIS 
Title: 
A Multicenter Study for the Long-term Follow-up of HLH 
Patients who Received Treatment with NI-0501, an Anti-
interferon Gamma Monoclonal Antibody 
Sponsor: 
Sobi AG, Switzerland 
Study Type: 
International, 
multicenter, 
long-term, 
follow-up 
study 
of 
haemophagocytic lymphohistiocytosis (HLH) patients who have 
received NI-0501 (INN assigned name: emapalumab) in the 
context of a previous NI-0501 clinical study in which no long-term 
follow-up is planned. Patients having received NI-0501 under a 
compassionate use (CU) treatment protocol may also be 
considered for enrolment, whenever appropriate. 
NI-0501-05 study is performed both in the US and in Europe 
according to twin protocols called NI-0501-05-P-IND #111015 
and NI-0501-05-EudraCT #2012-005753-23, respectively 
Study Population: 
HLH patients who have received at least one dose of NI-0501 
during a previous NI-0501 clinical study or under a CU treatment 
protocol. 
In the event that an appropriate donor has not been identified, at 
the end of NI-0501 induction treatment in study NI-0501-04, or in 
case 
of 
the 
need 
to 
delay 
Hematopoietic 
Stem 
Cell 
Transplantation 
(HSCT) 
for 
reasons 
unrelated 
to 
the 
administration of NI-0501, patients originally enrolled in study 
NI0501-04 may continue NI-0501 treatment in the context of this 
protocol upon request of the treating physician after having 
established a favourable benefit/risk from NI-0501 treatment. 
Given the fact that patients with different forms of HLH (pHLH or 
sHLH) can be enrolled in this study, the present protocol has to 
account for different patient characteristics, namely for: 
 Patients who have received NI-0501 treatment in the context of 
a NI-0501 clinical study or a CU treatment protocol, and have 
received/will receive HSCT. Transplant may have been already 
performed, or may be performed under this protocol. Long-
term follow-up will be conducted up to 1 year post-HSCT (see 
Table 1). 
 Patients who have received NI-0501 treatment in the context of 
an NI-0501 clinical study or a CU treatment protocol, and for 
whom HSCT is not planned. Patients will enter this study for a 
long-term follow-up lasting up to 1 year after the last infusion 
of NI-0501 (see Table 2). 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 6 of 42 
 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
Different flow charts and Schedules of Assessments (SoA) will be 
applied, depending on the above patient’s characteristics. 
Patients will enter study NI-0501-05 after the last infusion of NI-
0501 or at the end of the short-term follow up in the parent study, 
depending on the design of the parent study. Whenever some of 
the visits described in the SoA have been already conducted 
before entry in study NI-0501-05, the patient will proceed with the 
next planned visit. 
Main Inclusion Criteria: 1. Having received at least one dose of NI-0501 during a previous 
NI-0501 study or under a CU treatment protocol. 
2. Having signed the Informed Consent by the patient or the 
patient’s legal representative(s), as applicable, with the assent 
of patients who are legally capable of providing it. 
Study Objectives: 
 
 To monitor the long-term safety profile of NI-0501  
 To assess HLH patients’ survival after NI-0501 treatment 
 To assess duration of response to NI-0501 treatment (i.e. 
maintenance of HLH control) 
 To assess post-HSCT outcome measures, if applicable 
 To assess background disease activity, in patients with 
secondary forms of HLH 
 To study the elimination profile of NI-0501 
 To evaluate the pharmacodynamic (PD) effects (levels of 
circulating Total IFNγ, CXCL9, CXCL10) 
 To assess the profile of relevant HLH biomarkers, e.g., sCD25 
 To assess the immunogenicity of NI-0501 
Study Drug: 
 
No investigational medicinal product (IMP) will be administered 
during the course of this long-term follow-up study. 
However, in the event that, upon request of the treating physician, 
NI-0501 treatment needs to be prolonged beyond Week 8 in 
patients originally enrolled in study NI-0501-04, patients will 
continue receiving NI-0501 in the context of this study. In this 
case NI-0501 will be managed as the IMP.   
Investigating Sites: 
All sites where patients have been recruited in NI-0501 clinical 
studies in which no long-term follow-up is already planned. Sites 
where patients have been treated under a CU treatment protocol 
may also be involved (whenever appropriate).  
Study Duration and 
Study End Definition: 
 For patients who underwent or will undergo HSCT, the study 
will continue until data at 12 months post-HSCT are collected 
 For patients not undergoing HSCT, the study will continue 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 7 of 42 
 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
until data at 12 months after the last infusion of NI-0501 are 
collected 
 Study end is defined as the date of last patient`s last visit 
Concomitant Medications  Any treatment ongoing at the time of study entry will be 
continued as deemed necessary by the Investigator 
 Patients receiving prophylactic treatments for infections (e.g. 
antiviral) at study entry will continue therapy as long as NI-
0501 concentrations are detectable in serum 
 There is no restriction in the use of medications, except for live 
or attenuated live vaccinations that should be avoided as long 
as NI-0501 concentrations are detectable in serum. 
In the event that NI-0501 treatment, upon request of the 
treating physician, needs to be continued beyond week 8 in 
patients originally enrolled in study NI-0501-04 and entering 
the NI-0501-05 study, the use of concomitant medications 
needs to follow the instructions given in the context of the NI-
0501 study in which the patient was recruited. 
Study Parameters: 
 Vital signs, including body temperature 
 Physical examination, including liver and spleen sizes  
 Laboratory parameters: complete blood count, coagulation tests 
(aPTT, PT, d-Dimers and fibrinogen), erritin, CRP, LDH, 
glucose, triglycerides, liver, alanine aminotransferase, aspartate 
aminotransferase, gamma glutamyl transferase, total bilirubin 
and alkaline phosphatases) and renal function tests (creatinine, 
albumin and urea) 
 Pharmacokinetics: circulating NI-0501 concentration  
 Pharmacodynamics: 
circulating 
IFNγ 
levels, 
CXCL9, 
CXCL10, and exploratory markers of disease activity (e.g. 
sCD25) 
 Anti-drug antibodies (ADAs)  
Study Endpoints: 
 Safety will be assessed as follows: 
- 
Incidence, seriousness, intensity, possible relationship 
to NI-0501 and outcomes of Adverse Events (AEs) 
- 
Evolution 
over 
time 
of 
vital 
signs, 
physical 
examination and laboratory values over time   
 Efficacy (as relevant, depending on the different patients’ 
characteristics): 
 Duration of Response after completion of NI-0501 
treatment (assessed according to the definitions set in 
the parent study) 
 Survival time up to one year post-HSCT (including 
survival to HSCT and survival post-HSCT) or one year 
after last NI-0501 infusion (if transplant is not 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 8 of 42 
 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
performed) 
 Post-HSCT outcome indices, e.g. engraftment rate, 
donor chimerism, incidence of acute and chronic Graft 
versus Host Disease (GvHD) (it applies to patients who 
receive HSCT) 
 Monitoring of background disease activity (it applies to 
patients with secondary forms of HLH)  
 Pharmacokinetics: NI-0501 elimination  
 Pharmacodynamics: IFNγ total 
 Immunogenicity: presence of ADAs 
 Exploratory PD parameters/endpoints: e.g. additional markers 
of disease activity (scD25) 
Statistical Analysis 
 Duration of Response and Survival time will be presented 
using Kaplan-Meier curves with medians calculated if 
available. 95% confidence intervals will be calculated for the 
median for each of these endpoints  
 Endpoints based on binary outcomes, including post-HSCT 
outcome measures, will be converted to proportions and 
associated 95% confidence intervals calculated. 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 9 of 42 
 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
CONTENTS 
 
INVESTIGATOR AGREEMENT ............................................................................................................................... 3 
NI-0501-05 SYNOPSIS .......................................................................................................................................... 5 
LIST OF ABBREVIATIONS ................................................................................................................................... 11 
1. 
STUDY RATIONALE ................................................................................................................................... 16 
2. 
OBJECTIVES .............................................................................................................................................. 17 
3. 
STUDY DESIGN ......................................................................................................................................... 17 
3.1. 
OVERALL DESIGN ....................................................................................................................................... 17 
3.2. 
STUDY END ............................................................................................................................................... 19 
4. 
TARGET POPULATION & ELIGIBILITY CRITERIA ......................................................................................... 19 
5. 
PATIENT BACKGROUND TREATMENT AND CARE ..................................................................................... 19 
6. 
ENDPOINTS .............................................................................................................................................. 20 
7. 
STUDY PROCEDURES ................................................................................................................................ 20 
8. 
SAFETY MONITORING .............................................................................................................................. 23 
8.1. 
DESCRIPTION OF STUDY PARAMETERS ............................................................................................................ 23 
8.2. 
RECORDING AND REPORTING SAFETY PARAMETERS........................................................................................... 24 
8.2.1. 
Adverse events ................................................................................................................................. 24 
8.2.2. 
Serious Adverse Events ..................................................................................................................... 24 
8.2.3. 
SUSAR reporting ............................................................................................................................... 25 
8.2.4. 
Managing Abnormal Laboratory Test Values .................................................................................. 26 
8.3. 
FOLLOW-UP OF SAFETY PARAMETERS ............................................................................................................ 26 
8.3.1. 
Treatment and Follow-up of Adverse Events ................................................................................... 26 
8.3.2. 
Follow-up of Abnormal Laboratory Test Values ............................................................................... 26 
8.3.3. 
Pregnancy ........................................................................................................................................ 26 
9. 
BENEFIT/RISK MANAGEMENT .................................................................................................................. 27 
9.1. 
POTENTIAL BENEFITS .................................................................................................................................. 27 
9.2. 
RISKS ANALYSIS .......................................................................................................................................... 27 
9.2.1 Risks related to the target ..................................................................................................................... 27 
9.2.2 Risk related to the study population ...................................................................................................... 28 
9.2.3 Risk minimization measures .................................................................................................................. 28 
10. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .......................................................................... 29 
11. 
ETHICAL AND LEGAL ASPECTS .................................................................................................................. 30 
11.1. 
GOOD CLINICAL PRACTICE ........................................................................................................................... 30 
11.2. 
INVESTIGATOR’S RESPONSIBILITIES ................................................................................................................ 30 
11.3. 
CONSENT ................................................................................................................................................. 30 
11.4. 
CONFIDENTIALITY AND DATA PRIVACY............................................................................................................ 31 
11.5. 
PROTOCOL AMENDMENTS ........................................................................................................................... 31 
11.6. 
APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS ..................................................................... 32 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 10 of 42 
 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
11.7. 
ONGOING INFORMATION FOR IRB ................................................................................................................ 32 
11.8. 
CLOSURE OF THE STUDY .............................................................................................................................. 32 
11.9. 
RECORD RETENTION ................................................................................................................................... 33 
11.10. 
LIABILITY AND INSURANCE ....................................................................................................................... 33 
11.11. 
FINANCIAL DISCLOSURE .......................................................................................................................... 33 
11.12. 
DISCLOSURE OF PROTOCOL AND STUDY RESULTS AND PUBLICATION POLICY ..................................................... 33 
12. 
MONITORING AND AUDITING.................................................................................................................. 35 
12.1. 
STUDY MONITORING AND SOURCE DATA VERIFICATION .................................................................................... 35 
12.2. 
ON-SITE AUDITS ........................................................................................................................................ 35 
12.3. 
SERIOUS GCP BREACHES ............................................................................................................................. 35 
13. 
DOCUMENTATION AND USE OF STUDY FINDINGS ................................................................................... 36 
13.1. 
DOCUMENTATION OF STUDY RESULTS............................................................................................................ 36 
13.2      USE OF COMPUTERIZED SYSTEMS AT THE CLINICAL TRIAL CENTER .......................................................................... 36 
14. 
REFERENCES ............................................................................................................................................. 37 
15. 
APPENDICES ........................................................................................................................................ 39 
APPENDIX A – SCHEDULE OF ASSESSMENTS FOR PATIENTS STILL CONTINUING NI-0501 TREATMENT ................................ 40 
APPENDIX B - INVESTIGATIONAL MEDICINAL PRODUCT (IMP) PREPARATION AND HANDLING ................................................... 42 
 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 11 of 42 
 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
LIST OF ABBREVIATIONS 
Abbreviation Term 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
ATG 
Anti-thymocyte globulin 
CBC 
Complete blood cell count 
CRF 
Case report form 
CRP 
C-reactive protein 
eCRF 
Electronic case report form 
γGT 
Gamma Glutamyl Transferase 
HLH 
Hemophagocytic Lymphohistiocytosis 
HSCT 
Hematopoietic stem cell transplantation 
HZ 
Herpes Zoster 
ICMJE 
International Committee of Medical Journal Editors  
IFNγ 
Interferon gamma 
IFPMA 
International Federation of Pharmaceutical Manufacturers & Associations 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
LDH 
Lactate Dehydrogenase 
NaCl 
Sodium Chloride 
PCR 
Polymerase Chain Reaction 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB 
Tuberculosis 
TMF 
Trial Master File 
WD 
Withdrawal 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH 
Page 12 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
Table 1: Schedule of Assessments for the Long-term Follow-Up of Patients Who Underwent or Will Undergo HSCT 
Assessments 
Follow-up pre-HSCT 
HSCT 
Follow-up post-HSCT 
UV 8 
Baseline 
visit 1 
Weekly 
visits pre-
HSCT 2 
Pre 
Condi-
tioning 
visit 3 
Pre 
HSCT  
Weekly visits 
wk 1 – 2 – 3 4 
D+30  
visit 5 
D+60  
visit 5 
D+100  
visit 5 
6 month  
visit 6 
1 year 
visit 6 / WD 7 
 
