Clinical trial NCT04558918
Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
Keywords: Paroxysmal nocturnal hemoglobinuria Hemoglobin Anemia LNP023 eculizumab ravulizumab
Sponsor: Novartis Pharmaceuticals
Start date: 2021-01-25; Completion date: 2023-03-06
Enrollment: 97 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was a multi-center, randomized, open-label, active comparator-controlled, parallel group study.

The purpose of this Phase 3 study in PNH patients presenting with residual anemia despite treatment with anti-C5 antibody, was to determine whether iptacopan is efficacious and safe for the treatment of PNH through demonstration of superiority of iptacopan compared to anti-C5 antibody treatment.

Detailed description:
The study comprised three periods:

* A screening period lasting up to 8 weeks (unless there was a need to extend it for vaccinations required for inclusion, vaccinations were started as early as possible to avoid extension of the screening period)
* A 24-week randomized, open-label, active controlled, treatment period for the primary efficacy and safety analyses. Patients who met the eligibility criteria at screening were stratified based on the type of prior anti-C5 antibody treatment (eculizumab or ravulizumab) and based on the transfusion history as reported during the last 6 months prior to randomization (i.e. transfusion received/not received). Patients were randomized to one of the two treatment groups in an 8:5 ratio to either iptacopan monotherapy at a dose of 200 mg orally b.i.d. or i.v. anti-C5 antibody treatment (patients continued with the same regimen during the randomized treatment period as they were prior to randomization), respectively.
* A 24-week open-label, iptacopan treatment extension period. The patients randomized to the active comparator group were offered to switch to iptacopan on Day 168 (Week 24 visit) and entered the treatment extension period, after receiving a last dose of anti-C5 antibody treatment (eculizumab or ravulizumab). For patients in the comparator group not agreeing to switch treatment, Week 24 visit was the End of Study visit for the trial with no participation in the treatment extension period. For patients agreeing to switch to oral iptacopan, the Extension treatment started on the day after completion of the Week 24 visit. The patients in the iptacopan group who, in the opinion of investigator, benefitted from treatment and were taking iptacopan at Week 24 visit (i.e. did not permanently discontinue study medication), were offered the opportunity to continue oral iptacopan treatment during the treatment extension period.
* Data cut-off date used for the primary results submission was 26- Sep-2022

Arms: arm 1: Iptacopan 200mg b.i.d. hard gelatin capsule. After 24 weeks of LNP023 200mg b.i.d. treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive an additional 24 weeks of LNP023 200mg b.i.d. arm 2: In the Randomized Treatment Period patients randomized to receive Anti-C5 antibody continued with the same stable regimen of Anti-C5 antibody therapy as they had received prior to randomization. For eculizumab (administered as intravenous infusion every 2 weeks), the maintenance dose was a fixed dose, whereas for ravulizumab (administered as intravenous infusion every 8 weeks), the maintenance dose was based on body weight. After 24 weeks of Anti-C5 antibody treatment in the Randomized Treatment Period, participants had the option to enter the Extension Treatment Period to receive 24 weeks of LNP023 200mg b.i.d.
Interventions: intervention 1: LNP023 intervention 2: Eculizumab intervention 3: Ravulizumab
Intervention descriptions: intervention 1: Taken Orally b.i.d. Dosage Supplied: 200 mg Dosage form: Hard gelatin capsule Route of Administration: Oral intervention 2: Administered as intravenous infusion every 2 weeks as per the stable regimen, the maintenance dose is a fixed dose.

Dosage Supplied: 300 mg/30mL Dosage form: Concentrate solution for infusion intervention 3: Administered as intravenous infusion every 8 weeks, the maintenance dose is based on body weight.

Dosage Supplied: 300 mg/30mL Dosage form: Concentrate solution for infusion

Protocol documents:
Prot_003.pdf: 
Novartis Research and Development
LNP023 (Iptacopan) 
Clinical Trial Protocol CLNP023C12302
A randomized, multicenter, active-comparator controlled, 
open-label trial to evaluate efficacy and safety 
of oral, twice daily LNP023 
in adult patients with PNH and residual anemia, 
despite treatment with an intravenous anti-C5 antibody
Document type:
Amended Clinical Trial Protocol
EUDRACT number:
2019-004665-40
Version number:
02 (Clean)
Clinical Trial Phase:
III
Release date:
23-Nov-2021
Property of Novartis 
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.0 (31-Jan-2020)


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Table of contents
Table of contents..................................................................................................................2
List of tables.........................................................................................................................6
List of figures.......................................................................................................................6
List of abbreviations ............................................................................................................7
Glossary of terms...............................................................................................................10
Protocol summary..............................................................................................................16
1
Introduction........................................................................................................................19
1.1
Background............................................................................................................19
1.2
Purpose...................................................................................................................21
2
Objectives and endpoints...................................................................................................22
2.1
Primary estimands..................................................................................................23
2.2
Secondary estimands..............................................................................................24
3
Study design.......................................................................................................................26
4
Rationale ............................................................................................................................29
4.1
Rationale for study design......................................................................................29
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 ..................................33
4.5
Risks and benefits ..................................................................................................33
4.6
Rationale for Public Health Emergency mitigation procedures.............................36
5
Study Population................................................................................................................36
5.1
Inclusion criteria ....................................................................................................36
5.2
Exclusion criteria ...................................................................................................37
6
Treatment...........................................................................................................................39
6.1
Study treatment ......................................................................................................40
6.1.1
Investigational and control drugs ..........................................................40
6.1.2
Additional study treatments...................................................................41
6.1.3
Treatment arms/group ...........................................................................41
6.1.4
Treatment duration ................................................................................41
6.2
Other treatment(s) ..................................................................................................41
6.2.1
Concomitant therapy .............................................................................41
6.2.2
Prohibited medication............................................................................42


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6.2.3
Rescue medication.................................................................................43
6.3
Participant numbering, treatment assignment, randomization...............................43
6.3.1
Participant numbering ...........................................................................43
6.3.2
Treatment assignment, randomization...................................................44
6.4
Treatment blinding.................................................................................................44
6.5
Dose escalation and dose modification..................................................................44
6.6
Additional treatment guidance...............................................................................45
6.6.1
Treatment compliance ...........................................................................45
6.6.2
Recommended treatment of adverse events ..........................................45
6.7
Preparation and dispensation .................................................................................46
6.7.1
Handling of study treatment and additional treatment ..........................47
6.7.2
Instruction for prescribing and taking study treatment..........................47
7
Informed consent procedures.............................................................................................48
8
Visit schedule and assessments..........................................................................................49
8.1
Screening................................................................................................................56
8.1.1
Information to be collected on screening failures .................................56
8.1.2
Hemoglobin assessments and transfusion during Screening.................56
8.1.3
Absolute Reticulocytes Count during Screening...................................57
8.2
Participant demographics/other baseline characteristics........................................57
8.3
Efficacy..................................................................................................................57
8.3.1
Hemoglobin, reticulocytes, LDH and other PNH-related laboratory 
parameters..............................................................................................58
8.3.2
Red blood cell transfusion.....................................................................58
8.3.3
Breakthrough hemolysis........................................................................59
8.3.4
Patient Reported Outcomes (PRO) – FACIT-Fatigue...........................59
8.3.5
PNH-related signs & symptoms............................................................60
8.3.6
Major Adverse Vascular Events (MAVEs)...........................................60
8.3.7
Appropriateness of efficacy assessments ..............................................61
8.4
Safety .....................................................................................................................62
8.4.1
Laboratory evaluations..........................................................................62
8.4.2
Electrocardiogram (ECG)......................................................................63
8.4.3
Pregnancy and assessments of fertility..................................................64
8.4.4
Coagulation panel/thrombosis...............................................................64
8.4.5
Reproductive and thyroid hormones monitoring...................................64
8.4.6
Urine albumin creatinine ratio (UACR)................................................65
8.4.7
Appropriateness of safety measurements ..............................................65


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8.5
Additional assessments ..........................................................................................65
8.5.1
Clinical Outcome Assessments (COAs)................................................65
8.5.2
Pharmacokinetics...................................................................................67
8.5.3
Biomarkers ............................................................................................68
8.6
Off-site research nursing (ORN) visits ..................................................................69
9
Study discontinuation and completion...............................................................................71
9.1
Discontinuation and completion ............................................................................71
9.1.1
Study treatment discontinuation and study discontinuation..................71
9.1.2
Withdrawal of informed consent...........................................................73
9.1.3
Lost to follow-up...................................................................................74
9.1.4
Early study termination by the sponsor.................................................74
9.2
Study completion and post-study treatment...........................................................75
10 Safety monitoring and reporting........................................................................................75
10.1
Definition of adverse events and reporting requirements......................................75
10.1.1
Adverse events.......................................................................................75
10.1.2
Serious adverse events...........................................................................77
10.1.3
SAE reporting........................................................................................78
10.1.4
Pregnancy reporting...............................................................................79
10.1.5
Reporting of study treatment errors including misuse/abuse ................79
10.2
Additional Safety Monitoring................................................................................80
10.2.1
Liver safety monitoring.........................................................................80
10.2.2
Data Monitoring Committee..................................................................81
10.2.3
Steering Committee...............................................................................81
11 Data Collection and Database management ......................................................................81
11.1
Data collection .......................................................................................................81
11.2
Database management and quality control ............................................................82
11.3
Site monitoring.......................................................................................................82
12 Data analysis and statistical methods.................................................................................83
12.1
Analysis sets...........................................................................................................83
12.2
Participant demographics and other baseline characteristics.................................84
12.3
Treatments..............................................................................................................84
12.4
Analysis of the primary endpoint(s)/estimand(s)...................................................84
12.4.1
Definition of primary endpoint(s)/estimand(s)......................................84
12.4.2
Statistical model, hypothesis, and method of analysis ..........................85
12.4.3
Handling of remaining intercurrent events of primary estimand ..........87
12.4.4
Handling of missing values not related to intercurrent event................87


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12.4.5
Sensitivity analyses for primary endpoint/estimand..............................87
12.4.6
Supplementary analysis.........................................................................87
12.4.7
Supportive analyses...............................................................................88
12.5
Analysis of secondary endpoints/estimands ..........................................................88
12.5.1
Safety endpoints ....................................................................................90
12.5.2
Pharmacokinetics...................................................................................92
12.5.3
Patient reported outcomes .....................................................................92
12.6
.........................................................................93
12.7
Interim analyses .....................................................................................................94
12.8
Sample size calculation..........................................................................................94
12.8.1
Primary endpoint(s)...............................................................................94
12.8.2
Secondary endpoint(s)...........................................................................95
13 Ethical considerations and administrative procedures.......................................................95
13.1
Regulatory and ethical compliance........................................................................95
13.2
Responsibilities of the investigator and IRB/IEC..................................................95
13.3
Publication of study protocol and results...............................................................95
13.4
Quality Control and Quality Assurance.................................................................96
14 Protocol adherence.............................................................................................................96
14.1
Protocol amendments.............................................................................................96
15 References..........................................................................................................................97
16 Appendices.......................................................................................................................100
16.1
Appendix 1: Clinically notable laboratory values................................................100
16.2
Appendix 2: Liver event and laboratory trigger definitions & follow-up 
requirements.........................................................................................................101
16.3
Appendix 3: Full description of graphical procedure used for testing of 
primary and secondary endpoints ........................................................................104


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List of tables
Table 2-1
Objectives and related endpoints for the Randomized Treatment 
period.....................................................................................................22
Table 2-2
Objectives and related endpoints for the Treatment Extension 
period.....................................................................................................23
Table 6-1
Investigational and control drug............................................................40
Table 6-2
LNP023 dose and treatment schedule ...................................................47
Table 8-1
Assessment schedule - Randomized treatment period ..........................51
Table 8-2
Assessment Schedule - Treatment Extension period.............................54
Table 8-3
Breakthrough definition.........................................................................59
Table 8-4
Assessments and specifications.............................................................62
Table 8-5
Laboratory tests .....................................................................................63
Table 8-6
PK blood log: participants Randomized to LNP023 arm......................67
Table 8-7
PK blood log: participants Randomized to comparator arm .................68
Table 8-8
List of the assessments to be performed during by off-site research 
nursing visit ...........................................................................................71
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse..........................................................................................79
Table 16-1
 Definitions of Triggers, Actions and Follow-up requirements for 
liver events...........................................................................................101
List of figures
Figure 3-1
Study design ..........................................................................................26
Figure 12-1
Graphical display of multiple testing procedure ...................................86


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List of abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
b.i.d.
bis in die/twice a day
BMF
Bone Marrow Failure
BTH
Breakthrough hemolysis
BUN
Blood Urea Nitrogen
CDS
Core Data Sheet
CK
Creatinine Kinase
CMO&PS 
Chief Medical Office and Patient Safety
CO
Country Organization
COA
Clinical Outcome Assessment
COVID-19
Coronavirus Disease 2019
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical Study Report
CV
Coefficient of Variation
DBP
Diastolic Blood Pressure
DMC
Data Monitoring Committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EORTC QLQ-
C30
European Organization For The Research And Treatment Of Cancer Quality Of Life 
Questionnaire
EVH
Extravascular Hemolysis
EOS
End of Study
ePRO
Electronic Patient Reported Outcome
EQ-5D-5L
EuroQol - 5 Dimensions- 5 Level
eSAE
Electronic Serious Adverse Event
ESA
Erythropoiesis Stimulating Agent
eSource
Electronic Source
FAS
Full Analysis Set
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GCS
Global Clinical Supply
GGT
Gamma-glutamyl transferase
h
Hour
HIF-PHI
Hypoxia-inducible factor prolyl hydroxylase inhibitors
HIV
Human immunodeficiency virus
HRQoL
Health-Related Quality of Life


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i.v.
Intravenous
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
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IVH
Intravascular Hemolysis
LDH
Lactate dehydrogenase
LFT
Liver Function Test 
LLOQ
Lower Limit Of Quantification
MAVE
Major Adverse Vascular Event
MedDRA
Medical Dictionary for Regulatory Activities 
mg
Milligram(s)
mL
Milliliter(s)
OATP
Organic Anion-Transporting Polypeptide 
ORN
Off-site Research Nursing
PGIS
Patient Global Impression of Severity
P-gp
Permeability glycoprotein
p.o.
oral(ly)
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PNH
Paroxysmal nocturnal hemoglobinuria
PPD
Premature Participant Discontinuation
PRO
Patient Reported Outcomes
PT
prothrombin time
QD
Once a day
QMS 
Quality Management System
QTcF
QT interval corrected by Fridericia’s formula
RAP
The Report and Analysis Plan 
RBC
Red Blood Cell(s)
RDC
Remote Data Capture
REB
Research Ethics Board
REP
Roll-over Extension Program
RU
Resource Utilization
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
sCR
serum creatinine
SD
Standard Deviation
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBL
Total Bilirubin


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TD
Study Treatment Discontinuation
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
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in the protocol, 
but not as an investigational medicinal product or control drug (e.g. any background 
therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study participant 
Cohort
A specific group of participants fulfilling certain criteria and generally treated at the same 
time
Control drug
A study drug (active or placebo) used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug
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 EOS of the last participant as defined by the 
protocol
Enrollment
Point/time of participant entry into the study at which informed consent must be obtained 
Estimand 
A precise description of the treatment effect reflecting the clinical question posed by the 
trial objective. It summarizes at a population-level what the outcomes would be in the 
same patients under different treatment conditions being compared. Attributes of an 
estimand include the population, variable (or endpoint) and treatment of interest, as well 
as the specification of how the remaining intercurrent events are addressed and a 
population-level summary for the variable.
Healthy volunteer
A person with no known significant health problems who volunteers to be a study 
participant 
Intercurrent events
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest.
Investigational 
drug/ treatment
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication kits
Mis-randomized 
participants
Mis-randomized participants are those who were not qualified for randomization and who 
did not take study treatment, but have been inadvertently randomized into the study 
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. concomitant 
or rescue therapy)
Part 
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a multiple 
dose part, or a part in participants with established disease and in those with newly-
diagnosed disease
Participant
A trial participant (can be a healthy volunteer or a patient)
Participant number
A unique number assigned to each participant upon signing the informed consent. This 
number is the definitive, unique identifier for the participant and should be used to 
identify the participant throughout the study for all data collected, sample labels, etc.
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in clinical 
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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
Randomization 
number
A unique identifier assigned to each randomized participant
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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Protocol summary
Protocol number
CLNP023C12302
Full Title
A randomized, multicenter, active-comparator controlled, open label trial to evaluate 
efficacy and safety of oral, twice daily LNP023 in adult patients with PNH and residual 
anemia, despite treatment with an intravenous anti-C5 antibody
Brief Title
Study of efficacy and safety of twice daily oral LNP023 in adult PNH patients with residual 
anemia despite anti-C5 antibody treatment
Sponsor and 
Clinical Phase
Novartis
Phase III
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this Phase 3 study is to determine whether LNP023 is efficacious and 
safe for the treatment in PNH through demonstration of superiority of LNP023 compared 
to anti-C5 antibody treatment in adult PNH patients presenting with residual anemia 
despite treatment with anti-C5 antibody therapy
Primary 
Objective(s)
The primary objectives are to:

Demonstrate superiority of LNP023 compared to anti-C5 antibody treatment in the 
proportion of participants achieving a sustained increase in hemoglobin levels from 
baseline of ≥ 2 g/dL in the absence of red blood cell transfusions.

Demonstrate superiority of LNP023, compared to anti-C5 antibody treatment, in the 
proportion of participants achieving sustained hemoglobin levels ≥ 12 g/dL in the 
absence of red blood cell transfusions.
The primary clinical questions of interest are: What is the treatment effect of LNP023 at a 
dose of 200 mg b.i.d. versus anti-C5 antibody treatment in PNH patients with residual 
anemia, regardless of discontinuation of study medication and occurrence of 
breakthrough hemolysis or Major Adverse Vascular Events (MAVEs), on the odds of 
being a responder, with the endpoints defined as a composite of 

An increase in Hb levels from baseline ≥ 2 g/dL

Hb levels ≥ 12 g/dL
both assessed between Day 126 and Day 168 and of not requiring RBC transfusions 
between Day 14 and Day 168.
Secondary 
Objectives

To demonstrate superiority of LNP023, compared to anti-C5 antibody treatment in 
transfusion avoidance as the proportion of participants who remain free from 
transfusions by assessing the proportion of participants not receiving any packed red 
blood cell transfusions per protocol established criteria between Day 14 and Day 168

To demonstrate superiority of LNP023, compared to anti-C5 antibody treatment, in 
average change in hemoglobin by assessing the change from baseline in 
hemoglobin (g/dL) as mean of visits between Day 126 and Day 168

To demonstrate superiority of LNP023, compared to anti-C5 antibody treatment, in 
improving fatigue, using the FACIT-Fatigue questionnaire by assessing the change 
from baseline in FACIT-Fatigue scores as mean of visits between Day 126 and Day 
168

To demonstrate superiority of LNP023, compared to anti-C5 antibody treatment, in 
average change in reticulocyte counts by assessing the change from baseline in 
reticulocyte count (109/L) as mean of visits between Day 126 and Day 168

To demonstrate superiority of LNP023, compared to anti-C5 antibody treatment, 
in average percent change in LDH by assessing the percent change from baseline in 
LDH levels (U/L) as mean of visits between Day 126 and Day 168

To demonstrate superiority of LNP023, compared to anti-C5 antibody treatment, in 
the rate of breakthrough hemolysis (BTH) of participants with breakthrough 
hemolysis reported between Day 1 and Day 168


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
To assess rates of MAVEs (incl. thrombosis) of LNP023, compared to anti-C5 
antibody treatment occurring between Day 1 and Day 168

The assessment of safety and tolerability of LNP023 compared to anti-C5 antibody 
treatment 
Study design
This study is a multi-center, randomized, open-label, active comparator-controlled, 
parallel group study, which is comprised of a screening period, a 24-week, active 
controlled, parallel group treatment period and a 24-week LNP023 treatment extension 
period.
Study population
Approximately ninety one (91) patients diagnosed with PNH, who are treated with a 
stable regimen of anti-C5 antibody (Standard of Care (SoC); either eculizumab or 
ravulizumab) for at least 6 months prior to Randomization, but still presenting with 
residual anemia (i.e., Hb < 10 g/dL) will be enrolled.
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 WBCs granulocyte/monocyte clone 
size ≥ 10%

Stable regimen (dose and intervals) of anti-C5 antibody treatment (either eculizumab 
or ravulizumab) for at least 6 months prior to randomization

Mean hemoglobin level <10 g/dL 
Over a minimum of 4 months before screening visit 
Confirmed by central laboratory assessment during screening

Vaccination against Neisseria meningitidis infection is required prior to the start of 
treatment. If the patient has not been previously vaccinated, or if a booster is 
required, vaccine should be given according to local regulations, at least 2 weeks 
prior to first dosing.

If not received previously, vaccination against Streptococcus pneumoniae and 
Haemophilus influenzae infections should be given, if available and according to 
local regulations. The vaccines should be given at least 2 weeks prior to first dosing.
Key Exclusion 
criteria

Participants on a stable eculizumab dose but with a dosing interval of 11 days or less 
or participants on stable ravulizumab dose but with a dosing interval of less than 8 
weeks.

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 <500x106/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/1.73 m2,dialysis) , advanced cardiac disease (e.g., NYHA 
class IV), 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.
Study treatment
LNP023
Anti-C5 antibodies (either eculizumab or ravulizumab)
Treatment of 
interest
The randomized treatment (the investigational treatment LNP023 200 mg b.i.d. or stable 
regimen of anti-C5 antibody therapy (SoC)) regardless of whether patient discontinues 
treatment (treatment policy). 
Efficacy 
assessments

Hemoglobin, reticulocytes, LDH and other PNH-related laboratory parameters

Red blood cell transfusions

Breakthrough hemolysis


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
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 
An assessment of patient-reported outcomes is planned in this trial using European 
Organization For The Research And Treatment Of Cancer Quality Of Life Questionnaire 
(EORTC QLQ-C30), EuroQol - 5 Dimensions- 5 Level (EQ-5D-5L), and Patient Global 
Impression of Severity of fatigue (PGIS). Exploration of the meaningfulness of the change 
demonstrated in patient report outcomes will be performed with an optional Patient 
Interview.
Data analysis
All efficacy analyses will use the full analysis set (FAS) that includes all patients 
randomized into the study.
Primary efficacy estimands represented by the following endpoints:

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 transfusions 
between Day 14 and Day 168 

Proportions of participants achieving sustained hemoglobin levels ≥ 12 g/dL between 
Day 126 and Day 168 in the absence of transfusions between Day 14 and Day 168 
Superiority of LNP023 compared to anti-C5 antibody treatment will be determined using 
an odds ratio and tested by a simultaneous weighted permutation test derived from a 
conditional logistic model accounting for the stratification factors used at randomization 
and with adjustment for baseline hemoglobin levels and sex, used in the analysis of the 
two endpoints. Besides the odds ratio a marginal logistic model adjusting for stratification 
factors and covariates will be used to compare the proportions of both treatments using 
standardization.
Secondary efficacy estimands represented by the following endpoints:

Proportions of participants who are transfusion free by protocol specified criteria 
between Day 14 and Day 168

Differences in average change from baseline in hemoglobin levels between Day 126 
and Day 168 estimated under the hypothetical condition of being free from transfusion 
between Day 14 and Day 168

Differences in average score changes from baseline evaluated between Day 126 and 
Day 168 of FACIT-Fatigue

Differences in average changes from baseline in reticulocyte counts evaluated 
between Day 126 and Day 168

Differences in average percent change from baseline in LDH evaluated between Day 
126 and Day 168

Rates of breakthrough hemolysis between Day 1 and Day 168 

Rates of MAVEs between Day 1 and Day 168
Following successful rejection of the hypotheses associated with the primary estimands, 
the secondary estimand hypotheses will be tested applying weighted Simes’ tests with 
pre-defined weights allocated to the different levels of secondary hypotheses. The testing 
procedure applies alpha propagation rules according to the principles of graphical 
procedures for multiplicity adjustment. The estimands of interest as well as methods for 
obtaining comparisons are described in detail in the corresponding sections.
Key words
LNP023, eculizumab, ravulizumab, anti-C5, 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 (Brodsky 2014). 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.
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 hydrogenase (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 (Brodsky 2014, 
Hill et al 2013). Thromboembolism is the leading cause of morbidity and mortality in patients 
with PNH and can occur at any site; although venous is more common (80–85%), it can also be 
arterial (15–20%) (Hillmen et al 2007).
Eculizumab and Ravulizumab (engineered from eculizumab with prolonged dosing interval) 
are approved anti-C5 antibody therapies for the treatment of PNH and the current Standard of 
Care (SoC) where available. The introduction of eculizumab has significantly reduced the 
thromboembolic risk of PNH patients improving morbidity and mortality and largely improved 
the quality of life (QoL) of PNH patients.
Although the anti-C5 antibody treatment is generally effective in treating intravascular 
hemolysis (IVH), there remains a high unmet medical need for PNH. Different authors reported 
heterogeneous hematological response with eculizumab and a substantial proportion of patients 
not achieving normal or near normal hemoglobin levels (McKinley et al 2017, 
DeZern et al 2013, Hill et al 2010, Risitano et al 2009). In the study of Risitano and colleagues, 
approximately one third of patients treated with eculizumab achieved normal or near normal 
hemoglobin levels (hemoglobin ≥ 11 g/dL) without requiring red blood cell transfusions 
(Risitano et al 2009). 
Until recently, well defined response categories to complement inhibitor therapy have not been 
established. A classification of hematological response with anti-complement agents has been 
proposed by the Severe Aplastic Anemia (SAA) Working Party of the European group for Bone 
Marrow Transplantation (EBMT) (Risitano et al 2019). The classification has been applied to 
a large cohort of 93 PNH patients retrospectively and results have been reported 
(Debureaux P-E 2019) after the first six months of treatment with eculizumab (n=80). 










