A Phase 2 Randomized Double-Blinded Placebo-Controlled Study to Evaluate the Safety and Efficacy of Subcutaneous Sarilumab in Improving the Quality of Life in Subjects With Indolent Systemic Mastocytosis
Phase: PHASE2
Conditions: Indolent Systemic Mastocytosis
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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A Phase 2 Randomized Double-Blinded Placebo-Controlled Study to Evaluate the Safety 
and Efficacy of Subcutaneous Sarilumab in Improving the Quality of Life in Subjects with 
Indolent Systemic Mastocytosis 
NIH Protocol Number: 19-I-0027 
Investigational New Drug (IND) Sponsored by: 
Office of Clinical Research Policy and Regulatory Operations (OCRPRO) 
Division of Clinical Research (DCR) 
National Institute of Allergy and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
Pharmaceutical Support Provided by: 
 
Sanofi US Services Inc./Genzyme Corporation 
50 Binney St. 
Cambridge, MA 02142 
Attn: Global Medical Operations 
  
IND Number: 140983 
Principal Investigator (PI):  
Hirsh Komarow, MD 
Laboratory of Allergic Diseases (LAD), NIAID, NIH 
Building 10 Room 6D44A 
10 Center Drive 
Bethesda, MD 20814 
301-594-2197 
komarowh@mail.nih.gov  
Version Number: 6.0 
Date: 18 Nov 2020 
 
 

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Table of Contents 
 
List of Figures ................................................................................................................................. 4 
List of Tables .................................................................................................................................. 4 
List of Abbreviations ...................................................................................................................... 5 
Protocol Summary .......................................................................................................................... 7 
Précis ........................................................................................................................................... 10 
1 
Background Information and Scientific Rationale ........................................................... 11 
 
Background on Mastocytosis ......................................................................................... 11 
 
Sarilumab ....................................................................................................................... 12 
 
Scientific Rationale ........................................................................................................ 12 
2 
Study Objectives ............................................................................................................... 12 
 
Primary Objective .......................................................................................................... 12 
 
Secondary Objectives ..................................................................................................... 12 
 
Exploratory Objectives ................................................................................................... 13 
3 
Study Design ..................................................................................................................... 13 
 
Description of the Study Design .................................................................................... 13 
 
Study Endpoints ............................................................................................................. 14 
 
Primary Endpoints ................................................................................................ 14 
 
Secondary Endpoints ............................................................................................ 14 
 
Exploratory Endpoints .......................................................................................... 14 
4 
Study Population ............................................................................................................... 14 
 
Recruitment Plan ............................................................................................................ 14 
 
Participant Inclusion Criteria ......................................................................................... 15 
 
Participant Exclusion Criteria ........................................................................................ 16 
 
Justification for Exclusion of Special Populations ......................................................... 17 
5 
Study Agent/Interventions ................................................................................................ 17 
 
Disposition and Dispensation ......................................................................................... 17 
 
Formulation, Packaging, and Labeling ................................................................. 17 
 
Study Agent Storage and Stability ................................................................................. 17 
 
Randomization and Blinding/Unblinding Procedures ................................................... 17 
 
Emergency Unblinding ......................................................................................... 18 
 
Preparation, Administration, and Dosage of Sarilumab and Placebo ............................ 18 
 
Study Product Accountability Procedures...................................................................... 19 
 
Concomitant Medications and Procedures ..................................................................... 19 
 
Prohibited Medications and Procedures ......................................................................... 19 
6 
Study Schedule.................................................................................................................. 19 
 
Screening (Days −60 to −2) ........................................................................................... 20 
 
Randomized, Double-Blinded, Placebo-Controlled Treatment Period .......................... 20 
 
Baseline (Days −2 to 0) ........................................................................................ 20 
 
First Dose (Day 0) ................................................................................................. 21 
 
Doses 2-8 (weeks 2, 4, 6, 8, 10, 12, 14 ± 4 days) ................................................. 21 
 
Peak Treatment (Week 16 ± 7 days) ..................................................................... 23 
 
Post-treatment Visit (Week 28 ± 7 days) .............................................................. 23 
 
Early Termination Visit ........................................................................................ 24 

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Optional Open-label Treatment Period .......................................................................... 25 
 
Open Administration Follow-up Visits (week 7 ± 7 days, and weeks 19, 31, and 
43 all ± 14 days) .................................................................................................................... 25 
 
Final Study Visit (week 55 ± 14 days).................................................................. 25 
 
Early Termination Visit ........................................................................................ 26 
 
Pregnancy ....................................................................................................................... 26 
7 
Study Procedures/Evaluations .......................................................................................... 26 
8 
Potential Risks and Benefits ............................................................................................. 28 
 
Potential Risks ................................................................................................................ 28 
 
Potential Benefits ........................................................................................................... 31 
9 
Research Use of Stored Human Samples, Specimens, or Data ........................................ 31 
10 
Data Sharing Plan ............................................................................................................. 32 
11 
Remuneration Plan for Participants .................................................................................. 33 
12 
Assessment of Safety ........................................................................................................ 33 
 Definitions ...................................................................................................................... 33 
 Documenting, Recording, and Reporting Adverse Events ............................................ 35 
 Investigator Assessment of Adverse Events .................................................................. 36 
 
Severity ................................................................................................................. 36 
 
Causality ............................................................................................................... 36 
 Investigator Reporting Responsibilities to the Sponsor ................................................. 37 
 
Adverse Events ..................................................................................................... 37 
 
Serious Adverse Events ........................................................................................ 37 
 
Unanticipated Problems ........................................................................................ 37 
 
Pregnancy .............................................................................................................. 38 
 Sponsor’s Reporting Responsibilities ............................................................................ 38 
 Pausing Rules for Individual Participants ...................................................................... 38 
 
Reporting a Pause ................................................................................................. 39 
 
Resumption of a Paused Participant ..................................................................... 39 
 
Discontinuation of Study Agent for Individual Participants................................. 39 
 Halting Rules for the Protocol ........................................................................................ 39 
 
Reporting a Study Halt.......................................................................................... 40 
 
Resumption of a Halted Study .............................................................................. 40 
 
Discontinuation of Study Agent............................................................................ 40 
 Withdrawal Criteria for an Individual Participant.......................................................... 40 
 
Additional Participant Randomization Following Withdrawn Participant or 
Participants Who Discontinue Study Treatment ................................................................... 41 
 Safety Oversight ............................................................................................................. 41 
 
Safety Review and Communications Plan ............................................................ 41 
 
Sponsor Medical Monitor ..................................................................................... 41 
 
Data and Safety Monitoring Board ....................................................................... 41 
13 
Reporting Procedures ........................................................................................................ 42 
 Reporting to the NIH IM IRB ........................................................................................ 42 
 Reporting to the NIAID Clinical Director...................................................................... 42 
14 
Site Monitoring Plan ......................................................................................................... 42 
15 
Statistical Considerations .................................................................................................. 43 
 Study Hypotheses ........................................................................................................... 43 

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 Sample Size Justification ............................................................................................... 43 
 Description of the Analyses ........................................................................................... 44 
 Planned Interim Analyses............................................................................................... 44 
 Final Analysis Plan......................................................................................................... 44 
16 
Ethics/Protection of Human Participants .......................................................................... 46 
 Informed Consent Process .............................................................................................. 46 
 Participant Confidentiality ............................................................................................. 46 
17 
Data Handling and Record Keeping ................................................................................. 46 
 Data Capture and Management ...................................................................................... 46 
 Record Retention ............................................................................................................ 47 
18 
Scientific References ........................................................................................................ 48 
Appendix A: Schedule of Procedures/Evaluations ....................................................................... 50 
Appendix B: Blood Volumes for Specimen Collection ................................................................ 53 
Appendix C: Mastocytosis Quality of Life Questionnaire ........................................................... 54 
Appendix D: Scoring of Mastocytosis (SCORMA) Index ........................................................... 58 
Appendix E: Memory Symptom Assessment Scale (MSAS) ....................................................... 60 
Appendix F: The Mastocytosis Quality of Life Questionnaire (MQLQ) ..................................... 63 
Appendix G: The Mastocytosis Symptoms Assessment Form (MSAF) ...................................... 69 
Appendix H: Side Effect and Medication Change Diary .............................................................. 71 
Appendix I: Sarilumab Memory Aid ............................................................................................ 75 
 
List of Figures 
Figure 1 Study Schedule ............................................................................................................... 13 
 
List of Tables 
Table 1: Common Adverse Reactions in Adults with Moderately to Severely Active Rheumatoid 
Arthritis ......................................................................................................................................... 29 
Table 2: Incidence of Liver Enzyme Elevations in Adults with Moderately to Severely Active 
Rheumatoid Arthritis .................................................................................................................... 30 
 
 
 

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List of Abbreviations 
AE 
Adverse event 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
AR 
Adverse reaction 
AST 
Aspartate transaminase 
BTRIS 
Biomedical Translational Research Information System 
CBC/diff 
Complete blood count with differential 
CC 
Clinical Center 
CFR 
Code of Federal Regulations 
CRIMSON 
Clinical Research Information Management System of the NIAID 
CRP 
C-reactive protein 
CSO 
Clinical Safety Office 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 isozyme 
DCR 
Division of Clinical Research 
DMARD 
Disease-modifying antirheumatic drug 
DSMB 
Data and safety monitoring board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GRIS 
Genomic Research Integration System 
GTT 
Green top tube 
HRPP 
Human Research Protections Program 
ICH 
International Council on Harmonisation 
IL-6 
Interleukin 6 
IL-6R 
Interleukin 6 receptor 
IND 
Investigational new drug 
IRB 
Institutional review board 
ISM 
Indolent systemic mastocytosis 
ITT 
Intent to treat 
IV 
Intravenous(ly) 
LAD 
Laboratory of Allergic Diseases 
LTT 
Lavender top tube 
MC-QoL 
Mastocytosis Quality of Life Questionnaire 
mITT 
Modified intent to treat 
mITT2 
Second modified intent to treat 
mITT3 
Third modified intent to treat 
MQLQ 
Mastocytosis Quality of Life Questionnaire 
MSAF 
Mastocytosis Symptom Assessment Form 
MSAS 
Memorial Symptom Assessment Scale 
NIAID 
National Institute of Allergy and Infectious Diseases  
NIH 
National Institutes of Health 
OCRPRO 
Office of Clinical Research Policy and Regulatory Operations 
OHRP 
Office for Human Research Protections 

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OHSRP 
Office of Human Subjects Research Protections 
PCR 
Polymerase chain reaction 
PI 
Principal investigator 
PP 
Per protocol 
PT/PTT 
Prothrombin/partial thromboplastin time 
Q2W 
Once every 2 weeks 
QoL 
Quality of life 
SAE 
Serious adverse event 
SAR 
Suspected adverse reaction 
SC 
Subcutaneous(ly) 
SCORMA 
Scoring of mastocytosis index 
SERF 
Safety expedited report form 
SRCP 
Safety review and communications plan 
SST 
Serum separator tube 
SUSAR 
Serious and unexpected suspected adverse reaction 
ULN 
Upper limit of normal 
UP 
Unanticipated problem 
 
 

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Protocol Summary 
Full Title:  
A Phase 2 Randomized Double-Blinded Placebo-Controlled Study 
to Evaluate the Safety and Efficacy of Subcutaneous Sarilumab in 
Improving the Quality of Life in Subjects with Indolent Systemic 
Mastocytosis 
 
Short Title: 
Sarilumab for Treatment of ISM 
 
Clinical Phase: 
2 
 
IND Sponsor: 
OCRPRO/DCR/NIAID/NIH  
 
Conducted by:  
LAD/NIAID 
 
PI: 
Hirsh Komarow, MD 
 
Sample Size: 
N = 30 
 
Accrual Ceiling: 
N = 60 
 
Study Population: 
Participants will be aged 18 to 74 years-old who have been 
diagnosed with indolent systemic mastocytosis (ISM). 
 
Accrual Period: 
5 years 
 
Study Design: 
This will be a randomized, placebo-controlled double-blinded 
study. Thirty participants will be randomized (1:1) to receive 
8 subcutaneous (SC) injections of 200 mg of sarilumab (trade 
name Kevzara) or placebo once every 2 weeks (Q2W) for 
16 weeks. Participants will be evaluated at each study visit for 
improvement of symptoms of ISM and safety. Study visits for dose 
4, 6, and 8 of study agent administration may be self administered 
at home without study assessments.   After a 12-week washout 
period, all participants will be offered the opportunity to continue 
200-mg sarilumab SC Q2W for 52 more weeks, with regular safety 
checkups.   
 
Study Duration: 
Start Date: October 2018 
End Date: July 2027 
Participants will be on study for up to 91 weeks, from screening 
through the end of the 1-year for open-label administration. 
 
Study Agent/ 
Intervention Description: 
Kevzara (sarilumab, Sanofi/Genzyme [Cambridge, MA. USA]), 
200 mg/dose or placebo via SC injection Q2W for 16 weeks 

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(8 doses), with the option to continue sarilumab at 200 mg Q2W 
for 52 more weeks. 
 
Primary Objective: 
To determine the efficacy and safety of 8 doses of sarilumab in 
improving the quality of life (QoL) in participants with ISM. 
 
Secondary Objectives: 
1. To assess the need for symptomatic relief with standard 
medicines. 
2. To assess the effect of sarilumab on serum tryptase. 
3. To investigate the effect of sarilumab on the allelic frequency of 
D816V KIT in peripheral blood. 
4. To investigate the effects of sarilumab on bone marrow mast cell 
infiltrates. 
 
Exploratory Objectives:  
1. To assess the effect of sarilumab on end-organ targets of 
mastocytosis. 
 
2. To evaluate the effect of sarilumab on skin manifestations. 
 
3. To evaluate the effect of sarilumab on markers of bone marrow 
resorption and deposition. 
 
4. To determine the long-term safety of sarilumab in participants 
with ISM. 
 
Primary Endpoints: 
1. QoL at 16 weeks post-initiation of study drug/placebo using the 
Mastocytosis Quality of Life Questionnaire (MC-QoL).   
2. Frequency and severity of adverse events (AEs) during the 
randomized double-blinded placebo-controlled treatment period. 
 
Secondary Endpoints:  
1. Percent improvement in QoL from baseline to 16 weeks 
post-initiation of study drug/placebo using the MC-QoL. This is 
computed as [(Baseline QoL – 16-week QoL)/Baseline QoL] × 
100. 
2. Percent improvement in QoL using scoring of mastocytosis 
index (SCORMA), Memorial Symptom Assessment Scale (MSAS) 
the Mastocytosis Quality of Life Questionnaire (MQLQ), and the 
Mastocytosis Symptoms Assessment Form (MSAF). 
3. Reduction in use of medicines for symptomatic relief. 
4. Reduction in serum levels of tryptase.  
5. Decrease in the allelic frequency of D816V using allele-specific 
polymerase chain reaction (PCR). 
6. Reduction in percentage infiltrating mast cells in bone marrow.  
 
Exploratory Endpoints: 
1. Reduction in size of liver and spleen, as visualized by 
ultrasound. 
2. Reduction in number of cutaneous lesions, as determined by 
SCORMA and photography. 

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3. Assessment of metabolic bone disease and bone turnover as 
determined by the peripheral blood markers, bone-specific alkaline 
phosphatase, osteocalcin, N terminal propeptide of type I 
procollagen, and crosslinked telopeptides of type I collagen. 
4. Frequency and severity of AEs during the open-label treatment 
period. 
 