Subject 
information 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history / 
relevant treatment 
X 
 
 
 
 
 
 
 
 
 
 
Clinical 
Assessments 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical 
examination9  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
Duration of 
response to 
treatment 
 
 
X 
X 
 
X 
 
X 
 
X 
 
Post-HSCT 
outcome measures10 
 
 
 
 
X 
X 
X 
X 
X 
X  
 
Survival 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
Laboratory 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Biochemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
Search for 
infections11 
TB, 
Adenovirus, 
EBV, CMV  
X11 
X11 
X11 
 
 
X11 
 
X11 
X11 
X11 
 
X11 
X11 
 
Imaging  
Chest X ray11 
X11 
X11 
X11 
 
 
X11 
X11 
X11 
X11 
 
X11 
X11 
 
Abdominal 
ultrasound12 
X 
 
X 
 
 
X 
 
X 
 
X 
 
AE recording14 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications and 
procedures recording 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
PK/PD (NI-0501 concentrations / 
total IFNγ  & other biomarkers) 
X 
X 
X 
X 
X 
X 
X13 
X13 
X13 
X13 
 
Immunogenicity (ADA) 
X 
 
 
 
 
 
 
X  
 
X  
 
CBC: complete blood count (white blood cells and subsets, red blood cells including reticulocytes and platelets, hemoglobin and hematocrit). Coagulation tests: aPTT, PT, d-Dimers and fibrinogen 
Biochemistry: glucose, CRP, ferritin, triglycerides, liver (AST, ALT, γGT, LDH, ALP, bilirubin) and renal function (albumin, creatinine and urea).  
1 = Baseline visit: Patients may enter the study at any time-point before or after HSCT, depending on the SoA of the parent study. The required Baseline assessments do not have to be repeated if available from the last 
visit of a previous NI-0501 clinical study or CU treatment protocol, if occurred within 5 days from the Baseline visit.  
2 = Weekly visits pre-HSCT: to be performed weekly up to 4 weeks after last NI-0501 infusion, then bi-weekly until start of conditioning (±2 day window is allowed).  


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH 
Page 13 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
3 = Pre-conditioning visit:  if this visit is no more than 48 hrs apart from one of the follow-up visit pre-HSCT, then these visits may be combined following the most demanding SoA.  
4 = Weekly visit post-HSCT:  a ±2 day window is allowed  
5 = D+30, D+60, D+100 visits: a ±1 week window is allowed 
6 = 6-mo, 1-yr visits: a ±4 week window is allowed 
7 = WD (Withdrawal visit): assessments to be performed in case of premature study discontinuation, performing all assessments as indicated for this last study visit  
8 = UV (Unscheduled visit): assessments to be performed as clinically indicated  
9 = Physical examination: includes spleen and liver size assessments (in cm from costal grill by palpation) 
10 = Post-HSCT Outcome Measures: engraftment rate, donor chimerism, incidence of acute and chronic GvHD 
11 = Search for infections and Chest X-ray: TB, Adenovirus, EBV, CMV searches to be performed every 2 weeks as long as NI-0501 is detectable. Chest X-ray only if clinically indicated 
12 = Abdominal ultrasound: it has to include longitudinal measure of spleen 
13 = PK: as long as NI-0501 serum concentrations are measurable; PD: as long as NI-0501 serum concentrations are measurable, thereafter only if clinically indicated 
14= AE recording: once NI-0501 is no longer detectable, only SAEs will be recorded 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH 
Page 14 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
Table 2: Schedule of Assessments for the Long-Term Follow-Up of Patients for Whom HSCT is not Planned 
Assessments 
Follow-up after last NI-0501 infusion 
UV 4 
Baseline 
visit 1 
Week 2 
visit 2 
Week 3 
visit 2 
Day+30  
visit 2 
Day+60  
visit 2 
Day+100  
visit 2 
6 month  
visit 2 
1 year 
visit 2 / WD 3 
Subject 
information 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history / 
relevant treatment 
X 
 
 
 
 
 
 
 
 
Clinical 
Assessment
s 
Vital signs  
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical 
examination5  
X 
X 
X 
X 
X 
X 
X 
X  
 
Duration of response 
to treatment 
 
 
 
X 
 
X 
 
X 
 
Background Disease 
Activity 
X 
 
 
X 
 
X 
 
X  
 
Survival 
X 
X 
X 
X 
X 
X 
X 
X  
 
Laboratory 
CBC 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
 
Biochemistry 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
 
X 
X 
X 
X 
X 
 
Search for 
infections6 
TB, 
Adenovirus, 
EBV, CMV  
X6 
 
 
 
X6 
X6 
X6 
 
X6 
X6 
 
Imaging  
Chest X ray6 
X6 
 
X6 
 
X6 
X6 
X6 
X6 
 
X6 
X6 
 
Abdominal 
ultrasound7 
X 
 
 
X 
 
X 
 
X 
 
AE recording9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications and 
procedures recording 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK/PD (NI-0501 concentrations / 
total IFNγ  & other biomarkers) 
X 
X 
X 
X 
X8 
X8 
X8 
X8 
 
Immunogenicity (ADA) 
X 
 
 
 
 
X  
 
X  
 
CBC: complete blood count (white blood cells and subsets, red blood cells including reticulocytes and platelets, hemoglobin and hematocrit). Coagulation tests: aPTT, PT, d-Dimers and fibrinogen 
Biochemistry: glucose, CRP, ferritin, triglycerides, liver (AST, ALT, γGT, LDH, ALP, bilirubin) and renal function (albumin, creatinine and urea).  
1 = Baseline visit: Patients may enter the study at any time-point, depending on the SoA of the parent study.  The required Baseline assessments do not have to be repeated if available from the last visit of a previous 
NI-0501 clinical study or CU treatment protocol, if occurred within 5 days from the Baseline visit.  
2 = Time interval starts from the last NI-0501 infusion. For the allowed time window around visits, please refer to Table 1. These visits may have been conducted as part of the parent study; in such case, they do not 
need to be repeated. 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH 
Page 15 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
3 = WD (Withdrawal visit): assessments to be performed in case of premature study discontinuation, as indicated for this last study visit  
4 = UV (Unscheduled visit): assessments to be performed as clinically indicated  
5 = Physical examination: includes spleen and liver size assessments (in cm from costal grill by palpation) 
6 = Search for infections and Chest X-ray: search for infections to be performed every 4 weeks as long as NI-0501 serum concentrations are measurable, thereafter only if clinically indicated. Chest X-ray only if 
clinically indicated 
7 = Abdominal ultrasound: it has to include longitudinal measure of spleen 
8 = PK: as long as NI-0501 serum concentrations are measurable; PD: as long as NI-0501 serum concentrations are measurable, thereafter only if clinically indicated 
9 = AE recording: once NI-0501 is no longer detectable, only SAEs will be recorded 
 
 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 16 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
1. STUDY RATIONALE 
NI-0501 (assigned INN name: emapalumab) is a fully human immunoglobulin G1 anti-interferon 
gamma (IFNγ) monoclonal antibody (mAb) which binds and neutralizes IFNγ.  
IFNγ is one of the most potent and pleiotropic cytokines of the immune system and it is considered 
critical for innate and adaptive immunity against viral and intracellular bacterial infections1. 
Haemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by a severe impairment or 
absence of cytotoxic function by CD8+ T cells, with a striking activation of the immune system, 
which presents typically as hypercytokinemia and lymphohistiocytic infiltrates2. Among the cytokines 
elevated in HLH patients are: IFNγ, interleukin (IL)-6, IL-10, tumor necrosis factor (TNF) α, IL-8, 
macrophage colony stimulating factor (MCSF) and granulocyte-macrophage colony-stimulating 
factor (GM-CSF). 
HLH comprises primary forms, genetically determined, and secondary forms, which are consequent to 
infections, inflammatory/autoimmune diseases or malignancies3. 
Based on data from relevant animal models of HLH4;5 and from the assessment of IFNγ levels in HLH 
patients6, neutralization of IFNγ represents a potential therapeutic objective in this patient population 
to achieve non-active disease (induction treatment) through a targeted therapy, which might prevent 
the use of chemotherapy. Of note is that hypercytokinemia and organ infiltration by activated 
lymphocytes and histiocytes are responsible for all symptoms of HLH patients and are dependent on 
CD8+ T cells hyperactivity and high IFNγ levels7-10.  
Therefore inhibiting IFNγ is believed to be a viable option for the development of a targeted therapy 
for HLH, required to be efficacious with no or limited toxicity11. IFNγ transient blockade is believed 
to be potentially less toxic and far less immunosuppressive than VP-16 or ATG, which are currently 
part of the induction regimen of HLH. 
Macrophage Activation Syndrome (MAS) is a secondary form of HLH often observed in patients 
suffering from a rheumatic disease, such as systemic Juvenile Idiopathic Arthritis (sJIA) and Systemic 
Lupus Erythematosus (SLE). 
MAS, like HLH, is characterized by sustained immune cell activation and an associated cytokine 
storm of pro-inflammatory cytokines with overproduction of IFNγ and other cytokines.15, 16Beyond the 
demonstration of the safety, tolerability and efficacy of NI-0501 as induction treatment for HLH and 
as treatment for MAS, there is a need to establish the mid- and long-term safety of NI-0501 treatment 
and its influence on survival of patients. NI-0501 has been administered to adult Healthy Volunteers 
(HV) as a single i.v. infusion up to 3 mg/kg without any mid- or long-term adverse events reported 
during a maximum follow-up of 6 months (study NI-0501-03). At the moment a pilot Phase II study 
(NI-0501-04) is open for recruitment of patients with primary HLH in whom the disease has 
reactivated.  
Currently, 2 interventional studies are ongoing: an open-label Phase 2/3 study in patients with pHLH 
(protocol NI-0501-04) and a pilot study in MAS in sJIA patients (protocol NI-0501-06).  
In addition, NI-0501 has been administered under a compassionate use treatment protocol to HLH 
patients that exhausted all available therapeutic options. 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 17 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
Study NI-0501-05 allows a systematic collection of long-term data in patients previously exposed to 
NI-0501 during the course of the studies mentioned above (and potentially other studies not yet 
ongoing) or who have received NI-0501 in compassionate use. 
2. OBJECTIVES 
 
To monitor the long-term safety profile of NI-0501  
 
To assess HLH patients’ survival after NI-0501 treatment 
 
To assess duration of response to NI-0501 treatment (i.e. maintenance of HLH control) 
 
To assess post-HSCT outcome measures, if applicable 
 
To assess background disease activity, in patients with secondary forms of HLH  
 
To study the elimination profile of NI-0501 
 
To evaluate the pharmacodynamic (PD) effects (levels of circulating total IFNγ, CXCL9, 
CXCL10) 
 