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medication and occurrence of breakthrough hemolysis or MAVEs, on the odds of being a 
responder, with the endpoint defined as a composite of Hb levels ≥ 12 g/dL assessed between 
Day 126 and Day 168 without requiring RBC transfusions between Day 14 and Day 168?
The justification of this primary estimand is that it will capture the hematological benefit of the 
study drug as a normalization of hemoglobin levels that is achieved free from RBC transfusions 
(which are regarded as treatment failure).
Further details can be found in Section 12.
The two primary estimands share the following attributes:

Population: Patients with PNH who are on a stable regimen of SoC (anti-C5 antibody 
treatment) and have residual anemia (Hb < 10 g/dL). Further details about the population 
are provided in Section 5.

Treatment of interest: the randomized treatment (the investigational treatment LNP023 200 
mg b.i.d. or anti- C5 therapy (SoC)) regardless of whether patient discontinues treatment 
(treatment policy). Further details about the investigational treatment and control treatment 
are provided in Section 6.

Intercurrent events: Transfusions will be considered treatment failures whereas 
discontinuations of study medication for any reason, breakthrough hemolysis events, and 
MAVEs will be handled with a treatment policy strategy.

The summary measure: the probability of being a responder on each treatment in the studied 
patient population tested as an odds ratio.
However, the estimands differ in the definition of the associated endpoints as the proportion of 
responders where the responder definitions are as follows:

Responder defined as a participant having Hb ≥ 2 g/dL increase from baseline between Day 
126 and Day 168 and who has not received a RBC transfusion between Day 14 and Day 
168 of the randomized treatment period.

Responder defined as a participant having Hb ≥ 12 g/dL between Day 126 and Day 168 and 
who has not received a RBC transfusions between Day 14 and Day 168 of the randomized 
treatment period.
In addition to odds ratios, estimates of the proportions of responders in each treatment and their 
differences as well as the ratio of proportions between treatments will be derived as a supportive 
estimand to quantify the magnitude of the effect of treatment with LNP023 compared to anti-C5 
antibody treatment. 
For the purpose of efficacy assessment, a supplementary estimand has been added considering 
the use of rescue therapy as treatment failure. The supplementary estimand will have the same 
population, treatment of interest, summary measure as the primary estimand and the analysis 
and details are stated in Section 12.4.6.
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 


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primary estimands. The proposed approach in the case of transfusion handling will be described 
in the estimand definition, while discontinuations of study medication, breakthrough hemolysis 
events, and MAVEs 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:

Proportions of participants not receiving any transfusions between Day 14 and Day 168 
(Transfusion Avoidance). The summary measure is the same as for the two primary 
endpoints.

Difference in achieved hemoglobin changes from baseline 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 comparison of the mean changes from baseline in hemoglobin levels assessed between 
Day 126 and Day 168.

Difference in 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 comparison of mean changes from baseline 
in FACIT fatigue scores assessed between Day 126 and Day 168.

Difference in 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 
comparison of the mean changes from baseline in reticulocyte counts assessed between Day 
126 and Day 168.

Difference in 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 the 
comparison of the log transformed LDH ratio to baseline assessed between Day 126 and 
Day 168.

Rates of breakthrough hemolysis occurring between Day 1 and Day 168. The summary 
measure is a rate difference.

Rates of MAVE between Day 1 and Day 168. The summary measure is a rate difference.
Estimand considerations in case of COVID-19 pandemic impact
The overarching principle for primary and secondary estimands, is answering questions of 
treatment effect of LNP023 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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3
Study design
This study is a multi-center, randomized, open-label, active comparator-controlled, parallel 
group study, which is comprised of three periods (see Figure 3-1):

A screening period lasting up to 8 weeks (unless there is a need to extend it for vaccinations 
required for inclusion, vaccinations should be started at the earliest possible to avoid 
extension of the screening period)

A 24-week randomized, open-label, active controlled, parallel group treatment period for 
the primary efficacy and safety analyses

A 24-week open-label, LNP023 treatment extension period
The study will enroll PNH patients with residual anemia, defined as hemoglobin < 10 g/dL, 
despite stable regimen of anti-C5 antibody treatment (eculizumab or ravulizumab) in the last 6 
months before randomization, with approximately 40% of participants having received at least 
1 packed-RBC transfusion in the 6 months prior to randomization.
A total of approximately 91 participants will be randomized 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.
Figure 3-1
Study design
The database of the study will be locked for the randomized treatment period when the last 
participant has completed the Day 168 visit in the study or EOS (End of Study) for participants 
who discontinue from the study prior to the treatment extension period. The final database lock 
will take place when the last participant has completed the last visit (Day 336 or EOS) in the 
treatment extension period.
Screening
Screening period starts at the time of ICF signing and lasts until the day preceding Day 1 of the 
randomized treatment period.


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Participants will be asked to review and sign the informed consent form prior to proceeding for 
the screening assessments. After signing ICF, during this visit, inclusion and exclusion criteria 
will be assessed to verify participants' eligibility for enrollment into 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 following records: hemoglobin 
levels reported at least during the last 4 months; the numbers of transfusions and unit numbers 
of packed-RBC received in the last 12 months prior to Screening; Major Adverse Vascular 
Events (MAVEs) reported prior to screening (History of MAVE); and the anti-C5 antibody 
regimen they have followed for the last 6 months up to randomization (History of anti-C5 
antibody treatment).
Vaccinations should be completed as per Inclusion criteria defined in Section 5.1. Vaccines 
should cover as many serotypes as possible (including meningococcal serotypes A, C, Y, W-135 
and B). To minimise participant burden, the use of multivalent vaccines is recommended as 
locally available and per local guidelines and regulations (e.g. quadrivalent vaccine for 
N. meningitidis which covers serotypes A, C, Y and W-135 and Pneumovax-23 which covers 
23 S. pneumoniae serotypes). For the vaccination type and booster requirements use local 
guidelines, and locally available vaccines (and refer to the package insert of those, or local 
guidelines). The screening period may be extended to allow vaccination procedures to be 
completed, in case of multiple vaccination needs and local/country requirements. This is 
applicable for vaccinations only, while all the other screening assessments must be performed 
as indicated in the Assessment Schedule Table 8-1.Vaccinations should be started at the earliest 
possible to avoid extension of screening period. There is a possibility that administration of a 
vaccine to a patient with PNH could stimulate complement production and worsen hemolysis. 
In order to mitigate this possibility, it may be preferred to start treatment with iptacopan within 
2 weeks after vaccination. In this case, the 2-weeks post-vaccination period should be covered 
by treatment with prophylactic antibiotics. 
To fulfill the hemoglobin eligibility criterion, participants will have two different samples 
collected during the screening period and tested by the central laboratory with the mean 
<10 g/dL, prior to Randomization. In case the participant has received a RBC transfusion 
following the initial sample collection, the patient is eligible based on the initial central 
hemoglobin value if < 10 g/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 randomization. The participant can be re-
screened as described in detail in Section 8.1.


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Investigators should refer to the locally approved label of eculizumab and ravulizumab for 
recommendation of use and in accordance with local practice.
Randomization
The randomization will be stratified into four strata (defined by the combination of the 
stratification factors). Participants who meet the eligibility criteria at screening will be stratified 
based on the type of prior anti-C5 antibody treatment (eculizumab or ravulizumab) and based 
on the transfusion history as reported during the last 6 months prior to randomization (i.e. 
transfusion received/not received). It is assumed that approximately 40% of randomized 
participants having received at least one packed red blood cell (pRBC) transfusion in the 6 
months prior to randomization.
Participants will be randomized to one of the two treatment arms in a 8:5 ratio to either LNP023 
monotherapy at a dose of 200 mg orally b.i.d. (approximately 56 participants), or i.v. anti-C5 
antibody treatment (approximately 35 participants continuing with the same regimen during the 
randomized treatment period as they were on prior to randomization), respectively.
Randomized Treatment period
Treatment will start on the first day of dosing (Day 1) and continue for 24 weeks with study 
visits and corresponding assessments according to schedule described in Table 8-1.
Participants assigned to the comparator arm will continue receiving the same type, and regimen 
of anti-C5 antibody treatment as received prior to randomization, while those randomized to 
the LNP023 treatment arm will start taking LNP023 at dose of 200 mg b.i.d. Please refer to 
Section 6 for details on study medication and timing for starting LNP023 treatment in relation 
to the prior anti-C5 antibody treatment ensuring a seamless switch with an overlap of at least 
one (eculizumab) or two (ravulizumab) weeks of prior anti-C5 and LNP023 treatment.
Please refer to Section 8.3.2 which provides details about the protocol-specific guidelines for 
participants to receive a packed-RBC transfusion in the randomized treatment period.
The randomized treatment period will end with completion of the Week 24 visit assessments 
and, on that visit, participants in the active comparator arm will receive the last dose of anti-C5 
infusion as part of the study treatment.
For participants who permanently discontinue LNP023 administration during the randomized 
treatment period, close monitoring and treatment proposals are indicated in Section 9.1.1 
Participants should complete all visits and assessments up to Week 24 visit.
Because of the known risk of complement inhibitor treatment for 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 of antibiotic treatment as soon as possible. 
Upon completion of the Week 24 visit, participants may enter the treatment extension period, 
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Treatment Extension period 
The participants randomized to the active comparator arm will be offered to switch to 
LNP023 on Day 168 (Week 24 visit) and enter the treatment extension period, after receiving 
a last dose of anti-C5 (eculizumab or ravulizumab) antibody treatment. For participants in the 
comparator arm not agreeing to switch treatment, Week 24 will be the End of Study visit for 
the trial and there will be no participation in the treatment extension period. For participants 
agreeing to switch to oral LNP023, the Extension treatment will start on the day after 
completion of the Week 24 visit.
After switching to LNP023, the participants in the comparator arm will follow study visits and 
assessments according to schedule described in Table 8-2. 
The participants in the LNP023 arm, who benefit from treatment and are taking LNP023 at 
Week 24 visit (i.e. did not permanently discontinue study medication), will be offered to 
continue the oral treatment during the treatment extension period, with study visits and 
assessments according to schedule detailed in Table 8-2. For participants not agreeing to 
continue in the treatment extension 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 LNP023 treatment during the treatment extension 
period, please refer to Section 9.1.1 
The treatment extension period will last 24 weeks. After completion of the treatment extension 
period, the participant will be able to join the Roll-over extension program (REP), which will 
provide access to LNP023 and enable long-term safety monitoring. 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
4
Rationale
4.1
Rationale for study design
CLNP023C12302 is designed as a multicenter, open-label, randomized, active-comparator 
controlled, parallel group study for demonstration of superiority of LNP023 at a dose of 200 
mg b.i.d. orally compared to intravenous anti-C5 antibody treatment on hematological response 
parameters and patient reported outcome measures for fatigue, in patients with PNH that present 
with residual anemia despite treatment with a stable regimen of anti-C5 antibody treatment 
(SoC).
The study population consists of PNH patients with residual anemia defined by a mean 
hemoglobin value below 10 g/dL (with approx. 40% requiring RBC transfusions in the past 6 
months) for inclusion in the study despite treatment with SoC, i.e., anti-C5 antibody treatment 
of eculizumab or ravulizumab. This represents a population for which there remains a need 
for improved efficacy. In a retrospective analysis of a cohort of 93 PNH patients classifying 
hematological response to eculizumab treatment, it has been shown that after 6 months of 
eculizumab treatment (n=80), 54% of participants have a hemoglobin value of less than 10 
g/dL with or without the need of RBC transfusions during that period 


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(Debureaux P-E et al 2019). The 54% included patients meeting the criteria for partial, minor 
or no hematological response according to the novel classification of hematological response 
to eculizumab (Risitano et al 2019).
Approximately 40% of randomized participants are required to have received at least one 
packed red blood cell (pRBC) transfusion in the 6 months prior to randomization. In the 
eculizumab registration trials TRIUMPH and SHEPHERD, transfusion independence has been 
achieved in 51% of eculizumab treated patients after 26 weeks of treatment (Hillmen et al 2006) 
and 51% of eculizumab treated patients after 52 weeks of treatment (Brodsky et al 2008), 
respectively. More recently, transfusion avoidance rates after 26 weeks of treatment were 
reported with 66.1% and 73.6% in eculizumab and ravulizumab treated patients respectively 
(Lee et al 2019).
The randomization will be stratified based on prior anti-C5 antibody treatment (eculizumab or 
ravulizumab) and by the presence or not of transfusion dependence (any transfusion 
administered in the 6 months prior to Randomization), both factors that could impact 
hematological response.
A multicenter setting has been chosen to ensure adequate recruitment and enrollment into the 
study in this rare indication. A randomized, active-comparator controlled study design for the 
main treatment period has been selected to appropriately assess LNP023’s efficacy and safety 
and demonstration of superior efficacy compared to anti-C5 antibody treatment in support of 
its registration.
The randomization ratio of 8:5 has been chosen in order to maximize the number of PNH 
participants who are treated with LNP023 and increase the efficacy and safety data collected 
with LNP023 in this rare population. The initiation of LNP023 treatment has an overlap of 1 
(eculizumab) or 2 (ravulizumab) weeks with prior anti-C5 antibody treatment to ensure that 
participants are not at risk of breakthrough hemolysis while minimizing potential carry-over 
effects of prior anti-C5 antibody treatment. 
An open-label design is appropriate for the selected primary and majority of secondary efficacy 
endpoints, which are objectively measured (i.e. hematological response parameters, 
hemoglobin, LDH, reticulocytes, transfusion avoidance and breakthrough hemolysis). Protocol-
specific guidelines (see Section 8.3.2) were defined to reduce potential bias in the determination 
of endpoints including transfusion avoidance.
The randomized treatment period of 24 weeks is considered appropriate to assess the effect of 
LNP023 on the primary and secondary efficacy endpoints as well as on safety and tolerability, 
similar to the treatment duration of the Phase 3 studies with eculizumab and ravulizumab
(Lee et al 2019; Kulasekararaj et al 2019). Because the comparator arm includes both 
eculizumab and ravulizumab, the potential carry-over effects of the longer acting ravulizumab 
were taken into account by the choice of 24 weeks randomized treatment period instead of 
e.g. 16 weeks reported in the PEGASUS trial with only eculizumab as comparator 
(ClinicalTrials.gov Identifier: NCT03500549).
Two hematological responder endpoints will be used for the primary efficacy analysis of the 
randomized treatment period:


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1. A hematological responder defined as a participant achieving an increase from baseline in 
hemoglobin levels ≥ 2 g/dL (assessed during the last 6 weeks of the 24 weeks randomized 
treatment period) without the need of RBC transfusions from Day 14 to Day 168. This 
endpoint comprises 1) a sustained 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. The choice of an increase of at least 2 g/dL in hemoglobin in the 
absence of transfusions is because it approximates an increase that can be achieved with 
the administration of a RBC transfusion (1-2 units), thereby considered clinically relevant.
2. 2. A hematological responder defined as a participant achieving hemoglobin levels ≥ 12 
g/dL (assessed during the last 6 weeks of the 24 weeks randomized treatment period) 
without the need of RBC transfusions from Day 14 to Day 168. This endpoint comprises 
1) hemoglobin normalization and 2) transfusion independence for treatment success, also 
both clinically important treatment goals in PNH.
An interval of six weeks at the end of the randomized treatment period with four assessments, 
and 3 out of 4 meeting the criterion, has been selected to demonstrate a durable hematological 
response. Furthermore the last six weeks of the 24 weeks randomized treatment period are used 
for determining hematological response (≥ 2 g/dL hemoglobin increase from baseline; 
hemoglobin ≥12 g/dL) to ensure that it reflects the actual treatment effect of either LNP023 or 
anti-C5 antibody treatment.
Considering that some patients may present with very low hemoglobin levels (e.g. < 7 g/dL), 
and thereby require a red blood cell transfusion during the first two weeks of the randomized 
treatment period, transfusions administered during these first 2 weeks will not be considered 
for the transfusion avoidance definition.
Secondary efficacy endpoints include transfusion avoidance and breakthrough hemolysis, a 
patient reported outcome measure for fatigue (FACIT-Fatigue) as well as changes in 
reticulocytes and LDH and MAVEs. They were selected to supplement the primary efficacy 
endpoints and are clinically meaningful endpoints for hemolytic PNH.
A treatment extension period of 24 weeks will provide further safety and efficacy data on 
LNP023 in PNH patients.
4.2
Rationale for dose/regimen and duration of treatment
The dose of 200 mg LNP023 b.i.d. as continuous treatment has been selected for this study 
primarily based on the available efficacy and safety data obtained at the time of interim analyses 
from the two ongoing Phase 2 PNH studies and is supported by PKPD modeling results.
In the CLNP023X2201 study in patients with active hemolysis despite treatment with 
eculizumab, LNP023 at a dose of 200 mg b.i.d. was administered to 10 PNH participants 
(cohort 1) and at a dose of 50 mg b.i.d. to 6 PNH participants (cohort 2). An interim analysis 
(IA) was conducted after 10 participants (cohort 1) completed at least 13 weeks of treatment 
with LNP023 200 mg b.i.d. add-on treatment to eculizumab.
In the CLNP023X2204 study in PNH patients not treated with eculizumab/complement 
inhibition, participants were randomized to LNP023 monotherapy in two sequences with forced 
titration after 4 weeks from LNP023 25 mg b.i.d. to 100 mg b.i.d (sequence 1) or LNP023 50 


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mg b.i.d. to 200 mg b.i.d. (sequence 2). An IA was conducted after the first 8 patients were 
randomized and 7 patients completed Week 8 visit assessments.
The dose of 200 mg b.i.d. is expected to provide optimal efficacy required for PNH as 
monotherapy with an adequate safety profile based on the following key findings of the two 
interim analyses:

Participants treated with LNP023 200 mg b.i.d. (as add-on to eculizumab) had clinical 
benefits not achieved with eculizumab that included control of IVH demonstrated by LDH 
reduction, control of EVH demonstrated by reduction of bilirubin, reticulocytes and increase 
in haptoglobin resulting in normalization of hemoglobin in the majority of patients in the 
absence of red blood cell transfusions. The hematological response participants achieved 
with LNP023 200 mg b.i.d. add-on therapy was maintained with LNP023 monotherapy 
during the extension period (at the time of the IA) when eculizumab treatment was 
discontinued in 5/10 participants who continued with LNP023 monotherapy. Following the 
IA, several additional participants discontinued eculizumab treatment. C3 deposition was 
fully reversed by addition of LNP023 at a dose of 200 mg b.i.d. and survival of PNH red 
blood cells prolonged further supporting control of EVH by LNP023 at a dose of 200 mg 
b.i.d. There was sustained inhibition of the complement alternative pathway and profound 
and sustained reduction of Fragment Bb demonstrating target engagement.

Participants receiving LNP023 monotherapy showed that LNP023 at dose levels ≥ 25 mg 
b.i.d. had LDH reduction of more than 60% from baseline in all participants and early 
transfusion-free hemoglobin increase in the majority of participants. Other hemolysis 
relevant laboratory values indicated that LNP023 administered as monotherapy controls 
both, intra (LDH reduction) and extravascular hemolysis (decrease of reticulocytes and 
bilirubin, increase in haptoglobin).
Preliminary information from cohort 2 in CLNP023X2201 suggests that the LNP023 dose of 
50 mg b.i.d. may not provide optimal efficacy required for LNP023 monotherapy in PNH. There 
was suboptimal response in most participants requiring up-titration to the dose of 200 mg b.i.d.
LNP023 at a dose of 200 mg b.i.d. was safe and well tolerated by participants in both studies in 
PNH, as well as at the same dose in patients with IgA nephropathy (study CLNP023X2203) 
and C3 glomerulopathy (CLNP023X2202), supporting its use in this study.
The exposure-response model developed with data from the First In Human (FIH) study with 
LNP023 in healthy volunteers predicts that a dose of about 200 mg b.i.d. would be needed to 
achieve > 90% inhibition of the alternative pathway (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 LNP023 Investigator 
Brochure.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
For this study, an active control has been selected due to the life-threatening nature of the 
disease. To date the only approved, targeted therapies for treatment of PNH are eculizumab and 


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ravulizumab, two anti-C5 monoclonal antibodies inhibiting cleavage of C5 to C5a and C5b. 
The study allows inclusion of patients treated with either eculizumab or ravulizumab, at stable 
regimen. For eculizumab (administered as intravenous infusion every 2 weeks), the 
maintenance dose is a fixed dose, whereas for ravulizumab (administered as intravenous 
infusion every 8 weeks), the maintenance dose is based on body weight.
Eculizumab is the current Standard of Care (SoC) for PNH patients with hemolysis and the 
clinical program with eculizumab demonstrated prevention of intravascular hemolysis, 
hemoglobin stabilization, and reduction/avoidance of red blood cell transfusions 
(Brodsky et al 2008, Hillmen et al 2006) as well as reduction of the thromboembolic risk 
(Hillmen et al 2007). Its approval in 2007 and subsequent introduction has significantly changed 
the disease course where available and improved morbidity and mortality. 
Ravulizumab (engineered from eculizumab with prolonged dosing interval) approved in 2019 
for the treatment of PNH is expected to replace eculizumab as SoC, given the added 
convenience of an 8-week administration regimen. Data from two clinical trials demonstrated 
non-inferiority of ravulizumab to eculizumab (Lee et al 2019; Kulasekararaj et al 2019) 
providing justification for the choice of ravulizumab and eculizumab in the control arm.
While anti-C5 agents are effective in inhibiting intravascular hemolysis in most patients, only 
a small proportion of patients achieve normal to near normal hemoglobin values and there 
remains an unmet medical need to inhibit extravascular hemolysis not prevented by anti-C5 
antibody treatment (please refer to Section 1.1). Participants are expected to continue with their 
stable anti-C5 antibody treatment regimen (which they were on during the six months prior to 
randomization) throughout the randomized treatment period. Any changes in dose and/or 
infusion interval should be avoided.
4.4
Purpose and timing of interim analyses/design adaptations
Periodic monitoring of safety data and emerging risk/benefit will be carried out by a Data 
Monitoring Committee (DMC). To this end, interim reports with analysis results using 
treatment group labels available only to the DMC will be generated by an independent statistical 
group not involved in the conduct of the trial. The randomization list will be made available in 
a firewalled area for the purpose of generating interim analysis reports.
4.5
Risks and benefits
The risks associated with the use of LNP023 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 LNP023 Investigator Brochure. The 
safety results from the CLNP023X2201 study (PNH patients treated with eculizumab) as well 
as CLNP023X2204 study (anti-C5 treatment-naïve PNH patients) are summarized in the 
Investigator Brochure. LNP023 at a dose of 200 mg b.i.d. has been generally safe and well 
tolerated in these studies. 
Appropriate eligibility criteria, as well as study specific stopping rules for the investigational 
drug with guidance to ensure continued treatment of PNH are included in this protocol. 
Recommended guidelines for monitoring of and management of infections are provided in 


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Section 6.6.2. The risk to participants in this trial will be minimized by compliance with the 
eligibility criteria and study procedures of participants including vaccinations prior to starting 
study treatment, close clinical monitoring with appropriate risk mitigation strategies, and 
periodic review of the safety data by an independent DMC. This study does not involve any 
risks regarding study procedures (e.g. no invasive research procedures). 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.
LNP023 did not show any mutagenic, teratogenic or genotoxic potential in completed standard 
battery of genotoxicity testing. In addition, LNP023 was tested in embryo-fetal development 
studies in rats and rabbits and no LNP023-related adverse fetal findings were detected in any 
of the studies. However, LNP023 has not been used in pregnant women, therefore, women of 
child-bearing potential must be informed that taking the study treatment may involve unknown 
risks to the fetus if pregnancy were to occur during the study, and agree that in order to 
participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the participant will not reliably comply, they 
should not be entered or continue in the study.
Based on the preliminary results from the CLNP023X2201 study as well as CLNP023X2204 
study (Section 4.2 for details), patients randomized to LNP023 may have clinical benefits over 
and above the SoC including:

Increase of hemoglobin to normal/near normal values in the absence of red blood cell 
transfusions

Control of extravascular hemolysis

Reduction of LDH
It is expected that the improved hematological response upon LNP023 treatment will translate 
into improved quality of life, most importantly an improvement in fatigue. More details about 
the preliminary results of the Phase 2 studies can be found in Section 1.1 and the Investigators 
Brochure. Patients randomized to anti-C5 antibody treatment may benefit from participating in 
this clinical trial and the possibility to switch to LNP023 treatment at the end of the randomized 
treatment period. 
The main safety risk for complement inhibitors is considered to be infection caused by 
encapsulated bacteria. To date, no infections have been reported in preclinical studies with 
LNP023 and no infections caused by encapsulated bacteria have been reported in clinical trials.
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. Serum bactericidal activity studies of serum 
from vaccinated patients against meningococci showed that C5 inhibitors block killing of 
meningococci, whereas AP inhibitors have less inhibitory effect on meningococcal killing 
(Konar and Granoff 2017). Vaccination is therefore predicted to be an effective mitigation 
strategy to reduce the risk for individuals treated with LNP023. Participants will be vaccinated 
against meningococcal, pneumococcal and H. influenzae infections according to local 
guidelines and availabilities, since these are all encapsulated bacteria.


