A Randomized, Placebo-controlled, Parallel-group, Investigator- and Participant-blinded Phase 2a Study to Investigate the Efficacy, Safety, and Tolerability of DFV890 and MAS825 for Inflammatory Marker Reduction in an Adult Population With Coronary Heart Disease and Clonal Hematopoiesis of Indeterminate Potential (CHIP)
Phase: PHASE2
Conditions: Coronary Heart Disease, Clonal Hematopoiesis of Indeterminate Potential (CHIP)
Sponsor: Novartis Pharmaceuticals

 
 
 
 
Novartis Research and Development 
Clinical Trial Protocol Title: 
A randomized, placebo-controlled, parallel-group, 
investigator- and participant-blinded Phase 2a study to 
investigate the efficacy, safety, and tolerability of DFV890 
and MAS825 for inflammatory marker reduction in an adult 
population with coronary heart disease and Clonal 
Hematopoiesis of Indeterminate Potential (CHIP) 
Clinical Trial Protocol Number: CADPT15A12201 
Version Number: v00 (Original Protocol) 
Compound: ADPT15 
Brief Title: A study to investigate the efficacy, safety, and tolerability of DFV890 and 
MAS825 for inflammatory marker reduction in adult participants with coronary heart 
disease and Clonal Hematopoiesis of Indeterminate Potential (CHIP) 
Study Phase: IIa 
Sponsor Name: Novartis Pharma AG or its affiliates outside of the EEA (where 
applicable) 
Sponsor Address in the EEA: Novartis Pharma AG, Lichtstrasse 35, 4056 Basel, 
Switzerland 
Regulatory Agency Identifier Number(s): IND Number 167,653; EU CT Number 
2023-506741-34 
Approval Date: 28-Jul-2023 (content final) 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 5.0 dated 14-Jan-2022 

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Table of contents 
Table of contents ............................................................................................................. 2 
List of tables ................................................................................................................... 6 
List of figures .................................................................................................................. 6 
1 
Protocol summary ........................................................................................................... 7 
1.1 
Summary ............................................................................................................. 7 
1.2 
Schema .............................................................................................................. 11 
1.3 
Schedule of activities (SoA) ............................................................................... 11 
2 
Introduction .................................................................................................................. 16 
2.1 
Study rationale ................................................................................................... 16 
2.2 
Background ....................................................................................................... 16 
2.3 
Benefit/Risk assessment ..................................................................................... 18 
2.3.1 
Risks shared by both DFV890 and MAS825 ...................................... 19 
2.3.2 
DFV890 compound risks ................................................................... 22 
2.3.3 
MAS825 compound risks ................................................................... 24 
2.3.4 
Blood sample volume ........................................................................ 24 
3 
Objectives, endpoints, and estimands ............................................................................ 25 
3.1 
Primary estimands ............................................................................................. 26 
3.2 
Secondary estimands .......................................................................................... 27 
4 
Study design ................................................................................................................. 28 
4.1 
Overall design .................................................................................................... 28 
4.2 
Scientific rationale for study design ................................................................... 29 
4.3 
Justification for dose .......................................................................................... 32 
4.4 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs .................................................................................................................. 34 
4.5 
Rationale for public health emergency mitigation procedures ............................. 34 
4.6 
Purpose and timing of interim analyses/design adaptations ................................ 34 
4.7 
End of study definition ....................................................................................... 35 
5 
Study population ........................................................................................................... 35 
5.1 
Inclusion criteria ................................................................................................ 35 
5.2 
Exclusion criteria ............................................................................................... 36 
5.3 
Lifestyle considerations ..................................................................................... 39 
5.3.1 
Meals and dietary restrictions ............................................................. 39 
5.4 
Screen failures ................................................................................................... 40 
5.4.1 
Replacement policy ............................................................................ 40 
5.4.2 
Participant numbering ........................................................................ 40 
6 
Study treatment(s) and concomitant therapy .................................................................. 41 

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6.1 
Study treatment(s) .............................................................................................. 41 
6.1.1 
Additional study treatments................................................................ 42 
6.1.2 
Treatment arms/group ........................................................................ 42 
6.2 
Preparation, handling, storage, and accountability .............................................. 42 
6.2.1 
Handling of study treatment ............................................................... 43 
6.2.2 
Handling of other treatment ............................................................... 43 
6.2.3 
Instruction for prescribing and taking study treatment ........................ 44 
6.3 
Measures to minimize bias: randomization and blinding .................................... 46 
6.3.1 
Treatment assignment, randomization ................................................ 46 
6.3.2 
Treatment blinding ............................................................................. 46 
6.3.3 
Emergency breaking of assigned treatment code ................................ 48 
6.4 
Study treatment compliance ............................................................................... 49 
6.4.1 
Recommended treatment of adverse events ........................................ 49 
6.5 
Dose modification .............................................................................................. 49 
6.6 
Continued access to study treatment after the end of the study ........................... 50 
6.6.1 
Post trial access .................................................................................. 50 
6.7 
Treatment of overdose ....................................................................................... 50 
6.7.1 
Reporting of study treatment errors including misuse/abuse ............... 50 
6.8 
Concomitant and other therapy .......................................................................... 50 
6.8.1 
Concomitant therapy .......................................................................... 50 
6.8.2 
Prohibited medication ........................................................................ 53 
7 
Discontinuation of study treatment and participant discontinuation/withdrawal ............. 55 
7.1 
Discontinuation of study treatment ..................................................................... 55 
7.2 
Participant discontinuation from the study ......................................................... 56 
7.3 
Withdrawal of informed consent and exercise of participants’ data privacy 
rights ................................................................................................................. 56 
7.4 
Lost to follow-up ............................................................................................... 57 
7.5 
Study stopping rules........................................................................................... 57 
7.6 
Early study termination by the Sponsor .............................................................. 58 
8 
Study Assessments and Procedures ............................................................................... 58 
8.1 
Screening ........................................................................................................... 58 
8.2 
Participant demographics/other baseline characteristics ..................................... 59 
8.3 
Efficacy assessments .......................................................................................... 59 
8.3.1 
IL-6 and IL-18 cytokines ................................................................... 59 
8.3.2 
Exploratory efficacy assessments ....................................................... 60 
8.3.3 
Appropriateness of efficacy assessments ............................................ 60 

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8.4 
Safety/tolerability assessments ........................................................................... 61 
8.4.1 
Physical examinations ........................................................................ 61 
8.4.2 
Vital signs .......................................................................................... 62 
8.4.3 
Electrocardiograms ............................................................................ 62 
8.4.4 
Clinical safety laboratory tests ........................................................... 63 
8.4.5 
Pregnancy testing ............................................................................... 65 
8.4.6 
Appropriateness of safety measurements ............................................ 65 
8.5 
Additional assessments ...................................................................................... 65 
8.5.1 
Skin microbiome collection................................................................ 65 
8.6 
Adverse events (AEs), serious adverse events (SAEs), and other safety 
reporting ............................................................................................................ 66 
8.6.1 
Adverse events ................................................................................... 66 
8.6.2 
Serious adverse events ....................................................................... 68 
8.6.3 
SAE reporting .................................................................................... 69 
8.6.4 
Pregnancy .......................................................................................... 70 
8.6.5 
Disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs ................................................................. 71 
8.7 
Pharmacokinetics ............................................................................................... 71 
8.7.1 
PK blood/serum collection ................................................................. 71 
8.8 
Biomarkers ........................................................................................................ 71 
8.9 
Immunogenicity assessments ............................................................................. 73 
8.9.1 
Immunogenicity blood sample collection and handling ...................... 73 
8.9.2 
Immunogenicity analytical method(s) ................................................ 73 
8.10 
Health economics OR Medical resource utilization and health economics .......... 74 
9 
Statistical considerations ............................................................................................... 74 
9.1 
Analysis sets ...................................................................................................... 74 
9.2 
Statistical analyses ............................................................................................. 74 
9.2.1 
General considerations ....................................................................... 74 
9.2.2 
Participant demographics and other baseline characteristics ............... 74 
9.2.3 
Treatments ......................................................................................... 74 
9.3 
Primary endpoint(s)/estimand(s) analysis ........................................................... 75 
9.3.1 
Definition of primary endpoint(s) ....................................................... 75 
9.3.2 
Statistical model, hypothesis, and method of analysis ......................... 75 
9.3.3 
Handling of intercurrent events of primary estimand (if applicable) ... 76 
9.3.4 
Handling of missing values not related to intercurrent event ............... 76 
9.3.5 
Sensitivity analyses ............................................................................ 76 
9.3.6 
Supplementary analysis ...................................................................... 77 

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9.4 
Secondary endpoint(s)/estimand(s) analysis ....................................................... 77 
9.4.1 
Safety endpoints ................................................................................ 77 
9.4.2 
Pharmacokinetics ............................................................................... 78 
9.5 
Exploratory endpoint(s)/estimand(s) analysis ..................................................... 78 
9.5.1 
Biomarkers ........................................................................................ 78 
9.5.2 
DNA .................................................................................................. 79 
9.6 
(Other) Safety analyses ...................................................................................... 79 
9.7 
Other analyses ................................................................................................... 79 
9.8 
Interim analysis ................................................................................................. 79 
9.9 
Sample size determination ................................................................................. 79 
9.9.1 
Primary endpoint(s) ........................................................................... 79 
10 Supporting documentation and operational considerations ............................................. 81 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations .................. 81 
10.1.1 
Regulatory and ethical considerations ................................................ 81 
10.1.2 
Informed consent process ................................................................... 82 
10.1.3 
Data protection .................................................................................. 83 
10.1.4 
Committees structure ......................................................................... 83 
10.1.5 
Data quality assurance ....................................................................... 84 
10.1.6 
Source documents .............................................................................. 85 
10.1.7 
Publication policy .............................................................................. 85 
10.1.8 
Protocol adherence and protocol amendments .................................... 86 
10.2 
Appendix 2: Abbreviations and definitions ........................................................ 87 
10.2.1 
List of abbreviations .......................................................................... 87 
10.2.2 
Definitions ......................................................................................... 89 
10.3 
Appendix 3: Clinical laboratory tests ................................................................. 92 
10.3.1 
Clinically notable laboratory values and vital signs ............................ 92 
10.4 
Appendix 4: Participant Engagement ................................................................. 93 
10.5 
Appendix 5: Liver safety monitoring.................................................................. 94 
10.5.1 
Liver event and laboratory trigger definitions & follow-up 
requirements ...................................................................................... 95 
10.6 
Appendix 6: Renal safety monitoring ................................................................. 98 
10.6.1 
Specific Renal Alert Criteria and Actions and Event Follow-up ......... 98 
11 References .................................................................................................................. 100 

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List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 7 
Table 1-2 
Assessment Schedule ......................................................................... 13 
Table 3-1 
Objectives and related endpoints ........................................................ 25 
Table 3-2 
Intercurrent events for the primary estimand ...................................... 26 
Table 4-1 
Rationale for study design .................................................................. 29 
Table 6-1 
Investigational and control drug ......................................................... 41 
Table 6-2 
DFV890 dose and treatment schedule ................................................ 44 
Table 6-3 
Dose and treatment schedule .............................................................. 45 
Table 6-4 
Blinding and unblinding plan ............................................................. 48 
Table 6-5 
Drugs to be used with caution with DFV890 ...................................... 52 
Table 6-6 
Prohibited drugs due to DDI with DFV890 (CYP3A and CYP2C9 
modulators) ........................................................................................ 54 
Table 6-7 
Prohibited medication ........................................................................ 54 
Table 8-1 
Safety laboratory evaluations ............................................................. 64 
Table 10-1 
Liver event and laboratory trigger definitions ..................................... 95 
Table 10-2 
Follow up requirements for liver laboratory triggers - ALT, AST, 
TBL ................................................................................................... 95 
Table 10-3 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia ............................................................................ 97 
Table 10-4 
Specific renal alert criteria and actions ............................................... 98 
Table 10-5 
Renal Event Follow-Up ..................................................................... 99 
List of figures 
Figure 1-1 
Study design ...................................................................................... 11 
Figure 1-2 
Recommended order of assessments .................................................. 11 
Figure 6-1 
Treatment arms .................................................................................. 42 
Figure 8-1 
Recommended order of assessments .................................................. 62 
 

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1 
Protocol summary 
1.1 
Summary 
Protocol Title: 
A randomized, placebo-controlled, parallel-group, investigator- and participant-blinded Phase 
2a study to investigate the efficacy, safety, and tolerability of DFV890 and MAS825 for 
inflammatory marker reduction in an adult population with coronary heart disease and Clonal 
Hematopoiesis of Indeterminate Potential (CHIP) 
Brief Title: 
A study to investigate the efficacy, safety, and tolerability of DFV890 and MAS825 for 
inflammatory marker reduction in adult participants with coronary heart disease and Clonal 
Hematopoiesis of Indeterminate Potential (CHIP) 
Purpose 
The purpose of this study is to evaluate the efficacy, safety, and tolerability of intra-individual 
dose escalation of oral DFV890 or a single subcutaneous (s.c.) dose of MAS825 in reducing 
circulating levels of inflammatory markers in adult participants with known coronary heart 
disease and the presence of CHIP. The results of the study will be used to inform future 
development plans for DFV890 and MAS825 in cardiovascular disease (CVD) event risk 
reduction. 
Study Indication /Medical Condition: 
Coronary heart disease, CHIP 
Treatment type 
Drug 
Study type 
Interventional 
Objectives, Endpoints, and Estimands: 
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To evaluate the effect of various dose levels 
of DFV890 versus placebo to reduce 
circulating levels of inflammatory markers in 
participants with coronary heart disease and 
CHIP 
Serum levels of Interleukin (IL)-6 and IL-18 at 3 
weeks after the start of a DFV890 dosing period 

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Objective(s) 
Endpoint(s) 
• 
To evaluate the effect of MAS825 versus 
placebo to reduce circulating levels of 
inflammatory markers in participants with 
coronary heart disease and CHIP 
Serum level of IL-6 at 3 weeks after a single s.c. 
dose of MAS825 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate the safety and tolerability of 
DFV890 and MAS825 in participants with 
coronary heart disease and CHIP 
• 
Adverse events, and parameters from safety 
assessments, including vital signs, 
electrocardiograms, and laboratory 
assessments (urine and blood) 
• 
To assess the pharmacokinetics of DFV890 
in participants with coronary heart disease 
and CHIP 
• 
Plasma trough concentrations (Ctrough) of 
DFV890 at steady-state 
• 
To assess the pharmacokinetics of MAS825 
in participants with coronary heart disease 
and CHIP 
• 
Serum concentrations of MAS825 after a 
single s.c. dose of MAS825 
Primary estimand/analysis: 
The primary estimand will address potential intercurrent events that may influence the primary 
endpoints, IL-6 and IL-18 (DFV890 only), largely with a hypothetical strategy, which aims to 
estimate the effect of treatment under research-like conditions. The primary analysis for 
DFV890 will assess the effect on the change in IL-6 and IL-18 after 3 weeks of treatment at 
each dose level as compared to placebo in a dose-response model, separately for the two 
biomarkers. The primary analysis for MAS825 will assess the effect on the change in IL-6 
compared to placebo after 3 weeks of treatment. 
Trial Design: 
• Parallel-group, placebo-controlled, multi-center Phase 2a study 
• Patients with coronary heart disease and TET2 or DNMT3A CHIP (variant allele frequency 
[VAF] ≥2%) 
• Investigator- and participant-blinded; matching placebo 
• Randomization on Day 1 
The trial will be comprised of: 
• A total study duration of approximately 21 weeks 
• A screening period of up to 30 days 
• A treatment duration of approximately 12 weeks 
• Intra-individual study drug uptitration at approximately 3-week intervals over 4 dosing 
periods 
• The visit frequency will include one Screening visit within the 30-day screening period 
followed by visits at approximately Day 1, 22, 43, 64, 85, 92, and a safety follow-up 
phone call at Day 114 

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Brief Summary: 
Cardiovascular diseases (CVD) remain the leading cause of disease burden in the world. 
Persistent inflammation is common in populations at increased risk of CVD events and 
medications that reduce inflammation have been linked to improved CVD outcomes. Inhibition 
of IL-1β and IL-18, either by inhibition of the NOD-, LRR- and pyrin domain-containing 
protein 3 (NLRP3) inflammasome or direct neutralization with a bispecific monoclonal 
antibody (mAb), may safely and effectively lower the risk of CVD among people with known 
heart disease and TET2 or DNMT3A CHIP (VAF ≥2%). This Phase 2a clinical trial will 
evaluate the effectiveness, safety, and tolerability of increasing dose strengths of an oral daily 
medication, DFV890, administered for 12 weeks, or a single s.c. dose of MAS825, to reduce 
key markers of inflammation related to CVD risk, such as IL-6 and IL-18, in approximately 
28 people with known coronary heart disease and TET2 or DNMT3A CHIP (VAF ≥2%). 
Treatment of interest 
The treatment of interest is oral daily DFV890 at various dose levels (10 milligram (mg), 25 mg, 
50 mg and 100 mg daily), or a single s.c. dose of MAS825 (
 mg), or placebo. 
Number of Participants: 
The study population is comprised of male and female adults. A total of approximately 
28 participants will be enrolled to study intervention. 
Key Inclusion criteria 
• Male and female participants aged between 18 - 80 years (inclusive) at the start of 
screening will be included. 
• Participants must have a body mass index (BMI) within the range of 18 - 40 kg/m2 at 
screening. BMI = Body weight (kg) / [Height (m)]2. 
• Documented spontaneous myocardial infarction (MI) (diagnosed according to the 
universal MI criteria with or without evidence of ST segment elevation) at least 30 days 
before the start of screening (Thygesen et al 2007). 
• Known presence of CHIP, restricted to driver mutations in TET2 or DNMT3A with a VAF 
≥2%, as documented in the participant's medical history. 
• For participants on statin therapy (HMG-CoA reductase inhibitor) as clinically indicated, 
participants must be on a stable regimen (at least 4 weeks before randomization), with no 
planned statin dose changes over the course of the trial treatment period. Unplanned statin 
dose changes during the trial treatment period may occur. 
Key Exclusion criteria 
• Patients receiving concomitant medications that are known to be strong or moderate 
inducers of cytochrome CYP2C9 enzyme and/or strong inducers of CYP3A, strong 
inhibitors of CYP2C9 and/or strong or moderate inhibitors of CYP3A and the treatment 
cannot be discontinued or switched to a different medication within 5 half-lives or 1 week 
(whichever is longer) prior to Day 1 and for the duration of the study. 
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• At screening, pre-malignant clonal cytopenias or clonal cytopenia of unknown 
significance (CCUS). 
• History of ongoing, chronic, or major recurrent infectious disease, at the discretion of the 
Investigator, at the start of screening. 
• Patients with suspected or proven immunocompromised state at screening. 
• Use of any biologic drugs targeting the immune system within 26 weeks of Day 1. 
• Major non-cardiac surgical or major endoscopic procedures within the past 6 months prior 
to the start of screening. 
• Multi-vessel coronary artery bypass graft (CABG) surgery within the past 3 years prior to 
the start of screening. 
• Planned coronary revascularization (percutaneous coronary intervention (PCI) or CABG) 
or any other major surgical procedure during the study (until End of Study (EOS)). 
• Symptomatic Class IV heart failure (New York Heart Association [NYHA]) at the start of 
screening. 
• Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception for at 
least 3 months prior to first drug administration (Day 1), during dosing and for 5 months 
after Day 1. 
Treatment Groups: 
Active treatment: DFV890 administered orally once daily (QD) at various doses (0 mg 
[matching placebo], 10 mg, 25 mg, 50 mg, 100 mg) over four dosing periods of approximately 
3 weeks each, for a total of approximately 12 weeks of treatment or a single s.c.dose (
mg) 
of MAS825 or matching placebo. Randomized to one of five treatment sequences comprised of 
various doses of DFV890, or a single s.c. dose of MAS825, and/or placebo. Investigational 
study treatment dose adjustments and/or interruptions are not permitted. 
Data Monitoring/Other Committee: No 
Key words 
Coronary heart disease, CHIP, inflammatory marker reduction, NLRP3 inflammasome 
inhibitor 
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1.2 
Schema 
Figure 1-1 
Study design 
 
1.3 
Schedule of activities (SoA) 
The SoA lists all of the assessments when they are performed. All data obtained from these 
assessments must be supported in the participant’s source documentation. The “X” in the table 
denotes the assessments to be recorded in the clinical database or received electronically from 
a vendor. The “S” in the table denotes the assessments that are only in the participant’s source 
documentation and do not need to be recorded in the clinical database. 
Participants should be seen for all visits/assessments as outlined in the SoA or as close to the 
designated day/time as possible. Missed or rescheduled visits should not lead to automatic 
discontinuation. 
Participants who discontinue from study should be scheduled for a final evaluation visit if they 
agree, as soon as possible, at which time all of the assessments listed for the EOS visit will be 
performed. At this final visit, all dispensed investigational product should be reconciled, and 
the adverse events (AEs) and concomitant medications not previously reported must be 
recorded on the Case Report Form (CRF). 
Every effort will be made to take pharmacokinetic (PK) samples at the protocol-specified time. 
The preferred sequence of assessments and data collection during study visits is shown below 
in Figure 1-2. For visits during which the participant is scheduled to take study treatment, all 
assessments will be conducted pre-dose administration. 
Figure 1-2 
Recommended order of assessments 
 
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As per Section 4.5, 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) (OHP) 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 OHP, 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. 