To assess the profile of relevant HLH biomarkers, e.g., sCD25 
 
To assess the immunogenicity of NI-0501 
3. STUDY DESIGN 
3.1. OVERALL DESIGN 
This is an international, multicenter, long-term, follow-up study of HLH patients who have received at 
least one dose of NI-0501 in the context of a previous NI-0501 clinical study in which no long-term 
follow-up is already planned. Patients having received NI-0501 under a compassionate use (CU) 
treatment protocol may also be considered for enrolment, whenever appropriate. 
The NI-0501-05 study is performed both in the US and in Europe according to twin protocols called 
NI-0501-05-P-IND #111015 and NI-0501-05-EudraCT #2012-005753-23, respectively. 
In the event that an appropriate donor has not been identified by Week 8 or in case of the need to 
delay transplantation for reasons unrelated to the administration of NI-0501, patients from study NI-
0501-04- US-P-IND#111015 can continue receiving NI-0501 treatment beyond the foreseen 8 weeks 
upon request of the Investigator, providing a favorable benefit/risk has been established. A close 
monitoring of these patients will be performed in the context of this study (NI-0501-05), according to 
the schedule of assessment reported in Appendix A, where the end of treatment period visit of the NI-
0501-04 study will be the first visit for these patients entering NI-0501-05 study (refer to NI-0501-04-
US Study Protocol, Table 2). Due to the probability that, by Week 8, patients may be receiving NI-
0501 infusions less frequently than every 3 days, the schedule of assessment, as described in 
Appendix A, may be adapted to suit the schedule of administration, maintaining the safety and 
efficacy assessments visits at least on a weekly basis. After NI-0501 discontinuation, patients will be 
monitored weekly for a period of 4 weeks (4-week follow-up) before entering the long-term follow-up 
study described above. 
Study NI-0501-05 enrolls 2 different groups of patients: patients who underwent or will undergo 
HSCT, and patients for whom HSCT is not envisioned. The follow-up of these 2 different patients` 
groups is generally similar. The study design and visits` schedule for each patients`group is 
specifically described in Sections 3.1.1 and 3.1.2, respectively. 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 18 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
3.1.1. Patients who underwent or will undergo HSCT 
This section refers to patients who have received or are planned to receive HSCT after NI-0501 
treatment in a previous NI-0501 clinical study or in a CU treatment protocol.   
Patients may enter the NI-0501-05 study at any time point after NI-0501 treatment or after completion 
of the short-term follow-up in the parent study, as applicable. 
Patients will undergo: 
 
Baseline visit: it corresponds to the first study visit. The date of informed consent signature has to 
be recorded. If the last visit that the patient underwent in the parent study required all the 
assessments to be collected at Baseline in NI-0501-05 and occurred within 5 days from Baseline, 
data collected during that visit will constitute the baseline for the present study, and the visit will 
not need to be repeated or will be performed only to cover for any missing assessments. The 
Baseline visit will be combined with any other study visit depending on when the patient enters 
this study [for example, if the patient enters the study after having already performed HSCT, the 
Baseline visit will be combined with the relevant post-HSCT follow-up visit]. 
 
Weekly visits pre-HSCT: they have to be performed weekly until HSCT for 4 weeks from the 
end of NI-0501 treatment. If HSCT occurs beyond this time frame, the additional visits will be 
performed every 2 weeks until start of conditioning.    
 
Pre-conditioning visit: it should occur up to 3 days prior to the start of conditioning and 
assessments must be performed prior to the first administration of conditioning drug(s). This visit 
can be combined with any other follow-up visit before HSCT visit, provided that they are no more 
than 48 hours apart.  
 
Pre-HSCT visit: it should occur no more than 2 days prior to transplant. 
 
Post-HSCT visits: weekly visits will take place during the first 4 weeks after transplant until 
Day+30, and subsequently at Day+60, Day+100, 6 months, and 12 months post-HSCT.  
For the allowed time windows, please see section 7.  
Additional visits (unscheduled) may be required depending on the patient’s clinical conditions. 
3.1.2 Patients for whom HSCT is not planned 
This section refers to patients who have received NI-0501 treatment in the context of an NI-0501 
clinical study or under a CU treatment protocol, and for whom HSCT is not planned based on disease 
characteristics and/or physician’s assessment of benefit/risk of the transplant procedure in that 
individual patient. 
Patients may enter the NI-0501-05 study at any time point after NI-0501 treatment (and completion of 
the short-term follow-up, if required in the parent study).  
Patients will undergo: 
 
Baseline visit: it corresponds to the first study visit. The date of informed consent signature has to 
be recorded. If the last visit that the patient underwent in the previous NI-0501 protocol required 
all the assessments to be collected at Baseline in NI-0501-05 and occurred within 5 days from 
Baseline, data collected during that visit will constitute the baseline for the present study, and the 
visit will not need to be repeated or will be performed only to cover for any missing assessments. 
The Baseline visit will be combined with any other study visit depending on when the patient 
enters this study. 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 19 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
 
Follow-up visits after last NI-0501 infusion: unless already performed in a previous NI-0501 
clinical study, weekly visits will take place until Day+30 after last NI-0501 infusion, and 
thereafter at Day+60, Day+100, 6 months, and 12 months after the last NI-0501 infusion.  
Additional visits (unscheduled) may be required depending on the patient’s clinical conditions. 
For the allowed time windows, please see Section 7. 
3.2. STUDY END 
The end of the study is defined as last patient last visit. 
In case of an ongoing serious adverse event (SAE), patients 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. 
4. TARGET POPULATION & ELIGIBILITY CRITERIA 
The study population comprises HLH patients who have received at least one dose of NI-0501 in the 
context of a previous NI-0501 clinical study in which no long-term follow-up is already planned. 
Patients having received NI-0501 under a CU treatment protocol may also be considered for 
enrolment where appropriate. 
Patients must fulfil the following inclusion criteria: 
1. Having received at least one dose of NI-0501 during a previous NI-0501 study or under a 
CU treatment protocol.  
2. Having signed the Informed Consent of this study by the patient or the patient’s legal 
representative(s), as applicable, with the assent of patients who are legally capable of 
providing it.  
3. Having agreed to continue using adequate methods of birth control until 6 months 
after the last administered dose of NI-0501, when relevant Males with partners(s) of 
child-bearing potential must agree to take appropriate precautions to avoid fathering a child 
until 6 months after receiving last dose of NI-0501. 
There are no exclusion criteria. 
5. PATIENT BACKGROUND TREATMENT AND CARE  
There is no restriction in the use of medications for either pre-Transplantation conditioning or for 
post-Transplantation medical care. 
 
Any treatment ongoing at the time of study entry will be continued as deemed necessary by the 
Investigator. 
 
Patients receiving prophylactic treatments for infections (e.g. antiviral) at study entry will 
continue therapy as long as NI-0501 concentrations are detectable in serum.  
 
There is no restriction in the use of medications, except for live or attenuated-live vaccines that 
should be avoided as long as NI-0501 concentrations are detectable in the serum. 
 
All relevant treatments prescribed to patients (dose, frequency and duration) will be recorded 
throughout the NI-0501-05 study course. 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 20 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
In the event that, upon request of the treating physician, a patient receives NI-0501 treatment beyond 
the foreseen duration of the NI-0501 protocol (i.e. Week 8), NI-0501 should be prepared and 
administered as described in Appendix B of this protocol (Investigational Medicinal Product 
preparation and handling). With regards to the use of concomitant medications, the recommendations 
stated in the NI-0501 treatment protocol in which the patient was originally enrolled should be 
followed by the Investigator, in particular as to the need for prophylactic treatment and restricted use 
of some other treatments (e.g. refer to NI-0501-04-US Study Protocol, Section 6.3). Each patient 
receiving NI-0501 treatment for more than 8 weeks should continue to carry a card similar to the one 
given to him/her during their previous NI-0501 study, but indicating the references of the NI-0501-05 
study (i.e. the card giving details on the name of the drug, name of the responsible physician, and the 
address and telephone number of the study site).  
6. ENDPOINTS 
 
Safety will be assessed as follows: 
- 
The incidence, seriousness, intensity, possible relationship to NI-0501 and outcomes 
of AEs. 
- 
Evaluation over time of vital signs, physical examination and laboratory values: 
evolution over time.  
 
Efficacy (as relevant, depending on the different patients’ characteristics): 
- 
Duration of Response after completion of NI-0501 treatment (assessed according to 
the definitions set in the parent study) 
- 
Survival time up to one year post-HSCT (including survival to HSCT and survival 
post-HSCT) or one year after last NI-0501 infusion (if transplant is not performed) 
- 
Post-HSCT outcome indices, e.g. engraftment rate, donor chimerism achieved, 
incidence of acute and chronic Graft versus Host Disease (GvHD) (it applies to 
patients who receive HSCT) 
- 
Monitoring of background disease activity (it applies to patients with secondary 
forms of HLH)  
 
Pharmacokinetics: 
- 
NI-0501 elimination profile 
 
Pharmacodynamics: 
- 
IFNγ total  
- 
Exploratory PD parameters/disease markers such as: sCD25, CXCL9, CXCL10  
 
Immunogenicity: 
- 
Presence of anti-drug antibodies (i.e. ADAs) 
7. STUDY PROCEDURES 
The Informed Consent form must be signed by the patient or his/her legal representative prior to any 
study-related procedures, with the assent of patients who are legally capable of providing it, at the 
latest at the Baseline visit.  
Analyses done on blood samples will favor as much as possible the use of micro-sampling techniques.  


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 21 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
When limiting blood drawing is needed, laboratory safety parameters (which would have been done 
as normal disease monitoring) will be prioritized.  
Please refer to the schedule of assessments in Table 1 and Table 2 for an overview of the procedures 
to be performed during this long-term follow-up study. 
If conditioning and/or transplantation have occurred before entry in this follow-up protocol, the 
corresponding visits will not be performed in the NI-0501-05 protocol. In this case when a patient 
enters the NI-0501-05 study, he/she will start to be monitored according to the NI-0501-05 remaining 
visits to be performed in the SOA. 
During the study, the following time-windows are allowed around visits: 
- 
Weekly visits pre-HSCT: 2 days 
- 
Pre-conditioning: if this visit is no more than 48 hrs apart from one of the weekly visit 
pre-HSCT, then these visits may be combined following the most demanding SoA  
- 
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 above described time windows apply to the follow-up visits required to 
occur after the last NI-0501 infusion. 
The following assessments will be performed in all patients: 
Clinical assessments: 
at each visit 
 
Vital signs: body temperature, heart rate, blood pressure 
and respiratory rate  
 
Physical examination with particular attention being 
paid to: 
- 
height (at pre-Transplant visit, 100-days, 6-
month and 12-month post-Transplant visits), 
weight 
- 
occurrence of skin rashes, jaundice, purpura, 
bleeding, edema 
- 
signs of infections  
- 
neurological examination  
- 
liver and spleen size (in cm from costal grill)  
Laboratory: 
at each visit 
 
CBC 
 
Coagulation tests: aPTT, PT, D-dimers and fibrinogen 
 
Biochemistry: glucose, ferritin, CRP, AST, ALT, γGT, 
ALP, LDH, bilirubin, albumin, creatinine, urea, 
triglycerides 
 
Urinalysis: glucose, blood, protein, leucocytes, ketones, 
pH and specific gravity (only at Baseline, D+30, D+60, 
D+100 visit, 6 months and 1 year/WD visits) 
Imaging:  
 
Chest X-ray if clinically indicated 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 22 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
 
 
Abdominal ultrasound at Baseline, pre-conditioning (as 
applicable), D+30, D+100 visit and 1 year/WD visits 
Search for infections:  
every 2 weeks, as long as NI-0501 is 
detectable in serum 
 
Tuberculosis either via polymerase chain reaction [PCR] 
in any relevant specimen (e.g. blood, urine, broncho-
alveolar lavage, gastric aspirate) or by any method 
agreed to be used in the parent protocol or CU treatment 
protocol at a given site 
 
Adenovirus, EBV, CMV by quantitative PCR 
Pharmacokinetics: 
at each visit as long as relevant 
 
NI-0501 serum concentration if concentration still 
detectable at previous visit 
Pharmacodynamics/Exploratory 
Parameters: 
at each visit as long as NI-0501 is 
detectable 
 
sCD25, other exploratory markers (e.g. CXCL-9, 
CXCL-10) 
 
