A Subject and Investigator Blinded, Randomized, Placebo-controlled, Repeat-dose, Multicenter Study to Investigate Efficacy, Safety, and Tolerability of CMK389 in Patients With Chronic Pulmonary Sarcoidosis
Phase: PHASE2
Conditions: Pulmonary Sarcoidosis
Sponsor: Novartis Pharmaceuticals

Novartis Institutes for BioMedical Research
CMK389
Clinical Trial Protocol CCMK389X2201 / NCT04064242
A subject and investigator blinded, randomized, placebo-
controlled, repeat-dose, multicenter study to investigate 
efficacy, safety, and tolerability of CMK389 in patients with 
chronic pulmonary sarcoidosis
Document type:
Amended Protocol Version 
EUDRACT number:
2018-000381-11
Version number:
v08 (Clean)
Clinical Trial Phase:
II
Release date:
23-Jun-2022
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis

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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not form part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as summarized 
below. Refer to Section 9.2 of the protocol for SAE criteria and additional requirements. See 
also page 2 of the Site Operations Manual (SOM) for further details on the method of reporting 
a SAE.

Complete SAE report

Submit SAE report to Novartis Chief Medical Office and Patient Safety 
(CMO&PS) within 24 hours after awareness of the SAE

Notify the Novartis Medical Lead

The fax number(s) and email address(es) are located in the SOM.

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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................8
List of abbreviations............................................................................................................9
Pharmacokinetic definitions and symbols.........................................................................12
Glossary of terms...............................................................................................................13
Protocol summary..............................................................................................................28
1
Introduction .......................................................................................................................31
1.1
Background............................................................................................................31
1.2
Nonclinical data.....................................................................................................32
1.3
Clinical data...........................................................................................................33
1.3.1
Human safety and tolerability data .......................................................33
1.3.2
Human pharmacokinetic data................................................................34
1.3.3
Human pharmacodynamic data.............................................................34
1.4
Study purpose ........................................................................................................34
2
Objectives and endpoints...................................................................................................34
2.1
Primary objective(s)...............................................................................................34
2.2
Secondary objective(s)...........................................................................................34
2.3
Exploratory objective(s) ........................................................................................35
3
Investigational plan ...........................................................................................................35
3.1
Study design...........................................................................................................35
3.2
Rationale for study design .....................................................................................39
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3.3
Rationale for dose/regimen, route of administration and duration of treatment....40
3.4
Rationale for choice of comparator .......................................................................40
3.5
Rationale for choice of background therapy..........................................................40
3.6
Purpose and timing of interim analyses/design adaptations..................................41
3.7
Risks and benefits..................................................................................................41
3.7.1
Blood sample volumes ..........................................................................43
4
Population..........................................................................................................................43
4.1
Inclusion criteria ....................................................................................................43
4.2
Exclusion criteria...................................................................................................44
5
Restrictions for Study Subjects .........................................................................................47
5.1
Contraception requirements...................................................................................47
5.2
Prohibited treatment...............................................................................................47
5.3
Dietary restrictions and smoking...........................................................................48
5.4
Other restrictions ...................................................................................................48
6
Treatment...........................................................................................................................48
6.1
Study treatment......................................................................................................48
6.1.1
Investigational treatment and control drug(s) .......................................48
6.1.2
Bio-batch retention samples..................................................................48
6.1.3
Additional study treatment....................................................................48
6.2
Treatment arms......................................................................................................48
6.3
Treatment assignment and randomization.............................................................49
6.4
Treatment blinding.................................................................................................49
6.5
Treating the subject................................................................................................51
6.6
Permitted dose adjustments and interruptions of study treatment.........................51
6.7
Emergency breaking of assigned treatment code ..................................................51
6.8
Treatment exposure and compliance .....................................................................51
6.9
Recommended treatment of adverse events ..........................................................52
6.10
Rescue medication.................................................................................................52
6.11
Concomitant treatment...........................................................................................52
7
Study completion and discontinuation ..............................................................................53
7.1
Study completion and post-study treatment ..........................................................53
7.2
Discontinuation of study treatment........................................................................53
7.3
Withdrawal of informed consent ...........................................................................54
7.4
Lost to follow-up ...................................................................................................54
7.5
Study Stopping rules..............................................................................................55
7.6
Early study termination by the sponsor .................................................................55

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8
Procedures and assessments ..............................................................................................55
8.1
Assessment schedule .............................................................................................55
8.2
Informed consent procedures.................................................................................61
8.3
Subject screening...................................................................................................62
8.4
Subject demographics/other baseline characteristics.............................................62
8.4.1
Concomitant therapies...........................................................................62
8.4.2
Discontinue Sarcoidosis Immunosuppressant Therapy ........................63
8.4.3
Tuberculosis status................................................................................63
8.4.4
Hepatitis and HIV Screen......................................................................63
8.4.5
Inclusion / Exclusion criteria ................................................................63
8.4.6
Medical history/current medical conditions..........................................63
8.4.7
Smoking history ....................................................................................63
8.4.8
Cotinine test ..........................................................................................63
8.5
Efficacy / Pharmacodynamics ...............................................................................64
8.5.1
6-Minute Walk Test ..............................................................................64
8.5.2
Patient Reported Outcomes (PROs)......................................................64
8.5.3
Diffusion Capacity (DLCO)..................................................................65
8.5.5
Steroid Titration ....................................................................................65
8.5.6
Spirometry.............................................................................................66
8.5.7
FDG-PET/CT........................................................................................66
8.6
Safety.....................................................................................................................67
8.6.1
Adverse Events......................................................................................67
8.6.2
Body Temperature.................................................................................67
8.6.3
Clinical Chemistry ................................................................................67
8.6.4
Blood Pressure and Pulse Rate..............................................................68
8.6.5
ECG evaluation.....................................................................................68
8.6.6
Hematology...........................................................................................68
8.6.7
Pregnancy and assessments of fertility .................................................68
8.6.8
Physical Examination............................................................................69
8.6.9
Urinalysis ..............................................................................................69
8.6.10
Body Weight and Height.......................................................................69
8.7
Pharmacokinetics...................................................................................................69
8.7.1
PK blood collection...............................................................................70
8.8
Other assessments..................................................................................................70
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8.8.2
High Resolution CT of Chest................................................................70
8.8.4
Fasting lipid panel.................................................................................71
8.9
Use of residual biological samples ........................................................................72
9
Safety monitoring..............................................................................................................73
9.1
Adverse events.......................................................................................................73
9.2
Serious adverse event reporting.............................................................................74
9.2.1
Definition of SAE .................................................................................74
9.2.2
SAE reporting........................................................................................75
9.3
Liver safety monitoring .........................................................................................76
9.4
Renal safety monitoring.........................................................................................77
9.5
Reporting of study treatment errors including misuse/abuse ................................78
9.6
Pregnancy reporting...............................................................................................78
9.7
Prospective suicidality assessment ........................................................................79
9.8
Early phase safety monitoring ...............................................................................79
10 Data review and database management.............................................................................79
10.1
Site monitoring ......................................................................................................79
10.2
Data collection.......................................................................................................80
10.3
Database management and quality control............................................................80
10.4
Data Monitoring Committee..................................................................................81
10.5
Adjudication Committee........................................................................................81
11 Data analysis......................................................................................................................81
11.1
Analysis sets ..........................................................................................................81
11.2
Subject demographics and other baseline characteristics......................................82
11.3
Treatments .............................................................................................................82
11.4
Analysis of the primary variable(s) .......................................................................82
11.4.1
Primary Variable(s)...............................................................................82
11.4.2
Statistical model, hypothesis, and method of analysis..........................82
11.4.3
Handling of missing values/censoring/discontinuations.......................83
11.4.4
Summary statistics of safety..................................................................83
11.4.5
Summary statistics of pharmacokinetics...............................................83
11.4.6
Sensitivity analyses ...............................................................................83
11.5
Analysis of secondary variable(s)..........................................................................83
11.5.1
Efficacy / Pharmacodynamics...............................................................83
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11.5.2
Safety.....................................................................................................84
11.5.3
Pharmacokinetics ..................................................................................84
11.5.4
Pharmacokinetic / pharmacodynamic interactions................................85
11.5.5
Other assessments .................................................................................85
11.7
Sample size calculation..........................................................................................86
11.8
Power for analysis of key secondary variables......................................................86
11.9
Interim analyses.....................................................................................................86
12 Ethical considerations........................................................................................................86
12.1
Regulatory and ethical compliance........................................................................86
12.2
Responsibilities of the investigator and IRB/IEC..................................................86
12.3
Publication of study protocol and results...............................................................87
12.4
Quality Control and Quality Assurance.................................................................87
13 Protocol adherence ............................................................................................................87
13.1
Protocol Amendments ...........................................................................................88
14 References .........................................................................................................................89
15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................92
16 Appendix 2: Specific Renal Alert Criteria and Actions ....................................................95
17 Appendix 3: Relative Potencies of Glucocorticoids..........................................................97
List of tables
Table 6-1
Overview of study medication ..............................................................48
Table 6-2
Blinding levels ......................................................................................50
Table 7-1
Sampson Criterion #1 for diagnosing anaphylaxis ...............................54
Table 8-1
Assessment Schedule ............................................................................56
Table 9-1
Guidance for capturing study treatment errors......................................78
Table 15-1
Liver Event Definitions.........................................................................92
Table 15-2
Actions required for Liver Events.........................................................93
Table 15-3
Exclusion of underlying liver disease ...................................................94
Table 16-1
Specific Renal Alert Criteria and Actions.............................................95
Table 16-2
Renal Event Follow Up.........................................................................96
Table 17-1
Steroid Equivalents ...............................................................................97
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List of figures
Figure 3-1
Study Design Schematic .......................................................................36
Figure 3-2
Clinical Status Evaluation (CSE) and Clinical Status Determination 
(CSD) ....................................................................................................37
Figure 3-3
Patient pathway as determined by clinical status..................................37
Figure 3-4
Steroid dose levels.................................................................................38

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List of abbreviations
6MWD
6-minute walk distance
6MWT
6-minute walk test
[18F]FDG
fluorine-18 fluorodeoxyglucose
ADA
Anti-drug antibody
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
ATS
American Thoracic Society
BMI
Body Mass Index
BUN
blood urea nitrogen
CFR
U.S. Code of Federal Regulation
CK
creatinine kinase
CMO&PS
Chief Medical Office & Patient Safety
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSD
Clinical Status Determination
CSE
Clinical Status Evaluation
DAR
dose administration record
DLCO
Diffusion capacity of the lung for carbon monoxide
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
EOS
end of study
ERS
European Respiratory Society
FDA
Food and Drug Administration
FEV1
forced expiratory volume in one second
FVC
Forced vital capacity
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
h
hour
HBsAG
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HRCT
high resolution computed tomography
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i.v.
intravenous
IB
Investigators Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IG
immunogenicity
IgG1-LALA
human immunoglobulin IgG1 with fragment crystallizable region substitutions at 
leucine (L) 234 to alanine (A) and L235 to A
INR
International Normalized Ratio
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine system
LDH
lactate dehydrogenase
MAR
missing at random
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
NCG
Non-caseating granuloma
NGS
Next Generation Sequencing
NIRT
Novartis Interactive Response Technology
NOAEL
no-observed-adverse-effect-level
PD
pharmacodynamic(s)
PET/CT
positron emission tomography/computed tomography
PFT
Pulmonary Function Test
PK
pharmacokinetic(s)
QTcF
Fridericia QT correction formula
RBC
red blood cell(s)
RoW
Rest of world
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
SUVmax
maximum standardized uptake value
SUVmean
mean standardized uptake value
TB
tuberculosis
TBL
total bilirubin
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TCR
T cell receptor
ULN
upper limit of normal
ULOQ
upper limit of quantification
VA
Volume alveolar
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent
WOCBP
Women of childbearing potential

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Pharmacokinetic definitions and symbols
AUC0-t
The area under the plasma (or serum or blood) concentration-time curve from time zero 
to time 't' where t is a defined time point after administration [mass x time / volume]
AUCinf
The area under the plasma (or serum or blood) concentration-time curve from time zero 
to infinity [mass x time / volume]
CL
The systemic (or total body) clearance from plasma (or serum or blood) following 
intravenous administration [volume / time]
Cmax
The observed maximum plasma (or serum or blood) concentration following drug 
administration [mass / volume]
Ctrough
The lowest concentration reached by a drug before the next dose is administered
t1/2
the terminal elimination half-life [time]
Tmax
The time to reach the maximum concentration after drug administration [time]

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Control drug
A study drug (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess internal 
study validity, and/or evaluate comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which are 
used to capture data transcribed from paper source forms used at the point 
of care.
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained
Epoch
Interval of time in the planned conduct of a study. An epoch is associated 
with a purpose (e.g. screening, randomization, and treatment follow-up) 
which applies across all arms of a study.
Investigational drug/ 
treatment
The drug whose properties are being tested in the study
Patient
An individual with the condition of interest
Personal data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Randomization 
number
A unique identifier assigned to each randomized subject
Run-in Failure
A subject who is screened but not randomized/treated after the run-in period 
(where run-in period requires adjustment to subject’s intervention or other 
treatment)
Screen Failure
A subject who did not meet one or more criteria that were required for 
participation in the study
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed 
consent by the first subject
Study treatment
Any single drug or combination of drugs or intervention administered to the 
subject as part of the required study procedures
Study treatment 
discontinuation
When the subject permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject and 
should be used to identify the subject throughout the study for all data 
collected, sample labels, etc.