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Table 1-2 
Assessment Schedule 
Period 
Screening 
Treatment 
Follow-Up 
 
Visit Name 
Screening 
Day 12 
Day 222 
Day 432 
Day 642 
EOT 
EOS 
Safety Follow Up Call 
Visit Numbers1 
1 
101 
102 
103 
104 
199 
299 
 
Days 
-30 to -1 
1 
22 
±2 
43 
±2 
64 
±2 
85 
±2 
92 
±2 
114 
±5 
Informed consent 
X 
  
  
  
  
  
  
  
Genetic consent 
X 
  
  
  
  
  
  
  
Inclusion / Exclusion criteria 
X 
  
  
  
  
  
  
  
Demography 
X 
  
  
  
  
  
  
  
Medical history/current 
medical conditions 
X 
  
  
  
  
  
  
  
Pregnancy and assessments 
of fertility3 
S 
S 
S 
S 
S 
S 
S 
  
Physical Examination 
S 
S4 
S4 
S4 
S4 
S 
S 
  
Body Height 
X 
  
  
  
  
  
  
  
Body Weight 
X 
  
  
  
  
X 
X 
  
Body Temperature 
X 
X 
X 
X 
X 
X 
X 
  
Pulse rate 
X 
X 
X 
X 
X 
X 
X 
  
Blood Pressure 
X 
X 
X 
X 
X 
X 
X 
  
Electrocardiogram (ECG) 
X 
  
  
  
  
X 
X 
  
Clinical Chemistry 
X 
X 
X 
X 
X 
X 
X 
  
Hematology 
X 
X 
X 
X 
X 
X 
X 
  
Coagulation Panel 
X 
X 
  
  
  
X 
X 
  
Urinalysis 
X 
X 
  
  
  
X 
X 
  
Randomization 
  
S 
  
  
  
  
  
  
Dose administration 
  
X5 
  
  
Dose uptitration 
  
  
S 
S 
S 
  
  
  
Drug accountability6 
  
  
S 
S 
S 
S 
  
  

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Period 
Screening 
Treatment 
Follow-Up 
 
Visit Name 
Screening 
Day 12 
Day 222 
Day 432 
Day 642 
EOT 
EOS 
Safety Follow Up Call 
Visit Numbers1 
1 
101 
102 
103 
104 
199 
299 
 
Days 
-30 to -1 
1 
22 
±2 
43 
±2 
64 
±2 
85 
±2 
92 
±2 
114 
±5 
hsCRP 
X 
X 
X 
X 
X 
X 
X 
  
IL-6 and IL-18 cytokines 
X 
X 
X 
X 
X 
X 
X 
  
PK blood collection for 
DFV890 
  
  
X7 
X7 
X7 
X7 
X 
  
PK blood collection for 
MAS825 
  
X 
X 
X 
X 
X 
  
  
Immunogenicity 
  
X 
  
X 
  
X 
  
  
Blood collection for soluble 
biomarkers8 
  
X 
X 
X 
X 
X 
  
  
Immunophenotyping9 
  
X 
X 
X 
X 
X 
X 
  
Lipid Parameters 
  
X 
X 
X 
X 
X 
X 
  
Target capture biomarker for 
MAS82510 
  
X 
X 
X 
X 
X 
  
  
CYP genotyping11 
  
X 
  
  
  
  
  
  
CHIP genotyping11 
  
X 
  
  
  
X 
  
  
Skin microbiome collection12 
  
X 
X 
X 
X 
X 
  
  
Exploratory DNA Sampling 
(optional)13 
  
X 
  
  
  
  
  
  
Concomitant medications 
X 
  
Adverse Events 
X 
  
Serious Adverse Events 
X 
Study completion 
information 
  
  
  
  
  
  
X 
  

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Period 
Screening 
Treatment 
Follow-Up 
 
Visit Name 
Screening 
Day 12 
Day 222 
Day 432 
Day 642 
EOT 
EOS 
Safety Follow Up Call 
Visit Numbers1 
1 
101 
102 
103 
104 
199 
299 
 
Days 
-30 to -1 
1 
22 
±2 
43 
±2 
64 
±2 
85 
±2 
92 
±2 
114 
±5 
Safety Follow up Call 
  
  
  
  
  
  
  
S 
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 structure given for internal programming purpose only 
2 All assessments should be done pre-dose 
3 Serum pregnancy test 
4 Brief physical exam, including rash assessment 
5 Last dose administration on Day 84 at home prior to EOT visit on Day 85 
6 IMP administration in the final 2 days before the next study visit as well as timing of the final dose before the next study visit should be confirmed with the participant 
7 The sample taken on the study visit day must be taken approximately 24h (+/-2h) after the dose from previous day (ex: Day 22 pre-dose sample is 24 hours +/-2 hours 
after the timing of the Day 21 dose). Sample to be taken pre-dose. 
8 May include but not limited to sASC, hsIL-1b, CXCL9, CXCL10, hsIFNg, vWF, protein profiling etc. in serum/plasma 
9 May include but not limited to myeloid/lymphoid cell activation/enumeration, Whole Blood/PBMCs, etc. 
10 Serum for total IL-18, IL-18 binding protein, and total IL-1b 
11 To be performed for exploratory assessment only at End of Study 
12 Assessment may or may not be performed based on participant's exposure to antimicrobial treatments 
13 Genetic ICF must be obtained before the optional DNA sampling 

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2 
Introduction 
2.1 
Study rationale 
The purpose of this study is to evaluate the efficacy, safety, and tolerability of intra-individual 
dose escalation of oral DFV890 or a single subcutaneous (s.c.) dose of MAS825 in reducing 
circulating levels of inflammatory markers in adult participants with known coronary heart 
disease and presence of Clonal Hematopoiesis of Indeterminate Potential (CHIP). The results 
of the study will be used to inform future development plans for DFV890 and MAS825 in 
cardiovascular disease (CVD) event risk reduction. 
2.2 
Background 
CVD remains the leading cause of disease burden in the world. The estimated global prevalence 
of CVD doubled from 271 million in 1990 to 523 million in 2019 (Roth et al 2020). 
A substantial residual risk for CVD events related to chronic inflammation remains despite 
standard of care (SoC) management of classic risk factors (diabetes, hypertension, lipids, etc.). 
Atherosclerotic CVD is a condition commonly characterized by an elevated inflammatory state. 
Arterial inflammation and endothelial dysfunction play key roles at all stages of the 
atherothrombotic process. Inflammatory mediators are intimately implicated with the cascade 
of events leading to atherosclerotic plaque initiation, progression and rupture. Vascular 
endothelial cells express a variety of adhesion molecules that recruit monocytes when 
chronically exposed to noxious stimuli or pathological conditions. Adverse conditions such as 
hyperlipidemia are associated with enrichment of a pro-inflammatory subset of monocytes. 
These monocytes apparently enter the intima under the influence of chemotactic stimuli and 
engulf modified low density lipoprotein (LDL) and cholesterol crystals (Duewell et al 2010). 
The material internalized by phagocytes induces phagolysosomal damage and subsequent 
leakage of contents into cytosol to activate inflammasomes and caspase 1, and consequently the 
generation of interleukin-1β (IL-1β) from pro-interleukin-1β. 
Interleukins are key mediators in the chronic vascular inflammatory response in CVD and have 
been demonstrated in animal models and in humans to be potent modulators of 
pro-inflammatory processes. The fact that these cytokines and their receptors are highly 
expressed and are functional in almost all cell types implicated in the pathogenesis of 
atherosclerosis including smooth muscle cells, certain subset of macrophages and T cells, as 
well as endothelium, support the role of interleukins in vascular disease. For example, IL-1β is 
a potent smooth muscle cell mitogen, an activator of endothelial cells and increases extra 
cellular matrix and collagen deposition, which plays a role in plaque burden and arterial 
thickening. Furthermore, lack of IL-1β or ablation of IL-1 receptor has been shown to decrease 
severity of atherosclerosis in apoE deficient mice. 
Clinical evidence from the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome 
Study) clinical trial demonstrated that IL-1β neutralization with canakinumab can reduce 
cardiovascular risk by approximately 15% in patients who have had a prior myocardial 
infarction (MI) and elevated high-sensitivity C-reactive protein (hsCRP). Patients in the 
CANTOS trial that had lower on-treatment levels of IL-6 and hsCRP had even greater CVD 

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benefit (approximately 25-35%). IL-1β signalling promotes the release of IL-6 and hsCRP, and 
lower on-treatment levels may identify post-MI patients with the greatest potential CVD 
benefit. In post-hoc subgroup analyses in CANTOS, two populations demonstrated 
substantially increased residual risk of CVD that was not completely addressed by IL-1β 
neutralization. First, patients with increased IL-18 levels at baseline in CANTOS had an 
increased risk of major adverse cardiovascular event (MACE) (15% increase in risk [95% 
confidence interval (CI) 3-29%, p=0.02] for each tertile increase in baseline IL-18), 
corroborating other preclinical findings implicating IL-18 in CVD pathogenesis 
(Ridker et al 2020). Second, patients in CANTOS with evidence at baseline of CHIP were 
found to have higher risk of MACE during the trial follow-up as compared to patients without 
CHIP (Svensson et al 2022). 
CHIP refers to the presence of clonal populations of hematopoietic stem cells that occur in 
absence of diagnostic criteria for hematologic malignancy, in absence of morphological 
variation in blood cells, and with candidate driver gene mutations at variant allele frequency 
(VAF) of at least 2% in peripheral blood (Steensma et al 2015). CHIP is a disorder of aging 
with about 15% of people affected by 75 years of age. The risk of coronary heart disease for 
individuals with CHIP is approximately 2-times greater than in non-carriers matched for CVD 
factors including age, sex, type 2 diabetes and smoking history, with higher cardiovascular risk 
among individuals with large clones (VAF >10%) (Jaiswal et al 2017). Small hematopoietic 
clones (eg. VAF >0.03%) can be found in almost all healthy 50 - 60 year old adults; however, 
the functional and clinical significance are unclear (Marnell et al 2021). 
In murine models, there is data suggesting a causative role of CHIP in development of both 
atherosclerosis and cardiac dysfunction (Fuster et al 2017, Sano et al 2018). CHIP likely 
contributes to CVD risk through enhanced inflammation, including increased NOD-, LRR- and 
pyrin domain-containing protein 3 (NLRP3) activation. Analysis of the CANTOS data revealed 
that patients with CHIP, particularly CHIP due to somatic mutations in the TET2 gene, were 
found to have over 60% higher risk of MACE during the trial follow-up as compared to patients 
without CHIP (Svensson et al 2022). Mutations in epigenetic regulators (DNMT3A and TET2) 
account for approximately 80% of CHIP and are linked to a pro-inflammatory state 
(Marnell et al 2021). 
CVD is a heterogenous disorder, and the presence of CHIP may mark individuals with a greater 
inflammatory driven contribution to CVD pathogenesis and potentially greater response to 
targeted anti-inflammatory therapies. Therapeutic approaches that target additional 
inflammatory pathways (either upstream with NLRP3 inhibition via DFV890 or downstream 
with IL-1β and IL-18 cytokine capture with MAS825) and selecting populations with the 
potential for greater response to anti-inflammatory therapy (i.e., CHIP) may further attenuate 
the residual CVD risk seen in CANTOS. 
DFV890 is a potent, small molecule inhibitor of the NLRP3 inflammasome pathway. DFV890 
blocks IL-1β secretion, IL-18 secretion and pyroptotic cell death in response to a wide variety 
of NLRP3-dependent danger signals in vitro and in mechanistic mouse models in vivo, 
suggesting that NLRP3 inhibition could have improved efficacy over canakinumab in diseases 
where IL-1β and IL-18 both drive pathology. Through the production of IL-1β and IL-18, the 
NLRP3 inflammasome has been implicated as a major driver of inflammation associated with 
chronic inflammatory diseases. Mechanistically, NLRP3 senses a diverse range of danger 

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signals, and reacts by forming an inflammasome protein complex that drives an ensuing 
inflammatory response. Via genetic knockouts (Duewell et al 2010) or pharmacological 
inhibition (Hettwer et al 2022), abrogation of NLRP3 function is protective in mouse models 
of atherosclerosis, exerting a beneficial effect on both peripheral inflammatory leukocytes and 
cytokines, and local anti-inflammatory effects in the atherosclerotic plaque. 
DFV890 was evaluated in a completed Phase 1 first-in-human (FIH) trial in healthy volunteers 
(CDFV890A02101), a Phase 2 SARS-CoV-2 (COVID-19) trial (CDFV890D12201) and is 
being assessed in ongoing Phase 2 clinical trials in familial cold auto-inflammatory syndrome 
(CDFV890A12201), osteoarthritis (CDFV890B12201), and myelodysplastic syndrome 
(CDFV890G12201). 
MAS825 is a 
 bispecific monoclonal antibody (mAb) against human IL-1β and 
human IL-18 derived from 
(anti-IL-1β or 
) and 
 (anti-
IL-18) antibodies. MAS825 was evaluated in a completed Phase 1 FIH trial in healthy 
volunteers (CMAS825A02101), a Phase 2 COVID-19 trial (CMAS825F12201) and is being 
assessed in ongoing Phase 2 clinical trials in patients with nucleotide-binding oligomerization 
domain-like receptor family caspase activation and recruitment domain-containing 4 protein 
(NLRC4) gain-of-function (NLRC4-GoF) mutations (CMAS825D12201) and hidradenitis 
suppurativa (HS) (platform study CCFZ533H12201BC). 
MAS825 can neutralize IL-1β and IL-18 driven effects regardless of the source of the cytokines, 
while DFV890 can reduce NLRP3 inflammasome driven production of IL-1β and IL-18. 
The relative contribution of the NLRP3 inflammasome to circulating cytokine levels in the 
CHIP population with known coronary heart disease is unknown. DFV890 tablets are taken 
orally (daily administration evaluated in this study) and MAS825 solution is injected 
subcutaneously (
 
, with only a single dose being evaluated in this study). A key marker of response, 
IL-6 levels, which robustly predicted CVD benefit in the CANTOS trial, will be used as a 
primary endpoint in this trial. In addition, for DFV890, IL-18 levels will be used a co-primary 
endpoint to capture the additional potential benefit above and beyond the IL-1β/IL-6/hsCRP 
pathway. IL-18 levels cannot be accurately used as an endpoint for MAS825 as the mAb binds 
to IL-18; although exploratory assays of total IL-18 and downstream markers of IL-18 
activation, such as interferon-γ (IFN-γ), CXCL9, and CXCL10 will be incorporated. 
Through the inhibition of IL-1β and IL-18, DFV890 and MAS825 have the potential to 
significantly reduce cardiovascular risk in patients. The safety profile, pharmacodynamic (PD) 
effects, and risk-benefit ratio support further studies of DFV890 and MAS825 to reduce 
inflammatory markers, and eventually MACE, in patients with known coronary heart disease 
and CHIP. 
2.3 
Benefit/Risk assessment 
It is not known whether there will be a benefit for participants with known coronary heart 
disease and CHIP with DFV890 or MAS825 treatment. The CANTOS trial demonstrated 
reduction in cardiovascular risk in this population with canakinumab and IL-1β inhibition. 
Improved efficacy over canakinumab may be achieved by inhibiting both IL-1β and IL-18 with 
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either NLRP3 inhibition or direct neutralization with a bispecific mAb; however, this has not 
yet been demonstrated. 
Based on the clinical experience with DFV890 and MAS825 from Phase 1 FIH studies 
(CDFV890A02101 and CMAS825A02101), the Phase 2 studies in patients with COVID-19 
(CDFV890D12201 and CMAS825F12201), safety monitoring in ongoing clinical trials, 
relevant non-clinical findings, the biological understanding of the pathways and their relevance 
to CVD, the overall risk-benefit of both compounds is, to date, considered favorable. The 
available clinical, safety, and laboratory assessments from the FIH studies and the COVID-19 
study show that DFV890 and MAS825 are generally well-tolerated and have manageable safety 
profiles. Potential compound risks are described in more detail in the following sections and the 
respective Investigator's Brochures (IBs). 
In summary, based on the available non-clinical and clinical data, the potential risks to be 
considered shared by both DFV890 and MAS825 include potential risks related to: 1) 
infections, 2) vaccinations, 3) changes in hematologic parameters, 4) hypersensitivity to any 
component of the drug product, and 5) considerations for women of child-bearing potential 
(WOCBP). The potential risks to be considered for DFV890 include: 1) self-limiting skin 
rash/pruritis, 2) renal abnormalities in preclinical models, and 3) drug interactions linked to 
metabolism by CYP2C9 and CYP3A4 enzymes. The potential risks to be considered for 
MAS825 include: 1) immunogenicity (IG) and 2) metabolic abnormalities. In addition to the 
risks noted above, there may be risks for DFV890 or MAS825 that are unforeseen and serious. 
The risk to participants in this trial may be minimized by adherence to the eligibility criteria, 
study procedures, stopping rules, and close clinical monitoring. Appropriate eligibility criteria, 
and specific dose-limiting toxicity definitions, as well as specific stopping rules, are included 
in this protocol. Please refer to the IBs for additional information. 
2.3.1 
Risks shared by both DFV890 and MAS825 
2.3.1.1 
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. Moreover, the target 
NLRP3 is not essential for health (NLRP3 deficient mice are viable and fertile). 
 
 
 
 
 
 
 These findings 
were not seen in a previous 13-week toxicology monkey study, which had higher systemic 
exposures. 
Similarly, MAS825 is not expected to elicit broad immune suppression, rather selectively 
neutralize the pro-inflammatory IL-1β and free/bioactive IL-18. 
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The risk for patients in currently ongoing trials is considered low based on safety margins and/or 
short treatment duration. To mitigate potential risks of immune suppression and infection in this 
study, immune suppressive treatments are prohibited to be administered 28 days or 5 half-lives, 
whichever is longer, prior to screening and concurrent use of these treatments is also prohibited. 
Participants with known or suspected immunodeficiency state or evidence of active or latent, 
serious bacterial, fungal or viral infections will also be excluded. See Section 5.2. 
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 thereof (e.g., prompt antibiotic 
therapy for bacterial infections, anti-viral treatment for herpes simplex or zoster or SARS-CoV-
2, etc.) in consultation with infectious disease experts, as appropriate. 
2.3.1.2 
Potential risk and guidance on vaccinations 
To mitigate the risk from live vaccinations, participants who have received live vaccinations 
within one month prior to the first dose of the study will be excluded from entry in this study. 
Additionally, it is recommended that all participants should complete all immunizations in 
accordance with current immunization guidelines at least one month prior to administration of 
the first dose (Day 1). 
Approved (including Health Authorities’ conditional marketing authorization) killed, 
inactivated, peptide, DNA and RNA vaccines are permitted according to the investigator’s 
discretion and per local guidance.  Due to the mechanism of action of DFV890 and MAS825, 
specifically targeting the NLRP3 inflammasome or downstream cytokines IL-1β and IL-18, it 
is unlikely that treatment with this compound would interfere with vaccination responses. 
However, no specific preclinical nor clinical investigations of vaccine efficacy have been 
conducted to date with DFV890 or MAS825. 
2.3.1.3 
Potential risk and recommended monitoring of hematological 
parameters 
For DFV890, transient asymptomatic decreases in absolute neutrophil count (ANC) and white 
blood cell (WBC) were observed in the CDFV890A02101 FIH and CDFV890D12201 COVID-
19 studies. These transient self-limiting decreases in ANC and WBC were not associated with 
an increased risk of infection which could be consistent with a PD effect of DFV890 resulting 
from inhibition of IL-1β signaling downstream of NLRP3 (NLRP3 blockade, similar to known 
effects of canakinumab). 

