An Observational, Multicenter Study to Evaluate Levels of Interferon Gamma (IFNγ) and Other Inflammatory Mediators in Adult Patients With Hemophagocytic Lymphohistiocytosis (A-HLH)
Conditions: Hemophagocytic Lymphohistiocytoses
Sponsor: Swedish Orphan Biovitrum

Official Title: 
An observational, multicenter study to evaluate levels of 
Interferon gamma (IFNγ) and other inflammatory mediators 
in Adult Patients with Hemophagocytic Lymphohistiocytosis 
(AHLH) 
NCT Number: 
N/A 
Document Date: 
11-Jun-2016 
 

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Protocol NI-0501-08 Version 1.0, dated 18 April 2016 
 
An observational, multicenter study to evaluate levels of  
Interferon gamma (IFN ) and other inflammatory mediators  
in Adult Patients with Hemophagocytic Lymphohistiocytosis (A-
HLH) 
 
 
Protocol number: 
NI-0501-08 
Version: 
Version 1.0 
Date: 
11 June 2016 
Sponsor: 
NovImmune S.A. 
14 Chemin des Aulx 
1228 Plan-les-Ouates 
Switzerland 
Principal Investigator: 
Nancy Berliner, M.D.  
Chief, Division of Hematology  
Brigham and Women's Hospital  
Professor of Medicine 
Harvard Medical School 
Mid-Campus 3  
75 Francis Street, Boston, MA 02115 
Confidentiality Agreement 
This document is a confidential communication of NovImmune S.A. 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constitutes the agreement by the recipient that no unpublished information contained within will be 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. 
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Contact list 
 
Investigator: 
Nancy Berliner, MD  
Brigham and Women's Hospital  
Boston  
Sponsor: 
Novimmune S.A. 
14 Chemin des Aulx 
1228 Plan les Ouates 
Switzerland 
Novimmune staff: 
 
 
 
 
 
Clinical Science Leader (primary contact): 
 
 
Phone: 
 
Email: 
 
 
 
 
Phone: 
 
Email: 
 
 
Exploratory Science and Translational Medicine 
Head: 
 
 
 
 
Phone: 
 
Email: 
 
 
Data Management: 
 
Phone: 
 
Email: 
 
 
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Protocol signature page 
 
Name 
Signature 
Date 
On behalf of Novimmune: 
 
  
 
 
Investigator: 
Nancy Berliner, MD 
 
 
 
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Table of Contents 
Contact list .................................................................................................................................... 2 
Protocol signature page ................................................................................................................. 3 
Table of Contents .......................................................................................................................... 4 
Background and Rationale ............................................................................................................ 5 
Study Title ..................................................................................................................................... 9 
Study Code .................................................................................................................................... 9 
Study Objectives: .......................................................................................................................... 9 
Sample Size: .................................................................................................................................. 9 
Study Population: .......................................................................................................................... 9 
Inclusion Criteria: ......................................................................................................................... 9 
Study Design and Procedures: ..................................................................................................... 10 
Study Duration: ........................................................................................................................... 11 
Parameters: ................................................................................................................................. 11 
Statistical Analysis: ..................................................................................................................... 12 
Medications: ................................................................................................................................ 12 
Informed consent: ....................................................................................................................... 13 
Data collection and patient confidentiality: ................................................................................. 13 
Study administration: .................................................................................................................. 13 
References ................................................................................................................................... 16 
 
