Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
Keywords: Paroxysmal nocturnal hemoglobinuria Hemoglobin Anemia LNP023 Iptacopan
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 40
Healthy volunteers: no

Brief summary:
The purpose of this Phase 3 study was to determine whether iptacopan is efficacious and safe for the treatment of Paroxysmal nocturnal hemoglobinuria (PNH) patients who were naïve to complement inhibitor therapy.

Detailed description:
This study was a multicenter, single-arm, open-label trial which was comprised of 8 weeks screening period, 24-week core treatment period and 24-week extension treatment period.

Eligible PNH patients with hemolysis (LDH \> 1.5 ULN) and anemia (hemoglobin \<10 g/dL), who were naive to complement inhibitor therapy, including anti-C5 antibody treatment, received iptacopan monotherapy at a dose 200 mg orally b.i.d.

Arms:
arm 1: Participants receive LNP023 at a dose of 200 mg orally b.i.d

Interventions: intervention 1: Iptacopan (LNP023)
Intervention descriptions: intervention 1: Taken orally b.i.d. Dosage supplied: 200mg Dosage form: Hard gelatin capsule Route of Administration: oral

Protocol document:
Prot_002.pdf: 


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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...............................................................................................................11
Amendment 3 (28-Mar-2022)............................................................................................13
Amendment 2 (23-Nov-2021) ...........................................................................................14
Amendment 1 (17-Aug-2021) ...........................................................................................15
Protocol summary..............................................................................................................17
1
Introduction........................................................................................................................21
1.1
Background............................................................................................................21
1.2
Purpose...................................................................................................................23
2
Objectives and endpoints...................................................................................................23
2.1
Primary estimand ...................................................................................................25
2.2
Secondary estimands..............................................................................................25
3
Study design.......................................................................................................................27
4
Rationale ............................................................................................................................30
4.1
Rationale for study design......................................................................................30
4.2
Rationale for dose/regimen and duration of treatment...........................................31
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs.......................................................................................................................32
4.4
Purpose and timing of interim analyses/design adaptations ..................................32
4.5
Risks and benefits ..................................................................................................32
4.6
Rationale for Public Health Emergency mitigation procedures.............................35
5
Study Population................................................................................................................35
5.1
Inclusion criteria ....................................................................................................35
5.2
Exclusion criteria ...................................................................................................36
6
Treatment...........................................................................................................................38
6.1
Study treatment ......................................................................................................38
6.1.1
Investigational drug...............................................................................38
6.1.2
Additional study treatments...................................................................39
6.1.3
Treatment arms/group ...........................................................................39
6.1.4
Treatment duration ................................................................................39
6.2
Other treatment(s) ..................................................................................................39
6.2.1
Concomitant therapy .............................................................................39
6.2.2
Prohibited medication............................................................................40


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6.2.3
Rescue medication.................................................................................41
6.3
Participant numbering, treatment assignment, randomization...............................41
6.3.1
Participant numbering ...........................................................................41
6.3.2
Treatment assignment, randomization...................................................42
6.4
Treatment blinding.................................................................................................42
6.5
Dose escalation and dose modification..................................................................42
6.6
Additional treatment guidance...............................................................................42
6.6.1
Treatment compliance ...........................................................................42
6.6.2
Recommended treatment of adverse events ..........................................42
6.7
Preparation and dispensation .................................................................................43
6.7.1
Handling of study treatment..................................................................44
6.7.2
Instruction for prescribing and taking study treatment..........................44
7
Informed consent procedures.............................................................................................45
8
Visit schedule and assessments..........................................................................................46
8.1
Screening................................................................................................................53
8.1.1
Information to be collected on screening failures .................................53
8.1.2
Hemoglobin and LDH assessments and transfusion during 
Screening...............................................................................................53
8.1.3
Absolute reticulocytes count during Screening.....................................54
8.2
Participant demographics/other baseline characteristics........................................54
8.3
Efficacy..................................................................................................................54
8.3.1
Hemoglobin, reticulocytes, LDH and other PNH-related laboratory 
parameters..............................................................................................55
8.3.2
Red blood cell transfusion.....................................................................55
8.3.3
Breakthrough hemolysis........................................................................56
8.3.4
Patient Reported Outcomes (PRO) - FACIT-Fatigue ...........................57
8.3.5
PNH-related signs & symptoms............................................................58
8.3.6
Major Adverse Vascular Events (MAVEs)...........................................58
8.3.7
Appropriateness of efficacy assessments ..............................................59
8.4
Safety .....................................................................................................................59
8.4.1
Laboratory evaluations..........................................................................60
8.4.2
Electrocardiogram (ECG)......................................................................61
8.4.3
Pregnancy and assessments of fertility..................................................62
8.4.4
Coagulation panel/thrombosis...............................................................62
8.4.5
Reproductive and thyroid hormones monitoring...................................62
8.4.6
Urine albumin creatinine ratio (UACR)................................................63
8.4.7
Appropriateness of safety measurements ..............................................63


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8.5
Additional assessments ..........................................................................................63
63
8.5.2
Pharmacokinetics...................................................................................65
8.5.3
DNA sampling.......................................................................................66
8.6
Off-site visits..........................................................................................................67
9
Study discontinuation and completion...............................................................................69
9.1
Discontinuation and completion ............................................................................69
9.1.1
Study treatment discontinuation and study discontinuation..................69
9.1.2
Withdrawal of informed consent...........................................................71
9.1.3
Lost to follow-up...................................................................................71
9.1.4
Early study termination by the sponsor.................................................71
9.2
Study completion and post-study treatment...........................................................72
10 Safety monitoring and reporting........................................................................................72
10.1
Definition of adverse events and reporting requirements......................................72
10.1.1
Adverse events.......................................................................................72
10.1.2
Serious adverse events...........................................................................74
10.1.3
SAE reporting........................................................................................75
10.1.4
Pregnancy reporting...............................................................................76
10.1.5
Reporting of study treatment errors including misuse/abuse ................76
10.2
Additional Safety Monitoring................................................................................77
10.2.1
Liver safety monitoring.........................................................................77
10.2.2
Data Monitoring Committee..................................................................78
10.2.3
Steering Committee...............................................................................78
11 Data Collection and Database management ......................................................................78
11.1
Data collection .......................................................................................................78
11.2
Database management and quality control ............................................................79
11.3
Site monitoring.......................................................................................................79
12 Data analysis and statistical methods.................................................................................80
12.1
Analysis sets...........................................................................................................80
12.2
Participant demographics and other baseline characteristics.................................80
12.3
Treatments..............................................................................................................81
12.4
Analysis of the primary endpoint(s)/estimand(s)...................................................81
12.4.1
Definition of primary endpoint(s)/estimand(s)......................................81
12.4.2
Statistical model, hypothesis, and method of analysis ..........................81
12.4.3
Handling of remaining intercurrent events of primary estimand ..........82
12.4.4
Handling of missing values not related to the intercurrent event..........82


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12.4.5
Sensitivity analyses for primary endpoint/estimand..............................82
12.4.6
Supplementary analysis.........................................................................82
12.4.7
Supportive analyses...............................................................................82
12.5
Analysis of secondary endpoints/estimands ..........................................................83
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s) ....................................83
12.5.2
Safety endpoints ....................................................................................84
12.5.3
Pharmacokinetics...................................................................................85
12.5.4
Patient reported outcomes .....................................................................86
87
12.7
Interim analyses .....................................................................................................87
12.8
Sample size calculation..........................................................................................88
12.8.1
Primary endpoint(s)...............................................................................88
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...............................................................89
13.4
Quality Control and Quality Assurance.................................................................90
14 Protocol adherence.............................................................................................................90
14.1
Protocol amendments.............................................................................................90
15 References..........................................................................................................................92
16 Appendices.........................................................................................................................95
16.1
Appendix 1: Clinically notable laboratory values..................................................95
16.2
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements...........................................................................................................96


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List of tables
Table 2-1
Objectives and related endpoints for the Core treatment period ...........23
Table 2-2
Objectives and related endpoints for the Extension treatment period...25
Table 6-1
Investigational drug...............................................................................38
Table 8-1
Assessment schedule – Core treatment period ......................................48
Table 8-2
Assessment Schedule - Extension treatment period..............................51
Table 8-3
Breakthrough hemolysis definition .......................................................57
Table 8-4
Assessments and specifications.............................................................60
Table 8-5
Laboratory tests .....................................................................................60
Table 8-6
PK blood log..........................................................................................66
Table 8-7
List of the assessments to be performed during off-site research 
nursing visit ...........................................................................................68
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse..........................................................................................77
Table 12-1
Precision of response rate with N = 40..................................................88
Table 16-1
Definitions of Triggers, Actions and Follow-up requirements for 
liver events.............................................................................................96
List of figures
Figure 3-1
Study design ..........................................................................................27




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ePRO
Electronic Patient Reported Outcome
ESA
Erythropoiesis-stimulating agent
eSAE
Electronic Serious Adverse Event
eSource
Electronic Source
EU
European Union
EudraCT
European Union Drug Regulatory Authorities Clinical Trial
FAS
Full Analysis Set
FB
Factor B
FDA
Food and Drug Administration
FIH
First-In-Human
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GLDH
Glutamate dehydrogenase
GPI
Glycophosphatidylinositol
H
Hour
Hb
Hemoglobin
HBV
Hepatitis-B-Virus
HBsAg
HBV surface antigen
HCV
Hepatitis-C-Virus
HIF-PHI
Hypoxia inducible factor prolyl hydroxylase inhibitor
HIV
Human immunodeficiency virus
HR
Heart rate
HRQoL
Health-Related Quality of Life
hsCRP
hs-C-reactive protein
IA
Interim Analyses
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
IN
Investigator Notification
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine device
IUS
Intrauterine system
LDH
lactate dehydrogenase
LH
Luteinizing hormone
LLOQ
Lower limit of quantification


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LOAEL
Lowest Observed Adverse Effect Level
MAVE
Major Adverse Vascular Events
MedDRA
Medical dictionary for regulatory activities 
mg
Milligram(s)
mL
Milliliter(s)
MRI
Magnetic Resonance Imaging
NO
Nitric oxide
NTI
Narrow therapeutic index
NYHA
New York Heart Association
OATP
Organic Anion-transporting Polypeptide
OATP1B1
Organic Anion-transporting Polypeptide 1B1
ORN
Off-site research nursing
PA
Posteroanterior
PD
Pharmacodynamic(s)
P-gp
P-glycoprotein
PIGA
Phosphatidylinositol N-acetylglucosaminyltransferase subunit A
PK
Pharmacokinetic(s)
PNH
Paroxysmal nocturnal hemoglobinuria
pRBC
packed Red blood cell transfusions 
PRO
Patient Reported Outcomes
PT
Prothrombin time
PTA
Post-trial access
QMS 
Quality Management System
QoL
Quality of life
QTcF
QT interval corrected by Fridericia’s formula
RBC
Red blood cell(s)
REP
Rollover extension program
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Steering Committee
sCR
Serum creatinine
SD
Standard deviation
SMQ
Standardized MedDRA Query
SoC
Standard of care
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
T3
Triiodothyronine
T4
Thyroxine
TA
Transfusion avoidance
TBL
Total bilirubin


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TSH
Thyroid stimulating hormone
UK
United Kingdom
ULN
Upper limit of normal
WBC
White blood cell(s)
WHO
World Health Organization 
WoC
Withdrawal of Consent


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Glossary of terms
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 
Cohort
A specific group of participants fulfilling certain criteria and generally treated at 
the same time
Dosage
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive 
voice response systems and clinical laboratory interfaces. EDC includes the use 
of Electronic Case Report Forms (eCRFs) which are used to capture data 
transcribed from paper source forms used at the point of care
End of the clinical 
trial
The end of the clinical trial is defined as the last visit of the last participant or at 
a later point in time as defined by the protocol 
Enrollment
Point/time of participant entry into the study at which informed consent must be 
obtained 
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, allowing 
for the real time collection of clinical trial information to sponsors and other 
oversight authorities, as appropriate
Estimand 
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment conditions 
being compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level summary 
for the variable.
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
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.


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Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis
Personal data
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples.
Premature 
participant 
withdrawal
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned
Screen Failure
A participant who did not meet one or more criteria that were required for 
participation in the study
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent 
by the first participant
Study treatment
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy
Study treatment 
discontinuation
When the participant permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or may 
not also be the point/time of study discontinuation 
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts.
Treatment of 
interest
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations 
of interventions administered concurrently, e.g. as add-on to standard of care, 
or might consist of an overall regimen involving a complex sequence of 
interventions. This is the treatment of interest used in describing the related 
clinical question of interest, which might or might not be the same as the study 
treatment.
Variable (or 
endpoint)
The variable (or endpoint) to be obtained for each participant that is required to 
address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event.
Withdrawal of 
study consent 
(WoC)
Withdrawal of consent from the study occurs only when a participant does not 
want to participate in the study any longer and does not allow any further 
collection of personal data


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Amendment 3 (28-Mar-2022)
Amendment rationale 
This amendment is being implemented to address the request from the Chinese Health Authority 
(CDE (Center for Drug Evaluation)) to collect additional historical data in Chinese trial 
participants. The retrospective data collection of laboratory values for hemoglobin, LDH and 
absolute reticulocyte count (ARC) over 6 months before screening for participants from China 
is intended to support the regulatory filing in China.
Major revisions are made to:
Section 8.2: Added that “For participants in China, historical data on hemoglobin, LDH and 
absolute reticulocyte count (ARC) laboratory values will be retrospectively collected for the 6 
months preceding Screening.” 
The rest of changes in the current amendment have been implemented to correct errors in the 
Table 8-2 footnote and Section 10.1.2. 
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, if applicable.
The changes described in this amended protocol require IRB/IEC and Health Authority 
approval according to local regulations.  
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, if applicable. 








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Protocol summary
Protocol number
CLNP023C12301
Full Title
A multicenter, single-arm, open-label trial to evaluate efficacy and safety of 
oral, twice daily iptacopan in adult PNH patients who are naive to complement 
inhibitor therapy
Brief title
Study of efficacy and safety of twice daily oral iptacopan in adult PNH patients 
who are naive to complement inhibitor therapy
Sponsor and 
Clinical Phase
Novartis 
Phase III
Investigation type
Drug
Study type
Interventional
Purpose 
and 
rationale
The purpose of this single arm, open label study is to determine whether 
iptacopan is efficacious and safe for the treatment of PNH patients who are 
naïve to complement inhibitor therapy, including anti-C5 antibody
Primary 
Objective(s)
The primary objective is to assess the effect of iptacopan on proportion of 
participants treated with iptacopan achieving a sustained increase from 
baseline in hemoglobin levels of ≥ 2 g/dL in the absence of red blood cell 
transfusion.
The primary clinical questions of interest are: What is the effect of iptacopan, 
regardless of discontinuations of study drug or occurrence of breakthrough 
hemolysis (BTH) or Major Adverse Vascular Events (MAVEs) on the primary 
endpoint (a composite of improvement in hemoglobin levels and absence of 
RBC transfusions), as assessed by the proportion of responders? The 
endpoints are defined as a composite of an increase in Hb levels from baseline 
≥ 2 g/dL assessed between Day 126 and Day 168, and the absence of red 
blood cell (RBC) transfusions between Day 14 and Day 168.
Secondary 
Objectives
The secondary objectives are:
To assess the effect of iptacopan on the proportion of participants achieving 
sustained hemoglobin levels ≥ 12 g/dL in the absence of red blood cell 
transfusions.
To assess the effect of iptacopan on transfusion avoidance (TA) defined as the 
proportion of participants who remain free from transfusions.
To assess the effect of iptacopan on average change in hemoglobin.
To assess the effect of iptacopan on average percent change in LDH.
To assess the effect of iptacopan on the rate of breakthrough hemolysis (BTH).
To assess the effect of iptacopan on average change in reticulocyte counts.
To assess the effect of iptacopan on improving fatigue, using the FACIT-
Fatigue questionnaire.
To assess the rates of Major Adverse Vascular Events (MAVEs incl. 
Thrombosis).
To assess safety and tolerability of iptacopan.
Study design
This study is a multicenter, single-arm, open-label trial, which is comprised of 
an up to 8-week screening period, a 24-week, open-label Core treatment 
period, and a 24-week Extension treatment period.
Study population
This study will enroll PNH patients with hemolysis (LDH > 1.5 upper limit of 
normal (ULN)) and anemia (hemoglobin <10 g/dL), who are naive to 
complement inhibitor therapy, including anti-C5 antibody treatment with 


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approximately 40% of all participants having received at least one RBC 
transfusion within 6 months prior to starting study treatment. 
A total of approximately 40 participants will be starting study treatment. 
Key Inclusion 
criteria

Male and female participants ≥ 18 years of age with a diagnosis of PNH 
confirmed by high-sensitivity flow cytometry with RBCs and white blood 
cells (WBCs) (granulocyte/monocyte) clone size ≥ 10%.

Mean hemoglobin level <10 g/dL confirmed by central laboratory 
assessment during Screening and prior to starting study treatment:

By two hemoglobin measurements (mean < 10 g/dL), two to eight weeks 
apart, for patients not receiving a RBC transfusion during Screening.

By one hemoglobin measurement (<10 g/dL) carried at the first Screening 
visit for patients receiving a RBC transfusion after which he/she will be 
eligible. 

LDH > 1.5 x Upper Limit of Normal (ULN) for at least two central laboratory 
measurements two to eight weeks apart during the screening period.

Vaccination against Neisseria meningitidis infection is required, and is 
recommended at least 2 weeks prior to initiation of iptacopan treatment. 
However, administration of these vaccines less than 2 weeks prior to start 
of iptacopan treatment or up to 2 weeks (up to Day 14) after iptacopan 
initiation, is at the discretion of the investigator. If iptacopan treatment is 
started less than 2 weeks post-vaccination or before a specific vaccination 
is given, participant must be given prophylactic antibiotic at the start of 
iptacopan and for at least 2 weeks after vaccination.

If not received previously, vaccination against Streptococcus pneumoniae 
and Haemophilus influenzae should be given (if available and according to 
local/national regulations), and are recommended at least 2 weeks prior to 
initiation of iptacopan treatment. However, administration of these 
vaccines less than 2 weeks prior to start of iptacopan treatment or up to 2 
weeks (up to Day 14) after iptacopan initiation, is at the discretion of the 
investigator. If iptacopan treatment is started less than 2 weeks post-
vaccination or before a specific vaccination is given, participant must be 
given prophylactic antibiotic at the start of iptacopan and for at least 2 
weeks after vaccination.
Key Exclusion 
criteria

Prior treatment with a complement inhibitor, including anti-C5 antibody.

Known or suspected hereditary complement deficiency at screening.

History of hematopoietic stem cell transplantation.

Patients with laboratory evidence of bone marrow failure (reticulocytes 
<100x109/L; platelets <30x109/L; neutrophils <0.5x109/L).

Active systemic bacterial, viral (incl. COVID-19) or fungal infection within 
14 days prior to study drug administration.

A history of recurrent invasive infections caused by encapsulated 
organisms, e.g. meningococcus or pneumococcus. 

Major concurrent comorbidities including but not limited to severe kidney 
disease (e.g., eGFR<30 mL/min/1.73m2, dialysis), advanced cardiac 
disease (e.g., New York Heart Association (NYHA) class IV), severe 
pulmonary disease (e.g., severe pulmonary hypertension (World Health 
Organization (WHO) class IV)), or hepatic disease (e.g., active hepatitis) 


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that in the opinion of the investigator precludes participant's participation 
in the study.
Study treatment
Iptacopan
Treatment of 
interest
The investigational treatment iptacopan at a dose of 200 mg b.i.d regardless 
of whether the patient discontinues treatment (treatment policy).
Efficacy 
assessments

Hemoglobin, reticulocytes, LDH and other PNH-related laboratory 
parameters

Red blood cell transfusions

Breakthrough hemolysis

Patient Reported Outcomes (PRO) – FACIT-Fatigue

Major Adverse Vascular Events (MAVEs) incl. thrombosis
Key safety 
assessments

Laboratory evaluations in blood and urine

Adverse event monitoring

ECG

Coagulation panel/thrombosis

Reproductive and thyroid hormones monitoring
Other 
assessments 
Pharmacokinetic samples will be obtained and evaluated in all participants 
taking iptacopan.  
Data analysis
All efficacy analyses will use the full analysis set (FAS) that includes all patients 
to whom study treatment has been assigned.
Primary efficacy estimand represented by the endpoint: proportions of 
participants achieving a sustained increase in hemoglobin levels from baseline 
≥ 2 g/dL between Day 126 and Day 168 in the absence of transfusion between 
Day 14 and Day 168.
Effect of iptacopan will be determined using the probability of being a 
responder, standardized to the population of patients assigned to iptacopan in 
this study. The primary analysis of the primary endpoint will be a logistic 
regression model with covariates including sex, age (categorical), an indicator 
variable of baseline hemoglobin above 8 g/dL and an indicator of transfusion 
dependence at enrollment. The proportion of responders will be derived from 
the estimated marginal probabilities derived from the model fit as the mean of 
the individual logistic model predications, together with the 95% confidence 
intervals, where the standard error will be derived by the bootstrap method.
Lower bound of the two-sided 95% confidence interval ≥ 15%  is sufficient for 
demonstration that iptacopan improves hematological response in PNH 
patients with hemolysis and anemia in the absence of transfusions.
Secondary efficacy estimands represented by the following endpoints:

Response defined as having hemoglobin levels ≥ 12 g/dL between 
Day 126 and Day 168 in the absence of red blood cell transfusion 
between Day 14 and Day 168

Absence of administration of packed-red blood cell transfusions 
(pRBC) between Day 14 and Day 168


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
Change from baseline in hemoglobin (g/dL) as mean of visits 
between Day 126 and Day 168

Percent change from baseline in LDH levels (U/L) as mean of visits 
between Day 126 and Day 168

Occurrences of breakthrough hemolysis reported between Day 1 
and Day 168

Change from baseline in reticulocyte counts (109/L) as mean of 
visits between Day 126 and Day 168

Change from baseline FACIT-Fatigue scores as mean of visits 
between Day 126 and Day 168

Occurrences of MAVEs occurring between Day 1 and Day 168
Proportions of participants achieving sustained hemoglobin levels and 
remaining free from transfusions will be evaluated by means of standardized 
marginal proportions derived similarly to the estimation applied to the primary 
estimand. All continuous endpoints will be derived from a longitudinal repeated 
measures model. The estimations of rates of MAVEs and BTH will be carried 
out using negative binomial model. 
Key words
LNP023, Iptacopan, PNH, LDH, hemoglobin, anemia


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1
Introduction
1.1
Background
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hemolytic disorder 
characterized by complement-mediated intravascular hemolysis, bone marrow failure (BMF) 
and severe thrombophilia (Risitano 2012). It begins with the clonal expansion of a 
hematopoietic stem cell that has acquired a somatic mutation in the phosphatidylinositol N-
acetylglucosaminyltransferase subunit A (PIGA) gene.  Consequently, PNH blood cells lack 
the glycophosphatidylinositol (GPI) anchor protein and are deficient in the membrane-bound 
complement inhibitory proteins CD55 and CD59. As a result, PNH type red blood cells (RBCs) 
are attacked by complement leading to complement-mediated lysis (Brodsky 2014).  
The clinical spectrum of PNH varies and signs and symptoms include: anemia, thrombosis, 
smooth muscle dystonia, fatigue, hemoglobinuria, chronic kidney disease and pulmonary 
hypertension. The clinical presentation is driven by uncontrolled complement activation on 
CD55 and CD59 deficient PNH type RBCs culminating with hemolysis and the release of free 
hemoglobin and platelet activation (Hill et al 2013). Hemolysis results in release of intracellular 
hemoglobin and lactate dehydrogenase (LDH) into the circulation. Irreversible binding to and 
inactivation of nitric oxide (NO) by hemoglobin and inhibition of NO synthesis with consequent 
vasoconstriction and tissues ischemia, result in abdominal pain, dysphagia, erectile dysfunction, 
platelet activation and a prothrombotic status (Hill et al 2013, Brodsky 2014). 
Thromboembolism is the leading cause of mortality in patients with PNH, accounting for 
between 40% and 67% of deaths with known causes (Hill et al 2013), impacting morbidity and 
life expectancy of PNH patients.
Eculizumab and ravulizumab (engineered from eculizumab with prolonged dosing interval) are 
approved anti-C5 antibody therapies for the treatment of PNH and have become the current 
standard of care (SoC) in European Union (EU), US and Japan, improving survival and quality 
of life (QoL). However, eculizumab and ravulizumab are not available to PNH patients in all 
countries and even where available, many patients do not have access, and the i.v. route of 
administration presents a burden to many patients.
Furthermore, in countries where eculizumab or ravulizumab is available, there remains a high 
unmet medical need for PNH. Heterogeneous hematological response has been reported with 
eculizumab and a substantial proportion of patients do not achieve normal or near normal 
hemoglobin levels (Risitano et al 2009, Hill et al 2010, DeZern et al 2013, McKinley et al 2017). 
The heterogeneous response to eculizumab or other anti-C5 therapies can, in part, be explained 
through its mechanism of action inhibiting only the terminal part of the complement cascade. 
Therefore, deposition of C3 fragments on the cell surface of PNH type erythrocytes lacking 
CD55 is not impacted, rendering the cells susceptible to extravascular hemolysis. This response 
is inconspicuous in untreated PNH patients, because signs and symptoms of intravascular 
hemolysis dominate. However, extravascular hemolysis eventually emerges once the 
therapeutic inhibition with anti-C5 agents prevents intravascular hemolysis. In fact, it can 
become the main mechanism of hemolysis in patients treated with eculizumab (Risitano et al 
2009) and C3-mediated extravascular hemolysis represents an unmet medical need. Residual 
chronic anemia greatly impacts the patients’ QoL that currently can only be treated with red 
blood cell transfusions (McKinley et al 2017) with possible complications such as iron overload.


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In countries where anti-C5 antibody therapy is not available, therapy focuses on managing the 
clinical manifestations of PNH but do not target the underlying pathophysiology and have little 
impact on long-term outcomes in PNH patients (Risitano and Rotoli 2008). Hemolysis and 
anemia in PNH are treated with corticosteroids, androgens (for both chronic and acute 
hemolysis) and transfusions. Patients are usually given iron supplements, folate and vitamin 
B12 as supportive therapy for the increased erythropoiesis (Parker et al 2005). When PNH is 
associated with other bone marrow diseases such as aplastic anemia, immunosuppressive 
therapy has also been used (Risitano and Rotoli 2008). As thromboembolism is leading cause 
of death in PNH, anticoagulant therapy is used as a prophylaxis as well as in acute setting. 
Hematopoietic stem cell transplantation remains the only curative option, however its use is 
limited to specific cases due to the increased morbidity and mortality (De Latour et al 2012). 
With such supportive therapies, the median survival rate was approximately 10 years. Therefore, 
there is a high-unmet medical need for effective and targeted therapies addressing the 
underlying pathophysiology in PNH patients where anti-C5 is not available (Hillmen et al 1995, 
Socie et al 1996, De Latour et al 2008).


