Clinical trial NCT04008069
Conditions: Sarcoidosis
Keywords: glucocorticoid-dependent
Sponsor: Stanford University
Start date: 2019-09-03; Completion date: 2022-09-09
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the effectiveness and the safety of sarilumab in patients with glucocorticoid-dependent sarcoidosis.

Detailed description:
The purpose of this study is to compare the effectivness and the safety of sarilumab in patients with glucocorticoid-dependent sarcoidosis. To demonstrate that sarilumab treatment will be effective for inducing and maintaining glucocorticoid-free remission in male or female patients with biopsy proven active, glucocorticoid-dependent sarcoidosis affecting the lungs, lymph nodes, liver, kidneys, spleen, bone, soft tissues, skin, and/or eyes.

Arms: arm 1: On entering the study, all participants receive open-label sarilumab every two weeks for 16 weeks. arm 2: After completing the open-label period, participants are randomized in blinded fashion to receive sarilumab every two weeks for 12 weeks. arm 3: After completing the open-label period, participants are randomized in blinded fashion to receive placebo every two weeks for 12 weeks.
Interventions: intervention 1: Sarilumab intervention 2: Placebo
Intervention descriptions: intervention 1: Sarilumab 200 mg administered subcutaneously intervention 2: Placebo administered subcutaneously

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
A Phase II, Single-Site, Double-Blind, Placebo-Controlled Randomized 
Withdrawal Study Assessing the Efficacy and Safety of Sarilumab in 
Patients With Glucocorticoid-Dependent Sarcoidosis 
Study Protocol and Statistical Analysis Plan 
NCT04008069 
May 19, 2020 


 
 
 
TITLE: A phase II, single-site, double-blind, placebo-controlled randomized withdrawal 
study assessing the efficacy and safety of sarilumab in patients with glucocorticoid-dependent 
sarcoidosis 
 
Coordinating Center 
Stanford Rheumatology 
 
Palo Alto, CA 94304 
 
Protocol Director  
Matthew C. Baker, M.D. 
 
Palo Alto, CA 94304 
 
mbake13@stanford.edu 
 
Co-Investigators 
Yashaar Chaichian, M.D. 
 
Palo Alto, CA 94304 
 
ychaich@stanford.edu 
 
Study Coordinator 
 
 
Palo Alto, CA 94304 
 
 
 
Version 3 / Version Date:   19May2020 
 
 
 
 


 
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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS .............................................................................................................. 4 
SCHEMA ....................................................................................................................................... 7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 8 
1. OBJECTIVES ....................................................................................................................... 10 
1.1. 
PRIMARY OBJECTIVE .................................................................................................... 10 
1.2. 
SECONDARY OBJECTIVES ............................................................................................. 10 
2. BACKGROUND ................................................................................................................... 10 
2.1 
SARCOIDOSIS ................................................................................................................ 10 
2.2 
SARILUMAB .................................................................................................................. 10 
2.3 
RATIONALE .................................................................................................................. 13 
2.4 
STUDY DESIGN ............................................................................................................. 14 
2.5 
CORRELATIVE STUDIES BACKGROUND......................................................................... 14 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ........................ 14 
3.1 
INCLUSION CRITERIA .................................................................................................... 14 
3.2 
EXCLUSION CRITERIA ................................................................................................... 15 
3.3 
INFORMED CONSENT PROCESS ..................................................................................... 16 
3.4      
RANDOMIZATION PROCEDURES .................................................................................... 16 
3.5 
STUDY TIMELINE .......................................................................................................... 16 
4. TREATMENT PLAN .......................................................................................................... 16 
4.1 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ............. 17 
4.2 
CRITERIA FOR REMOVAL FROM STUDY ........................................................................ 17 
4.3 
ALTERNATIVES ............................................................................................................. 18 
5. INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION ................. 18 
5.1 
SARILUMAB .................................................................................................................. 18 
5.1.1 
SUMMARY OF NONCLINICAL STUDIES .......................................................................... 18 
5.1.2 
SUMMARY OF CLINICAL STUDIES ................................................................................. 19 
5.1.3 
INTERVENTION ............................................................................................................. 21 
5.2 
AVAILABILITY .............................................................................................................. 21 
5.3 
AGENT ORDERING ........................................................................................................ 22 
5.4 
AGENT ACCOUNTABILITY ............................................................................................ 22 
6. DOSE MODIFICATIONS ................................................................................................... 22 
7. ADVERSE EVENTS AND REPORTING PROCEDURES ............................................ 22 
7.1 
POTENTIAL ADVERSE EVENTS ...................................................................................... 22 
7.2 
ADVERSE EVENT REPORTING ....................................................................................... 22 
7.2.1 
SERIOUS ADVERSE EVENTS .......................................................................................... 23 
8. CORRELATIVE/SPECIAL STUDIES .............................................................................. 23 
8.1 
LABORATORY CORRELATIVE STUDIES ......................................................................... 23 
9. STUDY CALENDAR ........................................................................................................... 24 
10. MEASUREMENT .............................................................................................................. 25 


 
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10.1  
PRIMARY AND SECONDARY OUTCOME MEASURES ....................................................... 25 
11. REGULATORY CONSIDERATIONS ............................................................................ 25 
11.1 
INSTITUTIONAL REVIEW OF PROTOCOL ........................................................................ 25 
11.2 
DATA AND SAFETY MONITORING PLAN ....................................................................... 26 
11.3 
DATA MANAGEMENT PLAN .......................................................................................... 26 
12. STATISTICAL CONSIDERATIONS .............................................................................. 26 
12.1 
STATISTICAL DESIGN ................................................................................................... 26 
12.2 
RANDOMIZATION .......................................................................................................... 27 
12.3 
SAMPLE SIZE ................................................................................................................ 27 
13. REFERENCES ................................................................................................................... 28 
 


 
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PROTOCOL SYNOPSIS 
 
 
TITLE 
A phase II, single-site, double-blind, placebo-
controlled randomized withdrawal study 
assessing the efficacy and safety of sarilumab in 
patients with glucocorticoid-dependent 
sarcoidosis 
STUDY PHASE 
Phase IIb 
INDICATION 
Glucocorticoid-dependent sarcoidosis 
INVESTIGATIONAL PRODUCT OR 
PROCEDURE 
Sarilumab 
PRIMARY OBJECTIVE(S) 
To demonstrate that sarilumab treatment is 
effective for inducing and maintaining 
glucocorticoid-free remission in male or 
female patients aged 18 to 75 with biopsy 
proven, active, glucocorticoid-dependent 
sarcoidosis 
SECONDARY OBJECTIVE(S) 
To determine the number of patients in 
glucocorticoid-free remission and the change 
in prednisone dose compared to baseline at 
Week 16, after the open-label period (Period 
1) of the study.  Additional secondary 
objectives at both Week 16 and Week 28 are 
to demonstrate that sarilumab treatment is 
effective for reducing disease manifestation-
specific metrics, for improving laboratory 
parameters, and for reducing cumulative 
prednisone dose.  An important secondary 
objective is to demonstrate safety in this 
patient population. 
TREATMENT SUMMARY 
During Period 1 of this study, fifteen 
patients will receive sarilumab 200mg 
subcutaneously every two weeks in an open-
label fashion.  Subjects will continue their 
background disease modifying anti-
rheumatic drug (DMARD) therapies and 
current glucocorticoid dose (prednisone ≥ 10 
mg and ≤ 60 mg daily or alternate 
glucocorticoid equivalent is required for 
study entry).  During the screening period, 
all patients will change their glucocorticoid 
to prednisone with stable dosing for at least 
14 days before their baseline visit.  If a 
patient is on a prednisone dose between 40 
mg daily and 60 mg daily, the dose will be 


 
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reduced to 40 mg daily by the end of week 3 
at the clinician’s discretion.  Starting at week 
4, all patients will begin a scheduled 
prednisone taper that will take place from 
week 4 until week 16.   
 
