Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH) With Signs of Active Hemolysis
Keywords: Complement alternative pathway paroxysmal nocturnal hemoglobinuria hemolysis
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 16
Healthy volunteers: no

Brief summary:
This was a Phase 2, open label, single arm, multiple dose study to assess efficacy, safety, pharmacokinetics and pharmacodynamics of iptacopan when administered in addition to Standard of care (SoC) in patients with paroxysmal nocturnal hemoglobinuria (PNH) with signs of active hemolysis.

Detailed description:
LNP023 is a novel oral small molecular weight compound that inhibits factor B (FB) of the alternative pathway (AP). Blockade of the AP with oral LNP023 has the potential to prevent both intra - and extravascular hemolysis.

This two-cohort study consisted of a screening period of up to 68 days, a baseline visit, and Treatment periods Part 1 and Part 2. The planned duration of Treatment Part 1 was 13 weeks; the planned duration of Treatment Part 2 (treatment extension for patients who benefit from LNP023 treatment in Part 1 of the study based on reduced hemolytic parameters) was between approximately 2 to 3 years.

Cohort 1: Orally administered iptacopan 200 mg b.i.d. in Part 1 and Part 2 in addition to SoC.

Cohort 2: Orally administered iptacopan 50 mg b.i.d. for a minimum of 2 weeks in addition to SoC; this could be increased to iptacopan 200 mg b.i.d. at study day 15 or at any time later in the study if LDH was not within limit of normal or reduced by at least 60% as compared to baseline values.

End of Study (EoS) visit happened 2 weeks after last LNP023 administration for patients not joining the roll over extension program (REP).

A safety follow-up call was conducted 30 days after last administration of study treatment (applicable only for patients not joining the REP).

Arms:
arm 1: Orally administered iptacopan 200 mg b.i.d. in Part 1 and Part 2 arm 2: Orally administered iptacopan 50 mg b.i.d. for a minimum of 2 weeks in addition to SoC; this could be increased to iptacopan 200 mg b.i.d. at study day 15 or at any time later in the study if LDH was not within limit of normal or reduced by at least 60% as compared to baseline values.

Interventions: intervention 1: iptacopan intervention 2: Standard of Care
Intervention descriptions: intervention 1: iptacopan bid orally administered intervention 2: Standard of Care (SoC) is defined as an antibody with anti C5 activity. At the time of study start, eculizumab was the only available SoC; eculizumab will be hereafter referred to as SoC.

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
LNP023
Clinical Trial Protocol CLNP023X2201 / NCT03439839
An open label, single arm, multiple dose study to assess 
efficacy, safety, pharmacokinetics and pharmacodynamics 
of LNP023 when administered in addition to Standard of 
Care (SoC) in patients with paroxysmal nocturnal 
hemoglobinuria (PNH) with signs of active hemolysis
Document type:
Amended Protocol Version
EUDRACT number:
2017-000888-33
Version number:
v05 (Clean)
Clinical Trial Phase:
II
Release date:
26-Jul-2021
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis/Sponsor


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not form part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as summarized 
below. Refer to Section 9.2 of the protocol for SAE criteria and additional requirements.  See 
also page 2 of the Site Operations Manual for further details on the method of reporting a SAE.

Complete SAE report

Submit SAE report to Chief Medical Office and Patient Safety (CMO & PS) within 
24 hours after awareness of the SAE

Notify the Novartis Medical Lead

The fax number(s) and email address(es) are located in the Site Operations Manual. 


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................8
List of figures ......................................................................................................................8
List of abbreviations............................................................................................................9
Pharmacokinetic definitions and symbols.........................................................................13
Glossary of terms...............................................................................................................14
Protocol summary..............................................................................................................23
1
Introduction .......................................................................................................................28
1.1
Background............................................................................................................28
1.2
Nonclinical data.....................................................................................................29
1.3
Clinical data...........................................................................................................31
1.4
Study purpose ........................................................................................................33
2
Objectives and endpoints...................................................................................................33
2.1
Primary objective(s)...............................................................................................33
2.2
Secondary objective(s)...........................................................................................33
2.3
Exploratory objective(s) ........................................................................................34
3
Investigational plan ...........................................................................................................34
3.1
Study design...........................................................................................................34
3.2
Rationale of study design.......................................................................................36
3.3
Rationale for dose/regimen, route of administration and duration of treatment....37
3.4
Rationale for choice of comparator .......................................................................38
3.5
Rationale for choice of background therapy..........................................................38
3.6
Purpose and timing of interim analyses/design adaptations..................................38
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3.7
Risks and benefits..................................................................................................39
3.7.1
General ..................................................................................................39
3.7.2
Potential risks........................................................................................39
3.7.3
Blood sample volumes..........................................................................42
3.7.4
Risk mitigation strategy ........................................................................43
3.7.5
Rationale for Public Health Emergency mitigation procedures............43
4
Population..........................................................................................................................44
4.1
Inclusion criteria ....................................................................................................44
4.2
Exclusion criteria...................................................................................................45
5
Restrictions for Study Subjects .........................................................................................47
5.1
Contraception requirements...................................................................................47
5.2
Prohibited treatment...............................................................................................47
5.3
Dietary restrictions and smoking...........................................................................48
5.4
Other restrictions ...................................................................................................48
6
Treatment...........................................................................................................................49
6.1
Study treatment......................................................................................................49
6.1.1
Investigational treatment and control drug(s) .......................................49
6.1.2
Bio-batch retention samples..................................................................49
6.1.3
Additional study treatment....................................................................49
6.2
Treatment arms......................................................................................................50
6.3
Treatment assignment and randomization.............................................................50
6.4
Treatment blinding.................................................................................................50
6.5
Treating the subject................................................................................................50
6.6
Permitted dose adjustments and interruptions of study treatment.........................51
6.7
Emergency breaking of assigned treatment code ..................................................51
6.8
Treatment exposure and compliance .....................................................................51
6.9
Recommended treatment of adverse events ..........................................................51
6.10
Rescue medication.................................................................................................51
6.11
Concomitant treatment...........................................................................................52
7
Study completion and discontinuation ..............................................................................53
7.1
Study completion and post-study treatment ..........................................................53
7.2
Discontinuation of study treatment........................................................................53
7.3
Withdrawal of informed consent ...........................................................................54
7.4
Lost to follow-up ...................................................................................................55
7.5
Study stopping rules ..............................................................................................55
7.6
Early study termination by the sponsor .................................................................55
8
Procedures and assessments ..............................................................................................56


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8.1
Assessment schedule .............................................................................................56
8.2
Informed consent procedures.................................................................................61
8.3
Subject screening...................................................................................................62
8.4
Subject demographics/other baseline characteristics.............................................62
8.4.1
PNH clone size......................................................................................62
8.4.2
Demography..........................................................................................62
8.4.3
Medical history/current medical conditions..........................................62
8.4.4
Pregnancy and assessments of fertility .................................................62
8.5
Efficacy / Pharmacodynamics ...............................................................................63
8.5.1
LDH.......................................................................................................63
8.5.2
C3 fragment deposition and PNH-type red blood cells ........................63
8.6
Safety.....................................................................................................................64
8.6.1
Electrocardiogram (ECG) .....................................................................64
8.6.2
Clinical Chemistry ................................................................................64
8.6.3
Hematology...........................................................................................65
8.6.4
Markers of thrombosis ..........................................................................65
8.6.5
Urinalysis ..............................................................................................65
8.6.6
Patient diary ..........................................................................................65
8.6.7
Vital signs and body measurements......................................................65
8.6.8
Physical Examination............................................................................66
8.6.9
Vaccinations..........................................................................................66
8.6.10
Incidence of transfusion........................................................................66
8.6.11
Patient reported outcomes.....................................................................66
8.7
Pharmacokinetics...................................................................................................66
8.8
Other assessments..................................................................................................67
8.8.1
Exploratory biomarkers in serum..........................................................67
8.8.2
Exploratory biomarkers in plasma ........................................................68
8.9
Use of residual biological samples ........................................................................68
9
Safety monitoring..............................................................................................................69
9.1
Adverse events.......................................................................................................69
9.2
Serious adverse event reporting.............................................................................70
9.2.1
Definition of SAE .................................................................................70
9.2.2
SAE reporting........................................................................................71
9.3
Liver safety monitoring .........................................................................................73
9.4
Reporting of study treatment errors including misuse/abuse ................................73
9.5
Pregnancy reporting...............................................................................................74
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9.6
Early phase safety monitoring ...............................................................................74
10 Data review and database management.............................................................................75
10.1
Site monitoring ......................................................................................................75
10.2
Data collection.......................................................................................................75
10.3
Database management and quality control............................................................76
10.4
Data Monitoring Committee..................................................................................76
10.5
Adjudication Committee........................................................................................77
11 Data analysis......................................................................................................................77
11.1
Analysis sets ..........................................................................................................77
11.2
Subject demographics and other baseline characteristics......................................77
11.3
Treatments .............................................................................................................77
11.4
Analysis of the primary variable(s) .......................................................................77
11.4.1
Primary Variable(s)...............................................................................77
11.4.2
Statistical model, hypothesis, and method of analysis..........................78
11.4.3
Handling of missing values/censoring/discontinuations.......................78
11.4.4
Sensitivity analyses ...............................................................................79
11.5
Analysis of secondary variable(s)..........................................................................79
11.5.1
Efficacy / Pharmacodynamics...............................................................79
11.5.2
Safety.....................................................................................................79
11.5.3
Pharmacokinetics ..................................................................................80
11.5.4
Pharmacokinetic / pharmacodynamic interactions................................80
11.5.5
Other assessments .................................................................................80
11.6
Analysis of exploratory variables ..........................................................................80
11.6.1
Exploratory biomarkers.........................................................................80
11.6.3
Other Exploratory biomarkers...............................................................81
11.7
Sample size calculation..........................................................................................81
11.8
Power for analysis of key secondary variables......................................................81
11.9
Interim analyses.....................................................................................................81
12 Ethical considerations........................................................................................................82
12.1
Regulatory and ethical compliance........................................................................82
12.2
Responsibilities of the investigator and IRB/IEC..................................................82
12.3
Publication of study protocol and results...............................................................82
12.4
Quality Control and Quality Assurance.................................................................82
13 Protocol adherence ............................................................................................................83
13.1
Protocol Amendments ...........................................................................................83
14 References .........................................................................................................................84
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15 Appendix 1: Liver Event Definitions and Follow-up Requirements.................................86
16 Appendix 2: Specific Renal Alert Criteria and Actions....................................................88


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List of tables
Table 5-1
Prohibited medication ...........................................................................48
Table 8-1
Assessment Schedule ............................................................................57
Table 9-1
Guidance for capturing study treatment errors......................................74
Table 15-1
Liver Event Definitions.........................................................................86
Table 15-2
Actions required for Liver Events.........................................................86
Table 15-3
Exclusion of underlying liver disease ...................................................87
Table 16-1
Specific Renal Alert Criteria and Actions.............................................88
Table 16-2
Follow-up of renal events......................................................................89
List of figures
Figure 3-1
Study design..........................................................................................36
Figure 11-1
Forest plot of LDH final mean estimates at from 6 studies of 
various lengths ......................................................................................78
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List of abbreviations
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANA
Antinuclear Antibodies
AP
Alternative Pathway
aPTT
Activated Partial Thromboplastin Time
AhR
Aryl Hydrocarbon Receptors
ASMA
Anti-Smooth Muscle Antibodies
AST
Aspartate Aminotransferase
b.i.d.
bis in die (twice a day)
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CFR
U.S. Code of Federal Regulations
CK
Creatinine Kinase
CMO
Chief Medical Office
CMO&PS
Chief Medical Office & Patient Safety
CO2
Carbon Dioxide
CRF
Case Report/Record Form (Paper or Electronic)
CRO
Contract Research Organization
CT
Computerized Tomography
CTC
Common Toxicity Criteria
CV
Coefficient of Variation
CYP2C8
Cytochrome P4502C8
CYP450
Cytochrome P450
DDI
Drug-Drug Interactions
DHT
Dihydrotestosterone
DRF
Dose Range Finding
ECG
Electrocardiogram
eCRF
Electronic Case Report Form (s)
EDC
Electronic Data Capture
EOS
End of Study