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1.2
Purpose
The purpose of this single arm, open label study is to determine whether iptacopan is efficacious 
and safe for the treatment of PNH patients who are naive to complement inhibitor therapy, 
including anti-C5 antibody. The study will evaluate the effects of 200 mg iptacopan given twice 
daily (b.i.d) on a range of efficacy assessments relevant to PNH including hematological 
response endpoints, transfusion avoidance and breakthrough hemolysis (BTH) as well as patient 
reported outcome (PRO) for fatigue (FACIT-fatigue). 
The 24-week Core treatment period (up to Day 168) of this study will be used to assess the key 
efficacy and safety analysis. The 24-week extension treatment period (up to Day 336) will 
provide long-term safety and efficacy data on iptacopan in PNH patients.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints for the Core treatment period
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoint(s) for primary objective(s)

To assess the effect of iptacopan on 
proportion 
of 
participants 
treated 
with 
iptacopan achieving a sustained increase 
from baseline in hemoglobin levels of ≥ 2 g/dL 
in the absence of red blood cell transfusion

Response defined as having an increase from 
baseline in Hb ≥ 2 g/dL assessed between 
Day 126 and Day 168, in the absence of 
packed red blood cell (pRBC) transfusions 
between Day 14 and Day 168 
Secondary Objective(s)
Endpoint(s) for secondary objective(s)

To assess the effect of iptacopan on the 
proportion of participants achieving sustained 
hemoglobin levels ≥ 12 g/dL in the absence 
of red blood cell transfusions

 Response defined as having Hb levels ≥ 12 
g/dL between Day 126 and Day 168 in 
absence of red blood cell transfusion 
between Day 14 and Day 168

To assess the effect of iptacopan on 
transfusion avoidance (TA) defined as the 
proportion of participants who remain free 
from transfusions

Absence of administration of packed-red 
blood cell transfusions between Day 14 and 
Day 168


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Objective(s)
Endpoint(s)

To assess the effect of iptacopan on average 
change in hemoglobin  

 Change from baseline in hemoglobin (g/dL) 
as mean of visits between Day 126 and Day 
168

To assess the effect of iptacopan on average 
percent change in LDH  

Percent change from baseline in LDH levels 
(U/L) as mean of visits between Day 126 and 
Day 168

To assess the effect of iptacopan on the rate 
of breakthrough hemolysis (BTH) 

Occurrences 
of 
breakthrough 
hemolysis 
reported between Day 1 and Day 168 

To assess the effect of iptacopan on average 
change in reticulocyte counts

Change from baseline in reticulocyte counts 
(109/L) as mean of visits between Day 126 
and Day 168

To assess the effect of iptacopan on 
improving fatigue, using the FACIT-Fatigue 
questionnaire

Change from baseline in FACIT-Fatigue 
scores as mean of visits between Day 126 
and Day 168

To assess the rates of Major Adverse 
Vascular Events (MAVEs incl. thrombosis)

Occurrences of MAVEs occurring between 
Day 1 and Day 168

To assess safety and tolerability of iptacopan

Safety 
assessments 
(including 
adverse 
events/serious 
adverse 
events, 
safety 
laboratory parameters, vital signs etc.) 
between Day 1 and Day 168


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Table 2-2
Objectives and related endpoints for the Extension treatment period
Objective(s)
Endpoint(s)

To assess long term safety, tolerability and 
efficacy of iptacopan 

Safety 
assessments 
including 
adverse 
events/serious 
adverse 
events, 
safety 
laboratory 
parameters, 
vital 
signs 
etc. 
through End of Study visit 

Efficacy endpoints including hematological 
response parameters, transfusion avoidance, 
BTH, FACIT-fatigue score, MAVEs through 
End of Study visit 
2.1
Primary estimand
The primary clinical question of interest is:
What is the effect of iptacopan, regardless of discontinuations of study drug or occurrence of 
BTH or MAVEs, on the primary endpoint (a composite of improvement in hemoglobin levels 
and absence of RBC transfusions), as assessed by the proportion of responders?
This primary estimand captures both the hematological effect of the study drug (as evaluated 
by a clinically relevant increase of ≥ 2 g/dL in hemoglobin levels) and the absence of RBC 
transfusions which are regarded as treatment failure. Further details can be found in Section 12.
The attributes of the primary estimand are:

Population: PNH Patients ≥ 18 years old with hemolysis (LDH > 1.5 ULN) and anemia 
(hemoglobin <10 g/dL), and who have not received any complement inhibitor therapy 
(including anti-C5 antibody). Further details about the population are provided in Section 
5.

Treatment of interest: the investigational treatment iptacopan at a dose of 200 mg b.i.d 
regardless of whether the patient discontinues treatment (treatment policy). Further details 
about the investigational treatment are provided in Section 6. 

Intercurrent events: Transfusions (after Day 14) will be considered treatment failures and 
as such captured in the endpoint. Discontinuations of study medication for any reason, BTH 
events, and MAVEs will be handled with a treatment policy strategy. 

The summary measure: the probability of being a responder, standardized to the population 
of patients assigned to iptacopan in this study.
2.2
Secondary estimands
The population associated with the secondary estimands is the same as for the primary 
estimands. For these secondary estimands we consider the same intercurrent events as for the 
primary estimands. The proposed approach in the case of transfusion handling will be described 
in the endpoint definition, while discontinuations of study medication, breakthrough hemolysis 


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events, and MAVEs whose impact is expected to be reflected in the respective endpoints, will 
be handled with a treatment policy strategy.
The secondary estimands are defined by the evaluation of treatment effect on the following 
endpoints and summary measures:

Response defined as having Hb levels ≥ 12 g/dL between Day 126 and Day 168 in 
absence of red blood cell transfusion between Day 14 and Day 168. The summary 
measure is the same as for the primary endpoint. 

Absence of administration of packed red blood cell transfusions (pRBC) between Day 
14 and Day 168. Proportions of participants not receiving any transfusions between Day 
14 and Day 168 (Transfusion Avoidance). The summary measure is the same as for the 
primary endpoint.

Changes from baseline in hemoglobin between Day 126 and Day 168 where 
transfusions occurring between Day 14 and Day 168 are treated within a hypothetical 
strategy (as if the participants had not received any transfusions). The summary measure 
is the mean change from baseline in hemoglobin levels assessed between Day 126 and 
Day 168.

Percent change from baseline in LDH between Day 126 and Day 168 where the strategy 
applied to transfusions is treatment policy. The summary measure is derived from the 
mean log transformed ratio to baseline in LDH between Day 126 and Day 168.

Rates of BTH occurring between Day 1 and Day 168. The summary measure is 
occurrences per year.

Change from baseline in reticulocytes counts between Day 126 and Day 168 where the 
strategy applied to transfusions is treatment policy. The summary measure is the mean 
change from baseline in reticulocytes counts assessed between Day 126 and Day 168. 

Change from baseline in scores of fatigue using the FACIT Fatigue questionnaire 
between Day 126 and Day 168, where the strategy applied to transfusions is treatment 
policy. The summary measure is the mean change from baseline in scores of fatigue 
assessed between Day 126 and Day 168.

Rates of Major Adverse Vascular Events (MAVE) occurring between Day 1 and Day 
168. The summary measure is occurrences per year.
Estimand considerations in case of COVID-19 pandemic impact
The overarching principle for primary and secondary estimands, is answering questions of 
treatment effect of iptacopan that are valid in conditions when the COVID-19 pandemic is no 
longer present. Data capture and clinical evaluation activities include possible adaptations to 
restrictions for patient access to investigational sites in case of a new infection wave. The 
planned analyses in Section 12 could be supplemented by supportive analyses as well as 
sensitivity analyses if required by the presence of deviations from the normal methods of patient 
follow up and data capture.




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Participants will be asked to review and sign the ICF prior to starting the screening assessments. 
After signing the ICF, inclusion and exclusion criteria will be assessed to verify participants' 
eligibility for starting study treatment in the study. This will be followed by the visit's 
assessments as outlined in Table 8-1, as applicable.
By signing the ICF, the participants will provide access to the medical records including 
numbers of transfusions, unit numbers of packed-RBC received in the last 12 months prior to 
Screening and history of Major Adverse Vascular Events (MAVEs).
Participants should be vaccinated as outlined in Section 5.1 Inclusion criteria. 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 according to local/national vaccination 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/national vaccination guidelines, and locally available vaccines (refer to 
the package insert of those). 
The screening period may be extended in case of multiple vaccination needs. This is applicable 
for vaccinations only, while all the other screening assessments must be performed as indicated 
in the Assessment Schedule Table 8-1. 
It is recommended to administer vaccines at least 2 weeks prior to initiation of iptacopan. 
However, administration of these vaccines less than 2 weeks prior to start of iptacopan or up to 
2 weeks (up to Day 14) after iptacopan initiation, is at the discretion of the investigator. If 
iptacopan treatment is started less than 2 weeks post-vaccination or before a specific vaccination 
is given, participant must be given prophylactic antibiotic at the start of iptacopan and for at 
least 2 weeks after vaccination.
To fulfill the hemoglobin and LDH eligibility criteria, participant will have two different 
samples collected during the screening period and tested by the central laboratory prior to 
starting study treatment. In case the participant has received a RBC transfusion following the 
initial Screening visit, the participant is eligible based on the initial central hemoglobin if 
< 10g/dL.
The absolute reticulocytes count will be measured at Screening to determine eligibility with 
regards to exclusion criterion # 6.  Due to the kinetics of maturation of reticulocytes into mature 
red blood cells and turnaround time from reticulocytes sample collection and analysis by central 
laboratory, local reticulocytes testing can be performed at the same time as the central testing 
during the Screening period. In the event that the absolute reticulocytes count as assessed by 
the central laboratory during the Screening period is below the protocol defined threshold 
(absolute reticulocytes <100x109/L) and only in this scenario, the results from the local lab 
testing can be used to determine participant’s eligibility. The results of the local laboratory 
values (including reference ranges) should be included in the eCRF to document eligibility. 
If eligibility criteria are not met due to any assessment, the participant should be considered as 
having failed the screening and does not proceed to the Core treatment period. However, the 
participant can be rescreened as described in Section 8.1.


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Core treatment period
Participants who meet the eligibility criteria will proceed to the Core treatment period. 
Treatment with iptacopan at a dose of 200 mg b.i.d. will start on the first day (Day 1) and 
continue for 24 weeks with study visits and corresponding assessments according to the 
schedule described in Table 8-1.
Please refer to Section 8.3.2 which provides details about the protocol-specific guidelines for 
participants who need to receive a packed-RBC transfusion during the Core treatment period.
Because of the known increased risk of complement inhibitor treatment of infections with 
encapsulated bacteria, most importantly Neisseria meningitidis, all participants will be provided 
with a Participant Safety Card. Participants will be instructed to be vigilant for any clinical sign 
of bacterial infections and to contact the investigator or local physician immediately in case of 
suspicion of infection and start antibiotic treatment as soon as possible. 
For participants who permanently discontinue iptacopan administration, close monitoring and 
treatment proposals are indicated Section 9.1.1. Participants, if possible, should complete all 
visits and assessments up to Week 24 visit. 
The Core treatment period will end with the completion of the Week 24 visit assessments. Upon 
completion of the Week 24 visit, participants may enter the Extension treatment period, as 
described below.
Extension treatment period 
Participants who benefit from treatment and are taking iptacopan at Week 24 visit (i.e. did not 
permanently discontinue study medication), will be offered to continue iptacopan treatment 
during the extension treatment period of 24 weeks with study visits and assessments according 
to schedule detailed in Table 8-2. For participants not agreeing to continue iptacopan treatment 
in the Extension treatment period after completing Day 168 visit, End of Study will be after 
completing recommended procedures defined in Section 9.1.1. 
For participants permanently discontinuing iptacopan treatment during the Extension treatment 
period, Section 9.1.1 provides guidance for recommended procedures.
The Extension treatment period will last 24 weeks. After completion of the Extension treatment 
period, participants will be able to join the Roll-over extension program (REP), which will 
provide access to iptacopan and enable long-term safety monitoring. Post-trial access (PTA) 
will be provided until one of the following is met: participant no longer derives clinical benefit, 
investigator discontinues treatment, launch or reimbursement (where applicable), treatment 
fails to achieve registration in the trial participant’s country, or the clinical program is 
discontinued for any other reason. 
For participants not agreeing to continue in the Roll-over extension program (REP) after 
completing Day 336 visit, End of Study will be after completing recommended procedures 
defined in Section 9.1.1.


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4
Rationale
4.1
Rationale for study design
CLNP023C12301 is a multicenter, single arm, open-label study designed to evaluate the 
efficacy and safety of iptacopan at a dose of 200 mg b.i.d. orally in adult PNH patients who are 
naive to any complement therapy, including anti-C5 antibody. A single arm design is chosen 
for this study for the following reasons: 

The study is the pivotal study to support the registration of iptacopan as treatment of PNH 
in countries where anti-C5 treatment (current SoC for PNH in countries where approved) is 
not available. As such, an active-comparator controlled design is not possible. The study 
will also provide supportive data for the global registration of iptacopan which will be based 
on a randomized controlled pivotal phase 3 trial comparing iptacopan vs anti-C5 treatment.

A placebo-controlled design is deemed unethical with the compelling evidence of benefit 
of iptacopan in patients with PNH based on the IAs of the two Phase 2 PNH studies 
(LNP023X2201, LNP023X2204). Furthermore, a placebo arm is not considered appropriate 
with severe, life threatening diseases such as PNH. 
The single arm, open-label design is widely used in rare diseases due to challenges associated 
with conducting studies in these patient populations (Bell and Smith 2014). Several measures 
have been included in the study design to minimize biases associated with this single arm open- 
label design, including

Primary and majority of secondary, efficacy endpoints are objectively measured via 
laboratory assessments (i.e. hematological response parameters, hemoglobin, LDH, 
reticulocytes, transfusion avoidance and BTH). 

Protocol-specific guidelines (see Section 8.3.2) are defined to reduce potential bias due to 
events (such as transfusions) that may affect the main endpoints. 
A hematological responder endpoint will be used for the primary efficacy analysis of the Core 
treatment period. A responder is defined as a participant achieving a hemoglobin increase from 
baseline ≥ 2 g/dL (assessed during the last 6 weeks of the 24 weeks Core treatment period) 
without the need of RBC transfusions from Day 14 to Day 168. This endpoint comprises 1) an 
improvement in hemoglobin of at least 2 g/dL from baseline and 2) transfusion independence 
for treatment success, both clinically important treatment goals in PNH. In the absence of a 
transfusion, an increase of 2 g/dL in hemoglobin has been chosen since it is approximates an 
increase that can be achieved with the administration of a RBC transfusion (1-2 units), thereby 
clinically relevant. 
A treatment duration of 24 weeks is considered appropriate to assess the effect of iptacopan on 
the primary and secondary efficacy endpoints as well as on safety and tolerability. The 24-week 
treatment duration has been previously used in studies with PNH patients, including the recent 
Phase 3 studies with eculizumab and ravulizumab (Lee et al 2019, Kulasekararaj et al 2019). 
An interval of six weeks at the end of the Core treatment period with four assessments, and 3 
out of 4 meeting the criterion, has been selected to demonstrate a durable and sustained 
hematological response. Moreover, the treatment duration of 24 weeks is implemented in the 
randomized iptacopan study in PNH patients (CLNP023C12302); thus ensuring alignment 
within the program.




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
Control of both, intra- (LDH reduction) and extravascular hemolysis 
 
 with normalization of hemoglobin in 
the majority of patients in the absence of RBC transfusions. 

The hematological response achieved was maintained with iptacopan monotherapy during 
the extension period when in 5/10 participants (at the time of the IA) eculizumab treatment 
was discontinued and participants continued with iptacopan monotherapy. Following the IA, 
additional participants discontinued eculizumab treatment. 

C3 deposition fully reversed and survival of PNH RBC prolonged, providing additional 
evidence of the control of extravascular hemolysis by iptacopan. There was sustained 
inhibition of the complement alternative pathway and profound and sustained reduction of 
Fragment Bb demonstrating target engagement. 

Based on cohort 2 data following the IA, iptacopan dose of 50 mg b.i.d. may not provide 
optimal efficacy required for iptacopan monotherapy in PNH. There was suboptimal 
response in most participants requiring up-titration to the iptacopan dose of 200 mg b.i.d 
(add-on treatment to eculizumab). 
The exposure-response model developed with data from the First-In-Human (FIH) study with 
iptacopan in healthy volunteers predicts that a dose of about 200 mg b.i.d. would be needed to 
achieve >90% inhibition of the AP (Wieslab assay) in >70% of subjects. Given the risk of 
hemolysis and breakthroughs in cases of insufficient inhibition of complement activity, full 
inhibition is desired and modelling results provide additional support for the choice of the dose 
of 200 mg b.i.d. for PNH.  For further details, please refer to the iptacopan Investigator Brochure.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Not applicable as this is a single arm study.
4.4
Purpose and timing of interim analyses/design adaptations
An independent Data Monitoring Committee (DMC) will conduct periodic monitoring of safety 
data and will assess risk/benefit for participants in the study. The reports compiled for DMC 
review will be provided by an independent statisticians and an independent programmer.
A clinical study report (CSR) will be produced for submission at the time the last participant 
has completed the Core treatment period. In addition, if deemed required (e.g. to support 
regulatory submissions to Health Authorities) interim safety analyses may be produced while 
the study is still ongoing. If there is an interim lock for safety analyses, 
 
4.5
Risks and benefits
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 Brochure. The safety 
results from the Phase 2 PHN studies (CLNP023X2204 and CLNP023X2201) are summarized 


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in the Investigator Brochure. Iptacopan at a dose of 200 mg b.i.d. has been generally safe and 
well tolerated in PNH patients enrolled in these studies. 
Appropriate eligibility criteria, as well as study specific stopping rules for the study drug and 
recommended procedures are included in this protocol (see Section 9.1.1). The risk to 
participants in this trial will be minimized by compliance with the eligibility criteria and study 
procedures, including vaccinations prior to or up to 2 weeks after iptacopan initiation, close 
clinical monitoring with appropriate risk mitigation strategies, and periodic review of the safety 
data by an independent DMC. There is minimal risk to participants due to study procedures 
(mainly blood draws for laboratory assessments). One theoretical risk which is specific to PNH 
patients is the risk of hemolysis following discontinuation of treatment with a complement 
inhibitor. This is managed by specific discontinuation procedures outlined in Section 9.1.1. 
Additionally, there is the possibility that vaccinations could increase complement activation and 
worsen hemolysis. 
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 drug 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. 
If there is any question that the participant will not reliably comply, they should not be entered 
or continue in the study.
The main safety risk for complement inhibitors is infections caused by encapsulated bacteria. 
To date, no infections have been reported in preclinical studies with iptacopan and one infection 
caused by encapsulated bacteria (pneumococcal pneumonia leading to sepsis) has been reported 
in a clinical trial patient with C3 glomerulopathy and a kidney transplant who was also taking 
cyclosporine, mycophenolate and prednisone.
Translational research has shown that the serological response to meningococcal infection is 
maintained during AP blockade but that it is markedly reduced after blockade of the classical 
pathway (CP) with C5-blockers like eculizumab. Studies of serum bactericidal activity from 
patients vaccinated against meningococci, showed that C5-inhibitors block the killing of 
meningococci, whereas AP inhibitors have less inhibitory effect on meningococcal killing 
(Konar and Granoff 2017). Vaccination is predicted to be an effective mitigation strategy to 
reduce the risk for individuals treated with iptacopan. Participants will be vaccinated against 
meningococcal, pneumococcal and H. influenzae infections, according to local/national 
guidelines and availabilities.
Participants will also be closely monitored for signs and symptoms of infection (listed on a 
“Participant Safety Card” for participant awareness) and will be instructed to contact the 
investigator or a local physician if they experience any of these symptoms. The investigator will 
employ clinical judgement to determine an appropriate course of treatment. Antibiotic treatment 
should be started immediately for infections caused by encapsulated bacteria, with action taken 
with study medication considered on a case-by-case basis. Recommended guidelines for the 
monitoring and management of infections are provided in Section 6.6.2. For 


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immunocompromised participants with a higher risk of infections, precautionary actions (e.g. 
prophylactic antibiotics) should be considered by the investigator.
Other safety risks with iptacopan are based on preclinical data, with no relevant findings in 
clinical studies performed to date. These include potential risks of testicular effects, bone 
marrow toxicity with severe anemia, aorta mineralization and heart weight increase, and thyroid 
changes, summarized blow. Please refer to the Investigator Brochure for additional details on 
these preclinical findings.
In the iptacopan clinical studies, to date, there have been no serious testicular adverse events or 
clinically relevant changes from baseline in reproductive hormones reported..  In preclinical 
studies conducted in dogs, the testicular effects were mild and reversible with no notable effect 
on sperm morphology, numbers or motility, or hormone levels. In addition, considering the 17-
fold safety margin between the unbound concentrations of iptacopan achieved in the dog at the 
lowest dose where an effect was seen (LOAEL), and the concentrations achieved in man at the 
200 mg b.i.d. dose, the relevance of the findings to man is considered questionable. Testicular 
adverse events (AEs) and reproductive hormone levels will continue to be monitored in Phase 
3 studies.
Although a severe bone marrow effect on erythropoiesis was seen pre-clinically in one dog, it 
occurred at the highest dose level, for which the exposure to iptacopan for unbound levels was 
more than 80-fold greater than that observed with the 200 mg b.i.d. dose of iptacopan in humans 
(see Investigator’s Brochure). In clinical studies, there have been no adverse events or 
laboratory values compatible with this type of bone marrow toxicity. Hematological parameters 
will continue to be closely monitored in Phase 3 studies.
Minimal and reversible thyroid changes have been observed in preclinical studies. There have 
been no clinically relevant thyroid adverse events or changes in thyroid hormone levels in 
clinical trials to date. Thyroid hormone levels will continue to be monitored in Phase 3 studies.
Increases in heart weight and mineralization of the aortic wall were observed at dose levels ≥ 
30 mg/kg/day in very young dogs (4 weeks old at the start of treatment, equivalent to 6-12 
months of age in humans) after 52 weeks of treatment. These findings were not seen in adult 
dogs, even after chronic exposure (39 weeks). Blood pressure decrease concurrent with heart 
rate increase was consistently observed in both young and adult dogs at doses of 150 mg/kg/day, 
but in adult dogs these effects diminished over time whereas they persisted in the young dogs. 
It is not confirmed whether the aorta mineralization and increased heart weight are associated 
with these effects on blood pressure and heart rate but it is considered likely. Since these effects 
are seen only in very young dogs, likely because of an increased sensitivity related to their age, 
the risk of aorta mineralization and heart weight increase is considered unlikely to be relevant 
to adult patients. Increased heart rate and decreased blood pressure has not been seen following 
administration of iptacopan to humans to date.
Safety results from completed studies in 108 healthy volunteers exposed to iptacopan (84 to 
single doses and 24 to multiple doses over two weeks) indicated that treatment with iptacopan 
was well tolerated. Overall, there were no deaths, no serious adverse events (SAEs) or AEs 
leading to study drug discontinuation. Compared to placebo, no imbalance was observed in the 
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Similarly, the two Phase 2 studies in PNH (29 participants exposed to iptacopan), as well as 
studies carried out in complement-driven renal diseases (IgA nephropathy study, n=87 
participants exposed to iptacopan; C3G n=27 participants exposed to iptacopan) confirmed the 
favorable safety profile of iptacopan and supported the continuation of its development program. 
Based on IA data from the CLNP023X2204 and CLNP023X2201 (Section 4.2), PNH patients 
treated with iptacopan may have clinical benefits including increases of hemoglobin to 
normal/near normal values in the absence of RBC transfusions, control of intra- and 
extravascular hemolysis, and reduction of LDH. Additionally, the benefit of iptacopan may 
exceed the ones reported with anti-C5 antibody, as per the IA results of Study LNP023X2201 
(Section 4.2). It is expected that the improved hematological response with iptacopan treatment 
will translate into improved quality of life, most importantly an improvement in fatigue. 
Furthermore, participants may benefit from enrollment in a clinical study with close monitoring 
of their condition and frequent clinic visits and laboratory assessments as included in the 
assessment schedule. 
In summary, the benefit-risk relationship for iptacopan in PNH is positive supporting the start 
of this study.
4.6
Rationale for Public Health Emergency mitigation procedures
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. 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 will enroll adult patients diagnosed with PNH who have never been treated with 
complement inhibitor, including anti-C5 antibody with approximately 40% of all participants 
having received at least one RBC transfusion within 6 months prior to starting study treatment. 
A total of approximately 40 male and female participants will be starting study treatment in the 
trial. 
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study.
2. Male and female participants ≥ 18 years of age with a diagnosis of PNH confirmed by high-
sensitivity flow cytometry (Borowitz et al 2010) with RBCs and WBCs 
(granulocyte/monocyte) clone size ≥ 10%.
3. Mean hemoglobin level <10 g/dL confirmed by central laboratory assessment during 
Screening and prior to start of study treatment:
a. By two hemoglobin measurements (mean < 10 g/dL), two to eight weeks apart, for 
patients not receiving a RBC transfusion during Screening. Or


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b. By one hemoglobin measurement (<10 g/dL) carried out at the first Screening visit for 
patients receiving a RBC transfusion after which he/she will be eligible. 
4. LDH > 1.5 x Upper Limit of Normal (ULN) for at least two central laboratory measurements 
two to eight weeks apart during the screening period.
5. Vaccination against Neisseria meningitidis infection is required, and is recommended at 
least 2 weeks prior to initiation of iptacopan treatment. However, administration of these 
vaccines less than 2 weeks prior to start of iptacopan treatment or up to 2 weeks (up to Day 
14) after iptacopan initiation, is at the discretion of the investigator. If iptacopan treatment 
is started less than 2 weeks post-vaccination or before a specific vaccination is given, 
participant must be given prophylactic antibiotic at the start of iptacopan and for at least 2 
weeks after vaccination.
6. If not received previously, vaccination against Streptococcus pneumoniae and Haemophilus 
influenzae should be given (if available and according to local/national regulations), and are 
recommended at least 2 weeks prior to initiation of iptacopan treatment. However, 
administration of these vaccines less than 2 weeks prior to start of iptacopan treatment or 
up to 2 weeks (up to Day 14) after iptacopan initiation, is at the discretion of the investigator. 
If iptacopan treatment is started less than 2 weeks post-vaccination or before a specific 
vaccination is given, participant must be given prophylactic antibiotic at the start of 
iptacopan and for at least 2 weeks after vaccination.
7. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. Participation in any other investigational drug trial or use of other investigational drugs at 
the time of enrollment, or within 5 elimination half-lives of enrollment, or within 30 days 
of enrollment, whichever is longer; or longer if required by local regulations.
2. Prior treatment with a complement inhibitor, including anti-C5 antibody.
3. History of hypersensitivity to iptacopan or any of its excipients or to drugs of similar 
chemical classes.
4. Known or suspected hereditary complement deficiency.
5. History of hematopoietic stem cell transplantation.
6. Patients with laboratory evidence of bone marrow failure (reticulocytes <100x109/L, 
platelets <30x109/L, neutrophils <0.5x109/L).
7. Active systemic bacterial, viral (incl. COVID-19) or fungal infection within 14 days prior 
to study drug administration.
8. Presence of fever ≥ 38 °C (100.4 °F) within 7 days prior to study drug administration.
9. Human immunodeficiency virus (HIV) infection (known history of HIV or test positive for 
HIV antibody at Screening).
10. History of recurrent invasive infections caused by encapsulated organisms, e.g. 
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11. Major concurrent comorbidities including but not limited to: severe kidney disease (e.g., 
eGFR<30 mL/min/1.73m2, dialysis), advanced cardiac disease (e.g., NYHA class IV heart 
failure), severe pulmonary disease (e.g., severe pulmonary hypertension (WHO class IV)), 
or hepatic disease (e.g., active hepatitis) that in the opinion of the investigator precludes 
participant's participation in the study.
12. Liver disease, such as active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection 
defined as HBsAg positive or HCV RNA positive, or liver injury as indicated by abnormal 
liver function tests at Screening: 

Any single parameter of alanine aminotransferase (ALT), gamma-glutamyl transferase 
(GGT), alkaline phosphatase must not exceed 3 × ULN.
13. Unstable medical condition including, but not limited to, myocardial ischemia, active 
gastrointestinal bleeding, coexisting chronic anemia unrelated to PNH, or unstable 
thrombotic event not amenable to active treatment as judged by the investigator at Screening.
14. History of malignancy of any organ system (other than localized basal cell carcinoma of the 
skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of 
whether there is evidence of local recurrence or metastases.
15. Any medical condition deemed likely to interfere with the patient’s participation in the study.
16. Concomitant use of any of the following medications is prohibited if not on a stable regimen 
for the time period indicated below prior to Screening and those listed in Section 6.2.2:

Erythropoiesis-stimulating agents (ESAs) for at least 8 weeks. 

