Clinical trial NCT05086744
Conditions: Immune Thrombocytopenia (ITP) Cold Agglutinin Disease (CAD)
Keywords: LNP023 Iptacopan Immune thrombocytopenia Cold agglutinin disease Autoimmune benign hematological disorders
Sponsor: Novartis Pharmaceuticals
Start date: 2021-12-21; Completion date: 2024-05-17
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study was to evaluate the efficacy and safety of iptacopan in participants with autoimmune benign hematological disorders such as primary immune thrombocytopenia and primary cold agglutinin disease.

Detailed description:
This was an open-label, single-arm (within each cohort), multi-center, non-confirmatory basket study to assess the efficacy, safety and pharmacokinetics of iptacopan in participants with autoimmune benign hematological disorders. The study was set up as a basket study to allow inclusion of new cohorts (indications). The study included 2 cohorts: primary immune thrombocytopenia (ITP) and primary cold agglutinin disease (CAD). Participants in Cohort 1 (ITP) were stratified in two groups according to high/low complement activation (i.e., based on sC5b-9 level at screening). No additional cohorts were added during the study.

The study consisted of a screening period, a 12-week treatment period (Part A), a washout (for responders)/follow-up (for non-responders) period after Part A, and, for responders only, an additional treatment extension period for up to 24 months (Part B). Non-responders who had signs of clinical benefit according to the Investigator's assessment could also continue treatment with iptacopan in Part B. The washout period prior to the start of part B lasted up to 4 weeks.

Arms: arm 1: Iptacopan 200 mg twice daily (BID) in participants with primary ITP and primary CAD
Interventions: intervention 1: Iptacopan
Intervention descriptions: intervention 1: Iptacopan 200 mg BID given orally (capsule)

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
LNP023 
Clinical Trial Protocol CLNP023L12201 / NCT05086744 
An open-label, multi-center, phase 2 basket study to 
assess efficacy, safety and pharmacokinetics of iptacopan 
(LNP023) in participants with autoimmune benign 
hematological disorders 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2021-002039-40 
Version number: 
v03 (Clean) 
Clinical Trial Phase: 
II 
Release date: 
26-Apr-2022
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 4.0 dated 15-Feb-2021 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Amendment 3 (April 2022) ............................................................................................... 13 
Amendment 2 (December 2021) ....................................................................................... 15 
Amendment 1 (October 2021) ........................................................................................... 17 
Protocol summary .............................................................................................................. 19 
1 
Introduction ....................................................................................................................... 23 
1.1 
Background ............................................................................................................ 23 
1.1.1 
Cohort 1: Immune thrombocytopenia (ITP) ......................................... 24 
1.1.2 
Cohort 2: Cold agglutinin disease (CAD) ............................................. 24 
1.2 
Purpose .................................................................................................................. 25 
2 
Objectives, endpoints and estimands ................................................................................. 25 
2.1 
Primary estimands ................................................................................................. 27 
2.2 
Secondary estimands ............................................................................................. 28 
3 
Study design ...................................................................................................................... 28 
3.1 
Cohort specific details ........................................................................................... 30 
3.1.1 
Cohort 1: primary ITP ........................................................................... 30 
3.1.2 
Cohort 2: primary CAD ........................................................................ 30 
3.1.3 
Cohort 3 ................................................................................................. 30 
3.1.4 
Cohort 4 ................................................................................................. 30 
3.2 
Off-site Procedures ................................................................................................ 31 
3.2.1 
Responsibility of Investigators .............................................................. 31 
3.2.2 
Responsibility of OHPs ......................................................................... 31 
3.2.3 
Telemedicine ......................................................................................... 32 
3.2.4 
Data Flow .............................................................................................. 32 
4 
Rationale ............................................................................................................................ 33 
4.1 
Rationale for study design ..................................................................................... 33 
4.1.1 
Rationale for choice of background therapy ......................................... 34 
4.1.2 
Rationale for off-site visits .................................................................... 34 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 34 
4.3 
Rationale for choice of control drugs (comparator/placebo) ................................. 34 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 35 


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4.5 
Risks and benefits .................................................................................................. 35 
4.5.1 
Blood sample volume ............................................................................ 37 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 37 
5 
Study Population ............................................................................................................... 37 
5.1 
Inclusion criteria .................................................................................................... 38 
5.1.1 
Cohort 1 specific inclusion criteria ....................................................... 38 
5.1.2 
Cohort 2 specific inclusion criteria ....................................................... 38 
5.2 
Exclusion criteria ................................................................................................... 39 
5.2.1 
Cohort 1 specific exclusion criteria ....................................................... 41 
5.2.2 
Cohort 2 specific exclusion criteria ....................................................... 42 
6 
Treatment ........................................................................................................................... 42 
6.1 
Study treatment ...................................................................................................... 42 
6.1.1 
Investigational and control drugs .......................................................... 42 
6.1.2 
Additional study treatments .................................................................. 42 
6.1.3 
Treatment arms/group ........................................................................... 42 
6.1.4 
Post Trial Access ................................................................................... 42 
6.2 
Other treatment(s) .................................................................................................. 43 
6.2.1 
Concomitant therapy ............................................................................. 43 
6.2.2 
Prohibited medication ........................................................................... 44 
6.2.3 
Rescue medication ................................................................................ 46 
6.2.4 
Restriction for study participants .......................................................... 46 
6.3 
Preparation and dispensation ................................................................................. 46 
6.3.1 
Handling of study treatment and other treatment .................................. 47 
6.3.2 
Instruction for prescribing and taking study treatment ......................... 48 
6.4 
Participant numbering, treatment assignment, randomization .............................. 48 
6.4.1 
Participant numbering ........................................................................... 48 
6.4.2 
Treatment assignment, randomization .................................................. 48 
6.5 
Treatment blinding ................................................................................................. 48 
6.6 
Dose escalation and dose modification .................................................................. 49 
6.7 
Additional treatment guidance ............................................................................... 49 
6.7.1 
Treatment compliance ........................................................................... 49 
6.7.2 
Recommended treatment of adverse events .......................................... 49 
6.7.3 
Emergency breaking of assigned treatment code .................................. 49 
7 
Informed consent procedures ............................................................................................ 50 
8 
Visit schedule and assessments ......................................................................................... 51 
8.1 
Screening ............................................................................................................... 59 


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8.1.1 
Information to be collected on screening failures ................................. 60 
8.2 
Participant demographics/other baseline characteristics ....................................... 60 
8.3 
Efficacy .................................................................................................................. 60 
8.3.1 
Appropriateness of efficacy assessments .............................................. 61 
8.4 
Safety ..................................................................................................................... 61 
8.4.1 
Laboratory evaluations .......................................................................... 62 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 63 
8.4.3 
Pregnancy and assessments of fertility ................................................. 64 
8.4.4 
Appropriateness of safety measurements .............................................. 64 
8.5 
Additional assessments .......................................................................................... 65 
 
 65 
8.5.2 
Pharmacokinetics .................................................................................. 66 
 
 66 
9 
Discontinuation and completion ........................................................................................ 68 
9.1 
Discontinuation from study treatment and from study .......................................... 68 
9.1.1 
Discontinuation from study treatment ................................................... 68 
9.1.2 
Discontinuation from study ................................................................... 69 
9.1.3 
Lost to follow-up ................................................................................... 69 
9.2 
Withdrawal of informed consent/Opposition to use data/biological samples ....... 69 
9.3 
Study stopping rules .............................................................................................. 70 
9.4 
Study completion and post-study treatment .......................................................... 71 
9.5 
Early study termination by the sponsor ................................................................. 71 
10 Safety monitoring, reporting and committees ................................................................... 72 
10.1 
Definition of adverse events and reporting requirements ...................................... 72 
10.1.1 
Adverse events ...................................................................................... 72 
10.1.2 
Serious adverse events .......................................................................... 73 
10.1.3 
SAE reporting........................................................................................ 74 
10.1.4 
Pregnancy reporting .............................................................................. 75 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 76 
10.2 
Additional Safety Monitoring ................................................................................ 76 
10.2.1 
Liver safety monitoring ......................................................................... 76 
10.3 
Committees ............................................................................................................ 77 
11 Data Collection and Database management ...................................................................... 77 
11.1 
Data collection ....................................................................................................... 77 
11.2 
Database management and quality control ............................................................ 78 
11.3 
Site monitoring ...................................................................................................... 78 


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12 Data analysis and statistical methods ................................................................................ 79 
12.1 
Analysis sets .......................................................................................................... 79 
12.2 
Participant demographics and other baseline characteristics ................................. 79 
12.3 
Treatments ............................................................................................................. 79 
12.4 
Analysis supporting primary objectives ................................................................ 80 
12.4.1 
Definition of primary endpoint(s) ......................................................... 80 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 80 
12.4.3 
Handling of intercurrent events of primary estimand ........................... 81 
12.4.4 
Handling of missing values not related to intercurrent event ............... 81 
12.4.5 
Sensitivity analyses ............................................................................... 81 
12.4.6 
Supplementary analysis ......................................................................... 81 
12.5 
Analysis supporting secondary objectives ............................................................. 81 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 81 
12.5.2 
Safety endpoints .................................................................................... 82 
12.5.3 
Pharmacokinetics .................................................................................. 83 
12.5.4 
Biomarkers ............................................................................................ 84 
 84 
 84 
 85 
 85 
 85 
 86 
 86 
12.7 
Interim analyses ..................................................................................................... 86 
12.8 
Sample size calculation .......................................................................................... 87 
12.8.1 
Primary endpoint(s) ............................................................................... 87 
13 Ethical considerations and administrative procedures ...................................................... 89 
13.1 
Regulatory and ethical compliance ........................................................................ 89 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 89 
13.3 
Publication of study protocol and results............................................................... 90 
13.4 
Quality Control and Quality Assurance ................................................................. 90 
13.5 
Participant Engagement ......................................................................................... 90 
14 Protocol adherence ............................................................................................................ 91 
14.1 
Protocol amendments ............................................................................................. 91 
15 References ......................................................................................................................... 92 


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16 Appendices ........................................................................................................................ 94 
16.1 
Appendix 1: Clinically notable laboratory values ................................................. 94 
16.2 
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements .......................................................................................................... 95 
 98 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 25 
Table 4-1 
Rationale for study design ..................................................................... 33 
Table 6-1 
Investigational drug ............................................................................... 42 
Table 6-2 
Prohibited medication ........................................................................... 44 
Table 8-1 
Assessment Schedule, Part A and washout ........................................... 53 
Table 8-2 
PK blood collection – Part A ................................................................ 56 
Table 8-3 
Assessment Schedule, Part B ................................................................ 57 
Table 8-4 
Eligibility based on hepatitis B and C test results ................................. 59 
Table 8-5 
Safety assessments ................................................................................ 61 
Table 8-6 
Safety laboratory evaluations ................................................................ 63 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 76 
Table 12-1 
Non-compartmental pharmacokinetic parameters ................................ 84 
Table 16-1 
Definitions of Triggers, Actions and Follow-up requirements for 
liver events ............................................................................................ 95 
 98 
List of figures 
Figure 1-1 
Basket study design ............................................................................... 24 
Figure 3-1 
Study design .......................................................................................... 28 
Figure 12-1 
Probability of observed response rate of ≥50 percent vs. true 
response rate .......................................................................................... 88 
Figure 12-2 
Probability of observed response rate of ≥30 percent vs. true 
response rate .......................................................................................... 89 


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List of abbreviations 
ADCC 
Antibody-Dependent Cellular Cytotoxicity 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
aHUS 
Atypical Hemolytic Uremic Syndrome 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AP 
Alternative (complement) Pathway 
APTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical  
b.i.d. 
Bis in die/twice a day 
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte 
BDR 
Bioanalytical Data Report  
BM 
Biomarker 
BMI 
Body Mass Index 
C1 
Complement Component 1 
C3 
Complement Component 3 
C3G 
C3 Glomerulopathy 
C4 
Complement Component 4 
C5 
Complement Component 5 
CAD 
Cold Agglutinin Disease 
CK 
Creatinine Kinase 
CKD 
Chronic Kidney Diseases 
 
 
CMO&PS  
Chief Medical Office and Patient Safety 
CO 
Country Organization 
 
 
CP 
Classical (complement) Pathway 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CV 
Coefficient of Variation 
 
 
DDC 
Direct Data Capture  
DHT 
Dihydrotestosterone 
DQF 
Data Query Form 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
eSAE 
Electronic Serious Adverse Event 
eSource 
Electronic Source  


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FB 
Complement Factor B 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-Glutamyl Transferase 
h 
Hour 
HBcAg 
Hepatitis B core antigen  
HBsAg 
Hepatitis B surface Antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
IA 
Interim Analysis 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgAN 
IgA Nephropathy 
iMN 
Idiopathic Membranous Nephropathy 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITP 
Immune Thrombocytopenia 
IVIG 
Intravenous Immunoglobulins 
k 
Thousand, 103 
k/µL 
Thousand per Microliter, 103/µL 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Test 
LH 
Luteinizing Hormone  
LLOQ 
Lower Limit of Quantification 
LP 
Lectin Pathway 
MAC 
Membrane Attack Complex 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram(s) 
mL 
milliliter(s) 
NTI 
Narrow Therapeutic Index  
OHP 
Off-site healthcare Professional  
P-gp 
P-glycoprotein 


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PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PNH 
Paroxysmal Nocturnal Hemoglobinuria 
PoC 
Proof of Concept 
 
 
PT 
Prothrombin Time 
QMS  
Quality Management System 
 
 
QTcF 
QT interval corrected by Fridericia’s formula 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sC5b-9 
soluble Complement Component 5 fraction "b" linked to Complement Component 9 
sCR 
serum Creatinine 
SD 
Standard Deviation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T3 
Triiodothyronine 
T4 
Thyroxine  
TBC 
To be confirmed 
TBL 
Total Bilirubin 
TPO-RA 
Thrombopoietin Receptor Agonist 
TSH 
Thyroid Stimulating Hormone  
TTP 
Thrombotic Thrombocytopenic Purpura 
ULN 
Upper Limit of Normal 
ULOQ 
Upper Limit of Quantification 
wAIHA 
Warm Autoimmune Hemolytic Anemia 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 


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Glossary of terms 
Additional treatment 
Medicinal products that may be used during the clinical trial as 
described in the protocol, but not as an investigational medicinal 
product (e.g. any background therapy) 
Assessment 
A procedure used to generate data required by the study 
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 
Control drug 
A study drug (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess 
internal study validity, and/or evaluate comparative effects of the 
investigational drug 
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 drug 
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 paper source 
forms used at the point of care 
Electronic Source Direct 
Data Capture (eSource 
DDC) 
Any technology that allows the capture of clinical study source data 
electronically by investigator site staff at the point of care, into an 
electronic form that has been validated to capture clinical data. 
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  
Estimand  
A precise description of the treatment effect reflecting the clinical 
question posed by the trial objective. It summarizes at a population-
level what the outcomes would be in the same patients under different 
treatment conditions being compared. Attributes of an estimand include 
the population, variable (or endpoint) and treatment of interest, as well 


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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  
Hybrid Trial Design 
Flexible model incorporating both onsite (traditional site based) and off-
site (decentralized) elements within the same study design 
Intercurrent events 
Events occurring after treatment initiation that affect either the 
interpretation or the existence of the measurements associated with the 
clinical question of interest. 
Investigational drug/ 
treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Off-site 
Describes trial activities that are performed at an off-site location by an 
off-site healthcare professional, such as procedures performed at the 
participant's home. 
Off-site healthcare 
Professional (OHP) 
A qualified healthcare professional, such as include those used in the 
study e.g. Nurse, Phlebotomist, Physician, who performs certain 
protocol procedures for the participant in an off-site location such as a 
participant's home. 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study 
(i.e. concomitant or rescue therapy) 
Part  
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single 
dose part and a multiple dose part, or a part in participants with 
established disease and in those with newly-diagnosed disease 
Participant 
A trial participant (can be a healthy volunteer or a patient) 
Participant number 
A unique number assigned to each participant upon signing the 
informed consent. This number is the definitive, unique identifier for the 
participant and should be used to identify the participant throughout the 
study for all data collected, sample labels, etc. 
 
 
 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-
up) which are described in the Protocol. Periods define the study 
phases and will be used in clinical trial database setup and eventually 
in analysis 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data 
includes participant identifier information, study information and 
biological samples. 
Re-screening 
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 


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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 
Telemedicine 
Electronic information and telecommunications technologies (both 
video-based and audio-only) to facilitate the delivery of health care and 
health related education where participant and health care professional 
are not in the same location. 
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. 
Unique Prior Therapy 
Any pharmaceutical agent or type of non-pharmacological intervention 
(e.g., splenectomy, plasmapheresis) administered with the intention to 
treat the indications under study. Transfusions of blood products are 
not accounted as prior therapies. Any unique prior therapy will be 
counted once, even if it is stopped and restarted or given in different 
combinations. Different corticosteroids will be counted as a single 
unique prior therapy, whereas different members of other drug classes 
such as thrombopoietin receptor agonists will be counted as different 
unique prior therapies. 
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 study 
consent (WoC) / 
Opposition to use of data 
/biological samples 
Withdrawal of consent from the study occurs when the participant 
explicitly requests to stop use of their data and biological samples 
(opposition to use data and 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. 
Opposition to use data/biological samples occurs in the countries 
where collection and processing of personal data is justified by a 
different legal reason than consent. 


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Amendment 3 (April 2022) 
Amendment rationale 
The purpose of this amendment is to update the eligibility criteria related to liver disease or 
injury as follows: 
• As per the inclusion criteria, Cohort 2 CAD participants are required to have ongoing 
hemolysis with elevated LDH or total bilirubin at baseline. Though high serum aspartate 
transaminase (AST) is typically considered a biomarker of hepatocellular damage, it may 
also be elevated due to hemolysis only. To account for this, the acceptable levels for AST 
have been increased from 2x to 5x upper limit of normal (ULN) for CAD participants.  
• In addition, for all participants, the acceptable limit for the liver enzymes (ALT, AST, 
GGT, alkaline phosphatase) was increased from 2x to 2.5x ULN to account for the patient 
populations of interest, particularly for participants with cold agglutinin disease, who may 
be expected to have mildly elevated liver enzymes. 
This amendment also incorporates the following changes: 
• In non-malignant hematological diseases, the prior administered therapies are more 
commonly referred to as unique prior therapies rather than lines of prior therapies. These 
are defined as any pharmaceutical agent or type of non-pharmacological intervention 
administered with the intention to treat the indications under study. To align with this 
more commonly used terminology, the respective inclusion criterion has been updated 
accordingly for both ITP and CAD participants.   
• As the screening period can last up to 8 weeks and during this period study participants 
may require the administration of rescue therapy, additional wording has been added to 
the relevant sections in the protocol in order to further clarify the time when rescue 
therapy may be administered in relation to treatment initiation. 
Other minor changes have been incorporated to improve clarity and correct inconsistencies. 
Study Status 
The study has started enrollment on 21-Dec-2021. As of March 2022, 1 ITP and 3 CAD 
participants have been treated in the study. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• The Glossary of terms was updated to include the definition of unique prior therapy and to 
remove the premature participant withdrawal since it is not used in the protocol. 
• The protocol summary was updated to reflect the modifications of the main document. 
• Section 1.1.2: Correction was made to list red blood cell transfusions as a supportive 
therapy for cold agglutinin disease.   


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• Section 5.1.1: Inclusion criteria 102 and 205 have been updated to further define the prior 
therapies for ITP and CAD participants. Section 2.1 has been updated to reflect this 
change.  
• Section 5.2: Exclusion criterion 18 has been updated to allow AST values up to 5xULN 
for CAD participants if attributed to ongoing hemolysis alone. The allowed values for the 
liver function parameters have been updated to up to 2.5xULN for all participants. 
• Section 5.2.1: The wording in the exclusion criterion 102 has been updated to provide 
better clarity for the permitted ITP-directed background therapy and to align with the 
changes in Table 6-2. Section 3.1.1 and Section 4.1.1 have been updated accordingly to 
reflect this change.  
• Section 6.2.2 – Table 6-2. For better clarity, the definition of the period for the prohibited 
medications has been updated from baseline to first iptacopan dose. 
• Section 6.2.3: Clarification has been added for the use of rescue therapy during the 
screening period.  
• Table 8-1: The assessments of blood pressure and pulse rate have been added to the 
baseline visit as per exclusion criterion 22. 
• Section 10.1.3: The option of the paper backup Serious Adverse Event (SAE) Report form 
is added for the SAE reporting. 
• Section 12.4.2: Correction was made that for the calculation of the success rate for the 
primary endpoint, all participants who were treated in the study will be included. 
• Section 12.5.1.1: Correction was made that time to first response will be presented.   
• Section 16.2 – Table 16-1: Action required for Jaundice related to hospitalization has been 
updated to align with the rest of the table. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Amendment 2 (December 2021) 
Amendment rationale 
The purpose of this amendment is to address a comment received from South Korean Health 
Authority (HA): 
• Inclusion criterion #102 was supplemented with South Korea specific instructions. 
Participants must have received at least 2 prior lines of ITP-directed therapy, unless they 
do not qualify for available second-line treatment options per the investigator’s 
assessment. 
In addition, other changes have been incorporated to improve clarity and correct 
inconsistencies. 
Changes to the protocol 
• The protocol summary was updated to reflect the modifications of the main document. 
• Section 2: It was clarified that PK will be assessed in the respective target populations as 
available data suggest that exposure may differ between indications. 
• Section 3.2 and Section 4.1.2: Off-site procedures are not applicable to Cohort 2 because 
CAD blood samples require incubation at 37-39°C immediately upon collection until 
further processing and/or analysis to minimize the risk of spontaneous in vitro RBC 
agglutination. This cannot be supported at off-site locations, nor during transportation to 
the analyzing lab. Same change applied in Section 7, Table 8-1 and Table 8-3. 
• Section 5.1.1: Inclusion criterion #102 was supplemented with South Korea specific 
instructions as per request from South Korean HA participants must have received at least 
2 prior lines of ITP-directed therapy, unless they do not qualify for available second-line 
treatment options per the investigator’s assessment. 
• Section 5.1.2: Inclusion criterion #201 was amended to include more detailed definitions 
of splenomegaly, hepatomegaly and lymphadenopathy as recommended by investigators. 
• Section 6.2.1.1: Section was updated to correct that CYP2C8 is most prominent route of 
iptacopan metabolism. This aligns this section with Table 6-2. 
• Assessment schedules: 
• Table 8-1: Footnote #3 has been split in two footnotes (#3 and #7) to increase clarity. 
• Table 8-1 and Table 8-3: Timing of follow-up call was updated to align with Section 3 
and Section 10.1.3. Follow-up call is conducted 30 days after last visit. 
• Table 8-2 and Table 8-3: Timing for some PK samples was clarified to be directly 
before dosing (0 hours). 
• Table 8-3: Remote visit is out of scope on Day 29 in Part B due to physical 
examination for Cohort 1. 
• Section 8.1: Table 8-4 was added to simplify review of eligibility for HCV and HBV. In 
addition, clarification added that, for Cohort 2, local results can be used for eligibility. 
 