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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 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 
monitoring and management of infections are provided in Section 6.6.2. For 
immunocompromised participants with a higher risk of infections, precautionary actions (e.g. 
prophylactic antibiotics) should be considered by the investigator.
Other safety risks are based on preclinical data, with no relevant findings in clinical studies 
performed to date. There are potential risks of testicular effects, bone marrow toxicity with 
severe anemia, aorta mineralization and increase in heart weight and thyroid changes. The 
preclinical findings are described in more detail in the Investigator Brochure.
In the LNP023 clinical studies, there have been no serious testicular adverse events or changes 
from baseline in reproductive hormones reported to date. Since the testicular effects seen in 
preclinical studies have been shown to be mild and reversible with no notable effect on sperm 
or hormone levels in dogs, and a reasonable safety margin when comparing unbound 
concentrations achieved in the dog at the lowest dose where an effect was seen (LOAEL) and 
the concentrations achieved in man at the 200 mg twice daily dose, the relevance of the findings 
to man is considered questionable. Testicular AEs and reproductive hormone levels will 
continue to be monitored in Phase 3.
Although a severe bone marrow effect was seen pre-clinically in a single dog, it occurred at the 
highest dose level for which the exposure to LNP023 for unbound levels was more than 80-fold 
greater than that observed with the 200 mg b.i.d. dose of LNP023 in the clinic (see Investigator’s 
Brochure). There have been no adverse events or blood chemistry values reported which are 
relevant to the bone marrow toxicity seen in the dog. Hematological parameters 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. Blood pressure decrease concurrent with heart rate increase was consistently observed in 
both young and adult dogs soon after dosing, but in adult dogs these effects diminished over 
time, whereas they persisted in the young dogs. Since the aorta mineralization and increased 
heart weight are considered to be seen only in young dogs because of an increased sensitivity 
related to age, the risk is considered unlikely to be relevant to adult patients.
Preclinical thyroid effects have been observed; however, they were minimal and reversible. 
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.
In addition, safety results from completed studies in 108 healthy volunteers exposed to LNP023 
(84 to single doses and 24 to multiple doses over two weeks) indicated that treatment was well 
tolerated. Overall, no deaths or SAEs were reported, no imbalances from placebo in rates of 


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AEs and no AEs which led to study drug discontinuation. Similarly, the two Phase 2 studies in 
patients with PNH (29 patients exposed to LNP023), studies carried out in complement-driven 
renal disease (IgA nephropathy study, in which 87 patients were exposed to LNP023 and C3G 
studies, in which 27 patients were exposed to LNP023) confirmed that the safety profile was 
favorable and supported continuation of development.
In summary, the benefit risk relationship for LNP023 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
Patients diagnosed with PNH, who are treated with a stable regimen of anti-C5 monoclonal 
antibody treatment (Standard of Care; either eculizumab or ravulizumab) for at least 6 months 
prior to randomization, but still presenting with residual anemia (i.e., Hb < 10 g/dL) will be 
enrolled. Approximately 40% of participants having received at least 1 packed-RBC 
transfusions in the 6 months prior to randomization are to be enrolled. A total of approximately 
91 participants will be randomized in the trial. 
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female participants ≥ 18 years of age with a diagnosis of PNH confirmed by 
high-sensitivity flow cytometry (Borowitz et al 2010) with RBCs and with WBCs 
granulocyte/monocyte clone size ≥ 10%.
3. Stable regimen (dose and intervals) of anti-C5 antibody treatment (either eculizumab or 
ravulizumab) for at least 6 months prior to Randomization.
4. Mean hemoglobin level <10 g/dL:
Documented by at least 2 measurements over a minimum of 4 months (medical 
history data) before Screening visit
And confirmed by central laboratory assessment during Screening and prior to 
Randomization:

By two hemoglobin measurements (mean <10 g/dL), two up to eight weeks 
apart, for patients not receiving a pRBC transfusion during Screening.

By one hemoglobin measurement (<10 g/dL) carried at the first Screening visit 
for patients receiving a pRBC transfusion after which he/she will be eligible.


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5. Vaccination against Neisseria meningitidis infection is required prior to the start of 
treatment. If the patient has not been previously vaccinated, or if a booster is required, 
vaccine should be given according to local regulations, at least 2 weeks prior to first dosing. 
If treatment has to start earlier than 2 weeks post vaccination, prophylactic antibiotic 
treatment must be initiated.
6. If not received previously, vaccination against Streptococcus pneumoniae and 
Haemophilus influenzae infections should be given, if available and according to local 
regulations. The vaccines should be given at least 2 weeks prior to first dosing. If LNP023 
treatment has to start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment 
must be initiated.
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. Participants on a stable eculizumab dose but with a dosing interval of 11 days or less or 
participants on stable ravulizumab dose but with a dosing interval of less than 8 weeks.
3. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes.
4. Known or suspected hereditary complement deficiency at screening.
5. History of hematopoietic stem cell transplantation.
6. Patients with laboratory evidence of bone marrow failure (reticulocytes <100x109/L, (or 
<100x106/mL); platelets <30x109/L, (or <30x 106/mL); neutrophils <500x106/L, (or 
<500x103/mL).
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. A history of recurrent invasive infections caused by encapsulated organisms, e.g. 
meningococcus or pneumococcus. 
11. Major concurrent comorbidities including but not limited to severe kidney disease 
(e.g., eGFR < 30 mL/min/1.73 m2, dialysis), advanced cardiac disease (e.g., NYHA class 
IV), 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 HBV or HCV infection defined as HBsAg positive or HCV 
RNA positive, or liver injury as indicated by: abnormal liver function tests at Screening:


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
Any single parameter of ALT, GGT, alkaline phosphatase must not exceed 3×upper 
limit of normal (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) or immunosuppressants for at least 8 weeks
Systemic corticosteroids given for hematological conditions (less than 1 mg/kg) for at 
least 4 weeks
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 (DOACs) 
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 
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 study treatment and for 1 week after stopping LNP023, 5 months after stopping 
eculizumab and 8 months after stopping ravulizumab. 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
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks before 
taking study treatment. 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 m prior to screening). For female participants on the study, 
the vasectomized male partner should be the sole partner for that participant


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Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/vaginal 
suppository
Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS)
In case of use of oral contraception women should 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
Participants will be randomized in an 8:5 ratio to either LNP023 monotherapy given orally b.i.d. 
(where the anti-C5 antibody treatment will be stopped – See below for timing), or intravenous 
anti C5 antibody treatment (continuing with the same dose as that received prior to 
randomization).
LNP023 first administration (Day 1 visit)
The timing of the first LNP023 administration will provide a seamless switch from prior anti-
C5 antibody treatment to LNP023, allowing for some overlap of exposure to anti-C5 antibody 
treatment when starting the oral agent while limiting the potential risk of breakthrough 
hemolysis, as the LNP023 exposure builds-up.

First LNP023 dose administration of participants on prior eculizumab regimen must occur 
at days 7 to 8 after last infusion

First LNP023 dose administration for participants on prior ravulizumab regimen must occur 
at days 41 to 43 after the last infusion
Participants will then continue taking 200 mg LNP023 b.i.d. monotherapy.


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Anti-C5 first administration in the study (Day 1 visit)
Participants assigned to the comparator arm will continue receiving the anti-C5 infusion as per 
their stable regimen. It will be ensured that the participants and their physicians have relevant 
educational material and eculizumab or ravulizumab specific Participant Safety cards. However, 
the day of the next administration of anti-C5 for the ‘study start’ should coincide with ‘Day 1’ 
study day. The investigator is encouraged to ‘count back’ from the schedule date for the planned 
infusion.
Treatment Extension period: LNP023 administration for comparator group 
At Week 24 visit, participants in the comparator arm will receive the last anti-C5 infusion, and 
will start with the first LNP023 dose administration the morning after the visit (Day 169).
With participants starting in the treatment extension period taking LNP023 starting on Day 169, 
the visit schedule will be harmonized, with the exception of Day 175, where only participants 
formerly assigned to the comparator arm will return for PK and safety assessments.
6.1
Study treatment
6.1.1
Investigational and control drugs
In this study, the ''study treatment'' includes the investigational drug, LNP023, and the active 
comparators of anti-C5 antibodies (either eculizumab or ravulizumab).
Table 6-1
Investigational and control drug
Investigational/ 
Comparator
Pharmaceutical dosage 
form
Route of 
administration
Supply type
LNP023, 200 mg
Hard gelatin capsule
Oral use
Open label, patient 
specific kits
Eculizumab, 300 mg/30mL
Concentrate solution for 
infusion
Intravenous infusion
Open label, vial
Ravulizumab, 300 mg/30 
mL
Concentrate solution for 
infusion
Intravenous infusion
Open label, vial
Ravulizumab, 300 mg/3 
mL**
Concentrate solution for 
infusion
Intravenous infusion
Open label, vial
Ravulizumab, 1100 mg/11 
mL**
Concentrate solution for 
infusion
Intravenous infusion
Open label, vial
LNP023, 10* mg
Hard gelatin capsule
Oral use
Open label, patient 
specific kits
*used only during tapering down of LNP023 dose – see Section 9.1.1 for details
**If available commercially and provided by manufacturer
The investigational drug, LNP023 as 10 mg and 200 mg capsules, will be prepared by Novartis 
and supplied to investigator sites as open-label participant packs.
Eculizumab and ravulizumab will be provided locally by the study site, subsidiary or designee 
as commercially available or by Novartis, in each participating country according to local 
practices and local regulations.


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6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
Participants will be randomized to one of the two treatment arms in an 8:5 ratio to LNP023 
monotherapy at a dose of 200 mg orally b.i.d. (approximately 56 participants), or i.v. anti-C5 
antibody treatment (approximately 35 participants continuing with the same stable regimen as 
that prior to randomization), respectively.
6.1.4
Treatment duration
The duration of the randomized Treatment period is 24 weeks. If a participant’s treatment with 
LNP023 is discontinued and participant is switched back to the prior anti-C5 antibody treatment, 
every effort will be made to continue with the study assessments up to the Week 24 visit. 
The treatment extension period will last up to 24 weeks, where participants randomized to 
LNP023 arm during the randomized treatment period will be offered to continue with LNP023 
treatment, and participants randomized to anti-C5 arm will be offered to switch to LNP023 
monotherapy. If a participant permanently discontinues LNP023 during the treatment extension 
period, the Investigator should follow the recommended procedures for discontinuation (see 
Section 9.1.1). If possible, participant should continue with the study assessments up to the 
Week 48 visit.
After completion of the treatment extension period, participants may receive post-trial access 
(PTA) by joining the Roll-over extension program (REP) to allow participants access to 
LNP023 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.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
All medications, procedures, and significant non-drug therapies (including physical therapy) 
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. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue participation 
in the study.


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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. 
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 ESA and/or HIF-PHIs dose by 50% if 
hemoglobin is ≥ 12 g/dL and/or to stop ESA 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. 
LNP023 has been shown to have a weak inhibition potential for the liver uptake transporter 
OATP1B1. Calculation revealed that the exposure (AUC) of respective sensitive substrates may 
be increased by <1.5 fold. Although the expected effect on the exposure of respective co-
medications is small and may not be clinically relevant it is recommended to combine LNP023 
with sensitive OATP1B1 substrates or those having a narrow therapeutic index 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.
LNP023 has also been shown to inhibit the efflux-transporter P-glycoprotein (P-gp) on the 
intestinal level but not the liver. Therefore, the direct oral anti-coagulation drugs apixaban, 
rivaroxaban and edoxaban which are P-gp substrates should be used with caution. For edoxaban 
a staggered dosing (see below) is recommended, in particular for participants with impaired 
kidney function.
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 >3hrs following oral 
administration of LNP023. Alternatively, compounds with a short Tmax of around < 2 hours 
(i.e., fast absorption) can be given >1hr prior to LNP023. The staggered dosing will avoid 
increases in systemic exposure of co-administered drugs due to P-gp inhibition by LNP023 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 LNP023 (single assessment).
6.2.2
Prohibited medication
Use of the treatments listed below are not allowed during LNP023 administration.

Live vaccines are prohibited for the entire study treatment duration

Preclinical studies have shown that systemic disposition of LNP023 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 
direct biliary excretion (around 5 to 10%) is anticipated. LNP023 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 


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LNP023 (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 
LNP023 dose until end of LNP023 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 
LNP023 dose until end of LNP023 treatment (and replaced with another appropriate 
medication used for that indication)

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 
LNP023 (interrupted 48 hours before first LNP023 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 LNP023 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 informed consent form, the participant is assigned 
to the next sequential Participant No. available.
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No.


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6.3.2
Treatment assignment, randomization
During screening and after hemoglobin eligibility is confirmed, all eligible participants will be 
randomized via Interactive Response Technology (IRT) to one of the treatment arms. 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 randomization number to the 
participant, which will be used to link the participant to a treatment arm and will specify a 
unique medication number for the first package of study treatment (for LNP023, and when 
applicable for anti-C5) to be dispensed to the participant.
Randomization should occur as closely as possible to the planned Day 1 (see Section 6) while 
taking into consideration availability of assigned treatment arm on site.
The randomization numbers will be generated ensuring that treatment assignment is unbiased 
and concealed from participants and investigator staff as is described in the following: A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Global Clinical Supply (GCS) using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment.
Randomization will be stratified by the type of prior anti-C5 antibody treatment (eculizumab or 
ravulizumab) and based on transfusion history as reported during the last 6 months prior to 
randomization (i.e. transfusion received / not received).
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
Treatment will be open to participants, investigator staff, and the CTT. The CTT will have 
access to standard reports of participants profiles and other listings as necessary to fulfill data 
review activities and patient safety. No aggregated data reports by treatment groups will be 
created and made available to the CTT. Dummy treatment assignments will be used to test 
statistical analysis programs and the randomization list will be kept strictly confidential until 
the database lock at the end of the randomized treatment period. During the randomized 
treatment period, the randomization list will be released only to a firewalled area to those 
designated to access it to serve the purposes of creating reports for the DMC or the PK analysis.
6.5
Dose escalation and dose modification
LNP023 will be administered at 200 mg b.i.d. and anti-C5 antibody treatment will be 
administered at the stable regimen participants were on in the prior 6 months before 
randomization for the duration of the study. There are no dose adjustments planned for LNP023 
or anti-C5 antibody treatment.


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6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by providing detailed instructions to the participant 
to take the study treatment exactly as prescribed and by stating that compliance is necessary for 
the participant safety and the validity of the study. The participant must also be instructed to 
immediately contact the investigator if he/she is unable for any reason to take the study 
treatment as prescribed and appropriate actions will be taken.
Compliance for LNP023 will be assessed by the investigator and/or study personnel using 
capsule counts and information provided by the participant. This information should be 
captured in the source document at each visit.
Participants on LNP023 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.
For the comparator arm, study treatment is administered intravenously under the supervision 
of the Investigator or designee, thereby ensuring compliance with study medication 
administration.
All study treatments dispensed and returned must be recorded in the Drug Accountability Log.
6.6.2
Recommended treatment of adverse events
Infections
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 
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 
LNP023 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 LNP023 treatment is to be permanently discontinued, please refer to Section 9.1.1 for the 
appropriate actions. 
If the participant is in the anti-C5 antibody treatment arm at the time of diagnosis of a serious 
bacterial infection, they should be treated immediately with appropriate antibiotics and any 


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guidance in the local label for the anti-C5 inhibitor should be followed.
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF.
LNP023 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 serious bacterial infection and to contact the 
investigator or local physician immediately in case of suspicion of infection, in which case 
antibiotic treatment should be started as soon as possible.
Comparator Participant Safety Card
All participants randomized to continue on eculizumab or ravulizumab will be provided with 
the specific relevant Participant Safety card if they do not already have one. Participants will 
be instructed to be vigilant for any clinical sign or symptom of meningococcal infection and to 
contact the investigator or local physician immediately in case of suspicion of meningococcal 
infection, in which case antibiotic treatment should be started as soon as possible.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs 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 IMP directly to a participant’s home may be permitted (if allowed by Local or 
Regional Health Authorities and Ethics Committees as appropriate) in the 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 IMP from the site to the participant’s home remains under the accountability of 
the Investigator. Each shipment/provisioning will be for a maximum of 1-month supply. In this 
case, regular phone calls or virtual contacts (as per scheduled visits or more frequently if needed) 
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.
LNP023
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 
participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document.


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Anti-C5 antibody treatment (eculizumab, ravulizumab)
Preparation and dispensation should follow the locally approved label and local practice. During 
the 24-week randomized Treatment Period, participants randomized to anti-C5 antibody 
treatment must continue with same dose and schedule as they were before entering the study.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels (comparators) or in the Investigator’s Brochure (LNP023).
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
LNP023
Participants should take LNP023 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 all study 
assessments.
Table 6-2
LNP023 dose and treatment schedule
Dose level
Posology
LNP023 dose strength
200 mg b.i.d.
1 capsule twice daily
200 mg
Participants should take LNP023 irrespective of food intake. Each dose should be taken with a 
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Participants should be instructed to swallow capsules whole and not to chew or open them.
If vomiting occurs during the course of treatment, participants should not take the study 
treatment (LNP023) 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.
Anti-C5 antibody treatment (eculizumab, ravulizumab)
Preparation and dispensation should follow the locally approved label and local practice. 
Participants randomized to anti-C5 antibody treatment must continue with same dose and 
schedule as they were before entering the study. A specific eculizumab or ravulizumab 
Participant Safety card and relevant educational material will be provided to participants 
receiving anti-C5 therapy, and study investigator. 
All kits of study treatment will be recorded in the IRT system.
7
Informed consent procedures
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
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 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) (and/or CDS for marketed drugs). 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 


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conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Health Authority.
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.).
The following informed consents are included in this study:

Main study consent, which also includes:

An additional signature page for participants moving to Treatment extension 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

Informed Consent Form for Optional Off-site Research Nursing (ORN) visits during a 
pandemic 

Informed Consent Form for Optional Off-site Research Nursing (ORN) visits for 
Week 2 (Day 14) and/or Week 6 (Day 42) visits or in special circumstances

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.
Unless specified (i.e. post dose PK samples), all assessments should be performed prior to dose 
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Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Tables 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, and 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 certain countries and sites 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 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 off-site visits will comply with all assessments indicated in Table 8-1 for those visits.
The off-site 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 the delegation of the 
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.).
Participants who discontinue LNP023 treatment during the randomized treatment period should 
continue in the study up to Week 24 visit, completing all scheduled visits assessments. The 
same applies to anti-C5 antibody treatment. Please, refer to Section 9.1.1 for details on the 
recommended procedures to follow in case of permanent discontinuation. 
Participants who discontinue LNP023 treatment during the treatment extension period of the 
study for any reason, should continue in the study up to the Week 48 visit completing all 
scheduled visit assessments. The same guidance for managing LNP023 permanent 
discontinuation as in the randomized treatment period applies.
At this final visit, all dispensed investigational product should be reconciled, and the adverse 
event and concomitant medications recorded on the CRF.
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. Phone calls, virtual contacts (e.g. tele consult) or visits by home nursing service 
to the participant´s home depending on local regulations and capabilities, can replace on-site 
study visits, for the duration of the disruption or until it is safe for the participant to visit the site 
again. For more details refer to Section 8.6.


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Table 8-1
Assessment schedule - Randomized treatment period
Period
Screening
Randomized treatment period
Visit Name
Screening Screening
Hb confirmation
Day 1
Day 7
Day 14 Day 28 Day 42 Day 56 Day 84
Day 
112
Day 
126
Day 
140
Day 
154
Day9 
168
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
X11
Entry criteria
X
X
Demography
X
Medical history/current medical 
conditions
X
Vaccination history & Vaccination
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
X
X
X
Body temperature
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test1
S
S
S
S
Clinical Chemistry (full)
X
X
X
X
X
Clinical Chemistry (abbreviated)
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
Panel of hormones blood 
samples
X
X
X
X
X
X
X
X






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Table 8-2
Assessment Schedule - Treatment Extension period
Period
Treatment Extension Period
Visit Name
[Day 175]
x-comparator only **
Day 196
Day 224
Day 252
Day 280
Day 308
Day336/EOS3
Days
175 ± 1
196 ± 5
224 ± 5
252 ± 5
280 ± 5
308 ± 5
336 ± 5
Weeks
25
28
32
36
40
44
48
Blood pressure and pulse rate
X
X
X
X
X
X
X
Physical examination
S
Body weight
X
Body temperature
X
X
X
X
X
X
X
Pregnancy test
S
Clinical Chemistry (full)
X
X
Clinical Chemistry (abbreviated)
X
X
X
X
X
Hematology (full)
X
X
X
X
X
X
X
Coagulation/markers of thrombosis
X
X
X
X
X
X
Panel of safety hormones blood samples
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (dipstick)
X
X
X
X
X
X
X
Urine Albumin/Creatinine ratio
X
X
Breakthrough hemolysis
X
X
X
X
X
X
X
X
RBC transfusion
X
12-lead Electrocardiogram (ECG)
X
Adverse Events
X
Major Adverse Vascular Events
X
Concomitant medications
X
X


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Period
Treatment Extension Period
Visit Name
[Day 175]
x-comparator only **
Day 196
Day 224
Day 252
Day 280
Day 308
Day336/EOS3
Days
175 ± 1
196 ± 5
224 ± 5
252 ± 5
280 ± 5
308 ± 5
336 ± 5
Weeks
25
28
32
36
40
44
48
Surgical and medical procedures
X
Patient reported outcomes
X
X
X
X
X
X
IRT
X
X
X
X
X
X
X
LNP023 Dispensing
X
X
X
X
X
Study Drug Administration2 
b.i.d. from Day 169
Disposition
X
**Visit [Day 175] will be completed only by those participants that were taking comparator treatment on Week-24 visit and progressing into the treatment extension period
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
2Study drug Administration: LNP023 to be administered b.i.d. daily to all participants in the treatment extension period.
3For 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. 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 participant 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 Hemoglobin laboratory 
assessment) at screening is outside of the range specified in the entry criteria, the assessment 
may be repeated once prior to randomization. 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 reason for screen failure should be entered on the 
applicable Case Report Form. The demographic information, informed consent, and 
Inclusion/Exclusion eCRFs must also be completed for screen failure participants. No other 
data will be entered into the clinical database for participants who are screen failures, unless the 
participant experienced a serious adverse event during the screening phase (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 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 assessments and transfusion during Screening
When signing the Informed Consent Form, the participants allows the retrospective review and 
reporting of hemoglobin values at least during the last 4 months prior to screening. The 
mean/average of at least 2 values must be below 10 g/dL to proceed with screening activities.
During the screening period, mean hemoglobin <10 g/dL will be confirmed by central 
laboratory assessment prior to randomization evaluated by two hemoglobin measurements, 
(mean <10 g/dL), two up 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 conditions 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 (central laboratory), he/she will be eligible without an additional 
hemoglobin assessment by the central laboratory.