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EoT
End of Treatment
eSource
Electronic Source
FACIT
Functional Assessment of Chronic Illness Therapy
FB
Factor B
FDA
Food and Drug Administration
FE
Food Effect
FIH
First In Human
FIR
First Interpretable Results
FSH
Follicle-Stimulating Hormone
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase
GLP
Good Laboratory Practice
GPI
Glycosylphosphotatidylinositol
h
Hour
HBsAg
Hepatitis B Surface Antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HV
Healthy Volunteers
i.v.
intravenous
IB
Investigators Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine System
LDH
Lactate Dehydrogenase


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LFT
Liver Function Test
LH
Luteinizing Hormone
LLN
Lower Limit of Normal
LOAEL
Lowest Observed Adverse Effect Level
MABEL
Minimum Anticipated Biological Effect Level
MAC
Membrane Attack Complex
MAD
Multiple Ascending Dose
MAR
Missing At Random
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram(s)
mL
Milliliter(s)
MMF
Mycophenolate Mofetil
MMRM
Mixed Model Repeated Measures 
MRI
Magnetic Resonance Imaging
NOAEL
No Observed Adverse Effect Level
NYHA
New-York Heart Association
OATP
Organic Anion-Transporting Polypeptide
OC
Oral Contraceptives
P-gp
Permeability Glycoprotein
p.o.
Oral
PA
Posteroanterior
PC
Personal Computer
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PNH
Paroxysmal Nocturnal Hemoglobinuria
PRO
Patient Reported Outcome(s)
PS
Patient Safety
PXR
Pregnane X Receptor
PSD
Premature Subject Discontinuation
PT
q.d.
Prothrombin Time
Once daily
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RAP
Reporting and Analysis Process
RBC
Red Blood Cell(s)
REP
Roll-over Extension Program
s.c.
Subcutaneous
SAD
Single Ascending Dose
SAE
Serious Adverse Event
sCR
Serum Creatinine
SD
Standard Deviation
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SoC
Standard of Care
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
T3
Triiodothyronine
T4
Thyroxine
TBL
Total Bilirubin
TD
Study Treatment Discontinuation
TDI
Time Dependent Inhibition
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
ULQ
Upper Limit of Quantification
US
Ultrasound
WBC
White Blood Cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent
WOCBP
Women of Child Bearing Potential
β-hCG
Beta-Human Chorionic Gonadotropin


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Pharmacokinetic definitions and symbols
Ae0-t
Amount of drug (or defined metabolite) excreted into the urine from time zero 
to time 't' where t is a defined time point after administration [mass units or % 
of dose]
AUC0-t
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to time 't' where t is a defined time point after administration [mass x 
time / volume]
AUCinf
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to infinity [mass x time / volume]
AUClast
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the time of the last quantifiable concentration [mass x time / 
volume]
AUCtau
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the end of the dosing interval tau [mass x time / volume]
AUCtau,ss
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the end of the dosing interval tau at steady state [mass x time / 
volume]
Cav,ss
The average steady state plasma (or serum or blood) concentration during 
multiple dosing
CL/F
The apparent systemic (or total body) clearance from plasma (or serum or blood) 
following extravascular administration [volume / time]
CLr
The renal clearance from plasma (or serum or blood) [volume / time]
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
Cmax,ss
The observed maximum plasma (or serum or blood) concentration following 
drug administration at steady state [mass / volume]
Cmin,ss
The lowest plasma (or serum or blood) concentration observed during a dosing 
interval at steady state [mass / volume]
Racc
The accumulation ratio
T1/2
The terminal elimination half-life [time]
T1/2,acc
The effective half-life based on drug accumulation at steady state [time]
Tmax
The time to reach the maximum concentration after drug administration [time]
Vss/F
The apparent volume of distribution at steady state following extravascular 
administration [time]
Vz/F
The apparent volume of distribution during the terminal elimination phase 
following extravascular administration [volume]


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug(s) (an active drug or an inactive drug, such as a placebo) which 
is used as a comparator to the investigational drug being tested in the 
trial
Dosage
Dose of the study treatment given to the subject 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.
Enrollment
Point/time of subject entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described 
in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is associated 
with a purpose (e.g. screening, randomization, treatment, follow-up) 
which applies across all arms of a study.
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource combines source 
documents and case report forms (eCRFs) into one application, allowing 
for the real time collection of clinical trial information to sponsors and 
other oversight authorities, as appropriate.
Healthy volunteer
A person with no known significant health problems who volunteers to 
be a study participant 
Hemolysis
The rupturing or lysis of red blood cells leading to the release of the cells 
contents into the surrounding fluid.
Investigational 
drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug,” 
"Investigational Medicinal Product," or “test substance”
Medication pack 
number
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: 
a single dose part and a multiple dose part, or a part in patients with 
established disease and in those with newly-diagnosed disease.


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Patient
Personal Data
An individual with the condition of interest
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding 
to a specific treatment arm assignment
Run in Failure
A subject who is screened but not randomized/treated after the run-in 
period (where run-in period requires adjustment to subject’s medications 
or other intervention)
Screen Failure
A subject who is screened but is not treated or randomized
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
Study treatment
Any drug or combination of drugs 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 subject permanently stops taking study treatment prior to the 
defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed 
subject, corresponding to a specific treatment arm 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal of 
study consent 
Withdrawal of consent from the study occurs only when a subject 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
CLNP023X2201
Full Title
An open label, single arm, multiple dose study to assess efficacy, safety, 
pharmacokinetics and pharmacodynamics of LNP023 when administered in 
addition to Standard of Care (SoC) in patients with paroxysmal nocturnal 
hemoglobinuria (PNH) with signs of active hemolysis
Brief title
Efficacy, safety, pharmacokinetics and pharmacodynamics study of LNP023 
in patients with paroxysmal nocturnal hemoglobinuria 
Sponsor and
Clinical Trial 
Phase
Novartis
Phase II
Intervention type
Drug
Study type
Interventional 
Purpose and 
rationale
LNP023 is a novel oral small molecular weight compound, with first-in-class 
potential, that inhibits factor B (FB) of the alternative pathway (AP). Blockade 
of the AP with oral LNP023 has the potential to prevent both intra - and 
extravascular hemolysis and may, therefore, offer therapeutic superiority to the 
existing eculizumab Standard of Care (SoC) therapy that currently require 
intravenous (i.v.) infusions every second week.
The main purpose of this study is to evaluate the efficacy of LNP023 in patients 
with PNH, showing signs of active hemolysis despite treatment with SoC 
(defined as an antibody with anti C5 activity).
Primary 
Objective(s)
To assess the effect of LNP023 on the reduction of chronic hemolysis in PNH 
patients when administered in addition to SoC (monoclonal antibody with anti 
C5 activity).
Secondary 
Objectives
To assess the safety and tolerability of LNP023 in patients with PNH when 
administered in addition to SoC (monoclonal antibody with anti C5 activity).
To assess the effect of LNP023 on markers of intra and extravascular 
hemolysis when administered in addition to SoC (monoclonal antibody with 
anti C5 activity)
To assess the plasma PK of LNP023 in PNH patients


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Study design
This is a non-confirmatory, open label, multiple dose study in patients with 
PNH. Two cohorts will be included into the study. Assessment schedule will 
be identical for both cohorts.
For Cohort 1 (approximately 10 patients) this study includes:

a screening period of up to 68 days,

a baseline visit,

Treatment Part 1: 13 weeks of treatment with 200 mg LNP023 b.i.d.
administered orally in addition to SoC,

Treatment Part 2: Treatment extension for  approximately 2 to 3 years
with the same treatment regimen as used in Part 1 in patients who
benefit from LNP023 treatment in Part 1 (see Section 4.1). Note that
patients can complete Part 2 any time after a minimal total duration of
LNP023 treatment of 2 years (i.e., after V130) without being
considered early discontinuations, for example, to transition to the roll-
over extension program (REP),


an End of Study (EoS) visit 2 weeks after last LNP023 administration
for patients not joining the REP; for patients joining the REP, the last 
treatment visit will become the EoS visit.

a safety follow-up call conducted 30 days after last administration of
study treatment (applicable only for patients not joining the REP).
For Cohort 2 (approximately 5 patients) this study includes:

a screening period of up to 68 days,

a baseline visit,

Treatment Part 1: Minimum of 2 weeks of treatment with
LNP023 b.i.d. administered orally in addition to SoC.  

Treatment Part 2: Treatment extension for  approximately 2 to 3 years
with the same treatment regimen as used in Part 1 in patients who
benefit from LNP023 treatment in Part 1 (see Section 4.1). For patients
receiving 
 the dose may be escalated as described for Part
1. Note that patients can complete Part 2 any time after a minimal total
duration of LNP023 treatment of 2 years (i.e., after V130) without
being considered early discontinuations, for example, to transition to
the roll-over extension program (REP),


an End of Study (EoS) visit 2 weeks after last LNP023 administration
for patients not joining the REP; for patients joining the REP, the last 
treatment visit will become the EoS visit.

a safety follow-up call conducted 30 days after last administration of
study treatment (applicable only for patients not joining the REP).
For all patients:
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
The baseline visit can be skipped if Screening and Day 1 visit are not 
more than 7 days apart (Figure 3-1). If possible, study visits should be
aligned with SoC administration. On Day 1 and any other visits when 
both SoC and LNP023 are administered, LNP023 is administered prior 
to SoC.

The expected study duration is between approximately 2.5 and 3.5 
years.
Population
Up to 15 PNH patients with signs of active hemolysis will be included in the 
study.
Key Inclusion 
criteria

Written informed consent must be obtained before any assessment is 
performed.

Male and female patients between the age of 18-80 (inclusive) at 
baseline with a diagnosis of PNH based on documented clone size of 
≥10% by RBCs and/or granulocytes, measured by GPI-deficiency on 
flow cytometry (screening or medical history data acceptable).

For Cohort 1 only: LDH values ≥ 1.5x upper limit of the normal range 
for at least 3 pre-SoC dosing measurements taken in relation to 3 
different SoC dosing dates over a maximum of 10 weeks prior to Day 
1 (screening, baseline or medical history data acceptable). All other 
screening pre-SoC LDH values have to be >1x upper limit of normal 
range (for pre-SoC samples collected at the same day as SoC 
administration).

For Cohort 2 only: LDH values ≥ 1.25x upper limit of the normal range 
for at least 3 pre-SoC dosing measurements taken in relation to 3 
different SoC dosing dates over a maximum of 10 weeks prior to Day 
1 (screening, baseline or medical history data acceptable). All other 
screening pre-SoC LDH values have to be >1x upper limit of normal 
range (for pre-SoC samples collected at the same day as SoC 
administration).

For Cohort 2 only: Hemoglobin level <10.5 g/dL at baseline.

PNH patients on stable regimen of standard of care complement 
blockade (monoclonal antibody with anti C5 activity) for at least 
3 months prior to first treatment with LNP023.

Previous vaccination against Neisseria meningitidis types A, C, Y and 
W-135 is required at least 4 weeks prior to first dosing with LNP023.
Vaccination against N. meningitidis type B should be conducted if 
available and acceptable by local regulations, at least 4 weeks prior to 
first dosing with LNP023. If LNP023 treatment has to start earlier than 
4 weeks post vaccination, prophylactic antibiotic treatment must be 
initiated.

Previous vaccination for the prevention of S. pneumoniae and 
H. influenzae at least 4 weeks prior to first dosing with LNP023. 
If LNP023 treatment has to start earlier than 4 weeks post vaccination, 
prophylactic antibiotic treatment must be initiated.

Able to communicate well with the investigator, to understand and 
comply with the requirements of the study.

For Part 2 of the study, patients who as per judgment of Investigator
benefit from LNP023 treatment based on reduced hemolytic 
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Key Exclusion 
criteria

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, whichever is longer; or 
longer if required by local regulations

Known or suspected hereditary complement deficiency at screening

History of hematopoietic stem cell transplantation as verified both at
screening and at baseline (unless baseline was skipped)

Patients with laboratory evidence of bone marrow failure (reticulocytes 
<60x10E9/l, platelets <30x10E9/l neutrophils <1x10E9/l) as verified 
both at screening and at baseline (unless baseline was skipped)

A positive HIV, Hepatitis B (HBV) or Hepatitis C (HCV) test result at 
screening

Presence or suspicion (based on judgment of the investigator) of 
active infection within 2 weeks prior to first dose of LNP023, or history 
of severe recurrent bacterial infections

History of recurrent meningitis, history of meningococcal infections 
despite vaccination as verified both at screening and at baseline 
(unless baseline was skipped)

Patients on the immunosuppressive agents such as but not limited to 
cyclosporine, MMF, tacrolimus, cyclophosphamide, methotrexate less 
than 8 weeks prior to first treatment with LNP023 unless on a stable 
regimen for at least 3 months prior to first LNP023 dose.