Total IFNγ  
Immunogenicity: 
At Baseline, Day+100 visit, 1 
year/WD visit 
 
Presence of anti-NI-0501 antibodies (ADA) 
Adverse Events recording at each 
visit  
Relevant concomitant medications 
and procedures recording 
at each visit 
 
Any new AE which has occurred since the last visit 
should be recorded as well as evolution of ongoing AEs 
should be checked  
Duration of response to treatment: 
At pre-Conditioning (for patients 
undergoing 
HSCT), 
Day+30, 
Day+100, 1 year visits 
 
Through assessment of:  
- 
HLH disease activity (as defined in the parent 
protocol in which the patient was originally 
enrolled) 
 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 23 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
In addition, assessment of survival is to be performed in all patients at each visit. 
Background disease activity will be assessed in the relevant population (i.e. patients with secondary 
HLH) at Baseline, Day+30, Day+100, 1 year visits. 
Post-HSCT outcome measures will be collected in the relevant population at each visit post-HSCT.  
Unplanned visits may occur should the Investigator need to assess or treat any clinical condition that 
arises during the study. In the event that, upon the request of the treating physician, NI-0501 treatment 
needs to be continued beyond Week 8 in patients enrolled in study NI-0501-04, patients will continue 
receiving NI-0501 in the context of this study at a dose either carried forward from the last 
administered NI-0501 dose as part of the NI-0501 treatment study the patient was enrolled in, or at an 
adjusted dose if necessary and depending on NI-0501 PK profile. 
NI-0501 infusions will be performed at a dose and frequency which will be determined by the 
Sponsor based on the observed PK profile of the drug and on the patient’s clinical response. 
The last dose of dexamethasone administered as part of study NI-0501-04 will be carried forward. If 
tapering is required, it should be performed in accordance to the general corticosteroid tapering rules, 
and dose modifications will be recorded in the eCRF. 
The stopping rules described in study protocol NI-0501 the patient was part of (e.g. NI-0501-04-US-
P-IND-111015, Section 10) still apply for patients on drug to decide whether the patient should 
continue to receive NI-0501 infusion. If a patient is not receiving anymore NI-0501 infusions in the 
context of NI-0501-05 study, he remains in the NI-0501-05 as it is an observational study collecting 
long term data, unless the patient or his/her legal guardian withdraw their consent.  
Patients still receiving NI-0501 treatment will be followed-up to monitor safety and efficacy of NI-
0501 treatment until treatment discontinuation and will be followed for 4 weeks as described in the 
NI-0501 treatment protocol they were part of (e.g. NI-0501-04-US-P-IND-111015) and as detailed in 
the specific Schedule of Assessment for patients continuing to receive NI-0501 beyond Week 8 (see 
Appendix A). Upon discontinuation of NI-0501 treatment, assessments described above will be 
performed as part of the long-term follow-up of these patients.  
8. SAFETY MONITORING 
8.1. DESCRIPTION OF STUDY PARAMETERS 
Evaluation of NI-0501 tolerability and safety will be based on the following parameters: 
 
Adverse events (AEs), with special attention being paid to the occurrence of infections 
 
Laboratory parameters: 
- 
CBC and hemoglobin 
- 
coagulation tests (aPTT, PT, d-Dimers and fibrinogen)  
- 
inflammatory markers such as CRP and ferritin,  
- 
biochemistry: glucose, triglycerides and liver enzymes (AST, ALT, ALP, γGT, LDH, 
total bilirubin), albumin, creatinine and urea 
 
Vital signs: body temperature, heart and respiratory rate, blood pressure 
 
Physical examination and changes over time (see Section 7) 
 
Immunogenicity: development of anti-NI-0501 antibodies  


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 24 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
8.2.       RECORDING AND REPORTING SAFETY PARAMETERS 
The Safety Reporting Requirements for INDs and BA/BE Studies issued in December 2012 will be 
followed.  
8.2.1. Adverse events 
Adverse events are defined as any undesirable experience occurring to a subject during the study, 
whether or not considered related to the investigational product (IMP). The IMP remains NI-0501 
during this study even if the patient is off drug. All AEs reported spontaneously by the patients or 
his/her relatives or observed by the Investigator or his staff during the clinical study up to and 
including the end-of-study visit will be reported on the AE data collection form. For all AEs, the 
following will be assessed and recorded: intensity, seriousness, relationship to test substance, action 
taken regarding test substance, any treatment received and outcome to date.  
Intensity of AEs will be graded on a three-points scale (mild, moderate, severe) using the modified 
WHO (World Health Organization) toxicity scale (Grade 3 and 4 are considered to be the severe 
grade). If AE severity 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 3-points scale 
mentioned above) reported during its course. The relationship of adverse events to NI-0501 will be 
assessed by the Investigator using a “Yes/No” classification. A “Yes” relationship infers that there is a 
reasonable suspected causal relationship to NI-0501. The expression “reasonable causal relationship” 
is meant to convey that there are facts, evidence or arguments to suggest a causal relationship. 
All AEs including local and systemic reactions not meeting the criteria for Serious AEs will be 
captured in the appropriate eCRF section. All AEs occurring while a patient is participating in the 
study must be documented appropriately, regardless of relationship. All AEs will be followed to 
adequate resolution.  
Any AE that is present at the time that the patient enters the NI-0501-05 study will continue to be 
monitored in the frame of previous NI-0501 study (for serious AEs, until resolution or until the 
outcome of the event is known and stable). Therefore it will not be recorded as an AE of the NI-0501-
05 study, unless in case of worsening. In this case a new AE will be recorded as a worsening of a 
previous condition. 
8.2.2. Serious Adverse Events 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor, 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; 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 25 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
The term severe is a measure of intensity/severity: thus a severe AE is not necessarily serious. For 
example, nausea of several hours’ duration may be rated as severe, but may not be clinically serious. 
For the purposes of this study, the following will not be considered as SAEs: 
 
Elective hospitalizations or surgical procedures that are a result of a patient’s pre-existing 
condition(s) which have not worsened since receiving IMP. Such events triggering the 
procedure or the hospitalization should still be recorded as AEs in the eCRF; 
 
Hospitalization as requested per protocol for NI-0501infusion and study visits. 
Any serious clinical AE must be communicated by the Investigator to Sobi AG, by fax or electronic 
transmission, within 24 hours of awareness. 
For the initial SAE report, the Investigator should report all available case details concerning the 
patient and the event, using the Sobi AG SAE reporting standard form.  
Sobi AG contact information for SAE reporting: 
Fax: 
 
E-mail: 
 
Relevant follow-up information on SAEs should be forwarded to Sobi 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 Sobi 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 through to resolution 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 (21 CFR 312.32(a) and 312.32(c)(1)).  
8.2.3. SUSAR reporting 
Unexpected adverse reactions are all untoward and unintended responses to an investigational product 
related to any dose administered 
These reactions are SUSARs if the following three conditions are met: 
1) the event must be serious (see Section 8.2.2 above); 
2) there must be a certain degree of probability that the event is a harmful and an undesirable reaction 
to the medicinal product under investigation, regardless of the administered dose; 
3) the event is not listed as an expected serious reaction in the Reference Safety Information (RSI) of 
the IB.Under 21 CFR 312.32(c), the Sponsor (directly or through a delegated third party) is required 
to notify FDA and all participating Investigators in an IND safety report (i.e. 7- or 15-day expedited 
report) of potentially serious risks from clinical trials or any other source as soon as possible, but no 
later than 7 calendar days for fatal or life-threatening events and 15 calendar days for all other events, 
after the Sponsor receives the safety information and determines that the information qualifies for 
reporting. 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 26 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
US Investigators are required to promptly report to the Institutional Review Board (IRB) all 
unanticipated problems involving risk to human subjects or others, including adverse events that 
should be considered unanticipated problems (21 CFR 312.66), such as IND safety reports. 
Sobi 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.  
8.2.4. Managing Abnormal Laboratory Test Values  
All safety laboratory tests (hematology and blood biochemistry provided by the site for each visit 
time-point, should be captured in the database in the laboratory page and should not be reported as 
AEs even if qualified as `clinically significant` at site, unless specific treatment is given for the 
abnormality or if qualifying as grade 4 as per WHO recommendations. Treatment does not refer to 
platelets or RBC transfusions administered during conditioning and post HSCT or when patient has 
sign of HLH.  If a laboratory abnormality leads to a new clinical diagnosis (e.g., high white cell count 
is found to be due to incidental leukemia), the new clinical diagnosis should be reported as an AE 
rather than the laboratory abnormality. 
8.3. FOLLOW-UP OF SAFETY PARAMETERS 
8.3.1. Treatment and Follow-up of Adverse Events 
Adverse events, especially those for which the relationship to the study drug has been assessed as 
‘Yes’, should be followed-up until the event has returned to baseline status or has stabilized. All SAEs 
must be followed-up until the event has either resolved or reached a stable clinical outcome. 
8.3.2. Follow-up of Abnormal Laboratory Test Values 
In the event of unexplained clinically relevant abnormal laboratory test values, the tests should be 
repeated immediately and followed-up until the values have returned to within normal range and/or an 
adequate explanation of the abnormality is found.  
8.3.3. Pregnancy 
In the event that a pregnancy occurs during the trial course, it must be reported to Sobi AG within 24 
hours of awareness. This includes pregnancies occurring in partners of male enrolled patients. All 
information pertaining to pregnancies should be reported using the Sobi AG Pregnancy form. 
Pregnancies should be followed until conclusion to obtain outcome information. 
No patient will be withdrawn from the study due to pregnancy. 
In the event of a pregnancy of a patient still receiving NI-0501, the IMP administration will be 
discontinued and the patient will enter the 4 week follow-up and then the long-term follow-up 
periods. 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 27 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
9. BENEFIT/RISK MANAGEMENT 
9.1. POTENTIAL BENEFITS 
As this study is intended to monitor the long-term safety following the administration of NI-0501, as 
well as the impact on survival, the main benefit for the patient is to be closely monitored, enabling the 
early detection of a potential issue.  
However, in case the patient would continue to receive NI-0501 in the context of this study after 
having successfully completed the NI-0501-04 protocol, the expected benefit is to maintain the 
therapeutic effects of NI-0501 treatment, enabling transplantation to be performed without using 
immune chemotherapy that has short and long term risks.  
9.2. RISKS ANALYSIS 
As NI-0501 is a monoclonal antibody and is characterized by a long half-life, the Investigator should 
be aware of the risks reported below.  
9.2.1 Risks related to the target 
IFNγ neutralization by NI-0501 clinically mimics that of complete IFNγ deficiency.     
Patients with IFNγ R deficiency are prone to developing mycobacterial infections and, although to a 
lesser extent, Salmonella infections12;13. 
The mean age of a first infection is 3.1 and 13.4 years in patients with complete and partial deficiency, 
respectively. No systematic prophylaxis has been recommended in these patients. 
If infection occurs, appropriate antibiotic treatment based on sensitivity of isolated species is 
prescribed. In this patient population infections usually respond to antibiotics, however they often 
relapse when antibiotics are discontinued14. 
Toxicological studies carried out with NI-0501 have shown an increased susceptibility to enteral 
pathogen infection when the pathogen is already latent in the intestinal tract. However this risk is 
considered to be of limited relevance to humans.  
To date, NI-0501 has been administered to Healthy Volunteers (14 subjects) in a single ascending 
dose study, which confirmed the absence of off-target toxicity. However, a reactivation of herpes 
zoster (HZ) virus was observed in one healthy volunteer at a dose of 3 mg/kg, and it may have been 
due to the pharmacological effect of the drug. Although it is difficult to draw firm conclusions from 
this one case, prophylaxis against HZ for all patients, as long as the activity of NI-0501 is measurable, 
is to be maintained in the context of this study.  
In addition, as of 30 June 2017, NI-0501 has been administered to 34 patients (16 M, 18 F) in study 
NI-0501-04. Infections reported by HLH patients during or after administration of NI-0501 are 
commonly observed in immunocompromised patients or described in pediatric population (seasonal 
viral infections). They did not prevent initiation of NI-0501 treatment when present prior to the first 
infusion, and did not result in the discontinuation or dose decrease of NI-050, except in one patient 
who has experienced a disseminated histoplasmosis which has resulted into treatment discontinuation; 
infection resolved with proper antifungal treatment. Infections resolved when treated appropriately 
and not associated with a refractory disease status.  Severe infections were generally reported in 
patients with previous recent significant exposure to immunosuppressive treatments as they added an 
additional risk factor for infection development.  