Patients will be required to adhere to this 
tapering protocol.  If a violation in the 
tapering schedule occurs, the patient will be 
deemed a nonresponder.  Patients will be 
required to fill out a daily steroid diary to 
clearly document their daily prednisone 
intake. All attempts will be made to perform 
a pill count at each visit. 
 
During Period 2 of the study (starting at 
Week 16), the patients that responded in 
Period 1 will be randomized to withdraw 
from sarilumab.  Patients will be assigned in 
a blinded, 1:1 fashion to receive either 
sarilumab 200mg subcutaneously every two 
weeks or matching placebo.   
SAMPLE SIZE  
15 patients 
STATISTICAL CONSIDERATIONS 
The sample size for Period 1 of the trial of 
15 patients was calculated based on the 
assumption that 80% of the patients will 
respond to open-label sarilumab, allowing 
for 12 patients to enroll in the randomized 
withdrawal Period 2 of the study.  The 
sample size of 12 for Period 2 was 
calculated based on the assumption that 85% 
of the placebo group (roughly 5 out of 6) 
will flare (i.e., require reinitiation of 
prednisone) over the subsequent 12 weeks 
compared to 15% (roughly 1 out of 6) in the 
sarilumab group.  This relative hazard of 
0.20 gives a power of 80% with an alpha of 
0.05 to detect a difference between treatment 
groups assuming Kaplan-Meier analysis.   
 
A sample size of 15 was deemed recruitable 
at Stanford after searching the Stanford 
medicine Research data Repository 
(STARR), which is a clinical data warehouse 
containing all patients seen at Stanford 
Hospital and Clinics.  A search for patients 


 
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between the ages of 18 and 75 who were 
given the diagnosis code for sarcoidosis on 
at least two separate occasions within the 
last year and who are currently on 
prednisone, yields 200 potential patients.  
Assuming half of these are coded correctly, 
and one-third of those truly have 
glucocorticoid-dependent, refractory disease, 
that leaves roughly 30 patients to screen, 
half of which we anticipate will be eligible 
for, and willing to participate in, the study.  
Our IRB will allow us to identify specific 
patients within STARR whom we can 
contact to determine their interest in the 
study. 
 
 


 
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SCHEMA 
 


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ACE 
Angiotensin converting enzyme 
ADL 
Activities of daily living 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANA 
Anti-nuclear autoantibody 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
BSA 
Body surface area 
CBC 
Complete blood count 
CIB 
Clinical investigation brochure 
CK 
Creatinine kinase 
CNS 
Central nervous system 
CRF 
Case report/Record form 
CR 
Complete response 
DMARDs 
Disease modifying anti-rheumatic drugs 
DLT 
Dose Limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
FACIT 
Functional assessment of chronic illness therapy 
GI 
Gastrointestinal 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
IL-6 
Interleukin-6 
IL-6-R 
Interleukin-6 receptor 
IP 
Investigational product 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LLN 
Lower limit of normal  
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OS 
Overall survival  
PFTs 
Pulmonary function tests 
PK 
Pharmacokinetic 
PLT 
Platelet 
PR 
Partial response 
QD 
Once daily 
RBC 
Red blood cells 
RF 
Rheumatoid factor 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
Standard deviation 
SEM 
Standard error of the mean 


 
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SJC 
Swollen joints count 
TB 
Tuberculosis 
TEAEs 
Treatment emergent adverse events 
TJC 
Tender joints count 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UNK 
Unknown 
VAS 
Visual analog scale 
WBC 
White blood cell 
WHO 
World Health Organization 
 


 
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1. 
OBJECTIVES 
 
1.1. 
Primary Objective  
The primary objective of this study is to determine if sarilumab treatment is effective for inducing 
and maintaining glucocorticoid-free remission in male or female patients aged 18 to 75 with biopsy 
proven, active, glucocorticoid-dependent sarcoidosis affecting any organ other than the heart or the 
central nervous system.   
 
1.2. 
Secondary Objectives 
 
Secondary objectives of this study are to determine the number of patients in glucocorticoid-free 
remission and the change in prednisone dose compared to baseline at Week 16, after the open-label 
period (Period 1) of the study.  Additional secondary objectives at both Week 16 and Week 28 are 
to demonstrate that sarilumab treatment is effective for reducing disease manifestation-specific 
metrics, for improving laboratory parameters, and for reducing cumulative prednisone dose.  An 
important secondary objective is to demonstrate safety in this patient population. 
 
2. 
BACKGROUND 
 
2.1 
Sarcoidosis 
Sarcoidosis is a rare disease, but one that carries a high risk of morbidity and mortality with a 5 and 
10-year mortality rate of 4 and 9% [1].  The prevalence is estimated at 10-20 per 100,000 of the 
general population, with roughly 50,000 people affected in the United States [2].  The incidence 
varies by region and ethnicity; the disease is roughly four times more common in blacks.  
Sarcoidosis typically presents between the ages of 20 and 60 and a higher mortality exists in 
patients older than 55, non-Hispanic African Americans, and women [1].  The lungs are affected in 
the vast majority of patients (~90%), leading to fatigue, dyspnea, and often pulmonary fibrosis 
which can result in death.  When the liver is affected, it can cause hepatic failure requiring 
transplantation.  Ocular inflammation can permanently damage the eye, skin rashes are disfiguring, 
enlarged lymph nodes and glands can be painful, and inflammatory arthritis can be debilitating.  
 
Sarcoidosis is often chronic, requiring long-term immunosuppression.  There are no established 
guidelines for the treatment of sarcoidosis, but the mainstay therapy is glucocorticoids.  It is well 
established that prolonged use of glucocorticoids has a number of harmful effects, including 
glucose intolerance, osteoporosis, weight gain, hypertension, hyperlipidemia, infection, insomnia, 
cataracts, gastrointestinal perforation, and mood changes [3-5].  Thus, it is essential for patients 
who do not respond to glucocorticoids to be treated with additional agents in hopes of minimizing 
exposure to steroids.  Typically, a disease modifying anti-rheumatic drug (DMARD), such as 
methotrexate or azathioprine, is added to prednisone.  When this fails, and for severe 
manifestations, more potent drugs are used such as cyclophosphamide or a biologic drug such as a 
TNF-inhibitor.  Despite these therapies, many patients have ongoing sarcoidosis symptoms and 
organ injury.  
 
2.2 
Sarilumab 
Sarilumab is a recombinant human monoclonal antibody of the immunoglobulin G1 (IgG1) kappa 
isotype directed against the interleukin-6 receptor α-subunit (IL-6Rα). Sarilumab binds to human 


 
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IL-6Rα and has been demonstrated to block interleukin-6 (IL-6) mediated signaling. Sarilumab, 
formulated for subcutaneous (SC) injection at doses of 150 and 200 mg every 2 weeks (q2w), was 
approved for the treatment of RA in Canada on 12 January 2017, the United States (US) on 22 May 
2017, European Union (EU), Norway, Iceland, and Liechtenstein on 23 June 2017, and Japan on 27 
September 2017. Sarilumab is also in Phase 2 development for the treatment of polyarticular-course 
juvenile idiopathic arthritis (pcJIA) in pediatric patients. 
 
As of 12 January 2018, the global sarilumab RA clinical development program consisted of 10 
Phase 1clinical pharmacology studies and 9 Phase 2/3 studies. 
 
Phase 1 studies: 
Of the 10 Phase 1 clinical pharmacology studies, 8 studies were conducted in patients 
with RA receiving methotrexate (MTX) and 1 study was conducted in healthy subjects. All but 
2 of these studies (TDR10805/6R88-RA-0802 and INT12684) were single dose studies. 
 