Systemic corticosteroids administered at the dose of ≥10 mg per day 
prednisone equivalent within less than 4 weeks prior to first treatment 
with LNP023

Severe concurrent co-morbidities, e.g. patients with severe kidney 
disease (dialysis), advanced cardiac disease (NYHA class IV), severe 
pulmonary arterial hypertension (WHO class IV), unstable thrombotic 
event not amenable to active treatment as judged by the investigator
both at screening and at baseline (unless baseline was skipped)

Any medical condition deemed likely to interfere with the patient’s 
participation in the study, or likely to cause serious adverse events 
during the study

Female patients who are pregnant or breastfeeding, or intending to 
conceive during the course of the study

Women 
of 
child-bearing 
potential, 
defined 
as 
all 
women 
physiologically capable of becoming pregnant, unless they are using 
highly effective methods of contraception from first dosing with 
LNP023 until EOS.
Study treatment

LNP023

SoC (defined as an antibody with anti C5 activity)
Pharmacokinetic 
assessments

PK blood collection
Efficacy/PD 
assessments

LDH

C3 fragment deposition

PNH-type red blood cells
Key safety 
assessments

ECG

Blood Chemistry, hematology, urinalysis

Markers of thrombosis


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
Patient diary

Vital signs

Physical examination

Vaccinations

Incidence of transfusion

PRO

AE/SAE monitoring
Other 
assessments

Biomarkers (in serum and plasma)

Data analysis
The primary variable for assessing the effect of LNP023 (in addition to SoC) is 
the LDH value which is measured at multiple times during the study.
A mixed model repeated measures (MMRM) analysis of variance model will 
be fitted to LDH levels over time. The model will include timepoint (as study 
day relative to start of study treatment) as a fixed effect, and baseline LDH as 
a fixed covariate. Baseline is defined to be the mean of the last 3 
measurements prior to randomization. An unstructured variance-covariance 
matrix will be used.
Results from this modelling will be presented as the estimated mean value of 
LDH at week 13 together with the 95% confidence interval. These results will 
also be presented graphically in a forest plot also showing published data from 
trials of eculizumab, as shown in Figure 11-1. 
Key words
Complement, alternative pathway, paroxysmal nocturnal hemoglobinuria, 
hemolysis
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1
Introduction
1.1
Background
Paroxysmal nocturnal hemoglobinuria (PNH) is a life threatening condition caused by a somatic 
mutation in hematopoietic stem cells leading to loss of cell surface complement regulatory 
proteins (CD55 & CD59) on all progeny cells including red blood cells (RBCs).
Without the glycophosphatidylinositol (GPI) anchor, CD59 is less expressed on the cell surface 
hence allowing for C5b-9 formation and erythrocyte lysis in process called intravascular 
hemolysis (Brodsky 2014). C3-coated erythrocytes can also undergo complement-mediated 
destruction by reticuloendothelial macrophages in the liver and spleen (opsonophagocytosis). 
In healthy subjects, this extravascular hemolysis is blocked by CD55, which prevents assembly 
of the C3 and C5 convertases on the cell surface and hence blocks C3 deposition of the cells.
Hemolysis in PNH is mainly due to complement-dependent intravascular hemolysis, which 
normally is blocked by CD59 (protectin) preventing the final stage of complement assembly. 
Without the GPI anchor, CD59 is less expressed on the cell surface hence allowing for MAC 
formation and erythrocyte lysis (Brodsky 2014). In untreated PNH patients, the anemia is 
dominated by the intravascular hemolysis (Subias Hidalgo et al 2017). In patients treated with 
eculizumab formation of the terminal complex is blocked, but there is accumulation of 
erythrocytes opsonized with C3 fragments, which makes them prone to undergo extravascular 
hemolysis (Hill et al 2010, Risitano et al 2009). In particular, C3dg fragments are strong signals 
for erythrophagocytosis (Lin et al 2015).
Indeed, patients with PNH treated with C5-blockade (eculizumab) often develop a 
Coombs-positive hemolytic anemia that is C3-positive, IgG-negative
(Hill et al 2010, 
Risitano et al 2009). The ongoing hemolysis is a burden for the patients leading to severe 
anemia, iron deficiency, pain due to vasospasm and fatigue
Treatment of PNH with eculizumab, drastically reduce the intravascular hemolysis, but the 
patients show evidence of being suboptimally treated for their anemia. Thus, serum LDH levels 
remain elevated in most patients, 50% of patients are anemic and some require intermittent 
transfusions (Peffault de Latour et al 2015). PNH patients with extravascular hemolysis often 
display erythrocytes opsonized with C3, C3b, iC3b and C3dg, the direct Coombs-test is often 
positive, there is a high percentage of reticulocytes, bilirubin is elevated and the LDH levels are 
slightly elevated (Hill et al 2010, Risitano et al 2009). LNP023 blocks the AP and prevents C3 
fragments from opsonizing the erythrocytes. Thereby, patients with PNH should experience less 
of extravascular and intravascular hemolysis (Risitano 2016, Subias Hidalgo et al 2017).
LNP023 is a novel oral small molecular weight compound, with first-in-class potential, that 
inhibits factor B (FB) of the alternative pathway (AP). Blockade of the AP with oral LNP023 
has the potential to prevent both intra - and extravascular hemolysis and may, therefore, offer 
therapeutic superiority to the existing eculizumab Standard of Care (SoC) therapy that currently 
require intravenous (i.v.) infusions every second week.


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1.2
Nonclinical data
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1.3
Clinical data
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1.4
Study purpose
The main purpose of this study is to evaluate the efficacy of LNP023 in patients with PNH, 
showing signs of active hemolysis despite treatment with SoC (defined as an antibody with anti 
C5 activity). 
2
Objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To assess the effect of LNP023 on the 
reduction of chronic hemolysis in PNH 
patients when administered in addition to
SoC (monoclonal antibody with anti C5 
activity)

LDH level at study week 13
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To assess the safety and tolerability of 
LNP023 in patients with PNH when 
administered in addition to SoC 
(monoclonal antibody with anti C5 
activity)

All safety parameters including: blood 
chemistry, hematology, urinalysis, ECG 
evaluation, vital signs, adverse events, 
transfusions, PROs, patient diary

To assess the effect of LNP023 on 
markers of intra and extravascular 
hemolysis when administered in 
addition to SoC (monoclonal antibody 
with anti C5 activity)

Total and free hemoglobin, reticulocytes, 
LDH, C3 fragment deposition, PNH-type
red blood cells, haptoglobin, bilirubin, red 
blood cell count, freedom from 
transfusion

To assess the plasma PK of LNP023 in 
PNH patients

Non-compartmental PK parameters or 
LNP023 in plasma, including but not 
limited to Cmax, Tmax and AUC and 
Ctrough.
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2.3
Exploratory objective(s)
Exploratory objective(s)
Endpoints related to exploratory objective(s)

To explore mechanism of action and 
PK-PD relationship of LNP023 in PNH 
patients when administered in addition 
to SoC (monoclonal antibody with anti 
C5 activity)

Biomarker assessments may include but
are not limited to Wieslab Assay, CH50,
Bb, sC5b-9

Population PK and PD model parameters. 
Correlation analysis and/or PK-PD 
modelling of biomarkers using total and/or
unbound drug levels, as determined by 
means of ex-vivo dialysis, may also be 
explored

To evaluate if co-treatment with 
LNP023 results in sustainable increases 
in hemoglobin

Change in total hemoglobin level from 
baseline 

To assess LNP023-induced changes in 
quality of life

Functional Assessment of Chronic Illness 
Therapy (FACIT)-Fatigue

To assess the effect of LNP023 on 
markers associated with risk of 
thrombosis in PNH patients

Assessments may include but are not 
limited to prothrombin time, partial 
prothrombin time, D-dimer
3
Investigational plan
3.1
Study design
This is a non-confirmatory, open label, multiple dose study in patients with PNH. Two cohorts 
will be included into the study.
For Cohort 1 (approximately 10 patients) this study includes:

a screening period of up to 68 days,

a baseline visit,

Treatment Part 1: 13 weeks of treatment with 200 mg LNP023 b.i.d. administered orally 
in addition to SoC,

Treatment Part 2: Treatment extension for  approximately 2 to 3 years with the same 
treatment regimen as used in Part 1 in patients who benefit from LNP023 treatment in 
Part 1 (see Section 4.1). Note that patients can complete Part 2 any time after a minimal 
total duration of LNP023 treatment of 2 years (i.e., after V130) without being considered 
early discontinuations, for example, to transition to the roll-over extension program 
(REP), 
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
an End of Study (EoS) visit 2 weeks after last LNP023 administration for patients not
joining the REP; for patients joining the REP, the last treatment visit will become the
EoS visit.

a safety follow-up call conducted 30 days after last LNP023 administration on
CLNP023X2201 study (applicable only for patients not joining the REP).
For Cohort 2 (approximately 5 patients) this study includes:

a screening period of up to 68 days,

a baseline visit,

Treatment Part 1: Minimum of 2 weeks of treatment with 
 LNP023 b.i.d.
administered orally in addition to SoC. Dose of study medication can be increased to
200 mg LNP023 b.i.d. at study day 15 or anytime later in the study if LDH is not within
limit of normal or reduced by at least 60% as compared to baseline values,

Treatment Part 2: Treatment extension for  approximately 2 to 3 years with the same
treatment regimen as used in Part 1 in patients who benefit from LNP023 treatment in
Part 1 (see Section 4.1). For patients receiving 
 the dose may be escalated
as described for Part 1. Note that patients can complete Part 2 any time after a minimal
total duration of LNP023 treatment of 2 years (i.e., after V130) without being considered
early discontinuations, for example, to transition to the roll-over extension program
(REP),

an End of Study (EoS) visit 2 weeks after last LNP023 administration for patients not
joining the REP; for patients joining the REP, the last treatment visit will become the
EoS visit.

a safety follow-up call conducted 30 days after last administration of study treatment
(applicable only for patients not joining the REP).
For all patients:

The baseline visit can be skipped if Screening and Day 1 visits are not more than 7 days
apart (Figure 3-1). If possible, study visits should be aligned with SoC administration.
On Day 1 and any other visits when both SoC and LNP023 are administered, LNP023
is administered prior to SoC. Adjustments of the SoC dose or regimen are not allowed
for the first 6 months of the treatment with LNP023.