 

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Précis 
Systemic mastocytosis is a disorder caused by clonal mast cell proliferation and release of mast 
cell mediators including tryptase. As a result, mast cell numbers may increase and affect target 
organs including the dermis (maculopapular cutaneous mastocytosis/urticaria pigmentosa, 
flushing), gastrointestinal tract (abdominal pain, diarrhea), skeletal system (osteoporosis), 
hematological system (anemia, thrombocytopenia), and spleen and liver (organomegaly). 
Patients with indolent (non-aggressive) systemic mastocytosis (ISM) are not candidates for 
cytoreductive therapy and are generally treated with symptomatic therapy that only partly 
decreases symptoms. There is, however, a documented association between severity of 
mastocytosis and elevated serum levels of interleukin (IL)-6. Furthermore, mast cells have been 
shown to double their rate of division and exhibit increased reactivity and release of mediators 
when cultured in the presence of IL-6. In addition, in an animal model of mastocytosis, anti-IL-6 
has been shown to slow disease progression. In this study, adults with ISM will thus be 
randomized and treated with sarilumab, a recombinant monoclonal antibody directed against the 
IL-6 receptor, or receive placebo. Sarilumab is marketed in the United States as Kevzara 
(Sanofi/Genzyme [Cambridge, MA, USA ]) and is approved by the Food and Drug 
Administration for the treatment of rheumatoid arthritis. Binding of sarilumab to the IL-6 
receptor inhibits IL-6-associated human mast cell signaling and proliferation with a resultant 
decrease in proliferation and reactivity (decreased mediator release), and therefore is a rational 
choice for the treatment of ISM. 
In this study, participants will be randomized with approximately half of the participants 
receiving study drug, which will be administered at 200 mg via subcutaneous (SC) injection once 
every 2 weeks (Q2W) for a total of 16 weeks. The other participants will receive a placebo 
administered via SC injection Q2W for 16 weeks. Participants will return for a follow-up visit 
2 weeks after the final dose (treatment peak), and then again 12 weeks later. Evaluations at study 
visits will include quality of life and symptom assessments and measurement of serum tryptase 
levels. Bone marrow examination will be performed at the onset and conclusion of the study. 
After the week 28 visit, all participants will have the option to continue sarilumab for 52 more 
weeks, at 200 mg administered via SC injections. Participants will continue to be monitored on a 
regular basis for safety concerns, as instructed in the study drug’s package insert. 
 
 

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1 
Background Information and Scientific Rationale 
 
Background on Mastocytosis 
Mastocytosis is clonal disorder of mast-cell proliferation that results in an increase in mast cells in 
the skin, bone marrow, and other organs systems.1 Clinical features of mastocytosis include 
flushing, pruritus, abdominal pain, diarrhea, hypotension, syncope, and musculoskeletal pain. 
These features are attributed to both the local and systemic release of mast-cell mediators. The 
skin is almost always involved in adult patients with ISM in addition to the clinical features 
described. Greater than 90% of adult patients with ISM have an activating mutation in KIT, the 
receptor for stem cell factor (mast cell growth factor), which results in ligand-independent 
activation of KIT that is associated with disease pathogenesis. Life-threatening forms of 
mastocytosis including aggressive mastocytosis, systemic mastocytosis associated with a 
hematologic neoplasm, and mast cell leukemia are treated with cytoreductive therapy targeting 
this receptor, which may prolong life, but does not result in disease remission. 
ISM, in contrast, is a less severe systemic variant, and patients with ISM are generally managed 
over the long term with symptomatic therapy that includes mediator blocking agents like H1 and 
H2 anti-histamines and leukotriene antagonists. Patients with ISM are not candidates for 
cytoreductive agents due to potential toxic side effects that outweigh the benefits. Unfortunately, 
symptomatic therapy is often unsuccessful in controlling symptoms and in most cases, disease 
continues to progress with both an increase in mast cell burden and symptoms. 
Interleukin 6 (IL-6) is a pleiotropic cytokine involved in inflammation, infection, and cancer. 
IL-6 is produced by a number of cells including T cells, mast cells, and macrophages in response 
to infection and acute inflammation.2 It facilitates interaction between stromal and immune cells, 
and has been associated with the pathogenesis of several human mast cell–related diseases.3 IL-6 
levels in peripheral blood have been correlated with severity of disease not only in systemic 
mastocytosis, but also in acute and chronic urticaria, and asthma.4-8 Increased IL-6 levels in 
mastocytosis are correlated with bone marrow pathology, organomegaly, osteoporosis, levels of 
tryptase,4 and risk for progression of systemic disease.7 In vivo, IL-6 has also been shown to 
promote mast-cell maturation, proliferation, reactivity, and down-regulation of the soluble IL-6 
receptor (IL-6R), thus promoting inflammation,9 and IL-6 inhibition reduced oxidative stress in 
mutant mast cells.10 Treatment of ISM with an IL-6 antagonist is thus a logical approach toward 
decreasing mast cell mediator release and the associated symptoms. 
Based on this approach, we treated one patient who had severe cutaneous disease and ISM with 
tocilizumab for 6 months (8 mg/kg/month). This patient had been experiencing significant skin 
symptoms (pruritus, flushing) and gastrointestinal (GI) manifestations (daily vomiting, diarrhea, 
bloating, and abdominal pain) in addition to daily fatigue and joint pain. The patient tolerated the 
medication without any treatment-related AEs and showed a dramatic clinical response as 
assessed monthly using the MC-QoL.11 Percentage improvement in comparison to baseline 

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assessment was determined to be between 67%-80% in the four QoL categories assessed 
(general, emotions, skin, social life) and total QoL scores. This response exceeded our 
expectation as defined by a primary endpoint of 50% improvement in overall QoL parameters. 
An improvement of 50% in QoL has been identified as clinically meaningful in other studies 
using tocilizumab in rheumatoid arthritis.12 Our findings in this patient support the need for a 
blinded study that can more definitively provide data on efficacy and safety.  
 
Sarilumab 
As developed by Sanofi/Genzyme, sarilumab is a fully human anti-IL-6Rα monoclonal antibody 
that binds membrane-bound and soluble human IL-6R and has been shown to inhibit IL-6 
signaling.13 In 2017, the United States Food and Drug Administration (FDA) approved sarilumab 
for the treatment of rheumatoid arthritis. The drug’s mechanism of action, in addition to its 
application in related inflammatory disorders14 (eg, ankylosing spondylitis15 and uveitis16) 
positions it as a plausible candidate for treatment of patients with systemic mastocytosis. 
 
Scientific Rationale 
Current treatment for ISM is directed at reduction of symptoms and improvement of QoL. The 
role of IL-6 in mast-cell proliferation and mediator release9 suggests antagonist therapy has the 
potential to treat ISM, as well. Antagonist therapy with anti-IL-6R would be expected to 
decrease the release of mediators from mast cells and possibly mast cell number, thus providing 
a significant relief of symptoms. This is supported by our experience treating one ISM patient 
with the IL-6R antagonist tocilizumab, an FDA-approved treatment for rheumatoid arthritis, 
another disorder associated with IL-6-associated disease. Sarilumab, which is also an anti-IL-6R 
antibody that is indicated for treatment of rheumatoid arthritis, demonstrates a similar safety 
profile to tocilizumab. Sarilumab has also demonstrated a greater affinity for human IL-6R 
compared with tocilizumab,17 so a clinical study to investigate its use in treating ISM is timely. 
2 
Study Objectives 
 
Primary Objective 
The primary objective of this study will be to determine the efficacy and safety of 8 doses of 
sarilumab in improving QoL in participants with ISM. 
 
Secondary Objectives 
The secondary objectives will be: 
1. To assess the need for symptomatic relief with standard medicines. 
2. To assess the effect of sarilumab on serum tryptase. 

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3. To investigate the effect of sarilumab on the allelic frequency of D816V KIT in 
peripheral blood. 
4. To investigate the effects of sarilumab on bone marrow mast cell infiltrates. 
 
Exploratory Objectives 
The exploratory objectives will include:   
1. To assess the effect of sarilumab on end-organ targets of mastocytosis.  
2. To evaluate the effect of sarilumab on skin manifestations.  
3. To evaluate the effect of sarilumab on markers of bone marrow resorption and deposition.  
4. To determine the long-term safety of sarilumab in participants with ISM. 
3 
Study Design 
 
Description of the Study Design 
This is a phase 2, double-blinded, randomized, placebo-controlled study to evaluate the efficacy 
of sarilumab as treatment for ISM. Patients with ISM will receive either 200 mg of sarilumab or 
placebo via SC injection Q2W for a total of 16 weeks (8 doses). Participants will return for a 
follow-up visit 2 weeks after the final dose (treatment peak), and then again 12 weeks later. 
Participants will be evaluated for clinical improvement of ISM-related symptoms, drug-related 
AEs, and molecular markers of ISM. After the week 28 visit, all participants will have the option 
to continue sarilumab for 52 more weeks, at 200 mg administered via SC injections. Participants 
will continue to be monitored on a regular basis for safety concerns, as instructed in the study 
drug’s package insert. 
Throughout the study, if a participant’s lab results meet pausing criteria (section 12.6), then at 
the discretion of the PI, CSO, and data and safety monitoring board (DSMB), the dose may be 
temporarily reduced to 150 mg until the lab values return to normal. 
A schematic of the study design is presented in Figure 1. 
Figure 1 Study Schedule 
 
Screening
Days −60 to −2
Baseline and 
randomization
Days −2 to 0
Study drug 
administration
Day 0 to week 
14
Peak treatment 
visit
Week 16
Post-treatment 
visit
Week 28
Optional open-
label 
administration
Weeks 28-83

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Study Endpoints 
 
Primary Endpoints 
1. QoL at 16 weeks post-initiation of study drug/placebo using the MC-QoL.  
2. Frequency and severity of AEs during the randomized double-blinded placebo-controlled 
treatment period. 
 
Secondary Endpoints 
1. Percent improvement in QoL from baseline to 16 weeks post-initiation of study 
drug/placebo using the MC-QoL. This is computed as [(Baseline QoL − 16-week 
QoL)/Baseline QoL] × 100.  
2. Percent improvement in QoL using SCORMA, MSAS and MQLQ/MSAF. 
3. Reduction in use of medicines for symptomatic relief. 
4. Reduction in serum levels of tryptase.  
5. Decrease in the allelic frequency of D816V using allele-specific PCR. 
6. Reduction in percentage infiltrating mast cells in bone marrow. 
 
Exploratory Endpoints 
1. Reduction in size of liver and spleen, as visualized by ultrasound. 
2. Reduction in number of cutaneous lesions, as determined by SCORMA and photography. 
3. Assessment of metabolic bone disease and bone turnover as determined by the peripheral 
blood markers, bone-specific alkaline phosphatase, osteocalcin, N-terminal propeptide of 
type I procollagen, and crosslinked telopeptides of type I collagen. 
4. Frequency and severity of AEs during the open-label treatment period. 
4 
Study Population 
 
Recruitment Plan 
All participants will be recruited from the NIAID study 02-I-0277, “Regulation of the 
Proliferation and Survival of Normal and Neoplastic Human Mast Cells.” Participants will also 
be screened on that study. 
Recruitment of NIH staff: NIH staff, NIH contractors, NIH fellows and members of their 
immediate families may participate in this protocol. We will follow the Guidelines for the 
Inclusion of Employees in NIH Research Studies and will give each employee a copy of the 
“NIH Information Sheet on Employee Research Participation.” 

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For NIH staff members: 
• NIH staff may be a vulnerable class of participants. 
• Neither participation nor refusal to participate will have an effect, either beneficial or 
adverse, on the participant’s employment or work situation. 
• The employee participant’s privacy and confidentiality will be preserved in accordance 
with NIH CC and NIAID policies, which define the scope and limitations of the 
protections. 
• For NIH staff participants, consent will be obtained by an individual independent of the 
staff member’s team. Those in a supervisory position to any staff member and co-workers 
of the staff member will not obtain consent. 
• The importance of maintaining confidentiality when obtaining potentially sensitive and 
private information from co-workers or subordinates will be reviewed with the study staff 
at least annually and more often if warranted. 
 
Participant Inclusion Criteria 
Participants must meet all of the following criteria to be enrolled in this study: 
1. Male or female participant ≥ 18 and < 75 years of age at screening. 
2. Enrolled on NIAID protocol 02-I-0277. 
3. Documented pathologic diagnosis of ISM. 
4. MC-QoL score of at least 25% (which suggests participant is at least somewhat affected 
by all McQoL questions). 
5. Willing and able to undergo a bone marrow biopsy and aspirate. 
6. Absolute neutrophil count (ANC) ≥ 2000/µL. 
7. Hemoglobin ≥ 12.0 g/dL (males), ≥ 11 g/dL (females). 
8. Platelet count > 150,000/µL. 
9. Alanine transaminase (ALT) and aspartate transaminase (AST) < 1.5 times the upper 
limit of normal (ULN). 
10. Willing to allow storage of blood and bone marrow for future use in medical research. 
11. Willing to allow genetic testing on biospecimens. 
12. Able to provide informed consent. 
13. Participants who can become pregnant must agree to use adequate contraception when 
engaging in sexual activities that can result in pregnancy. Adequate contraception must 
be used consistently, beginning at least 1 month before the beginning of dosing and 
lasting until 3 months after the final dose of study drug. Acceptable methods of 
contraception include the following: 
o Hormonal contraception (non-oral only). 
o Male or female condom with spermicide. 
o Diaphragm or cervical cap with a spermicide. 

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o Intrauterine device. 
 
Participant Exclusion Criteria 
Individuals meeting any of the following criteria will be excluded from study participation: 
1. Any abnormality that would be scored as a Grade 4 toxicity on the Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. Only clinically 
significant lab results will deem the subject ineligible 
2. Infected with HIV or has other known immunodeficiency. 
3. Has an active infection, including localized infection. 
4. Active diverticulitis. 
5. Active or chronic viral hepatitis. 
6. Active or latent tuberculosis. 
7. Use of any other anti-IL-6 or anti-IL-6R agent within 1 year prior to the date informed 
consent was obtained.  
8. Use of cytoreductive therapy for mastocytosis within 1 year prior to the date informed 
consent was obtained.  
9. Known lymphoma or advanced and metastatic solid tumors on active therapy (including 
chemotherapy) within 1 year prior to the date informed consent was obtained. 
10. Use of chemotherapy within 1 year prior to the date informed consent was obtained.  
11. Receipt of any marketed (eg, omalizumab) or investigational biologic or monoclonal 
antibody reported to affect mast cell activation within 5 half-lives prior to date informed 
consent was obtained. 
12. Receipt of intravenous (IV) immunoglobulin within 30 days prior to the date informed 
consent was obtained.  
13. Receipt of live attenuated vaccines within 30 days prior to the date informed consent was 
obtained.  
14. History of alcohol or drug/abuse within 12 months prior to date informed consent was 
obtained. 
15. Is allergic to any component of the sarilumab formulation. 
16. Pregnant or breastfeeding. 
17. Any condition that, in the opinion of the investigator, contraindicates participation in this 
study. 
Co-enrollment guidelines: Co-enrollment in other trials is restricted, other than enrollment on 
observational studies. Study staff should be notified of co-enrollment as it may require the 
approval of the investigator. 

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Justification for Exclusion of Special Populations 
Exclusion of pregnant women: It is not known whether this drug can cause fetal harm or 
adversely affect reproductive capacity in humans. The limited human data with this drug in 
pregnant women are not sufficient to inform drug-associated risk for major birth defects and 
miscarriage. Monoclonal antibodies are actively transported across the placenta during the third 
trimester of pregnancy and may affect immune response in the in utero–exposed infant. Levels of 
immunoglobulin G, in response to antigen challenge, may be reduced in the fetus/infant of 
treated mothers. Therefore, to reduce risk, pregnant participants are excluded from this study. 
Exclusion of breastfeeding women: There is an unknown but potential risk for sarilumab to be 
excreted in human milk, so there is the potential risk of AEs in nursing infants. Therefore, 
breastfeeding must have been discontinued before treatment with sarilumab begins. 
Exclusion of children: Mastocytosis that is diagnosed in children often resolves by 18 years of 
age. This drug has also not been evaluated in pediatric patients. Therefore, the risk-benefit ratio 
would not justify targeting this population.   
5 
Study Agent/Interventions 
 
Disposition and Dispensation 
Sanofi/Genzyme will supply pre-filled syringes of sarilumab and placebo. Study agent and 
placebo will be distributed via the NIH pharmacy according to standard pharmacy procedures.  
 
Formulation, Packaging, and Labeling 
Each package will be individually labeled in the NIH pharmacy with the patient ID number, 
dosing instructions, recommended storage conditions, the name and address of the manufacturer, 
and that the agent should be kept out of reach of children. 
 