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For MAS825, transient decreases in WBC and ANC may also occur with mAb inhibition of 
IL-1β as seen in the CANTOS study with canakinumab. In addition, transient decreases in 
platelet counts were observed following canakinumab treatment of inflammatory disorders, and 
dose-dependent decreases in platelet counts were observed in small numbers of patients in 
CANTOS. Based on the safety data available from the canakinumab clinical trials program, no 
correlation between reduced platelet counts and bleeding has been identified. 
As a precaution, all patients with suspected or known immunodeficiencies will be excluded 
from this study. In addition, patients with cytopenias (such as persistent neutropenia 
(ANC < 1.8 × 109/L), and/or thrombocytopenia (platelets < 150 × 109/L)) will also be excluded 
from entry into this study (see Section 5.2). Complete blood counts will be monitored in this 
study. Subjects should be alert for the appearance of symptoms (bleeding from gums or nose) 
and signs of thrombocytopenia (purpura, petechiae, ecchymoses). Investigators should consider 
treatment of severe thrombocytopenia (<50x109/L) based on clinical assessment and/or 
evidence of bleeding in consultation with a hematologist, as appropriate. 
2.3.1.4 
Potential risk and recommended treatment of hypersensitivity 
reactions 
Treatment with DFV890 is contraindicated in people with hypersensitivity to any component 
of the drug product. 
As with most biologic compounds, administration of MAS825 carries the risk of anaphylaxis 
and/or hypersensitivity-type reactions. In the event of such a reaction, treatment with 
antihistamines and glucocorticoids may be considered, as clinically indicated. Depending on 
severity, patients may also require supplemental oxygen, volume expansion, catecholamines, 
and transfer to an intensive care setting. Plasmapheresis to decrease the systemic concentration 
of MAS825 may be considered dependent on the patient's condition. Patients should be 
observed for at least four hours after resolution of signs and symptoms, and those who have 
experience severe infusion reactions should be closely observed for 24 hours after resolution 
because of the risk of a biphasic episode. Based on the clinical experience to date with MAS825, 
 (
, anti-IL-1β mAb component), and 
 (anti-IL-18 mAb 
component), the risk of a hypersensitivity reaction is considered low. 
2.3.1.5 
Potential risks and guidance related to WOCBP 
At this stage of development, DFV890 has not yet been studied in reproductive toxicology 
studies, and WOCBP and sexually active males must be informed that taking the study 
treatment may involve unknown risks to the fetus if pregnancy were to occur during the study, 
and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. Based on an in vitro induction of CYP3A4, there 
is a slight potential risk for a drug-drug interaction (DDI) of DFV890 with hormonal 
contraception at high exposures, therefore oral hormonal contraception is allowed, but must be 
supplemented with a barrier method, preferably a male condom. If there is any question that the 
participant will not reliably comply, they should not be entered or continue in the study. 
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There is no available reproductive toxicity data for MAS825 nor clinical experience with the 
mAb in human pregnancies. 
 to other 
 antibodies, MAS825 may have 
cross-placental transfer. The potential of placental transfer can be influenced by many 
factors (maternal level of the total 
 specific antibodies and their subclasses, gestational 
age and placental integrity) (Palmeira et al 2012). 
Thus, WOCBP can be included if they fulfill the following criteria: 
• Practice highly effective contraception for at least  months prior to screening;  
• Have a negative pregnancy test at the time of screening; pregnancy tests at each treatment 
visit, follow-up visit and at the end of the follow-up period; 
• Practice highly effective contraception during the treatment period (with oral hormonal 
contraception supplemented by a barrier method, preferably a male condom), 
• Practice highly effective contraception for months following the first drug 
administration on Day 1 (when participants may have received a single dose of MAS825 
s.c., which is longer than the guidance for DFV890 for highly effective contraception until 
7 days following completion of DFV890 treatment) 
Pregnant and/or lactating women are also excluded. 
Additionally, WOCBP should avoid becoming pregnant while their male partners are 
participating in this study. Male participants must agree to abstain from donating sperm and 
from either any sexual activity with a female partner or to practice highly effective 
contraception, i.e., barrier protection (condom) with a female partner who is using an 
intrauterine device (IUD) or hormonal contraception and for at least 90 days following 
completion of treatment and should not father a child in this period. 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 during study treatment and for at 
least 90 days following completion of treatment. 
2.3.2 
DFV890 compound risks 
2.3.2.1 
Potential risk of skin rash and recommended monitoring 
In the CDFV890A02101 FIH study, 12 subjects out of 94 treated with DFV890 reported 
maculopapular rash and/or pruritus. The subjects had been administered DFV890, either after 
a single dose of 100 milligram(s) (mg) as crystalline tablet (n=1) or 600 mg as a spray-dried 
dispersion (SDD) suspension (n=1), or after 30 mg once daily (QD) as crystalline suspension 
(n=2), 100 mg QD (n=3) or 200 mg QD (n=2) as SDD suspension, or 50 mg twice daily (b.i.d.) 
as encapsulated crystalline tablet (n=3). For 10 of these subjects, these adverse events (AEs) 
led to treatment discontinuation. These AEs were transient, of mild to moderate intensity, and 
not associated with other symptoms, clinical findings, or changes in laboratory parameters. 
These AEs generally started within 1 to 17 days after initiation of treatment with DFV890 
(within 1 to 9 days after a single dose, or within 7 to 17 days after initiation of multiple dose 
administration). They resolved within 1 to 18 days after onset (rashes within 3 to 18 days and 
pruritus within 1 to 5 days); in all cases without concomitant treatment.  None of these were 
associated with other symptoms, clinical findings or changes in clinical laboratory parameters. 
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In the completed CDFV890D12201 Phase 2 study in COVID-19, 70 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, with 
treatment administered to 6 out of the 7 participants. 
In this trial with patients with known coronary heart disease and CHIP, up-titration of DFV890 
doses may reduce incidence of rash; however, that has yet to be demonstrated. 
Investigators should be vigilant for symptoms of pruritus and signs of rash (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 6.4.1 for recommended management of maculopapular/pruritic rashes. 
2.3.2.2 
Potential risk of renal abnormalities and recommended monitoring 
In non-clinical studies of DFV890, analysis of the data from the 13-week GLP repeat-dose study 
in rats showed unexpected adverse effects in kidneys consistent with obstructive nephropathy 
at doses ≥100 mg/kg/day accompanied by changes in kidney-specific urinary and blood 
parameters. In the non-clinical monkey studies, up to 13 weeks (4- and 13-week GLP studies, 
at doses up to 
 mg/kg/day) no adverse effects on kidneys or renal function were 
observed. 
 
 
 
 
Clinically, in the CDFV890A02101 FIH and CDFV890D12201 COVID-19 studies, based on 
available clinical safety data from both studies, there has been no evidence of adverse effects 
on kidneys or renal function related to DFV890 administration in COVID-19 participants and 
healthy participants. 
Although it is not clear whether there are potential effects of DFV890 on kidney in humans, 
markers of renal function including electrolytes, creatinine and blood urea nitrogen 
(BUN)/Urea, and urinalysis will be monitored in this study (see Section 8.4.4 for further details 
and guidance). 
2.3.2.3 
Potential risk due to CYP2C9 polymorphism and guidance on prior 
and concomitant medications and other substances 
Clinical studies to investigate drug-drug interactions using cytochrome P450 (CYP) 
substrates/modulators and DFV890 have not been performed yet, but, based on in vitro data, 
DFV890 PK may be affected by CYP2C9 and/or CYP3A4 interactions. Due to the polymorphic 
character of CYP2C9, the major enzyme involved in DFV890 metabolism, patients who are 
intermediate or poor CYP2C9 metabolizers can have up to -fold higher exposure to DFV890 
compared to patients with normal CYP2C9 function. An additional risk of increased DFV890 
plasma exposure exists when co-administered with CYP2C9 and CYP3A inhibitors due to DDI, 
which is most pronounced for poor CYP2C9 metabolizers. A risk of decreased DFV890 
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exposure to sub-therapeutic levels exists when co-administered with CYP2C9 and CYP3A 
inducers (for more details see IB and Section 6.8). Therefore, strong and moderate inducers of 
CYP2C9 enzyme, strong inducers of CYP3A, strong inhibitors of CYP2C9, and/or strong or 
moderate inhibitors of CYP3A are prohibited in the study (Section 6.8.2). 
Due to its in vitro weak-to-moderate CYP3A4 induction potential, DFV890 can potentially 
decrease systemic exposure of sensitive CYP3A4 substrates by approximately 2-fold of some 
oral hormonal contraceptives which are CYP3A4 substates (e.g., ethinylestradiol), by 20-30%. 
Therefore, oral hormoned-based contraceptives may not be considered as highly effective 
contraception method (unless supplemented by a barrier method, preferably a male condom) 
until the DDI risk is evaluated in dedicated clinical studies. 
Considering clinical safety profile of DFV890, treatment duration and/or dose and sufficient 
safety margins, administration of DFV890 is considered safe. 
2.3.3 
MAS825 compound risks 
2.3.3.1 
Potential risk for immunogenicity 
As with other therapeutic antibodies, there is a possibility of MAS825 inducing an immune 
response in human subjects. The consequence of IG may be altered pharmacokinetics (PK) and 
PD properties of the drug, leading to a potential loss in efficacy. There is also a theoretical 
possibility of immune-mediated reactions. It is important to note that the occurrence of anti-drug 
antibodies (ADA) and resulting ADA-mediated immune reactions in animals are generally not 
considered predictive of the same responses in humans and that severe responses to mAb in 
humans are rare (Bugelski, Treacy 2004, Rojko et al 2014). Regardless, ADA monitoring is 
included in this study. 
In vitro evaluation of MAS825 has shown a low risk for immunogenicity. In the FIH study with 
MAS825 (CMAS825A02101), immunogenicity in response to MAS825 
 
across different cohorts and time points 
. 
 
exhibited an unexpected PK/PD profile or experienced adverse effects suggestive for 
immunogenicity. 
2.3.3.2 
Potential risk for metabolic abnormalities 
In preclinical studies of MAS825, two isoforms of LDL receptor (LDLR) were identified as 
 off-targets; however, no effects on cholesterol nor LDL were observed in the 
26-week toxicity study in non-human primates (marmosets). MAS825 was tested in a functional 
assay by monitoring uptake of LDL in 
 (human cell line expressing LDLR). MAS825 
inhibited LDL uptake from 
 μg/mL, reaching 
% inhibition at  mg/mL, 
providing a further safety factor of 
 to the predicted Cmax of 
 μg/mL 
at 
mg/kg intravenous (i.v.) for human. Lipid parameters will be monitored in this study. 
2.3.4 
Blood sample volume 
A volume smaller than a typical blood donation is planned to be collected over a period of 
approximately 22 weeks, from each participant as part of the study.  Additional samples may 
be required for safety monitoring. 
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Timings of blood sample collection are outlined in Section 1.3, SoA. 
3 
Objectives, endpoints, and estimands 
Table 3-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To evaluate the effect of various 
dose levels of DFV890 versus 
placebo to reduce circulating levels 
of inflammatory markers in 
participants with coronary heart 
disease and CHIP 
• 
Serum levels of IL-6 and IL-18 at 3 weeks after the 
start of a DFV890 dosing period 
• 
To evaluate the effect of MAS825 
versus placebo to reduce circulating 
levels of inflammatory markers in 
participants with coronary heart 
disease and CHIP 
• 
Serum level of IL-6 at 3 weeks after a single s.c. 
dose of MAS825 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate the safety and 
tolerability of DFV890 and MAS825 
in participants with coronary heart 
disease and CHIP 
• 
Adverse events, and parameters from safety 
assessments, including vital signs, 
electrocardiograms (ECGs), and laboratory 
assessments (urine and blood) 
• 
To assess the PK of DFV890 in 
participants with coronary heart 
disease and CHIP 
• 
Plasma trough concentrations (Ctrough) of DFV890 
at steady-state 
• 
To assess the PK of MAS825 in 
participants with coronary heart 
disease and CHIP 
• 
Serum concentrations of MAS825 after a single s.c. 
dose of MAS825 
Exploratory objective(s) 
Endpoint(s) for exploratory objective(s) 
• 
To assess the PK of IBW042 
a metabolite of DFV890 in plasma 
• 
Plasma Ctrough of IBW042 at various dose levels of 
DFV890 
• 
To explore whether individual 
variation in the CYP2C9 gene 
related to drug metabolism confer 
differential PK response to DFV890 
• 
Plasma Ctrough of DFV890 and its metabolite, 
IBW042, as well as CYP2C9 genotype 
• 
To assess the effect of DFV890 and 
MAS825 on PD and inflammation-
related, and CVD-related biomarkers 
(including PK/PD relationships) 
• 
PD and inflammation-related markers may include 
but are not limited to hsCRP, soluble ASC, total IL-
1β, CXCL9, CXCL10, hsIFN-γ, vWF, 
myeloid/lymphoid cell activation/enumeration by flow 
cytometry, and total IL-18 (MAS825 only) 
• 
CVD-related biomarkers may include but are not 
limited to lipid parameters (e.g., LDL, Lp(a), 
apolipoproteins) 
• 
DFV890 and MAS825 concentrations at or up to 
corresponding time point 

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Objective(s) 
Endpoint(s) 
• 
To explore genetic and proteomic 
drug-related response mechanisms, 
to understand the disease and/or the 
safety and efficacy of DFV890 and 
MAS825 
• 
Exploratory genetic and proteomic endpoints may 
include but are not limited to: 
• 
Presence of genetic polymorphisms 
• 
Presence of somatic mutations (CHIP) and 
their change from baseline 
• 
Serum or plasma proteins and their change 
from baseline 
• 
To explore the effect of DFV890 on 
changes to the skin microbiome 
• 
Skin microbiome at various visits 
3.1 
Primary estimands 
The primary clinical question of interest is: What is the effect of DFV890 and MAS825 in 
addition to SoC CVD prevention medication in patients with known coronary heart disease and 
presence of CHIP on the inflammatory markers IL-6 and IL-18 (IL-18 applicable for DFV890 
only), assuming patients continue treatment with reasonable adherence and there are no new 
major cardiovascular events, initiations of prohibited medication, or febrile infections, but 
without regard to changes in SoC CVD prevention medication? 
The justification for the estimand is that it will capture the effect of the investigational 
treatments versus placebo under research-like conditions, where participants adhere to their 
assigned treatment regimen and there is no impact of other intercurrent events on the primary 
endpoints (aside from potential changes in SoC CVD prevention medication). 
The estimand is defined by the following attributes: 
1. Population: participants with known coronary heart disease and TET2 or DNMT3A CHIP 
(VAF ≥2%) and potential SoC CVD prevention medication 
2. Endpoints: Serum levels of IL-6 and IL-18 at 3 weeks after the start of a dosing period for 
DFV890 and serum level of IL-6 at Week 3 for MAS825 
3. Treatment of interest: MAS825 or placebo single dose, DFV890 QD or DFV890 placebo 
QD 
4. Handling of intercurrent events: see Table 3-2 
5. Summary measure: the model-based difference in variable means between treatments. 
Table 3-2 
Intercurrent events for the primary estimand 
Intercurrent event 
Details (if necessary) 
Handling of event 
Permanent discontinuation of 
study treatment 
- 
Data collected after this 
intercurrent event will not be 
used for this estimand 
Incidence of a new major CVD 
event (e.g., myocardial 
infarction, stroke, etc.) 
- 
Data collected after this 
intercurrent event will not be 
used for this estimand 
Change in SoC CVD 
prevention medication 
- 
All data collected after this 
intercurrent event will be used 
for this estimand 

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Intercurrent event 
Details (if necessary) 
Handling of event 
Initiation of a prohibited 
medication for a comorbid 
condition 
Unforeseen use of any 
medication expected to have a 
sustained effect on the primary 
endpoints (i.e., any systemic 
corticosteroids) 
Data collected after this 
intercurrent event will not be 
used for this estimand 
Unforeseen use of medication 
expected to have a limited 
effect on the primary endpoints 
(i.e., any other prohibited 
medications) 
Only the assessment 
immediately following the event 
will be excluded for the 
purpose of this estimand 
New-onset febrile infection 
Febrile infection around time of 
assessment (details to be 
provided in the statistical 
analysis plan) 
Only the assessment 
immediately following the event 
will be excluded for the 
purpose of this estimand 
Nonadherence to study 
treatment (DFV890 only) 
Greater than 20% of missed 
daily doses within 3 weeks 
prior to an assessment 
Only the assessment 
immediately following the event 
will be excluded for the 
purpose of this estimand 
Any missed dose within the 2 
days prior to an assessment 
Only the assessment 
immediately following the event 
will be excluded for the 
purpose of this estimand 
The handling of each intercurrent event specified in Table 3-2, with the exception of changes 
in SoC CVD prevention medication, reflects what is referred to as the hypothetical strategy, 
which aims to mimic a scenario in which the intercurrent event did not actually occur and all 
participants had adhered to the randomized treatment throughout the course of the study. 
To enable this strategy, data from various assessments taking place after the event will be 
excluded from the primary analysis, as described in the table. The exception to this is changes 
to SoC CVD prevention medication, which will be handled by a treatment policy strategy, in 
which any occurrence of the event is ignored and the subsequent data are included in the 
analysis. 
Additional information on the handling of the intercurrent events in the primary analysis is 
described in Section 9.3.3. 
3.2 
Secondary estimands 
Not applicable. 

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4 
Study design 
4.1 
Overall design 
This is a multi-center, randomized, placebo-controlled, participant- and investigator-blinded 
study to evaluate the efficacy, safety, and tolerability of intra-individual dose escalation of 
DFV890 or a single s.c. dose of MAS825 for inflammatory marker reduction in participants 
with coronary heart disease and TET2 or DNMT3A CHIP (VAF ≥2%). The study consists of a 
screening period up to 30 days; a treatment period of approximately 12 weeks with an end of 
treatment (EOT) visit on Day 85, which is one day after the last dose of DFV890 or placebo; a 
follow-up period of approximately 1 week; and a standard safety follow-up call approximately 
30 days following the last dose. The overall study duration is approximately 21 weeks. 
Approximately 28 participants will be randomized into the trial, of which a minimum of 
approximately 40% of randomized participants will be CHIP with TET2 somatic mutations. 
For subgroup allocation, patients with TET2 or DNMT3A CHIP will be determined based on 
their most common mutation (e.g., patients with mutations in both DNMT3A + TET2 will be 
allocated to the subgroup based on the mutation with the highest VAF). Blood samples collected 
for CHIP genotyping on Day 1 and at the EOT visit will be analyzed at a central laboratory at 
EOS to explore changes in VAF, and will not be used for eligibility or subgroup allocation 
purposes. 
Participants meeting all eligibility criteria will be randomized in a 4:4:4:1:1 ratio to one of the 
five 
treatment 
sequences 
as 
shown 
in Figure 1-1 (1 
MAS825+placebo 
sequence, 
3 DFV890+placebo sequences, and 1 placebo-only sequence). Within each DFV890+placebo 
sequence, participants will start on either oral placebo or DFV890 10 mg QD. 
On Day 1, participants will receive the first oral dose of DFV890 or placebo and the single s.c. 
dose of either MAS825 or placebo. None of the treatment sequences include a combination of 
both active DFV890 and active MAS825. After initial dosing, assessments will be conducted at 
site, as specified in Section 1.3, the SoA. Participants will then be provided with a sufficient 
amount of study medication for daily dosing until their next scheduled visit. 
If applicable, the dose of DFV890 will be uptitrated (according to the specific treatment 
sequence to which the participant is assigned) approximately every three weeks at the scheduled 
visits on Days 22, 43 and 64 as shown in the study design figure (Figure 1-1). At these visits, 
efficacy, safety and tolerability assessments will be performed. Participants will take oral daily 
doses of DFV890 or placebo for a total of approximately 12 weeks. Participants will return for 
an EOT period visit on Day 85. 
After the EOT visit, participants will return approximately 1 week later on Day 92 for an End 
of Study (EOS) visit. 
All assessments specified in the SoA will be conducted at each visit. 

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4.2 
Scientific rationale for study design 
Table 4-1 
Rationale for study design 
Study Design Aspect 
Rationale 
Overall 
In this study, participants will be randomized to 
one of five treatment sequences comprised of 
various uptitrating doses of DFV890, or a single 
s.c. dose of MAS825, and/or placebo. The 
rationale behind the up-titration of DFV890 
doses within sequences is the efficiency for 
evaluating cytokine reductions that result from 
intra-individual measurements. Uptitration also 
may improve tolerability by decreasing the risk 
for rash; however, this has yet to be 
demonstrated. Clinical experience from prior 
clinical trial data with DFV890 suggests that 
most AEs, especially the emergence of rash, 
should occur within the first 17 days of dosing 
and therefore limited carry-over of the initiation 
of AEs into subsequent dosing periods is 
expected to occur. 
The uptitration of DFV890 doses and 
progressive further inhibition of the NLRP3 
inflammasome is expected to result in a peak 
cytokine reduction similar to what would be seen 
regardless of prior dose exposures. This could 
be further evaluated in a subsequent Phase 2b 
dose-range finding study. 
 A cross-over design including placebo after 
active DFV890 was not implemented as this 
could potentially confound the interpretation of 
the primary endpoints, as it is not known 
precisely when cytokine levels return to baseline 
after DFV890 with the NLRP3 inflammasome 
activation profile in this population (which may 
differ from trial populations in prior or ongoing 
studies). 
Primary Endpoints 
Serum levels of IL-6 and IL-18 at 3 weeks after 
the start of a dosing period were chosen as the 
primary endpoints for DFV890 because both 
cytokines are linked to increased risk of CVD in 
numerous clinical populations. In addition, 
preclinical models implicated IL-6 and IL-18 in 
CVD pathogenesis. In the CANTOS clinical trial 
of IL-1β inhibition, participants that had the 
lowest on-treatment IL-6 levels had the greatest 
CVD benefit. While IL-18 is associated with CVD 
risk in human populations and preclinical 
evidence supports a causal role, no 
pharmacologic intervention trials have yet 
demonstrated that IL-18 inhibition reduced CVD 
risk. 