Any immunosuppressants for at least 8 weeks.

Systemic corticosteroids given for hematological conditions (less than 0.25 
mg/kg/d) for at least 4 weeks (see Section 6.2.1.1 during the Core treatment period). 

Vitamin K antagonists (e.g., warfarin) with a stable international normalized ratio (INR) 
for at least 4 weeks.

Low-molecular-weight heparin, and the direct oral anticoagulants rivaroxaban, 
apixaban and edoxaban, for at least 4 weeks.

Iron supplements, vitamin B12, or folic acid for at least 4 weeks.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) such as roxadustat 
for at least 8 weeks. 

Androgens for at least 4 weeks.
17. Female patients who are pregnant or breastfeeding, or intending to conceive during the 
course of the study.
18. 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 stopping of investigational drug. Effective 
contraception methods include:

Total abstinence (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.


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
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 
United 
Kingdom 
(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 have been stable on the same pill for 
a minimum of 3 months before taking investigational drug.
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 bilateral 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.
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF.
19. Ongoing drug or alcohol abuse that could interfere with patient's participation in the trial.
6
Treatment 
6.1
Study treatment
All participants starting study treatment in this single arm open label study will receive LNP023 
(iptacopan) 200 mg b.i.d.
6.1.1
Investigational drug
The investigational drug LNP023 (iptacopan) as 10 mg and 200 mg capsules, will be prepared 
by Novartis and supplied to investigator sites as open-label participant packs.  
Table 6-1
Investigational drug
Investigational 
Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global 
or local)
LNP023, 200 mg
Hard gelatin 
capsule
Oral use
Open label, patient 
specific kits 
Sponsor (global)


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Investigational 
Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global 
or local)
LNP023, 10 mg*
Hard gelatin 
capsule
Oral use
Open label, patient 
specific kits 
Sponsor (global)
* Used only during tapering down of LNP023 (iptacopan) dose – see Section 9.1.1 for details
6.1.2
Additional study treatments
No other treatment beyond iptacopan are included in this trial.
6.1.3
Treatment arms/group 
This is a single arm study; all participants will receive iptacopan at a dose of 200 mg orally 
b.i.d. 
6.1.4
Treatment duration
The planned duration of the Core treatment period is 24 weeks. If a participant’s study treatment 
is discontinued for any reason, every effort must be made to continue with the study assessments 
up to Week 24.
An Extension treatment period of 24 weeks is offered to participants who complete the Core 
treatment period. In the event a participant’s study treatment is discontinued during the 
Extension treatment period for any reason, and if possible, participants should continue with 
the study assessments up to Week 48.
Please refer to Section 9.1.1 for recommendations for participants who discontinue iptacopan 
for any reason during the Core or Extension treatment period.
Participants who complete this trial and continue to derive clinical benefit from the treatment 
based on the investigator’s evaluation may join the Rollover extension program (REP).
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. Please refer to Section 8.3.2 for the red blood 
cell transfusions and protocol specific guidelines for its administration.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication during screening period. 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
Erythropoiesis-stimulating agents (ESAs) and hypoxia inducible factors prolyl hydroxylase 
inhibitors (HIF-PHIs) are allowed to be used if on stable dose at least 8 weeks before Screening. 


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During the study, it is recommended to adjust the dose and/or discontinue dosing of ESAs 
and/or HIF-PHIs based on participant’s hemoglobin level as per local guidelines and practice. 
As a general guide, it is recommended to reduce the ESAs and/or HIF-PHIs dose by 50% if 
hemoglobin is ≥ 12 g/dL and/or to stop ESAs and/or HIF-PHIs dosing if hemoglobin is ≥ 13 
g/dL. Use particular caution in participants with coexisting cardiovascular disease, stroke and 
chronic kidney disease.
Systemic corticosteroids are allowed to be used for hematological conditions if on stable dose 
(less than 0.25 mg/kg/d) at least 4 weeks before Screening. During the study, the dose should 
not be changed during the Core treatment period (up to Day 168 Visit). During the extension 
treatment period, the dose of systemic corticosteroids can be adjusted based on participant’s 
condition and local guidelines.
Iptacopan has been shown to have a weak inhibition potential for the liver uptake transporter 
Organic Anion-transporting Polypeptide 1B1 (OATP1B1). Calculation revealed that the 
exposure (area under the curve (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 (NTI) with caution or apply a 
staggered dosing (see below). A list of OATP1B1 substrates to be used with caution will be 
provided to the investigators.
Iptacopan has also been shown to inhibit the efflux-transporter P-glycoprotein (P-gp) on the 
intestinal level but not the liver. Therefore, direct oral anti-coagulants 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.
For narrow therapeutic index (NTI) immunosuppressants (e.g. cyclosporine, sirolimus, 
tacrolimus on a stable dose) 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) can be given >1hour 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).
6.2.2
Prohibited medication
Use of the treatments listed below are not allowed during iptacopan administration.

Any other complement inhibitors, including anti-C5 antibody, are prohibited for the entire 
study treatment. If anti-C5 antibody is started, the patient should permanently discontinue 
iptacopan. 

Live vaccines are prohibited for the entire study treatment duration.

Preclinical studies have shown that systemic disposition of iptacopan is primarily mediated 
by metabolic clearance, predominantly by CYP2C8 and to a smaller extent by direct 
glucuronidation. In addition, some contribution from direct renal (approximately 20%) and 


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direct biliary excretion (around 5 to 10%) is anticipated. iptacopan is also a substrate for the 
organic anion-transporting polypeptide (OATP) hepatic uptake transporter (see above). To 
ensure participant safety, co-medications that inhibit multiple disposition mechanisms of 
iptacopan (e.g. Gemfibrozil) are prohibited. The same applies to strong CYP2C8 inhibitors 
(main clearance pathway) such as clopidogrel.

Gemfibrozil (a potent inhibitor of metabolizing enzymes CYP2C8, UGT1A and liver 
uptake transporter OATP1B1) 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 must be interrupted 7 days before first 
iptacopan dose until end of iptacopan treatment (and replaced with another appropriate 
medication).

Medications that are either “sensitive substrates” for the efflux transporter P-gp or have a 
narrow therapeutic index (NTI) and are substrates for P-gp should not be administered with 
iptacopan (interrupted 48 hours before first iptacopan dose). Typical examples are digoxin, 
quinidine, paclitaxel, fentanyl and phenytoin. However, if no alternative treatment is 
available, a staggered dosing approach is recommended (refer to Section 6.2.1.1). The anti-
coagulation drug dabigatran which is also a P-gp substrate should not be used in 
combination with iptacopan and a staggered dosing is also not recommended.
Concomitant medication listed under exclusion criterion 16 is prohibited if not on a stable 
regimen prior to Screening, for the time periods indicated. 
6.2.3
Rescue medication
Rescue medication is allowed to treat serious complications such as thrombosis with anti-
thrombotic treatment and management of this complication as per local guidelines and practice. 
For significant breakthrough hemolysis requiring rescue medication in the opinion of the 
investigator, rescue medication is allowed and should be managed as per local guidelines and 
practice. 
6.3
Participant numbering, treatment assignment, randomization 
6.3.1
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the ICF, the participant is assigned to the next 
sequential Participant No. available.
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No.


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6.3.2
Treatment assignment, randomization
No randomization will be performed in this study. 
All eligible participants will be assigned medication kits via Interactive Response Technology 
(IRT). The investigator or his/her delegate will contact the IRT after confirming that the 
participant fulfills all the inclusion/exclusion criteria. The IRT will assign a unique medication 
number for the first package of study treatment (iptacopan) to be dispensed to the participant.
6.4
Treatment blinding 
Treatment will be open to participants, Novartis Clinical Trial Team (CTT), the investigator 
staffs and persons performing the assessments. The CTT will have access to standard reports of 
patient profiles and other listings necessary to fulfill data review. There will be an Independent 
Statistician and an Independent Programmer who will provide analyses of safety data for the 
review of the members of the DMC at periodic intervals.
6.5
Dose escalation and dose modification
Iptacopan will be administered at a dose of 200 mg b.i.d. Dose adjustments and/or interruptions 
are not planned.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by explaining 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 with iptacopan will be assessed by the investigator and/or study personnel at each 
visit using capsule counts and information provided by the participant. This information should 
be captured in the source document at each visit. 
Participants will be given the opportunity to use a generic reminder application (app) that will 
synchronize with the participant mobile phone calendar to remind participants to take their 
medication.  The participants may choose to report compliance to the study site staff through 
the app.  The use of this application and the compliance reporting feature are entirely voluntary 
and not mandated for use.
All study treatment dispensed and returned must be recorded in the Drug Accountability Log.
6.6.2
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 at minimum at the times of symptoms of 
presumed infection. Participants will be instructed to contact the study physician immediately 


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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 could 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. 
If iptacopan treatment is to be permanently discontinued, please refer to Section 9.1.1 for the 
appropriate actions.
Medication used to treat adverse events (AEs) must be recorded on the appropriate case report 
form (CRF).
LNP023 (Iptacopan) Participant Safety Card
All participants will be provided with a Participant Safety Card. Participants will be instructed 
to be vigilant for any clinical sign or symptom of infection and to contact the investigator or 
local physician immediately. In case of suspicion of bacterial infection, further evaluation 
should be initiated and antibiotic treatment should be started as soon as possible.
6.7
Preparation and dispensation
Each study site will be supplied with iptacopan in packaging as described under 
investigational drug section. 
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 limits or prevents on-site study visits, 
delivery of iptacopan directly to a participant’s home may be permitted (if allowed by Local or 
Regional Health Authorities and Ethics Committees as appropriate)  in the event the 
Investigator has decided that an on-site visit by the participant is no longer appropriate or 
possible, and that it is in the interest of the participant’s health to continue administration of the 
study treatment even without performing an on-site visit. 
The dispatch of iptacopan from the site to the participant’s home remains under the 
accountability of the Investigator. Each shipment/provisioning will be for a maximum of 1-
month supply. In this case, regular phone calls or virtual contacts (as per scheduled visits) will 
occur between the site and the participant for instructional purposes, safety monitoring, drug 
accountability, 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.
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label), immediately before dispensing the medication kit to the 


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participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document.
6.7.1
Handling of study treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified in the Investigator’s Brochure. 
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 
monitors during site visits or remotely and at the completion of the trial. 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.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the 
investigator folder at each site.
6.7.2
Instruction for prescribing and taking study treatment
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
Participants should take iptacopan at the dose of 200 mg twice per day (in the morning and in 
the evening) at approximately the same times each day and ideally with 12-hours interval 
between morning and evening dosing. On study visit days, the participants should not take that 
day's morning dose until instructed by the site staff following the completion of study 
assessments.
Participants should take iptacopan irrespective of food intake. Each dose should 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 study 
treatment (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 dose should be omitted and the participant should continue treatment with 
the next scheduled dose.


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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), Institutional Review Board/Independent Ethics Committee 
(IRB/IEC)-approved informed consent.
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her understanding. If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document.
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 Good Clinical Practice (GCP) guidelines and regulatory 
requirements and is considered appropriate for this study. Any changes to the proposed consent 
form suggested by the investigator must be agreed by Novartis before submission to the 
IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the 
participant informed consent and should be discussed with the participant during the study as 
needed. Any new information regarding the safety profile of the investigational drug that is 
identified between IB updates will be communicated as appropriate, for example, via an 
investigator notification or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the participant.
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 Heath 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.).
The following informed consents are included in this study:

Main study consent, which also included:

An additional signature page for participants moving to Extension treatment period

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

A subsection that requires a separate signature for the ‘Optional Consent for Patient 
Interview’

Informed Consent Optional for genetic research


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
Informed Consent Form for Optional Home Nursing visits during a pandemic

Informed Consent Form for Optional Off-site Research Nursing (ORN) visits for Week 2 
and/or Week 6 visits 

As applicable, Pregnancy Outcomes Reporting Consent for female participants who took 
study treatment
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
The study includes an optional DNA component which requires a separate signature if the 
participant agrees to participate. It is required as part of this protocol that the Investigator 
presents this option to the participants, as permitted by local governing regulations. The process 
for obtaining consent should be exactly the same as described above for the main informed 
consent.
Declining to participate in these optional assessments (DNA) will in no way affect the 
participant’s ability to participate in the main research study.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
8
Visit schedule and assessments
The assessment schedule (Table 8-1 and Table 8-2) lists all of the assessments when they are 
performed. All data obtained from these assessments must be supported in the participant’s 
source documentation.
Except for obtaining the 2 hour post-dose PK sample, all assessments should be performed prior 
to dose administration the day of visits.
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1 and Table 8-2) or as close to the designated day/time as possible. Missed or 
rescheduled visits should not lead to automatic discontinuation. 
At the investigator’s discretion, and based on benefit-risk considerations of the participant’s 
clinical condition, as well as the local availability of services, some qualifying participants may 
be offered the option to receive home nursing to perform Week 2 and /or Week 6 visits.  These 
off-site visits will be offered in select countries and sites if Sponsor, Investigator and local 
regulations and conditions allow.  
Participants, that the investigator identifies as benefitting from off-site visits, must provide (a 
separate) consent in the optional Off-site Research Nursing Informed Consent. The participants 
are under no obligation to participate in off-site visits, as they can decide to continue with on-
site visits at the study site. 
The home nursing visits will comply with all assessments indicated in Table 8-1 for those visits.
The home nursing visits will be carried out by a third-party vendor centrally sourced by the 
Sponsor that can provide qualified research nurses who will perform study assessments under 
the oversight of the Investigator. The qualified nurses will be under delegation of the 


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investigator. The investigator will retain accountability for participant’s oversight and all 
medical decisions (i.e. protocol specified medical procedures, AE/SAE assessment and 
reporting, changes in medication, etc.).
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster or in special circumstances, that limits or 
prevents on-site study visits, alternative methods of providing continuing care may be 
implemented by the investigator as the situation dictates. If allowed by local Health Authority 
and depending on operational capabilities, phone calls, virtual contacts (e.g. tele consult) or 
visits by site staff/home nursing staff to the participant´s home can replace on-site study visits, 
for the duration of the disruption until it is safe for the participant to visit the site again. For 
more details refer to Section 8.6.
Participants who prematurely discontinue iptacopan treatment for any reason during the Core 
treatment period should continue in the study up to Week 24 visit, completing all scheduled 
visits assessments.  Please, refer to Section 9.1.1 for details on the recommended procedures to 
follow in case of permanent discontinuation.
Participants who prematurely discontinue iptacopan treatment during the Extension treatment 
period of the study for any reason, and if possible, should continue in the study up to the Week 
48 visit completing all scheduled visit assessments. The same guidance for managing iptacopan 
permanent discontinuation as in the Core treatment period applies (Section 9.1.1).
At this final visit, all dispensed investigational product should be reconciled, and the adverse 
event and concomitant medications should be recorded on the CRF.


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Table 8-1
Assessment schedule – Core treatment period
Period
Screening
Core treatment period
Visit Name Screening
Hb /LDH confirm.
Day 1
Day 7
Day 
14
Day 
28
Day 42
Day 
56
Day 
84
Day 
112
Day 
126
Day 
140
Day 
154
Day 
1687
Visit Numbers
1
1
101
102
103
104
105
106
107
108
109
110
111
112
Days
-56 to -1
-56 to -1
1
7
±1
14
±1
28
±1
42
±3
56
±3
84
±3
112
±3
126
±3
140
±3
154
±3
168
±3
Weeks
-8 to -1
-8 to -1
1
1
2
4
6
8
12
16
18
20
22
24
Informed consent
X
 
 
 
 
 
 
 
 
 
 
 
 
S
Eligibility criteria
X
X
Demography
X
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/current medical 
conditions
X
 
 
 
 
 
 
 
 
 
 
 
Vaccination1
X
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and Smoking history
X
Hepatitis B, C and HIV screen
X
Physical examination
S
 
S
 
 
S
 
 
 
 
 
 
S
Blood pressure and pulse rate
X
 
X
X
X
X
X
X
X
X
X 
X
X 
X
Body height
X
 
 
 
 
 
 
 
 
 
 
 
 
Body weight
X
 
 
 
 
 
 
X
Body temperature
X
 
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test (serum)
S
Pregnancy test (urine)
 
S
 
 
 
S
 
 
S
Clinical Chemistry (full)
X
 
X
X
X
X
Clinical Chemistry (abbreviated)
X(LDH only)
X
X
X
X
X
X
X
X
Hematology (full)2
X
X (Hb only)
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation/Markers of 
thrombosis
X
 
X
X
X
X
X
X
X


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Period
Screening
Core treatment period
Visit Name Screening
Hb /LDH confirm.
Day 1
Day 7
Day 
14
Day 
28
Day 42
Day 
56
Day 
84
Day 
112
Day 
126
Day 
140
Day 
154
Day 
1687
Visit Numbers
1
1
101
102
103
104
105
106
107
108
109
110
111
112
Days
-56 to -1
-56 to -1
1
7
±1
14
±1
28
±1
42
±3
56
±3
84
±3
112
±3
126
±3
140
±3
154
±3
168
±3
Weeks
-8 to -1
-8 to -1
1
1
2
4
6
8
12
16
18
20
22
24
Panel of hormones blood 
samples
X
 
 X
 
 
X
 
X
X
X
 
X
 
X
PK blood collection3
 
 
X
 
X
 
X
 
 
 
 
X
DNA sample collection 
(optional)4
X
Urinalysis
X
 
X
X
X
X
X
X
X
Urine Albumin/Creatinine ratio
X
X
X
Breakthrough hemolysis
X
MAVE
X
RBC transfusion 
X
12-lead Electrocardiogram 
(ECG)
X
X
X
 
 
 
 
X
Adverse Events
X
Concomitant medications
X
Surgical and medical procedures
X
Patient reported outcomes
X5
X
X6
X
X
X
X
X
X
X
Iptacopan DAR 
X
Disposition
 
 X


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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 It is recommended to administer vaccines at least 2 weeks prior to initiation of iptacopan. However, administration of these vaccines less than 2 weeks prior to start of 
iptacopan or up to 2 weeks (up to Day 14) after iptacopan initiation, is at the discretion of the investigator. If iptacopan treatment is started less than 2 weeks post-
vaccination or before a specific vaccination is given, participant must be given prophylactic antibiotic at the start of iptacopan and for at least 2 weeks after vaccination.
2 Local reticulocytes testing can be performed at the same time as the central testing during the Screening period. In the event that the absolute reticulocytes count as 
assessed by the central laboratory during the Screening period is below the protocol defined threshold (absolute reticulocytes <100x109/L) and only in this scenario, the 
results from the local lab testing can be used to determine participant’s eligibility.
3 PK samples will be taken pre-dose and approximately 2h post-dose.
4 If the DNA sample is not taken at Day 1 visit, it can be taken at any visit thereafter.
5 First PRO completion should occur at a screening visit prior to Day 1 and before any other assessment at that visit. 
6 Only FACIT-Fatigue
 will be carried out on Day 7.
7 For participants not agreeing to continue in the Extension treatment period after completing Day 168 visit, End of Study will be after completing recommended 
procedures defined in Section 9.1.1, for participants prematurely discontinuing study treatment before Day 168 but remaining in the study for abbreviated visits, please 
refer to Section 9.1.1 for the close monitoring and additional assessments/visits to be performed in between abbreviated visits.


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Table 8-2
Assessment Schedule - Extension treatment period  
Period
Extension treatment Period
Visit Name
Day 196
Day 224
Day 252
Day 280
Day 308
Day336/EOS
Visit Numbers
201
202
203
204
205
99991
Days
196 ± 5
224 ± 5
252 ± 5
280 ± 5
308 ± 5
336 ± 5
Weeks
28
32
36
40
44
48
Blood pressure and pulse rate
X
X
X
X
X
X
Physical examination
 
 
 
S
Body weight
 
 
 
X
Body temperature
X
X
X
X
X
X
Pregnancy test(urine)
S
Clinical Chemistry (full)
X
X
Clinical Chemistry (abbreviated)
X
X
X
X
Hematology (full)
X
X
X
X
X
X
Coagulation/markers of thrombosis
X
X
X
X
X
X
Panel of hormones blood samples
 X
X
X
X
Urinalysis
X
X
X
X
X
X
Urine Albumin/Creatinine ratio
X
X
Breakthrough hemolysis
X
MAVE
X
RBC transfusion
X
12-lead Electrocardiogram (ECG)
X
Adverse Events
X
Concomitant medications
X
Surgical and medical procedures
X
Patient reported outcomes
X
X
X
X
X
X


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Period
Extension treatment Period
Visit Name
Day 196
Day 224
Day 252
Day 280
Day 308
Day336/EOS
Visit Numbers
201
202
203
204
205
99991
Days
196 ± 5
224 ± 5
252 ± 5
280 ± 5
308 ± 5
336 ± 5
Weeks
28
32
36
40
44
48
Iptacopan DAR
X
Disposition
X
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
Chemistry abbreviated: LDH, Albumin, ALT, aspartate aminotransferase (AST), GGT, estimated glomerular filtration rate (eGFR), hs-C-reactive protein, Serum creatinine, 
Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, Total Protein, Blood Urea Nitrogen (BUN)/Urea, Ferritin
1 For participants not agreeing to continue in the Rollover extension program after completing Day 336 visit, End of Study will be after completing recommended 
procedures defined in Section 9.1.1, for participants prematurely discontinuing study treatment before Day 336 but remaining in the study for abbreviated visits, please 
refer to Section 9.1.1 for the close monitoring and additional assessments/visits to be performed in between abbreviated visits.


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8.1
Screening
Screening activities (Table 8-1) must be initiated only after the patient has signed the ICF.
Rescreening participants
It is permissible to re-screen a participant if the participant fails the first screening, however, 
each case must be discussed and agreed with Novartis on a case-by-case basis. 
In the case where a safety laboratory assessment (this excludes Hb and LDH laboratory 
assessment) at screening is outside of the range specified in the entry criteria, the assessment 
may be repeated once prior to starting study treatment. If the repeat value remains outside of 
the specified ranges, the participant must be excluded from the study.
8.1.1
Information to be collected on screening failures
Participants who sign an informed consent form and are subsequently found to be ineligible 
will be considered a screen failure. The following must be completed for screen failure 
participants on the applicable Case Report Form: reason for screen failure, demographic 
information, informed consent, and Inclusion/Exclusion criteria which excluded the participant 
from the study. No other data will be entered into the clinical database for participants who are 
screen failures, unless the participant experienced a serious adverse event during the screening 
phase (see Section 10.1.3). Adverse events that are not SAEs will be followed by the 
investigator and collected only in the source data.
Participants who sign an informed consent form and are considered eligible but fail to be started 
on treatment for any reason will be considered an early terminator. The reason for early 
termination should be captured on the appropriate disposition Case Report Form.
8.1.2
Hemoglobin and LDH assessments and transfusion during Screening
During the Screening period, mean hemoglobin < 10 g/dL and LDH >1.5 ULN will be 
determined by central laboratory assessments prior to starting study treatment evaluated by two 
measurements (hemoglobin mean < 10 g/dL; both LDH values >1.5 ×ULN), two to eight weeks 
apart; or by one hemoglobin measurement (<10 g/dL) from the first assessment for patients 
receiving a pRBC transfusion after the first assessment. 
Transfusion administered based on hemoglobin during the Screening period
If, in the Investigator’s judgment, a participant meets the conditions for transfusion as per local 
requirements, the participant must be transfused with packed-RBC.
If a participant receives a packed-RBC transfusion following the first assessment carried out 
for the Screening visit (Hb value < 10 g/dL by central laboratory), he/she will be eligible without 
an additional hemoglobin assessment by the central laboratory.
Transfusion administration will be recorded on a dedicated CRF page, where signs and 
symptoms are also reported as needed. If a participant refused to receive a blood transfusion, 
the CRF page must be completed indicating that the packed-RBC was not administered per 
participant’s decision.