Study Agent Storage and Stability 
Syringes of sarilumab should be stored at 2°C-8°C and away from the light. Do not freeze. 
Syringes may also be stored in their outer carton at room temperature (< 25°C) for up to 14 days. 
The drug should not be used past the expiration date printed on the carton.13  
 
Randomization and Blinding/Unblinding Procedures 
Eligible participants will be allocated 1:1 to study agent or placebo. A randomization scheme 
will be generated by the study statistician who will provide a randomized list of arm assignments 
to the NIH CC Pharmacy. A permuted block approach, with varying block sizes, will be used for 
the randomization process. 

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The participants, the investigators, and all who are involved in the evaluation of the study 
participants including study monitors and central laboratory personnel are blinded to a 
participant’s treatment assignment until all participants have completed the week 16 visit. The 
NIH research pharmacist is identified as the unblinded third party who will be in charge of 
treatment assignment, maintaining study supplies/inventory list, and preparing the blinded study 
medication for each participant. The NIH research pharmacist will be independent of any study 
assessments. To maintain blinding, any discussion of the treatment assignment between the 
clinicians and the pharmacy staff is prohibited until the study is unblinded. Unblinding will occur 
when the final participant completes their week 28 visit (section 6.2.5), or in the case of early 
termination or study drug discontinuation, after the participant’s final study visit. 
Participants will be assigned a screening number after completion of the protocol consent for 
enrollment in the study in the Clinical Research Information Management System of the NIAID 
(CRIMSON). The study statistician will generate the randomization codes. These codes will be 
maintained by the NIH research pharmacist. A study allocation number (1, 2, etc) will be 
assigned when the participant is ready to be randomized. Randomization is defined as the time 
that the pharmacy is notified that this new participant, with this study allocation number, is being 
enrolled. This should coincide with the day that the first dose of study drug is administered. 
Randomization will continue until there are 30 participants who initiate study drug and have at 
least the first post-baseline QoL measurement at 4 weeks. Note that  participants who do not 
meet these criteria still remain in the study, and attempts to obtain subsequent QoL measures 
should be made. 
 
Emergency Unblinding 
If a participant experiences an AE whose management (eg, diagnostic procedures, treatment) in 
the opinion of the principal investigator (PI) or designee would differ depending on the study 
arm, or in the case of pregnancy, then the PI or designee will contact the NIH CC Pharmacy for 
release of the randomization code. The sponsor and DSMB executive secretary will be informed 
within 1 business day of any request for unblinding. The participant will remain enrolled in the 
study and the data will be used for analysis. 
 
Preparation, Administration, and Dosage of Sarilumab and Placebo 
Sarilumab is supplied in single-use pre-filled syringes (150 or 200 mg/1.14 mL) for SC injection. 
Placebo will be supplied by Sanofi/Genzyme in the same fashion in pre-filled syringes. The 
volume of the placebo dose is also 1.14 mL. 
The pausing criteria are described in section 12.6. Participants who resume after a pause as a 
result of lab abnormalities may have their dose temporarily reduced from 200 to 150 mg, at the 
discretion of the PI (in consultation with the CSO), until these values return to stated thresholds 
(section 12.6.2), per the sarilumab package insert.13 

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Study Product Accountability Procedures 
The NIH pharmacy will maintain accurate drug accountability records. A binder containing 
instructions and the required accountability documentation will be provided to the study 
pharmacist. When the study is completed, the accountability documentation will be maintained at 
the NIH CC per standard procedures. All unused study drug must be disposed of upon 
authorization by NIAID or its designee. All records regarding the disposition of study drug must 
be available for inspection by the study monitors and regulatory authorities. 
 
Concomitant Medications and Procedures 
All concomitant prescription and nonprescription (including over-the-counter) medications taken 
during study participation will be recorded. Reduction in medication use will be noted and 
documented based on clinic intake and participants will be required to maintain a medication 
change diary (Appendix H) for monitoring of medications. For this protocol, a prescription 
medication is defined as a medication that can be prescribed only by a properly 
authorized/licensed clinician. 
Various in vitro and limited in vivo human studies have shown that cytokines and cytokine 
modulators can influence the expression and activity of specific cytochrome P450 (CYP) 
enzymes and therefore have the potential to alter the pharmacokinetics of concomitantly 
administered drugs that are substrate of these enzymes. Liver CYPs are downregulated by IL-6, 
so inhibition of IL-6 may restore liver CYP activity. Drug doses therefore may need to be 
modified in light of increased CYP-mediated metabolism, especially in drugs with a narrow 
therapeutic index. The effect of sarilumab on CYPs can persist for weeks after sarilumab therapy 
ends.13 Therefore, drugs with a narrow therapeutic that are CYP metabolized will be identified 
and monitored for clinical effects and blood levels if necessary. 
 
Prohibited Medications and Procedures 
Participants may not receive any live vaccine while they are being treated with sarilumab 
because inhibition of IL-6 may obstruct the normal immune response.13 
6 
Study Schedule 
All visits will take place at the NIH CC. Study participation will include an optional inpatient 
stay for approximately 3 days (baseline testing, randomization, and first dose administration), 
two full clinic days (screening and peak treatment, which both include a bone marrow 
examination), 4 half clinic days (doses 3, 5, 7, final study visit), and 4 short clinic visits (doses 2, 
4, 6, 8) for AE assessment and injection only. For subjects opting to self administer study agent 
at home at doses 4, 6, and 8, a visit to NIH will not take place.  No history, physical exam, AE 
collection, pregnancy test or diary review will take place for these subjects.  A table of the study 

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schedule and procedures/evaluations is provided in Appendix A. A table of blood volumes to be 
collected at each visit is provided in Appendix B. 
 
Screening (Days −60 to −2) 
Informed consent will be obtained before the following screening tests are conducted:  
1. Physical exam with vital signs, including height and weight. 
2. Medical history/medication overview. 
3. Assessment of ISM symptoms. 
4. Blood draw for clinical evaluations: 
a. Complete blood count with differential (CBC/diff). 
b. Acute care, hepatic, and mineral panels. 
c. Serum tryptase. 
d. Prothrombin/partial thromboplastin time (PT/PTT). 
e. HIV test (anti-HIV-1/2 antibodies). 
f. Hepatitis B and C antibody test, B DNA, and C RNA. 
g. QuantiFERON Gold tuberculosis test. 
5. Serum or urine pregnancy test (participants of childbearing potential only). 
6. MC-QoL. 
7. SCORMA. 
8. MSAS. 
9. MQLQ/MSAF 
10. Bone marrow biopsy and aspirate (if not done at NIH within the last 150 days on protocol 
02-I-0277). 
11. KIT D816V mutation analysis on bone marrow and blood (if not done at NIH within the 
last 150 days) 
12. Flow cytometry on bone marrow and blood (if not done at NIH within the last 150 days). 
13. Ultrasound of abdomen. 
14. Photography of affected areas. 
 
Randomized, Double-Blinded, Placebo-Controlled Treatment Period 
 
Baseline (Days −2 to 0) 
After eligibility has been confirmed, participants will visit the NIH CC for baseline testing. 
Participants may be admitted as inpatients and will be randomized to receive sarilumab or 
placebo. The following procedures will then be done at baseline:  
1. Physical exam with vital signs. 
2. Overview of medical/medication history. 
3. Assessment of baseline symptoms of ISM. 

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4. Assessment of AEs. 
5. Blood draw for clinical evaluations: 
a. CBC/diff. 
b. Acute care, hepatic, and mineral panels.  
c. PT/PTT. 
d. Total protein. 
e. Lipid panel. 
f. Serum tryptase. 
g. C-reactive protein (CRP). 
6. Urine or serum pregnancy test (for participants of childbearing potential only). 
7. Blood draw for DNA and RNA collection. 
8. Collection of serum (8 mL serum separator tube [SST]) for storage. 
9. Serum IL-6 levels. 
10. Serum markers of bone marrow resorption and deposition. 
11. Plasma for storage (10 mL green top tube [GTT]). 
12. Whole blood for storage (3 mL lavender top tube [LTT]). 
13. MC-QoL. 
14. SCORMA. 
15. MSAS. 
16. MQLQ/MSAF. 
17. KIT D816V mutation analysis on blood. 
18. Flow cytometry on blood. 
19. Photography of affected areas (optional). 
20. Skin punch biopsy (optional). 
 
First Dose (Day 0) 
Participants will receive either 200 mg of sarilumab or placebo via SC injection (see section 5.4). 
The participant will be monitored during administration and for 1 hour after to observe for any 
immediate drug-related AEs. Participants of childbearing potential must have had a negative 
pregnancy test at baseline before dose administration. Participants will be discharged after 
postdose monitoring if they have not experienced any serious hypersensitivity reactions. 
Hypersensitivity reactions will be treated as clinically appropriate. Before discharge, participants 
will be provided with a side effect and medication change diary (Appendix H), with instructions 
to fill it out in between visits as appropriate, and to bring it in for review to all future study visit. 
 
Doses 2-8 (weeks 2, 4, 6, 8, 10, 12, 14 ± 4 days) 
Participants will return to the NIH CC once every 2 weeks (± 4 days) to receive their next dose 
of study drug or placebo. The exception will be subjects at doses 4, 6, and 8 who have not 
experienced reactions to the agent.  These subjects may opt to self-administer the study agent at 
home.   At each visit where agent will be administered at NIH, before dose administration, the 

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participant will undergo a physical exam with vital signs, overview of medical history, diary 
review, and assessment of AEs. At each visits where participants of childbearing potential 
receive study agent at NIH, they will also have a urine or serum pregnancy test, which must be 
negative before administration of the study drug. In addition, at the visits for doses 3, 5, and 7 
(weeks 4, 8, and 12), participants will undergo the following procedures before dose 
administration:  
1. Blood draw for clinical evaluations: 
a. CBC/diff. 
b. Acute care, hepatic, and mineral panels. 
c. PT/PTT. 
d. Total protein. 
e. Lipid panel. 
f. Serum tryptase. 
g. CRP. 
2. Collection of serum (8 mL SST) for storage. 
3. Serum IL-6 levels. 
4. Plasma for storage (10 mL GTT). 
5. Whole blood for storage (3 mL LTT). 
6. MC-QoL. 
7. SCORMA. 
8. MSAS. 
9. MQLQ/MSAF. 
10. Photography of affected areas (optional). 
As at the first dose visit, participants will be monitored during their injection and for 1 hour after 
the injection to observe for any immediate drug-related AEs and hypersensitivity reactions. 
Hypersensitivity reactions will be treated as clinically appropriate.  
Participants who have not experienced reactions to the injection after the second dose may, at the 
request of the participant and the discretion of the PI, be trained to self-inject the study 
drug/placebo for the fourth, sixth, and eighth doses (weeks 6, 10, and 14). There is no known 
increase in risks for self injection. Subjects will be provided with dosing materials to take home 
and instructions for storage and administration. These participants will not have study visits 
(including pregnancy test, AE evaluation, study diary review or history and physical exam at the 
NIH for these doses.  When a dose is to be self-injected at home, study staff will contact subject 
to ensure administration took place, and document this in the NIH medical record.    

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Peak Treatment (Week 16 ± 7 days) 
Two weeks (± 7 days) after the eighth and final dose of sarilumab, the participant will return to 
the NIH CC and undergo the following procedures. This visit will take 1-2 days, and participants 
will be seen as outpatients. 
1. Physical exam with vital signs. 
2. Overview of medical/medication history. 
3. Assessment of AEs. 
4. Blood draw for clinical evaluations: 
a. CBC/diff. 
b. Acute care, hepatic, and mineral panels. 
c. PT/PTT. 
d. Total protein. 
e. Lipid panel. 
f. Serum tryptase. 
g. CRP. 
5. Urine or serum pregnancy test (for participants of childbearing potential only). 
6. Blood draw for RNA collection. 
7. Collection of serum (8 mL SST) for storage. 
8. Serum IL-6 levels. 
9. Serum markers of bone marrow resorption and deposition. 
10. Plasma for storage (10 mL GTT]. 
11. Whole blood for storage (3 mL LTT). 
12. MC-QoL. 
13. SCORMA. 
14. MSAS. 
15. MQLQ/MSAF 
16. Bone marrow biopsy and aspirate. 
17. KIT D816V mutation analysis on blood and bone marrow. 
18. Flow cytometry on bone marrow and blood. 
19. Ultrasound of abdomen. 
20. Photography of affected areas. 
21. Skin punch biopsy (optional). 
22. Diary review. 
 
Post-treatment Visit (Week 28 ± 7 days) 
The participant will return to the NIH CC for a post-treatment visit 12 weeks (± 7 days) after the 
peak treatment follow-up visit (section 6.2.4). The participant will undergo the following 
procedures: 

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1. Physical exam with vital signs. 
2. Overview of medical/medication history. 
3. Assessment of AEs. 
4. Blood draw for clinical evaluations: 
a. CBC/diff. 
b. Acute care, hepatic, and mineral panels. 
c. PT/PTT. 
d. Total protein. 
e. Lipid panel. 
f. Serum tryptase. 
g. CRP. 
5. Pregnancy test (serum or urine, for participants of childbearing potential only). 
6. Collection of serum (8 mL SST) for storage. 
7. Serum IL-6 levels. 
8. Serum markers of bone marrow resorption and deposition. 
9. Plasma for storage (10 mL GTT). 
10. Whole blood for storage (3 mL LTT). 
11. MC-QoL.  
12. SCORMA. 
13. MSAS. 
14. MQLQ/MSAF 
15. KIT D816V mutation analysis on blood. 
16. Flow cytometry on blood. 
17. Photography of affected areas. 
18. Diary review. 
At the end of this visit, participants who continue to meet all eligibility criteria (sections 4.2 and 
4.3) will be offered the opportunity to continue on sarilumab for another 52 weeks. Prior to 
beginning the open-label treatment, a safety assessment of any AEs that may have occurred 
during the randomized treatment period will be reviewed with the participant. Participants who 
decline will end their participation after this visit. Those who accept will continue on the study as 
described below (section 6.3). 
 
Early Termination Visit 
All effort will be made to conduct an early termination visit for participants who withdraw from 
the study during the randomized, double-blinded portion. This visit will include all of the 
procedures performed at the normal peak treatment visit (see section 6.2.4). 

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Optional Open-label Treatment Period 
For the optional open-label portion of the study, participants will receive 200-mg sarilumab SC 
Q2W for 52 weeks (26 doses). Participants will be trained by the study team to self-administer 
the injection at home. The first dose will be given following the post-treatment visit 
(section 6.2.5), which will be considered week 1 for this portion of the study. Therefore, the final 
dose will be administered on week 51. The participant will be provided with a memory aid 
(Appendix I), in addition to the side effect/medication change diary, to keep track of self-
administered doses of sarilumab. 
For this first dose, the participant will be monitored during administration and for 1 hour after to 
observe for any immediate drug-related AEs. Participants will be discharged after postdose 
monitoring if they have not experienced any serious hypersensitivity reactions. Hypersensitivity 
reactions will be treated as clinically appropriate. 
 
Open Administration Follow-up Visits (week 7 ± 7 days, and weeks 19, 31, and 
43 all ± 14 days) 
Participants will return for follow-up visits approximately 6 weeks after starting this treatment 
period, and every 3 months thereafter. The following procedures will be done at each visit: 
1. Physical exam with vital signs. 
2. Overview of medical/medication history. 
3. Assessment of AEs. 
4. Blood draw for clinical evaluations: 
a. CBC/diff. 
b. Acute care, hepatic, and mineral panels. 
c. Serum tryptase 
d. Lipid panel (weeks 7 and 31 only). 
5. Pregnancy test (serum or urine, for participants of childbearing potential only). 
6. Diary and memory aid review. 
After these procedures, the participant will receive their dose of sarilumab, administered by 
themselves or by study staff. As at the first open-label dose, participants will be monitored 
during their injection and for 1 hour after the injection to observe for any immediate drug-related 
AEs and hypersensitivity reactions. Hypersensitivity reactions will be treated as clinically 
appropriate. 
 
Final Study Visit (week 55 ± 14 days) 
A final study visit will be done approximately 1 month after the last dose, and the following 
procedures will be done: 

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1. Physical exam with vital signs. 
2. Overview of medical/medication history. 
3. Assessment of AEs. 
4. Blood draw for clinical evaluations: 
a. CBC/diff. 
b. Acute care, hepatic, and mineral panels. 
c. Serum tryptase 
5. Pregnancy test (serum or urine, for participants of childbearing potential only). 
6. Diary and memory aid review. 
Participation in this study ends after this visit. 
 