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Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts.
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Withdrawal of study 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does not 
want to participate in the study any longer and does not allow any further 
collection of personal data

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Protocol summary
Protocol number
CCMK389X2201
Full Title
A subject and investigator blinded, randomized, placebo-controlled, repeat-
dose, multicenter study to investigate efficacy, safety, and tolerability of 
CMK389 in patients with chronic pulmonary sarcoidosis
Brief title
Study of efficacy, safety and tolerability of CMK389 in patients with chronic 
pulmonary sarcoidosis
Sponsor and 
Clinical Trial Phase
Novartis
Phase II
Intervention type
Biologic
Study type
Interventional
Purpose and 
rationale
The purpose of this proof-of-concept study is to determine whether CMK389 
displays the safety and efficacy profile to support further development in 
chronic pulmonary sarcoidosis
Primary 
Objective(s)
To assess the efficacy of CMK389 in subjects with chronic pulmonary 
sarcoidosis by looking at the change from baseline to end-of-treatment 
(16 weeks of treatment) in forced vital capacity (FVC)
Secondary 
Objectives
To assess the impact of CMK389 on a composite index of pulmonary 
physiology and exercise capacity from baseline to end-of-treatment
To assess the safety and tolerability of CMK389 by evaluating adverse 
events, vital signs and routine safety laboratory results from baseline to end-
of treatment
To explore the impact of CMK389 observed with [18F]-fluorodeoxyglucose 
positron emission tomography/computed tomography ([18F]-FDG-
PET/CT) imaging (SUVmax and SUVmean) from baseline to week 16
To assess the impact of CMK389 on forced expiratory volume in one second 
(FEV1) and diffusion capacity (DLCO) between baseline and week 16
To assess the impact of CMK389 on 6 min walk distance between baseline 
and week 16
To assess the impact of CMK389 on steroid use (mg-days) for each arm 
between baseline and end-of-treatment
To assess the pharmacokinetics of CMK389 after multiple doses in 
sarcoidosis patients at times specified at doses 1, 2, 3 and 4
Study design 
This is a subject and investigator blinded, randomized, placebo-controlled, 
parallel-group, repeat-dose, multicenter, non-confirmatory study of the safety 
and efficacy of CMK389 administered intravenously every 4 weeks for a total 
of 4 doses in chronic pulmonary sarcoidosis patients. Approximately 66 
patients will be randomized in a 1:1 ratio to receive either CMK389 or 
placebo. The expected total duration of participation for men and women of 
non-childbearing potential is approximately 38 weeks. For women of 
childbearing potential the expected duration of participation is approximately 
46 weeks
Population
This study will recruit male and female patients 18 to 75 years of age with 
biopsy proven chronic pulmonary sarcoidosis diagnosed for > 1 year

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Key Inclusion 
criteria

Written informed consent must be obtained before any assessment is
performed

Subjects must have a body mass index (BMI) at screening within the
range of 18 - 46 kg/m2. BMI = Body weight (kg) / [Height (m)]2

Pulmonary Sarcoidosis present > 1 year prior to screening with a
historical biopsy (from any organ or body part) confirming diagnosis prior
to screening

Scadding stage II, III or IV as determined by the most recent chest x-ray
obtained within 12 months prior to screening or at screening

HRCT extent of fibrosis <20% (confirmed by the central imaging reader)

Treatment with 5-15 mg/day prednisone (or prednisone equivalents) for
≥ 6 consecutive months prior to screening and with a minimum of 80%
compliance with treatment each month as determined by the
investigator.

Co-medication with methotrexate or azathioprine for ≥ 6 consecutive
months prior to screening and with a minimum of 80% compliance with
treatment each month as determined by the investigator (Note:
hydroxychloroquine is allowed as background therapy but not required)

Able to perform reliable, reproducible pulmonary function test maneuvers
per American Thoracic Society/European Respiratory Society
(ATS/ERS) guidelines
Key Exclusion 
criteria

Diagnosis of significant pulmonary hypertension (WHO group 5)
requiring pharmacological treatment

Active cardiac sarcoidosis requiring treatment. Inactive cardiac
sarcoidosis or stable cardiac sarcoidosis not requiring treatment are
permissible.

A known diagnosis of neurosarcoidosis

Forced vital capacity (FVC) <50% of predicted at screening (central
read)

Modified British Medical Research Council (mMRC) dyspnea scale ≥3
at screening

Concomitant treatment with leflunomide, cyclophosphamide,
mycophenolate, infliximab, etanercept, adalimumab, golimumab,
ustekinumab, roflumilast, pentoxifylline, and abatacept within 12 weeks
of screening.

Prior treatment with rituximab, canakinumab, anakinra, and tocilizumab

Current smokers, defined as inhaled use of tobacco products

Any conditions or significant medical problems which, in the opinion of
the investigator in consultation with the sponsor, immunocompromises
the patient and/or places the patient at unacceptable risk for
immunomodulatory therapy

Contraindication to FDG-PET scan investigations such as severe
claustrophobia or uncontrolled diabetes

History or current diagnosis of ECG abnormalities indicating significant
risk of safety for patients participating in the study.

A diagnosis of Lofgren’s syndrome

A history of pancreatitis

Other pulmonary disease (i.e., asthma, bronchiectasis, COPD, etc.)
unrelated to sarcoid as determined by the investigator

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Study treatment

Two treatment arms in a ratio of 1:1: CMK389 versus placebo-controlled
dose group
Pharmacokinetic 
assessments

Serum CMK389 concentrations
Efficacy/PD 
assessments

Spirometry

DLCO

Six-minute walk test

[18F]FDG-PET/CT

mMRC dyspnea scale
Key safety 
assessments

Physical examination, including vital signs and height/weight

Hematology, clinical chemistry, urinalysis

Electrocardiogram (ECG)

Serious Adverse Events and Adverse Events

2-hour post-dose observation period for monitoring of acute infusion or
hypersensitivity reactions.
Other 
assessments
Data analysis
The change from baseline in percent predicted FVC will be analyzed using a 
Bayesian model for repeated measurements. The model will investigate 
effects for treatment by time (included as a class variable) interaction, baseline 
FVC by time interaction, prior sarcoidosis immunosuppressant therapy 
(stratification factor) and baseline prednisone dose. The correlation among 
the repeated measures collected on the same subject will be assessed via an 
unstructured covariance matrix. The stratification factor may be removed in 
case of strata with low sample sizes impacting on the convergence of the 
model.
Uninformative priors will be utilized to obtain the posterior estimates. Baseline 
is defined as Day 1.
The posterior probability that CMK389 is better than placebo in terms of 
change from baseline in percent predicted FVC at 16 weeks will be calculated. 
If it is at least 90%, it will be considered a sign of efficacy of CMK389 in this 
patient population.
Key words
Chronic pulmonary sarcoidosis
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1
Introduction
1.1
Background
Unmet Medical Need
Sarcoidosis is a multi-system inflammatory disease of unknown etiology characterized by the 
formation of non-caseating granulomatous (NCG) inflammation in various organs. NCG 
contain a core of monocyte-derived epithelioid histiocytes and multi-nucleated giant cells; the 
outer rim consists of CD4+T cells, regulatory T
cells, B cells and fibroblasts 
(Dastoori et al 2013; Newman 2000).
The incidence of sarcoidosis in the U.S. has been estimated at 10-36/100,000; with variability 
dependent upon ethnic background. U.S. mortality increased by 3% per year, during the period 
between 1988 and 2007; with the primary causes of morbidity and mortality being pulmonary 
hypertension, 
pulmonary 
fibrosis 
and 
heart 
failure 
(secondary 
to 
sarcoidosis) 
(Chen and Moller 2011). The overall risk of death from sarcoidosis in the U.S. is 8%; mortality 
rates are 10-fold higher in African-Americans and Asians, as compared to Caucasians.
Sarcoidosis most often impacts the lungs, skin or eyes; but may affect other tissues and organ 
systems. In two-thirds of cases, sarcoidosis presents as an asymptomatic, self-limited disease, 
incidentally detected on a routine chest radiograph; in such cases, complete remission of 
sarcoidosis is typically observed within the first 2 years after diagnosis (Iannuzzi et al 2007). 
The remainder of patients with sarcoidosis develops a persistent form of the disease that can 
last for 2 or more years; spontaneous remission is rare within this cohort. Spontaneous remission 
is even rarer in patients who present with cutaneous sarcoidosis, sinus manifestations, or fibrotic 
lung changes.
Currently, there are no FDA/EMA-approved therapies for sarcoidosis. Standard therapy 
consists of non-specific immunosuppression with corticosteroids and/or a cytotoxic agent (such 
as methotrexate or azathioprine). However, the benefit of these interventions has not been fully 
proven 
by 
randomized-controlled 
interventional 
studies 
(Chen and Moller 2011). 
Additionally, such non-specific immunosuppressant agents carry the burden of severe adverse 
reactions associated with chronic administration and the long-term benefit remains unclear.
In addition, rigorous evaluations of anti-TNF agents in the treatment of sarcoidosis have shown 
mixed results and their utility in the treatment of this disease remains in question 
(Baughman et al 2006; Utz et al 2003). Recent investigation of an anti-IL-12/23 mAb 
(Benson et al 2011) demonstrated a lack of efficacy (Baughman et al 2013; Judson et al 2013).
Rationale for IL-18 Antagonism in Sarcoidosis
The etiology of sarcoidosis is poorly understood. However, the oligoclonal, restricted T cell 
receptor (TCR) rearrangement of T cells in sarcoidosis suggests response to a “specific” antigen. 
It has been suggested that sarcoidosis is triggered by serum amyloid A (AA) in response to 
mycobacterial infection (Chen and Moller 2011; Gupta et al 2012); other possible triggers 
include common bacterial, viral or fungal infections; dusts and metals. Granulomatous 
inflammation develops around the nidus of antigenic material (e.g., serum amyloid, bacteria, 
etc.). In response, the innate immune cells engulf, then display, the antigenic material on the 

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surface of MHC class I and class II molecules. This triggers an adaptive immune system 
response with T cells, polarized toward the expression of TH1-affiliated cytokines 
(Romagnani 2006). The TH1-polarized cytokine response orchestrates the formation of NCG 
associated with sarcoidosis.
IL-18 is a pleiotropic pro-inflammatory cytokine which, in synergy with IL-12, increases IL-18 
receptor expression. Activation of the IL-18 receptor by IL-18 induces MyD88, IRAK, TRAF6, 
NF-κB and other downstream signaling pathways that are pivotal for maximal generation of 
IFN-γ and induction of polarized TH1 responses (Okamura et al 1995; Yoshimoto et al 1998).
CMK389
CMK389 is a fully human, IgG1-LALA, high affinity monoclonal antibody that has been shown 
to selectively bind to IL-18 and potently inhibit IL-18 activity.
CMK389 is expected to neutralize the bioactivity of IL-18, thereby reducing NCG formation 
and the tissue damage associated with excessive IFN-γ-driven immune responses.
Thus, CMK389 is proposed for the treatment of chronic, persistent pulmonary sarcoidosis.
1.2
Nonclinical data
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1.3
Clinical data
1.3.1
Human safety and tolerability data
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1.3.2
Human pharmacokinetic data
1.3.3
Human pharmacodynamic data
1.4
Study purpose
The purpose of this proof-of-concept study is to determine whether CMK389 displays the safety 
and efficacy profile to support further development in chronic pulmonary sarcoidosis.
2
Objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To assess the efficacy of CMK389 in
subjects with chronic pulmonary
sarcoidosis

Change in forced vital capacity, % of
predicted, (FVC%) between baseline and
Week 16, between CMK389 and placebo.
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To assess the impact of CMK389 on
steroid use (mg days)

Difference in steroid usage for each arm of the
study between baseline and end of treatment

To assess the impact of CMK389 on a
composite index of pulmonary physiology
and exercise capacity

Proportion of patients who deteriorate from
baseline to Week 16, defined as: relative
reduction in FVC ≥ 10% or relative reduction in
FEV1 ≥ 10% or relative reduction of DLCO
≥15% or relative reduction of 6MWD ≥ 50 m
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Secondary objective(s)
Endpoints related to secondary objective(s)

To explore the impact of CMK389
observed with [18F]-fluorodeoxyglucose
positron emission tomography/computed
tomography ([18F]-FDG-PET/CT) imaging

Change in [18F]-FDG-PET/CT (SUVmax and
SUVmean) from baseline and Week 16

To assess the pharmacokinetics of
CMK389

Pharmacokinetic parameters (Cmax/End of
infusion, Ctrough) of CMK389

To assess the safety and tolerability of
CMK389

Adverse events, vital signs and routine safety
laboratory results.