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8.1.3
Absolute reticulocytes count during Screening
The absolute reticulocytes count will be measured at Screening to determine eligibility with 
regards to exclusion criterion # 6.  Due to the kinetics of maturation of reticulocytes into mature 
red blood cells and turnaround time from reticulocytes sample collection and analysis by central 
laboratory, local reticulocytes testing can be performed at the same time as the central testing 
during the Screening period. In the event that the absolute reticulocytes count as assessed by 
the central laboratory during the Screening period is below the protocol defined threshold 
(absolute reticulocytes <100x109/L) and only in this scenario, the results from the local lab 
testing can be used to determine participant’s eligibility. The results of the local laboratory 
values (including reference ranges) should be included in the eCRF to document eligibility.
8.2
Participant demographics/other baseline characteristics
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
Participants demographic: full date (only if required and permitted) or year of birth or age, sex, 
race/predominant ethnicity (if permitted) and baseline characteristic data will be collected on 
all participants. Participant race/ethnicity are collected and analyzed to identify variations in 
safety and/or efficacy due to these factors as well as to assess the diversity of the study 
population as required by Health Authorities.
Relevant medical history/current medical conditions will include: date for diagnosis of PNH 
(and age for diagnosis and disease duration will be derived up to the date of screening), 
vaccination history, and MAVE history (dates and type). In addition, the number of transfusions 
and unit numbers of packed-RBC will be collected for the 12 months preceding Screening. For 
participants in China, historical data on hemoglobin, LDH and absolute reticulocyte count 
(ARC) laboratory values will be retrospectively collected for the 6 months preceding Screening. 
Relevant medical history, smoking and alcohol history will also be collected.  
Prior concomitant medications (including vitamins, herbal preparations, over the counter 
medications, and those medications highlighted in the entry criteria) and procedures (any 
therapeutic intervention including surgery, biopsies, or non-pharmacological therapy) taken 
prior to Screening will be recorded in the CRFs. Medications for the treatment of PNH 
preceding screening will be collected in the CRF.
Investigators have the discretion to record abnormal test findings on the medical history eCRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.3
Efficacy
Efficacy/pharmacodynamics assessments are specified below. Please refer to Table 8-
1 and Table 8-2 for the time points when the assessments are performed. Section 2 shows the 
correlation of the assessments with the objectives.




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During the Extension treatment period, the need for administration of RBC transfusion will be 
monitored continuously until the end of study visit following the same criteria and guidance 
described above.
8.3.3
Breakthrough hemolysis
The occurrence of BTH will be monitored continuously during the Core treatment period. 
The criteria for clinical breakthrough is defined in Table 8-3 below if either one of the two 
clinical criteria is met, in presence of the laboratory evidence of intravascular hemolysis and 
should  be reported in the 'Breakthrough hemolysis' CRF page in addition to the AE page. 
In contrast to clinical breakthrough as defined, the isolated laboratory evidence of increased 
intravascular hemolysis, without meaningful decrease in hemoglobin and without other clinical 
signs or symptoms of hemolysis (per Table 8-3) is defined as subclinical breakthrough 
hemolysis, and should not be reported in the 'Breakthrough hemolysis' CRF page.


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Table 8-3
Breakthrough hemolysis definition
Clinical criteria
Laboratory criteria
Hemoglobin levels
Signs or symptoms
LDH level
Clinical 
breakthrough*
Decrease equal to or 
more than 2 g/dL 
(compared to the latest 
assessment, or within 15 
days)
Gross hemoglobinuria, 
painful crisis, dysphagia 
or any other significant 
clinical PNH-related signs 
& symptoms
> 1.5-times ULN and 
increased as 
compared to the last 
2 assessments
Subclinical 
breakthrough
Decrease less than 2 g/dL 
(compared to the latest 
assessment, or within 15 
days)
No clinical signs or 
symptoms, except 
moderate hemoglobinuria
> 1.5-times ULN and 
increased as 
compared to the last 
2 assessments
LDH:  lactate dehydrogenase; ULN:  Upper Limit of Normal;  
*The breakthrough is defined clinical if either one of the two clinical criteria is demonstrated, in presence of 
laboratory evidence of intravascular hemolysis (LDH level)
During the Extension treatment period, breakthrough hemolysis will be monitored continuously 
until the end of study visit following the same criteria and guidance described above.
The assessment could be based on local laboratory results.  However, the investigator should 
also collect at the same time a sample for the central laboratory assessment of hemoglobin and 
LDH, whenever possible.
8.3.4
Patient Reported Outcomes (PRO) - FACIT-Fatigue
The FACIT-Fatigue is a 13-item questionnaire that assesses self-reported fatigue and its impact 
upon daily activities and function.  It will be used to assess patient-reported fatigue. FACIT-
Fatigue is one of many different FACIT scales part of a collection of health-related quality of 
life (HRQoL) questionnaires referred to as the FACIT Measurement System (Yellen et al 1997, 
Webster et al 2003). The use of the FACIT-F in PNH patients has been reported in several 
publications and is sensitive to changes in disease status, allowing demonstration of statistically 
significant and clinically meaningful results (Brodsky et al 2008, Ueda et al 2018, Kulasekararaj 
et al 2019).  All FACIT scales are scored so that a high score is better. As each of the 13 items 
of the FACIT-F Scale ranges from 0-4, the range of possible scores is 0-52, with 0 being the 
worst possible score and 52 the best. For additional Patient Reported Outcomes (PROs) 
assessed in the study, please refer to Section 8.5.1. 
The PROs will be completed by participants on an electronic PRO (ePRO) device, first PRO 
completion should occur at a screening visit prior to Day 1. The PROs will be completed before 
any other procedure or assessment at the screening and Day 1 visits. The questionnaires should 
be completed in the language with which the respondent is most familiar. The participant should 
be given sufficient space and time to complete the questions. The participant should be made 
aware that completed questionnaires are not reviewed by the investigator/ study personnel.
Following the Day 1 visit, the participant will take home the ePRO device to be able to complete 
the PROs at home prior to visits to the clinic site. Detailed instructions describing administrative 
procedures of the PROs including participant completion via ePRO will be provided to the sites.


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If a participant is not able to self-administer the ePRO (e.g. due to illiteracy or blindness) or 
refuses to complete the questionnaires, this should be documented in the source documents. A 
participant's inability or refusal to complete a questionnaire(s) is not a protocol deviation.
Detailed instructions describing administrative procedures of the PROs including participant 
completion via ePRO will be provided to the sites.
8.3.5
PNH-related signs & symptoms
Paroxysmal nocturnal hemoglobinurias (PNHs) signs and symptoms will be collected according 
to Table 8-1 for the Core treatment period. The investigator (or designee) will record the 
presence of the following signs and symptoms:

Reddish or cola-colored urine especially in the morning / or hemoglobinuria

Feeling weak or tired

Shortness of breath / dyspnea

Dysphagia / difficulty swallowing

Chest pain

Abdominal / belly pain

Erectile dysfunction / impotency
These signs and symptoms of PNH will be reported in the CRF at each visit.
During the extension treatment period, PNHs signs and symptoms will be collected according 
to Table 8-2.
8.3.6
Major Adverse Vascular Events (MAVEs)
Assessments of MAVEs occur according to Table 8-1 and Table 8-2 and will be reported in the 
dedicated CRF page, in addition to the AE page. The description of the MAVEs including 
diagnosis (i.e., ultrasound, angiogram, magnetic resonance imaging, etc.), date of diagnosis. 
Start date, end date (if applicable) and status (ongoing / resolved) will be collected in the CRFs. 
A MAVE is defined as per the list below.

Acute peripheral vascular occlusion

Amputation (non-traumatic; nondiabetic)

Cerebral arterial occlusion/cerebrovascular accident

Cerebral venous occlusion

Dermal thrombosis

Gangrene (non-traumatic; nondiabetic)

Hepatic/portal vein thrombosis (Budd‐Chiari syndrome)

Mesenteric/visceral arterial thrombosis or infarction

Mesenteric/visceral vein thrombosis or infarction

Myocardial infarction

Pulmonary embolus




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Table 8-4
Assessments and specifications
Assessment
Specification
Physical examination
A complete physical examination will include the examination of 
general appearance, skin, neck (including thyroid), eyes, ears, nose, 
throat, lungs, heart, abdomen, back, lymph nodes, extremities, 
vascular, and neurological. If indicated, based on medical history 
and/or symptoms, rectal, external genitalia, breast, and pelvic exams 
will be performed.
Information for all physical examinations must be included in the 
source documentation at the study site. Clinically relevant findings that 
are present prior to signing informed consent must be recorded on the 
appropriate CRF that captures medical history. Significant findings 
made after signing informed consent which meet the definition of an 
Adverse Event must be recorded as an adverse event.
Vital signs
Vital signs include blood pressure (BP) and pulse measurements. 
After the participant has been sitting for five minutes, with back 
supported and both feet placed on the floor, systolic and diastolic 
blood pressure will be measured with an appropriately sized cuff. If 
the value reported is out of range, a repeat sitting measurements will 
be made at 5 - 10 minute later and the second measurement will be 
used/entered in the CRFs. 
Height and weight
Height in centimeters (cm) is collected at Screening only; body weight 
(to the nearest 0.1 kilogram (kg) assessed in indoor clothing, but 
without shoes) will be measured.
Body temperature 
The same route (temporal, tympanic, or axillary) and modality 
(temporal scanner, tympanic probe, thermometer) should be used for 
ongoing patient observations, as to allow for accurate temperature 
trend evaluation.
8.4.1
Laboratory evaluations
Unless specified in the table below, a central laboratory will be used for the analysis of the 
specimens collected.  Details of collection, shipment, and reporting by the Laboratory is 
provided to the investigator in the laboratory manual.
If participants cannot visit the site for protocol specified safety lab assessments, an alternative 
lab (local) may be used as defined in Table 8-7.
Clinically notable laboratory findings are defined in Appendix 1.
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate.
Table 8-5
Laboratory tests
Test Category
Test Name
Hematology - full list 
Hematocrit, total Hemoglobin, Mean corpuscular hemoglobin, Haptoglobin, 
Reticulocytes counts, Red blood cells (RBC) count, RBC distribution 
width, RBC mean corpuscular volume, White blood cell (WBC) count with 
differentials and Platelet count 




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Single 12-lead ECGs will be collected in this study with ECG machines available at the site. 
The original ECGs and a certified copy on non-heat sensitive paper, appropriately signed, must 
be collected and archived at the study site.
For any ECGs with participants’ safety concerns (see Appendix 1 for notable abnormalities), 
two additional ECGs must be performed to confirm the safety finding. If confirmed, a copy of 
the assessment should be sent to the Novartis global team for expedited review. Clinically 
significant abnormalities must be recorded on the CRF as either medical history/current medical 
conditions or adverse events, as appropriate. Any identifier details must be redacted e.g. 
participant initials, date of birth.
8.4.3
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing 
performed locally. Refer to the Assessment Schedule in Table 8-1 and Table 8-2 for timing of 
the required assessments. Additional pregnancy testing might be performed if requested by local 
requirements.
At screening, a serum pregnancy test will be performed, while during the study urinary 
pregnancy tests will be performed.  Local pregnancy tests and associated results will not be 
collected on CRF.
The participant should inform the investigator if they believe they might be pregnant. Please 
refer to Section 9.1.1 on recommendations for iptacopan therapy in case of a pregnancy.
Assessments of fertility
Refer to Section 5.2 for criteria to determine women that are not of child bearing potential.
Medical documentation of oophorectomy, hysterectomy, or bilateral 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:

Surgical bilateral oophorectomy without a hysterectomy

Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening/baseline.
8.4.4
Coagulation panel/thrombosis
Blood samples will be analyzed at the central laboratory for the following panel: D-dimer, 
fibrinogen, prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT).
8.4.5
Reproductive and thyroid hormones monitoring
The assessments indicated below will be done in all participants as per the Assessment 
schedules in Table 8-1 and Table 8-2.


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Testosterone, follicle stimulating hormone (FSH), dihydrotestosterone (DHT), luteinizing 
hormone (LH), thyroid stimulating hormone (TSH) and thyroid hormones (T3, T3 reverse, T4) 
will be regularly monitored.
8.4.6
Urine albumin creatinine ratio (UACR)
At the scheduled study visit indicated in Table 8-1 and Table 8-2, a urine sample will be taken 
while the participant is at the site to measure albumin and creatinine, and calculate UACR.
8.4.7
Appropriateness of safety measurements
The safety assessments selected are appropriate for this indication/patient population and the 
potential risks associated with iptacopan. The risk of infection caused by encapsulated 
bacteria will be closely monitored throughout the study. Participant vigilance for early signs 
and symptoms of infection is required and supported by providing an appropriate tool 
(Participant Safety Card) to enhance awareness and vigilance. Reproductive and thyroid-related 
hormones, vital signs and ECGs will be collected in order to evaluate the clinical significance 
of findings observed in preclinical toxicity studies.
8.5
Additional assessments 


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8.5.2
Pharmacokinetics
PK samples will be collected at the visits defined in the assessment schedule (Table 8-1) and as 
highlighted below. 
In the event of a pandemic or in special circumstances that limits or prevents on-site study visits, 
or if visits by site staff to a participant’s home are not feasible, and in case that an ORN visits 
are planned at that site (see Section 8.6), the collection of samples may be modified by Novartis 
and will be communicated to the Investigator.
The first sample of the day must be collected in the morning and immediately prior to taking 
the first daily iptacopan dose (pre-dose). The Investigator should remind the participant prior 
to the visit that during that specific visit the iptacopan morning dose will be administered at the 
site after collection of the blood sample. 
There is a second sample collected approximately 2 hours after dose administration. The 
Investigator should also remind the participants of the requirement for a second sample 
collection. Investigator should encourage participants to report vomiting that occurs within 5h 
after dosing as this need to be captured in the dedicated eCRF page.
Follow instructions outlined in the laboratory manual regarding sample collection, numbering, 
processing and shipment. See the potential use of residual samples for more information.




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8.6
Off-site visits 
In addition to the option to receive home nursing to perform Week-2 and /or Week-6 visits 
(Section 8), at the investigator’s discretion and based on benefit-risk consideration of the 
participant’s clinical condition, qualifying participants may be offered the option of off-site 
research nursing visits to unburden the participants while ensuring patient safety, engagement 
and retention during pandemic or the emergency similar to that of a pandemic such as the 
physical inability of a participant to visit the site. 
The off-site visits will be offered in select countries and sites and may replace on-site visits if 
Sponsor, Investigator and local regulations and conditions allow.
Participants, that the investigator identifies as suitable benefitting from off-site visits, must 
provide (a separate) consent in the optional Home Nursing and/or Off-site Research Nursing 
Informed Consent. Participants are under no obligation to participate in off-site visits, as they 
can decide to continue with on-site visits at the study site.
The off-site location is not a site location where the investigator will conduct the trial and where 
source data will be maintained, but is for example the participant’s home or another safe 
location if assessed as suitable by the Off-site Research Nurse (ORN) and ultimately decided 
by the Investigator. 
The off-site visit schedule will be determined in discussion between the participant, Investigator, 
and the Sponsor.
Conditions to enable off-site visits
Procedures conducted in an off-site location are carried out with the same level of scientific 
integrity as assessments conducted on-site. 
The following conditions must be met for off-site visits to occur:

Off-site visits may occur during the study duration under exceptional circumstances and if 
agreed between investigator and Sponsor.

The participant must have completed at least Day 1 visit (i.e., confirmed eligibility and 
completed all Day 1 visit assessments).

If a participant has begun off-site visits and s/he suffers from either (1) a severe AE or an 
SAE (possibly related to study medication), and/or (2) any concurrent medical conditions 
which, in the opinion of the Investigator, could cause unacceptable safety risks, then the 
participant must resume on-site visits. The participant may resume off-site visits when, 
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** Results obtained from the local laboratory are entered in the appropriate local laboratory CRF 
pages.
***Iptacopan pharmacokinetic samples will be collected during the ORN visits only when more details 
on feasibility (e.g. stability at ambient temperature) are available and the approach has been fully 
validated. Details will be included in the manual provided by the ORN service provider.
9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration 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.
Study treatment must be discontinued under the following circumstances:

Participant/guardian decision

Any situation in which study participation might result in a safety risk to the participant
If a female becomes pregnant during the study, it is recommended to discontinue treatment with 
LNP023. However, after an individual benefit-risk assessment by the investigator, LNP023 
continuation may be considered in exceptional circumstances. Counseling should be provided 
to the participant on the appropriate treatment for PNH during pregnancy. The outcome of the 
discussion with the participant, reflecting benefit-risk considerations, should be documented in 
the participant's file.
If treatment with iptacopan has to be discontinued immediately, i.e. because of a significant 
safety risk, appropriate replacement therapy must be offered to participants based on 
investigator’s judgment and local availability (including starting anti-C5 antibody treatment if 
available). 
Close monitoring of participants for signs and symptoms of hemolysis should be performed 
upon iptacopan discontinuation. It is recommended to monitor at minimum for: increase in 
LDH, decrease in hemoglobin level 
 increase in serum creatinine, 
thrombosis, and change in mental status. If serious hemolysis occurs, the Investigator should 
consider the following supportive treatments (and record them in the appropriate CRF pages):

Blood transfusion (packed RBCs)

Exchange transfusion if the PNH RBCs are >50% of the total RBCs by flow cytometry

Corticosteroids

Anticoagulation

Any other supportive treatment or therapy as judged by the investigator 
A visit one week after permanent discontinuation of iptacopan should occur for the following 
assessments: LDH, creatinine, hemoglobin, coagulation/thrombosis markers (Prothrombin time 


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(PT)/INR, activated partial thromboplastin time (aPTT), D-dimer, and fibrinogen),
 
 dipstick urinalysis, 
and all adverse events. All data collected 
will be entered in the appropriate CRF page.
If treatment with iptacopan is discontinued prematurely but it is not warranted to immediately 
discontinue iptacopan treatment, e.g., discontinuation due to participant/guardian decision, it is 
recommended to consider appropriate replacement therapy based on investigator’s judgment 
and local availability (including starting anti-C5 antibody treatment if available). In addition, it 
should be considered to taper down iptacopan over a period of 14 days, as follows:

3 capsules of 10 mg iptacopan taken in the evening (once daily) for 7 days

1 capsule of 10 mg iptacopan taken in the evening (once daily) for 7 days
The investigator should consider the proposed monitoring and supportive treatments listed 
above in case serious hemolysis occurs. For iptacopan tapering, weekly visits are recommended 
until one week after last iptacopan dose for the following assessments: LDH, creatinine, 
hemoglobin, coagulation/thrombosis markers (PT/INR, aPTT, D-dimer, and fibrinogen), 
 
 dipstick urinalysis, 
 and all adverse events. All data 
collected will be entered in the appropriate CRF page.
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information.
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see 'Withdrawal of Informed Consent' Section 9.1.2). 
Where possible, they should return for the assessments indicated in the Assessment 
Schedule. If they fail to return for these assessments for unknown reasons, every effort (e.g. 
telephone, e-mail, letter) should be made to contact the participant/pre-designated contact as 
specified in the lost to follow-up section. This contact should preferably be done according to 
the study visit schedule. 
Participants who permanently discontinue study medication during the Core treatment period, 
should complete the visits as scheduled up to Week 24. 
Participants who permanently discontinue study medication during the Extension treatment 
period, and if possible, should complete the visits as scheduled up to Week 48.
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

New / concomitant treatments

Safety laboratory assessments

Adverse Events / Serious Adverse Events


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All dose changes must be recorded on the appropriate CRF. The investigator must also contact 
the IRT to register the participant’s discontinuation from study treatment.
9.1.2
Withdrawal of informed consent
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant:

Does not want to participate in the study anymore,
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
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 his/her consent and 
record this information.
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of 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.
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table.
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
9.1.3
Lost to follow-up
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study. 
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk to participants enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data


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
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 (for an 
EOS visit) and treated as a prematurely withdrawn participant. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the participant’s interests. The investigator or sponsor depending 
on local regulation will be responsible for informing IRBs/IECs of the early termination of the 
trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last participant finishes their End of Study visit and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision.
After completion of the Extension treatment period, participants may receive post-trial access 
(PTA) by joining the Rollover extension program (REP) to allow participants’ access to 
iptacopan and to enable long-term safety monitoring. PTA will be provided until one of the 
following is met: participant no longer derives clinical benefit, investigator discontinues 
treatment, launch or reimbursement (where applicable), treatment fails to achieve registration 
in the trial participant’s country, or the clinical program is discontinued for any other reason.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of each 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.
For participants who permanently discontinue iptacopan administration during the course of the 
study, or do not continue into the roll-over extension program (REP), AEs will be collected for 
7 days after last dose of study drug or until EOS, whichever is longer.


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For participants who continue to the REP, AEs will be collected in the database for this study 
until participant’s last study visit (Day 336/EOS). 
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 if the event is ongoing, an outcome of not recovered/not 
resolved must be reported
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
6. Its outcome
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 at least until 7 days after the last dose of study 
medication, or until the first day of dosing in the REP.
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).


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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.
10.1.1.1 Adverse events of special interest
Adverse events of special interest (AESIs) 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. Adverse events of special interest are defined on the basis 
of potential safety risks for the product, class effects and data from preclinical studies.
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:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

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 
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
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.
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 24 
hours of obtaining knowledge of events (Note: If more stringent, local regulations regarding 
reporting timelines prevail). Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site. Information about 
all SAEs is collected and recorded on the (eSAE with paper back up) Serious Adverse Event 
Report Form; all applicable sections of the form must be completed in order to provide a 
clinically thorough report.
For participants NOT entering the REP, any SAEs experienced by participants up to 30 
days after EOS should be reported to the Novartis Safety office using a paper SAE form.
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.


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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
Pregnancies
If a female trial participant becomes pregnant, the stopping of investigational drug should be 
considered as described in Section 9.1.1, and the trial participant must be asked to read and sign 
the pregnancy consent form to allow the Study Doctor ask about her pregnancy. To ensure 
participant safety, each pregnancy occurring after signing the study informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up for 12 months after the birth 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) on a Pharmacovigilance Pregnancy Form. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment any pregnancy outcome. Any SAE experienced 
during pregnancy must also be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (European Medicines Agency (EMA) definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE 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 immediately, without undue 
delay, under no circumstances later than within 24 hours of Investigator’s awareness. (Note: If 
more stringent, local regulations regarding reporting timelines prevail).


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Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (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 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, etc.) to confirm elevation.
These liver chemistry repeats will be performed using the central laboratory. If results will not 
be available from the central laboratory, then the repeats can also be performed at a local 
laboratory to monitor the safety of the participant. If a liver event is subsequently reported, any 
local liver chemistry tests previously conducted that are associated with this event should have 
results recorded on the appropriate CRF.

If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to Section 9.1.1), if appropriate

Hospitalization of the participant if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include:

Obtaining a more detailed history of symptoms and prior or concurrent diseases.

Obtaining a history of concomitant drug use (including nonprescription medications 
and herbal and dietary supplement preparations), exposure to environmental chemical 
agents, alcohol use, recreational drug use, and special diets.

Exclusion of underlying liver disease
These investigations can include based on investigator’s discretion:

Imaging such as abdominal US, Computed Tomography (CT) or Magnetic Resonance 
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
Considering gastroenterology or hepatology consultations.
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.
10.2.2
Data Monitoring Committee
This study will include a Data Monitoring Committee (DMC) which will function 
independently of all other individuals associated with the conduct of this clinical trial, including 
the site investigators participating in the study. The DMC will assess at defined intervals the 
progress of a clinical trial, safety data, and critical efficacy variables of value for assessing 
benefit/risk to study participants, and recommend to the sponsor whether to continue, modify, 
or terminate a trial.
Specific details regarding composition, responsibilities, data monitoring, meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate charter that is established between the sponsor and the DMC. Analyses reviewed by 
the DMC will be performed by an independent statistical group that will have access to 
randomization codes in accordance to procedures described in the charter and its appendices.
10.2.3
Steering Committee
The Steering Committee (SC) will be established comprising investigators participating in the 
trial, i.e. not being members of the DMC and Novartis representatives from the Clinical Trial 
Team.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the steering committee charter.
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 on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site.


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All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated contract research organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Dates of screenings, screen failures, and study completion, and data about all study treatment 
(s) dispensed to the participant and all dosage changes will be tracked using an Interactive 
Response Technology (IRT). The system will be supplied by a vendor, who will also manage 
the database. The data will be sent electronically to Novartis (or a designated CRO) at specific 
timelines.
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 at the end of the 
Core treatment period. Before this, IRT information will also be made available to the 
Independent Statistician and Independent Programmer for carrying out analyses for the periodic 
safety review of data by the DMC. 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/delegated CRO representative will review the protocol and data capture requirements 
(i.e. eSource DDE or eCRFs) with the investigators and their staff. During the study, 
Novartis employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The field monitor will visit the site to check the completeness 
of participant records, the accuracy of data capture / data entry, the adherence to the protocol 
and to 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. 
Continuous remote monitoring of each site’s data may be performed by Novartis/delegated 
CRO/CRA organization. Additionally, a central analytics organization may analyze data & 
identify risks & trends for site operational parameters, and provide reports to Novartis clinical 
teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 


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information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
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 CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed.
12
Data analysis and statistical methods
A clinical study report (CSR) will be produced for submission at the time the last participant 
has completed the Core treatment period.  This section describes the methods associated with 
this report.
An additional CSR will be produced when the last participant has completed the last visit in the 
Extension treatment period, and the final study database has been locked.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The Enrolled Set comprises all participants enrolled in the study.
The Full Analysis Set (FAS) comprises all participants with confirmed eligibility to whom study 
treatment has been assigned. This will be the data set used for analysis of all efficacy endpoints.
The Safety Set includes all participants who received at least one dose of study treatment. 
Participants will be analyzed according to the study treatment they received, where treatment 
received is defined as the assigned treatment if the participant took at least one dose of that 
treatment.
The analysis set including the complete follow up of participants up to the completion of the 
Extension treatment period will be defined in the corresponding statistical analysis plan (SAP).
12.2
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for the FAS. In addition, summaries of relevant past or current 
medical conditions will be presented.
Categorical data will be presented as frequencies and percentages. The summary statistics 
shown for continuous data will be mean, standard deviation, median, 25th and 75th percentiles, 
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12.3
Treatments 
The Safety set will be used for the analyses of exposure to iptacopan described below. 
The duration of exposure (in days) to iptacopan as well as the dose intensity (computed as the 
ratio of actual cumulative dose received and actual duration of exposure) and the relative dose 
intensity (computed as the ratio of dose intensity and planned dose intensity) will be 
summarized by means of descriptive statistics using the safety set.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system.
12.4
Analysis of the primary endpoint(s)/estimand(s)
In the study protocol, 'absence of transfusions' or 'not requiring transfusions' refers to not 
receiving transfusions and not meeting the criteria for administration of transfusions as per 
Section 8.3.2.
12.4.1
Definition of primary endpoint(s)/estimand(s)
The primary endpoint related to increase in Hb will define a participant as a responder if 

The change from baseline in hemoglobin is ≥ 2 g/dL on three out of four measurements 
taken at the visits occurring in last six weeks (from Day 126 to Day 168) of the Core 
treatment period, and

The participant has not required (i.e. not received and not met the criteria for administration 
as per Section 8.3.2) any packed-red blood cells transfusions between Day 14 and Day 168.