The expected study duration is between approximately 2.5 and 3.5 years.
Up to 15 PNH patients treated with SoC (defined as an antibody with anti C5 activity) with 
signs of active hemolysis will be included in the study. The presence of hemolysis will be 
verified based on LDH values, as specified in the Section 4.1. Pre-SoC sample collection for 
the LDH measurement used for inclusion purpose should be taken at the same day as planned 
SoC administration. LDH medical history data can be taken into consideration for inclusion 
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purpose. If medical history data is not available, the screening period may consist of up to 
5 visits for LDH verification.
All patients need to complete vaccinations against N. meningitidis, S. pneumoniae and 
H. influenzae at least 4 weeks prior to starting LNP023 treatment. If LNP023 treatment has to
start earlier than 4 weeks post vaccination, prophylactic antibiotic treatment must be initiated.
After initial immunization, booster doses of the vaccinations should be administered according
to the label of the vaccination used. The screening period may be extended to allow vaccination
procedures to be completed. This is applicable for vaccinations only and all the other screening
assessments should be performed within the period described in the assessment schedule.
Patients who benefit from LNP023 treatment in Part 1 of the study based on reduced hemolytic 
parameters (see inclusion criteria Section 4.1) can continue study treatment in extension Part 2.
Please refer to the Assessment schedule for details regarding assessments to be performed.
Assessment schedule is identical for cohort 1 and cohort 2.
Figure 3-1
Study design
3.2
Rationale of study design
It has been demonstrated that over 40% of the PNH patients protected from intravascular 
hemolysis by an anti-C5 monoclonal antibody still show signs of active hemolysis 
(Peffault de Latour et al 2015). It is hypothesized that one important reason for elevated LDH 
levels in these patients is extravascular hemolysis mediated by accumulation of C3 fragment on 
red blood cells thereby leading to opsonization of erythrocytes. LNP023 specifically targets the 
alternative complement pathway and has been shown in-vitro to reduce the opsonization of the-
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erythrocytes by C3 fragments (unpublished data). Therefore, to account for both intravascular 
and extravascular hemolysis and to build confidence of efficacy of LNP023, LNP023 will be 
administered in addition to any antibody with anti C5 activity that is currently available and 
used as SoC in this patient population. In addition, for patients already on C5 blockade, 
discontinuation of SoC in favor of LNP023 is not warranted at this time because the efficacy of 
LNP023 as a monotherapy in this indication is not confirmed yet. Modifications of the SoC 
regimen are allowed in study patients who respond to LNP023 after at least 6 months of 
concomitant treatment as per discretion of the Investigator after careful consideration of risk-
benefit. As exposure to anti-complement activity of patients on SoC is known to reach 
sub-optimal levels towards the end of standard treatment interval of 2 weeks (increasing CH50 
values, Peffault de Latour et al 2015), consequent changes in PD markers (such as LDH) can 
be observed in most patients on SoC when used at the label dose. It is expected that the addition 
of LNP023 to SoC will produce a constant complete complement blockade in these patients 
through the additional effect of factor B blockade. Therefore, overall hemolysis during the study 
is expected to decrease or disappear. We will investigate the relationship between alternative 
complement pathway blockade in the presence of varying exposures to SoC anti C5 activity and 
residual, extravascular hemolysis.
This is a non-placebo-controlled study since the absence of a placebo response in this patient 
population has been demonstrated (Hillmen et al 2006), and is expected given the nature of the 
primary outcome measure, which is a biochemical parameter. In addition considering available 
treatment options restricting PNH patients to placebo treatment would not be ethical.
To reduce the risk of infections, all the patients are either receiving prophylactic antibiotics or 
are vaccinated prior to first treatment with LNP023. The study will include an up to 68-day 
screening period to allow time to assure development of protective immunity. This long 
screening period also allows assessment of hemolysis based on the consistently elevated LDH 
levels. In addition, to reduce risk of infection, prophylactic antibiotics will be required for 
patients with any signs of infection as described in Section 3.1.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
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3.4
Rationale for choice of comparator
Not applicable.
3.5
Rationale for choice of background therapy
To build confidence in efficacy of LNP023, it will be administered in addition to any antibody 
with anti C5 activity that is currently available and used as SoC in this patient population. 
Discontinuation of SoC in favor of LNP023 is not warranted at this time in Part 1 of the study
because the efficacy of LNP023 in this indication is not confirmed yet, and the risk benefit 
evaluation is in favor of continuing C5 blockade until data of LNP023 in PNH becomes 
available. Change in the SoC treatment regimen will be allowed after minimum of 6 months of 
LNP023 treatment in Part 2 of the study that is open only to patients who respond to LNP023 
treatment.
3.6
Purpose and timing of interim analyses/design adaptations
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3.7
Risks and benefits
3.7.1
General
The risk to subjects in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, early stopping rules, periodic review of the safety data, and guidance for 
the investigators in the IB. The most relevant risks are described below. A complete list of 
toxicological findings is available in the Investigator Brochure Section 4.3.2.
Women of child bearing potential (WOCBP) 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 highly effective contraception 
requirements outlined in the Section 4.2 (Exclusion Criteria). If there is any question that the 
subject will not reliably comply, they should not be entered or continue in the study.
3.7.2
Potential risks
The potential risk of LNP023 can only be assessed indirectly by analyzing the pharmacological 
profile, preclinical safety studies and clinical studies.
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3.7.2.1
Infections
In this study, LNP023 is used to block the complement AP. Patients with mutations of factor B 
(FB) are generally healthy, but have impaired resistance against bacterial infections. 
Of particular concern are rare, but serious, meningococcal or pneumococcal infections. In the 
general population the annual incidence of invasive infections with Neisseria meningitidis is 
between 0.1-2.0 cases per 100,000 with great variation between regions (Sridhar et al 2015).
For infections with Streptococcus pneumoniae, the annual risk is 35 cases per 100,000 for 
individuals <2 or >65 years of age, while it is 4 cases per 100,000 in individuals between 18 
and 35 years of age (Alanee et al 2007). The current risk for invasive infections with 
Hemophilus influenzae is 1.6 per 100,000 in the US (MacNeil et al 2011).
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 CP with 
C5-blockers like eculizumab (Konar et al 2016). Vaccination is predicted to be an effective 
mitigation strategy to reduce the risk for individuals treated with LNP023.
After a single injection of meningococcal vaccine, high titers are achieved after two weeks, but in 
most studies data on titers at Day 28 are reported (Gossger et al 2012, Keyserling et al 2005).
Similar effects are seen with pneumococcal vaccines (McFetridge et al 2015, Bryant et al 2015).
Complement is important to trigger a serological response. Hence, the serological response to
certain vaccinations is most likely blunted during active LNP023 treatment. Thus, important
vaccinations should be performed prior to initiation of LNP023. Importantly, no live vaccines
should be given to individuals during LNP023 treatment.
During the one-month run in phase, vaccination will be done according to local regulation and 
practice at least four weeks prior to the first dose to effectively increase the serological titers 
and reduce the risk for the individual in the unlikely event of bacterial infection with 
N. meningitides, S. pneumoniae or H. influenzae. The vaccines and the vaccination procedures 
recommended vary between countries and the details are therefore described in the SOM.
Patients will be closely monitored for signs and symptoms of infection. Patients will be 
instructed to contact the investigator if they suspect infection/experience potential symptoms of 
infection between visits (please refer to Section 3.7.4). The investigator will employ clinical 
judgement to determine an appropriate course of treatment and report infections as an AE. If 
symptoms of severe bacterial infections are reported, LNP023 treatment will be interrupted, 
bacterial cultures taken, and treatment with appropriate antibiotics immediately initiated.
With the prophylactic antibiotics, vaccinations and close monitoring described above, the risk 
for serious infection during LNP023 treatment is considered to be low.
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3.7.3
Blood sample volumes
Total maximum blood volume collected during this study will be 1400 mL:

A maximum of 500 mL of blood is planned to be collected over a period of 
approximately 15 weeks from each patient in Part 1 of the study. 

Additional approximately 900 mL will be collected from patients participating in Part 2 
of the study during approximately 3 years of treatment extension. In case patients finish 
the study after approximately 2 years of treatment, the additional blood volume collected 
in Part 2 will be approximately 700 mL.
Additional samples may be required for safety monitoring.
Timings of blood sample collection are outlined in the Assessment schedule Section 8.1.
A summary of the blood log is provided in the Site Operations Manual. Complete instructions 
for all sample collections, processing, storage and shipment information are available in the 
SOM and central Laboratory Manual.
See Section 8.9 regarding the potential use of residual samples. 
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3.7.4
Risk mitigation strategy
All study patients will be clinically managed as if in severe neutropenia regardless of their actual 
neutrophils count. Specifically, the patients and treating staff need to be instructed to be vigilant 
for any clinical signs of infections (e.g. malaise, chills, fever, bone pain) and to measure the 
body temperature daily in Part 1 and at minimum at time of physical symptoms in Part 2 of the 
study until one week post last LNP023 treatment. Patients will be instructed to contact the study 
investigator immediately in case of suspicion of infection or elevated body temperature 
(>38.3°C by oral or tympanic method) for a phone consultation. 
In case of a suspected infection, patients should either be admitted for emergency evaluation or 
empirically treated with an oral fluoroquinolone plus amoxicillin/clavulanate (or plus 
clindamycin if penicillin allergic), unless fluoroquinolone prophylaxis was used before fever 
developed (please refer to guidance provided in Flowers et al 2013, (Vol 31; p799, 
recommendation B4).
In order to mitigate the risk of the hemolytic events after LNP023 treatment discontinuation, 
2 weeks of the LNP023 taper down period was implemented for patients discontinuing LNP023 
treatment. In addition, the guidance was added on how to monitor the patients after study 
treatment discontinuation.
Patients will return to the clinic on a regular basis. During these visits safety, tolerability, 
efficacy and PK/PD data will be collected. Standard safety assessments will include vital signs, 
physical examinations, ECGs, clinical laboratory evaluations (hematology, blood chemistry and 
urinalysis), and AEs as outlined in the Assessment schedule. In addition to standard clinical 
laboratory assessments, subjects will be monitored regularly for signs and symptoms of 
infections, inflammation, and hematologic and renal function as outlined below. 
3.7.5
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.
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4
Population
Study inclusion/exclusion criteria
Approximately 15 PNH patients with signs of active hemolysis will be included in the study. 
4.1
Inclusion criteria
Study inclusion/exclusion criteria eligible for inclusion in this study must fulfill all of the 
following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female patients between the age of 18-80 (inclusive) at baseline with a diagnosis 
of PNH based on documented clone size of ≥10% by RBCs and/or granulocytes, measured 
by GPI-deficiency on flow cytometry (screening or medical history data acceptable).
3. For Cohort 1 only: LDH values ≥1.5x upper limit of the normal range for at least 3 pre-SoC 
dosing measurements taken in relation to 3 different SoC dosing dates over a maximum of 
10 weeks prior to Day 1 (screening, baseline or medical history data acceptable). All other 
screening pre-SoC LDH values have to be > 1x upper limit of normal range (for pre-SoC 
samples collected at the same day as SoC administration).
4. For Cohort 2: LDH values ≥1.25x upper limit of the normal range for at least 3 pre-SoC 
dosing measurements taken in relation to 3 different SoC dosing dates over a maximum of 
10 weeks prior to Day 1 (screening, baseline or medical history data acceptable). All other 
screening pre-SoC LDH values have to be > 1x upper limit of normal range (for pre-SoC 
samples collected at the same day as SoC administration).
5. For Cohort 2 only: Hemoglobin level <10.5 g/dL at Baseline.
6. PNH patients on stable regimen of standard of care complement blockade (monoclonal 
antibody with anti C5 activity) for at least 3 months prior to first treatment with LNP023.
7. Previous vaccination against Neisseria meningitidis types A, C, Y and W-135 is required at 
least 4 weeks prior to first dosing with LNP023.Vaccination against N. meningitidis type B 
should be conducted if available and acceptable by local regulations, at least 4 weeks prior 
to first dosing with LNP023. If LNP023 treatment has to start earlier than 4 weeks post 
vaccination, prophylactic antibiotic treatment must be initiated.
8. Previous vaccination for the prevention of S. pneumoniae and H. influenzae at least 4 weeks 
prior to first dosing with LNP023. If LNP023 treatment has to start earlier than 4 weeks post 
vaccination, prophylactic antibiotic treatment must be initiated.
9. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
10. For Part 2 of the study patients who as per judgment of Investigator benefit from LNP023 
treatment based on reduced hemolytic parameters as compared to Screening and Baseline.


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4.2
Exclusion criteria
Study inclusion/exclusion criteria fulfilling 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, 
whichever is longer; or longer if required by local regulations
2. Known or suspected hereditary complement deficiency at screening
3. History of hematopoietic stem cell transplantation as verified both at screening and at 
baseline (unless baseline was skipped)
4. Patients with laboratory evidence of bone marrow failure (reticulocytes <60x109/l, or
platelets <30x109/l, or neutrophils <1x109/l) as verified both at screening and at baseline 
(unless baseline was skipped)
5. A positive HIV, Hepatitis B (HBV) or Hepatitis C (HCV) test result at screening  
6. Presence or suspicion (based on judgment of the investigator) of active infection within 
2 weeks prior to first dose of LNP023, or history of severe recurrent bacterial infections
7. History of recurrent meningitis, history of meningococcal infections despite vaccination as 
verified both at screening and at baseline (unless baseline was skipped)
8. Patients on the immunosuppressive agents such as but not limited to cyclosporine, MMF, 
tacrolimus, cyclophosphamide, methotrexate less than 8 weeks prior to first treatment with 
LNP023 unless on a stable regimen for at least 3 months prior to first LNP023 dose.
9. Systemic corticosteroids administered  at the dose of ≥ 10 mg per day prednisone equivalent 
within less than 4 weeks prior to first treatment with LNP023
10. Severe concurrent co-morbidities, e.g. patients with severe kidney disease (dialysis), 
advanced cardiac disease (NYHA class IV), severe pulmonary arterial hypertension 
(WHO class IV), unstable thrombotic event not amenable to active treatment as judged by 
the investigator both at screening and at baseline (unless baseline was skipped)
11. Any medical condition deemed likely to interfere with the patient’s participation in the study, 
or likely to cause serious adverse events during the study
12. Female patients who are pregnant or breastfeeding, or intending to conceive during the 
course of the study
13. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception from 
first dosing with LNP023 until EOS. Highly effective contraception methods include:

Total abstinence from heterosexual intercourse (when this is in line with the preferred and 
usual lifestyle of the subject). Periodic abstinence (e.g. calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug.  In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female subjects on the study 
the vasectomized male partner should be the sole partner for that subject.


