Clinical trial NCT04868968
Conditions: Familial Cold Autoinflammatory Syndrome
Keywords: Familial Cold Auto-inflammatory Syndrome FCAS DFV890 NLRP3 inhibitor, inflammasome inhibition Cryopyrin-associated periodic syndromes CAPS
Sponsor: Novartis Pharmaceuticals
Start date: 2021-09-20; Completion date: 2023-05-05
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this phase II study was to assess the safety, tolerability and efficacy of DFV890 in participants with FCAS.

Detailed description:
This was an open-label, single-arm, multiple dose, phase II study to assess safety, tolerability and clinical efficacy of DFV890 in participants with FCAS who showed evidence of inflammatory activity after the cold challenge performed during screening.

The study included a screening period, a treatment period and a follow-up period.

Arms: arm 1: DFV890
Interventions: intervention 1: DFV890
Intervention descriptions: intervention 1: 100 mg of DFV890 film coated tablets twice daily (b.i.d.). for 3 days starting in the morning of Day 1 and 100 mg of DFV890 in the morning on the fourth day.

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
DFV890
Clinical Trial Protocol CDFV890A12201 / NCT04868968
An open-label, single arm phase II study of DFV890 to 
assess the safety, tolerability and efficacy in participants 
with familial cold auto-inflammatory syndrome (FCAS)
Document type:
Amended Protocol Version
EUDRACT number:
2020-005948-33
Version number:
v04 (Clean)
Clinical Trial Phase:
II
Release date:
19-May-2022
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020


Novartis
Confidential
Page 2 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Table of contents
Table of contents..................................................................................................................2
List of tables.........................................................................................................................6
List of figures.......................................................................................................................6
List of abbreviations ............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol summary..............................................................................................................22
1
Introduction........................................................................................................................26
1.1
Background............................................................................................................26
1.1.1
DFV890.................................................................................................27
1.1.2
Non-clinical data ...................................................................................27
1.1.3
Clinical data...........................................................................................29
1.2
Purpose...................................................................................................................31
2
Objectives and endpoints...................................................................................................31
2.1
Primary estimand ...................................................................................................32
3
Study design.......................................................................................................................32
4
Rationale ............................................................................................................................35
4.1
Rationale for study design......................................................................................35
4.2
Rationale for dose/regimen and duration of treatment...........................................36
4.3
Rationale for choice of control drugs (comparator/placebo) .................................38
4.4
Rationale for public health emergency mitigation procedures ..............................38
4.5
Purpose and timing of interim analyses/design adaptations ..................................38
4.6
Risks and benefits ..................................................................................................38
4.6.1
Potential benefits to study participants..................................................38
4.6.2
Potential risks to study participants.......................................................39
4.6.3
Potential risk and recommended management of skin rash ..................40
4.6.4
Potential risk of renal abnormalities and recommended monitoring.....41
4.6.5
Potential risk and recommended monitoring of hematological 
parameters..............................................................................................41
4.6.6
Potential risk and recommended treatment of infection........................41
4.6.7
Potential risk and guidance on vaccinations..........................................42
4.6.8
DFV890 potential for higher systemic exposure and for drug-drug 
interactions ............................................................................................42
Commercially Confidential Information (CCI)


Novartis
Confidential
Page 3 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
4.6.9
Potential risk to women of child-bearing potential ...............................43
4.6.10
Blood sample volume............................................................................43
4.6.11
Overall Risk Benefit..............................................................................43
5
Study Population................................................................................................................43
5.1
Inclusion criteria ....................................................................................................44
5.2
Exclusion criteria ...................................................................................................44
6
Treatment...........................................................................................................................47
6.1
Study treatment ......................................................................................................47
6.1.1
Investigational and control drugs ..........................................................47
6.1.2
Additional study treatments...................................................................47
6.1.3
Treatment arms/group ...........................................................................48
6.2
Other treatment(s) ..................................................................................................48
6.2.1
Concomitant therapy .............................................................................48
6.2.2
Prohibited medication............................................................................50
6.2.3
Rescue medication.................................................................................51
6.2.4
Restriction for study participants...........................................................52
6.3
Participant numbering, treatment assignment, randomization...............................52
6.3.1
Participant numbering ...........................................................................52
6.3.2
Treatment assignment, randomization...................................................52
6.4
Treatment blinding.................................................................................................52
6.5
Dose escalation and dose modification..................................................................53
6.6
Additional treatment guidance...............................................................................53
6.6.1
Treatment compliance ...........................................................................53
6.6.2
Recommended treatment of adverse events ..........................................53
6.6.3
Emergency breaking of assigned treatment code ..................................54
6.7
Preparation and dispensation .................................................................................54
6.7.1
Handling of study treatment and additional treatment ..........................54
6.7.2
Instruction for prescribing and taking study treatment..........................54
7
Informed consent procedures.............................................................................................55
8
Visit schedule and assessments..........................................................................................57
8.1
Screening................................................................................................................64
8.1.1
Eligibility screening...............................................................................64
8.1.2
Information to be collected on screening failures .................................64
8.2
Participant demographics/other baseline characteristics........................................65
8.3
Efficacy..................................................................................................................66
8.3.1
Inflammatory markers ...........................................................................66
8.3.2
Clinical Outcome Assessments (COAs)................................................66


Novartis
Confidential
Page 4 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
8.3.4
Appropriateness of efficacy assessments ..............................................68
8.4
Safety .....................................................................................................................68
8.4.1
Laboratory evaluations..........................................................................69
8.4.2
Electrocardiogram (ECG)......................................................................71
8.4.3
Pregnancy and assessments of fertility..................................................71
8.4.4
Appropriateness of safety measurements ..............................................72
8.5
Additional assessments ..........................................................................................72
9
Study discontinuation and completion...............................................................................75
9.1
Discontinuation and completion ............................................................................75
9.1.1
Study treatment discontinuation and study discontinuation..................75
9.1.2
Withdrawal of informed consent and exercise of participants’ data 
privacy rights.........................................................................................76
9.1.3
Lost to follow-up...................................................................................77
9.1.4
Study stopping rules ..............................................................................77
9.1.5
Early study termination by the sponsor.................................................78
9.2
Study completion and post-study treatment...........................................................79
10 Safety monitoring and reporting........................................................................................79
10.1
Definition of adverse events and reporting requirements......................................79
10.1.1
Adverse events.......................................................................................79
10.1.2
Serious adverse events...........................................................................80
10.1.3
SAE reporting........................................................................................81
10.1.4
Pregnancy reporting...............................................................................82
10.1.5
Reporting of study treatment errors including misuse/abuse ................83
10.2
Additional Safety Monitoring................................................................................83
10.2.1
Liver safety monitoring.........................................................................83
10.2.2
Renal safety monitoring ........................................................................84
11 Data Collection and Database management ......................................................................84
11.1
Data collection .......................................................................................................84
11.2
Database management and quality control ............................................................85
11.3
Site monitoring.......................................................................................................85
12 Data analysis and statistical methods.................................................................................86
12.1
Analysis sets...........................................................................................................86
12.2
Participant demographics and other baseline characteristics.................................86
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 5 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
12.3
Treatments..............................................................................................................86
12.4
Analysis of the primary endpoint(s)/estimand(s)...................................................86
12.4.1
Definition of primary endpoint(s)/estimand(s)......................................87
12.4.2
Statistical model, hypothesis, and method of analysis ..........................87
12.4.3
Handling of remaining intercurrent events of primary estimand ..........87
12.4.4
Handling of missing values not related to intercurrent event................87
12.5
Analysis of secondary endpoints/estimands ..........................................................88
12.5.1
Safety endpoints ....................................................................................88
12.5.2
Efficacy and/or Pharmacodynamic endpoint(s) ....................................88
12.5.3
Patient reported outcomes .....................................................................89
12.7
Interim analyses .....................................................................................................91
12.8
Sample size calculation..........................................................................................91
12.8.1
Primary endpoint(s)...............................................................................91
13 Ethical considerations and administrative procedures.......................................................92
13.1
Regulatory and ethical compliance........................................................................92
13.2
Responsibilities of the investigator and IRB/IEC..................................................92
13.3
Publication of study protocol and results...............................................................92
13.4
Quality Control and Quality Assurance.................................................................92
14 Protocol adherence.............................................................................................................93
14.1
Protocol amendments.............................................................................................93
15 References..........................................................................................................................94
16 Appendices.........................................................................................................................96
16.1
Appendix 1: Liver event and laboratory trigger definitions & follow-up 
requirements...........................................................................................................96
16.2
Appendix 2: Specific Renal Alert Criteria and Actions and Event Follow-up......99
16.3
Appendix 3: Cold challenge description and follow up procedures....................101
16.4
Appendix 4: Physician Global Assessment of Autoinflammatory Disease 
Activity.................................................................................................................102
16.5
Appendix 5: Physician's Severity Assessment of Autoinflammatory Disease 
Signs and Symptoms............................................................................................103
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 6 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
16.6
Appendix 6: Patients Global Assessment of Disease Activity ............................104
List of tables
Table 2-1
Objectives and related endpoints...........................................................31
Table 6-1
Investigational drug...............................................................................47
Table 6-2
Concomitant medications to be used with caution................................49
Table 6-3
Prohibited medication............................................................................50
Table 6-4
Dose and treatment schedule.................................................................55
Table 8-1
Assessment Schedule.............................................................................58
Table 8-2
Assessments and Specifications ............................................................69
Table 8-3
Clinical Laboratory Safety Assessments (local)....................................70
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse..........................................................................................83
Table 12-1
Non-compartmental pharmacokinetic parameters.................................90
Table 16-1
Liver event and laboratory trigger definitions.......................................96
Table 16-2
Follow up requirements for liver laboratory triggers with liver 
symptoms...............................................................................................97
Table 16-3
Follow up requirements for liver laboratory triggers ............................98
Table 16-4
Specific Renal Alert Criteria and Actions.............................................99
Table 16-5
Renal Event Follow up........................................................................100
List of figures
Figure 3-1
Study Design .........................................................................................33
Figure 12-1
Probability of success with 6 participants, varying ratio of fold 
changes, SD=0.5....................................................................................91
Figure 16-1
Physician Global Assessment of Autoinflammatory Disease 
Activity................................................................................................102
Figure 16-2
Physician's Severity Assessment of Autoinflammatory Disease 
Signs and Symptoms ...........................................................................103
Figure 16-3
Patients Global Assessment of Disease Activity.................................104
Commercially Confidential Information


Novartis
Confidential
Page 7 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
List of abbreviations
AE
Adverse Event
AIDS
Acquired Immune Deficiency Syndrome
ALB
Albumin
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
anti-HBc
Hepatitis B core antibody
APTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
b.i.d.
bis in die / twice a day
BMI
Body Mass Index
BP
Blood Pressure
BUN
Blood Urea Nitrogen
CAPS
Cryopyrin-Associated Periodic Syndromes
CINCA
Chronic, Infantile, Neurological, Cutaneous and Articular Syndrome
CK
Creatine Kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
ClinRO
Clinician Reported Outcomes
CMO & PS 
Chief Medical Office and Patient Safety
CO
Country Organization
COA
Clinical Outcome Assessment
CRO
Contract Research Organization
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Trough concentration
CV
Coefficient of Variation
CXCL10
C-X-C motif chemokine ligand 10
CYP
Cytochrome P450
DDE
Direct Data Entry
DDI
Drug-Drug Interaction
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case Report/Record Form
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
eSource
Electronic Source
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 8 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
FCAS
Familial Cold Autoinflammatory Syndrome
FIH
First in Human
FMF
Familial Mediterranean Fever
FSH
Follicle Stimulating Hormone
G-GT
Gamma-Glutamyl Transferase
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
h
Hour
HBsAg
Hepatitis B surface antigen
hCG
Human Serum Chorionic Gonadotropin
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
IC50
Half maximal inhibitory concentration
IC90
Concentration required to achieve 90% of inhibition
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IFN-γ
Interferon-gamma
IL-1
Interleukin-1
IL-18
Interleukin-18
IL-18BP
IL-18 binding protein
IL-1β
Interleukin-1beta
IL-6
Interleukin-6
IN
Investigator Notification
INR
International Normalized Ratio
IRB/IEC
Institutional Review Board / Independent Ethics Committee
IUD
Intrauterine Device
IUS
Intrauterine System
KIM-1
Kidney Injury Molecule-1
LC-MS/MS
Liquid chromatography coupled with tandem mass spectrometry
LDH
Lactate Dehydrogenase
LFT
Liver Function Test
LPLV
Last Participant Last Visit
LPS
Lipopolysaccharide
MAD
Multiple Ascending Dose
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
mL
milliliter(s)
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 9 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
MWS
Muckle-Wells Syndrome
NGAL
Neutrophil Gelatinase-Associated Lipocalin
NLRP3
Nucleotide-binding oligomerization domain-like receptor family, pyrin domain-
containing 3
NOAEL
No Observed Adverse Effect Level
NOMID
Neonatal Onset Multisystem Inflammatory Disease
NSAID
Non-Steroidal Anti-Inflammatory Drug
PBMC
Peripheral Blood Mononuclear Cells
PCR
Protein-Creatinine Ratio
PD
Pharmacodynamic(s)
PI
Principal investigator
PRO
Patient Reported Outcomes
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
q.d.
quaque die / once a day
QTcF
QT interval corrected by Fridericia’s formula
R Value
ALT/ALP x ULN
RBC
Red Blood Cell(s)
RNA
Ribonucleic acid
SAD
Single Ascending Dose
SAE
Serious Adverse Event
SD
Standard Deviation
SDD
Spray-Dried Dispersion
SoC
Standard of Care
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBL
Total Bilirubin
TLR
Toll-like receptor
ULN
Upper Limit of Normal
WCC
White Cell Count
WHO
World Health Organization 
WOCBP
Women of child bearing potential 
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 10 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy)
Assessment
A procedure used to generate data required by the study
Baseline
Refers to the information found prior to initiating a treatment or after all effects 
triggered by a treatment have ceased
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant 
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 participant 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
End of the clinical 
trial
The end of the clinical trial is defined as the last visit of the last participant or at 
a later point in time as defined by the protocol
Enrollment
Point/time of participant entry into the study at which informed consent must be 
obtained 
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and eCRFs into one application, allowing for the real time 
collection of clinical trial information to sponsors and other oversight 
authorities, as appropriate
Estimand 
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment conditions 
being compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable
Healthy volunteer
A person with no known significant health problems who volunteers to be a 
study participant 
Intercurrent 
events
Events occurring after treatment initiation that affect either the interpretation or 
the existence of the measurements associated with the clinical question of 
interest
Investigational 
drug/ treatment
The drug whose properties are being tested in the study
Medication 
number
A unique identifier on the label of medication kits
Mis-randomized 
participants
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study 
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)


Novartis
Confidential
Page 11 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Participant
A trial participant (can be a healthy volunteer or a patient)
Participant 
number
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc.
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis
Personal data
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples.
Premature 
participant 
withdrawal
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned
Screen Failure
A participant 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 participant
Study treatment
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy
Study treatment 
discontinuation
When the participant 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 
Variable (or 
endpoint)
The variable (or endpoint) to be obtained for each participant that is required to 
address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event
Withdrawal of 
consent
Withdrawal of consent from the study occurs when a participant explicitly 
requests to stop use of their data and/or biological samples AND no longer 
wishes to receive study treatment AND does not agree to further protocol 
required assessments. This request should be in writing (depending on local 
regulations) and recorded in the source documentation.
This request should be distinguished from a request to discontinue the study. 
Other study participant's privacy rights are described in the corresponding 
informed consent form.


Novartis
Confidential
Page 12 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 13 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 14 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 15 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 16 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 17 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 18 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 19 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 20 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 21 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 22 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Protocol summary
Protocol number
CDFV890A12201
Full title
An open-label, single arm phase II study of DFV890 to assess the safety, 
tolerability and efficacy in participants with familial cold auto-inflammatory 
syndrome (FCAS)
Brief title
Study of safety, tolerability and efficacy of DFV890 in participants with familial 
cold auto-inflammatory syndrome (FCAS)
Sponsor and 
Clinical Phase
Novartis, Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this phase II study is to assess the safety, tolerability and 
efficacy of DFV890 in participants with FCAS
Primary 
Objective(s) 
The primary objective of this study is to assess the efficacy of DFV890 to 
reduce cold-induced inflammation in participants with FCAS
Secondary 
Objectives
The secondary objectives of the study are:
•
To assess safety and tolerability of DFV890
•
To assess the efficacy of DFV890 to improve the signs and symptoms 
of FCAS
•
To assess the effect of DFV890 on patient reported outcomes
Study design
This is an open-label, single-arm, multiple dose, phase II study to assess 
safety, tolerability and clinical efficacy of DFV890 in participants with FCAS. 
The study includes three periods:
•
Screening period including a screening cold challenge up to 6 months 
(and up to 12 months for participants with a historical screening cold 
challenge prior to protocol amendment 04)
•
Treatment period including a second cold challenge (total of 5 days 
duration)
•
Follow up period concluded with a Study completion visit (10 days after 
dose administration)
At most, the study will last up to 7 months (and up to 13 months for 
participants with a historical screening cold challenge prior to protocol 
amendment 04)
Study population
Approximately 6 adult male or female participants with FCAS, who show 
evidence of inflammatory activity after the cold challenge performed during 
screening, will be included into the study


Novartis
Confidential
Page 23 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Key Inclusion 
criteria
•
Written informed consent must be obtained before any study-specific 
assessment is performed
•
Male and female participants aged between 18-80 years inclusive (for 
France 18-60)
•
Body mass index within the range of 18-35 kg/m2
•
Participants with a genetic diagnosis of FCAS
•
Participants with a clinical history and investigations consistent with 
FCAS, in the absence of a history or diagnosis of amyloidosis and/or 
organ damage (e.g. deafness, periorbital edema, lymphadenopathy, 
and serositis)
•
Participants who have evidence of inflammatory activity after the 
screening cold challenge, as assessed by a relative increase in WCC of 
at least 40 % compared to pre-challenge
•
Evidence of inflammatory disease activity during the screening 
period before the admission to the screening cold challenge, captured 
by the Physician global assessment of autoinflammatory disease 
activity > minimal, recorded at Screening Cold Challenge Admission 
visit
Key Exclusion 
criteria
•
 
 
 
•
Anti-rejection and/or immunomodulatory drugs must be discontinued:
▪
Anakinra at least 1 day prior to the screening cold challenge and 
until study completion
▪
Canakinumab and rilonacept at least 3 half-lives prior to the 
screening cold challenge, at least 5 half-lives prior to Day 1 and 
until study completion
▪
Other anti-rejection/immune modulatory therapies must be 
discontinued at least 3 half-lives prior to screening cold challenge, 
at least 5 half-lives prior to Day 1 and until study completion
▪
Ad hoc use of anakinra is permitted for the interval between the 
screening cold challenge and Day 1, if it can be discontinued at 
least 5 half-lives prior to Day 1
▪
Ad hoc use of paracetamol and non-steroidal anti-inflammatory 
drugs (NSAIDs, as per local regulations/practice) is permitted for 
symptomatic relief
•
Clinically significant, suspected active or chronic bacterial (including 
Mycobacterium tuberculosis), viral or fungal infection within 30 days 
prior to Day 1
•
Participants with innate (e.g. TLR immunodeficiencies, defects in IFN-γ 
signaling) or acquired immune deficiencies (e.g. AIDS)
•
Presence of human immunodeficiency virus (HIV) infection, hepatitis B 
surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc), or 
hepatitis C antibodies at screening
•
Live vaccines within 4 weeks of Day 1
•
Absolute peripheral blood neutrophil count of ≤1000/mm3
Commercially Confidential Information


Novartis
Confidential
Page 24 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
•
A history of renal disease, including nephrolithiasis, and/or an estimated 
GFR (eGFR) ≤90 mL/min/1.73m2 (based on Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula)
•
History or current diagnosis of ECG abnormalities indicating significant 
safety risk for participant enrolled
•
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 human serum chorionic gonadotropin 
(hCG) laboratory test
•
Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective 
methods of contraception during dosing and for 10 days after stopping 
of study treatment
•
Any significant concurrent medical condition (e.g. anemia) that, in the 
opinion of the investigator, could affect the participant’s ability to 
tolerate or complete the study
Study treatment
DFV890 100 mg b.i.d. orally for 3 days and once in the morning of the 
fourth day
Treatment of 
interest
The study treatment is DFV890 (no placebo or comparator will be 
administered)
Efficacy 
assessments
•
White Cell Count (WCC)
•
Physician global assessment of autoinflammatory disease activity
•
Physician’s severity assessment of autoinflammatory disease signs and 
symptoms 
•
Patient’s global assessment of disease activity 
Key safety 
assessments
•
Physical examination
•
Vital signs
•
ECG parameters
•
Pregnancy and assessment of fertility
•
Monitoring of laboratory markers in blood and urine
•
Adverse event and serious adverse event monitoring
Other assessments
•
 
 
 
Data analysis
The primary objective will be achieved and DFV890 will be considered 
efficacious in treating cold-induced inflammation in participants with FCAS if 
the estimated ratio of fold change from pre-challenge to highest post 
challenge WCC between treatment and screening period is: statistically 
significant (p<0.10) and less than 80%.
 