The baseline hemoglobin will be the mean of the two measurements confirming the 
hemoglobin entry criterion in participants who do not receive a transfusion between the first 
and second confirmatory measurements. In participants who receive a transfusion after the 
first confirmatory measurement, the baseline will be the first measurement.
Intercurrent events stemming from discontinuation of treatment, breakthrough hemolysis events 
and MAVEs, expected to be reflected in the respective endpoint, will be handled with a 
treatment policy strategy.
12.4.2
Statistical model, hypothesis, and method of analysis
The primary analysis of the primary endpoint will be a logistic regression to estimate the 
response probability. The covariates include sex, age (categorical), an indicator variable of 
baseline hemoglobin above 8 g/dL and an indicator of transfusion dependence at enrollment.
This means that the proportion of responders will be derived from the estimated marginal 
probabilities derived from the model fit as the mean of the individual logistic regression model 
predictions, together with the 95% confidence intervals (CI), where the standard error will be 
derived by the bootstrap method.
The primary analysis of primary endpoint is the assessment of the proportion of patients 
reaching the status of responder.  The lower bound of the two-sided 95% confidence interval of 
the response rate obtained from primary analysis will be compared to a threshold of 15%. Lower 


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bound of the two-sided 95% confidence interval ≥ 15% is sufficient for demonstration that 
iptacopan improves hematological response in PNH patients with hemolysis and anemia in the 
absence of transfusions. The derivation of the threshold is explained in Section 12.8.1.
12.4.3
Handling of remaining intercurrent events of primary estimand
Reaching the protocol established criteria for RBC transfusions will be handled using a 
composite strategy for the primary endpoint.
Intercurrent events stemming from discontinuation of treatment, breakthrough hemolysis events, 
and MAVEs, whose impact is expected to be reflected, in the endpoint are handled with a 
treatment policy strategy.
12.4.4
Handling of missing values not related to the intercurrent event
For the primary response definitions, RBC transfusion will qualify the participant as a non-
responder, hence missing hemoglobin data following having met the criteria for RBC 
transfusion does not impact the primary analyses.
Missing hemoglobin data due to withdrawal from study in the event that a participant did not 
have a prior RBC transfusion, will be imputed based on pattern mixture models which aims to 
be consistent with the inclusion of hemoglobin data under the treatment policy strategy 
following all other intercurrent events. For participants with intermittent missing data during 
study follow up where reasons for missingness are assumed to be unrelated to response or 
compliance status, their missing data will be handled with a missing at random approach and 
imputed consequently. The full specification will be provided in the SAP.
12.4.5
Sensitivity analyses for primary endpoint/estimand 
The sensitivity of the primary estimands with respect to the treatment of missing data described 
above will be evaluated using a tipping point analysis. This assessment will be detailed in the 
SAP.
12.4.6
Supplementary analysis 
A supplementary estimand considering the use of rescue therapy (as defined in Section 6.2.3) 
under intercurrent event as treatment failure, for the purpose of efficacy assessment, will be 
performed. The supplementary estimand will have the same population, treatment of interest, 
summary measure as the primary estimand in Section 2.1. For this analysis, transfusions will 
be considered treatment failures whereas discontinuations of study medication for any reason 
will be handled with treatment policy strategy. 
12.4.7
Supportive analyses 
The estimation of proportions described above will be further displayed for subgroup categories 
defined by previous transfusion dependence, length of time since diagnosis, prior supportive 
therapy (e.g. steroids, androgens etc.), age categories, sex, and baseline hemoglobin.


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Other supportive analyses
Potential impact of a new wave of COVID-19 infections affecting measurements have been 
minimized through the measures proposed in Section 8. Other impact that at this stage cannot 
be excluded such as withdrawal from study follow up due to infection which would require 
dealing with such events as additional intercurrent events. This would define additional 
estimands, possibly primary and secondary estimands all of which would deal with the COVID-
19 related intercurrent events so that inference would still concern treatment effects in a world 
that is not in the midst of an extraordinary pandemic situation. The methodology for the analyses 
targeting these estimands and additional sensitivity analyses for cases of missing data due to 
the impact of COVID-19 infections will be specified in detail in an amendment to the SAP 
developed in the event of renewed COVID-19 infection waves. Decisions on handling of 
possible increases in background risks impacting study endpoints will also take into 
consideration relevant epidemiological information on local incidence of COVID-19 infections.
12.5
Analysis of secondary endpoints/estimands 
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
Handling of RBC transfusions will depend on the endpoint and this is described below. In the 
case of discontinuation of study medication, breakthrough hemolysis, or MAVEs, these are 
intercurrent events which are expected to be reflected in the endpoints, hence the treatment 
policy strategy will be applied. 
The proportion of participants achieving sustained hemoglobin levels ≥ 12 g/dL in the absence 
of red blood cell transfusions will be evaluated by means of standardized marginal proportions.
Transfusion avoidance will be evaluated as the proportion of participants not requiring (i.e. not 
received and not met the criteria for administration as per Section 8.3.2) any transfusion 
between Day 14 and Day 168, and the estimation will be evaluated by means of standardized 
marginal proportions derived similarly to the estimation applied to the primary estimand. 
Change from baseline in hemoglobin levels is estimated under the hypothetical situation in 
which participants would not have received transfusions on iptacopan treatment. This will be 
accomplished by the use of imputed values based on a normal distribution whose mean is 
restricted to a range consistent with not having received an RBC transfusion and the within visit 
covariance matrix will borrow from the observed within participant covariance matrix, to 
replace hemoglobin values following a transfusion. The model for the estimation is a repeated 
measures model with an unstructured covariance structure, and including visit and baseline 
hemoglobin levels and the interaction between visit and baseline levels. Additional covariates 
will be age (categorical), sex and transfusion dependency. The treatment estimates will be 
computed as the mean changes corresponding to the average of hemoglobin levels measured in 
the last 6 weeks of treatment (that is the visits occurring between Day 126 and Day 168). 
Changes from baseline in scores of fatigue using the FACIT-Fatigue questionnaire will be 
derived from a longitudinal repeated measures model including test scores collected as all visits. 
The baseline is defined as the mean of levels obtained pre-treatment (Screening visit) and Day 
1 value. The estimation will be an average of treatment estimates derived for visits occurring 


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between Day 126 and Day 168. Main effects will be transfusion dependency and interaction 
terms will be the same as those used to compare changes in hemoglobin. 
The estimation of the change from baseline in reticulocyte counts will be derived from a 
longitudinal repeated measures model including data collected throughout the study and where 
baseline is defined as the value on Day 1. In this model, transfusion dependency, baseline 
covariates as well as interaction terms will be the same as for changes in hemoglobin. The 
estimation will use the average of model derived estimates obtained at visits occurring between 
Day 126 and Day 168.
The treatment effect on percent change from baseline in LDH will be assessed using a 
longitudinal repeated measures model of log transformed ratio to baseline based on all 
observations collected during follow-up. The model is the same to the model described for all 
continuous endpoints.  Estimation will be derived based on the average of the log transformed 
ratio estimated between Day 126 and Day 168. 
The estimation of rates of Major Adverse Vascular Events (MAVE) will be carried out using a 
negative binomial model. Due to the expected low frequency of occurrences, no covariates are 
planned to be included.
The estimation of rates of breakthrough hemolysis (BTH) will be carried out using a negative 
binomial model. Transfusion dependency and covariates will be included similarly as for the 
other endpoints.
In all estimations based on a longitudinal model, missing data will be imputed multiple times 
under a model that considers the reasons for missingness. The imputed datasets will be used in 
the estimation of the longitudinal model. For the analysis of change from baseline Hb and/or 
where missing data are imputed, the model comparisons will be derived using Rubin’s 
combination rules.
12.5.2
Safety endpoints
The analysis set used for all safety analyses will be the safety set (SAF). All tables will be 
presented. The complete details of all safety summaries will be provided in the SAP. The 
following mentions safety outcomes of interest and provides a non-exhaustive description of 
principles to be followed in the preparation of outputs.
Safety summaries (tables, figures) 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 of death events including on treatment and post treatment 
deaths will be provided if appropriate.
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 iptacopan which covers slightly more than 5 
times the estimated half-life of iptacopan.
Adverse events
All information obtained on adverse events will be displayed by participant.


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The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of treatment 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 discontinuation of study medication, and for iptacopan tapering if this is followed 
prior to complete study dose discontinuation.
The number (and proportion) of participants with adverse events of special interest/related to 
identified and potential risks will be summarized.
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.
Vital signs
Summary statistics will be provided by visit/time. Summary occurrence of abnormalities may 
be provided if appropriate.
12-lead ECG
PR, QRS, QT, QTcF and PP 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/QTc interval data based on the number of participants meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these participants will be produced.
Summary statistics will be provided by visit/time.
Clinical laboratory evaluations
Laboratory data for participants with relevant abnormalities will be listed by participant and 
visit/time relative to the start of study medication. Summary statistics will be provided by 
visit/time. Shift tables using the low/normal/high/ (low and high) classification may be provided 
as appropriate to compare baseline to the worst on-treatment value. Other displays using based 
on fold increases or decreases of interest will be provided as appropriate.


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12.5.4
Patient reported outcomes
In addition to the analyses below, a comprehensive analysis of PRO will be provided as a 
separate PRO report and documented in a separate statistical analysis plan.
In this study, the question addressed by the analysis of PRO measurements is whether treatment 
with iptacopan improves patient-reported fatigue symptoms as measured by the FACIT-Fatigue 
and this analysis is a secondary endpoint described with the secondary endpoints/estimands. 
This section briefly describes supportive analyses of FACIT-Fatigue as well as supportive 
analyses using a secondary clinical outcome instrument.
Further, responder analyses derived from changes in FACIT-Fatigue will be performed. 
Response is defined as at least a 5-point improvement in the FACIT-Fatigue total score from 
baseline at a patient-level. Given the greater variability at the patient-level, a 5-point change is 
recommended as a meaningful important difference. 
The above analyses will include data from participants with an evaluable baseline and at least 
one post baseline score. Handling of missing forms due to missed visits will follow the 
principles applied to all other missing data throughout the study.






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The patient-level hemoglobin data were not available for these historical studies, and hence 
direct estimation of the proportion of patients who achieved hemoglobin increases from 
baseline ≥ 2 g/dL in the absence of transfusions was not feasible. However, an indirect approach 
through simulation indicates that the probability of being a responder (defined as change of 
hemoglobin ≥ 2 g/dL regardless of transfusions) is 14.7% (95% CI: 5.0% - 21.1%) for 
ALXN1210-PNH-301 and is 4.49% (95% CI: 0.5% - 11.0%) for TRIUMPH. The difference in 
estimated probability of being a responder between ALXN1210-PNH-301 and TRIUMPH is 
likely due to the difference in populations, with the TRIUMPH population consisting of all 
transfusion dependent patients, while ALXN1210-PNH-301 included less severe patients due 
to availability of SoC.
Please note these estimates (14.7% and 4.49%) actually overestimate the hematological effect 
for eculizumab in the studies because the hemoglobin levels correspond to all patients at Week 
26 including those who have received transfusions during treatment. 
The 15% threshold is chosen to be above the estimated hemoglobin increases regardless of 
transfusions in both historical studies, and exceeding this threshold is sufficient for 
demonstration that iptacopan improves hematological response in PNH patients with hemolysis 
and anemia in the absence of transfusions. R® software was used for the calculations (R Core 
2017). Further details about simulation approach will be provided in Statistical Analysis Plan. 
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 
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 European Union Drug Regulatory Authorities Clinical Trial (EudraCT). In 


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addition, after study completion 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.
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.


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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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Risitano AM, Marotta S, Ricci P, et al (2019) Anti-complement treatment for Paroxysmal 
Nocturnal Hemoglobinuria: Time for Proximal Complement Inhibition? A Position Paper from 
the SAAWP of the EBMT. Front Immunol; 10:1157.
Risitano AM, Rotoli B. (2008) Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural 
history and treatment options in the era of biological agents. Biologics; 2(2):205-22.
Socié G, Mary JY, De Gramont, A, et al. (1996) Paroxysmal nocturnal haemoglobinuria: long-
term followup and prognostic factors. French Society of Haematology. Lancet; 348 (9027):573-
7.
Socie G, Tosi MP, Marantz JL, et al (2019) Eculizumab in paroxysmal nocturnal 
haemoglobinuria and atypical haemolytic uraemic syndrome: 10-year pharmacovigilance 
analysis.  Br J Haematol; 185:297-310.
Staunton H, Willgoss T, Nelsen L, et al (2019) An overview of using qualitative techniques to 
explore and define estimates of clinical important change on clinical outcome assessments. 
Journal of Patient Reported Outcomes; 3(16):1-10. 
Ueda Y, Obara N, Yonemura Y, et al (2018) Effects of eculizumab treatment on quality of life 
in patients with paroxysmal nocturnal hemoglobinuria in Japan. Int J Hematol; 107:656-65.
Ultomiris 
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assessment-report_en.pdf> (Accessed 01 Jul 2021).
Webster K, Cella D, and Yost K (2003) The functional assessment of chronic illness therapy 
(FACIT) measurement system: properties, applications, and interpretation. Health Qual Life 
Outcomes; 16:1-79.
Weitz I, Meyers G, Lamy T, et al (2012) Cross-sectional validation study of patient-reported 
outcomes in patients with paroxysmal nocturnal haemaglobinuria. Intern Med J; 43:298-307.
Yellen SB, Cella DF, Webster K, et al (1997) Measuring fatigue and other anemia-related 
symptoms with functional assessment of cancer therapy (FACT) measurement system. J Pain 
Symptom Manage; 13(2):33-74.


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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.


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Amended Clinical Trial Protocol Version 04 (Clean)                                 Protocol No. CLNP023C12301
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
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolution 
(frequency at Investigator 
discretion)


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Amended Clinical Trial Protocol Version 04 (Clean)                                 Protocol No. CLNP023C12301
Criteria
Actions required
Follow-up monitoring
Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF
> 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 
(patient 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 if 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 the participant
Establish causality (investigate alternative 
etiologies)a
Study drug can be restarted only if 
alternative etiology is identified and liver 
enzymes return to baseline
ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolution 
(frequency at Investigator 
discretion)
Monitor symptomsb
Report outcomec


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Amended Clinical Trial Protocol Version 04 (Clean)                                 Protocol No. CLNP023C12301
Criteria
Actions required
Follow-up monitoring
Record the AE and contributing factors 
(e.g. con meds, med hx, lab) in the 
appropriate eCRF
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. 
ALP: alkaline phosphatase; GLDH: glutamate dehydrogenase TBL: total bilirubin; ULN: upper limit 
of normal

SAP_003.pdf: 








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Date 
Time point 
Reason for update 
Outcome for update 
Section and title 
impacted (Current) 
16-
November-
2022 
SAP 
Amendment 
2:  
Addressing 
issues 
identified 
during 
programming 
for Dry Run  
Approach defined 
for the primary 
analysis, in case zero 
cells across 
categories defined 
by the covariates 
lead to convergence 
issues 
Added simple 
proportion  
Added  details of 
statistical methods 
Sections 2.5.2.2, 
2.5.5, 2.5.6.1, 
2.6.1.1, 2.6.1.2, 
5.2.2.2 
 
 
 
The additional 
details address the 
analysis 
considerations for 
sparse data. The 
analyses for 
breakthrough 
hemolysis and 
MAVE (secondary 
endpoints) are 
aligned with those in 
protocol. The zero 
inflated models 
specified in previous 
versions of SAP lead 
to convergence 
issues and hence 
switching to 
protocol specified 
negative binomial 
model. 
Propose alternate 
methods for non-
convergence 
Added alternative 
models and model 
selection procedure 
Sections 2.6.1.7, 
2.6.1.8 
 
 
Definition for 
baseline hemoglobin 
is clarified, with 
respect to dealing 
with data from 
unplanned visits  
Added more details 
for baseline 
hemoglobin and 
baseline PRO 
computation  
Section 2.1.1.2 


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Date 
Time point 
Reason for update 
Outcome for update 
Section and title 
impacted (Current) 
Clarity needed for 
baseline 
computation of 
certain PROs 
 
 
 
Transfusion 
dependency should 
be prior to study 
treatment instead of 
prior to screening 
Update transfusion 
dependency definition 
Section 2.3.2 
 
 
Details needed for 
implementation of 
multiple imputation 
Add more detail to 
multiple mutation 
model 
Add criteria to handle 
the 
case 
where 
imputed values are out 
of constrained range 
Sections 2.5.3, 2.6.2 
 
 
The “indicator 
variable of baseline 
hemoglobin” should 
not be included in 
MMRM model since 
baseline 
(continuous) is 
already in the model 
Remove “indicator 
variable of baseline 
hemoglobin” 
Sections 2.6.1.3, 
2.6.1.4, 2.6.1.5, 
2.6.1.6, 
 
 
Present the 
geometric mean for 
LDH expressed as a 
% for alignment 
with protocol 
Update to percentage 
change (reduction or 
increase) from 
baseline 
Section 2.6.1.6 
 
 
More sensitivity and 
supportive analysis 
need to be added in 
this summary table. 
Update Table 5-1 
Section 5.2.1 


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Date 
Time point 
Reason for update 
Outcome for update 
Section and title 
impacted (Current) 
 
 
Added sensitivity 
analysis to assess the 
robustness of 
handling missing 
hemoglobin data  
under different 
assumptions of  
missing signs and 
symptoms’ 
Add sensitivity 
analysis to address the 
issue 
Section 2.5.4, 2.6.3 
 
 
The result based on 
treatment policy for 
primary analysis 
may be of interest 
The result based on 
hypothetical strategy 
for LDH, FACIT 
and reticulocytes 
may be of interest 
Add additional 
supportive analysis 
Section 2.6.4 
 
 
 
 
 
China specific 
outputs will not 
include in global 
CSR 
Move the sensitivity 
analysis regarding 
different transfusion 
criteria between 
Chinese patients and 
non-Chinese patients 
to China specific SAP 
Sections 2.5.4, 
2.5.6.2 
 
 
Current definition 
regarding prior, 
concomitant and 
post therapy need 
update in order to 
align with project 
level updates 
Improve language 
Section 2.4.2 


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Date 
Time point 
Reason for update 
Outcome for update 
Section and title 
impacted (Current) 
 
 
Make method for 
calculation of 
exposure-adjusted 
incidence rate robust 
to low frequency 
count data 
Update statistical 
models and improve 
the language 
Sections 2.7.1, 
2.7.1.1 
 
 
Added clarification 
regarding the 
approach to handle 
abnormal 
measurements  
Liver toxicity 
summary needed 
more detail 
Improved the language 
and added more 
details 
Section 2.7.3 
 
 
Thresholds needed 
for blood pressure 
and temperature 
Added thresholds  
Section 2.7.3,2 
 
 
Addressed 
typographical errors 
Improve current 
language or remove 
the duplicated 
language 
Sections 2.1, 2.4.1, 
5.2.2, 5.2.3 


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Table of contents 
Table of contents ................................................................................................................. 9 
List of tables ...................................................................................................................... 10 
List of figures .................................................................................................................... 10 
List of abbreviations .......................................................................................................... 11 
1 
Introduction ....................................................................................................................... 13 
1.1 
Study design........................................................................................................... 13 
1.2 
Study objectives and endpoints ............................................................................. 15 
1.2.1 
Primary estimands ................................................................................. 17 
1.2.2 
Secondary estimands ............................................................................. 18 
2 
Statistical methods ............................................................................................................. 20 
2.1 
Data analysis general information ......................................................................... 20 
2.1.1 
General definitions ................................................................................ 20 
2.2 
Analysis sets .......................................................................................................... 21 
 
 22 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 22 
2.3.1 
Patient disposition ................................................................................. 22 
2.3.2 
Relevant Medical History and current medical conditions ................... 23 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 23 
2.4.1 
Study treatments .................................................................................... 23 
2.4.2 
Prior, concomitant and post therapies ................................................... 25 
2.5 
Analysis of the primary objective .......................................................................... 26 
2.5.1 
Primary endpoint(s)/Primary estimand(s) ............................................. 26 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 27 
2.5.3 
Handling of missing values not related to intercurrent event. .............. 28 
2.5.4 
Sensitivity analyses for primary endpoint/estimand ............................. 28 
2.5.5 
Supplementary analyses ........................................................................ 29 
 
 29 
2.6 
Analysis of secondary endpoints/estimands .......................................................... 30 
2.6.1 
Secondary endpoints/secondary estimands ........................................... 30 
2.6.2 
Handling of missing values for secondary endpoints ........................... 33 
2.6.3 
Sensitivity analyses ............................................................................... 34 
2.6.4 
Supportive analyses ............................................................................... 34 
2.7 
Safety analyses ....................................................................................................... 34 
2.7.1 
Adverse events (AEs) ............................................................................ 34 
2.7.2 
Deaths .................................................................................................... 36 


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2.7.3 
Laboratory data ..................................................................................... 36 
 
 41 
 
 41 
2.10 
Patient-reported outcomes ..................................................................................... 41 
 
 42 
 
 43 
2.13 
Interim analysis ...................................................................................................... 43 
3 
Sample size calculation ..................................................................................................... 44 
4 
Change to protocol specified analyses .............................................................................. 44 
5 
Appendix ........................................................................................................................... 44 
5.1 
Imputation rules ..................................................................................................... 44 
5.1.1 
AE date imputation ............................................................................... 44 
5.1.2 
Concomitant medication date imputation ............................................. 46 
5.2 
Statistical models ................................................................................................... 48 
5.2.1 
Tabular view of estimands and associated estimation methods ............ 48 
5.2.2 
Primary analysis .................................................................................... 54 
5.2.3 
Rule of exclusion criteria of analysis sets ............................................. 58 
6 
Reference ........................................................................................................................... 58 
 
List of tables 
Table 1-1 
Objectives and related endpoints for the Core treatment period ........... 15 
Table 1-2 
Objectives and related endpoints for the Extension treatment period ... 17 
Table 1-3 
Justification of handling of intercurrent events ..................................... 18 
Table 2-1 
Summary on dose intensity and transfusions for patients on 
iptacopan ............................................................................................... 25 
Table 2-2 Liver Toxicities ........................................................................................................ 38 
Table 2-3 Definition of symptoms and AEs for liver toxicities ............................................... 39 
Table 3-1 Precision of response rate with N = 40 .................................................................... 44 
Table 5-1 
Overview of estimands and estimation methods ................................... 48 
 
List of figures 
Figure 1-1 
Study design .......................................................................................... 14 




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mg 
 
 
PNH 
 
Milligram(s) 
 
 
Paroxysmal nocturnal hemoglobinuria 
 
pRBC 
PRO 
Packed Red blood cell transfusions 
Patient-reported Outcomes 
PT 
PT 
PTA 
QTcF 
RAP 
Prothrombin time 
Preferred Term 
Post-trial access 
QT interval corrected by Fridericia’s formula 
Reporting & Analysis Process 
RBC 
REP 
 
SAE 
SAF 
SAP 
SAS 
SBP 
sCR 
SD 
SOC 
SoC 
T3 
T4 
TA 
Red blood cell(s) 
Rollover extension program 
 
Serious Adverse Event 
Safety Set 
Statistical Analysis Plan 
Statistical Analysis System 
Systolic blood pressure 
Serum creatinine 
Standard deviation 
System Organ Class 
Standard of care 
Triiodothyronine 
Thyroxine 
Transfusion avoidance    
TBL 
TEAE 
TFLs 
Total bilirubin 
Treatment emergent adverse event 
Tables, Figures, Listings 
TSH 
ULN 
WBC 
WHO 
Thyroid stimulating hormone 
Upper limit of normal 
White blood cell(s) 
World Health Organization 


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1 
Introduction 
The purpose of the document is to describe the statistical analyses to be included in the clinical 
study report (CSR) to be produced for submission at the time the last patient has completed the 
core treatment period in study CLNP023C12301. Hence the document covers the efficacy 
analysis on the core treatment period and the safety analysis on the data in the core treatment 
period, as well as the safety data in the extension treatment period collected till the data cut off 
for the submission of the CSR mentioned before.     
An additional CSR will be produced when the last participant has completed the last visit in the 
extension treatment period, when the final study database has been locked. The statistical 
analyses for that CSR will be mentioned in a separate document.  
1.1 
Study design 
Study CLNP023C12301 is a multicenter, single-arm, open-label trial in adult PNH patients who 
are naive to complement inhibitor therapy, including anti-C5 antibody treatment. This study is 
comprised of three periods (see Figure 1-1): 
• A Screening period lasting up to 8 weeks (unless there is a need to extend it for 
vaccinations required for inclusion) 
• A 24-week single arm, open-label Core treatment period for the primary efficacy and 
safety analysis 
• A 24-week open-label, iptacopan treatment Extension period 
This study will enroll PNH patients with hemolysis (LDH > 1.5 ULN) and anemia (hemoglobin 
<10 g/dL), who are naive to complement inhibitor therapy, including anti-C5 antibody 
treatment, with approximately 40% of all participants having received at least one (1) packed-
RBC transfusion within 6 months prior to starting study treatment.  
A total of approximately 40 participants will be starting study treatment in the trial.  All 
participants must provide written informed consent prior to start of any study-related activities. 
The study design is shown in the schematic below. 




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testing can be used to determine participant’s eligibility. The results of the local laboratory 
values (including reference ranges) should be included in the eCRF to document eligibility.  
If eligibility criteria are not met due to any assessment, the participant should be considered as 
having failed the screening and cannot start study treatment. The participant can be re-screened 
as described in detail in Section 8.1 in study protocol. 
Core treatment period 
Participants who meet the eligibility criteria will proceed to the Core treatment period. 
Treatment with iptacopan at a dose of 200 mg b.i.d. will start on the first day (Day 1) and 
continue for 24 weeks with study visits and corresponding assessments according to the 
schedule described in Table 8-1 of CLNP023C12301 clinical study protocol. 
The Core treatment period will end with the completion of the Week 24 visit assessments. Upon 
completion of the Week 24 visit, participants may enter the Extension treatment period, as 
described below. 
Extension treatment period  
Participants who benefit from treatment and are taking iptacopan at Week 24 visit (i.e. did not 
permanently discontinue study medication), will be offered to continue iptacopan treatment 
during the extension treatment period of 24 weeks with study visits and assessments according 
to schedule detailed in Table 8-2 of CLNP023C12301 clinical study protocol. For participants 
not agreeing to continue iptacopan treatment in the Extension treatment period after completing 
Day 168 visit, End of Study will be after completing recommended procedures defined in 
Section 9.1.1 of CLNP023C12301 clinical study protocol.  
The extension treatment period will last 24 weeks. After completion of the extension treatment 
period, the participant will be able to join the Roll-over extension program, which will provide 
access to iptacopan and enable long-term safety monitoring. For participants not agreeing to 
continue in the Roll-over extension program after completing Day 336 visit, End of Study will 
be after completing recommended procedures defined in Section 9.1.1 of the study protocol. 
 