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Study Design Aspect 
Rationale 
For MAS825, the only primary endpoint is IL-6 
levels measured 3 weeks after a single s.c. 
dose (IL-18 is not a primary endpoint for 
MAS825) as the bispecific mAb binds to IL-18 
and IL-18 levels cannot be robustly measured in 
this context but downstream markers of IL-18 
will be evaluated. 
Analysis of primary endpoints 
For participants randomized to receive active 
DFV890 treatment, each participant will 
contribute data on levels of IL-6 and IL-18 after 3 
weeks of oral daily treatment with DFV890 at up 
to 3 different dose levels, and/or placebo, 
depending on treatment sequence assignment. 
A dose-response modeling approach, which 
integrates the IL-6 and IL-18 levels across all 
dose levels and fits a dose-response 
relationship, will be utilized to quantify placebo-
adjusted reductions at the highest tested dose 
level, 100 mg daily DFV890. The rationale for 
analyzing all of the IL-6 and IL-18 data from the 
end of each 3-week dosing period together in a 
dose-response model is to take advantage of the 
efficiencies introduced by the up-titration design. 
The model treats each dosing period as 
independent of the prior period, which is justified 
because cytokine levels are expected to reach a 
maximum reduction within 7-14 days for DFV890 
and therefore the 3-week timepoint is expected 
to be at steady state reduction. The fact that 
dosing occurs in a monotonically increasing 
manner ensures that no washout between doses 
is required, as the effect is only expected to be 
greater with higher doses. It is possible that 
subsequent dose levels may reach steady state 
cytokine reduction sooner than if drug had not 
already been on board, but this will not impact 
the analysis as only the 3-week measurement is 
collected and used in the analysis. 
For participants randomized to receive active 
MAS825 treatment, the uptitration and dose-
response modeling is not applicable to a single 
dose in the MAS825 active treatment sequence. 
The IL-6 response to MAS825 will be measured 
at approximately 3 week intervals 
(corresponding to DFV890 uptitration intervals) 
during the approximately 12 week treatment 
period after only a single dose level. The level of 
IL-6 obtained 3 weeks after the single dose of 
mg MAS825 s.c. will be used for the primary 
endpoint, as the peak observed reduction of IL-6 
(when measured q3 weeks over the 12 week 
treatment period) is expected to occur at that 
point. 
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Study Design Aspect 
Rationale 
Treatment Sequences 
In Treatment Sequence 2 and Treatment 
Sequence 3, participants begin with placebo 
treatment and are followed with increasing 
doses of DFV890. Treatment Sequence 4 and 
Treatment Sequence 5 were primarily included 
to maintain the blind in each dosing period so 
that there is both active and placebo within each 
dosing period. Treatment Sequence 5, in 
addition, will generate more placebo data, which 
is useful for the primary analysis. More 
participants are allocated to Treatment 
Sequence 2 and Treatment Sequence 3 as they 
will contribute intra-individual placebo data, 
thereby making analyses more efficient. 
Treatment Sequence 1 is the only sequence that 
contributes data for a single dose of active 
MAS825. 
Randomization 
Participants will be randomized in a 4:4:4:1:1 
ratio to the 5 treatment sequences. 
Randomization is used to limit selection bias and 
decrease the chance of an imbalance in 
participant characteristics between sequences, 
thereby facilitating an unbiased assessment of 
the effect of treatment. However, with a modest 
sample size and 5 treatment sequences, 
baseline clinical characteristic imbalances may 
occur across the sequences. This has limited 
consequence in this study design as most of the 
participants serve as their own placebo controls 
with intra-individual dose-response modeling 
rather than comparison between two equal 
active and placebo treatment arms. 
Blinding 
Blinding of participants and investigators during 
the study allows for an unbiased assessment of 
study endpoints. 
Duration of study periods 
DFV890 treatment sequences: the treatment 
period of approximately 12 weeks allows for a 
gradual up-titration (up-titration occurs 
approximately every 3 weeks) to the maximal 
dose of 100 mg of DFV890. From prior clinical 
trials with DFV890, the expected peak reduction 
of cytokines occurs within the first 7-14 days, 
and therefore, approximately three weeks for 
each dosing period should allow adequate 
assessment of cytokine reduction efficacy and 
tolerability at each dose level. 
MAS825 treatment: the single dose allows 
benchmarking of NLRP3 inhibition effects 
relative to direct biologic neutralization of IL-1β 
and IL-18. MAS825 will result in the 
 reduction of 
 IL-1β and IL-18 
levels in serum and effective neutralization of IL-
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Study Design Aspect 
Rationale 
1β as well as IL-18 with reductions captured at 
each 3 week assessment in the 12 week 
treatment period. The follow-up period up to Day 
114 allows for adequate safety monitoring over a 
period of approximately 5 half-lives. 
Placebo comparator 
The use of placebo provides a comparison 
group for an unbiased collection and 
assessment of safety, tolerability, efficacy, and 
PD parameters. The study design includes both 
inter- and intra-individual placebo comparators. 
4.3 
Justification for dose 
DFV890 
In this study, film-coated tablets with 10 or 25 mg DFV890 will be administered orally to 
achieve doses of 10 mg, 25 mg, 50 mg, and 100 mg. Depending on the randomization to one of 
five treatment sequences, participants will start with either placebo or DFV890 10 mg dose 
given QD for approximately three weeks. Participants will then receive three up-titrating 
DFV890 doses up to 100 mg (or placebo), each for approximately three weeks as shown in the 
study design figure (Figure 1-1). The dose range 10-100 mg was selected based on data from 
the FIH study in healthy volunteers (Study CDFV890A02101). In the FIH study, an ex vivo 
whole blood assay of lipopolysaccharides (LPS)-stimulated IL-1β secretion was used as a PD 
readout to estimate pharmacological activity. 
 
 
 
 
 
 
 
 
 the highest dose of 100 mg 
DFV890 given QD is proposed in this study. 
As indicated above, a positive food effect on PK (2.05-fold increase in Cmax and 1.49-fold 
increase in AUClast) was demonstrated with a 100 mg tablet after a high-fat/high-calorie meal 
in the FIH study. A less pronounced effect, especially on Cmax, is expected for the 10 and 
25 mg doses due to a better solubility; however, to maximize the effect and to limit variability, 
all tablets should be taken with a meal. The type of food should not have any impact on DFV890 
exposure based on physiology-based PK simulation. The apparent terminal elimination half-life 
of DFV890 tablet under fed conditions is approximately 10 hours and the steady state is 
anticipated the next day after starting each dose treatment. 
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With the exception of maculopapular skin rash and/or pruritus, DFV890 was, in general, well 
tolerated in healthy participants and patients when dosed for up to 2 weeks in completed clinical 
studies (refer to IB for further details). Skin reactions were reported when dosed with 30 mg, 
100 mg, or 200 mg suspension QD, or 50 mg tablet b.i.d. Skin reactions were not reported when 
dosed as 10 mg suspension QD or 25 mg tablet b.i.d. All skin-related events were graded to be 
of mild or moderate intensity, started 5 to 17 days after treatment initiation and resolved 
following treatment discontinuation within 1 to 18 days after onset. Skin-related events were 
not reported in any animal toxicology studies and the mechanism causing rash is likely T-cell 
driven. The response-exposure is not yet well understood, however skin reactions, especially 
for 50 and 100 mg QD doses cannot be ruled out. 
Metabolism by CYP2C9 and CYP3A4 is considered to be the major clearance mechanism for 
DFV890 with fractional hepatic contributions of 
% and 
% respectively. CYP2C9 is a 
polymorphic enzyme. Based on the physiology-based PK prediction, the systemic DFV890 
exposure in participants who are poor CYP2C9 metabolizers (e.g., *3*3) is likely to be 
approximately -fold higher compared to normal (extensive) metabolizers (e.g., *1*1) due to 
decreased or no CYP2C9 activity. 
The safety for the DFV890 doses and treatment duration is supported by GLP toxicology studies 
in rat and cynomolgus monkey. Overall, on average for 100 mg QD of DFV890, the safety 
margins are  (
) and  (
 
) based on PK in healthy participants 
(majority were normal CYP2C9 metabolizers). Up to -fold lower safety margins are expected 
in patients who are intermediate or poor CYP2C9 metabolizers (for further details see IB). 
Supported by sufficient safety margins, all eligible participants irrespective of CYP2C9 
genotype are allowed to participate in the study. 
MAS825 
Depending on the randomization to one of five treatment sequences, a single dose of 
 mg 
MAS825 or placebo will be injected subcutaneously on Day 1. 
MAS825 has been evaluated in a FIH single ascending dose study up to 
 mg/kg i.v. and 
 mg s.c. in healthy volunteers, in COVID-19 patients (single dose with 10 mg/kg i.v.), in 
HS patients (
 mg every 
 or every 
) as well as in NLRC4-GoF patients 
(
 mg/kg i.v. every 
) without any drug-related Serious Adverse Events (SAEs); the PK 
of MAS825 in humans is 
 
. 
In a FIH single ascending dose study MAS825 peak serum concentrations were observed 
 the 
 i.v. infusion. The median Tmax was approximately 3 hours from the 
start of the infusion (120 minutes). The Cmax and AUCinf increased with increasing doses in 
a 
 manner. The mean terminal elimination half-life (T1/2) is ranging 
from approximately 
 days at 
 mg/kg to approximately 
 days at 
mg/kg. Volume of 
distribution was 
 with the mean Vz between 
 L and 
 L. 
Additionally, MAS825 was administered subcutaneously at a dose of 
 mg, 
 mg and 
mg. The mean Cmax of MAS825 ranged from 
 to 
 ug/mL at about 
days post 
dose. Exposure in 
 at 
mg/kg i.v. is approximately 1.16-fold higher as in 
 subjects while after 
mg s.c. the exposure was 1.25-fold higher compared to 
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the 
 subjects based on AUCinf. For 
cohorts 
 mg s.c. dose compared 
to the 
mg/kg i.v. dose, bioavailability was approximately 
%. For 
 cohorts 
 mg s.c., 
 mg s.c. and 
 mg s.c. dose compared to the 
 mg/kg i.v. dose, 
bioavailability were approximately 
%, 
% and 
%. 
The single s.c. dose of MAS825 
 mg is justified by: the dose is predicted to lead to rapid 
and 
 neutralization of all systemic free IL-1β and IL-18. The exposure after
 mg 
s.c. will exceed the in-vitro 
 for IL-1β and IL-18 for more than 150 days after a single dose. 
The dose and the Cmax is lower than the well tolerated MAS825 dose administered to healthy 
volunteers with no identified safety concerns (
 mg/kg i.v.). 
 (anti-IL-18 mAb) has 
been administered to healthy subjects in doses up to 
 mg/kg i.v. and was well tolerated. Phase 
2 studies with 
 in 
 and 
 patients with 
 mg/kg 
i.v. monthly are currently ongoing. In the 
 study, an arm with a roughly three 
fold lower dose of 
 mg s.c. monthly is included. In addition, 
 (anti-IL1b mAb) 
is approved in doses up to 300 mg every 4 weeks. In the MAS825 26-week toxicology study, 
in non-human primates (marmoset), the highest tested dose, 
 mg/kg i.v., 
, did 
not result in any MAS825-related effects. 
IG in response to MAS825 
 across different cohorts and time 
points in the FIH study 
. These results suggest that MAS825 can be safely used 
for further clinical trials for indications. 
4.4 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Placebo treatment will be used as a comparator to provide objective control for the evaluation 
of efficacy, safety, and tolerability during the 12 week treatment with DFV890 or MAS825. 
For DFV890, the oral tablet formulation will contain either active drug or placebo, and will be 
indistinguishable in appearance and taste. 
For MAS825, matching placebo in individual  mL glass vials each containing 0 mg/1 mL as a 
liquid solution will be provided, and will be indistinguishable in appearance. 
4.5 
Rationale for public health emergency mitigation procedures 
During a public health emergency as declared by local or regional authorities e.g., pandemic, 
epidemic, or natural disaster, mitigation procedures to ensure participant safety and trial 
integrity may be implemented. Notification of the public health emergency as declared by local 
or regional authorities should be discussed among investigators and Novartis. All procedures 
adapted to the situation must be submitted, if required as per local regulations, through a 
protocol amendment for approval by local or regional Health Authorities and Ethics 
Committees prior to implementation of mitigation procedures. 
4.6 
Purpose and timing of interim analyses/design adaptations 
No interim analysis is planned for this study, but ad-hoc 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. 
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4.7 
End of study definition 
The EOS is defined as the date of the last visit of the last participant in the study. 
Study completion is defined as when the last participant finishes their last study visit and any 
repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator. 
All treated participants should have a safety follow-up conducted at least 30 days after last 
administration of study treatment. This follow up may be a phone call or a study site visit. 
The information collected is kept as source documentation. SAE reporting continues during this 
time period as described in Section 8.6.3. Documentation of attempts to contact the participant 
are required to be recorded in the source documentation. 
5 
Study population 
The study population is adults with known coronary heart disease and CHIP with somatic 
mutations in TET2 or DNMT3A (VAF ≥2%). In this study, approximately 28 participants will 
be randomized. 
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 assessment is performed. 
2. Male and female participants aged between 18 - 80 years (inclusive) at the start of 
screening will be included. 
3. Subjects must have a body mass index (BMI) within the range of 18 - 40 kg/m2. BMI = 
Body weight (kg) / [Height (m)]2 at screening. 
4. Documented spontaneous MI (diagnosed according to the universal MI criteria with or 
without evidence of ST segment elevation) at least 30 days before the start of screening 
(Thygesen et al 2007). 
Diagnosis of the qualifying MI should be based on medical history of clinical symptoms 
consistent with myocardial ischemia associated with elevation of cardiac biomarkers 
above the 99th percentile of the upper reference limit (preferably troponin) OR 
development of new pathological Q waves regardless of symptoms (for details, refer to the 
Universal Definition of MI (Thygesen et al 2007)). 
Documentation in the medical history to support evidence of prior MI may include: 
• Evidence of an acute MI in hospitalization or medical records: 
• requires documentation of a rise and/or fall of cardiac biomarkers (preferably 
troponin) with at least one value above the 99th percentile of the upper reference 
limit or above criteria diagnostic for MI 
AND 
• Evidence of myocardial ischemia as demonstrated by at least one of the following: 
• Symptoms of ischemia 

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• ECG changes indicative of new ischemia (new ST-T changes or new Left bundle 
branch block (LBBB)) 
• Development of pathologic Q waves 
• Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality 
If no documented evidence of an acute MI in the medical record, then evidence of a prior 
MI may include: 
• Development of pathological Q waves with or without symptoms 
• Imaging evidence of a region of loss of viable myocardium that is thinned and fails to 
contract in the absence of a non-ischemic cause 
• Pathologic findings of a healed or healing MI 
5. Known presence of CHIP, restricted to driver mutations in TET2 or DNMT3A with a VAF 
≥2%, as documented in the participant's medical history. 
Participants may have a second or additional mutation in a different CHIP driver gene 
(e.g., DNMT3A + JAK2); however, the most common mutation (highest VAF) must be in 
either TET2 or DNMT3A. Patients may have more than one different CHIP-driver 
mutation in the same gene (e.g., two unique known CHIP mutations in TET2) but at least 
one unique mutation must be present at VAF ≥2%. 
6. For participants on statin therapy (HMG-CoA reductase inhibitor) as clinically indicated, 
participants must be on a stable regimen (at least 4 weeks before randomization), with no 
planned statin dose changes over the course of the trial treatment period. Unplanned statin 
dose changes during the trial treatment period may occur but must be documented as 
described in Section 6.2.2. 
7. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Patients receiving concomitant medications (see list of prohibited drugs, Section 6.8.2) 
that are known to be: 
• strong or moderate inducers of CYP2C9 enzyme, or 
• strong inducers of CYP3A, or 
• strong inhibitors of CYP2C9, or 
• strong or moderate inhibitors of CYP3A 
• and the treatment cannot be discontinued or switched to a different medication within 
5 half-lives or 1 week (whichever is longer) prior to Day 1 and for the duration of the 
study. 
2. Use of other investigational drugs within 5 half-lives of Day 1, or until the expected PD 
effect has returned to baseline, whichever is longer. 
3. History of hypersensitivity to any of the study treatments or excipients or to drugs of 
similar chemical classes. 

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4. History of drug abuse or unhealthy alcohol use within the 12 months prior to the start of 
screening, per Investigator judgement. 
Unhealthy alcohol use may be considered with a history of, or current, alcohol 
misuse/abuse or “Five or more drinks on the same occasion on each of 5 or more days in 
the past 30 days." However unhealthy alcohol use may be considered at lower level per 
investigator judgement based on participant's history. 
5. Any diagnosed psychiatric condition that includes, but is not limited to, a history of mania, 
bipolar disorder, psychotic disorder, schizophrenia, or schizoaffective disorder, depression 
or anxiety, which may jeopardize patient safety or compliance with study procedures, as 
judged by the Investigator. 
6. WOCBP, defined as all women physiologically capable of becoming pregnant, unless they 
are using highly effective methods of contraception for at least 3 months prior to first drug 
administration (Day 1), during dosing and for 5 months after the single s.c.dose 
administration of MAS825 or placebo dose. 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 IUD or intrauterine system, or other forms of 
hormonal contraception that have comparable efficacy (failure rate < 1%), for 
example hormone vaginal ring or transdermal hormone contraception. 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, thus hormonal contraceptives must be 
supplemented by a barrier method, preferably a male condom. In case of use of oral 
contraception, women should be stable on the same pill for a minimum of 3 months 
before taking study treatment. 
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 prior to Day 1. 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 8.4.5 (Pregnancy Testing). 

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7. Pregnant or nursing (lactating) women. 
8. Sexually active males unwilling to use a condom during intercourse while taking study 
treatment and for 90 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 for the time period specified above. 
9. History of lymphoproliferative disease or any known malignancy or history of malignancy 
of any organ system within the past 5 years of the start of screening (except for basal cell 
carcinoma or actinic keratoses that have been treated with no evidence of recurrence in the 
past 3 months, or carcinoma in situ of the cervix or non-invasive malignant colon polyps 
that have been removed). 
10. At screening, pre-malignant clonal cytopenias or clonal cytopenia of unknown 
significance (CCUS). Cytopenia in the context of clonal abnormalities is defined as an 
acquired and persistent anemia (hemoglobin < 12 g/dL in females and < 13 g/dL in males), 
neutropenia (ANC < 1.8 × 109/L), and/or thrombocytopenia (platelets < 150 × 109/L) that is 
not explained by another known or identifiable condition. 
11. History of ongoing, chronic, or major recurrent infectious disease, at the discretion of the 
Investigator, at the start of screening. 
12. Live vaccinations within 1 month prior to Day 1 or live vaccinations planned during the 
trial. 
13. Patients with suspected or proven immunocompromised state at screening, including: 
(a) known clinical diagnosis of Human Immunodeficiency Virus (HIV) infection. Patients 
on systemic anti-retroviral therapy are also excluded from the trial; 
(b) those with any other medical condition which in the opinion of the Investigator places 
the patient at unacceptable risk for participation in immunomodulatory therapy 
or (c) those requiring systemic or local treatment with any immune modulating agent in 
doses with systemic effects, e.g., high dose oral or i.v. steroids (>20 mg prednisone orally 
daily for >14 days, >5 mg prednisone orally daily or equivalent dose of i.v. steroid) or 
high dose methotrexate (>15 mg weekly). Topical, inhaled, local steroid use in doses that 
are not considered to cause systemic effects are permitted. 
14. Use of any biologic drugs targeting the immune system (for example, but not limited to: 
tumour necrosis factor (TNF) blockers, anakinra, rituximab, abatacept, tocilizumab, or 
canakinumab) within 26 weeks of Day 1. Refer to Section 6.8.2. 
15. Known diagnosis of a systemic auto-immune disease (e.g., systemic lupus erythematosus, 
etc.). 
16. Current use or within 5 half-lives of use of colchicine at start of screening. 
17. Participants with a MI resulting from percutaneous coronary interventions (PCI) or 
coronary artery bypass graft (CABG) procedures. 
18. Major non-cardiac surgical or major endoscopic procedure within the past 6 months prior 
to the start of screening. 
19. Multi-vessel CABG surgery within the past 3 years prior to the start of screening. 

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20. Planned coronary revascularization (PCI or CABG) or any other major surgical procedure 
during the study (until EOS). 
21. Symptomatic Class IV heart failure (New York Heart Association [NYHA]) at the start of 
screening. 
22. History or current diagnosis of ECG abnormalities indicating significant risk of safety for 
participants participating in the study such as: 
• Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker 
• History of familial long QT syndrome or known family history of Torsades de Pointe 
23. Uncontrolled hypertension (defined as systolic blood pressure (SBP) >160 mmHg or 
diastolic blood pressure (DBP) >100 mmHg) at screening. 
24. Uncontrolled diabetes, as defined by the Investigator, at screening. Clinical and laboratory 
evidence of uncontrolled diabetes may include but are not limited to: hemoglobin 
A1C >9%, recurrent fasting glucose >200 mg/dL, frequent urination/thirst not explained 
by other causes, etc. 
25. Known nephrotic syndrome diagnosis, or eGFR <30 mL/min calculated using the CKD-
EPI formula (https://www.kidney.org/professionals/KDOQI/gfr calculator), or ≥2+ protein 
on urine dipstick testing at screening. 
26. History of clinically significant liver disease or liver injury at screening as indicated by 
abnormal liver enzymes or function tests (as defined below) including but not limited to 
Alanine Aminotransferase (ALT), Aspartate Transaminase (AST), Serum Glutamic 
Oxaloacetic Transaminase (SGOT), Serum Glutamic Pyruvic Transaminase (SGPT), 
alkaline phosphatase (ALP), serum bilirubin, albumin and prothrombin time. The 
Investigator should be guided by the following criteria: 
• Any single parameter may not exceed 2x upper limit of normal (ULN) 
27. Uncontrolled asthma at the start of screening, as defined by the Investigator, with high 
likelihood of requiring systemic corticosteroids during the treatment period. 
5.3 
Lifestyle considerations 
For the duration of the study, participants should be informed and reminded of the restrictions 
outlined in this section. 
5.3.1 
Meals and dietary restrictions 
Participants are to take DFV890 or placebo QD at approximately the same time each day. 
No grapefruit or grapefruit juice is to be consumed from first day of dosing until 7 days 
following the last dose. 
No St. John's wort (Hypericum perforatum) is to be consumed 14 days before start of treatment 
until 7 days following the last dose. 

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5.4 
Screen failures 
Participants who sign an ICF and are subsequently found to be ineligible prior to randomization 
will be considered as screen failures. The reason for screen failure should be recorded on the 
appropriate Case Report Form (CRF). The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure participants. No other data 
will be entered into the clinical database for participants who are screen failures, unless the 
participant experienced a SAE during the screening period (see Section 8.6.3 for reporting 
details). If the participant fails to be randomized, the Interactive Response Technology (IRT) 
must be notified within 2 days of the screen fail that the participant was not randomized. Data 
and samples collected from participants prior to screen failure may still be analyzed. 
Participants who are randomized and fail to start treatment, e.g., participants randomized in 
error, will be considered an early terminator. The reason should be recorded on the appropriate 
CRF. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. Each case of re-screening must be discussed and agreed with Novartis on a 
case-by-case basis. 
Participants who failed their initial screening due to elevated blood pressure (BP) may be 
re-screened if anti-hypertensive therapy has been started or increased as a result of initial 
screening BP above these limits. 
Participants who are re-screened will be assigned a new participant number, and will be 
reconsented. 
5.4.1 
Replacement policy 
The proposed sample size accounts for dropouts at rates depending on the dose level of DFV890 
or placebo (as described in Section 9.9.1), therefore discontinued patients will not be replaced. 
5.4.2 
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 rescreened. The Participant No. consists of the Site 
Number (Site 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 rescreen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. 