 


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• Section 10.1.3: SAE reporting wording was updated to consider different local 
requirements. 
• Section 12.7: Interim analysis 2 details were updated to align with Section 4.4. 
• Minor additions and corrections have been done throughout the protocol to increase 
clarity. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. 
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Amendment 1 (October 2021) 
Amendment rationale 
The purpose of this amendment is to address questions raised by the Bundesinstitut für 
Arzneimittel und Medizinprodukte (BfArM). The following changes were made to the 
inclusion/exclusion criteria: 
• Inclusion criterion #101 was revised to clarify  immune thrombocytopenia (ITP) should be 
persistent or chronic and diagnosed at least 3 months prior to baseline. 
• Exclusion criterion #10 was revised to exclude participants with any severe concurrent co-
morbidities. 
• Several inclusion/exclusion criteria have been newly added: 
• To include participants with a weight of at least 35 kg 
• To exclude participants with active severe bleeding or history of intracranial 
hemorrhage. 
• To exclude participants with liver disease or liver injury as indicated by abnormal 
liver function tests 
• To exclude participants with unstable medical conditions such as myocardial ischemia 
or unstable thrombotic events to complement revised exclusion criterion #10 
• To exclude participants with an estimated Glomerular Filtration Rate (eGFR) of less 
than 45 mL/min/1.73 m2 
• To exclude participants with ECG and vital signs out of range (as defined in exclusion 
criteria #21 and #22). 
In addition to BfArM requests, the protocol is amended as per investigators comments to 
account for the high risk of spontaneous red blood cell agglutination in blood samples from cold 
agglutinin disease (CAD) patients at room temperature. The amendment will implement 
analysis of hematology samples (including complete blood count, reticulocytes, DAT) from 
CAD patients at local clinical diagnostic laboratories. This change will allow sites to maintain 
local routines whereby CAD patient samples are incubated at 37-39°C immediately upon 
collection until they are further processed and/or analyzed, thus minimizing the risk of 
spontaneous red blood cell agglutination in vitro. 
Changes to the protocol 
• The protocol summary was updated to reflect the modifications of the main document. 
• Section 5.1: Addition of criterion #5 as described above. 
• Section 5.1.1: Modifications of criterion #101 as described above. 
• Section 5.2: Criteria #10 was updated and criteria #17-22 have been added as described 
above. 
• Assessment schedules: 
• Table 8-1 and Table 8-3: Footnote and assessment schedule were updated to clarify 
local vs central analysis of hematology and DAT samples. 


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• Section 8.4.1: Section updated to allow for local lab to be used for Cohort 2 (see rationale 
above). Addition of estimated GFR to allow to determine eligibility based on new 
exclusion criterion. 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations prior to implementation. 
The changes herein affect the Informed Consent.  Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Protocol summary 
Protocol number 
CLNP023L12201 
Full Title 
An open-label, multi-center, phase 2 basket study to assess efficacy, safety 
and pharmacokinetics of iptacopan (LNP023) in participants with 
autoimmune benign hematological disorders  
Brief title 
A basket study to assess efficacy, safety and PK of iptacopan (LNP023) in 
autoimmune benign hematological disorders 
Sponsor and 
Clinical Phase 
Novartis 
Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose 
The main purpose of this study is to evaluate the efficacy and safety of 
iptacopan in participants with autoimmune benign hematological disorders 
such as primary immune thrombocytopenia (ITP) and primary cold agglutinin 
disease (CAD). 
Primary 
Objective(s)  
Cohort 1: To assess the ability of iptacopan to induce a clinically meaningful 
increase in platelet count in participants with primary ITP 
Cohort 2: To assess the ability of iptacopan to induce a clinically meaningful 
increase in hemoglobin levels in participants with primary CAD 
Secondary 
Objectives 
• 
To assess the time to first response 
• 
To assess the duration of response during Part A 
• 
To assess the magnitude of response during Part A 
• 
To assess the need for rescue therapy during Part A 
• 
Cohort 2: To assess the effect of iptacopan on relevant disease 
biomarkers (BM) not covered in the primary objective during Part A 
• 
To assess the safety and tolerability of iptacopan in participants with 
benign hematological disorders 
• 
To assess the pharmacokinetics of iptacopan in the respective target 
populations 
Study design 
This is an open-label, single-arm (within each cohort), multi-center, non-
confirmatory basket study to assess the efficacy, safety and 
pharmacokinetics of iptacopan in participants with autoimmune benign 
hematological disorders. The study is set up as a basket study to allow 
inclusion of new cohorts (=indications). The study consists of a screening 
period, a 12-week treatment period (Part A), a washout (responders)/follow-
up (non-responders) after Part A, and, for responders only, an additional 
treatment extension period of up to 24 months (Part B). The total study 
duration from screening until end-of-study visit (EOS) is approximately 
6 months for participants not meeting the primary endpoint (non-responders) 
and up to 31 months for participants meeting the primary endpoint 
(responders). 
Rationale 
The rationale and purpose is to evaluate the efficacy and safety of iptacopan 
in participants with autoimmune benign hematological disorders such as 
primary ITP and primary CAD. 


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Study population 
The study population will comprise a total of approximately 30 enrolled 
participants: 
• 
Cohort 1: Approximately 20 participants with primary ITP will be enrolled; 
approximately 10 participants each, with high and low complement 
activation, respectively. 
• 
Cohort 2: Approximately 10 participants with primary CAD will be 
enrolled. 
Key Inclusion 
criteria 
All Cohorts: 
• 
Written informed consent 
• 
Vaccination against Neisseria meningitidis and Streptococcus 
pneumoniae infections is required and vaccination against Haemophilus 
influenzae infection is recommended prior to the start of treatment. 
• 
Weight of at least 35 kg 
Cohort 1 specific inclusion criteria: 
• 
Male and female participants aged ≥ 18 years at baseline with a 
diagnosis of persistent or chronic primary ITP (diagnosed at least 3 
months prior to baseline) 
• 
Participants must have received at least 1 unique prior therapy  
administered with the intention to treat ITP 
• 
Sustained thrombocytopenia 
Cohort 2 specific inclusion criteria: 
• 
Male and female participants aged ≥18 years at baseline with a diagnosis 
of primary CAD, including CAD arising in the setting of a low-grade 
lymphoproliferative disorder a) not requiring any therapy and b) without 
evidence of significant splenomegaly, hepatomegaly, or diffuse 
lymphadenopathy (as per Section 5.1.2) 
• 
Positive direct antiglobulin test for C3d only and cold agglutinin titer of 
≥64 at 4°C 
• 
Laboratory evidence of ongoing hemolysis 
• 
Sustained anemia 
• 
Participants must have received at least 1 unique prior therapy 
administered with the intention to treat CAD 
Key Exclusion 
criteria 
All cohorts: 
• 
Use of other investigational drugs at the time of enrollment, or within 5 
half-lives of enrollment, or within 30 days, whichever is longer; or longer if 
required by local regulations 
• 
Past or concomitant use of medications prohibited by the protocol 
• 
Known or suspected hereditary or acquired complement deficiency 
• 
History of primary or secondary immunodeficiency, including a positive 
HIV test result 
• 
Chronic infection with Hepatitis B or C virus  
• 
History of recurrent invasive infections caused by encapsulated 
organisms, including N. meningitidis, S. pneumoniae, or H. influenzae 
• 
Presence or suspicion (based on judgment of the investigator) of any 
active infection within 14 days prior to first study drug administration. 


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• 
Any medical condition deemed likely to interfere with the participant’s 
participation in the study 
• 
Any malignant disease diagnosed within the past 5 years, with the 
exception of localized non-melanoma skin cancer, in situ cervical cancer, 
or, for CAD, a low-grade lymphoproliferative disorder. 
• 
History of bone marrow/hematopoietic stem cell or solid organ 
transplantation. 
• 
Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using effective methods 
of contraception during dosing of investigational drug and for 1 week 
after last iptacopan dose 
• 
Active severe bleeding or history of intracranial hemorrhage 
• 
Liver disease, or liver injury as indicated by abnormal liver function tests 
• 
Severe concurrent co-morbidities or unstable medical conditions 
Cohort 1 specific exclusion criteria: 
• 
Secondary ITP, as may arise in the setting of certain autoimmune 
disorders, immunodeficiency syndromes, infections, malignancies, and 
drug treatments 
• 
No ITP-directed background therapy permitted, with the exception 
of either a thrombopoietin receptor agonist (TPO-RA) or low-dose 
corticosteroid, as long as stable dosage for at least 4 weeks prior to first 
iptacopan dose 
• 
Abnormal coagulation screening labs (PT/INR, PTT). 
Cohort 2 specific exclusion criteria: 
• 
Secondary cold agglutinin syndrome, as may arise in the setting of 
certain infections, autoimmune disorders, and malignancies (with the 
exception of a low-grade lymphoproliferative disorder) 
• 
No CAD-directed background therapy permitted 
Study treatment 
Iptacopan 200 mg b.i.d. 
Treatment of 
interest 
The treatment of interest is iptacopan with or without the allowed background 
medication for the indication studied. The dose of the allowed background 
medication must remain stable during Part A and can be tapered after two 
weeks of treatment in Part B 
Efficacy 
assessments 
Cohort 1: Platelet count 
Cohort 2: Hemoglobin level 
Pharmacokinetic 
assessments 
The pharmacokinetic profile of iptacopan will be established in the different 
indications at two different visits in Part A, and PK parameters (AUCtau, 
AUClast, Cmax, Tmax) will be calculated from plasma samples collected up 
to 6 hours post dose. 
Key safety 
assessments 
Adverse event monitoring, physical examinations, vital signs, ECGs, 
monitoring of laboratory markers in blood and urine 
Other 
assessments  


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Data analysis 
The primary endpoints of this study are, 
• 
Cohort 1 (ITP): A clinically meaningful response, defined by a platelet 
count of ≥50 k/µL sustained for at least 2 consecutive weeks during the 
main, 12-week treatment part without the use of rescue therapy. 
• 
Cohort 2 (CAD): A clinically meaningful response, defined by a 
hemoglobin level increase of ≥1.5 g/dL above baseline sustained for at 
least 2 consecutive weeks during the main, 12-week treatment part 
without the use of rescue therapy. 
Use of any rescue therapy (see Section 6.2.3) before response criteria are met 
is considered an unfavorable outcome, and, therefore, the participants will be 
considered as non-responders. Conversely, use of rescue therapy after the 
primary endpoint is met, does not impact the response status with respect to 
that endpoint. 
A positive sign of efficacy will be defined separately for each cohort. In Cohort 
1, this will be defined as having a response rate of at least 30% in all-comers, 
or 50% in the patients with activated complement at screening. In Cohort 2, 
this will be defined as a response rate of at least 50%. 
Additional analyses include the platelet count (Cohort 1) and hemoglobin levels 
(Cohort 2) which will be summarized by Cohort, group (if applicable), visit and 
time point. This will be done for both the raw values and change from baseline.  
Key words 
Iptacopan, LNP023, Benign Hematology, Immune Thrombocytopenia 
(ITP), Cold Agglutinin Disease (CAD) 


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1 
Introduction 
1.1 
Background 
Iptacopan (LNP023) is a novel, orally administered, low molecular-weight, first-in-class and 
selective inhibitor of complement factor B (FB), a key component of the complement alternative 
pathway (AP) C3 and C5 convertases. By inhibiting both AP C3 and C5 convertases, iptacopan 
blocks both AP-dependent C3 activation and membrane attack complex (MAC) formation 
(Schubart et al 2019). Iptacopan also blocks the amplification loop of the complement system, 
which, independently of the initiating trigger, is an important contributor to overall MAC 
formation in vitro (Harboe et al 2004). Importantly, iptacopan does not interfere with 
amplification-independent, direct activation initiated via the classical (CP) and lectin pathways 
(LP) – consequently, in immunized individuals, MAC-dependent killing of Neisseria spp. (for 
example) through activation of the CP is expected to be maintained. 
In non-clinical studies, iptacopan has demonstrated a dose-dependent inhibition of the AP and 
a good safety profile (Schubart et al 2019, Mainolfi et al 2020). Inhibition of complement 
activation was confirmed in translational assays using samples from patients with paroxysmal 
nocturnal hemoglobinuria (PNH), C3 glomerulopathy (C3G) and atypical hemolytic uremic 
syndrome (aHUS) as well as in a rat model of glomerulonephritis (passive Heyman nephritis). 
The safety/tolerability and preliminary efficacy of iptacopan in humans is supported by data 
from three completed phase 1 studies in healthy volunteers and by emerging positive data from 
several phase 2 and 3 trials across different indications, including PNH (Risitano et al 2020), 
C3G, IgA nephropathy (IgAN), and idiopathic membranous nephropathy (iMN). For a more 
detailed overview of the non-clinical and clinical data on iptacopan to date, please refer to the 
Investigator’s Brochure. 
The encouraging efficacy and reassuring safety profile of iptacopan seen in early clinical trials 
involving patients with AP-driven diseases and the established role of the AP in the 
amplification loop have raised hope that AP inhibition with iptacopan could also benefit patients 
with autoantibody-mediated diseases with high CP-mediated complement activation. The aim 
of this proof-of-concept study is to assess the potential for iptacopan treatment in different 
autoantibody-mediated benign hematology disorders with evidence of complement activation 
in at least a subset of patients. The study is designed as a basket study (Figure 1-1) with two 
initial cohorts/indications, namely primary immune thrombocytopenia (ITP) and primary cold 
agglutinin disease (CAD). Further cohorts/indications, such as warm autoimmune hemolytic 
anemia (wAIHA) and/or thrombotic thrombocytopenic purpura (TTP), with similar study 
design and assessments, may be added via substantial protocol amendment. 


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Figure 1-1 
Basket study design 
 
1.1.1 
Cohort 1: Immune thrombocytopenia (ITP) 
Primary immune thrombocytopenia (ITP) is an autoimmune, mostly IgG-mediated 
thrombocytopenia, which usually presents acutely with signs and symptoms of bleeding in the 
absence of a specific underlying cause. Though considered a rare disease, with an annual 
incidence of 33/million in adults (50-100/million in children) and an estimated prevalence in 
the U.S. of 86,000, it is the most common autoimmune hematological disorder. 
Standard of care for newly diagnosed primary ITP, beyond watchful waiting and supportive 
therapy, consists of corticosteroids, intravenous immunoglobulins (IVIG), or anti-Rho(D) 
immunoglobulin. However, most adults receiving these treatments will eventually relapse and 
require further therapy, with subsequent treatment options including thrombopoietin receptor 
agonists (TPO-RA), including eltrombopag, avatrombopag and romiplostim, as well as 
rituximab, fostamatinib, and splenectomy. Despite these options, there continues to be an unmet 
medical need, namely for therapies inducing durable remissions in relapsed / refractory patients 
and for targeted therapies with predictive biomarkers. 
In terms of pathophysiology, whereas platelet destruction is thought to be primarily mediated 
in the spleen via antibody-dependent cellular cytotoxicity (ADCC), several lines of evidence 
indicate significant complement activation in at least a subset (roughly 30-50%) of ITP patients 
(Peerschke et al 2010; 
Cheloff et al 2020; 
Castelli et al 2020). 
Importantly, 
several 
complement component 1 (C1) inhibitors have recently shown preliminary efficacy in patients 
with refractory primary ITP (Roesch and Broome 2016; Broome et al 2020). 
1.1.2 
Cohort 2: Cold agglutinin disease (CAD) 
Primary cold agglutinin disease (CAD) is an autoimmune hemolytic anemia, often triggered by 
cold temperatures or viral infections. Although the term “primary” implies the absence of a 
specific underlying cause, recent evidence suggests that the majority of patients actually have 
a low-grade lymphoproliferative disorder (Berentsen et al 2019). As a rare disease with an 
annual incidence of 1/million and an estimated prevalence in the U.S. of 5,000, primary CAD 
usually manifests acutely with signs and symptoms of hemolytic anemia and almost exclusively 
affects adults, with a median age of 67 years at presentation. 


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Standard of care for acute primary CAD, beyond watchful waiting and supportive therapy 
(including red blood cell transfusions), consists of plasmapheresis and/or intravenous 
immunoglobulins (IVIG). The main treatment option for refractory cases consists of rituximab, 
with or without bendamustine. Despite these options, there continues to be an unmet medical 
need, namely for therapies inducing durable remissions in relapsed / refractory patients and for 
targeted therapies with predictive biomarkers. 
In terms of pathophysiology, hemolysis is triggered by cold-reacting autoantibodies (mostly 
IgM) targeting different red blood cell surface antigens, resulting in complement-dependent, 
extra- and intravascular hemolysis. Importantly, several complement inhibitors (eculizumab, 
sutimlimab) have shown preliminary benefit in patients with refractory primary CAD 
(Röth et al 2018; Jäger et al 2019; Röth et al 2021). 
1.2 
Purpose 
The main purpose of this study is to evaluate the efficacy and safety of iptacopan in participants 
with autoimmune benign hematological disorders such as primary ITP and primary CAD. 
2 
Objectives, endpoints and estimands 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
Cohort 1: To assess the ability of 
iptacopan to induce a clinically 
meaningful increase in platelet count 
in participants with primary ITP  
• 
A clinically meaningful response, defined by a 
platelet count of ≥50 k/µL sustained for at least 2 
consecutive weeks during the main, 12-week 
treatment part without the use of rescue therapy 
• 
Cohort 2: To assess the ability of 
iptacopan to induce a clinically 
meaningful increase in hemoglobin 
levels in participants with primary 
CAD  
• 
A clinically meaningful response, defined by a 
hemoglobin level increase of ≥1.5 g/dL above 
baseline sustained for at least 2 consecutive weeks 
during the main, 12-week treatment part without the 
use of rescue therapy 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess the time to first response 
• 
Cohort 1: Time to first platelet count ≥50 k/μL 
• 
Cohort 2: Time to first hemoglobin level 
≥1.5 g/dL above baseline 
• 
To assess the duration of response 
during Part A 
• 
Cohort 1: Duration during which platelet count 
remains ≥50k/μL without the use of rescue therapy 
• 
Cohort 2: Duration during which hemoglobin level 
remains ≥1.5 g/dL above baseline without the use 
of rescue therapy 
• 
To assess the magnitude of response 
during Part A 
• 
Cohort 1: Magnitude of platelet count increase 
from baseline 
• 
Cohort 2: Magnitude of hemoglobin increase from 
baseline 


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Objective(s) 
Endpoint(s) 
• 
To assess the need for rescue 
therapy during Part A 
• 
Use of rescue therapy 
• 
Cohort 2 only: To assess the effect 
of iptacopan on relevant disease 
biomarkers (BM) not covered in the 
primary objective during Part A 
• 
Lactate dehydrogenase (LDH), total bilirubin, 
reticulocyte count and haptoglobin 
• 
To assess the safety and tolerability 
of iptacopan in participants with 
benign hematological disorders 
• 
Safety parameters include vital signs, adverse 
events, hematology, blood chemistry, reproductive 
and thyroid hormones, coagulation, urinalysis and 
ECG evaluation. 
• 
To assess the pharmacokinetics (PK) 
of iptacopan in the respective target 
populations 
• 
Iptacopan PK parameters including but not limited 
to Cmax, AUCtau, AUClast, Ctrough and Tmax. 


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2.1 
Primary estimands 
The primary clinical question of interest is: What is the effect of iptacopan treatment for 
12 weeks on the platelet count in patients with primary ITP and on the hemoglobin level in 
patients with primary CAD considering the use of rescue medication as an indicator of lack of 
efficacy. 
The justification for targeting this treatment effect is to estimate the effect of the study drug for 
the full duration in the absence of concomitant treatments that could confound the primary 
assessment of efficacy. 
Cohort 1: primary ITP  
The primary estimand is described by the following attributes: 
1. Population: Adult participants diagnosed with primary ITP with sustained 
thrombocytopenia after at least 1 unique prior therapy administered with the intention to 
treat ITP (see Section 5). 
2. Primary variable: Response, where the response is defined as a platelet count of ≥50 k/µL 
sustained for at least 2 consecutive weeks during the main, 12-week treatment part, a) in 
the absence of rescue therapy or prohibited medications to treat ITP and b) without study 
drug discontinuation. 
3. Treatment of interest: Investigational treatment with iptacopan 200 mg b.i.d. 
4. The summary measure: Proportion of participants who respond.  
Cohort 2: primary CAD 
The primary estimand is described by the following attributes: 
1. Population: Adult participants diagnosed with primary CAD with sustained anemia and 
laboratory evidence of ongoing hemolysis after at least 1 unique prior therapy 
administered with the intention to treat CAD (see Section 5). 
2. Primary variable: Response, where the response is defined as a hemoglobin level increase 
of ≥1.5 g/dL above baseline sustained for at least 2 consecutive weeks during the main, 
12-week treatment part, a) in the absence of rescue therapy or prohibited medications to 
treat CAD and b) without study drug discontinuation.  
3. Treatment of interest: Investigational treatment with iptacopan 200 mg b.i.d. 
4. The summary measure: Proportion of participants who respond. 


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2.2 
Secondary estimands 
Not applicable. 
3 
Study design 
This is an open-label, single-arm (within each cohort), multi-center, non-confirmatory basket 
study to assess the efficacy, safety and pharmacokinetics of iptacopan in participants with 
autoimmune benign hematological disorders. As outlined in Section 1.1, the study is set up as 
a basket study (Figure 1-1) to allow inclusion of new cohorts (=indications). 
The study starts with two initial cohorts/indications and participants will be assigned to the 
relevant cohort based on their diagnosis: 
• Cohort 1: participants diagnosed with primary ITP 
• Cohort 2: participants diagnosed with primary CAD 
Inclusion of up to two additional cohorts (e.g., wAIHA, TTP) will only be proposed via 
substantial protocol amendment and will only be implemented upon review by HAs/EC/IRBs. 
The study design / participant journey is illustrated in Figure 3-1. 
Figure 3-1 
Study design 
 
The total study duration from screening until end of study visit (EOS) is approximately 
6 months for participants not meeting the primary endpoint (non responders). Participants 
meeting the primary endpoint (responders) will be offered to join Part B after a washout. 
In Part B, responders gain long-term access to iptacopan (24 months of treatment). The total 
study duration for responders will be up to 31 months (see Figure 3-1). Safety and efficacy 
assessments will be conducted at visits as specified in the Assessment Schedule (Table 8-1 and 
Table 8-3). Pharmacokinetic (PK) 
 samples will also be collected.  


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The study includes: 
• Screening/Baseline: A screening period of up to 8 weeks to assess eligibility and vaccinate 
participants (see Section 6.2.1.2). Participants who meet the eligibility criteria at screening 
will move to baseline visit, where eligibility is confirmed and baseline evaluations are 
performed. 
• Treatment in Part A: Part A includes a treatment period of 12 weeks (Day 1 to Day 85) 
with twice daily (b.i.d.) administration of 200 mg iptacopan. Any pre-existing background 
therapy (if allowed, see cohort-specific exclusion criteria in Section 5.2) must remain 
unchanged during Part A. Participants will have weekly visits for the first 4 weeks, followed 
by visits every 2 weeks for the latter 8 weeks. Safety and efficacy assessments will be 
conducted 
 at visits as specified in the Assessment 
Schedule for Part A (Table 8-1). There will also be two PK profiling days in Part A. 
• Follow-up/washout after Part A: At the end of Part A, participants will be classified as 
responders or as non-responders based on whether or not they meet the cohort-specific 
primary endpoint (see Table 2-1 and Section 12.4.1) any time during Part A. 
• Non-responders (and responders not wanting to move on to Part B) will have a safety 
follow-up period of 4 weeks. Participants will undergo study completion 
evaluations and will complete the study during EOS visit approximately 4 weeks after 
the last study drug administration. All participants will have a follow-up call 
approximately 30 days after the last visit. 
• Responders will be offered to join the optional treatment extension in Part B. Prior to 
the start of Part B, all eligible participants will have a washout period lasting up to 4 
weeks. After the washout period the participants will have the EOS Part A/Day 1 Part 
B visit. Participants reaching a critical safety cut-off level (as defined in the cohort-
specific details in Section 3.1) at any follow-up/washout visit will have the opportunity 
to shorten the washout and move to EOS Part A/Day 1 Part B visit before completion 
of the 4 weeks of washout. 
• Treatment in Part B: In Part B, iptacopan will be administered at 200 mg b.i.d. for up to 
24 months. Any pre-existing background therapy (if allowed, see cohort-specific exclusion 
criteria in Section 5.2) may be tapered off earliest after 2 weeks of iptacopan treatment in 
Part B (see cohort-specific details in Section 3.1 for additional guidance). Assessments 
during Part B are described in the Assessment Schedule for Part B (Table 8-3). Notes: 
• Part B is optional, a responder may continue with Part B at the investigator`s or 
participant`s discretion. It is the investigator's responsibility to discuss all the available 
treatment options with the participant before the participant would enter into Part B. 
The discussion should be documented in the source document. If the participant is a 
responder but decides not to continue in Part B it should be documented in the electronic 
case report form (eCRF). 
• If a participant does not meet the primary endpoint but the investigator considers the 
response to be clinically meaningful and wants to continue with iptacopan treatment, 
the participation in Part B needs to be discussed and agreed with the Sponsor upfront 
on a case by case basis. 