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Background and Rationale 
HLH and rationale for targeting Interferon gamma (IFN )  
HLH is a syndrome of severe immune activation and deregulation characterized by hyperactive 
macrophages and lymphocytes, pro-inflammatory cytokine hypersecretion, hemophagocytosis, 
and tissue and organs damage. HLH occurs as either a primary (pHLH, familial) or secondary 
(sHLH, sporadic) disorder (Henter et al., 1998; Janka, 1983).  
Primary HLH is an autosomal recessive disease with an incidence of 1/50,000 live-born children 
(Henter et al. 1991; Arico et al. 1996). pHLH typically presents in the first years of life with or 
without a positive family history. It is caused by homozygous mutations in the genes coding for 
perforin, Munc13-4, Syntaxin 11, Munc18-2 and other proteins involved in cytotoxic granule 
activation, polarization, priming, fusion, or function  (Jordan et al., 2011; Zhang et al.,  2014). 
These mutations result in impaired cytotoxic function, and lead to an uncontrolled inflammatory 
response with activation of histiocytes, and pathognomic clinical manifestations of HLH.  
Secondary HLH has been generally reported to occur as a result of pathological immune 
activation in response to a trigger, in the absence of homozygous mutations in known HLH 
causative genes. It can occur in children or adults, typically in a setting of malignancies, 
infections or autoimmune disorders (Dhote et al., 2003; Rouphael et al., 2007; Li et al., 2014; 
Rivière et al., 2014). 
In recent years, an apparent inexplicable rise in the reported cases of HLH has been observed 
especially in the adult population, although the incidence of HLH in adults is still unknown 
(Schram and Berliner, 2015).     
Case series from the United States (Parikh et al., 2014), France (Rivière et al., 2014), Japan 
(Takahashi N et al., 2001) and China (Li et al., 2014) all reported that the majority of adult 
patients had a malignancy (commonly non-Hodgkin lymphoma and acute leukemia), with 
infections (mostly EBV) being the second more frequent triggers. Rheumatologic diseases, 
namely adult-onset Still disease (AOSD) and systemic lupus erythematosus (SLE), were also 
reported and, of note, in a consistent proportion of patients (ranging from 6% up to 23%) no 
trigger could be identified and HLH was defined of unknown origin or idiopathic.  
When HLH occurs in the setting of a rheumatologic disease, HLH is usually termed macrophage 
activation syndrome (MAS). Reports have recently described patients who developed MAS on 
the background of systemic juvenile idiopathic arthritis (sJIA), but were identified to be 
heterozygous for rare variants in the primary HLH-associated genes (Zhang et al., 2014) 
highlighting potential etiological, clinical, and pathological similarities between familial and 
acquired forms of HLH. A link between mutations in the perforin gene and predisposition to 
hematological malignancies has also been described (Clementi et al., 2005; Zhang et al., 2014). 
Although pHLH and sHLH have historically been considered separate entities, it is now thought 
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that overlaps between primary and secondary forms is more than previously recognized 
(Voskoboinik et al, 2013; Lehmberg 2015).  
The presentation of sHLH is clinically the same as pHLH and the HLH-2004 diagnostic criteria 
developed for primary forms (Henter et al., 2007) generally apply. Acute clinical signs and 
symptoms of immune activation including fever, spleno/hepatomegaly, adenopathy, rash are 
accompanied by high serum levels of pro-inflammatory cytokines including interferon gamma 
(IFN ), tumor necrosis factor  (TNF- ), interleukin 6 (IL-6), IL-10, and macrophage colony-
stimulating factor (M-CSF) (Akashi et al., 1994; Ohga et al., 1993). Furthermore, biopsies of 
lymphoid tissues or histological examination of liver tissue from HLH patients reveal highly 
activated macrophages and lymphocytes, further supporting striking activation of the immune 
system. Therefore, categorizing patients into primary or secondary HLH based on clinical 
manifestations is often difficult and may be of limited value. Treatment should be initiated 
expeditiously if the diagnosis of HLH is suspected, regardless of the classification/trigger, in 
order to control the overactive immune system and to halt any underlying trigger.  
Secondary forms of HLH in adults are reported to carry a significant mortality rate, with the 
worse prognosis for patients with malignancy-associated HLH. In a series of 103 adult patients 
(Li et al., 2014), among patients with malignancy-related HLH only 20.4% of patients survived, 
among patients with infection-related HLH survival was 33% (but none of patients with bacterial 
infections survived), in autoimmune-related HLH survival was 43%. In 24 patients HLH was of 
unknown origin and outcome was very poor with only 4 patients achieving clinical improvement 
and surviving. 
Although statistics are limited by the small number of cases, case series of adults treated with 
different regimens report an overall mortality rate from 40% to 75% (Takahashi N et al., 2001; 
Shabbir et al., 2011; Park et al., 2012; Parikh et al., 2014; Ramos-Casals et al., 2014; Arca et al, 
2015).  
The therapeutic approach to adult HLH is matter of discussion, since no prospective multicenter 
studies have been conducted so far. Generally, treatment of adult HLH has been based on the 