Phase 2/3 studies in RA:  
Of the 9 Phase 2 and 3 studies of the global RA program, 5 studies have been completed 
(EFC11072/SARIL-RA-MOBILITY, EFC10832/SARIL-RA-TARGET, 
SFY13370/SARIL-RA-ASCERTAIN, EFC13752/ SARIL-RA-ONE, MSC12665/SARIL-RA-
EASY); 2 were prematurely terminated (ACT11575 and EFC11574/SARIL-RA-COMPARE) due 
to the operational feasibility and lack of ability to provide a timely result versus the plan but not due 
to any safety issue; and 2 studies are ongoing: the open-label extension part of EFC14092/SARIL-
RA-MONARCH (double-blind part of this study has been completed) and the uncontrolled 
extension Phase 3 study LTS11210 (SARIL-RA-EXTEND) that enrolled patients from studies 
EFC11072, EFC10832, EFC13752, SFY13370, and ACT11575.  
 
The global RA program has enrolled patients with RA from over 40 countries worldwide, who 
required alternatives to oral disease-modifying anti-rheumatic drugs (DMARDs) or tumor necrosis 
factor alpha (TNF-α) antagonists because of inadequate control of disease activity or intolerance to 
these agents. This program entered Phase 2/3 with an operationally seamless study, EFC11072, 
consisting of a combined dose-ranging (Phase 2) part and a confirmatory (Phase 3) part, which was 
conducted in patients with active RA who were inadequate responders to MTX therapy. 
 
In the dose-ranging part of the study (EFC11072/Part A), 5 dose regimens (100 mg q2w, 
150 mg q2w, 200 mg q2w, 100 mg every week [qw], and 150 mg qw) and placebo were tested in 
306 randomized patients. The demographic and disease characteristics at baseline were similar 
across all treatment groups. 
 
Based on an in-depth analysis of the Phase 2 study results, the 150 mg q2w and 200 mg q2w 
doses were selected for evaluation in 2 pivotal Phase 3 trials in RA (EFC11072 Part B and 
EFC10832) where sarilumab was tested as a combination therapy with a conventional DMARD. 
 
In the Phase 3 confirmatory part of EFC11072 (Part B), both sarilumab dose groups showed 
clinically relevant and statistically significant (p<0.0001) improvements compared with placebo 
in all 3 co-primary endpoints: improvement in signs and symptoms of RA at 24 weeks (as defined 
by 20% improvement on American College of Rheumatology [ACR] definition of improvement 


 
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criteria [ACR20]), improvement in physical function (as assessed by Health Assessment 
Questionnaire Disability Index [HAQ-DI]) at Week 16 and inhibition of progression of structural 
damage at Week 52. Study EFC11072 Part B, Cohort 2 (where patients were randomized to either 
placebo or one of 2 selected doses: 150 mg q2w or 200 mg q2w) demonstrated that sarilumab 200 
mg q2w and 150 mg q2w inhibited the 1-year rate of radiographic progression by 91% and 68% 
relative to placebo, respectively. 
 
In addition to study EFC11072, efficacy of sarilumab was demonstrated in study EFC10832, 
conducted in patients who had an inadequate response or intolerance to one or more TNF-α 
antagonists. For the primary endpoints of ACR20 at Week 24 and HAQ-DI at Week 12, significant 
improvement was observed in patients treated with sarilumab 200 mg q2w and 150 mg q2w 
compared with placebo, showing that patients who previously had an inadequate response or 
intolerance to TNF-α antagonists responded to treatment with sarilumab.  
 
Although demonstration of efficacy was not the primary objective for the other Phase 3 clinical 
trials in RA where sarilumab was administered either as monotherapy (EFC13752, EFC14092) or 
with concomitant DMARD therapy (SFY13370 and MSC12665), clinical efficacy profiles in these 
studies were consistent with results from the active-controlled Phase 3 studies in the global program 
(EFC11072 Part B, and EFC10832).  
 
Patients who completed studies EFC11072, EFC10832, EFC13752, and SFY13370 had the option 
to enroll in the ongoing long-term extension study LTS11210 at the highest tested dose (200 mg 
q2w). In this study, the efficacy of sarilumab administered concomitantly with DMARDs was 
sustained for the duration of the available follow-up period: approximately 3.8 years and 2.1 years 
for patients initially randomized in EFC11072 Part B and EFC10832, respectively. The persistence 
of efficacy was consistent across all the domains of treatment of RA, namely signs and symptoms, 
structural damage, and physical function. 
 
Safety: 
For the patients treated with sarilumab and concomitant DMARD, a higher incidence of 
treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and TEAEs leading 
to discontinuation were observed in the sarilumab treatment groups compared to the placebo 
group. The incidence of TEAEs leading to death was similar in sarilumab and placebo groups. 
 
In the placebo-controlled population, compared to the placebo group, higher incidences of 
TEAEs, SAEs, and TEAEs leading to discontinuation were observed in sarilumab 200 mg q2w or 
150 mg q2w + DMARD treatment groups relative to the placebo + DMARD group. These 
differences were generally attributable to higher rates of the AESIs associated with IL-6 
blockade, specifically infections and laboratory abnormalities (including decrease in absolute 
neutrophil count (ANC) and platelet count, increase in transaminase and lipids) in the 
sarilumab + DMARD groups. 
 
The observations with regards to adverse event (AE) and laboratory parameters with long-term 
administration were consistent with what was observed in the placebo-controlled population, and 
no safety findings were identified as attributable to long-term administration. 
 


 
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Other diseases: 
Sarilumab was studied in ankylosing spondylitis (AS) patients in the DRI11073 study. Patients 
who completed the DRI11073 study had the possibility of enrolling in the LTS11298 long-term 
safety study if appropriate. The DRI11073 study failed to demonstrate clinical efficacy and the 
clinical development in this indication has been terminated. Consequently the LTS11298 study 
was prematurely discontinued. Overall, the safety observations from these studies conducted in 
patients with AS were consistent with has been observed in patients with RA. 
 
Sarilumab was also evaluated in a randomized double-blind Phase 2 study of patients with 
noninfectious uveitis (NIU) (ACT13480/SARIL-NIU-SATURN). Although the primary efficacy 
endpoint of a 2 step reduction in vitreous haze (VH) or reduction in steroid dose was not met, 
significant improvements were observed for key secondary endpoints such as change from 
baseline in adjudicated VH at Week 16, change from baseline in best-corrected visual acuity 
(BCVA) at Week 16, and change from baseline central retinal thickness (CRT) at Week 16. 
Furthermore, changes in adjudicated VH, BCVA, and CRT were maintained at Week 52. No new 
safety signals have been detected with sarilumab use in NIU compared with other indications. The 
AEs and laboratory changes were consistent with results observed in studies with sarilumab in RA 
patients and with IL-6 inhibition. 
 
The FDA has approved sarilumab for the treatment of rheumatoid arthritis.  It is not FDA approved 
for the treatment of sarcoidosis, however this clinical investigation is exempt from an IND as it 
meets the following requirements: 
- 
Sarliumab is lawfully marketed in the United States 
- 
The investigation is not intended to be reported to the FDA as a well-controlled study in 
support of a new indication and there is no intent to use it to support any other significant 
change in the labeling of the drug 
- 
The investigation is not intended to support a significant change in the advertising for the 
drug 
- 
The investigation does not involve a route of administration, dose, patient population, or 
other factor that significantly increases the risk associated with the drug 
- 
The investigation is conducted in compliance with the requirements for review by the 
Stanford IRB and with the requirements for informed consent 
- 
The investigation is not intended to promote or commercialize the drug 
 
2.3 
Rationale 
Sarcoidosis is a chronic illness, requiring long-term immunosuppression.  There are no established 
guidelines for the treatment of sarcoidosis, but the mainstay therapy is glucocorticoids.  It is well 
established that prolonged use of glucocorticoids has a number of harmful effects, including 
glucose intolerance, osteoporosis, weight gain, hypertension, hyperlipidemia, infection, insomnia, 
cataracts, gastrointestinal perforation, and mood changes [3-5].  Thus, it is essential for patients 
who do not respond to glucocorticoids to be treated with additional agents in hopes of minimizing 
exposure to steroids.  Typically, a disease modifying anti-rheumatic drug (DMARD), such as 
methotrexate or azathioprine, is added to prednisone.  When this fails, and for severe 
manifestations, more potent drugs are used such as cyclophosphamide or a biologic drug such as a 
TNF-inhibitor.  Despite these therapies, many patients have ongoing sarcoidosis symptoms and 
organ injury.  