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
Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) or 
other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception
In case of use of oral contraception, women should be stable on the same pill for a minimum of 
3 months before taking investigational drug.
If local regulations deviate from the contraception methods listed above and require more 
extensive measures to prevent pregnancy, local regulations apply and will be described in the 
ICF.
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. 
In the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential. 
Additional patients might be enrolled to replace patients who discontinue the study or treatment 
for reasons other than safety or lack of efficacy.
The investigator must ensure that all patients being considered for the study meet the eligibility
criteria. No additional criteria should be applied by the investigator, in order that the study 
population will be representative of all eligible patients.
Patient selection is to be established by checking through all eligibility criteria at screening 
and/or baseline as specified below. A relevant record (e.g. checklist) of the eligibility criteria 
must be stored with the source documentation at the study site.
Deviation from any entry criterion excludes a subject from enrollment into the study.
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.


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5
Restrictions for Study Subjects
For the duration of the study, the subjects should be informed and reminded of the restrictions 
outlined in this section: 

to use contraception as specified in below Section 5.1.

to monitor body temperature and  to contact the investigator immediately in case of  
suspicion of infection or elevated body temperature (>38.3°C by oral or tympanic method)

to record any non-compliance in LNP023 intake in a dosing diary
5.1
Contraception requirements
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 requirement outlined in the 
Section 4.2 (Exclusion Criteria). If there is any question that the subject will not reliably comply, 
they should not be entered or continue in the study.
Male subjects should be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information. Please refer to Section 4.2 (Exclusion criteria) for details of 
contraception requirements for the study.
5.2
Prohibited treatment
Use of the treatments displayed in the table below is NOT allowed.
Preclinical studies have shown that systemic disposition of LNP023 is likely cleared to be 
primarily mediated by metabolism clearance, in particular by the CYP450 family 
(primarily CYP2C8) as well as by direct glucuronidation. In addition, some minor contribution 
from direct renal and intestinal excretion is anticipated, and a contribution of OATP in hepatic 
uptake of LNP023 cannot be ruled out. 
While drugs that interact with individual disposition pathways of LNP023 are unlikely to lead 
to a major increase in AUC for LNP023, co-administered drugs that inhibit multiple disposition 
mechanisms of LNP023 (e.g., Gemfibrozil) should be avoided.
Most importantly, LNP023 at the highest dose of 200 mg, may have an inhibitory effect on 
intestinal P-gp which could lead to an 2-4 fold increase in AUC of sensitive substrates. 
Therefore, it is recommended to use P-gp substrate with a narrow therapeutic index with caution 
and in a staggered dosing paradigm (victim drug such as cyclosporine, tacrolimus at least 
3 hours after administration of LNP023). The investigator should consult Novartis for advice 
as needed.


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Table 5-1
Prohibited medication
Medication
Prohibited 
period
Action to be taken
Immunosuppressive agents such as but not limited 
to cyclosporine, MMF, tacrolimus, 
cyclophosphamide, methotrexate unless on a 
stable regimen for at least 3 months before study 
Day 1
8 weeks before 
first LNP023 
dose until EOS
To discontinue study 
treatment
Systemic corticosteroids
4 weeks before 
first LNP023 
dose until EOS
To discontinue prohibited 
concomitant medication
Live vaccinations
4 weeks before 
first LNP023 
dose until EOS
To discontinue study 
treatment
Gemfibrozil (PK interaction expected)
48h before first 
LNP023 dose 
until EOS
To discontinue study 
treatment
Strong CYP2C8 inhibitors (e.g., clopidogrel)
48h before first 
LNP023 dose 
until EOS
To discontinue prohibited 
concomitant medication
SoC dose or regimen* adjustments during first 6 
months of LNP023 treatment
From Day 1 until 
Day 180
Decision to continue 
treatment with study 
medication: to by decided 
on the case by case basis 
*Window of +/-2 days acceptable
5.3
Dietary restrictions and smoking
Not applicable.
5.4
Other restrictions
Not applicable.


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6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual (SOM).
6.1.1
Investigational treatment and control drug(s)
6.1.2
Bio-batch retention samples
Not applicable.
6.1.3
Additional study treatment
No additional treatment beyond investigational drug and SoC are included in this trial.
6.1.3.1
Standard of Care
Standard of Care (SoC) is defined as a monoclonal antibody with anti C5 activity. As per 
Section 4.1, patients should be on stable SoC regimen for at least 3 months prior to first 
treatment with LNP023. If possible, study visits need to be aligned with SoC administration. 
On Day 1 and any other visits when both SoC and LNP023 are administered, LNP023 is 
administered prior to SoC. Adjustment of the SoC dose or regimen is not allowed during the 
first 6 months of the study. However, for stable patients without signs of active hemolysis who 
are at least for 6 months in the trial and having received continued concomitant treatment with 
LNP023 and eculizumab at a dose level of at least 900 mg IV q2w, the dose of eculizumab 
might be adjusted as per the investigator’s discretion (e.g., a dose of 1’200 mg q2w might be 
reduced to 900 mg q2w).
Time and dose of SoC administered will be recorded in CRF. SoC is to be procured and 
administered by the site locally.
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6.2
Treatment arms
Cohort 1:  study patients will receive 200 mg of LNP023 twice per day (b.i.d.) in Part 1 and 
Part 2 of the study.
Cohort 2: study patients will receive 
 of LNP023 twice per day (b.i.d.) for at least 2 weeks.  
Dose of study medication can be increased to 
 LNP023 b.i.d. at study day 15 or anytime 
later in the study depending on the LDH level (Section 3.1).
6.3
Treatment assignment and randomization
This is a non-randomized open-label study. Patient screening number (generated as described 
in the Site Operation Manual) will serve as each patient’s identifier.
6.4
Treatment blinding
Not applicable.
6.5
Treating the subject
LNP023 will be administered orally at the patients’ home or at the study center. On Day 1 and 
any other visits when both SoC and LNP023 are administered, LNP023 is administered prior to 
SoC.
As per Section 3.7.5, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of 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 administer the study treatment even without
performing an on-site visit. The dispatch of IMP from the site to the participant’s home 
remains under the accountability of the Investigator. In this case, regular phone calls or virtual 
contacts (frequency as per planned visit) will occur between the site and the participant for 
instructional purposes, safety monitoring, investigation of any adverse events, ensuring 
participants continue to benefit from treatment, and discussion of the participant's health status 
until the participants can resume visits at the study site.
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CCI


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Sponsor qualified medical personnel will be readily available to advise on trial-related medical 
questions or problems.
6.6
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments that are not part of the study design and/or interruptions are 
not permitted.
6.7
Emergency breaking of assigned treatment code
Not applicable.
6.8
Treatment exposure and compliance
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all subjects 
treated with LNP023, as detailed in Section 8.7.
6.9
Recommended treatment of adverse events
All study patients will be clinically managed as if in severe neutropenia regardless of their actual 
neutrophils counts. Specifically, the patients and treating staff need to be instructed to be 
vigilant for any clinical signs of infections (e.g. malaise, chills, fever, bone pain) and to measure 
the body temperature starting from first LNP023 administration until end of study. Patients will 
be instructed to contact the investigator 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 infection, patients should either be admitted for emergency evaluation or 
empirically treated with an oral fluoroquinolone plus amoxicillin/clavulanate (or plus 
clindamycin if penicillin allergic), unless fluoroquinolone prophylaxis was used before fever 
developed (please refer to guidance provided in Flowers et al 2013.
Please refer to Section 7.2 for guidance regarding treatment of AEs related with LNP023 
discontinuation.
6.10
Rescue medication
Not applicable.


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6.11
Concomitant treatment
The investigator must instruct the subject to notify the study site about any new medications 
he/she takes after the subject was enrolled into the study.
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the timeframe 
defined in the entry criteria prior to the start of the study and during the study, must be recorded 
on the Concomitant medications/Significant non-drug therapies CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact Novartis before including the patient in 
the study or, if the subject is already enrolled, to determine if the subject should continue 
participation in the study.


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7
Study completion and discontinuation
7.1
Study completion and post-study treatment
Each patient will be required to complete the study in its entirety. Patients benefiting from 
LNP023 treatment will have the option to join the REP after a minimum of two years of 
treatment with LNP023. The end of treatment (EoT) visit will become the EoS visit for patients 
joining REP.
Study completion is defined as when the last patient completes the Study Completion visit, and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.
All randomized and/or treated subjects, who are not joining the REP study, should have a safety 
follow-up call conducted 30 days after last administration of study treatment. All SAEs reported 
during this time period must be reported as described in Section 9.2. Documentation of attempts 
to contact the patients should be recorded in the source documentation at the sites.
7.2
Discontinuation of study treatment
Discontinuation of study treatment for a patient occurs when study treatment is stopped earlier 
than the protocol planned duration. Discontinuation of study treatment can be decided by either 
the patient, the investigator, or sponsor.
Study treatment must be discontinued under the following circumstances:

Patient decision - patient may choose to discontinue study treatment for any reason at any time.

The investigator believes that continuation would negatively impact the safety of the 
subject or the risk/benefit ratio of trial participation.

Any protocol deviation that results in a significant risk to the patient’s safety.

Pregnancy (see Section 8.6 (Safety) and Section 9.5 (Pregnancy reporting))

Use of prohibited treatment as outlined in Table 5-1.
If discontinuation of study treatment occurs, investigator must determine the primary reason for 
the subject’s premature discontinuation of study treatment and record this information on the 
Dosage Administration CRF.
Patients who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 7.3, Withdrawal of Informed Consent). Where possible, they should 
return for EOS visit within 14 days after last study medication administration. If they fail to 
return for EOS visit for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be 
made to contact the subject/pre-designated contact as specified in Section 7.4 (Lost to follow-
up). This contact should preferably be done according to the study visit schedule.
If any patient discontinues study or study treatment with LNP023 they should be closely 
monitored for signs and symptoms of hemolysis. If possible, two weeks taper down is 
recommended for the patients who discontinue LNP023 treatment.


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In case of the LNP023 treatment discontinuation parameters below are suggested to be closely 
monitored:

greater than 25% absolute decrease in PNH clone size (in the absence of dilution due 
to transfusion) in one week or less; 

increase in LDH level;

an hemoglobin level of < 8 g/dL or a decrease of > 4 g/dL in one week or less;

angina pectoris;

change in mental status;

a 50% increase in serum creatinine level; or

thrombosis.
If serious hemolysis occurs after LNP023 discontinuation, the following procedures/treatments
should be considered by the investigator:

blood transfusion (packed RBC), or exchange transfusion if the PNH RBC are > 50% 
of the total RBCs by flow cytometry;

anticoagulation; corticosteroids; or

other rescue medication.
7.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time.
Withdrawal of consent occurs only when a subject:

   Does not want to further participate in the study, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
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 subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis/sponsor will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law.   
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 


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For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
7.4
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject cannot be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred.
7.5
Study stopping rules
Overall study stopping rules:
Enrollment in the study and dosing of affected patient(s) with LNP023 will be paused if any of 
the following occurs during the study:

One or more fatal or life-threatening SAE that is considered by the Investigator as 
potentially related to LNP023

Two or more SAEs that are considered by the Investigator as potentially related to LNP023;

At least 2 or more patients experience a similar AE which was assessed as severe in intensity, 
and are considered as potentially related to LNP023;

The Sponsor or DMC considers that the number and/or severity of AEs, abnormal safety 
monitoring tests or abnormal laboratory findings justify putting the study on hold.
The study may resume following the safety review, if the Investigator, DMC and Sponsor agree 
it is safe to proceed.
In case of SAEs that signal safety risks that might directly affect other individuals that are still 
on treatment the safety lead will conduct a risk benefit assessment and decide whether to 
continue dosing in the unaffected individuals or not.
7.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. Should this be necessary, subjects must 
be seen as soon as possible and treated as a prematurely discontinued subject. 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 subject’s interests. The investigator will be 
responsible for informing IRBs/IECs of the early termination of the trial.