HLH-94 study, the only published prospective study conducted in children with HLH. However, 
the complex etiology and the inducing triggers need to be considered in the selection of the 
treatment regimen. As an example, it is yet unclear if immunosuppressive regimens, such as 
etoposide, dexamethasone, alemtuzumab, are suitable depending of the different underlying 
causes of HLH in adults (e.g., history of immunosuppression, presence of infective triggers). 
Furthermore, although short-term immunosuppressive regimens may control the excessive 
inflammatory status, they may not be tolerated if the therapy needs to be prolonged while 
assessing the long-term strategy with regard to potential hematopoietic stem cell transplantation. 
The availability of new agents, ideally non-immunosuppressive, would be of great value to 
improve the therapeutic armamentarium to tackle this severe and increasingly diagnosed disease 
in adult patients.    
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NI-0501 is a fully human anti-
. NovImmune is developing NI-0501 as the first targeted therapy for HLH. 
Several lines of evidence support the relevance of IFN  as a target in HLH: 
1. Two animal models of pHLH and two animal models of sHLH have been investigated: 
Perforin knockout mice and Rab27-deficient mice develop all the diagnostic and many of 
the clinical and laboratory characteristics of human primary HLH when infected with 
lymphocytic choriomeningitis virus (LCMV) as a trigger. Neutralization of the high 
in both animal models led to the reversal of HLH clinical and 
laboratory abnormalities, and dramatically improved survival in the animal model 
characterized by high mortality (pfp -/-  mice) (Pachalopnik Schmid et al., 2009, Jordan et 
al., 2004).  
Repeated administration of CpG, causing TLR9 stimulation, has been used to mimic a 
chronic severe hyperstimulation in healthy mice as a model of HLH secondary to 
infection. Although these mice do not necessarily die, they develop typical clinical and 
laboratory features of HLH (Behrens et al., 2011). Administration of an anti-
antibody led to reversal of clinical and laboratory features of HLH. Importantly, in this 
model it was demonstrated that administration of the anti-
 to full 
Buatois 
et al, submitted). 
An animal model has been generated using IL-6 transgenic mice expressing high levels of 
IL-6, to mimic what occurs in patients with sJIA. When triggered with TLR ligands, these 
mice die with many of the features of the human HLH (Stippoli et al. 2012). In these 
mice, when 
 neutralized by administration of an anti-
was markedly improved and HLH laboratory parameters reverted. 
In conclusion, in all presented animal 
has been shown to be a key 
pathological effector in disease onset and progression. 
2. Primary and secondary HLH patients have hypercytokinemia with elevated levels of several 
pro-
 (Henter et al., 1991; Janka et al., 1998; Xu et al. 
2012). Mor
secondary to infections and in sJIA patient developing MAS (Buatois et al., manuscript 
submitted; Bracaglia et al. manuscript submitted). The levels of CXCL9, CXCL10 and 
-inducible chemokines were found to significantly 
correlate with laboratory parameters of disease severity, such as ferritin, platelet count and 
transaminases. 
3.
An international multicenter study is presently ongoing to evaluate the efficacy and safety of 
treatment with NI-0501 in pHLH in children and young adults. Based on data gathered so 
far, NI-0501 treatment has been well tolerated and has shown a favorable impact on relevant 
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clinical and laboratory features of HLH such as fever, splenomegaly, cytopenia, 
hyperferritinemia, hypofibrinogenemia, and also CNS signs/symptoms (Jordan et al, 2015). 
The numerous pathophysiological and clinical features shared by primary HLH and HLH 
secondary to inflammatory/autoimmune diseases or infections strongly suggests that IFN
may 
play a key role in adult HLH (Brisse et al., 2015).  
Objectives and brief outline of the study  
The present observational study is designed to provide a better understanding of IFN  and IFN -
inducible chemokines as markers of HLH disease activity in adults, and of the potential of IFN  
to represent a therapeutic target in this patient population. 
Adult patients ( 18 years old) are eligible, if having consented to the use of their clinical data for 
research purposes.  
Clinical data and sample collection may be performed either retrospectively (provided that 
sufficient clinical information is available to allow for a meaningful interpretation of the 
biomarker results) and prospectively. 
If retrospective cases are evaluated, the presence of a malignancy and the diagnosis of primary 
HLH (defined as homozygous mutation in a known HLH causative gene) represent exclusion 
criteria for the study. On the contrary, if prospective patients are considered, inclusion in the 
study may occur before the diagnostic work-up has been completed. In case the diagnosis of 
malignancy-related HLH or primary HLH (as above defined) is made, the data collected will be 
analyzed separately. In particular, malignancy-HLH cases will be considered in the parallel 
observational protocol NI-0501-07. 
The present study will be conducted in the United States and in Europe, until the required number 
of patients has been recruited.        
The detailed study outline is presented below. 
 