 
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Interleukin-6 (IL-6) is elevated in the blood and bronchoalveolar (BAL) fluid of patients with 
sarcoidosis [6, 7].  This inflammatory cytokine leads to B cell differentiation into antibody-
secreting cells.  Patients with sarcoidosis have elevated blood levels of immunoglobulins, consistent 
with B cell hyperactivation [7].  In addition, these activated B cells can serve as highly affinity-
matured antigen presenting cells for T cells.  IL-6 also stimulates T cells directly and specifically 
induces Th17 T cell development.  Th17 cells are elevated in sarcoidosis and likely contribute to 
disease pathogenesis through secretion of IL-17 and interferon-gamma (IFN-γ) [8-10].  IL-6 
additionally inhibits Treg differentiation, thereby decreasing the population of cells responsible for 
restraining the effector T cell response [11]. 
 
Sarilumab binds the IL-6 receptor and prevents its activity.  It has been studied extensively in 
rheumatoid arthritis (RA), and has been shown to improve disease activity, radiographic findings, 
and markers of inflammation [12-15].  Given sarilumab’s efficacy and favorable safety profile, it is 
now FDA-approved for the treatment of RA.  Sarilumab has never been tested in sarcoidosis 
patients, and we believe it will have similar efficacy when given to this patient population.  There 
are limited options in the management of sarcoidosis, and determining whether novel approaches 
such as sarilumab are useful for improving patients’ quality of life and for decreasing morbidity and 
mortality is critical. 
 
2.4 
Study Design 
The primary purpose of this study is to evaluate sarilumab in the treatment of sarcoidosis.  The first 
period of this trial, Period 1, is single-arm and open-label, in which all patients will receive 
sarilumab.  The second period, Period 2, is a two-arm, randomized withdrawal study in which half 
of the patients will receive sarilumab and half will receive matching placebo.  Period 2 will be 
double blind.  The primary outcome of the study is designed to evaluate efficacy of sarilumab in the 
treatment of sarcoidosis. 
 
2.5 
Correlative Studies Background 
A plasma sample (5 ml) will be collected for future biomarker analysis at Baseline, Week 16, and 
Week 28.  This will be used to study cytokines including IL-6 levels.  Peripheral blood 
mononuclear cells will also be collected at Baseline, Week 16, and Week 28.  These will be used to 
characterize the immune response before and after treatment. 
 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 
Inclusion Criteria 
(1.) Men and women of all races and ethnicities age 18 to 80. 
(2.) Biopsy proven non-caseating granulomas consistent with sarcoidosis, with negative infectious 
studies including AFB and fungal stains, and with compatible clinical and/or radiographic 
manifestations of sarcoidosis. 
(3.) Involvement of the lungs (stage II or III pulmonary sarcoidosis), lymph nodes, liver, kidneys, 
spleen, bone, soft tissues, skin, and/or eyes. 
(4.) At least one active manifestation, defined by the need for ongoing glucocorticoid treatment to 
control a sign or symptom of sarcoidosis, which requires treatment with prednisone (or equivalent 


 
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corticosteroid) ≥ 10 mg and ≤ 60 mg daily (i.e. glucocorticoid dependence), with stable dosing for ≥ 
28 days prior to baseline.  If patients are taking a glucocorticoid other than prednisone, they will be 
changed to prednisone at the equivalent dose and take this daily for ≥ 14 days prior to baseline.   
(5.) DMARDs including methotrexate, leflunomide, azathioprine, mycophenolate mofetil, and/or 
anti-malarials (i.e. hydroxychloroquine) will be permitted, but the regimen must be stable for ≥ 28 
days prior to baseline and remain stable during follow-up. 
(6.) Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
(1.) Patients < 18 years of age or > 80 years of age. 
(2.) Stage IV pulmonary sarcoidosis. 
(3.) Central nervous system sarcoidosis. 
(4.) Cardiac sarcoidosis. 
(5.) Prior treatment with an anti-IL-6 therapy. 
(6.) Treatment with a biologic agent including rituximab, belimumab, TNF inhibitors, abatacept, or 
IL-17 inhibitors administered within 28 days prior to baseline (6 months for rituximab). 
(7.) Treatment with cyclophosphamide within 3 months prior to baseline. 
(8.) Treatment with prednisone < 10 mg or > 60 mg daily. 
(9.) Known hypersensitivity or allergy to the study drug. 
(10.) History of, or current, inflammatory or autoimmune disease other than sarcoidosis which 
would present a safety issue or confound interpretation of the data. 
(11.) Prior or current history of other significant concomitant illness that, according to the 
investigator’s judgment, would adversely affect the patient’s participation in the study.  These 
include, but are not limited to, cardiovascular (including stage III or IV cardiac failure according to 
the New York Heart Association classification), neurological (including demyelinating disease), 
active infectious diseases, or history of diverticulitis or gastrointestinal perforation. 
(12.) Patients currently pregnant or breast-feeding. 
(13.) Women of childbearing potential (WOCBP) who are unwilling to utilize adequate 
contraception and unwilling to not become pregnant during the full course of the study (must be 
willing to be tested for pregnancy). Adequate contraceptive measures include oral contraceptives 
(continuous use, as per prescription, for 2 or more cycles prior to screening), intrauterine devices, 
contraceptive sponges, condoms or diaphragms plus foam, or jelly, or surgical procedures such as 
bilateral tubal ligation or vasectomy in partner. 
(14.) Administration of a live/attenuated vaccine within 30 days. 
(15.) Evidence of active tuberculosis, HIV, or hepatitis B or C infection. 
(16.) History of cancer other than non-melanoma skin cancer. 
(17.) Patients with any of the following laboratory abnormalities at the screening visit: hemoglobin 
<8.5 g/dL, white blood cells <3000/mm3, neutrophils <2000/mm3, platelet count <150,000 
cells/mm3, aspartate aminotransferase (AST) or ALT >1.5 x ULN, and/or bilirubin (total) above the 
upper limit of normal (unless Gilbert’s disease has been determined by genetic testing and 
documented). 
(18.) Presence of severe uncontrolled hypercholesterolemia (>350 mg/dL, 9.1 mmol/L) or 
hypertriglyceridemia (>500 mg/dL, 5.6 mmol/L) at screening or baseline. 
(19.) Patients with calculated creatinine clearance <30 mL/minute (using Cockroft-Gault formula). 
(20.) History of alcohol or drug abuse within 5 years prior to the screening visit. 
(21.) Participation in any clinical research study evaluating another investigational drug or therapy 


 
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within 5 half-lives or 60 days of first investigational medicinal product (IMP) administration, 
whichever is longer. 
(22.) Any patient who has had surgery within 4 weeks prior to the screening visit or with planned 
surgery during the course of the study. 
 
3.3 
Informed Consent Process 
All participants will be provided a consent form describing the study with sufficient information for 
participants to make an informed decision regarding their participation.  Participants must sign the 
IRB approved informed consent prior to participation in any study specific procedure. The 
participant will receive a copy of the signed and dated consent document.  The original signed copy 
of the consent document will be retained in the medical record or research file.  
 
3.4       Randomization Procedures 
In Period 2 of the study, patients will be randomized to sarilumab or matching placebo.  This will 
be done by our administrative assistant Angelica Aberia using a computer-generated random 
number.  An odd number will be assigned to sarilumab and an even number will be assigned to 
placebo.  Only Angelica will be aware of the assignment and she will communicate this directly to 
the Investigational Pharmacy.  The investigators and patients will remain blinded.  The codebook 
with the patient assignments will be stored by Angelica in a secure, locked file cabinet. 
 
 
3.5 
Study Timeline 
Primary Completion: 
The study will reach primary completion 15 months from the time the study opens to accrual. 
 
Study Completion: 
The study will reach study completion 24 months from the time the study opens to accrual. 
 