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6 
Study treatment(s) and concomitant therapy 
Details on the requirements for storage and management of MAS825 and instructions to be 
followed for prescribing/dispensing and administering MAS825 are outlined in the Pharmacy 
Manual. 
Refer to the  Section 5.3.1 for details of dosing and food intake related to DFV890. 
6.1 
Study treatment(s) 
The investigational drugs, DFV890, MAS825, or placebo, will be prepared by the Sponsor as 
indicated in Table 6-1. DFV890 or placebo will be administered orally with food QD. MAS825 
or placebo will be administered subcutaneously once on Day 1. 
Table 6-1 
Investigational and control drug 
Treatment Title 
DFV890 10 
mg 
DFV890 25 
mg 
DFV890 10 
mg Placebo 
DFV890 
25mg 
Placebo 
MAS825 
MAS825 
Placebo 
Treatment 
Description 
10 mg tablet 
QD 
25 mg tablet 
QD 
0 mg tablet 
QD 
0 mg tablet 
QD 
 mg 
single 
injection 
0 mg single 
injection 
Type 
Drug 
Drug 
Drug 
Drug 
Biologic 
Biologic 
Dose 
Formulation 
Tablet 
Tablet 
Tablet 
Tablet 
Solution for 
injection 
Solution for 
injection 
Unit Dose 
Strength(s) 
10 mg 
25 mg 
0 mg 
0 mg 
 mg/mL 
0 mg/mL 
Dosage 
Level(s) 
10 mg QD 
25 mg QD 
0 mg QD 
0 mg QD 
 mg 
single dose 
0 mg single 
dose 
Route of 
Administration 
Oral 
Oral 
Oral 
Oral 
Injection 
Injection 
Use 
Experimental 
Experimental 
Placebo 
Placebo 
Experimental 
Placebo 
IMP 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Sourcing 
Provided 
centrally by 
the Sponsor 
Provided 
centrally by 
the Sponsor 
Provided 
centrally by 
the Sponsor 
Provided 
centrally by 
the Sponsor 
Provided 
centrally by 
the Sponsor 
Provided 
centrally by 
the Sponsor 
Packaging and 
Labeling 
Study 
treatment will 
be provided 
in blinded 
HDPE bottles 
of 35 tablets. 
Each bottle 
will be 
labeled as 
required per 
country 
requirement 
Study 
treatment will 
be provided 
in blinded 
HDPE bottles 
of 35 tablets. 
Each bottle 
will be 
labeled as 
required per 
country 
requirement 
Study 
treatment 
will be 
provided in 
blinded 
HDPE 
bottles of 35 
tablets. 
Each bottle 
will be 
labeled as 
required per 
country 
requirement 
Study 
treatment 
will be 
provided in 
blinded 
HDPE 
bottles of 35 
tablets. 
Each bottle 
will be 
labeled as 
required per 
country 
requirement 
Study 
treatment will 
be provided 
in vials via 
open label 
supply. Each 
vial will be 
labeled as 
required per 
country 
requirement 
Study 
treatment 
will be 
provided in 
vials via 
open label 
supply. 
Each vial 
will be 
labeled as 
required per 
country 
requirement 
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6.1.1 
Additional study treatments 
No other treatment beyond investigational drug and control drug are included in this trial. 
6.1.2 
Treatment arms/group 
Participants will be assigned at Day 1 to one of the following 5 treatment sequences in a ratio 
of 4:4:4:1:1, as shown in Figure 6-1 below. 
Figure 6-1 
Treatment arms 
 
6.2 
Preparation, handling, storage, and accountability 
Each study site will be supplied with study treatment in packaging as described under Table 6-1. 
Unblinded Investigator staff will identify the treatment to administer to the participant by 
contacting the IRT and obtaining the treatment assignment. 
MAS825 
Unblinded Investigator staff will select the study treatment to administer to the participant and 
record the batch number on the accountability logs accordingly. 
DFV890 
A unique medication number is printed on the study medication label of each bottle. Investigator 
staff will identify the study medication kits to dispense to the participant contacting the IRT and 
obtaining the medication number(s). DFV890 drug accountability and reconciliation data is 
recorded in the IRT system. 
As per Section 4.5, 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, delivery 
of Investigational Medicinal Product (IMP) directly to a participant's home may be permitted 
(if allowed by local or regional health authorities and ethics committees, as appropriate) in the 
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event the Investigator has decided that an on-site visit by the participant is no longer appropriate 
or possible, and that it is in the interest of the participant's health to administer the study 
treatment even without performing an on-site visit. The dispatch of IMP from the site to the 
participant’s home remains under the accountability of the Investigator. Each 
shipment/provisioning will be for a maximum of 1-month supply. In this case, regular phone 
calls or virtual contacts (every 2 weeks or more frequently if needed) will occur between the 
site and the participant for instructional purposes, safety monitoring, investigation of any AEs, 
ensuring participants continue to benefit from treatment, and discussion of the participant's 
health status until the participants can resume visits at the study site. 
6.2.1 
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 study 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 Quality Assurance. 
MAS825 and placebo will be provided as open-label bulk supply. All study treatment must be 
prepared by an unblinded pharmacist to ensure treatment masking. Please refer to the Pharmacy 
Manual for complete preparation instructions. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The Investigator or designated site staff (blinded or unblinded, as applicable) must maintain an 
accurate record of the shipment and dispensing of study treatment in a drug accountability log. 
All bottles of DFV890 or placebo assigned by the IRT will be recorded in the IRT system. 
Monitoring of drug accountability will be performed by field monitors during site or remote 
monitoring visits, and at the completion of the trial. The Investigator must provide 
accountability also for locally sourced materials used for administration of MAS825 or placebo 
(e.g., syringes). 
As DFV890 or placebo study treatment is administered at home, e.g., oral medication, 
participants will be asked to return all unused study treatment and packaging at the end of the 
study or at the time of discontinuation of study treatment. 
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging, as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the Investigator will return all unused study 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. 
6.2.2 
Handling of other treatment 
Not applicable. 

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6.2.3 
Instruction for prescribing and taking study treatment 
Participants will be randomized to one of five treatment sequences. Based on the treatment 
sequence assignments, participants will start on either a combination of MAS825 and placebo, 
DFV890 and placebo, or placebo and placebo on Day 1, and then, within each DFV890 
treatment sequence, participants will receive up-titrating doses of DFV890 or placebo at the 
corresponding study visits. 
Participants will be dispensed with DFV890 double-blind high density polyethylene (HDPE) 
bottle packs for each 3-week dosing period to ensure the appropriate dosage is being taken while 
maintaining the blind. 
Table 6-2 
DFV890 dose and treatment schedule 
Dosing period 
Dose/strength 
Investigational / Control Drug 
(Name and Strength) + 
Number of Tablets 
Frequency 
and/or regimen 
Dosing Period 1 
(Day 1 to Day 21)* 
DFV890 10 mg 
1 tablet of DFV890 10 mg 
QD with food for 3 
weeks 
DFV890 0 mg 
1 tablet of 10 mg matching 
placebo 
Dosing Period 2 (Day 
22 to 42) 
DFV890 25 mg 
1 tablet of DFV890 25 mg +1 
tablet of 10 mg matching 
placebo 
QD with food for 3 
weeks 
DFV890 10 mg 
1 tablet of DFV890 10 mg + 1 
tablet of 25 mg matching 
placebo 
DFV890 0 mg 
1 tablet of 10 mg matching 
placebo + 1 tablet of 25 mg 
matching placebo 
Dosing Period 3 (Day 
43 to 62) 
DFV890 50 mg 
2 tablets of DFV890 25 mg 
QD with food for 3 
weeks 
DFV890 25 mg 
1 tablet of DFV890 25 mg + 1 
tablet of 25 mg matching 
placebo 
DFV890 0 mg 
2 tablets of 25 mg matching 
placebo 
Dosing Period 4 (Day 
63 to 84) 
DFV890 100 mg 
4 tablets of DFV890 25 mg 
QD with food for 3 
weeks 
DFV890 0 mg 
4 tablets of 25 mg matching 
placebo 
*Participants assigned to Treatment Sequence 1 will receive a single s.c. dose of MAS825 
 mg on 
Day 1 and then receive DFV890 0 mg matching placebo the remainder of the treatment period; 
participants assigned to Treatment Sequences 2-5 will receive a single s.c. dose of MAS825 0 mg 
matching placebo on Day 1 and then receive DFV890 active or placebo according to their assigned 
treatment sequence. 
DFV890 up-titration will occur at the study visits during the Treatment Period as indicated 
in Section 1.3, SoA. 
Each 3-week dosing period (i.e., Day 1-21, Day 22-42, Day 43-63, and Day 64-84) is 
approximately 21 days in duration but must be at least 17 days in duration. The following/next 
visit should be scheduled the day after the last dose of that current dosing period. In the event 
that an up-titration visit cannot be scheduled within the allowed visit windows, the participants 
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should continue to take their dose up to a maximum of 35 days (i.e., the maximum number of 
tablets dispensed for a given dosing period) and every effort should be made to schedule the 
visit before the participant's supply of tables for the given period runs out. 
If a participant runs out of tablets before the next visit can be scheduled, a visit should be 
scheduled as soon as possible to only perform safety assessments described in Section 8.4. 
Other non-safety assessments described in Section 8.3 must not be performed. Participants will 
then start the next dosing period as applicable. 
The last DFV890 dose will be taken on Day 84 prior to the EOT visit on Day 85. Allowable 
visit windows are listed in Section 1.3, SoA. To achieve the target doses for each time period, 
please refer to Table 6-3 below. 
Table 6-3 
Dose and treatment schedule 
Investigational / 
Control Drug (Name 
and Strength) 
Dose 
Number of tablets 
Frequency and/or 
Regimen 
MAS825 
mg/mL 
 mg 
N/A 
Once on Day 1 by s.c. 
injection 
MAS825 0 mg/mL 
0 mg 
N/A 
Once on Day 1 by s.c. 
injection 
DFV890 10 mg or 
matching placebo 
10 mg 
1 
QD with food for 3 
weeks 
DFV890 25 mg or 
matching placebo 
25 mg 
1 
QD with food for 3 
weeks 
DFV890 25 mg or 
matching placebo 
50 mg 
2 
QD with food for 3 
weeks 
DFV890 25 mg or 
matching placebo 
100 mg 
4 
QD with food for 3 
weeks 
Participants are to take DFV890 or placebo QD at approximately the same time each day. 
On days of study visits with dose administration, the participants should not take their daily 
dose until they are on-site and instructed to do so by the site staff. On days that pre-dose PK 
samples are obtained, the participant should take DFV890 or placebo after collection of the pre-
dose PK samples, as instructed by site staff. In the event that the participants have taken their 
daily dose on the visit day prior to arriving for their on-site visit, the visit and associated 
assessments should be rescheduled as soon as possible (e.g., next day or after the weekend). 
Participants should take DFV890 or placebo with food or no later than 5 minutes after 
completion of the meal with a glass of water or any non-alcoholic beverage 
(see Section 5.3.1 for dietary restrictions). Participants should be instructed to swallow whole 
tablets and not to chew or break them. On days of study visits with dose administration, DFV890 
or placebo does not need to be taken with food. 
If vomiting occurs during the course of treatment, participants should not take the study 
treatment (DFV890 or placebo) again before the next scheduled dose. 
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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 12 hours after the approximate time of the usual 
daily dosing. That day's dose should be omitted, and the participant should continue treatment 
with the next scheduled dose. 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
6.3 
Measures to minimize bias: randomization and blinding 
6.3.1 
Treatment assignment, randomization 
On Day 1, all eligible participants will be randomized via IRT to one of the treatment arms. 
The unblinded pharmacist or his/her unblinded delegate will contact the IRT after confirming 
that the participant fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the participant, which will be used to link the participant to a treatment 
arm and will specify a unique medication number for the first bottle of study treatment to be 
dispensed to the participant and assignment to either MAS825 or placebo. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and Investigator staff. 
A participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. 
These randomization numbers are linked to the different treatment arms, which in turn are 
linked to medication numbers. A separate medication list will be produced by or under the 
responsibility of Novartis Global Clinical Supply (GCS) using a validated system that 
automates the random assignment of medication numbers to packs containing the study 
treatment. 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office or by a designated member following Contract Research Organization 
(CRO) procedures. 
6.3.2 
Treatment blinding 
This is a participant- and Investigator-blinded study. Participants and Investigators will remain 
blinded to study treatment throughout the study, except where indicated below. 
The identity of treatments will be concealed by the use of study drugs that are all identical in 
packaging, labeling, schedule of administration, appearance and odor. 
Site staff 
With the exception of any unblinded site staff identified below, all site staff (including study 
Investigator and study nurse) will be blinded to study treatment throughout the study. 
Unblinding a single participant at site for safety reasons (necessary for participant management) 
will occur via an emergency system in place at the site. 

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MAS825 and matching placebo will be supplied as open-label bulk supply, thus an unblinded 
pharmacist who is independent of the study team will be required in order to maintain the blind. 
The unblinded pharmacist or delegate will receive randomization assignments via the IRT 
system. Appropriate measures must be taken by the unblinded pharmacist or delegate to ensure 
that the treatment assignments are concealed from the rest of the site staff. 
Sponsor staff or delegate 
The following unblinded sponsor roles are required for this study: 
• Unblinded field monitor(s): The unblinded field monitors are required to review drug 
accountability and allocation at site. The unblinded monitors are not provided with a 
randomization list directly but will be unblinded through review of source documentation 
compiled by the unblinded pharmacist, which details treatment allocation to individual 
participants. 
• Unblinded clinical staff managing drug re-supply to site: The unblinded clinical staff 
managing drug re-supply will be notified directly by the unblinded field monitors or 
unblinded site staff that additional drug supply is needed for drug administration at the 
site. The unblinded clinical staff will have no other study responsibilities. 
• Unblinded sample analyst(s) (PK, IG): The unblinded sample analysts will receive a copy 
of the randomization schedule (via a request to the Randomization Office) to facilitate 
analysis of the samples. The sample analysts will provide the sample data to the study 
team under blinded conditions unless otherwise allowed. 
The study statistician will be able to access the randomization list at any time throughout the 
study and is allowed to share unblinded information with the rest of the clinical team as 
appropriate for internal decision making purposes, as outlined in Table 6-4. For example, 
unblinded summaries and unblinded individual data can be shared with the team for interim 
analyses. 
Study programmers and other personnel involved in study data analyses (e.g., biomarker expert, 
pharmacometrician, and potentially others) are also allowed to access treatment assignment 
information at any time throughout the study for the purpose of conducting data analyses. 
The clinical trial team (CTT) is allowed to share unblinded results with other sponsor staff 
(e.g., decision boards) as required for internal decision making on the study or the project at the 
time of interim analyses while the study is ongoing. 
All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above. 
Following final database lock, all roles may be considered unblinded. 

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Table 6-4 
Blinding and unblinding plan 
Role 
Time or Event 
Randomization 
list generated 
Treatment 
allocation 
& dosing 
Safety event 
(single 
subject 
unblinded) 
Interim 
Analysis/ 
dose 
escalation/ 
safety review 
Participants 
B 
B 
UI 
B 
Site Staff 
B 
B 
UI 
B 
Global Clinical Supply 
UI 
UI 
UI 
UI 
Randomization Office 
UI 
UI 
UI 
UI 
Statistician/statistical 
programmer/ data analysts 
(e.g. biomarker, PK) 
B 
UI 
UI 
UI 
Unblinded site staff, e.g. 
pharmacy staff 
B 
UI 
UI 
UI 
Unblinded Sponsor staff, e.g. 
for study treatment re-supply, 
unblinded monitor(s), sample 
analyst(s) 
B 
UI 
UI 
UI 
Sponsor CTT 
B 
B 
UI 
UI 
All other Sponsor staff not 
identified above (i.e. project 
team, management & decision 
boards, support functions) 
B 
B 
UI 
UI 
B Complete blinded 
UI Unblinded to individual participant treatment codes 
6.3.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. 
Most often, discontinuation from study treatment and knowledge of the possible treatment 
assignments are sufficient to treat a study participant who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
Investigator contacts the system to break a treatment code for a participant, he/she must provide 
the requested participant identifying information and confirm the necessity to break the 
treatment code for the participant. The Investigator will then receive details of the 
investigational drug treatment for the specified participant and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
study team that the code has been broken. 
It is the Investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The Investigator 
will provide: 
• protocol number 
• participant number 

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In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
6.4 
Study 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. The participant must also be instructed to contact the 
Investigator if he/she is unable for any reasons to take the study treatment as prescribed. 
Compliance will be assessed by the Investigator and/or study personnel at each visit using pill 
counts and information provided by the participant. This information should be captured in the 
source document at each visit. Compliance measures documented in the CRF, as reported by 
the participant, include: 1) dosing period percent compliance, assess by pill count; 2) any missed 
doses within the 2 days prior to the study visit; and 3) time the participant took the last dose on 
the day prior to the study visit. Assessments of compliance at study visits are reflected 
in Section 1.3, SoA. 
All study treatment dispensed and returned must be recorded in the Drug Accountability and 
Returns Management functionality in the IRT system. 
6.4.1 
Recommended treatment of adverse events 
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., pruritis, burning) with symptomatic treatment (e.g., topical 
steroids) and close monitoring of the participant's response. 
• For skin rashes covering >10% body surface area (corresponding to a Common 
Terminology Criteria (CTC) AE grade 2 or higher), 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 corticosteroids (e.g., prednisone 1 to 2 mg/kg per day 
for 5 to 7 days) may be considered. 
• At an assessment for a rash AE, a skin swab may be obtained for exploratory skin 
microbiome assessments (as described in Section 8.5.1). Therapies to manage the rash 
should not be delayed in order to obtain a skin swab of the rash. However, if practical, 
skin swabs of the rash prior to initiating topical therapy are preferable. 
At present, there is insufficient information to provide specific recommendations regarding 
treatment of other potential AEs in this participant population. 
Medications used to treat AEs must be recorded on the appropriate CRF. 
6.5 
Dose modification 
Investigational or other study treatment dose adjustments and/or interruptions are not permitted. 

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6.6 
Continued access to study treatment after the end of the study 
Investigational drug will not be provided to participants following the end of the study. 
6.6.1 
Post trial access 
Not applicable. 
6.7 
Treatment of overdose 
In the event of an overdose, the Investigator/treating physician should: 
• Contact the medical monitor immediately. 
• Evaluate the participant to determine, in consultation with the medical monitor, whether 
study treatment should be interrupted or whether the dose should be reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
DFV890 can no longer be detected systemically (at least 7 days). 
• Obtain a plasma sample for PK analysis within 7-10 days from the date of the last dose of 
study treatment if requested by the medical monitor (determined on a case-by-case basis). 
• Document the quantity of the excess dose as well as the duration of the overdose. 
6.7.1 
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 (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE. Study treatment 
errors and uses outside of what is foreseen in the protocol, 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. For more information on AE and SAE definition and 
reporting requirements, please see the respective sections. 
6.8 
Concomitant and other therapy 
6.8.1 
Concomitant therapy 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate CRFs. 