To assess the impact of CMK389 on
pulmonary physiology

Change in forced expiratory volume in one
second (FEV1) and diffusion capacity for
carbon monoxide (DLCO) between baseline
and Week 16

To assess the impact of CMK389 on
exercise capacity

Change in 6-minute walk distance (6MWD)
between baseline and Week 16
2.3
Exploratory objective(s)
3
Investigational plan
3.1
Study design
This is a subject and investigator blinded, randomized, placebo-controlled, parallel-group, 
repeat-dose, multicenter, non-confirmatory study of CMK389 in chronic pulmonary sarcoidosis. 
This study will investigate the safety and efficacy of 10 mg/kg CMK389 administered 
intravenously (i.v.) every 4 weeks for a total of 4 doses, versus placebo 
(Figure 3-1). After obtaining signed informed consent, a screening epoch of 28 days will be 
used to assess subject eligibility. The population will consist of patients with biopsy-proven 
pulmonary sarcoidosis, in Scadding stages II, III, or IV as determined by the most recent chest 
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x-ray. A high resolution computed tomography (HRCT) scan (historical or performed at
screening (Day -70 to -43)) will be reviewed to select subjects with minimal fibrosis (< 15%
reticular markings on a volumetric basis). Eligible patients must be treated with 5-15 mg daily
prednisone (or equivalent) and methotrexate or azathioprine for ≥ 6 months prior to screening.
Hydroxychloroquine is allowed as background therapy but not required. Approximately 66
subjects will be randomized in a 1:1 ratio to receive CMK389 or placebo. Randomization will
be stratified by prior sarcoidosis immunosuppressant therapy (azathioprine or methotrexate).
Figure 3-1
Study Design Schematic
Run-in Epoch
A 6-week run-in epoch will commence on Day -42. First, eligible patients will discontinue 
methotrexate and azathioprine. Hydroxychloroquine will be allowed to continue as background 
therapy. Then, on Day -28 (2 weeks after discontinuation of methotrexate or azathioprine), 
patients will undergo a full safety assessment, a "Clinical Status Evaluation (CSE)", and enter 
into a steroid (prednisone or equivalent; see Table 17-1-Appendix 3) titration algorithm. CSE 
will consist of a 6-minute walk test, spirometry assessments, and an assessment of dyspnea 
(Modified Medical Research Council [mMRC] breathlessness scale). The CSE serves as an 
additional safety evaluation and will serve to establish the patient's current clinical status 
(Clinical Status Determination [CSD]) as compared to their status at Day -42 (Figure 3-2). 
The CSE will be performed at each subsequent visit, prior to the titration of steroids, and the 
CSD will guide selection of the next dose of steroids (Figure 3-3). Steroid titration will continue 
through the run-in epoch; and steroid titration will also continue through the treatment epoch. 
Patients with CSD of "improved" or "stable" will decrease steroid dose by 1-step on the dosing 
scale (Figure 3-4). (Note: To prevent Addisonian crisis, steroids will not be tapered below a 
physiologic dose (2.5 mg/day); and steroid tapering will follow a very slow regimen, as per 
protocol – i.e., modest decreases in dose, no more frequent than every four weeks). Patients with 
CSD of "deteriorating" will be ineligible to continue the study (if “deteriorating” is determined 
during the run-in epoch); or they will increase their steroid dose by 1-step (if “deteriorating” is 
Day 253
Week 30
V499

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determined during the treatment epoch). [18F]-FDG PET/CT will be performed prior to the first 
dose (Day -2 (± 1)) and again at the end of the treatment epoch (Day 113). 
Figure 3-2
Clinical Status Evaluation (CSE) and Clinical Status Determination 
(CSD)
Figure 3-3
Patient pathway as determined by clinical status

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Figure 3-4
Steroid dose levels
* Prednisone (or equivalent) cannot be less than 2.5 mg/day or more than 15 mg/day during the Run-
In and Treatment epochs.
Treatment Epoch
A 16-week treatment epoch will commence on Day 1. Patients with a CSD of “deteriorating” 
at this visit will be ineligible to continue in the study. Patients with a CSD of “improved" or 
"stable” will decrease steroid dose by 1-step. (Note: Steroids will not be tapered below 
2.5 mg/day) Then, the patients will be randomized to receive CMK389 or placebo, stratified by 
prior sarcoidosis immunosuppressant therapy (Stratum 1: azathioprine or Stratum 2: 
methotrexate).
During the treatment epoch, steroid dose will be guided by the results of CSE/CSD 
(Figure 3-3). During the treatment epoch, adverse events will be monitored on an ongoing basis. 
Monthly visits are scheduled to assess safety and efficacy. Physical exam, vital signs, blood 
draw (safety labs, pharmacokinetic [PK] samples, 
), spirometry, 6MWT, mMRC and 
will be 
performed during the treatment epoch every 4 weeks or as described in the Assessment 
Schedule (Table 8-1). 
Every effort should be put in place to adhere to this algorithm, but in cases where the 
Investigator feels that, during the Treatment Epoch, a subject’s increase in steroids outside of 
the specified incremental dose-steps indicated or re-initiation of methotrexate or azathioprine 
is clinically indicated, this therapy can be started/adjusted. All the actual treatments should be 
reported in the CRF and all the PD parameters collected after therapy adjustment will be 
excluded from the primary analysis.
Safety Follow-up Epoch
After the treatment epoch, the safety follow-up epoch will last 12 weeks. This enables the 
assessment of safety in adults with sarcoidosis for ~5 half-lives following the last administration 
of CMK389. During the safety follow-up epoch, physical exam, adverse events, safety labs, 
PK and 
 samples, 
 will be collected every four weeks. 
During the safety follow-up epoch, treatment for sarcoidosis will be guided by the Investigator; 
if necessary, methotrexate and/or azathioprine may be reintroduced and corticosteroid doses 
may be adjusted.
*
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Pregnancy Testing Period (WOCBP only)
Due to hypothetical effects on the fetus (see Section 3.2), WOCBP will be followed for an 
additional 8 weeks after EOS #1 (V399) (or 24 weeks total after their last treatment with 
CMK389) to ensure that they continue to use highly effective contraception. 
3.2
Rationale for study design
The rationale for key elements of this study are as follows:

Placebo controls: The placebo group is used to define the natural history of disease under
the study's conditions. Comparison of placebo to the active group provides the most rigorous
test of efficacy. Since no drugs are currently approved for the treatment of sarcoidosis,
inclusion of a placebo arm is considered to be ethical; and the risk-benefit of placebo
treatment is considered to be favorable. (Note: the potential benefits of alternative
treatments, such as TNF inhibitors, are unproven/unknown, risk-benefit of alternative
treatments are unfavorable, and such treatments are prohibited by this protocol).

Randomization: Randomization is used to avoid "selection bias" in the assignment of
subjects to treatment groups. Randomization also serves to balance the treatment groups
with respect to many known and unknown confounding variables; and randomization forms
the basis of assumptions for our statistical tests.

Blinding: Conscious and unconscious biases are avoided ("detection bias" and "reporting
bias", pertaining to outcome assessment) by ensuring that patients and investigators are
unaware of treatment assignment.

Run-in epoch: During this epoch, adjustments are made to background therapy in an effort
to harmonize all the patients before commencement of the treatment epoch.

Discontinuation of methotrexate and azathioprine during the run-in epoch: In clinical
practice, immunosuppressants are often interrupted while the patient is closely observed for
evidence of clinical change. This protocol mimics the immunosuppressant interruption that
is frequently employed in clinical practice. This design allows a more robust evaluation of
the efficacy of CMK389 while minimizing the potentially masking effects of
immunosuppressant therapy.

Steroid titration algorithm: Judicious titration of corticosteroids is common practice for a
patient with sarcoidosis who is doing well; conversely, the dose of steroids is typically
increased for a patient with sarcoidosis who is doing poorly. Within the context of this
clinical trial, adjustment of steroids will be allowed. However, to avoid the introduction of
"performance bias" by individual sites and investigators, all steroid titrations will be
performed according to the rules of a pre-determined algorithm.
To prevent Addisonian crisis, steroids will not be tapered below a physiologic dose
(2.5 mg/day); and steroid tapering will follow a very slow regimen, as per protocol.

Pregnancy Testing Period (WOCBP only): IL-18 is expressed at the maternal-fetal
interface (Tokmadzić et al 2002) and could potentially play a role, with other cytokines, in
the pro-inflammatory events of early pregnancy such as ovulation, implantation decidual
remodeling and placentation as well as contributing to the pro-inflammatory response
promoting parturition (Laskarin et al 2005; Wilson et al 2004). However, there is also a
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pregnancy, with reported links to preterm labor, recurrent abortion, intrauterine growth 
retardation, 
pre-eclampsia 
and 
spontaneous 
fetal 
resorption
(El-Kabarity and Naguib 2011; Chau et al 2016). IL-18 knockout mice show no alteration 
in litter size, sex ratio, and weight gain and no structural abnormalities (Takeda et al 1998). 
IL-18 knockout mice develop hyperphagy, obesity and insulin resistance at 6 months of age 
(Netea et al 2006), which represents a theoretical risk to the neonate, although post-natal 
exposure to CMK389 through maternal transfer will be much shorter duration in humans 
relative to lifespan than in mice. Hence CMK389 treatment could have both positive and 
negative impacts on pregnancy. This represents a hypothetical risk to the developing fetus. 
Therefore, WOCBP will be followed up to 24 weeks after their last 
treatment with CMK389 to ensure that highly effective contraception is used and fetal risks 
are avoided. 
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
The selection of dose, 10 mg/kg, for CMK389 is based on identification of the "maximum 
feasible dose", 
Additionally, based on the 
prediction of nonclinical modeling and simulation, monthly dosing at 10 mg/kg would have a 
near complete inhibition (>90%) of interferon gamma release in humans. Therefore, 10 mg/kg, 
the highest dose, is selected to maximize the chances for detecting efficacy in this proof-of-
concept trial.
Monthly 10 mg/kg repeat-dosing is planned to achieve trough drug concentrations that are 
above (~50-fold) the EC80 (7.4 nM) of the in vitro whole blood assay for the inhibition of 
IFN-gamma release. Four monthly repeated doses of CMK389 at 10 mg/kg are anticipated to 
result in a peak concentration (~440 µg/mL) 
3.4
Rationale for choice of comparator
In this study, the placebo to CMK389 will be used as comparator to provide objective evidence 
of potential AEs and other safety data as well as clinical efficacy and PD data generated from 
patients exposed to CMK389.
3.5
Rationale for choice of background therapy
There are no FDA/EMA-approved therapies for sarcoidosis. It is common practice for patients 
to be treated with non-specific immunosuppressants: corticosteroids, with or without the 
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addition of a cytotoxic agent (such as methotrexate, azathioprine, or hydroxychloroquine). 
Due to potential confounding factors and the absence of proven efficacy, methotrexate and 
azathioprine will be discontinued during the run-in epoch. However, corticosteroid medications 
and hydroxychloroquine will be allowed as background therapy during this study, in order to 
test the efficacy of CMK389 in a "real-world" setting.
3.6
Purpose and timing of interim analyses/design adaptations
3.7
Risks and benefits
Potential benefit:

There is no proven direct medical benefit for subjects who will participate in this study.
However, the patient's participation in this study will facilitate and advance research in the
field of drug development for the treatment of sarcoidosis, which is still a significant unmet
medical need (Section 1.1).
Potential risk: 


Based on clinical observation: 
Therefore, to date, no 
specific risks have been identified through clinical observation.

Based on mechanism of action (i.e., drug class): CMK389 is an immunosuppressant;
therefore patients undergoing treatment with CMK389 are theoretically at risk for infection.
CMK389 is a biologic compound; therefore patients who receive CMK389 are theoretically
at risk of acute infusion and/or hypersensitivity reactions.

Based on COVID-19 pandemic: CMK389 has been shown to selectively bind to IL-18
and potently inhibit IL-18 activity. Blocking IL-18 may impair the innate and cytotoxic
immune responses that play a role in viral clearance. IL-18 contributes to antiviral immune
responses by promoting IFN-γ production by T cells, natural killer cells, and natural killer
T cells and supports the induction of cytotoxic T cells. Impaired cytotoxic T cell responses
may impair the killing of virus-infected cells. However, data generated to-date to assess the
impact of CMK389 on immune function support a lack of a broad immunosuppressive effect.
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CMK389 is not expected to impair the production of viral-specific antibodies, including 
those against SARS-CoV-2. The inflammasome and the pivotal mediators IL-1β, IL-18, and 
NLRP3 contribute to the hyper-inflammatory response that results in severe pulmonary 
tissue damage after initial SARS-CoV and SARS-CoV-2 infections. Patients with severe 
COVID-19 and respiratory failure have elevated levels of IL-1β and its downstream 
cytokine IL-6, as well as IFN-γ and 
, both downstream markers of IL-18 
pathway activation. Hence, blocking IL-18 with CMK389 could theoretically play a 
protective role in suppressing the hyper-inflammatory response to these viruses. 
Novartis is committed to supporting the safety and well-being of our study participants, 
investigators, and site staff. All local regulations and site requirements should be applied in 
the countries that are affected by the COVID-19 pandemic. The Novartis clinical trial team 
will review the situation in each participating country and work with Investigators to continue 
to ensure the safety of participants during the conduct of the trial. A benefit/risk assessment 
has been made and has been determined to not significantly change for the participants that 
are planned to be enrolled in the proposed clinical trial. As the COVID-19 situation evolves, 
Investigators must use their best judgement to minimize risk to participants during the 
conduct of the study.
Risk mitigation strategy:

The risk to subjects in this trial will be minimized by adherence to the eligibility criteria,
close clinical monitoring, and compliance with criteria for treatment interruption outlined
in the protocol (Section 7.2).

Drug-drug interactions are unlikely with biologics, however, sites and patients must
strictly observe and adhere to the list of prohibited medications listed in the protocol
(Section 5.2).

Women of childbearing potential must be informed that taking the study treatment may
involve unknown risks to the fetus if pregnancy were to occur during the study; and agree
that, in order to participate in the study, they must adhere to the contraception
requirements outlined in Section 4.2 (Exclusion Criteria). If there is any question that the
subject will not reliably comply, they should not be entered into or continue in the study.