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• Follow-up after Part B: After completion of the treatment period, the participants will 
move to a 4-week follow-up and complete the study at EOS for Part B. All participants will 
have a follow-up call approximately 30 days after the last visit. 
3.1 
Cohort specific details 
3.1.1 
Cohort 1: primary ITP 
Approximately 20 participants diagnosed with primary ITP and sustained thrombocytopenia 
will be enrolled. Participants will be stratified based on complement activity (sC5b-9 levels) at 
screening in to one of two groups until approximately 10 participants have been assigned to 
each group: 
• sC5b-9 high (≥ 200 ng/mL) 
• sC5b-9 low (< 200 ng/mL) 
Depending on the distribution of baseline sC5b-9 levels amongst the first 10 enrolled 
participants, the threshold of 200 ng/mL may be modified (e.g., if most participants are below 
or above). 
Washout period cut-off: If during the washout period for responders the platelet count drops 
to <30 k/μL and/or the participant experiences a bleeding episode, the participant will be 
allowed to skip the remaining follow-up visits and move directly to EOS Part A/Day 1 Part B. 
Tapering of pre-existing background therapy in Part B: Participants on pre-existing, 
background either TPO-RA or low-dose corticosteroid therapy will be allowed to taper and 
eventually discontinue this therapy starting earliest after 2 weeks of iptacopan therapy in Part 
B, as long as the platelet count is and remains ≥50 k/μL. Tapering may be done per the 
investigator's discretion, taking into account the respective label as well as standard practice 
and/or current literature guidance (such as Cuker et al 2020 for TPO-RA). Given the risk of 
rebound thrombocytopenia, it is not recommended to discontinue TPO-RA therapy without 
tapering, and additional platelet count monitoring is recommended during tapering. 
3.1.2 
Cohort 2: primary CAD 
Approximately 10 participants diagnosed with primary CAD and sustained anemia and 
evidence of ongoing hemolysis will be enrolled.  
Washout period cut-off: If during the washout period for responders the hemoglobin level 
drops to <10 g/dL, the participant will be allowed to skip the remaining follow-up visits and 
move directly to EOS Part A/Day 1 Part B. 
3.1.3 
Cohort 3 
Placeholder for a potential 3rd Cohort. Additional details will be provided in a substantial 
protocol amendment. 
3.1.4 
Cohort 4 
Placeholder for a potential 4th Cohort. Additional details will be provided in a substantial 
protocol amendment. 


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3.2 
Off-site Procedures 
At the investigator's direction and based on benefit-risk considerations of the participant's 
clinical condition, qualifying participants may be offered the option to have certain clinical trial 
procedures performed at an off-site location, as defined in Section 8. A hybrid model is planned 
for this study, incorporating both onsite and off-site visits. The off-site procedures will be 
offered in certain countries and sites as determined by Novartis based on national and local 
regulations. Participants have the option of participating in one or more off-site visits, based on 
participant preference and investigator discretion. 
One or more of the following elements may be implemented to support off-site visits where 
allowed by national and local regulations: 
• Telemedicine 
• Off-site healthcare professionals (OHP) 
• Direct-to-participant shipment of study supplies 
• Direct-to-participant shipment of study treatment (refer to Section 6) 
• Electronic Source (eSource) Direct Data Capture (DDC) 
Off-site procedures are not applicable to Cohort 2 because CAD blood samples require 
incubation at 37-39°C immediately upon collection until further processing and/or analysis to 
minimize the risk of spontaneous in vitro RBC agglutination. This cannot be supported at 
off-site locations, nor during transportation to the analyzing lab. 
3.2.1 
Responsibility of Investigators 
Procedures that are performed off-site remain under the oversight of the investigator, who 
retains accountability for the conduct of all safety and efficacy assessments delegated to an 
OHP, and will ensure the rights, safety and wellbeing of participants. This includes ensuring 
the following (including, but not limited to): 
• the identification, management and reporting of adverse events (AEs) and serious adverse 
events (SAEs) are performed in accordance with the protocol and applicable regulations 
• OHPs have appropriate qualifications, training, and experience to successfully conduct 
off-site procedures 
• source data collected off-site are reviewed and evaluated in a timely manner 
• the investigator or delegate is available to be contacted by the OHP if any issues or 
concerns are noted during an off-site visit 
• where relevant, the investigator or delegate will be present via telemedicine for a portion 
of the off-site visit to support the physical examination 
3.2.2 
Responsibility of OHPs 
OHPs must have the required qualifications, training, and experience to conduct 
off-site assessments. OHPs are responsible to conduct delegated assessments and collect 
relevant data at off-site visits in accordance with the clinical trial protocol, International 
Conference for Harmonization (ICH) Good Clinical Practice (GCP) guidelines, and national 
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The OHPs will be provided by a third-party vendor sourced by Novartis. Where a site wishes 
to use OHPs that are not provided by Novartis this must be agreed with Novartis before use. 
Any issues or safety concerns identified by the OHP will be promptly communicated to the 
investigator or delegate according to a pre-defined communication plan. 
3.2.3 
Telemedicine 
Telemedicine is optional and subject to local and national regulations (see Section 3.2). 
The sponsor has qualified and contracted a third-party vendor to provide telemedicine platform 
technology for this study. The selected platform is a validated system complying with relevant 
ICH E6 GCP guidelines. Trial participants can interact with site personnel using online 
communication tools built into the platform, enabling the following capabilities: 
• Secure videoconferencing which allows the participant, OHP and site personnel to be 
connected 
• Reminders to be automatically sent to participants (e.g. visit or dosing compliance) 
• eSource Direct Data Capture (DDC) (see Section 3.2.4) 
3.2.4 
Data Flow 
The OHPs will enter data at off-site visits into electronic source documentation forms contained 
in an eSource DDC platform, which has been validated for use in clinical research. Where paper 
source documentation exists, images of documentation will be uploaded electronically into the 
same platform as certified copies, and the original documentation will then be sent to the trial 
site. 
Data contained in the platform are available to site and sponsor staff based on role-based access 
and permissions, and will be stored in a robust and secure cloud-based back-end environment. 
Only sponsor staff who are responsible for field monitoring activities will have access to the 
source data, which may include some personally identifiable information, consistent with the 
access that is provided to a field monitor in a traditional onsite clinical trial model. 
Relevant data in the eSource DDC platform may be manually transcribed by site staff into the 
study electronic data capture (EDC) system. Alternatively, the platform allows for 
configuration that enables data to be automatically exported into the study EDC system. 
Certified copies of data in the eSource DDC platform will be provided to investigator and/or 
site personnel, and promptly and regularly uploaded into the participant’s medical records, 
according to local guidelines. 
Investigators will have continuous, near real time access to assigned studies and all participant 
records within their studies in the eSource DDC platform, with the ability to add, edit, review 
and sign forms within participant records. 
The platform maintains a secure, GCP-compliant audit trail and uses measures such as 
encryption and access controls to ensure that data privacy and security is maintained. Additional 
details will be contained in a separate Site Manual. 


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4 
Rationale 
4.1 
Rationale for study design 
Table 4-1 
Rationale for study design 
Study Design Aspect 
Rationale 
Basket 
The basket design allows for incorporation of additional benign 
hematology indications with high unmet medical need, such as 
wAIHA and/or TTP. This will result in an improved and more 
efficient inclusion of participants. In addition, since patients with the 
initial (i.e., ITP, CAD) and potential further indications (e.g., wAIHA, 
TTP) are expected to visit the same investigators/sites, and 
considering the shared study design and similar assessments 
across the indications, the basket study design is expected to 
reduce the operational burden for the participating sites. 
Open-label, single-arm 
The open-label, single-arm design of this non-confirmatory study 
will allow all participants to receive iptacopan in rare indications with 
unmet medical need. The primary endpoint is a lab parameter with 
low potential for bias, and the underlying/spontaneous response 
rate (in the absence of rescue therapy) in these refractory patient 
populations is expected to be negligible (e.g., Jurczak et al 2018, 
Bussel et al 2014). 
Vaccines/prophylactic 
antibiotics 
To reduce the risk of Neisseria meningitidis, Streptococcus 
pneumoniae, and Haemophilus influenzae infections, all participants 
will either be vaccinated prior to first treatment with iptacopan or, if 
not vaccinated adequately, receive prophylactic antibiotic treatment. 
The study will include a longer screening period to allow time to 
assure development of protective immunity after vaccinations. In 
addition, prophylactic antibiotics are mandatory throughout study 
Part A for all participants with prior splenectomy. 
Duration of study periods 
Part A: 12 weeks of treatment are expected to be sufficient to detect 
responses and also assess if response can be sustained for several 
weeks. 
Part B: The 24-month treatment duration will allow the participants 
to have prolonged access to iptacopan treatment and additional 
long-term safety data can be collected in the proposed study 
populations. 
Washout prior to Part B 
The study includes a study drug washout after Part A, followed by a 
re-start in Part B, to further strengthen any evidence and specificity 
of efficacy seen in Part A. Participants with lab parameters 
worsening during washout are allowed to shorten washout time to 
minimize participant burden. 
Part B 
The purpose of Part B is to offer responders prolonged access to 
iptacopan treatment and collect additional long-term safety and 
efficacy data. 
Stratification (Cohort 1 only) 
Since only a subset of primary ITP patients (roughly 30-50%) has 
evidence of complement activation (Peerschke et al 2010; 
Cheloff et al 2020; Castelli et al 2020), the assignment of ITP 
participants into 2 subgroups based on complement activation 
(sC5b-9) at screening should ensure that the sample size for both 
subgroups is sufficient to assess the impact of complement 


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Study Design Aspect 
Rationale 
activation on the response to iptacopan treatment. The threshold 
was selected based on publically available and Novartis-internal 
data in both healthy volunteers and ITP patients. 
Since hemolysis is known to be largely complement-mediated in 
CAD, no stratification is deemed necessary for this cohort. 
4.1.1 
Rationale for choice of background therapy 
In principle, the purpose of this study is to evaluate the potential of iptacopan monotherapy in 
the selected indications. However, taking into account standard-of-care practices, for Cohort 1 
(primary ITP) only, participants may receive a concomitant therapy with either a 
thrombopoietin receptor agonist (TPO-RA) or low-dose corticosteroid, as long as it has been 
stable for at least 4 weeks prior to first iptacopan dose. The impact of this on the primary and 
secondary endpoints should be minimal as participants are required to have sustained 
thrombocytopenia at baseline irrespectively. No further background therapy directed against 
the indication under study is permitted (see Section 6.2.2 for further details). 
4.1.2 
Rationale for off-site visits 
Off-site procedures are planned in this study to minimize burden on participants, and offer them 
increased flexibility to participate in the study from an off-site location (as described in 
Section 3.2 and defined in Section 8). This has the potential to broaden access to clinical trials 
for both participants and investigators. The hybrid approach will allow participants to maintain 
contact with the investigator, both face-to-face during clinic visits at site and through the 
telemedicine platform during off-site participation. 
The scope of off-site procedures was determined based on a thorough operational feasibility 
review of the assessment schedule to assure comparability with onsite assessments, together 
with consideration of participant safety. 
Off-site procedures do not apply to Cohort 2 because blood sample handling requires special 
attention to avoid spontaneous in vitro RBC agglutination. 
4.2 
Rationale for dose/regimen and duration of treatment 
Iptacopan has been investigated in several renal (IgAN, C3G) and non-renal (PNH) indications. 
Based on exposure-response modelling, the 200 mg b.i.d. dose regimen was selected as the 
highest pharmacological dose, but doses down to 10 mg b.i.d. have been investigated. Clinical 
phase 2 data showed that, in all these indications (PNH, IgAN, C3G), the 200 mg b.i.d. dose 
regimen provided the highest response rate without any major safety concerns, and this was 
also supported by PKPD modelling and target occupancy data collected in these studies (see 
Investigator's Brochure). Consequently, 200 mg b.i.d. was selected for this study. 
4.3 
Rationale for choice of control drugs (comparator/placebo) 
Not applicable. 


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4.4 
Purpose and timing of interim analyses/design adaptations 
Interim Analyses (IA) 
Data from different cohorts will be analyzed separately. Database freezes/data cleanings may 
be combined for operational reasons if last data included in the IA is generated at similar 
timepoints (within same cohort or across different cohorts). The following IAs are planned for 
each cohort: 
• A first IA is planned after approximately half of the participants within a cohort complete 
12 weeks of treatment. For these participants the efficacy data up to week 12 (along with 
relevant safety and potentially PK data) will be examined as a preliminary evaluation of 
proof of concept. 
• A second IA is planned after all participants within a cohort complete 12 weeks of 
treatment. Relevant data up to Part A EOS will be examined. 
Additional IAs 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. 
Additional information is presented in the interim analysis Section 12.7. 
Design adaptations 
This basket study will allow for inclusion of new cohorts as described in Section 3, via 
submission of subsequent substantial protocol amendments. 
4.5 
Risks and benefits 
Based on the evidence of complement activation and its role in disease pathogenesis, as well as 
the early efficacy reported with several complement inhibitors, including the C1s inhibitor 
sutimlimab (see Section 1.1) (Broome et al 2020, Röth et al 2021), there is reason to believe 
that at least a subset of patients with either primary ITP or primary CAD, particularly those 
refractory to standard-of-care treatments, may benefit from complement inhibition with 
iptacopan. However, since iptacopan has not been studied in these indications, no conclusive 
statement regarding the efficacy of iptacopan in either ITP or CAD can be made. 
The risks associated with the use of iptacopan are those inferred by its pharmacology and the 
results of preclinical safety studies. The most relevant risks are described below and a complete 
description of preclinical safety findings is available in the Investigator's Brochure. The risks 
will be minimized by adherence to the eligibility criteria, close clinical monitoring, early 
stopping rules, periodic review of the safety data, and guidance for the investigators in the 
Investigator’s Brochure. 
Based on their mechanism of action, the main risk of complement inhibitors is that of infections 
with encapsulated bacteria, in particular with Neisseria meningitidis, Streptococcus 
pneumoniae, and Haemophilus influenzae. However, translational research has shown that the 
serological response to meningococcal infection, while markedly reduced after classical 
pathway (CP) blockade with anti-C5 inhibitors like eculizumab, is maintained during AP 
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showed that C5 inhibitors block killing of meningococci, whereas AP inhibitors have less 
inhibitory effect (Konar and Granoff 2017). 
To date, while no infections were reported in pre-clinical studies with iptacopan, a single 
infection with encapsulated bacteria has been reported in clinical trials. The affected patient, 
with C3 glomerulopathy and a history of kidney transplantation, experienced acute respiratory 
distress syndrome with pneumococcal pneumonia and septic shock 11 months after starting 
treatment with iptacopan 200 mg b.i.d., while also receiving multiple concomitant 
immunosuppressants. The mitigation strategy to reduce the risk of infections includes 
vaccination against N. meningitidis, S. pneumoniae, and H. influenzae according to local 
guidelines and availabilities, antibiotic prophylaxis where indicated (particularly for 
participants with additional immunosuppression such as prior splenectomy), close monitoring 
of signs and symptoms of infection, and prompt triaging, workup and treatment in case of any 
suspected infection. With this, the risk of serious infection during iptacopan treatment is 
considered to be low. Of note, there is a potential for vaccinations to worsen thrombocytopenia 
in patients with ITP and hemolysis in patients with CAD, however, the benefit of vaccination 
is thought to outweigh this risk. 
Other safety risks, including the potential risks of testicular effects, bone marrow toxicity with 
severe anemia, aorta mineralisation and increased heart weight, as well as thyroid effects, are 
based on preclinical data, with no relevant findings in clinical studies performed to date. 
They will be assessed through regular monitoring of reproductive hormone levels, of 
hematological parameters, of heart rate and blood pressure, of thyroid hormone levels and of 
respective adverse events. Please refer to the Investigator's Brochure for more detailed 
information regarding these potential risks. 
Safety results from the completed healthy volunteer studies and ongoing clinical trials in 
paroxysmal nocturnal hemoglobinuria (PNH) and several complement-driven renal diseases 
show iptacopan to be overall well tolerated and safe. In particular, no additional safety risks 
have been identified based on this early clinical data. More detailed information is available in 
the Investigator's Brochure. 
Iptacopan did not show any mutagenic, teratogenic or genotoxic potential in completed standard 
battery of genotoxicity testing. In addition, iptacopan was tested in embryo-fetal development 
studies in rats and rabbits and no iptacopan-related adverse fetal findings were detected in any 
of the studies. However, iptacopan has not been used in pregnant women, therefore, women of 
child-bearing potential must be informed that taking the study treatment may involve unknown 
risks to the fetus if pregnancy were to occur during the study, and agree that in order to 
participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria (Section 5.2). If there is any question that the participant will not reliably 
comply, they should not be entered or continue in the study. 
No invasive procedures are planned as part of this study, with the exception of blood draws. 
In summary, the risk-benefit relationship for treatment of primary ITP and primary 
CAD patients with iptacopan is positive, supporting the start of this study. 


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Risks related to off-site visits 
Participants are not anticipated to be exposed to greater risks when participating in 
off-site assessments. OHPs will perform assessments according to the same processes and 
instructions defined in the protocol and study manuals for onsite visits wherever possible, thus 
data integrity is also expected to be comparable to onsite assessments. Safety management in 
an off-site setting will adhere to the same quality standards as for the traditional onsite model 
and remains under the responsibility of the investigator (refer to Section 3.2.1). 
4.5.1 
Blood sample volume 
A volume smaller than a typical blood donation is planned to be collected over a period of 
6 months (Part A) or 25 months (Part B), from each participant as part of the study. 
The approximate volumes are mentioned in the ICF. Additional samples may be required for 
safety monitoring. 
Timings of blood sample collection are outlined in the Assessment Schedule (Table 8-1 and 
Table 8-3). 
A summary blood log is provided in the laboratory manual. Instructions for sample collection, 
processing, storage and shipment are also available in the laboratory manual. 
See Section 8.5.3.2 on the potential use of residual samples. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
In addition to the planned off-site procedures, in the event of a Public Health emergency as 
declared by Local or Regional authorities, i.e., pandemic, epidemic or natural disaster, 
additional mitigation procedures to ensure participant safety and trial integrity may be 
implemented. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by Off-site Health 
Professionals (OHP) to the participant´s home, can replace on-site study visits (in addition to 
the already planned off-site visits), for the duration of the disruption until it is safe for the 
participant to visit the site again. 
Notification of the Public health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures, and permitted/approved by Local or Regional Health 
Authorities and Ethics Committees as appropriate. 
5 
Study Population 
The study population will comprise a total of approximately 30 enrolled participants: 
• Cohort 1: Approximately 20 participants with primary ITP will be enrolled; approximately 
10 participants each with high and low complement activity, respectively. 
• Cohort 2: Approximately 10 participants with primary CAD will be enrolled. 
Participants may be replaced if they discontinue treatment early (for any reasons other than 
safety, see Section 6.4.2.1). See Section 8.1 for more details on screening and re-screening. 


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Each inclusion and exclusion criterion specifies whether the criterion should be assessed at 
screening and/or baseline. Pre-dose assessments on Day 1 are not considered for study 
eligibility. A relevant record (e.g., checklist) of the eligibility criteria must be stored with the 
source documentation at the study site. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in any cohort of this study must meet all of the following 
criteria. In addition, participants must meet the cohort-specific criteria specified in the relevant 
subsections below. 
1. Written informed consent must be obtained before any assessment is performed. 
2. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study. 
3. Vaccination against Neisseria meningitidis and Streptococcus pneumoniae infections is 
required prior to the start of treatment. If the patient has not been previously vaccinated, or 
if a booster is required, the vaccine(s) should be given according to local regulations, at 
least 2 weeks prior to first dosing. If treatment has to start earlier than 2 weeks post 
vaccination, prophylactic antibiotic treatment must be initiated. 
4. If not received previously, or if a booster is required, vaccination against Haemophilus 
influenzae infection should be given, if available and according to local regulations, at 
least 2 weeks prior to first dosing. 
5. Weight of at least 35 kg and body mass index (BMI) of at least 15 kg/m2. 
5.1.1 
Cohort 1 specific inclusion criteria 
101. 
Male and female participants aged ≥18 years at baseline with a diagnosis of persistent 
or chronic primary ITP (diagnosed at least 3 months prior to baseline). 
102. 
Participants must have received at least 1 unique prior therapy, defined as any 
pharmaceutical agent or type of non-pharmacological intervention (e.g., splenectomy) 
administered with the intention to treat ITP. Transfusions of blood products are not 
accounted as prior therapies. For South Korea, participants must have received at least 2 
unique prior therapies to treat ITP, unless they do not qualify for available treatment 
options per the investigator’s assessment. 
103. 
Sustained thrombocytopenia (platelets <30 k/µL), as documented at baseline plus 
in ≥2 additional assessments separated by at least 1 week in the prior 3 months. 
5.1.2 
Cohort 2 specific inclusion criteria 
201. 
Male and female participants aged ≥18 years at baseline with a diagnosis of primary 
CAD, including CAD arising in the setting of a low-grade lymphoproliferative disorder 
a) not requiring any therapy and b) without evidence of diffuse lymphadenopathy (lymph 
nodes at multiple stations measuring >2 cm) or of significant hepatosplenomegaly, i.e., the 
liver edge should be <5cm and the spleen <3 cm below the costal margin on physical 
examination, or, if the size has been determined radiographically (imaging is not required 
for eligibility), the craniocaudal dimension should be <18 cm for each organ. 


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202. 
Positive direct antiglobulin test for C3d only (or predominantly) and cold agglutinin 
titer of ≥64 at 4°C at screening or documented in the prior 3 months. 
203. 
Laboratory evidence of ongoing hemolysis (LDH or total bilirubin above ULN) at 
baseline. 
204. 
Sustained anemia (Hb <10 g/dL), as documented at baseline plus in ≥2 additional 
assessments separated by at least 1 week in the prior 3 months. 
205. 
Participants must have received at least 1 unique prior therapy, defined as any 
pharmaceutical agent or type of non-pharmacological intervention (e.g., plasmapheresis) 
administered with the intention to treat CAD. Transfusions of blood products are not 
accounted as prior therapies. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
Additional cohort-specific exclusion criteria are listed in the relevant subsections and apply 
only to the specific cohort. 
1. History of hypersensitivity to any of the study treatments or excipients or to drugs of 
similar chemical classes. 
2. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or within 30 days, whichever is longer; or longer if required by local 
regulations. 
3. Past or concomitant use of medications prohibited by the protocol (see Section 6.2.2 
(Prohibited medication) or Table 6-2 (Prohibited medications)). 
4. Known or suspected hereditary or acquired complement deficiency. 
5. History of primary or secondary immunodeficiency, including a positive HIV test result. 
6. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). A positive HBV surface 
antigen (HBsAg) test, or if standard local practice, a positive HBV core antigen test, 
excludes a participant. Participants with a positive HCV antibody test must have HCV 
RNA levels measured. Participants with positive (detectable) HCV RNA must be 
excluded. See also Table 8-4. 
7. History of recurrent invasive infections caused by encapsulated organisms, including 
N. meningitidis, S. pneumoniae, or H. influenzae. 
8. Presence or suspicion (based on judgment of the investigator) of any active infection 
within 14 days prior to first study drug administration. 
9. Any medical condition deemed likely to interfere with the patient’s participation in the 
study. 
10. Severe concurrent co-morbidities including but not limited to patients with severe kidney 
disease (CKD stage 4, dialysis), advanced cardiac disease (NYHA class IV) or severe 
pulmonary disease (e.g., severe pulmonary hypertension (WHO class IV)) , as judged by 
the investigator, both at screening and baseline. 
11. Any malignant disease diagnosed within 5 years of screening, with the exception of 
localized non-melanoma skin cancer, in situ cervical cancer, or, for CAD, a low-grade 
lymphoproliferative disorder (see Section 5.1.2). 


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12. History of bone marrow/hematopoietic stem cell or solid organ transplantation. 
13. Thromboembolic event within 3 months prior to baseline. 
14. Ongoing drug or alcohol abuse that could interfere with patient's participation in the trial. 
15. Female participants who are pregnant or breastfeeding, or intending to conceive during the 
course of the study. 
16. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing of investigational drug and for 1 week after last iptacopan dose. 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 bilateral 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. 
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/vaginal 
suppository 
• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS) 
In case of use of oral contraception women should be stable on the same pill for a 
minimum of 3 months before taking study drug. 
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 ICF. 
Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, 
history of vasomotor symptoms). Women are considered not of child bearing potential if 
they are post-menopausal or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment is she considered not of child bearing potential. 
Refer to Section 8.4.3 (Pregnancy and Assessments of Fertility). 