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Each concomitant drug must be individually assessed against all exclusion criteria and 
prohibited medication. If in doubt, the Investigator should contact the Novartis medical monitor 
before randomizing 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. 
6.8.1.1 
Permitted concomitant therapy requiring caution and/or action 
Clinical studies to investigate DDIs between DFV890, MAS825, and concomitant medications 
have not been performed. Evaluation and recommendations are based on in vitro / preclinical 
data and physiology-based PK simulations. 
DDI with DFV890 as a victim (exposure of DFV890 may increase) 
DFV890 is expected to be eliminated mainly via hepatic CYP-mediated metabolism with 
CYP2C9 (
%) and CYP3A4 (
%) as the main contributing enzymes. DFV890 may therefore 
be affected by CYP2C9 and/or CYP3A4 interactions. In particular: 
• Chronic dosing with drugs, which are dual CYP2C9/CYP3A4 inducers (e.g., rifampicin) 
is expected to induce both enzymes, thereby may reduce DFV890 exposure by 
approximately -fold in participants with normal CYP2C9 activity to sub-therapeutic 
levels. Lower impact is foreseen for intermediate and poor CYP2C9 metabolizers. 
• Co-administration of DFV890 with strong inhibitors of CYP2C9 is expected to reduce 
enzymatic metabolic capacity, thereby may increase DFV890 drug exposure by 
approximately -fold.When dosing DFV890 together with strong or moderate CYP3A 
inhibitors or moderate dual CYP3A/CYP2C9 inhibitor, 
 effect is 
expected for participants with normal CYP2C9 activity and intermediate metabolizers 
(AUC-fold increase 
), while 
 effect is very likely for poor CYP2C9 
metabolizers (AUC-fold change 
). 
DDI with DFV890 as perpetrator (exposure of concomitant medication may 
decrease) 
Due to its in vitro weak-to-moderate CYP3A4 induction potential, DFV890 can potentially 
decrease systemic exposure of sensitive CYP3A4 substrates by approximately 2-fold or some 
oral hormonal contraceptives (e.g., ethinylestradiol) by 20-30%. As a consequence, decreased 
efficacy of those concomitant medications cannot be excluded. 
Considering DDI risk, certain concomitant medications when dosed with DFV890 are required 
to be used with caution or they are prohibited. List of concomitant medications to be used with 
caution is presented in Table 6-5 and prohibited drugs are listed in Table 6-6. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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Table 6-5 
Drugs to be used with caution with DFV890 
Narrow therapeutic index substrates of CYP3A 
abemaciclib, acalabrutinib, alectinib amiodarone, 
amitriptyline, astemizole, axitinib, baricitinib, 
bosutinib, brigatinib, cabazitaxel, cabozantinib, 
clomipramine, cobimetinib, copanlisib, 
cyclosporine, dabrafenib, dasatinib, 
dihydroergotamine, docetaxel, entrectinib, 
erdafitinib, ergotamine, everolimus, imipramine, 
ixazomib, lomitapide, midostaurin, neratinib, 
panobinostat, pexidartinib, pimozide, ponatinib, 
quinidine, regorafenib, romidepsin, sirolimus, 
sonidegib, sorafenib, sunitinib, tacrolimus, 
tamoxifen, temsirolimus, tolvaptan, trabectedin, 
venetoclax, vinblastine, zanubrutinib 
Sensitive substrates of CYP3A 
abemaciclib, acalabrutinib, alisporivir, 
almorexant, alfentanil, 
alpha‑dihydroergocryptine, aplaviroc, 
asunaprevir, atorvastatin, avanafil, avapritinib, 
blonanserin, bosutinib, brecanavir, brigatinib, 
brotizolam, budesonide, buspirone, cabazitaxel, 
capravirine, cobimetinib, cyclosporine, 
danoprevir, darifenacin, dasatinib, ebastine, 
eletriptan, eliglustat, elvitegravir, entrectinib, 
eplerenone, everolimus, felodipine, fluticasone, 
grazoprevir, ibrutinib, indinavir, itacitinib, 
ivabradine, ivacaftor, levomethadyl (LAAM), 
lomitapide, lopinavir, lovastatin, lumefantrine, 
lurasidone, maraviroc, midazolam, midostaurin, 
morphothiadin, naloxegol, neratinib, nisoldipine, 
paritaprevir, perospirone, quetiapine, 
ridaforolimus, sildenafil, simeprevir, simvastatin, 
sirolimus, tacrolimus, ticagrelor, tilidine, 
tipranavir, tolvaptan, triazolam, ubrogepant, 
ulipristal, vardenafil, venetoclax, vicriviroc, 
vilaprisan, voclosporin, zanubrutinib 
Moderate inhibitor of CYP2C9 
amiodarone, ataciguat, azapropazone, 
benzbromarone, bucolome, milk thistle 
(silymarin, silibinin)1, nitisinone, oxandrolone, 
phenylbutazone, piperine2, tienilic acid 
1 Herbal product 
2 Food product 

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Investigators at their discretion may administer concomitant medications known to be 
metabolized by CYP3A. All participants receiving such medications may however require 
higher doses of the concomitant drug as efficacy might be reduced by DFV890. Particularly, 
caution is advised when DFV890 is co-administered with drugs that are sensitive substrates of 
CYP3A and/or have a narrow therapeutic index. For example, blood concentrations of statins, 
such as atorvastatin, may be decreased with concomitant therapy with DFV890. Low density 
lipoprotein (LDL) cholesterol levels will be monitored at study visits approximately every 
3 weeks and statin doses may be changed, if clinically indicated, during the course of the study 
to achieve appropriate LDL goal levels specific to a patient's cardiovascular risk profile. Statin 
dose changes during the trial should be recorded, as described in Section 6.2.2. 
If it cannot be replaced by other medications, Investigators may, at their discretion, 
co-administer known moderate inhibitors of CYP2C9. Their duration, however, should be kept 
as short as possible, and participants must be closely monitored. 
The participant and the Investigator should be aware of potential signs of DDIs of the 
concomitant medication and in the event of suspected toxicity; administration of concomitant 
medication should be discontinued according to Investigator judgment and an unscheduled PK 
sample should be taken to evaluate systemic exposure to DFV890. 
MAS825 
No formal DDI studies have been conducted with MAS825. Elimination pathways of mAb are 
distinct from metabolic pathways of small molecules. These molecules are cleared from the 
body by a combination of non-enzymatic metabolism processes whereas small molecular 
weight drugs are typically eliminated through CYP450-mediated oxidation pathways. 
Therefore, small molecular weight drugs are not expected to affect the PK of MAS825. 
The expression of hepatic CYP450 enzymes may be suppressed by the cytokines that stimulate 
chronic inflammation, such as IL-1β and IL-18. Thus, CYP450 expression may be normalized 
when potent cytokine inhibitory therapy, such as MAS825, is introduced. This is clinically 
relevant for CYP450 substrates with a narrow therapeutic index where the dose is individually 
adjusted. On initiation of MAS825 in patients being treated with this type of medicinal product, 
therapeutic monitoring of the effect or of the active substance concentration should be 
performed and the individual dose of the medicinal product adjusted as necessary. 
6.8.2 
Prohibited medication 
Strong or moderate inhibitors of CYP3A and/or strong inhibitors of CYP2C9 are prohibited. 
Strong or moderate inducers of CYP2C9 and/or strong inducers of CYP3A or strong or 
moderate dual inhibitors of CYP2C9 / CYP3A are prohibited. For a detailed list, please 
see Table 6-6 below (please note that the list may not be comprehensive). 
Considering the DDI potential for DFV890, should a participant have an incidental and limited 
need for a prohibited medication to be taken within the restricted timeframe, Investigators 
should discuss the case with the sponsor. The administration of any prohibited concomitant 
medication may require the participant to be withdrawn or DFV890 treatment to be put on hold. 
Use of the treatments displayed in the below table is prohibited approximately 5 half-lives or 
1 week (whichever is longer) prior to Day 1 until the EOS as described in Table 6-7. 

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Table 6-6 
Prohibited drugs due to DDI with DFV890 (CYP3A and CYP2C9 
modulators) 
Category of interaction 
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, 
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, fluconazole, grapefruit juice, imatinib, 
isavuconazole, istradefylline, lefamulin, letermovir, 
Magnolia vine (Schisandra sphenanthera)3, 
netupitant, nilotinib, ravuconazole, tofisopam, 
verapamil, voxelotor 
Strong inhibitors of CYP2C9 
miconazole, sulfaphenazole, tasisulam 
Strong inducers of CYP2C9 
None reported to date 
Moderate inducers of CYP2C9 
enzalutamide, rifampicin 
Strong inducers of CYP3A 
apalutamide, avasimibe, carbamazepine, 
enzalutamide, ivosidenib, lumacaftor, mitotane, 
phenobarbital, phenytoin, rifampicin, rifapentine, 
St. John’s wort (Hypericum perforatum)3 
1 Combination therapy 
2 The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and 
preparation-dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” 
when a certain preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A 
inhibitor” when another preparation was used (e.g., low dose, single strength). 
3 Herbal product 
Table 6-7 
Prohibited medication 
Medication 
Prohibition period 
Action taken 
Inhibitors and 
inducers of 
CYP3A or 
CYP2C9 
according 
to Table 6-6 
5 half-lives or 1 week 
(whichever is longer) prior to 
Day 1 through EOS 
Discontinue study treatment 
Other 
investigational 
drugs 
Within 5 half-lives of Day 1 
through EOS 
Discontinue study treatment 

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Medication 
Prohibition period 
Action taken 
Systemic or 
local 
treatment with 
any immune 
modulating 
agent in 
doses with 
systemic 
effects 
4 weeks prior to Day 1 
through EOS 
Discontinue study treatment 
Biologic drugs 
targeting the 
immune 
system 
26 weeks prior to Day 1 until 
EOS 
Discontinue study treatment 
Colchicine 
Within 5 half lives of the time 
of screening through EOS 
Discontinue study treatment 
Live 
vaccinations 
4 weeks prior to Day 1 
through EOS 
Discontinue study treatment 
7 
Discontinuation of study treatment and participant 
discontinuation/withdrawal 
7.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study treatment administration, if 
any) and 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 of repeat dosing of MAS825 study treatment is not applicable as only a single 
s.c. dose of MAS825 on Day 1 is evaluated in this study. 
Discontinuation from study treatment is required under the following circumstances: 
• Participant/guardian decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which continued study participation might result in a safety risk to the 
participant 
• Following emergency unblinding 
• Emergence of the following adverse events: 
• An AE of severe intensity (corresponding to CTCAE Grade 3 or higher) or life-
threatening SAE, considered to be related to DFV890 treatment 
• Skin rashes greater than mild (covering >10% of the body surface area, corresponding 
to CTCAE Grade 2 or higher) and considered to be related to DFV890 treatment 

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• Any laboratory abnormalities, that in the judgment of the investigator, taking into 
consideration of the participant's overall status, prevents the participant from 
continuing participation in the study. 
• Any situation, in the judgment of the investigator, in which study participation might 
result in a safety risk to the patient 
• Severe hypersensitivity reaction occurs, including any of the following: anaphylaxis, 
fever, chills, urticaria, dyspnea, headache, myalgia, hypotension. 
If a liver or renal event occurs, follow guidelines outlined in Section 10.5 and Section 10.6 
regarding discontinuation of study treatment. 
If discontinuation from study treatment occurs, the Investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information. 
Participants who discontinue from study treatment agree to return for the end of treatment and 
follow-up visits indicated in Section 1.3 SoA. 
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 discontinuation from study treatment, 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 
The Investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
7.2 
Participant discontinuation from the study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in Section 1.3, SoA. 
7.3 
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 
• No longer wishes to receive study treatment 
and 

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• 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 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 very 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 Section 1.3, SoA. 
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding ICF. 
7.4 
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. 
7.5 
Study stopping rules 
The study will be stopped, and no further dosing will occur pending a full safety review, if 
any/all of the following criteria are met: 
• One or more SAEs occur that are considered to be related to DFV890 or MAS825 study 
treatment; 
• Two or more participants experience hypersensitivity reactions of moderate to severe 
intensity that are considered to be related to DFV890 or MAS825 study treatment; 
• Two or more participants experience a similar AE which was assessed as severe in 
intensity and are considered to be related to DFV890 or MAS825 study treatment; 
• Novartis considers that the number and/or severity of AEs, abnormal safety monitoring 
tests, or abnormal laboratory findings justifies putting the study on hold. 

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Dependent on regional guidance, any restart following a temporary hold due to stopping rules 
being met will require prior submission and approval of a substantial modification to the 
competent authorities. 
7.6 
Early study termination by the Sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination (but not limited to): 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study treatment development for CVD event risk reduction. 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, instructions will be communicated at the time of 
notification. 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 Novartis depending on local regulation will be responsible for informing 
Institutional Review Board/Independent Ethics Committee (IRBs/IECs) of the early 
termination of the trial. 
8 
Study Assessments and Procedures 
Study procedures and their timing are summarized in Section 1.3, SoA. Adherence to the study 
design requirements, including those specified in Section 1.3, SoA, is essential and required for 
study conduct. Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with Novartis upon occurrence or awareness to 
determine if the participant should continue or discontinue study treatment. 
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded personnel until the study has been unblinded. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
8.1 
Screening 
The screening assessments should be completed as per Section 1.3, SoA, starting with informed 
consents. The assessments should be performed as outlined in Figure 1-2. Screening 
assessments (including safety laboratory assessments) may be repeated once (twice for vitals, 
see Section 8.4.2) at the discretion of the Investigator if there are questionable results or if 
abnormalities are felt to be due to inherent variability of the test procedure. If the repeat value 
remains outside the specified range, the participant will be considered a screen failure 
(see Section 5.4 for more details about screen failures). During screening, the Investigator 
should detect any active infections that would disqualify the participant from this study. 

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The decision to locally test the participant for COVID-19 infection in order to evaluate 
eligibility is at the Investigator's discretion and should be in adherence to local policies or 
regulations. However, it is highly recommended that polymerase chain reaction or antigen 
testing for COVID-19 be completed within 1 week prior to first dosing. If testing is performed, 
negative test results are required prior to enrollment into the study. PCR or antigen testing for 
COVID-19 is mandatory where required by the local Health Authority and/or by local 
regulations. COVID-19 testing should be completed via nasal or throat swabs. 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. 
8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
Participant demographics: age, sex, race/predominant ethnicity (if permitted) and relevant 
medical history/current medical conditions (until date of signature of informed consent), and 
date of prior MI will be recorded in the electronic CRF (eCRF). Participant race/ethnicity data 
are collected and analyzed to identify any differences in the safety and/or efficacy profile of the 
treatment due to these characteristics. In addition, these data are necessary to assess the diversity 
of the study population as required by Health Authorities. 
All prescription medications, over-the-counter drugs, and significant non-drug therapies prior 
to the start of the study must be documented. Please see Section 6.8.1 Concomitant therapy for 
further details on the information that must be recorded on the appropriate page of the eCRF. 
8.3 
Efficacy assessments 
The efficacy assessments (reduction of IL-6 and IL-18 cytokines) described in this section will 
be evaluated in all participants. Samples will be collected as defined in Section 1.3, SoA. 
8.3.1 
IL-6 and IL-18 cytokines 
The circulating serum levels of the cytokines IL-6 and IL-18 (IL-18 applicable for DFV890 
only) will be measured by enzyme-linked immunosorbent assay (ELISA) at a qualified vendor. 
Detailed descriptions of the assays will be included in the bioanalytical data reports and assay 
validation reports. 
Planned time points for all assessments are provided in Section 1.3, SoA. 
Participants will contribute data on levels of IL-6 and IL-18 after 3 weeks of oral daily treatment 
with DFV890 at up to 3 different dose levels, or levels of IL-6 after a single s.c. dose of 
MAS825, and/or placebo, depending on the treatment sequence assignment. 
For DFV890, a dose-response modeling approach will be utilized that integrates each of the 
primary endpoints, IL-6 and IL-18 levels, at each dose level and fits a dose-response 
relationship to extrapolate reductions at the highest tested dose, 100 mg daily DFV890, which 
is expected to achieve Ctrough exposures > 
 for inhibition of the NLRP3 inflammasome. 
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For MAS825, the effect of a single s.c. dose on the change in IL-6 compared to placebo after 
3 weeks of treatment (primary) and persistence of effect over 12 weeks will be assessed. 
See Section 9.3 for additional details on the analysis. 
8.3.2 
Exploratory efficacy assessments 
Not applicable. 
8.3.3 
Appropriateness of efficacy assessments 
The result of the NLRP3 inflammasome formation is the production of IL-1β from pro-IL‑1β. 
Similarly, pro-IL-18 is cleaved into its active form, IL-18. These cytokines are released to 
activate a variety of inflammatory cells and produce IL-6, which stimulates the production of 
CRP from the liver and amplifies the inflammatory cascade within the vessel wall. 
Abrogation of NLRP3 inflammasome function is protective in mouse models of atherosclerosis, 
exerting a beneficial effect on both peripheral inflammatory leukocytes and cytokines, and local 
anti-inflammatory effects in the atherosclerotic plaque. Measures of local anti-inflammatory 
effects in the atherosclerotic plaque are not well-established surrogate outcomes of CVD risk 
reduction and are challenging to measure in clinical trials (usually done with non-invasive 
imaging with or without specific tracers), especially in relatively small samples sizes over short 
treatment periods. Therefore, the reduction in circulating cytokines will be examined as primary 
efficacy markers in this early exploratory Phase 2a trial. For example, reductions in IL-6 with 
IL-1β neutralization with canakinumab in Phase 2 trials preceded the demonstration of CVD 
risk benefit in the CANTOS trial. Through the production of IL-1β and IL-18, the NLRP3 
inflammasome has been implicated as a major driver of inflammation associated with chronic 
inflammatory diseases. As the magnitude of IL-1β reduction is not clearly benchmarked to CVD 
reduction in the CANTOS trial (due to canakinumab binding), IL-6 is one of the key 
downstream cytokines of focus in this trial (NLRP3 activation -> IL-1β -> IL-6 -> CRP). In the 
CANTOS trial, participants had mean IL-6 reductions from baseline of approximately 35% and 
approximately 45% after approximately 3 months of 150 mg and 300 mg of canakinumab 
treatment administered every 3 months. This corresponded to an approximately 15% reduced 
risk of MACE in the 150 mg/300 mg treatment arms (Ridker et al 2017). 
Increased levels of IL-18 are also the result of NLRP3 inflammasome activation. IL-18 levels 
were not reduced in the CANTOS trial with IL-1β neutralization and were markers of residual 
CVD risk. Patients with increased IL-18 levels at baseline in CANTOS had a 15% increased 
risk of MACE [95% CI 3-29%, p=0.02] for each tertile increase in baseline IL-18 
(Ridker et al 2020). The CANTOS findings corroborated population studies associating IL-18 
levels with CVD risk and preclinical studies linking IL-18 with CVD pathogenesis. However, 
interventional studies evaluating the reduction of IL-18 on risk of MACE have not yet been 
conducted. 
DFV890 is an inhibitor of the NLRP3 inflammasome pathway. Therefore, IL-6 and IL-18 are 
being measured as PD biomarkers (primary endpoints) to determine pathway inhibition. 
NLRP3 inhibition could have improved efficacy over canakinumab in diseases where IL-1β and 
IL-18 both drive pathology. Through the inhibition of IL-1β and IL-18, DFV890 has the 
potential to significantly reduce cardiovascular risk in patients. In this Phase 2a study, reduction 

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of IL-6 and IL-18 are the primary efficacy endpoints but change in a range of cytokines and 
immunophenotyping will also be evaluated. 
Participants will contribute data on levels of IL-6 and IL-18 after 3 weeks of oral daily treatment 
with DFV890 at up to 3 different dose levels and/or placebo, depending on treatment sequence 
assignment. A dose-response modeling approach will be utilized that integrates IL-6 or IL-18 
levels at each dose level and fitting a dose-response relationship to extrapolate reductions at the 
highest tested dose, 100mg QD, which is expected to achieve Ctrough exposures >
 for 
inhibition of the NLRP3 inflammasome. See Section 9.3 for additional details on the analysis 
of the primary endpoint. 
For MAS825, an alternate approach to inhibiting the production of IL-1β and IL-18 
(via inhibition of the NLRP3 inflammasome) is to directly neutralize the circulating cytokines 
with a bispecific mAb. Therefore the same rationale for the appropriateness of downstream 
reduction of IL-6 applies.  IL-6 is the only primary endpoint for MAS825 (measured at Week 
3 after a single s.c. dose of MAS825) as MAS825 directly binds to IL-18 and therefore cannot 
be robustly measured in this context. Exploratory biomarkers for IL-18 in the context of 
MAS825 binding (e.g., target capture assays for total IL-18 and IL-18 binding protein) and 
cytokines downstream of IL-18 (e.g., IFN-γ, CXCL9, CXCL10, etc.) will be assessed. 
8.4 
Safety/tolerability assessments 
Safety assessments are specified below with Section 1.3, SoA, detailing the timing of each 
assessment. Safety assessments include: 
• Physical examination 
• Vital signs (BP, pulse rate, body temperature) 
• ECG 
• Clinical safety laboratory assessments 
• Height and weight 
For details on AE collection and reporting, refer to Section 8.6. 
As per Section 4.5, 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 (every 3 weeks or more frequently if needed) for 
safety monitoring and discussion of the participant's health status until it is safe for the 
participant to visit the site again. 
8.4.1 
Physical examinations 
A complete physical examination will include the examination of general appearance, skin 
(including rash assessment), neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular, and neurological. Information for all 
physical examinations must be included in the source documentation at the study site. 
Clinically-relevant findings that are present prior to signing informed consent must be recorded 
on the appropriate CRF that captures medical history. Significant findings made after signing 
informed consent, which meet the definition of an AE, must be recorded as an AE. 
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A brief physical examination will include the examination of general appearance, a skin 
assessment for rash, a brief cardiorespiratory assessment, and vital signs (oral body temperature, 
blood pressure [SBP and DBP] and pulse rate). 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes) will be measured at the time points specified in Section 1.3, SoA. Body 
weight will be measured on a calibrated scale and under similar conditions (e.g., in similar 
indoor clothing and at a similar time of day). 
8.4.2 
Vital signs 
Vital signs will include the collection of oral body temperature (recorded in C), BP and pulse 
rate measurements. 
After the participant has been sitting for 3 minutes, with back supported and both feet placed 
on the floor, SBP and DBP will be measured using an automated validated device, e.g., 
OMRON with an appropriately sized arm cuff. In case the arm cuff sizes available are not large 
enough for the participant's arm circumference, a sphygmomanometer with an appropriately 
sized cuff may be used. 
If vital signs are out-of-range at screening (see Exclusion Criteria Section 5.2 of the protocol 
for details), two additional readings can be obtained, so that up to three consecutive assessments 
are made, with the participant seated quietly for approximately five minutes preceding each 
repeat assessment. The last reading must be within the ranges provided in the eligibility criteria 
in order for the participant to qualify. 
In case of repeated vital assessments, the eCRF should contain the qualifying results. 
8.4.3 
Electrocardiograms 
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
In the case of a series of assessments, ECG should be the first assessment obtained while the 
participant is at rest. 
Figure 8-1 
Recommended order of assessments 
 
The Fridericia QT correction formula (QTcF) must be used for clinical decisions. 
The Investigator must calculate QTcF if it is not auto-calculated by the ECG machine. 