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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.
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 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 or disease duration will be derived up to the date of screening); vaccination history; 
MAVE history (dates and type); the packed-RBC transfusion received in the last 12 months 
prior to 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, as well as start date of 
anti-C5 treatment) and procedures (any therapeutic intervention including surgery, biopsies, 
or non-pharmacological therapy) taken prior to Screening will be recorded in the CRFs.
Prior anti-C5 antibody treatment regimen for PNH (eculizumab or ravulizumab), which must 
be stable for the 6 month preceding randomization, will be recorded in a dedicated CRF page.
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 timepoints when these assessments are performed. Section 2 shows 
the correlation of the assessments with the objectives.


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8.3.1
Hemoglobin, reticulocytes, LDH and other PNH-related laboratory 
parameters
Blood samples for hematology, clinical chemistry and 
 
 will be collected according to Table 8-1 for the randomized treatment period. 
The following laboratory parameters will be assessed: Hemoglobin 
, 
reticulocyte count and bilirubin (as markers for extravascular hemolysis), LDH (as a marker for 
intravascular hemolysis), 
During the treatment extension period, the assessment will be carried out as per Table 8-2.
Please refer to central laboratory manual regarding sample collection, numbering, processing 
and shipment.
8.3.2
Red blood cell transfusion
The need for administration of red blood cell transfusion will be monitored continuously during 
the randomized treatment period.
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 ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a 
transfusion

Hemoglobin of ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms
The level of hemoglobin, the number and unit of transfusion administered as well as the signs 
and/or symptoms if applicable will be recorded in the CRFs. Symptoms typically associated 
with or precipitating participant’s need for transfusion are listed below:

Severe or worsening of fatigue

Severe or worsening dyspnea / shortness of breath

Palpitation/angina (or worsening symptoms)

Change in mental status (syncope, light-headedness, confusion, stroke, transient ischemic 
attack)
If a participant meets the transfusion criterion, the Investigator will determine the appropriate 
number of units of packed-RBC to be transfused.
The hemoglobin value on which the investigator will base the need for administering a packed-
RBC transfusion may be from the local laboratory due to the turnaround time for central lab 
results. However, the investigator must collect a separate sample for hemoglobin assessment by 
the central laboratory for analysis at the same time as taking a sample for local lab analysis.
It is recommended that the transfusion is administered within 2-3 days of the assessment of the 
hemoglobin/event that triggered the requirement. In case the investigator or participant decides 
not to give or receive a transfusion despite meeting the criteria specified above, the reason 
should be clearly documented in the CRF page.


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During the treatment extension period, the need for administration of red blood cell 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 breakthrough hemolysis will be monitored continuously during the 
randomized 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.
Table 8-3
Breakthrough 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 treatment extension 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 the 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 
(Webster et al 2003, Yellen et al 1997). The use of the FACIT-F in PNH patients has been 
reported in several publications and is sensitive to changes in disease status, allowing 
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
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

Renal arterial thrombosis

Renal vein thrombosis

Thrombophlebitis / deep vein thrombosis

Transient ischemic attack

Unstable angina

Other, please specify
8.3.7
Appropriateness of efficacy assessments
The efficacy assessments including laboratory parameters hemoglobin (to determine the degree 
of anemia), LDH (as marker for intravascular hemolysis), reticulocytes, bilirubin and 
haptoglobin (as markers for extravascular hemolysis), and the need of red blood cell 
transfusions are important parameters for assessing treatment response in PNH. In fact, 
hemoglobin, the need of RBC transfusions are the determining parameters for classifying 
treatment response to complement inhibitor therapy with LDH and reticulocytes as ancillary 
parameters (Risitano et al 2019). Breakthrough hemolysis is a phenomenon reported with 
eculizumab and also ravulizumab, therefore is part of the efficacy assessments in this study. 
Although the incidence of MAVEs is expected to be very low in the study population, it is 
important to assess it for a new complement inhibitor treatment. The majority of these efficacy 
assessments have been used in the eculizumab and ravulizumab registrations studies and will 
provide clinically relevant results for PNH. 
The FACIT-Fatigue Scale will measure various aspects of fatigue, one of the most debilitating 
and commonly reported symptom generally among PNH patients (Hill et al 2007), and among 
patients currently treated with eculizumab (Socie et al 2019). 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 
(Kulasekararaj et al 2019, Ueda et al 2018, Brodsky et al 2008). It has been well validated in 
general populations (Webster et al 2003; Yellen et al 1997) and content validity has been 
completed specifically in PNH patients (Weitz et al 2012).


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8.4
Safety
Safety assessments are specified below with the assessment schedules (Table 8-1 and Table 8-2) 
detailing when each assessment is to be performed.
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, and in case that an Off-site Research Nursing (ORN) visits are 
planned at that site (see Section 8.6), regular phone or virtual calls may occur (as per scheduled 
visits) for safety monitoring and discussion of the participant´s health status until the participant 
can again visit the site.
For details on AE collection and reporting, refer to AE Section 10.1.1.
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 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 as 
specified in Table 8-1 and Table 8-2.
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.
As per Section 4.6, if participants cannot visit the site for protocol specified safety lab 
assessments, an alternative lab (local) may be used as defined in Table 8-8.
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.




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Single 12-lead ECGs are to be collected 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 participant safety concerns (please refer to 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 test 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 LNP023 therapy.
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:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening/baseline.
8.4.4
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 carried out as per the Assessment schedules in 
Section 8, and will be assessed in all participants.












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Participants, that the investigator identifies as suitable 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 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 for Week-2 and /or Week-6 visits or 
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 visit assessments).

At least the first anti-C5 infusions must have occurred during the on-site period for 
participants on comparator arm (albeit performed as per local regulations and conditions)

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 the on-site visits. The participant may resume the off-site visits 
when, based on the Investigator’s judgment, there are no further safety risks for the 
participant.
Off-site research nursing (ORN) personnel
The off-site visits will use a third-party vendor (wherever possible) centrally sourced by the 
Sponsor or other similar services available locally and agreed by Novartis, that can provide 
qualified research nurses who will perform study assessments under the oversight of the 
Investigator. Qualified ORN will be under delegation of the investigator. The investigator will 
retain accountability for participants’ oversight and all medical decisions (i.e. protocol specified 
medical procedures, AE/SAE assessment and reporting, changes in medication, etc.).
More details of the off-site research nursing process will be outlined in a separate manual 
provided to the sites participating in the off-site research nursing visits.
The ORN may collect and process Laboratory samples according to Table 8-8, which will then 
be shipped to the Central Laboratory. However, if results of these samples collected by ORN 
are obtained from the local laboratory then these results need to be entered in the appropriate 
local laboratory CRF pages.




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Study treatment must be discontinued under the following circumstances:

Participant/guardian decision

Any situation in which study treatment might result in a significant safety risk to the 
participant 
If a female on LNP023 becomes pregnant during the study, it is recommended to discontinue 
treatment. 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 a female on anti-C5 therapy becomes pregnant during the study, the continuation of anti-C5 
therapy may be considered following an individual benefit-risk assessment by the investigator. 
Guidance on pregnancy provided in the local label for the anti-C5 inhibitor should be followed. 
If treatment with LNP023 has to be discontinued immediately, i.e. because of a significant 
safety risk which warrants immediately stopping LNP023 treatment, it is recommended to 
promptly re-initiate anti-C5 antibody treatment, as judged by the investigator. 
Close monitoring of participants for signs and symptoms of hemolysis should be performed 
upon LNP023 discontinuation. It is recommended to monitor at minimum for: increase in LDH, 
decrease in hemoglobin level and 
 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),

Or 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 LNP023 should occur for the following 
assessments: LDH, creatinine, hemoglobin, coagulation/thrombosis markers (PT/INR, aPTT, 
D-dimer, and fibrinogen), 
, dipstick urinalysis, PNH signs and symptoms and 
all adverse events. All data collected will be entered in the appropriate CRF page.
If treatment with LNP023 has to be discontinued but it is not warranted to immediately 
discontinue LNP023 treatment, e.g., discontinuation due to participant/guardian decision, it is 
recommended to consider re-initiating the anti-C5 antibody treatment, as judged by the 
investigator. In addition, it should be considered to taper down LNP023 over a period of 14 
days, as follows:

3 capsules of 10 mg LNP023 taken in the evening (once daily) for 7 days

1 capsule of 10 mg LNP023 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 LNP023 tapering, weekly visits are recommended 
while tapering, and one week after the last LNP023 dose for the following assessments: LDH, 


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creatinine, hemoglobin, coagulation/thrombosis markers (PT/INR, aPTT, D-dimer, and 
fibrinogen), 
, dipstick urinalysis, PNH signs and symptoms and all adverse 
events. All data collected will be entered in the appropriate CRF page.
Anti-C5 permanent discontinuation
For the permanent discontinuation of anti-C5, refer to the local label for recommended 
monitoring upon discontinuation.
Overall considerations
All dose changes must be recorded on the appropriate CRF.
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). 
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, and 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 randomized treatment 
period, should complete the visits as scheduled up to Week 24. 
Participants who permanently discontinue study medication during the treatment extension 
period, should complete the visits as scheduled up to Week 48.
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.
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, including the need of RBC transfusions

Safety laboratory assessments

Adverse Events / Serious Adverse Events
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:


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
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 and 
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

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 


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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 treatment extension period, participants may receive post-trial access 
(PTA) by joining the Roll-over extension program (REP) to allow participants’ access to 
LNP023 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 LNP023 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.
For participants who roll-over to the REP, AEs will be collected in the database for this study 
until participant 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):


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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 with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

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 the last study visit.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy


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Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, 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 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 


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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 within 
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 SAE’s 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 roll-over extension program (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 CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.


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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 study treatment 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 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. After consent is provided, the pregnancy be 
followed-up for one year after the estimated date of delivery.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate 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).
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


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Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE eCRF
Complete SAE form
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 also outlined in 
Table 16-1. Repeat liver chemistry tests (i.e. ALT 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 the Discontinuation of study treatment 
section), if appropriate

Hospitalization of the participant if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include:

Obtaining 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, CT or MRI, as appropriate

Considering gastroenterology or hepatology consultations.
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.


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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.
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.


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11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an 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 the treatment codes will be released and made 
available for data analysis of the randomized treatment period. Before this it will be made 
available in a restricted area to be accessed by the independent programmer and statistician who 
will prepare reports for 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 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of participant records, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits.
Continuous remote monitoring of each site’s data may be performed by Novartis. Additionally, 
a central analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on 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).


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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 randomized treatment period. This section describes the methods associated 
to this report.
An additional CSR will be produced when the last participant has completed the last visit in the 
treatment extension period, when 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 Randomized Analysis Set (RAS) consists of all randomized participants. This data set will 
not be used for any analyses, and solely for providing complete information on how participants 
were randomized. 
The Full Analysis Set (FAS) comprises all participant to whom study treatment has been 
assigned by randomization, and will exclude participants to whom a randomization number has 
been assigned in error (mis-randomized participants). According to the intent to treat principle, 
participants will be analyzed according to the treatment they have been assigned to, taking into 
account the strata in which they were included during the randomization procedure. 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 randomized/assigned treatment if the participant took at least one dose 
of that treatment or the first treatment received if the randomized/assigned treatment was never 
received.
The analysis set including the complete follow up of participants up to the completion of the 
treatment extension period will be defined in the corresponding SAP.


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12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by treatment group 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.
12.3
Treatments
The Safety set will be used for the analyses of exposure to LNP023 and anti-C5 antibody 
treatment 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 LNP023 and anti-C5 antibody treatment as well as the 
dose intensity and the relative dose intensity will be summarized by means of descriptive 
statistics using the safety set.
In addition, the duration of exposure (in days) reflecting the compared treatment strategies: 
LNP023 + transfusions and anti-C5 antibody treatment + transfusions, will be summarized to 
describe exposure corresponding to treatment policy.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system, by treatment group.
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)
Here we define the two primary endpoints corresponding to the primary estimands. 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 
randomized treatment period, and

The participant has not met the criteria (i.e. not received and not met the criteria for 
administration as per Section 8.3.2) for administration of RBC transfusions 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 participants who do not receive a 
transfusion between the first and second confirmatory measurement. In participants who 


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receive a transfusion after the first confirmatory measurement, the baseline will be the first 
measurement.
The primary endpoint defines response as the achievement of sustained hemoglobin levels and 
a participant will be a responder if:

The hemoglobin levels are ≥ 12 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 randomized 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 RBC transfusions between Day 14 and Day 168. 
12.4.2
Statistical model, hypothesis, and method of analysis
The overall study Type I error is one-sided 0.025. Superiority of LNP023 in achieving a larger 
proportion of participants who reach a sustained hemoglobin response compared to anti-C5 
antibody treatment will be tested by the null hypothesis comparing the probability of response 
in LNP023 (
) to the probability of response on anti-C5 antibody treatment (
) for 
both endpoints as:
The test of hypothesis will be implemented by fitting a conditional logistic regression model, 
which conditions on a sufficient statistic for each stratum within which participants were 
randomized, and includes as covariates both sex, age (indicator of age ≥ 45 years), and an 
indicator variable of baseline hemoglobin above 9 g/dL, the same for each of the two endpoints.
The multiplicity adjustment to be applied for the test of two primary endpoints as well as to the 
secondary endpoints for which the study wise Type I error is controlled, is described graphically 
in Figure 12.1.
To adjust for multiplicity of the simultaneous test of two primary endpoints, we will apply a 
weighted permutation test with equal weights to each of the two endpoints. In order to account 
for the correlation between the two primary endpoints due to the overlap in participants who 
would be positive for both criteria as well as for the small sample size, the reference distribution 
of the p-values will be derived using 50,000 permuted realizations of the treatment labels within 
each randomization stratum and obtaining the p-values of each of the two endpoints for each 
realization of permuted treatment labels. The observed p-values from each fit with the actual 
treatment labels will be compared with the 1.25th percentiles of the 50,000 resulting p-values 
from fits with permuted treatment labels for each of the two endpoints (Westfall and 
Troendle 2008, Westfall and Wolfinger 1997, Westfall et al1993).


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The summary measure provided will be the odds ratio derived as the coefficient for treatment 
effect from the conditional logistic regression. This corresponds to an overall estimate where 
the intercept parameter is dropped from the likelihood by conditioning on the within stratum 
non-responders. The estimated odds ratios and their confidence intervals will be provided for 
each of the two endpoints as well as the corresponding p-values.
The secondary endpoint hypotheses are described in Section 12.5. Figure 12-1 describes an 
abbreviated version of the alpha propagation rules following principles described in 
Bretz et al. (2009, 2011) which can be summarized as follows:
1. Hypotheses H1 and H2 are tested using the permutation test described above. The 
available ½ study alpha may be distributed between the two as shown in the figure by 
shifting 10% from a successfully rejected hypothesis.
2. Secondary endpoints H3 and hypotheses H41, H42, and H43 denoted by the node H4i if a 
primary endpoint hypothesis is rejected, are tested by a weighted Simes procedure with 
50% of weight available for secondary endpoints (45%) given to H3 and the other 50% of 
the corresponding weight (45%) given equally to hypotheses in H4i.
3. Secondary endpoints in H5i: H51, H52, and H53 are tested after successful rejection of 
hypotheses in H1, H2, H3, and H4i.
The alpha weights as shown in the graph are only schematic and should not be interpreted as 
compatible with the principles of the intended graphical procedure. Full details including 
complete alpha propagation rules not available in the abbreviated version here are provided in 
Appendix 3.
Figure 12-1
Graphical display of multiple testing procedure 


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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 both primary endpoints.
Intercurrent events stemming from discontinuation of treatment, breakthrough hemolysis events 
and MAVEs, expected to be reflected in the endpoint, are handled with a treatment policy 
strategy.
12.4.4
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 following having met the criteria for transfusion 
does not impact the primary analyses. 
Missing hemoglobin data caused 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 inclusion of hemoglobin data under the treatment policy strategy 
following all other intercurrent events. The impact on the need for transfusion would then be 
derived from this imputation. Furthermore, the impact on hemoglobin levels will also take into 
account the treatment participants were on at the time of withdrawal from study.

For participants withdrawing from study follow up after discontinuation of LNP023, the 
model implemented will recover a return to pre-treatment levels of Hb. This would be 
implemented by borrowing from the control group (anti-C5 antibody treatment) whose on 
treatment response would be considered similar to the pre-treatment levels in participants 
in the LNP023 arm.

For anti-C5 randomized participants withdrawing from study, missing data will be imputed 
by borrowing from participants in the anti-C5 antibody treatment arm.

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. An additional sensitivity analysis of the 
use of a conditional logistic regression model including covariates will be carried out using a 
Cochran-Mantel Haenszel test instead. This assessment will be detailed in the SAP.
12.4.6
Supplementary analysis
A supplementary analysis for each of the two primary endpoints considering the use of rescue 
therapy (as defined in Section 6.2.3) as treatment failure will be performed. The supplementary 
estimand will have the same population, treatment of interest, summary measure as the primary 
estimand in Section 2.1. The intercurrent events for the supplementary estimand will be the 
following: 


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Transfusions will be considered treatment failures whereas discontinuations of study 
medication for any reason will be handled with treatment policy strategy. Use of rescue 
medication (to treat serious complications such as thrombosis or for significant breakthrough 
hemolysis) will be defined as an intercurrent event and handled using a composite strategy: 
patients receiving rescue medication will be considered as treatment failure.
12.4.7
Supportive analyses
A key supportive estimand reflecting the proportions of responders for each of the two primary 
endpoints will be derived from fitting a logistic regression model with a common intercept, 
where the stratum indicator will be a covariate in the model, together with the rest of covariates 
specified for the primary analysis model. The estimated probabilities will be derived as a 
standardized estimator, to reflect the marginal probability of response for all participants in the 
study if they had received LNP023 or anti-C5 antibody treatment. The confidence intervals for 
the difference as well as for the ratio of proportions will be derived by use of bootstrap. Cases 
of non-convergence due to sparsity will be handled within a penalized likelihood (Firth) 
approach.
The comparisons of proportions described above will be further displayed for subgroup 
categories defined by previous transfusion dependence, previous anti-C5 antibody treatment, 
length of time since diagnosis, age categories, sex, and baseline hemoglobin. 
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 
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
The secondary estimands described below will be tested after successful rejection of the null 
hypothesis associated with the primary estimands following the pre-defined weighting scheme 
applied to the tests of secondary endpoints and the alpha propagation rules synthesized in the 
graphical scheme. In addition to the analysis of the secondary estimands, we also show the 
hypothesis identifier used in Figure 12-1.
For all estimands defined in this section, we consider the same intercurrent events as for the 
primary estimands, except in the case when the intercurrent event itself is considered an 
endpoint. For RBC transfusions, the treatment given to it will depend on the endpoint and this 
is described below. In the case of discontinuation of study medication, breakthrough hemolysis 


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events, and MAVEs expected to be reflected in the endpoint the analysis will apply treatment 
policy, for all endpoints.
H3: Transfusion avoidance will be evaluated comparing the proportion of participants not 
receiving (i.e. not receiving and not met the criteria for administration as per Section 8.3.2) any 
RBC transfusion during Day 14 and Day 168, similarly to the comparison applied to the primary 
estimand by means of the odds ratio with standardized marginal proportions derived similarly 
(including in both cases the randomization strata and covariates).
H41: Comparison of change from baseline in hemoglobin levels under the hypothetical 
situation in which participants would not have received RBC transfusions on any of the 
treatments. This will be accomplished by the of 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 comparison between treatments is a repeated measures model with an unstructured 
covariance structure, with stratification factors and including main effect of treatment, visit and 
baseline, and the interactions between visits and treatment and visits and baseline levels. 
Additional covariates will be age (as binary indicator) and sex. The treatment contrasts will be 
computed as the comparison of treatments corresponding to the average measured in the last 6 
weeks of randomized treatment (that is the visits occurring between Day 126 and Day 168). 
H42: The endpoint consists of changes from baseline in scores of fatigue using the FACIT-
Fatigue questionnaire where baseline is defined as the mean of levels obtained pre-
randomization (Screening visit) and the Day 1 value. As for the other endpoints, the longitudinal 
model will be a repeated measures model including test scores collected at all visits. The 
comparison between treatments will be an average of treatment estimates derived for visits 
occurring between Day 126 and Day 168. Main effects will be stratification factors and baseline 
covariates and interaction terms will be similar as those used to compare changes in hemoglobin.
H43: The comparison 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, stratification factors, baseline 
covariates as well as interaction terms will be the same as for changes in hemoglobin. The 
comparison between treatments will use the average of model derived estimates for each 
treatment obtained at visits occurring between Day 126 and Day 168.
H51: 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 similar to the model described for all 
continuous endpoints. Treatment comparisons will be derived based on the average of the log 
transformed ratio in each treatment estimated between Day 126 and Day 168. 
H52: The comparison of rates of breakthrough hemolysis will be carried out using a negative 
binomial model. Stratification factors and covariates will be included similarly as for the other 
endpoints.


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H53: The comparison 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.
Supportive analyses
To complement the secondary estimand analysis of average changes in hemoglobin under a 
hypothetical strategy, the analysis comparing average changes in hemoglobin will be repeated 
using a treatment policy approach, to obtain the comparison of the combination of LNP + 
transfusions as needed to anti-C5 antibody treatment + transfusions as needed.
In addition the comparison of changes from baseline in hemoglobin will also be carried out 
quantifying the effect of the treatments compared that is mediated by the use of RBC 
transfusions.
Missing data for secondary endpoints
Missing data during study follow up will be imputed following the same principles as for the 
primary estimands/endpoints. This treatment involves pattern mixture models for withdrawal 
from study follow up using the reason for withdrawal modeled to capture the impact on 
hematological response or the need for RBC transfusions. In case of intermittent missing data, 
when reasons for missingness were consistent with the assumption of missing at random, the 
missing observations will be imputed under this assumption. 
The imputation approach used for hemoglobin data that were missing following a transfusion, 
in the case of intermittent missing data will be the same as for the hypothetical estimand. In the 
case of definitive withdrawal of study follow up following a transfusion only hemoglobin levels 
at visits during 30 days following the transfusion would be imputed under the this approach, 
while the hemoglobin and other measurements involved in the secondary estimands will be 
imputed using a pattern mixture model according to principles described in Section 12.4.4.
In all comparisons 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 comparing hemoglobin levels) and missing 
data are imputed or where only missing data are imputed, the model comparisons will be derived 
using Rubin’s combination rules.
Treatment Extension period
The efficacy endpoints of interest will still be the same as during the randomized treatment 
period, namely, proportions achieving response, hemoglobin, scores of FACIT-Fatigue, 
reticulocyte counts, LDH, as well as occurrences of breakthrough hemolysis and MAVEs 
throughout the 48 weeks of follow up. These analyses will be fully detailed in the extension 
SAP.
12.5.1
Safety endpoints
The analysis set used for all safety analyses will be the safety set (SAF). All tables will be 
presented by treatment group. The complete details of all safety summaries will be provided in 


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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 LNP023 which covers slightly more than 5 
times the estimated half-life of LNP023.
Adverse events
All information obtained on adverse events will be displayed by treatment group and participant.
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 randomized 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways:

by treatment, primary system organ class and preferred term.

by treatment, 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 LNP023 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 by treatment.
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 treatment and visit/time. Summary occurrence of 
abnormalities may be provided by treatment group if appropriate.
12-lead ECG
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each participant 
during the study. ECG data will be read and interpreted locally. 
Categorical Analysis of QT/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 (by treatment 
group).