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17. Patients with any active severe bleeding or history of intracranial hemorrhage within last 
12 months. 
18. Liver disease, or liver injury as indicated by abnormal liver function tests at Screening: 
• Any single parameter of ALT, AST, GGT, alkaline phosphatase must not exceed 2.5x 
upper limit of normal (ULN). For Cohort 2 CAD participants, AST levels up to 
5xULN are acceptable if attributed to ongoing hemolysis alone.  
19. Unstable medical condition as judged by the investigator at Screening, including but not 
limited to myocardial ischemia or unstable thrombotic event. 
20. Patients with estimated GFR (using the CKD-EPI formula) <45 mL/min/1.73 m2 at 
screening 
21. History of clinically significant ECG abnormalities, or any of the following ECG 
abnormalities at screening or baseline visit: 
• QTcF >450 msec (males) 
• QTcF >460 msec (females) 
• History of familial long QT syndrome or known family history of Torsades de Pointes 
• Use of agents known to prolong the QT interval unless they can be permanently 
discontinued for the duration of the study 
22. Sitting vital signs as follows at time of baseline visit: 
• Body temperature persistently <35.0 or >37.5 ºC 
• Systolic blood pressure <90 or >180 mm Hg 
• Diastolic blood pressure <50 or >110 mm Hg 
• Resting pulse rate <50 or >90 bpm. 
Below 50 bpm is acceptable, if no other clinically significant ECG abnormalities as per 
investigator decision. For subjects with heart rates less than 50 bpm, evidence should be 
provided that they have no history of a) moderate or severe valvular disease; b) history of 
coronary artery disease, myocardial infarction, hypertension or diabetes mellitus; c) 
history of cardiomyopathy, congenital heart defect, open heart surgery, or ongoing 
arrhythmia; d) family history of sudden death in a first degree relative 
5.2.1 
Cohort 1 specific exclusion criteria 
101. Secondary ITP, as may arise in the setting of certain autoimmune disorders, 
immunodeficiency syndromes, infections, malignancies, and drug treatments. 
102. No ITP-directed background therapy permitted, with the exception of either a single 
thrombopoietin receptor agonist (TPO-RA) or low-dose corticosteroid (prednisone-
equivalent of ≤10 mg daily), as long as stable dosage for at least 4 weeks prior to first 
iptacopan dose. 
103. Abnormal coagulation screening labs (PT/INR, PTT). 


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5.2.2 
Cohort 2 specific exclusion criteria 
201. Secondary cold agglutinin syndrome, as may arise in the setting of certain infections, 
autoimmune disorders, and malignancies (with the exception of a low-grade 
lymphoproliferative disorder, see Section 5.1.2). 
202. No CAD-directed background therapy permitted. 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
Please see Table 6-1 for details on investigational drug. No control drugs will be used in this 
study. 
Table 6-1 
Investigational drug 
Investigational 
Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Presentation 
Sponsor (global 
or local) 
Iptacopan 
(LNP023) 200 mg 
Capsule 
Oral use 
Open label 
participant 
specific supplies 
Novartis 
6.1.2 
Additional study treatments 
No additional treatment beyond investigational drug are included in this trial. 
6.1.3 
Treatment arms/group 
There is only one treatment arm per cohort. All participants will be assigned at Day 1 visit to 
the treatment arm of iptacopan 200 mg b.i.d. for 12 weeks (Part A). 
Responders (as defined by the primary endpoint) and potentially non-responders with a 
clinically meaningful response (see Section 3) may join the treatment extension part after a 
washout period to receive iptacopan 200 mg b.i.d. for up to 24 months (Part B).  
6.1.4 
Post Trial Access 
Responders will be offered extended access to iptacopan during the extension part of this study 
(Part B) for up to an additional 24 months beyond the main treatment part (Part A). Beyond 
this, responders may benefit from post trial access based on local regulations. 


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6.2 
Other treatment(s) 
6.2.1 
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 Case Report Forms. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
enrolling a participant or allowing a new medication to be started. If the participant is already 
enrolled, contact Novartis to determine if the participant should continue participation in the 
study. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Iptacopan has multiple disposition pathways of which oxidative metabolism by CYP2C8 is the 
most prominent. Iptacopan is not a potent inhibitor of metabolic enzymes or transporters. 
However, an inhibition of P-glycoprotein (P-gp) at the intestinal level cannot be excluded. 
Iptacopan is also not a potent inducer, indicating that iptacopan can be safely co-administered 
with oral contraceptives. Until completion of the full assessment of potential drug-drug 
interactions in the currently ongoing clinical DDI study CLNP023A2104, some concomitant 
medications are either prohibited (see Section 6.2.2) or should be used with caution. 
Iptacopan has been shown to have a weak inhibition potential for the liver uptake transporter 
OATP1B1. Calculation revealed that the exposure (AUC) of respective sensitive substrates may 
be increased by <1.5 fold. Although the expected effect on the exposure of respective 
co-medications is small and may not be clinically relevant, it is recommended to combine 
iptacopan with sensitive OATP1B1 substrates or those having a narrow therapeutic index with 
caution. A list of OATP1B1 substrates to be used with caution may be provided to the 
investigators upon request. 
Iptacopan has also been shown to inhibit the efflux transporter P-gp on the intestinal level but 
not the liver. Therefore, the direct oral anti-coagulation drugs apixaban, rivaroxaban and 
edoxaban which are P-gp substrates should be used with caution. For edoxaban a staggered 
dosing (see below) is recommended, in particular for participants with impaired kidney 
function. 
Unless prohibited for other reasons (see Section 6.2.2), for narrow therapeutic index (NTI) 
drugs (e.g., digoxin, fentanyl, phenytoin, quinidine, tolvaptan) which are substrates for the 
efflux transporter P-gp with no alternative treatment available, a staggered dosing approach is 
recommended. This can be accomplished by administering the respective co-medication >3 
hours following oral administration of iptacopan. Alternatively, compounds with a short Tmax 
of around < 2 hours (i.e., fast absorption) may be given >1 hour prior to iptacopan. The 
staggered dosing will avoid increases in systemic exposure of co-administered drugs due to P-
gp inhibition by iptacopan at the intestinal level. For participants receiving immunosuppressants 
(stable dose) and if their exposure is no longer monitored, it is advisable to resume therapeutic 
drug monitoring after start of treatment with iptacopan (single assessment). 


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6.2.1.2 
Vaccinations 
Required/recommended vaccinations should be completed as per inclusion criteria defined 
in Section 5.1. These vaccines should cover as many serotypes as possible (including 
meningococcal serotypes A, C, Y, W-135 and B). To minimize participant burden, the use of 
multivalent vaccines is recommended as locally available and per local guidelines and 
regulations (e.g., quadrivalent vaccine for N. meningitidis which covers serotypes A, C, Y and 
W-135; and Pneumovax-23 which covers 23 S. pneumoniae serotypes). For the vaccination 
type and booster requirements use local guidelines, and locally available vaccines (and refer to 
the package insert of those or local guidelines). The screening period may be extended to allow 
vaccination procedures to be completed, in case of multiple vaccination needs and local/country 
requirements. This is applicable for vaccinations only, while all the other screening assessments 
must be performed as indicated in the Assessment Schedule Table 8-1. Vaccinations should be 
started at the earliest possible to avoid extension of screening period. 
Other vaccinations, including COVID-19 vaccination, should preferably be given prior to 
enrollment, but, if indicated, they may be given during the course of the study as well, with the 
exception of live vaccinations, which are prohibited as per Table 6-2. Based on pre-clinical 
data, iptacopan is not expected to interfere with the antibody response to vaccination. 
All vaccinations should be recorded in eCRF. 
6.2.1.3 
Prophylactic antibiotic treatment 
Antibiotic prophylaxis per local standard of care is mandatory throughout the entire main 
treatment period (Part A) for any participant with a prior history of splenectomy; the decision 
to maintain or discontinue antibiotic prophylaxis during the extension (Part B) may be made by 
the investigator on a case-by-case basis. In addition, antibiotic prophylaxis should be initiated 
in case iptacopan treatment is started earlier than 2 weeks post-vaccination for N. meningitides 
and S. pneumoniae. 
For treatment of suspected infections, see Section 6.7.2. 
6.2.2 
Prohibited medication 
Use of the treatments displayed in the below table are not allowed. 
Table 6-2 
Prohibited medication 
Medication 
Prohibition period 
Action taken 
Complement inhibitor 
therapy other than iptacopan 
Any time 
prior to enrollment until EOS 
Discontinue study treatment 
Targeted B-lymphocyte 
depleting therapy (incl. 
rituximab)  
3 months prior to first iptacopan 
dose until EOS 
Discontinue study treatment 
Systemic corticosteroids 
2 weeks prior to first iptacopan 
dose until EOS.  
Exceptions: Rescue therapy 
from Day 1 onwards (see 
Section 6.2.3) or one-time 
prophylaxis for hypersensitivity 
Discontinue study treatment, 
unless covered by exceptions. 


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Medication 
Prohibition period 
Action taken 
reactions. In addition, for 
participants with ITP, low-dose 
corticosteroids (prednisone-
equivalent of ≤10 mg daily) are 
allowed as long as dosage 
stable for at least 4 weeks prior 
to first iptacopan dose. 
Other immunosuppressive or 
antineoplastic agents, including 
but not limited to anti-
Rho(D) IG, bendamustine, 
bortezomib, cyclosporine, 
cyclophosphamide, 
IVIG, mycophenolate mofetil, 
vincristine 
1 month prior to first iptacopan 
dose until EOS. 
Exception: Rescue therapy 
from Day 1 onwards 
(see Section 6.2.3). 
Discontinue study treatment, 
unless covered by exception 
Other regimens to treat the 
primary indication 
2 weeks prior to first iptacopan 
dose until EOS. Exceptions: 
Thrombopoietin receptor 
agonists (TPO-RAs) (single 
agent allowed for ITP 
participants only as long as 
stable dosage for at least 
4 weeks prior to first iptacopan 
dose). 
Discontinue study treatment, 
unless covered by exceptions 
Anti-thrombotic or anti-platelet 
therapy 
Prohibited for ITP Cohort 1 
only: 2 weeks prior to first 
iptacopan dose until EOS. 
Discontinue study treatment, 
unless covered by exception 
Live vaccines 
Prohibited for the entire study 
treatment duration 
  
Gemfibrozil 
Gemfibrozil must be interrupted 
at least 48 hours before first 
iptacopan dose until end of 
iptacopan treatment (and 
replaced with another 
appropriate medication used 
for that indication) 
  
Strong inhibitors of CYP2C8 
such as clopidogrel  
Strong inhibitors of 
CYP2C8 must be interrupted 
7 days before first iptacopan 
dose until end of iptacopan 
treatment (and replaced with 
another appropriate medication 
used for that indication) 
  
“Sensitive substrates” for the 
efflux transporter P-gp or P-gp 
substrates with narrow 
therapeutic index (NTI) (e.g., 
digoxin, fentanyl, phenytoin, 
quinidine, tolvaptan) 
Medication to be interrupted 
12 hours before first iptacopan 
dose. Exception: if staggered 
dosing can be applied 
(see Section 6.2.1.1) 
  


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6.2.3 
Rescue medication 
Rescue therapy, if indicated, may be initiated at the investigator's discretion.  
However, if rescue therapy is given during the screening period, i.e., prior to the start of 
iptacopan treatment on Day 1, the prohibition period as defined in Table 6-2 must still be 
followed. Consequently, the start of the treatment period (Day 1) may need to be shifted and 
any affected assessments at screening or baseline may need to be repeated accordingly. 
Importantly, in case a transfusion of blood products is necessary during the screening period, 
treatment start must not occur earlier than 7 days following the transfusion and any affected 
assessments may need to be repeated accordingly.  
From Day 1 onwards, if there is need to use rescue therapy before response criteria are met, the 
participants will be treated as non-responders. Conversely, use of rescue therapy after the 
primary endpoint is met, does not impact the response status with respect to that endpoint. 
• For ITP (Cohort 1), rescue therapy generally consists of corticosteroids, intravenous 
immunoglobulins (IVIG) or anti-Rho(D) immunoglobulin and may be indicated in case of 
worsening thrombocytopenia and/or signs or symptoms of bleeding. 
• For CAD (Cohort 2), rescue therapy generally consists of plasmapheresis, IVIG and/or red 
blood cell transfusions and may be indicated in case of worsening anemia and/or critical 
hemolysis. 
6.2.4 
Restriction for study participants 
For the duration of the study, participants should be informed and reminded of the restrictions 
outlined: 
• Contraception requirements as listed in Section 5.2 
• Prohibited medications as listed in Section 6.2.2 
6.2.4.1 
Dietary restrictions and smoking 
There are no specific dietary restrictions. 
6.2.4.2 
Other restrictions 
Not applicable. 
6.3 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described in Section 6.1.1. 
A unique medication number is printed on the study medication label. 
As per the treatment assigned to the participant, investigator staff will select the study treatment 
to dispense to the participant. The study medication has a 2-part label (base plus tear-off label), 
immediately before dispensing the package to the participant, site personnel will detach the 
outer part of the label from the package and affix it to the participant's source document. 


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On each study visit (including on-site visits and potential home nursing visits), investigator staff 
should ensure that the IMP is stored appropriately in the participant's home and that the 
participant is taking the IMP in compliance with the study requirements (see in Section 6.3.2). 
Where delivery of IMP directly to a participant's secure off-site location (e.g. home) is permitted 
by national and local governing regulations then dispatch of IMP from either the site, or a 
pharmacy, to the participant will be performed under the accountability of the Investigator. 
In case IMP is couriered from a pharmacy, site personnel will contact the pharmacy for 
dispensing and the 2-part label will not be utilized. The provisioning of supply will be for a 
maximum of 8 weeks supply. In this case, regular contacts will occur between the site and the 
participant for instructional purposes, safety monitoring, investigation of any adverse events, 
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. 
In the US, study treatment and all required clinical study supplies may be distributed direct to 
the participant utilizing an extension of the IND for compliance purposes. 
6.3.1 
Handling of study treatment and other treatment 
6.3.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all 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 CO Quality Assurance. 
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 must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
field monitors during site or remote monitoring visits, and at the completion of the trial. 
The treatment for off-site administration will be handled and shipped in line with the protocol 
and required procedures for shipping. 
If 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. 


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6.3.2 
Instruction for prescribing and taking study treatment 
• Participants should take 200 mg iptacopan b.i.d. orally at approximately the same time 
each day in the morning and approximately 12 hours later in the evening (total daily dose 
of 400 mg). Each dose consists of 1 capsule of 200 mg. 
• The first dose should be administered on site. On days that PK samples are obtained, the 
participant should take iptacopan after the pre-dose PK samples and prior to post-dose PK 
samples, when instructed by the study staff. 
• Participants may take iptacopan without regard to food. Each dose may be taken with a 
glass of water. 
• Participants should be instructed to swallow whole capsules and not to chew or open them 
• If vomiting occurs during the course of treatment, participants should not take the 
iptacopan again before the next scheduled dose. 
• Participants should be instructed not to make up missed doses. A missed dose is defined as 
a case when the full dose is not taken within 4 hours after the approximate time of the 
usually daily dosing. That day's dose should be omitted and the participant should 
continue treatment with the next scheduled dose. 
6.4 
Participant numbering, treatment assignment, randomization 
6.4.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available. 
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. 
6.4.2 
Treatment assignment, randomization 
No randomization will be performed in this study. The assignment of a participant to a particular 
cohort will be coordinated by the sponsor. 
6.4.2.1 
Replacement policy 
Participants may be replaced if they discontinue treatment early to ensure the required number 
of participants complete Part A for every cohort. Participants discontinuing treatment for safety 
reasons will not be replaced. 
6.5 
Treatment blinding 
Not applicable, as this study is open-label without any randomization. 


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6.6 
Dose escalation and dose modification 
Investigational or other study treatment dose adjustments and/or interruptions are not permitted. 
6.7 
Additional treatment guidance 
6.7.1 
Treatment compliance 
The investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant’s 
safety and the validity of the study. The participant must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed. 
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 
counts and information provided by the participant. This information should be captured in the 
source document at each visit. In addition, participants will be asked to complete a diary to 
record any missed doses. All study treatment dispensed and returned must be recorded in the 
Drug Accountability Log. 
Off-site treatment administration compliance will be assessed by the off-site healthcare 
professional and information provided to the Investigator and/or study personnel. 
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
participants treated with iptacopan as detailed in Section 8.5.2. 
6.7.2 
Recommended treatment of adverse events 
The participants and treating staff need to be instructed to be vigilant for any clinical signs of 
bacterial infections (e.g., malaise, chills, fever, nausea, photophobia, generalized muscle and 
joint pain) and to measure the body temperature as per assessment schedule and at the times of 
symptoms of presumed infection. Participants will be instructed to contact the study physician 
immediately in case of suspicion of infection or elevated body temperature (> 38.3°C by oral 
or tympanic method) for a ‘phone-directed’ triage. 
In case of a suspected bacterial infection, participants should be immediately considered for 
emergency evaluation and empirically treated with an appropriate antibiotic course. 
In case of any (bacterial and non-bacterial incl. COVID-19) severe infection, interruption of 
iptacopan dosing should be considered, on a case-by-case basis. However, every effort should 
be taken to keep the participant on study treatment unless the risk outweighs the benefit in the 
opinion of the investigator. 
Medication used to treat adverse events (AEs) must be recorded on the appropriate eCRF. 
6.7.3 
Emergency breaking of assigned treatment code 
Not applicable. 


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7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH E6 GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational treatment can 
be found in the Investigator's Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant during the study as needed. Any 
new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an investigator 
notification or an aggregate safety finding. New information might require an update to the 
informed consent and then must be discussed with the participant. 
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 
 
 
• As applicable, home nursing and/or participant transport consent (either as part of main 
consent or a dedicated consent) 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
 
 
 
 
 
 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 


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The study includes the option for the participant to have certain study procedures performed 
off-site by an off-site healthcare professional instead of at the study site (not applicable for 
Cohort 2), for which a separate signature is required if the participant agrees. As applicable, this 
study includes optional support by a vendor to organize participants travel and accommodation 
if needed, for which a separate signature is required if the participant agrees. It is required as 
part of this protocol that the Investigator presents these options to the participant, as permitted 
by national and local governing regulations. The process for obtaining consent should be exactly 
the same as described above for the main informed consent. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Health Authority. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.). 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1 and Table 8-3) lists all of the assessments and indicates 
when they are performed. All data obtained from these assessments must be supported in the 
participant’s source documentation. 
Participants should be seen for all visits/assessments as outlined in the Assessment Schedule 
(Table 8-1 and Table 8-3) or as close to the designated day/time as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. 
Participants who discontinue study treatment should return for the end-of-treatment visit as 
soon as possible and attend the follow-up visits as outlined in the schedule. 
Participants who discontinue from study or withdraw their consent/oppose the use of their 
data/biological samples 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 final visit (if treatment 
discontinuation EOT assessments, if FU discontinuation EOS assessments) will be performed. 
At this final visit, all dispensed investigational product should be reconciled, and the adverse 
event and concomitant medications not previously reported must be recorded on the eCRF. 
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. 


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When the following assessments are scheduled to be performed at the same time point, the 
following sequence is proposed: 
1. 
 
2. ECGs 
3. Vital signs 
4. Blood sample collections 
5. Drug administration 
For PK profiling days, every effort should be made to take the PK sample at the protocol-
specified time. Other assessments, e.g., 
ECGs and vital signs, can be taken after the PK 
sample. 
In case the investigator deems an unscheduled visit necessary, some or all of the following 
assessments may be conducted: Vital signs, physical exams, collection of safety lab and/or 
PK samples, and ECGs. Unscheduled PK samples should be taken as soon as possible but no 
later than 24 hours after the last dose of iptacopan. 


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Table 8-1 
Assessment Schedule, Part A and washout 
Period 
Screening 
Treatment Part A 
Follow-up/Washout Part A 
Visit Name Screening Baseline 
Treatment 
EOT 
Follow-up 
EOS 
Part 
A 
Post Study 
Safety 
Contact 
Days Part A -56 to -4 
-7 to -2 
1 
82 
15 
222 
29 
432 
572 
712 
85 
922,7 
997 
1062,3,7 1134 
143 
Weeks Part A 
-8 to -1 
-1 
1 
2 
3 
4 
5 
7 
9 
11 
13 
14 
15 
16 
17 
21 
Time (post-dose) 
- 
- 
- 
- 
0h 
2h 
- 
- 
- 
0h 
- 
- 
- 
- 
- 
- 
- 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / Exclusion criteria 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history/current medical 
conditions 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Prior medications 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vaccination 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hepatitis and HIV Screen 
S 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Body Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Body Weight 
X 
  
X 
  
X 
  
  
X 
  
X 
  
X 
  
  
  
X 
  
Complete Physical Examination 
S 
  
S 
  
  
  
  
S 
  
  
  
S 
  
  
  
S 
  
Body Temperature 
X 
X 
X 
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
X 
  
Blood Pressure 
X 
X 
X 
  
X 
X 
  
X 
  
  
  
X 
  
  
  
X 
  
Pulse rate 
X 
X 
X 
  
X 
X 
  
X 
  
  
  
X 
  
  
  
X 
  
Electrocardiogram (ECG) 
X 
  
X 
  
X 
  
  
  
  
  
  
X 
  
  
  
X 
  
Pregnancy and assessments of 
fertility 
S 
S 
  
  
  
  
  
S 
  
S 
  
S 
  
  
  
S 
  
Hematology1 
X 
X 
X 
X5 
X 
  
X5 
X 
X5 
X5 
X5 
X 
X5 
X 
X5 
X 
  
Clinical Chemistry 
X 
  
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
Coagulation Panel 
X 
  
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  


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Period 
Screening 
Treatment Part A 
Follow-up/Washout Part A 
Visit Name Screening Baseline 
Treatment 
EOT 
Follow-up 
EOS 
Part 
A 
Post Study 
Safety 
Contact 
Days Part A -56 to -4 
-7 to -2 
1 
82 
15 
222 
29 
432 
572 
712 
85 
922,7 
997 
1062,3,7 1134 
143 
Weeks Part A 
-8 to -1 
-1 
1 
2 
3 
4 
5 
7 
9 
11 
13 
14 
15 
16 
17 
21 
Time (post-dose) 
- 
- 
- 
- 
0h 
2h 
- 
- 
- 
0h 
- 
- 
- 
- 
- 
- 
- 
Urinalysis 
X 
  
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
Reproductive and thyroid 
hormones 
X 
  
  
  
X 
  
  
X 
  
  
  
X 
  
  
  
X 
  
PK blood collection 
See table below 
Patient diary 
  
  
As required 
  
  
  
  
  
Study drug administration 
  
  
Daily b.i.d. 
  
  
  
  
  
Concomitant medications 
As required 
  
Adverse events/SAEs 
As required 
Study completion information 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Safety Follow up Call 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
S 
Cohort 1 specific assessments 
sC5b-9 for stratification 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


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Period 
Screening 
Treatment Part A 
Follow-up/Washout Part A 
Visit Name Screening Baseline 
Treatment 
EOT 
Follow-up 
EOS 
Part 
A 
Post Study 
Safety 
Contact 
Days Part A -56 to -4 
-7 to -2 
1 
82 
15 
222 
29 
432 
572 
712 
85 
922,7 
997 
1062,3,7 1134 
143 
Weeks Part A 
-8 to -1 
-1 
1 
2 
3 
4 
5 
7 
9 
11 
13 
14 
15 
16 
17 
21 
Time (post-dose) 
- 
- 
- 
- 
0h 
2h 
- 
- 
- 
0h 
- 
- 
- 
- 
- 
- 
- 
Cohort 2 specific assessments 
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 Samples will be assessed at central lab for Cohort 1 (ITP) and locally for Cohort 2 (CAD)  
2 Visit may be performed at an off-site location as allowed by local laws and regulations (not applicable for Cohort 2).  
3 Visit only applicable to treatment responders. 
4 The Day 1 Part B visit is on the same day as EOS for Part A. Assessments listed in the Part A assessment schedule are applicable to all participants. Assessments 
listed in Part B assessment schedule are in addition and only applicable to responders continuing into Part B. 
5 No reticulocytes will be assess at this visit 
7 Responders reaching a critical cut-off level during washout (as defined in Section 3.1 in the cohort specific details) will have the opportunity to skip remaining follow-up 
visits and move to EOS Part A/Day 1 Part B visit before completion of the 4 weeks of washout. 