1.2 
Study objectives and endpoints 
Table 1-1 
Objectives and related endpoints for the Core treatment period 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
Endpoint(s) for primary objective(s) 
• 
To assess the effect of iptacopan on 
proportion of participants treated with 
iptacopan achieving a sustained increase 
from baseline in hemoglobin levels of ≥ 2 
g/dL in the absence of red blood cell 
transfusion 
• Response defined as having an increase 
from baseline in Hb ≥ 2 g/dL assessed 
between Day 126 and Day 168, in the 
absence of packed red blood cell (pRBC) 
transfusions between Day 14 and Day 168  
Secondary Objective(s) 
Endpoint(s) for secondary objective(s) 
• To assess the effect of iptacopan on the 
proportion of participants achieving 
•  Response defined as having Hb levels ≥ 12 
g/dL between Day 126 and Day 168 in 


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Objective(s) 
Endpoint(s) 
sustained hemoglobin levels ≥ 12 g/dL in the 
absence of red blood cell transfusions 
absence of red blood cell transfusion 
between Day 14 and Day 168 
• To assess the effect of iptacopan on 
transfusion avoidance (TA) defined as the 
proportion of participants who remain free 
from transfusions 
• Absence of administration of packed-red 
blood cell transfusions between Day 14 and 
Day 168 
• To assess the effect of iptacopan on average 
change in hemoglobin   
•  Change from baseline in hemoglobin (g/dL)  
as mean of visits between Day 126 and Day 
168 
• To assess the effect of iptacopan on average 
percent change in Lactate Dehydrogenase 
(LDH) 
• Percent change from baseline in LDH levels 
(U/L) as mean of visits between Day 126 
and Day 168 
• To assess the effect of iptacopan on the rate 
of  breakthrough hemolysis (BTH) 
• Occurrences of breakthrough hemolysis 
reported between Day 1 and Day 168 
• To assess the effect of iptacopan on average 
change in reticulocyte counts 
• Change from baseline in reticulocyte counts 
(109/L) as mean of visits between Day 126 
and Day 168 
• To assess the effect of iptacopan on 
improving fatigue, using the FACIT-Fatigue 
questionnaire 
• Change from baseline in FACIT-Fatigue 
scores as mean of visits between Day 126 
and Day 168 
• To assess the rates of Major Adverse 
Vascular Events (MAVEs incl. thrombosis) 
• Occurrences of MAVEs occurring between 
Day 1 and Day 168 
• To assess safety and tolerability of iptacopan 
• Safety assessments (including adverse 
events/serious adverse events, safety 
laboratory parameters, vital signs etc.) 
between Day 1 and Day 168 


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Table 1-2 
Objectives and related endpoints for the Extension treatment period 
Objective(s) 
Endpoint(s) 
• To assess long term safety, tolerability and 
efficacy of iptacopan  
• Safety assessments including adverse 
events/serious adverse events, safety 
laboratory parameters, vital signs etc. 
through End of Study visit  
• Efficacy endpoints including hematological 
response parameters, transfusion 
avoidance, BTH, FACIT-fatigue score, 
MAVEs through End of Study visit  
1.2.1 
Primary estimands 
The primary clinical question of interest is: 
What is the effect of iptacopan, regardless of discontinuations of study drug or occurrence of 
Breakthrough hemolysis (BTH) or Major Adverse Vascular Events (MAVEs) on the primary 
endpoint (a composite of improvement in hemoglobin levels and absence of RBC transfusions), 
as assessed by the proportion of responders? 
This primary estimand captures both the hematological effect of the study drug (as evaluated 
by a clinically relevant increase of ≥ 2 g/dL in hemoglobin levels) and the absence of RBC 
transfusions after Day 14 which are regarded as treatment failure.  
The attributes of the primary estimand are: 
• Population: PNH Patients ≥ 18 years old with hemolysis (LDH > 1.5 ULN) and anemia 
(hemoglobin <10 g/dL), and who have not received any complement inhibitor therapy 
(including anti-C5 antibody).  
• Treatment of interest: the investigational treatment iptacopan at a dose of 200 mg b.i.d 
regardless of whether the patient discontinues treatment (treatment policy).  
• Intercurrent events: Transfusions (after Day 14) will be considered treatment failures and 
as such captured in the endpoint. Discontinuations of study medication for any reason, BTH 
events, and MAVEs will be handled with a treatment policy strategy.  
• The summary measure: the probability of being a responder, standardized to the population 
of patients assigned to iptacopan in this study. 
 


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The justification of handling of intercurrent events is in Table 1-3. The overview of estimands 
and estimation methods is in Table 5-1 in Section 5.2.  
 
Table 1-3 
Justification of handling of intercurrent events 
Intercurrent event 
Handling strategy  
Justification 
Discontinuation of study 
medication 
Treatment policy 
The effect of treatment will be assessed 
even when participants discontinue study 
medication. Data collection will be 
maintained and available 
measurements post-treatment 
discontinuation used maintaining the 
treatment label as assigned at enrollment. 
Breakthrough hemolysis events 
Treatment policy 
The effect of treatment will be assessed. 
Breakthrough hemolysis may affect the 
endpoints considered in the study, hence  
data collection will be maintained and 
available measurements collected after 
breakthrough hemolysis event keeping the 
treatment label as assigned at enrollment. 
MAVEs 
Treatment policy 
The effect of treatment will be assessed, 
in particular in the presence or after the 
occurrence of MAVEs. Data collection 
will be maintained and available 
measurements collected after MAVEs 
used under the treatment assigned at 
enrollment. 
 
1.2.2 
Secondary estimands 
The population associated with the secondary estimands is the same as for the primary 
estimands. For these secondary estimands we consider the same intercurrent events as for the 
primary estimands. The proposed approach in the case of transfusion handling will be described 
in the endpoint definition, while discontinuations of study medication, breakthrough hemolysis 
events, and MAVEs whose impact is expected to be reflected in the respective endpoints, will 
be handled with a treatment policy strategy. 
The secondary estimands are defined by the evaluation of treatment effect on the following 
endpoints and summary measures: 
• Response defined as having Hb levels ≥ 12 g/dL between Day 126 and Day 168 in 
absence of red blood cell transfusion between Day 14 and Day 168. The summary 
measure is the same as for the primary endpoint.  
• Absence of administration of packed red blood cell transfusions (pRBC) between Day 
14 and Day 168. Proportions of participants not receiving any transfusions between Day 


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14 and Day 168 (Transfusion Avoidance). The summary measure is the same as for the 
primary endpoint. 
• Changes from baseline in hemoglobin between Day 126 and Day 168 where 
transfusions occurring between Day 14 and Day 168 are treated within a hypothetical 
strategy (as if the participants had not received any transfusions). The summary measure 
is the mean change from baseline in hemoglobin levels assessed between Day 126 and 
Day 168. 
• Percent change from baseline in LDH between Day 126 and Day 168 where the strategy 
applied to transfusions is treatment policy. The summary measure is derived from the 
mean log transformed ratio to baseline in LDH between Day 126 and Day 168. 
• Rates of BTH occurring between Day 1 and Day 168. The summary measure is 
occurrences per year. 
• Change from baseline in reticulocytes counts between Day 126 and Day 168 where the 
strategy applied to transfusions is treatment policy. The summary measure is the mean 
change from baseline in reticulocytes counts assessed between Day 126 and Day 168.  
• Change from baseline in scores of fatigue using the FACIT Fatigue questionnaire 
between Day 126 and Day 168, where the strategy applied to transfusions is treatment 
policy. The summary measure is the mean change from baseline in scores of fatigue 
assessed between Day 126 and Day 168. 
• Rates of Major Adverse Vascular Events (MAVE) occurring between Day 1 and Day 
168. The summary measure is occurrences per year. 
Estimand considerations in case of COVID-19 pandemic impact 
The overarching principle for primary and secondary estimands, is answering questions of 
treatment effect of iptacopan that are valid in conditions when the COVID-19 pandemic is no 
longer present. 
Data capture and clinical evaluation activities include possible adaptations to restrictions for 
patient access to investigational sites in case of a new infection wave. The planned analyses 
could be supplemented by supportive analyses as well as sensitivity analyses if required by the 
presence of deviations from the normal methods of patient follow up and data capture.  
Potential impact of a new wave of COVID-19 infections affecting measurements have been 
minimized through the measures proposed in the study protocol. However other impact that at 
this stage cannot be excluded such as withdrawal from study follow up due to infection which 
would require dealing with such events as additional intercurrent events. This would define 
additional estimands, possibly primary and secondary estimands all of which would deal with 
the COVID-19 related intercurrent events so that inference would still concern treatment effects 
in a world that is not in the midst of an extraordinary pandemic situation. The methodology for 
these estimands and additional sensitivity analyses for cases of missing data due to the impact 
of COVID-19 infections will be specified in detail in an amendment to the document developed 
in the event of renewed COVID-19 infection waves. Decisions on handling of possible increases 
in background risks impacting study endpoints will also take into consideration relevant 
epidemiological information on local incidence of COVID-19 infections. 


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2 
Statistical methods 
2.1 
Data analysis general information 
The final analysis will be performed by the sponsor. Data will be analyzed according to Section 
12 of the CLNP023C12301 clinical study protocol. The most recent version of SAS and 
R®  softwares available in the statistical programming environment will be used for the analysis. 
All analyses of data to be provided to the DMC will be carried out by an independent statistical 
group (CRO) as described in the DMC charter; the statistical analyses for the DMC will be 
drafted in a separate document. 
2.1.1 
General definitions  
2.1.1.1 
Study day 
Study day is defined as the number of days since the date of first dose of study treatment. The 
date of first dose of study treatment is defined as Day 1 and the day before the first dose of 
study treatment is defined as Day -1. 
Therefore, for a particular date, study day will be calculated as follows: 
• for dates on or after the first date of study treatment, 
Study day = Assessment date – Date of first dose of study treatment + 1; 
• for dates prior to the first date of study treatment, 
Study day = Assessment date – Date of first dose of study treatment. 
If a patient never took study treatment, one day after the date of completion of screening 
assessments will be used instead of the date of first dose of study treatment. In that case, one 
day after the date of completion of screening assessments is defined as Day 1 and the day before 
the date of completion of screening assessments is defined as Day -1. 
2.1.1.2 
Baseline definition 
For the analysis on efficacy and safety data in the core treatment period on the analysis sets 
FAS and SAF as defined in Section 2.2, the baseline value is defined to be the last result 
obtained at or prior to start of study treatment (Day 1) for baseline demographics, medical 
history, lab values, vital signs and ECGs. Most variables will have their baseline at Day 1, 
unless otherwise specified. For assessments not performed at Day 1, the assessment at the 
screening visit or most recent assessment prior to start of study treatment will be used as 
baseline. For baseline derivation of laboratory parameters, central lab measurements will be 
used. If there are no central lab data available, then local lab measurements will be used for 
baseline computations only. 
• The baseline hemoglobin will be the mean of the two confirmatory measurements 
(planned) taken during screening that confirm the hemoglobin entry criterion in 
patients who do not receive a transfusion between the first and second confirmatory 
measurement. In patients who receive a transfusion after the first confirmatory 
measurement, the baseline will be the first measurement. 




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The Full Analysis Set (FAS) comprises all participants with confirmed eligibility to whom 
study treatment has been assigned. This will be the data set used for analysis of all efficacy 
endpoints. 
The Safety Set (SAF) includes all participants who received at least one dose of study treatment.  
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Demographic and other baseline data including disease characteristics will be  summarized 
descriptively for the FAS. In addition, summaries of relevant past or current medical conditions 
will be presented. 
Categorical data will be presented as frequencies and percentages. The summary statistics 
shown for continuous data will be mean, standard deviation, median,  minimum, and maximum. 
2.3.1 
Patient disposition 
Core treatment period 
The number of patients screened, screened but not treated, treated, completed and discontinued 
from the study in the core treatment period will be summarized. The reasons for screen failure 
will be provided. Participants discontinued from the study in the core treatment period will also 
be summarized with reasons for discontinuation. In addition, number of participants who 
discontinued study treatment, reason for discontinuation of study treatment and number of 
patients who discontinued study treatment but stayed in the core treatment period will be 
summarized. Participants who discontinued study treatment but continued in the study during 
the core treatment period are defined as participants with the date of study discontinuation or 
Day 168 visit - the end date of study treatment > 0. 
Extension treatment period 
The number of participants who completed and discontinued from the study in the Extension 
treatment period will be summarized. The reasons for discontinuation will be provided. 




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Duration of treatment in the core treatment period 
The duration of treatment iptacopan 200 mg b.i.d in the core treatment period is defined as the 
duration from the date of first administration of study treatment in the core treatment period to 
the date of last administration of iptacopan (any dose) in the core treatment period. 
The end of the core treatment period is the date of last administration (any dose) in the core 
treatment period.  
Duration of treatment in extension treatment period  
The duration of iptacopan 200 mg b.i.d treatment in extension treatment period will be defined 
as the duration from the first date of administration of iptacopan 200 mg b.i.d in the day after 
Day 168 or the first administration of iptacopan 200 mg b.i.d  in the extension treatment period 
to the date of last administration of iptacopan 200 mg b.i.d in the extension treatment period. 
Overall duration of treatment 
An overall duration of iptacopan 200 mg b.i.d treatment would include both core treatment 
period and extension treatment periods, with a start date and a stop date as described above for 
core treatment period and extension treatment periods, respectively. 
Exposure and Dose Intensity for iptacopan  
The Safety set (SAF) will be used for the analyses of exposure to iptacopan described 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) to iptacopan  as well as the dose intensity and the relative 
dose intensity of iptacopan 200 mg b.i.d will be summarized by means of descriptive statistics 
using SAF during the core treatment period and for overall. 
Duration of exposure to study treatment will be calculated as the number of days between the 
first  dose date and the last dose date exposed to Iptacopan 200 mg b.i.d over the specified period 
but excluding temporary treatment interruptions (expressed as: Duration of exposure = Date of 
last known dose of study drug – Date of first dose of study drug + 1 excluding interruptions).  
The duration of exposure to study treatment will be computed and summarized as the duration 
of treatment, but excluding temporary treatment interruptions. To establish the start of an 
interruption, the same rules should apply as for end of the duration of treatment described above. 
An interruption will be defined as at least one full day without any dose. 
Cumulative duration exposure on iptacopan 200 mg b.i.d based on SAF will be summarized as 
a categorical variable classified into ≤4, ≤8, ≤12, ≤16, ≤20, ≤24, ≤28, ≤32, ≤36, ≤40, ≤44, ≤48 
weeks.  
The duration of exposure will be the basis for the computation of the dose intensity and the 
relative dose intensity. The dose intensity for patients on iptacopan 200 mg bid will be computed 
as the ratio of actual cumulative dose received and actual duration of exposure. Relative dose 
intensity for patients on iptacopan 200 mg b.i.d will be computed as the ratio of dose intensity 


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and planned dose intensity. The planned dose intensity for patients on iptacopan 200 mg bid 
will be 400 mg/day. The dose intensity for patients on iptacopan will be summarized as a 
categorical variable classified into the categories stated in Table 2-1. Relative dose intensity 
will also be summarized on a continuous scale as well as considering categories (%): ≤ 75, > 
75, > 90-100 and summaries on dose intensities will be presented on SAF.  
The information on iptacopan +transfusions will be  summarized as a categorical variable 
considering the dose intensity and tranfusions in the core treatment period. Summaries on the 
categories stated in Table 2-1. Such summaries will be presented on SAF.  
For participants on iptacopan, the calculation of duration of treatment, exposure, dose intensity 
and relative dose intensity will include the investigational treatment iptacopan 200 mg b.i.d as 
well as the iptacopan tapering doses (if applicable).  
Table 2-1 
Summary on dose intensity and transfusions for patients on 
iptacopan  
Dose intensity 
Dose intensity and transfusions 
 
 
<400 mg/day 
<400 mg/day + no transfusion 
400 mg/day  
<400 mg/day + 1 transfusion 
 
<400 mg/day + ≥2 transfusions 
 
400 mg/day + no transfusion 
 
400 mg/day + 1 transfusion 
 
400 mg/day + ≥2 transfusions 
For participants on iptacopan, an interruption will be defined as at least one full day without 
any dose. The number of participants with interruptions, number of interruptions and durations 
of interruptions will be summarized on SAF. The information on study medication intake for  
participants having at least one interruption will be listed. The number of participants with 
missed doses and number of missed doses will be summarized on SAF. 
2.4.2 
Prior, concomitant and post therapies 
Medications and significant non-drug therapies started and stopped prior to study treatment, 
and those taken concomitantly, will be summarized based on SAF. Among the concomitant 
medications, rescue medications will be summarized based on SAF. The medications and 
significant non-drug therapies will be classified into “prior”, “concomitant”, “post-treatment” 
based on the start/end dates. The rescue therapy will be used for analysis as it is reported by the 
investigator under the subcategory of Rescue Medications/Therapy on the Concomitant 
Medication, Surgical and Medical Procedures CRF pages.Prior: Any medication and significant 
non-drug therapy with a start date and end date before Day 1. 
Concomitant: Any medication or significant non-drug therapy administered at least once during 
the duration of the treatment (as defined in Section 2.4.1). It does not include 7 days after the 
last dose of iptacopan as in the definition of the on-treatment period for treatment emergent 
adverse event (TEAE). Medications started prior to first day of study drug intake and continuing 
after study drug start will be counted as concomitant. 


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Post-treatment medications will be defined as any medication with start date after the end of 
treatment (any dose).  
A therapy started within 7 days after the last dose of iptacopan is not considered as concomitant 
although some TEAEs leading to concomitant medications may be reported in that period. The 
objective of this convention is to avoid reporting as concomitant medication some post 
treatment therapies targeting the study indication. 
Prior, concomitant, post-treatment medications will be summarized according to the 
Anatomical Therapeutic Chemical (ATC) classification system. More than one ATC class per 
medication is possible and the medication will be reported under all applicable classes. 
Prior, concomitant, post-treatment therapies will be recorded and summarized separately for 
surgical and medical procedures. 
All vaccinations received by patients any time during the study (including core treatment period, 
extension treatment period) will be tabulated by serogroup/polyvalent and for each period. All 
vaccinations will also be recorded as prior and/or concomitant medication, as appropriate. 
2.5 
Analysis of the primary objective 
For all efficacy analyses based on laboratory data (e.g. hemoglobin, reticulocytes etc.) 
addressing primary and secondary objectives, the information obtained from the central lab will 
be used. 
2.5.1 
Primary endpoint(s)/Primary estimand(s) 
The primary endpoint defines the response as sustained increase in hemoglobin and a participant 
as a responder if :  
• The change from baseline in hemoglobin is ≥ 2 g/dL on three out of four measurements 
taken at the visits occurring in last six weeks (from Day 126 to Day 168) of the Core 
treatment period, and 
• The participant has not met the criteria for administration of RBC transfusions nor received 
a transfusion between Day 14 and Day 168. 
• The baseline hemoglobin will be the mean of the two measurements taken during screening 
that confirm the hemoglobin entry criterion in patients who do not receive a transfusion 
between the first and second confirmatory measurement. In patients who receive a 
transfusion after the first confirmatory hemoglobin measurement, the baseline will be the 
first measurement. 
Criteria for administration of RBC transfusions 
To standardize criteria for administration, transfusion criteria have been established and will 
apply starting from Day 1 of the study. 
Packed-RBC transfusions will be administered to participants in the following cases: 
• Hemoglobin level of ≤9 g/dL (≤8 g/dL for Chinese population) with signs and/or symptoms 
of sufficient severity to warrant a transfusion 
• Hemoglobin of ≤7 g/dL (≤6 g/dL for Chinese population), regardless of presence of clinical 
signs and/or symptoms 


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The transfusions information will be collected on the ‘Transfusion-during the study’ CRF page.  
Handling of intercurrent events of primary estimand 
Reaching the protocol established criteria for RBC transfusions will be handled using a 
composite strategy for primary endpoint. 
Intercurrent events stemming from discontinuation of treatment, breakthrough hemolysis events 
and MAVEs, expected to be reflected in the endpoint, will be handled with a treatment policy 
strategy. 
2.5.2 
Statistical hypothesis, model, and method of analysis  
2.5.2.1 
Summary statistics for the primary variable 
All descriptive statistics supportive of the primary variable will be based on non-imputed and 
observed data. For patients who did not require any RBC transfusion (i.e. not met the criteria 
for administration of RBC transfusions nor received a transfusion) between Day 14 and Day 
168 separate summaries will be presented on the following information: 
Number of patients having no-missing hemoglobin data in the in last six weeks (from Day 126 
to Day 168), number of patients having an increase in hemoglobin ≥ 2 g/dL from baseline on 
three out of four measurements taken at the visits occurring in last six weeks (from Day 126 to 
Day 168) of the Core treatment period.  
2.5.2.2 
Statistical model for primary variable 
The primary analysis of the primary endpoint will be a logistic regression  to estimate the 
response probability. The covariates in logistic regression include sex, age (indicator of age ≥ 
45 years), an indicator variable of baseline hemoglobin ≥ 8 g/dL and an indicator of transfusion 
dependence (i.e. whether the patient had any transfusion in the last 6 months prior to starting 
study treatment) . 
This means that the proportion of responders will be derived from the estimated marginal 
probabilities derived from the model fit as the mean of the individual logistic regression model 
predictions. The 95% confidence intervals will be derived by the bootstrap method 
(Steingrimsson et al 2017). Refer to Section 5.2.2.2 for details.  
In the case that any of the 24 cells (given 4 covariates with 2 categories) have zero responders 
quasi-complete separation (Lu, 2016) may be observed. Moreover, in some imputed datasets or 
bootstrap samples, all participants are responders/non-responders, and this case will cause fit 
failure in logistic regression model.  
Theoretically it can be shown that point estimate of the marginal probability from the logistic 
regression model and the simple response probability without the covariates are the same (Refer 
to Section 5.2.2.2). Since bootstrap is used to calculate the confidence interval, the confidence 
interval is also the same from the estimate from the logistic regression model and the simple 
proportion. Hence, the only reason why there can be a discrepancy in the results is due to a 
convergence issue (e.g. when all patients are responders/non-responders, quasi-complete 
separation issues due to covariates) of the logistic regression. However computation using 
simple proportion does not lead to such convergence issues and hence provide valid estimates. 


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The results from protocol specified logistic regression method and 95% CI using bootstrap 
will be computed. If the logistic regression fails to convergence in at least one of the imputed 
datasets or the bootstrap samples, then the estimates will be obtained using simple proportion. 
The 95% CI using simple proportion will also be obtained using the bootstrap method. Refer 
to Section 5.2.2.2 for details. 
The primary analysis of primary endpoint is the assessment of the proportion of patients 
reaching the status of responder (as defined in Section 2.5.1). The lower bound of the two-sided 
95% confidence interval of the response rate obtained from primary analysis will be compared 
to a threshold of 15%. Lower bound of the two-sided 95% confidence interval ≥ 15% is 
sufficient for demonstration that iptacopan improves hematological response in PNH patients 
with hemolysis and anemia in the absence of transfusions. The derivation of the threshold is 
explained in Section 5.2.2.3. 
2.5.3 
Handling of missing values not related to intercurrent event. 
For the primary response definitions, RBC transfusion will qualify the participant as a non-
responder, hence missing hemoglobin data after meeting the criteria for transfusion or after 
receiving a transfusion during Day 14 to Day 168 does not impact the primary analysis.  
Missing hemoglobin data due to withdrawal from study in the core treatment period in the event 
that a participant did not have a prior RBC transfusion, will be imputed in a multiple imputation 
framework based on pattern mixture models. This aims to be consistent with the inclusion of 
hemoglobin data under the treatment policy strategy following all other intercurrent events. The  
need for transfusion will then be derived from this imputation with imputed values ≤ 9 g/dL (≤ 
8 g/dL for Chinese population) considered sufficient to warrant a transfusion. This means 
assuming conservatively that all patients with imputed hemoglobin between 9 g/dL and 7 g/dL 
(between 8 g/dL and 6 g/dL for chinese patients) would have presented symptoms waranting 
transfusion. 
• For participants withdrawing from study after discontinuation of iptacopan, the model 
implemented will recover a return to pre-treatment levels of Hb. This would be 
implemented by imputing missing values from a normal distribution with mean and 
standard deviation derived from all baseline hemoglobin values. 
• For participants with intermittent missing data, their missing data will be handled with 
a missing at random approach and imputed consequently. 
The model for imputation will be Markov chain Monte Carlo (MCMC) method and only 
baseline hemoglobin will be included in the imputation model. 
2.5.4 
Sensitivity analyses for primary endpoint/estimand 
Sensitivity analyses on the primary endpoint will be performed where missing central lab 
hemoglobin data will be replaced by available local lab data collected at the same visit. The 
logistic regression model and simple proportion without any covariate adjustment which are 
used for primary efficacy analysis will be performed for these sensitivity analyses. 
Additional sensitivity analyses on the primary analysis will be performed:  


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• Considering the  need for transfusion derived from imputation with imputed values ≤ 7 
g/dL (≤ 6 g/dL for Chinese population) to be sufficient to warrant a transfusion. 
This means assuming that none of the patients with imputed hemoglobin between 9 g/dL 
and 7 g/dL (between 8 g/dL and 6 g/dL for chinese patients) would have presented 
symptoms waranting transfusion. 
• Considering administered transfusions. 
2.5.5 
Supplementary analyses 
A supplementary estimand considering the use of rescue therapy (as defined in the study 
protocol) under intercurrent event as treatment failure, for the purpose of efficacy assessment, 
will be performed. The supplementary estimand will have the same population, treatment of 
interest, and summary measure as the primary estimand. The logistic regression model or simple 
proportion which is used for primary efficacy analysis will be performed for these 
supplementary analyses (see Section 2.5.2.2). For this analysis the following will be considered: 
• Participant meeting the criteria for administration of RBC transfusions or having 
received a transfusion between Day 14 and Day 168 will be considered treatment 
failures. 
• Use of rescue medication during the core treatment period between Day 1 and Day 168 
will be considered treatment failures. The rescue therapy will be used for analysis as it 
is reported by the investigator under the subcategory of Rescue Medications/Therapy 
on the Concomitant Medication, Surgical and Medical Procedures CRF page. 
• Discontinuations of study medication for any reason will be handled with treatment 
policy strategy. 
The marginal proportions /response probabilities will be estimated using a logistic regression 
or simple proportion as for the primary variable (Section 5.2.2.2). 


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2.6 
Analysis of secondary endpoints/estimands 
2.6.1 
Secondary endpoints/secondary estimands 
Descriptive statistics and summaries on the secondary endpoints based on FAS will be provided. 
2.6.1.1 
Proportion of participants achieving sustained hemoglobin levels ≥ 12 
g/dL in the absence of red blood cell transfusions 
The number and percentage of patients reaching a fixed threshold ≥ 12 g/dL on three out of four 
measurements taken at the visits occurring in last six weeks (from Day 126 to Day 168). 
The analysis of the secondary endpoint will be a logistic regression and simple proportion to 
estimate the response probability. The covariates in logistic regression include sex, age 
(indicator of age ≥ 45 years), an indicator variable of baseline hemoglobin ≥ 8 g/dL and an 
indicator of transfusion dependence prior to starting study treatment. 
This means that the proportion of responders will be derived from the estimated marginal 
probabilities derived from the model fit as the mean of the individual logistic regression model 
predictions, together with the 95% confidence intervals, where the standard error will be derived 
by the bootstrap method (Steingrimsson et al 2017). 
The marginal proportions /response probabilities will be estimated using a logistic regression 
or simple proportion as for the primary variable (Section 5.2.2.2). 
 