 
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 25 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Key words
Familial Cold Auto-inflammatory Syndrome (FCAS), DFV890, NLRP3 
inhibitor, inflammasome inhibition, Cryopyrin-associated periodic syndromes 
(CAPS)


Novartis
Confidential
Page 26 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
1
Introduction
1.1
Background
Cryopyrin-associated periodic syndromes (CAPS) is a group of rare diseases characterized by 
skin, musculoskeletal, ocular, and neurological symptoms and chronic systemic inflammation 
that may lead to organ damage and/or amyloidosis and are caused by heterozygous gain-of-
function mutations in the nucleotide-binding oligomerization domain-like receptor family, 
pyrin domain-containing 3 (NLRP3) gene. CAPS are classified into three clinical phenotypes 
based on a spectrum of disease severity: familial cold autoinflammatory syndrome (FCAS), 
Muckle Wells syndrome (MWS) and neonatal onset multisystem inflammatory disease 
(NOMID) also called chronic, infantile, neurological, cutaneous and articular syndrome 
(CINCA) (Hoffman et al 2019).
FCAS represents the mildest CAPS clinical phenotype and symptoms are typically limited to 
low grade fever, general rash, conjunctivitis and polyarthralgia, triggered 1-2 hours following 
cold exposure and resolve within 24 hours with warmth (Shpall et al 2004). Clinically it is 
important to distinguish between FCAS and cold urticaria, that are not related, are distinct in 
their etiology, clinical presentation, response to type of cold exposure (generalized for FCAS 
versus local for cold urticaria), pathophysiology (IL-1 mediated for FCAS versus histamine 
for cold urticaria) and natural history (throughout life for FCAS versus spontaneous resolution for 
cold urticaria) (Wanderer and Hoffman 2004). In addition, many patients with FCAS also show 
evidence of chronic inflammation between attacks, particularly a daily pattern of rash 
developing in the afternoon that can be associated with headache, myalgia, and fatigue by the 
evening though chronic inflammation rarely leads to amyloidosis (~2%) in this patient 
population (Hoffman et al 2019).
Chronic inflammation and abnormal immune activity underlie and drive many serious human 
diseases ranging from rare and acute inflammatory diseases, rheumatologic indications, 
cardiovascular and metabolic diseases, neurodegenerative diseases, and cancer. In these settings, 
molecular danger signals produced by dying cells, metabolic dysregulation, environmental 
toxins, or the diet may function as stimuli to activate NLRP3 inflammasome 
(Mangan et al 2018). Once activated, NLRP3 nucleates assembly of an inflammasome complex 
that orchestrates innate and adaptive immune responses to drive a strong inflammatory response 
(Evavold and Kagan 2018). Inflammasomes are large cytoplasmic, multimeric protein 
complexes assembled in response to danger signals, and inflammasome activation results in 
caspase-1 mediated production of interleukin-1β (IL-1β) and interleukin-18 (IL-18) as well as 
pyroptosis (inflammatory mediated cell death) (Dinarello 2011).
The role of IL-1β in several diseases has been well established in the clinic. The drugs anakinra 
(recombinant soluble IL-1 receptor antagonist) and canakinumab (anti-IL-1β) are approved for 
treatment of a range of autoinflammatory diseases including CAPS and familial Mediterranean 
fever (FMF). Canakinumab (anti-IL-1β monoclonal antibody) reduces cardiovascular risk in 
patients who have previously had a myocardial infarction (Ridker et al 2017a). Further analysis 
of the CANTOS study found that canakinumab treatment reduced lung cancer incidence 
(Ridker et al 2017b) 
and 
knee 
and 
hip 
replacements 
in 
osteoarthritis 
patients 
(Schieker et al 2020), suggesting that IL-1β blockade could be beneficial in a broad range of 
common inflammatory diseases. Potentially NLRP3 inhibition with DFV890, blocking IL-1β, 


Novartis
Confidential
Page 27 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
IL-18, and pyroptosis, in these and other settings may provide a treatment for conditions where 
persistent inflammasome activation results in pathology (Ridker et al 2018). To support this 
extrapolation from clinical experience with IL-1β blockade to NLRP3 inhibition, an extensive 
body of published literature based on genetic knockout or pharmacologic inhibition of NLRP3 
provides validation for the assessment that NLRP3 is a promising therapeutic target 
(Mangan et al 2018).
DFV890 is a potent small molecule inhibitor of NLRP3.
DFV890 is a small molecule NLRP3 inhibitor that has reached clinical stage, and its therapeutic 
benefits in a NLRP3-driven disease has yet to be shown in humans.
 
Therefore, we propose a proof of concept for DFV890 in participants with 
FCAS, a known NLRP3-specific disease, to understand its clinical response profile.
1.1.1
DFV890
DFV890 was developed as an orally administered small molecule to treat diseases in which 
inflammation or aberrant immune responses caused by activation of the NLRP3 inflammasome 
initiates or mediates pathology. 
inflammasome has been implicated as a major driver of inflammation associated with 
autoinflammatory, acute and chronic inflammatory diseases, such as CAPS.
1.1.2
Non-clinical data
Commercially Confidential Information
Commercially Cofidential Information  
CCI 
Commercially Confidential Information


Novartis
Confidential
Page 28 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 29 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
1.1.3
Clinical data
Clinical human pharmacokinetics
DFV890 is a highly permeable compound with solubility-limited absorption of crystalline 
material at high doses. 
Specific studies to investigate drug-drug interactions (DDIs) have not been conducted with 
DFV890. Weak to moderate DDI effects are expected for DFV890 as a victim with concomitant 
administration of strong and moderate CYP2C9 and CYP3A4 inhibitors for patients, who are 
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 30 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
normal and intermediate CYP2C9 metabolizers. High DDI risk (≥5 up to 25-fold increase in 
DFV890 AUC) is expected for patients, who are poor CYP2C9 metabolizers. When dosed with 
a strong CYP3A4 inducer or moderate dual CYP2C9/CYP3A inducer, moderate DFV890 
exposure reduction by ~4-fold is predicted for normal CYP2C9 metabolizers. Weaker effect of 
inducers is expected for patients with reduced CYP2C9 activity. As a perpetrator, DFV890 has 
weak potential to induce CYP3A4 and therefore may reduce AUC of strong CYP3A4 substrates 
by up to ~2-fold (refer to the Investigator’s Brochure for further details).
Clinical safety
As of 17-May-2022, 266 subjects have been enrolled into the DFV890 clinical development 
program, of which approximately 164 subjects or patients have received DFV890 at various 
doses and 100 placebo or standard of care (SoC). The final clinical study report is available for 
 CDFV890D12201 (COVID-19) 
studies.
In the completed Phase 2 study (CDFV890D12201) in patients with COVID-19 pneumonia and 
impaired respiratory function, 143 participants were enrolled to the study (DFV890+SoC or 
SoC alone groups), of whom 70 participants received DFV890 at a dose of 50 mg b.i.d. for 14 
days. DFV890 was generally well tolerated with drug exposures as expected 
 
. The overall incidences of reported AE and SAE were 
similar between the DFV890 and SoC groups with no unexpected or new safety findings in this 
COVID-19 population. There were no events related to the musculoskeletal/connective tissue 
systems for DFV890 or SoC arms and no unexpected renal events or serious infections in 
hospitalized COVID-19 population. There was as anticipated a higher incidence of mild to 
moderate rash events observed in participants who received DFV890. Maculopapular/pruritic 
skin rashes considered related to DFV890 were reported in 7 participants (approximately 10%), 
of whom 2 participants discontinued the study treatment. These events were of mild and 
moderate severity, started 5 to 14 days after initiation of DFV890 treatment and resolved within 
5 to 16 days after onset.
In summary, there were no unexpected events for this disease indication and patient population. 
The safety findings are consistent with the early clinical safety profile 
 
Commercially Confidential Information
Commercially Confidential Information
CCI
CCI


Novartis
Confidential
Page 31 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
A Phase 2 study is currently ongoing (CDFV890B12201) in participants with symptomatic knee 
osteoarthritis 
1.2
Purpose
The purpose of this phase II study is to assess the safety, tolerability and efficacy of DFV890 
in participants with FCAS. 
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
•
To assess the efficacy of DFV890 to reduce
cold-induced inflammation in participants with
FCAS
•
Ratio of fold change from pre-challenge
to the highest post-challenge value of
white cell count (WCC) between
treatment and screening period
Secondary objective(s)
Endpoint(s) for secondary objective(s)
•
To assess safety and tolerability of DFV890
•
Safety endpoints (including vital signs,
ECG parameters, safety laboratory
assessment and adverse events)
•
To assess the efficacy of DFV890 to improve
the signs and symptoms of FCAS
•
Change from pre-challenge to post-
challenge between treatment and
screening period in:
•
Physician global assessment of
autoinflammatory disease activity
•
Physician's severity assessment of
autoinflammatory disease signs and
symptoms
•
To assess the effect of DFV890 on patient
reported outcomes
•
Change from pre-challenge to post-
challenge between treatment and
screening period in:
•
Patients global assessment of
disease activity
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information 


Novartis
Confidential
Page 32 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
2.1
Primary estimand
The primary clinical question of interest is: does DFV890 prevent flares triggered by the cold 
challenge as indicated by proportional reduction in the fold change from pre-challenge to the 
highest post-challenge value of WCC between treatment and screening periods in participants 
with FCAS?
It has been shown (Hoffman et al 2004) that the fold change in WCC from pre-challenge to 
post-challenge can capture the treatment effect in the acute flare situation triggered by the cold 
challenge. Hence the choice of the primary estimand is considered as the ratio of fold change 
from pre-challenge to highest post-challenge WCC values between treatment and screening.
The primary estimand is described by the following attributes:
1. Population: participants with a genetic diagnosis of FCAS in association with a clinical
history and investigations consistent with FCAS, who show evidence of inflammatory
activity after the cold challenge performed during screening. Further details about the
population are provided in Section 5.
2. Endpoint: fold change from pre-challenge to the highest post-challenge value of WCC.
This is measured as the ratio of highest post-challenge and the pre-challenge value of
WCC. The highest post-challenge value is based only on post-challenge measurements
within the cold challenge visit (up to and including 8 hours post-challenge; i.e. 9 hours
post-dose).
3. Treatment of interest: DFV890
4. Summary measure: ratio of treatment fold change and screening fold challenge of WCC
value.
3
Study design
This is an open-label, single-arm, multiple dose, phase II study to assess safety, tolerability and 
efficacy of DFV890 in participants with FCAS who show evidence of inflammatory activity 
after the cold challenge performed during screening. Approximately 6 participants with FCAS 
and confirmed NLRP3 gain-of-function mutations will be enrolled in the CDFV890A12201 
study.
Commercially Confidential Information


Novartis
Confidential
Page 33 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
The study consists of three periods: screening, treatment and follow-up. During the screening 
period the participant's eligibility will be assessed at a screening visit and a cold challenge will 
be performed. Eligible participants (defined as those participants who respond to the cold 
challenge) will then enter the treatment period where they will be administered oral DFV890 
100 mg b.i.d. for 3 days, one last dose will be administered in the morning of Day 4 followed 
by a cold challenge. The Study completion visit will be conducted approximately 10 days after 
last dose and a post study safety contact will occur 30 days after last dose. Assessments are 
outlined in the assessment schedule (Table 8-1). The total study duration from screening until 
study completion is expected to be up to 7 months (and up to 13 months for participants with a 
historical screening cold challenge prior to protocol amendment 04).
Figure 3-1
Study Design
Screening period
A period of up to 6 months (and up to 12 months for participants with a historical screening 
cold challenge prior to protocol amendment 04), to confirm that the study eligibility criteria are 
met and to conduct the first cold challenge. The required assessments may be conducted over 
several days if it is in the best interest of the participant, or for logistical reasons. The screening 
period also allows for the safe treatment discontinuation in participants treated with therapeutics 
targeting the IL-1β pathway. 
Screening visit: Informed consent will be collected, and participants evaluated for eligibility. 
For those participants that qualify for the screening cold challenge, prohibited medication will 
be stopped (Section 6.2.2). Results from laboratory samples collected at the Screening visit, as 
well as reports of active disease from the participant, must be available prior to scheduling the 
screening cold challenge.
Screening Cold Challenge: The participants will be domiciled for three days in connection with 
the screening cold challenge. On the first day (Day -10), the participants will be admitted in the 
morning, go through safety assessments and then stay in a room with ambient temperature, 
preferably above 23°C, to ensure stable conditions prior to the cold challenge. On the second 
day (Day -9), after pre-challenge assessments and breakfast, participants will undergo a cold 
challenge for 45 minutes (see Section 16.3 for further details) followed by monitoring over the 


Novartis
Confidential
Page 34 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
next 23 hours. On the third day (Day -8), the participants will be discharged after the last 
assessment, or later at the discretion of the investigator. Participants should have a minimum of 
one week of recovery from cold challenge prior to enrollment and initiation of treatment. The 
screening cold challenge can be conducted any time during the screening period, provided that 
Day 1 is conducted within 6 months (and within 12 months for participants with a historical 
screening cold challenge prior to protocol amendment 04; see below) of the Screening visit and 
all inclusion and none of the exclusion criteria are met. Historical screening cold challenge 
conducted in this study under the previous protocol version is acceptable, provided that Day 1 
is conducted within 12 months of the Screening visit, and all inclusion and none of the exclusion 
criteria based on this amendment are met.
To mitigate potential SARS-CoV-2 infections among participants, guidance and requirements 
provided by the local regulatory authorities or local site-specific standard operating procedures 
(SOPs) will be followed (e.g. participants may be screened for SARS-CoV-2 by polymerase 
chain reaction or comparable approved methodology prior to admission at the study/hospital 
site for any overnight stays following local site-specific SOPs).
Treatment period
Treatment initiation visit: Participants who meet all inclusion and no exclusion criteria, 
including showing evidence of inflammatory activity after the cold challenge performed during 
screening, will be enrolled on Day 1 and treatment will be initiated. Evidence of inflammatory 
activity is defined in Inclusion criterion 8, Section 5.1.
The first dose of DFV890 will be administered in the clinic and study treatment will be 
dispensed to the participant for continued treatment at home. Participants may be domiciled 
during the treatment period for convenience of the participants and/or logistical aspects, at the 
discretion of the participant and investigator.
Cold Challenge: Participants will be admitted to the clinic in the morning of Day 3, the day 
prior to cold challenge, and will be domiciled for a total of three days or longer if mandated by 
the investigator or by local regulations. On Day 3, participants will undergo safety assessments 
and then stay in a room with ambient temperature, preferably above 23°C, to ensure stable 
conditions prior to the cold challenge. On the morning of Day 4, pre-challenge assessments will 
be performed and breakfast will be served. Directly after breakfast, a pre-dose PK sample will 
be collected and the last dose of study treatment will be administered. One hour after study 
treatment administration, another PK sample will be collected, and the cold challenge will be 
initiated. The cold challenge lasts for 45 minutes. After the end of the cold challenge, 
participants will be monitored until the next morning (Day 5). The participants will be 
discharged after the last assessment on Day 5 or later, at the discretion of the investigator.
Follow up period
Participants will be followed-up for an end of study evaluation at the Study completion visit, 
approximately 10 days after last dose. The Study completion visit may be performed at an 
alternative Sponsor-approved site (e.g. satellite site that may be more convenient to the 
participant) if agreed by the principal investigator (PI) who will maintain the investigator 
responsibilities, and only as permitted by local regulations.