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Table 8-2 
PK blood collection – Part A 
Period 
Visit Name 
Days Part A 
Weeks Part A 
Time (post-dose) 
PK blood collection 
Treatment Part A 
Treatment 
1 
1 
- 
 
81 
2 
- 
 
15 
3 
0h 
X2 
0.5h 
X 
1h 
X 
2h 
X 
4h 
X 
6h 
X 
221 
4 
- 
 
29 
5 
0h 
X2 
431 
7 
- 
 
571 
9 
0h 
X2 
0.5h 
X 
1h 
X 
2h 
X 
4h 
X 
6h 
X 
711 
11 
- 
 
EOT 
85 
13 
- 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
1 Visit may be performed at an off-site location as allowed by local laws and regulations.  
2 Directly before dosing 


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Table 8-3 
Assessment Schedule, Part B 
Period 
Treatment Part B 
Follow-up Part B 
Visit Name Day 1 Part B 
Treatment 
EOT Follow-up 
EOS 
Part B 
Post Study 
Safety Contact 
Days Part B 
12 
15 
29 573 
85 
169 
2533 337 4213 505 6173 
729 7363 743 
757 
787 
Weeks Part B 
1 
3 
5 
9 
13 
25 
37 
49 
61 
73 
89 
105 
106 
107 
109 
113 
Time (post-dose) 
- 
0h 
- 
0h 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Body Weight 
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
Complete Physical Examination 
  
  
S 
  
S 
S 
  
S 
  
S 
  
S 
  
  
S 
  
Body Temperature 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Blood Pressure 
  
  
X 
  
X 
X 
  
X 
  
X 
  
X 
  
  
X 
  
Pulse rate 
  
  
X 
  
X 
X 
  
X 
  
X 
  
X 
  
  
X 
  
Electrocardiogram (ECG) 
  
  
  
  
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
Hematology5 
  
X 
X4 
X4 
X 
X 
X4 
X 
X4 
X 
X4 
X 
X4 
X 
X 
  
Clinical Chemistry 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
Coagulation Panel 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
Urinalysis 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
Reproductive and thyroid hormones 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
  
PK blood collection 
  
X6 
  
X6 
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy and assessments of fertility 
  
  
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
  
  
S 
  
Patient diary 
As required 
  
  
  
  
Study drug administration 
Daily b.i.d. 
  
  
  
  
Concomitant medications 
As required 
  
Adverse events/SAEs 
As required 
Study completion information 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Safety Follow up Call 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
S 
Cohort 1 specific assessments 


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Period 
Treatment Part B 
Follow-up Part B 
Visit Name Day 1 Part B 
Treatment 
EOT Follow-up 
EOS 
Part B 
Post Study 
Safety Contact 
Days Part B 
12 
15 
29 573 
85 
169 
2533 337 4213 505 6173 
729 7363 743 
757 
787 
Weeks Part B 
1 
3 
5 
9 
13 
25 
37 
49 
61 
73 
89 
105 
106 
107 
109 
113 
Time (post-dose) 
- 
0h 
- 
0h 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Cohort 2 specific assessments 
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 Measured at local labs (if available) 
2 The Day 1 Part B visit is on the same day as EOS for Part A. Assessments listed in the Part A assessment schedule are applicable to all participants. Assessments 
listed in Part B assessment schedule are in addition and only applicable to responders continuing into Part B. 
3 Visit may be performed at an off-site location as allowed by local laws and regulations (not applicable to Cohort 2).  
4 No reticulocytes will be assessed at this visit 
5 Samples will be assessed at central lab for Cohort 1 (ITP) and locally for Cohort 2 (CAD) 
6 Directly before dosing 


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8.1 
Screening 
Screening and re-screening 
It is permissible to re-screen a participant if s/he fails the initial screening; however, each case 
must be discussed and agreed with the Sponsor on a case-by-case basis. 
In the case where a safety laboratory assessment at screening and/or baseline is outside of the 
range specified in the eligibility criteria, the assessment may be repeated once prior to treatment 
assignment. If the repeat value remains outside of the specified ranges, the participant must be 
excluded from the study. 
Use of medical history lab assessments 
Medical history lab data can be taken into consideration for inclusion purposes when several 
repeat assessments are required to confirm eligibility (e.g., platelet count in Cohort 1 or 
hemoglobin level in Cohort 2). However, at least the baseline value must be from the study 
central laboratory (except for Cohort 2). If medical history lab data is used, values must be 
recorded in the eCRF. 
If medical history data is not available, the screening period may consist of several visits for 
verification of these lab assessments. 
Hepatitis screen, HIV screen 
All participants will be screened for Hepatitis B surface antigen (HBsAg) and, if standard local 
practice, Hepatitis B core antigen (HBcAg). Screening for Hepatitis C will be based on HCV 
antibodies and, if positive, HCV RNA levels should be determined. 
Table 8-4 
Eligibility based on hepatitis B and C test results 
 
Scenario 1 
Scenario 2 
Scenario 3 
Scenario 4 
HBsAg/HBcAg 
+ 
- 
- 
- 
HCV Ab 
Any 
+ 
+ 
- 
HCV RNA 
Any 
+ 
- 
N/A 
Eligibility 
Not eligible 
Not eligible 
Eligible 
Eligible 
Evaluation for HIV seropositivity will be performed, and, if positive, confirmation by a second 
technique available at the laboratory site, e.g., Western blot. Appropriate counseling will be 
made available by the Investigator in the event of a positive confirmatory test. Notification of 
state and federal authorities, as required by law, will be the responsibility of the Investigator. 


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8.1.1 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. The reason for screen failure should be entered on the applicable 
eCRF. 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 serious 
adverse event (SAE) during the screening period (see Section 10.1.3 for SAE reporting details). 
Participants who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason will be considered early terminators. The reason for early termination 
should be captured on the appropriate disposition eCRF. 
8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with the eCRF. 
Participant demographics: year of birth or age, sex, race/predominant ethnicity (if permitted) 
and relevant medical history/current medical conditions (until date of signature of informed 
consent) will be recorded in the eCRF. Where possible, the diagnosis and not symptoms should 
be recorded. 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, we need 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. See the protocol Section 6.2.1 for further details on 
what information must be recorded on the appropriate page of the eCRF. 
8.3 
Efficacy 
 
Cohort 1 
The primary efficacy endpoint is based on platelet counts which will be measured as part of the 
hematology panel as described in Section 8.4.1. 
Samples will be collected at the timepoints defined in the Assessment Schedule (Table 8-1 and 
Table 8-3). Follow instructions outlined in the Laboratory manual regarding sample collection, 
numbering, processing, and shipment. 
Cohort 2 
The primary efficacy endpoint is based on hemoglobin levels which will be measured as part 
of the hematology panel as described in Section 8.4.1. 
Samples will be collected at the timepoints defined in the Assessment Schedule (Table 8-1 and 
Table 8-3). Follow instructions outlined in the Laboratory manual regarding sample collection, 
numbering, processing, and shipment. 


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8.3.1 
Appropriateness of efficacy assessments 
Cohort 1 - ITP 
Efficacy assessments (platelet count) are standard, as done in daily clinical practice and driven 
by relevant guidelines: ASH 2019 guidelines for ITP (Neunert et al 2019) and updated 
international consensus report on the investigation and management of primary ITP 
(Provan et al 2019). 
Cohort 2 - CAD 
Efficacy assessments (hemoglobin level) are standard, as done in daily clinical practice and 
driven by relevant literature (Berentsen 2021). 
8.4 
Safety 
Safety assessments are specified below with the Assessment Schedule (Table 8-1 and 
Table 8-3) detailing when each assessment is to be performed. 
For details on AE collection and reporting, refer to AE Section 10.1. 
Table 8-5 
Safety assessments 
Assessment 
Specification 
Physical examination 
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, vascular, and 
neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed. 
A short physical exam will include the examination of general appearance. 
A short physical exam will be at all visits starting from Day 1 except where 
a complete physical examination is required (see above). 
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are 
present prior to signing informed consent must be recorded on the 
appropriate eCRF that captures medical history. Significant findings made 
after signing informed consent which meet the definition of an Adverse 
Event must be recorded as an adverse event. 
Vital signs 
Vital signs will include the collection of body temperature (recorded in °C), 
blood pressure and pulse measurements. 
The same route (temporal, tympanic, or axillary) and modality (temporal 
scanner, tympanic probe, thermometer) for body temperature monitoring 
should be used for ongoing participants to allow for accurate evaluation of 
the temperature trend. 
After the participant has been sitting for 3 minutes, with back supported 
and both feet placed on the floor, systolic and diastolic blood pressure will 
be measured using an automated validated arm device, e.g., OMRON 
with an appropriately sized cuff. In case the cuff sizes available are not 
large enough for the participant's arm circumference, a 
sphygmomanometer with an appropriately sized cuff may be used. 
If vital signs are out-of-range two additional readings can be obtained, so 
that up to three consecutive assessments are made, with the participant 


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Assessment 
Specification 
seated quietly for approximately five minutes preceding each repeat 
assessment. 
In case of repeated vital assessments, the eCRF should contain the last 
results. 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram 
(kg) in indoor clothing, but without shoes) will be measured. 
Body mass index (BMI) will be calculated using the following formula: 
• 
BMI = Body weight (kg) / [Height (m)]2 
8.4.1 
Laboratory evaluations 
Safety laboratory evaluations are listed in Table 8-6 and the Assessment Schedule (Table 8-1 
and Table 8-3) specifies when they should be performed. 
Safety samples should be collected on site or off-site as specified in the Assessment Schedule. 
A central laboratory will be used for analysis of safety specimens collected as per assessment 
schedule. Details on the collection, shipment of samples and reporting of results by the central 
laboratory are provided to investigators in the central laboratory manual. 
In order to minimize the risk of spontaneous RBC agglutination in vitro, hematology samples 
from CAD patients will be analyzed at local clinical diagnostic laboratories for the following 
parameters: complete blood count, reticulocytes 
. All CAD samples will be processed 
per specific instructions as outlined in the lab manual. 
If participants cannot visit the site for protocol-specified safety lab assessments, an alternative 
(local) laboratory may be used for safety sample collection. Where samples are collected and 
analyzed at a local instead of the central laboratory, Novartis will ensure the results reported 
are equivalent to central laboratory collection and analysis. 
Clinically notable laboratory findings are defined in Appendix 1 (Section 16.1). Clinically 
significant abnormalities must be recorded as either medical history/current medical conditions 
or adverse events 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 the sponsor) and shall be based, in part, upon the nature and degree of the 
observed abnormality. The assessment may be repeated once prior to treatment assignment. 
All abnormal lab results must be evaluated for criteria defining an adverse event and reported 
as such if the criteria are met. For those lab adverse events, repeated evaluations are mandatory 
until normalization of the result(s) or until the result is no longer considered to be clinically 
significant. 
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. 


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Table 8-6 
Safety laboratory evaluations 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Ery. Mean Corpuscular Hemoglobin, Ery. Mean 
Corpuscular HGB Concentration, Ery. Mean Corpuscular Volume, Platelets, 
Erythrocytes, Leukocytes, Erythrocyte Cell Morphology (if available at local 
lab and indicated based on flagged blood count results), Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands), 
Reticulocytes (selected visits as per assessment schedule) 
Chemistry 
Albumin, Alkaline phosphatase (ALP), ALT, AST, Gamma-glutamyl-
transferase (GGT), Lactate dehydrogenase (LDH), Calcium, Magnesium, 
Phosphate, Chloride, Sodium, Potassium, Creatinine, Creatine kinase, Direct 
Bilirubin, Indirect Bilirubin, Total Bilirubin, Total Cholesterol, Triglycerides, 
Ferritin, Urea Nitrogen or Urea, Uric Acid, Amylase, Lipase, Glucose, 
Haptogloblin (Cohort 2 CAD only), estimated GFR 
Urinalysis1 
Dipstick measurements for protein, bilirubin, blood, glucose, ketones, nitrites, 
pH, specific gravity and urobilinogen, and WBC/leukocytes will be performed 
at the site’s local laboratory. 
If dipstick measurement results are positive (abnormal), results will be 
captured in the eCRF. Microscopy must be assessed locally following an 
abnormal dipstick test. 
Coagulation 
Prothrombin time (PT), International normalized ratio (INR), Activated partial 
thromboplastin time (APTT) 
Thyroid 
Triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH) and 
reverse T3 
Reproductive 
hormones 
Testosterone,  Dihydrotestosterone (DHT), Luteinizing Hormone (LH) and 
Follicle Stimulating Hormone (FSH) 
Hepatitis markers 
Hepatitis B Virus Surface Antigen (HBsAg), Hepatitis C Virus (HCV) 
antibodies; 
If HCV antibodies is positive, HCV RNA will be analyzed 
HIV 
HIV seropositivity testing will be performed as detailed in the Central 
laboratory manual and in line with local regulatory requirements 
Hepatic follow-up 
These tests are in addition to routine testing, to be performed only in follow-
up to safety events as indicated in Appendix 2 (Section 16.2), hepatic event 
follow-up 
Pregnancy Test 
Serum / Urine pregnancy test (see Section 8.4.3) 
1A midstream urine sample (approx. 30 mL) will be obtained, in order to avoid contamination with 
epithelial cells and sediments, and allow proper assessments. 
8.4.2 
Electrocardiogram (ECG) 
Electrocardiograms (ECGs) must be recorded after 10 minutes rest in the supine position to 
ensure a stable baseline. 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. 
ECGs will be locally collected and evaluated. Interpretation of the tracing must be made by a 
qualified physician and documented on the appropriate eCRF. 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 eCRF. Clinically 


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significant findings must be discussed with Novartis prior to enrolling the participant in the 
study. New or worsened clinically significant findings occurring after informed consent must 
be recorded as adverse events. 
The original ECGs on non-heat-sensitive paper or a certified copy 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 
(please refer to Appendix 1 (Section 16.1) for notable abnormalities), two additional ECGs must 
be performed to confirm the safety finding. Single 12 lead ECGs are to be recorded 
approximately 2 minutes apart. ECG safety monitoring, or a review process, should be in place 
for clinically significant ECG findings at baseline before administration of study treatment and 
during the study. 
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or adverse events as appropriate. 
8.4.3 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have pregnancy testing as per the 
Assessment Schedule (see Table 8-1 and Table 8-3). At screening and baseline serum pregnancy 
tests are required. At further visits urine test will be done. A positive urine test needs to be 
confirmed by a serum test. Additional pregnancy testing might be performed if requested by 
local requirements. Additional local requirements would be specified in the local ICF. 
If participants cannot visit the site to have serum pregnancy tests 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, 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 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of 
child-bearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy 
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening/baseline. 
8.4.4 
Appropriateness of safety measurements 
The safety assessments selected are standard for the indications/participant populations. 


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8.5 
Additional assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Patient Diary 
Patient diaries will be used to record any missed administration of iptacopan. 
8.5.2 
Pharmacokinetics 
PK samples will be collected at the visits defined in the Assessment Schedule (Table 8-1 and 
Table 8-3). Instructions regarding sample collection, numbering, processing and shipment are 
outlined in the laboratory manual. See Section 8.5.3.2 for the potential use of residual samples. 
At the Day 15 and Day 57 visits, a PK profile will be collected up to 6 hours post dose. At other 
specified visits, trough levels will be collected by sampling just before receiving the morning 
or evening dose. 
Plasma samples for analysis of PK parameters will be obtained and evaluated in all participants 
receiving iptacopan. No whole blood or urine samples will be collected for PK analysis. 
 
 
 
Iptacopan will be determined by a validated LC-MS/MS method with a previously established 
Lower Limit of Quantification (LLOQ) of 1 ng/mL. Iptacopan plasma concentration will be 
expressed in mass per volume units (ng/mL) and refer to the free base. Due to the limited 
sampling interval of 6 hours, the calculated PK parameters will be limited to the following, 
determined using the actual recorded sampling times and non-compartmental method(s) with 
Phoenix WinNonlin (Version 8 or higher): Cmax, Tmax, AUClast and AUCtau. The latter will 
be calculated by the "last observation carried forward" approach, assuming that, at steady-state, 
trough levels at T=0hr are the same as for T=12hr (tau). The approach will be applied as 
sampling times are limited to 6 hours and the extrapolation of AUClast (0-6hrs) to AUCtau 
(0-12hrs) is likely to exceed the accepted value of 20% of the total AUC. The linear trapezoidal 
rule will be used for AUC calculation.  
Concentrations below the LLOQ will be reported as zero and missing data will be labeled as 
such in the Bioanalytical data report (BDR). 
 
 
 
 
 
 


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9 
Discontinuation and completion 
9.1 
Discontinuation from study treatment and from study 
9.1.1 
Discontinuation from 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 drug 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 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 6.2.2 
• Any situation in which continued study participation might result in a safety risk to the 
participant 
• If a liver event occurs, follow the Hepatotoxicity Clinical Safety Standard Guideline, 
outlined in Appendix 2 (Section 16.2) regarding discontinuation of study treatment. 
• Increases in QTcF to >500 ms or of >60 ms over baseline 
• Unsatisfactory therapeutic effect (decision to be taken after consultation with Sponsor). 
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 
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Participants who discontinue from study treatment are to return for the end of treatment and 
follow-up visits indicated in the Assessment Schedule (refer to Section 8). 
After discontinuation from study treatment, participants (responders, in particular) should be 
closely monitored for a drop in their peripheral blood counts and associated signs and 
symptoms, in line with their underlying disease (e.g., platelet count for ITP, hemoglobin level 
for CAD). Any rescue therapy should be initiated as clinically indicated. 
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. 
At a minimum, in abbreviated visits, the following data should be collected at clinic visits or 
via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 
9.1.2 
Discontinuation from 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 the assessment table (refer to Section 8). 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue from study treatment or discontinue from study or withdraw 
consent/oppose to the use of their data/biological samples, the investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the participant, e.g. 
dates of telephone calls, registered letters, etc. A participant should not be considered as lost to 
follow-up until due diligence has been completed or until the end of the study. 
9.2 
Withdrawal of informed consent/Opposition to use 
data/biological samples 
Withdrawal of consent/opposition to use data/biological samples occurs when a participant: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be in writing (depending on local regulations) and recorded in the source 
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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/opposition to use data/biological samples and record this information. 
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of their Personal Data. 
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/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8). 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition. 
9.3 
Study stopping rules 
The Sponsor will review emergent safety data on an ongoing basis to react as soon as there is a 
possibility that a stopping rule could apply. The Sponsor will review all SAEs as individual 
cases and review summaries of non-serious AEs for patterns and trends, after excluding any 
events clearly not related to iptacopan treatment (e.g., SAE that occurred during the 
pre-treatment screening period, or disease-related SAE expected in the population under study). 
The following stopping rules apply separately to each cohort. Enrollment in the affected cohort 
and dosing of affected participant(s) with iptacopan will be paused if any of the following 
occurs during the study: 
• Two or more SAEs within the same cohort considered by the Investigator to be potentially 
related to iptacopan OR 
• One life-threatening or fatal SAE considered by the Investigator to be potentially related 
to iptacopan 
The cohort may resume following a full safety review if both the Investigator and Sponsor agree 
it is safe to proceed. Dependent on regional guidances, any restart following a temporary hold 
due to stopping rules being met will require prior submission and approval of a substantial CTA 
amendment to the competent authorities. 


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9.4 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit 
(either EOS for Part A or Part B) and any repeat assessments associated with this visit have 
been documented and followed-up appropriately by the Investigator or, in the event of an early 
study termination decision, the date of that decision. Each participant will be required to 
complete the study in its entirety. 
Once planned enrollment numbers are met, participants who already signed the consent but not 
yet treated will be allowed to continue into the study. 
All treated participants should have a safety follow-up call conducted 30 days after last visit. 
The information collected is kept as source documentation. All SAEs reported during this time 
period must be reported as described in Section 10.1.3. Documentation of attempts to contact 
the participant should be recorded in the source documentation. 
Please see Section 6.1.4 for post trial access. 
Continuing care should be provided by the investigator and/or referring physician after the 
EOS visit as per local standard of care. 
9.5 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination may include: 
• 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 drug development 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a participant who discontinued from study treatment: Participants who discontinue from 
study treatment are to return for the end of treatment and follow-up visits indicated in the 
Assessment Schedule (Section 8). The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
participant’s interests. The investigator or sponsor depending on local regulation will be 
responsible for informing IRBs/IECs of the early termination of the trial. 


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10 
Safety monitoring, reporting and committees 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events 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. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade: 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
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 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken regarding with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 


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• Drug interrupted/permanently discontinued 
6. Its outcome 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Appendix 1 (Section 16.1). 
10.1.1.1 Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are of scientific and medical interest specific to Novartis’s product or program, for which 
ongoing monitoring may be appropriate. Such events may require further investigation in order 
to characterize and understand them. AESI for iptacopan are defined on the basis of potential 
safety risks for the product, class effects, data from preclinical studies and include infections 
caused by encapsulated bacteria. 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
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• 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 
• 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. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred (see Section 10.1.5). 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the last study visit 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 electronic Serious Adverse Event (eSAE) 


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Report Form with paper backup; all applicable sections of the form must be completed in order 
to provide a clinically thorough report. 
SAEs occurring after the participant has provided informed consent until the time the participant 
is deemed a Screen Failure must be reported to Novartis. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Chief Medical Office and 
Patient Safety (CMO & PS) Department associate may urgently require further information 
from the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
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. 
10.1.4 
Pregnancy reporting 
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 the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the investigational 
treatment any pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
Post-natal follow up should occur at 1, 3 and 12 months after delivery. 


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10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (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 eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 
10.2 
Additional Safety Monitoring 
10.2.1 
Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
Please refer to Table 16-1 in Appendix 2 (Section 16.2) for complete definitions of liver 
laboratory triggers. 
Once a participant is exposed to study treatment, every liver event defined in Table 16-1 should 
be followed up by the investigator or designated personnel at the trial site, as summarized 
below. Additional details on actions required in case of liver events are outlined in Table 16-1 
Repeat liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm 
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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 eCRF. 
Following should be considered when managing the participant: 
• 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 
• Obtaining more detailed history of symptoms and prior or concurrent diseases 
• Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), alcohol use, recreational drug use, 
and special diets. 
• Exclusion of underlying liver disease 
The investigator can include based on investigator's discretion: 
• Imaging such as abdominal US, CT or MRI, as appropriate 
• Considering gastroenterology or hepatology consultations. 
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF. 
10.3 
Committees 
Not applicable. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (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 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/entered into eCRF) 
is complete, accurate, and that entry and updates are performed in a timely manner. 
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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. 
11.2 
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 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis/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. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis or 
delegated CRO representative will review the protocol and data capture requirements (i.e. 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 


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study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
12 
Data analysis and statistical methods 
Data analysis will be conducted separately for each cohort. 
Any analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
Study data will be presented by cohort (ITP, CAD) and, in addition, for ITP, by sC5b-9 
stratification group (sC5b-9 high, sC5b-9 low). 
12.1 
Analysis sets 
For all analysis sets, participants will be analyzed according to the study treatment(s) received. 
The safety analysis set will include all participants who received any study drug. 
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 drug and with no 
protocol deviations with relevant impact on PK data. 
The PD analysis set will include all participants who received any study drug and with no 
protocol deviations with relevant impact on PD data. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed 
and summarized descriptively by cohort and group for the full analysis set. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by cohort and group. 
12.3 
Treatments 
The Safety set will be used for the analyses below. 
Categorical data will be summarized as frequencies and percentages. For continuous data, 
mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. 
The duration of exposure in days/weeks to iptacopan 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 summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system, by cohort and group. 