2.6.1.2 
Transfusion Avoidance 
The number and percentage of patients not receiving and not meeting the criteria for 
administration of  packed RBC tranfusions in the core treatment period will be summarized 
overall and by transfusion history during the last 6 months prior to starting study treatment (i.e. 
transfusion received/not received). The number and percentage of patients not receiving and 
not meeting the criteria for administration of any RBC transfusion between Day 14 and Day 
168 will be summarized overall and by transfusion during the last 6 months prior to start of 
study treatment (i.e. transfusion received/not received). Time to first packed RBC transfusion 
from start of study treatment (Day 1) will be plotted using Kaplan Meier curves for overall and 
by transfusion during the last 6 months prior to start of study treatment (i.e. transfusion 
received/not received).  
For RBC transfusions during the study, the hemoglobin level criterion deemed appropriate by 
the investigator for requiring the transfusion and signs and symptoms reported prior to receiving 
transfusion will be summarized. The information will be summarized based on the 
‘Transfusion-during the study’ CRF page.  
Transfusion avoidance will be evaluated as the proportion of participants not receiving and not 
meeting the criteria of administration of RBC transfusion between Day 14 and Day 168, and 
similarly to the estimation applied to the primary estimand (Section 2.5.2) by means of 
standardized marginal proportions. The logistic regression model will include sex, age 
(indicator of age ≥ 45 years), an indicator variable of baseline hemoglobin ≥ 8 g/dL and an 
indicator of transfusion dependence.  


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The marginal proportions /response probabilities will be estimated using a logistic regression 
or simple proportion as for the primary variable (Section 5.2.2.2). 
2.6.1.3 
Change from baseline in hemoglobin levels 
Estimation of change from baseline in hemoglobin levels is under the hypothetical situation in 
which participants would not have received transfusions on iptacopan treatment. For this 
analysis, if a participant had a transfusion during the core treatment period then the hemoglobin 
values 30 days following the transfusion will be considered missing and hemoglobin data will 
be imputed. In practice, this would be implemented considering participants on iptacopan to 
have data imputed assuming missing at random. This will be accomplished by the use of 
imputed values (Section 2.5.3).  
The model for the estimation is a mixed model for repeated measures (MMRM) considering an 
unstructured covariance structure. The model will include transfusion dependence, age 
(indicator of age ≥ 45 years), sex, visit, baseline hemoglobin and the interactions between visits 
and baseline levels. The treatment estimates will be computed as the mean changes from 
baseline corresponding to the average of hemoglobin levels measured in the last 6 weeks of 
treatment (that is the visits occurring between Day 126 and Day 168).  
The estimated least square mean estimate of the treatment effect and the associated 95% 
confidence interval will be plotted over time. Refer to Section 5.2.3 for detail.  
2.6.1.4 
Change from baseline in FACIT-Fatigue scores 
The endpoint consists of changes from baseline in scores of fatigue using the FACIT-Fatigue 
questionnaire where baseline is defined as in Section 2.1.1.2. As for the other endpoints, the 
longitudinal model will be a repeated measures model including test scores collected at all visits. 
The model for the estimation is a MMRM considering an unstructured covariance strucure. The 
model will include transfusion dependence, age (indicator of age ≥ 45 years), sex, visit, baseline 
in scores of fatigue and the interactions between visits and baseline levels. The estimation will 
be an average of treatment estimates derived for visits occurring between Day 126 and Day 168. 
The estimated least square mean estimate of the treatment effect and the associated 95% CI will 
be plotted over time.  
2.6.1.5 
Change from baseline in reticulocyte counts 
The estimation of the change from baseline in absolute reticulocyte counts will be derived from 
a MMRM including data collected throughout the study and where baseline is defined as the 
value on Day 1. The model for the estimation is a MMRM considering an unstructured 
covariance structure. The model will include transfusion dependence, age (indicator of age ≥ 
45 years), sex, visit, baseline reticulocyte counts and the interactions between visits and baseline 
levels.  
The estimation will use the average of model derived estimates obtained at visits occurring 
between Day 126 and Day 168. The estimated least square mean estimate of the treatment effect 
and the associated 95% CI will be plotted over time.  


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2.6.1.6 
Percent change from baseline in LDH 
The treatment effect on percent change from baseline in LDH will be assessed using a MMRM 
of log transformed ratio to baseline based on all observations collected during follow-up. The 
model for the estimation is a MMRM considering an unstructured covariance structure. The 
model will include transfusion dependence, age (indicator of age ≥ 45 years), sex, visit, log-
transformed baseline LDH and the interactions between visits and log-transformed baseline 
levels. Estimation will be derived based on the average of the log transformed ratio from 
baseline estimated between Day 126 and Day 168. Percentage change from baseline (reduction 
or increase) and associated 95% confidence intervals will be plotted for treatment effect over 
time. 
2.6.1.7 
Rates of Major Adverse Vascular Events (MAVE) 
Information of MAVEs as collected on the ‘MAVE’ CRF page will be used for analysis and 
the information will also be reported as a part of the adverse event summaries. The number and 
percentage of participants with treatment-emergent (MAVEs) in the core treatment and 
extension treament periods will be summarized by reported term. The information on MAVEs 
(including those in the screening period) will be listed and the treatment emergent events will 
be flagged. 
Based on FAS, the estimation of rates of  MAVEs will be carried out using a negative binomial 
model. Due to the expected low frequency of occurrences, no covariates are planned to be 
included. Following the treatment policy strategy for handling treatment discontinuations, the 
offset variable will be defined as the time from Day 1 till minimum (end of study, end of core 
treatment period). 
If the model fails to converge, then a Poisson model without covariates will be fitted. If both 
negative binomial and Poisson model fail to converge, the Wilson (Miettinen and Nurminen, 
1985) method will be implemented to produce 95% CI. 
2.6.1.8 
Rates of clinical breakthrough hemolysis 
Information of clinical breakthrough events as collected on the ‘Breakthrough Hemolysis’ CRF 
page will be used for analysis and the information will also be reported as a part of the adverse 
event summaries. The number and percentage of patients experiencing treatment emergent 
clinical breakthrough hemolysis events in the core treatment and extension treatment periods 
will be summarized. The information on whether the patient received packed-RBC transfusions 
and the quantity of packed-RBC tranfusions due to clinical breakthrough hemolysis will be 
summarized. Clinical breakthrough hemolysis events (including those in the screening period) 
will be listed and the treatment emergent events will be flagged. 
Based on FAS, the estimation of rates of  clinical breakthrough hemolysis will be carried out 
using a  negative binomial model . The model will include the following covariates: transfusion 
dependence, age (indicator of age ≥ 45 years), sex, indicator variable of baseline hemoglobin ≥ 
8 g/dL. Following the treatment policy strategy for handling treatment discontinuations, the 
offset variable will be defined as the time from Day 1 till minimum (end of study, end of core 
treatment period). 


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If the above model fails to converge due to low frequency of occurrences, then the model will 
be run considering no covariates in the  negative binomial model. If the model fails to converge, 
then a Poisson model without covariates will be fitted. If both negative binomial and Poisson 
model fail to converge, the Wilson (Miettinen and Nurminen, 1985) method will be 
implemented. 
2.6.2 
Handling of missing values for secondary endpoints 
Missing data during study follow up will be imputed following the same principles as for the 
primary estimands/endpoints: intermittent missing data will be imputed according to the 
missing at random (MAR) principle. Missing data due to withdrawal from the study or 
discontinuation for iptacopan treatment will be imputed by recovering a return to pre-treatment 
levels. This would be implemented by imputing missing values from a normal distribution with 
mean and standard deviation derived from all baseline values. In case of intermittent missing 
data, their missing data will be handled with a missing at random approach and imputed 
consequently.  
The model for imputation will be Markov chain Monte Carlo (MCMC) method, and only 
baseline values will be included in the imputation model. 
For the transfusion avoidance endpoint the handling of missing data will be very similar to the 
handling of missing data for the primary endpoints and the same multiple imputed datasets can 
be used.  
For the specific case of missing hemoglobin due to withdrawal, the imputation will reflect 
whether or not data were missing following a transfusion.  
In the case of definitive withdrawal of study follow up following a transfusion only hemoglobin 
levels at visits during 30 days following the transfusion and until treatment discontinuation 
would be imputed under the MAR assumption. The missing hemoglobin after treatment 
discontinuation will be imputed by recovering a return to pre-treatment levels of hemoglobin. 
This would be implemented by imputing missing values from a normal distribution with mean 
and standard deviation derived from all baseline values.  More specifically a patient should be 
first imputed in the hypothetical scenario for hemoglobin until end of treatment.  In case of 
definite withdrawal of study follow up without transfusion missing data will be imputed as 
stated in Section 2.5.3.  
In all estimation based on a longitudinal model, missing data will be imputed multiple times. 
The imputed datasets will be used in the estimation of the longitudinal model. Where both 
intercurrent events (as for the hypothetical estimand estimating hemoglobin levels) and missing 
data are imputed or where only missing data are imputed, the model estimation will be derived 
using Rubin’s combination rules. 
For endpoints, eg. FACIT-fatigue which are constrained to be in a finite range of values, if some 
imputed values are lower than the limit, then they will be truncated to the lower limit and if 
some imputed values exceed the upper limit then they will be truncated to the upper limit. 


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2.6.3 
Sensitivity analyses 
Sensitivity analyses will be performed where missing central lab data will be replaced by 
available local lab data collected at the same visit. MMRM for analysis of change from baseline 
in hemoglobin under a hypothetical strategy, change from baseline in reticulocytes, and change 
from baseline in LDH levels stated in Section 2.6.1.1, 2.6.1.2, 2.6.1.3, 2.6.1.5, 2.6.1.6, 
respectively, will be performed.  
Additional sensitivity analyses will be performed for hemoglobin normalization (Section 
2.6.1.1) and transfusion avoidance (Section 2.6.1.2):  
• Considering the  need for transfusion derived from imputation with imputed values ≤ 7 
g/dL (≤ 6 g/dL for Chinese population) to be sufficient to warrant a transfusion. 
• Considering administered  transfusions. 
2.6.4 
Supportive analyses 
To complement the secondary estimand analysis of average changes in hemoglobin under a 
hypothetical strategy, the analysis evaluating average changes in hemoglobin will be repeated 
using a treatment policy approach, to obtain the estimation of the combination of 
Iptacopan+transfusions as needed. 
Supportive analyses on the secondary endpoints: change from baseline in LDH, FACIT, 
reticulocytes will be performed under a hypothetical strategy. For these analyses, the values on 
these 3 endpoints in the 30 days following transfusion will be considered missing and the values 
will be imputed. The imputation methods will be similar to those outlined in Section 2.6.2. 
2.7 
Safety analyses 
Unless otherwise specified all safety summaries will be presented by SAF. Safety summaries 
based on only core treatment period and overall (based on information from core treatment 
period and extension treatment period) will be produced as appropriate. 
Safety summaries (tables, figures) 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 of death events including on treatment and post treatment 
deaths will be provided if appropriate. 
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 (including core treatment period, extension 
treatment period and tapering procedures after permanent treatment discontinuation) of 
iptacopan which covers slightly more than 5 times the estimated half-life of iptacopan. 
2.7.1 
Adverse events (AEs) 
All information obtained on AEs will be displayed by participant.  
The number (and percentage) of participants with treatment emergent AEs (events starting after 
the first dose of study medication or events present prior to start of treatment but increased in 


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severity based on preferred term) and treatment emergent serious adverse events (SAEs) will 
be summarized in the following ways: 
• by primary system organ class (SOC) and preferred term (PT). 
• by primary SOC, PT and maximum severity. 
Separate summaries will be provided for study treatment emergent AEs, death, SAEs, and AEs 
leading to discontinuation of study medication, and for iptacopan tapering if this is followed 
prior to complete study dose discontinuation. For patients receiving iptacopan, treatment 
emergent SAEs and AEs with PTs in the AESI ‘PNH haemolysis and thrombosis’ occurring 
after dicontinuation of iptacopan 200 mg b.i.d will be reported separately. 
A participant with multiple AEs within a primary SOC is only counted once towards the total 
of the primary SOC. 
Most frequent AEs, most frequent SAEs, AEs leading to treatment discontinuation will be 
presented by preferred term. 
Summaries presenting exposure adjusted incidence rates and associated 95% CI based on 
TEAEs and treatment emergent SAEs will be provided. AEs (including pre-treatment, on-
treatment, post-treatment events)  will be listed.  
In order to address the issue of variable follow-up duration within study, the exposure adjusted 
incidence rate of TEAE will be presented by primary SOC and PT.  
For the most common AEs, the 95% CI of the exposure adjusted incidence rate of TEAE can 
be presented. 
Exposure adjusted incidence rate and 95% confidence interval 
For summary tables  on exposure-adjusted AEs, the number of episodes per 100 patient years 
will be presented. The occurrence rate (number of episodes per 100 patient years) will be 
calculated as 100*(the total number of AE episodes from all patients in the population divided 
by the total number of patient-years). A patient may have multiple occurrences of the same 
event. All occurrences are counted. Total patient years will be computed as (sum of the duration 
of on-treatment periods over patients, in days)/365.25. The approximately 95% CIs for the 
occurrence rate will be calculated with correation for overdispersion using the asymptotically 
robust method (Scosyrev 2016,  Scosyrev and Pethe 2022). 
This method will account for the length of follow-up time under the assumption that events 
would occur with the same frequency at any point in time. Although this analysis is referred to 
as “Exposure adjusted” it actually uses by default the on-treatment (Section 2.7) which includes 
periods of interruption during which there is no exposure. 
2.7.1.1 
Adverse events of special interest / grouping of AEs 
Adverse events of special interest (AESI) are defined in the latest version of the compound 
electronic Case Retrieval Strategy (eCRS) that is stored in the Global Programing System (GPS).  
This classification reflects the safety topics of interest identified in the current version of the 
iptacopan Development Safety Profiling Plan, and may be updated based on review of 
accumulating data. At the time of analyses, the latest version of the eCRS will be used to identify 
the AESIs. Safety topics of interest to be reported are identified by the flag “SP”. 


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The number (and percentage) of participants with treatment-emergent adverse events of special 
interest/related to identified and potential risks will be summarized. The frequency and 
percentage of participants with treatment emergent adverse events of special interest (TEAESI) 
and serious TEAESI will be summarized by preferred team. The exposure adjusted incidence 
rates and associated 95% CI (as stated in Section 2.7.1) will be presented for each safety topic 
of interest AEs/SAEs.  
A listing of participants experiencing AESIs will also be provided. The eCRS safety topic 
definitions to identify AESIs will be provided as a listing. 
For patients receiving iptacopan, treatment-emergent and all AESI within the search ‘PNH 
haemolysis and thrombosis’ occurring after discontinuation of iptacopan 200 mg b.i.d will be 
reported.  All such AEs  occuring after iptacopan 200 mg b.i.d will be listed and the TEAEs 
will be flagged.  
2.7.1.2 
Adverse events reporting for safety disclosure 
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on TEAEs 
which are not SAEs with an incidence greater than a certain threshold and on TESAEs and SAE 
suspected to be related to study treatment, will be provided by SOC and PT on the safety set 
population. 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. 
2.7.2 
Deaths 
The number of deaths resulting from TEAEs will be summarized by SOC and PT. Death refers 
to TEAEs with fatal outcome. In addition, a separate summary of death events including on 
treatment and post treatment deaths will be provided if appropriate. 
All the deaths in the clinical database will be listed.  
2.7.3 
Laboratory data 
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.  


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Laboratory evaluations’ summaries will be presented for groups of laboratory data (clinical 
chemistry, clinical hematology, urinalysis, UACR, coagulation/markers of thrombosis and 
reproductive and thyroid hormone panel).  
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. The on-treatment laboratory values 
will be defined as in Section 2.7. 
For categorical laboratory parameters and categorical urinalysis parameters, a frequency table 
of results will be produced by laboratory parameter, scheduled visit and time-point.  
It is to be noted that for analysis on SAF, different baseline values need to be considered as 
mentioned in Section 2.1.1.2. 
For summary tables on laboratory parameters considering values, which are lower or greater 
than the limit of quantification:  
• The values less than Lower Limit of Quantification (LLoQ) will be imputed to 0.5×LLoQ 
and the values greater than Upper Limit of Quantification (ULoQ) will be imputed to 
1.5×ULoQ. 
• The number and percentage of values below the LLoQ and above the ULoQ will be 
presented.  
For the figures, imputed values will be displayed. 
Plots of arithemic mean (SD) for all lab values will be provided. Note that displays of 
reproductive hormone level parameters (Testosterone, DHT, LH, FSH) will be further split by 
sex.  
The lab abnormalities using the CTCAE grading will be reported. The version 4.03 of the 
CTCAE grading will be used at the time of reporting and the following reports will be provided: 
• New or worsening abnormalities based on CTCAE grade (hematology, chemistry) 
• Shift tables based on CTCAE grade (hematology, chemistry). 
For selected laboratory parameters, abnormalities occurring at any time-point from scheduled, 
unscheduled and premature discontinuation visits considering all post-baseline on-treatment 
data will be summarized. Where normal ranges are available, abnormalities in laboratory data 
will be listed by participant and visit/time. 
Liver toxicities 
A criterion-based table for selected liver function tests and AEs will be presented including the 
number and percentage of the events described in Table 2-2. In the PNH indication, aspartate 
aminotransferase (AST) can increase for reasons not related to liver toxicity and therefore 
should not be considered in the derivation of liver toxicities. Moreover INR is routinely 
monitored and can be used for the definition of liver function events. Events for the PNH 
indication are described in Table 2-2. 
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 


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to liver toxicities (Jaundice, AE potentially indicative of a liver toxicity) will either be reported 
separately in a specific table or will simply be displayed as part of the general AE tables. 
Table 2-2 Liver Toxicities 
Definition  
Label for output display 
Potential Hy’s Law case 
(ALT or AST > 3 × ULN) and TBL > 2 × ULN and ALP to ≤ 2 × ULN 
in the absence of bone pathologya 
(ALT or AST > 3 × ULN) and TBL > 2 × ULN and ALP to ≤ 3 × ULN 
in the presence of bone pathologya 
Potential Hy’s Law case 
ALT elevations  
If ALT ≤ ULN at baseline: 
 (ALT > 3 × ULN) and INR > 1.5 
 
If ALT > ULN at baseline then criteria for ALT are defined as  
ALT > 2 x baseline or > 300 U/L and INR > 1.5 
(ALT > 3 × ULN) and INR > 1.5 
ALT > 8 × ULN 
ALT > 8 × ULN 
If ALT ≤ ULN at baseline: 
ALT > 5 to ≤ 8 × ULN 
 
If ALT > ULN at baseline then criteria for ALT are defined as  
ALT > 3 x baseline or > 300 U/L  
ALT > 5 to ≤ 8 × ULN 
 
If ALT ≤ ULN at baseline: 
ALT > 3 to ≤ 5 × ULN (accompanied by symptoms)a 
 
If ALT > ULN at baseline then criteria for ALT are defined as  
ALT > 2 x baseline or > 300 U/L (accompanied by symptoms)a 
ALT > 3 to ≤ 5 × ULN with 
symptoms 
If ALT ≤ ULN at baseline: 
ALT > 3 to ≤ 5 × ULN (patient is asymptomatic)a 
 
If ALT > ULN at baseline then criteria for ALT are defined as  
ALT > 2 x baseline or > 300 U/L (patient is asymptomatic)a 
ALT > 3 to ≤ 5 × ULN no 
symptoms 
ALP (isolated) 
ALP > 2 × ULN (in the absence of known bone pathology)a 
 
ALP >3 x ULN (if bone pathologya is present) 
ALP > 2 × ULN (>3 x ULN if 
bone pathology is present) 
TBL: total bilirubin 
ALT: alanine aminotransferase 
a concomitance between abnormal laboratory values and symptoms or disease (bone disease, 
Gilbert syndrome) will be established based on reported AEs or medical history with a start date prior 
to laboratory measurement and stop date posterior to laboratory measurement. 
Selection of AEs and medical History is described in Table 2-3 and provided in eCRS 
b Selection of AEs described in Table 2-3 and provided in eCRS 


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When a criterion contains multiple laboratory parameters (e.g. ALT or AST > 3 × ULN), the 
criterion should considered as met only if the elevation in parameters occurs on the same sample 
day (as evidenced by the same date that the lab samples were taken). 
Table 2-3 Definition of symptoms and AEs for liver toxicities 
 
Term in table 
MedDRA term(s) 
Bone pathology 
HLGT = Bone disorders (excl congenital and 
fractures) 
Symptoms:  
 
Severe Fatigue (1) 
PT = Fatigue 
Abdominal pain right upper quadrant 
PT = Abdominal pain upper 
Nausea 
PT = Nausea 
Vomiting 
PT = Vomiting 
General malaise 
PT = Malaise 
Rash with eosinophilia 
PT = Drug reaction with eosinophilia and 
systemic symptoms 
 
Gilbert syndrome 
PT = Gilbert’s syndrome 
 
Jaundice 
PT = Jaundice 
PT = Jaundice cholestatic 
 
AEs indicative of liver toxicity 
 
Hepatic failure 
HLT = Hepatic failure and associated disorders 
Hepatic fibrosis and cirrhosis 
HLT = Hepatic fibrosis and cirrhosis 
 
PT = Hepatic cirrhosis 
Non-infectious hepatitis 
PT = Hepatitis 
PT = Hepatitis acute 
PT = Hepatitis toxic 
PT = Hepatitis fulminant 
PT = Hepatitis chronic active 
PT = Hepatitis chronic persistent 
Liver neoplasm 
HLGT = Hepatobiliary neoplasms 
HLT: High Level Term 
HLGT: High Level Group Term 
MedDRA codes listed above are based on version 23.1 The list will be updated for each MedDRA 
version change and will be included in the eCRS. eCRS will be the reference for analyses. 
(1) presence of Fatigue term with severity ≥ “Severe” 
Renal alert values will be summarized where renal alert values are identified as: 
• Serum creatinine increase ≥ 25% compared to baseline during normal hydration status 
• New onset dipstick proteinuria ≥ 3+  


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2.7.3.1 
Electrocardiogram (ECG) 
The following ECG parameters will be obtained during the study and summarized descriptively: 
ECG mean heart rate, RR interval, PR interval, QRS duration, QT interval and corrected QT 
interval by the Fridericia criteria (QTcF). Summary statistics (absolute values and change from 
baseline) for all ECG parameters will be provided by time point; the number of participants 
with values outside the normal range will be displayed. Where normal ranges are available, 
participants with abnormalities in ECG data will be listed by visit/time.  
Categorical summary statistics for ECG alert values will also be provided based on the number 
and proportion of participants meeting or exceeding the following predefined limits any time 
post baseline:  
• 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 
• HR decrease from baseline ≥ 25%  
• HR > 130 bpm 
In addition, a listing of these participants will be produced. A listing of all newly occurring or 
worsening abnormalities will be provided.  
Noticeable ECG abnormalities such as ventricular tachychardia, new complete heart block 
(Grade III AV block) and Mobitz II AV block are reported as AEs and will be described as part 
of AEs.  
When ECG is performed in triplicate at each visit, the average between the 3 values must be 
used for summaries and before identification of the abnormalities listed above. 
2.7.3.2 
Vital signs 
 
Vital signs measurements include systolic blood pressure (SBP) and diastolic blood pressure 
(DBP), pulse rate, body temperature, height and body weight. Summary statistics (absolute on-
treatment values and change from baseline) will be provided for all vital signs data (weight, 
temperature, pulse rate, SBP, DBP) by visit/time. On-treatment values will be defined as in 
Section 2.7. 
Where ranges are available, abnormalities will be summarized and listed by participant and 
visit/time.  Arithmetic mean (SD)  of absolute values over time for SBP , DBP and pulse rate 
will also be provided. 
Frequency tables displaying the number of patients with abnormal blood pressure or heart rate 
values (by visit or worst post baseline) can be displayed. 
Boundaries are the following: 
• Blood pressure (BP): 
1. Systolic BP: 100 – 140 mmHg 


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2. Diastolic BP: 65 – 95 mmHg 
• Heart rate: 
1. <=50 bpm 
2. >=120 bpm 
• Temperature > 38.3 °C (>101 °F) 
2.10 
Patient-reported outcomes 
In this study, the question addressed by the analysis of PRO measurements is whether treatment 
with iptacopan improves patient-reported fatigue symptoms as measured by the FACIT-Fatigue.  




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2.13 
Interim analysis 
No formal interim analyses of efficacy are planned in this study. A data cut-off will be applied 
and a clinical study report (CSR) will be produced for submission at the time the last patient 
has completed the core treatment period.  An additional CSR will be produced when the last 
participant has completed the last visit in the extension treatment period, when the final study 
database has been locked. In addition, if deemed required (e.g. to support regulatory 
submissions to Health Authorities) interim safety analyses may be produced while the study is 
still ongoing.  If there is an interim lock for safety analyses, 
 
 The interim report will not consider inferences based on efficacy.  
Safety data will be monitored by an independent DMC, and analyses to the effect of this 
evaluation will be performed during the course of the study with the frequency to be determined 
in the DMC Charter. Access to a limited number of efficacy measurements by the DMC will be 


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provided solely for the purpose of evaluating benefit of treatment with iptacopan against any 
risk. The DMC will function under the the DMC Charter which has been finalized. The Charter 
includes guidelines for communication concerning safety of participants between the DMC and 
the sponsor representative to ensure that these are in keeping with the sensitive nature of the 
open label trial and do not introduce bias.  
3 
Sample size calculation 
The sample size is calculated based on the half-width (the margin of error in the estimate) of a 
2-sided 95% confidence interval for the proportion of participants reaching the status of 
responder (primary endpoint). The proposed sample size of 40 participants is sufficient to 
achieve a target absolute margin of error not larger than 0.155.   
The different scenarios of observed response rate and its 95% confidence intervals are shown 
in Table 3-1.  
Table 3-1 Precision of response rate with N = 40 
Sample Size 
Observed Response Rate 
Unadjusted 95% Confidence 
Interval 
40 
30% 
(15.8%,44.2%) 
40 
40% 
(24.8%,55.2%) 
40 
50% 
(34.5%, 65.5%) 
40 
60% 
(44.8%,75.2%) 
The lower bound of the two-sided 95% confidence interval of the response rate obtained from 
the primary analysis will be compared to a threshold of 15% and exceeding the threshold is 
sufficient for demonstration that iptacopan improves hematological response in PNH patients 
with hemolysis and anemia in the absence of transfusions.  
For the sample size of 40 participants, given the observed proportion of responders is 40%, 
there is 96.4% probability that the lower bound of the 2-sided 95% CI will exclude a threshold 
of 15%.  
4 
Change to protocol specified analyses 
The “indicator of transfusion dependence” is defined to be “prior to starting study treatment” 
instead of “at enrollment” (defined in study protocol Section 12.4.2). 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
AE date imputation 
5.1.1.1 
AE end date imputation 
Rules for imputing  AE end dates are stated below. Date of last contact in the study has been 
defined as in Section 2.1.1.5 .  