Patients with current, active or latent infection are excluded from this study. In addition,
investigators will remain vigilant for signs of intercurrent infections (i.e., nausea,
vomiting, fever, rash, confusion, or muscle aches).
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Risk of Imaging Procedures:
The total radiation effective dose in this protocol will be less than 15 mSv; 4 mSv from HRCT 
scanning and 11 mSv from [18F]FDG-PET/CT scans, including attenuation correction scans. 
In large and obese patients, a higher injected [18F]FDG activity may be required but the total 
radiation exposure in these patients will not exceed 20 mSv. This amount of radiation is 
considered to be a moderate risk, category III (ICRP 1991) and is balanced against the 
substantial societal benefit gained from the trial.
Miscellaneous:
There may be unknown risks of CMK389 which may be serious.
3.7.1
Blood sample volumes
A maximum of 493 mL of blood is planned to be collected over a period of 9 months, from 
each subject as part of the study. Additional samples may be required for safety monitoring.
Timings of blood sample collection are outlined in the Assessment schedule (Section 8.1).
A summary blood log is provided in the Site Operations Manual (SOM). Instructions for all 
sample collection, processing, storage and shipment information is also available in the SOM 
and Central Laboratory Manual.
See Section 8.9 regarding the potential use of residual samples.
4
Population
The investigator must ensure that all subjects being considered for the study meet the below 
eligibility criteria. No additional criteria should be applied by the investigator in order that the 
study population will be representative of all eligible subjects.
Subject selection is to be established by checking through all eligibility criteria at screening. 
A relevant record (e.g., checklist) of the eligibility criteria must be stored with the source 
documentation at the study site prior to randomization.
Deviation from any entry criteria excludes a subject from enrollment into the study.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
4.1
Inclusion criteria
Subjects eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed
2. Male and female subjects ages 18-75 years of age inclusive at screening
3. Subjects must have a body mass index (BMI) at screening within the range of
18 - 46 kg/m2. BMI = Body weight (kg) / [Height (m)]2
4. Pulmonary Sarcoidosis present > 1 year prior to screening with a historical biopsy (from
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5. Scadding stage II, III or IV as determined by the most recent chest x-ray obtained within
12 months prior to screening or at screening (confirmed by the investigator)
6. HRCT extent of fibrosis <20% (confirmed by the central imaging reader) on an HRCT
obtained within 12 months prior to screening or at screening
7. Treatment with 5-15 mg/day prednisone (or prednisone oral equivalents) for
≥ 6 consecutive months prior to screening and with a minimum of 80% compliance with
treatment each month as determined by the investigator.
8. Co-medication with methotrexate or azathioprine for ≥ 6 months prior to screening and
with a minimum of 80% compliance with treatment each month as determined by the
investigator (Note: hydroxychloroquine is allowed as background therapy but not
required)
9. Able to perform reliable, reproducible pulmonary function test maneuvers per American
Thoracic Society/European Respiratory Society (Culver et al 2017; Miller et al 2005;
Graham et al 2017) guidelines
10. Able to communicate well with the investigator, to understand and comply with the
requirements of the study
4.2
Exclusion criteria
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study:
1. History of hypersensitivity to the study drug, or to drugs of similar chemical classes
(i.e., IgG-1 related biologic agents)
2. Diagnosis of significant pulmonary hypertension (WHO group 5) requiring
pharmacological treatment
3. Active cardiac sarcoidosis requiring treatment. Inactive cardiac sarcoidosis or stable
cardiac sarcoidosis not requiring treatment are permissible.
4. A known diagnosis of neurosarcoidosis
5. Forced vital capacity (FVC) <50% of predicted at screening (central read)
6. Modified British Medical Research Council (mMRC) dyspnea scale ≥ 3 at screening
7. Concomitant treatment with leflunomide, cyclophosphamide, mycophenolate, infliximab,
etanercept, adalimumab, golimumab, ustekinumab, roflumilast, pentoxifylline, and
abatacept within 12 weeks of screening
8. Any prior treatment with rituximab, canakinumab, anakinra, and tocilizumab
9. Use of other investigational drugs within 5 half-lives of screening, or until the expected
PD effect has returned to baseline, whichever is longer; or longer if required by local
regulations
10. Current use of any inhaled substance, including but not limited to tobacco, marijuana
products and the use of any electronic cigarette or vaping device (note that respiratory
inhalers or nebulizers for delivery of prescribed medication for pulmonary sarcoidosis are
allowed).
11. Any conditions or significant medical problems which, in the opinion of the investigator
and in consultation with the sponsor, immunocompromises the patient and/or places the
patient at unacceptable risk for immunomodulatory therapy
12. Any one of the following screening values of complete blood count laboratory values:

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
Hemoglobin levels below 8.0 g/dL

Total leukocyte count less than 2,000/μL

Platelets <100.0 x 109/L

Absolute neutrophil count (ANC) <1.5 x 109/L
13. Active viral, bacterial or other infections requiring systemic treatment at the time of
screening, or within 3 months from screening in case of a known or suspected COVID-19
infection, unless resolution is confirmed radiographically as determined by the
Investigator.
14. History of primary or secondary immunodeficiency, or a positive Human
Immunodeficiency Virus (HIV) (Enzyme-linked Immunosorbent Assay (ELISA) and
Western blot) test result at screening
15. Positive hepatitis B surface antigen (HBsAg) with concurrent negative hepatitis B surface
antibody (anti-HBs); or positive total hepatitis B core antibody (anti-HBc) with concurrent
negative anti-HBs; or positive hepatitis C antibody (anti-HCV) unless it can be
documented that the patient has received highly-effective HCV-specific antiviral therapy,
HCV RNA levels are measured, and HCV RNA is undetectable at least 12 weeks after the
conclusion of HCV-specific antiviral therapy; i.e., any acute or chronic infection with
hepatitis B or hepatitis C
16. Evidence of active or latent tuberculosis (TB) infection, as determined by Quantiferon test
at screening (Note: if Quantiferon test is indeterminate, it may be repeated once.
Two indeterminate Quantiferon tests will be considered as evidence of TB infection.
Furthermore, after anti-TB treatment, patients with history of or latent TB may become
eligible according to national guidelines)
17. Receipt of live/attenuated vaccine within a 1 month period before first dose of CMK389
(V201)
18. Contraindication to FDG-PET scan investigations such as severe claustrophobia or
uncontrolled diabetes
19. History of confirmed malignancy of any organ system (other than localized carcinoma of
the skin (for example: basal, squamous) or in situ cervical carcinoma), treated or
untreated, within 5 years of screening, regardless of whether there is evidence of local
recurrence or metastases
20. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception and until the termination of gestation, confirmed by a positive hCG
laboratory test
21. Women of childbearing potential (WOCBP) (see definition below), unless they are using
highly effective methods of contraception during dosing and for an additional 6 months
after the last dose (infusion)
Women of childbearing potential
WOCBP are defined as all women physiologically capable of becoming pregnant,
including women whose career, lifestyle, or sexual orientation precludes intercourse with
a male partner and women whose partner have been sterilized by vasectomy or other
means.

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Women of non-childbearing potential
Women are considered post-menopausal and not of childbearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age 
appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six 
weeks prior to screening. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment is she 
considered not of childbearing potential.
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception

Male/female sterilization

Use of oral, injected or implanted hormonal methods of contraception or placement of
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal
contraception that have comparable efficacy (failure rate <1%), for example hormone
vaginal ring or transdermal hormone contraception
In case of use of oral contraception, women should be stable on the same pill for a minimum
of 3 months before taking investigational drug.
22. Other history or current diagnosis of ECG abnormalities not due to cardiac sarcoidosis at
screening as determined by the investigator and based on the totality of the safety
information to indicate significant safety risk. The following should be considered by the
investigator  in guiding the determination as part of the overall assessment, but should not
be considered in isolation:

PR > 200 msec

QRS complex > 120 msec

QTcF > 450 msec (males)

QTcF > 460 msec (females)
23. Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular
tachycardia, and clinically significant second or third degree AV block without a
pacemaker
24. Significant illness which has not resolved within two weeks prior to initial dosing
25. Donation or loss of 400 mL or more of blood within eight weeks prior to initial dosing, or
longer if required by local regulation
26. Any surgical or medical condition which might significantly alter the absorption,
distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in
case of participation in the study. The investigator should make this determination in
consultation with the sponsor and in consideration of the subject’s medical history and/or
clinical or laboratory evidence.
27. Clinical Status Determination (CSD) of "deteriorating" at Day-28 (V102) or Day 1 (V201)

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28. A diagnosis of Lofgren’s syndrome
29. History of pancreatitis
30. Other pulmonary disease (i.e.. asthma, bronchiectasis, COPD, etc.) unrelated to sarcoid as
determined by the investigator
31. Active drug or alcohol abuse (as defined by the investigator) within 3 months prior to
screening.
5
Restrictions for Study Subjects
For the duration of the study, the subjects should be informed and reminded of the restrictions 
outlined in this section.
5.1
Contraception requirements
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirement outlined in
Section 4.2 (Exclusion Criteria). If there is any question that the subject will not reliably comply, 
they should not be entered or continue in the study.
5.2
Prohibited treatment
Use of the following treatments are NOT allowed in the timeframes reported in Table 5-1.
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5.3
Dietary restrictions and smoking
Use of any inhaled substance, including but not limited to tobacco or marijuana products or use 
of any electronic cigarette or vaping device is not allowed during the study. Respiratory inhalers 
or nebulizers for delivery of prescribed medication for pulmonary sarcoidosis are allowed. 
Patients will be asked to not eat or drink anything (except water) for 8 hours before completing 
the chemistry and fasting lipid panel assessment at each applicable visit.
5.4
Other restrictions
No strenuous physical exercise is allowed within 30 minutes of Spirometry and DLCO 
assessments.
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the Pharmacy Manual.
6.1.1
Investigational treatment and control drug(s)
Table 6-1
Overview of study medication
Study Drug 
Formulation
Appearance
Unit dose
Packaging
Provided by
CMK389
Powder for 
Solution for 
Infusion
a white to off-
white 
lyophilisate
150 mg 
powder in a 6 
mL glass vial
open label 
bulk
Novartis
6.1.2
Bio-batch retention samples
Not applicable
6.1.3
Additional study treatment
No additional treatment beyond investigational drug and placebo control drug are included in 
this trial.
Pre-medication (prior to infusion of CMK389) with corticosteroids, NSAIDs and paracetamol
is not allowed.
Note: in the event of hypersensitivity reaction, refer to Section 6.9.
6.2
Treatment arms
Subjects will be assigned to one of the following 2 treatment arms in a ratio of 1:1.
Study treatments are defined as:

four doses of CMK389 10 mg/kg i.v. (one dose q4 weeks)

four doses of matching placebo i.v. (one dose q4 weeks)

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6.3
Treatment assignment and randomization
Randomized treatment will be assigned to individual subjects by way of a randomization 
number, which will be in the range of 5101-5200, 5201-5300, for the 2 strata (azathioprine or
methotrexate), respectively.
The randomization number is only used to identify which treatment the subjects have been 
randomized to receive. The Subject number assigned to a subject at screening remains the 
unique identifier for the subject throughout the study. For information on subject numbering, 
please see ‘Subject numbering’ section in the SOM.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. 
A randomization list will be produced by the NIRT provider using a validated system that 
automates the random assignment of subject numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms.
Randomization will be stratified by prior sarcoidosis immunosuppressant therapy (azathioprine
or methotrexate).
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
Follow the details outlined in the SOM regarding the process and timing of treatment 
assignment and randomization of subjects.
6.4
Treatment blinding
This is a subject and investigator blinded study. Subjects and investigators will remain blinded 
to study treatment throughout the study, except where indicated below.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, and odor.
Site staff
With the exception of an unblinded pharmacist, all site staff (including study investigator and 
study nurse) will be blinded to study treatment throughout the study. See Section 7.2 for details 
on early discontinuation. For detailed information about the scheduled unblinding of subjects, 
please refer to the SOM.
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.7).
Drug product will be supplied as open label bulk so an unblinded pharmacist who is independent 
of the study team will be required in order to maintain the blind. This unblinded pharmacist will 
receive the treatment allocation from the NIRT system. Appropriate measures must be taken by 
the unblinded pharmacist to ensure that the treatment assignments are concealed from the rest 
of the site staff.

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Sponsor staff or delegate
The following unblinded sponsor roles are required for this study:
Unblinded clinical staff managing drug re-supply to site
Unblinded sample analyst(s) (PK, 
)
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed.
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical trial team (CTT) as 
appropriate for internal decision purposes, as outlined in Table 6-2. For example, unblinded 
summaries and unblinded individual data can be shared with the team for interim analyses.
Study programmers and other personnel involved in study data analysis 
 are 
allowed to access treatment assignment information for the purpose of conducting interim analyses.
The CTT is allowed to share unblinded results with other sponsor staff (e.g. decision boards) as 
required for internal decision making on the study or the project at the time of interim analyses 
while the study is ongoing.
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above.
Following final database lock all roles may be considered unblinded.
Table 6-2
Blinding levels
Role
Time or Event
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject
unblinded)
Subjects/Patients
B
B
UI
Site staff
B
B
UI
Unblinded site staff (see 
text for details) 
B
UI
UI
Drug Supply and 
Randomization Office
UI
UI
UI
Unblinded sponsor staff 
(see text for details)
B
UI
UI
Statistician/statistical 
programmer/data analysts
B
B
UI
All other sponsor staff not 
identified above
B
B
UI
B Remains blinded
UI Allowed to be unblinded on individual patient level
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6.5
Treating the subject
CMK389 will be administered to the subject via i.v. infusion for approximately one hour at the 
study site. See the pharmacy manual for further details.
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
6.6
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments and/or missed doses are not permitted.
For instructions regarding infusion interruptions, refer to the Pharmacy Manual.
6.7
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when knowledge of the assigned treatment is 
required to in order to treat the subject safely. Most often, study treatment discontinuation and 
knowledge of the possible treatment assignments are sufficient to treat a study subject who 
presents with an emergency condition. Emergency treatment code breaks are performed using 
the NIRT. When the investigator contacts the system to break a treatment code for a subject, 
he/she must provide the requested subject identifying information and confirm the necessity to 
break the treatment code for the subject. The investigator will then receive details of the 
investigational drug treatment for the specified subject and a fax or email confirming this 
information. The system will automatically inform the study monitor for the site and the Study 
Team that the code has been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to allow 
access to the NIRT at any time in case of emergency. The investigator will need to provide:

protocol number

study drug name (if available)

subject number.
In addition, the investigator must provide oral and written information to inform the subject 
how to contact his/her backup in cases of emergency when he/she is unavailable to ensure that 
un-blinding can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject 
and, if applicable, whether the subject can continue with follow up assessments. 
6.8
Treatment exposure and compliance
Subjects will receive all study medication at the Investigator site. Study medication will be 
administered by site personnel, compliance will be ensured by appropriate training of site 
personnel. The date and time of administration of study drug will be recorded in the dosage 
administration record section of the eCRF.

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6.9
Recommended treatment of adverse events
Acute infusion or hypersensitivity reactions: Study participants are required to undergo 
observation for a minimum of two hours post-infusion prior to leaving the site (or longer if 
deemed necessary by the Investigator). In the event of an acute infusion or hypersensitivity 
reaction, the investigator should consider the criteria for treatment discontinuation (Section 7.2), 
and the patient should be treated with antihistamines and glucocorticoids. Depending on 
severity, patients may also require supplemental oxygen, volume expansion, catecholamines 
and transfer to an intensive care setting. Plasmapheresis to decrease the systemic concentration 
of CMK389 may be considered dependent on the patient’s condition. Patients should be 
observed for at least four hours after resolution of signs and symptoms; and those who have 
experienced severe infusion reactions should be closely observed for 24 hours after resolution 
because of the risk for a biphasic episode.
Infections: In the event of an infection, the investigator should consider the criteria for 
treatment discontinuation (Section 7.2), as well as consider early treatment with specific 
antimicrobial therapy on the basis of clinical diagnosis or suspicion thereof (e.g., antiviral 
treatment for herpes simplex or zoster) in consultation with infectious disease experts, as 
appropriate.
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
6.10
Rescue medication
Use of rescue medication is not allowed in the context of this study. Therefore, if the 
investigator believes that continuation of the study is potentially detrimental to a patient's health, 
such patient should be withdrawn from the study.
6.11
Concomitant treatment
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the timeframe 
defined in the entry criteria prior to the start of the study and during the study, must be recorded 
on the Concomitant medications/Significant non-drug therapies section of the CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact Novartis before randomizing a subject 
or, if the subject is already enrolled, to determine if the subject should continue participation in 
the study.