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12.4 
Analysis supporting primary objectives 
The primary objective of the study is to assess the efficacy of iptacopan in participants with 
benign hematological disorders such as primary ITP and primary CAD with an increase in 
platelet count and in hemoglobin being considered a favorable outcome in ITP and CAD 
participants, respectively. 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoints of this study are: 
• Cohort 1 (ITP): A clinically meaningful response, defined by a platelet count of ≥50 k/µL 
sustained for at least 2 consecutive weeks during the main, 12-week treatment part without 
the use of rescue therapy. 
• Cohort 2 (CAD): A clinically meaningful response, defined by a hemoglobin level increase 
of ≥1.5 g/dL above baseline sustained for at least 2 consecutive weeks during the main, 
12-week treatment part without the use of rescue therapy. 
A study participant will be considered a responder if he/she meets all of the below criteria: 
Cohort 1 (ITP): 
1. Platelet count of ≥50 k/µL sustained for at least 2 consecutive weeks during the main, 
12-week of treatment part; 
2. Absence of rescue therapy or prohibited medications to treat ITP; 
3. Lack of treatment discontinuation. 
Cohort 2 (CAD): 
1. Hemoglobin level increase of ≥1.5 g/dL above baseline sustained for at least 2 consecutive 
weeks during the main, 12-week treatment part; 
2. Absence of rescue therapy or prohibited medications to treat CAD; 
3. Lack of treatment discontinuation. 
For both cohorts, occurrence of any of the events #2-3 prior to meeting event #1 would make 
the study participant a non-responder, whereas occurrence after would not affect his/her 
qualification as a responder with respect to the primary endpoint. 
Please refer to Section 2.1 for a description of the primary estimand. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
For calculation of the success rate for the primary endpoint, all participants treated in the study 
in respective cohorts will be included. 
Cohort 1 
For the purpose of this study, a positive sign of efficacy in primary ITP participants is defined 
as an observed response rate of at least 30% in all-comers, or 50% in the participants with 
activated complement at screening. 


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The platelet counts will be summarized by visit and time point for both groups in Cohort 1 
separately and combined. Summary statistics will be presented for raw and change from 
baseline for platelet counts by group, visit and time point and combined for both groups. 
Cohort 2 
For the purpose of this study, a positive sign of efficacy in primary CAD participants is defined 
as an observed response rate of at least 50%. 
The hemoglobin levels will be summarized by visit and time point. Summary statistics will be 
presented for raw and change from baseline hemoglobin levels by visit and time point. 
12.4.3 
Handling of intercurrent events of primary estimand 
The intercurrent events of the primary estimands are part of the primary variable, defined 
in Section 2.1. 
12.4.4 
Handling of missing values not related to intercurrent event 
Missing data imputations will be discussed in the Statistical Analysis Plan (SAP) in detail. 
12.4.5 
Sensitivity analyses 
Not applicable 
12.4.6 
Supplementary analysis 
Not applicable 
12.5 
Analysis supporting secondary objectives 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
In this section, all the measurements collected will be summarized descriptively by cohort and 
group and listed. 
12.5.1.1 Time to the first response 
Cohort 1: The first time that a participant has a platelet count ≥50 k/μL will be collected. 
Cohort 2: The first time that a participant has a hemoglobin level  ≥1.5 g/dL above baseline 
will be collected. 
Summary statistics will be provided for the time to first response by cohort and group. 
In addition, time to first response will be presented graphically for all the participants by cohort 
and group. Additional analysis will be detailed in the SAP. 
12.5.1.2 Duration of response during Part A 
Cohort 1: The duration of time during which a participant's platelet count remains  ≥50 k/μL 
without the use of rescue therapy will be collected. 


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Cohort 2: The duration of time during which a participant's hemoglobin level remains 
≥1.5 g/dL above baseline without the use of rescue therapy will be collected. 
Summary statistics will be provided for duration of response by cohort and group. In additional, 
duration of response will be presented graphically for all the participants by cohort and group. 
12.5.1.3 Magnitude of response during Part A 
Cohort 1: The magnitude of increase in platelet counts compared to baseline will be derived 
for each participant at each visit and time point. 
Cohort 2: The magnitude of increase in hemoglobin levels compared to baseline will be derived 
for each participant at each visit and time points. 
Summary statistics for change from baseline will be presented by cohort, group and visit and 
time point. The magnitude of response will be categorized by cohort and group. The response 
categories will be provided in SAP. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented 
by cohort (for ITP, both groups (sC5b-9 high and sC5b-9 low) will be pooled). 
Safety summaries (tables, figures) will include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In particular, summary tables for adverse events (AEs) will summarize 
only on-treatment events, with a start date during the on-treatment period (treatment-emergent 
AEs). In addition, a separate summary for deaths, including on-treatment and post-treatment 
deaths will be provided in case deaths occur during the study.  
The on-treatment period lasts from the date of first administration of study treatment to 7 days 
after the date of the last actual administration of any study treatment. 
Adverse events 
All information obtained on adverse events will be displayed by cohort, group and participant. 
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication but increased in severity based on preferred term) 
will be summarized in the following ways: 
• by primary system organ class and preferred term. 
• by primary system organ class, preferred term and maximum severity. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment. 
The number (and proportion) of participants with adverse events of special interest/related to 
identified and potential risks will be summarized by cohort and group. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 


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Adverse events 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 drug relationship, or developed into SAEs 
after the start of the treatment period. 
Vital signs 
All vital signs data will be listed by cohort, group, participant, and visit/time, and if ranges are 
available, abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by cohort, group and visit/time. 
Clinical laboratory evaluations 
All laboratory data parameters will be listed by cohort, group, participant, and visit/time and if 
normal ranges are available abnormalities will be flagged. Summary statistics will be provided 
by cohort, group and visit/time. Shift tables using the low/normal/high/ (low and high) 
classification will be used to compare baseline to the worst on-treatment value. 
12-lead ECG 
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each participant 
during the study. ECG data will be read and interpreted locally. 
Categorical analysis of QT/QTcF interval data based on the number of participants meeting or 
exceeding predefined limits in terms of absolute QT/QTcF intervals or changes from baseline 
will be presented. In addition, a listing of these participants will be produced by cohort and 
group. 
All ECG data will be listed by cohort, group, participant, and visit/time; abnormalities will be 
flagged. Summary statistics will be provided by cohort, group and visit. 
12.5.2.1 The need for rescue therapy during Part A 
The need and use of rescue therapy during Part A will be assessed. The rescue therapy will be 
summarized by cohort, group and listed by cohort, group and visit/time point. 
12.5.3 
Pharmacokinetics 
Descriptive summary statistics of iptacopan plasma concentration data will be provided by 
treatment, and visit/sampling time point, including the frequency (n, %) of concentrations below 
the LLOQ and reported as zero. 
Descriptive summary statistics for PK parameters will include mean (arithmetic and geometric), 
SD, and CV (arithmetic and geometric), median, minimum, and maximum. An exception to this 
is Tmax where median, minimum, and maximum will be presented. 


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Table 12-1 
Non-compartmental pharmacokinetic parameters 
AUClast 
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1) 
AUCinf 
The AUC from time zero to infinity (mass x time x volume-1) 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x 
time x volume-1) 
Cmax 
The maximum (peak) concentration observed in plasma, after oral administration 
(mass x volume-1) of iptacopan 
Tmax 
The time to reach maximum (peak) plasma concentration after oral administration 
(time) of iptacopan 
Lambda_z 
Smallest (slowest) disposition (hybrid) rate constant (time-1) may also be used for 
terminal elimination rate constant (time-1) 
T1/2 
The elimination half-life associated with the terminal slope (λz) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives 
12.5.4 
Biomarkers 
The effect of iptacopan on relevant disease biomarkers not covered in the primary objective 
during Part A will be assessed. The biomarkers includes lactate dehydrogenase (LDH), total 
bilirubin, reticulocyte count and haptoglobin. 
Descriptive statistics and change from baseline will be summarized by cohort and group. 
 
 
 
 
 
 
  
 
 
 
 
• 
 
• 
 
 
 
 
• 
 


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• 
 
 
 
 
 
 
• 
 
• 
 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
 
• 
 
 
 
 
 
 
 


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12.7 
Interim analyses 
The following interim analyses are planned for each cohort:  
• An interim analysis is planned after approximately half of the participants within a cohort 
complete 12 weeks of treatment. For these participants the efficacy data up to week 12 
(along with relevant safety and/or PK data) will be examined as a preliminary evaluation 
of proof of concept (PoC). 
• A second interim analysis is planned after all participants within a cohort complete 
12 weeks of treatment. Relevant data up to Part A EOS will be examined. 
Additional IAs might be conducted during the study to support decision making concerning the 
current clinical study, the sponsor’s 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. 
Interim results may be used to prepare publications, abstracts and/or presentations at scientific 
meetings. 


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12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
12.8.1.1 Cohort 1: ITP (N=20) 
Approximately 20 participants diagnosed with primary ITP and sustained thrombocytopenia 
will be enrolled. Participants will be stratified based on complement activation (sC5b-9 levels) 
at screening in to one of the two groups (complement-activated vs. not complement-activated) 
until approximately 10 participants have been assigned to each group. 
Complement-activated group (N=10): 
With 10 participants, this group has 80% probability to meet the efficacy criterion of 50% or 
more responders if the true response rate is 58%. For lower true response rates, the probability 
of having at least 50% responders is appropriately lower; for example, 62%, 37% and 15% for 
true response rates of 50, 40 and 30%, respectively. 
With 10 participants, 
• the probability of a false-positive readout (i.e., probability of meeting the efficacy 
criterion, when the true response rate with iptacopan treatment is smaller or equal to the 
presumed underlying response rate of 10%) is < 1%. 
• the probability of a false-negative readout (i.e., probability of not meeting the efficacy 
criterion, when the true response rate is at least 58%) is 20%. 


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Figure 12-1 
Probability of observed response rate of ≥50 percent vs. true 
response rate 
 
All-comers (N=20): 
With 20 participants, the combined groups (full cohort) have 80% probability to meet the 
efficacy criterion of 30% or more responders if the true response rate is 37%. For lower true 
response rates, the probability of having at least 30% responders is appropriately lower; for 
example, 58.4% and 20% for true response rates of 30 and 20% respectively. 
With 20 participants, 
• the probability of a false-positive readout (i.e., probability of meeting the efficacy 
criterion, when the true response rate with iptacopan treatment is smaller or equal to the 
presumed underlying response rate of 10%) is 1%. 
• the probability of a false-negative readout (i.e., probability of not meeting the efficacy 
criterion, when the true response rate is at least 37%) is 20%. 


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Figure 12-2 
Probability of observed response rate of ≥30 percent vs. true 
response rate 
 
12.8.1.2 Cohort 2: CAD (N=10) 
The proposed sample size for CAD cohort is 10 and hence the sample size calculations are the 
same as for the ITP complement-activated group (see Section 12.8.1.1). 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 


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to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last participant last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
13.5 
Participant Engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available and approved locally, for distribution to study participants at the timepoints 
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 treatment information - after database lock 


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14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
References are available upon request 
Berentsen S (2021) How I treat cold agglutinin disease. Blood; 137(10):1295-1303. 
Berentsen S, Röth A, Randen U, et al (2019) Cold agglutinin disease: current challenges and 
future prospects. J Blood Med; 10:93-103. 
Broome CM, et al (2020) Long-term safety and efficacy of sutimlimab in patients with 
chronic immune thrombocytopenia. ASH Meeting Abstract. 
Bussel JB, Kuter DJ, Aledort LM, et al (2014) A randomized trial of avatrombopag, an 
investigational thrombopoietin-receptor agonist, in persistent and chronic immune 
thrombocytopenia. Blood; 123(25):3887–3894. 
Castelli R, Lambertenghi Delilliers G, Gidaro A, et al (2020) Complement activation in 
patients with immune thrombocytopenic purpura according to phases of disease course. Clin 
Exp Immunol; 201(3):258-265. 
 
 
Cheloff AZ, Kuter DJ, Al-Samkari H (2020) Serum complement levels in immune 
thrombocytopenia: Characterization and relation to clinical features. Res Pract Thromb 
Haemost; 4(5):807-812. 
Cuker A, Despotovic JM, Grace RF, et al (2020) Tapering thrombopoietin receptor agonists in 
primary immune thrombocytopenia: Expert consensus based on the RAND/UCLA modified 
Delphi panel method. Res Pract Thromb Haemost; 5(1):69-80. 
Harboe M, Ulvund G, Vien L, et al (2004) The quantitative role of alternative pathway 
amplification in classical pathway induced terminal complement activation. Clin Exp 
Immunol; 138(3):439-46. 
Jäger U, D'Sa S, Schörgenhofer C, et al (2019) Inhibition of complement C1s improves severe 
hemolytic anemia in cold agglutinin disease: a first-in-human trial. Blood; 133(9): 893-901. 
Jurczak W, Chojnowski K, Mayer J, et al (2018) Phase 3 randomised study of avatrombopag, 
a novel thrombopoietin receptor agonist for the treatment of chronic immune 
thrombocytopenia. Br J Haematol; 183(3):479-490. 
Kaufman RM, Djulbegovic B, Gernsheimer T, et al (2015) Platelet transfusion: a clinical 
practice guideline from the AABB. Ann Intern Med; 162(3):205-13. 
Konar M, Granoff DM (2017) Eculizumab treatment and impaired opsonophagocytic killing 
of meningococci by whole blood from immunized adults. Blood; 130(7):891-899. 
Mainolfi N, Ehara T, Karki RG, et al (2020) Discovery of 4-((2S,4S)-4-Ethoxy-1-((5-
methoxy-7-methyl-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic Acid (LNP023), a Factor B 
Inhibitor Specifically Designed To Be Applicable to Treating a Diverse Array of Complement 
Mediated Diseases. J Med Chem; 63(11):5697-5722. 


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Mathias SD, Bussel JB, George JN, et al (2007) A disease-specific measure of health-related 
quality of life in adults with chronic immune thrombocytopenic purpura: psychometric testing 
in an open-label clinical trial. Clin Ther; 29(5):950-962. 
Neunert C, Terrell DR, Arnold DM, et al (2019) American Society of Hematology 2019 
guidelines for immune thrombocytopenia. Blood Adv; 3(23):3829-3866. 
Provan D, Arnold DM, Bussel JB, et al (2019) Updated international consensus report on the 
investigation and management of primary immune thrombocytopenia. Blood Adv; 
3(22):3780-3817. 
Risitano AM, et al (2020) LNP023 - A new oral complement factor-B inhibitor normalizes 
hemoglobin in paroxysmal nocturnal hemoglobinuria patients with poor response to 
eculizumab, both as add-on and monotherapy. EBMT Meeting Abstract. 
Roesch E, Broome C (2016) Complement blockade with C1 esterase inhibitor in refractory 
immune thrombocytopenia. Am J Hemat Onc; 12(6):20-5. 
Röth A, Barcellini W, D'Sa S, et al (2021) Sutimlimab in Cold Agglutinin Disease. N Engl J 
Med; 384(14):1323-1334. 
Röth A, Bommer M, Hüttmann A, et al (2018) Eculizumab in cold agglutinin disease 
(DECADE): an open-label, prospective, bicentric, nonrandomized phase 2 trial. Blood Adv; 
2(19):2543-2549. 
Schubart A, Anderson K, Mainolfi N, et al (2019) Small-molecule factor B inhibitor for the 
treatment of complement-mediated diseases. Proc Natl Acad Sci USA; 116(16):7926-7931. 
 


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16 
Appendices 
16.1 
Appendix 1: Clinically notable laboratory values 
Renal alert values 
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 
• New onset dipstick proteinuria ≥ 3+ 
Abnormal renal event findings must be confirmed after ≥24 hours but ≤ 5 days after first 
assessment. Causes and possible interventions should be considered. 
ECG alert values 
• Resting heart rate sinus rhythm < 30 or a HR decrease ≥ 25% or 
• HR > 130 [bpm] 
• QRS >120 or increase >25% compared to predose baseline [msec] 
• QTcF >500 or increase >60 compared to predose baseline [msec]* 
• Ventricular tachycardia 
• New complete heart block (Grade III AV block) or Mobitz II AV block 
For any ECGs with participant safety concerns, two additional ECGs must be performed to 
confirm the safety finding. 
*Please check Section 9.1.1 for study treatment discontinuation. 


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16.2 
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements 
Table 16-1 
Definitions of Triggers, Actions and Follow-up requirements for liver 
events 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law case 
(Elevated ALT/AST > 3 × 
ULN and TBL > 2 × ULN 
but without notable 
increase in ALP to > 2 × 
ULN – or 3 x ULN in the 
presence of bone 
pathology) 
· Discontinue the study treatment 
immediately (if possibly related to study 
treatment) 
· Hospitalize, if clinically appropriate 
· Establish causality (investigate 
alternative etiologies)a 
· Record the AE and contributing factors 
(e.g. concomitant medication, medical 
history, laboratory value) in the 
appropriate eCRF 
· ALT, AST, TBL, Alb, 
PT/INR, ALP, GGT, CK and 
GLDH (frequency at 
Investigator discretion) 
· Monitor for symptomsb 
· Report outcomec 
ALT  
> 8 × ULN 
· Interrupt the study treatment (if 
possibly related to study treatment) 
· Hospitalize if clinically appropriate 
· Establish causality (investigate 
alternative etiologies)a 
· Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF 
· ALT, AST, TBL, Alb, 
PT/INR, ALP and GGT 
(frequency at Investigator 
discretion) 
· Monitor for symptomsb 
· Report outcomec 
> 3 × ULN and INR > 1.5 
(in the absence of 
anticoagulation) 
If elevated at baseline: 
> 2 x baseline 
or > 300 U/L (whichever 
occurs ﬁrst) 
· Interrupt the study treatment (if 
possibly related to study treatment) 
· Hospitalize if clinically appropriate 
· Establish causality (investigate 
alternative etiologies)a 
• 
Study drug can be restarted only if 
alternative etiology is identified and 
liver enzymes return to baseline 
· Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF 
· ALT, AST, TBL, Alb, 
PT/INR, ALP and GGT until 
resolution (frequency at 
Investigator discretion) 
> 5 to ≤ 8 × ULN 
If elevated at baseline: 
> 3 x baseline 
or > 300 U/L (whichever 
occurs ﬁrst) 
· Repeat LFT within 48 hours 
· If elevation persists, continue follow-up 
monitoring 
· If elevation persists for more than 2 
weeks, discontinue the study drug 
· Establish causality (investigate 
alternative etiologies)a 
· Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF 
· ALT, AST, TBL, Alb, 
PT/INR, ALP and GGT until 
resolution (frequency at 
Investigator discretion) 


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Criteria 
Actions required 
Follow-up monitoring 
> 3 × ULN to ≤ 5 × ULN 
(accompanied by 
symptoms)b 
If elevated at baseline: 
> 2 x baseline 
or > 300 U/L (whichever 
occurs ﬁrst) 
· Interrupt the study treatment (if 
possibly related to study treatment) 
· Hospitalize if clinically appropriate 
· Establish causality (investigate 
alternative etiologies)a 
• 
Study drug can be restarted only if 
alternative etiology is identified and 
liver enzymes return to baseline 
· Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF 
· ALT, AST, TBL, Alb, 
PT/INR, ALP and GGT until 
resolution (frequency at 
Investigator discretion) 
· Monitor for symptomsb 
· Report outcomec 
> 3 to ≤ 5 × ULN 
(participant is 
asymptomatic)b 
If elevated at baseline: 
> 2 x baseline 
or > 300 U/L (whichever 
occurs ﬁrst) 
· Repeat LFT within the next week 
· If elevation is confirmed, initiate close 
observation of the participant 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks 
ALP (isolated) 
> 2 × ULN (in the absence 
of known bone pathology) 
>3 x ULN in the presence 
of bone pathology 
· Repeat LFT within 48 hours 
· If elevation persists, establish causality 
(investigate alternative etiologies)a 
· Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF 
Investigator discretion 
Monitor LFT within 1 to 4 
weeks or at next visit 
Liver events 
Jaundice 
· Interrupt the study treatment (if 
possibly related to study treatment) 
· Hospitalize if clinically appropriate 
· Establish causality (investigate 
alternative etiologies)a 
• 
Study drug can be restarted only if 
alternative etiology is identified and 
liver enzymes return to baseline 
· Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF 
· ALT, AST, TBL, Alb, 
PT/INR, ALP and GGT until 
resolution (frequency at 
Investigator discretion) 
· Monitor symptomsb 
· Report outcomec 


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Criteria 
Actions required 
Follow-up monitoring 
Any AE potentially 
indicative of a liver 
toxicityd 
· Consider study treatment interruption 
or discontinuation 
· Hospitalization if clinically appropriate 
· Establish causality (investigate 
alternative etiologies)a 
· Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF 
Investigator discretion 
a 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 
bSevere fatigue, malaise (general), abdominal pain (right upper quadrant), nausea, vomiting or rash 
with eosinophilia 
cResolved = return to Day 1 values; Condition unchanged = stable values at three subsequent 
monitoring visits at least 2 weeks apart; Condition deteriorated = values worsen or liver 
transplantation; and Fatal. 
dThese events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms. 