Early Termination Visit 
All effort will be made to conduct an early termination visit for participants who withdraw from 
the study during the open-label treatment portion. This visit will include all of the procedures 
performed at the final study visit (see section 6.3.2). 
 
Pregnancy 
• If a participant becomes pregnant during the course of the study, then they will 
discontinue the study agent and research procedures but continue to be followed for 
safety assessments. There is a pregnancy exposure registry that monitors pregnancy 
outcomes in women exposed to KEVZARA during pregnancy. Pregnant women will be 
encouraged to register themselves by calling 1-877-311-8972 and 
MotherToBaby@ucsd.edu. If the study team is informed before a pregnant woman 
registers, the study team will enroll participant in pregnancy registry.  
7 
Study Procedures/Evaluations 
Blood draw: Blood will be collected for clinical safety evaluations (CBC/diff; acute care, 
hepatic, and mineral panels; total protein; PT/PTT; lipids; serum tryptase; and CRP), storage, 
collection of DNA and RNA, and to examine serum IL-6 levels and markers of bone marrow 
resorption and deposition. Blood will also be used to test for HIV, hepatitis B, hepatitis C, and 
tuberculosis, to determine if the participant’s blood cells carry the D816V mutation in the KIT 
gene, which is characteristic of adult ISM and for markers of ISM using flow cytometry. The 
amount of blood drawn for research purposes will be within the limits allowed for adult research 
participants by the NIH CC (Medical Administrative Policy 95-9, Guidelines for Limits of Blood 
Drawn for Research Purposes in the Clinical Center: http://cc-
internal.cc.nih.gov/policies/PDF/M95-9.pdf). 

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Bone marrow biopsy/aspirate: Bone marrow specimens will be evaluated to determine if the 
participant’s bone marrow carries the D816V mutation in the KIT gene and for evaluation of the 
extent of mast cell infiltration, markers, and morphology. 
Abdominal ultrasound: Ultrasound of the participant’s abdominal area will be conducted to 
evaluate enlargement of the liver and spleen. 
MC-QoL assessment: The MC-QoL is a validated health-related QoL survey for adult patients 
with mastocytosis that consists of 27 items and is divided into four domains: symptoms, social 
life/functioning, emotions, and skin.11 The overall disease impairment on QoL is measured by 
assessing both the total score and the scores of each domain. The MC-QoL is provided in 
Appendix C. 
SCORMA assessment: SCORMA evaluates three measures of mastocytosis in a 
semi-quantitative fashion: extent of skin involvement, lesion activity, and subjective 
symptoms.18 The SCORMA chart is provided in Appendix D. 
MSAS assessment: The MSAS is used to evaluate a patient’s experience with 32 symptoms 
over the course of the previous week.19 Symptoms are evaluated by severity and distress for eight 
of the symptoms, and also for frequency for the remaining 24. The MSAS is provided in 
Appendix E. 
MQLQ/MSAF assessment: The MQLQ is disease specific quality of life questionare valided in 
mastocytosis consisting of 49 questions to assess the effect of mastoctyosis on daily life. It is 
complemented with the MSAF which is a symptom scoring form. The MQLQ is provided in 
Appendix F and the MSAF is in Appendix G. 
Photographs: Photographs will be taken at screening, at baseline before study drug is 
administered (optional), at the treatment peak, and at the post-treatment visit, and may also be 
taken at other visits to document physical findings. Identifiable photographs will be kept in a 
secure database. Participants will sign the standard NIH photography consent form before photos 
are taken. 
Skin punch biopsy (optional) : The biopsy site may be numbed using a cream or spray before a 
local anesthetic is injected. A small circle of skin (2-5 mm) will be removed using a punch and 
the area will then be closed with gel foam, steri-strips, or non-absorbable sutures and covered 
with a dressing. 
Research evaluation on biopsies will include immunohistologic staining to detect the presence 
and number of mast cells and/or maculopapular cutaneous mastocytosis and may include genetic 
studies. 

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8 
Potential Risks and Benefits 
 
Potential Risks 
Sarilumab: Adverse reactions (ARs) have been determined in clinical trials conducted primarily 
in patients with rheumatoid arthritis and on combination therapy with disease-modifying 
antirheumatic drugs (DMARDs, eg, Imuran, cyclophosphamide, and methotrexate). Our patients 
with ISM in general are not being treated with DMARDs. In clinical trials as reported in the 
package insert13 and summarized below and in Table 1, the most frequent ARs (occurring in at 
least 3% of patients treated with sarilumab in combination with DMARDs) were neutropenia, 
increased liver enzymes, injection site erythema, upper respiratory infections, and urinary tract 
infections. 
Premature discontinuation due to ARs occurred in 8%, 6%, and 3% of patients treated with 
sarilumab at 200 mg, sarilumab at 150 mg, and placebo, respectively. The most common ARs 
(greater than 1%) that resulted in discontinuation of therapy with sarilumab was neutropenia.  
The most commonly reported infections (2%-4% of patients) were upper respiratory tract 
infections, urinary tract infections, and nasopharyngitis. The most frequently observed serious 
infections included pneumonia and cellulitis. There is a theoretical risk for tuberculosis 
activation or shingles reactivation.  
Reports of GI perforation were primarily reported as complications of diverticulitis including 
lower GI perforation and abscess. Most patients who developed GI perforations were taking 
concomitant nonsteroidal anti-inflammatory medications (NSAIDs) or corticosteroids. The 
contribution of these concomitant medications relative to sarilumab in the development of GI 
perforations is not known. 
Injection site reactions were reported in 7% of patients receiving sarilumab at 200 mg, 6% 
receiving sarilumab at 150 mg, and 1% receiving placebo. These injection site reactions 
(including erythema and pruritus) were mild in severity for the majority of patients and 
necessitated drug discontinuation in 2 (0.2%) patients receiving sarilumab. 

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Table 1: Common Adverse Reactions in Adults with Moderately to Severely Active 
Rheumatoid Arthritis 
Preferred Term 
Placebo + DMARD  
(N = 579) 
Sarilumab 150 mg + DMARD  
(N = 579) 
Sarilumab 200 mg + 
DMARD (N = 582) 
Neutropenia 
0.2% 
7% 
10% 
ALT increased 
2% 
5% 
5% 
Injection site erythema 
0.9% 
5% 
4% 
Injection site pruritus 
0.2% 
2% 
2% 
Upper respiratory tract 
infection 
2% 
4% 
3% 
Urinary tract infection 
2% 
3% 
3% 
Hypertriglyceridemia 
0.5% 
3% 
1% 
Leukopenia 
0% 
0.9% 
2% 
Adverse reactions occurring in 2% or more in the 150 mg sarilumab + DMARD or 200 mg sarilumab + DMARD groups 
and greater than observed in placebo + DMARD. Pre-rescue, placebo-controlled population. 
ALT = alanine transaminase; DMARD = disease-modifying antirheumatic drug. 
 
Laboratory Abnormalities 
Decreased neutrophil count less than 1000/µL occurred in patients on combination therapy and 
occurred in 6% and 4% of patients in the 200-mg sarilumab + DMARD and 150-mg sarilumab + 
DMARD groups, respectively, compared to no patients in the placebo + DMARD groups. 
Decrease in ANC was not associated with the occurrence of infections, including serious 
infections. Decreases in platelet counts less than 100,000/µL occurred in 1% and 0.7% of 
patients on 200- and 150-mg sarilumab + DMARD, respectively, compared to no patients on 
placebo + DMARD, without associated bleeding events. Liver enzyme elevations in the 
pre-rescue placebo-controlled population (sarilumab + DMARD or placebo + DMARD) are 
summarized in Table 2. 
Liver elevation was not associated with clinically relevant increases in direct bilirubin or clinical 
evidence of hepatitis or hepatic impairment. 
Lipid abnormalities (low-density lipoproteins, high-density lipoproteins, and triglycerides) were 
observed at 4 weeks after initiation of therapy with no additional increases observed thereafter.  

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Table 2: Incidence of Liver Enzyme Elevations in Adults with Moderately to Severely 
Active Rheumatoid Arthritis 
Placebo + DMARD 
N = 579 
Sarilumab 150 mg + DMARD 
N = 579 
Sarilumab 200 mg + DMARD 
N = 582 
AST 
> 1× ULN to 3× ULN 
15% 
27% 
30% 
> 3× ULN to 5× ULN 
0% 
1% 
1% 
> 5× ULN 
0% 
0.7% 
0.2% 
ALT 
> 1× ULN to 3× ULN 
25% 
38% 
43% 
> 3× ULN to 5× ULN 
1% 
4% 
3% 
> 5× ULN 
0% 
1% 
0.7% 
Phase 3 placebo-controlled safety population through the pre-rescue period. ALT = alanine transaminase; AST = aspartate 
transaminase; DMARD = disease-modifying antirheumatic drug; ULN = upper limit of normal. 
 
Malignancies 
In the 52-week placebo-controlled population, 9 malignancies (exposure-adjusted event rate of 
1.0 event per 100 patient-years) were diagnosed in patients receiving sarilumab + DMARD 
compared to 4 malignancies in patients in the control group (exposure-adjusted event rate of 
1.0 event per 100 patient-years). 
Other Adverse Reactions 
Because sarilumab is a monoclonal antibody, there is the risk of allergic or anaphylactic 
reactions. The most frequent hypersensitivity reactions observed in clinical trials were rash at the 
injection site rash or other parts of the body and urticaria. 
While there are no nonclinical data suggesting risks to fertility or embryofetal development, 
sarilumab has not be evaluated in pregnant humans. There is an unknown but potential risk for 
sarilumab to be excreted in human milk. Therefore, participants should not be pregnant, planning 
to become pregnant, or breastfeeding while participating in this study. 
There may be additional risks of sarilumab that are currently unknown. 
Bone marrow biopsy/aspirate: Bone marrow biopsy and aspirate are commonly performed 
medical procedures that are associated with low risk, which includes the potential for some 
bleeding or infection at the site that may or may not require antibiotic treatment. There is usually 
some pressure-like discomfort during needle insertion, and the procedure may also result in a 
bruise and/or some discomfort at the site or surrounding tissue for a day or two after the 
anesthetic wears off. Standard procedures will be followed for all bone marrow biopsies and 
aspirates to minimize pain and the possibility of infection from the procedure. 
Conscious sedation: Participants may request conscious sedation in addition to local anesthesia 
for bone marrow biopsy and aspirate. Sedative drugs will be provided by experienced 

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anesthesiologists of the NIH CC and IV administered. Side effects from sedative medications 
include cardiovascular and respiratory depression, manifested by bradycardia, hypotension, 
respiratory acidosis, and apnea. Additional ARs reported with these drugs are stinging or pain at 
the injection site, hiccoughs, nausea, vomiting, postoperative drowsiness and headache, and 
hypersensitivity reactions. Participants will be closely monitored and appropriate 
countermeasures will be taken as necessary. 
Skin punch biopsy: Pain or discomfort may occur during and after the biopsy, even with the use 
of the local anesthetic. There may be a mild burning sensation when the numbing medicine is 
injected into the skin. The anesthetic may irritate the skin or rarely cause an allergic reaction, 
which can be treated with medicine. There may be bleeding at the biopsy site, which would 
require application of pressure to stop the bleeding. Rarely, biopsy sites become infected. In 
certain individuals, the biopsy will heal with a keloid. This is more likely to occur if it has 
happened in the past. 
Blood draw and insertion of IV catheter: The risks of drawing blood and inserting an 
IV catheter for administration of sedative drugs include pain, swelling, redness, bruising, 
bleeding, and, rarely, fainting or infection.  
Photographs: Taking pictures of the face and body may be embarrassing to some people. These 
photographs may be published in medical journals, without identifying the participant. We will 
attempt to preserve the anonymity of the participant as much as possible, while providing the 
information needed to support the research being published. Participants may decline 
photographs or place restrictions on their use. Participants will be given the opportunity to 
discuss this with the investigator. 
 
Potential Benefits 
Participants may not receive any benefit from this study. There is the potential that a 16-week 
treatment regimen of sarilumab will alleviate or resolve symptoms related to ISM. The results of 
this study may improve the investigators’ understanding of anti-IL-6 therapy as treatment for 
ISM. 
9 
Research Use of Stored Human Samples, Specimens, or Data 
Intended Use: Samples, specimens, and data collected under this protocol may be used to study 
mastocytosis. Genetic testing may be performed in the future.  
Storage: All the stored study research samples are labeled by a code that only the investigators 
can link to the participant. Samples are stored in LAD storage space, which is a secure facility 
with limited access. Data will be kept in password-protected computers. Only investigators or 
their designees will have access to the samples and data.  

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Tracking: Samples and data acquired under this protocol will be tracked using the CRIMSON 
database system. 
Disposition at the Completion of the Protocol: 
• In the future, other investigators (both at NIH and outside) may wish to study these 
samples and/or data. If the planned research falls within the category of “human subjects 
research” on the part of the NIH researchers, IRB review and approval will be obtained. 
This includes the NIH researchers sending out coded and linked samples or data and 
getting results that they can link back to their participants. 
• At the time of protocol termination, samples will either be destroyed or, after IRB 
approval, transferred to another existing protocol. Data will be archived by the study 
team in compliance with requirements for retention of research records; alternatively, 
after IRB and study sponsor approval, the data may be either destroyed or transferred to 
another repository. 
Reporting the Loss or Destruction of Samples/Specimens/Data to the IRB: 
• Any loss or unanticipated destruction of samples (for example, due to freezer 
malfunction) or data (for example, misplacing a printout of data with identifiers) that 
meets the definition of a reportable event will be reported to the NIH IM IRB according 
to NIH Human Research Protections Program (HRPP) Policy 801.  
• Additionally, participants may decide at any point not to have their samples stored. In this 
case, the PI will destroy all known remaining samples and report what was done to both 
the participant and to the IRB. This decision will not affect the individual participant’s 
participation in this protocol or any other protocols at NIH. 
10 Data Sharing Plan 
Human data generated in this study will be shared for future research as follows: 
• De-identified data in an NIH-funded or approved public repository. 
• De-identified data in another public repository. 
• Identified data in the Biomedical Translational Research Information System (BTRIS, 
automatic for activities in the CC) and the Genomic Research Integration System (GRIS). 
• De-identified or identified data with approved outside collaborators under appropriate 
agreements. 
When will the data be shared? 
Data may be shared with Sanofi/Genzyme shortly before publication. 

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11 Remuneration Plan for Participants 
All participants may be reimbursed for travel and lodging, as per the NIAID policy. Participants 
will not receive any other remuneration. 
12 Assessment of Safety  
 Definitions 
The NIAID Clinical Safety Office (CSO) is responsible for sponsor safety oversight of this 
study, and the definitions below comply with CSO requirements. 
Adverse Event: An AE is any untoward or unfavorable medical occurrence in a human 
participant, including any abnormal sign (eg, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the individual’s participation in the research, 
whether or not considered related to the research. 
Adverse Reaction: An AE that is caused by an investigational agent (drug or biologic). 
Suspected Adverse Reaction (SAR): An AE for which there is a reasonable possibility that the 
investigational agent caused the AE. ‘Reasonable possibility’ means that there is evidence to 
suggest a causal relationship between the drug and the AE. An SAR implies a lesser degree of 
certainty about causality than AR, which implies a high degree of certainty. 
Serious Adverse Event (SAE): An SAE is an AE that results in one or more of the following 
outcomes: 
• death 
• a life-threatening event (places the participant at immediate risk of death from the event 
as it occurred) 
• an inpatient hospitalization or prolongation of an existing hospitalization 
• a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• a congenital anomaly/birth defect 
• based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition (examples of such events include allergic bronchospasm requiring intensive 
treatment in the 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). 
Unexpected Adverse Event: An AE is unexpected if it is not listed in the investigator’s 
brochure or package insert (for marketed products) or is not listed at the specificity or severity 
that has been observed. It is the responsibility of the IND sponsor to make this determination. 