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Single local 12-lead ECGs are collected. ECGs will be locally collected and evaluated. 
Interpretation of the tracing must be made by a qualified physician and documented on the 
appropriate CRF. Each ECG tracing should be labeled with the study number, participant 
initials (where regulations permit), participant number, date, and kept in the source documents 
at the study site. Clinically significant abnormalities present at screening should be reported on 
the appropriate CRF. Clinically significant findings must be discussed with Novartis prior to 
randomizing the participant in the study. New or worsened clinically significant findings 
occurring after informed consent must be recorded as AEs. 
The original ECGs on non-heat-sensitive paper, appropriately signed, must be archived at the 
study site. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the Investigator at 
any time during the study as clinically indicated. For any ECGs with participant safety concerns, 
two additional ECGs must be performed to confirm the safety finding. ECG safety monitoring, 
or a review process, should be in place for clinically significant ECG findings at Day 1 before 
administration of study treatment and during the study. 
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or AEs as appropriate. 
8.4.4 
Clinical safety laboratory tests 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or AEs as appropriate. 
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 and/or initial baseline, a decision regarding 
whether the result is of clinical significance or not shall be made by the Investigator 
(in consultation with Novartis, as needed) and shall be based, in part, upon the nature and degree 
of the observed abnormality. The assessment may be repeated once prior to randomization. 
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. 
A central laboratory will be used for analysis of all safety specimens collected. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to Investigators in the central laboratory manual. 
As per Section 4.5, 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. 
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. 

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Table 8-1 
Safety laboratory evaluations 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, Red blood cells, 
WBCs and Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Bands) 
Chemistry 
Albumin, ALP, ALT, AST, Gamma-glutamyl-
transferase (GGT), Lactate dehydrogenase (LDH), 
Bicarbonate, Calcium, Chloride, Magnesium, 
Phosphate, Potassium, Sodium, Creatine kinase 
(CK), Creatinine, Total Bilirubin, Direct Bilirubin, 
Indirect Bilirubin, LDL Cholesterol (non-fasting), Urea 
Nitrogen or Urea, Urate, Amylase, Lipase, Glucose 
(non-fasting), eGFR 
Urinalysis 
Macroscopic Panel (Dipstick) (Color, Bilirubin, Occult 
Blood, Macroscopic Blood, Glucose, Ketones, 
Leukocytes esterase, Nitrite, pH, Protein, Specific 
Gravity, Urobilinogen) 
If macroscopic panel results in abnormal values: 
Microscopic panel (Erythrocytes, Leukocytes, Casts, 
Crystals, Bacteria and yeast cells, Epithelial cells) 
Coagulation panel 
Prothrombin time (PT)*, International normalized ratio 
(INR), Partial Thromboplastin Time (PTT)*, Activated 
partial thromboplastin time (APTT) 
*PT and PTT only at screening 
Liver Event Testing and Liver Follow-Up Testing 
ALT, ALP, AST, GGT, total bilirubin (TBIL), INR, 
albumin, CK, glutamate dehydrogenase (if available, 
[GLDH]), PT 
To evaluate for hemolysis: reticulocytes, haptoglobin, 
unconjugated (indirect) bilirubin 
These tests are in addition to routine testing, to be 
performed only in follow-up to safety events when 
indicated in Section 10.5 Liver safety monitoring 
Renal follow-up Testing 
Serum: albumin, total protein, creatinine, cystatin C, 
BUN, electrolytes (sodium, potassium, phosphate, 
calcium), bicarbonate and uric acid 
Urine: protein, creatinine, albumin, dipstick (specific 
gravity, pH, heme, protein, glucose, leukocyte 
esterase and nitrite) and sediment microscopy 
(crystals, casts, red blood cells, WBCs, epithelial 
cells)  
Calculate urine albumin-to-creatinine ratio (may be 
done on a spot urine), urine protein-to-creatinine ratio 
(may be done on a spot urine) 
These tests are in addition to routine testing, to be 
performed only in follow-up to safety events when 
indicated in Section 10.6, Renal safety monitoring 
Pregnancy Test 
Serum pregnancy test 
Inclusion/Exclusion 
For inclusion or exclusion criteria testing not already 
included above, please refer 
to Section 5.1 and Section 5.2. 
Urinalysis 
A midstream urine sample (approximately 30 mL) will be obtained, in order to avoid 
contamination with epithelial cells and sediments, and allow proper assessments. 

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8.4.5 
Pregnancy testing 
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 during study 
treatment and for 90 days after stopping study treatment. In addition, male participants should 
not donate sperm while taking study treatment, and for 90 days after stopping study treatment. 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. Serum 
pregnancy testing is required at all time points indicated in Section 1.3, SoA. 
As per Section 4.5, 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 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 
A woman is considered of childbearing potential from menarche and until becoming post 
menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. Medical documentation of oophorectomy, 
hysterectomy, or tubal ligation must be retained as source documents. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause and an appropriate clinical profile. 
In absence of the medical documentation confirming permanent sterilization, or if the post-
menopausal status is not clear, the investigator should use his medical judgment to appropriately 
evaluate the fertility state of the woman and document it in the source document. 
8.4.6 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
8.5 
Additional assessments 
8.5.1 
Skin microbiome collection 
The skin swab samples collected will be used for microbiome DNA extraction and sequencing 
with the goal of characterizing the skin microbiome composition at 2 different skin sites where 
rash has been previously reported with DFV890 (i.e., chest and upper arms). Skin swab samples 
will be collected from all participants from two different skin sites: chest and upper arm. 
Microbiome DNA sequencing will be performed only if the extracted DNA is of sufficient 
quantity and quality. 

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These samples will be collected at times specified in Section 1.3. Depending on participant's 
exposure to antimicrobial treatments for adverse events, collection of skin swab samples may 
or may not be performed. Refer to the sample collection and processing instructions as outlined 
in the central laboratory manual. 
8.6 
Adverse events (AEs), serious adverse events (SAEs), and other 
safety reporting 
The definitions of AEs and SAEs can be found in Section 8.6. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 8.6.3. 
8.6.1 
Adverse events 
An 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 8.6.2): 
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 

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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 
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 ongoing) and the outcome must be reported 
4. Whether it constitutes a SAE (see Section 8.6.2 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/permanently discontinued 
6. Its outcome: 
• not recovered/not resolved 
• recovered/resolved 
• recovered/resolved with sequelae 
• fatal; or unknown 
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 for at least 30 days following the last dose of study 
treatment. 
Once an AE is detected, it must be followed until its resolution or until it is judged to be not 
recovered/not resolved (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 

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Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit. 
8.6.2 
Serious adverse events 
A 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 
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, fetal death or a congenital abnormality or 
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. 
All reports of intentional misuse and abuse of the product are also considered SAEs irrespective 
of whether a clinical event has occurred. 

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Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
8.6.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until approximately 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. Information about all SAEs is collected and recorded 
on the eSAE with paper backup SAE Report Form; all applicable sections of the form must be 
completed in order to provide a clinically thorough report. 
Screen Failures 
SAEs occurring after the participant has provided informed consent until the time the participant 
is deemed a Screen Failure must be reported to Novartis. 
Randomized OR treated participants 
SAEs are collected between the time the participant signs the ICF until approximately 30 days 
after the participant discontinued from study treatment. 
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 Novartis Chief Medical Office & 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 Clinical Trial 
Regulation 536/2014 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the 30-day period after the last study visit should only be reported 
to Novartis Safety if the Investigator suspects a causal relationship to study treatment, unless 
otherwise specified by local law/regulations. 

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8.6.4 
Pregnancy 
• Details of all pregnancies in female participants will be collected after the start of study 
treatment and until 5 months after the single dose administration of MAS825 or placebo 
on Day 1. If indicated, details of all pregnancies in female partners of male participants 
will be collected after the start of study treatment and until 90 days after the end of study 
drug administration. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy for medical reasons will be reported as an AE or 
SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• Any post study pregnancy-related SAE considered reasonably related to the study 
treatment by the Investigator will be reported to Novartis as described in Section 8.6.3. 
While the Investigator is not obligated to actively seek this information in former study 
participants/pregnant female partner, he or she may learn of an SAE through spontaneous 
reporting. 
Any female participant who becomes pregnant while participating in the study will discontinue 
study treatment or be withdrawn from the study. 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the Investigator to collect and report information regarding the 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 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 any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported. 
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 

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8.6.5 
Disease-related events and/or disease-related outcomes not qualifying 
as AEs or SAEs 
Not applicable. All AEs and SAEs will be reviewed. 
8.7 
Pharmacokinetics 
PK plasma samples will be collected at the visits defined in Section 1.3 SoA. Follow 
instructions outlined in the laboratory manual regarding sample collection, numbering, 
processing and shipment. See the potential use of residual samples for more information. In case 
needed (e.g., due to suspected toxicity, AEs), an unscheduled sample should be collected as 
near as possible to the event in order to assess a potential PK relationship. 
PK samples will be obtained from all participants. The analysis of MAS825 concentration in 
serum will be done only from MAS825-treated patients and the DFV890/IBW042 concentration 
analysis in plasma will be done only from DFV890-treated patients. 
DFV890 
DFV890 and its metabolite IBW042 will be determined in plasma by a validated LC-MS/MS 
combo method; the anticipated lower limit of quantification (LLOQ) is 1 ng/mL. 
Due to sparse sampling only plasma Ctrough will be available. 
MAS825 
MAS825 serum concentrations will be determined using a validated target-based sandwich 
ELISA. The LLOQ is 25.0 ng/mL in human serum. 
8.7.1 
PK blood/serum collection 
For details on PK blood collection and processing, labeling, and shipment instructions, see 
laboratory manual. 
The exact clock time of dosing, as well as actual sample collection date and time will be entered 
on the PK blood collection summary page of the CRF. Sampling problems will be noted in the 
relevant field of the CRF. 
8.8 
Biomarkers 
The primary endpoint cytokines, IL-6 and IL-18 (IL-18 applicable for DFV890 only) are 
addressed in Section 8.3. The current section describes the exploratory biomarker strategy. 
The exploratory biomarker analyses will be used to further investigate the effect of DFV890 or 
MAS825 at the molecular level and cellular level, for example the composition of various 
immune cells that can be affected by NLRP3 inhibition. Additional biomarkers will be utilized 
to investigate changes that may relate to pathway inhibition or mechanism of action. 
In addition, cardiovascular markers, for example lipid parameters, will be measured to 
understand disease-related effect. Further potential predictive biomarkers of efficacy will be 
explored, including but not limited to markers which are present in the known downstream 
process of the inhibited pathway or other inflammatory mechanisms (e.g., hsCRP). 

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While the goal of the biomarker assessments is to provide supportive data for the clinical study, 
there may be circumstances when a decision is made to stop a collection, or not perform or 
discontinue an analysis due to either practical or strategic reasons (e.g., inadequate sample 
number, issues related to the quality of the sample or issues related to the assay that preclude 
analysis, impossibility to perform correlative analyses, etc.). Therefore, depending on the 
results obtained during the study, sample analysis may be omitted at the discretion of Novartis. 
Samples will be collected from all participants in this study as specified in Section 1.3, SoA. 
The biomarker strategy may include, but is not limited to, biomarkers that will inform on: 
• Pharmacodynamic, inflammation-related biomarkers: 
• Inflammatory biomarkers: hsCRP 
• Soluble Biomarkers: sASC (for DFV890), hsIL-1β (for DFV890), CXCL9, CXCL10, 
hsIFN-γ, vWF 
• Immunophenotyping: myeloid / lymphoid cell activation/enumeration by flow 
cytometry (whole blood/PBMC) 
• Target capture biomarkers for MAS825, i.e., total IL-1β, total IL-18 and IL-18bp 
• CVD-related biomarkers 
• Lipid parameters: Total cholesterol, high-density lipoprotein (HDL), triglycerides 
(TGs), LDL, Lp(a), apolipoproteins 
• Further exploratory biomarkers may be investigated based on study outcomes. 
These markers may include but are not limited to MPO and free elastase, MMPs, 
fibrinogen, fibrosis (Biomarker plasma/serum) 
• Genetic markers that may impact primary and exploratory readouts or PK (to be done as 
part of the EOS analysis and will not be used for eligibility purposes) 
• CHIP mutations and variant allele frequency at baseline and 12 weeks 
• CYP2C9 polymorphism assessment 
Profiling in serum and plasma 
Samples collected in serum and plasma may be investigated in multiplex hypotheses-free 
platforms where relevant to better understand the disease profile, or for markers that may be 
associated with treatment response or predict response to treatment. 
Residual Samples 
Samples and data may be used for another protocol specified endpoint or may be used for 
exploratory analyses related to the NLRP3 pathway, inflammation, CVD, and/or PK. This may 
include, but is not limited to additional analysis for bioanalytical purposes, protein binding, 
metabolite profiling or quantification, indicators of transporter or enzymatic activity, 
assessment of impact on clinical outcome, and the identification of potential biomarkers that 
may be predictive of benefit from treatment with DFV890 or MAS825. Given the exploratory 
nature of the work, the method used for the analyses may not be validated, and as such, the 
results from this exploratory analysis may not be included in the clinical study report (CSR). 

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Optional Biomarker Samples 
Optional Genetics 
The study includes an optional genetic research component which requires a separate informed 
consent signature if the participant agrees to participate. As permitted by local governing 
regulations and by IRB/EC, it is required as part of this protocol that the Investigator present 
these options to the participant. The purpose of genetic research may be to better understand 
the safety and efficacy of DFV890 or MAS825, or to learn more about human diseases, or to 
help develop ways to detect, monitor and treat diseases. As technology changes over time, the 
most appropriate technology will be used at the time the exploratory genetic research is 
performed. This may include the study of the entire genome. Laboratory manuals will be 
provided with detailed information on sample collection, handling, and shipment. 
DNA samples 
The use of DNA to search for biomarkers of disease and drug action is exploratory. Any results 
from this DNA study will not be placed in the participant’s medical records. As an additional 
confidentiality measure, sample information is stored in one secured database while genetic 
data is stored in an independent secured database. 
Optional Additional Research 
If the participant agrees, by signing the optional consent for Additional Research, biological 
samples and data that remain after analysis is completed may be used for additional research to 
help better understand how the study treatment works, learn more about the disease, improve 
the way clinical studies are conducted, or to help develop ways to detect, monitor or treat human 
diseases. A decision to perform such exploratory research studies would be based on outcome 
data from this study or from new scientific findings related to the drug class or disease, as well 
as assay availability. 
8.9 
Immunogenicity assessments 
IG samples will be obtained from all patients and evaluated in all patients who received 
MAS825. 
8.9.1 
Immunogenicity blood sample collection and handling 
Follow instructions outlined in the laboratory manual regarding sample collection, numbering, 
processing, and shipment. 
8.9.2 
Immunogenicity analytical method(s) 
For MAS825, IG (production of anti-MAS825 antibodies) will be evaluated in serum in a 
validated three-tiered assay approach. All samples, as defined in the assessment schedule, will 
be screened for potential anti-MAS825 antibodies. Any positive screen results are confirmed 
using a confirmatory assay where sample screening signal suppression upon addition of drug in 
excess is investigated. Samples that are confirmed positive for the presence of anti-MAS825 
antibodies will be further analyzed using a titration assay. Further details on sample collection, 
numbering, processing and shipment are provided in the central laboratory manual. 

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The detailed methods for IG assessment will be described in the Bioanalytical Data Report. 
8.10 
Health economics OR Medical resource utilization and health 
economics 
Medical resource utilization (RU) and health economics parameters are not evaluated in this 
study. 
9 
Statistical considerations 
9.1 
Analysis sets 
For all analyses, unless specified otherwise, treatment will be defined as MAS825, a given dose 
level of DFV890, or placebo (placebo, DFV890 10 mg, DFV890 25 mg, DFV890 50 mg, 
DFV890 100 mg, or MAS825). Participants will be analyzed according to either the 
treatment(s) received or to the assigned treatment sequence, depending on the analysis. 
The safety analysis set will include all participants that received any study treatment. 
The PK analysis set will include all participants with at least one available valid (i.e., not flagged 
for exclusion) PK concentration measurement, who received any study treatment and with no 
protocol deviations that impact on PK data. 
The PD analysis set will include all participants that received study treatment and had no 
protocol deviations with relevant impact on PD data. 
9.2 
Statistical analyses 
9.2.1 
General considerations 
Unless stated otherwise, baseline for all calculations will be the last measurement recorded prior 
to dosing on Day 1. 
9.2.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed by 
treatment sequence for the safety analysis set. Relevant medical histories and current medical 
conditions at baseline will be listed by system organ class and preferred term by treatment 
sequence. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation (SD), median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented where applicable. 
9.2.3 
Treatments 
The Safety set will be used for the analyses below. Data for study drug administration and 
concomitant medications and significant non-drug therapies will be listed by treatment and 
subject. 

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The Safety set will be used for the analyses below. 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 duration of exposure in weeks to investigational drugs will be summarized by means of 
descriptive statistics using the safety set. 
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 classification 
system by treatment sequence for the safety analysis set. 
Compliance will be reported as (1) the percentage of participants who took 80% of doses within 
a dosing period and (2) the percentage of patients that took all doses within 2 days of the dosing 
period. 
9.3 
Primary endpoint(s)/estimand(s) analysis 
The primary endpoints are the ratio to baseline in IL-6 and the ratio to baseline in IL-18. 
9.3.1 
Definition of primary endpoint(s) 
The primary endpoints are the serum levels of IL-6 and IL-18 at 3 weeks after the start of a 
dosing period for DFV890 and the serum level of IL-6 at Week 3 for the single dose of MAS825. 
The definition of the primary estimand is provided in Section 3.1. 
9.3.2 
Statistical model, hypothesis, and method of analysis 
The primary analysis for DFV890 will assess the effect on the change in IL-6 and IL-18 
compared to placebo in a dose-response model, separately for the two biomarkers. 
An Emax model will be fit to the post-baseline values for each biomarker, with a random effect 
(reflecting between-participant variability) on the placebo response E0 and on ED50 (the dose 
that produces half the maximal effect), a covariate on E0 for the baseline value of the biomarker, 
and a covariate on ED50 for baseline body weight. All biomarker measurements will be 
logarithm-transformed prior to the analysis. 
An additional random effect reflecting between-participant variability on Emax may be 
incorporated if the data allows. 
Additional details of the model will be specified in the Statistical Analysis Plan (SAP). 
From the model, the predicted response at each treatment and associated 80% CI will be 
extracted, along with the difference to placebo for each DFV890 dose level, the corresponding 
2-sided 80% CI. The estimated response and the difference to placebo will be back-transformed 
and reported on the ratio scale. 
In case of convergence issues, a linear mixed effects model will be fit in place of the Emax model 
(to be referred to as 'traditional model'). The model will include treatment as a fixed effect, a 
random intercept effect for participant, and the baseline value of the biomarker and baseline 
body weight as covariates. All biomarker measurements will be logarithm-transformed prior to 
the analysis. 

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The least square (LS) mean and associated 80% CI for each treatment, and the estimated mean 
difference to placebo for each DFV890 dose level and 2-sided 80% CI will be extracted from 
the model and back-transformed to the ratio scale for reporting. 
The primary analysis for MAS825 will assess the effect on the change in IL-6 compared to 
placebo after 3 weeks of treatment. For this analysis, the Week 3 measurements of IL-6 on 
MAS825 and all Week 3 (i.e., Dosing Period 1) placebo measurements from the other 
sequences will be used. 
A linear model of IL-6 at Week 3 with treatment as a fixed effect, and the baseline value of the 
biomarker as a covariate will be used for the analysis. All biomarker measurements will be 
logarithm-transformed prior to the analysis. 
The LS mean and associated 80% CI for each treatment, and the estimated mean difference to 
placebo, the p-value, and 2-sided 80% CI will be extracted from the model and 
back-transformed to the ratio scale for reporting. 
A time course profile of Treatment Sequence 1 (MAS825 as compared to corresponding Dosing 
Period 1 placebo) will be plotted to investigate how long the effect is sustained. 
9.3.3 
Handling of intercurrent events of primary estimand (if applicable) 
As described in Section 3.1, the intercurrent events will be handled according to a hypothetical 
strategy, reflecting a scenario in which a given participant with an event had not actually 
experienced the event, with the exception of a change to SoC CVD prevention medication. 
To enable this strategy, depending on the type of event, either (1) the biomarker assessment at 
the visit immediately following the event will be set to missing for the primary analysis or (2) all 
subsequent biomarker assessments will be set to missing for the primary analysis, as described 
in that section. 
The data from these assessments will be implicitly imputed in the primary analysis under the 
assumption that the outcome in the affected participant would be no different than in the 
population of participants assigned to the same treatment but that did not experience the event. 
Although measurements collected after the events handled by this strategy are not used for the 
analysis, the planned assessments will take place for possible evaluation of supportive 
estimands. If no measurements are collected after the intercurrent event is experienced, these 
missing measurements will not be imputed. 
9.3.4 
Handling of missing values not related to intercurrent event 
Missing data not related to intercurrent events are expected to be intermittent and will be 
assumed to be missing at random. These data will not be explicitly imputed. 
9.3.5 
Sensitivity analyses 
As a sensitivity analysis to the Emax model described for DFV890 in Section 9.3.2, a Hill 
coefficient other than 1 may be explored. 
If the Emax model converges on either of the two primary endpoints, the traditional model 
described in Section 9.3.2 will be performed as a sensitivity analysis on that endpoint. 