Novartis
Confidential
Page 35 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Unscheduled visits
Participants will be instructed to contact the investigator if they develop rash or pruritus between 
visits from Day 1 to the Study completion visit. An unscheduled visit should be considered 
based on clinical findings and severity of rash or pruritus and related assessments performed. 
Unscheduled visits may be performed at an alternative Sponsor-approved site (e.g. satellite site 
that may be more convenient to the participant) if agreed by the PI who will maintain the 
investigator responsibilities, and only as permitted by local regulations.
4
Rationale
4.1
Rationale for study design
Study design
The design supports the assessment of the safety, tolerability, as well as the evaluation of the 
proof of concept and efficacy of DFV890 in participants with FCAS.
This study design includes a cold challenge that was developed to study 
the acute inflammatory mechanisms after general cold exposure in FCAS patients and to 
investigate the effect of pretreatment with IL-1 blocking therapeutics to enable the clinical 
development of such therapeutics to treat FCAS patients (Hoffman et al 2004, Ross et al 2008).
Based on the analysis of the results from Hoffman et al 2004, the sample size (6 patients) is 
calculated assuming that the geometric mean of the ratio in fold changes of WCC between 
treatment and screening periods will be at most 50% (see Section 12.8.1 for further details). 
This approach also excludes non-responders during the screening/control period, lowering the 
risk of false negatives and ensuring only those participants with FCAS who respond to the cold 
challenge are administered DFV890 and undergo a second cold challenge as part of the study. 
In addition, the primary endpoint (WCC) is unlikely subject to bias, further justifying the open-
label design.
The Screening visit will be used to confirm that the study inclusion and exclusion criteria are 
met and for performing clinical observations and biological sampling. 
 The screening cold challenge will be conducted and 
treatment phase started as soon as the defined wash-out for background therapy is fulfilled. This 
wash-out period for previously treated participants ensures that only participants with sufficient 
wash-out of background medication will undergo the screening cold challenge.
Following the screening cold challenge only the participants who have evidence of 
inflammatory activity (e.g. elevation in WCC) will be enrolled to the treatment period and 
will be administered DFV890 prior to a second cold challenge. The DFV890 treatment is 
anticipated to provide full inhibition of the NLRP3 inflammasome in FCAS participants 
potentially reducing or ablating inflammatory responses to cold temperatures. 
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 36 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Pre-challenge and post-challenge measurements of WCC, 
 as well as clinical signs and symptoms using 
physician and patient reported outcomes (PROs) will be conducted. These assessments have 
been widely used in clinical studies of inflammation.
The follow-up period ensures participants' safety after discontinuation of DFV890 and 
recovery from the cold challenge.
Targeted study population
The rationale for including participants with FCAS is the following: FCAS is a mild CAPS 
phenotype that may not require treatment. Furthermore, in the case of participants on treatment, 
it is safe to temporary discontinue treatment as per medical judgment for the limited period of 
the study. Participants with a history of CAPS-related organ damage and/or amyloidosis will 
be excluded to ensure no overlap with MWS. A potential risk of DFV890 and in general for 
small molecule inhibitors of NLRP3 is the recently described differential binding affinities of 
such molecules to wild type versus mutant NLRP3, resulting in reduced efficacy in the latter 
(Vande Walle et al 2019). Therefore, participants carrying NLRP3 gene mutations not 
responsive to DFV890 inhibition including but not limited to L353P carriers, will be excluded. 
As an experimental cold challenge is used to trigger an inflammatory response, only participants 
showing evidence of inflammatory activity after the cold challenge during screening (as defined 
above) will be included.
Duration of study periods
A screening period of up to 6 months (and up to 12 months for participants with a historical 
screening cold challenge prior to amendment 04) has been selected to allow for wash-out of 
previous IL-1β/NLRP3 blocking therapy, the conduct of the screening cold challenge, as well 
as to accept historical screening cold challenge conducted in this study under the previous 
protocol version.
4.2
Rationale for dose/regimen and duration of treatment
A dose of 100 mg administered b.i.d. as a tablet has been selected for this study. DFV890 tablets 
will be administered shortly after completion of a meal and all doses should be taken 
approximately 12 h apart (±1h).
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
CCI


Novartis
Confidential
Page 37 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Considering the short treatment duration of 4 days and sufficient safety margins, administration 
of DFV890 in this study is considered safe.
Commercially Confidential Information


Novartis
Confidential
Page 38 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
4.3
Rationale for choice of control drugs (comparator/placebo)
Not applicable.
4.4
Rationale for public health emergency mitigation procedures
In the event of a public health emergency as declared by local or regional authorities (i.e. 
pandemic, epidemic or natural disaster), mitigation procedures may be required to ensure 
participant safety and trial integrity and are listed in relevant sections of the study protocol. 
Notification of the public health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures and permitted/approved by local or regional health 
authorities and ethics committees as appropriate.
4.5
Purpose and timing of interim analyses/design adaptations
No interim analysis is planned for this trial.
Interim analyses may be conducted to support decision making concerning the current clinical 
study, the sponsor’s clinical development projects in general or in case of any safety concerns.
4.6
Risks and benefits
4.6.1
Potential benefits to study participants
There is no benefit expected for participants in this study given the limited duration of DFV890 
treatment, though participants with FCAS will contribute to the development of a potential new 
oral therapy.
From a patient perspective, there exists significant unmet medical need for large segments of 
patients across the diseases in which NLRP3 is a driver of inflammation and mediates 
consequent immune damage. For patients with NLRP3-driven diseases who do not respond to 
approved therapies, and therefore for whom no standard therapeutic alternatives are available 
or for whom available therapeutic alternatives are associated with significant risks of side 
effects, DFV890 represents a promising alternative.
Commercially Confidential Information


Novartis
Confidential
Page 39 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
4.6.2
Potential risks to study participants
The risk to participants with FCAS in this trial may be minimized by compliance with the 
eligibility criteria and study procedures, as well as close clinical monitoring, follow-up, minimal 
duration of the study treatment and pre-specified study stopping rules.
The cold challenge procedure was developed to study the acute inflammatory mechanisms after 
general cold exposure in FCAS patients and to investigate the effect of pretreatment with IL-1 
blocking therapeutics to enable the clinical development of such therapeutics. Participants with 
a clinical history of transient self-limiting rash, fever and/or arthralgia that are pathognomonic 
of FCAS following cold exposure that resolve with warmth will undergo two controlled cold 
challenges while domiciled at the clinical site under medical supervision to trigger a transient 
and monitorable inflammatory response. Following the 45-minute cold challenge, participants 
will be returned to an ambient temperature of approximately 23°C for at least 24 hours at the 
clinical site, to ensure resolution of the inflammatory response.
The design of the cold challenge procedure is based on the clinical characteristics of the acute 
episodes in FCAS patients where a mean duration of generalized cold exposure of 52 minutes 
(range 5-180 minutes) was reported to trigger a self-limiting episode with onset of symptoms 
150 minutes (range 10-480 minutes) after generalized cold exposure, with the absolute change 
in temperature (ambient to low) being an important factor in precipitating episodes 
(Hoffman et al 2001, Johnstone et al 2003). Importantly, environmental generalized cold 
exposure (e.g. cold damp weather) would similarly cause an inflammatory episode in many 
untreated FCAS patients experiencing baseline daily symptoms, often with diurnal pattern of 
episodes in the afternoon or evening that resolve by morning following rewarming in bed 
overnight. The cold challenge as described in the present protocol models the real life situation 
of exposure to mildly cold weather conditions and is expected to trigger typical signs and 
symptoms of an acute episode in FCAS patients including a low-grade fever, rash and arthralgia 
beginning approximately 1 hour after challenge, peaking at 4-8 hours and abating with warming 
by the next day with no reports of acute complications during the challenge or long-term 
sequelae in patients (Hoffman et al 2004, Ross et al 2008).
Importantly, the cold challenge induces cold stress (body temperature 35.0-37.0°C 
(Dow et al 2019)) but not hypothermia (body temperature 35.0-32.0°C, clear consciousness 
with shivering (Durrer et al 2003)) requiring treatment. FCAS patients are able to normally 
function during the challenge with physiological responses to cold including shivering to raise 
body temperature and metabolic rate. This is followed by IL-1 mediated response post 
challenge that includes a self-limiting low-grade fever that resolves on warming 
(Ross et al 2008).
Study specific assessments will be performed following local procedures by investigators and 
site staff experienced in the care of FCAS patients. Participants with FCAS will be domiciled 
for the cold challenges to ensure close clinical monitoring during the rewarming until discharge 
(approximately 22 hours after end of cold challenge), and the protocol contains a recovery 
period of more than one week between the first and second challenge in eligible patients. The 
use of paracetamol/acetaminophen or NSAIDs is also permitted for symptom relief. The cold 
challenge as described in this protocol (see Section 16.3) models the real-world exposure of 
FCAS patient to mild cold weather conditions for a limited duration with careful monitoring 
under medical supervision during and after the cold challenge including pre specified stopping 


Novartis
Confidential
Page 40 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
rules for the cold challenge. Based on the available clinical, safety and laboratory assessments 
and the clinical experience of the cold challenge in FCAS patients and the CDFV890A12201 
protocol specific measures, the overall risk-benefit of the cold challenge is considered 
acceptable. Any potential risks are considered to be adequately mitigated with the indicated 
measures.
The potential risks of DFV890 summarized below are based on preclinical and clinical data 
from the completed 
 CDFV890D12201 COVID-
19 studies, based on the final clinical study report from both studies. Recommended guidelines 
for management of study AEs are provided in Section 6.6.2.
4.6.3
Potential risk and recommended management of skin rash
In the completed CDFV890D12201 Phase 2 study in COVID-19, participants in the active arm 
were administered DFV890 50 mg b.i.d. + SoC for 14 days. Maculopapular/pruritic skin rashes 
considered related to DFV890 were reported in 7 participants, of whom 2 participants 
discontinued the study treatment. These events were of mild and moderate severity, started 5 to 
14 days after initiation of DFV890 treatment and resolved within 5 to 16 days after onset.
To reduce the potential risks of the development of maculopapular and/or pruritic rashes, for 
early patient studies b.i.d. dosing will be employed to achieve maximal, sustained inhibition of 
the NLRP3 target while minimizing DFV890 Cmax and the potential for triggering skin rash if 
driven by Cmax.
Investigators should be vigilant for symptoms of pruritus and signs of rashes (e.g. 
maculopapular on upper trunk, spreading centripetally and usually associated with pruritus) and 
should instruct participants to contact the investigator if they develop rash or pruritus to ensure 
a rapid clinical assessment (see Section 6.6.2 for recommended management of 
maculopapular/pruritic rashes).
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 41 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
4.6.4
Potential risk of renal abnormalities and recommended monitoring
Although it is not clear whether there are potential effects of DFV890 on kidney in humans, 
markers of renal function including electrolytes, creatinine and BUN/Urea, urine-creatine ratio 
and urinalysis will be monitored in this study (see Section 10.2.2 for further details 
and guidance).
4.6.5
Potential risk and recommended monitoring of hematological 
parameters
Transient asymptomatic decreases in ANC and WCC were observed in the 
 
 and CDFV890D12201 COVID-19 studies. These transient self-limiting 
decreases in 
 were not associated with an increased risk of infection which could 
be consistent with a PD effect of DFV890 
 
 To reduce 
the risk of developing neutropenia in participants treated with DFV890, all participants with 
evidence of an ANC count < 1000/mm3 should be excluded from entry into this study (see 
Section 5.2).
4.6.6
Potential risk and recommended treatment of infection
As with any immune-modulating compound, there is a theoretical risk of immune system 
impairment which might increase risk of infection in treated participants. However, DFV890 is 
not expected to elicit broad immune suppression. 
 
. To mitigate potential risks of immune 
suppression and infection in this study, exclusion criteria include other immune suppressive 
treatments administered 28 days or 5 half-lives, whichever is longer, prior to screening cold 
challenge, or concurrent use thereof. Participants will also be excluded with known or suspected 
immunodeficiency state or evidence of active or latent, serious bacterial, fungal or viral 
infections. See Section 5.2.
Commercially Confidential Information
Commercially Confidential Information
CCI
CCI
CCI


Novartis
Confidential
Page 42 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
In response to the COVID-19 pandemic site-specific procedures should be implemented to 
minimize COVID-19 infection risks for participants and site staff as per local guidance. 
These documents may cover, but are not limited to, local COVID-19 testing, infection 
prevention/control, hygiene and social distancing measures. 
Investigator must instruct participants to contact the investigator immediately if the participants 
develop any symptoms and/or signs of infection (e.g. fever, loss of smell, loss of taste, muscle 
aches, persistent or productive cough, abdominal pain, vomiting, nausea, shortness of breath, 
dysuria and/or diarrhea). 
In the event of an infection, investigators should consider early treatment with specific 
antimicrobial therapy based on clinical diagnosis or suspicion there of (e.g. anti-viral treatment 
for herpes simplex or zoster or SARS-CoV-2) in consultation with infectious disease experts, 
as appropriate.
4.6.7
Potential risk and guidance on vaccinations
To mitigate the risk from live vaccinations, participants who have received live vaccinations 
within 1 month prior to the first dose of study will be excluded from entry into this study. 
Additionally, it is recommended that all participants should complete all immunizations in 
accordance with current immunization guidelines at least 1 month prior to administration of the 
first dose DFV890.
Approved (including Health Authorities’ conditional marketing authorization) killed, 
inactivated, peptide, DNA and RNA vaccines may be permitted according to the investigator’s 
discretion and per local guidance. Due to the mechanism of action of DFV890, specifically 
targeting the NLRP3 inflammasome, it is unlikely that treatment with this compound would 
interfere with vaccination responses. However, no specific preclinical or clinical investigations 
have been conducted to date with DFV890.
4.6.8
DFV890 potential for higher systemic exposure and for drug-drug 
interactions
Clinical studies to investigate drug-drug interactions between DFV890 and CYP3A and or 
CYP2C9 substrates/modulators have not been performed yet. 
 
Commercially Confidential Information
CCI


Novartis
Confidential
Page 43 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
 Restrictions on concomitant 
medications are described in Section 6.2.
4.6.9
Potential risk to women of child-bearing potential
At this stage of development, DFV890 has not been assessed in developmental and reproductive 
toxicity studies or experience in human pregnancies and all menarchal females and sexually 
active males must be informed that exposure to DFV890 may involve unknown risks to the 
fetus if pregnancy were to occur. Therefore, pregnant women are excluded from enrollment into 
this study, and women of child-bearing potential (WOCBP) and sexually active males must 
agree to that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria (Section 5.2). If there is any question that the 
participant will not reliably comply, they should not be enrolled or continue the study.
4.6.10
Blood sample volume
A volume equivalent to a typical blood donation is planned to be collected over a period of 
13 months, from each participant as part of the study. A maximum blood volume of 150 mL 
will be collected during the Screening period, 210 mL during the Treatment period (plus 25 mL 
in case an unscheduled visit has to take place) and 35 mL at the Study completion visit. 
Additional samples may be required for safety monitoring.
Sample volume may vary according to local laboratory standard. A total maximal volume of 
420 mL of blood per participant will be collected during his/her participation in the study.
Timings of blood sample collection are outlined in the assessment schedule (Table 8-1).
See the Section 8.5.3.2 on the potential use of residual samples.
4.6.11
Overall Risk Benefit
Based on the clinical experience with DFV890 in the 
 
, the CDFV890D12201 phase II study in COVID-19, relevant nonclinical findings, the 
biological understanding of the pathways and their relevance to FCAS, the overall risk-benefit 
of DFV890 is, to date, considered favorable. The clinical, safety and laboratory assessments 
from the completed 
 COVID-19 studies show that DFV890 is generally well 
tolerated and has a manageable safety profile.
 
In addition to the risks noted above, there may be 
risks to DFV890 that are serious and unforeseen. Therefore, the risks to FCAS participants in 
this trial will be minimized by adherence to the eligibility criteria, close clinical monitoring 
including markers of renal function, frequent follow up, minimal duration of the study and 
stopping rules.
5
Study Population
The study population includes approximately 6, but not more than 10, adult participants with 
FCAS who show evidence of inflammatory activity after the cold challenge performed during 
screening.
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
CCI


Novartis
Confidential
Page 44 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any study-specific assessment is
performed.
2. Participants must be able to communicate well with the investigator and to understand and
comply with the requirements of the study.
3. Male and female participants aged between 18 - 80 years (for France 18 - 60 years)
inclusive at the time of screening will be included.
4. Participants must have a body mass index (BMI) within the range of 18 - 35 kg/m2 (BMI
= Body weight (kg) / [Height (m)]2) at Screening, Screening Cold Challenge Admission
visit and Day 1 pre-dose.
5. Participant with a genetic diagnosis of FCAS (this analysis may be performed as part of
screening if not readily available).
6. Clinical history and investigations consistent with FCAS, in the absence of a history or
diagnosis of amyloidosis and/or organ damage (e.g. deafness, periorbital edema,
lymphadenopathy, and serositis).
7. Evidence of inflammatory disease activity during the screening period before the
admission to the screening cold challenge, captured by the Physician global assessment of
autoinflammatory disease activity > minimal, recorded at Screening Cold Challenge
Admission visit.
8. Participants who have evidence of inflammatory activity after the screening cold
challenge, as assessed by a relative increase in WCC of at least 40% compared to pre-
challenge.
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1.
2. Anti-rejection and/or immunomodulatory drugs must be discontinued (see Section 6.2.2):
•
Anakinra at least 1 day prior to the screening cold challenge and until study
completion
•
Canakinumab and rilonacept at least 3 half-lives prior to the screening cold challenge,
at least 5 half-lives prior to Day 1 and until study completion
•
Other anti-rejection/immune modulatory therapies at least 3 half-lives prior to
screening cold challenge, at least 5 half-lives prior to Day 1 and until study completion
•
Ad hoc use of anakinra is permitted for the interval between the screening cold
challenge and Day 1, if it can be discontinued at least 5 half-lives prior to Day 1
•
Ad hoc use of paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs, as per
local regulations/practice) is permitted for symptomatic relief
3. Participants currently being treated with drugs known to be strong or moderate inducers of
isoenzyme CYP2C9 and/or strong inhibitors of CYP2C9 and/or strong inducers of
Commercially Confidential Information