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SAP_001.pdf: 
Clinical Development 
LNP023 
CLNP023L12201 / NCT05086744
An open-label, multi-center, phase 2 basket study to assess 
efficacy, safety and pharmacokinetics of iptacopan (LNP023) in 
participants with autoimmune benign hematological disorders 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
21-May-2024
Number of pages: 
38 
Property of Novartis 
 Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 4.0, Effective from 23-Apr-2021 


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Document History – Changes compared to previous final version of SAP 
Date 
Time 
point 
Reason 
for 
update 
Outcome for update 
Section and title 
impacted (Current) 
02-
Dec-
2021 
First 
version 
N/A - First version 
N/A 
11-
Nov-
2022 
Prior 
to 
iDBL 
V1.1 
Added definition of unique prior 
therapy. 
Section 
2.3.2.1 
Definition of unique 
prior therapy 
 
 
Added CTCAE statements to safety 
analysis. 
Section 2.7 Safety 
analysis 
Added notable changes of ECG data 
and vital sign data. 
Section 2.7.4 Other 
safety data 
Updated summary of biomarker data 
to geometric mean and arithmetic 
mean are kept for reference. 
Section
2.11
Biomarkers 
Updated 
Criteria 
that 
cause 
participants to be excluded for PD and 
safety set. 
Section 5.5 Rule of 
exclusion criteria of 
analysis sets 
10-
Sep-
2023 
Prior 
to IA2 
DBL 
V1.2 
Added definition of change from 
baseline. 
Section 2.1.1 General 
definitions 
 
Added disease characteristics. 
Section 
2.3.2 
Demographics 
and 
other 
baseline 
characteristics 
Updated category of duration of 
exposure. 
Section 2.4.1 Study 
treatment/compliance 
Added decoded terms from field of 
medical history. 
Section 2.4.2 Prior, 
concomitant and post 
therapies 


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Date 
Time 
point 
Reason 
for 
update 
Outcome for update 
Section and title 
impacted (Current) 
 
 
 
Updated 
content 
in 
tables 
for 
laboratory parameters with/without 
CTCAE grade. 
Added analysis on newly occurring 
liver enzyme abnormalities. 
Added analysis on drug-induced liver 
injury (DILI). 
2.7.3.2 Data analysis 
 
 
 
Added analysis on ECG alert values. 
2.7.4.1 
ECG 
and 
cardiac imaging data 
 
 
 
 
 
 
 
 
 
20-
Apr-
2024 
Prior 
to final 
DBL 
V1.3 
Added time window to match the 
individual data to its closest visit. 
2.1 
Data 
analysis 
general information 
 
 
 
 
 
 
 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 4 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
1 
Introduction ......................................................................................................................... 9 
1.1 
Study design............................................................................................................. 9 
1.2 
Study objectives, endpoints and estimands ........................................................... 10 
1.2.1 
Primary estimand(s) .............................................................................. 12 
1.2.2 
Secondary estimand(s) .......................................................................... 13 
2 
Statistical methods ............................................................................................................. 13 
2.1 
Data analysis general information ......................................................................... 13 
2.1.1 
General definitions ................................................................................ 13 
2.2 
Analysis sets .......................................................................................................... 14 
2.2.1 
Subgroup of interest .............................................................................. 15 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 15 
2.3.1 
Patient disposition ................................................................................. 15 
2.3.2 
Demographics and other baseline characteristics ................................. 15 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 16 
2.4.1 
Study treatment / compliance ................................................................ 16 
2.4.2 
Prior, concomitant and post therapies ................................................... 16 
2.5 
Analysis supporting primary objective(s) .............................................................. 17 
2.5.1 
Primary endpoint(s) ............................................................................... 17 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 18 
2.5.3 
Handling of intercurrent events ............................................................. 18 
2.5.4 
Handling of missing values not related to intercurrent event ............... 18 
2.6 
Analysis supporting secondary objectives ............................................................. 18 
2.6.1 
Secondary endpoint(s) ........................................................................... 18 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 20 
2.6.3 
Handling of intercurrent events ............................................................. 20 
2.6.4 
Handling of missing values not related to intercurrent event ............... 20 
2.7 
Safety analyses ....................................................................................................... 20 
2.7.1 
Adverse events (AEs) ............................................................................ 20 
2.7.2 
Deaths .................................................................................................... 22 
2.7.3 
Laboratory data ..................................................................................... 22 


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2.7.4 
Other safety data ................................................................................... 25 
2.8 
Pharmacokinetic endpoints .................................................................................... 26 
 
 27 
 
 27 
 
 28 
 
 28 
 
 29 
 
 30 
 
 31 
 
 31 
 
 31 
2.10 
Interim analysis ...................................................................................................... 31 
3 
Sample size calculation ..................................................................................................... 32 
3.1 
Primary endpoint(s) ............................................................................................... 32 
3.1.1 
Cohort 1: ITP (N=20) ............................................................................ 32 
4 
Change to protocol specified analyses .............................................................................. 33 
5 
Appendix ........................................................................................................................... 33 
5.1 
Imputation rules ..................................................................................................... 33 
5.1.1 
Study drug ............................................................................................. 33 
5.1.2 
AE date imputation ............................................................................... 34 
5.1.3 
Concomitant medication date imputation ............................................. 35 
5.2 
AEs coding/grading ............................................................................................... 37 
5.3 
Laboratory parameters derivations ........................................................................ 37 
5.4 
Statistical models ................................................................................................... 38 
5.4.1 
Analysis supporting primary objective(s) ............................................. 38 
5.4.2 
Analysis supporting secondary objective(s).......................................... 38 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 38 
6 
Reference ........................................................................................................................... 38 
 
 
 
List of tables 
Table 2-1 
Laboratory parameters with a CTCAE grade ........................................ 23 
Table 2-2 
Laboratory parameters with no CTCAE grade ..................................... 24 
Table 2-3 
Definition of liver toxicities based on laboratory parameters ............... 24 


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 28 
Table 5-1 
Criteria leading to exclusion ................................................................. 38 
List of figures 
Figure 1-1 
Study design .......................................................................................... 10 
Figure 3-1 
Probability of observed response rate of ≥50 percent vs. true 
response rate .......................................................................................... 32 
Figure 3-2 
Probability of observed response rate of ≥30 percent vs. true 
response rate .......................................................................................... 33 


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List of abbreviations 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ATC 
Anatomical Therapeutic Classification 
b.i.d. 
Twice a day 
BM 
Biomarkers 
C3 
Complement Component 3 
C4 
Complement Component 4 
CAD 
Cold Agglutinin Disease 
CRO 
Contract research organization 
CSR 
Clinical Study report 
CV 
Coefficient of variation 
DAT 
Direct Antiglobulin Test 
ECG 
Electrocardiogram 
EoS 
End of study 
 
 
IA 
Interim Analysis  
IRB 
Institutional Review Board 
ITP 
Immune Thrombocytopenia 
 
 
KDQoL 
Kidney Disease Quality of Life questionnaire 
LDH 
Lactate Dehydrogenase 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
mg 
Milligram(s) 
PD 
Pharmacodynamics 
PDS 
Programming Datasets Specification 
PK 
Pharmacokinetics 
PoC 
Proof of concept 
PR 
PR interval 
 
 
PT 
Preferred Term 
 
 
QT 
QT interval 
QTcF 
QT interval corrected by Fridericia’s formula 
Q1 
Lower quartile 
Q3 
Upper quartile 
RAP 
Report and Analysis Plan 
RBC 
Red blood cell(s) 
RR 
RR interval 
SAE 
Serious adverse event 


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SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
sC5b-9 
soluble Complement Component 5 fraction "b" linked to Complement 
Component 9 
SD 
Standard deviation 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
TTP 
Thrombotic Thrombocytopenic Purpura 
ULN 
Upper limit of normal 
ULOQ 
Upper limit of quantification 
wAIHA 
Warm Autoimmune Hemolytic Anemia 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
Introduction 
The Report Analysis Plan (RAP) documents contain detailed information to aid the production 
of Statistics & Programming input into the Clinical Study Report (CSR) for study 
“CLNP023L12201”. 
The Statistical analysis plan (SAP) describes the implementation of the statistical analyses 
planned in the protocol, including planned interim analyses (see Section 2.10) and the full 
analysis after the final database lock. 
The final study protocol, version v03, 26 Apr 2022 is available at the time of finalization of 
Statistical Analysis Plan. 
1.1 
Study design 
This is an open-label, single-arm (within each cohort), multi-center, non-confirmatory basket 
study to assess the efficacy, safety and pharmacokinetics of iptacopan in participants with 
autoimmune benign hematological disorders. The study is set up as a basket study to allow 
inclusion of new cohorts (=indications).  
The study starts with two initial cohorts/indications and participants will be assigned to the 
relevant cohort based on their diagnosis: 
• Cohort 1: participants diagnosed with primary Immune Thrombocytopenia (ITP) 
• Cohort 2: participants diagnosed with primary Cold Agglutinin Disease (CAD) 
Inclusion of up to two additional cohorts (e.g., Warm Autoimmune Hemolytic Anemia 
(wAIHA), Thrombotic Thrombocytopenic Purpura (TTP)) will only be proposed via substantial 
protocol amendment and will only be implemented upon review by HAs/EC/IRBs. 
Data analysis will be conducted separately for each cohort. Any analysis carried out 
independently by the investigator should be submitted to Novartis before publication or 
presentation. 
Study data will be presented by cohort (ITP, CAD) and, in addition, for ITP, by soluble 
Complement Component 5 fraction "b" linked to Complement Component 9 (sC5b-9) 
stratification group (sC5b-9 high, sC5b-9 low). 
The study design / participant journey is illustrated in Figure 1-1. 


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Figure 1-1 
Study design 
 
The study consists of a screening period, a 12-week treatment period (Part A), a washout 
(responders)/follow-up (non-responders) after Part A, and, for responders only, an additional 
treatment extension period of up to 24 months (Part B). The total study duration from screening 
until end-of-study visit (EOS) is approximately 6 months for participants not meeting the 
primary endpoint (non-responders) and up to 31 months for participants meeting the primary 
endpoint (responders). 
1.2 
Study objectives, endpoints and estimands  
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
Cohort 1: To assess the ability of 
iptacopan to induce a clinically 
meaningful increase in platelet count 
in participants with primary ITP 
• 
Cohort 2: To assess the ability of 
iptacopan to induce a clinically 
meaningful increase in hemoglobin 
levels in participants with primary 
CAD 
• 
A clinically meaningful response, defined by a 
platelet count of ≥50 k/μL sustained for at least 2 
consecutive weeks during the main, 12-week 
treatment part without the use of rescue therapy 
• 
A clinically meaningful response, defined by a 
hemoglobin level increase of ≥1.5 g/dL above 
baseline sustained for at least 2 consecutive weeks 
during the main, 12-week treatment part without the 
use of rescue therapy 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess the time to first response 
• 
Cohort 1: Time to first platelet count ≥50 k/μL 
• 
Cohort 2: Time to first hemoglobin level ≥1.5 g/dL 
above baseline 
• 
To assess the duration of response 
during Part A 
• 
Cohort 1: Duration during which platelet count 
remains ≥50k/μL without the use of rescue therapy 


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Objective(s) 
Endpoint(s) 
• 
Cohort 2: Duration during which hemoglobin level 
remains ≥1.5 g/dL above baseline without the use of 
rescue therapy 
• 
To assess the magnitude of 
response during Part A 
• 
Cohort 1: Magnitude of platelet count increase from 
baseline 
• 
Cohort 2: Magnitude of hemoglobin increase from 
baseline 
• 
To assess the need for rescue 
therapy during Part A 
• 
Use of rescue therapy 
• 
Cohort 2 only: To assess the effect 
of iptacopan on relevant disease 
biomarkers (BM) not covered in the 
primary objective during Part A 
• 
Lactate dehydrogenase (LDH), total bilirubin, 
reticulocyte count and haptoglobin 
• 
To assess the safety and tolerability 
of iptacopan in participants with 
benign hematological disorders 
• 
Safety parameters include vital signs, adverse 
events, hematology, blood chemistry, reproductive 
and thyroid hormones, coagulation, urinalysis and 
ECG evaluation. 
• 
To assess the pharmacokinetics 
(PK) of iptacopan 
• 
Iptacopan PK parameters including but not limited to 
Cmax, AUCtau, AUClast, Ctrough and Tmax. 


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1.2.1 
Primary estimand(s) 
The primary clinical question of interest is: What is the effect of iptacopan treatment for 12 
weeks on the platelet count in patients with primary ITP and on the hemoglobin level in patients 
with primary CAD considering the use of rescue medication as an indicator of lack of efficacy. 
The justification for targeting this treatment effect is to estimate the effect of the study drug for 
the full duration in the absence of concomitant treatments that could confound the primary 
assessment of efficacy. 
Cohort 1: primary ITP 
The primary estimand is described by the following attributes: 
1. Population: Adult participants diagnosed with primary ITP with sustained 
thrombocytopenia after at least 1 prior line of ITP-directed therapy. 
2. Primary variable: Response, where the response is defined as a platelet count of ≥50 
k/µL sustained for at least 2 consecutive weeks during the main, 12-week treatment part, 
a) in the absence of rescue therapy or prohibited medications to treat ITP and b) without 
study drug discontinuation. 
3. Treatment of interest: Investigational treatment with iptacopan 200 mg b.i.d. 
4. The summary measure: Proportion of participants who respond. 


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Cohort 2: primary CAD 
The primary estimand is described by the following attributes: 
1. Population: Adult participants diagnosed with primary CAD with sustained anemia and 
laboratory evidence of ongoing hemolysis after at least 1 prior line of CAD-directed 
therapy. 
2. Primary variable: Response, where the response is defined as a hemoglobin level 
increase of ≥1.5 g/dL above baseline sustained for at least 2 consecutive weeks during 
the main, 12-week treatment part, a) in the absence of rescue therapy or prohibited 
medications to treat CAD and b) without study drug discontinuation. 
3. Treatment of interest: Investigational treatment with iptacopan 200 mg b.i.d. 
4. The summary measure: Proportion of participants who respond.  
1.2.2 
Secondary estimand(s) 
Not applicable. 
2 
Statistical methods 
2.1 
Data analysis general information 
Data will be analyzed using SAS® version 9.4 (or higher). 
Unless otherwise specified, descriptive summary statistics for continuous variables will include 
number of non-missing observations (n), mean (arithmetic and geometric), SD, CV (arithmetic 
and geometric), median, minimum and maximum, as appropriate, while for categorical 
variables frequencies and percentages will be reported. 
Graphical presentations of individual and summary data will be provided, as applicable. 
All data collected at unscheduled visits will not be used in ‘by-visit’ tabulations or graphs, but 
they will be included in analyses based on all post-baseline values such as summary statistics 
of clinically notable abnormalities of laboratory data. All data collected at both scheduled and 
unscheduled visits will be included in data listings. 
2.1.1 
General definitions  
The term ‘study treatment’ or ‘study drug’ refers to the Novartis investigational drug, LNP023, 
dispensed by the investigators during the study.  
The term ‘date of first administration of study drug/treatment’ refers to the date on which the 
study drug/treatment was given for the first time in each study part. 
The term ‘date of last administration of study drug/treatment’ refers to the date on which the 
study drug/treatment was given for the last time in each study part. 
The term ‘study day’ refers to the Analysis Relative Day, Relative Start Day or Relative End 
Day, as applicable. Study Day is defined relative to the Analysis reference date, which is the 
date of first administration of the study drug/treatment in each study part; 


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• The study day in each study part for a scheduled or unscheduled visit on or after the 
Analysis reference date is defined as:  
Study day = (Date of visit) – (Analysis reference date) + 1; 
• The study day for a scheduled or unscheduled visit before the Analysis reference date 
(applicable only for Part A) is defined as:  
Study day = (Date of visit) – (Analysis reference date). 
Thus, the Analysis reference date in each study part will be study day 1. For Part A only, 
the date directly prior to the Analysis reference date is defined as Study Day -1 (there is 
no Study Day 0).  
For Part A, the term ‘baseline’ refers to the last measurement before dose administration, unless 
otherwise specified. For Part B, baseline is defined as study day 1. Exceptionally, for platelets 
(ITP) / hemoglobin (CAD), ‘baseline’ is defined as the actual baseline visit. 
The term ‘on-treatment period’ refers to the period from the date of first administration of study 
treatment in the study to 7 days after the date of the last actual administration of any study 
treatment. 
When ‘change from baseline’ is of interest, the following formula will be used for each 
scheduled visit and time point where baseline and post-baseline values are both available: 
Change from baseline = post-baseline value – baseline value 
If baseline or post-baseline values are missing, then the change from baseline will be missing. 
For display of summary statistics of endpoints by visit in overlaying individual plots and 
summary tables, a time window will be implemented to match the actual visit to its closest 
nominal visit. For Part A, +/- 7days of each nominal visit will be considered as the length of 
time window. For Part B the +/-7-day time window for the first 2 visits will be applied, while 
+/-14-day window will be applied to the next 2 visits and a +/-28-day window to the remaining 
ones. Out-of-window EOT data will be matched to the closest planned visit if it falls within the 
respective window. However, out-of-window F/U and EOS data will not be matched to other 
time points since patients will discontinue treatment starting with EOT. 
2.2 
Analysis sets  
The following analysis sets will be defined for the statistical analysis conducted separately for 
each study part/cohort: 
The Full Analysis Set (FAS) and Safety Set are defined in the same way and comprise all 
patients who received at least one dose of 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 drug and with no 
protocol deviations or adverse events (for example, vomiting with 4 hours of dosing) which 
may impact iptacopan PK. 


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The PD analysis set will include all participants who received any study drug and with no 
protocol deviations with relevant impact on PD data. 
If a participant received rescue medication during the treatment period, the values of 
 
 collected within 30 days following the end day of rescue medication 
will be treated as missing. If end day is not available, the values collected within 30 days 
following the start day of rescue medication will be treated as missing. This rule will be applied 
to PD Analysis. 
The number and frequency (%) of participants in each analysis set will be presented. 
Participants with major protocol deviations will be presented for all participants. 
2.2.1 
Subgroup of interest 
Besides the all group analysis, the following subgroups will be considered only for ITP 
participants (Cohort 1): 
• sC5b-9 high stratification group 
• sC5b-9 low stratification group 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
The number and percentage of participants in the safety analysis set who completed the study 
or prematurely discontinued, and the reason for discontinuation, will be presented. 
2.3.2 
Demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by cohort and group. 
Disease characteristics will include:  
For ITP cohort: Number of unique prior therapies, number of background therapies, and 
baseline platelet count and sC5b-9 levels at screening.  
For CAD cohort: Number of unique prior therapies, number of background therapies, and 
baseline hemoglobin, LDH and total bilirubin values. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented. 
Relevant medical histories and current medical conditions at baseline will be listed by 
participant and summarized by system organ class and preferred term, by cohort and group. 


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2.3.2.1 
Definition of unique prior therapy 
A unique prior therapy is defined as any pharmaceutical agent or type of non-pharmacological 
intervention (e.g., splenectomy, plasmapheresis) administered with the intention to treat the 
indications under study (i.e. primary ITP for Cohort 1 or primary CAD for Cohort 2). 
Transfusions of blood products are not accounted as prior therapies. Any unique prior therapy 
will be counted once, even if it is stopped and restarted or given in different combinations. 
Different corticosteroids will be counted as a single unique prior therapy, whereas different 
members of other drug classes such as thrombopoietin receptor agonists will be counted as 
different unique prior therapies. The total number of unique prior therapies administered to each 
patient will be captured in the eCRF. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
The duration of exposure in weeks to iptacopan will be summarized by means of descriptive 
statistics. Duration of exposure will be categorized by cohort and group as follows: <4 weeks, 
≥4/<9 weeks, ≥9/<12 weeks. 
2.4.2 
Prior, concomitant and post therapies 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed by participant and summarized according to the Anatomical 
Therapeutic Chemical (ATC) classification system, by cohort and group. 
The need and use of rescue therapy will be assessed. The rescue therapy will be summarized by 
cohort, group and listed by cohort, group and visit/time point. 
For cohorts allowing background therapy, this will be listed and summarized by cohort, 
participant, and visit/time. For Part B only, the ability to taper or discontinue any concomitant 
background therapy in responders will be listed and summarized. 
The following decoded terms from field of medical history will be used to determine indication 
of ITP/CAD: 
1. Immune thrombocytopenia 
2. Cold type hemolytic anaemia 
The definition for rescue therapy, prior therapy and background therapy are as follows: 
• Rescue therapy: any therapy with above listed indications started on or after Day 1. 
• Unique prior therapy: any therapy with above listed indications started before 
Screening visit. 
• Background therapy: any therapy with above listed indications started before Day 1 
and ongoing during treatment (from Day 1 and onwards). Also check for PD for the 
subject. 


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For Prior or Concomitant non-drug therapies/procedures, System or Organ Class is considered 
instead of ATC class since the latter is not collected for procedures. Also, for procedures, 
additional derivation logic was added to not consider transfusion data for prior and background 
therapy and to exclude SOC “Investigations” while flagging the therapies. 
The unique prior therapies will be sorted by descending frequency. 
2.5 
Analysis supporting primary objective(s) 
The primary objective of the study is to assess the efficacy of iptacopan in participants with 
benign hematological disorders such as primary ITP and primary CAD with an increase in 
platelet count and in hemoglobin being considered a favorable outcome in ITP and CAD 
participants, respectively. 
2.5.1 
Primary endpoint(s) 
The primary efficacy endpoints of this study are: 
• Cohort 1 (ITP): A clinically meaningful response, defined by a platelet count of ≥50 
k/μL sustained for at least 2 consecutive weeks during the main, 12-week treatment part 
without the use of rescue therapy. 
• Cohort 2 (CAD): A clinically meaningful response, defined by a hemoglobin level 
increase of ≥1.5 g/dL above baseline sustained for at least 2 consecutive weeks during 
the main, 12-week treatment part without the use of rescue therapy. 
A study participant will be considered a responder if he/she meets all of the below criteria: 
Cohort 1 (ITP): 
1. Platelet count of ≥50 k/μL sustained for at least 2 consecutive weeks during the main, 
12- week of treatment part; 
2. Absence of rescue therapy or prohibited medications to treat ITP; 
3. Lack of treatment discontinuation. 
Cohort 2 (CAD): 
1. Hemoglobin level increase of ≥1.5 g/dL above baseline sustained for at least 2 
consecutive weeks during the main, 12-week treatment part; 
2. Absence of rescue therapy or prohibited medications to treat CAD; 
3. Lack of treatment discontinuation. 
For both cohorts, occurrence of any of the events #2-3 prior to meeting event #1 would make 
the study participant a non-responder, whereas occurrence after would not affect his/her 
qualification as a responder with respect to the primary endpoint. 
Descriptive analysis 
For calculation of the success rate for the primary endpoint, all participants enrolled in the study 
in respective cohorts will be included. 


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The number and proportion of responders will be determined and summarized/listed by cohort. 
Cohort 1 (ITP) 
For the purpose of this study, a positive sign of efficacy in primary ITP participants is defined 
as an observed response rate of at least 30% in all-comers, or 50% in the participants with 
activated complement at screening.  
The platelet counts will be summarized by visit and time point for both groups in Cohort 1 
separately and combined. Summary statistics will be presented for raw and change from 
baseline for platelet counts by group, visit and time point and combined for both groups. 
Cohort 2 (CAD) 
For the purpose of this study, a positive sign of efficacy in primary CAD participants is defined 
as an observed response rate of at least 50%. 
The hemoglobin levels will be summarized by visit and time point. Summary statistics will be 
presented for raw and change from baseline hemoglobin levels by visit and time point. 
2.5.2 
Statistical hypothesis, model, and method of analysis  
Not applicable. The statistical evaluation of all primary efficacy data will be descriptive. 
Hypothesis testing will not be performed. 
2.5.3 
Handling of intercurrent events  
The intercurrent events of the primary estimands are part of the primary variable, defined in 
Section 2.5.1. 
2.5.4 
Handling of missing values not related to intercurrent event 
The analysis will include all available data up to the point of treatment discontinuation for 
participants who permanently discontinue. Descriptive statistics will not be adjusted for missing 
values. 
2.6 
Analysis supporting secondary objectives  
The secondary PD objectives of the study are: 
• To assess the time to first response 
• To assess the duration of response during Part A  
• To assess the magnitude of response during Part A 
• Cohort 2 only: To assess the effect of iptacopan on relevant disease biomarkers (BM) 
not covered in the primary objective during Part A 
2.6.1 
Secondary endpoint(s) 
2.6.1.1 
Time to the first response 
Cohort 1: The first time that a participant has a platelet count ≥50 k/μL will be collected. 


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Cohort 2: The first time that a participant has a hemoglobin level ≥1.5 g/dL above baseline will 
be collected. 
Descriptive analysis 
Time to the first response will be summarized from responders only. Summary statistics will be 
provided for the time to first response by cohort and group. In addition, time to response will 
be listed and presented graphically using a swimmer plot for all the participants by cohort and 
group. 
2.6.1.2 
Duration of response during Part A 
Cohort 1: The duration of time during which a participant's platelet count remains ≥50 k/μL 
without the use of rescue therapy will be collected. 
Cohort 2: The duration of time during which a participant's hemoglobin level remains ≥1.5 g/dL 
above baseline without the use of rescue therapy will be collected. 
Descriptive analysis 
Duration of response will be summarized for responders only. The duration of response would 
be considered as cumulative if there are non-continuous periods of response. For each visit up 
to Week 5, the duration of response will be considered 1 week (7 days) and, for each visit from 
Week 7 onwards, it will be considered 2 weeks (14 days). Summary statistics will be provided 
for duration of response by cohort and group. In addition, duration of response will be listed 
and presented graphically using a swimmer plot for all the participants by cohort and group. 
2.6.1.3 
Magnitude of response during Part A 
Cohort 1: The magnitude of increase in platelet counts compared to baseline will be derived for 
each participant at each visit and time point. 
Cohort 2: The magnitude of increase in hemoglobin levels compared to baseline will be derived 
for each participant at each visit and time point. 
Descriptive analysis 
The magnitude of increase from baseline of platelet counts and hemoglobin levels respectively 
will be summarized by cohorts and group. In addition, the magnitude of response will be 
categorized and summarized by cohort and group as below: 
For ITP, absolute platelet counts <50, ≥50/<100, ≥100/<150, and ≥150 k/uL. 
For CAD, Hb increase from baseline by <1, ≥1 and <1.5,  ≥1.5 and <2, and ≥2 g/dL, as well as 
absolute Hb <10, ≥10/<12, ≥12 g/dL, and ≥LLN for each gender. 
2.6.1.4 
Effect of iptacopan on relevant disease biomarkers (BM) not covered 
in the primary objective during Part A 
For Cohort 2-CAD only: Lactate dehydrogenase (LDH), total bilirubin, reticulocyte count and 
haptoglobin. 
Descriptive analysis 


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Please refer to Section 2.9.3. 
2.6.2 
Statistical hypothesis, model, and method of analysis 
Not applicable. The statistical evaluation of all secondary efficacy data will be descriptive. 
Hypothesis testing will not be performed. 
2.6.3 
Handling of intercurrent events  
The intercurrent events of the primary estimands are part of the secondary variables, defined in 
Section 2.6.1. 
2.6.4 
Handling of missing values not related to intercurrent event 
The analysis will include all available data up to the point of treatment discontinuation for 
participants who permanently discontinue. Descriptive statistics will not be adjusted for missing 
values. 
2.7 
Safety analyses 
All participants within the Safety analysis set will be included in the safety data analysis. All 
listings and tables will be presented by cohort (for ITP, both groups (sC5b-9 high and sC5b-9 
low) will be pooled).  
The assessment of safety is based on the type and frequency of Adverse Events (AEs) as well 
as on the number of laboratory values that fall outside of pre-determined ranges (Common 
Toxicity Criteria for Adverse Events (CTCAE version 5.0) grading limits or normal ranges as 
appropriate). Other safety data include electrocardiogram and vital signs. 
2.7.1 
Adverse events (AEs) 
2.7.1.1 
Data handling 
Adverse events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
and assessed according to severity grade: mild/moderate/severe, respectively.  
Note: The latest available MedDRA version at the time of the analyses will be used. The 
MedDRA version used will be specified in the footnote of relevant tables.  
2.7.1.2 
Data analysis 
All information obtained on adverse events will be displayed by cohort, group and participant. 
The number (and percentage) of participants with treatment-emergent adverse events (events 
started after the first dose of study medication but increased in severity based on preferred term) 
will be summarized in the following ways. 
• by primary system organ class (SOC) and preferred term (PT). 
• by primary system organ class, preferred term and maximum severity. 