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7
Study completion and discontinuation
7.1
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them.
The study is considered completed when the last subject completes their End of Study (EOS)
visit, for males and women not of childbearing potential (EOS#1 V399) and for WOCBP 
(EOS#1 V399 and EOS#2 V499), and any repeat assessments associated with this visit have 
been documented and followed-up appropriately by the investigator, or in the event of an early 
study termination decision, the date of that decision.
All SAEs reported during this time period must be reported as described in Section 9.2 and the 
SOM. Documentation of attempts to contact the subject should be recorded in the source 
documentation.
7.2
Discontinuation of study treatment
Subjects may voluntarily discontinue study treatment for any reason at any time.
The investigator must discontinue study treatment for a given subject if, on balance, he/she 
believes that continuation would be detrimental to the subject’s well-being.
Study treatment must be discontinued under the following circumstances:

Subject is non-compliant with study treatment, as defined by missing any dose

Subject withdraws consent

Pregnancy

Severe infection

Use of a prohibited treatment as outlined in Table 5-1

Any situation in which study participation might result in a safety risk to the patient.

Severe allergic reaction or anaphylaxis, as defined by Sampson criterion #1
(Sampson et al 2006) (Table 7-1), following administration of the study drug

Any protocol deviation that results in a significant risk to the subject’s safety
The appropriate personnel from the site and Novartis will assess whether study treatment should be 
discontinued for any subject whose treatment code has been broken inadvertently for any reason.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent. Where possible, they should return for the assessments indicated for EOS#1 
(V399) in the Assessment Schedule (Table 8-1). WOCBP should also complete urine pregnancy 
tests at home every 4 weeks after the last dose received, for 40 weeks. If they fail to return for 
these assessments for unknown reasons, every effort (e.g. telephone, email, letter) should be 
made to contact them.

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Table 7-1
Sampson Criterion #1 for diagnosing anaphylaxis
Criteria #1
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-
tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
a.
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
b.
Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence)
7.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table (Table 8-1).
Novartis will continue to keep and use collected study information (including any data resulting from 
the analysis of a subject’s samples until their time of withdrawal) according to applicable law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
7.4
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject (e.g. dates of telephone 
calls, registered letters, etc.). A subject cannot be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred.

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7.5
Study Stopping rules
The study will be paused for a full safety review in the event of:

2 or more drug-related SAEs are reported

3 or more patients experience infectious complications of at least moderate severity
related to study drug

3 or more patients experience the same (or similar) unexpected severe AE related to study
drug

2 or more patients experience a hypersensitivity reaction related to study drug

2 or more patients experience a severe infusion reaction related to study drug
Any restart of the study following a full safety review will require notification to health 
authorities or submission and approval of a substantial amendment, whichever is appropriate 
based on local requirements.
7.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. Should this be necessary, subjects must 
be seen as soon as possible and treated as a prematurely discontinued subject. The investigator 
may be informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subject’s interests. The investigator will be 
responsible for informing IRBs/IECs of the early termination of the trial.
8
Procedures and assessments
8.1
Assessment schedule
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible.
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the final visit will be performed. At this 
final visit, all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications recorded on the CRF.

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Table 8-1
Assessment Schedule
Epoch Screening
Run-in
Treatment Period
Safety Follow-up
Visit Name Screening
Run-in
Treatment Period
Follow-Up
End 
of 
Study 
#1
Visit Numbers1
1
101
102 199
201
202
203
204
299 301
302
399
Days
-70 to -43
-42
±1
-28
±1
-2
±1
1
29
±3
57
±3
85
±3
113
±3
141
±3
169
±3
197
±3
Time (post-dose)
-
-
-
-
0min2 60min 180min 0min2 60min 180min 0min2 60min 180min 0min2 60min 180min
-
-
-
-
Informed consent
X
Inclusion / Exclusion 
criteria
X
X
X
Medical 
history/current 
medical conditions
X
Concomitant 
therapies
X
Demography
X
Physical Examination
S
S
S
S3
S
S
S
S
S
S
S
Body Weight
X
X
X
Body Height
X
Smoking history
X
Cotinine test
S
Hepatitis and HIV 
Screen
S
Tuberculosis status4
S
Pregnancy and 
assessments of 
fertility
X5
S3, 6
S6
S6
S6
S6
S6
S6
X5
Clinical Chemistry7
X
X
X3
X
X
X
X
X
X
X
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Epoch Screening
Run-in
Treatment Period
Safety Follow-up
Visit Name Screening
Run-in
Treatment Period
Follow-Up
End 
of 
Study 
#1
Visit Numbers1
1
101
102 199
201
202
203
204
299 301
302
399
Days
-70 to -43
-42
±1
-28
±1
-2
±1
1
29
±3
57
±3
85
±3
113
±3
141
±3
169
±3
197
±3
Time (post-dose)
-
-
-
-
0min2 60min 180min 0min2 60min 180min 0min2 60min 180min 0min2 60min 180min
-
-
-
-
Hematology
X
X
X3
X
X
X
X
X
X
X
Urinalysis
X
X
X3
X
X
X
X
X
X
X
Fasting Lipid Panel
X
X
X3
X
X
X
X
X
X
X
Body Temperature
X
X
X
X3
X
X
X
X
X
Blood Pressure and 
Pulse Rate
X
X
X
X3
X
X
X
X
X
ECG evaluation
X
X3
X
X
Chest x-ray8
S
High Resolution CT 
of Chest (HRCT)9
X
[18F]FDG-PET/CT
X
X10
Fasting glucose11
X
X10
6-Minute Walk Test
X
X
X3
X
X
X
X
mMRC dyspnea 
scale
X
X
X
X3
X
X
X
Spirometry
X
X
X
X3
X
X
X
X
Diffusion Capacity 
(DLCO)
X3
X
X
X
X
Clinical Status 
Determination Form12
X
X3
X
X
X
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Epoch Screening
Run-in
Treatment Period
Safety Follow-up
Visit Name Screening
Run-in
Treatment Period
Follow-Up
End 
of 
Study 
#1
Visit Numbers1
1
101
102 199
201
202
203
204
299 301
302
399
Days
-70 to -43
-42
±1
-28
±1
-2
±1
1
29
±3
57
±3
85
±3
113
±3
141
±3
169
±3
197
±3
Time (post-dose)
-
-
-
-
0min2 60min 180min 0min2 60min 180min 0min2 60min 180min 0min2 60min 180min
-
-
-
-
Randomization
X
Discontinue 
Sarcoidosis 
Immunosuppressant 
Therapy13
X
Steroid Titration14
X
X
X
X
X
Study drug 
administration
X
X
X
X
2h post-dose 
observation period
S
S
S
S
PK blood collection 
X16
X17
X18
X16
X17
X16
X17
X16
X17
X18
X
X
X
X
Adverse Events
X
Study/Epoch 
completion 
information
X
X
X
X
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Epoch
Pregnancy Testing Period (WOCBP Only)22
Visit Name
Pregnancy Testing (WOCBP Only)
End of Study #2
Visit Numbers1
401
499
Days
225
±3
253
±3
Pregnancy and assessments of fertility
S6
S6
Serious Adverse Event - Only Pregnancies Reported23
X
X
Study/Epoch completion information
X

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X Assessment to be recorded in the clinical database or received electronically from a vendor
S- source documentation at the study site
1 Visit structure given for internal programming purpose only
2 Unless specified otherwise, assessments at 0 min should be done pre-dose
3 Can be done at Day -1 instead of Day 1 if needed.
4 Determined by QuantiFERON TB-Gold test
5 Serum pregnancy test
6 Urine pregnancy test
7 Chemistry panel must be done under fasting conditions at all visits
8 Only for patients who don’t have an historical chest x-ray within 12 months from screening
9 HRCT at screening should be performed after all other screening assessments for eligibility. A historical HRCT 
obtained within 12 months prior to screening may be used instead and sent to the central reader for analysis.
10 Fasting glucose and [18F]FDG-PET/CT must be done on a different day than the other assessments of V299 or after 
all other V299 assessments are completed on the same day.
11 The [18F]FDG-PET/CT requires a blood glucose level below 11 mmol/L. The measurement is performed by
finger prick at site before [18F]FDG-PET/CT is performed
12 Clinical Status Determination includes the following: 6-minute walk distance, FVC, FEV1 and mMRC dyspnea    
score. Complete the form (found in the SOM) and use as a guide for CSE
13 Discontinue methotrexate and azathioprine
14 Patients with CSD of "deteriorating" will be ineligible to continue the study (during the run-in epoch); or they will
increase steroid dose by 1-step (during the treatment epoch). See study design Section 3.1
16 pre-dose (within 2 hours prior to infusion)
17 In the event that the infusion must be lengthened beyond 60 minutes, then this sample is collected at the end of the 
infusion (+ 5 minutes)
18 +/- 60 minutes
19
20
21
22 Pregnancy tests done at home by the patient and results collected over the phone by site staff. Pregnancy tests may 
be done at the clinical site instead of at-home during the Pregnancy Testing Period (WOCBP only) if required per local 
regulations. See SOM for more details about these visits
23 See Section 9.6 Pregnancy Reporting
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8.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject’s representative gives consent (if allowed according to 
local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate assent by 
personally signing and dating the written informed consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators a proposed informed consent (ICF) form that complies 
with the ICHE6 GCP guideline and regulatory requirements and is considered appropriate for 
this study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the subject agrees to future research. 
The procedures set out in the main consent form concerning the storage, maintenance of privacy, 
and release of the data or specimens for the main study will also be adhered to for any future 
research. Any changes to the proposed consent form suggested by the investigator must be 
agreed to by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an Investigator Notification or 
an Aggregate Safety Finding. New information might require an update to the informed consent 
and then must be discussed with the subject.
Ensure subjects are informed of the contraception requirements outlined in the Section 4.2
(Exclusion criteria) and in Section 5.1 (Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
Refer to the SOM for a complete list of ICFs included in this study.
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8.3
Subject screening
Screening assessments (e.g., clinical laboratory assessments or Pulmonary Function Tests
(PFTs)) may be repeated one time at the discretion of the Investigator if there are questionable 
results or if abnormalities are felt to be due to inherent variability of the test procedure. 
In general, it is permissible to re-screen a subject once if s/he fails the initial screening; however, 
each case must be discussed and agreed with the Sponsor.
If a subject must be rescreened for study entry, results from previous screening assessments 
may be used, as long as the screening windows for those assessments are met and all spirometry 
data used for subject qualification are derived from a single day. If any PFTs are to be repeated, 
only the tests that are felt to be questionable should be repeated (i.e., spirometry, DLCO).
Initial screening HRCT and chest x-ray (including historical ones) are valid and can be used in 
case of re-screening up to 365 days after the initial assessment date if the subject does not report 
clinically significant changes in PFTs or symptoms (qualitative or quantitative) as determined 
by the Investigator.
Information on what data should be collected for screening failures is outlined in the SOM.
8.4
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects. Relevant 
medical history/current medical conditions data will also be collected until signature of 
informed consent. Details are outlined in the SOM.
Investigators have the discretion to record abnormal test findings on the medical history CRF,
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.4.1
Concomitant therapies
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study.
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the timeframe 
defined in the entry criteria prior to the start of the study and during the study, must be recorded 
on the Concomitant medications/Significant non-drug therapies CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact Novartis before randomizing a subject 
or, if the subject is already enrolled, to determine if the subject should continue participation in 
the study.
For eligible patients, the investigator must have previous records of steroid treatment and 
immunosuppressant therapy, such as prednisone and either methotrexate or azathioprine, for 
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8.4.2
Discontinue Sarcoidosis Immunosuppressant Therapy
During the run-in epoch eligible patients will discontinue methotrexate and azathioprine. The 
patient’s immunosuppressant therapy may be restarted after V299 is completed, at the 
Investigator’s discretion.
8.4.3
Tuberculosis status
Determination of tuberculosis (TB) status will be required before administration of study 
treatment and should be determined at screening by Quantiferon TB Gold test. Note: if 
Quantiferon test is indeterminate, it may be repeated once. Two indeterminate Quantiferon tests 
will be considered as evidence of TB infection. Furthermore, after anti-TB treatment, patients 
with history of or latent TB may become eligible according to national guidelines.
Any significant findings will be recorded in the "Relevant medical/history/Current medical 
conditions" section of the eCRF. 
8.4.4
Hepatitis and HIV Screen
All subjects will be screened for HIV, Hepatitis B and C. See the SOM for details.
8.4.5
Inclusion / Exclusion criteria
The investigator must ensure that all subjects being considered for the study meet the inclusion 
and exclusion criteria. No additional exclusions should be applied by the investigator, in order 
that the study population will be representative of all eligible subjects.
Subject selection is to be established by checking through all inclusion/exclusion criteria 
at screening, V102 and V201. A relevant record (e.g. checklist) must be stored with the 
source documentation at the study site. Deviation from any entry criterion excludes a subject 
from enrolment into the study. The investigator or his/her deputy must promote compliance to 
inclusion/exclusion criteria for the duration of the study.
8.4.6
Medical history/current medical conditions
Relevant medical history and current medical conditions will be recorded on the CRF until 
signature of the informed consent.
Where possible, diagnoses and not symptoms will be recorded.
Any event or change in the subject’s condition or health status occurring prior to informed 
consent will be reported in the Relevant medical history / Current medical conditions section of 
the CRF.
8.4.7
Smoking history
Smoking history including usage status, type of substance used, amount consumed and date 
stopped will be collected.
8.4.8
Cotinine test
All subjects will be screened for cotinine. See SOM for details.