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Serious and Unexpected Suspected Adverse Reaction (SUSAR): A SUSAR is an SAR that is 
both serious and unexpected. 
Unanticipated Problem: A UP is any event, incident, experience, or outcome that meets all of 
the following criteria: 
1. Unexpected (in terms of nature, severity, or frequency) given (a) the research risks that 
are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document, and (b) the characteristics of the participant 
population being studied; and 
2. Related or possibly related to participation in the research (possibly related means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused 
by the procedures involved in the research); and 
3. Suggests that the research places participants or others (which may include research staff, 
family members, or other individuals not directly participating in the research) at a 
greater risk of harm (including physical, psychological, economic, or social harm) related 
to the research than was previously known or expected. (Per the IND sponsor, an AE 
with a serious outcome will be considered increased risk.) 
Unanticipated Problem that is not an Adverse Event (UPnonAE): A UP that does not fit the 
definition of an AE, but which may, in the opinion of the investigator, involve risk to the 
participant, affect others in the research study, or significantly impact the integrity of research 
data. Such events would be considered non-serious UPs. For example, we will report occurrences 
of breaches of confidentiality, accidental destruction of study records, or unaccounted-for study 
drug. 
Protocol Deviation: Any change, divergence, or departure from the IRB-approved research 
protocol. 
1. Major deviations: Deviations from the IRB-approved protocol that have, or may have the 
potential to, negatively impact, the rights, welfare or safety of the subject, or to 
substantially negatively impact the scientific integrity or validity of the study. 
2. Minor deviations: Deviations that do not have the potential to negatively impact the 
rights, safety, or welfare of subjects or others, or the scientific integrity or validity of the 
study. 
Non-compliance: Failure of investigator(s) to follow the applicable laws, regulations, or 
institutional policies governing the protection of human subjects in research, or the requirements 
or determinations of the IRB, whether intentional or not. 
1. Serious non-compliance: Non-compliance, whether intentional or not, that results in harm 
or otherwise materially compromises the rights, welfare and/or safety of the subject. 

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Non-compliance that materially affects the scientific integrity or validity of the research 
may be considered serious non-compliance, even if it does not result in direct harm to 
research subjects. 
2. Continuing non-compliance: A pattern of recurring non-compliance that either has 
resulted, or, if continued, may result in harm to subjects or otherwise materially 
compromise the rights, welfare and/or safety of subjects, affect the scientific integrity of 
the study or validity of the results. The pattern may comprise repetition of the same 
non-compliant action(s), or different noncompliant events. Such non-compliance may be 
unintentional (e.g., due to lack of understanding, knowledge, or commitment), or 
intentional (e.g., due to deliberate choice to ignore or compromise the requirements of 
any applicable regulation, organizational policy, or determination of the IRB). 
 Documenting, Recording, and Reporting Adverse Events 
All AEs occurring from the baseline visit through the final study visit will be documented, 
recorded, and reported. 
At each contact with the participant, information regarding AEs will be elicited by appropriate 
questioning and examinations and will be: 
• immediately documented in the participant’s medical record/source document, 
• recorded in CRIMSON, and 
• reported as outlined below (eg, IND sponsor, IRB, and FDA). 
If a diagnosis is clinically evident (or subsequently determined), the diagnosis rather than the 
individual signs and symptoms or lab abnormalities will be recorded as the AE. 
A laboratory abnormality will not be reported as an AE if ALL of the following criteria are met: 
• It is no more than “Grade 1” or “Mild” per the protocol-specified toxicity table (or 
investigator assessment if not listed on the table); AND 
• It does NOT require an intervention (eg, discontinuation of treatment, dose 
reduction/delay, additional assessments, or treatment); AND 
• It is assessed by the PI as NOT related to the study agent(s); AND 
• It is assessed by the PI as NOT clinically significant (eg, the abnormal value does NOT 
suggest a disease or organ toxicity). 
All abnormal laboratory findings will be reviewed on a routine basis by the PI to identify 
potential safety signals. An abnormal lab not included on the toxicity table should be assessed in 
a similar fashion to the criteria above. 

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 Investigator Assessment of Adverse Events 
The investigator will assess all AEs with respect to seriousness (criteria listed above), severity 
(intensity or grade), and causality (relationship to study agent and relationship to research) 
according to the following guidelines. 
 
Severity 
The Investigator will grade the severity of each AE according to the CTCAE v 5.0, which can be 
found at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
Causality 
Causality (likelihood that the event is caused by the study agent) will be assessed considering the 
factors listed under the following categories: 
Definitely Related 
• reasonable temporal relationship 
• follows a known response pattern 
• clear evidence to suggest a causal relationship 
• there is no alternative etiology 
Probably Related 
• reasonable temporal relationship 
• follows a suspected response pattern (based on similar agents) 
• no evidence of a more likely alternative etiology 
Possibly Related 
• reasonable temporal relationship 
• little evidence for a more likely alternative etiology 
Unlikely Related 
• does not have a reasonable temporal relationship 
OR 
• good evidence for a more likely alternative etiology 
Not Related 
• does not have a temporal relationship 
OR 
• definitely due to an alternative etiology 

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Note: Other factors (eg, dechallenge, rechallenge) should also be considered for each causality 
category when appropriate. Causality assessment is based on available information at the time of 
the assessment of the AE. The investigator may revise the causality assessment as additional 
information becomes available. 
 Investigator Reporting Responsibilities to the Sponsor 
 
Adverse Events 
AE data will be submitted to the IND sponsor when requested for periodic safety assessments, 
review of IND annual reports, review of IND safety reports, and preparation of final study 
reports. 
 
Serious Adverse Events 
All SAEs (regardless of relationship and whether or not they are also UPs) must be reported on 
the safety expedited report form (SERF) and sent to the CSO by fax or email attachment. Deaths 
and immediately life-threatening SAEs must be reported to the CSO within 1 business day after 
the site becomes aware of the event. All other SAEs must be reported within 3 business days of 
site awareness. 
CSO CONTACT INFORMATION: 
Clinical Safety Office 
5705 Industry Lane 
Frederick, MD 21704 
Phone: 301-846-5301 
Fax: 301-846-6224 
E-mail: rchspsafety@mail.nih.gov   
SAEs that have not resolved by the end of the follow-up period are followed until final outcome 
is known. If it is not possible to obtain a final outcome for an SAE (eg, the participant is lost to 
follow-up), the reason a final outcome could not be obtained will be recorded by the investigator 
on the AE case report form and the SERF. 
SAEs that occur after the final study visit that are reported to and are assessed by the investigator 
to be possibly, probably, or definitely related to study drug must be reported to the CSO. 
 
Unanticipated Problems 
Ups that are also AEs must be reported to the CSO by fax or e-mail attachment using the NIH 
Problem Report Form no later than 7 calendar days of site awareness of the event. UPs that are 
not AEs are not reported to the CSO.  

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Pregnancy 
All pregnancies will be reported on the Pregnancy Notification/Outcome Form to the CSO 
within 1 business day from site awareness. 
Pregnancy outcome data (eg, delivery outcome, spontaneous or elective termination of the 
pregnancy) will be reported to the CSO within 3 business days of the site’s awareness. 
Although pregnancy itself is not an AE, events that meet SAE criteria during pregnancy, 
delivery, or in the neonate (eg, congenital anomaly/birth defect) are reportable on the SERF. 
In the event of pregnancy, the following steps will be taken: 
• Discontinue the study agent and procedures but continue to follow-up for safety. 
• Unblind the participant. 
• Study team will enroll participant in pregnancy registry. 
• Report to the DSMB. 
• Advise research participant to notify the obstetrician of study participation and study 
agent exposure. 
 Sponsor’s Reporting Responsibilities 
SUSARs, as defined in Title 21 of the United States Code of Federal Regulations (CFR) 
Part 312.32 and determined by the IND sponsor, will be reported to FDA and all participating 
investigators as IND Safety Reports. 
The IND sponsor will also submit an IND Annual Report of the progress of the investigation to 
the FDA as defined in 21 CFR 312.33. 
 Pausing Rules for Individual Participants 
Pausing is the suspension of administration of study agent to a single participant until a decision 
is made whether or not to resume administration of the study agent. 
The pausing criteria for a single participant in this study include any of the following: 
• A participant experiences an SAE that is unexpected and possibly, probably, or definitely 
related to a study agent. 
• A participant experiences two grade 3 or greater AE that is unexpected and possibly, 
probably, or definitely related to a study agent. 
• A participant develops a serious infection or an opportunistic infection, per the sarilumab 
package insert.13 
• A participant develops one of the following lab abnormalities, per the sarilumab package 
insert:13 

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o ANC < 1000/µL. 
o Platelet count < 100,000/µL. 
o ALT or AST > 3.0 × ULN. 
• Any safety issue that the site investigator determines should pause administration of a 
study agent to a single participant. 
 
Reporting a Pause 
If a pausing criterion is met, then a description of the AE(s) or safety issue must be reported by 
the PI or designee within 1 business day to the CSO and the DSMB by fax or email, and to the 
IRB according to their requirements. 
 
Resumption of a Paused Participant 
The CSO, in collaboration with the PI, will determine whether or not it is safe to resume 
administration of the study agent to the participant. The PI will notify the IRB of the decision on 
resumption of the study agent. If the pause was initiated because of lab abnormalities, then per 
the sarilumab package insert upon resumption, the sarilumab dose may be reduced from 200 to 
150 mg after lab values return to stated thresholds.13 The decision to modify the dose will be 
made by the PI in consultation with the CSO, and reported to the DSMB. The sarilumab dose can 
be raised to 200 mg again as clinically appropriate, at the discretion of the PI, CSO, and/or 
DSMB. 
 
Discontinuation of Study Agent for Individual Participants 
Permanent discontinuation of study drug will occur per the sarilumab package insert if:13 
• ANC < 500/mL. 
• Platelet count < 50,000/µL. 
• ALT > 5 × ULN 
Participants who do not resume study agent during the randomized, double-blind portion of the 
study will continue to be followed for 16 weeks, and then be encouraged to have an early 
termination visit (section 6.2.6). Participants who do not resume study agent during the 
open-label portion will be encouraged to have an early termination visit (section 6.3.3) shortly 
after the decision is made not to resume. 
 Halting Rules for the Protocol 
Halting the study requires immediate discontinuation of study agent administered for all 
participants and suspension of enrollment until a decision is made whether or not to continue 
enrollment and study agent administration. 

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The halting rules are: 
• 2 or more participants experience the same or similar SAEs that are unexpected and 
possibly, probably, or definitely related to the study agent; 
OR 
• 2 or more of the same or similar AEs in different participants that are grade 3 or above 
and are unexpected and possibly, probably, or definitely related to the study agent; 
OR 
• any safety issue that the PI determines should halt the study. 
The PI and/or CSO will determine if the study should be halted. In addition, the FDA may halt 
the study at any time following review of any safety concerns. 
 
Reporting a Study Halt 
If a halting rule is met, then a description of the AE(s) or safety issue must be reported by the PI 
or designee within 1 business day to the CSO and the DSMB by fax or email, and to the IRB 
according to their requirements. 
 
Resumption of a Halted Study 
The IND sponsor, in collaboration with the PI, the DSMB, and any specified safety review team 
will determine if it is safe to resume the study. The PI will notify the IRB of the decision on 
resumption of the study. 
 
Discontinuation of Study Agent 
Participants who do not resume study agent during the randomized, double-blind portion of the 
study will continue to be followed for safety for 16 weeks, and then be encouraged to have an 
early termination visit (section 6.2.6). Participants who do not resume study agent during the 
open-label portion will be encouraged to have an early termination visit (section 6.3.3) shortly 
after the decision is made not to resume. 
 Withdrawal Criteria for an Individual Participant 
An individual participant will be withdrawn for any of the following: 
• An individual participant’s decision. (The investigator should attempt to determine the 
reason for the participant’s decision.) 
• Non-compliance with study procedures to the extent that it is potentially harmful to the 
participant or to the integrity of the study data. 
• A participant misses more than 1 dose of study drug during the randomized portion of the 
study. 

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• The investigator determines that continued participation in the study would not be in the 
best interest of the participant. 
Participants who wish to withdraw from the study will be encouraged to have an early 
termination visit (sections 6.2.6 or 6.3.3). 
 
Additional Participant Randomization Following Withdrawn Participant or 
Participants Who Discontinue Study Treatment 
Any participant who does not complete the study or misses a dose or requires dose reduction 
through the post-treatment visit (section 6.2.5) may be replaced by an additional randomized 
participant. However, all randomized participants will be strongly encouraged to complete all 
study follow-up, and all randomized participants will be included in the data set for analysis even 
if their follow-up assessments are incomplete. 
 Safety Oversight 
 
Safety Review and Communications Plan 
A safety review and communications plan (SRCP) has been developed for the protocol. The 
SRCP is an internal communications document between the PI and the CSO, which delineates 
the safety oversight responsibilities of the PI, the CSO, and other stakeholders. The SRCP also 
includes the overall plan for conducting periodic safety surveillance assessments. 
 
Sponsor Medical Monitor 
A medical monitor, representing the IND sponsor (OCRPRO), has been appointed for oversight 
of safety in this clinical study. The sponsor medical monitor will be responsible for performing 
safety assessments as outlined in the SRCP. 
 
Data and Safety Monitoring Board 
The NIAID intramural DSMB includes independent experts that do not have direct involvement 
in the conduct of the study and have no significant conflicts of interests as defined by NIAID 
policy. The DSMB will review the study prior to initiation and twice a year thereafter, and may 
convene additional reviews as necessary. The board will review the study data to evaluate the 
safety, efficacy, study progress, and conduct of the study. These reports will be confidential to 
the DSMB, with data partially unblinded (ie, by treatment group with dummy labels). All SAEs, 
all Ups, and all IND Safety Reports will be reported by the PI to the DSMB at the same time 
they are submitted to the IND sponsor. The PI will notify the DSMB of any cases of intentional 
or unintentional unblinding in writing within 1 business day after site awareness and as soon as 
possible via email to the DSMB mailbox (niaiddsmbia@niaid.nih.gov) outlining the reason for 
the unblinding and the date it occurred. The PI will notify the board at the time pausing or 

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halting criteria are met and obtain a recommendation concerning continuation, modification, or 
termination of the study. 
13 Reporting Procedures  
 Reporting to the NIH IM IRB 
UPs, non-compliance, and other reportable events will be reported to the NIH IM IRB according 
to NIH HRPP Policy 801. 
 Reporting to the NIAID Clinical Director 
The principal investigator will report UPs, major protocol deviations, and deaths to the NIAID 
clinical director according to institutional timelines. 
14 Site Monitoring Plan 
According to the International Council on Harmonisation (ICH) E6(R2) Good Clinical Practice 
(GCP) guidelines section 5.18, and 21 CFR 312.50, clinical protocols are required to be 
adequately monitored by the study sponsor. This study monitoring will be conducted according 
to the “NIAID Intramural Clinical Monitoring Guidelines.” Monitors under contract to the 
NIAID/OCRPRO will visit the clinical research site to monitor aspects of the study in 
accordance with the appropriate regulations and the approved protocol. The objectives of a 
monitoring visit will be: 1) to verify the existence of signed informed consent documents and 
documentation of the consent process for each monitored participant; 2) to verify the prompt and 
accurate recording of all monitored data points in CRIMSON and prompt reporting of all SAEs; 
3) to compare abstracted information entered into CRIMSON with individual participants’ 
records and source documents (participants’ charts, laboratory analyses and test results, 
physicians’ progress notes, nurses’ notes, and any other relevant original participant 
information); and 4) to help ensure investigators are in compliance with the protocol. The 
monitors also will inspect the clinical site regulatory files to ensure that regulatory requirements 
(Office for Human Research Protections [OHRP], FDA) and applicable guidelines (ICH GCP) 
are being followed. During the monitoring visits, the investigator (and/or designee) and other 
study personnel will be available to discuss the study progress and monitoring visit. 
The investigator (and/or designee) will make study documents (eg, consent forms, CRIMSON 
data abstracts) and pertinent hospital or clinical records, including CRIMSON, readily available 
for inspection by the local IRB, FDA, the site monitors, and the NIAID staff for confirmation of 
the study data. 
A specific protocol monitoring plan will be discussed with the PI and study staff prior to 
enrollment. The plan will outline the frequency of monitoring visits based on such factors as 
study enrollment, data collection status, and regulatory obligations. 