Novartis
Confidential
Page 45 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
cytochrome P450, family 3, subfamily A (CYP3A) or dual strong or moderate inhibitors 
of CYP2C9/CYP3A (see list of prohibited drugs Table 6-3) and the treatment cannot be 
discontinued or switched to a different medication by 5 half-lives or 1 week (whichever is 
longer) prior to Day 1 and for the duration of the study.
4. Participation in any other investigational trials within 5 half-lives or within 30 days of 
screening (e.g. investigational small molecules) or until the expected PD effect has 
returned to baseline (e.g. investigational biologics), whichever is longer; or longer if 
required by local regulations with the exception of treatment with anakinra, canakinumab, 
rilonacept and/or other investigational IL-1/NLRP3 binding or blocking therapy.
5. Participants with innate (e.g. Toll-like receptor (TLR) immunodeficiencies, defects in 
interferon-gamma (IFN-γ) signaling) or acquired immune deficiencies (e.g. AIDS).
6. Presence of human immunodeficiency virus (HIV) infection, hepatitis B surface antigen 
(HBsAg) or hepatitis B core antibody (anti-HBc), or hepatitis C antibodies at Screening.
7. Participants who have undergone solid organ or stem cell transplantation.
8. Live vaccines within 4 weeks of Day 1.
9. Clinically significant, suspected active or chronic bacterial (including Mycobacterium 
tuberculosis), viral or fungal infection within 30 days prior to Day 1.
COVID-19 specific: It is highly recommended that testing with polymerase chain reaction 
or other approved diagnostic methodology for COVID-19 to be completed within 1 week 
prior to first dosing. If testing is performed, negative test results are required prior to 
enrolment into the study. Additional testing may occur at the discretion of the investigator. 
If testing is not performed, the investigator must document their discussion with the 
participant regarding testing, and the rationale for not testing, in the source documentation. 
This requirement may be ignored if the pandemic is declared ended by the country where 
the site is located and resumed if the pandemic recurs.
10. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in situ cervical cancer), treated or untreated, within the past 5 years prior to 
Screening, regardless of whether there is evidence of local recurrence or metastases.
11. Absolute peripheral blood neutrophil count of ≤1000/mm3 at Screening, Screening Cold 
Challenge Admission visit and at Day 1 pre-dose.
12. A history of renal disease, including nephrolithiasis, and/or an estimated GFR (eGFR) ≤90 
mL/min/1.73m2 (based on Chronic Kidney Disease Epidemiology Collaboration (CKD-
EPI) formula) at Screening, Screening Cold Challenge Admission visit and at Day 1 pre-
dose.
13. History of clinically significant liver disease or liver injury as indicated at Screening, 
Screening Cold Challenge Admission visit and at Day 1 pre-dose by abnormal liver 
function tests (as defined below) such as aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (ALP), or serum bilirubin. The Investigator 
should be guided by the following criterion:
•
Any single parameter may not exceed 2x upper limit of normal (ULN).
14. History or current diagnosis of ECG abnormalities indicating significant safety risk for 
participant enrolled in the study such as:


Novartis
Confidential
Page 46 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
•
Concomitant clinically significant cardiac arrhythmias; e.g. sustained ventricular 
tachycardia, and clinically significant second- or third-degree atrioventricular block 
without a pacemaker
•
History of familial long QT syndrome or known family history of Torsades de Pointes
15. 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 human 
serum chorionic gonadotropin (hCG) laboratory test.
16. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 10 days after stopping of study treatment. Highly effective 
contraception methods include:
•
Total abstinence from heterosexual intercourse (when this is in line with the preferred 
and usual lifestyle of the participant). Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods 
of contraception.
•
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment.
•
Male sterilization (at least 6 months prior to screening). For female participants on the 
study the vasectomized male partner should be the sole partner for that participant.
•
Use of oral (estrogen and progesterone), 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 have been stable on the same pill 
for a minimum of 3 months before taking study treatment.
•
Based on an in vitro induction of CYP3A4, there is a slight potential risk for a DDI of 
DFV890 with hormonal contraception at high exposures (Section 4.6.8), therefore 
hormonal contraception must be supplemented with a barrier method, preferable a 
male condom.
If local regulations deviate from the contraception methods listed above and require more 
extensive measures to prevent pregnancy, local regulations apply and will be described in 
the informed consent form ICF.
Women are considered post-menopausal and not of child-bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. 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 child-bearing potential. Refer to Section 8.4.3 (Pregnancy and Assessments of 
Fertility).


Novartis
Confidential
Page 47 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
17. Sexually active males unwilling to use a condom during intercourse while taking study 
treatment and for 10 days after stopping study treatment. A condom is required for all 
sexually active male participants to prevent them from fathering a child AND to prevent 
delivery of study treatment via seminal fluid to their partner. In addition, male participants 
must not donate sperm while taking study treatment and for 10 days after stopping study 
treatment.
18. Participants unwilling to comply with restrictions related to use of alcohol (see 
Section 6.2.4.1).
19. Participants with the CYP2C9 *3/*3 genotype defined as homozygous carriers of the 
CYP2C9*3 allele.
20. Donation or loss of 400 mL or more of blood within 8 weeks prior to Screening, or longer 
if required by local regulation, plasma donation (>200 mL) within 30 days prior to Day 1.
21. History of hypersensitivity to any of the study treatments or its excipients or to drugs of 
similar chemical classes.
22. Any significant concurrent medical condition (e.g. anemia) that, in the opinion of the 
investigator, could affect the participant’s ability to tolerate or complete the study.
23. Participants with cold urticaria (e.g. acquired cold urticaria) or immediate systemic 
reactions (e.g. tachycardia, hypotension, fainting) to cold or during aquatic activities
6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for prescribing/dispensing, and taking study treatment are outlined in Section 6.1.1 
and Section 6.7. A separate Pharmacy Manual will not be provided.
6.1.1
Investigational and control drugs
The investigational drug DFV890 25 mg tablets will be provided by Novartis Global Clinical 
Supply. Investigational drug will be supplied to the investigator as open-label 
participant-specific supplies. DFV890 100 mg will be administered orally shortly after 
completion of a meal b.i.d. approximately 12 hours apart (morning and evening). 
The investigational drug should not be stored above 25 °C.
Table 6-1
Investigational drug
Investigational Drug
(Name and Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor 
(global or local)
DFV890 25 mg
Film coated 
tablet
Oral
Open label 
participant-
specific supplies 
Novartis Pharma 
AG
6.1.2
Additional study treatments
No other treatment beyond investigational drug is included in this trial.


Novartis
Confidential
Page 48 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
6.1.3
Treatment arms/group
All study participants will receive 100 mg of DFV890 b.i.d. for 3 days and 100 mg of DFV890 
in the morning on the fourth day, starting on morning of Day 1. At each administration, 4 tablets 
of 25 mg DFV890 each will be taken.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
Participants should remain on their current medication wherever possible for the duration of the 
study; if additions to chronic medications are required, these should be discussed with the 
sponsor.
The investigator must instruct the participants to notify the study site about any new medications 
he/she takes after the participant provided consent to the study.
All relevant medications , procedures, and significant non-drug therapies (including physical 
therapy and blood transfusions) administered from 30 days prior to the participant's consent 
until the Study completion visit must be recorded on the appropriate electronic Case Report 
Forms (eCRF). 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 the Novartis medical monitor before 
enrolling a participant or allowing a new medication to be started. If the participant is already 
enrolled, contact Novartis to determine if the participant should continue participation in the 
study.
Decisions regarding replacements of participants requiring concomitant medication will be 
discussed with the sponsor on a case-by-case basis.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Clinical studies to investigate DDIs with Cytochrome P450 (CYP) substrates/modulators and 
DFV890 have not been performed yet.
Commercially Confidential Information 


Novartis
Confidential
Page 49 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
In this clinical study protocol, modulators (strong or moderate inducers and strong inhibitors) 
of CYP2C9 and/or strong inducers of CYP3A are prohibited (Section 6.2.2) and hormone-based 
contraceptives must be supplemented with a barrier method, preferable a male condom.
Investigators at their discretion may administer concomitant medications known to be 
metabolized by CYP3A4/5. Participants receiving such medications may require dose titration 
or increase of the concomitant drug. Particularly, caution is advised when DFV890 is 
co-administered with drugs that are sensitive substrates of CYP3A and/or have a narrow 
therapeutic index (Table 6-2). Strong and moderate inhibitors of CYP3A should be avoided. If 
they cannot be replaced by other medications, investigators may, after consultation with the 
sponsor, co-administer known strong or moderate inhibitors of CYP3A, but their duration 
should be kept as short as possible, and participants must be closely monitored.
Table 6-2
Concomitant medications to be used with caution
Category
Drug Names
Strong inhibitors of CYP3A
boceprevir, ceritinib, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir1, elvitegravir/ritonavir1, grapefruit juice2, 
idelalisib, indinavir, indinavir/ritonavir1, itraconazole, 
josamycin, ketoconazole, lopinavir/ritonavir1, 
nirmatrelvir/ritonavir1, mibefradil, mifepristone, nefazodone, 
nelfinavir, ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira 
Pak)1, posaconazole, ribociclib, ritonavir, saquinavir, 
saquinavir/ritonavir1, telaprevir, telithromycin, 
tipranavir/ritonavir1, troleandomycin, tucatinib, voriconazole
Moderate inhibitors of CYP3A
aprepitant, amprenavir, atazanavir, atazanavir/ritonavir1, 
casopitant, cimetidine, ciprofloxacin, crizotinib, darunavir, 
darunavir/ritonavir1, diltiazem, dronedarone, duvelisib, 
erythromycin, faldaprevir, fedratinib, grapefruit juice, imatinib, 
isavuconazole, istradefylline, lefamulin, letermovir, Magnolia 
vine (Schisandra sphenanthera)3, netupitant, nilotinib, 
ravuconazole, tofisopam, verapamil, voxelotor
Narrow therapeutic index 
substrates of CYP3A
abemaciclib, acalabrutinib, alectinib amiodarone, 
amitriptyline, astemizole, axitinib, baricitinib, bosutinib, 
brigatinib, cabazitaxel, cabozantinib, ceritinib, clomipramine, 
cobimetinib, conivaptan, copanlisib, crizotinib, cyclosporine, 
dabrafenib, dasatinib, dihydroergotamine, docetaxel, 
dronedarone, entrectinib, erdafitinib, ergotamine, everolimus, 
imipramine, ixazomib, lomitapide, midostaurin, neratinib, 
nilotinib, panobinostat, pexidartinib, pimozide, ponatinib, 
quinidine, regorafenib, romidepsin, sirolimus, sonidegib, 
sorafenib, sunitinib, tacrolimus, tamoxifen, temsirolimus, 
tolvaptan, trabectedin, venetoclax, vinblastine, zanubrutinib
Commercially Confidential Information


Novartis
Confidential
Page 50 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Category
Drug Names
Sensitive substrates of CYP3A
abemaciclib, acalabrutinib, alisporivir, almorexant, alfentanil, 
alpha-dihydroergocryptine, aplaviroc, aprepitant, asunaprevir, 
atazanavir, atorvastatin, avanafil, avapritinib, blonanserin, 
bosutinib, brecanavir, brigatinib, brotizolam, budesonide, 
buspirone, cabazitaxel, capravirine, casopitant, cobicistat, 
cobimetinib, conivaptan, cyclosporine, danoprevir, 
darifenacin, darunavir, dasatinib, dronedarone, ebastine, 
eletriptan, eliglustat, elvitegravir, entrectinib, eplerenone, 
everolimus, felodipine, fluticasone, grazoprevir, ibrutinib, 
indinavir, isavuconazole, itacitinib, ivabradine, ivacaftor, 
levomethadyl (LAAM), lomitapide, lopinavir, lovastatin, 
lumefantrine, lurasidone, maraviroc, midazolam, midostaurin, 
morphothiadin, naloxegol, neratinib, nisoldipine, paritaprevir, 
perospirone, quetiapine, ridaforolimus, saquinavir, sildenafil, 
simeprevir, simvastatin, sirolimus, tacrolimus, ticagrelor, 
tilidine, tipranavir, tolvaptan, triazolam, ubrogepant, ulipristal, 
vardenafil, venetoclax, vicriviroc, vilaprisan, voclosporin, 
voriconazole, zanubrutinib
1 Combination therapy
2 The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparation-dependent
3 Herbal product
6.2.2
Prohibited medication
Use of topical and systemic treatments displayed in the below table are not allowed during the 
time period noted below.
Novartis qualified medical personnel will be readily available to advise investigators on trial 
related medical questions about concomitant therapy and prohibited medications.
Table 6-3
Prohibited medication
Medication
Prohibition period
Action taken
Anakinraa
At least 1 day prior to 
screening cold challenge,
at least 1 day prior to Day 1 
and until study completion
Screen fail participant/
Discontinue study treatment
Canakinumab
At least 3 half-lives (78 days) 
prior to screening cold 
challenge,
at least 5 half-lives (130 days) 
prior to Day 1 and until study 
completion
Screen fail participant/
Discontinue study treatment
Rilonacept
At least 3 half-lives (26 days) 
prior to screening cold 
challenge,
at least 5 half-lives (43 days) 
prior to Day 1 and until study 
completion
Screen fail participant/
Discontinue study treatment


Novartis
Confidential
Page 51 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Medication
Prohibition period
Action taken
Other anti-rejection/immune 
modulatory therapies
At least 3 half-lives prior to 
screening cold challenge,
at least 5 half-lives prior to 
Day 1 and until study 
completion
Screen fail participant/
Discontinue study treatment
Live vaccineb
Four weeks prior to Day 1 (first 
DFV890 dose) until study 
completion
Screen fail participant/
Discontinue study treatment
Strong or moderate inducers of 
CYP2C9 or strong inducers of 
CYP3A including, but not 
limited to apalutamide, 
avasimibe, carbamazepine, 
enzalutamide, ivosidenib, 
lumacaftor, mitotane, 
phenobarbital, phenytoin, 
rifampicin, rifapentine and St. 
John’s wort (Hypericum 
perforatum)
5 half-lives or 1 week 
(whichever is longer) prior to 
Day 1 (first DFV890 dose) until 
study completion
Screen fail participant/
Discontinue study treatment
Strong inhibitors of CYP2C9 or 
dual strong or moderate 
inhibitors of CYP2C9/CYP3A 
(including, but not limited to 
miconazole, sulfaphenazole, 
fluconazole, tasisulam)
5 half-lives or 1 week 
(whichever is longer) prior to 
Day 1 (first DFV890 dose) until 
study completion
Screen fail participant/
Discontinue study treatment
Other investigational products
5 half-lives or within 30 days of 
screening visit (e.g. small 
molecules) or until the 
expected PD effect has 
returned to baseline 
(e.g. biologics), whichever is 
longer; or longer if required by 
local regulations, until study 
completion
Screen fail participant/
Discontinue study treatment
a Ad hoc use of anakinra is permitted for the interval between the screening cold challenge and Day 
1, if it can be discontinued at least 5 half-lives prior to Day 1. Ad hoc use of paracetamol and NSAIDs 
is permitted for symptomatic relief or as recue medication (as per local regulations/practice) 
(Section 6.2.3).
b No live vaccinations within 4 weeks prior Day 1 (first dose of DFV890) until study completion. 
Approved killed, inactivated, peptide, deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) 
vaccines may be permitted according to the investigator's discretion and per local guidance.
6.2.3
Rescue medication
The use of paracetamol/acetaminophen or NSAID is allowed as rescue medication for 
symptomatic relief.
Ad hoc use of anakinra is permitted for the interval between the screening cold challenge and 
Day 1, if it can be discontinued at least 5 half-lives prior to Day 1.
Any use of rescue medication must be recorded on the appropriate eCRF.


Novartis
Confidential
Page 52 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
6.2.4
Restriction for study participants
For the duration of the study, participants should be informed and reminded of the restrictions 
outlined in this section.
6.2.4.1
Dietary restrictions and smoking
1. No alcohol use 24 hours prior to and during the first cold challenge and for 48 hours 
thereafter. No alcohol use 24 hours prior to the initiation of the treatment, during treatment 
and until 48 hours after the second cold challenge.
2. Grapefruit or grapefruit juice should not be consumed for 14 days prior to dosing until 
7 days following the last dose.
3. Participants should take DFV890 b.i.d. at approximately the same time each day (±1 hour 
if possible) in the morning and evening shortly after completion of a meal and with a glass 
of water. The morning meal should consist of at least a continental breakfast.
6.2.4.2
Other restrictions
•
Participants will be required to adhere to the measures and procedures outlined by the 
study site, to prevent SARS-CoV-2 infections among trial participants and clinical site 
staff.
•
Strenuous physical exercise (e.g. heavy weight training, aerobics, football) should not be 
performed within 24 hours prior to any study visit, during the two cold challenges and 
during the treatment period.
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the ICF, the participant is assigned to the next 
sequential Participant No. available.
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No.
6.3.2
Treatment assignment, randomization
This is an open label single arm study. No randomization will be performed.
6.4
Treatment blinding
Not applicable.


Novartis
Confidential
Page 53 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
6.5
Dose escalation and dose modification
Investigational treatment dose adjustments and/or interruptions are not permitted. In the case 
that the Day 3 /Admission visit must be delayed, the treatment should be prolonged with one 
day (b.i.d. Day 4, once daily Day 5). This option should only be used under exceptional 
circumstances.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. Participants will be provided with a diary to capture date 
and time of study treatment intake as well to confirm the study treatment was taken shortly after 
completion of a meal. All completed diaries will be kept at the site as source documentation. 
The diaries will not be collected by the sponsor. The participant must also be instructed to 
contact the investigator if he/she is unable for any reason to take the study treatment as 
prescribed. Compliance will be assessed by the investigator and/or study personnel at each visit 
using pill counts (if applicable) and information provided by the participant. This information 
should be captured in the source document at each visit. All study treatment dispensed and 
returned must be recorded in the Drug Accountability Log.
6.6.2
Recommended treatment of adverse events
Treatment and management of skin rashes
The following recommendations for managing potential suspected DFV890-related skin rashes 
are provided.
Depending on severity, investigators can consider as per medical judgment early treatment of 
mild rashes (maculopapular rash covering < 10% body surface area with or without symptoms 
(e.g. pruritus, burning)) with symptomatic treatment (e.g. topical steroids) with close 
monitoring of the participant’s response.
For skin rashes covering > 10% body surface area, investigators should discontinue DFV890 
and closely monitor participants to ensure resolution of the rash. In the case of participants with 
systemic or cutaneous signs or symptoms suggesting a severe cutaneous reaction, a short course 
of systemic corticoids steroid (e.g. prednisone 1 to 2 mg/kg per day for five to seven days) may 
be considered.
Treatment of Overdose
There is no clinical experience with DFV890 overdose. Should an overdose occur, the 
participant should be carefully monitored for any potential symptoms, and if necessary, 
appropriate supportive care should be provided until the participant has recovered.
At present there is insufficient information to provide specific recommendations regarding 
treatment of other potential AEs in this patient population. Medication used to treat AEs must 
be recorded on the Concomitant medications/Significant non-drug therapies eCRF.


Novartis
Confidential
Page 54 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
6.6.3
Emergency breaking of assigned treatment code
Not applicable.
6.7
Preparation and dispensation
Each study site will be supplied with study treatment in packaging as described under 
investigational and control drugs section (Section 6.1.1).
A unique medication number is printed on the study treatment label. Investigator staff will 
dispense the study treatment to the participant. The study treatment has a 2-part label (base plus 
tear-off label), immediately before dispensing the bottle to the participant, site personnel will 
detach the outer part of the label from the bottle and affix it to the participant’s source document.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all investigational treatment must be stored according 
to the instructions specified on the labels.
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization (CO) Quality Assurance.
Medication labels will be in the local language (or in English in case allowed according to local 
regulation) and comply with the legal requirements of each country. They will include storage 
conditions for the investigational treatment but no information about the participant except for 
the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of 
investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by monitors during site visits or remotely and at the completion of the trial. 
Participants will be asked to return all unused investigational treatment upon last dose.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused investigational treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address provided 
in the investigator folder at each site. Alternatively following written approval from the Sponsor, 
destruction of all unused study treatment and packaging/drug labels may be performed at the 
site as per the site's Standard Operating Procedure (SOP). A copy of the destruction form and 
final drug accountability will then be provided to the Novartis address provided in the 
Investigator folder at the site.
6.7.2
Instruction for prescribing and taking study treatment
Participants should take DFV890 b.i.d. at approximately the same time each day (+/- 1 hour if 
possible) in the morning and evening shortly after completion of a meal and with a glass of 
water. The morning meal should consist of at least a continental breakfast.
Participants should be instructed to swallow whole tablets and not to chew them.