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assumption that the proportions are 35% on LNP023 treatment and 5% on anti-C5 antibody 
treatment and it is 89.1% for a significance level of 0.0125. The sample size/power calculations 
were carried out using the package exact 2x2 by Fay, Hunsberger, Nason, and Gabriel and R 
version 3.4.3. Power for the simultaneous test cannot be exactly derived but a minimum power 
corresponding to assuming a Bonferroni adjustment is approximately 95% for the above 
described marginal power assumptions.
12.8.2
Secondary endpoint(s)
Nominal power for prioritized secondary endpoints corresponding to hypotheses H3, H41, H42, 
and H43 is estimated to be between 85% and 90% at full study alpha (one-sided 0.025), without 
considering the adjustment for multiple testing derived from the procedure used. The three 
hypotheses tested as H51, H52 and H53 are estimated to have lower power, hence the alpha 
allocated is very small, leading to a test at full study alpha only after rejection of all primary 
endpoint hypotheses and secondary endpoint hypotheses H3 and H4i.
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 EudraCT. In 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.).


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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.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
References are available upon request.
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Treatment of Cancer QLQ-C30: A Quality-of-Life instrument for use in international clinical 
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Anthony L, Ervin C, Lapuerta P et al (2017) Understanding the Patient Experience with 
Carcinoid Syndrome: Exit Interviews from a Randomized, Placebo-controlled Study of 
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Borowitz MJ, Craig FE, DiGuseppe JA, et al (2010) Guidelines for the diagnosis and 
monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. 
Cytometry B Clin Cytom; 78B:211-30.
Bretz F,Maurer W, Brannath W, et al (2009) A graphical approach to sequentially rejective 
multiple test procedures. Stat Med; 28: 586-604.
Bretz F, Maurer W, and Hommel, G (2011) Test and power considerations for multiple 
endpoint analyses using sequentially rejective graphical procedures. Stat Med 30: 1489-501.
Brodsky RA, Young NS, Antonioli E, et al (2008) Multicenter phase 3 study of the 
complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal 
hemoglobinuria. Blood; 4:1840-7.
Brodsky RA (2014) Paroxysmal nocturnal hemoglobinuria. Blood; 124:2804–11.
Debureaux P-E, Cacace F, Silva BGP, et al (2019) Hematological Response to Eculizumab in 
Paroxysmal Nocturnal Hemoglobinuria: Application of a Novel Classification to Identify 
Unmet Clinical Needs and Future Clinical Goals. Blood; 134 (1 Supplement):3517.
DeZern AE, Dorr D, Brodsky RA, et al (2013) Predictors of hemoglobin response to 
eculizumab therapy in paroxysmal nocturnal hemoglobinuria. Eur J Haematol; 90: 16–24.
EuroQol Research Foundation. EQ-5D-5L User Guide (2019) Available from: 
//euroqol.org/publications/user-guides.
Fayers P, Bottomley A (2002) Quality of life research within the EORTC-the EORTC QLQ-
C30. Eur J Cancer; 38: 125S-33S. 
Hill A, Richards SJ, Hillmen P (2007) Recent developments in the understanding and 
management of paroxysmal nocturnal haemoglobinuria. Br J Haematol; 137:181-92.
Hill A, Rother RP, Arnold L, et al (2010) Eculizumab prevents intravascular hemolysis in 
patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular 
hemolysis occurring through C3 opsonization. Haematologica; 95:567-73.
Hill A, Kelly RJ, Hillmen P (2013) Thrombosis in paroxysmal nocturnal hemoglobinuria. 
Blood;121: 4985-96.
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paroxysmal nocturnal hemoglobinuria. N Eng J Med; 355:1233-43.


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Hillmen P, Muus P, Duhrsen U, et al (2007) Effect of the complement inhibitor eculizumab 
on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood; 
110:4123-8.
Konar M, Granoff DM (2017) Eculizumab treatment and impaired opsonophagocytic killing 
of meningococci by whole blood from immunized adults. Blood; 130:891-9.
Kulasekararaj AG, Hill A, Rottinghaus ST, et al (2019) Ravulizumab (ALXN1210) vs 
eculizumab in C5-inhibitor–experienced adult patients with PNH: the 302 study. Blood; 
133:540-9.
Lee JW, Sicre de Fontbrune F, Lee LWL, et al (2019) Ravulizumab (ALXN1210) vs 
eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood; 
133:530-9.
McKinley C, Richards SJ, Munir T, et al (2017) Extravascular Hemolysis Due to C3-Loading 
in Patients with PNH Treated with Eculizumab: Defining the Clinical Syndrome. ASH 
meeting abstract. Blood; 130(1 Suppl.):3471.
Nishimura J, Yamamoto M, Hayashi S, et al (2014) Genetic variants in C5 and poor response 
to eculizumab. N Engl J Med; 370:632-9.
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input (PFDD). Guidance for industry, food and drug administration staff, and other 
stakeholders. 
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Ann Med; 33:337-3.
Risitano AM, Notaro R, Marando L, et al (2009) Complement fraction 3 binding on 
erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria 
patients treated by eculizumab. Blood; 113:4094-100.
Risitano AM (2012) Paroxysmal nocturnal hemoglobinuria and other complement-mediated 
hematological disorders. Immunology; 217:1080-7.
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.
Staunton H, Willgoss T, Nelsen L et al (2019) An overview of using qualitative techniques to 
explore and define estimates of clinically important change on clinical outcome assessments. J 
Pat Rep Outcomes; 3(16): 1-10.
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.
Ueda Y, Obara N, Yonemura Y, et al (2018) Effects of eculizumab treatment on quality of life 
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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 
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outcomes in patients with paroxysmal nocturnal haemaglobinuria. Intern Med J; 43: 298-307.
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50:5:745-55.
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51(1):3-8.
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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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16.2
Appendix 2: Liver event and laboratory trigger definitions & 
follow-up requirements 
Table 16-1
 Definitions of Triggers, Actions and Follow-up requirements for liver 
events
Criteria
Actions required
Follow-up monitoring
Potential Hy’s 
Law case
(Elevated 
ALT/AST > 3 × 
ULN and TBL > 
2 × ULN but 
without notable 
increase in ALP 
to > 2 × ULN – or 
3 x ULN in the 
presence of bone 
pathology)

Discontinue the study treatment immediately 
(if possibly related to study treatment)

Hospitalize, if clinically appropriate

Establish causality (investigate alternative 
etiologies)a

Record the AE and contributing factors (e.g. 
concomitant medication, medical history, 
laboratory value) in the appropriate eCRF

ALT, AST, TBL, Alb, PT/INR, 
ALP, GGT, CK and GLDH 
(frequency at Investigator 
discretion)

Monitor for symptomsb

Report outcomec
ALT 
> 8 × ULN

Interrupt the study treatment (if possibly 
related to study treatment)

Hospitalize if clinically appropriate

Establish causality (investigate alternative 
etiologies)a

Record the AE and contributing factors (e.g. 
con meds, med hx, lab) in the appropriate 
eCRF

ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT (frequency at 
Investigator discretion)

Monitor for symptomsb

Report outcomec
> 3 × ULN and 
INR > 1.5 (in the 
absence of 
anticoagulation)
If elevated at 
baseline:
> 2 x baseline
or > 300 U/L 
(whichever 
occurs ﬁrst)

Interrupt the study treatment (if possibly 
related to study treatment)

Hospitalize if clinically appropriate

Establish causality (investigate alternative 
etiologies)a

Study drug can be restarted only if alternative 
etiology is identified and liver enzymes return 
to baseline

Record the AE and contributing factors (e.g. 
con meds, med hx, lab) in the appropriate 
eCRF

ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolution 
(frequency at Investigator 
discretion)
> 5 to ≤ 8 × ULN
If elevated at 
baseline:
> 3 x baseline
or > 300 U/L 
(whichever 
occurs ﬁrst)

Repeat LFT within 48 hours

If elevation persists, continue follow-up 
monitoring

If elevation persists for more than 2 weeks, 
discontinue the study drug

Establish causality (investigate alternative 
etiologies)a

Record the AE and contributing factors (e.g. 
con meds, med hx, lab) in the appropriate 
eCRF

ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolution 
(frequency at Investigator 
discretion)
> 3 × ULN to ≤ 5 
× ULN 

Interrupt the study treatment (if possibly 
related to study treatment)

ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolution 


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Criteria
Actions required
Follow-up monitoring
(accompanied by 
symptoms)b
If elevated at 
baseline:
> 2 x baseline
or > 300 U/L 
(whichever 
occurs ﬁrst)

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
(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 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

Record the AE and contributing factors (e.g. 
con meds, med hx, lab) in the appropriate 
eCRF

ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolution 
(frequency at Investigator 
discretion)

Monitor symptomsb

Report outcomec
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


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Criteria
Actions required
Follow-up monitoring
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. 
TBL: total bilirubin; ULN: upper limit of normal


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16.3
Appendix 3: Full description of graphical procedure used for 
testing of primary and secondary endpoints
Hypotheses H51, H52 and H53 are tested only after successful rejection of H1, 
H2, H3, H41, H42, and H43 
1. The primary endpoint hypotheses are both tested at ½ alpha (0.025/2=0.0125) each, with 
the p-value level corresponding to rejection derived using the permutation method described 
above. If only one of the 2 hypotheses, H1 (increase in hemoglobin ≥ 2 g/dL from baseline) 
and H2 (reaching a fixed threshold ≥ 12 g/dL) is rejected using the 1.25% percentile of the 
permuted p-values, the rejected hypothesis may pass 10% of the local alpha to the other 
hypothesis. The increased alpha fraction available is equivalent to using the 1.375% 
percentile of the permuted p-values to be compared with the observed p-value for the 
hypothesis that failed to be rejected using the 1.25% percentile.
2. If a primary endpoint hypothesis is rejected, its local alpha is the passed on to the set of four 
secondary endpoint hypotheses H3, H41, H42, and H43. The test of these hypotheses is a 
weighted Simes closed testing procedure, and the alpha propagation rules reflect the weights 
given: ½ of the local alpha available for the secondary endpoint hypotheses (45%) is passed 
on to H3, while the other 45% is propagated using equal weights to the 3 hypotheses denoted 
as H41, H42, and H43. If rejected H3 passes the available local alpha equally to all 3 


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hypotheses H41, H42, and H43. The alpha propagation between the 3 hypotheses denoted 
H41, H42, and H43 gives them equal weights. When all of H41, H42, and H43 have been 
rejected, their local alpha will be propagated back to the primary endpoint hypotheses 
(represented by the 2 epsilon edges from H43 to H1 and to H2).
3. If all hypotheses (H1, H2, H3, H4i) are rejected, the three hypotheses in H5i will be tested 
using a weighted Simes’ closed testing procedure at full study alpha, where weights of 
0.475 are given to each of H51 and H52, and 0.05 to H53. If one of H51 or H52 is 
rejected, its local alpha up to 90% will be passed to the other hypothesis at the same 
weight level, and 10% to H53. The weights for alpha propagation from H53 are described 
in the graph.


Approval Signatures
Compound:
LNP023
Document Title:
CLNP023C12302-protocol v02
Document Name:
02.01.0201 Protocol - v02
Document Version:
2.0
Username
User ID
Signing Reason
Date
Content Approval
2021-11-26
15:11:24 (UTC)
Content Approval
2021-11-26
16:05:22 (UTC)
Content Approval
2021-11-26
16:31:03 (UTC)
Document electronically signed

SAP_001.pdf: 
  
 
 
 
Clinical Development  
LNP023/Iptacopan 
CLNP023C12302 
A randomized, multicenter, active-comparator controlled, open-label trial 
to evaluate efficacy and safety of oral, twice daily LNP023 in adult 
patients with PNH and residual anemia, despite treatment with an 
intravenous anti-C5 antibody 
Statistical Analysis Plan (SAP)   
 
 
Document type: 
SAP Documentation Amendment 3 
Document status: 
Final 
Release date: 
12-Oct-2022 
Number of pages: 
63 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 3.0, Effective from 01-Jul-2020 


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Table of contents 
Table of contents ................................................................................................................. 6 
List of tables ........................................................................................................................ 7 
List of figures ...................................................................................................................... 8 
List of abbreviations ............................................................................................................ 9 
1 
Introduction ....................................................................................................................... 10 
1.1 
Study design .......................................................................................................... 10 
1.2 
Study objectives and endpoints ............................................................................. 13 
1.2.1 
Primary estimands ................................................................................. 15 
1.2.2 
Secondary estimands ............................................................................. 16 
2 
Statistical methods ............................................................................................................. 18 
2.1 
Data analysis general information ......................................................................... 18 
2.1.1 
General definitions ................................................................................ 18 
2.2 
Analysis sets .......................................................................................................... 19 
2.2.1 
Subgroup of interest .............................................................................. 20 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 21 
2.3.1 
Patient disposition ................................................................................. 21 
2.3.2 
Relevant Medical History and current medical conditions ................... 21 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 22 
2.4.1 
Study treatments .................................................................................... 22 
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 .......................... 26 
2.5.3 
Handling of missing values not related to intercurrent event. .............. 31 
2.5.4 
Sensitivity analyses for primary endpoint/estimand ............................. 33 
2.5.5 
Supplementary analyses ........................................................................ 33 
2.5.6 
Supportive analyses ............................................................................... 34 
2.6 
Analysis of secondary endpoints/estimands .......................................................... 35 
2.6.1 
Secondary endpoints/secondary estimands ........................................... 35 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 38 
2.6.3 
Handling of missing values for secondary endpoints ........................... 38 
2.6.4 
Supportive analyses ............................................................................... 39 
2.6.5 
Sensitivity analyses ............................................................................... 40 
2.7 
Safety analyses....................................................................................................... 40 
2.7.1 
Adverse events (AEs) ............................................................................ 40 


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2.7.2 
Deaths .................................................................................................... 43 
2.7.3 
Laboratory data ..................................................................................... 43 
2.8 
 .................................................................................... 48 
2.9 
 ........................................................................................ 48 
2.10 
Patient-reported outcomes ..................................................................................... 48 
2.11 
 ............................................................................................................. 48 
2.12 
.................................................................................... 49 
2.13 
Interim analysis ...................................................................................................... 50 
3 
Sample size calculation ..................................................................................................... 50 
3.1 
Primary endpoint(s) ............................................................................................... 50 
3.2 
Secondary endpoint(s) ........................................................................................... 51 
4 
Change to protocol specified analyses .............................................................................. 51 
5 
Appendix ........................................................................................................................... 51 
5.1 
Imputation rules ..................................................................................................... 51 
5.1.1 
AE date imputation ............................................................................... 51 
5.1.2 
Concomitant medication date imputation ............................................. 53 
5.2 
Statistical models ................................................................................................... 55 
5.2.1 
Tabular view of estimands and associated estimation methods ............ 55 
5.2.2 
Analysis considerations ......................................................................... 60 
5.2.3 
Rule of exclusion criteria of analysis sets ............................................. 62 
6 
Reference ........................................................................................................................... 62 
 
List of tables 
Table 1-1 
Objectives and related endpoints for the Randomized Treatment 
period..................................................................................................... 13 
Table 1-2 
Objectives and related endpoints for the Treatment Extension 
period..................................................................................................... 14 
Table 1-3 
Justification of handling of intercurrent events ..................................... 16 
Table 2-1 
Summary on dose intensity and transfusions for patients on 
LNP023 ................................................................................................. 24 
Table 2-2 
Selected thyroid and reproductive hormone level parameters .............. 44 
Table 2-3 Liver Toxicities ........................................................................................................ 44 
Table 2-4  Definition of symptoms and AEs for liver toxicities .............................................. 45 
Table 5-1 
Overview of estimands and estimation methods ................................... 55 
 


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List of figures 
Figure 1-1 
Study design .......................................................................................... 10 
Figure 2-1 
Graphical display of multiple testing procedure ................................... 28 
Figure 2-2 
Detailed description of graphical procedure used for testing of 
primary and secondary endpoints .......................................................... 29 
 


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List of abbreviations 
AE 
AESI 
CRF 
CSR 
DMS 
Adverse Event 
Adverse Event of Special Interest 
Case Report Form 
Clinical Study Report 
Document Management System 
EOS 
End of Study 
FAS 
IA 
Full Analysis Set 
Interim Analyses 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PRO 
Patient-reported Outcomes 
MAP 
Master Analysis Plan 
RAP 
Reporting & Analysis Process 
SAP 
SAS 
Statistical Analysis Plan 
Statistical Analysis System 
SD 
Standard Deviation 
TFLs 
Tables, Figures, Listings 
WHO 
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 
randomized treatment period in study CLNP023C12302. Hence the document covers the 
efficacy analysis on the randomized treatment period and the safety analysis on the data in the 
randomized treatment period, as well as the safety data in the treatment extension 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 
treatment extension 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 
This study is a multi-center, randomized, open-label, active comparator-controlled, parallel 
group study, which 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, vaccinations should be started at the earliest possible 
time to avoid extension of the screening period) 
• A 24-week randomized, open-label, active controlled, parallel group treatment period for 
the primary efficacy and safety analyses 
• A 24-week open-label, LNP023 treatment extension period 
The study will enroll PNH patients with residual anemia, defined as hemoglobin < 10 g/dL, 
despite stable regimen of anti-C5 antibody treatment (eculizumab or ravulizumab) in the last 6 
months before randomization, with approximately 40% of participants having received at least 
1 packed-RBC transfusion in the 6 months prior to randomization. 
A total of approximately 91 participants will be randomized 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. 
Figure 1-1 
Study design 
 


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The database of the study will be locked for the randomized treatment period when the last 
participant has completed the Day 168 visit in the study or End of Study (EOS) for participants 
who discontinue from the study prior to the treatment extension period. The final database lock 
will take place when the last participant has completed the last visit (Day 336 or EOS) in the 
treatment extension period. 
Screening 
Screening period starts at the time of ICF signing and lasts until the day preceding Day 1 of the 
randomized treatment period. 
Participants will be asked to review and sign the informed consent form prior to proceeding for 
the screening assessments. After signing ICF, during this visit, inclusion and exclusion criteria 
will be assessed to verify participants' eligibility for enrollment into the study. This will be 
followed by the visit's assessments as outlined in Table 8-1 in the study protocol, as applicable. 
By signing the ICF, the participants will provide access to the following records:  hemoglobin 
levels reported during the last 4 months; the number of transfusions and unit numbers of packed-
RBC received in the last 12 months prior to Screening; Major Adverse Vascular Events 
(MAVEs) reported during the screening (History of MAVE); and the anti-C5 antibody regimen 
they have followed for the last 6 months up to randomization (History of anti-C5 antibody 
treatment). 
Vaccinations should be completed as per Inclusion criteria (Section 5.1 in the study protocol). 
To fulfill the hemoglobin eligibility criterion, participants will have two different samples 
collected during the screening period and tested by the central laboratory with the mean 
<10 g/dL, prior to Randomization. In case the participant has received a RBC transfusion 
following the initial sample collection, the patient is eligible based on the initial central 
hemoglobin value if < 10 g/dL. 
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) 
will be included in the eCRF to document eligibility. 
If eligibility criteria are not met due to any measurement falling outside the inclusion criteria, 
the participant should be considered as having failed the screening and does not proceed to 
randomization. The participant can be re-screened once as described in detail in Section 8.1 in 
the study protocol. 
Randomization 
The randomization will be stratified into four strata (defined by the combination of the 
stratification factors). Participants who meet the eligibility criteria at screening will be stratified 
based on the type of prior anti-C5 antibody treatment (eculizumab or ravulizumab) and based 
on the transfusion history as reported during the last 6 months prior to randomization (i.e. 
transfusion received/not received). It is assumed that approximately 40% of randomized 
participants will have received at least one packed red blood cell (pRBC) transfusion in the 6 


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months prior to randomization. For all analysis, the stratification factors as used for 
randomization will be used.  
Participants will be randomized to one of the two treatment arms in an 8:5 ratio to either 
LNP023 monotherapy at a dose of 200 mg orally b.i.d. (approximately 56 participants), or i.v. 
anti-C5 antibody treatment (approximately 35 participants continuing with the same regimen 
during the randomized treatment period as they were on prior to randomization), respectively. 
Randomized Treatment period 
Treatment will start on the first day of dosing (Day 1) and continue for 24 weeks with study 
visits. 
Participants assigned to the comparator arm will continue receiving the same type, and regimen 
of anti-C5 antibody treatment as received prior to randomization, while those randomized to 
the LNP023 treatment arm will start taking LNP023 at a dose of 200 mg b.i.d. Please refer to 
Section 6 in the study protocol for details on study medication and timing for starting LNP023 
treatment in relation to the prior anti-C5 antibody treatment ensuring a seamless switch with an 
overlap of at least one (eculizumab) or two (ravulizumab) weeks of prior anti-C5 and LNP023 
treatment. 
The randomized treatment period will end with completion of the Week 24 visit assessments 
and, on that visit, participants in the active comparator arm will receive the last dose of anti-C5 
infusion as part of the study treatment. 
For participants who permanently discontinue LNP023 administration during the randomized 
treatment period, close monitoring and treatment proposals are indicated in Section 9.1.1 in the 
study protocol. Participants should complete all visits and assessments up to the Week 24 visit. 
Upon completion of the Week 24 visit, participants may enter the treatment extension period, 
as described below. 
Treatment Extension period  
The participants randomized to the active comparator arm will be offered to switch to LNP023 
on Day 168 (Week 24 visit) and enter the treatment extension period, after receiving a last dose 
of anti-C5 (eculizumab or ravulizumab) antibody treatment. For participants in the comparator 
arm not agreeing to switch treatment, Week 24 will be the EOS visit for the trial and there will 
be no participation in the treatment extension period. For participants agreeing to switch to oral 
LNP023, the Extension treatment will start on the day after completion of the Week 24 visit. 
After switching to LNP023, the participants in the comparator arm will follow study visits and 
assessments according to the schedule described in Table 8-2 in the study protocol.   
The participants in the LNP023 arm, who benefit from treatment and are taking LNP023 at the 
Week 24 visit (i.e. did not permanently discontinue study medication), will be offered to 
continue the oral treatment during the treatment extension period. For participants not agreeing 
to continue in the treatment extension period after completing the Day 168 visit, EOS will be 
after completing the recommended procedures defined in Section 9.1.1 in the study protocol.  


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The treatment extension period will last 24 weeks. After completion of the treatment extension 
period, the participant will be able to join the Roll-over extension study, which will provide 
access to LNP023 and enable long-term safety monitoring. For participants not agreeing to 
continue in the Roll-over extension study after completing the Day 336 visit, EOS will be after 
completing the recommended procedures defined in Section 9.1.1 in the study protocol. 
 