4. 
TREATMENT PLAN 
At Screening, vital signs will be obtained, a physical examination performed, and complete medical 
history obtained.  Routine clinical laboratory tests (including a chemistry panel, complete blood 
count, urinalysis, spot urine protein and creatinine, C-reactive protein (CRP), erythrocyte 
sedimentation rate (ESR), urine pregnancy test), sarcoidosis-related laboratory tests (including 
angiotensin converting enzyme (ACE), total immunoglobulins (IgG), urine calcium, 25-hydroxy 
vitamin D, and safety laboratory tests (including serum pregnancy test for females, HIV test, 
hepatitis B test, hepatitis C test, and quantiferon test for tuberculosis) will be performed.  An 
electrocardiogram and chest x-ray will also be obtained.  At Baseline and Week 16, routine clinical 
laboratory tests and sarcoidosis-related laboratory tests will be repeated, and in addition the 
following tests will be performed at Baseline (and only repeated at Week 16 if abnormal at 
Baseline): pulmonary function tests, chest computed tomography, creatinine kinase (CK), aldolase, 
and lactose dehydrogenase (LDH).  At Week 28, routine clinical laboratory tests and sarcoidosis-
related laboratory tests will be repeated.  At visits 3-11, vital signs, a physical examination, a 
medical history, and routine clinical laboratory tests will be obtained, urine pregnancy test for 
WOCBP.  At Baseline, Week 16, and Week 28 the ePOST, global patient VAS, global physician 
VAS, HAQ, and FACIT-F will be assessed.  Also at Baseline, Week 16, and Week 28, eight green 


 
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top tubes will be collected and processed for plasma and peripheral blood mononuclear cells, which 
will be stored at -80°C for future research. 
 
During Period 1 (Baseline through Week 16), all subjects will receive 200mg of sarilumab 
subcutaneously every two weeks.  During Period 2 (Week 16 through Week 28), half of the subjects 
who responded in Period 1 will receive 200mg of sarilumab subcutaneously every two weeks and 
half of the subjects will receive matching placebo in a double-blinded fashion. 
 
4.1 General Concomitant Medication and Supportive Care Guidelines 
Patients will be allowed to continue background DMARDs including methotrexate, leflunomide, 
azathioprine, mycophenolate mofetil, and/or anti-malarials.  These are standard drugs used in the 
treatment of sarcoidosis.  The regimen must be stable for ≥ 28 days prior to baseline and remain 
stable during follow-up.  Patients will also be on ≥ 10 mg and ≤ 60 mg daily of prednisone or 
equivalent glucocorticoid to be eligible for the study and will follow a scheduled taper.  Patients 
will undergo blood draws during the study.  During blood draws, a patient may have pain and/or 
bruising at the place on his/her arm where blood is taken.  Blood clots may form and infections may 
occur, but these events are rare. He or she may feel faint or lightheaded.  They will also have an 
electrocardiogram.  There may be minor discomfort and/or skin irritation at the site where the 
electrodes (sticky pads) are placed on the skin for the recording of the ECG.  They will also have a 
chest x-ray.  Radiation exposure from a chest x-ray is equivalent to the amount of radiation 
exposure one would experience from 10 days of natural radiation (such as sunlight).  They will also 
have a non-contrast chest computed tomography.  Radiation exposure from a computed tomography 
of the chest is equivalent to roughly 70 times the amount of radiation from a chest x-ray.  They will 
undergo pulmonary function testing.  There may be minor discomfort from the deep breathing 
required to complete pulmonary function testing.  If they have known or suspected ocular 
sarcoidosis, they will have an ophthalmologic evaluation with fluorescein angiography.  This will 
involve dilating the pupils, which often makes it difficult to see clearly and in bright lights after the 
eye exam for a few hours.  For the angiography, patients will receive an injection of a dye called 
fluorescein. There may be minor discomfort from the needle at the site of injection. There may also 
be bruising at the site of injection. The most common side effects of this dye are nausea and 
vomiting; however, occasional allergic reactions, fainting, breathing difficulties, or shock may 
occur. The dye may stain your skin and urine; which may last approximately for 1 day. Mild 
reactions such as itching, swelling, or redness near where the dye is put in your vein are more 
common and have been estimated to happen in about 1 out of 100 times. Rare severe allergic 
reactions can also happen during the fluorescein dye test. People allergic to shellfish may be at 
increased risk for an allergic reaction to fluorescein or other dye. However, individuals with 
allergies to shellfish can receive a medication before the dye test to minimize allergic responses. 
Serious allergic reactions such as severe swelling and difficulty breathing can happen in 1 out of 
10,000 patients and about 1 out of 222,000 patients can have a heart attack, stroke, or even die from 
the fluorescein dye administration. 
 
4.2 
Criteria for Removal from Study 
The study will be placed on hold for safety monitoring board review in the case of a death, a serious 
adverse event related to the drug, or a Grade 4 treatment emergent adverse event or laboratory 


 
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abnormality.  The safety monitoring committee will determine if the study can resume and if the 
patient should remain in the study or be removed.  A patient may withdraw from the study at any 
time if they choose to withdraw their consent. 
 
4.3 
Alternatives 
Risks to the patient will be minimized through frequent clinic visits and appropriate laboratory 
testing.  In addition, all data will be reviewed by the investigators, as well as the safety monitoring 
board, which will meet every 6 months.   
 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
 
5.1 
 Sarilumab 
Sarilumab (SAR153191), also designated as REGN88, is co-developed by Sanofi and Regeneron. 
Sarilumab is a recombinant human monoclonal antibody of the IgG kappa isotype directed against 
the alpha subunit of the IL-6 receptor (IL-6Rα). Sarilumab is a potent and specific inhibitor of IL-6 
mediated signaling. By binding to IL-6Rα with high affinity, sarilumab blocks the binding of IL-6 
and interrupts the cytokine-mediated signaling cascade. Interleukin-6 is a key element in the 
etiology of rheumatic conditions and inhibition of its signaling is a critical part of the mechanism of 
action of sarilumab. 
 
For complete information on mechanism of action, summaries of animal and clinical studies, non-
clinical and clinical pharmacokinetics, major route of elimination, safety profile, please see the 
Investigator’s Brochure. 
 
5.1.1  Summary of nonclinical studies 
Sarilumab has been evaluated in a series of in vitro experiments to quantify the affinity of the 
antibody for IL-6Rα and the ability to block the binding and signaling of IL-6. In addition, the 
role of the Fc effector function in the mechanism of action of the antibody was evaluated in vitro. 
The equilibrium binding affinity (KD) of sarilumab to human IL-6Rα was determined by surface 
plasmon resonance (SPR) Biacore to be approximately 54 pM. Similar studies with cynomolgus 
monkey IL-6Rα indicate a KD of 123 pM. The similar affinities of sarilumab for monkey and 
human IL-6Rα indicate that monkeys are a relevant species for performing nonclinical studies. In 
contrast, no binding of sarilumab to murine IL-6Rα was observed, suggesting that rodents are not a 
useful model system for pharmacology or toxicology studies.  In vitro, sarilumab completely 
blocked the binding of a 200 nM concentration of human IL-6 to human IL-6Rα, as demonstrated 
by SPR-Biacore; in a competition enzyme-linked immunosorbent assay, sarilumab blocked binding 
of a 100 pM constant concentration of dimeric human IL-6Rα to human IL-6 with an IC50 of 108 
pM. In vitro cell-based assays demonstrate that sarilumab blocks IL-6-dependent signal transducer 
and activator of transcription 3 (STAT3) activation in the HepG2 human hepatocarcinoma cell line, 
and blocks trans-signaling induced by a combination of IL-6 and soluble IL-6Rα in an engineered 
human embryonic kidney 293 (HEK-293) cell line that overexpresses gp130 but does not express 
IL-6Rα. No detectable Fc effector function activity was associated with sarilumab, as determined in 
vitro in cell-based assays for antibody-dependent cell-mediated cytotoxicity and complement-


 
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dependent cytotoxicity. In total, these in vitro data are consistent with sarilumab exerting its actions 
through blockade of the IL-6/IL-6Rα interaction. 
 