Novartis
Confidential
Page 55 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
If vomiting occurs during the course of treatment, participants should not take the study 
treatment again before the next scheduled dose.
Participants should be instructed not to make up missed doses. A missed dose is defined as a 
case when the full dose is not taken within 4 hours after the approximate time of the usually 
daily dosing. That dose should be omitted, and the participant should continue treatment with 
the next scheduled dose.
The first dose will be administered in the clinic, subsequent doses on Day 1 and 2 will be 
self-administered by the participant. Participants will be provided with individual diary cards 
to record each intake of study treatment and to confirm that study treatment was taken shortly 
after completion of a meal. The diary will be checked by site staff on Day 3. 
On Day 3, the participant will administer the morning and evening dose of DFV890 after 
admission to the clinic, when instructed by the study staff. The last dose will be administered 
on the morning of Day 4. Participants will be provided a breakfast which should be consumed 
within 30 minutes. The study treatment should be administered within 5 minutes after 
completion of the meal.
Table 6-4
Dose and treatment schedule
Investigational Drug
(Name and Strength)
Dose
Frequency and/or Regimen
DFV890 25 mg
100 mg (4 x 25 mg)
Twice daily (Day 1-3)
Once daily (Day 4)
7
Informed consent procedures
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
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 participant source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed 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 
participant informed consent and should be discussed with the participant 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 (IN) or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the participant.
The investigator may conduct any informed consent discussion remotely (e.g. via telephone or 
videoconference) where feasible as per medical judgment. Guidance issued on this by local 
regulatory bodies prevails and must be appropriately implemented and documented (e.g. the 


Novartis
Confidential
Page 56 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
presence of an impartial witness, sign/dating separate ICFs by trial participant and person 
obtaining informed consent, etc.).
The following informed consents are included in this study:
•
Main study consent, which also includes: 
•
A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study
•
Optional consent for activities that may be done outside of the study site
•
As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment
•
Patient information sheet for female partners of any male participants who took study 
treatment
•
 
Women of child bearing 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.
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
The study includes the option for the participant to have certain study procedures performed 
off-site by an off-site healthcare professional instead of at the study site, for which a separate 
signature is required if the participant agrees, as permitted by national and local governing 
regulations. The process for obtaining consent should be exactly the same as described above 
for the main informed consent.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 57 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments and when they are performed. 
All data obtained from these assessments must be supported in the participant’s source 
documentation.
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Participants 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 eCRF. 
Unscheduled visits and the Study completion visit may be performed at an alternative Sponsor-
approved site (e.g. satellite site that may be more convenient to the participant) if agreed by the 
principal investigator who will maintain the investigator responsibilities, and only as permitted 
by local regulations. 
As per Section 4.4, during a public health emergency as declared by local or regional authorities 
(i.e. pandemic, epidemic or natural disaster) that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowable by a local health authority, national and local regulations and 
depending on operational capabilities, phone calls, virtual contacts (e.g. tele consultation) or 
visits by site staff/ off-site healthcare professional(s) staff to the participant´s home, can replace 
certain protocol assessments, for the duration of the disruption until it is safe for the participant 
to visit the site again. If the investigator delegates tasks to an off-site healthcare professional, 
the investigator must ensure the individual(s) is/are qualified and appropriately trained to 
perform assigned duties. The investigator must oversee their conduct and remain responsible 
for the evaluation of the data collected.


Novartis
Confidential
Page 58 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Table 8-1
Assessment Schedule
Epoch
Screening27
Open Label Treatment
Visit Name
Screening
Admission 
18,19
Screening Cold 
Challenge18
Discharge 
18
Day 
12,20
Day 
3/Admission3,4
Day 4/ Cold Challenge
Day 
5/Discharge
Rash 21, 22
Visit Numbers1
1
2
3
4
101
102
103
104
105
Days -183 to -11
-10
-9
-8
1
3
4
5
unscheduled
Time (post-dose)26
-
-
-1h 0h 1h 2h 3h 5h 9h
24h
-
-
-1h 0h 1h 2h 3h 5h 9h
24h
-
Informed consent
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion criteria
X
X
 
 
 
 
 
 
 
 
X
 
 
 
 
 
 
 
 
 
 
Medical 
history/current 
medical conditions
X
 
 
 
 
 
 
 
 
 
X
 
 
 
 
 
 
 
 
 
 
Smoking history
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis and HIV 
Screen
S
 
 
 
 
 
 
 
 
 
S23 
 
 
 
 
 
 
 
 
 
 
Tuberculosis test
S
 
 
 
 
 
 
 
 
 
S23
 
 
 
 
 
 
 
 
 
 
Pregnancy test and 
assessment of 
fertility25
S
S
 
 
 
 
 
 
 
 
S
 
 
 
 
 
 
 
 
 
 
Physical 
Examination (full)
S
 
 
 
 
 
 
 
 
 
S
 
 
 
 
 
 
 
 
 
 
Physical 
Examination (short)
 
 
S
 
 
S
S
S
S
S
 
S
S
 
 
S
S
S
S
S
S
Vital signs and 
body 
measurements
X
X
X
 
S16 X
X
X
X
X
X
X
X
 
S16 X
X
X
X
X
X
Body Height
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight
X
X
 
 
 
 
 
 
 
 
X
 
 
 
 
 
 
 
 
 
 
Commercially Confidential Information


Novartis
Confidential
Page 59 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Epoch
Screening27
Open Label Treatment
Visit Name
Screening
Admission 
18,19
Screening Cold 
Challenge18
Discharge 
18
Day 
12,20
Day 
3/Admission3,4
Day 4/ Cold Challenge
Day 
5/Discharge
Rash 21, 22
Visit Numbers1
1
2
3
4
101
102
103
104
105
Days -183 to -11
-10
-9
-8
1
3
4
5
unscheduled
Time (post-dose)26
-
-
-1h 0h 1h 2h 3h 5h 9h
24h
-
-
-1h 0h 1h 2h 3h 5h 9h
24h
-
Electrocardiogram 
(ECG)
X
 
 
 
 
 
 
 
 
 
X
X
 
 
 
 
 
 
 
 
 
Participants 
domiciled6
 
S
 
S
 
 
Study drug 
administration
 
 
 
 
 
 
 
 
 
 
X
X
 
X
 
 
 
 
 
 
 
Meal record
 
 
 
S
 
 
 
 
 
 
S
 
 
Cold challenge7
 
 
 
 
X
 
 
 
 
 
 
 
 
 
X
 
 
 
 
 
 
Patients Global 
Assessment of 
Disease Activity
 
 
X
 
 
X
X
X
X
X
X
X
X
 
 
X
X
X
X
X
 
Physician Global 
Assessment of 
Autoinflammatory 
Disease Activity
 
X17
X
 
 
X
X
X
X
X
X
X
X
 
 
X
X
X
X
X
 
Physician's Severity 
Assessment of 
Autoinflammatory 
Disease Signs and 
Symptoms
 
 
X
 
 
X
X
X
X
X
X
X
X
 
 
X
X
X
X
X
 
Urinalysis
X
X
 
 
 
 
 
 
 
X24
X
X
 
 
 
 
 
 
X
X
Hematology
X
X
 
 
 
 
 
 
 
X24
 
X
 
 
 
 
 
 
X
X
Clinical Chemistry
X
X
 
 
 
 
 
 
 
X24
 
X
 
 
 
 
 
 
X
X
Commercially Confidential Information


Novartis
Confidential
Page 60 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Epoch
Screening27
Open Label Treatment
Visit Name
Screening
Admission 
18,19
Screening Cold 
Challenge18
Discharge 
18
Day 
12,20
Day 
3/Admission3,4
Day 4/ Cold Challenge
Day 
5/Discharge
Rash 21, 22
Visit Numbers1
1
2
3
4
101
102
103
104
105
Days -183 to -11
-10
-9
-8
1
3
4
5
unscheduled
Time (post-dose)26
-
-
-1h 0h 1h 2h 3h 5h 9h
24h
-
-
-1h 0h 1h 2h 3h 5h 9h
24h
-
Mandatory CYP2C9 
genotyping for 
confirmation of 
eligibility5
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Events
As Required
Serious Adverse 
Events
As Required
Concomitant 
medications
As Required
Study completion 
information
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Follow up 
Call
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Commercially Confidential Information


Novartis
Confidential
Page 61 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Epoch
Post-Treatment Follow-Up
Post-Treatment Follow-Up
Visit Name
Study Completion14, 22
Post Study Safety Contact15
Visit Numbers1
201
301
Days
14
-0 +7
34
±3
Time (post-dose)
-
-
Informed consent
 
 
Inclusion / Exclusion criteria
 
 
Medical history/current medical conditions
 
 
Smoking history
 
 
Demography
 
 
Hepatitis and HIV Screen
 
 
Tuberculosis test
 
 
Pregnancy test and assessment of fertility25
S
 
Physical Examination (full)
 
 
Physical Examination (short)
S
 
Vital signs and body measurements
X
 
Body Height
 
 
Body Weight
 
 
Electrocardiogram (ECG)
X
 
Participants domiciled6
 
 
Study drug administration
 
 
Commercially Confidential Information


Novartis
Confidential
Page 62 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Epoch
Post-Treatment Follow-Up
Post-Treatment Follow-Up
Visit Name
Study Completion14, 22
Post Study Safety Contact15
Visit Numbers1
201
301
Days
14
-0 +7
34
±3
Time (post-dose)
-
-
Meal record
 
 
Cold challenge7
 
 
Patients Global Assessment of Disease Activity
X
 
Physician Global Assessment of Autoinflammatory 
Disease Activity
X
 
Physician's Severity Assessment of Autoinflammatory 
Disease Signs and Symptoms
X
 
Urinalysis
X
 
Hematology
X
 
Clinical Chemistry
X
 
White Cell Count with differentials8
X
 
Adverse Events
As Required
Serious Adverse Events
As Required
Concomitant medications
As Required
Study completion information
X
 
Safety Follow up Call
 
S
Commercially Confidential Information


Novartis
Confidential
Page 63 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Visit Numbers given for internal programming purpose only
2 Assessments to be conducted prior to first dose
3 Assessments to be conducted prior to the morning dose
4 Admission can be delayed with a maximum of one day and treatment hence prolonged to with one day. This option should only be used under exceptional 
circumstances 
5 To confirm eligibility, available historical CYP2C9 genotyping results confirming the absence of the CYP2C9*3/*3 variant previously issued in frame of this study are 
acceptable for re-screened participants
6 Participant domiciliation may be prolonged at the discretion of the investigator and patient
7 The start of the cold challenge is at 1 h and the duration is 45 minutes. The screening cold challenge should be initiated 1 h after meal and treatment cold challenge 1 h 
after treatment administration.
8 Where possible, white cell count should be included as part of hematology sampling, rather than collecting a separate sample
9
10 To be collected at 0 h prior to morning dose and 12 h after previous evening dose the day before
11 To be collected at 1 h postdose, prior to initiation of cold challenge
12
13
14 Also applicable in case of early discontinuation
15 30 days after last dose
16 Vital signs to be collected every 10 minutes during the cold challenge and at the end of the cold challenge
17 The Physician Global Assessment of Autoinflammatory Disease Activity conducted at the Screening Cold Challenge Admission visit must capture evidence of disease 
flare (> minimal) occurring during the screening period
18 The screening cold challenge can be conducted any time during the screening period (the visits “Admission”, “Screening Cold Challenge” and “Discharge” must occur 
on 3 consecutive days), provided that Day 1 is conducted within 6 months (and within 12 months for participants with a historical screening cold challenge prior to protocol 
amendment 04) of the Screening visit
19 Participants can be admitted to the Screening Cold Challenge visit only when all eligibility criteria are confirmed, except inclusion criterion 8 which is assessed during 
the screening cold challenge
20 Participants can enter the treatment period after at least one week of recovery after the Screening Cold Challenge Discharge visit
21 An unscheduled visit should be considered based on clinical findings and severity of rash or pruritus
22 May be performed at an alternative Sponsor-approved site (e.g. satellite site that may be more convenient to the participant) if agreed by the principal investigator who 
will maintain the investigator responsibilities, and only as permitted by local regulations
23 Hepatitis and HIV Screen, tuberculosis test may be repeated according to the investigator’s discretion, if performed more than 6 months prior to Day 1
24 Hematology, clinical chemistry and urinalysis results must be available before the first dose is administered on Day 1 to confirm eligibility of the participant. For logistical 
reasons sampling may be performed the day before Day 1 instead of Day 1
25 Serum pregnancy test should be performed at Screening and Study completion visits, urine pregnancy test at all other visits
26 The sampling time points during the screening period are referring to pre/post-meal, since there is no dose administered during the screening period
27 The screening period is up to 6 months (and up to 12 months for participants with a historical screening cold challenge prior to protocol amendment 04)
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 64 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
8.1
Screening
Screening
It is permissible to re-screen a participant if s/he fails the assessments done during the screening 
period; however, each case must be discussed and agreed with the Sponsor on a case-by-case 
basis.
In the case where a safety laboratory assessment at screening is outside of the range specified 
in the exclusion criteria, the assessment may be repeated once prior to enrolment. If the repeat 
value remains outside of the specified ranges, the participant must be excluded from the study.
8.1.1
Eligibility screening
8.1.1.1
Hepatitis screen, HIV screen
All participants will be screened for Hepatitis B surface antigen (HBsAg) and, if standard local 
practice, Hepatitis B core antigen (HBcAg). Screening for Hepatitis C will be based in 
Hepatitis C Virus (HCV) antibodies and if positive, HCV RNA levels should be determined.
Evaluation for HIV seropositivity will be performed, and, if positive, confirmation by a second 
technique available at the laboratory site; e.g. Western blot. Appropriate counseling will be 
made available by the Investigator in the event of a positive confirmatory test. Notification of 
state and federal authorities, as required by law, will be the responsibility of the Investigator.
Samples will be collected and processed according to local procedures and analyzed at the local 
laboratory.
Hepatitis and HIV Screen may be repeated according to the investigator’s discretion, if 
performed more than 6 months prior to Day 1.
8.1.1.2
Tuberculosis (TB) testing
In order to evaluate the tuberculosis (TB) status of the participants, a TB test should be performed at 
Screening as per local regulations/guidelines using one or both of the following methods:
•
QuantiFERON®-TB assay
•
Tuberculin skin testing
Samples will be collected and processed according to local procedures and analyzed at the local 
laboratory. Negative test results from the previous 3 months may be used if available. 
Tuberculosis test may be repeated according to the investigator’s discretion, if performed more than 
6 months prior to Day 1.
Any significant findings will be recorded in the Relevant medical history/Current medical conditions 
section of the eCRF as necessary.
8.1.2
Information to be collected on screening failures
Participants who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. This applies also to participants who are considered screen failures 
after the screening cold challenge. The reason for screen failure should be entered on the 


Novartis
Confidential
Page 65 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
applicable eCRF. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure participants. Additional data may be entered to 
support the eligibility decision, such as – but not limited to – medical history, relevant prior and 
concomitant medications, hematology, clinical chemistry. SAEs will also be collected for 
screen failed participants (see SAE section (Section 10.1.3) for reporting details).
Participants who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason will be considered an early terminator. The reason for early termination 
should be captured on the appropriate disposition eCRF.
8.2
Participant demographics/other baseline characteristics
Demographic information
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with eCRF. Participant race and ethnicity are collected and 
analyzed to identify variations in safety or efficacy due to these factors as well as to assess the 
diversity of the study population as required by Health Authorities.
Participant demographics: year of birth (age), sex, race, predominant ethnicity (if permitted), 
child-bearing potential (women only), relevant medical history/current medical conditions 
(until date of signature of informed consent), specific NLRP3 mutation (if available) and 
nicotine use will be recorded in the eCRF. Where possible, the diagnosis and not symptoms 
should be recorded. Vaccination status (12 months prior to the participant’s consent until the 
Study completion visit) should be recorded as part of the collection of medical history/current 
medical conditions. 
All prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start of the study must be documented. See the protocol Section 6.2.1 Concomitant Therapy 
for further details on what information must be recorded on the appropriate page of the eCRF.
FCAS medical history and diagnosis
The following should be recorded in the participants medical records
•
Molecular diagnosis of NLRP3 mutations
•
Absence of L353P mutation
•
Presence of mutation with documented responsiveness to DFV890 in ex vivo testing if 
available
•
Clear documentation of use of and response to previous treatment therapeutics targeting 
the IL-1β pathway if available
•
Presence of active disease following discontinuation of current treatment as outlined in 
Section 5.1.
•
Any available documentation of previous medical assessments (e.g. auditory brainstem 
response, neurological and ophthalmological assessments) to document absence of organ 
damage and/or amyloidosis


Novartis
Confidential
Page 66 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
8.3
Efficacy
Efficacy assessments will be performed at the timepoints defined in the Assessment Schedule 
(Table 8-1).
8.3.1
Inflammatory markers
WCC (primary endpoint) 
 
 will be assessed at the timepoints defined in the Assessment Schedule (Table 8-1). 
Samples will be collected and processed according to local procedures and analysed at the local 
laboratory. Where possible, WCC, 
 will be included as part of hematology and 
clinical chemistry sampling respectively, rather than collecting separate samples.
8.3.2
Clinical Outcome Assessments (COAs)
Two Clinician Reported Outcomes (ClinRO), the physician global assessment of 
autoinflammatory disease activity and physician's severity assessment of autoinflammatory 
disease signs and symptoms, as well as one Patient reported outcomes (PRO), the patient’s 
global assessment of disease activity, are described in this section.
As per Section 4.4, during a public health emergency as declared by local or regional authorities 
(i.e. pandemic, epidemic or natural disaster) that limits or prevents on-site study visits, COA 
data may be collected remotely.
Physician global assessment of autoinflammatory disease activity
The physician global assessment on autoinflammatory disease activity (secondary endpoint and 
to confirm participant eligibility (Section 5.1)) will be performed at the timepoints defined in 
the Assessment Schedule (Table 8-1). The assessment recorded at the Admission visit prior to 
the screening cold challenge captures evidence of symptoms occurring during the screening 
period. It is encouraged that the same Investigator assesses the participant throughout the study 
to ensure consistency between assessments.
The physician global assessment on autoinflammatory disease activity will be based on a 
5-point scale of disease-associated clinical signs and symptoms (see Section 16.4):
0 = Absent
1 = Minimal
2 = Mild
3 = Moderate
4 = Severe
The assessments will be entered in the eCRF. In case an alternative Sponsor-approved site is 
utilized (e.g. satellite site that may be more convenient to the participant), the main site principal 
investigator must consult with the additional site investigator either during or shortly after the 
participant visit to consult and document a signed agreement on the outcome of the physician 
global assessment of autoinflammatory disease activity.
Commercially Confidential Information
CCI


Novartis
Confidential
Page 67 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Physician's Severity Assessment of Autoinflammatory Disease Signs and 
Symptoms
Physician’s severity assessment of autoinflammatory disease signs and symptoms (secondary 
endpoint) will be performed at the timepoints defined in the Assessment Schedule (Table 8-1). 
It is encouraged that the same Investigator assesses the participant throughout the study to 
ensure consistency between assessments.
The following items will be assessed using a 5-point scale (ranging from absent to severe, see 
Section 16.5):
•
Assessment of skin disease (urticarial skin rash)
•
Assessment of arthralgia
•
Assessment of myalgia
•
Assessment of headache/migraine
•
Assessment of conjunctivitis
•
Assessment of fatigue/malaise
•
Assessment of other symptoms related to autoinflammatory syndrome
•
Assessment of other symptoms not related to autoinflammatory syndrome
The assessments will be entered in the eCRF. In case an alternative Sponsor-approved site is 
utilized (e.g. satellite site that may be more convenient to the participant), the main site principal 
investigator must consult with the additional site investigator either during or shortly after the 
participant visit to consult and document a signed agreement on the outcome of the physician's 
severity assessment of autoinflammatory disease signs and symptoms.
Patients Global Assessment of Disease Activity
Patient’s global assessment of disease activity (secondary endpoint) will be collected by a 
handwritten diary. The diary will be completed by the participant prior to any clinical 
assessments at the timepoints defined in the Assessment Schedule (Table 8-1). The investigator 
or site staff should not give verbal or non-verbal cues to influence the answers to the diary. 
The investigator or site staff will only be allowed to review the diary for completeness. 
The Investigator will review the participant’s diary before performing the Physician's global 
assessment of autoinflammatory disease activity.
The patient global assessment on disease activity will be based on a 5-point scale of disease-
associated clinical signs and symptoms (see Section 16.6):
0 = Absent
1 = Minimal
2 = Mild
3 = Moderate
4 = Severe
The diary will be transcribed into the eCRF by the site staff.