1.2 
Study objectives and endpoints 
Table 1-1 
Objectives and related endpoints for the Randomized Treatment 
period 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
• 
To demonstrate superiority of LNP023 
compared to anti-C5 antibody treatment in 
the proportion of participants achieving a 
sustained increase in hemoglobin levels 
from baseline of ≥ 2 g/dL in the absence of 
red blood cell transfusions 
Endpoint(s) for primary objective(s) 
• 
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 
transfusions between Day 14 and Day 168  
• To demonstrate superiority of LNP023, 
compared to anti-C5 antibody treatment, in 
the proportion of participants achieving 
sustained hemoglobin levels ≥ 12 g/dL in the 
absence of red blood cell transfusions 
• 
Response defined as having Hb ≥ 12 g/dL 
between Day 126 and Day 168 in the 
absence of packed-red blood cell 
transfusions between Day 14 and Day 168 
Secondary Objective(s) 
• 
To demonstrate superiority of LNP023, 
compared to anti-C5 antibody treatment in 
transfusion avoidance as the proportion of 
participants who remain free from 
transfusions 
Endpoint(s) for secondary objective(s) 
• 
Absence of administration of packed-red 
blood cell transfusions between Day 14 and 
Day 168   
• 
To demonstrate superiority of LNP023, 
compared to anti-C5 antibody treatment, in 
average change in hemoglobin 
• 
Change from baseline in hemoglobin (g/dL) 
as mean of visits between Day 126 and Day 
168 
• 
To demonstrate superiority of LNP023, 
compared to anti-C5 antibody treatment, in 
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 demonstrate superiority of LNP023, 
compared to anti-C5 antibody treatment, in 
average change in reticulocyte counts 
• Change from baseline in reticulocyte count 
(109/L) as mean of visits between Day 126 
and Day 168 
• To demonstrate superiority of LNP023, 
compared to anti-C5 antibody treatment, 
in 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 demonstrate superiority of LNP023, 
compared to anti-C5 antibody treatment, in 
the rate of breakthrough hemolysis (BTH)   
• Occurrences of breakthrough hemolysis 
reported between Day 1 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 


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Objective(s) 
Endpoint(s) 
of LNP023, compared to anti-C5 antibody 
treatment 
• To assess safety and tolerability of LNP023 
compared to anti-C5 antibody treatment* 
• Safety evaluations (including adverse 
events/serious adverse events, safety 
laboratory parameters, vital signs etc.) 
*The assessment of safety and tolerability is not included among the secondary estimands nor in 
the multiple testing strategy. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1-2 
Objectives and related endpoints for the Treatment Extension period 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
Endpoint(s) for primary objective(s) 
• To assess long term safety, tolerability and 
efficacy of LNP023  in PNH participants 
• 
Safety evaluations 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. 


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1.2.1 
Primary estimands 
The primary clinical questions of interest are: 
• What is the treatment effect of LNP023 at a dose of 200 mg b.i.d. versus anti-C5 antibody 
treatment in PNH patients with residual anemia, regardless of discontinuation of study 
medication and occurrence of breakthrough hemolysis or MAVEs, on the odds of being a 
responder, with the endpoint defined as a composite of an increase in Hb levels ≥ 2 g/dL 
from baseline assessed between Day 126 and Day 168 without requiring RBC transfusions 
between Day 14 and Day 168? 
The justification of this first primary estimand is that it will capture both the 
hematological benefit of the study drug as a clinically relevant increase in hemoglobin 
levels and the absence of RBC transfusions (which are regarded as treatment failure). 
• What is the treatment effect of LNP023 at a dose of 200 mg b.i.d. versus anti-C5 antibody 
treatment in PNH patients with residual anemia, regardless of discontinuation of study 
medication and occurrence of breakthrough hemolysis or MAVEs, on the odds of being a 
responder, with the endpoint defined as a composite of Hb levels ≥ 12 g/dL assessed 
between Day 126 and Day 168 without requiring RBC transfusions between Day 14 and 
Day 168? 
The justification of this second primary estimand is that it will capture the hematological 
benefit of the study drug as a normalization of hemoglobin levels that is achieved free 
from RBC transfusions (which are regarded as treatment failure). 
The two primary estimands share the following attributes: 
1) Population: Patients with PNH who are on a stable regimen of SoC (anti-C5 antibody 
treatment) and have residual anemia (Hb < 10 g/dL).  
2) Treatment of interest: the randomized treatment (the investigational treatment LNP023 
200 mg b.i.d. or anti- C5 therapy (SoC)) regardless of whether patient discontinues 
treatment (treatment policy).  
3) Intercurrent events: Transfusions after day 14 will be considered treatment failures 
whereas discontinuations of study medication for any reason, breakthrough hemolysis 
events, and MAVEs will be handled with a treatment policy strategy. 
4) The summary measure: the probability of being a responder on each treatment in the 
studied patient population tested as an odds ratio. 
However, the estimands differ in the definition of the associated endpoints as the proportion of 
responders where the responder definitions are as follows: 
• Responder defined as a participant having Hb ≥ 2 g/dL increase from baseline between 
Day 126 and Day 168 and who has not received a RBC transfusion between Day 14 and 
Day 168 of the randomized treatment period. 
• Responder defined as a participant having Hb ≥ 12 g/dL between Day 126 and Day 168 and 
who has not received a RBC transfusion between Day 14 and Day 168 of the randomized 
treatment period. 
In addition to odds ratios, estimates of the proportions of responders in each treatment and their 
differences as well as the ratio of proportions between treatments will be derived as a supportive 


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estimand to quantify the magnitude of the effect of treatment with LNP023 compared to anti-C5 
antibody treatment. 
 
Table 1-3 
Justification of handling of intercurrent events 
Intercurrent event 
Handling strategy  
Justification 
Discontinuation of study 
medication 
Treatment policy 
The effect of randomized 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 
randomization. 
Breakthrough hemolysis events 
Treatment policy 
The effect of randomized 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 labels as assigned at 
randomization. 
MAVEs 
Treatment policy 
The effect of randomized 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 randomization. 
 
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 estimand definition, while discontinuations of study medication, breakthrough hemolysis 
events, and MAVEs 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: 
• Proportions of participants not receiving any transfusions between Day 14 and Day 168 
(Transfusion Avoidance). The summary measure is the same as for the two primary 
endpoints. 


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• Difference in achieved hemoglobin changes from baseline 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 comparison of the mean changes from baseline in hemoglobin levels assessed between 
Day 126 and Day 168. 
• Difference in 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 comparison of mean changes from baseline 
in FACIT fatigue scores assessed between Day 126 and Day 168. 
• Difference in 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 
comparison of the mean changes from baseline in reticulocyte counts assessed between 
Day 126 and Day 168. 
• Difference in 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 the 
comparison of the log transformed LDH ratio to baseline assessed between Day 126 and 
Day 168. 
• Rates of breakthrough hemolysis occurring between Day 1 and Day 168. The summary 
measure is a rate difference. 
• Rates of MAVE between Day 1 and Day 168. The summary measure is a rate difference. 
An overview of estimands and associated estimation methods are presented in Section 5.2.1 
Estimand considerations in case of COVID-19 pandemic impact 
The overarching principle for primary and secondary estimands, is answering questions of 
treatment effect of LNP023 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 has 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 


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in background risks impacting study endpoints will also take into consideration relevant 
epidemiological information on local incidence of COVID-19 infections. 
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 CLNP023C12302 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 using randomization codes 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, the randomization date will be used instead of the date 
of first dose of study treatment. In that case, the randomization date is defined as Day 1 and the 
day before the randomization is defined as Day -1. 
2.1.1.2 
Baseline definition 
For the analysis on efficacy and safety data in the randomized 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 


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measurements. In patients who receive a transfusion after the first confirmatory 
measurement, the baseline will be the first measurement. 
If there is only one confirmatory measurement but additional unplanned measurements taken 
during screening, for patients who do not receive transfusion in the screening period, then the 
mean of the first measurement and the second measurement taken within 2 to 8 weeks after the 
first measurement will be considered to be the baseline. In patients who receive a transfusion 
after the first measurement, the baseline will be the first measurement. For patients with 
transfusion on same day, but hemoglobin measurement taken before transfusion, the baseline 
hemoglobin should be the average of the measurements considering the hemoglobin 
measurement before transfusion. 
• The baseline score of fatigue using the FACIT-Fatigue questionnaire will be defined as 
the mean of first assessment prior to Day 1 and the Day 1 value. Baseline derivation for 
EORTC QLQ-C30 will be similar to the baseline derivation of FACIT-Fatigue 
questionnaire. Baseline derivations for all other patient reported outcomes (PGIS,  and 
EQ-5D-5L) will be at Day 1 or the last value before start of study treatment.  
For the analysis on long term safety data on patients receiving LNP023 200 mg b.id. in the 
randomized treatment period or the treatment extension period (on the analysis set Comb. SAF 
as defined in Section 2.2), the baseline value for patients who received anti-C5 antibody in the 
randomized period will be defined as the last result obtained prior to the start of LNP023 200 
mg b.i.d. in the treatment extension period. 
2.1.1.3 
Post baseline measurement 
Post baseline measurements are defined as those assessments after the start of study treatment.   
2.1.1.4 
Change from baseline 
When change from baseline is of interest the following formula will be used for each scheduled 
visit and time-point where baseline and post-baseline values are both available: 
Change from baseline = post-baseline value – baseline value; and 
If baseline or post-baseline values are missing, then the change from baseline will be missing. 
2.1.1.5 
Completion and last contact 
A patient will complete the randomized treatment period when the patient has completed the 
Day 168 visit in the study or EOS for participants who discontinue from the study prior to the 
treatment extension period. The maximum of the date of last visit in the randomized treatment 
period, date of withdrawal of consent (in case of withdrawal from study), would be the date of 
last contact for the patient in the randomized treatment period.  
2.2 
Analysis sets 
The Screening set (SCR) consists of all patients who have been screened. If a patient has been 
screened multiple times then the patient should be included for his/her last screening. 
The purpose of the screening set is to describe the number of patients in screen failures. Screen 
failures are the patients included in the screening set but not in the randomized set.  


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The Randomized Analysis Set (RAS) consists of all randomized participants. This data set 
will not be used for any analyses, and is solely for providing complete information on how 
patients were randomized.  
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned by randomization, and will exclude participants to whom a randomization number has 
been assigned in error (mis-randomized participants). According to the intent to treat principle, 
participants will be analyzed according to the treatment they have been assigned to, taking into 
account the strata in which they were included during the randomization procedure. This will 
be the data set used for analysis of all efficacy endpoints. For efficacy analysis, the data on the 
randomized treatment period will be analyzed.  
It is expected that the Randomized Set and Full Analysis Set will be identical. For that reason, 
the Randomized set will be described only once and all the  analyses (disposition in particular) 
will be produced on the Full Analysis Set, with the following exceptions: Randomized set will 
be used for the description of protocol deviations and the description of patients randomized by 
country.  
The Safety Set (SAF) 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 randomized/assigned treatment if the participant took at least one dose 
of that treatment or the first treatment received if the randomized/assigned treatment was never 
received. 
The LNP023 combined Safety Set (comb. SAF) includes all participants who received at least 
one dose of LNP023 200 mg b.i.d either in the randomized treatment period or in the treatment 
extension period. The analysis set will be used for analyzing long term safety data on LNP023 
and will consider analysis of the data collected after the first administration of LNP023. Note 
that for this specific safety set a specific baseline will be defined (see Section 2.1.1.2). 
 
2.2.1 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• 
 
 
 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by treatment group 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 
Randomized treatment period 
The number of patients screened, screened but not randomized, randomized, completed and 
discontinued from the study in the randomized treatment period will be summarized. The 
reasons for screen failure will be provided. Participants who discontinued from the study in the 
randomized 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 participants who discontinued study treatment but stayed in 
the randomized treatment period will be summarized. Participants who discontinued study 
treatment but stayed in the study during the randomized treatment period are defined as 
participants with the date of study discontinuation or Day 168 visit - the end date of study 
treatment > 0.  
Treatment extension period 
The number of participants who completed and discontinued from the study in the Treatment 
extension period will be summarized. The reasons for discontinuation will be provided. 
For each treatment group, the number of participants with protocol deviations will be tabulated 
by deviation category and deviation for the RAS.  
Based on the RAS, the number of participants randomized by country will be presented.  
2.3.2 
Relevant Medical History and current medical conditions 
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology using the most recent version at the time when the last participant has 
completed the randomized treatment period. Medical history terms will be summarized by 
primary system organ class and preferred term. Hemoglobin history prior to screening (defined 
as mean result for hemoglobin obtained over a minimum of 4 months prior to screening),  
disease duration (as derived from the start date of PNH in Medical History page up to the date 
of screening), and duration of anti-C5 treatment will be summarized separately.  


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History of MAVE  (MAVEs prior to screening) will be summarized by medical history term. 
Anti-C5 antibody medication history 6 months prior to randomization will be summarized by 
medication (eculizumab, ravulizumab) and dose administered. Transfusion history (the 
numbers of transfusions and unit numbers of packed-RBC received in the last 12 months prior 
to screening), transfusions up to 6 months prior to randomization (yes, no) will be presented. 
Additionally, type of transfusions and number of units of packed RBC transfused will be 
summarized.  Vaccination history will be presented by serogroup/polyvalent.  
Alcohol history will be reported based on usage (never, current, former). Smoking and vaping 
history will be presented based on type of substance (e-liquids, tobacco) and usage (never, 
current, former).  
PNH related signs and symptoms at baseline will be tabulated. Percentage of C3d positive PNH-
type RBCs (Type I, Type II and Type III RBC), PNH Type I, Type II and III RBC, total PNH 
clone size in RBC, PNH clone size in WBCs (granulocyte, monocyte), total C3 positive PNH-
type RBCs (C3d positive PNH Type II and Type III RBC) at baseline will also be reported. The 
total PNH clone size in RBC will be calculated as the sum of PNH Type II RBC and Type III 
RBC. 
All the summaries will be presented on FAS and for both treatment groups.   
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatments 
Treatment of interest 
The randomized treatment (the investigational treatment LNP023 200 mg b.i.d. or stable 
regimen of anti- C5 antibody therapy (SoC)) regardless of whether the participant discontinues 
treatment (treatment policy). 
Duration of treatment in the randomized treatment period 
The duration of randomized treatment in the randomized treatment period is defined as the 
duration from the date of first administration of study treatment in the randomized treatment 
period to the maximum of the following: 
• Date of last administration in the randomized treatment period 
• Minimum between: 
• Date before the planned next administration after the last administration 
• Date before any treatment administration in the treatment extension period  
• Date of death 
In the case of LNP023, the end of the randomized treatment period is the date of last 
administration (any dose) which is also the day before the next planned administration. 
In the case of anti-C5 administered at fixed time intervals, the end of the randomized treatment 
period is until one day before the next planned dose, except if the participant has received open-


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label LNP023 earlier (for instance the day after the last dose) in which case the participant is 
not considered in the randomized treatment period anymore. 
Duration of treatment in the treatment extension period  
The duration of LNP023 treatment in the treatment extension period will be defined as the 
duration from the first date of administration of LNP023 200 mg b.i.d in the treatment extension 
period to the date of last administration of LNP023 (any dose) in the treatment extension period. 
Overall iptacopan duration of treatment 
An overall duration of iptacopan (LNP023) treatment would include both randomized treatment 
period and treatment extension periods, with a start date and a stop date as described above for 
randomized treatment period and treatment extension periods respectively. 
Exposure and Dose Intensity for LNP023  
The Safety sets will be used for the analyses of exposure to LNP023 (based on SAF and Comb. 
SAF separately) 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 LNP023 as well as the dose intensity and the relative dose 
intensity of LNP023 and anti-C5 treatments will be summarized by means of descriptive 
statistics using SAF during the randomized treatment period and for overall (for LNP023  in the 
Comb. SAF).  
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 that treatment 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. 
For instance a patient receiving eculizumab 3 weeks apart while the administration scheme is 
every 2 weeks will have an interruption of 7 days starting 2 weeks after the first dose and lasting 
until the last day before the next dose. 
For patient on LNP023, an interruption will be defined as at least one full day without any 
dose. 
Cumulative exposure for the randomized treatment period based on SAF will be summarized 
as a categorical variable classified into ≤4, ≤8, ≤12, ≤16, ≤20, ≤24 weeks.  Cumulative exposure 
on LNP023 based on Comb. 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 LNP023 will be computed as the ratio 
of actual cumulative dose received and actual duration of exposure. Relative dose intensity for 
patients on LNP023 will be computed as the ratio of dose intensity and planned dose intensity. 


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The planned dose intensity for patients on LNP023 will be 400 mg/day. The dose intensity for 
patients on LNP023 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, > 90-100  and  summaries on dose intensities 
will be presented on SAF and Comb. SAF separately.  
The information on LNP023+transfusions will be  summarized as a categorical variable 
considering the dose intensity and tranfusions in the randomized treatment period. Summaries 
on the categories stated in Table 2-1 will be considered. Such summaries will be presented on 
SAF and Comb. SAF separately.  
For participants on LNP023 the calculation of duration of treatment, exposure, dose intensity 
and relative dose intensity will include the investigational treatment LNP023 200 mg bid as 
well as the LNP023 tapering doses (if applicable).  
Table 2-1 
Summary on dose intensity and transfusions for patients on LNP023
 
 
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 LNP023, an interruption will be defined as at least one full day without any 
dose. The number of participants on LNP023 with interruptions, number of interruptions and 
durations of interruptions will be summarized separately on SAF and comb. SAF. The 
information on study medication intake for the LNP023 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. 
 
Dose Intensity for anti-C5 treatment 
Relative dose intensity for each participant on anti-C5 treatment in the randomized treatment 
period will be defined as the ratio of actual cumulative dose received and planned cumulative 
dose. The actual cumulative dose received by a participant is defined as the stable dose of anti-
C5 medication*number of infusions received by the participant in the study. The planned 
cumulative dose is defined as the stable dose of anti-C5 medication*number of infusions the 
participant should have received as per protocol considering the duration of treatment in the 
study.  
Based on SAF, for participants receiving the anti-C5 antibody treatment in the randomized 
treatment period, the information will be summarized according to the number of participants 


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receiving specific doses and regimens of anti-C5 antibody treatment (eculizumab or 
ravulizumab).  Based on SAF, the information on anti-C5 antibody+transfusions will be  
summarized as a categorical variable considering the number of participants receiving specific 
doses and regimens of anti-C5 antibody treatment (eculizumab or ravulizumab) and 
transfusions in the randomized treatment period. The following categories for transfusions will 
be considered: no transfusion, 1 transfusion,  ≥2 transfusions. 
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 by treatment group separately based on 
SAF and Comb. SAF. Among the concomitant medications, rescue medications will be 
summarized separately by treatment group based on SAF and Comb. SAF. The medications  
and significant non-drug therapies will be classified into “prior”, “concomitant”, or “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 page 
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 LNP023 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.  
Post-treatment medication 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 LNP023 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, by treatment group. More than 
one ATC class per medication is possible and the medication will be reported under all 
applicable classes. 
Prior, concomitant, and post-treatment therapies will be recorded and summarized separately 
for surgical and medical procedures. 
Booster vaccinations received by participants any time during the study (including randomized 
treatment period, treatment extension 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 


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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 two primary endpoints corresponding to the primary estimands are defined. The first 
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 the last six weeks (from Day 126 to Day 168) of the 
randomized 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 measurement, the baseline will be the first 
measurement. 
The second primary endpoint defines response as the achievement of sustained hemoglobin 
levels and a participant as a responder if: 
• The hemoglobin levels  are ≥ 12 g/dL on three out of four measurements taken at the visits 
occurring in the last six weeks (from Day 126 to Day 168) of the randomized 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 .  
Handling of intercurrent events of primary estimand 
Reaching the protocol established criteria for RBC transfusions will be handled using a 
composite strategy for both primary endpoints. 
Intercurrent events stemming from discontinuation of treatment, breakthrough hemolysis events 
and MAVEs, expected to be reflected in the endpoint, are handled with a treatment policy 
strategy. 
2.5.2 
Statistical hypothesis, model, and method of analysis  
2.5.2.1 
Primary null hypotheses 
Superiority of LNP023 in achieving a larger proportion of participants who reach a sustained 
hemoglobin response compared to anti-C5 antibody treatment will be tested by the null 
hypothesis comparing the probability of response in LNP023 (
) to the probability of 
response on anti-C5 antibody treatment (
) for both endpoints as: 


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2.5.2.2 
Familywise type I error rate control 
The overall study Type I error is one-sided 0.025.  The multiplicity adjustment to be applied for 
the test of two primary endpoints as well as to the secondary endpoints for which the study wise 
Type I error is controlled, is described graphically in Figure 2-1.  
The secondary endpoint hypotheses are described in Section 2.6. Figure 2-1 describes an 
abbreviated version of the alpha propagation rules following principles described in Bretz et al. 
(2009, 2011) which can be summarized as follows: 
1: Hypotheses H1 and H2 are tested using the permutation test. The available ½ study alpha 
may be distributed between the two as shown in the figure by shifting 10% from a successfully 
rejected hypothesis. 
2: Secondary endpoints H3 and hypotheses H41, H42, and H43 denoted by the node H4i if a 
primary endpoint hypothesis is rejected, are tested by a weighted Simes procedure with 50% of 
weight available for secondary endpoints (45%) given to H3 and the other 50% of the 
corresponding weight  (45%) given equally to hypotheses in H4i (see Figure 2-2). 
3: Secondary endpoints in H5i: H51, H52, and H53 are tested after successful rejection of 
hypotheses in H1, H2, H3, and all H4i. 
The alpha weights as shown in the graph are only schematic and should not be interpreted as 
compatible with the principles of the intended graphical procedure. Full details including 
complete alpha propagation rules are provided in Figure 2-2. 
H1: Increase in hemoglobin ≥ 2 g/dL from baseline 
H2: Reaching a fixed threshold ≥ 12 g/dL 
H3: Transfusion avoidance 
H41: Change from baseline in hemoglobin levels 
H42: Change from baseline in FACIT-fatigue scores 
H43: Change from baseline in reticulocyte counts 
H51: Percent change from baseline in LDH 
H52: Rates of breakthrough hemolysis 
H53: Rates of Major Adverse Vascular Events 


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Figure 2-1 
Graphical display of multiple testing procedure 
 


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Figure 2-2 
Detailed description of graphical procedure used for testing of 
primary and secondary endpoints 
Hypotheses H51, H52 and H53 are tested only after successful rejection of H1, H2, 
H3, H41, H42, and H43  
 
 
1. The primary endpoint hypotheses are both tested at ½ alpha (0.025/2=0.0125) each, with the 
p-value level corresponding to rejection derived using the permutation method described below 
(Section 2.5.2.4). If only one of the 2 hypotheses, H1 (increase in hemoglobin ≥ 2 g/dL from 
baseline) and H2 (reaching a fixed threshold ≥ 12 g/dL) is rejected using the 1.25% percentile 
of the permuted p-values, the rejected hypothesis may pass 10% of the local alpha to the other 
hypothesis. The increased alpha fraction available is equivalent to using the 1.375% percentile 
of the permuted p-values to be compared with the observed p-value for the hypothesis that failed 
to be rejected using the 1.25% percentile. 
2. If a primary endpoint hypothesis is rejected, its local alpha is the passed on to the set of four 
secondary endpoint hypotheses H3, H41, H42, and H43. The test of these hypotheses is a 
weighted Simes closed testing procedure, and the alpha propagation rules reflect the weights 
given: ½ of the local alpha available for the secondary endpoint hypotheses (45%) is passed on 
to H3, while the other 45% is propagated using equal weights to the 3 hypotheses denoted as 
H41, H42, and H43. If rejected H3 passes the available local alpha equally to all 3 hypotheses 
H41, H42, and H43. The alpha propagation between the 3 hypotheses denoted H41, H42, and 


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H43 gives them equal weights. When all of H41, H42, and H43 have been rejected, their local 
alpha will be propagated back to the primary endpoint hypotheses (represented by the 2 epsilon 
edges from H43 to H1 and to H2). 
3. If all hypotheses (H1, H2, H3, H4i) are rejected, the three hypotheses in H5i will be tested 
using a weighted Simes’ closed testing procedure at full study alpha, where weights of 0.475 
are given to each of H51 and H52, and 0.05 to H53. If one of H51 or H52 is rejected, its local 
alpha up to 90% will be passed to the other hypothesis at the same weight level, and 10% to 
H53. The weights for alpha propagation from H53 are described in the graph. 
Unadjusted p-values and unadjusted 95% CI for all the endpoints stated in Figure 2-2 will be 
presented. The unadjusted p-values and CI will not be reflective of the pre-specified multiplicity 
scheme and hence should not be interpreted as a basis for claiming significance. 
2.5.2.3 
Summary statistics for the primary variable 
All descriptive statistics supportive of the 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 by treatment group on the following information: 
Number of participants having no missing hemoglobin data in the last six weeks (from Day 126 
to Day 168), number of participants having an increase in hemoglobin ≥ 2 g/dL from baseline 
on three out of four measurements taken at the visits occurring in the last six weeks (from Day 
126 to Day 168), Number of participants reaching a fixed threshold ≥ 12 g/dL on three out of 
four measurements taken at the visits occurring in the last six weeks (from Day 126 to Day 
168), Number of participants having both an increase in hemoglobin ≥ 2 g/dL from baseline 
and reaching a fixed threshold ≥ 12 g/dL on three out of four measurements taken at the visits 
occurring in the last six weeks (from Day 126 to Day 168). 
2.5.2.4 
Statistical model for primary variable 
The test of hypothesis will be implemented by fitting a conditional logistic regression model, 
which conditions on the stratum within which participants were randomized, and includes as 
covariates treatment, sex, age (indicator of age ≥ 45 years), and an indicator variable of baseline 
hemoglobin ≥ 9 g/dL, the same for each of the two endpoints. 
In case of non-convergence in any of the multiple imputed datasets arising from sparsity or no 
response in one of the treatment arms in at least one imputed dataset, the logistic regression 
model 
based 
on 
Firth’s 
penalized 
maximum 
likelihood 
method 
(Heinze 
and 
Schemper 2002; Firth 1993) as stated in Section 2.5.6 will be implemented. The documentation 
of the covergence issues will be provided in an appendix of the clinical study report. The same 
analysis model will be used for all steps of the primary analysis including the permutation test 
procedure with multiply imputed data (Section 2.5.3) and for evaluation of the distribution of 
the permutation of the test statistics.  In such a situation, the test of hypothesis will be 
implemented by fitting a logistic regression model, based on Firth’s penalized maximum 
likelihood method,  which includes as covariates stratum, treatment, sex, age (indicator of age 
≥ 45 years), and an indicator variable of baseline hemoglobin ≥ 9 g/dL, the same for each of the 
two endpoints.   