Sarilumab does not bind to mouse IL-6R; therefore, the surrogate REGN844 antibody (an IL-6R 
antibody that cross reacts with mouse receptor) was used for the murine model experiments. In 
vitro, REGN844 binds specifically to mouse IL-6Rα with high affinity and inhibits IL-6 stimulated 
mouse B-cell proliferation. A study with sarilumab was performed in double-humanized (IL-6hu/hu 
IL-6Rαhu/hu) mice expressing human IL-6 and the human ectodomain of IL-6Rα instead of the 
equivalent mouse gene products. In double-humanized IL-6/IL-6Rα mice, sarilumab prevents 
turpentine-induced elevation of serum amyloid A (SAA), a key biomarker of the acute phase 
inflammatory response. For studies in wild type mice, REGN844 was tested. In concordance with 
the PD activity of sarilumab in double-humanized mice, REGN844 prevents turpentine-induced 
elevation of SAA and mitigated disease incidence, severity and bone erosion in a collagen induced 
arthritis model. 
 
5.1.2  Summary of clinical studies 
 
As of 12 January 2018, the global sarilumab RA clinical development program consisted of 10 
Phase 1clinical pharmacology studies and 9 Phase 2/3 studies. 
 
Phase 1 studies: 
Of the 10 Phase 1 clinical pharmacology studies, 8 studies were conducted in patients 
with RA receiving methotrexate (MTX) and 1 study was conducted in healthy subjects. All but 
2 of these studies (TDR10805/6R88-RA-0802 and INT12684) were single dose studies. 
 
Phase 2/3 studies in RA:  
Of the 9 Phase 2 and 3 studies of the global RA program, 5 studies have been completed 
(EFC11072/SARIL-RA-MOBILITY, EFC10832/SARIL-RA-TARGET, 
SFY13370/SARIL-RA-ASCERTAIN, EFC13752/ SARIL-RA-ONE, MSC12665/SARIL-RA-
EASY); 2 were prematurely terminated (ACT11575 and EFC11574/SARIL-RA-COMPARE) due 
to the operational feasibility and lack of ability to provide a timely result versus the plan but not due 
to any safety issue; and 2 studies are ongoing: the open-label extension part of EFC14092/SARIL-
RA-MONARCH (double-blind part of this study has been completed) and the uncontrolled 
extension Phase 3 study LTS11210 (SARIL-RA-EXTEND) that enrolled patients from studies 
EFC11072, EFC10832, EFC13752, SFY13370, and ACT11575.  
 
The global RA program has enrolled patients with RA from over 40 countries worldwide, who 
required alternatives to oral disease-modifying anti-rheumatic drugs (DMARDs) or tumor necrosis 
factor alpha (TNF-α) antagonists because of inadequate control of disease activity or intolerance to 
these agents. This program entered Phase 2/3 with an operationally seamless study, EFC11072, 
consisting of a combined dose-ranging (Phase 2) part and a confirmatory (Phase 3) part, which was 
conducted in patients with active RA who were inadequate responders to MTX therapy. 
 
In the dose-ranging part of the study (EFC11072/Part A), 5 dose regimens (100 mg q2w, 
150 mg q2w, 200 mg q2w, 100 mg every week [qw], and 150 mg qw) and placebo were tested in 
306 randomized patients. The demographic and disease characteristics at baseline were similar 


 
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across all treatment groups. 
 
Based on an in-depth analysis of the Phase 2 study results, the 150 mg q2w and 200 mg q2w 
doses were selected for evaluation in 2 pivotal Phase 3 trials in RA (EFC11072 Part B and 
EFC10832) where sarilumab was tested as a combination therapy with a conventional DMARD. 
 
In the Phase 3 confirmatory part of EFC11072 (Part B), both sarilumab dose groups showed 
clinically relevant and statistically significant (p<0.0001) improvements compared with placebo 
in all 3 co-primary endpoints: improvement in signs and symptoms of RA at 24 weeks (as defined 
by 20% improvement on American College of Rheumatology [ACR] definition of improvement 
criteria [ACR20]), improvement in physical function (as assessed by Health Assessment 
Questionnaire Disability Index [HAQ-DI]) at Week 16 and inhibition of progression of structural 
damage at Week 52. Study EFC11072 Part B, Cohort 2 (where patients were randomized to either 
placebo or one of 2 selected doses: 150 mg q2w or 200 mg q2w) demonstrated that sarilumab 200 
mg q2w and 150 mg q2w inhibited the 1-year rate of radiographic progression by 91% and 68% 
relative to placebo, respectively. 
 
In addition to study EFC11072, efficacy of sarilumab was demonstrated in study EFC10832, 
conducted in patients who had an inadequate response or intolerance to one or more TNF-α 
antagonists. For the primary endpoints of ACR20 at Week 24 and HAQ-DI at Week 12, significant 
improvement was observed in patients treated with sarilumab 200 mg q2w and 150 mg q2w 
compared with placebo, showing that patients who previously had an inadequate response or 
intolerance to TNF-α antagonists responded to treatment with sarilumab.  
 
Although demonstration of efficacy was not the primary objective for the other Phase 3 clinical 
trials in RA where sarilumab was administered either as monotherapy (EFC13752, EFC14092) or 
with concomitant DMARD therapy (SFY13370 and MSC12665), clinical efficacy profiles in these 
studies were consistent with results from the active-controlled Phase 3 studies in the global program 
(EFC11072 Part B, and EFC10832).  
 
Patients who completed studies EFC11072, EFC10832, EFC13752, and SFY13370 had the option 
to enroll in the ongoing long-term extension study LTS11210 at the highest tested dose (200 mg 
q2w). In this study, the efficacy of sarilumab administered concomitantly with DMARDs was 
sustained for the duration of the available follow-up period: approximately 3.8 years and 2.1 years 
for patients initially randomized in EFC11072 Part B and EFC10832, respectively. The persistence 
of efficacy was consistent across all the domains of treatment of RA, namely signs and symptoms, 
structural damage, and physical function. 
 
Safety: 
For the patients treated with sarilumab and concomitant DMARD, a higher incidence of 
treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and TEAEs leading 
to discontinuation were observed in the sarilumab treatment groups compared to the placebo 
group. The incidence of TEAEs leading to death was similar in sarilumab and placebo groups. 
 
In the placebo-controlled population, compared to the placebo group, higher incidences of 


 
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TEAEs, SAEs, and TEAEs leading to discontinuation were observed in sarilumab 200 mg q2w or 
150 mg q2w + DMARD treatment groups relative to the placebo + DMARD group. These 
differences were generally attributable to higher rates of the AESIs associated with IL-6 
blockade, specifically infections and laboratory abnormalities (including decrease in absolute 
neutrophil count (ANC) and platelet count, increase in transaminase and lipids) in the 
sarilumab + DMARD groups. 
 
The observations with regards to adverse event (AE) and laboratory parameters with long-term 
administration were consistent with what was observed in the placebo-controlled population, and 
no safety findings were identified as attributable to long-term administration. 
 
Other diseases: 
Sarilumab was studied in ankylosing spondylitis (AS) patients in the DRI11073 study. Patients 
who completed the DRI11073 study had the possibility of enrolling in the LTS11298 long-term 
safety study if appropriate. The DRI11073 study failed to demonstrate clinical efficacy and the 
clinical development in this indication has been terminated. Consequently the LTS11298 study 
was prematurely discontinued. Overall, the safety observations from these studies conducted in 
patients with AS were consistent with has been observed in patients with RA. 
 
Sarilumab was also evaluated in a randomized double-blind Phase 2 study of patients with 
noninfectious uveitis (NIU) (ACT13480/SARIL-NIU-SATURN). Although the primary efficacy 
endpoint of a 2 step reduction in vitreous haze (VH) or reduction in steroid dose was not met, 
significant improvements were observed for key secondary endpoints such as change from 
baseline in adjudicated VH at Week 16, change from baseline in best-corrected visual acuity 
(BCVA) at Week 16, and change from baseline central retinal thickness (CRT) at Week 16. 
Furthermore, changes in adjudicated VH, BCVA, and CRT were maintained at Week 52. No new 
safety signals have been detected with sarilumab use in NIU compared with other indications. The 
AEs and laboratory changes were consistent with results observed in studies with sarilumab in RA 
patients and with IL-6 inhibition. 
 