Novartis
Confidential
Page 68 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
8.3.4
Appropriateness of efficacy assessments
The efficacy endpoints selected for this study are clinically relevant and in line with those used 
in 
other 
studies 
of 
patients 
with 
CAPS 
(e.g. 
ACZ885D2307, 
NCT00288704 
(Hoffman et al 2008))
8.4
Safety
Safety assessments are specified below with the assessment schedule (Table 8-1) detailing 
when each assessment is to be performed.
For details on AE collection and reporting, refer to AE section (Section 10).
As per Section 4.4, during a public health emergency as declared by local or regional authorities 
(i.e. pandemic, epidemic or natural disaster) that limits or prevents on-site study visits, regular 
phone or virtual calls can occur for safety monitoring and discussion of the participant´s health 
status until it is safe for the participant to visit the site again.
Commercially Confidential Information


Novartis
Confidential
Page 69 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Table 8-2
Assessments and Specifications
Assessment
Specification
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.
A short physical exam will include the examination of general 
appearance and the skin. 
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 eCRF that captures medical history. Significant findings 
made after signing informed consent which meet the definition of an AE 
must be recorded as an AE.
Vital Signs 
Vital signs will include the collection of 
, blood pressure 
(BP) and pulse measurements.
After the participant has been sitting for 3 minutes, with back supported 
and both feet placed on the floor, systolic and diastolic BP will be 
measured using an automated validated device with an appropriately 
sized cuff. In case the cuff sizes available are not large enough for the 
participant's arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used.
During the cold challenge the site staff must continuously monitor the 
participant’s vital signs, collecting them at least every 10 minutes and at 
the end of the cold challenge. Equipment used during the cold challenge 
may differ from the one mentioned above.
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram 
(kg) in indoor clothing, but without shoes) will be measured.
BMI will be calculated using the formula below and rounded to the 
nearest whole number:
BMI = Body weight (kg) / [Height (m)]2
The Screening Visit height measurement will be used for BMI 
calculations throughout the study. 
8.4.1
Laboratory evaluations
Blood and urine samples for the evaluation of safety will be collected at the timepoints defined 
in the Assessment Schedule (Table 8-1) in accordance with local procedures and analyzed at 
the local laboratory. Additional parameters may be measured as part of a standard laboratory 
panel as per local practice however not entered into the eCRF. This would not be considered a 
protocol deviation.
Results will be entered into the eCRF with the exception of the results of the pregnancy test that 
is recorded in medical records only. Clinically significant abnormalities must be recorded as 
either medical history/current medical conditions or AEs as appropriate.
Commercially Confidential Information
CCI


Novartis
Confidential
Page 70 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
In the case where a laboratory range is not specified by the protocol, but a value is outside the 
reference range for the laboratory at screening, a decision regarding whether the result is of 
clinical significance or not shall be made by the investigator (in consultation with the sponsor) 
and shall be based, in part, upon the nature and degree of the observed abnormality. 
The assessment may be repeated once prior to enrollment. In all cases, the Investigator must 
document in the source documents, the clinical considerations (i.e. result was/was not clinically 
significant and/or medically relevant) in allowing or disallowing the participant to continue in 
the study.
All abnormal lab results must be evaluated for criteria defining an AE and reported as such if 
the criteria are met. For those lab AEs, repeated evaluations are mandatory until normalization 
of the result(s) or until the result is no longer considered to be clinically significant.
As per Section 4.4, during a public health emergency as declared by local or regional authorities 
(i.e. pandemic, epidemic or natural disaster) that limits or prevents on-site study visits, if 
participants cannot visit the site for protocol-specified safety lab assessments, an alternative lab 
(local) collection site may be used.
Urinalysis
A midstream urine sample (approx. 30 mL) will be obtained, in order to avoid contamination 
with epithelial cells and sediments and allow proper assessments. Please follow local 
procedures for analysis.
Table 8-3
Clinical Laboratory Safety Assessments (local)
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils)
Chemistry
Albumin (ALB), ALP, ALT, AST, Gamma-glutamyl transferase (G-GT), 
Lactate dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, 
Phosphorus, Sodium, Potassium, Creatinine, Creatine kinase (CK), Total 
Bilirubin (TBL)a, Total Protein, Triglycerides, BUN or Urea, Uric Acid, 
Amylase, Lipase, Glucose (fasting or non-fasting), SAA, hsCRP
Urinalysis
Microscopic Panel (Red Blood Cells, White Blood Cells, Casts, Crystals, 
Bacteria, Epithelial cells)
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, 
Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
Coagulation b
Prothrombin time (PT), International normalized ratio (INR), Partial 
thromboplastin time (PTT), Activated partial thromboplastin time (APTT) 
Pregnancy Test
Serum pregnancy test
a If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, direct and 
indirect reacting bilirubin should be differentiated
b Coagulation assessment should include only those tests routinely performed according to local 
standard of care


Novartis
Confidential
Page 71 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
8.4.2
Electrocardiogram (ECG)
ECGs must be recorded after 10 minutes of rest in the supine position to ensure a stable baseline. 
In the case of a series of assessments, ECG should be first assessment obtained while the 
participant is at rest.
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
Unless auto-calculated by the ECG machine, the investigator must calculate QTcF at the 
Screening visit to assess eligibility according to the following formula:
Single 12-lead ECGs are to be collected with ECG machines available at the site. Single 12‑lead 
ECGs are collected, and results are entered into the appropriate eCRF page. The original ECGs 
on non-heat-sensitive paper and a certified copy on non-heat sensitive paper, appropriately 
signed, must be collected and archived at the study site.
Each ECG tracing must be labeled with study number, participant initials, participant number, 
date and time, and filed in the study site source documents.
Investigator should document clinical evaluation in source. For any ECGs with 
participant safety concerns, two additional ECGs must be performed to confirm the safety 
finding. Clinically significant ECG findings at Day 1 must be discussed with the sponsor before 
administration of study treatment.
Clinically significant abnormalities must be recorded on the relevant section of the medical 
history/Current medical conditions/AE eCRF as appropriate.
8.4.3
Pregnancy and assessments of fertility
Pregnancy
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, 
male participants should not donate sperm while taking study treatment and for 10 days after 
stopping study treatment.
All pre-menopausal women who are not surgically sterile will have pregnancy testing 
performed at the timepoints defined in the Assessment Schedule (Table 8-1). Serum pregnancy 
testing is required at Screening and Study completion visit, but urine pregnancy testing at all 
other visits. The samples will be collected in accordance with local procedures and analyzed at 
the local laboratory. Additional pregnancy testing might be performed if requested by local 
requirements. Local pregnancy test and associated results will not be collected on eCRF.
As per Section 4.4, during a public health emergency as declared by local or regional authorities 
(i.e. pandemic, epidemic or natural disaster) that limits or prevents on-site study visits, if 


Novartis
Confidential
Page 72 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
participants cannot visit the site to have serum pregnancy tests, urine pregnancy test kits may 
be used. Relevant participants can perform the urine pregnancy test at home and report the result 
to the site. It is important that participants are instructed to perform the urine pregnancy test 
first and only if the test result is negative proceed with the administration of the study treatment. 
A communication process should be established with the participant so that the site is informed 
and can verify the pregnancy test results (e.g. following country specific measures).
Assessments of fertility
Women are considered post-menopausal and not of child-bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. 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 child-bearing 
potential.
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile.
In the absence of the above medical documentation, Follicle Stimulating Hormone (FSH) 
testing is required of any female participant regardless of reported reproductive/menopausal 
status at screening.
8.4.4
Appropriateness of safety measurements
The safety assessments selected are appropriate for this protocol, which utilizes a compound 
which has not previously been used in this patient population and where the safety profile has 
not therefore been established. The assessments will enable determination of both safety and 
therapeutic response in this setting.
8.5
Additional assessments
Commercially Confidential Information


Novartis
Confidential
Page 73 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 74 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 75 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation
Discontinuation of cold challenge
The cold challenge will be stopped, if any of the following criteria are met:
•
The participant requests to discontinue the cold challenge
•
The participant’s body temperature is 35.0 °C or below (mild hypothermia*) on two
consecutive temperature readings
•
The criteria for an overall study stopping rule are met Section 9.1.4
Following stopping of the cold challenge the participant should immediately proceed to 
rewarming with monitoring, clinical assessments and complete other trial related procedures.
* Mild (hypothermia I) – 35.0-32.0 °C, clear consciousness with shivering, as defined by
International Commission for Mountain Emergency Medicine (Durrer et al 2003).
Discontinuation of study treatment
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason prior to the protocol planned completion of study treatment 
administration. Discontinuation of study treatment can be initiated by either the participant or 
the investigator.
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being.
Discontinuation from study treatment is required under the following circumstances:
•
Participant decision
•
Pregnancy
•
Use of prohibited treatment as per recommendations in the prohibited treatment section
(see Section 6.2.2)
•
Any situation in which continued study participation might result in a safety risk to the
participant
•
Emergence of at least one of the following AEs:
•
A life-threatening adverse event (corresponding to a CTCAE Grade 4 or higher)
unless clearly unrelated to DFV890 and/or the cold challenge
•
An adverse event of severe intensity (corresponding to a CTCAE Grade 3 or higher)
unless clearly unrelated to DFV890 and/or the cold challenge
•
Skin rash, other than related to FCAS, greater than mild (covering >10% of the body
surface area, corresponding to CTCAE grade 2 or higher), unless clearly unrelated to
DFV890
•
If an abnormal renal event is confirmed, and other causes are excluded, the study drug will
be discontinued in the case of:


Novartis
Confidential
Page 76 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
•
Serum creatinine increase of 50% (i.e. acute kidney injury)
•
New onset dipstick proteinuria ≥3+
•
Protein-creatinine ratio (PCR, gCr) ≥1 g/g
•
New evidence of clinically significant crystals on microscopy
Please refer to Section 10.2.2 (Renal safety monitoring) and Section 16.2, Table 16-4 and 
Table 16-5 for further instructions and monitoring.
•
Any laboratory abnormalities that in the judgment of the investigator, taking into
consideration the participant’s overall status, prevents the participant from continuing
participation in the study
•
If a liver event occurs, follow guidelines outlined in Section 16.1 regarding
discontinuation of study treatment
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information.
Participants 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 (see Section 9.1.2 'Withdrawal of Informed Consent' section). Where possible, 
they should return for the assessments indicated in the Assessment Schedule (Table 8-1). 
If they fail to return for these assessments for unknown reasons, every effort (e.g. telephone, 
e-mail, letter) should be made to contact the participant/pre-designated contact as specified in
the lost to follow-up section (see Section 9.1.3). This contact should preferably be done
according to the study visit schedule.
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:
•
New / concomitant treatments
•
AEs / SAEs
9.1.1.1
Replacement policy
Replacements are not planned. Approximately 6 participants, but not more than 10, will be 
enrolled in order for 6 participants to complete the cold challenge included in the treatment 
period.
9.1.2
Withdrawal of informed consent and exercise of participants’ data 
privacy rights
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant:
•
Explicitly requests to stop use of their data
and


Novartis
Confidential
Page 77 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
•
No longer wishes to receive study treatment
and
•
Does not want any further visits or assessments (including further study-related contacts)
This request should be as per local regulations (e.g. in writing) and recorded in the source 
documentation.
Withdrawal of consent impacts the ability to further contact the participant, collect follow-up 
data (e.g. to respond to data queries) and potentially other country-specific restrictions. It is 
therefore important to ensure accurate recording of withdrawal vs. discontinuation based on the 
protocol definitions of these terms.
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/exercise data privacy rights and record this information. The investigator shall clearly 
document if the participant has withdrawn his/her consent for the use of data in addition to a 
study discontinuation.
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 participant are not allowed unless safety findings require 
communicating or follow-up.
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data privacy rights should be made as detailed in the assessment table 
(Table 8-1).
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding informed consent form.
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
9.1.3
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent (or exercise other participants’ 
data privacy rights), the investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the participant, e.g. dates of telephone calls, registered letters, 
etc. A participant should not be considered as lost to follow-up until due diligence has been 
completed or until the end of the study.
9.1.4
Study stopping rules
Overall study stopping rules
The study will be stopped, and no further dosing and/or new recruitment will occur, pending 
full safety review by the sponsor and the investigator, if any of the following criteria are met:


Novartis
Confidential
Page 78 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
•
Any death or life-threatening event (corresponding to CTCAE grade 4 or higher) unless
clearly unrelated to DFV890 and/or the cold challenge
•
Any SAE (other than death or life-threatening event, corresponding to CTCAE grade 3 or
higher) unless clearly unrelated to DFV890 and/or the cold challenge
•
Two (2) or more participants are discontinued due to a renal event as defined in
Section 16.2
•
Two (2) participants experience an AE of similar type which is assessed as severe in
intensity (corresponding to CTCAE grade 3 or higher) unless clearly unrelated to DFV890
•
Number and/or severity of AEs, abnormal safety monitoring tests, or abnormal laboratory
findings justify putting the study on hold
The safety review will be conducted jointly between medically qualified representatives of the 
sponsor and the investigators. The study may resume following the safety review, if the 
investigator and sponsor agree it is safe to proceed and necessary approvals have been obtained 
from authorities.
9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination
•
Unexpected, significant, or unacceptable safety risk to participants enrolled in the study
•
Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible 
(instructions for contacting the participant, when the participant should stop taking drug, when 
the participant should come in for a final visit, will be provided at that time) and treated as a 
prematurely withdrawn participant. 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 
participant’s interests. The investigator or sponsor depending on local regulation will be 
responsible for informing IRBs/IECs of the early termination of the trial.


Novartis
Confidential
Page 79 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
9.2
Study completion and post-study treatment
Study completion is defined as when the last participant finishes their Study completion visit 
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. Each participant will be required to complete the study in its entirety and 
thereafter no further study treatment will be made available to them.
All treated participants should have a safety follow-up call conducted 30 days after last 
administration of study treatment. The information collected is kept as source documentation. 
All SAEs reported during this time period must be reported as described in Section 10.1.3. 
Documentation of attempts to contact the participant should be recorded in the source 
documentation.
Continuing care should be provided by the investigator and/or referring physician. No further 
study treatment will be provided.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual participant and 
identifying AEs.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of AEs must be sought by non-directive questioning of the participant at each 
visit during the study. AEs also may be detected when they are volunteered by the participant 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments.
AEs must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. The severity grade
•
mild: usually transient in nature and generally not interfering with normal activities
•
moderate: sufficiently discomforting to interfere with normal activities
•
severe: prevents normal activities
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression
of underlying illness (i.e. progression of the study indication) the assessment of causality


Novartis
Confidential
Page 80 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant
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 10.1.2 for definition of SAE) and which
seriousness criteria have been met
5. Action taken regarding with study treatment. All AEs must be treated appropriately.
Treatment may include one or more of the following:
•
Dose not changed
•
Dose reduced/increased
•
Drug interrupted/withdrawn
6. Its outcome (i.e. recovery status or whether it was fatal)
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms.
AE monitoring should be continued until the end of the study visit.
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g. continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the IB.
Abnormal laboratory values or test results constitute AEs 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 must be identified through a 
review of values outside of normal ranges, significant changes from baseline or the previous 
visit, or values which are considered to be non-typical in participant with the underlying disease.
10.1.2
Serious adverse events
An SAE is defined as any AE [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:
•
fatal
•
life-threatening


Novartis
Confidential
Page 81 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Life-threatening in the context of a SAE refers to a reaction in which the participant 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 the ICH-E2D Guidelines).
•
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 signing the informed consent
•
social reasons and respite care in the absence of any deterioration in the participant’s 
general condition
•
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
•
is medically significant; e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
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 participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” 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 the 
ICH-E2D Guidelines).
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered SAE irrespective 
if a clinical event has occurred.
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety immediately, without undue delay, but under no 
circumstances later than within 24 hours of obtaining knowledge of the events (Note: if more 
stringent, local regulations regarding reporting timelines prevail). Detailed instructions 
regarding the submission process and requirements are to be found in the investigator folder 
provided to each site.