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 28 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
For more details, refer to the latest Investigator’s Brochure. 
For patients originally enrolled in study NI-0501-04 who will continue receiving NI-0501 \ (Section 
3.1), the risk analysis described in the NI-0501-04 study protocol will apply unless new information is 
available. This information will be part of the Development Safety Risk Management Plan.  
9.2.2 Risk related to the study population 
Most of the patients are expected to be children of a young age, affected by a life-threatening disease. 
They may have already received the conventional treatment regimen for HLH. All information 
collected with regards to disease stage and previous treatments will be taken into account for the 
analysis of AEs. Duration of NI-0501 treatment will also be taken into account. Concomitant 
medications given during or after the administration of NI-0501 may also potentially expose patients 
to AEs; however their benefits may outweigh their risks.  
At present, the potential impact of NI-0501 treatment on conditioning and Transplantation is 
unknown. 
9.2.3 Risk minimization measures 
The risks listed above, in view of the expected benefits, are considered to be manageable in this 
patient population, if adequate prevention and minimization measures are put in place. The following 
specific measures have been introduced to minimize the patient’s risk: 
 
Patients are cared for in specialized centers for the treatment of HLH, which are used to 
managing severely immuno-compromised patients 
 
Prophylaxis for herpes zoster to avoid occurrence of these infections will be administered as 
long as deemed necessary, either because of residual NI-0501 activity or because of the 
patient’s current treatment 
 
Close monitoring of potential infections through careful physical examination and monitoring 
of laboratory parameters  
The NI-0501 Development Safety Risk Management Plan will address risks, identify signals for early 
detection of safety concerns and propose mitigating actions. It will be part of the study documentation 
shared with Investigators and any relevant third party involved in the study. 
Risk minimization measures as described in corresponding protocol section of the NI-0501 study the 
patients were part of (e.g. section 9.5.2.3 of NI-0501-04-US-P-IND#111015 protocol) still apply in 
the event that patients continue receiving NI-0501 treatment beyond the foreseen 8 weeks in study NI-
0501-04, upon request of the Investigator, providing a favourable benefit/risk has been established.  


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 29 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
 
10. STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
Full details of all statistical aspects 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. 
Statistical methods will focus on summarizing the data collected, using appropriate graphical and 
tabular presentations. For measurements of continuous endpoints, summary statistics will include n, 
mean, median, standard deviation, minimum and maximum values. Duration of Response and 
Survival time will be presented using Kaplan-Meier curves with medians calculated if available. 95% 
confidence intervals will be calculated for the median for each of these endpoints. Endpoints based on 
binary outcomes, including post-HSCT outcome measures, will be converted to proportions and 
associated 95% confidence intervals calculated. 
Data collected in this study may be analyzed on multiple occasions as the study proceeds, in order to 
facilitate the development program for NI-0501 and to optimize the dissemination of information 
which may help patient care. The timing and nature of these interim analyses cannot be specified in 
advance and will depend on the numbers of patients recruited into the study and the nature of the 
outcomes seen.  
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.  
For each clinical laboratory test, individual patient values will be listed and summarized and change 
from baseline values calculated and summarized. Any values outside the standard reference ranges 
will be flagged. Summaries of out-of-range values and shift tables will be tabulated for each 
laboratory test. 
All PD data will be summarized using appropriate graphical and tabular presentations. Exploratory 
statistical models may be fitted, and correlation analyses undertaken, to investigate the relationships 
between PD data, other biomarkers and other endpoints recorded in the study. 
Other exploratory analyses of data collected in this study, including summaries for various subsets of 
patients, may also be conducted, including comparisons with appropriate historical data extracted 
from published literature, from external databases, and from other studies, if considered appropriate. 
No imputations of missing data will be performed.   


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 30 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
 
11. ETHICAL AND LEGAL ASPECTS 
11.1. 
GOOD CLINICAL PRACTICE 
The procedures set out in this study protocol pertaining to the conduct, evaluation, and documentation 
of this study are designed to ensure that Sobi AG, its authorised representative, and investigator abide 
by Good Clinical Practice (GCP), as described in International Conference on Harmonization (ICH) 
Guideline E6 and in accordance with the general ethical principles outlined in the Declaration of 
Helsinki. The study will receive approval from an Institutional Review Board (IRB) 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. 
11.2. 
INVESTIGATOR’S 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 have signed an informed consent document to enter the study. Patients not 
participating in the NI-0501-05 study, despite having participated in a previous NI-0501 protocol, 
must have the reason(s) recorded in their source documents and the study participant log. 
In the event that N-0501 treatment needs to be prolonged beyond Week 8, the treating physician has 
to comply with local requirements and regulations. 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/institution should maintain a record of the location(s) of the essential documents 
(which include source documents). The storage system (irrespective of the media used) should 
provide for document identification, search, and retrieval. 
The Investigator should promptly notify Sobi AG or designee of any inspections scheduled by any 
regulatory authorities and promptly forward to Sobi AG copies of any inspection reports received. 
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 
patient’ 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 CRFs and queries. 
11.3. 
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 are most stringent). The document must be in a 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 31 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
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 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’s Trial Master File (TMF). 
After reading and understanding the informed consent document, the patient (or the 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 unless 
specified by local regulations. 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 their TMF. 
11.4. 
CONFIDENTIALITY AND DATA PRIVACY 
Sobi AG affirms the patient's right to protection against invasion of privacy and to be in compliance 
with ICH and other local regulations (whichever is more stringent). Sobi AG requires the Investigator 
to permit Sobi AG representatives and when necessary, representatives from regulatory authorities, to 
review and/or copy any medical records relevant to the study in accordance with local laws (any 
copies of patients’ records must be duly anonymized to protect patients’ confidentiality). 
Should direct access to medical records require a waiver or 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. 
11.5. 
PROTOCOL AMENDMENTS 
Substantial amendments will be submitted to the IRB 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 should specifically reference the 
Principal Investigator’s name, protocol number, study title and amendment number(s) that is/are 
applicable. 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 32 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
11.6. 
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 with a cover letter or a form listing the documents 
submitted, their dates of issue, and the site (or region or area of jurisdiction, as applicable) for which 
approval is sought. If applicable, the documents will also be submitted to the authorities in accordance 
with local legal requirements. 
Sobi AG can initiate the NI-0501-05 study at any site which has already participated in a previous NI-
0501 clinical trial or a CU treatment protocol, as soon as Sobi AG, or their authorized representative, 
has received documentation on all ethical and legal requirements for starting the study at this site. 
Sobi AG can only supply NI-0501 to an Investigator of an initiated site and for patients requiring, as 
per the treating physician’s request, to continue receiving NI-0501 beyond the 8-week treatment in 
study NI-0501-04.  
This documentation must also include a list of the members of the IRB and their occupations and 
qualifications. If the IRB 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 should preferably mention the study title, study code, study site, and any 
other documents reviewed. It must mention the date on which the decision was made and must be 
officially signed by a committee member (chairman or secretary of the IRB). Before the first patient is 
enrolled in the study, all ethical and legal requirements must be met. 
The IRB 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 and, if applicable, between a 
coordinating Investigator and the IRB. This statement also applies to any communication between the 
Investigator (or coordinating Investigator, if applicable) and regulatory authorities. 
Before any documents are given to patients or their legal representative, they must first be reviewed 
and approved by Sobi AG, and upon approval by Sobi AG, submitted to and reviewed and approved 
by the competent IRB. These include but are not limited to the informed consent form, patient 
information sheet, assent form, advertisements, training materials, etc. 
11.7. 
ONGOING INFORMATION FOR IRB 
If required by legislation or the IRB, the Investigator must submit to the IRB: 
 
Information on SAEs or SUSARs, as per local applicable rules and timelines;  
 
Periodic reports on the progress of the study; 
 
Deviations from the protocol or anything that may involve added risk to subjects. 
11.8. 
CLOSURE OF THE STUDY 
Sobi AG reserves the right to terminate this study at any time for reasonable medical or administrative 
reasons. Any premature discontinuation will be appropriately documented according to local 
requirements (e.g. IRB, regulatory authorities). 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 33 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
11.9. 
RECORD RETENTION 
The Investigator will ensure that essential records are kept in a secure archiving facility for the 
retention period stipulated in the study contract. Essential documents include, but are not limited to, 
the following: 
 
Signed informed consent documents for all patients 
 
Patient identification code list, screening log (if applicable), and enrolment log 
 
Record of all communications between the Investigator and the IRB 
 
Composition of the IRB 
 
Record of all communications between the Investigator, Sobi AG and their authorized 
representative 
 
List of sub-investigators and other appropriately qualified persons to whom the Investigator 
has delegated significant trial-related duties, together with their roles in the study, curricula 
vitae and their signatures 
 
Copies of CRFs and of documentation of corrections for all patients 
 
“Drug accountability” records, if applicable 
 
Record of any body fluid or tissue samples retained 
 
All other source documents (patient records, hospital records, laboratory records, etc.) 
 
All other documents as listed in Section 8 of the ICH consolidated guideline on GCP 
(Essential Documents for the Conduct of a Clinical Trial) 
Normally, these records will be held in the Investigator’s archives. If the Investigator is unable to 
meet this obligation, the Investigator must ask Sobi AG for permission to make alternative 
arrangements. Details of these arrangements should be documented in the clinical trial center’s TMF. 
11.10. 
LIABILITY AND INSURANCE 
Liability and insurance provisions for this study are provided in the Investigator contract. 
11.11. 
 FINANCIAL DISCLOSURE 
Investigators are required to provide financial disclosure information to allow Sobi AG to submit 
complete and accurate certification or disclosure statements in accordance with applicable national 
and local regulations. In addition, Investigators must provide Sobi AG with a commitment to 
promptly update this information if any relevant changes occur during the course of the clinical trial 
and for one year following the completion of the study. 
11.12. 
 DISCLOSURE OF PROTOCOL AND STUDY RESULTS AND 
PUBLICATION POLICY 
Information about this trial will be posted following the principles of the International Committee of 
Medical Journal Editors (ICMJE), the International Federation of Pharmaceutical Manufacturers & 
Associations (IFPMA) Industry Position Paper and applicable national or regional regulations and 
laws.  
The results of this study may be published or presented at scientific meetings. If this is foreseen, the 
Investigator agrees to submit all manuscripts or abstracts to Sobi AG prior to submission. This allows 
Sobi AG to protect proprietary information and to provide comments based on information from other 
studies that may not yet be available to the Investigator. 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 34 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
Sobi AG will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, Sobi AG will support publication of multicenter trials only in 
their entirety and not as individual center data. In this case, a coordinating Investigator will be 
designated by mutual agreement prior to the start of the trial. 
Authorship will be determined by mutual agreement and in line with ICMJE authorship requirements. 
Any formal publication of the study in which contribution of Sobi AG personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the Investigator and the 
appropriate Sobi AG personnel. 
So-called ‘ghost writing’ is not permitted. All contributors who do not meet the criteria for authorship 
should be listed in an acknowledgments section. Examples of those who might be acknowledged 
include a person who provided purely technical help, writing assistance, or a department chairperson 
who provided only general support. 
Any inventions and resulting patents, improvements, and/or know-how originating from the use of 
data from this study will become and remain the exclusive and unburdened property of Sobi AG, 
except where agreed otherwise. 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 35 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
 
12. MONITORING AND AUDITING 
All aspects of the study will be monitored by Sobi AG or its representative for this study (Sobi 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 by the Investigator. 
12.1. 
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 
study related documents (e.g. IRB correspondence, investigational product and supplies shipment 
manifests if applicable, monitoring logs, or correspondence with Sobi AG and with any of its 
representatives for this study, etc). 
12.2. 
ON-SITE AUDITS 
Investigators and institutions involved in the study will permit trial-related monitoring, audits, IRB 
review, and domestic or foreign regulatory inspection(s) by providing direct access to source 
documents, CRFs, and all other study documentation. 
12.3. 
SERIOUS GCP BREACHES 
Sobi AG is required to report a serious GCP Breach within 7 days to applicable health authorities. 
Therefore, should an Investigator become aware of a possible serious GCP breach, e.g. a protocol 
violation, or non-reporting of critical safety information that has the potential of jeopardizing patients’ 
safety and/or the scientific value of the study, Sobi AG must be notified within 24 hours. 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 36 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
 