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8.5
Efficacy / Pharmacodynamics
8.5.1
6-Minute Walk Test
A standardized six-minute walk test (6MWT) will be carried out by a trained technician in 
accordance with the guidelines (Holland et al 2014). See SOM for details.
8.5.2
Patient Reported Outcomes (PROs)
mMRC dyspnea scale
The mMRC Dyspnea Scale is a widely used, rapidly administered, 5-point scale based on 
degrees of various physical activities that precipitate breathlessness (Bestall et al 1999; 
Mahler and Wells 1988). Patients read the descriptive statements and then select the number 
which best fits his or her shortness of breath. The mMRC dyspnea scale is a component of the 
study inclusion criteria and will be used in patient screening. mMRC dyspnea score is also used 
during the patient’s Clinical Status Evaluation (CSE). See SOM for additional details.
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8.5.3
Diffusion Capacity (DLCO)
Diffusion capacity will be determined according to ATS guidelines (Graham et al 2017). 
Measurements will include DLCO and Volume alveolar (VA). DLCO will be over read by 
pulmonary function testing vendor. Additional information is provided in the SOM.
8.5.5
Steroid Titration
The Clinical Status Evaluation (CSE) serves as a safety evaluation and will serve to establish 
the patient's clinical status (Clinical Status Determination [CSD]) (Figure 3-2). CSE will be 
performed at visits (V102, V201, V202, V203, and V204) prior to the titration of steroids, and 
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the CSD will guide selection of the next dose of steroids (Figure 3-3). Titration will continue 
throughout the run-in and treatment epochs. Patients with CSD of "improved" or "stable" will 
decrease steroid dose by 1-step on the dosing scale (Figure 3-4). Patients with CSD of 
"deteriorating" will be ineligible to continue the study (during the run-in epoch or at V201); or 
they will increase steroid dose by 1-step (during the treatment epoch).
8.5.6
Spirometry
Spirometry testing will be performed according to the ATS guidelines (Miller et al 2005); 
(Culver et al 2017) at screening to assess patients’ eligibility for the study and as detailed in the 
Assessment schedule (Section 8.1).
The spirometry equipment will be supplied to each site for the study. The same spirometry 
equipment should be used for all assessments performed by a subject. A limited number of staff, 
as designated by the investigator, will evaluate all patients at all visits throughout the entire trial. 
Where possible the same technician should perform all maneuvers for an individual subject. All 
staff conducting the spirometry tests must have received appropriate training which must be 
documented. Information on the procedure can be found in the SOM.
8.5.7
FDG-PET/CT
In this study, [18F]FDG-PET/CT imaging will provide early evidence for anti-inflammatory 
effects of IL-18 blockade by CMK389 on the sarcoidosis process. [18F]FDG-PET/CT has been 
shown to detect lung parenchymal involvement at any chest X-ray stage, including therapy-
resistant disease, and can also provide information on extra-pulmonary disease. Lung FDG-
PET uptake in sarcoidosis has been shown to correlate with important sarcoidosis BAL 
biomarkers, including percentage neutrophils and CD4:CD8 ratio. In two previous sarcoidosis 
trials, the [18F]FDG-PET/CT endpoint was shown to be decreased by 53-55% on treatment 
(Keijsers et al 2008; Milman et al 2012). Improvements in FVC over a 24 week period have been 
correlated with decreases in [18F]FDG-PET/CT compared to baseline, with evidence of improvement 
by serial [18F]FDG-PET/CT detected in sarcoid patients reported as early as 1-2 months
(Brudin et al 1994; Braun et al 2008; Imperiale et al 2013). Furthermore, [18F]FDG-PET/CT 
imaging 
was 
able 
to 
predict 
subsequent 
decreases 
in 
FVC 
and 
DLCO
(Sobic-Saranovic et al 2013;Vorselaars et al 2015).
In this study, all patients will undergo whole-body head to mid-thigh [18F]FDG-PET/CT 
imaging on a state-of-the-art, 3D PET/CT scanner with a reconstructed resolution of ≤5 mm. 
Subjects with glucose levels above 11 mmol/L (200 mg/dL) should have their scan delayed or 
be rescheduled as appropriate. The blood glucose level measured prior to the radiotracer 
administration should be recorded in the image transmittal form. Subjects will have the 
radiotracer administered through an i.v. line, whereafter they will be positioned comfortably in 
a supine position to rest for 60 min, while the radiotracer distributes through the body. Near the 
end of this 60 min rest, subjects will be asked to void their bladder prior to the scanning 
procedure. A whole body low-dose attenuation CT will be acquired with a whole body effective 
dose of 1.5 mSv. A maximum injected radioactivity dose of 200 MBq will result in a whole 
body effective dose of 4 mSv (ICRP 2008). Higher [18F]FDG doses and/or extended scanning 
time may be required in large or obese patients to ensure sufficient imaging quality but the 
injected activity will not exceed 350 MBq. One further imaging scan will be performed at week 

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16 according to the schedule on enrolled patients and the results compared to baseline findings 
using centralized quantitative reading. Detailed information will be provided in a separate 
[18F]FDG-PET/CT imaging manual. Total injected activity and body weight will be recorded 
and used to compute standardized uptake values (SUVs). The total radiation dose for all 
PET/CT scanning (excluding HRCT) in this protocol will be maximally 11 mSv (or 16 mSv if 
[18F]FDG injected dose is 350 MBq). In all subjects, the baseline and follow-up PET/CT scan 
(at week 16) should be performed where possible on the same scanner.
Refer to the Imaging Acquisition Guidelines and Imaging Investigator Site Operations Manual 
for [18F]FDG-PET/CT.
The coded medical images will be used primarily for analysis as described in this protocol; 
however, the images may also be used for the development and evaluation of new analysis 
methods directly related to the area of research that this study covers. Incidental findings are 
beyond the scope of central imaging vendor. If an investigator/radiologist recognizes any 
incidental finding in the images during the course of conducting the clinical trial, the 
investigator should follow up as part of his/her duty of care to ensure the safety and wellbeing 
of the participant.
8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the SOM, with the Assessment schedule (Section 8.1) detailing when each assessment is to be 
performed.
8.6.1
Adverse Events
Safety assessments are specified below; methods for assessment and recording are specified in 
the SOM, with Assessment schedule (Section 8.1) detailing when each assessment is to be 
performed. The safety assessments include:

Adverse events, vital signs, physical exams, safety labs (hematology, chemistry,
urinalysis), and electrocardiogram (ECG).

CSE (Section 8.6.3)
8.6.2
Body Temperature
Body temperature will be measured at multiple time points during the study. The same method 
of measurement should be used throughout study. Please refer to the Assessment schedule 
(Section 8.1).
8.6.3
Clinical Chemistry
The fasting chemistry panel will include: albumin, alkaline phosphatase, total bilirubin, calcium, 
chloride, serum bicarbonate, creatinine, creatine kinase (CK), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), α-amylase, γ- glutamyltransferase (GGT), glucose, sodium, 
potassium, inorganic phosphorus, total protein, lactate dehydrogenase (LDH), magnesium, 
blood urea nitrogen (BUN), uric acid, lipase and serum ketones. 

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If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, direct 
and indirect reacting bilirubin should be differentiated.
Please refer to the Assessment schedule (Section 8.1).
8.6.4
Blood Pressure and Pulse Rate
Blood pressure and pulse rate will be recorded at multiple time points during the study. 
Please refer to the Assessment schedule (Section 8.1) and the SOM for additional information.
8.6.5
ECG evaluation
Full details of all procedures relating to the ECG collection and reporting are contained in the 
SOM.
ECG parameters will include: PR interval, QRS duration, heart rate, RR interval, QT interval, 
QTcF. The Fridericia QT correction formula (QTcF) calculated with the RR interval expressed 
in seconds should be used for clinical decisions.
Clinically significant abnormalities must be reported in the AE CRF.
8.6.6
Hematology
The hematology panel will include: hemoglobin, hematocrit, red blood cell (RBC) count, white 
blood cell (WBC) count with differentials (e.g. neutrophils, basophils, eosinophils, monocytes, 
lymphocytes) and platelet count will be measured. Please refer to the Assessment schedule 
(Section 8.1) and SOM.
8.6.7
Pregnancy and assessments of fertility
Pregnancy Testing
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Serum pregnancy testing is required at Screening (V1) and EOS#1 (V399). Urine pregnancy 
testing is required at V201, V202, V203, V204, V299, V301, V302 and for an additional 8 
weeks (V401, and EOS#2 V499; for all urine pregnancy testing, record the results in source 
documentation at the study site). 
See the Assessment schedule (Section 8.1), for timing of the protocol required pregnancy 
testing*. A positive urine pregnancy test requires immediate interruption of study treatment 
until serum β-hCG is performed and found to be negative.
*Additional pregnancy testing might be performed if requested per local requirements.
Refer to Section 9.6 for details on Reporting Pregnancy.
Assessments of Fertility
Refer to Section 4.2 for criteria to determine women that are not of childbearing potential.
Medical documentation of oophorectomy, hysterectomy, or bilateral tubal ligation must be 
retained as source. Subsequent hormone level assessment to confirm the woman is not of 
childbearing potential must also be available as source documentation in the following cases:

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
surgical bilateral oophorectomy without a hysterectomy

reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
subject, regardless of reported reproductive/menopausal status at Screening.
8.6.8
Physical Examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
Information for all physical examinations must be included in the source documentation at the 
study site. Clinically relevant findings that are present prior to signing informed consent must 
be recorded on the appropriate CRF that captures medical history. Significant findings made 
after signing informed consent which meet the definition of an Adverse Event must be recorded 
as an adverse event.
8.6.9
Urinalysis
A urine sample (approx. 30 mL) will be obtained midstream in order to avoid contamination 
with epithelial cells and sediments, and to allow proper assessments.
Semi-quantitative ‘dipstick’ evaluation of the urine for the following parameters will be 
performed centrally: specific gravity, pH, glucose, protein, bilirubin, ketones, nitrite, leukocytes 
and blood.
If the dipstick result is positive for nitrite, leucocytes and/ or blood, the sample will be sent for 
culture and for microscopic analysis of white blood cells, red blood cells and casts.
8.6.10
Body Weight and Height
Body weight and height will be recorded at multiple time points during the study. Refer to the 
Assessment schedule (Section 8.1).
8.7
Pharmacokinetics
PK samples will be collected at the time points defined in the Assessment schedule (Section 8.1). 
Follow instructions outlined in the Site Operations Manual regarding sample collection, 
numbering, processing and shipment. See Section 8.9 regarding the potential use of residual 
samples.
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume collected 
will not exceed those stated in the SOM. If patients experience suspected immunologically-
related AE such as infusion-related reaction, hypersensitivity, cytokine release syndrome and 
anaphylaxis (as defined by Sampson criterion #1; Sampson et al 2006), an unscheduled PK 
blood sample should be obtained as close as possible to the event occurrence. The date and time 
of the last dose and the time of PK blood draw should be recorded.

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An ELISA based assay will be used to analyze the CMK389 concentration in PK samples. 
PK samples will be obtained and evaluated in all subjects, all samples will be analyzed except 
the placebo group.
For standard PK abbreviations and definitions see the list provided at the beginning of this 
protocol.
The following PK parameters will be determined using the actual recorded sampling times and 
non-compartmental analysis using Phoenix WinNonlin: Ctrough, Cmax, Tmax, and if feasible 
AUC0-t, AUCinf, t1/2, Vz and CL from CMK389 serum concentration-time data.
The linear trapezoidal rule will be used for AUC calculation. Regression analysis of the terminal 
plasma elimination phase for the determination of t1/2 will include at least 3 data points after 
Cmax. If the adjusted R2 value of the regression analysis of the terminal phase will be less than 
0.75, no values will be reported for t1/2, AUCinf and CL.
8.7.1
PK blood collection
For PK assessment, pre-dose blood samples will be collected before each dose administration. 
Blood samples will also be collected at designated time points after dosing.
For details on PK blood collection and processing, labeling, and shipment instructions, 
see laboratory manual.
The exact clock time of dosing, as well as actual sample collection date and time will be entered 
on the PK blood collection summary page of the CRF. Sampling problems will be noted in the 
relevant field of the CRF.
8.8
Other assessments
As outlined in Section 4.1 Inclusion Criteria, investigator must assess the Scadding stage II, III 
or IV as determined by the most recent chest x-ray obtained within 12 months prior to screening. 
If necessary, the chest x-ray may be obtained during screening. Original x-ray film, 
appropriately labeled, will be archived at study site.
8.8.2
High Resolution CT of Chest
An HRCT scan of the lung will be completed at screening to assess reticular pattern for the 
purpose of fulfilling eligibility criteria. The HRCT scans, without contrast agent, will be 
acquired at full inspiration according to parameters as listed in a separate imaging acquisition 
manual. Inclusion scans will be read by a central reader (expert radiologist) contracted through 
imaging vendor. The total whole body effective dose per subject from the HRCT scanning 
(excluding [18F]FDG-PET/CT) will be maximally 4 mSv. 
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An historical HRCT obtained within 12 months from screening may also be sent to the central 
reader for over-read.
Refer to the Imaging Acquisition Guidelines and Imaging Investigator Site Operations Manual 
for HRCT details and requirements for historical HRCT.
The coded medical images will be used primarily for analysis as described in this protocol; 
however, the images may also be used for the development and evaluation of new analysis 
methods directly related to the area of research that this study covers. Incidental findings are 
beyond the scope of central imaging vendor. If an investigator/radiologist recognizes any 
incidental finding in the images during the course of conducting the clinical trial, the 
investigator should follow up as part of his/her duty of care to ensure the safety and wellbeing 
of the participant.
8.8.4
Fasting lipid panel
A fasting lipid panel will be performed, measuring cholesterol, direct LDL, HDL cholesterol, 
LDL cholesterol, and triglycerides.
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Sample(s) will be collected at the timepoint(s) defined in the Assessment schedule (Section 8.1). 
Detailed instructions for sample collection, numbering, processing and shipment will be 
provided in the Central Lab Manual.
8.9
Use of residual biological samples
Residual blood and urine samples may be used for another protocol specified endpoint.
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9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject 
after providing written informed consent for participation in the study until the end of study 
visit. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
AEs of Special Interest comprise hypersensitivity reactions such as serum sickness and
anaphylaxis (as defined by Sampson criterion #1; Sampson et al 2006).
In addition, all reports of intentional misuse and abuse of the study treatment are also considered 
an adverse event irrespective if a clinical event has occurred. See Section 9.5 for an overview 
of the reporting requirements.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination finding, laboratory test 
finding, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver and kidney related events are 
included in Appendix 1 and Appendix 2, respectively.
Adverse events should be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
1. The severity grade
a.
Adverse events will be primarily assessed and graded according to the “Toxicity
Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in
Preventive Vaccine Clinical Trials”. A copy of the Toxicity Grading Scale can be
found in the Investigator Portal.
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b. For any adverse event not listed in the “Toxicity Grading Scale for Healthy Adult
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials”, the
adverse event will be assessed and graded according to the “Common
Terminology Criteria for Adverse Events”, version 5.0 (CTCAE v5.0). A copy of
the CTCAE Grading Scale can be found in the Investigator Portal.
c.
For infusion-related reactions, event will also be assessed and graded according to
the CTCAE v5.0
2. Its relationship to the study treatment