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8
Procedures and assessments
8.1
Assessment schedule
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible.
Missed or rescheduled visits should not lead to automatic discontinuation. Please refer to 
Section 7.2 for guidance regarding discontinuation of study treatment.
As per Section 3.7.5, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff/ home nursing
staff to the participant´s home, can replace on-site study visits, for the duration of the 
disruption until it is safe for the participant to visit the site again.


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Table 8-1
Assessment Schedule
Epoch
Visit Name Screening Baseline2
Visit Numbers1
1
2
102 103 104 105
106
107 108 109 110 111
112
8
15
22
36
43
57
71
85
92 11
±1
±1
±1
±1
±1
±1
±2
±2
±2
week
2
3
5
6
8
10
12
13
Time (post-dose)
-
-
pre-dose
0.25h 1h 2h 4h 6h
-
 -
 -
-
pre-dose 0.25h 1h 2h 4h 6h
-
-
-
-
-
-
Informed consent
X
Medical history/current medical 
conditions
X
Vaccinations
X
Hepatitis and HIV Screen
S
Demography
X
Pregnancy3
S
S
S
S
S
Study drug administration4
Physical Examination5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulse rate5
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood Pressure5
X
X
X
X
X
X
X
X
X
X
X
X
X
Body Temperature5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body Height
X
Body Weight
X
X
X
X
X
X
X
X
Electrocardiogram (ECG)5
X
X
X
X
X
X
X
X
X
X
Hematology5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry5,9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Markers of thrombosis6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK blood collection5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PNH Clone size
X
Exploratory Biomarkers in Serum6
X
X
X
X
X
X
X
X
X
X
Exploratory Biomarkers in Plasma6
X
X
X
X
X
X
X
X
X
X
C3 deposition, PNH-type red blood cells6
X
X
X
X
X
X
X
X
X
Patient reported outcomes
X
X
X
X
X
X
X
X
X
X
Patient diary7
Incidence of transfusion10
Adverse Events
Concomitant medications
Comments
Study completion information
Days
-70 to -3
-2 to -1
1
2
X
X
X
Screening
X
X
Treatment
Treatment part 1
101
1
4
29
±1
X
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Epoch
Visit Name
Visit Numbers1 113
114
115
116
118
119
120
121
122
113
127
141
155
197
225
253
281
309
±2
±2
±2
±2
±2
±3
±3
±3
±3
week
16
18
20
22
28
32
36
40
44
Time (post-dose)
pre-dose
0.25h 1h 2h
4h
6h
pre-dose
0.25h 1h 2h
4h
6h
Informed consent
Medical history/current medical conditions
Vaccinations
Hepatitis and HIV Screen
Demography
Pregnancy3
S
S
S
S
S
S
S
Study drug administration4
Physical Examination5
X
X
X
X
X
X
X
X
X
Pulse rate5
X
X
X
X
X
X
X
X
X
Blood Pressure5
X
X
X
X
X
X
X
X
X
Body Temperature5
X
X
X
X
X
X
X
X
X
X
X
Body Height and weight
Electrocardiogram (ECG)5
X
X
X
X
X
X
X
X
X
Hematology5
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry5,9
X
X
X
X
X
X
X
X
X
X
X
Urinalysis5
X
X
X
X
X
X
X
X
X
X
X
Markers of thrombosis6
X
X
X
X
X
X
X
X
X
X
X
PK blood collection5
X
X
X
X
X
X
X
X
X
X
X
X
PNH Clone size
Exploratory Biomarkers in Serum6
X
X
X
X
X
Exploratory Biomarkers in Plasma6
X
X
X
X
X
C3 deposition, PNH-type red blood cells6
X
X
X
X
X
Patient reported outcomes
X
X
X
X
X
Patient diary7
Incidence of transfusion10
Adverse Events
Concomitant medications
Comments
Study completion information
X
X
X
X
X
Treatment 
Treatment Part 2, 1st year
117
123
24
48
S
S
X
Days
169
337
±2
±3
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8.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject’s representative gives consent (if allowed according to 
local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate assent by 
personally signing and dating the written informed consent document or a separate assent form.
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 subject source documents.
Novartis will provide to investigators a proposed informed consent form that complies with the 
ICHE6 GCP guideline and regulatory requirements and is considered appropriate for this study. 
The informed consent form will also include a section related to optional future research which 
will require a separate signature if the subject agrees to future research. The procedures set out 
in the main consent form concerning the storage, maintenance of privacy, and release of the 
data or specimens for the main study will also be adhered to for any future research. 
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject 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 subject.
Ensure subjects are informed of the contraception requirements outlined in the Section 4.2
(Exclusion criteria) and in Section 5.1 (Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
Refer to the Site Operations Manual for a complete list of Informed Consent Forms included in 
this study.
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8.3
Subject screening
It is permissible to re-screen a subject if s/he fails the initial screening; however, each case must 
be discussed and agreed with the Sponsor on a case-by-case basis.
8.4
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects. Hepatitis 
and HIV tests will be performed for samples collected at screening. Relevant medical 
history/current medical conditions data will also be collected until signature of informed 
consent.  Details are outlined in the Site Operations Manual.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.4.1
PNH clone size
PNH cells lack the surface proteins CD55 and CD59. If no historic data is available flow 
cytometry will be performed to confirm diagnosis of PNH based on documented clone size of 
≥10% by RBCs and/or granulocytes, measured by GPI-deficiency. Data will be entered into the 
eCRF.
8.4.2
Demography
Subject demographic and baseline characteristic data will be collected on all subjects.  
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent.  Details are outlined in the Site Operations Manual.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.4.3
Medical history/current medical conditions
Relevant medical history and current medical conditions will be recorded on the CRF until 
signature of the informed consent.
Where possible, diagnoses and not symptoms will be recorded.
Any event or change in the subject’s condition or health status occurring prior to informed 
consent will be reported in the Relevant medical history / Current medical conditions section of 
the CRF.
8.4.4
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing.  See the 
Assessment schedule, for timing of the protocol required pregnancy testing; additional 
pregnancy testing may be performed to meet local requirements*. A positive urine pregnancy 
test requires immediate interruption of study treatment until serum β-hCG is performed and 
found to be negative.
*Additional pregnancy testing might be performed if requested per local requirements.  
Refer to Section 9.5 for details on Reporting Pregnancy.


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Assessments of Fertility
Refer to Section 4.2 for criteria to determine women that are not of child bearing potential.
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source. Subsequent hormone level assessment to confirm the woman is not of child bearing 
potential must also be available as source documentation in the following cases:

surgical bilateral oophorectomy without a hysterectomy

reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
subject who states that they are of non-child bearing potential, regardless of reported 
reproductive/menopausal status at screening/baseline.
8.5
Efficacy / Pharmacodynamics
Efficacy in this study will be measured based on the clinical chemistry parameter lactate 
dehydrogenase (LDH),C3 fragment deposition and PNH-type red blood cells. 
8.5.1
LDH
Serum LDH is a measure for intravascular hemolysis and is usually elevated in PNH patients. 
In order to help characterize disease status and progression, historical values of serum LDH 
prior to the informed consent signature (if available), may be recorded in the eCRF as part of 
the medical history assessment and to verify inclusion/exclusion criteria. The blockade of 
complement mediated lysis of erythrocytes is expected to result in reduction of serum LDH 
levels. LDH will be determined in serum by a validated assay. Detailed methodological
description of the assay will be included in the bioanalytical data report. Please refer to 
Assessment Schedule for timepoints when clinical chemistry is done. All the LDH values 
collected during the screening should be recorded in the CRF. If available as a part of the 
patients’ medical history, at least the 5 most recent LDH values recorded prior to screening 
visit should be recorded in the CRF in order to characterize the pre-treatment LDH profile over 
time.
8.5.2
C3 fragment deposition and PNH-type red blood cells
In patients treated with anti C5 antibody there is an accumulation of CD59 negative cells 
positive for C3 fragments. These cells are prone to phagocytosis causing extravascular 
hemolysis.
Level of C3 deposition on red blood cells, as well as the proportion of PNH-type red blood cells
will be quantified. Whole blood samples will be collected at the clinical sites at the time point 
described in the Assessment schedule and samples will be shipped to the analytical lab as 
described in a Site Operations Manual / central laboratory manual. Detailed descriptions of the 
assays will be included in the bioanalytical data reports.


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8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment schedule Section 8.1 detailing when each 
assessment is to be performed.
8.6.1
Electrocardiogram (ECG)
Full details of all procedures relating to the ECG collection and reporting are contained in the 
ECG laboratory technical manual provided by ECG central reader.
In the event that a clinically significant ECG abnormality is identified at the site (e.g. severe 
arrhythmia, conduction abnormality of QTcF > 500 ms), then a copy of the assessment is sent 
to the core laboratory for expedited review if applicable, and the ECG is repeated to confirm 
the diagnosis. If the subject is hemodynamically compromised, the investigator or a medically 
qualified person must initiate appropriate safety procedures without delay (for example 
cardioversion).
These parameters should be recorded: PR interval, QRS duration, heart rate, RR interval, 
QT interval, QTc
The Fridericia QT correction formula (QTcF) must be used for clinical decisions.
Clinically significant abnormalities must be reported in the AE CRF.
8.6.2
Clinical Chemistry
Sodium, potassium, creatinine, urea, uric acid, chloride, albumin, calcium, alkaline phosphatase, 
total bilirubin, CRP, LDH, GGT, AST, ALT, aPTT, PT/INR, CK, glucose, total cholesterol, 
and triglycerides data will be collected.

Bilirubin: Bilirubin is released during hemolysis and is frequently increased in PNH 
patients. Serum levels will be determined using standard procedures. If the total bilirubin 
concentration is increased above 3 times above the baseline value, direct and indirect 
reacting bilirubin should be differentiated.

Ferritin: Ferritin levels have been reported to increase during treatment with eculizumab, 
and are a measure for iron overload. Serum levels will be determined using standard 
procedures. 

In the absence of the medical documentation specified in the Section 8.4.4, FSH testing is 
required of any female subject who states that they are of non-child bearing potential, 
regardless of reported reproductive/menopausal status at screening or baseline.
8.6.2.1
Blood hormone levels 
The hormones analyzed are: T3, T4, TSH, reversed T3, testosterone, FSH, LH and DTH. 
Blood hormone levels are measured at every visit when blood chemistry is done.