13. DOCUMENTATION AND USE OF STUDY FINDINGS 
13.1. 
DOCUMENTATION OF STUDY RESULTS 
All required information must be entered in the CRFs provided to record data for each subject. 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 in the CRF 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 Sobi AG or their authorized representative before these individuals 
start completing CRF information.  
The CRF pages must be reviewed and signed by the Investigator named in the study protocol or by a 
designated sub-investigator. Sobi AG will ensure that the CRF copies left with the Investigator (print-
outs and/or CD-ROM) have never been under the direct or indirect control of Sobi AG. 
13.2      USE OF COMPUTERIZED SYSTEMS AT THE CLINICAL TRIAL CENTER 
When clinical observations are entered directly into an investigational site’s computerized medical 
record system (i.e. in lieu of original hardcopy records), the electronic record can serve as the source 
document if the system has been validated in accordance with health authority requirements 
pertaining to computerized systems used in clinical research. An acceptable computerized data 
collection system allows preservation of the original entry of data. If original data are modified, the 
system should maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change. 
The system must allow the clinical research associate, auditors or inspectors to verify source data 
without infringing privacy rights of other patients, e.g. access must be restricted to records pertaining 
to the study patients and access to other patients must not be possible. 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 37 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
14. REFERENCES 
 
 1.  Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, 
mechanisms and functions. J.Leukoc.Biol. 2004;75:163-189. 
 2.  Henter JI, Elinder G, Soder O et al. Hypercytokinemia in familial hemophagocytic 
lymphohistiocytosis. Blood 1991;78:2918-2922. 
 3.  Freeman HR, Ramanan AV. Review of haemophagocytic lymphohistiocytosis. Arch.Dis.Child 
2010 
 4.  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;104:735-743. 
 5.  Pachlopnik SJ, Ho CH, Chretien F et al. Neutralization of IFNgamma defeats 
haemophagocytosis in LCMV-infected perforin- and Rab27a-deficient mice. EMBO Mol.Med. 
2009;1:112-124. 
 6.  Xu XJ, Tang YM, Song H et al. Diagnostic accuracy of a specific cytokine pattern in 
hemophagocytic lymphohistiocytosis in children. J.Pediatr. 2012;160:984-990. 
 7.  Risma K, Jordan MB. Hemophagocytic lymphohistiocytosis: updates and evolving concepts. 
Curr.Opin.Pediatr. 2011 
 8.  Takada H, Takahata Y, Nomura A et al. Increased serum levels of interferon-gamma-inducible 
protein 10 and monokine induced by gamma interferon in patients with haemophagocytic 
lymphohistiocytosis. Clin.Exp.Immunol. 2003;133:448-453. 
 9.  Tang Y, Liao C, Xu X et al. Evaluation of Th1/Th2 cytokines as a rapid diagnostic tool for 
severe infection in paediatric haematology/oncology patients by the use of cytometric bead 
array technology. Clin.Microbiol.Infect. 2011;17:1666-1673. 
 10.  Zoller EE, Lykens JE, Terrell CE et al. Hemophagocytosis causes a consumptive anemia of 
inflammation. J.Exp.Med. 2011;208:1203-1214. 
 11.  Tang YM, Xu XJ. Advances in hemophagocytic lymphohistiocytosis: pathogenesis, early 
diagnosis/differential diagnosis, and treatment. ScientificWorldJournal. 2011;11:697-708. 
 12.  Dorman SE, Holland SM. Interferon-gamma and interleukin-12 pathway defects and human 
disease. Cytokine Growth Factor Rev. 2000;11:321-333. 
 13.  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. 
 14.  Remus N, Reichenbach J, Picard C et al. Impaired interferon gamma-mediated immunity and 
susceptibility to mycobacterial infection in childhood. Pediatr.Res. 2001;50:8-13. 
15.  Put, K. et al. Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic 
lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-gamma. 
Rheumatology 54, 1507–1517 (2015). 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 38 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
 16. Bracaglia C. Elevated Circulating Levels of Interferon-Γ and Interferon-Γ-Induced Chemokines 
Characterise Patients with Macrophage Activation Syndrome Complicating Systemic Juvenile 
Idiopathic Arthritis. Ann Rheum Dis. 2017 Jan;76(1):166-172. 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH  
Page 39 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019 
CONFIDENTIAL 
15. APPENDICES 
Appendix A - Schedule of Assessment for patients still continuing NI-0501 treatment 
Appendix B - Investigational Medicinal product administration and handling 
 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH 
Page 40 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
APPENDIX A – SCHEDULE OF ASSESSMENTS FOR PATIENTS STILL CONTINUING NI-0501 TREATMENT 
Assessments 
NI-0501 
infusion visit 
Efficacy/Safety 
visit12 
Follow-Up post NI-0501 completion 
Week 113 
Week 213 
Week 313 
Week 4 or 
Withdrawal13&14 
Unscheduled 
visit (UV) 
Laboratory 
procedures 
Safety1 
 
X 
X 
X 
X 
X 
 
Clinical 
assessment 
Vital signs2 
X 
X 
X 
 X 
X 
X 
X9 
Continuous cardiac 
monitoring/pulse oxymetry3 
X 
 
 
 
 
 
 
Physical Examination4 
X 
X 
X 
X 
X 
X 
X9 
Procedure 
ECG 
X 
at the last infusion 
day only10 
 
 
 
 
X11 
 
Search for 
infections 
TB5, Adenoviruses, EBV, 
CMV6 
 
X  
at least every 2 
weeks 
 
X 
 
X 
 
Imaging 
Chest X-ray 
 
X 
every 3 weeks 
X 
if not performed 
at previous visit 
  
  
X 
 
PK7 
X 
pre and post inf.  
every 2 infusions 
 
 
X 
 
X 
 
PD7, 8 
X 
post inf. 
every 2 infusions 
 
 
X 
 
X 
 
ADA (Immunogenicity) 
 
 
 
 
 
X 
 
 
Please note: timing of the assessments may be adapted/adjusted depending on NI-0501 schedule of administration 
1 = Safety: CBC and hemoglobin; coagulation tests (aPTT, PT, and fibrinogen); inflammatory markers such as CRP and ferritin; biochemistry: glucose, 
triglycerides and liver enzymes, total bilirubin, albumin, creatinine and urea, as well as urinalysis (protein, glucose, blood, ketones, leucocytes, pH and 
specific gravity).  
 
 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH 
Page 41 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
 
2 = Vital signs: Temperature, heart rate, blood pressure, respiratory rate and skin aspect (rash, coloration and sweating). Oxygen saturation at infusion visits 
only. At infusion visit, to be measured pre infusion, during infusion about every 15 minutes until completion of infusion, and 4 hours post infusion. Patients 
can be discharged 4 hours after infusion upon decision of the treating physician.  
3 = Continuous cardiac monitoring/pulse oxymetry: pre infusion, during infusion, and post infusion up to 4 hours after infusion 
4 = Physical Examination: Particular attention paid to height (at last infusion visit and at week 4 or withdrawal visit), weight (at each infusion visit and at 
week 4 or withdrawal visit as well as at unscheduled visits), occurrence of edema or ascites, occurrence of signs of infections (e.g. tonsillitis, 
lymphadenopathies, cough and/or dyspnea), neurological examination, liver and spleen size (in cm from costal grill).  
5 = TB: search for tuberculosis mycobacteria by either PCR in any relevant specimen (e.g. blood, urine, broncho-alveolar lavage, gastric aspirate) or any 
method agreed to be used in the parent protocol or CU treatment protocol at a given site 
6 = Adenoviruses, EBV, CMV: search by quantitative PCR 
7 = PK and PD: sampling times may be adjusted if required  
8 = PD will look at IFNγ circulating levels and potential markers of disease activity (e.g. sCD25, CXCL10, CXCL9, CXCL11, IL-10…). 
9 = Vital signs and physical examination will be performed at minimum, but additional assessments may be added according to the clinical judgment of the 
Investigator. 
10 = ECG: to be done on the last NI-0501 infusion day as long as an ECKG has NOT been performed within the past 4 weeks.  
11 = ECG: to be performed at the Week 4 follow-up visit. In case of withdrawal prior to this Week 4 follow-up visit, an ECG is to be done at the withdrawal 
visit as long as an ECG has NOT been performed within the previous 4 weeks. 
12 = Efficacy/safety visits should occur every 6 days but can be combined with infusion visits, if infusion are separated by no more than 7 days 
13 = Assessments can be performed within 24h before or after the planned time-point during the follow-up Period. If the conditioning starts during the short 
term follow-up period and is not separated by more than 48h from a weekly follow-up visit, then the follow-up visit and the pre conditioning visit may be 
combined and all assessments scheduled for each individual visit should be performed. The same process applies if the Transplant occurs during the short 
term follow-up period. Then the patient will start to be monitored for the long term follow-up period according to the remaining visits to be performed in the 
SOA presented in table 1. 
14 = If a patient withdraws or is withdrawn at any time from the study, he/she will be asked to attend one last visit (i.e. equivalent to Week 4 visit) so that all 
final assessments can be performed. 
 
 
 


Study NI-0501-05 
NI-0501 Long-term Follow-up in HLH 
Page 42 of 42 
Protocol NI-0501-05-US-P-IND#111015 – VERSION 4.0 final – 31 October, 2019   CONFIDENTIAL 
APPENDIX 
B 
- 
INVESTIGATIONAL 
MEDICINAL 
PRODUCT 
(IMP) 
PREPARATION AND HANDLING 
Description of the Investigational Medicinal Product (IMP) 
NI-0501 is a fully human anti-IFNγ monoclonal antibody which binds and neutralizes IFNγ. 
NI-0501 is manufactured by a third party manufacturing facility duly qualified by Sobi AG and supplied to 
study sites in 2 mL-filled and 10 mL-filled single-use glass vials, at a concentration of 5 mg/mL for dilution 
prior to administration. 
The nominal composition of the NI-0501 sterile concentrate for infusion (per mL) is as follows: 
Ingredient 
Quantity (per mL) 
NI-0501 
5 mg 
L-Histidine 
1.55 mg 
L-Histidine monohydrochloride, monohydrate 
3.14 mg 
Sodium chloride (NaCl) 
7.31 mg 
Polysorbate 80  
0.05 mg 
pH 
6.0 ± 0.2 
The solution contains no antimicrobial preservative, and therefore each vial must be used only once. 
Dosing Regimen 
NI-0501 will be administered by infusion over a period of one hour (or more depending on the volume to infuse) 
at a dose either carried forward from the last administered NI-0501 dose as part of the NI-0501 treatment study 
the patient was enrolled in, or at an adjusted dose if necessary and depending on NI-0501 PK profile. 
NI-0501 infusions will be performed at a dose and frequency which will be determined by the Sponsor based on 
the observed PK profile of the drug and on patient’s clinical response. 
IMP Handling 
Packaging and Labeling 
NI-0501 will be supplied to study sites in glass vials. Labeling and packaging will be prepared to meet local 
regulatory requirements. 
IMP Supply 
NI-0501 will be supplied to the study site as open-label supplies. 
IMP Receipt and Storage 
The NI-0501 vials will be transported with temperature deviation alarms (TempTale 4 or equivalent device) in 
order to ensure consistent temperatures during transit.  When the study drug is received at the site, the 
Investigator, Pharmacist or appropriate delegate will check for accurate delivery and absence of temperature 
deviation alarm. 
The study drug is to 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, responsible study monitor or contract research organisation 
(CRO). Affected vials should not be used and quarantined until the Sponsor has authorized their use. 
Regular inspections of the NI-0501 vials are required (please refer to the study specific drug/pharmacy manual 
for more details). 
IMP Preparation, Administration, Accountability and Destruction 
Full instructions for the preparation, administration, accountability and destruction of NI-0501 will be further 
described in a study specific drug/pharmacy manual. 