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SOC will be sorted by descending frequency. PTs within SOC will be sorted by descending 
frequency in Investigational drug column of highest relevance, and within that column by 
subgroup of highest relevance (e.g. subgroup with highest N). 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment. 
A participant with multiple adverse events within a primary SOC is only counted once towards 
the total of the primary SOC and cohort. 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
-emergent adverse events which are not serious adverse events with an incidence greater than 
5% and on treatment-emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population. 
Adverse events 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 drug relationship, or developed into SAEs 
after the start of the treatment period. For the AE/SAE reporting, post-treatment will be 
considered to be any events that started or increased in severity after the end of the on-treatment 
period (i.e. more than 7 days after the last dose of study medication). 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE. 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT. 
2.7.1.2.1 Adverse events of special interest / grouping of AEs 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are of scientific and medical interest specific to Novartis’s product or program, for which 
ongoing monitoring may be appropriate. Such events may require further investigation in order 
to characterize and understand them. AESI for iptacopan are defined on the basis of potential 
safety risks for the product, class effects, and data from preclinical studies. 
The number (and proportion) of participants with AESI, including serious adverse events of 
special interest will be summarized by cohort. The frequency and percentage of participants 


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with treatment emergent adverse events of special interest (TEAESI) and serious TEAESI will 
be summarized by PT. 
A listing of participants experiencing AESIs will also be provided by cohort. The eCRS safety 
topic definitions used to identify AESIs will be provided as a listing. The Compound Case 
Retrieval Strategy (CRS) will be used to determine the MedDRA search criteria to be used to 
identify events of special interest (using the “SP” flag). The most recent list of AESI at the time 
of database lock will be used. 
2.7.2 
Deaths 
A summary for deaths, including on-treatment and post-treatment deaths will be provided in 
case deaths occur during the study. 
2.7.3 
Laboratory data 
2.7.3.1 
Data handling 
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of laboratory 
CTC grades will be based on the observed laboratory values only, clinical assessments will not 
be taken into account. The criteria to assign CTC grades are given in “Novartis internal criteria 
for CTC grading of laboratory parameters”. The latest available version of the document based 
on the underlying CTCAE version 5.0 at the time of analysis will be used.  
For laboratory tests where grades are not defined by CTCAE v5.0, results will be graded by the 
low/normal/high (or other project-specific ranges, if more suitable) classifications based on 
laboratory normal ranges.  
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 is not applicable (deaths will be summarized separately). For laboratory tests that are 
graded for both low and high values, summaries will be done separately and labeled by direction, 
e.g., sodium will be summarized as hyponatremia and hypernatremia. 
2.7.3.2 
Data analysis 
All laboratory data will be listed by cohort, group, participant, and visit/time and if normal 
ranges are available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a participant with any abnormal values. Summary statistics will be provided for 
all laboratory data by cohort, group and visit/time. For all continuous laboratory parameters, 
the absolute on-treatment laboratory values will be summarized with standard descriptive 
statistics (mean, median, standard deviation, minimum, maximum) by parameter, and scheduled 
visit/time point. 
Shift tables using the low/normal/high/ (low and high) classification will be used to compare 
baseline to the worst on-treatment value. Shift tables using CTCAE grading (version 5.0) may 
be provided as appropriate to compare participant’s baseline laboratory evaluation relative to 
the visit’s observed value. These summaries will be presented by laboratory parameter and visit. 


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Shift tables for biochemistry parameters that are not CTCAE graded (e.g. LDL, HDL) will also 
be provided to show patients with a change from normal to abnormal 
Boxplots to visualize trends in laboratory data will be created. 
On analyzing laboratory data from all sources (central and local laboratories (as applicable)) 
will be combined. For all safety analysis based on laboratory data, the information obtained 
from the central as well as local labs will be used. For summaries by visits, local lab data will 
be used when the corresponding central lab data are missing. For summaries on overall post-
baseline data, all available data (including central and local lab data) from scheduled and 
unscheduled visits will be used.  The summaries will include all assessments available for the 
lab parameter collected no later than last day of the on-treatment period.  
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment):  
• Worst post-baseline CTC grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline.  
• Shift tables using CTC grades to compare baseline to the worst on-treatment value  
• For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.  
HIV tests and hepatitis markers are only collected at screening and no shift tables nor box plots 
will be produced. For Urinalysis tests, shift table and box plot will not be produced either. 
Laboratory parameters with a CTCAE grade are listed in Table 2-1. Laboratory parameters with 
no CTCAE grade are listed in Table 2-2. 
Table 2-1 
Laboratory parameters with a CTCAE grade 
Test Category 
Laboratory Parameters 
Hematology 
Hemoglobin, Platelets, Leukocytes, Differential 
(Lymphocytes, Neutrophils), Prothrombin 
International normalized ratio (INR), Activated 
partial thromboplastin time (APTT) 
Chemistry 
Albumin, Alkaline phosphatase (ALP), ALT, 
AST, Gamma-glutamyl-transferase (GGT), 
Calcium, Magnesium, Sodium, Potassium, 
Creatinine, Creatine kinase, Total Bilirubin, Total 
Cholesterol, Triglycerides, Amylase, Glucose, 
Haptogloblin (Cohort 2 CAD only), estimated 
GFR 
Urinalysis 
Protein 


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Table 2-2 
Laboratory parameters with no CTCAE grade 
Test Category 
Laboratory Parameters 
Hematology 
Ery. Mean Corpuscular Volume, Erythrocytes, 
Erythrocyte Cell Morphology (if available at local 
lab and indicated based on flagged blood count 
results), Differential (Basophils, Eosinophils, 
Monocytes, Bands), Reticulocytes (selected 
visits as per assessment schedule) Ery. Mean 
Corpuscular HGB Concentration, Ery. Mean 
Corpuscular Hemoglobin, Hematocrit, 
Prothrombin Time 
Chemistry 
Direct Bilirubin, Indirect Bilirubin, Lactate 
dehydrogenase (LDH), Urea Nitrogen or Urea, 
Uric Acid, Phosphate, Chloride, Ferritin, Lipase, 
Dihydrotestosterone (DHT), Follicle Stimulating 
Hormone, Hepatitis B Virus Surface Antigen 
(HBsAg), Hepatitis C Virus (HCV) antibodies, 
Luteinizing Hormone (LH), Testosterone, 
thyroxine (T4), Triiodothyronine (T3), TSH, 
reverse T3 
The newly occurring liver enzyme abnormalities will be summarized by cohort. The categories 
of abnormalities are described in Table 2-3. For a participant to meet the criterion of a newly 
occurring clinically notable value, the participant needs to have a baseline value which is not 
clinically notable for that parameter. For a participant to meet the criterion of a worsening 
clinically notable value, the participant needs to have a baseline value which is clinically notable 
as well as a worsened post-baseline value. For participants with a missing baseline value, any 
post-baseline notable value will be considered as newly occurring. 
Table 2-3 
Definition of liver toxicities based on laboratory parameters  
Definition                                              
ALT >3x ULN  
ALT >5x ULN  
ALT >10x ULN  
ALT >20x ULN  
 
AST >3x ULN  
AST >5x ULN  
AST >10x ULN  
AST >20x ULN  
 
ALT or AST >3x ULN  
ALT or AST >5x ULN  
ALT or AST >8x ULN     
ALT or AST >10x ULN  
ALT or AST >20x ULN    
  
Total bilirubin (BILI) >2x ULN  
Total bilirubin (BILI) >3x ULN  
  


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ALP >2XULN (>3XULN in the presence of bone pathology*)  
  
Combined elevations post-baseline  
 AST and ALT =< ULN at baseline      
    ALT or AST >3x ULN & BILI >2x ULN  
    ALT or AST >3x ULN & BILI >2x ULN & ALP <2x ULN   
    ALT or AST >3x ULN & BILI >2x ULN & ALP >=2x ULN  
 ALT or AST > ULN at baseline      
    ALT or AST >3x Bsl or 8x ULN & BILI (>2x Bsl and 2x ULN)  
    ALT or AST >3x Bsl or 8x ULN & BILI (>2x Bsl and 2x ULN) & ALP <2x ULN  
    ALT or AST >3x Bsl or 8x ULN & BILI (>2x Bsl and 2x ULN) & ALP >=2x ULN  
* the presence of bone pathology is confirmed by reported AEs or medical history of HLGT = 
“Bone disorders (excl congenital and fractures)” with a start date prior to laboratory 
measurement and stop date posterior to laboratory measurement  
Liver toxicity finding based on laboratory values and accounting for presence of bone pathology, 
symptoms, Gilbert syndrome will be presented. AEs collected in the analysis dataset and related 
to liver toxicities (Jaundice, AE potentially indicative of a liver toxicity) will be presented as 
part of AEs by PT (either in a separate table or as part of the general AE tables). 
In addition, the number of patients meeting the following potential drug-induced liver injury 
(DILI) definitions will also be summarized and listed. If a patient met the criteria for more than 
one category, the patient is only counted once in the most severe case category, with Hy’s law 
case as the most severe category and cholestasis case the least severe category. 
• Hy’s Law defined as post-baseline TB elevation to >=2x ULN along with concurrent 
ALP <2x ULN, occurring on or within 30 days after a post-baseline ALT or 
AST elevation to >=3x ULN. 
• Temple’s corollary defined as ALT and/or AST >=3x ULN but there is no 
accompanying TB elevation or jaundice (defined as with non-missing TB reading <2x 
ULN on the same date as ALT/AST). 
• Cholestasis defined as Jaundice occurs (TB >=2x ULN) with no or minimal 
hepatocellular injury (defined as non-missing ALT and AST less than 3x ULN on the 
same date as TB). 
2.7.4 
Other safety data 
2.7.4.1 
ECG and cardiac imaging data 
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each participant 
during the study. ECG data will be read and interpreted locally. 
Categorical summary statistics for ECG alert values will be provided based on the number and 
proportion of participants meeting or exceeding the following predefined limits:  
• QRS > 120 ms 
• QRS increase from baseline > 25%   
• QTcF > 500 ms 
• QTcF increase from baseline > 60 ms 
• Resting heart rate sinus rhythm (HR) < 30 bpm 


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• HR decrease from baseline ≥ 25%  
• HR > 130 bpm 
In addition, a listing of these participants will be produced by cohort and group. 
All ECG data will be listed by cohort, group, participant, and visit/time; abnormalities will be 
flagged. Summary statistics will be provided by cohort, group and visit. In addition, the number 
and percentage of patients with notable ECG changes from baseline and a listing of ECG 
intervals will be presented by cohort. 
2.7.4.2 
Vital signs 
Vital signs measurements include systolic blood pressure (SBP) and diastolic blood pressure 
(DBP), pulse rate, body temperature, height, and body weight.  All vital signs data will be listed 
by cohort, group, participant, and visit/time and if ranges are available abnormalities (and 
relevant orthostatic changes) will be flagged. Summary statistics (absolute on-treatment values 
and change from baseline) for the on-treatment period will be provided by cohort, group and 
visit/time. Where ranges are available, abnormalities will be summarized and listed by 
participant and visit/time.  Arithmetic mean and SD of absolute values over time for SBP and 
DBP will also be provided.  The change from baseline to worst post-baseline value and shift 
tables based on notable values will be summarized. 
Boxplots to visualize trends in vital signs data will be created. 
 
2.8 
Pharmacokinetic endpoints   
All participants in the PK analysis set (PAS) will be included in the PK data analysis. The PAS 
will be defined separately for each cohort. 
The following plasma pharmacokinetic parameters will be determined using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 8 or 
higher): 
• AUClast, AUCtau, Cmax, Ctrough, Tmax. 
Other pharmacokinetic parameters may be calculated as appropriate. The linear trapezoidal rule 
will be used for AUC calculations. 
AUCtau will be calculated by the "last observation carried forward" approach, assuming that, 
at steady-state, the iptacopan plasma concentration at T=12hr (tau) is the same as the profile’s 
corresponding pre-dose (T=0) value. The approach will be applied because sampling times are 
limited to 6 hours postdose and the extrapolation of AUClast (0-6hrs) to AUCtau (0-12hrs) is 
likely to exceed the accepted value of 20% of the total AUC and be based on an unreliable half-
life estimate. 
Descriptive analyses 
Individual iptacopan plasma concentrations and PK parameters will be listed by cohort, 
participant, and visit/sampling time point. 


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Descriptive summary statistics of iptacopan plasma concentration data (unbound concentrations 
as available) will be provided by cohort and visit/sampling time point, including the number of 
subjects with evaluable values (n) and the number of subjects with quantifiable concentrations 
(≥LLOQ) (m). Summary statistics for concentration-time data will include mean (arithmetic 
and geometric), SD, CV (arithmetic and geometric), median, minimum and maximum. 
Concentrations below LLOQ will be treated as zero in summary statistics and for PK parameter 
calculations. Zero concentrations will be considered as missing for the geometric mean and 
geometric CV% calculations. Graphical methods will be employed to show mean and individual 
concentration-time profiles. 
Descriptive summary statistics for PK parameters will include mean (arithmetic and geometric), 
between-subject SD, and between-subject CV (arithmetic and geometric), median, minimum, 
and maximum. An exception to this is Tmax where only median, minimum, and maximum will 
be presented. Additionally, within-subject SD and CV (arithmetic and geometric) will be 
presented for Ctrough. 


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2.10 
Interim analysis 
The following IAs are planned for each cohort: 
• An interim analysis is planned after approximately half of the participants within a 
cohort complete 12 weeks of treatment. For these participants the efficacy data up to 
week 12 (along with relevant safety and potentially PK data) will be examined as a 
preliminary evaluation of proof of concept (PoC). 
• A second interim analysis is planned after all participants within a cohort complete 12 
weeks of treatment. Relevant data up to Part A EOS will be examined. 
Additional IAs 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. 
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. 


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Interim results may be used to prepare publications, abstracts and/or presentations at scientific 
meetings. 
3 
Sample size calculation 
3.1 
Primary endpoint(s) 
3.1.1 
Cohort 1: ITP (N=20) 
Approximately 20 participants diagnosed with primary ITP and sustained thrombocytopenia 
will be enrolled. Participants will be stratified based on complement activation (sC5b-9 levels) 
at screening in to one of the two groups (complement-activated vs. not complement-activated) 
until approximately 10 participants have been assigned to each group. 
Complement-activated group (N=10): 
With 10 participants, this group has 80% probability to meet the efficacy criterion of 50% or 
more responders if the true response rate is 58%. For lower true response rates, the probability 
of having at least 50% responders is appropriately lower; for example, 62%, 37% and 15% for 
true response rates of 50, 40 and 30%, respectively. 
With 10 participants, 
• the probability of a false-positive readout (i.e., probability of meeting the efficacy 
criterion, when the true response rate with iptacopan treatment is smaller or equal to the 
presumed underlying response rate of 10%) is < 1%. 
• the probability of a false-negative readout (i.e., probability of not meeting the efficacy 
criterion, when the true response rate is at least 58%) is 20%. 
Figure 3-1 
Probability of observed response rate of ≥50 percent vs. true 
response rate 
 


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All-comers (N=20): 
With 20 participants, the combined groups (full cohort) have 80% probability to meet the 
efficacy criterion of 30% or more responders if the true response rate is 37%. For lower true 
response rates, the probability of having at least 30% responders is appropriately lower; for 
example, 58.4% and 20% for true response rates of 30 and 20% respectively. 
With 20 participants, 
• the probability of a false-positive readout (i.e., probability of meeting the efficacy 
criterion, when the true response rate with iptacopan treatment is smaller or equal to the 
presumed underlying response rate of 10%) is 1%. 
• the probability of a false-negative readout (i.e., probability of not meeting the efficacy 
criterion, when the true response rate is at least 37%) is 20%. 
Figure 3-2 
Probability of observed response rate of ≥30 percent vs. true 
response rate 
 
4 
Change to protocol specified analyses 
No changes from protocol specified analysis were made. 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
No imputations will be done for the treatment start and end dates. 


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5.1.2 
AE date imputation 
As per Novartis standard AE date imputation rules, the following matrix explains the logic 
behind the imputation. 
 
MON MISSING MON<TRTM 
MON=TRTM 
MON>TRTM 
YYYY 
MISSING 
(1) 
No convention 
(1) 
No convention 
(1) 
No convention 
(1) 
No convention 
YYYY<TRTY 
(2.a) 
Before 
Treatment Start 
(2.b) 
Before 
Treatment Start 
(2.b) 
Before 
Treatment Start 
(2.b) 
Before 
Treatment Start 
YYYY=TRTY 
(4.a) 
Uncertain 
(4.b) 
Before 
Treatment Start 
(4.c) 
Uncertain 
(4.c) 
After Treatment 
Start 
YYYY>TRTY 
(3.a) 
After Treatment 
Start 
(3.b) 
After Treatment 
Start 
(3.b) 
After Treatment 
Start 
(3.b) 
After Treatment 
Start 
Before imputing AE start date, find the AE start reference date.  
1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment 
start date then AE start reference date = min(informed consent date, earliest visit date). 
2. Else AE start reference date = treatment start date 
Rules for imputing the AE start date: 
1. If the AE start date year value is missing, the date uncertainty is too high to impute a 
rational date.  Therefore, if the AE year value is missing, the imputed AE start date is 
set to NULL. 
2. If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment.  Therefore: 
a. If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY). 
b. Else if AE month is not missing, the imputed AE start date is set to the mid-
month point (15MONYYYY). 
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment.  Therefore: 
a. If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY). 
b. Else if the AE month is not missing, the imputed AE start date is set to the later 
of (month start point (01MONYYYY), AE start reference date + 1 day). 


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4. If the AE start date year value is equal to the treatment start date year value: 
a. And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day. 
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY). 
c. Else if the AE month is equal to the treatment start date month or greater than 
the treatment start date month, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day). 
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date. 
Rules for imputing the AE end date:  
1. If the AE end date month is missing, the imputed end date should be set to the earliest 
of the (treatment follow up period date, 31DECYYYY, date of death). 
2. If the AE end date day is missing, the imputed end date should be set to the earliest of 
the (treatment follow up period date, last day of the month, date of death). 
3. If AE year is missing or AE is ongoing, the end date will not be imputed. 
5.1.3 
Concomitant medication date imputation 
As per Novartis standard Concomitant medication date imputation, the following table explains 
the notation used in the logic matrix. Please note that missing start dates will not be imputed. 
 
Day 
Month 
Year 
Partial CMD Start 
Date 
Not used 
MON 
YYYY 
Treatment Start Date 
Not used 
TRTM 
TRTY 
The following matrix explains the logic behind the imputation. 
 
MON MISSING MON<TRTM 
MON=TRTM 
MON>TRTM 
YYYY 
MISSING 
(1) 
Uncertain 
(1) 
Uncertain 
(1) 
Uncertain 
(1) 
Uncertain 
YYYY<TRTY 
(2.a) 
Before 
Treatment Start 
(2.b) 
Before 
Treatment Start 
(2.b) 
Before 
Treatment Start 
(2.b) 
Before 
Treatment Start 
YYYY=TRTY 
(4.a) 
Uncertain 
(4.b) 
Before 
Treatment Start 
(4.a) 
Uncertain 
(4.c) 
After Treatment 
Start 
YYYY>TRTY 
(3.a) 
(3.b) 
(3.b) 
(3.b) 


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After Treatment 
Start 
After Treatment 
Start 
After Treatment 
Start 
After Treatment 
Start 
Rules for imputing the CM start date: 
1. If the CM start date year value is missing, the imputed CM start date is set to one day 
prior to treatment start date.  
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment.  Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the mid-year 
point (01JulYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY). 
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the year start 
point (01JanYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the 
month start point (01MONYYYY). 
4. If the CM start date year value is equal to the treatment start date year value: 
a. And the CM month is missing or the CM month is equal to the treatment start 
date month, then the imputed CM start date is set to one day prior treatment start 
date. 
b. Else if the CM month is less than the treatment start date month, the imputed 
CM start date is set to the mid-month point (15MONYYYY). 
c. Else if the CM month is greater than the treatment start date month, the imputed 
CM start date is set to the month start point (01MONYYYY). 
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date. 
Rules for imputing the CM end date: 
1. If CM end day is missing and CM month/year are non-missing then impute CM day as 
the minimum of treatment end date and the last day of the month. 
2. If CM end day/month are missing and CM year is non-missing then impute CM day as 
the minimum of treatment end date and the end of the year (31DECYYYY). 
3. If CM day/month/year is missing then use the treatment end date + 1 day as the imputed 
CM end date.  


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4. If imputed CM end date is less than the CM start date, use the CM start date as the 
imputed CM end date. 
The above imputation rules apply to both prior therapies and post therapies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
5.2 
AEs coding/grading 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. The AEs will be graded as Mild, Moderate and Severe for the severity grade. 
5.3 
Laboratory parameters derivations 
The laboratory parameters derivations will be performed by the Central Lab. 
In order to minimize the risk of spontaneous RBC agglutination in vitro, hematology samples 
from CAD patients will be analyzed at local clinical diagnostic laboratories for the following 
parameters: complete blood count, reticulocytes and DAT. All CAD samples will be processed 
per specific instructions as outlined in the lab manual. 
If participants cannot visit the site for protocol-specified safety lab assessments, an alternative 
(local) laboratory may be used for safety sample collection. Where samples are collected and 


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analyzed at a local instead of the central laboratory, Novartis will ensure the results reported 
are equivalent to central laboratory collection and analysis. 
Any quantitative clinical laboratory values given as “<X.X> or <X.X or >X.X” in the database 
will be imputed with the value of the number without the sign for the descriptive statistics and 
the calculation of changes from baseline, e.g., a value of “<2.2” will be imputed as 2.2 for the 
calculations.  
There will be no imputation in the data listings; all values will be displayed as recorded in the 
database. This is not applicable for lab parameter that falls under qualitative category. 
5.4 
Statistical models 
5.4.1 
Analysis supporting primary objective(s)  
Not applicable. 
5.4.2 
Analysis supporting secondary objective(s) 
Not applicable. 
5.5 
Rule of exclusion criteria of analysis sets 
All PDs will be assessed before database lock to determine whether these deviations may 
warrant the exclusion of a participant from the statistical analyses or summary statistics: 
Table 5-1 
Criteria leading to exclusion 
Analysis Set 
Criteria that cause participants to be excluded 
PK 
INCL01: Deviation from inclusion criterion 1 
(Written informed consent must be obtained 
before any assessment is performed) 
PD 
INCL01: Deviation from inclusion criterion 1 
(Written informed consent must be obtained 
before any assessment is performed) 
EXCL102: No ITP-directed background therapy 
permitted, with the exception of either a single 
thrombopoietin receptor agonist (TPO-RA) or 
low-dose corticosteroid (prednisone-equivalent of 
≤10 mg daily), as long as stable dosage for at 
least 4 weeks prior to first iptacopan dose. 
Safety 
INCL01: Deviation from inclusion criterion 1 
(Written informed consent must be obtained 
before any assessment is performed) 
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to 
DBL. 
6 
Reference 
1. Clinical Study Protocol, CLNP023L12201, Protocol Version v03, 26 Apr 2022.