5.1.3 Intervention 
 
In Period 1, patients will all receive sarilumab in an open-label fashion.  They will be provided with 
prefilled syringes containing 1.14 mL of sarilumab (equally 200mg), which they will administer 
subcutaneously every two weeks.  This dose was chosen based on studies in rheumatoid arthritis 
that showed efficacy at this dose, and this is the FDA approved dose for the treatment of 
rheumatoid arthritis.   In Period 2 of the study, patients will be randomized to withdraw from 
sarilumab and receive placebo or continue sarilumab.  Sarilumab and placebo will be provided in 
identically matched glass prefilled syringes.  Each prefilled syringe will contain 1.14 mL of 
sarilumab or matching placebo.   
 
5.2 
Availability 
Sarilumab and matching placebo will be provided by Regeneron. 
 


 
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5.3 
Agent Ordering 
Study IP and matching placebo will be sent from Regeneron to the Stanford University Hospital 
investigational pharmacy where it will be appropriately stored in a locked facility.  The drug 
shipment address is Stanford Health Care, Attention: Investigational Drug Service, 300 Pasteur 
Drive, Room H0302, Stanford, CA 94305.  Phone: 650-736-1990. 
 
5.4 
Agent Accountability 
All investigational drug supplies will be kept in appropriate, secure area (a locked refrigerator in  
the locked pharmacy room) under the responsibility of the Stanford Investigational Pharmacy and 
will be stored separately from other medication and in the original carton as per specification 
mentioned on the label.  
 
6. 
DOSE MODIFICATIONS 
Sarilumab will be provided as a subcutaneous injection of 200 mg every two weeks.  There will be 
no dosage modifications.   
 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
The adverse drug reactions in Phase 3 trials (i.e., events potentially associated with sarilumab 
administration) are upper respiratory tract infection, nasopharyngitis, oral herpes urinary tract 
infection, neutropenia, leukopenia, thrombocytopenia, hypertriglyceridemia, injection site 
erythema, injection site rash, rash, urticaria, increased aspartate aminotransferase, and increased 
ALT. 
 
Based on the preclinical and clinical studies of sarilumab as well as the safety profile of another 
IL-6 inhibitor (tocilizumab) and other biological DMARDs, hypersensitivity reactions, serious 
infections, and neutropenia, are an important identified risk with sarilumab administration. 
Important potential risks are thrombocytopenia and the potential risk of bleeding, clinically 
evident hepatic injury, an impact on CV outcome (MACE) secondary to LDL elevation, GI 
perforations, and malignancy. 
 
7.2 
Adverse Event Reporting 
All AEs regardless of seriousness or relationship to IMP/NIP, spanning from the signature of the 
informed consent form, until the end of the study as defined by the protocol for that patient, are to 
be recorded on the corresponding page(s) or screen(s) included in the CRF. Whenever possible, 
diagnosis or single syndrome should be reported instead of symptoms. The Investigator should 
specify the date of onset, intensity, action taken with respect to IMP, corrective treatment/therapy 
given, additional investigations performed, outcome and his/her opinion as to whether there is a 
reasonable possibility that the AE was caused by the IMP. Laboratory, vital signs or ECG 
abnormalities are to be recorded as AEs only if they are medically relevant: symptomatic or 
requiring either corrective treatment or consultation or leading to discontinuation or modification of 


 
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dosing and/or fulfilling a seriousness criterion and/or is defined as an AE with pre-specified 
monitoring. 
 
7.2.1  Serious Adverse Events 
In the case of a serious adverse event the Investigator must immediately: 
• ENTER (within 24 hours of knowledge) the information related to the SAE in the 
CRF and notify the DSMC. 
• SEND a copy of all examinations carried out and the dates on which these examinations 
were performed, to Regeneron. Care should be taken to ensure that 
the patient's identity is protected and the patient's identifiers in the Clinical Trial are 
properly mentioned on any copy of source document. For laboratory results, include the 
laboratory normal ranges. 
• All further data updates should be recorded in the CRF as appropriate, and further 
documentation as well as additional information (for Lab data, concomitant Medication, 
patient status) should be sent (by fax or e-mail) to the Monitoring Team within 24 hours of 
knowledge. In addition, any effort should be made to further document each Serious 
AE that is fatal or life threatening within the week (7 days) following initial notification. 
• Following review by the DSMC, events meeting the IRB definition of ‘Unanticipated 
Problem’ will be reported to the IRB using eProtocol within 10 working days of DSMC 
review, or within 5 working days for deaths or life-threatening experiences. 
 
8. 
CORRELATIVE/SPECIAL STUDIES  
8.1 
Laboratory Correlative Studies 
Patient blood will be drawn in the Stanford phlebotomy lab and transported to the main clinical lab 
in the Stanford University Hospital for processing.  The following blood and urine tests will be 
performed per the study calendar: chemistry panel, complete blood count with differential, 
erythrocyte sedimentation rate, C-reactive protein, angiotensin converting enzyme, quantitative 
immunoglobulins, 25-hydroxy vitamin D, serum pregnancy test, HIV-1/2 serology, hepatitis B 
serology, hepatitis C serology, quantiferon TB test, creatinine kinase, aldolase, lactate 
dehydrogenase, urine pregnancy test, urinalysis, urine protein/creatinine, and urine calcium.  In 
addition, roughly 40 mL of research blood will be collected in heparin containing tubes and sent to 
the Stanford Clinical and Translational Research Unit (CTRU).  Plasma and peripheral blood 
mononuclear cells (PBMCs) will be extracted.  Plasma samples will be stored at -70 degrees for 
future study.  PBMCs will be stored in liquid nitrogen for future study. 


 
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9. 
STUDY CALENDAR 
 
Screen 
Day 
-35 to 0 
Baseline 
Day 1 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
18 
Week 
20 
Week 
24 
Week 
28 
Week 
34 
ET 
Unscheduled 
visit 
Written IC 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete PE 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Limited PE 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
ePOST 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
Global VAS patient 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
Global VAS physician 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
FACIT-F and HAQ 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
Routine clinical labs: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Chemistry panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
     CBC w/diff 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
     Urinalysis, urine P/C 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
     ESR, CRP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
     Urine pregnancy 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sarcoidosis labs: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     ACE level 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
     Immunoglobulins 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
     Urine calcium 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
     25-hydroxy vit D 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
Safety labs: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Serum pregnancy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
     HIV-1/2 serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Hepatitis B serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Hepatitis C serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
     QuantiFERON TB 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening tests: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Chest x-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sarcoid-specific tests: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Pulm Function Test 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
     CT chest 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
     CK, aldolase, LDH 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Research labs: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Plasma 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
     PBMCs 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Review AEs and meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispensing 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
Drug accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 


 
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10. 
MEASUREMENTS 
 
10.1  Primary and Secondary Outcome measures 
Primary endpoint: The primary endpoint is the flare-free survival of sarilumab-treated patients 
compared to placebo-treated controls in the double-blind randomized withdrawal period (Period 2) 
from Week 16 to Week 28.  Patients will be considered to have flared if they receive rescue 
medication including increased glucocorticoids, or if they discontinue the study treatment in order 
to start a different therapy. 
 