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8.6.3
Hematology
Total and free hemoglobin, haptoglobin, hematocrit, red blood cell (RBC) count, reticulocyte
count, white blood cell (WBC) count with differentials and platelet count will be measured. 
Coagulation testing including prothrombin time (PT), reported as INR, and activated partial 
thromboplastin time (aPTT) will be measured.
8.6.4
Markers of thrombosis
Prothrombin time, partial prothrombin time, D-dimer will be measured.
8.6.5
Urinalysis
Dipstick measurements for protein, blood, and WBC/leukocytes will be performed.
If dipstick measurement results are positive (abnormal), results will be captured in the CRF. 
Microscopy must be assessed following an abnormal dipstick test with results captured in the 
CRF.
8.6.6
Patient diary
Patient diaries will be used to record any elevation of body temperature >38.3°C and also record
any missed administration of LNP023.
Body temperature should be measured daily in Part 1 of the study and at minimum at the time 
of physical symptoms in Part 2 of the study.  The investigator shall review the diary at every 
visit. As per the investigator’s decision, any clinically significant findings will be recorded in 
the CRF AE page. Patients 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 consultation. In case of a suspected infection, patients should either be 
admitted for emergency evaluation or empirically treated with an oral fluoroquinolone plus 
amoxicillin/clavulanate (or plus clindamycin if penicillin allergic), unless fluoroquinolone 
prophylaxis was used before fever developed (please refer to guidance provided in 
Flowers et al 2013).
In case of clinically significant abnormal values, it will be recorded in the AE CRF page (as per 
judgement of the investigator).
8.6.7
Vital signs and body measurements

Height

Body weight 

Body mass index (BMI) will be calculated (Body weight (kg) / [Height (m)]2)

Pulse rate 

Blood pressure

Body temperature


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8.6.8
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/or pelvic exams may be performed. Information about all 
physical examinations must be included in the source documentation at the study site. 
Clinically relevant findings that are present prior to informed consent are included in the 
Relevant Medical History CRF. Significant findings observed after informed consent signature 
which meet the definition of an Adverse Event must be appropriately recorded on the 
Adverse Event CRF.
8.6.9
Vaccinations
Vaccination will be performed according to local recommendations for patients with 
complement deficiencies, if prior vaccination cannot be confirmed. The choice of vaccine(s) 
should take into account the serotypes prevalent in the geographic areas in which study patients 
will be enrolled.
The vaccinations against N. meningitidis, S. pneumoniae, and H. influenzae should be 
administered at least 4 weeks prior to starting LNP023 treatment. If LNP023 treatment has to 
start earlier than 4 weeks post vaccination, prophylactic antibiotic treatment must be initiated.
Re-vaccinations during LNP023 therapy should be applied as per label of used vaccinations.
8.6.10
Incidence of transfusion
The number of blood transfusions (and number of units transfused) will be counted and recorded 
in the eCRF. The history of transfusions administered within one year before baseline and the 
number of transfusions while on treatment with LNP023 will be recorded.
8.6.11
Patient reported outcomes
The validated Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) will 
be administered to assess fatigue of PNH patients. FACIT will be completed by study patients
at the timepoints specified in the Assessment schedule.
8.7
Pharmacokinetics
PK samples will be collected at the time points defined in the Assessment schedule.
Pharmacokinetic (PK) samples will be obtained and evaluated in all subjects at all dose levels.
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Plasma PK samples remaining after completion of the determination of parent may be used for 
exploratory purposes to further characterize the PK or PK/PD of LNP023. This analysis may 
include assessment of e.g., metabolite profiling, plasma levels of Fb, or other bioanalytical 
purposes (e.g. stability assessment). Given the exploratory nature of the work, the analytical 
method used for those assessments will not be validated. As such the results from this 
exploratory analysis will not be included in the clinical study report.
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol.
The following pharmacokinetic parameters of LNP023 will be determined using the actual 
recorded sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 
6.2 or higher): 
Plasma: Cmax, Tmax, AUCtau after the first dose at Day 1
Plasma: Cmax,ss, Tmax,ss, AUCtau,ss, Cmin,ss, , T1/2 at Day 29. In addition Racc will also 
be determined. Other pharmacokinetic parameters as appropriate. To denote parameters 
determined at steady state “ss” will be used. 
The linear trapezoidal rule will be used for AUC calculation. Due to the limited PK sampling 
regression analysis of the terminal plasma elimination phase for the determination of T1/2 will 
likely not be possible. If the adjusted R2 value of the regression analysis of the terminal phase 
is less than 0.75, no values will be reported for T1/2 and AUCinf. 
Further details on sample collection, numbering, processing and shipment will be provided in 
the lab manual and/or SOM.
8.8
Other assessments
8.8.1
Exploratory biomarkers in serum
8.8.1.1
Alternative complement pathway activity (Wieslab assay)
The terminal complex activity of the complement system is expected to be inhibited by LNP023 
through inhibiting the alternative complement pathway. The degree of inhibition will be 
assessed using the Wieslab assay which is based on the in vitro formation of the C5b-9 complex, 
triggered by alternative pathway activation. 
A detailed description of the method used to quantify the complement activity will be included 
in the bioanalytical data report.
8.8.1.2
Classical complement pathway activity (CH50 assay)
Standard of care is expected to inhibit the terminal complex activity of the complement system. 
The degree of inhibition with SoC only (baseline) and with both SoC and LNP023 will be 
assessed using the CH50 assay which is based on the in vitro formation of the C5b-9 complex, 
triggered by classical pathway activation.
CH50 will be assessed using existing serum samples from the Wieslab assay. A detailed 
description of the method used to quantify the complement activity will be included in the 
bioanalytical data report.


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8.8.2
Exploratory biomarkers in plasma
Exploratory biomarkers in plasma will be evaluated as potential pharmacodynamics and mode-
of-action markers. They may include, but are not be limited to:

Circulating fragment of factor B (Bb) 

sC5b-9
The list may be changed or expanded further as it is recognized that more relevant or novel 
biomarkers may be discovered during the conduct of the study. Additional biomarkers related 
to the disease or patient’s treatment may also be measured from leftover samples. 
Detailed descriptions of the assays will be included in the bioanalytical data reports.
8.9
Use of residual biological samples
Residual blood and urine samples may be used for another protocol specified endpoint.
Any residual samples remaining after the protocol-defined analysis has been performed may be 
used for additional exploratory analysis. This may include, but is not limited to, using residual 
samples for protein binding, metabolite profiling, biomarkers of transporters or metabolic 
enzyme activity (such as 4-beta-hydroxycholesterol levels) or other bioanalytical purposes 
(e.g. cross check between different sites and/or stability assessment). Given the exploratory 
nature of the work, the analytical method used for those assessments will not be validated. 
As such, the results from this exploratory analysis will not be included in the clinical study 
report.
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9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject 
after providing written informed consent for participation in the study until the end of study 
visit. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also considered 
an adverse event irrespective if a clinical event has occurred. See Section 9.4 for an overview 
of the reporting requirements.
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination finding, laboratory test 
finding, or other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results should 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 patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver and kidney related events are 
included in Appendix 1 and Appendix 2, respectively. 
Adverse events should be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
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 

Yes or

No
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 9.2 for definition of SAE) and which seriousness 
criteria have been met  
5. Action taken regarding investigational treatment. 


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All adverse events must be treated appropriately. Treatment may include one or more of 
the following:

no action taken (e.g. further observation only)

investigational treatment dosage increased/reduced

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE)
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown). 
Information about common side effects already known about the investigational drug can be 
found in the IB or will be communicated between IB updates in the form of Investigator 
Notifications. Once an adverse event is detected, it must be followed until its resolution or until 
it is judged to be permanent, and assessment should be made at each visit (or more frequently, 
if necessary) of any changes in severity, the suspected relationship to the investigational drug, 
the interventions required to treat it, and the outcome.
The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes might 
reasonably be related to study treatment. This information must be recorded in the investigator’s 
source documents; however, if the AE meets the criteria of an SAE, it must be reported to Novartis.
*Refer to the Section 9.2.2.1 for data capture methodology regarding AE collection for subjects 
that fail screening.
9.2
Serious adverse event reporting
9.2.1
Definition of SAE
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:

is fatal or life-threatening

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 the start of study drug

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

social reasons and respite care in the absence of any deterioration in the subject’s general 
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
is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the subject 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 ICH-E2D Guideline 2003).
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 subject or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to ICH-E2D Guideline 2003).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Chief Medical Office and Patient Safety (CMO & PS) as per Section 9.2.2.
9.2.2
SAE reporting
Screen Failures
Note the following requirement for Screen Failures: SAEs occurring after the subject has 
provided informed consent until the time the subject is deemed a Screen Failure must be 
reported to Novartis. 
Treated Subjects
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent until 30 days after last dose must be reported to Novartis
immediately, without undue delay, and under no circumstances later than within 24 hours of 
learning of its occurrence as described below. The 30 day safety follow up will be completed 
as a part of the REP for patients joining roll-over extension. 
Any SAEs experienced after this period should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, and under no circumstances later than within 24 hours of 
the investigator receiving the follow-up information. 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.


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Follow-up information provided must describe whether the event has resolved or continues, 
if and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Chief Medical Office and 
Patient Safety (CMO& PS) Department associate may urgently require further information from 
the investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) 
will be collected and reported to the competent authorities and relevant ethics committees in 
accordance with EU Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries.
9.2.2.1
Reporting SAE for patients who fail screening
In the event a patient who fails screening reports an SAE, the following information should be 
captured in the CRF:

Visit 1 date

Demography

Informed consent

Study completion page for the screening epoch

Withdrawal of Informed Consent (if applicable)

Death page (only in case of death)

Reason for screen failure (e.g. Screening Study Disposition page)
9.2.2.2
How to report Serious Adverse Events (SAEs)
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the Serious Adverse Event Report Form; all applicable sections of the form must be 
completed in order to provide a clinically thorough report. The investigator must assess the 
relationship of each SAE to each specific component of study treatment, complete the SAE 
Report Form in English, and send the completed, signed form by fax within 24 hours after 
awareness of the SAE to the local Novartis Drug Safety and Epidemiology Department.
In addition, the Medical Lead should be immediately notified by email. The patient line of the 
email should be as follows:
“Re:  Urgent - SAE reported:  Study CLNP023X2201”. 
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with 
the case report form documentation at the study site.  Follow-up information should be provided 
using a new paper SAE Report Form stating that this is a follow-up to a previously reported 
SAE.


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9.3
Liver safety monitoring
To ensure subject 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 15-1-Appendix 1 for complete definitions of liver events.
Follow-up of liver events
Every liver event defined in Table 15-1-Appendix 1 should be followed up by the investigator 
or designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 15-2-Appendix 1.

Repeating liver chemistry tests (ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm 
elevation within 48-72 hours.
These liver chemistry repeats should always be performed using the central laboratory, with the 
results provided via the standard electronic transfer.  If results will not be available from the 
central laboratory within 24 hours, then the repeats can also be performed at a local laboratory 
to monitor the safety of the subject. 
All follow-up information, and the procedures performed must be recorded on the appropriate 
CRFs.  Refer to the Site Operations Manual for additional details. 
9.4
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, patient/subject 
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.
All study treatment errors and uses outside of what is foreseen in the protocol will be collected 
in the dose administration record (DAR) CRF. Study treatment errors are only to be reported to 
Chief Medical Office and Patient Safety (CMO& PS) department if the treatment error is 
associated with an SAE.
All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances of 
misuse or abuse must be reported to Novartis Chief Medical Office and Patient Safety (CMO& 
PS). As such, instances of misuse or abuse are also to be reported using the SAE form/CRF. 
Table 9-1 summarizes the reporting requirements.


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Table 9-1
Guidance for capturing study treatment errors
Treatment error type
Document in Dose 
Administration (DAR) CRF 
Document in AE 
CRF
Complete SAE 
form/CRF 
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated 
with an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a 
SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1 and Section 9.2, respectively.
9.5
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Chief Medical Office and Patient Safety (CMO& PS) 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
The study drug must be discontinued, though the subject may stay in the study, if she wishes to 
do so. All assessments that are considered as a risk during pregnancy must not be performed. 
The subject may continue all other protocol assessments.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
9.6
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly between 
medically qualified personnel representing the Sponsor and Investigator. Such evaluations may 
occur verbally, but the outcome and key discussion points will be summarized in writing 
(e-mail) and made available to both Sponsor and all Investigator(s). Criteria pertaining to 
stopping the study/treatment or adapting the study design are presented above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will advise 
the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any new, 
clinically relevant safety information reported from another site during the conduct of the study 
in a timely manner.


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10
Data review and database management
10.1
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 monitor will visit 
the site to check the completeness of subject records, the accuracy of data capture / data entry, 
the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, and 
ensure that study drug is being stored, dispensed, and accounted for according to specifications. 
Key study personnel must be available to assist the monitor during these visits.
Continuous remote monitoring of each site’s data may be performed by Novartis or CRO 
working on behalf of Novartis. Additionally, a central analytics organization may analyze data 
and 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 subject 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 
subject's file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
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 the recording of data that will be used for all primary and safety 
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 subjects will be disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF) using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies and, by 
generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify 
that the data entered into the Electronic Case Report Forms are complete and accurate. 
After database lock, the investigator will receive copies of the subject data for archiving at the 
investigational site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment schedule Section 8.1 and can be recorded directly on the CRFs. All other data 
captured for this study will have an external originating source (either written or electronic) 
with the CRF not being considered as source.