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15 Statistical Considerations 
 Study Hypotheses 
The primary hypothesis is that the MC-QoL at 16 weeks will be different in the 
sarilumab-treated participants than in the placebo participants. This is a two-sided alpha = 0.05 
test and will be covariate-adjusted by the baseline MC-QoL score. 
 Sample Size Justification 
The sample size of 15 per arm is limited by the number of patients available to study. In this 
section, statistical power is evaluated for a possible treatment effect. The distribution of the total 
MC-QoL measurement was informed by Siebenhaar et al.11 Since the data are not normally 
distributed and the scale is constrained between 0 and 100, a beta distribution with parameters 
1.30, 2.41 (multiplied by 100), to match the mean and standard deviation of 35 and 22 as seen in 
Table 7 of Siebenhaar was used to simulate power.11 This distribution appears quite consistent 
with the box plot shown in Figure 1 of Siebenhaar. The Siebenhaar paper also reports a high 
intraclass correlation of 0.9 for measurements 2 weeks apart, suggesting a strong correlation 
between the baseline and 16-week scores is plausible; thus, a correlation of 0.7 was assumed in 
the simulation. While the treatment effect is unknown, power was determined under the 
assumption that the percentage decline in MC-QoL in the sarilumab-treated arm would be 60% 
and 10% in the placebo arm (some improvement was anticipated in the placebo arm because 
these individuals know they might be getting an active treatment). As noted previously, this 
difference between the arms on MC-QoL is considered clinically meaningful.   
The simulation of the trial data was performed as follows. The first step was to generate bivariate 
standard normal variables with correlation of 0.7. Then the cumulative distribution function of 
each of these was applied to an inverse cumulative distribution function of a beta with 
parameters 1.30 and 2.41, yielding pairs of Beta (1.30, 2.41) variables with approximate 
correlation of 0.7. For example, if a pair of bivariate standard normal generated is 0.880 and 
0.642, then these values are transformed to 0.563 and 0.497, respectively, as the probability that 
a Beta (1.30, 2.41) variable is less than 0.563 equals Φ (0.880), and 0.497 is determined likewise. 
All beta variables were multiplied by 100 to match the MC-QoL scale. The first member of the 
pair represented the baseline MC-QoL, and since the protocol excludes MC-QoL under 25, pairs 
with baseline < 25 were then excluded from all simulated trials. Within each replication, 15 
eligible pairs were assigned to the active drug arm, and 15 to the placebo arm. The second 
member of each pair was multiplied by (1 – the assumed decline for their respective treatment 
group), representing the 16-week MC-QoL value. Finally, to reflect the integer scores of the 
scale, all baseline and 16-week values were rounded to the closest integer. 
Under the above assumptions, the simulation indicated that a baseline covariate adjusted 
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sarilumab-treated arm has superior MC-QoL to the placebo arm. It is noted that this power 
estimate could be too optimistic, as it is based on limited knowledge of and speculation about the 
distribution of MC-QoL scores, the correlation between baseline and 16 weeks, and the specific 
nature of the treatment benefit.   
Randomization will continue until there are 30 participants who initiate study drug and have at 
least the first post-baseline QoL measurement at 4 weeks. Note that participants who do not meet 
these criteria still remain in the study, and attempts to obtain subsequent QoL measures should 
be made. 
 Description of the Analyses 
• Safety analysis: descriptive tabulations of AEs will be constructed. These tabulations will 
also be stratified by severity. 
• Efficacy analysis: the primary analysis of the primary efficacy endpoint will compare 
treatment groups with a regression analysis, adjusted for baseline QoL. A number of 
sensitivity analyses are planned for the primary analysis if there are participants with 
missing data at 16 weeks. Baseline adjusted regression analysis and Wilcoxon rank sum 
tests will also be applied to a range of efficacy endpoints. Descriptive summaries and 
graphics will also be provided. 
 Planned Interim Analyses  
No interim analyses are planned. 
 Final Analysis Plan 
Several study populations are defined. The intent-to-treat (ITT) population includes all 
randomized participants. The modified intent-to-treat (mITT) population includes all participants 
who received at least one dose of sarilumab or placebo. The second modified intent-to-treat 
(mITT2) population further excludes the participants with no post-baseline data on the MC-QoL. 
The third modified intent-to-treat (mITT3) population excludes participants without 16-week 
MC-QoL data. The per protocol (PP) population only includes all participants with available data 
on 16-week MC-QoL and who report taking more than 80% of study drug. 
The primary analysis will compare the groups with respect to the primary endpoint, the 16-week 
MC-QoL score in the mITT population using linear regression with an indicator for treatment 
group and the baseline MC-QoL value as a covariate. While the goal is that all participants will 
have a 16-week MC-QoL regardless of whether they continue drug throughout, the last observed 
value of MC-QoL will be carried forward to serve as the primary endpoint in the primary 
analysis for those participants without 16-week values. (This includes carrying the baseline value 

Sarilumab for Treatment of ISM 
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18 NOV 2020 
 
Page 45 of 77 
forward, if there are no post-baseline measurements). The test will be two-sided with a 0.05 
alpha level.   
While the goal is to assess all participants at 16 weeks, regardless of whether they continue with 
study drug, it is possible that some participants will have missing MC-QoL at 16 weeks. The 
planned primary analysis, using last observation carried forward, implicitly assumes that study 
participants who stop getting QoL assessments will be in a stable state, such that the last 
observed measurement is a reasonable imputation for the 16 week visit. However, to assess the 
robustness of these results, several sensitivity analysis will be conducted, that implicitly make 
different assumptions. We will conduct a mixed effects model analysis incorporating all 
available MC-QoL measurements (this will test the treatment effect at week 16; specifically it 
will analyze the post-baseline visit timepoints as categorical, and will adjust for the baseline QoL 
as a covariate.). Another approach imputes participants with missing data at 16 weeks as having 
the worst scores with a Wilcoxon rank sum test on percent improvement, will be conducted in 
the mITT population. If there is more than 15% missing data on the 16-week MC-QoL in the 
mITT population, inverse probability weighting approaches to the linear regression analysis will 
be done as well in the mITT and ITT populations. Additionally, if the results remain unclear due 
to missing data, pattern mixture analyses allowing for worse than expected outcomes in those 
with missing data may be explored. 
Other sensitivity analyses will be conducted regardless of whether there are missing data at 
16 weeks. We will repeat the primary analysis in the PP population, the mITT2 and mITT3 
populations. We will repeat the regression analysis but with a log transformation to both QoL 
values. To be robust from non-normality, a Wilcoxon rank sum test will also be used to compare 
the 16-week QoL values in the various analysis populations. Finally, graphical representation of 
each participant’s MC-QoL trajectories over time, color coded by treatment assignment will be 
constructed. 
Baseline adjusted linear regression and Wilcoxon rank sum test will also be used for the 
secondary and exploratory endpoints. If critical to interpretation, some sensitivity analyses may 
be conducted. 
A 95% confidence interval of the difference in median percentage improvement will be 
calculated using a bootstrap. Similarly, standard normal 95% confidence intervals for difference 
in mean 16-week values, and difference in the mean change from baseline values will be 
presented. Graphical presentations of baseline and 16 weeks values changes will be completed.   
Exploratory analyses might consider analyses with additional covariates and results within 
subgroups. 
Analyses of AEs will be descriptive by study arm, and will also consider severity of AEs.   

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Page 46 of 77 
16 Ethics/Protection of Human Participants 
 Informed Consent Process 
Informed consent is a process where information is presented to enable persons to voluntarily 
decide whether or not to participate as a research subject. It is an ongoing conversation between 
the human research participant and the researchers which begins before consent is given and 
continues until the end of the participant’s involvement in the research. Discussions about the 
research will provide essential information about the study and include: purpose, duration, 
experimental procedures, alternatives, risks, and benefits. Participants will be given the 
opportunity to ask questions and have them answered. 
The participants will sign the informed consent document prior to undergoing any research 
procedures. The participants may withdraw consent at any time throughout the course of the trial. 
A copy of the informed consent document will be given to the participants for their records. The 
researcher will document the signing of the consent form in the participant’s medical record. The 
rights and welfare of the participants will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study. 
 Participant Confidentiality 
All records will be kept confidential to the extent provided by federal, state, and local law. The 
study monitors and other authorized representatives of the sponsor may inspect all documents 
and records required to be maintained by the investigator, including but not limited to, medical 
records. Records will be kept locked and all computer entry and networking programs will be 
done with coded numbers only. Clinical information will not be released without written 
permission of the participant, except as necessary for monitoring by the IRB, the FDA, NIAID, 
OHRP, the pharmaceutical supporter, or the sponsor’s designee. 
17 Data Handling and Record Keeping 
 Data Capture and Management  
Study data will be maintained in CRIMSON and collected directly from participants during 
study visits and telephone calls or will be abstracted from participants’ medical records. Source 
documents include all recordings of observations or notations of clinical activities and all reports 
and records necessary to confirm the data abstracted for this study. Data entry into CRIMSON 
will be performed by authorized individuals. The investigator is responsible for assuring that the 
data collected are complete, accurate, and recorded in a timely manner. 

Sarilumab for Treatment of ISM 
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Page 47 of 77 
 Record Retention 
The investigator is responsible for retaining all essential documents listed in the ICH GCP 
guidelines. Study records will be maintained by the PI according to the timelines specified in 
21 CFR 312.62 or a minimum of 5 to 7 years, and in compliance with institutional, IRB, state, 
and federal medical records retention requirements, whichever is longest. All stored records will 
be kept confidential to the extent required by federal, state, and local law. 
Should the investigator wish to assign the study records to another party and/or move them to 
another location, the investigator will provide written notification of such intent to 
OCRPRO/NIAID with the name of the person who will accept responsibility for the transferred 
records and/or their new location. NIAID will be notified in writing and written 
OCRPRO/NIAID permission shall be obtained by the site prior to destruction or relocation of 
research records. 

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18 Scientific References 
1. 
Horny HP, Metcalfe DD, Akin C, et al. Mastocytosis. In: Swerdlow SH, ed. WHO 
classification of tumours of haematopoietic and lymphoid tissues. Vol 4th ed. Lyon, 
France: International Agency for Research on Cancer; 2008:62-69. 
2. 
Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 
2015;16(5):448-457. 
3. 
Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M. IL-6/IL-6 receptor system 
and its role in physiological and pathological conditions. Clin Sci (Lond). 
2012;122(4):143-159. 
4. 
Brockow K, Akin C, Huber M, Metcalfe DD. IL-6 levels predict disease variant and 
extent of organ involvement in patients with mastocytosis. Clin Immunol. 
2005;115(2):216-223. 
5. 
Fujii K, Ohgou N. Up-regulation of IL-6 mRNA in peripheral blood mononuclear cells of 
patients with acute urticaria. J Dermatol. 2004;31(3):242-243. 
6. 
Kasperska-Zajac A, Sztylc J, Machura E, Jop G. Plasma IL-6 concentration correlates 
with clinical disease activity and serum C-reactive protein concentration in chronic 
urticaria patients. Clin Exp Allergy. 2011;41(10):1386-1391. 
7. 
Mayado A, Teodosio C, Garcia-Montero AC, et al. Increased IL6 plasma levels in 
indolent systemic mastocytosis patients are associated with high risk of disease 
progression. Leukemia. 2016;30(1):124-130. 
8. 
Morjaria JB, Babu KS, Vijayanand P, Chauhan AJ, Davies DE, Holgate ST. Sputum IL-6 
concentrations in severe asthma and its relationship with FEV1. Thorax. 2011;66(6):537. 
9. 
Desai A, Jung MY, Olivera A, et al. IL-6 promotes an increase in human mast cell 
numbers and reactivity through suppression of suppressor of cytokine signaling 3. J 
Allergy Clin Immunol. 2016. 
10. 
Kim DK, Beaven MA, Kulinski JM, et al. Regulation of Reactive Oxygen Species and 
the Antioxidant Protein DJ-1 in Mastocytosis. PloS one. 2016;11(9):e0162831. 
11. 
Siebenhaar F, von Tschirnhaus E, Hartmann K, et al. Development and validation of the 
mastocytosis quality of life questionnaire: MC-QoL. Allergy. 2016;71(6):869-877. 
12. 
Strand V, Burmester GR, Ogale S, Devenport J, John A, Emery P. Improvements in 
health-related quality of life after treatment with tocilizumab in patients with rheumatoid 
arthritis refractory to tumour necrosis factor inhibitors: results from the 24-week 
randomized controlled RADIATE study. Rheumatology. 2012;51(10):1860-1869. 
13. 
Kevzara [package insert]. Regeneron Pharmaceuticals, Inc., Tarrytown, NY; April 2018. 
http://products.sanofi.us/kevzara/kevzara.pdf  
14. 
June RR, Olsen NJ. Room for more IL-6 blockade? Sarilumab for the treatment of 
rheumatoid arthritis. Expert opinion on biological therapy. 2016;16(10):1303-1309. 
15. 
Sieper J, Braun J, Kay J, et al. Sarilumab for the treatment of ankylosing spondylitis: 
results of a Phase II, randomised, double-blind, placebo-controlled study (ALIGN). 
Annals of the rheumatic diseases. 2015;74(6):1051-1057. 
16. 
Lin P. Targeting interleukin-6 for noninfectious uveitis. Clinical ophthalmology. 
2015;9:1697-1702. 
17. 
Rafique A, Martin J, Blome M, Huant T, Ouyang A, Papadopoulos N. Evaluation of The 
Binding Kinetics and Functional Bioassay Activity of Sarilumab and Tocilizumab to the 

Sarilumab for Treatment of ISM 
Protocol Version 6.0 
18 NOV 2020 
 
Page 49 of 77 
Human IL-6 Receptor (IL-6R) Alpha. Abstract presented at: Annual European Congress 
of Rheumatology; June 12-15, 2013; Madrid, Spain. 
18. 
Heide R, Middelkamp Hup MA, Mulder PG, Oranje AP, Mastocytosis Study Group R. 
Clinical scoring of cutaneous mastocytosis. Acta dermato-venereologica. 
2001;81(4):273-276. 
19. 
Portenoy RK, Thaler HT, Kornblith AB, et al. The Memorial Symptom Assessment 
Scale: an instrument for the evaluation of symptom prevalence, characteristics and 
distress. European journal of cancer. 1994;30A(9):1326-1336. 