SAP_001.pdf: 


T a bl e  of  c o nt e nts 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


1   
A b b r e vi ati o ns  a n d  d efi niti o n  of t e r ms 




2   
I nt r o d u cti o n 
 
 
 
 
 


Fi g u r e  1 
O v e r vi e w  of t h e  p ati e nt  c o h o rts i n t h e  NI- 0 5 0 1- 0 5 st u d y 
3  
St u d y  o bj e cti v es  a n d  e n d p oi nts
3. 1  
St u d y  o bj e cti v es


 
 
 
 
 
3. 2   
St u d y  e n d p oi nts 
 
 
 
 
 
 
o  
o  
o  
 
 
 
 


 


T a bl e  1 
St u d y  O bj e cti v es  a n d  E n d p oi nts 
O bj e cti v e
  E n d p oi nts
 
P o p ul ati o n 1 


4   
St u d y  m et h o ds 
4. 1   
O v e r all st u d y  d esi g n  a n d  pl a n 
 
4. 2   
S el e cti o n  of st u d y  p o p ul ati o n 
4. 3   
M et h o d  of t r e at m e nt  assi g n m e nt  a n d  r a n d o mi z ati o n 


5   
S e q u e n c e  of  pl a n n e d  a n al ysis 
5. 1   
I nt e ri m  a n al ys es 
5. 2   
A n al ys es  a n d  r e p o rti n g 
6   
S a m pl e si z e  d et e r mi n ati o n 
7   
A n al ysis  p o p ul ati o ns 
 
 
 


7. 1   P r ot o c ol  d e vi ati o ns 
7. 2   C O VI D- 1 9 
8   
G e n e r al iss u es f o r st atisti c al  a n al ysis 


8. 1   
H a n dli n g  of  missi n g  d at a  a n d  o utli e rs 
8. 2   
M ulti c e nt e r st u di es 
8. 3   
M ulti pl e  c o m p a ris o ns  a n d  m ulti pli cit y 
8. 4   
A n al ysis  visit  wi n d o ws 


8. 5   
D e ri v e d  a n d  c o m p ut e d  v a ri a bl es 
 
o  
 
o  
 
 
 
 
 
 
 
 
 
 


T a bl e  2:  D efi niti o n  of  D r u g   A d mi nist r ati o n  V a ri a bl es 
St atisti cs f o r  E x p os u r e ( d osi n g)
NI- 0 5 0 1- 0 4  a n d  C U 
8. 5. 1   
Effi c a c y  v a ri a bl es:  E n r oll e d- 0 4  c o h o rt 
T a bl e  3:  D efi niti o n  of  R es p o ns e 
C o m pl et e  R es p o ns e
 
 
 
 
 
 
 
P a rti al  R es p o ns e
 
 
H L H i m p r o v e m e nt 
 


 
 
 
 
 
 
 
 
 
 
 
S u r vi v al:  


 
 
 
 
8. 5. 2   
Effi c a c y  v a ri a bl es:  E n r oll e d- 0 6  c o h o rt 
 
o  
o  
o  
o  
o  
 


S u r vi v al: 
9   
P ati e nt  dis p ositi o n 
 
 
 
 
 
1 0   
D e m o g r a p hi cs  a n d  m e di c al  hist o r y 
1 0. 1   
D e m o g r a p hi cs 


1 0. 2   
M e di c al  hist o r y 
1 1   
C o n c o mit a nt  m e di c ati o n 
1 2   
Effi c a c y  a n al ys es 
1 2. 1. 1   
Effi c a c y  a n al ys es:  E n r oll e d- 0 4  c o h o rt 
 


Bi n a r y  e n d p oi nts
  P ost  H S C T  e n g r aft m e nt  r at es: 
  P ost  H S C T  a c ut e  a n d  c h r o ni c  G v H D i n ci d e n c e: 
  D o n o r  c hi m e ris m: 
 
 
1 2. 1. 2   
Effi c a c y  a n al ys es:  E n r oll e d- 0 6  C o h o rt 
 
1 2. 1. 3   
Effi c a c y  a n al ys es:  E n r oll e d- C U  c o h o rt 
 
1 3   
S af et y  a n al ys es 


1 3. 1   
D r u g  e x p os u r e 
1 3. 1. 1   
E n r oll e d- 0 4  c o h o rt 
1 3. 1. 2   
E n r oll e d- 0 6  c o h o rt 
1 3. 1. 3   
E n r oll e d- C U  c o h o rt 
1 3. 2   
A d v e rs e  e v e nts 
 
 
 
 
 


 
 
 
 
 
1 3. 2. 1   
S e ri o us  a d v e rs e  e v e nts 
 
 
 


1 3. 2. 2   
A d v e rs e  e v e nts l e a di n g t o st u d y  d r u g  wit h d r a w al 
1 3. 2. 3   
D e at hs 
1 3. 2. 4   
I nf e cti o ns 
1 3. 3   
L a b o r at o r y  d at a 


1 3. 4   
Vit al si g ns 
1 3. 5   
P h ysi c al  e x a mi n ati o n 
1 3. 6   
P h a r m a c o ki n eti c/ p h a r m a c o d y n a mi c  a n al ysis 
 
 
1 3. 7   
I m m u n o g e ni cit y  –  a nti- d r u g  a nti b o di es ( A D As) 


1 3. 8   
F u rt h e r s af et y  e v al u ati o ns 
 
 
 
 
1 4   
C h a n g es t o  pl a n n e d  a n al ys es 
 
o  
o  
 
1 5   
T a bl es, listi n gs,  a n d fi g u r es 


 


1 6   
R ef e r e n c es 
 
 
 


1 7   
A p p e n di x 
1 7. 1   
Fl o w  di a g r a m f o r  p ati e nts  w h o  e nt e r e d  St u d y  NI- 0 5 0 1- 0 5  m o r e 
t h a n  o n c e 
P ati e n t I D f o r 
A n al ysis  
( e n r oll e d  c o h o rt) 
T e m p o r al  C o u rs e  of  St u d y  P a rti ci p ati o n   
1
  2
 3
 4
 
  
( 0 4  c o h o rt) 
  
( 0 4  c o h o rt) 
  
( 0 4  c o h o rt) 
  
( C U  c o h o rt) 


1 7. 2   
A d v e rs e  e v e nts  cl assifi c ati o n  b y s yst e m  o r g a n  cl ass  a n d  p r ef e r r e d 
t e r m f o r  a c ut e  a n d  c h r o ni c  G v H D  a n d  g r aft f ail u r e 
S yst e m 
O r g a n 
Cl ass  C o d e   S yst e m  O r g a n  Cl ass 
P r ef e r r e d 
T e r m 
C o d e 
  P r ef e r r e d 
 
T e r m 
 
A c ut e  a n d  C h r o ni c  G v H D 
G r aft  F ail u r e 


1 7. 3   
O v e r all  r es p o ns e  d et ail e d  d e ri v ati o n 
T a bl e  4:  H L H  P a r a m et e rs f o r  Ass ess m e nt 
H L H  P a r a m et e r    
V a ri a bl es  Us e d f o r  Ass ess m e nt    D efi niti o n  of  N o r m ali z ati o n 
P ar a m et ers t h at  ar e  m e as ur e d f or i m pr o v e m e nt 
P ar a m et ers t h at  ar e  m e as ur e d f or  w ors e ni n g  of  dis e as e
H L H  P a r a m et e r    
V a ri a bl es  Us e d f o r  Ass ess m e nt 
D efi niti o n  of  W o rs e ni n g


T a bl e  5:  D e ri v ati o n  of  O v e r all  R es p o ns e
R es p o ns e 
A p pli c ati o n  of  C rit e ri a  
E x a m pl e 
-  
-  
-  
-  
-  


R es p o ns e 
A p pli c ati o n  of  C rit e ri a  
E x a m pl e 
-  
-  
-  
-  
-  
-  
-  
-  


1 7. 4   
A d v e rs e  e v e nts i n di c ati n g  o r g a n f ail u r e  b y  M e d D R A  p r ef e r r e d 
t e r m  a n d  c o d e 
P r ef e r r e d  T e r m  C o d e    
P r ef e r r e d  T e r m 


1 7. 5   
C o n c o mit a nt  m e di c ati o ns f o r  H S C T  c o n diti o ni n g 
H S C T  C O N DI TI O NI N G 
C o n diti o ni n g  A g e nts t o  C o nsi d e r [ S D T M. C M] 
A T C  L e v el  4    
P r ef e r r e d  C o d e 
P r ef e r r e d  T e xt 
T h e n: 
-  
-  
-  




C ar b o n  C o p y  E v e nt s
St at u s
Ti m e st a m p
Wit n e s s  E v e nt s
Si g n at ur e
Ti m e st a m p
N ot ar y  E v e nt s
Si g n at ur e
Ti m e st a m p
E n v el o p e  S u m m ar y  E v e nt s
St at u s
Ti m e st a m p s
E n v el o p e  S e nt
H a s h e d/ E n cr y pt e d
3/ 2 9/ 2 0 2 1  4: 5 9: 5 6  P M
C ertifi e d  D eli v er e d
S e c urit y  C h e c k e d
3/ 3 0/ 2 0 2 1  9: 2 2: 5 9  A M
Si g ni n g  C o m pl et e
S e c urit y  C h e c k e d
3/ 3 0/ 2 0 2 1  9: 2 3: 2 6  A M
C o m pl et e d
S e c urit y  C h e c k e d
3/ 3 0/ 2 0 2 1  9: 2 3: 2 6  A M
P a y m e nt  E v e nt s
St at u s
Ti m e st a m p s
El e ctr o ni c  R e c or d  a n d  Si g n at ur e  Di s cl o s ur e


E L E C T R O NI C  R E C O R D  A N D  SI G N A T U R E  DI S C L O S U R E   
Fr o m ti m e t o ti m e,  V erist at ( w e,  us  or  C o m p a n y)  m a y  b e r e q uir e d  b y l a w t o  pr o vi d e t o  y o u 
c ert ai n  writt e n  n oti c es  or  dis cl os ur es.  D es cri b e d  b el o w  ar e t h e t er ms  a n d  c o n diti o ns f or  pr o vi di n g 
t o  y o u s u c h  n oti c es  a n d  dis cl os ur es  el e ctr o ni c all y t hr o u g h t h e  D o c u Si g n s yst e m.  Pl e as e r e a d t h e 
i nf or m ati o n  b el o w  c ar ef ull y  a n d t h or o u g hl y,  a n d if  y o u  c a n  a c c ess t his i nf or m ati o n  el e ctr o ni c all y 
t o  y o ur s atisf a cti o n  a n d  a gr e e t o t his  El e ctr o ni c R e c or d  a n d  Si g n at ur e  Dis c l os ur e ( E R S D),  pl e as e 
c o nfir m  y o ur  a gr e e m e nt  b y s el e cti n g t h e  c h e c k- b o x  n e xt t o ‘I  a gr e e t o  us e  el e ctr o ni c r e c or ds  a n d 
si g n at ur es’  b ef or e  cli c ki n g ‘ C O N TI N U E’  wit hi n t h e  D o c u Si g n s yst e m.  
 
G etti n g  p a p e r  c o pi es   
At  a n y ti m e,  y o u  m a y r e q u est fr o m  us  a  p a p er  c o p y  of  a n y r e c or d  pr o vi d e d  or  m a d e  a v ail a bl e 
el e ctr o ni c all y t o  y o u  b y  us.  Y o u  will  h a v e t h e  a bilit y t o  d o w nl o a d  a n d  pri nt  d o c u m e nts  w e s e n d 
t o  y o u t hr o u g h t h e  D o c u Si g n s yst e m  d uri n g  a n d i m m e di at el y  aft er t h e si g ni n g s essi o n  a n d, if  y o u 
el e ct t o  cr e at e  a  D o c u Si g n  a c c o u nt,  y o u  m a y  a c c e ss t h e  d o c u m e nts f or  a li mit e d  p eri o d  of ti m e 
( us u all y  3 0  d a ys)  aft er s u c h  d o c u m e nts  ar e first s e nt t o  y o u.  Aft er s u c h ti m e, if  y o u  wis h f or  us t o 
s e n d  y o u  p a p er  c o pi es  of  a n y s u c h  d o c u m e nts fr o m  o ur  offi c e t o  y o u,  y o u  will  b e  c h ar g e d  a 
$ 0. 0 0  p er- p a g e f e e.  Y o u  m a y r e q u est  d eli v er y  of s u c h  p a p er  c o pi es fr o m  us  b y f oll o wi n g t h e 
pr o c e d ur e  d es cri b e d  b el o w. 
 