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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). 
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. 
5.1.2 
Concomitant medication date imputation 
5.1.2.1 
Concomitant medication end date imputation 
Rules for imputing the CM end date are stated below. Date of last contact in the study has been 
defined as in Section 2.1.1.5. Concomitant medication end dates will not be imputed for ongoing 
records. 
 
1. If CM end day is missing and CM month/year are non-missing then impute CM day as 
the minimum of  date of last contact 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  date of last contact and the end of the year (31DECYYYY). 
3. If CM day/month/year is missing then use the date of last contact + 1 day as the imputed 
CM end date.  
4. If imputed CM end date is less than the CM start date, use the CM start date as the 
imputed CM end date. 
5.1.2.2 
Concomitant medication start date imputation 
Rules for imputing the CM start date: 




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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. 
5.2 
Statistical models  
5.2.1 
Tabular view of estimands and associated estimation methods 
Table 5-1 
Overview of estimands and estimation methods 
Estimand 
Endpoint  
Handling strategy of intercurrent events 
Summary 
measure 
 
 
Discontinuation 
of study 
medication 
Breakthrough 
hemolysis 
events 
MAVEs 
RBC 
transfusions 
 
Primary estimands 
Primary 
estimand  
composite of:  
increase in Hb 
levels ≥ 2 g/dL 
from baseline* 
without requiring 
RBC transfusions# 
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“returen to pre-
treatment” 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-
included in 
the composite 
estimand 
Proportion of 
responders 
Sensitivity 
analysis 
(Primary)1 
composite of:  
increase in Hb 
levels ≥ 2 g/dL 
from baseline* 
without requiring 
RBC transfusions# 
Treatment 
policy 
Missing 
hemoglobin 
central lab data 
replaced by 
local lab data at 
same visit. 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“return to pre-
treatment” 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-
included in 
the composite 
estimand 
Proportion of 
responders 
Sensitivity 
analysis 
(Primary) 2 
composite of:  
increase in Hb 
levels ≥ 2 g/dL 
from baseline* 
without requiring 
RBC transfusions# 
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“returen to pre-
treatment” 
Considering the  
need 
for 
transfusion 
derived 
from 
imputation with 
imputed values ≤ 
7 g/dL (≤ 6 g/dL 
for 
Chinese 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-
included in 
the composite 
estimand 
Proportion of 
responders 


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Estimand 
Endpoint  
Handling strategy of intercurrent events 
Summary 
measure 
population) to be 
sufficient 
to 
warrant 
a 
transfusion. 
 
Sensitivity 
analysis 
(Primary) 3 
composite of:  
increase in Hb 
levels ≥ 2 g/dL 
from baseline* 
without requiring 
RBC transfusions# 
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“returen to pre-
treatment” 
Considering 
administered 
imputation 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-
included in 
the composite 
estimand 
Proportion of 
responders 
Supplementary  estimands 
Supplementar
y estimand  
composite of:  
increase in Hb 
levels ≥ 2 g/dL 
from baseline* 
without requiring 
RBC transfusions# 
and not receiving 
rescue 
medication$f 
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“return to pre-
treatment” 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-
included in 
the composite 
estimand 
Proportion of 
responders 
Secondary estimands 
 
Secondary 
estimand 1 
composite of: 
having Hb levels 
≥ 12 g/dL* 
without requiring 
RBC transfusions 
# 
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“return to pre-
treatment” 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-
included in 
the composite 
estimand 
Proportion of 
responders 
Sensitivity 
analysis 
(Secondary) 
1.1 
composite of: 
having Hb levels 
≥ 12 g/dL* 
without requiring 
RBC transfusions 
# 
Treatment 
policy 
Missing 
hemoglobin 
central lab data 
replaced by 
local lab data at 
same visit. 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“return to pre-
treatment” 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-
included in 
the composite 
estimand 
Proportion of 
responders 


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Estimand 
Endpoint  
Handling strategy of intercurrent events 
Summary 
measure 
Sensitivity 
analysis 
(Secondary) 
1.2 
composite of: 
having Hb levels 
≥ 12 g/dL* 
without requiring 
RBC transfusions 
# 
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“returen to pre-
treatment” 
Considering the  
need 
for 
transfusion 
derived 
from 
imputation with 
imputed values ≤ 
7 g/dL (≤ 6 g/dL 
for 
Chinese 
population) to be 
sufficient 
to 
warrant 
a 
transfusion. 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-
included in 
the composite 
estimand 
Proportion of 
responders 
Sensitivity 
analysis 
(Secondary) 
1.3 
composite of: 
having Hb levels 
≥ 12 g/dL* 
without requiring 
RBC transfusions 
# 
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“returen to pre-
treatment” 
Considering 
administered 
imputation 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-
included in 
the composite 
estimand 
Proportion of 
responders 
Secondary 
estimand 2 
Proportions of 
participants not 
receiving any 
transfusions # 
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“return to pre-
treatment” 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event since 
this is the 
endpoint of 
interest 
Proportion of 
responders 
Sensitivity 
analysis 2.1 
Proportions of 
participants not 
receiving any 
transfusions # 
Treatment 
policy 
Missing 
hemoglobin 
central lab data 
replaced by 
local lab data at 
same visit. 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-
included in 
the composite 
estimand 
Proportion of 
responders 


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Estimand 
Endpoint  
Handling strategy of intercurrent events 
Summary 
measure 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“return to pre-
treatment” 
Sensitivity 
analysis 
(Secondary) 
2.2 
Proportions of 
participants not 
receiving any 
transfusions # 
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“returen to pre-
treatment” 
Considering the  
need 
for 
transfusion 
derived 
from 
imputation with 
imputed values ≤ 
7 g/dL (≤ 6 g/dL 
for 
Chinese 
population) to be 
sufficient 
to 
warrant 
a 
transfusion. 
 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-
included in 
the composite 
estimand 
Proportion of 
responders 
Sensitivity 
analysis 
(Secondary)  
2.3 
Proportions of 
participants not 
receiving any 
transfusions # 
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“returen to pre-
treatment” 
Considering 
administered 
imputation 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-
included in 
the composite 
estimand 
Proportion of 
responders 
Secondary 
estimand 3 
Hemoglobin 
changes from 
baseline**  
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“return to pre-
treatment” 
Treatment 
policy 
Treatment 
policy 
Transfusions# 
are treated 
within a 
hypothetical 
strategy (as if 
patients had 
not received 
any 
transfusions) 
Mean change 
from baseline 
in hemoglobin 
levels  
Sensitivity 
analysis 
(Secondary) 
3.1 
Hemoglobin 
changes from 
baseline** 
Treatment 
policy 
Treatment 
policy 
Treatment 
policy 
Same 
Mean change 
from baseline 
in hemoglobin 
levels 


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Estimand 
Endpoint  
Handling strategy of intercurrent events 
Summary 
measure 
Missing 
hemoglobin 
central lab data 
replaced by 
local lab data at 
same visit. 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“return to pre-
treatment” 
Supportive 
analysis 
(Secondary) 
3.1 
Hemoglobin 
changes from 
baseline** 
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“return to pre-
treatment” 
Treatment 
policy 
Treatment 
policy 
Treatment 
policy 
Mean change 
from baseline 
in hemoglobin 
levels 
Secondary 
estimand 4 
Change from 
baseline in scores 
of fatigue using 
the FACIT 
Fatigue 
questionnaire**  
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“return to pre-
treatment” 
Treatment 
policy 
Treatment 
policy 
Treatment 
policy 
Mean change 
from baseline 
in FACIT 
fatigue scores  
Supportive 
analysis 
(Secondary) 
4.1 
Change from 
baseline in scores 
of fatigue using 
the FACIT 
Fatigue 
questionnaire**  
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“return to pre-
treatment” 
Treatment 
policy 
Treatment 
policy 
Hypothetical 
Policy 
Mean change 
from baseline 
in FACIT 
fatigue scores  
Secondary 
estimand 5 
Change from 
baseline in 
reticulocytes 
counts**  
Treatment 
policy 
Treatment 
policy 
Treatment 
policy 
Treatment 
policy 
Mean change 
from baseline 
in reticulocyte 
counts  
Sensitivity 
analysis 
(Secondary) 
5.1 
Change from 
baseline in 
reticulocytes 
counts** 
Treatment 
policy 
Missing 
reticulocyte 
central lab data 
replaced by 
local lab data at 
same visit. 
Treatment 
policy 
Treatment 
policy 
Treatment 
policy 
Mean change 
from baseline 
in reticulocyte 
counts  


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Estimand 
Endpoint  
Handling strategy of intercurrent events 
Summary 
measure 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“return to pre-
treatment” 
Supportive 
estimand 
(Secondary) 
5.1 
Change from 
baseline in 
reticulocytes 
counts**  
Treatment 
policy 
Treatment 
policy 
Treatment 
policy 
Hypothetical 
Policy 
Mean change 
from baseline 
in reticulocyte 
counts  
Secondary 
estimand 6 
Percent change 
from baseline in 
LDH**  
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“return to pre-
treatment” 
Treatment 
policy 
Treatment 
policy 
Treatment 
policy 
The log 
transformed 
LDH ratio to 
baseline  
Sensitivity 
analysis 6.1 
Percent change 
from baseline in 
LDH** 
Treatment 
policy 
Missing LDH 
central lab data 
replaced by 
local lab data at 
same visit. 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“return to pre-
treatment” 
Treatment 
policy 
Treatment 
policy 
Treatment 
policy 
The log 
transformed 
LDH ratio to 
baseline  
Supportive 
estimand 
(Secondary) 
6.1 
Percent change 
from baseline in 
LDH**  
Treatment 
policy 
Missing data on 
iptacopan after 
study 
discontinuation 
imputed using 
“return to pre-
treatment” 
Treatment 
policy 
Treatment 
policy 
Hypothetical 
Policy 
The log 
transformed 
LDH ratio to 
baseline  
Secondary 
estimand 7 
Rates of 
breakthrough 
hemolysis  
Treatment 
policy 
Not an 
intercurrent 
event since 
this is the 
endpoint of 
interest 
Treatment 
policy 
Treatment 
policy 
Rate of 
occurrence of 
breakthrough 
hemolysis 
Secondary 
estimand 8 
Rates of MAVE s  
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event since 
this is the 
endpoint of 
interest 
Treatment 
policy 
Rate of 
occurrence of 
MAVEs  


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* between Day 126 and 168 (3 out of 4 scheduled measurements) 
** between Day 126 and 168  
# between Day 14 and Day 168 
$between Day 1 and Day 168 
f rescue indicates failure 
5.2.2 
Primary analysis 
5.2.2.1 
MMRM convergence issue 
For MMRM, by default, the correlations between visits (aka. Timepoints) within subjects will 
be modeled using an unstructured covariance matrix. 
In case of non-convergence issues the following steps should be taken: 
• Simplify covariance structure (possibly AR(1) then CS) 
• Simplify the model by removing some covariates (baseline value should always be kept 
in the model and visit x baseline value interaction can for instance be first removed) 
 
5.2.2.2 
Methods for calculation of marginal proportions and simple proportion 
Marginal proportion from Logistic regression 
The primary analysis of the primary endpoint will be a logistic regression to estimate the 
response probability.  
log
𝑃𝑃(𝑌𝑌= 1)
1 −𝑃𝑃(𝑌𝑌= 1) = 𝛽𝛽0 + 𝛽𝛽1𝑆𝑆+ 𝛽𝛽2𝐴𝐴+ 𝛽𝛽3𝐻𝐻+ 𝛽𝛽4𝑇𝑇 
Where P(Y = 1) refers to the probability to be responder, S refers to sex, A refers to indicator 
variable of age ≥ 45 years, H refers to indicator variable of baseline hemoglobin above 8g/dL 
and T refers to an indicator of transfusion dependence. 
The maximum likelihood estimator for 𝛽𝛽̂0, 𝛽𝛽̂1, 𝛽𝛽̂2, 𝛽𝛽̂3, 𝛽𝛽̂4  will be plugged in to obtain the 
probability to be a responder for each participant 
𝜃𝜃෠i = 𝑃𝑃෠(𝑌𝑌𝑖𝑖= 1) =
exp[𝛽𝛽
෢0 + 𝛽𝛽̂1𝑆𝑆𝑖𝑖+ 𝛽𝛽̂2𝐴𝐴𝑖𝑖+ 𝛽𝛽̂3𝐻𝐻𝑖𝑖+ 𝛽𝛽̂4𝑇𝑇𝑖𝑖]
1 + exp[𝛽𝛽
෢0 + 𝛽𝛽̂1𝑆𝑆𝑖𝑖+ 𝛽𝛽̂2𝐴𝐴𝑖𝑖+ 𝛽𝛽̂3𝐻𝐻𝑖𝑖+ 𝛽𝛽̂4𝑇𝑇𝑖𝑖] 
 
The proportion of responders will be derived from the estimated marginal probabilities (𝜃𝜃෠) 
derived from the model fit as the mean of the individual logistic regression model predictions,  
𝜃𝜃෠=
∑
𝜃𝜃෠𝑖𝑖
𝑁𝑁
𝑖𝑖=1 
𝑁𝑁
 
The 95% confidence intervals will be derived by the bootstrap method (Steingrimsson et al 
2017). Take 𝐵𝐵 bootstrap samples of (𝑌𝑌, 𝑆𝑆, 𝐴𝐴, 𝐻𝐻, 𝑇𝑇). For each bootstrap sample, obtain the 
proportion of responders. Then we will have 𝐵𝐵 estimators, denoted to be 𝜃𝜃1
{𝑏𝑏},  𝜃𝜃2
{𝑏𝑏}, … ,  𝜃𝜃𝐵𝐵
{𝑏𝑏}. 


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The 95% confidence interval is the 2.5% quantile and 97.5% quantile of these bootstrap 
estimator.  
In case of multiple imputation, the marginal probability and the associated two-sided 95% 
confidence intervals will be obtained by combining multiple imputations with bootstrapping as 
follows: 
1) Point estimate will be obtained by averaging across the estimates obtained from each 
multiple imputed dataset 
2) The 95% confidence interval will be obtained by bootstrapping each imputed dataset 
and selecting the 2.5th and 97.5th percentiles of the pooled distribution of bootstrapped 
parameter estimates as the confidence interval bounaries. 
Simple proportion 
For each imputed dataset, proportion of responders is 
θj =
∑
𝑌𝑌𝑖𝑖
𝑁𝑁
𝑖𝑖=1
𝑁𝑁
, 
where Yi = 1 denotes a participant is responder while Yi = 0 denotes a participant is non-
responder. Denote the number of imputed dataset to be L and denote  θj (𝑗𝑗= 1, … , 𝐿𝐿) to be the 
proportion of responders for each imputed dataset, simple proportion of responders is the mean 
of proportion of responders from all the imputed datasets, that is 
𝜃𝜃෠=
∑
𝜃𝜃𝑗𝑗
𝐿𝐿
𝑗𝑗=1 
𝐿𝐿
 
The 95% confidence intervals will be derived by the bootstrap method (Steingrimsson et al 
2017).  For each bootstrap sample, obtain the simple proportion of responders. Then we will 
have 𝐵𝐵 estimators, denoted to be 𝜃𝜃1
{𝑏𝑏},  𝜃𝜃2
{𝑏𝑏}, … ,  𝜃𝜃𝐵𝐵
{𝑏𝑏}. The 95% confidence interval is the 2.5% 
quantile and 97.5% quantile of these bootstrap estimator.  
In case of multiple imputation, the simple proportion of responders and the associated two-sided 
95% confidence intervals will be obtained by combining multiple imputations with 
bootstrapping as follows: 
1) Point estimate will be obtained by averaging across the estimates obtained from each 
multiple imputed dataset 
2) The 95% confidence interval will be obtained by bootstrapping each imputed dataset 
and selecting the 2.5th and 97.5th percentiles of the pooled distribution of bootstrapped 
parameter estimates as the confidence interval bounaries. 
It can be shown that the estimate of the marginal probabilities from logistic regression model 
and simple estimate of the response probability without any covariates are the same. 
From logistic regression,  
𝜃𝜃𝑖𝑖= Pr(𝑌𝑌𝑖𝑖= 1|𝑆𝑆𝑖𝑖, 𝐴𝐴𝑖𝑖,  𝐻𝐻𝑖𝑖,  𝑇𝑇𝑖𝑖) =  
exp [𝛽𝛽0 + 𝛽𝛽1𝑆𝑆𝑖𝑖+ 𝛽𝛽2𝐴𝐴𝑖𝑖+ 𝛽𝛽3𝐻𝐻𝑖𝑖+ 𝛽𝛽4𝑇𝑇𝑖𝑖]
1 + exp [𝛽𝛽0 + 𝛽𝛽1𝑆𝑆𝑖𝑖+ 𝛽𝛽2𝐴𝐴𝑖𝑖+ 𝛽𝛽3𝐻𝐻𝑖𝑖+ 𝛽𝛽4𝑇𝑇𝑖𝑖] 
The loglikelihood is 


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𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿ℎ𝑜𝑜𝑜𝑜𝑜𝑜=  ෍log[1 −𝜃𝜃𝑖𝑖] + (𝛽𝛽0 + 𝛽𝛽1𝑆𝑆𝑖𝑖+ 𝛽𝛽2𝐴𝐴𝑖𝑖+ 𝛽𝛽3𝐻𝐻𝑖𝑖+ 𝛽𝛽4𝑇𝑇𝑖𝑖)𝑌𝑌𝑖𝑖
𝑁𝑁
𝑖𝑖=1
 
Take the derivative of the log likelihood function with respective to 𝛽𝛽0, and let it equal to 0 to 
obtain 
1
𝑁𝑁෍𝜃𝜃𝑖𝑖
𝑁𝑁
𝑖𝑖=1
=  1
𝑁𝑁෍𝑌𝑌𝑖𝑖
𝑁𝑁
𝑖𝑖=1
 
This indicates that point estimate of the marginal probability from the logistic regression model 
and the simple response probability without the covariates are the same. 
The 95% confidence intervals from logistic regression model and the simple response 
probability will be obtained by selecting the 2.5th and 97.5th percentiles of the same pooled 
distribution of bootstrapped parameter estimates. Therefore, the confidence interval will also 
the same for the estimates obtained from the logistic regression model and simple proportion. 
5.2.2.3 
Derivation of the threshold 
As 
the 
patient-level 
hemoglobin 
data 
were 
not 
available 
for 
the 
historical 
eculizumab/ravulizumab studies, a direct estimation of the proportion of patients who achieved 
hemoglobin increases from baseline ≥ 2 g/dL in the absence of transfusions (responder 
definition on primary efficacy endpoint for study CLNP023C12301) was not feasible. 
Therefore, an indirect approach through simulation calculating the probability of being a 
responder (defined as increase from baseline of hemoglobin ≥ 2 g/dL) was used.  
Overview of reference studies 
This 15% threshold was derived by indirectly estimating hemoglobin response in two studies 
with eculizumab: Study ALXN1210-PNH-301 (Ultomiris CHMP Assessment Report 2019,  
Lee et al 2019, Brodsky et al 2021) that included a treatment naive population randomizing 
patients to either eculizumab or ravulizumab and the pivotal eculizumab study, TRIUMPH 
(Hillmen etal 2006, Dmytrijuk et al 2008)   
ALXN1210-PNH-301 was a Phase 3, open-label study that assessed the non-inferiority of 
ravulizumab to eculizumab in complement inhibitor-naive adults with PNH. The study recruited 
PNH patients ≥ 18 years of age, with red and white blood cells with granulocyte or monocyte 
clone size of at least 5%, with LDH  ≥ 1.5 times the upper limit of normal, with at least one 
protocol pre-defined PNH-related sign or symptom and with platelet count ≥ 30 X 10E9/L or 
absolute neutrophil count ≥ 0.5 X 10E9/L.  Patients were randomized 1:1 to receive ravulizumab 
or eculizumab for 183 days (N = 246). Co-primary efficacy endpoints were proportion of 
patients remaining transfusion-free and LDH normalization. Key secondary endpoints were 
percentage change from baseline in LDH, change from baseline in FACIT-Fatigue score, 
proportion of patients with breakthrough hemolysis, and proportion of patients with stabilized 
hemoglobin (defined as avoidance of a ≥ 2 g/dL decrease in hemoglobin level from baseline in 
the absence of transfusion). 69 (57.0%) of 121 PNH patients who were treated with eculizumab 
were male. The mean age at first study infusion was 46.2 (SD: 16.2). 105 (86.8%) patients had 
an LDH ratio > 3x ULN. The mean LDH at baseline was 1578.3 U/L (SD: 727.1). 21 (17.4%) 


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patients received no packed RBC transfusion within 1 year before study entry, and 22 (18.2%) 
patients received > 14 units of packed RBC within 1 year before study entry. 
 
TRIUMPH was a double-blind, randomized, placebo-controlled, multicenter, Phase 3 trial. The 
trial consisted of a 2-week screening period, an observation period of up to 3 months, and a 26-
week treatment period. Patients 18 years of age or older who had received at least four 
transfusions during the previous 12 months were eligible. A PNH type III erythrocyte 
proportion of 10% or more, platelet counts of at least 100,000 per cubic millimeter, and LDH 
levels that were at least 1.5 times the upper limit of the normal range were also required. The 
two primary endpoints were the stabilization of hemoglobin levels (defined as a hemoglobin 
value maintained above the level qualifying for transfusion, in the absence of transfusions 
during the 26-week treatment period), and the number of units of packed red cells transfused 
during the period. 23 (53.5%) of 43 patients who were treated with eculizumab were female. In 
the eculizumab group, the mean age at baseline was 41.0 (Range: 20-85) and the mean LDH at 
baseline was 2199.7 U/L (SD: 157.2 U/L). In the 6-month period before the study, the median 
number of units of packed red cells transfused per patient was 9.0 in the eculizumab cohort and 
the mean number of units of packed red cells transfused was 9.6 ± 0.6 
Assumptions for simulation and statistical aspects 
The assumptions used for simulation based on ALXN1210-301 data are summarized below: 
• Mean hemoglobin level at baseline was 9.6 g/dL from Brodsky et al 2021, 
• Mean hemoglobin level at Week 26 was 10.0 g/dL from Figure 20 of Ultomiris CHMP 
Assessment Report 2019, 
• Standard deviations of hemoglobin at baseline (Brodsky et al 2021) and Week 26 were 
assumed to be equal and the value was 1.70 g/dL  
The assumptions used for simulation based on TRIUMPH (Hillmen et al 2006) data are 
summarized below: 
• Mean hemoglobin level at baseline was 10.0 g/dL 
• Mean hemoglobin level at Week 26 was 10.1 g/dL 
• Standard deviation of hemoglobin at baseline and Week 26 was assumed to be equal and 
the value was calculated as   0.2√43 = 1.31 g/dL, where 0.2 g/dL was the standard error 
of mean 
The correlation value between hemoglobin level at baseline and at Week 26 was not available 
from published historical studies. This value was derived based on Hillmen et al 2004 which 
published hemoglobin levels before 12 months eculizumab treatment and after 3 months of 
eculizumab treatment for 11 PNH patients. The correlation was 0.87 for these 11 PNH patients. 
Considering the same sample size and different treatment periods, for simulation purposes, 
correlation values were drawn from a uniform distribution Unif (0.3, 0.85).  
Under the normal distribution assumption for hemoglobin data, patients’ hemoglobin values at 
baseline and at Week 26 were drawn from a bivariate normal distribution: 
 


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൬𝑥𝑥1𝑖𝑖
𝑥𝑥2𝑖𝑖
൰~𝑁𝑁൤൬𝜇𝜇1
𝜇𝜇2
൰, ൬𝜎𝜎1
2
𝜌𝜌𝜎𝜎1𝜎𝜎2
𝜌𝜌𝜎𝜎1𝜎𝜎2
𝜎𝜎2
2
൰൨, i = 1, … , N 
where  μ1 is the mean of hemoglobin level at baseline,  μ2 is the mean of hemoglobin level at 
Week 26,  σ1 is the standard deviation of hemoglobin at baseline,   σ2 is the standard deviation 
of hemoglobin at Week 26, and  ρ is the correlation. The proportion of drawn hemoglobin 
values that demonstrate increase from baseline in hemoglobin of ≥ 2 g/dL based on N draws 
from the bivariate normal distribution is summarized: 
                            
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑜𝑜𝑜𝑜 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅= 1
𝑁𝑁෍𝐼𝐼[𝑥𝑥2𝑖𝑖−𝑥𝑥1𝑖𝑖≥2],   𝐼𝐼 𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑒𝑒 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓
𝑁𝑁
𝑖𝑖
 
Results of simulation and inference 
10000 simulation runs indicate that the probability of being a responder (achieving a 
hemoglobin increase from baseline ≥ 2 g/dL) is 14.7% (95% CI: 5.0% - 21.1%) for ALXN1210-
301 study, and 4.49% (95% CI: 0.5% - 11.0%) for TRIUMPH. 
Please note that these estimates (14.7% and 4.49%) actually overestimate the hematological 
effect for eculizumab because the hemoglobin levels correspond to all patients at Week 26, and 
doesn’t account for administration of transfusion during treatment.  
Despite being aware of the overestimate of the hematological effect, the 15% threshold was 
chosen in order to be above the estimated hemoglobin increases in both historical studies. Thus, 
exceeding this threshold is sufficient to demonstrate that iptacopan improves the hematological 
response in PNH patients with hemolysis and anemia in the absence of transfusions. 
5.2.3 
Rule of exclusion criteria of analysis sets 
Considering the relatively low sample size in the study there are no protocol deviations which 
will lead to exclusion of patients from any analysis set. Data records containing confirmed cases 
of biological sample analysis after Withdrawal of Consent, when not allowed per ICF or local 
regulations, will be flagged and excluded from all analyses including listings. 
6 
Reference 
Brodsky RA, Peffault de Latour R, Rottinghaus ST, Roth A, Risitano AM, Weitz IC, Hillmen 
P, Maciejewski JP, Szer J, Lee JW, Kulasekararaj AG, Volles L, Damokosh AI, Ortiz S, Shafner 
L, Liu P, Hill A, Schrezenmeier H. Characterization of breakthrough hemolysis events observed 
in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal 
nocturnal hemoglobinuria. Haematologica. 2021 Jan 1; 106(1): 230-237. 
Patricia Berglund and Steven Heeringa (2014) Multiple imputation of missing data using SAS. 
SAS Institute 
Committee for Medicinal Products for Human USE (CHMP) (2019) Ultomiris Assessment 
Report. European Medicines Agency. 


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