Novartis
Confidential
Page 82 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
For Screen Failures (e.g. a participant who is screened but is not treated or randomized), SAEs 
occurring after the participant has provided informed consent until the time the participant is 
deemed a Screen Failure must be reported to Novartis.
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, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: if more stringent, local regulations 
regarding reporting timelines prevail). 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.
If the SAE is not previously documented in the IB 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.
Any SAEs experienced after the 30-day period following the last administration of study 
treatment should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment.
10.1.4
Pregnancy reporting
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant 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.
Pregnancy should be recorded and reported by the investigator to the Novartis CMO & PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment and pregnancy outcome. Any SAE 
experienced during pregnancy must be reported.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
Pregnancy outcomes will be followed-up at the following times:
•
1 month after the estimated date of delivery
•
3 months after the estimated date of delivery (for a live birth only), and
•
12 months after the estimate date of delivery (for a live birth only).


Novartis
Confidential
Page 83 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
10.1.5
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, participant or 
consumer (European Medical Association 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.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
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
Please see Section 10.1.1 and Section 10.1.2 for more information on definition and reporting 
requirements of AE and SAE, respectively.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure participant 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 16-1 in Section 16.1 for complete definitions of liver laboratory triggers.
Once a participant is exposed to study treatment, every liver event defined in Table 16-1 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 16-2 and 
Table 16-3.
•
Repeat liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm
elevation. These liver chemistry repeats should be performed using the local laboratory
used by the site. Repeated laboratory test results must be reported as appropriate
•
If the initial elevation is confirmed, close observation of the participant will be initiated,
including consideration of treatment interruption if deemed appropriate.


Novartis
Confidential
Page 84 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
•
Discontinuation of the investigational drug (refer to the Discontinuation of study treatment
section, Section 9.1.1), if appropriate
•
Hospitalization of the participant if appropriate
•
Causality assessment of the liver event
•
Thorough follow-up of the liver event. These investigations can include based on
investigator’s discretion: serology tests, imaging, and pathology assessments,
hepatologist’s consultancy; obtaining more detailed history of symptoms and prior or
concurrent diseases, history of concomitant drug use, exclusion of underlying liver disease
All follow-up information and procedures performed must be recorded as appropriate in the eCRF.
10.2.2
Renal safety monitoring
Once a participant is exposed to study treatment, the following two categories of abnormal renal 
laboratory alert values should be assessed during the study period:
•
Serum creatinine increase ≥25% compared to baseline during normal hydration status
•
Any one of the following:
•
Urine protein-creatinine ratio (PCR) ≥1g/g or ≥100 mg/mmol, OR
•
New onset dipstick proteinuria ≥3+, OR
•
New onset dipstick hematuria ≥3+ (after excluding menstruation, urinary tract
infection, extreme exercise, or trauma), OR
•
New evidence of clinically significant crystals on microscopy
Abnormal renal event findings must be confirmed within 24-48 hours after the first assessment.
Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events, 
as defined in Table 16-4, should be monitored and followed up by the investigator or designated 
trial staff as summarized in Table 16-5. 
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the eCRF. 
The eCRFs have been built using fully validated secure web-enabled software that conforms to 
21 CFR Part 11 requirements. Investigator site staff will not be given access to the Electronic 
Data Capture (EDC) system until they have been trained. Automatic validation programs check 
for data discrepancies in the eCRFs, allow modification and/or verification of the entered data 
by the investigator staff.
The investigator/designee is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. The Investigator must 
certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site.


Novartis
Confidential
Page 85 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated contract research organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator site 
staff are required to respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Medical history/current medical conditions and AEs will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) terminology.
Once all the necessary actions have been completed and the database has been declared to be complete 
and accurate, it will be locked and made available for data analysis. Any changes to the database after 
that time can only be made after written agreement by Novartis development management.
11.3
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 Direct Data 
Entry (DDE) 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 field monitor will visit the site to check the completeness 
of participant records, the accuracy of data capture / data entry, the adherence to the protocol 
and to GCP, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. Continuous remote monitoring of each site’s data 
may be performed by a centralized Novartis Clinical Research Associate organization. 
Additionally, a central analytics organization may analyze data & 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 participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original ICF signed by the participant 
(a signed copy is given to the participant).
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 of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the eCRFs are performed according 


Novartis
Confidential
Page 86 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
to the study-specific monitoring plan. No information in source documents about the identity 
of the participants will be disclosed.
12
Data analysis and statistical methods
The analysis will be conducted on all participant 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.
12.1
Analysis sets
The safety analysis set will include all participants that received any study drug.
The PD analysis set will include all participants with no protocol deviations with relevant 
impact on PD data.
12.2
Participant demographics and other baseline characteristics
The Safety set will be used for the analyses described in this section. Demographic and other 
baseline data including disease characteristics and smoking status will be summarized 
descriptively.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation (SD), median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be listed by system 
organ class and preferred term.
12.3
Treatments
The Safety set will be used for the analyses described in this section. Categorical data will be 
summarized as frequencies and percentages. For continuous data, mean, SD, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
The frequency of DFV890 doses will be displayed for each participant.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed according to the Anatomical Therapeutic Chemical (ATC) 
classification system.
12.4
Analysis of the primary endpoint(s)/estimand(s)
The primary aim of the study is to assess the efficacy of DFV890 to reduce cold-induced 
inflammation in participants with FCAS. The fold change in the highest value of total WCC 
following exposure to a cold challenge vs. pre-challenge levels will be compared between 
treatment and screening periods. Lower induction of total WCC is considered a favorable 
outcome. The PD set will be used for the analyses described in this section.
Commercially Confidential Information


Novartis
Confidential
Page 87 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
12.4.1
Definition of primary endpoint(s)/estimand(s)
The primary estimand, including the primary endpoint is defined in Section 2.1 of this protocol 
and is based on the fold change of WCC.
12.4.2
Statistical model, hypothesis, and method of analysis
The primary objective will be achieved and DFV890 will be considered efficacious in treating 
cold-induced inflammation in participants with FCAS if the estimated ratio of fold changes 
from pre-challenge to highest post-challenge WCC between treatment and screening period is:
1. statistically significant (p <0.10) and
2. less than 80%.
12.4.3
Handling of remaining intercurrent events of primary estimand
Interruption of study treatment for any reason will be ignored.
12.4.4
Handling of missing values not related to intercurrent event
Due to the limited sample size, all available data will be included in the model. This corresponds 
to assuming a missing at random strategy.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 88 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
12.5
Analysis of secondary endpoints/estimands
12.5.1
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
period.
Adverse events
All information obtained on adverse events will be displayed by period and participant.
Vital signs
All vital signs data will be listed by period, participant, and time and if ranges are available, 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by period and time.
ECG
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each participant 
during the study. ECG data will be read and interpreted locally. All ECG data will be listed by 
period, participant and time, abnormalities will be flagged. Summary statistics will be provided 
by period and time.
Clinical laboratory evaluations
All laboratory data will be listed by period, participant, and time and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by period and time. 
Shift tables using the low/normal/high/ (low and high) classification will be used to compare 
baseline to the worst on-treatment value.
12.5.2
Efficacy and/or Pharmacodynamic endpoint(s)
The secondary efficacy objective is to assess the effect of DFV890 on clinical outcomes in 
participants with FCAS. For the following analyses, the PD set will be used.
Physician global assessment of autoinflammatory disease activity
Summary statistics will be provided for physician global assessment of autoinflammatory 
disease activity by period and time. 
Physician's severity assessment of autoinflammatory disease signs and 
symptoms
Summary statistics will be provided for physician's severity assessment of autoinflammatory 
disease signs and symptoms by period and time. 
Patient's global assessment of disease activity
Summary statistics will be provided for patient's global assessment of disease activity by period 
and time.


Novartis
Confidential
Page 89 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
12.5.3
Patient reported outcomes
Please refer to Section 12.5.2 for detailed information on the patients global assessment of 
disease activity.
12.6
Analysis of exploratory endpoints
Commercially Confidential Information


Novartis
Confidential
Page 90 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 91 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
12.7
Interim analyses
No interim analysis is planned for this trial.
Interim analyses may be conducted to support decision making concerning the current clinical 
study, the sponsor’s clinical development projects in general or in case of any safety concerns.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
Previous results of a cross-over cold challenge design were reported with a maximum mean 
treatment effect of approximately -8x109/L in WCC and a standard deviation of the difference 
of approximately 3x109/L (Hoffman et al 2004). In the relative scale, the ratio of fold changes 
from pre-challenge to highest post challenge WCC between treatment and screening period is 
found to be a minimum of approximately 25%. Thus, assuming that with a treatment ratio 
(treatment vs screening period) in the geometric mean of fold changes in WCC of at most 50% 
and a corresponding standard deviation of the logarithmic fold change to be 0.5, 6 participants 
provide at least 90% probability to fulfill the combined success criterion described in 
Section 12.4.2.
Figure 12-1 shows the probability of success for a sample size of 6 participants with varying 
ratios (from 0.25 to 1) and SD equal to 0.5.
Figure 12-1
Probability of success with 6 participants, varying ratio of fold 
changes, SD=0.5


Novartis
Confidential
Page 92 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
13
Ethical considerations and administrative procedures
13.1
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 CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written ICF, consent form updates, participant recruitment 
procedures (e.g. advertisements) and any other written information to be provided to 
participants. Prior to study 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.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and posted 
in a publicly accessible database of clinical trial results, such as the Novartis clinical trial results 
website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
Summary results of primary and secondary endpoints will be disclosed based upon the global 
Last Participant Last Visit (LPLV) date, since multinational studies are locked and reported 
based upon the global LPLV.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System that includes all activities involved in 
quality assurance and quality control, to ensure compliance with written SOPs as well as 
applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
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.


Novartis
Confidential
Page 93 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
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.
14
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 participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain 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.
14.1
Protocol amendments
Any change or addition 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.
Only amendments that are required for participant safety 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 participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations


Novartis
Confidential
Page 94 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
15
References
References are available upon request
Coll RC, Robertson AA, Chae JJ, et al (2015) A small-molecule inhibitor of the NLRP3 
inflammasome for the treatment of inflammatory diseases. Nat. Med; 21(3):248-55.
Dinarello CA (2011) A clinical perspective of IL-1β as the gatekeeper of inflammation. Eur J 
Immunol; 41(5):1203-17.
Dow J, Giesbrecht GG, Danzl DF, et al (2019) Wilderness Medical Society Clinical Practice 
Guidelines for the Out-of-Hospital Evaluation and Treatment of Accidental Hypothermia: 
2019 Update. Wilderness Environ Med; 30(4S):S47-S69.
Durrer B, Brugger H, Syme D (2003) The medical on-site treatment of hypothermia: ICAR-
MEDCOM recommendation. High Alt Med Biol; 4(1):99-103.
Evavold CL, Kagan JC (2018) How Inflammasomes Inform Adaptive Immunity. J. Mol. Biol; 
430(2):217-237.
Hoffman HM, Kuemmerle-Deschner JB, Goldbach-Mansky R (2019) Cryopyrin-Associated 
Periodic Syndromes (CAPS). In: Hashkes P, Laxer R, Simon A (eds). Textbook of 
Autoinflammation. Springer, Cham. p. 347-365.
Hoffman HM, Rosengren S, Boyle DL, et al (2004) Prevention of cold-associated acute 
inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor 
antagonist. Lancet; 364(9447):1779-85.
Hoffman HM, Throne ML, Amar NJ, et al (2008) Efficacy and safety of rilonacept 
(interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from 
two sequential placebo-controlled studies. Arthritis Rheum; 58(8):2443-52.
Hoffman HM, Wanderer AA, Broide DH (2001) Familial cold autoinflammatory syndrome: 
Phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol; 
108(4):615-620.
Johnstone RF, Dolen WK, Hoffman HM (2003) A large kindred with familial cold 
autoinflammatory syndrome. Ann Allergy Asthma Immunol; 90:233-237.
Mangan MSJ, Olhava EJ, Roush WR, et al (2018) Targeting the NLRP3 inflammasome in 
inflammatory diseases. Nat Rev Drug Discov; 17(8):588-606.
Ridker PM, Everett BM, Thuren T, et al (2017a) Antiinflammatory Therapy with 
Canakinumab for Atherosclerotic Disease. N. Engl. J. Med; 377(12):1119-1131.
Ridker PM, Libby P, MacFadyen JG, et al (2018) Modulation of the interleukin-6 signalling 
pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from 
the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur. Heart J; 
39(38):3499-3507.
Commercially Confidential Information


Novartis
Confidential
Page 95 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Ridker PM, MacFadyen JG, Thuren T, et al (2017b) Effect of interleukin-1β inhibition with 
canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from 
a randomised, double-blind, placebo-controlled trial. Lancet; 390(10105):1833-1842.
Ross JB, Finlayson LA, Klotz PJ, et al (2008) Use of anakinra (Kineret) in the treatment of 
familial cold autoinflammatory syndrome with a 16-month follow-up. J Cutan Med Surg; 
12(1):8-16.
Schieker M, Conaghan PG, Mindeholm L, et al (2020) Effects of Interleukin-1β Inhibition on 
Incident Hip and Knee Replacement : Exploratory Analyses From a Randomized, Double-
Blind, Placebo-Controlled Trial. Ann Intern Med; 173(7):509-515.
Shpall RL, Jeffes EWB, Hoffman HM (2004) A case of familial cold autoinflammatory 
syndrome confirmed by the presence of a CIAS1 mutation. Br J Dermatol; 150(5):1029-31.
Wanderer AA, Hoffman HM (2004) The spectrum of acquired and familial cold-induced 
urticaria/urticaria-like syndromes. Immunol Allergy Clin North Am; 24(2):259-86.
Vande Walle L, Stowe IB, Šácha P, et al (2019) MCC950/CRID3 potently targets the 
NACHT domain of wild-type NLRP3 but not disease-associated mutants for inflammasome 
inhibition. PLoS Biol; 17(9):e3000354.
Commercially Confidential Information


Novartis
Confidential
Page 96 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
16
Appendices
16.1
Appendix 1: Liver event and laboratory trigger definitions & 
follow-up requirements
Table 16-1
Liver event and laboratory trigger definitions
Definition/ threshold
Liver laboratory triggers
If ALT, AST and total bilirubin 
normal at baseline:
•
ALT or AST >5 × ULN
•
ALP >2 × ULN (in the absence of known bone pathology)
•
Total bilirubin >3 × ULN (in the absence of known Gilbert 
syndrome)
•
ALT or AST >3 × ULN and INR >1.5
•
Potential Hy’s Law cases (defined as ALT or AST >3 × ULN 
and Total bilirubin >2 × ULN [mainly conjugated fraction] 
without notable increase in ALP to >2 × ULN)
•
Any clinical event of jaundice (or equivalent term)
•
ALT or AST >3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia
•
Any adverse event potentially indicative of a liver toxicity*
If ALT or AST abnormal at 
baseline:
•
ALT or AST >2x baseline or >300 U/L (whichever occurs 
first)
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant, and unspecified liver neoplasms 
ULN: upper limit of normal


Novartis
Confidential
Page 97 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Table 16-2
Follow up requirements for liver laboratory triggers with liver 
symptoms
 
ALT
TBL
Liver 
Symptoms
Action
ALT increase without bilirubin increase:
If normal at baseline:
ALT >3 x ULN
 
If elevated at 
baseline:
ALT >2 x baseline
or >300 U/L 
(whichever occurs 
ﬁrst)
Normal
For patients with 
Gilbert’s syndrome: No 
change in baseline TBL
None
•
No change to study 
treatment
•
Measure ALT, AST, 
ALP, GGT, TBIL, INR, 
albumin, CK, and 
GLDH in 48-72 hours.
•
Follow-up for 
symptoms.
If normal at baseline:
ALT >5 x ULN for 
more than two weeks
 
If elevated at 
baseline:
ALT >3 x baseline
or >300 U/L 
(whichever occurs 
ﬁrst) for more than two 
weeks
Normal
For patients with 
Gilbert’s syndrome: No 
change in baseline TBL
None
 
If normal at baseline:
ALT >8 x ULN
Normal
None
ALT increase with bilirubin increase:
If normal at baseline:
ALT >3 x ULN
 
If elevated at 
baseline:
ALT >2 x baseline
or >300 U/L 
(whichever occurs 
ﬁrst)
TBL >2 x ULN (or INR 
>1.5)
For patients with 
Gilbert’s syndrome: 
Doubling of direct 
bilirubin
None
If normal at baseline:
ALT >3 x ULN
 
If elevated at 
baseline:
ALT >2 x baseline
or >300 U/L 
(whichever occurs 
ﬁrst)
Normal or elevated
Severe 
fatigue, 
nausea, 
vomiting, 
right upper 
quadrant 
pain
•
Interrupt study drug
•
Measure ALT, AST, 
ALP, GGT, TBIL, INR, 
albumin, CK, and 
GLDH in 48-72 hours.
•
Follow-up for 
symptoms.
•
Initiate close 
monitoring and 
workup for competing 
etiologies.
•
Study drug can be 
restarted only if 
another etiology is 
identiﬁed and liver 
enzymes return to 
baseline.


Novartis
Confidential
Page 98 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
Table 16-3
Follow up requirements for liver laboratory triggers
Criteria
Actions required
Follow-up monitoring
Total Bilirubin (isolated)
>1.5 – 3.0 ULN
•
Maintain treatment
•
Repeat liver function tests
(LFTs) within 48-72 hours
Monitor LFTs weekly until 
resolutiona to ≤ Grade 1 or to 
baseline
>3 - 10 × ULN (in the absence
of known Gilbert syndrome)
•
Interrupt treatment
•
Repeat LFT within 48-72
hours
•
Hospitalize if clinically
appropriate
•
Establish causality
•
Record the AE and
contributing factors (e.g.
conmeds, med hx, lab) in
the appropriate eCRF
Monitor LFTs weekly until 
resolutiona to ≤ Grade 1 or to 
baseline (ALT, AST, total 
bilirubin, Alb, PT/INR, ALP and 
GGT)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
>10 x ULN
•
Discontinue the study
treatment immediately
•
Hospitalize the participant
•
Establish causality
•
Record the AE and
contributing factors(e.g.
conmeds, med hx, lab) in
the appropriate eCRF
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolutiona (frequency at 
investigator discretion)
Any AE potentially indicative of 
a liver toxicity*
•
Consider study treatment
interruption or
discontinuation
•
Hospitalization if clinically
appropriate
•
Establish causality
•
Record the AE and
contributing factors (e.g.
conmeds, med hx, lab) in
the appropriate eCRF
Investigator discretion
aResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms ULN:
upper limit of normal
Based on investigator’s discretion investigation(s) for contributing factors for the liver event 
can include: serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease.


Novartis
Confidential
Page 99 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
16.2
Appendix 2: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-4
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 50% +
•
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 participant 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
New evidence of clinically significant crystals on 
microscopy
Assess & document
•
Repeat assessment to confirm
•
Assess serum creatine, urea and
electrolytes
•
Consider causes and possible interventions
•
Consider drug interruption or discontinuation
unless other causes are diagnosed and
corrected
+ 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.)