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Page 50 of 77 
Appendix A: Schedule of Procedures/Evaluations 
 
Procedures/Evaluations 
Screening 
Baselinea 
Study Drug Administration  
Peak 
Treatment 
Visit 
Post-
treatment 
Visit  
Early 
Termination 
visit 
Day −60 to 
−2 
Day -2 to 0 
Day 0 
Weeks 2, 6, 10, 14b 
Weeks 4, 8, 12 
Week 16c 
Week 28 
 
 
 
 
± 4 days 
± 4 days 
± 7 days 
± 7 days 
 
 
 
Dose 1 
Doses 2, (4, 6, 8)k 
Doses 3, 5, 7 
 
 
 
Assessments 
Informed consent 
Xd 
 
 
 
 
 
 
 
Randomizatione 
 
X 
 
 
 
 
 
 
Physical exam with vital signs 
Xf 
X 
 
X 
X 
X 
X 
X 
Medical/medication history 
X 
X 
 
X 
X 
X 
X 
X 
Assessment of ISM symptoms 
X 
X 
 
 
 
 
 
 
Assessment of Aes 
 
X 
X 
X 
X 
X 
X 
X 
Study drug administration 
 
X 
Xg 
Xg 
 
 
 
Diary review 
 
 
 
X 
X 
X 
X 
X 
Laboratory Evaluations 
CBC/diff 
X 
X 
 
 
X 
X 
X 
X 
Acute care, hepatic, mineral 
panels 
X 
X 
 
 
X 
X 
X 
X 
PT/PTT 
X 
X 
 
 
X 
X 
X 
X 
Pregnancy test (serum or urine) 
X 
X 
 
X 
X 
X 
X 
X 
Anti-HIV ½ antibody test 
X 
 
 
 
 
 
 
 
Hepatitis B and C antibody test, 
HBV DNA, and HCV RNA 
X 
 
 
 
 
 
 
 
QuantiFERON tuberculosis test 
X 
 
 
 
 
 
 
 
Total protein 
 
X 
 
 
X 
X 
X 
X 
Lipid panel 
 
X 
 
 
X 
X 
X 
X 
Serum tryptase 
X 
X 
 
 
X 
X 
X 
X 
CRP 
 
X 
 
 
X 
X 
X 
X 
Ultrasound of abdomen 
X 
 
 
 
 
X 
 
X 
Research Evaluations 
Blood draw for DNA collection 
 
X 
 
 
 
 
 
 
Blood draw for RNA collection 
 
X 
 
 
 
X 
 
X 
Serum storage 
 
X 
 
 
X 
X 
X 
X 
Serum for IL-6 levels 
 
X 
 
 
X 
X 
X 
X 
Plasma storage 
 
X 
 
 
X 
X 
X 
X 

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Procedures/Evaluations 
Screening 
Baselinea 
Study Drug Administration  
Peak 
Treatment 
Visit 
Post-
treatment 
Visit  
Early 
Termination 
visit 
Day −60 to 
−2 
Day -2 to 0 
Day 0 
Weeks 2, 6, 10, 14b 
Weeks 4, 8, 12 
Week 16c 
Week 28 
 
 
 
 
± 4 days 
± 4 days 
± 7 days 
± 7 days 
 
 
 
Dose 1 
Doses 2, (4, 6, 8)k 
Doses 3, 5, 7 
 
 
 
Whole blood storage 
 
X 
 
 
X 
X 
X 
X 
Serum markers of bone marrow 
resorption and deposition 
 
X 
 
 
 
X 
X 
X 
MC-QoL 
X 
X 
 
 
X 
X 
X 
X 
SCORMA   
X 
X 
 
 
X 
X 
X 
X 
MSAS 
X 
X 
 
 
X 
X 
X 
X 
MQLQ/MSAF 
X 
X 
 
 
X 
X 
X 
X 
Bone marrow biopsy and aspirate 
Xh 
 
 
 
 
X 
 
X 
Blood and bone marrow KIT 
D816V mutation analysis 
Xh 
Xi 
 
 
 
X 
Xi 
Xi 
Blood and bone marrow flow 
cytometry 
Xh 
Xi 
 
 
 
X 
Xi 
Xi 
Photography 
X 
Xj 
 
 
Xj 
X 
X 
X 
Skin punch biopsy 
 
Xj 
 
 
 
Xj 
 
Xj 
AE = adverse event; HBV = hepatitis B virus; HCV = hepatitis C virus; IL = interleukin; ISM = indolent systemic mastocytosis; MC-QoL = Mastocytosis Quality of Life 
Questionnaire; MSAS = Memorial Symptom Assessment Scale; Q2W = once every 2 weeks; SCORMA = scoring of mastocytosis index; X = to be performed. 
A 
Participants may be admitted as inpatients for this study visit. Procedures will be performed just once during this period. 
B 
At the discretion of the study team, instead of coming to the NIH for study visits on weeks 6, 10 and 14, participants can self-administer study drug at home. No other procedures 
will be done at these time points for participants who self-administer. 
C 
This visit will take 1-2 days as outpatients. 
D 
Informed consent will be obtained before any study procedures are conducted on this protocol. 
E 
Patients will be randomized to receive sarilumab or placebo. 
F 
The screening physical exam will include measurement of vital signs, height, and weight. 
G 
Sarilumab/placebo will be administered after the other study procedures have been completed. 
H 
Will be done at screening only if not done within the last 150 days on protocol 02-I-0277 or this protocol. 
I 
Only blood will be collected for KIT mutation analysis and flow cytometry at these visits. 
j 
Optional at these visits. 
k 
At visits 4, 6, 8, subjects may self inject at home. At these self administered injection timepoints, no assessments will occur. 
 
 
 

Sarilumab for Treatment of ISM 
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Page 52 of 77 
 
Open Administration Visits 
Final Study Visit 
Early Termination 
Visit 
 
Week 1a 
Week 7 
Week 19 
Week 31 
Week 43 
Week 55 
 
Procedures/Evaluations 
 
± 7 days 
± 14 days 
± 14 days 
± 14 days 
± 14 days 
 
Physical exam 
 
X 
X 
X 
X 
X 
X 
Medical/medication history 
 
X 
X 
X 
X 
X 
X 
AE assessment 
 
X 
X 
X 
X 
X 
X 
CBC/diff 
 
X 
X 
X 
X 
X 
X 
Acute care, hepatic, and mineral panels 
 
X 
X 
X 
X 
X 
X 
Lipid panel 
 
X 
 
X 
 
 
 
Pregnancy test (serum or urine) 
 
X 
X 
X 
X 
X 
X 
Serum tryptase 
 
X 
X 
X 
X 
X 
X 
Diary review 
 
X 
X 
X 
X 
X 
X 
Memory aid review 
 
X 
X 
X 
X 
X 
X 
Study drug administrationb 
X 
X 
X 
X 
X 
 
 
AE = adverse event; CBC = complete blood count. 
a 
Week 1 of the open administration portion of this study immediately follows the post-treatment visit. 
b 
Study drug will be administered after all other procedures have been completed. 
 
 
 

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Appendix B: Blood Volumes for Specimen Collection 
Evaluation 
Study visita 
Randomized, double-blinded, placebo-controlled treatment 
Optional open-label treatment 
 
Screening 
(days −60 
to −0) 
Baseline 
(days −2 
to −0) 
W4 
(± 4 
days) 
W8 
(± 4 
days) 
W12 
(± 4 
days) 
W16 
(± 7 
days) 
W28 
(± 7 
days) 
W7 
(± 7 
days) 
W19 
(± 14 
days) 
W31 
(± 14 
days) 
W43 
(± 14 
days) 
W55 
(± 14 
days) 
Early 
termination 
visit 
HIV testb,c 
8 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis testc,d 
(8) 
 
 
 
 
 
 
 
 
 
 
 
 
QuantiFERON Gold 
1 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
CBC/diffe 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
Acute care panele 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
Hepatic panele 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
Mineral panele 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
Lipid panele 
 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
 
(4) 
 
 
(4) 
Total proteine 
 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
 
 
 
 
 
(4) 
CRPe 
 
(4) 
(4) 
(4) 
(4) 
(4) 
(4) 
 
 
 
 
 
(4) 
PT/PTT 
3 
3 
3 
3 
3 
3 
3 
 
 
 
 
 
3 
Serum tryptase 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
DNA 
 
10 
 
 
 
 
 
 
 
 
 
 
 
RNA 
 
10 
 
 
 
10 
 
 
 
 
 
 
10 
Serum storage 
 
8 
8 
8 
8 
8 
8 
 
 
 
 
 
8 
IL-6 levels 
 
8 
8 
8 
8 
8 
8 
 
 
 
 
 
8 
Serum markers of bone marrow 
resorption and deposition 
 
4 
 
 
 
4 
4 
 
 
 
 
 
4 
Plasma storage 
 
10 
10 
10 
10 
10 
10 
 
 
 
 
 
10 
Whole blood storage 
 
3 
3 
3 
3 
3 
3 
 
 
 
 
 
3 
KIT D816V mutation 
1  
1 
 
 
 
1 
1 
 
 
 
 
 
1 
Flow cytometryf 
(1) 
(1) 
 
 
 
(1) 
(1) 
 
 
 
 
 
(1) 
Daily volume (mL) 
25 
69 
44 
44 
44 
59 
49 
12 
12 
12 
12 
12 
63 
Cumulative volume (mL) 
25 
94 
138 
182 
226 
285 
334 
346 
358 
370 
382 
394 
 
CBC/diff = complete blood count with differential; CRP = C-reactive protein; IL-6 = interleukin 6 ; PT/PTT = prothrombin/partial thromboplastin time; W = week. 
a 
Blood volumes are presented in mL. 
b 
Anti-HIV-1/2 antibodies test. 
c 
A single volume of blood will be collected for HIV and hepatitis tests. 
d 
Test for anti-hepatitis B and C antibodies, and hepatitis B and C RNA. 
e 
A single volume of blood will be collected for CBC/diff, acute care, hepatic, and mineral panels, CRP, and total protein. 
f 
A single volume of blood will be collected for the KIT D816V mutation analysis and flow cytometry. 
 

Sarilumab for Treatment of ISM 
Protocol Version 6.0 
18 NOV 2020 
 
Page 54 of 77 
Appendix C: Mastocytosis Quality of Life Questionnaire 

Participant Signature:_______________________________________ Date: _____________ 
Page 1 of 3 
MC-QoL 
Questionnaire Regarding Patient's Quality of Life with Mastocytosis 
Instructions: Dear patients, in the following questionnaire you will find a variety of questions regarding 
your quality of life. Please read through each question carefully and select one of the following five answers 
that best describes your symptoms. Please do not think too much about your answers but be careful to 
answer all the questions. Please provide one answer per question, i.e. please mark only one box per question.  
 
None 
Some-
what 
Moderately 
Very 
Very 
Much 
How severely were you affected by the following 
symptoms in the last 2 weeks?  
 
 
 
 
 
1. Itching 
❏ 
❏ 
❏ 
❏ 
❏ 
2. Skin Redness/Swelling 
❏ 
❏ 
❏ 
❏ 
❏ 
3. Sudden feeling of warmth and reddening of the 
face (Flush episodes) 
❏ 
❏ 
❏ 
❏ 
❏ 
4. Diarrhea/loose stools  
❏ 
❏ 
❏ 
❏ 
❏ 
5. Fatigue/Exhaustion 
❏ 
❏ 
❏ 
❏ 
❏ 
6. Headache 
❏ 
❏ 
❏ 
❏ 
❏ 
7. Muscle or joint pain  
❏ 
❏ 
❏ 
❏ 
❏ 
8. Difficulty concentrating 
❏ 
❏ 
❏ 
❏ 
❏ 
 
None 
Some-
what 
Moderately 
Very 
Very 
Much 
Please indicate how often you have been limited in your 
daily life in the areas listed below during the past 2 
weeks because of your mastocytosis. 
 
 
 
 
 
9. School/University/Work 
❏ 
❏ 
❏ 
❏ 
❏ 
10. Sport/Physical Activity 
❏ 
❏ 
❏ 
❏ 
❏ 
11. Sleep 
❏ 
❏ 
❏ 
❏ 
❏ 

Participant Signature:_______________________________________ Date: _____________ 
Page 2 of 3 
12. Sexual activity 
❏ 
❏ 
❏ 
❏ 
❏ 
13. Leisure time 
❏ 
❏ 
❏ 
❏ 
❏ 
14. Relationships (Friends, Family, Partner, co-
workers) 
❏ 
❏ 
❏ 
❏ 
❏ 
 
Never 
Seldom 
Occasionally 
Often 
Very 
often 
We would like to further study difficulties and problems 
that may be associated with your mastocytosis using the 
following questions. Please answer according to your 
experiences from the past 2 weeks. 
 
 
 
 
 
15. In the past 2 weeks, were you tired during the 
day because you did not sleep well at night?  
❏ 
❏ 
❏ 
❏ 
❏ 
16. In the past 2 weeks, did you have to change 
your choices of foods and drinks due to your 
mastocytosis? 
❏ 
❏ 
❏ 
❏ 
❏ 
17. Have you felt less capable in the past 2 weeks 
due to your mastocytosis? 
❏ 
❏ 
❏ 
❏ 
❏ 
18. Have you been burdened by the symptoms of 
your mastocytosis in the past 2 weeks? 
❏ 
❏ 
❏ 
❏ 
❏ 
19. Has your choice of what to wear been restricted 
in the past 2 weeks due to mastocytosis? 
❏ 
❏ 
❏ 
❏ 
❏ 
20. In the past 2 weeks, were you ever afraid you 
might suffer an allergic reaction due to 
mastocytosis? 
❏ 
❏ 
❏ 
❏ 
❏ 
21. In the past 2 weeks, were you ever afraid that 
you might receive the wrong treatment if you 
became or unconscious or suffered an accident 
due to your mastocytosis?  
❏ 
❏ 
❏ 
❏ 
❏ 
22. Have you felt uncomfortable in public during 
the past 2 weeks due to mastocytosis? 
❏ 
❏ 
❏ 
❏ 
❏ 
23. In the past 2 weeks, have you ever been afraid 
of the further worsening of your mastocytosis? 
❏ 
❏ 
❏ 
❏ 
❏ 
 

Participant Signature:_______________________________________ Date: _____________ 
Page 3 of 3 
 
Never 
Seldom 
Occasionally 
Often 
Very 
often 
In the past 2 weeks did you feel 
 
 
 
 
 
24. ...a lack of motivation? 
❏ 
❏ 
❏ 
❏ 
❏ 
25. ...alone with your illness? 
❏ 
❏ 
❏ 
❏ 
❏ 
26. ...concerned? 
❏ 
❏ 
❏ 
❏ 
❏ 
27. ...sad? 
❏ 
❏ 
❏ 
❏ 
❏ 

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Appendix D: Scoring of Mastocytosis (SCORMA) Index 

Participant Signature:_______________________________________ Date: _____________ 
 
MD Signature                                                                                   Date:                    
:_______________________________________ 
 
 

Sarilumab for Treatment of ISM 
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Appendix E: Memory Symptom Assessment Scale (MSAS) 

Participant Signature:_______________________________________ Date: _____________ 
Page 1 of 2 
MEMORIAL SYMPTOM ASSESSMENT SCALE 
Name 
Date 
Section 1 
Instructions: We have listed 24 symptoms below. Read each one carefully. If you have had the symptom during this past 
week, let us know how OFTEN you had it, how SEVERE it was usually and how much it DISTRESSED or BOTHERED 
you by circling the appropriate number. If you DID NOT HAVE the symptom, make an "X" in the box marked "DID 
NOT HAVE." 
DURING THE PAST WEEK 
Did you have any of the following 
symptoms? 
D 
I 
D 
N 
O 
T 
H 
A 
V 
E 
IF YES 
How OFTEN did you 
have it? 
IF YES 
How SEVERE was it 
usually 
IF YES 
How much did it 
DISTRESS or BOTHER 
you? 
Rarely 
Occasionally 
Frequently 
Almost 
Constantly 
Slight 
Moderate 
Severe 
Very Severe 
Not at all 
A Little Bit 
Somewhat 
Quite a Bit 
Very Much 
Difficulty concentrating 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Pain 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Lack of energy 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Cough 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Feeling nervous 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Dry mouth 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Nausea 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Feeling drowsy 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Numbness/tingling in 
hands/feet 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Difficulty sleeping 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Feeling bloated 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Problems with urination 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Vomiting 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Shortness of breath 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Diarrhea 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Feeling sad 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Sweats 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Worrying 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Problems with sexual 
interest or activity 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Itching 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Lack of appetite 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Dizziness 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Difficulty swallowing 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Feeling irritable 
1 
2 
3 
4 
1 
2 
3 
4 
0 
1 
2 
3 
4 

Participant Signature:_______________________________________ Date: _____________ 
Page 2 of 2 
Section 2 
INSTRUCTIONS: We have listed 8 symptoms below. Read each one carefully. If you have had the symptom during this past week, let 
us know how SEVERE it was usually and how much it DISTRESSED or BOTHERED you by circling the appropriate number. If you 
DID NOT HAVE the symptom, make an "X" in the box marked "DID NOT HAVE." 
DURING THE PAST WEEK, 
Did you have any of the following 
symptoms? 
D 
I 
D 
N 
O 
T 
H 
A 
V 
E 
IF YES 
How SEVERE was it 
usually? 
IF YES 
How much did it DISTRESS 
or BOTHER 
you? 
Slight 
Moderate 
Severe 
Very Severe 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
Mouth sores 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Change in the way food tastes 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Weight loss 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Hair loss 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Constipation 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Swelling of arms or legs 
1 
2 
3 
4 
0 
1 
2 
3 
4 
"I don't look like myself" 
1 
2 
3 
4 
0 
1 
2 
3 
4 
Changes in skin 
1 
2 
3 
4 
0 
1 
2 
3 
4 
IF YOU HAD ANY OTHER SYMPTOMS DURING THE PAST WEEK, PLEASE LIST BELOW 
AND INDICATE HOW MUCH THE SYMPTOM HAS DISTRESSED OR BOTHERED YOU. 
Other: 
0 
1 
2 
3 
4 
Other: 
0 
1 
2 
3 
4 
Other: 
0 
1 
2 
3 
4 
 

Sarilumab for Treatment of ISM 
Protocol Version 6.0 
18 NOV 2020 
 
Page 63 of 77 
Appendix F: The Mastocytosis Quality of Life Questionnaire (MQLQ) 

Participant Signature:_______________________________________ Date: _____________ 
Page 1 of 6 
The Mastocytosis Quality of Life Questionnaire (MQLQ) 
The signs and symptoms of mastocytosis vary from person to person. The following 49 questions are 
indented to determine the symptoms you have as a result of your mastocytosis and the burden of these 
symptoms on your daily life. The questions can be answered by checking the box that is most applicable 
to you. There are seven possible answers: 
0 
 
None, or not 
applicable 
1 
 
Hardly 
2 
 
Somewhat 
3 
 
Moderately 
4 
 
Considerably 
5 
 
Severely 
6 
  
Worst possible 
To what extend does mastocytosis trouble you, because  
1. it causes your job to require more energy?  
0 
 
1 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
6 
  
 
2. it causes you to feel somber? 
 