 
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Study Title 
An observational, multicenter study to evaluate Interferon gamma 
(IFN ) and other inflammatory mediators  in Adult  Patients with 
Hemophagocytic Lymphohistiocytosis (A-HLH) 
Study Code 
NI-0501-08 
Study Objectives: 
To determine the levels of inflammatory markers including, but 
not limited to interferon gamma (IFN ), interleukin 1 beta (IL-
1 ), interleukin 6 (IL-6), interleukin 10 (IL-10), interleukin 17 
(IL-17), interleukin 18 (IL-18), soluble IL-2 Receptor  (sCD25), 
C-X-C chemokine ligand 9 (CXCL9), C-X-C chemokine ligand 
10 (CXCL10), C-X-C chemokine ligand 11 (CXCL11), soluble 
CD163 (sCD163), neopterin and Tumor Necrosis Factor alpha 
(
) in adult patients diagnosed with HLH and whenever 
possible, to monitor the evolution over time of these markers. 
To assess the relationship between the above mentioned
inflammatory cytokines and disease activity. 
To explore the presence of genetic variants of the genes typically
causing primary HLH in these patients and any association with 
the course of the HLH disease. 
Sample Size: 
A minimum of 14 (maximum of 40) adult patients with HLH will be 
studied, including a minimum of 7 patients with HLH of unknown 
origin (i.e. in whom a trigger for HLH cannot be identified).  
Retrospective patients may be considered with no limitation in their 
number, provided that sufficient medical history and clinical 
information is available. 
Study Population: 
Male and female adult ( 18 years old) patients who are diagnosed 
with HLH and meet the inclusion criteria listed below.  
Inclusion Criteria: 
 