Yes or

No
3. Its duration (start and end dates) or if the event is ongoing an outcome of not
recovered/not resolved must be reported.
4. Whether it constitutes a SAE (see Section 9.2 for definition of SAE) and which
seriousness criteria have been met
5. Action taken regarding investigational treatment.
All adverse events must be treated appropriately. Treatment may include one or more of
the following:

no action taken (e.g. further observation only)

investigational treatment dosage increased/reduced

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE)
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. Once an adverse event is detected, it must be followed until 
its resolution or until it is judged to be permanent, and assessment should be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
investigational drug, the interventions required to treat it, and the outcome.
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to 
Novartis.
*Refer to the Site Operations Manual for data capture methodology regarding AE collection for
subjects that fail screening.
9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

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
is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any
deterioration in condition

elective or pre-planned treatment for a pre-existing condition that is unrelated to the
indication under study and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the subject’s
general condition

is medically significant, e.g. defined as an event that jeopardizes the subject or may
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to ICH E2D Guideline 2004).
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to ICH E2D Guideline 2004).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Chief Medical Office and Patient Safety (CMO & PS) as per Section 9.2.2.
9.2.2
SAE reporting
Screen Failures & Run-In Failures
Note the following requirement for Screen Failures: SAEs occurring after the subject has 
provided informed consent until the time the subject is deemed a Screen Failure must be 
reported to Novartis.
For subjects considered Run-In Failures, SAEs occurring after the subject has provided 
informed consent until the time the subject is deemed a Run-In Failure must be reported to 
Novartis.

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Treated Subjects
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the End of Study visit must be reported to 
Novartis within 24 hours of learning of its occurrence as described below.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, and under no circumstances later than within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one must be 
reported separately as a new event.
Follow- up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment a Chief Medical Office and 
Patient Safety (CMO& PS) Department associate may urgently require further information from 
the investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) 
will be collected and reported to the competent authorities and relevant ethics committees in 
accordance with EU Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries.
Follow the detailed instructions outlined in the Site Operations Manual regarding the 
submission process for reporting SAEs to Novartis. Note: SAEs must be reported to Novartis 
within 24 hours of the investigator learning of its occurrence/receiving follow-up information.
9.3
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
Please refer to Table 15-1 Appendix 1 for complete definitions of liver events.
Follow-up of liver events
Every liver event defined in Table 15-1 Appendix 1 should be followed up by the investigator 
or designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 15-1 Appendix 1.

Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm
elevation within 48-72 hours.

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These liver chemistry repeats should always be performed using the central laboratory, with the 
results provided via the standard electronic transfer. If results will not be available from the 
central laboratory within 24 hours, then the repeats can also be performed at a local laboratory 
to monitor the safety of the subject. If a liver event is subsequently reported, any local liver 
chemistry tests previously conducted that are associated with this event should have results 
reported on the unscheduled local laboratory CRF.

If the initial elevation is confirmed, close observation of the subject will be initiated,
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to Section 7.2 (Discontinuation of study
treatment), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include:

Repeating liver chemistry tests two or three times weekly. Testing should include
ALT, AST, ALP, PT/INR, and GGT. If total bilirubin is elevated > 2 x ULN,
fractionation into direct and indirect bilirubin is required. To rule out muscular origin
of transaminase elevations, CPK should be measured along with liver chemistry tests.
Frequency of retesting can decrease to once a week or less if abnormalities stabilize or
the study drug has been discontinued and the subject is asymptomatic.
Retesting should be continued up to resolution.

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications
and herbal and dietary supplement preparations), alcohol use, recreational drug use,
and special diets.

Exclusion of underlying liver disease, as specified in Table 15-3 Appendix 1.

Imaging such as abdominal US, CT or MRI, as appropriate

Obtaining a history of exposure to environmental chemical agents.

Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the Site Operations Manual for additional details.
9.4
Renal safety monitoring
Every renal laboratory trigger or renal event must be followed up by the investigator or 
designated personnel at the trial site. Recommended follow-up assessments are listed in 
Appendix 2.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. Refer to the Site Operations Manual for additional details.

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9.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
All study treatment errors and uses outside of what is foreseen in the protocol will be collected 
in the dose administration record (DAR) CRF. Study treatment errors are only to be reported to 
Chief Medical Office and Patient Safety (CMO& PS) department if the treatment error is 
associated with an SAE.
All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances of 
misuse or abuse must be reported to Novartis Chief Medical Office and Patient Safety (CMO& 
PS). As such, instances of misuse or abuse are also to be reported using the SAE form/CRF. 
Table 9-1 summarizes the reporting requirements.
Table 9-1
Guidance for capturing study treatment errors
Treatment error type
Document in Dose 
Administration (DAR) 
CRF 
Document in AE CRF
Complete SAE 
form/CRF 
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1 and Section 9.2, respectively.
9.6
Pregnancy reporting
Reproductive toxicity and teratogenicity data are not available for the investigational drug at 
this time, therefore no guidelines on therapeutic recommendations in case of pregnancy are 
available. This study enrolls women on highly effective birth control and who are considered 
not to be of childbearing potential, thus pregnancy is not an expected outcome for any female 
study participant. However, in the case that a pregnancy in a female study participant should 
occur, please follow the below reporting guidelines.
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.

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Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Chief Medical Office and Patient Safety (CMO&PS) 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on an SAE form.
The study drug must be discontinued though the subject may stay in the study, if she wishes to 
do so. All assessments that are considered as a risk during pregnancy must not be performed. 
The subject may continue all other protocol assessments.
9.7
Prospective suicidality assessment
Not applicable.
9.8
Early phase safety monitoring
The investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly between 
medically qualified personnel representing the sponsor and investigator. Such evaluations may 
occur verbally, but the outcome and key discussion points will be summarized in writing (email) 
and made available to both sponsor and all investigator(s). Criteria pertaining to stopping the 
study/treatment or adapting the study design are presented above.
When two or more clinical site(s) are participating in the clinical study, the sponsor will advise 
the investigator(s) at all sites in writing (email) and by telephone, if possible, of any new 
clinically relevant safety information reported from another site during the conduct of the study 
in a timely manner.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an Investigator’s Meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource or eCRFs) 
with the investigators and their staff. During the study Novartis employs several methods of 
ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. The monitor 
will visit the site to check the completeness of subject records, the accuracy of data capture / 
data entry, the adherence to the protocol and to Good Clinical Practice, the progress of 
enrollment, and ensure that study drug is being stored, dispensed, and accounted for according 
to specifications. Key study personnel must be available to assist the monitor during these visits.
Continuous remote monitoring of each site’s data may be performed by Novartis or CRO 
working on behalf of Novartis. Additionally, a central analytics organization may analyze data 
and identify risks & trends for site operational parameters, and provide reports to Novartis 
Clinical Teams to assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 

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information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and the recording of data that will be used for all primary and safety 
variables. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about the 
identity of the subjects will be disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 requirements. 
Designated investigator site staff will not be given access to the EDC system until they have 
been trained. Automatic validation programs check for data discrepancies and, by generating 
appropriate error messages, allow the data to be confirmed or corrected before transfer of the 
data to the CRO working on behalf of Novartis. The investigator must certify that the data 
entered into the Electronic Case Report Forms are complete and accurate. After database lock, 
the investigator will receive copies of the subject data for archiving at the investigational site.
All data captured for this study will have an external originating source (either written or 
electronic) with the CRF not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
10.3
Database management and quality control
The CRO, working on behalf of Novartis will review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an electronic 
data query. Designated investigator site staff is required to respond to the query and confirm or 
correct the data. If the electronic query system is not used, a paper Data Query Form will be 
faxed to the site. Site personnel will complete and sign the faxed copy and fax it back to the
CRO, working on behalf of Novartis, who will make the correction to the database. The signed 
copy of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).

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Randomization codes and data about all study drug(s) dispensed to the subject and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis (or a designated CRO).
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. 
Any changes to the database after that time can only be made after written agreement by 
Novartis management.
10.4
Data Monitoring Committee
Not required.
10.5
Adjudication Committee
Not required.
11
Data analysis
The analysis will be conducted on all subject data at the time the trial ends. Any data analysis 
carried out independently by the investigator should be submitted to Novartis before publication 
or presentation.
11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects who received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations with relevant impact on PK data.
The PD analysis set will include all subjects with available PD data and no protocol deviations 
with relevant impact on PD data. Data collected after a change of the background therapy not 
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based on the CSE algorithm (see Section 3.1) will be excluded from the analysis set if assessed 
as having a potentially relevant impact on PD.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and subject. 
Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject. A summary of 
the steroid dose (prednisone) assigned at the start of the treatment phase and of the prior 
immunosuppressant therapy will be provided too.
11.3
Treatments
Data for study drug administration, rescue medication and concomitant therapies (including 
steroid dose) will be listed by treatment group and subject.
11.4
Analysis of the primary variable(s)
The primary aim of the study is to compare the effect of CMK389 versus placebo on the clinical 
disease activity of sarcoidosis patients as measured by the change from baseline in the percent 
predicted FVC at week 16 in the PD population. This will be assessed regardless by the background 
steroid dose and assuming all patients remained on their treatment throughout the study.
11.4.1
Primary Variable(s)
The primary variable will be the change from baseline in percent predicted FVC after 16 weeks 
from the first dose of the study drug.
11.4.2
Statistical model, hypothesis, and method of analysis
The change from baseline in percent predicted FVC will be analyzed using a Bayesian model 
for repeated measurements. The model will investigate effects for treatment by time (included 
as a class variable) interaction, baseline FVC by time interaction, prior sarcoidosis 
immunosuppressant therapy (stratification factor) and baseline prednisone dose. The correlation 
among the repeated measures collected on the same subject will be assessed via an unstructured 
covariance matrix. The stratification factor may be removed in case of strata with low sample 
sizes impacting on the convergence of the model.
Uninformative priors will be utilized to obtain the posterior estimates. Baseline is defined as 
Day 1.
The posterior probability that CMK389 is better than placebo in terms of change from baseline 
in percent predicted FVC at 16 weeks will be calculated. If it is at least 90%, it will be 
considered a sign of efficacy of CMK389 in this patient population.
The primary analysis will include all available data from patients in the PD analysis set with 
baseline and at least one post baseline assessment.
A supplementary analysis may be conducted including also FVC values collected after a change 
of the background therapy not based on the CSD algorithm.

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If data permits, additional subgroup analysis of the primary endpoint will be conducted for the 
following three subgroups: increased, no change and decreased prednisone dose at week 16 
compared to baseline.
11.4.3
Handling of missing values/censoring/discontinuations
Estimates of the missing values will be derived by the model under the missing at random (MAR) 
assumption. Alternative assumptions may be explored to investigate the robustness of the 
results under plausible non-missing at random situations.
11.4.4
Summary statistics of safety
All information obtained on adverse events will be displayed by treatment group and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system.
The number (and proportion) of subjects with AEs of Special Interest (Section 9.1) will be 
summarized by treatment.
11.4.5
Summary statistics of pharmacokinetics
Not applicable
11.4.6
Sensitivity analyses
The impact of the changes in steroid dose may be investigated performing two sensitivity 
analyses. In the first one all FVC data following an increase of the steroid dose will be set to 
missing and estimated via the model assuming MAR. In the second analysis a penalty will be 
applied to all the data following an increase of the steroid dose. Further details will be included 
in the statistical analysis plan (SAP).
11.5
Analysis of secondary variable(s)
11.5.1
Efficacy / Pharmacodynamics
Data from other secondary variables will be listed and summarized. Graphical representations 
over time will be presented. Models similar to the one described for the primary analyses will 
be carried-out to investigate treatment difference for the continuous variables collected at each 
visit of the treatment epoch. Pulmonary physiology scores will be analyzed via ANCOVA
model for repeated measures, while the percentage of subjects that, at Week 16, deteriorate 
(defined as: relative reduction from baseline in FVC ≥ 10% or in FEV1 ≥ 10% or in DLCO 
≥15% or relative of 6MWD ≥ 50 m) and the percentage of subjects who increased the steroid 
dose at least one time during the treatment epoch, will be analyzed using logistic regression. 
This analysis will be carried out if at least 20% of the subjects will show a deterioration/increase 
of the steroid dose.
The [18F]FDG-PET/CT imaging data will be analyzed to identify the maximum standardized 
uptake values in the following categories:

A maximum of 10 focal nodal uptake regions (mediastinal, hilar)

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
A maximum of 10 focal regions of uptake in lung parenchyma

A maximum of 10 extra-thoracic focal uptake regions on the whole body scan
[18F]FDG-PET/CT mean uptake in the reference tissue:

A region of lung parenchyma, unaffected by focal lesion uptake
The mean of the SUVmax (resp. SUVmean) for each category will be taken to obtain one 
SUVmax value (resp. SUVmean) per patient / time point / category.
The mean percent change from baseline in SUVmax in the lymph nodes after 16 weeks of 
treatment will be analyzed using ANCOVA with baseline SUVmax and baseline steroid doses 
as covariates, and treatment and prior sarcoidosis immunosuppressant therapy as factors.
The same analysis as for the percent change from baseline in SUVmax in the lymph nodes will 
be performed for the percent change from baseline in SUVmax in the lung parenchyma and the 
extra-thoracic regions, where available. It will also be repeated for SUVmean in the parenchyma.
The correlation between changes from initial FDG-PET scan in SUVmax and changes from 
baseline in FVC, FEV1 and 6MWT distance will be assessed with graphical methods.
11.5.2
Safety
Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment group, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit/time and if normal ranges 
are available abnormalities will be flagged. Summary statistics will be provided by treatment 
and visit/time.
11.5.3
Pharmacokinetics
CMK389 plasma concentration data will be listed by treatment, and visit/sampling time point. 
Descriptive summary statistics will be provided by visit/sampling time point, including the 
frequency (n, %) of concentrations below the LLOQ and reported as zero.
For pharmacokinetic parameter determination, please see Section 8.7.
The descriptive statistics (n, mean, CV%, standard deviation (SD), median, geometric mean, 
geometric CV%, minimum and maximum) will be presented by time of dosing (1st to 4th dose) 
for all PK parameters of CMK389 except Tmax, where only n, median, minimum and maximum 
will be presented

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11.5.4
Pharmacokinetic / pharmacodynamic interactions
Not applicable.
11.5.5
Other assessments
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11.7
Sample size calculation
We assume around 15% drop out, which should provide FVC data at week 16 from 56 patients 
(approximately 28 in each arm), if approximately 66 patients are randomized. 
The sample size is determined by calculations with respect to the Bayesian analyses 
(Fisch et al 2014); based on uninformative priors) of the change from baseline in the percent 
predicted FVC after 16 weeks of treatment. This was derived via simulations using the QTD 
software. With 28 patients per group providing data at week 16 and assuming a standard 
deviation of 9% (Judson et al 2014), there is approximately 80% power to meet the efficacy 
criterion (posterior probability that CMK389 is better than placebo >= 90%), if the true effect 
of CMK389 over placebo is 5%. Furthermore there is 10% probability of meeting the efficacy 
criterion if the true treatment difference is 0% (type I error rate).
11.8
Power for analysis of key secondary variables
Not applicable
11.9
Interim analyses
12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations 
Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles 
laid down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures 
(e.g. advertisements) and any other written information to be provided to subjects. Prior to study 
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start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis by the time of 
Last Patient Last Visit to be a reviewer and signatory for the clinical study report.
12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
12.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed or overseen by 
Novartis Pharma Auditing and Compliance Quality Assurance (or CRO working on behalf of 
Novartis), a group independent from those involved in conducting, monitoring or performing 
quality control of the clinical trial. The clinical audit process uses a knowledge/risk based 
approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators agree they will apply due diligence to avoid protocol deviations. If an investigator 
feels a protocol deviation would improve the conduct of the study this must be considered a 
protocol amendment, and unless such an amendment is agreed upon by Novartis and approved 
by the IRB/IEC and health authorities, where required, it cannot be implemented.

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13.1
Protocol Amendments
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed.

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References
References are available upon request.
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sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med; 174: p. 795-802.
Baughman RP, Judson MA, Costabel U, et al (2013) Efficacy Of Treatment With 
Ustekinumab Or Golimumab In Patients With Chronic Skin Sarcoidosis. Am J Respir Crit 
Care Med; 187: p. A1066.
Benson JM, Sachs CW, Treacy G, et al (2011) Therapeutic targeting of the IL-12/23 
pathways: generation and characterization of ustekinumab. Nat Biotechnol; 29 p. 615-24.
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Braun JJ, Kessler R, Constantinesco A, et al (2008) 18F-FDG PET/CT in sarcoidosis 
management: review and report of 20 cases. Eur J Nucl Med Mol Imaging; 35: p. 1537-1543.
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sarcoidosis measured with positron emission tomography. Eur J Nucl Med; 21: p. 297-305.
Chau A, Markley JC, Juang J, Tsen LC (2016). Cytokines in the perinatal period – Part I. Int J 
Obstet Anesth. 2016a May;26:39-47.
Chen ES, Moller DR (2011) Sarcoidosis - scientific progress and clinical challenges. Nat Rev 
Rheumatol; 7: p. 457-67.
Culver BH, Graham BL, Coates AL, et al (2017) Recommendations for a Standardized 
Pulmonary Function Report: An Official American Thoracic Society Technical Statement. 
Am J Respir Crit Care Med 196: 1463–1472.
Dastoori M, Fedele S, Leao JC, et al (2013) Sarcoidosis - a clinically orientated review. J Oral 
Pathol Med; 42: p. 281-9.
El-Kabarity RH and Naguib AH (2011). Serum levels of IL-18, IL-12 and TH-1/TH-2 ratio in 
patients with pre-eclampsia Egypt J Immunol; 18(1):1-8.
Fisch R, Jones I, Jones J, et al (2014) Bayesian Design of Proof-of-Concept Trials. 
Therapeutic Innovation & Regulatory Science; 49(1): p. 155-162.
Graham BL, Brusasco V, Burgos F, et al (2017) 2017 ERS/ATS standards for single-breath 
carbon monoxide uptake in the lung. Eur. Respir. J; 49: p. 1-31.
Gupta D, Agarwal R, Aggarwal AN, et al (2012) Sarcoidosis and tuberculosis: the same 
disease with different manifestations or similar manifestations of different disorders. Curr 
Opin Pulm Med; 18: p. 506-16.
Hwang AY, Smith SM, Grums JG, et al (2017) "Adrenal Gland Disorders." Pharmacotherapy: 
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onid=134128262. Accessed March 7, 2019.

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Holland AE, Spruit MA, Troosters T, et al (2014) An official European Respiratory 
Society/American Thoracic Society technical standard: field walking tests in chronic 
respiratory disease. Eur. Respir. J; 44: p. 1428-46.
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deficient mice: evidence for IL-1 receptor-related protein as an essential IL-18 binding 
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expedited reporting.
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ICRP; 22 (No. 3); p. 1-18.
ICRP (2008) Radiation dose to patients from radiopharmaceuticals. Addendum to ICRP 
publication 53. ICRP Publication 106. Approved by the Commission in Oct 2007 p. 1-197.
Iannuzzi MC, Rybicki BA, Teirstein AS (2007) Sarcoidosis. N Engl J Med; 357: p. 2153-65.
Imperiale A, Riehm S, Braun J-J (2013) Interest of [18F]FDG PET/CT for treatment efficacy 
assessment in aggressive phenotype of sarcoidosis with special emphasis on sinonasal 
involvement. Q J Nucl Med Mol Imaging; 57: p. 177-186.
Judson MA, Baughman RP, Costabel U, et al (2013) Safety And Efficacy Of Treatment With 
Ustekinumab Or Golimumab In Patients With Chronic Sarcoidosis. Am J Respir Crit Care 
Med; 187: p. A1065.
Judson MA, Baughman RP, Costabel U, et al (2014) Safety and efficacy of ustekinumab or 
golimumab in patients with chronic sarcoidosis. Eur Respir J. 2014 Nov;44(5): p. 1296-307.
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an observational study in 12 patients treated with infliximab. Sarcoidosis Vasc Diffuse Lung 
Dis; 25: p. 143-150.
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patients with recalcitrant sarcoidosis: a prospective observational study using FDG-PET. Clin 
Respir J; 6: p. 238-247.
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Immunopharmacology; 48: p. 329-31.

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Okamura H, Tsutsi H, Komatsu T, et al (1995) Cloning of a new cytokine that induces IFN-
gamma production by T cells. Nature; 378: p. 88-91.
Romagnani S (2006) Regulation of the T cell response. Clin Exp Allergy; 36: p. 1357-66.
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definition and management of anaphylaxis: Summary Report- Second National Institute of 
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Tokmadzić VS, Tsuji Y, Bogović T, et al (2002) IL-18 is present at the maternal-fetal 
interface and enhances cytotoxic activity of decidual lymphocytes. Am J Reprod Immunol. 
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progressive pulmonary sarcoidosis. Chest; 124: p. 177-85.
Vorselaars ADM, Crommelin HA, Deneer VHM, et al (2015) Effectiveness of infliximab in 
refractory FDG PET-positive sarcoidosis. Eur Respir J; 46: p. 175-185.
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interleukin 18 levels are associated with a poor outcome in women with a history of recurrent 
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Yoshimoto T, Takeda K, Tanaka T, et al (1998) IL-12 up-regulates IL-18 receptor expression 
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Commercially Confidential Information

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Appendix 1: Liver Event Definitions and Follow-up 
Requirements
Table 15-1
Liver Event Definitions
Definition
Thresholds
Potential Hy’s law cases

ALT or AST > 3 × ULN and TBL > 2 × ULN without
initial increase in ALP to > 2 × ULN
ALT or AST elevation with 
coagulopathy

ALT or AST > 3 × ULN and INR > 1.5 (in the absence
of anticoagulation)
ALT or AST elevation accompanied by 
symptoms

ALT or AST > 3 × ULN accompanied by (general)
malaise, fatigue, abdominal pain, nausea, or vomiting,
or rash, or eosinophilia
Isolated ALT or AST elevation

ALT or AST > 8 × ULN

5 x ULN < ALT/AST ≤ 8 x ULN

3 x ULN < ALT/AST ≤ 5 x ULN
Isolated ALP elevation

ALP > 2 × ULN (in the absence of known bone
pathology)
Others

Any clinical event of jaundice (or equivalent term)

Any adverse event potentially indicative of liver toxicity

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Table 15-2
Actions required for Liver Events
Criteria
Actions required
Potential Hy’s Law case

Discontinue the study treatment immediately

Hospitalize, if clinically appropriate

Establish causality

Complete CRFs per liver event guidance*
ALT or AST elevation with 
coagulopathy
ALT or AST elevation accompanied by 
symptoms
Isolated ALT or AST elevation > 8 × 
ULN
Jaundice
Isolated ALT or AST elevation > 5 to 
≤ 8 × ULN

If confirmed, consider interruption or discontinuation of 
study drug

If elevation persists for more than 2 weeks, 
discontinue the study drug

Establish causality

Complete CRFs per liver event guidance*
Isolated ALT or AST elevation > 3 to 
≤ 5 × ULN (patient is asymptomatic)

Monitor liver chemistry tests two or three times weekly
Isolated ALP elevation

Repeat liver chemistry tests within 48-72 hours

If elevation is confirmed, measure fractionated ALP; 
if >50% is of liver origin, establish hepatic causality

Complete CRFs per liver event guidance*
Any AE potentially indicative of liver 
toxicity

Consider study treatment interruption or 
discontinuation 

Hospitalize if clinically appropriate

Complete CRFs per liver event guidance*
*Liver event guidance for CRF completion is available in the Site Operations Manual

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Table 15-3
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E

IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-
HCV, HCV RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection

IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG 
anti-EBV
Autoimmune hepatitis

ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic steatohepatitis

Ultrasound or MRI
Hypoxic/ischemic hepatopathy

Medical history: acute or chronic CHF, hypotension, 
hypoxia, hepatic venous occlusion. Ultrasound or 
MRI.
Biliary tract disease

Ultrasound or MRI, ERCP as appropriate.
Wilson disease

Caeruloplasmin
Hemochromatosis

Ferritin, transferrin
Alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin

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Appendix 2: Specific Renal Alert Criteria and Actions
Table 16-1
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Confirmed serum creatinine increase 25 – 49%

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase ³ 50 % +
OR if <18 years old, eGFR < 35 mL/min/1.73 
m2

Consider causes and possible interventions

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected

Consider patient hospitalization and 
specialized treatment
New onset dipstick proteinuria ≥ 3+
OR
Protein-creatinine ratio (PCR) ≥ 1g/g Cr (or 
mg/mmol equivalent as converted by the 
measuring laboratory)

Consider causes and possible interventions

Assess serum albumin & serum total protein

Repeat assessment to confirm

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected
New onset hematuria ≥ 3+ on urine dipstick
Assess & document

Repeat assessment to confirm

Distinguish hemoglobinuria from hematuria

Urine sediment microscopy

Assess sCr

Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation

Consider bleeding disorder
+ Corresponds to KDIGO criteria for Acute Kidney Injury
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases, when a nephrologist considers a renal biopsy, it is recommended 
to make slide specimen available for evaluation by the RSG to potentially identify project-wide 
patterns of nephrotoxicity.)
Whenever a renal event is identified, a detailed patient history and examination are indicated to 
identify and potentially eliminate risk factors that may have initiated or contributed to the event:

Blood pressure assessment (after 5-minute rest, with an appropriate cuff size)

Signs and symptoms like fever, headache, shortness of breath, back or abdominal pain, 
dysuria or hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other diseases or 
causes, e.g., dehydration due to delirium, tumor lysis

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Table 16-2
Renal Event Follow Up
FOLLOW-UP OF RENAL EVENTS
Assess, document and record in CRF

Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells 
(dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial 
cells

Blood pressure and body weight

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and 
uric acid

Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc.) in the CRF
Monitor patient regularly (frequency at investigator’s discretion) until -

Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or ACR <300 mg/g Cr) or

Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months.

Analysis of urine markers in samples collected over the course of the DIN event

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Appendix 3: Relative Potencies of Glucocorticoids
Table 17-1
Steroid Equivalents
Glucocorticoid
Equivalent Potency (mg)+
Cortisone
25
Hydrocortisone
20
Prednisone
5
Prednisolone
5
Triamcinolone
4
Methylprednisolone
4
Betamethasone
0.6
Dexamethasone
0.75
+ Modified from (Hwang et al 2017).