Novartis
Confidential
Page 100 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
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
Table 16-5
Renal Event Follow up
Assess, document and record in eCRF
•
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 eCRF.
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


Novartis
Confidential
Page 101 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
16.3
Appendix 3: Cold challenge description and follow up 
procedures
•
Room:
•
Ambient temperature of 4ºC should be maintained. The temperature in the cold room
should be monitored with a validated temperature monitoring device during the cold
challenge. The temperature at the start and stop of the cold challenge should be
documented in the eCRF. Any deviations outside 4-6ºC should be documented in the
source documents
•
Forced cooled air to simulate the condition to trigger acute FCAS.
•
Prior to the cold challenge patient should remain at room temperature ideally greater
than 23°C
•
Total duration:
•
45 minutes from start to finish
•
Patient monitoring:
•
During the cold challenge the clinical site staff must continuously monitor the
participant to ensure the patient remains alert, oriented to time, place and person and
is able to mobilize
•
Vital signs should be collected at baseline and then at least every 10 minutes and at
completion of the cold challenge (captured in source documentation only)
•
Cold challenges should take place at sites with immediate access to equipment and
trained staff for treating participants with FCAS in the case of an adverse event.
•
The cold challenge must be stopped if any of the following criteria are met:
•
The participant requests to discontinue the cold challenge
•
The participant’s body temperature is 35.0°C or below on two consecutive
temperature readings
•
The criteria for an overall study stopping rule are met (see Section 9.1.4)
•
Participant instructions:
•
Participants should be wearing light clothing (e.g. t-shirt and shorts)
•
Participants can stand, sit or walk-around
•
Strenuous exercise is not allowed
•
Passive rewarming post cold challenge:
•
Participants will be returned to an ambient temperature of approximately 23°C for at
least 24 hours at the clinical site for clinical monitoring and to complete trial related
procedures, this period may be extended as per medical judgement
•
The participant should be covered with blankets and other types of insulation, until
normal temperature is restored, or fever develops as part of the FCAS episode
In addition, guidance and requirements provided by the local regulatory authorities or local site-
specific standard operating procedures must also be followed, as applicable.


Novartis
Confidential
Page 102 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
16.4
Appendix 4: Physician Global Assessment of Autoinflammatory 
Disease Activity
Figure 16-1
Physician Global Assessment of Autoinflammatory Disease Activity


Novartis
Confidential
Page 103 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
16.5
Appendix 5: Physician's Severity Assessment of 
Autoinflammatory Disease Signs and Symptoms
Figure 16-2
Physician's Severity Assessment of Autoinflammatory Disease Signs 
and Symptoms
 


Novartis
Confidential
Page 104 of 104
Amended Protocol Version v04 (Clean)
Protocol No. CDFV890A12201
16.6
Appendix 6: Patients Global Assessment of Disease Activity
Figure 16-3
Patients Global Assessment of Disease Activity

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
DFV890
CDFV890A12201 / NCT04868968
An open-label, single arm phase II study of DFV890 to assess the safety, 
tolerability and efficacy in participants with familial cold auto-inflammatory 
syndrome (FCAS)
Statistical Analysis Plan (SAP)
Document type:
SAP Documentation – NIBR 
Document status:
Amendment 1 Final
Release date:
17-Jul-2023
Number of pages:
22
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
Confidential
Page 2
SAP Amendment 1
CDFV890A12201
Commercially Confidential Information (CCI)


Novartis
Confidential
Page 3
SAP Amendment 1
CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 4
SAP Amendment 1
CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 5
SAP Amendment 1
CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 6
SAP Amendment 1
CDFV890A12201
Table of contents
Table of contents..................................................................................................................6
List of tables.........................................................................................................................7
List of figures.......................................................................................................................7
1
Introduction..........................................................................................................................8
1.1
Scope of document...................................................................................................8
1.2
Study reference documentation................................................................................8
1.3
Study objectives.......................................................................................................8
1.3.1. Primary objective...........................................................................................8
1.3.2. Secondary objective.......................................................................................8
1.4
Study design and treatment....................................................................................10
2
First interpretable results (FIR)..........................................................................................11
3
Interim analyses .................................................................................................................11
4
Statistical methods: Analysis sets......................................................................................11
6
Statistical methods for Pharmacodynamic (PD) parameters .............................................13
6.1
Primary objective...................................................................................................13
6.1.1
Variables................................................................................................13
6.1.2
Descriptive analyses..............................................................................14
6.1.3
Statistical model, assumptions and hypotheses.....................................14
6.2
Secondary objective...............................................................................................16
6.2.1
Variables................................................................................................16
6.2.2
Descriptive analyses..............................................................................16
6.3
Exploratory objectives ...........................................................................................16
7
Statistical methods for safety and tolerability data............................................................17
7.1
Variables ................................................................................................................17
7.2
Descriptive analyses...............................................................................................18
7.3
Graphical presentation ...........................................................................................20
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 7
SAP Amendment 1
CDFV890A12201
10 Consideration due to COVID-19 .......................................................................................22
List of tables
Table 4-1
Protocol deviation codes and analysis sets............................................12
List of figures
Figure 1-1
Study Design Schematic........................................................................10
Commercially Confidential Information


Novartis
Confidential
Page 8
SAP Amendment 1
CDFV890A12201
1
Introduction 
1.1
Scope of document
The Reporting and Analysis Plan (RAP) documents contain detailed information to aid the 
production of Statistics & Programming input into the Clinical Study Report (CSR) for trial 
“CDFV890A12201”.
The Statistical Analysis Plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
Final study protocol amendment (v04) is available at the time of finalization of SAP.
1.3
Study objectives
1.3.1. Primary objective
Primary objective
Endpoint for primary objective
•
To assess the efficacy of DFV890 to 
reduce cold-induced inflammation in 
participants with FCAS
•
Ratio of fold change from pre-
challenge to the highest post-
challenge value of white cell count 
(WCC) between treatment and 
screening period
1.3.2. Secondary objective
Secondary objective
Endpoint for secondary objective
•
To assess safety and tolerability of 
DFV890
•
Safety endpoints (including vital 
signs, ECG parameters, safety 
laboratory assessment and adverse 
events)
•
To assess the efficacy of DFV890 to 
improve the signs and symptoms of 
FCAS
•
Change from pre-challenge to post-
challenge between treatment and 
screening period in: 
•
Physician global assessment of 
autoinflammatory disease 
activity
•
Physician’s severity assessment 
of autoinflammatory disease 
signs and symptoms
•
To assess the effect of DFV890 on 
patient reported outcomes
•
Change from pre-challenge to post-
challenge between treatment and 
screening period in: 


Novartis
Confidential
Page 9
SAP Amendment 1
CDFV890A12201
•
Patients global assessment of 
disease activity
Commercially Confidential Information


Novartis
Confidential
Page 10
SAP Amendment 1
CDFV890A12201
1.4
Study design and treatment
This is an open-label, single-arm, multiple dose, phase II study to assess safety, tolerability and 
efficacy of DFV890 in participants with FCAS who show evidence of inflammatory activity 
after the cold challenge performed during screening. Approximately 6 participants with FCAS 
and confirmed NLRP3 gain-of-function mutations will be enrolled in the study.
Figure 1-1 summarizes the study design and shows the steps that will be followed in the study. 
The study consists of three periods: screening, treatment and follow-up.
Figure 1-1
Study Design Schematic 
Screening period: A period of up to 6 months (and up to 12 months for participants with a 
historical screening cold challenge prior to protocol amendment 04), when the participant’s 
eligibility will be assessed at a screening visit and a cold challenge will be performed. During 
the screening cold challenge, participants will be domiciled for three days following a minimum 
of one week of recovery from the cold challenge prior to enrollment and initiation of treatment. 
The screening cold challenge can be conducted any time during the screening period, provided 
that Day 1 is conducted within 6 months (and within 12 months for participants with a historical 
screening cold challenge prior to protocol amendment 04; see below) of the Screening visit and 
all inclusion and none of the exclusion criteria are met. Historical screening cold challenge 
conducted in this study under the previous protocol version is acceptable, provided that Day 1 
is conducted within 12 months of the Screening visit, and all inclusion and none of the exclusion 
criteria based on this amendment are met.
Treatment period: Eligible participants (defined as those participants who respond to the cold 
challenge) will then enter the treatment period where they will be administered oral DFV890 
100 mg b.i.d. for 3 days, one last dose will be administered in the morning of Day 4 followed 
by a cold challenge. Participants will be admitted to the clinic in the morning of Day 3 (the day 
prior to cold challenge) and will be domiciled for a total of three days or longer (if needed). On 
the morning of Day 4, pre-challenge assessments will be performed, and then cold challenge 


Novartis
Confidential
Page 11
SAP Amendment 1
CDFV890A12201
will last for 45 minutes. After the end of the cold challenge, participants will be monitored until 
the next morning (Day 5) and discharged after the last assessment on Day 5 or later. 
Follow up period: Participants will be then followed-up for an end of study evaluation at the 
study competition visit, approximately 10 days after last dose and a post study safety contact 
will occur 30 days after last dose. The total study duration from screening until study completion 
is expected to be up to 7 months (and up to 13 months for participants with a historical screening 
cold challenge prior to protocol amendment 04).
 
Unscheduled visits: Participants will be instructed to contact the investigator if they develop 
rash or pruritus between visits from Day 1 to the Study completion visit. An unscheduled visit 
should be considered based on clinical findings and severity of rash or pruritus and related 
assessments performed. Unscheduled visits may be performed at an alternative Sponsor-
approved site (e.g. satellite site that may be more convenient to the participant) if agreed by the 
PI who will maintain the investigator responsibilities, and only as permitted by local regulations.
2
First interpretable results (FIR)
3
Interim analyses 
No interim analysis is planned for this trial. 
Interim analyses may be conducted to support decision making concerning the current clinical 
study, the sponsor’s clinical development projects in general or in case of any safety concerns.
4
Statistical methods: Analysis sets
The safety analysis set will include all participants that received any study drug.
The PD analysis set will include all participants with no protocol deviations with relevant 
impact on PD data.
The analysis sets and protocol deviation codes are related as follows:
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 12
SAP Amendment 1
CDFV890A12201
Table 4-1
Protocol deviation codes and analysis sets
Category   
Deviation code
Text description of deviation
Data exclusion
Participants are excluded from safety analysis in case of 
these PDs:
Exclude participant from safety 
analysis set
INCL01
Informed consent form not obtained
Yes
Participants are excluded from PD analysis in case of these 
PDs:
Exclude participant from PD 
analysis set
INCL01
Informed consent form not obtained
Yes
INCL08
relative WCC increase <40% compared to pre-
challenge after cold challenge at screening 
period 
Yes
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to 
DBL.
The number and percentage of participants in each analysis set will be summarized. Participants 
excluded from any analysis set(s) along with the reason(s) for their exclusion will be listed.
All protocol deviations will be listed by participant and the number and percentage of 
participants with protocol deviations will be summarized.
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 13
SAP Amendment 1
CDFV890A12201
6
Statistical methods for Pharmacodynamic (PD) parameters
All participants within the PD analysis set will be included in the PD data analysis.
6.1
Primary objective
The primary efficacy objective of this study is to assess the efficacy of DFV890 to reduce cold-
induced inflammation in participants with FCAS. 
6.1.1
Variables 
Fold change from pre-challenge to the highest post-challenge value of total WCC is the primary 
efficacy variable. The highest post-challenge value is based only on post-challenge 
measurements within the cold challenge visit (up to and including 8 hours post-challenge). 
Lower induction of total WCC is considered a favorable outcome.
Fold change from pre-challenge to a post-challenge value of WCC is defined as the ratio of the 
post-challenge WCC value to the pre-challenge WCC value, i.e.:
Commercially Confidential Information


Novartis
Confidential
Page 14
SAP Amendment 1
CDFV890A12201
𝑭𝒐𝒍𝒅 𝒄𝒉𝒂𝒏𝒈𝒆= 𝒑𝒐𝒔𝒕 𝒄𝒉𝒂𝒍𝒍𝒆𝒏𝒈𝒆 𝑾𝑪𝑪
𝒑𝒓𝒆 𝒄𝒉𝒂𝒍𝒍𝒆𝒏𝒈𝒆 𝑾𝑪𝑪
6.1.2
Descriptive analyses
A geometric mean (SE) plot of fold change from pre-challenge to post-challenge over time will 
be provided by period.
6.1.3
Statistical model, assumptions and hypotheses
The primary objective will be achieved and DFV890 will be considered efficacious in treating 
cold-induced inflammation in participants with FCAS if the estimated ratio of fold changes 
from pre-challenge to highest post-challenge WCC between treatment and screening period is:
(1) Statistically significant (p-value<0.10), and
(2) Less than 80%.
Note: The highest post-challenge WCC value per period will be considered in the primary 
model analysis. This implies that the highest post-challenge WCC value will not necessarily 
occur at the same post-challenge time point in both periods.
6.1.3.1
Handling of remaining intercurrent events of primary estimand
Interruption of study treatment for any reason will be ignored.
6.1.3.2
Handling of missing values not related to intercurrent event
Due to the limited sample size, all available data will be included in the model. This corresponds 
to assuming a missing at random strategy. 
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 15
SAP Amendment 1
CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 16
SAP Amendment 1
CDFV890A12201
6.2
Secondary objective
The secondary efficacy objectives of this study are:
•
To assess the efficacy of DFV890 to improve the signs and symptoms of FCAS.
•
To assess the effect of DFV890 on patient reported outcomes.
6.2.1
Variables 
The secondary efficacy variables of this study are:
•
Physician global assessment of autoinflammatory disease activity.
•
Physician’s severity assessment of autoinflammatory disease signs and symptoms.
•
Patient’s global assessment of disease activity.
6.2.2
Descriptive analyses
Summary tables, including absolute and relative (%) frequencies of the different categories, 
will be provided by period and time for each secondary variable.
Overlaying individual plots (line plots) with the screening and treatment periods in separate 
panels will be provided for each secondary variable. Data from -2 to 23 hours post-challenge 
will be considered.
6.3
Exploratory objectives
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 17
SAP Amendment 1
CDFV890A12201
7
Statistical methods for safety and tolerability data
All participants within the Safety analysis set will be included in the safety data analysis.
The assessment of safety and tolerability of DFV890 is one of the secondary objectives of this 
study.
7.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as participant demographics, baseline characteristics, and 
treatment information.
Commercially Confidential Information


Novartis
Confidential
Page 18
SAP Amendment 1
CDFV890A12201
7.2
Descriptive analyses
Participant disposition, demographics and other baseline characteristics
The disposition information for each study phase will be listed by participant. The number and 
percentage (%) of participants who completed each study phase and who prematurely 
discontinued each study phase along with the primary reason for discontinuation will be 
presented by period.
All data for background and demographic variables including baseline disease characteristics 
and smoking status will be listed by participant and summary statistics will be provided. 
Summary tables for categorical data will include absolute and relative frequencies. The 
following variables will be included in the demographics and other baseline characteristics 
summary table:
•
Age
•
Age categories (<=65 years old & >65 years old)
•
Sex
•
Race
•
Ethnicity
•
Weight
•
Height
•
BMI
•
Country
Other variables may also be considered, as needed.
Screening failures (and the reasons for those) will be listed separately.
Data on informed consent and withdrawal of informed consent will also be listed separately.
Relevant medical histories and current medical conditions at baseline will be listed and 
summarized by system organ class and preferred term. 
Treatment
All data for study drug administration will be listed by participant.  The duration of exposure to 
study treatment in days will be summarized. The duration of exposure to study treatment in 
days will be calculated as study day of last non-missing dose – study day of first dose + 1.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed according to the Anatomical Therapeutic Chemical (ATC) 
classification system. Concomitant medications will also be summarized by medication class 
and preferred term.


Novartis
Confidential
Page 19
SAP Amendment 1
CDFV890A12201
Vital signs
All vital signs data will be listed by period, participant, and time and if ranges are available, 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by period and time.
ECG evaluations
All single 12-lead ECG data (included but not limited to PR, QRS, QT, QTcF and RR intervals) 
will be listed by period, participant and time, abnormalities will be flagged. Summary statistics 
will be provided by period and time.
Clinical laboratory evaluations
All laboratory data will be listed by period, participant, and time and if normal ranges are 
available abnormalities will be flagged. A separate listing is provided presenting all parameters 
in a participant with any abnormal values. 
Summary statistics will be provided by period and time. Shift tables using the low/normal/high/ 
(low and high) classification will be used to compare baseline (defined as Day 1 pre-first dose 
assessment) to the worst on-treatment value.
Adverse events
All information obtained on adverse events will be displayed by period and participant. Two 
separate listings for serious adverse events and adverse events leading to study discontinuation 
will also be provided.
The number and percentage of participants with adverse events will be tabulated by body system 
and/or preferred term with a breakdown by period. An adverse event starting in one period and 
continuing into the next period is counted only in the onset period. A participant with multiple 
adverse events within a body system and period is only counted once towards the total of this 
body system and period.
The number and percentage of participants with skin rash will be summarized by period. Skin 
rash data will also be listed. 
Separate summaries will be provided for AEs by maximum severity, drug-related AEs, serious 
AEs, drug-related serious AEs and cold challenge-related AEs by body system and preferred 
term with a breakdown by period.
The overall incidence of AEs including the number of events and the number (and percentage) 
of participants under specific AE categories will also be summarized by period in a separate 
table.
For the legal requirements of ClinicalTrials.gov and EudraCT, two tables are required: on 
treatment emergent adverse events which are not serious adverse events with an incidence 
greater than 5% and on treatment emergent serious adverse events and SAE suspected to be 
related to study treatment will be provided by system organ class and preferred term on the 
safety analysis set.


Novartis
Confidential
Page 20
SAP Amendment 1
CDFV890A12201
If for a same participant, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:
•
a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
•
more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. All information 
obtained on deaths will be listed.
Other safety evaluations
Cold challenge
All cold challenge data (challenge start and end datetime, temperature of cold room at start and 
end time (oC) and reason for interruption of the cold challenge) will be listed by participant.
7.3
Graphical presentation 
Scatterplots with overlaid median will be created to visualize trends in longitudinal safety data 
(vitals, ECG, lab parameter).
Commercially Confidential Information
Commercially Confidential Information


Novartis
Confidential
Page 21
SAP Amendment 1
CDFV890A12201
Commercially Confidential Information


Novartis
Confidential
Page 22
SAP Amendment 1
CDFV890A12201
10
Consideration due to COVID-19
Due to the COVID-19 pandemic, it may not be possible to perform some procedures as per 
protocol. All deviations due to COVID-19 will be listed separately to other deviations and may 
also be tabulated.
Observations that were impacted due to COVID-19, may be excluded from the primary 
analyses, for example including (but not limited to) observations taken at participant’s house 
instead of site, and separately explored to identify if there is an impact of them on the analyses.