Secondary endpoints: The following secondary endpoints will all be assessed at Week 16 and Week 
28 compared to baseline as a paired analysis: the change in the extrapulmonary physician organ 
severity tool (ePOST) score (17 organs rated 0-6, for a total score range of 0-102) [16], the change 
in global score of sarcoidosis using a visual analogue scale (VAS) by both the patient and physician 
(distance in mm measured on a 10 cm line), the change in FACIT-F score (fatigue scale ranging 
from 0-52 with higher score meaning less fatigue), the change in the Health Assessment 
Questionnaire (HAQ), the change in prednisone dose, the change in serum angiotensin converting 
enzyme (ACE), serum immunoglobulin G (IgG) levels, serum calcium, urine calcium, and serum 
25-hydroxy vitamin D (25-OH-vit D), the change in pulmonary function tests (FVC, FEV1, and 
DLCO), the change in ALT, AST, and alkaline phosphatase, the change in serum creatinine and 
urine protein levels, the change in the Sarcoidosis Activity and Severity Index for cutaneous 
sarcoidosis (7 parameters scored 0-4 for a total score range of 0-28) [17], the change in CK, 
aldolase, and LDH, and the change in size of sarcoidosis lesions (i.e. enlarged lymph nodes, hepatic 
nodules, pulmonary nodules) by CT imaging.  For patients with known or suspected ocular 
involvement, the secondary endpoint of change in ophthalmology global assessment of ocular 
sarcoidosis using a visual analogue scale (VAS) (distance in mm measured on a 10 cm line) [18] 
will be assessed, as well as the change in any one or more of the following parameters: best 
corrected visual acuity (BCVA), slit lamp examination (including grading of anterior chamber 
cells), tonometry, dilated indirect ophthalmoscopy (including grading of vitreous cells and haze), 
optical coherence tomography (OCT) and OCT angiography, color fundus photography, and 
fluorescein angiography.   
 
From Week 16 to Week 28, time to flare will be compared between sarilumab-treated patients and 
placebo-treated controls as well as the proportion of patients in glucocorticoid-free remission at 
Week 28 between the two groups as additional secondary endpoints.   
 
Safety will be assessed by counting and describing adverse events and abnormal laboratory results. 
 
11. 
REGULATORY CONSIDERATIONS 
11.1 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related to the 
study (e.g. advertisements used to recruit participants) will be reviewed and approved by the 
Stanford IRB.  Any changes made to the protocol will be submitted as a modification and will be 
approved by the IRB prior to implementation.  The Protocol Director will disseminate the protocol 
amendment information to all participating investigators. 


 
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11.2 
Data and Safety Monitoring Plan 
We will form a Data and Safety Monitoring Committee (DSMC) consisting of two experience 
rheumatology clinicians at Stanford University.  The DSMC will audit study-related activities to 
determine whether the study has been conducted in accordance with the protocol, local standard 
operating procedures, FDA regulations, and Good Clinical Practice (GCP).  This may include 
review of the following types of documents participating in the study: regulatory binders, case 
report forms, eligibility checklists, and source documents.  In addition, the DSMC will regularly 
review serious adverse events and protocol deviations associated with the research to ensure the 
protection of human subjects.  Results of the DSMC audit will be communicated to the IRB and the 
appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as 
needed. 
 
11.3 
Data Management Plan 
The Protocol Director and his team will prepare and maintain adequate and accurate participant 
case histories with observations and data pertinent to the study.  Study specific Case Report Forms 
(CRFs) will document treatment outcomes for data analysis.   Case report forms will be developed 
as paper forms and will be kept in a locked office, only accessible to the research team. 
 
12. 
STATISTICAL CONSIDERATIONS 
12.1 
Statistical Design 
Patient characteristics including demographics, medical history, and concomitant medications will 
be summarized. The summaries will be done using descriptive statistics, eg, mean, standard 
deviation, median, minimum and maximum for quantitative values and counts and percents for 
qualitative variables. 
 
The primary efficacy analysis of flare-free survival in Period 2 from Week 16 to Week 28 will use 
the intention-to-treat (ITT) population and will be assessed with Kaplan-Meier methods.  Patients 
will be considered to have flared in Period 2 if they receive rescue medication including 
increased glucocorticoids, or if they discontinue the study treatment in order to start a 
different immunosuppressive therapy.   
 
For Period 1, secondary endpoint variables will be treated as continuous and the values at Week 16 
will be compared to Baseline values using Wilcoxon signed-rank tests.  The number of patients in 
glucocorticoid-free remission at week 16 will be reported.  Patients will be considered non-
responders in Period 1 if they are unable to complete the glucocorticoid taper, receive rescue 
medication including increased glucocorticoids, or discontinue the study treatment in order to start a 
different therapy.  For Period 1 secondary efficacy endpoints, non-responders will be included in 
the analysis only if their prednisone dose is equal to or less than the starting dose and stable for the 
4 weeks preceding Week 16.  The rationale for this is that patients who flare despite sarilumab 
therapy might be given high doses of steroids, thus improving their endpoints and falsely attributing 
the success to sarilumab.  As a sensitivity analysis, we will also assess the secondary outcomes 
using the baseline observation carried forward (BOCF) for those patients deemed non-responders.   
 


 
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For Period 2, time to first flare will be compared using a 2-sided log-rank test.  The proportion of 
patients in glucocorticoid-free remission at week 28 in sarilumab-treated patients compared to 
placebo controls will be analyzed using a Fisher’s exact test.  The remaining secondary endpoint 
variables will be treated as continuous and the values at Week 28 will be compared to Week 16 and 
to Baseline values using Wilcoxon signed-rank tests.  We will not perform any corrections for 
multiple hypothesis testing due to the exploratory nature of this pilot study which solely aims to 
generate areas of potential future investigation. 
 
12.2    Randomization 
 
In Period 2 of the study, patients will be randomized to sarilumab or matching placebo.  This will be 
done by our administrative assistant Angelica Aberia.  This will be done using a computer-generated 
random number.  An odd number will be assigned to sarilumab and an even number will be assigned 
to placebo.  Only Angelica will be aware of the assignment and she will communicate this directly to 
the pharmacy.  The investigators and patients will remain blinded. 
 
12.3  Sample Size 
The sample size for Period 1 of the trial of 15 patients was calculated based on the assumption that 
80% of the patients will respond to open-label sarilumab, allowing for 12 patients to enroll in the 
randomized withdrawal Period 2 of the study.  The sample size of 12 for Period 2 was calculated 
based on the assumption that 85% of the placebo group (roughly 5 out of 6) will flare (i.e. require 
reinitiation of prednisone) over the subsequent 12 weeks compared to 15% (roughly 1 out of 6) in 
the sarilumab group.  This relative hazard of 0.20 gives a power of 80% with an alpha of 0.05 to 
detect a difference between treatment groups assuming Kaplan-Meier analysis.  There is no 
published data on the use of sarilumab in sarcoidosis on which to base these assumptions.  
However, a parallel can be drawn between glucocorticoid-dependent sarcoidosis and 
glucocorticoid-dependent recurrent pericarditis, as they are both inflammatory and refractory to 
typical treatments.  The latter condition has been studied with Anakinra, an interleukin 1β 
recombinant receptor antagonist [19].  In that study, 21 out of 21 patients (100%) had a complete 
response in Period 1 and were subsequently randomized to withdrawal during Period 2.  In Period 
2, 9 out of 10 (90%) patients receiving placebo had disease recurrence compared to 2 out of 11 
patients (18%) receiving Anakinra.  Although this is a different disease with a drug targeting a 
different inflammatory cytokine, there is precedent for a dramatic response in diseases like 
sarcoidosis using drugs like sarilumab.  A sample size of 15 was deemed recruitable at Stanford 
after searching the Stanford medicine Research data Repository (STARR), which is a clinical data 
warehouse containing all patients seen at Stanford Hospital and Clinics.  A search for patients 
between the ages of 18 and 75 who were given the diagnosis code for sarcoidosis on at least two 
separate occasions within the last year and who are currently on prednisone, yields 200 potential 
patients.  Assuming half of these are coded correctly, and one-third of those truly have 
glucocorticoid-dependent, refractory disease, that leaves roughly 30 patients to screen, half of 
which we anticipate will be eligible for, and willing to participate in, the study.  Our IRB will allow 
us to identify specific patients within STARR whom we can contact to determine their interest in 
the study. 


 
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13. 
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