 
1. Patients 18 years old diagnosed with active HLH as established 
by the treating physician.  
2. HLH forms of unknown origin or secondary to infections or
rheumatologic disorders.  
3. Primary HLH (diagnosed by the presence of homozygous 
mutations in a known HLH causative gene) and secondary HLH 
due to malignancy are excluded; should the diagnosis of pHLH 
or malignancy become apparent after inclusion, the data 
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collected will be analysed separately as additional cohorts. 
4. The patient must have consented to the use of their clinical data 
for research purposes at the site. 
Study Design and 
Procedures: 
This is a non-interventional study designed to determine the levels of 
pro-inflammatory markers (as listed above) in adult patients 
diagnosed with HLH and to assess the relationship between the 
biomarkers and disease activity. Whenever possible, the evolution of 
inflammatory markers will be followed during HLH treatment and 
the relationship with the disease outcome explored.  
Data collection may be performed retrospectively if sufficient 
clinical information is available to allow for a meaningful 
interpretation of the biomarker results. 
For biomarker analysis, a maximum of 5 ml of whole blood will be  
required per time point. Details on sample processing and shipment 
will be described in a separate brief laboratory manual provided to 
the site. Whenever possible, serum (and not plasma) should be 
obtained for shipment, as this is the preferred matrix for the 
biomarker analysis. 
Relevant clinical information gathered by the treating physician will 
be collected in a data collection form. This will include information 
on the clinical presentation of HLH, the assessments performed to 
characterize the secondary form, in particular those for identification 
of the potential HLH trigger, the date of onset of the background 
disease (if any) in relation to HLH manifestations, treatment regimen 
prior to and/or ongoing at the time of HLH onset, clinical and 
laboratory parameters relevant to HLH, specific HLH therapy with 
best response to the therapy, other concomitant medications, patient 
follow-up and disposition, stem cell transplant status, duration of 
response, and survival. As appropriate, collection of serum samples 
for biomarker analysis and relevant information should occur at 
HLH diagnosis, and at regular time intervals during the treatment 
course (not more than once a week) up to resolution of HLH. 
If patients present CNS involvement and lumbar puncture is being 
performed for diagnostic or therapeutic purposes, a CSF sample will 
be collected, if possible, for biomarker assessment, in particular 
CXCL9 and CXCL10. 
If feasible and consistent with the standard clinical practice at the 
site, genetic characterization will be performed. A specific consent 
for genetic testing must be given by the patient. Genetic samples 
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may also be collected from existing bank of samples (frozen whole 
blood in EDTA or frozen extracted DNA), if 
consent
has been previously obtained.  
Medical history, in particular all available information on search 
conducted for the identification of the potential HLH trigger needs to 
be collected. 
Study Duration: 
This study will gather information on adult HLH patients at
diagnosis and, as available, during treatment of the disease up to 
HLH resolution, and will last until completion of the planned 
recruitment. 
Parameters: 
1. Laboratory parameters, at the time of HLH diagnosis, to be 
assessed at the site laboratory, such as: 
Hemoglobin, Hematocrit, red blood cells, white blood cells
and differential count, platelets 
Fibrinogen 
Ferritin  
Fasting triglycerides 
AST, ALT, Alkaline Phosphatase 
BUN, serum creatinine  
Albumin 
Sodium (if available) 
Beta2 microglobulin (if available) 
Serum IgG levels (if available) 
Lactate dehydrogenase 
Total and conjugated Bilirubin  
D-dimers 
PT, aPTT 
CRP 
Functional tests, such as perforin expression and NK-cell 
activity (if performed)  
Results of additional tests performed for 
follow-up 
at regular time intervals during the treatment course (not more 
than once a week) up to resolution of HLH will be recorded, as 
available. 
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2. Other relevant parameters, at the time of sample collection, in 
particular body temperature, spleen and liver size (if available), 
findings in bone marrow biopsy. 
3. Inflammatory markers of disease activity. The following
assessments will include but not be limited to: 
IFN  
sCD25 
IL-1 , IL-6, IL-10, IL-17 IL-18 
 