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Odds ratio 
The summary measure provided will be the log odds ratio derived as the coefficient for 
treatment effect from the logistic regression. The estimated odds ratios and their confidence 
intervals will be provided for each of the two endpoints as well as the corresponding p-values. 
Log odds ratios obtained from multiple imputations will be combined using Rubin’s rule. 
Hypothesis testing 
To test for the two primary endpoints, we will apply a permutation test to each of the two 
endpoints. The reference distribution of the p-values will be derived using 50,000 permuted 
realizations of the treatment labels within each randomization stratum and obtaining the p-
values of each of the two endpoints for each realization of permuted treatment labels. The 
observed p-values with the actual treatment labels will be compared with the 1.25th percentiles 
(or 1.375th percentile as appropriate – See testing  strategy in Section 2.5.2.2) of the 50,000 
resulting p-values from fits with permuted treatment labels for each of the two endpoints 
(Westfall and Troendle 2008, Westfall and Wolfinger 1997, Westfall et al 1993).  
2.5.3 
Handling of missing values not related to intercurrent event. 
For the primary response definitions, RBC transfusion will qualify the patient 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 analyses.  
Missing hemoglobin data due to withdrawal from the study in the randomized treatment period 
in the event that a patient 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 
≤ 9g/dL considered sufficient to warrant a transfusion. Furthermore, the impact on hemoglobin 
levels will also take into account the treatment participants were on at the time of withdrawal 
from study: 
The details of missing data handling as well as additional details for implementing the analyses 
are as follows: 
• For participants withdrawing from the study after discontinuation of LNP023, the 
model implemented will recover a return to pre-treatment levels of Hb. This will be 
implemented by borrowing from the control group (anti-C5 antibody treatment) whose 
on-treatment response will be considered similar to the pre-treatment levels in 
participants in the LNP023 arm. 
In practice, imputation using the “copy-reference” will be used: this is achieved by 
imputing post-intercurrent event (I/C) values assuming the joint distribution of an 
LNP023 participant’s outcome data pre- and post-I/C is Multivariate Normal with 
mean vector and covariance matrix corresponding to that of the reference arm, 
regardless of when the I/C occurred [Carpenter et al 2013]  [Cro et al 2020].  
If an LNP023 group participant is above the reference group mean, then this positive 
residual will be reflected in subsequent draws from the conditional distribution of 
post-I/C data, to a degree dependent by the correlation. As a result, this LNP023 


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participant’s profile slowly reverts backs to the reference group for later visits 
[Carpenter et al 2013]. 
• For anti-C5 randomized participants withdrawing from the study, missing data will be 
imputed by borrowing from participants in the anti-C5 antibody treatment arm (missing 
at random (MAR) assumption). 
• For participants with intermittent missing data during randomized treatment period, 
where reasons for missingness are assumed to be unrelated to response or compliance 
status, their missing data will be handled with a MAR approach and imputed 
consequently. 
• For LNP023 randomized participants having missing data at the end of the follow-up 
(irrespective of whether they were immediately preceding treatment discontinuation or 
after treatment discontinuation will be imputed using “copy-reference” approach.  
The model for imputation will be mixed model for repeated measures (MMRM) considering an 
unstructured covariance matrix and include main effect of prior anti-C5 treatment, transfusion 
history, age (indicator of age ≥ 45 years), sex, treatment, visit, baseline hemoglobin.  
Implementing the permutation test procedure with multiply imputed data 
The process for implementing multiple imputation alongside the permutation test is as follows: 
1) Multiple imputation will be performed 100 times based on the randomized treatment labels, 
and following the imputation rules outlined in Section 2.5.3, resulting in 100 imputed 
datasets. The responder status of each participant will be derived within each imputed 
dataset. The conditional logistic regression model described in Section 2.5.2.4 will be fitted 
to each imputed dataset and a single p-value derived by combining the results (estimated 
log odds ratio and corresponding standard error) using Rubin’s rule. 
If in one or several of the imputations, it happens that no responses are observed in one of 
the treatment arms, the suggested multiple imputation method by Rubin’s rule cannot be 
applied due to the non-existence of treatment effect estimates in the approach. In case of 
sparse responder in one treatment arm, even if a treatment effect can be computed, the 
assumptions of asymptotically normal treatment effect estimates underlying the application 
of Rubin’s rule breaks down.  The use of Firth’s penalized likelihood method (as stated in 
Section 2.5.2.4) to estimate the treatment effects and their standard deviation allows to 
overcome this limitation.  
2) A set of 50,000 permutations of the randomized treatment labels will be created for each 
randomization stratum in each imputed dataset The same set of permutations of the 
randomized treatment labels will be used for all imputed datasets. 
3) The logistic regression model described in Section 2.5.2.4 will be fitted to each imputed 
dataset using each permutation of the treatment labels, i.e. 100 analyses will be performed 
for each permutation. 
4) For each permutation, the 100 results will be combined using Rubin’s rule to obtain a single 
p-value for each permutation. The resulting 50,000 p-values will form the basis of the 
permutation test described in Section 2.5.2.4. 


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5) The observed p-value calculated in Step 1) will be compared to the 1.25th percentile (or 
1.375th percentile as appropriate – See testing strategy in Section  2.5.2.2) of the 50,000 p-
values derived in Step 4). 
The same procedure will be applied to both primary endpoints simultaneously: imputation will 
be done on hemoglobin data from which the two primary endpoints will be derived. 
2.5.4 
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. 
In this method, missing values in each treatment group will be imputed separately as mentioned 
in Section  2.5.3 and an adjustment ‘delta’ for the LNP023 group will be applied to the imputed 
values. The delta values will lead to hemoglobin values being lower than those imputed in the 
LNP023 group. The primary analysis, as stated in Section 2.5.2.4 , will be repeated applying 
each of the delta values in the LNP023 group. The results will be displayed in a forest plot 
displaying the odds ratio and 95% confidence intervals as for the primary analysis (See Section 
2.5.2.4 ). 
Additional sensitivity analyses on the two primary endpoints will be performed where missing 
central lab hemoglobin data will be replaced by available local lab data collected at the same 
visit. The regression model which is used for primary efficacy analysis will be performed for 
the two primary endpoints. In addition, the marginal proportions, their difference and ratio will 
be computed using logistic regression model (see Section 2.5.6.1). 
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. In addition, the marginal proportions, 
their difference and ratio will be computed using logistic regression model (see Section 2.5.6.1).   
The regression model which is used for primary efficacy analysis will be performed for the 
supplementary analyses on the two primary endpoints. For the 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 and rescue therapy during the randomized 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. 


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2.5.6 
Supportive analyses 
A key supportive estimand reflecting the proportions of responders for each of the two primary 
endpoints will be derived from fitting a logistic regression model with a common intercept, 
where the stratum indicator (prior anti-C5 antibody treatment, transfusion history) will be  
covariates in the model, together with the covariates sex, age (indicator of age ≥ 45 years), and 
an indicator variable of baseline hemoglobin ≥ 9 g/dL.  The estimated probabilities will be 
derived as a standardized estimator, to reflect the marginal probability of response for all 
participants in the study if they had received LNP023 or anti-C5 antibody treatment. The 
confidence intervals for the difference as well as for the ratio of proportions will be derived by 
use of bootstrap. Cases of non-convergence due to sparsity or if there are no responders in one 
treatment arm in at least one imputed dataset will be handled within a penalized likelihood 
(Firth) approach. 
If there are convergence issues or quasi-complete separation in fitting a logistic regression 
model with covariates to any of the imputed datasets, then a logistic regression model with only 
treatment will be fitted.  If the logistic regression model with only treatment also leads to 
convergence or quasi-complete separation for any of the imputed datasets, then logistic 
regression with Firth approach including only treatment as a covariate will be implemented.  
The final model which is used for estimating the marginal treatment effect based on imputed 
datasets, will be used for bootstrap for derivation of the confidence intervals (Section 2.5.6.1).  
 
2.5.6.1 
Marginal proportion of responders  
In order to quantify the magnitude of the effect of treatment with LNP023 compared to anti-C5 
antibody treatment, estimates of the proportion of responders in each treatment group, as well 
as the difference and ratio between groups will be derived using the marginal standardization 
method (Section 5.2.2.2). 
This method uses the same fitted logistic model as described in Section 2.5.6, but involves using 
the model to predict, for each participant in the study, their outcome assuming assignment to 
each of the two treatment groups in turn, using observed values for the other covariates. 
Confidence intervals will be derived using bootstrap methods. 
In case of multiple imputation, the marginal proportions, their difference and ratio, and the 
associated two-sided 95% confidence intervals will be obtained by combining multiple 
imputations with bootstrapping as follows: 
1) Point estimates for each parameter of interest 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 
100 times and selecting the 2.5th and 97.5th percentiles of the pooled distribution of 
10,000 bootstrapped parameter estimates (obtained from 100 imputed datasets and 100 
bootstrap samples from each imputed dataset) as the confidence interval boundaries  


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2.5.6.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.5.6.3 
Additional supportive analyses 
A supportive analysis in order to address the primary estimand will be done by fitting a stratified 
Cochran Mantel Haenzel (CMH) test to each of the two primary endpoints separately.  Handling 
of missing data will be similar to that stated in Section 2.5.3 but the results from the CMH test 
applied on each imputed dataset will be combined using Rubin’s rules (Lu, 2020). 
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 
Transfusion avoidance 
The number and percentage of patients in each treatment group not receiving and not meeting 
the criteria for administration of packed RBC tranfusions in the randomized treatment period 
will be summarized overall and by transfusion during the last 6 months prior to randomization 
(i.e. transfusion received/not received). The number and percentage of patients in each 
treatment group not receiving and not meeting the criteria for administration of  RBC 
transfusion between Day 14 and Day 168 will be summarized overall and by transfusion during 
the last 6 months prior to randomization (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 randomization (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 
the transfusion will be summarized by treatment. The information will be summarized based on 
the ‘Transfusion- during the study’ CRF page.  


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Transfusion avoidance will be evaluated comparing the proportion of participants not receiving 
and not meeting the criteria of administration of RBC transfusion between Day 14 and Day 168, 
similarly to the comparison applied to the primary estimand by means of the odds ratio (as in 
Section 2.5.2.4) with standardized marginal proportions (as in Section 2.5.6.1) derived similarly 
(including in both cases the randomization strata and covariates). The logistic regression model 
will include the following covariates: prior anti-C5 treatment, transfusion history , sex, age 
(indicator of age ≥ 45 years), and an indicator variable of baseline hemoglobin ≥ 9 g/dL. 
In case of non-convergence arising from sparsity or no response in one of the treatment arms, 
the logistic regression model based on Firth’s penalized maximum likelihood method (Heinze 
and Schemper 2002; Firth 1993) as stated in Section 2.5.6 will be implemented. 
The p-value obtained from the model will be included in the multiple testing procedure 
mentioned in Figure 2-1 and Figure 2-2. 
2.6.1.2 
Change from baseline in hemoglobin levels 
Comparison of change from baseline in hemoglobin levels under the hypothetical situation in 
which participants would not have received RBC transfusions on any of the treatments. For this 
analysis, if a participant had a transfusion during the randomized 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 LNP023 and on anti-C5 to have data imputed assuming missing at random 
(Section 2.5.3).  
The model for the comparison between treatments is a mixed model for repeated measures 
(MMRM) considering an unstructured covariance structure. The model will include main effect 
of prior anti-C5 treatment, transfusion history, age (indicator of age ≥ 45 years), sex, treatment, 
visit, baseline hemoglobin and the interactions between visits and treatment and visits and 
baseline levels. The treatment contrasts will be computed as the comparison of treatments 
corresponding to the average measured in the last 6 weeks of randomized treatment (that is the 
visits occurring between Day 126 and Day 168). The p-value obtained from the model will be 
included in the multiple testing procedure mentioned in Figure 2-1 and Figure 2-2. 
The estimated least square mean estimate of the treatment effect and the associated 95%  will 
be plotted over time.  
2.6.1.3 
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 comparison between treatments is a MMRM considering an unstructured 
covariance structure. The model will include main effect of prior anti-C5 treatment, transfusion 
history, age (indicator of age ≥ 45 years), sex, treatment, visit and baseline in scores of fatigue, 
and the interactions between visits and treatment and visits and baseline levels. The comparison 
between treatments will be an average of treatment estimates derived for visits occurring 
between Day 126 and Day 168. The p-value obtained from the analysis will be included in the 


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multiple testing procedure mentioned in Figure 2-1 and Figure 2-2. The estimated least square 
mean estimate of the treatment effect and the associated 95%  will be presented over time.  
2.6.1.4 
Change from baseline in reticulocyte counts 
The comparison 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 comparison between treatments is a MMRM considering 
an unstructured covariance structure. The model will include main effect of prior anti-C5 
treatment, transfusion history, age (indicator of age ≥ 45 years), sex, treatment, visit, baseline 
reticulocyte count and the interactions between visits and treatment and visits and baseline 
levels. The comparison between treatments will use the average of model derived estimates for 
each treatment obtained at visits occurring between Day 126 and Day 168. The p-value obtained 
from the analysis will be included in the multiple testing procedure mentioned in Figure 2-1 
and Figure 2-2. The estimated least square mean estimate of the treatment effect and the 
associated 95%  will be presented over time.  
2.6.1.5 
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 randomized. The 
model for the comparison between treatments is a MMRM considering an unstructured 
covariance structure. The model will include main effect of prior anti-C5 treatment, transfusion 
history, age (indicator of age ≥ 45 years), sex, treatment, visit, log-transformed baseline LDH 
and the interactions between visits and treatment and visits and log-transformed baseline levels. 
Treatment comparisons will be derived based on the average of the log transformed ratio from 
baseline in each treatment estimated between Day 126 and Day 168. The p-value obtained from 
the analysis will be included in the multiple testing procedure mentioned in Figure 2-1 and 
Figure 2-2. Geometric means and associated 95% confidence intervals will be presented for 
treatment effect over time.  
2.6.1.6 
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 following analyses will be done on safety set. The number and percentage 
of patients experiencing treatment emergent clinical breakthrough hemolysis events in the 
randomized treatment and on the combined SAF will be summarized.. The information on 
whether the patient received packed-RBC transfusions and the quantity of packed-RBC 
transfusions due to clinical breakthrough hemolysis will be summarized by treatment group. 
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 comparison of rates of clinical breakthrough hemolysis will be carried out 
using a  negative binomial model. The model will include the following covariates: treatment, 
randomization strata (prior anti-C5 antibody treatment, transfusion history), sex, age (indicator 
of age ≥ 45 years), indicator variable of baseline hemoglobin ≥ 9 g/dL. Following the treatment 
policy strategy for handling treatment discontinuations, the offset variable will be defined as 


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the time from Day 1 till minimum (end of study, end of randomized treatment period). The p-
value obtained from the analysis will be included in the multiple testing procedure mentioned 
in Figure 2-1 and Figure 2-2.  
If the above model fails to converge or to give valid estimates (if all events are in one level of 
at least one of the covariates) due to low frequency of occurrences, then the model will be run 
considering only treatment as a factor in the  negative binomial model. If the model fails to 
converge or to give valid estimates then a Poisson model with treatment as a factor will be fitted. 
If there is one treatment with no observed events and rate ratio cannot be computed, then rate 
difference and corresponding p-value will be presented.  
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 major adverse vascular events (MAVE) in 
the randomized treatment (based on SAF) and on the combined SAF 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 comparison of rates of Major Adverse Vascular Events (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. Only treatment will be added as a factor in the  
negative binomial model. 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 randomized treatment period). The p-value obtained from the analysis will be 
included in the multiple testing procedure mentioned in Figure 2-1 and Figure 2-2. 
If the model fails to converge or to give valid estimates then a Poisson model with treatment as 
a factor will be fitted. If there is one treatment having no events and rate ratio cannot be 
computed, then rate difference and corresponding p-value will be presented. 
2.6.2 
Statistical hypothesis, model, and method of analysis 
The secondary estimands described in Section 2.6.1 will be tested after successful rejection of 
the null hypothesis associated with the primary estimands following the pre-defined weighting 
scheme applied to the tests of secondary endpoints and the alpha propagation rules synthesized 
in the graphical scheme.  
For all estimands defined in Section 2.6.1, we consider the same intercurrent events as for the 
primary estimands, except in the case when the intercurrent event itself is considered an 
endpoint. In the case of discontinuation of study medication, clinical breakthrough hemolysis 
events, and MAVEs expected to be reflected in the endpoint the analysis will apply treatment 
policy, for all endpoints. 
2.6.3 
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 MAR 
principle in both the arms.  Missing data due to withdrawal from the study will be imputed using 


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a “copy-reference” in the LNP023/iptacopan arm and according to MAR in the control arm (see 
Section 2.5.3). In general as in Section 2.5.3, the model for imputation will be mixed model for 
repeated measures (MMRM) considering an unstructu.red covariance structure and include 
main effect of prior anti-C5 treatment, transfusion history, age (indicator of age ≥ 45 years), 
sex, treatment, visit, baseline value. 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 theywill be 
truncated to the lower limit and if some imputed values exceed the upper limit then they will be 
truncated to the upper limit.  
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. Logistic regression model (as specified in Section 2.6.1.1) need to be run on each of 
the multiple imputed datasets and the results will be combined using Rubin’s rules.   
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 using a “copy-reference” in the LNP023/iptacopan arm and 
according to MAR in the control arm (see Section 2.5.3). More specifically a patient in the 
iptacopan arm should be first imputed in the hypothetical scenario for hemoglobin until end of 
treatment The imputed hemoglobin value at end of treatment will be the starting point for the 
“copy-reference”. 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 comparisons 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 comparing hemoglobin levels) and missing 
data are imputed or where only missing data are imputed, the model comparisons will be derived 
using Rubin’s combination rules. 
2.6.4 
Supportive analyses 
To complement the secondary estimand analysis of average changes in hemoglobin under a 
hypothetical strategy, the analysis comparing average changes in hemoglobin will be repeated 
using a treatment policy approach, to obtain the comparison of the combination of LNP + 
transfusions as needed to anti-C5 antibody treatment + transfusions as needed. 
The comparison of changes from baseline in hemoglobin will also be carried out using all 
collected values even following transfusions, to differentiate the effect on hemoglobin changes 
by either LNP023 or anti-C5 from the effect that is mediated by the use of RBC transfusions. 
The model for the comparison between treatments is an MMRM considering an unstructured 
covariance structure. The model will include the main effects of prior anti-C5 treatment, 
transfusion history, age (indicator of age ≥ 45 years), sex, treatment, visit, baseline hemoglobin 
and the interactions between visits and treatment and visits and baseline levels. The treatment 
contrasts will be computed as the comparison of treatments corresponding to the average 
measured in the last 6 weeks of randomized treatment (i.e. the visits occurring between Day 


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126 and Day 168). Missing hemoglobin data will be imputed following the same principles as 
in Section 2.6.3. However, hemoglobin data recorded in the 30 days following transfusion will 
be considered for analysis and will not be imputed.  
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 2.6.3.  
2.6.5 
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 Sections 2.6.1.1, 2.6.1.2,  2.6.1.4, 2.6.1.5, respectively, 
will be performed. 
2.7 
Safety analyses 
Unless otherwise specified all safety summaries will be presented by SAF and Comb. SAF. All 
tables will be presented by treatment group.  
Safety summaries (tables, figures) will include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In particular, summary tables for adverse events (AEs) will summarize 
only on-treatment events, with a start date during the on-treatment period (treatment-emergent 
AEs).  
The on-treatment period of LNP023 lasts from the date of first administration of study treatment 
to 7 days after the date of the last actual administration of LNP023 (including randomized 
treatment period, treatment extension period and tapering procedures after permanent treatment 
discontinuation) which covers slightly more than 5 times the estimated half-life of LNP023. 
The on-treatment period of anti-C5 antibody lasts from the date of first administration of anti-
C5 study treatment in the randomized treatment period to the date of the last actual 
administration of anti-C5 antibody in the randomized treatment period. 
2.7.1 
Adverse events (AEs) 
All information obtained on adverse events will be displayed by treatment group and participant. 
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 randomized 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways: 
• by treatment, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity. 
Separate summaries will be provided for study treatment related adverse events, deaths, serious 
adverse events and adverse events leading to discontinuation of study treatment, and for 


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LNP023 tapering if this is followed prior to complete LNP023 discontinuation. For patients 
receiving LNP023, treatment emergent SAEs and AEs with PTs in the AESI ‘PNH haemolysis 
and thrombosis’ occurring after discontinuation of LNP023 200 mg b.i.d will be reported 
separately. 
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. 
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 
treatment emergent adverse events and treatment emergent serious adverse events will be 
provided. Adverse events (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 System Organ Class (SOC) and Preferred 
Term (PT). 
For the most common adverse events the 95%CI of the exposure adjusted incidence rate of 
TEAE can be presented as well as the Incidence Rate Ratio between treatment arms. 
TEAE risk difference by SOC will be presented by a forest plot. The risk difference for most 
common TEAEs by PT will be also presented by a forest plot. The confidence intevals will be 
calculated using the Exact method. 
Risk difference and 95% confidence interval 
For an investigational drug group with n1 subjects at risk, independent from the control group 
(e.g. placebo or comparator) with n0 subjects at risk, of whom x1 and x0 experience a certain 
event, the risk difference is estimated as p1-p0 with p1= x1/n1 and p0=x0/n0.  
 
Risk differences will be estimated for LNP023 200 mg b.i.d versus anti-C5 antibody, with 95% 
CIs constructed by the method of [Agresti and Caffo (2000)].  
 