 
 
 
 
 
 
3. it makes it necessary for you to go to bed earlier 
on workdays? 
 
 
 
 
 
 
 
4 it reduces your capability or makes you unable to 
work under stressful conditions? 
 
 
 
 
 
 
 
5. you are required to always carry a epinephrine 
auto-injector (e.g. Epi-Pen, Jext or Anapen)? 
 
 
 
 
 
 
 
6. you experience (near)fainting during a large 
mastocytosis attack (anaphylactic reaction)? 
 
 
 
 
 
 
 
7. your family needs to be aware of what to do in 
the case of a large mastocytosis attack (anaphylactic 
reaction)? 
 
 
 
 
 
 
 
8. of your immediate wariness when spotting a bee 
or wasp? 
 
 
 
 
 
 
 
9. of your children's immediate wariness when 
spotting a bee or wasp? 
 
 
 
 
 
 
 
 
 

Participant Signature:_______________________________________ Date: _____________ 
Page 2 of 6 
0 
 
None, or not 
applicable 
1 
 
Hardly 
2 
 
Somewhat 
3 
 
Moderately 
4 
 
Considerably 
5 
 
Severely 
6 
  
Worst 
possible 
To what extend does mastocytosis trouble you, because of 
10. your embarrassment for your skin 
abnormality? 
0 
 
1 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
6 
  
 
11. your itchy skin? 
 
 
 
 
 
  
12. your lower back pain? 
 
 
 
 
 
  
13. your physically exhausting flushing 
attacks? 
 
 
 
 
 
  
14. your reduced capability or inability to 
drink alcohol due to alcohol being a trigger 
for symptoms? 
 
 
 
 
 
  
15. your reduction in height? 
 
 
 
 
 
  
 
To what extend are you troubled by: 
16. uncertainty whether or not a symptom is 
caused by your mastocytosis? 
0 
 
1 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
6 
  
 
17. uncertainty about the course of your 
mastocytosis? 
 
 
 
 
 
 
 
18. fear of your mastocytosis progressing to a 
worse form of mastocytosis? 
 
 
 
 
 
 
 
19.  incomprehension of mastocytosis by your 
social surroundings (friends, family, 
colleagues)?  
 
 
 
 
 
 
 
20. the difficulty for others to understand 
mastocytosis? 
 
 
 
 
 
 
 

Participant Signature:_______________________________________ Date: _____________ 
Page 3 of 6 
 
 

Participant Signature:_______________________________________ Date: _____________ 
Page 4 of 6 
0 
 
None, or not 
applicable 
1 
 
Hardly 
2 
 
Somewhat 
3 
 
Moderately 
4 
 
Considerably 
5 
 
Severely 
6 
  
Worst 
possible 
 
To what extend are you troubled by: 
21. an apparent lack of knowledge of 
mastocytosis by some physicians?  
0 
 
1 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
6 
  
 
22. your social life suffering from 
mastocytosis? 
 
 
 
 
 
 
 
23. a large mastocytosis attack (anaphylaxis) 
being stressful for you? 
 
 
 
 
 
 
 
24. your skin abnormality being cosmetically 
unappealing? 
 
 
 
 
 
 
 
25. physical stress being a trigger for your 
mastocytosis symptoms?  
 
 
 
 
 
 
 
26. mental stress being a trigger for your 
mastocytosis symptoms?  
 
 
 
 
 
 
 
27. a temperature change being a trigger for 
your mastocytosis symptoms? 
 
 
 
 
 
 
 
28. your skin abnormalities increasing in 
number or size over time? 
 
 
 
 
 
 
 
29. your skin abnormalities becoming more 
visible over time? 
 
 
 
 
 
 
 
 
 
 

Participant Signature:_______________________________________ Date: _____________ 
Page 5 of 6 
0 
 
None, or not 
applicable 
1 
 
Hardly 
2 
 
Somewhat 
3 
 
Moderately 
4 
 
Considerably 
5 
 
Severely 
6 
  
Worst 
possible 
How often do you, because of your mastocytosis: 
30. suffer from flushing attacks? 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
31. suffer from a warm, glowing feeling ? 
 
 
 
 
 
 
 
32. suffer from a decrease in stamina? 
 
 
 
 
 
 
 
33. suffer from fatigue? 
 
 
 
 
 
 
 
Do you, because of your mastocytosis: 
34. feel worn out despite of only mild exertion? 
0 
 
1 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
6 
  
 
35. suffer from impaired short term memory? 
 
 
 
 
 
 
 
36. suffer from a lack of mental acuity or a 
reduced ability to think clearly? 
 
 
 
 
 
 
 
37. have trouble paying attention to 
conversations? 
 
 
 
 
 
 
 
38. suffer from itchy skin predominantly at 
night? 
 
 
 
 
 
 
 
39. suffer from stomach aches? 
 
 
 
 
 
 
 
40. suffer from loose stools? 
 
 
 
 
 
 
 
41. suffer from a reduced ability to 
concentrate? 
 
 
 
 
 
 
 
 

Participant Signature:_______________________________________ Date: _____________ 
Page 6 of 6 
0 
 
None, or not 
applicable 
1 
 
Hardly 
2 
 
Somewhat 
3 
 
Moderately 
4 
 
Considerably 
5 
 
Severely 
6 
  
Worst 
possible 
Do you, because of your mastocytosis: 
 
To what extent are you: 
 
42. feel that at one time the lack of 
knowledge on mastocytosis by doctors  has 
withheld adequate treatment from you? 
0 
 
1 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
6 
  
 
43. avoid certain activities (e.g. 
skating/skiing) for fear of incurring a 
fracture?    
 
 
 
 
 
 
 
44. avoid strenuous lifting for fear of 
incurring back pain or fractures? 
 
 
 
 
 
 
 
45. afraid that doctors unfamiliar with 
mastocytosis could prescribe a drug that 
could trigger an (anaphylactic) attack?  
0 
 
1 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
6 
  
 
46. frustrated by the current lack of a 
curative treatment for mastocytosis?  
 
 
 
 
 
 
 
47. worried about a proper treatment of a 
(anaphylactic) mastocytosis attack when 
visiting abroad?  
 
 
 
 
 
 
 
48. afraid to fall due to your greater risk of 
osteoporosis as a result of your 
mastocytosis?  
 
 
 
 
 
 
 
49. afraid to incur fractures while exercising 
due to your greater risk of osteoporosis as a 
result of your mastocytosis? 
 
 
 
 
 
 
 

Sarilumab for Treatment of ISM 
Protocol Version 6.0 
18 NOV 2020 
 
Page 69 of 77 
Appendix G: The Mastocytosis Symptoms Assessment Form (MSAF) 

Participant Signature:_______________________________________ Date: _____________ 
Page 1 of 1 
 
The Mastocytosis Symptoms Assessment Form (MSAF) 
Please note the severity of your mastocytosis symptoms in the following table. Marking a 0 indicates that the symptom 
is absent; whereas a 10 indicates that the symptom is very severe.  If you suffer from one of the listed symptoms but 
personally feel that it is not related to mastocytosis then please score it as a 0. 
Symptoms 
          0   (absent)       to       10    (very severe) 
Comment 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10  
Itchy skin 
 
 
 
 
 
 
 
 
 
 
 
 
Dizziness 
 
 
 
 
 
 
 
 
 
 
 
 
Headache 
 
 
 
 
 
 
 
 
 
 
 
 
Fatigue  (during the last week) 
 
 
 
 
 
 
 
 
 
 
 
 
Runny nose 
 
 
 
 
 
 
 
 
 
 
 
 
Shortness of breath 
 
 
 
 
 
 
 
 
 
 
 
 
Chest pain/palpitations 
 
 
 
 
 
 
 
 
 
 
 
 
Nausea/vomiting 
 
 
 
 
 
 
 
 
 
 
 
 
Diarrhea, stomach ache, cramps 
 
 
 
 
 
 
 
 
 
 
 
 
Bone pain/ muscle pain 
 
 
 
 
 
 
 
 
 
 
 
 
Concentration problems 
 
 
 
 
 
 
 
 
 
 
 
 
Depression, somberness 
 
 
 
 
 
 
 
 
 
 
 
 
Other, namely: ………..…….. 
 
 
 
 
 
 
 
 
 
 
 
 
Attacks, with or without loss of 
consciousness. 
Frequency per month 
 
 
……. 
Flushing 
Frequency per week 
 
……. 
 
Rate with a number from 1 to 10 how much influence fatigue has had, in the last 24 
hours, on: 
 
 
0   (no influence)      to    10  (maximum influence)  
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Activities (general) 
 
 
 
 
 
 
 
 
 
 
 
 
Mood/temper 
 
 
 
 
 
 
 
 
 
 
 
 
Mobility 
 
 
 
 
 
 
 
 
 
 
 
 
Chores 
 
 
 
 
 
 
 
 
 
 
 
 
Relationships  
 
 
 
 
 
 
 
 
 
 
 
 
Happiness 
 
 
 
 
 
 
 
 
 
 
 
 
Other, namely: ………..…….. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Sarilumab for Treatment of ISM 
Protocol Version 6.0 
18 NOV 2020 
 
Page 71 of 77 
Appendix H: Side Effect and Medication Change Diary 

A Phase 2 Randomized Double-Blinded Placebo-Controlled Study to Evaluate the Safety 
and Efficacy of Subcutaneous Sarilumab in Improving the Quality of Life in Subjects with 
Indolent Systemic Mastocytosis 
Participant Name _______________________________________________ 
 
If you develop an infection or you need to talk with a member of the study team for any reason, 
then please contact Dr. Hirsh Komarow at 301-594-2197 or komarowh@mail.nih.gov, or Robin 
Eisch at 301-443-1720 or Robin.Eisch@niaid.nih.gov. After business hours, please contact Dr. 
Hirsh Komarow at 301-272-5699 or Dr. Melody Carter at 240-476-0872. For emergencies, 
immediately call 911. 
Instructions 
Complete this diary any day you experience a symptom. Only mark which symptoms you have. 
If you do not have any symptoms on a particular day, then you can skip that day. Bring all pages 
with you to every study visit. We will review the diary at every visit. 
Severity 
Some people have reactions after receiving their injection of sarilumab or placebo. If you 
experience any of the symptoms listed in the table, then use the following categories to describe 
how severe each symptom was: 
• 1 = Mild. Minor discomfort that did not affect your usual activities. 
• 2 = Moderate. Noticeable discomfort that bothered you enough that you did not do as much 
as you usually do. 
• 3 = Severe. The symptom could not be ignored and stopped you from doing something you 
wanted or had to do. 
Redness or Swelling at Injection Site 
Some people experience redness or swelling in the area 
where they got their injection. If you experience redness 
or swelling, then measure the area of redness or swelling 
using the centimeter (cm) ruler at the bottom of this 
page, and record the measurement in the table. 
To measure the area of redness or swelling, measure the 
widest part of the area from left to right or top to bottom. 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
 
Example 

A Phase 2 Randomized Double-Blinded Placebo-Controlled Study to Evaluate the Safety and Efficacy of Subcutaneous 
Sarilumab in Improving the Quality of Life in Subjects with Indolent Systemic Mastocytosis 
Participant Name _______________________________________________ 
 
 
Side Effect Diary 
Symptom 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
Date: 
Severity 
(1-3) 
Severity 
(1-3) 
Severity 
(1-3) 
Severity 
(1-3) 
Severity 
(1-3) 
Severity 
(1-3) 
Severity 
(1-3) 
Injection Site Pain 
 
 
 
 
 
 
 
Redness at Injection 
Site (size in cm) 
 
 
 
 
 
 
 
Swelling at Injection 
Site (size in cm) 
 
 
 
 
 
 
 
Itchiness at Injection 
Site 
 
 
 
 
 
 
 
Cold Symptoms 
(ex, runny nose, fever) 
 
 
 
 
 
 
 
Hives (not at injections 
site) 
 
 
 
 
 
 
 
Other 
(Describe) 
 
 
 
 
 
 
 

A Phase 2 Randomized Double-Blinded Placebo-Controlled Study to Evaluate the Safety 
and Efficacy of Subcutaneous Sarilumab in Improving the Quality of Life in Subjects with 
Indolent Systemic Mastocytosis 
Participant Name _______________________________________________ 
 
Medication Change Diary 
Please complete the following table each time there is a change in your medication. Changes 
include starting a new medication, stopping a current medication, or changing the dose of a 
current medication. Record the medication name, what the change was (started taking, stopped 
taking, or changed dose), the date of the change, the reason why you took it, and the daily dose. 
Medication 
Change 
Change Date 
Reason 
Daily Dose 
Example: 
Aspirin 
Started taking 
9/1/17 
Headache 
81 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Sarilumab for Treatment of ISM 
Protocol Version 6.0 
18 NOV 2020 
 
Page 75 of 77 
Appendix I: Sarilumab Memory Aid 
 
 

A Phase 2 Randomized Double-Blinded Placebo-Controlled Study to Evaluate the Safety 
and Efficacy of Subcutaneous Sarilumab in Improving the Quality of Life in Subjects with 
Indolent Systemic Mastocytosis 
Memory aid: Sarilumab injection (150 or 200 mg) once every 2 weeks. 
 
Participant Name _______________________________________________ 
 
*If you develop a serious side effect, or you need to talk with a member of the study team for any reason, then 
please contact Dr. Hirsh Komarow at 301-594-2197 or komarowh@mail.nih.gov, or Robin Eisch at 301-443-1720 
or Robin.Eisch@niaid.nih.gov. After business hours, please contact Dr. Hirsh Komarow at 301-272-5699 or Dr. 
Melody Carter at 240-476-0872. 
 
 
STUDY WEEK 
DOSE NUMBER 
DATE 
TOOK SARILUMAB? (Y/N) 
1 
1 
 
GIVEN AT NIH 
3 
2 
 
YES ☐      NO ☐ 
5 
3 
 
YES ☐      NO ☐ 
7 
4 
 
GIVEN AT NIH 
9 
5 
 
YES ☐      NO ☐ 
11 
6 
 
YES ☐      NO ☐ 
13 
7 
 
YES ☐      NO ☐ 
15 
8 
 
YES ☐      NO ☐ 
17 
9 
 
YES ☐      NO ☐ 
19 
10 
 
GIVEN AT NIH 
21 
11 
 
YES ☐      NO ☐ 
23 
12 
 
YES ☐      NO ☐ 
25 
13 
 
YES ☐      NO ☐ 
27 
14 
 
YES ☐      NO ☐ 
29 
15 
 
YES ☐      NO ☐ 
31 
16 
 
GIVEN AT NIH 
33 
17 
 
YES ☐      NO ☐ 
35 
18 
 
YES ☐      NO ☐ 
37 
19 
 
YES ☐      NO ☐ 
39 
20 
 
YES ☐      NO ☐ 
41 
21 
 
YES ☐      NO ☐ 
43 
22 
 
GIVEN AT NIH 
45 
23 
 
YES ☐      NO ☐ 
47 
24 
 
YES ☐      NO ☐ 
49 
25 
 
YES ☐      NO ☐ 
51 
26 
 
YES ☐      NO ☐