Wit h d r a wi n g  y o u r  c o ns e nt   
If  y o u  d e ci d e t o r e c ei v e  n oti c es  a n d  dis cl os ur es fr o m  us  el e ctr o ni c all y,  y o u  m a y  at  a n y ti m e 
c h a n g e  y o ur  mi n d  a n d t ell  us t h at t h er e aft er  y o u  w a nt t o r e c ei v e r e q uir e d  n oti c es  a n d  dis cl os ur es 
o nl y i n  p a p er f or m at.  H o w  y o u  m ust i nf or m  us  of  y o ur  d e cisi o n t o r e c ei v e f ut ur e  n oti c es  a n d 
dis cl os ur e i n  p a p er f or m at  a n d  wit h dr a w  y o ur  c o ns e nt t o r e c ei v e  n oti c es  a n d  dis cl os ur es 
el e ctr o ni c all y is  d es cri b e d  b el o w. 
 
C o ns e q u e n c es  of  c h a n gi n g  y o u r  mi n d   
If  y o u  el e ct t o r e c ei v e r e q uir e d  n oti c es  a n d  dis cl os ur es  o nl y i n  p a p er f or m at, it  will sl o w t h e 
s p e e d  at  w hi c h  w e  c a n  c o m pl et e  c ert ai n st e ps i n tr a ns a cti o ns  wit h  y o u  a n d  d eli v eri n g s er vi c es t o 
y o u  b e c a us e  w e  will  n e e d first t o s e n d t h e r e q uir e d  n oti c es  or  dis cl os ur es t o  y o u i n  p a p er f or m at, 
a n d t h e n  w ait  u ntil  w e r e c ei v e  b a c k fr o m  y o u  y o ur  a c k n o wl e d g m e nt  of  y o ur r e c ei pt  of s u c h 
p a p er  n oti c es  or  dis cl os ur es.  F urt h er,  y o u  will  n o l o n g er  b e  a bl e t o  us e t h e  D o c u Si g n s yst e m t o 
r e c ei v e r e q uir e d  n oti c es  a n d  c o ns e nts  el e ctr o ni c all y fr o m  us  or t o si g n  el e ctr o ni c all y  d o c u m e nts 
fr o m  us. 
 
All  n oti c es  a n d  dis cl os u r es  will   b e s e nt t o  y o u  el e ct r o ni c all y  


U nl ess  y o u t ell  us  ot h er wis e i n  a c c or d a n c e  wit h t h e  pr o c e d ur es  d es cri b e d  h er ei n,  w e  will  pr o vi d e 
el e ctr o ni c all y t o  y o u t hr o u g h t h e  D o c u Si g n s yst e m  all r e q uir e d  n oti c es,  dis cl os ur es, 
a ut h ori z ati o ns,  a c k n o wl e d g e m e nts,  a n d  ot h er  d o c u m e nts t h at  ar e r e q uir e d t o  b e  pr o vi d e d  or  m a d e 
a v ail a bl e t o  y o u  d uri n g t h e  c o urs e  of  o ur r el ati o ns hi p  wit h  y o u.  T o r e d u c e t h e  c h a n c e  of  y o u 
i n a d v ert e ntl y  n ot r e c ei vi n g  a n y  n oti c e  or  dis cl os ur e,  w e  pr ef er t o  pr o vi d e  all  of t h e r e q uir e d 
n oti c es  a n d  dis cl os ur es t o  y o u  b y t h e s a m e  m et h o d  a n d t o t h e s a m e  a d dr ess t h at  y o u  h a v e  gi v e n 
us.  T h us,  y o u  c a n r e c ei v e  all t h e  dis cl os ur es  a n d  n oti c es  el e ctr o ni c all y  or i n  p a p er f or m at t hr o u g h 
t h e  p a p er  m ail  d eli v er y s yst e m. If  y o u  d o  n ot a gr e e  wit h t his  pr o c ess,  pl e as e l et  us  k n o w  as 
d es cri b e d  b el o w.  Pl e as e  als o s e e t h e  p ar a gr a p h i m m e di at el y  a b o v e t h at  d es cri b es t h e 
c o ns e q u e n c es  of  y o ur  el e cti n g  n ot t o r e c ei v e  d eli v er y  of t h e  n oti c es  a n d  dis cl os ur es 
el e ctr o ni c all y fr o m  us. 
 
H o w t o  c o nt a ct  V e rist at:   
Y o u  m a y  c o nt a ct  us t o l et  us  k n o w  of  y o ur  c h a n g es  as t o  h o w  w e  m a y  c o nt a ct  y o u  el e ctr o ni c all y, 
t o r e q u est  p a p er  c o pi es  of  c ert ai n i nf or m ati o n fr o m  us,  a n d t o  wit h dr a w  y o ur  pri or  c o ns e nt t o 
r e c ei v e  n oti c es  a n d  dis cl os ur es  el e ctr o ni c all y  as f oll o ws: 
T o  c o nt a ct  us  b y  e m ail s e n d  m ess a g es t o:
 
T o  a d vis e  V e rist at  of  y o u r  n e w  e m ail  a d d r ess   
T o l et  us  k n o w  of  a  c h a n g e i n  y o ur  e m ail  a d dr ess  w h er e  w e s h o ul d s e n d  n oti c es  a n d  dis cl os ur es 
el e ctr o ni c all y t o  y o u,  y o u  m ust s e n d  a n  e m ail  m ess a g e t o  us  at 
a n d 
i n t h e  b o d y  of s u c h r e q u est  y o u  m ust st at e:  y o ur  pr e vi o us  e m ail  a d dr ess,  y o ur  n e w  e m ail 
a d dr ess.   W e  d o  n ot r e q uir e  a n y  ot h er i nf or m ati o n fr o m  y o u t o  c h a n g e  y o ur  e m ail  a d dr ess.  
If  y o u  cr e at e d  a  D o c u Si g n  a c c o u nt,  y o u  m a y  u p d at e it  wit h  y o ur  n e w  e m ail  a d dr ess t hr o u g h  y o ur 
a c c o u nt  pr ef er e n c es.  
 
T o  r e q u est  p a p e r  c o pi es f r o m  V e rist at   
T o r e q u est  d eli v er y fr o m  us  of  p a p er  c o pi es  of t h e  n oti c es  a n d  dis cl os ur es  pr e vi o usl y  pr o vi d e d 
b y  us t o  y o u  el e ctr o ni c all y,  y o u  m ust s e n d  us  a n  e m ail t o
a n d i n 
t h e  b o d y  of s u c h r e q u est  y o u  m ust st at e  y o ur e m ail  a d dr ess, f ull  n a m e,  m aili n g  a d dr ess,  a n d 
t el e p h o n e  n u m b er.  W e  will  bill  y o u f or  a n y f e es  at t h at ti m e, if  a n y. 
 
T o  wit h d r a w  y o u r  c o ns e nt  wit h  V e rist at   
T o i nf or m  us t h at  y o u  n o l o n g er  wis h t o r e c ei v e f ut ur e  n oti c es  a n d  dis cl os ur es i n  el e ctr o ni c 
f or m at  y o u  m a y: 


i.  d e cli n e t o si g n  a  d o c u m e nt fr o m  wit hi n  y o ur si g ni n g s essi o n,  a n d  o n t h e s u bs e q u e nt  p a g e, 
s el e ct t h e  c h e c k- b o x i n di c ati n g  y o u  wis h t o  wit h dr a w  y o ur  c o ns e nt,  or  y o u  m a y; 
ii. s e n d  us  a n  e m ail t o
a n d i n t h e  b o d y  of s u c h r e q u est  y o u  m ust 
st at e  y o ur  e m ail, f ull  n a m e,  m aili n g  a d dr ess,  a n d t el e p h o n e  n u m b er.  W e  d o  n ot  n e e d  a n y  ot h er 
i nf or m ati o n fr o m  y o u t o  wit h dr a w  c o ns e nt..   T he  c o ns e q u e n c es  of  y o ur  wit h dr a wi n g  c o ns e nt f or 
o nli n e  d o c u m e nts  will  b e t h at tr a ns a cti o ns  m a y t a k e  a l o n g er ti m e t o  pr o c ess.. 
 
R e q ui r e d  h a r d w a r e  a n d s oft w a r e   
T h e  mi ni m u m s yst e m r e q uir e m e nts f or  usi n g t h e  D o c u Si g n s yst e m  m a y  c h a n g e  o v er ti m e.  T h e 
c urr e nt s yst e m r e q uir e m e nts  ar e f o u n d  h er e:  htt ps://s u p p ort. d o c usi g n. c o m/ g ui d es/si g n er- g ui d e-
si g ni n g-s yst e m-r e q uir e m e nts .  
 
A c k n o wl e d gi n g  y o u r  a c c ess  a n d  c o ns e nt t o  r e c ei v e  a n d si g n  d o c u m e nts  el e ct r o ni c all y   
T o  c o nfir m t o  us t h at  y o u  c a n  a c c ess t his i nf or m ati o n  el e ctr o ni c all y,  w hi c h  will  b e si mil ar t o 
ot h er  el e ctr o ni c  n oti c es  a n d  dis cl os ur es t h at  w e  wi ll  pr o vi d e t o  y o u,  pl e as e  c o nfir m t h at  y o u  h a v e 
r e a d t his  E R S D,  a n d (i) t h at  y o u  ar e  a bl e t o  pri nt  o n  p a p er  or  el e ctr o ni c all y s a v e t his  E R S D f or 
y o ur f ut ur e r ef er e n c e  a n d  a c c ess;  or (ii) t h at  y o u  ar e  a bl e t o  e m ail t his  E R S D t o  a n  e m ail  a d dr ess 
w h er e  y o u  will  b e  a bl e t o  pri nt  o n  p a p er  or s a v e it f or  y o ur f ut ur e r ef er e n c e  a n d  a c c ess.  F urt h er, 
if  y o u  c o ns e nt t o r e c ei vi n g  n oti c es  a n d  dis cl osur es  e x cl usi v el y i n  el e ctr o ni c f or m at  as  d es cri b e d 
h er ei n, t h e n s el e ct t h e  c h e c k- b o x  n e xt t o ‘I  a gr e e t o  us e  el e ctr o ni c r e c or ds  a n d si g n at ur es’  b ef or e 
cli c ki n g ‘ C O N TI N U E’  wit hi n t h e  D o c u Si g n s yst e m.  
B y s el e cti n g t h e  c h e c k- b o x  n e xt t o ‘I  a gr e e t o  us e  el e ctr o ni c r e c or ds  a n d si g n at ur es’,  y o u  c o nfir m 
t h at: 
 
Y o u  c a n  a c c ess  a n d r e a d t his  El e ctr o ni c  R e c or d  a n d  Si g n at ur e  Dis cl os ur e;  a n d 
 
Y o u  c a n  pri nt  o n  p a p er t his  El e ctr o ni c  R e c or d  a n d  Si g n at ur e  Dis cl os ur e,  or s a v e  or s e n d 
t his  El e ctr o ni c  R e c or d  a n d  Dis cl os ur e t o  a l o c ati o n  w h er e  y o u  c a n  pri nt it, f or f ut ur e 
r ef er e n c e  a n d  a c c ess;  a n d 
 
U ntil  or  u nl ess  y o u  n otif y  V erist at  as  d es cri b e d  a b o v e,  y o u  c o ns e nt t o r e c ei v e  e x cl usi v el y 
t hr o u g h  el e ctr o ni c  m e a ns  all  n oti c es,  dis cl os ur es,  a ut h ori z ati o ns,  a c k n o wl e d g e m e nts,  a n d 
ot h er  d o c u m e nts t h at  ar e r e q uir e d t o  b e  pr o vi d e d  or  m a d e  a v ail a bl e t o  y o u  b y  V erist at 
d uri n g t h e  c o urs e  of  y o ur r el ati o ns hi p  wit h  V erist at.