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9.3.6 
Supplementary analysis 
A supplementary analysis will be used to examine the response to treatment with MAS825 and 
DFV890 within each CHIP subtype (TET2, DNMT3A) randomized in the study. This will be 
explored in the primary model as specified for each compound. Details will be described in the 
SAP. 
As an additional supplementary analysis, the primary analyses may be performed as described, 
except that some or all biomarker measurements collected after any change in SoC CVD 
prevention medication may be excluded from the analysis. 
9.4 
Secondary endpoint(s)/estimand(s) analysis 
Not applicable. 
9.4.1 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment sequence. 
Adverse events 
The number (and percentage) of participants with treatment emergent AEs will be summarized 
by overall count, by treatment/dose , primary system organ class, and preferred term. 
An additional summary by treatment sequence primary system organ class, preferred term, and 
maximum severity will be reported. 
Treatment-emergent AEs are those with an onset after the start of a specific dosing period, or 
which were present prior to the start of the dosing period but increased in severity, changed 
from being not suspected to being suspected of study treatment relationship, or developed into 
SAEs after the start of the dosing period. 
For the purposes of these summaries, a dosing period is defined as an approximate 3‑week 
interval between scheduled visits as given in the study design figure (Figure 1-1). For example, 
the first dosing period will begin at Day 1 (randomization) and end on the Day 22 visit, at which 
point the next treatment will be administered according to the specific treatment sequence. 
A participant with multiple AEs within a primary system organ class is only counted once 
towards the total of the primary system organ class. 
All information obtained on AEs will be displayed by treatment sequence and participant. 
A participant with multiple AEs within a primary system organ class is only counted once 
towards the total of the primary system organ class. 
AEs which will be counted for a specific treatment period are those which are treatment-
emergent. These events are those with an onset after the start of the treatment period, or which 
were present prior to the start of the treatment period but increased in severity, changed from 
being not suspected to being suspected of study treatment relationship, or developed into SAEs 
after the start of the treatment period. 

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Vital signs 
All vital signs data will be summarized by overall count (%) and by treatment/dose and 
visit/time. 
12-lead ECG 
All ECG data will be summarized by overall count (%) and by treatment/dose and visit/time. 
Clinical laboratory evaluations 
All laboratory data will be summarized by overall count (%) and by treatment/dose, and 
visit/time. An additional summary by treatment sequence, will be reported. 
Immunogenicity 
All IG results will be listed by overall count (%) and by treatment/dose, participant, and 
visit/time. An additional summary by treatment sequence, will be reported. 
9.4.2 
Pharmacokinetics 
Descriptive summary statistics of DFV890, IBW042 and MAS825 plasma or serum 
concentration data will be provided by treatment, and visit/sampling time point, including the 
frequency of concentrations below the LLOQ and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, and maximum. 
Drug concentrations below LLOQ will be treated as missing for the calculation of the geometric 
means and geometric CV%, and as zero for all other calculations including calculation of PK 
parameters. 
9.5 
Exploratory endpoint(s)/estimand(s) analysis 
Plasma Ctrough of DFV890 and its metabolite, IBW042, by CYP2C9 genotype will be 
summarised 
9.5.1 
Biomarkers 
The following inflammation-related exploratory biomarkers (hsCRP, soluble ASC, CXCL9, 
CXCL10, hsIFN-γ, IL-1β, and neutrophil activation/frequency in whole blood) and disease-
related biomarkers (LDL and Lp(a)) will be analyzed using a linear mixed effects model of the 
same form as the traditional model specified for the primary endpoints in Section 9.3.2. 
Biomarker values above the Upper Limit of Quantification (ULOQ) will be imputed as ULOQ 
and values below the LLOQ will be imputed as LLOQ/2 for these analyses. 

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9.5.2 
DNA 
Exploratory DNA studies are designed to investigate the association between genetic factors 
(genotypes) and clinical assessments (phenotypes) which are collected during the clinical trial. 
These can include, but are not limited, to longitudinal changes of CHIP VAF, additional to the 
planned baseline and week 12 assessments. Without prior evidence of a strong association, a 
number of possible associations are evaluated with exploratory analyses. A range of statistical 
tests are used for the analyses. Additional data, from other clinical trials, are often needed to 
confirm associations. Alternatively, if the number of participants randomized in the study is too 
small to complete proper statistical analyses, the data may be combined, as appropriate, with 
those from other studies to enlarge the dataset for analysis. 
Data generated on hypothesis-free platforms will be reported separately (e.g., CSR addendum). 
9.6 
(Other) Safety analyses 
Not applicable. 
9.7 
Other analyses 
To address the exploratory objective of assessing the effect of the CYP2C9 polymorphism on 
the PK of DFV890 and its metabolite IBW042, the trough concentrations of DFV890 and its 
metabolite will be summarized by CYP2C9 genotype and treatment, as feasible. 
In addition, the relationship between trough concentrations of DFV890 and selected biomarkers 
may be evaluated in a graphical manner. Details will be provided in the SAP. 
9.8 
Interim analysis 
No interim analysis is planned for this study. Ad-hoc interim analyses may be conducted to 
support decision making concerning the current clinical study, Novartis clinical development 
projects in general or in case of any safety concerns. The clinical team may communicate 
interim results (e.g., evaluation of PoC criteria or information needed for planning/modifying 
another study) to relevant Novartis teams for information, consulting and/or decision purposes. 
A blinded assessment of variability of IL-6 and IL-18 may be performed after approximately 
50% of participants have completed Dosing Period 4. 
9.9 
Sample size determination 
9.9.1 
Primary endpoint(s) 
Twenty-eight (28) randomized participants in a 4:4:4:1:1 allocation to the treatment sequences 
will result in, approximately, 8 participants randomized to each of the MAS825-only sequence 
and the first two ascending dose sequences of DFV890, and 2 participants to the third ascending 
dose sequence of DFV890 and to the placebo-only sequence. 

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This allocation of participants will provide at least 80% power of a statistically significant 
difference from pooled placebo and meeting criteria 1 below if the true, maximum effect of 
DFV890 on IL-6 and IL-18 within the dose range studied is a 30% reduction (i.e., log(0.7)=-
0.36, there is no effect on placebo (i.e., E0 = 0), and the ED50 is 20 mg and the within subject 
SD is 0.4. The variability was assessed from CANTOS trial of canakinumab using placebo-only 
data through 24 months. The assumed within subject variability of IL-18 is smaller than IL-6 
so the sample size is driven by IL-6. This calculation assumes no correlation between the two 
markers. 
The assumed true Emax is approximately -0.5, or log(0.6), representing a 40% reduction. 
From the model-based quantities, the following efficacy criteria will be evaluated at the median 
baseline value of the biomarker and the median baseline body weight: 
1. At least one of the following is observed in relation to placebo at the 100 mg dose: 
• IL-6 reduction ≥ 25%, or 
• IL-6 reduction ≥ 20% + IL-18 reduction ≥ 10%, or 
• IL-6 reduction ≥ 15% + IL-18 reduction ≥ 20%. 
2. For any of the above criteria that are achieved, the one-sided p-value for the comparison 
of DFV890 vs. placebo for the associated biomarker(s) is less than 0.1. 
Simulations have shown that there is at least 80% power in achieving statistical significance at 
the 10% level and the mean effect as shown above (with type 1 error of <=10%) 
This allocation of participants will also provide at least 80% power of showing a statistically 
significant difference between MAS825 and pooled placebo, if the true effect of MAS825 on 
IL-6 is a 45% reduction (i.e., log(0.55)=0.60, there is no effect on placebo, and the between 
subject SD of IL-6 is <= 0.5 using a 1 sided alpha of 10%.) 
If MAS825 is not different from placebo, there will be a 10% chance of achieving the efficacy 
criteria (Type 1 error). 

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10 
Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines 
• Applicable ICH Good Clinical Practice (GCP) guidelines 
• Applicable laws and regulations 
The 
protocol, 
protocol 
amendments, 
ICF, 
IB, 
and 
other 
relevant 
documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments/modifications to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 
• Signing 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 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), European Medical Device Regulation 2017/745 for clinical device 
research (if applicable), and all other applicable local regulations 
• Inform Novartis immediately if an inspection of the clinical site is requested by a 
regulatory authority 

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This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations 
(including European Directive 2001/20/EC or European Clinical Trial Regulation 536/2014, 
US CFR 21), and with the ethical principles laid down in the Declaration of Helsinki. 
10.1.2 
Informed consent process 
The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data protection 
requirements, where applicable, and the IRB/IEC or study center. 
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. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
A copy of the ICF(s) must be provided to the participant. 
Participants who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional additional research. The Investigator or authorized designee will explain to each 
participant the objectives of the additional research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any reason during 
the storage period. A separate signature will be required to document a participant’s agreement 
to allow any remaining specimens to be used for additional research. Participants who decline 
to participate in this optional additional research will document this. 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 
document. 
Information about common side effects already known about the investigational treatment can 
be found in the IB. This information will be included in the participant informed consent and 
should be discussed with the participant upon obtaining consent and also 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 IN or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the participant. 

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The following informed consents are included in this study: 
• Main study consent, which also included: 
• 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 
• 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 
• Optional Genetics Consent to provide a sample for exploratory DNA studies 
The study includes an optional sub studies/ DNA component which requires a separate signature 
if the participant agrees to participate. It is required as part of this protocol that the Investigator 
presents this option to the participants, as permitted by local governing regulations. The process 
for obtaining consent should be exactly the same as described above for the main informed 
consent. 
Declining to participate in these optional assessments will in no way affect the participant’s 
ability to join the main research study. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
10.1.3 
Data protection 
Participants will be assigned a unique identifier by Novartis. Any participant records or datasets 
that are transferred to Novartis will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used 
by Novartis in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws. 
10.1.4 
Committees structure 
Not applicable. 

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10.1.5 
Data quality assurance 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the monitoring plan. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of Novartis. No records may be transferred to 
another location or party without written notification to Novartis. 
10.1.5.1 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 (recorded on CRFs) (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. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
10.1.5.2 Database management and quality control 
Novartis personnel (or designated 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. 

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Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an IRT. The system will be supplied by a vendor, who 
will also manage the database. The data will be sent electronically to Novartis (or a designated 
CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request 
of Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 
10.1.6 
Source documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. 
The Investigator may need to request previous medical records or transfer records, depending 
on the study. Also, current medical records must be available. 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. The Investigator must also keep the original 
ICF signed by the participant (a signed copy is given to the participant). Definition of what 
constitutes source data and its origin can be found in, e.g., source data acknowledgment or 
monitoring guidelines. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. Study monitors will perform ongoing source data verification 
to confirm that data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory requirements. 
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. 
10.1.7 
Publication policy 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in CTIS public website. In addition, after study completion (defined as global Last 
Participant Last Visit [LPLV]) and finalization of the study report the results of this trial will 

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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 or CTIS public website 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 
LPLV date, since multinational studies are locked and reported based upon the global LPLV. 
10.1.8 
Protocol adherence and protocol amendments 
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. 
10.1.8.1 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. 

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10.2 
Appendix 2: Abbreviations and definitions 
10.2.1 
List of abbreviations 
ADA 
Anti-drug antibodies 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute neutrophil count 
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 
CABG 
Coronary artery bypass graft 
CANTOS 
Canakinumab Anti-Inflammatory Thrombosis Outcome Study 
CCUS 
Clonal cytopenia of unknown significance 
CHIP 
Clonal Hematopoiesis of Indeterminate Potential 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatine Kinase 
cm 
Centimeters 
CMO&PS 
Chief Medical Office and Patient Safety 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CTC 
Common Terminology Criteria 
Ctrough 
Trough concentrations 
CTT 
Clinical Trial Team 
CV 
coefficient of variation 
CVD 
Cardiovascular disease 
CYP 
Cytochrome P450 
DBP 
Diastolic Blood Pressure 
DDI 
drug-drug interaction 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
EOS 
End of Study 
EOT 
End of treatment 
FIH 
First in Human 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 

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GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate Dehydrogenase 
GLP 
Good laboratory practice 
h 
Hour 
HDL 
High-density lipoprotein 
HDPE 
High Density Polyethylene 
HIV 
Human immunodeficiency virus 
HS 
Hidradenitis suppurativa 
hsCRP 
high-sensitivity C-reactive protein 
i.v. 
intravenous 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IFN-γ 
interferon-γ 
IG 
Immunogenicity 
IgG 
Immunoglobulin G 
IL-1β 
interleukin-1β 
IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IRT 
Interactive Response Technology 
IUD 
Intrauterine device 
kg 
Kilogram 
LDH 
lactate dehydrogenase 
LDL 
Low density lipoprotein 
LDLR 
Low density lipoprotein receptor 
LLOQ 
lower limit of quantification 
LPLV 
Last Patient Last Visit 
LPS 
lipopolysaccharides 
LS 
Least square 
mAb 
Monoclonal antibody 
MACE 
Major adverse cardiovascular event 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
MI 
myocardial infarction 
mL 
milliliter(s) 
NLPR3 
NOD-, LRR- and pyrin domain-containing protein 3 
NLRC4 
Nucleotide-binding oligomerization domain-like receptor family caspase activation and 
recruitment domain-containing 4 protein 
NLRC4-
GoF 
nucleotide-binding oligomerization domain-like receptor family caspase activation and 
recruitment domain-containing 4 protein gain-of-function 
NYHA 
New York Heart Association 

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OHP 
Off-site Healthcare Professional 
PCI 
percutaneous coronary intervention 
PCR 
Protein-creatinine ratio 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PMBC 
Peripheral blood mononuclear cells 
PT 
prothrombin time 
PTT 
Partial Thromboplastin Time 
QD 
Once a day 
QTcF 
QT interval corrected by Fridericia’s formula 
RU 
Resource Utilization 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
standard deviation 
SDD 
Spray-dried dispersion 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SoA 
Schedule of Activities 
SoC 
Standard of Care 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBIL 
Total bilirubin 
TG 
Triglycerides 
ULN 
upper limit of normal 
VAF 
Variant allele frequency 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
Women of child-bearing potential 
10.2.2 
Definitions 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study participant 
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting of 
all clinical trial activities. Examples of team members include the Study 
Lead, Medical Monitor, Trial Statistician etc. 
Coded Data 
Personal Data which has been de-identified by the investigative center 
team by replacing personal identifiers with a code. 
Cohort 
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed-up or traced over time 

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Control drug 
A study intervention (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 
Discontinuation from 
study 
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for any 
reason. No specific request is made to stop the use of their samples or 
data. 
Discontinuation from 
study treatment 
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study 
intervention administration, if any). Participant agrees to the other protocol 
required assessments including follow-up. No specific request is made to 
stop the use of their samples or data. 
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 source data/documents 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. 
Enrollment 
Point/time of participant entry into the study at which informed consent 
must be obtained. The action of enrolling one or more participants 
Estimand 
As defined in the ICH E9(R1) addendum, estimand is 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 participants 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 
Product/ 
Investigational 
Medicinal product 
A pharmaceutical form of an active ingredient or placebo being tested or 
used as a reference (such as an active comparator) in a clinical trial, 
including a product with a marketing authorization when used or 
assembled (formulated or packaged) in a way different from the approved 
form, or when used for an unapproved indication, or when used to gain 
further information about an approved use. 
Medication number 
A unique identifier on the label of medication kits 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study 
(i.e. concomitant or rescue therapy) 
Participant 
A trial participant (can be a healthy volunteer or a patient). "Participant" 
terminology is used in the protocol whereas term "Subject" is used in data 
collection 

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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 
Perpetrator drug 
A drug which affects the pharmacokinetics of the other drug 
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. 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias. 
Randomization 
number 
A unique identifier assigned to each randomized participant 
Rescreening 
If a participant fails the initial screening and is considered as a Screen 
Failure, he/she can be invited once for a new Screening visit after medical 
judgment and as specified by the protocol 
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 
Treatment arm/group 
A treatment arm/group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts. 
Treatment of interest 
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a 
complex sequence of interventions. This is the treatment of interest used in 
describing the related clinical question of interest, which might or might not 
be the same as the study treatment. 
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 the 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. 

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10.3 
Appendix 3: Clinical laboratory tests 
10.3.1 
Clinically notable laboratory values and vital signs 
Not applicable. 

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10.4 
Appendix 4: Participant Engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the time points indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis. 
• Thank You letter 
• Plain language trial summary - after CSR publication 
• Individual study results - after CSR publication 

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10.5 
Appendix 5: 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 10-1 in Section 10.5 for complete definitions of liver laboratory triggers. 
Once a participant is exposed to study treatment, every liver event defined in Table 10-1 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 10-2. Repeat liver chemistry tests (i.e., ALT, AST, TBL, PT/INR, ALP and G-GT) to 
confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the participant. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate CRF. 
• If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate. 
• Hospitalization of the participant if appropriate. 
• Causality assessment of the liver event. 
• Thorough follow-up of the liver event should include 
• 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 
CRF. 

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10.5.1 
Liver event and laboratory trigger definitions & follow-up requirements 
Table 10-1 
Liver event and laboratory trigger definitions 
 
Definition/ threshold 
Liver laboratory triggers 
If ALT, AST and 
TBIL  normal at 
baseline: 
• 
ALT or AST > 5 × ULN 
• 
TBIL > 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 
TBIL > 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 AE potentially indicative of a liver toxicity 
If ALT or AST abnormal 
at baseline: 
• 
ALT or AST > 3x baseline or > 300 U/L (whichever occurs first) 
Table 10-2 
Follow up requirements for liver laboratory triggers - ALT, AST, TBL 
 
ALT 
TBL 
Liver Symptoms 
Action 
ALT increase without bilirubin increase: 
 
 
If normal at 
baseline: 
ALT > 3 x ULN 
Normal 
For 
participants with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• 
No Action 
If elevated at 
baseline: 
ALT > 2 x 
baseline 
or > 300 U/L 
(whichever 
occurs ﬁrst) 
 
If normal at 
baseline: 
ALT > 5 x ULN 
for more than two 
weeks 
Normal 
For 
participants with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• 
Interrupt 
study 
treatment 
• 
Measure 
ALT, AST, 
ALP, GGT, 
TBIL, INR, 
albumin, CK, 
and GLDH in 
48-72 hours. 
• 
Follow-up for 
symptoms. 
• 
Initiate close 
monitoring 
If elevated at 
baseline: 
ALT > 3 x 
baseline 
AND >5x ULN for 
more than two 
weeks 
or 
ALT ≥5x baseline 
AND ≥8x ULN 

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ALT 
TBL 
Liver Symptoms 
Action 
 
If normal at 
baseline: 
ALT > 8 x ULN 
Normal 
None 
and workup 
for competing 
etiologies. 
• 
Study 
treatment can 
be restarted 
only if 
another 
etiology is 
identiﬁed and 
liver enzymes 
return to 
baseline. 
ALT increase with bilirubin increase: 
 
If normal at 
baseline: 
ALT > 3 x ULN 
TBL > 2 x ULN 
(or INR > 1.5) 
For participants 
with Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at 
baseline: 
ALT > 2 x 
baseline 
AND >3x ULN 
 
If normal at 
baseline: 
ALT > 3 x ULN 
Normal or 
elevated 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain* 
If elevated at 
baseline: 
ALT > 2 x 
baseline 
AND >3x ULN 
* This situation suggests liver injury based on (i) elevation of ALT, and (ii) the presence of symptoms of 
liver injury. Even if bilirubin is normal, the presence of liver symptoms indicates potentially severe liver 
injury. 

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Table 10-3 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia 
Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin (isolated) 
 
 
>1.5 – 3.0 ULN 
• 
Maintain treatment 
• 
Repeat LFTs within 48-72 
hours 
Monitor LFTs weekly until 
resolution 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 CRF 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline (ALT, AST, TBIL, 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 CRF 
ALT, AST, TBIL, Alb, PT/INR, 
ALP and GGT until resolution 
(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 CRF 
Investigator discretion 
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. 

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10.6 
Appendix 6: 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, UTI, extreme 
exercise, or trauma) 
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 
should be monitored and followed up by the Investigator or designated trial staff as summarized 
in Section 10.5. 
10.6.1 
Specific Renal Alert Criteria and Actions and Event Follow-up 
Table 10-4 
Specific renal alert criteria and actions 
Renal Event 
Actions 
eGFR decrease 25-49% 
• 
Consider causes and possible interventions 
• 
Repeat laboratory values within 48 hours of 
receipt of abnormal test results. Assess 
patient for signs and symptoms of illness, 
AKI, etc. 
eGFR decrease ≥ 50 % * OR if <18 years old, 
eGFR < 35 mL/min/1.73 m2 
• 
Consider causes and possible interventions 
• 
Repeat assessment within 24-48 hours if 
possible 
• 
Repeat laboratory values within 48 hours of 
receipt of abnormal test results. Assess 
patient for signs and symptoms of illness, 
AKI, etc. 
• 
Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 
• 
Consider referral to nephrologist for 
diagnosis and management 
• 
Consider patient hospitalization and 
specialized treatment 
New onset dipstick proteinuria ≥ 3+ OR PCR ≥ 
1g/g Cr 
• 
Confirm presence of true proteinuria by 
quantification: protein-creatinine on first 
morning void 
• 
Consider causes and possible interventions 
• 
Assess serum albumin & serum total protein 

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Renal Event 
Actions 
• 
Repeat assessment to confirm 
• 
Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 
• 
Consider referral to a nephrologist 
New onset hematuria ≥ 3+ on urine dipstick 
• 
Obtain urine microscopy to distinguish 
hemoglobinuria or myoglobinuria from 
hematuria 
• 
Assess sCr 
• 
Exclude infection, trauma, calculi, bleeding 
from the distal urinary tract/bladder, 
menstruation 
• 
Consider bleeding disorder 
* Corresponds to KDIGO criteria for Acute Kidney Injury 
Table 10-5 
Renal Event Follow-Up 
FOLLOW-UP OF RENAL EVENTS 
Monitor patient regularly (frequency dependent on clinical course and consultant advisement) 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 PCR stabilization at a 
new level with ±50% variability over last 6 months. 
Analysis of urine renal markers in samples collected over the course of the DIN event 

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