CXCL9, CXCL10, CXCL11 
sCD163 and neopterin 
These tests will be performed at Novimmune Bioanalytical 
Laboratory and results will be 
treating physician and to the patient. 
4. Medical history, in particular any available additional 
information on the background disease considered to be the 
potential trigger of HLH, e.g.:   
Infections (including viral load, bacterial and/or fungal 
search) 
Rheumatologic diseases 
Statistical Analysis: 
All analyses are exploratory. Statistical analyses of the data collected 
in this study will be focused on providing tabular and graphical 
summaries of the levels of inflammatory markers and of the clinical 
features of the disease both at diagnosis and during the course of 
treatment. The degree of correlation between inflammatory markers,
and between inflammatory markers and the severity of clinical 
manifestations, response to therapy, and survival of the patients will 
be assessed. Analyses may also be performed to study these
relationships in various subgroups of patients, depending on the 
demographic, genetic and clinical characteristics observed (notably, 
HLH of unknown origin representing a specific subgroup of interest).
An a posteriori diagnostic classification of patients will be done, 
whenever possible, based on HLH-2004 diagnostic criteria (Henter et 
al., 2007) and HScore (Fardet et al., 2014).  
Medications: 
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welfare are given based on the decision of the treating physician. 
Informed consent: 
 
It is the responsibility of the investigator to obtain written informed 
consent from each patient participating in this study, after adequate 
explanation of the aims, methods and potential hazards of the study. 
An additional signature will be requested specifically for genetic 
analyses. 
Patients may withdraw their consent at any time; it is the
responsibility of the investigator to contact the sponsor for specific 
patient withdrawal of consent while maintaining the confidentiality 
by communicating only patient codes. The sponsor will proceed with 
the destruction of all left over patient material within 12 months. The 
sponsor will also inform and request confirmation from potential 
collaborators to destroy aliquots that may have been transferred 
under collaboration agreements for the purpose of the research 
described in this protocol. The data generated prior withdrawal of 
consent will be maintained. 
Data collection and 
patient confidentiality: 
Relevant clinical information including date of diagnosis, medical 
history and previous and current treatments will be gathered by the 
treating physician. 
maintained and that their identities are protected from unauthorized 
parties. On Data Collection Forms or other documents or material 
submitted to the sponsor, patients should not be identified by their 
names, but by an identification code.  
An electronic data capture will be used for data collection in this 
observational study, and a specific CRF will correspond to each 
subject. 
Novimmune 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). 
Study administration: 
 
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 
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Subject identification codes 
Record of all communications between the investigator and 
the IRB/IEC 
Composition of the IRB/IEC 
Record of communications between the investigator, 
Novimmune and their authorised representative 
These records will be held in the 
Investigator is unable to meet this obligation, the Investigator must 
ask Novimmune for permission to make alternative arrangements.  
Financial Disclosure 
 
Investigator is required to provide financial disclosure information to 
allow Novimmune to submit complete and accurate certification or 
disclosure statements in accordance with applicable national and 
local regulations upon request. In addition, investigator must provide 
Novimmune with a commitment to promptly update this information 
if any relevant changes occur during the course of the investigation 
and for 1 year following the completion of the study. 
Disclosure of Protocol and Study Results and Publication Policy 
Publication or communication of results will be decided upon 
completion of the study or earlier if data are considered sufficiently 
novel and robust. NovIimune will comply with the requirements for 
publication of results involving human research.  
Authorship will be determined by mutual agreement and in line with 
ICMJE authorship requirements. Any formal publication of the study 
in which contribution of Novimmune personnel exceeded that of 
conventional monitoring will be considered as a joint publication by 
the investigator and the appropriate Novimmune personnel. 
So-
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 Novimmune, 
except where agreed otherwise. 
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Study NI-0501-08 CSR_App 5.1.1 Study protocol
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Monitoring and Auditing 
As the aim of this study is mainly to test blood for research purpose 
no specific monitoring at site is foreseen by Novimmune. However 
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 to any audit or inspections. 
 
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Study NI-0501-08 CSR_App 5.1.1 Study protocol
Title:
Name:
DS-2021-023-8912
2021-12-06 15:50:48
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1.0
Study NI-0501-08 CSR_App 5.1.1 Study protocol
Title:
Name:
DS-2021-023-8912
2021-12-06 15:50:48
Version:
Exported date and time:
Approved on
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Approved