Exposure adjusted occurrence 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 Approximate 95% CIs for 
the occurrence rate will be calculated with correction 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 


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as “Exposure adjusted” it actually uses by default the on-treatment period (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 
LNP023 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”.  
The number (and percentage) of participants with treatment-emergent adverse events of special 
interest/related to identified and potential risks will be summarized by treatment. The frequency 
and percentage of participants with treatment emergent adverse events of special interest 
(TEAESI) and serious TEAESI will be summarized by treatment group and preferred term.. 
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. TEAE risk difference by SOC will be 
presented by a forest plot. The risk difference for treatment emergent adverse events of special 
interest by PT will be also presented by a forest plot. The confidence intervals will be calculated 
using the Exact method (as stated in Section 2.7.1).  
A listing of participants experiencing AESIs will also be provided by treatment group. The 
eCRS safety topic definitions to identify AESIs will be provided as a listing. 
For patients receiving LNP023, treatment-emergent and all AEs of special interest within the 
search ‘PNH haemolysis and thrombosis’ occurring after discontinuation of LNP023 200 mg 
b.i.d will be reported separately. All such AEs occuring after LNP023 200 mg b.i.d will be listed 
and the treatment emergent AEs 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 treatment-
emergent adverse events which are not serious adverse events with an incidence greater than a 
certain threshold and on treatment-emergent serious adverse events and SAE suspected to be 
related to study treatment, will be provided by system organ class and preferred term on the 
safety set population. 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. 


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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 treatment-emergent AEs will be summarized by SOC and 
PT. Death refers to treatment-emergent adverse events 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.  
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, scheduled visit/ time-point, and treatment. 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, and 
treatment.  
It is to be noted that for analysis on SAF and Comb. SAF analysis sets, 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 the Lower Limit of Quantification LLoQ will be imputed to 
0.5×LLoQ and the values greater than the 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. 
 
Shift tables using the low/normal/high (low and high) classification may be provided as 
appropriate to compare participant’s baseline laboratory evaluation relative to the visit’s 
observed value. For the shift tables, the standard low/normal/high (low and high) classifications 


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based on upper and lower limits of normal range will be used.. If a participant presents with 
both low and high values during the on-treatment period, then these participants will be counted 
for the shift table in a category “low and high”. These summaries will be presented by laboratory 
parameter, visit and treatment group. 
The version 4.03 of the CTCAE grading will be used at the time of reporting and the following 
reports could be used: 
• 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 treatment group, participant, and visit/time. 
 
Arithmetic mean (SD) of selected safety parameters (e.g. thyroid and reproductive hormone 
levels) over time will be provided by treatment group for each of the parameters listed in 
Table 2-2.  
Table 2-2 
Selected thyroid and reproductive hormone level parameters 
Thyroid hormone level 
Reproductive hormone level 
• 
T3 
• 
T4 
• 
Reverse T3 
• 
TSH 
 
• 
Testosterone 
• 
DHT 
• 
LH 
• 
FSH 
Note that displays of reproductive hormone level parameters will be further split by sex.  
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 2-3. 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 2-3. 
Liver toxicity finding based on laboratory values and accounting for presence of bone pathology, 
symptoms, Gilbert syndrome will be presented. AEs collected in the analysis dataset and related 
to liver toxicities (Jaundice, AE potentially indicative of a liver toxicity) will either be reported 
separately in a specific table or will simply be displayed as part of the general AE tables.  
Table 2-3 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 
Potential Hy’s Law case 


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(ALT or AST > 3 × ULN) and TBL > 2 × ULN and ALP to ≤ 3 × ULN 
in the presence of bone pathologya 
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) 
AEs indicative of liver toxicity 
Jaundiceb 
Jaundice 
Any AE potentially indicative of a liver toxicityb 
AE potentially indicative of a 
liver toxicity 
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 will be based on eCRS and is described in Table 2-4 for 
MedDRA version 23.1 
b Selection of AEs described in  Table 2-4 
 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 2-4  Definition of symptoms and AEs for liver toxicities 
Term in table 
MedDRA term(s) 


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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 with flag “OS”. eCRS will be the reference for 
analyses. 
(1) presence of Fatigue term with severity ≥ “Severe” 
 
Renal alert values will be summarized by treatment where renal alert values are identified as: 
• Serum creatinine increase ≥ 25% compared to baseline during normal hydration status 
• New onset dipstick proteinuria ≥ 3+  
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 treatment and time point; the number of 
participants with values outside the normal range will be displayed. Where normal ranges are 


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available, participants with abnormalities in ECG data will be listed by treatment group and 
visit/time.  
Categorical summary statistics for ECG 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 > 500ms 
• 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 by treatment group. 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 adverse events and will be 
described as part of AEs. 
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 treatment and visit/time. On-treatment values will be 
defined as in Section 2.7. 
Where ranges are available, abnormalities will be summarized and listed by treatment group, 
participant, and visit/time.  Arithmetic mean (sd) of absolute values over time for SBP and DBP 
and pulse rate will also be plotted by treatment group. 
 
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  
2. Diastolic BP: 65 – 95 mmHg 
 
• Heart rate :   
• <= 50 bpm  
• >=120 bpm  


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2.8 
   
 
2.9 
 
 
 
 
 
 
 
   
2.10 
Patient-reported outcomes 
In this study, the question addressed by the analysis of PRO measurements is whether treatment 
with LNP023 improves patient-reported fatigue symptoms as measured by the FACIT-Fatigue. 
 
 
 
 
Changes in scores of fatigue using the FACIT-Fatigue questionnaire are a secondary endpoint 
and the analysis is described in Section 2.6. 
To further calibrate the performance of the FACIT-Fatigue in the context of treatment with 
LNP023 and determine within-patient, anchor-based minimally important change in FACIT-
Fatigue scores, analyses of changes in FACIT-Fatigue scores will be examined by change in 
PGIS severity level by patient or based on patient exit interviews..  
All supportive analyses of the performance of the FACIT-F questionnaire (including responder 
analyses derived from a priori definition of a meaningful change) and of the behavior of 
meaningful change over time as well as of the impact of clinical endpoints as reflected in the 
FACIT-F will be detailed in a separate analysis plan for PROs. 
 
  
 
2.11 
 
 
 
  


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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 randomized treatment period.  An additional CSR will be produced when the 
last participant has completed the last visit in the treatment extension period, when the final 
study database has been locked. 
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 as definedin the 
DMC Charter. Access to a limited number of efficacy measurements by the DMC will be 
provided solely for the purpose of evaluating benefit of treatment with LNP023 against any risk. 
Such safety evaluations do not inflate the type I error for the primary efficacy hypothesis testing 
and thus no adjustment for multiplicity is considered necessary. All analyses of data using 
randomization codes to be provided to the DMC will be carried out by an independent statistical 
group (CRO) and communications concerning any findings between the DMC and the 
independent statistical group will be handled following the same process as for studies in which 
the treatment given is blinded. The DMC will function under 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 
3.1 
Primary endpoint(s) 
Power of the two primary endpoints is determined based on the summary measure used for 
testing: the odds ratio corresponding to the proportions of participants achieving the status of 
responder in the two treatment groups being compared. Due to the small sample size and 
possible sparseness of observations in the randomization strata, the test will be computed using 
exact methods, hence the probability of rejection at the study wise significance level is obtained 
from the distribution of Fisher’s exact test. The distribution of the test statistic is asymmetric 
with respect to a two tailed rejection region, hence the sample size has been calculated based 
on a one-sided rejection region for a Fisher’s exact test corresponding to a significance level of 
0.025.  


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Participants will be randomized to one of the two treatment arms in an 8:5 ratio to LNP023 
monotherapy at a dose of 200 mg b.i.d. (approximately 56 participants), or anti-C5 antibody 
treatment (approximately 35 participants continuing with the same stable regimen as that prior 
to randomization), respectively. 
Under an assumption that participants on LNP023 treatment would achieve a proportion of 50% 
of responders who achieve and increase of ≥ 2 g/dL from baseline to be compared to a 
proportion of 16% of responders on anti-C5 antibody treatment the sample size of 56 
participants on LNP023 and 35 participants on anti-C5 antibody treatment will provide 83.2 % 
power for this endpoint at a significance level of 0.0125. Power for the endpoint corresponding 
to the achievement of sustained levels of hemoglobin ≥ 12 g/dL is calculated under the 
assumption that the proportions are 35% on LNP023 treatment and 5% on anti-C5 antibody 
treatment and it is 89.1% for a significance level of 0.0125. The sample size/power calculations 
were carried out using the package exact2x2 by Fay, Hunsberger, Nason, and Gabriel and R 
version 3.4.3. Power for the simultaneous test cannot be exactly derived but a minimum power 
corresponding to assuming a Bonferroni adjustment is approximately 95% for the above 
described marginal power assumptions. 
3.2 
Secondary endpoint(s) 
Nominal power for prioritized secondary endpoints corresponding to hypotheses H3, H41, H42, 
and H43 is estimated to be between 85% and 90% at full study alpha (one-sided 0.025), without 
considering the adjustment for multiple testing derived from the procedure used. The three 
hypotheses tested as H51, H52 and H53 are estimated to have lower power, hence the alpha 
allocated is very small, leading to a test at full study alpha only after rejection of all primary 
endpoint hypotheses and secondary endpoint hypotheses H3 and H4i. 
4 
Change to protocol specified analyses 
In case of sparse data or if no responses are observed in one of the treatment arms the conditional 
logistic regression cannot be implemented for primary analysis. If such situation occurs, the 
statistical model based on logistic regression with Firth penalized method, as specified as a 
supportive analysis in protocol, will be implemented as the statistical model for primary analysis. 
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 .  
1. If the AE end date month is missing, the imputed end date should be set to the earliest 
of the (date of last contact, 31DECYYYY, date of death). 


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2. If the AE end date day is missing, the imputed end date should be set to the earliest of 
the (date of last contact, last day of the month, date of death). 
3. If AE year is missing or AE is ongoing, the end date will not be imputed. 
5.1.1.2 
AE start date imputation 
Rules for imputing the AE start date: 
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed. 
 
 
 
Day 
Month 
Year 
Partial Adverse Event Start Date 
Not used 
MON 
YYYY 
Treatment Start Date  
Not used 
TRTM 
TRTY 
 
The following matrix explains the logic behind the imputation.  
 
 
MON 
MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
 
( 1 ) 
No convention 
( 1 ) 
No convention 
( 1 ) 
No convention 
( 1 ) 
No convention 
YYYY < TRTY 
 
( 2.a ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
YYYY = TRTY 
 
( 4.a ) 
Uncertain 
( 4.b ) 
Before Treatment 
Start 
( 4.c ) 
Uncertain 
( 4.c ) 
After Treatment Start 
YYYY > TRTY 
 
( 3.a ) 
After Treatment Start 
( 3.b ) 
After Treatment Start 
( 3.b ) 
After Treatment Start 
( 3.b ) 
After Treatment Start 
Before imputing AE start date, find the AE start reference date.  
1. If the imputed AE end date is complete and the imputed AE end date < treatment start date 
then AE start reference date = min(informed consent date, earliest visit date). 
2. Else AE start reference date = treatment start date 
 
Impute AE start date -  
1. If the AE start date year value is missing, the date uncertainty is too high to impute a rational 
date.  Therefore, if the AE year value is missing, the imputed AE start date is set to NULL. 
2. If the AE start date year value is less than the treatment start date year value, the AE started 
before treatment.  Therefore: 
a. If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY). 


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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: 
The following table explains the notation used in the logic matrix. Please note that missing start dates 
will not be imputed. 


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Day 
Month 
Year 
Partial CMD Start Date 
Not used 
MON 
YYYY 
Treatment Start Date 
Not used 
TRTM 
TRTY 
 
The following matrix explains the logic behind the imputation. 
 
 
 
MON 
MISSING 
MON < TRTM 
MON = TRTM 
MON > TRTM 
YYYY 
MISSING 
 ( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
( 1 ) 
Uncertain 
YYYY < TRTY 
 
( 2.a )  
Before Treatment Start 
( 2.b ) 
Before Treatment Start 
( 2.b ) 
Before Treatment Start 
( 2.b ) 
Before Treatment Start 
YYYY = TRTY 
 
( 4.a ) 
Uncertain 
( 4.b ) 
Before Treatment Start 
( 4.a ) 
Uncertain 
( 4.c ) 
After Treatment Start 
YYYY > TRTY 
 
( 3.a ) 
After Treatment Start 
( 3.b ) 
After Treatment Start 
( 3.b ) 
After Treatment Start 
( 3.b ) 
After Treatment Start 
 
1. If the CM start date year value is missing, the imputed CM start date is set to one day 
prior to treatment start date.  
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment.  Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the mid-year 
point (01JulYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY). 
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore: 
a. If the CM month is missing, the imputed CM start date is set to the year start 
point (01JanYYYY). 
b. Else if the CM month is not missing, the imputed CM start date is set to the 
month start point (01MONYYYY). 
4. If the CM start date year value is equal to the treatment start date year value: 
a. And the CM month is missing or the CM month is equal to the treatment start 
date month, then the imputed CM start date is set to one day prior treatment start 
date. 
b. Else if the CM month is less than the treatment start date month, the imputed 
CM start date is set to the mid-month point (15MONYYYY). 
c. Else if the CM month is greater than the treatment start date month, the imputed 
CM start date is set to the month start point (01MONYYYY). 


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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 1 
composite of:  
increase in Hb 
levels ≥ 2 g/dL 
from baseline* 
without 
requiring RBC 
transfusions# 
Treatment 
policy 
 
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-included 
in the composite 
estimand 
Odds ratio 
 
 
Sensitivity 
analysis 1.1 
Same 
Treatment 
policy 
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Tipping point 
analysis for 
imputation of 
missing data  
Same 
Same 
Same 
Odds ratio 
 
 
Sensitivity 
analysis 1.2 
Same 
Treatment 
policy 
Missing 
hemoglobin 
central lab data 
replaced by 
local lab data at 
same visit.  
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Same 
Same 
Same 
Odds ratio 
 
 


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Estimand 
Endpoint  
Handling strategy of intercurrent events 
Summary 
measure 
Sensitivity 
analysis 1.3 
Same 
Same 
Same 
Same 
Same 
Difference and 
ratio of 
marginal 
proportions 
from a 
Logistic model 
with common 
intercept 
Primary 
estimand 2 
composite of: 
having Hb 
levels ≥ 12 
g/dL* without 
requiring RBC 
transfusions # 
Treatment 
policy 
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-included 
in the composite 
estimand 
Odds ratio 
 
  
Sensitivity 
analysis 2.1 
Same 
Treatment 
policy 
 
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Tipping point 
analysis for 
imputation of 
missing data  
Same 
Same 
Same 
Odds ratio 
 
 
Sensitivity 
analysis 2.2 
Same 
Treatment 
policy 
Missing 
hemoglobin 
central lab data 
replaced by 
local lab data at 
same visit.  
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Same 
Same 
Same 
Odds ratio 
 
 
Sensitivity 
analysis 2.3 
Same 
Same 
Same 
Same 
Same 
Difference and 
ratio of 
marginal 
proportions 
from a 
Logistic model 
with common 
intercept 
Supplementary estimands 


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Estimand 
Endpoint  
Handling strategy of intercurrent events 
Summary 
measure 
Supplementary 
estimand 1.1 
composite of an 
increase in Hb 
levels ≥ 2 g/dL 
from baseline* 
without 
requiring RBC 
transfusions# 
and not 
receiving 
rescue 
medication$ 
Treatment 
policy 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-included 
in the composite 
estimand 
Odds ratio 
 
 
Supplementary 
estimand 1.2 
Same 
Same 
Same 
Same 
Same 
Difference and 
ratio of 
marginal 
proportions 
from a 
Logistic model 
with common 
intercept 
Supplementary 
estimand 2.1 
composite of 
Hb levels ≥ 12 
g/dL* without 
requiring RBC 
transfusions#  
and not 
receiving 
rescue 
medication$ 
Treatment 
policy 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-included 
in the composite 
estimand 
Odds ratio 
 
 
Supplementary 
estimand 2.2 
Same 
Same 
Same 
Same 
Same 
Difference and 
ratio of 
marginal 
proportions 
Logistic model 
with common 
intercept 
Supportive analysis 
Supportive 
analysis 1.1 
composite of an 
increase in Hb 
levels ≥ 2 g/dL 
from baseline* 
without 
requiring RBC 
transfusions#  
Treatment 
policy 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-included 
in the composite 
estimand 
Difference and 
ratio of 
marginal 
proportions  
Logistic model 
with common 
intercept 
Supportive 
analysis 2.1 
composite of 
Hb levels ≥ 12 
g/dL* without 
requiring RBC 
transfusions#  
 
Treatment 
policy 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-included 
in the composite 
estimand 
Difference and 
ratio of 
marginal 
proportions 
Logistic model 
with common 
intercept 


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Estimand 
Endpoint  
Handling strategy of intercurrent events 
Summary 
measure 
Supportive 
analysis 1.2 
composite of an 
increase in Hb 
levels ≥ 2 g/dL 
from baseline* 
without 
requiring RBC 
transfusions#  
Treatment 
policy 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-included 
in the composite 
estimand 
Odds ratio 
estimated 
using CMH 
test 
Supportive 
analysis 2.2 
composite of 
Hb levels ≥ 12 
g/dL* without 
requiring RBC 
transfusions#  
 
Treatment 
policy 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event-included 
in the composite 
estimand 
Odds ratio 
estimated 
using CMH 
test 
Secondary estimands 
 
Secondary 
estimand 1 
Proportions of 
participants not 
receiving any 
transfusions # 
Treatment 
policy 
 
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event since this 
is the endpoint 
of interest 
Odds ratio 
Supportive 
analysis 
(secondary) 
1.1 
Same 
Same 
Same 
Same 
Same 
Difference and 
ratio of 
marginal 
proportions 
from a 
Logistic model 
with common 
intercept 
Secondary 
estimand 2 
Difference in 
achieved 
hemoglobin 
change from 
baseline**  
Treatment 
policy 
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Treatment 
policy 
Treatment 
policy 
Transfusions# 
are treated 
within a 
hypothetical 
strategy (as if 
patients had not 
received any 
transfusions) 
comparison of 
mean change 
from baseline 
in hemoglobin 
levels  
Sensitivity 
analysis 
(secondary) 
2.1 
Same 
Treatment 
policy 
Missing 
hemoglobin 
central lab data 
replaced by 
local lab data at 
same visit. 
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Same 
Same 
Same 
Same 


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Estimand 
Endpoint  
Handling strategy of intercurrent events 
Summary 
measure 
Supportive 
analysis 
(secondary) 
2.1 
Same 
Treatment 
policy 
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Same 
Same 
Treatment policy 
Same 
Secondary 
estimand 3 
Difference in 
change from 
baseline in 
scores of 
fatigue using 
the FACIT 
Fatigue 
questionnaire**  
Treatment 
policy 
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Treatment 
policy 
Treatment 
policy 
Treatment policy 
comparison of 
mean change 
from baseline 
in FACIT 
fatigue scores  
Supportive 
analysis 
(secondary) 
3.1 
Same 
Same 
Same 
Same 
Transfusions# 
are treated 
within a 
hypothetical 
strategy (as if 
patients had not 
received any 
transfusions) 
Same 
Secondary 
estimand 4 
Difference in 
change from 
baseline in 
reticulocyte 
counts**  
Treatment 
policy 
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Treatment 
policy 
Treatment 
policy 
Treatment policy 
comparison of 
the mean 
change from 
baseline in 
reticulocyte 
counts  
Sensitivity 
analysis 
(secondary) 
4.1 
Same 
Treatment 
policy 
Missing 
reticulocyte 
central lab data 
replaced by 
local lab data at 
same visit. 
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Same 
Same 
Same 
Same 
Supportive 
analysis 
(secondary) 
4.1 
Same 
Treatment 
policy 
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Same 
Same 
Transfusions# 
are treated 
within a 
hypothetical 
strategy (as if 
patients had not 
received any 
transfusions) 
Same 


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Estimand 
Endpoint  
Handling strategy of intercurrent events 
Summary 
measure 
Secondary 
estimand 5 
Difference in 
percent change 
from baseline 
in LDH**  
Treatment 
policy 
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Treatment 
policy 
Treatment 
policy 
Treatment policy 
comparison of 
the log 
transformed 
LDH ratio to 
baseline  
Sensitivity 
analysis 
(secondary) 
5.1 
Same 
Treatment 
policy 
Missing LDH 
central lab data 
replaced by 
local lab data at 
same visit. 
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Same 
Same 
Same 
Same 
Supportive 
analysis 
(secondary) 
5.1 
Same 
Treatment 
policy 
Missing data on 
LNP023 after 
study 
discontinuation 
imputed using 
copy reference 
Same 
Same 
Transfusions# 
are treated 
within a 
hypothetical 
strategy (as if 
patients had not 
received any 
transfusions) 
Same 
Secondary 
estimand 6 
Rates of 
breakthrough 
hemolysis 
occurring  
Treatment 
policy 
Not an 
intercurrent 
event since 
this is the 
endpoint of 
interest 
Treatment 
policy 
Treatment policy 
Rate 
difference 
between 
treatments  
Secondary 
estimand 7 
Rates of 
MAVE s  
Treatment 
policy 
Treatment 
policy 
Not an 
intercurrent 
event since 
this is the 
endpoint of 
interest 
Treatment policy 
Rate 
difference 
between 
treatments  
* between Day 126 and 168 ( at least 3 out of 4 scheduled measurements) 
** between Day 126 and 168  
# between Day 14 and Day 168 
$between Day 1 and Day 168 
5.2.2 
Analysis considerations 
For all inferential efficacy analysis, the analysis model will use the strata variables based on the 
assigned strata at randomization. However the imputation model for imputing missing data 
( Section 2.5.3 and Section 2.6.3) will use the strata variables based on the eCRF data.  


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5.2.2.1 
MMRM convergence issues 
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 
Method for calculation of marginal proportions 
Binary outcomes will be analyzed using a logistic regression model with treatment and 
randomization strata as fixed effect factors. Additional covariates can be included when relevant, 
including continuous baseline values.  
The marginal proportions, difference in marginal proportions and associated two-sided 95% 
confidence interval will also be provided. 
The marginal standardization method will be used to calculate the mean response rate in each 
treatment group as well as their difference. The logistic regression model to estimate the 
response probability is written as:  
log
𝑃𝑃(𝑌𝑌= 1)
1 −𝑃𝑃(𝑌𝑌= 1) = 𝛽𝛽0 + 𝛽𝛽1𝑋𝑋+ 𝛽𝛽2𝑇𝑇 
Where P(Y = 1) refers to the probability to be responder, X refers to the vector of covariates, 
T refers to treatment and N refers to number of participants. 
The maximum likelihood estimator for 𝛽𝛽̂0, 𝛽𝛽̂1, 𝛽𝛽̂2 will be plugged in to obtain the probability to 
be a responder for each participant i had he/she received treatment T  
𝜃𝜃෠iT = 𝑃𝑃෠(𝑌𝑌𝑖𝑖= 1) =
exp[𝛽𝛽
෢0 + 𝛽𝛽̂1𝑋𝑋𝑖𝑖+ 𝛽𝛽̂2𝑇𝑇]
1 + exp[𝛽𝛽
෢0 + 𝛽𝛽̂1𝑋𝑋𝑖𝑖+ 𝛽𝛽̂2𝑇𝑇] 
The proportion of responders will be derived for each treatment arm from the estimated 
marginal probabilities derived from the model fit as the mean of the individual logistic 
regression model predictions,  
𝜃𝜃෠𝑇𝑇= ∑
𝜃𝜃෠𝑖𝑖𝑖𝑖
𝑁𝑁
𝑖𝑖=1 
𝑁𝑁
 
The 95% confidence intervals will be derived by the bootstrap method. For the bootstrap 
method, multiple sets of patients will be bootstrapped from the initial population. For each set 
the steps (model fitting, predicting, averaging) will be repeated to obtain bootstrapped 𝜃𝜃෠𝑇𝑇. The 
2.5% quantile and 97.5% quantile of the distribution of bootstrapped 𝜃𝜃෠𝑇𝑇 will be used as 95% CI 
boundaries.  
 
 


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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 WoC, or when not allowed per ICF or local regulations, will 
be flagged and excluded from all analyses including listings. 
6 
Reference 
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Bretz F, Maurer W, and Hommel, G (2011) Test and power considerations for multiple 
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Cro S, Morris TP, Kenward MG, Carpenter JR (2020). Sensitivity analysis for clinical trials 
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Westfall, PH and Wolfinger RD (1997) Multiple tests with discrete distributions. Am Stat; 
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