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All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
10.3
Database management and quality control
Novartis staff or CRO working on behalf of Novartis review the data entered into the CRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an electronic 
data query. Designated investigator site staff is required to respond to the query and confirm or 
correct the data. If the electronic query system is not used, a paper Data Query Form will be 
faxed to the site. Site personnel will complete and sign the faxed copy and fax it back to CRO 
working on behalf of Novartis who will make the correction to the database. The signed copy 
of the Data Query Form is kept at the investigator site.
Concomitant medications entered into the database will be coded using the 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.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
ECG readings will be processed centrally and the results will be sent electronically to Novartis 
(or a designated CRO).
At the conclusion of the study, the occurrence of any emergency code breaks will be determined 
after return of all code break reports and unused drug supplies to Novartis.
The occurrence of relevant protocol deviations will be determined. After these actions have 
been completed and the database has been declared to be complete and accurate, it will be 
locked and the treatment codes will be unblinded and made available for data analysis. 
Any changes to the database after that time can only be made after written agreement by 
Novartis management. 
10.4
Data Monitoring Committee
An external, independent Data Monitoring Committee (DMC) will be created to review study 
data. The DMC will review the available safety data after the first 5 patients have completed 
4 weeks of LNP023 treatment, after all 10 patients have completed LNP023 treatment and after 
all study patients complete the treatment In case of any safety concerns identified during the study, 
additional DMC meetings will be scheduled. Further details will be provided in the DMC charter.
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10.5
Adjudication Committee
Not required.
11
Data analysis
The analysis will be conducted on all subject data at the time each Part ends. All outputs 
described below will be produced for Part 1 and at the end of the study extended into Part 2. 
Where appropriate, outputs will be split by Part, but longitudinal plots, for example, will cover 
both Parts at the end of the study analysis.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
The PD analysis set will include all subjects with available PD data and no protocol deviations 
with relevant impact on PD data.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by subject. Summary statistics 
will be provided.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by subject.
11.3
Treatments
Data for study drug administration and any concomitant therapies will be listed by subject.
11.4
Analysis of the primary variable(s)
The primary objective of this study is to assess the effect of LNP023 on the reduction of chronic 
hemolysis, as assessed by LDH over time, in PNH patients when LNP023 is administered in 
addition to SoC (monoclonal antibody with anti C5 activity).
11.4.1
Primary Variable(s)
The primary variable is LDH level and it is measured over time with week 13 (end of Part 1) 
considered the primary timepoint.


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11.4.2
Statistical model, hypothesis, and method of analysis
The primary variable for assessing the effect of LNP023 (in addition to SoC) is the LDH value 
which is measured at multiple times during the study in both Parts.
A mixed model repeated measures (MMRM) analysis of variance model will be fitted to LDH 
levels over time in Part 1. The model will include timepoint (as study day relative to start of 
study treatment) as a fixed effect, and baseline LDH as a fixed covariate. Baseline is defined to 
be the mean of the last 3 measurements prior to randomization. An unstructured 
variance-covariance matrix will be used.
Results from this modelling will be presented as the estimated mean value of LDH at week 13 
together with the 95% confidence interval. These results will also be presented graphically in a 
forest plot also showing published data from trials of eculizumab, as shown below in 
Figure 11-1. Two of the comparative studies are known to be at the same time point but all 
comparisons to this study’s estimate will be useful given their similarity.
Figure 11-1
Forest plot of LDH final mean estimates at from 6 studies of various 
lengths
11.4.3
Handling of missing values/censoring/discontinuations
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Given the severe nature of the indication and the need for close monitoring it is expected that 
there will be very little truly missing data. 
11.4.4
Sensitivity analyses
There is no obvious sensitivity analysis because with so few subjects, differences in results 
between different analyses are unlikely to be detected. However the effect of different ways of 
handling baseline LDH values, different variance-covariance structures and different fixed 
effect models could be examined to ensure robustness of results.
11.5
Analysis of secondary variable(s)
Secondary safety variables include blood chemistry, hematology, urinalysis, ECG evaluation, 
vital signs, adverse events, transfusions, and PROs. Secondary PK variables include total drug 
LNP023 non-compartmental PK parameters, including but not limited to Cmax and AUC and 
trough evaluation. Secondary PD variables as markers of disease activity include total and free 
hemoglobin, haptoglobin, reticulocytes, C3 fragment deposition, red blood cell count, and 
freedom from transfusion, as well as LDH values for patients in Part 2.
11.5.1
Efficacy / Pharmacodynamics
The continuous PD variables of total and free hemoglobin, LDH, haptoglobin, reticulocytes, 
C3 fragment deposition, PNH-type red blood cells and red blood cell count will be listed and 
plotted longitudinally by subject over both Parts. The number and timing of transfusions will 
be listed and each one shown on plots where relevant.
11.5.2
Safety
This study specifies blood chemistry, hematology, urinalysis, ECG evaluation, vital signs, 
adverse events, transfusions, and PROs as secondary objectives. Therefore continuous safety 
variables will also be plotted longitudinally as for LDH and PD variables, with events of interest 
such as transfusions also shown graphically. Otherwise the standard treatment of safety data is 
described below.
Vital signs
All vital signs data will be listed by subject and visit/time and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by visit/time.
ECG evaluations
All ECG data will be listed by subject and visit/time, and abnormalities will be flagged. 
Summary statistics will be provided by visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by subject and visit/time and if normal ranges are available 
abnormalities will be flagged. Summary statistics will be provided by visit/time.


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Adverse events
All information obtained on adverse events will be displayed by subject and summarised overall.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term. A subject with multiple adverse events within a body system is only counted 
once towards the total of this body system.
11.5.3
Pharmacokinetics
PK variables are total drug LNP023 non-compartmental PK parameters, including but not 
limited to Cmax, Tmax, AUC and trough evaluation.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. An exception to this is Tmax where median, 
minimum and maximum will be presented. 
 
 A geometric mean will not be reported 
if the dataset includes zero values. Pharmacokinetic parameters will be calculated as described 
in Section 8.7 and will be listed by subject.
11.5.4
Pharmacokinetic / pharmacodynamic interactions
 
 A possible additive or synergistic 
PD interactions with the SoC is part of the study objective. For safety aspects of PK or 
PD interactions please refer to inclusion/exclusion criteria (Section 4).
11.5.5
Other assessments
Not applicable.
11.6
Analysis of exploratory variables
Any statistical analyses of exploratory endpoints beyond listings and longitudinal plots by 
subject will be described in the RAP. 
11.6.1
Exploratory biomarkers
Biomarker assessments may include but are not limited to Wieslab Assay, CH50, Bb and sC5b-9.
All biomarker data will be listed by subject, and visit/time. Summary statistics will be provided 
by visit/time.
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11.6.3
Other Exploratory biomarkers
Change in total hemoglobin level from baseline to end of 13 weeks of LNP023 administration 
and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue are also exploratory 
endpoints, as well as prothrombin time, partial prothrombin time, and D-dimer.
11.7
Sample size calculation
11.8
Power for analysis of key secondary variables
Not applicable.
11.9
Interim analyses
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12
Ethical considerations
12.1
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 Code of Federal Regulations 
Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles 
laid down in the Declaration of Helsinki.
12.2
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, subject recruitment procedures 
(e.g. advertisements) and any other written information to be provided to subjects. 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.
For multi-center trials, a Coordinating Investigator will be selected by Novartis by the time of 
Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report the 
results of this trial will be either submitted for publication and/or posted in a publicly accessible 
database of clinical trial results.
12.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections.
Audits of investigator sites, vendors, and Novartis systems are performed or overseen by 
Novartis Pharma Auditing and Compliance Quality Assurance (or CRO working on behalf of 
Novartis), a group 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.


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13
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 subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
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.
13.1
Protocol Amendments
Any change 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.
Amendments that are intended to eliminate an apparent immediate hazard to subjects 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 subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed.


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References
References are available upon request.
Alanee SR, McGee, L, Jackson D, et al (2007) Association of serotypes of Streptococcus 
pneumoniae with disease severity and outcome in adults: an international study. Clin Infect Dis;
45(1):46-51.
Brodsky RA (2014) Paroxysmal nocturnal hemoglobinuria. Blood; 2804-11.
Bryant KA, Frenck R, Gurtman A, et al (2015) Immunogenicity and safety of a 13-valent 
pneumococcal conjugate vaccine in adults 18-49 years of age, naive to 23-valent pneumococcal 
polysaccharide vaccine. Vaccine; 33(43):5854-60.
Flowers CR, Seidenfeld J, Bow EJ, et al (2013) Antimicrobial prophylaxis and outpatient 
management of fever and neutropenia in adults treated for malignancy: American Society of 
Clinical Oncology clinical practice guideline. J Clin Oncol; 794-810.
Gossger N, Snape MD, Yu LM, et al (2012) Immunogenicity and tolerability of recombinant 
serogroup B meningococcal vaccine administered with or without routine infant vaccinations 
according to different immunization schedules: a randomized controlled trial. JAMA;
307(6):573-82.
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; 95:567-573. 
Hillmen P, Young NS, Schubert J, et al (2006) The complement inhibitor eculizumab in 
paroxysmal nocturnal hemoglobinuria. N Engl J Med; 1233-43.
ICH Harmonised Tripartite Guideline (2003). Post-approval safety data management: 
definitions and standards for expedited reporting E2D. 
Keyserling H, Papa T Koranyi K, et al (2005) Safety, immunogenicity, and immune memory 
of a novel meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid 
conjugate vaccine (MCV-4) in healthy adolescents. Arch Pediatr Adolesc Med; 159(10):
907-13.
Konar M, Lujan E, and Granoff D (2016) Effect of Complement Inhibition By Anti-C5 
(Eculizumab) or a Small Molecule Inhibitor of Factor D (ACH-4471) on Survival of 
Meningococci in Blood from Vaccinated Adults. In Paper Presented to the American Society 
of Hematology 58th Annual meeting, San Diego, CA.
Lin Z, Schmidt CQ, Koutsogiannaki S, et al
(2015) Complement C3dg-mediated 
erythrophagocytosis: implications for paroxysmal nocturnal hemoglobinuria. Blood;
126(7):891-4. doi: 10.1182/blood-2015-02-625871. 
MacNeil JR, Cohn AC, Farley M, et al (2011) Current epidemiology and trends in invasive 
Haemophilus influenzae disease--United States, 1989-2008. Clin Infect Dis; 53(12):1230-6.
McFetridge R, Meulen AS, Folkerth SD, et al (2015) Safety, tolerability, and immunogenicity 
of 15-valent pneumococcal conjugate vaccine in healthy adults. Vaccine; 33(24):2793-9.


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Peffault de Latour R, Fremeaux-Bacchi V, Porcher R, et al (2015) Assessing complement 
blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Blood;
775-83.
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(17):4094-100.
Risitano AM (2016) Paroxysmal nocturnal hemoglobinuria in the era of complement inhibition. 
American Journal of Hematology; Vol. 91, No. 4.
Sridhar S, Greenwood B, Head C, et al (2015) Global incidence of serogroup B invasive 
meningococcal disease: a systematic review. Lancet Infect Dis; 15(11:)1334-46. 
Subías Hidalgo M, Martin Merinero H, López A, et al (2017) Extravascular hemolysis and 
complement consumption in Paroxysmal Nocturnal Hemoglobinuria patients undergoing 
eculizumab treatment. Immunobiology; 222(2):363-371.


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Appendix 1: Liver Event Definitions and Follow-up 
Requirements
Table 15-1
Liver Event Definitions
Definition
Thresholds
Potential Hy’s law cases

ALT or AST > 3 × ULN and TBL > 2 × ULN without initial 
increase in ALP to > 2 × ULN
ALT or AST elevation with 
coagulopathy

ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation)
ALT or AST elevation 
accompanied by symptoms

ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash, or 
eosinophilia
Isolated ALT or AST 
elevation

ALT or AST > 8 × ULN

5 x ULN < ALT/AST ≤ 8 x ULN

3 x ULN < ALT/AST ≤ 5 x ULN
Isolated ALP elevation

ALP > 2 × ULN (in the absence of known bone pathology)
Others

Any clinical event of jaundice (or equivalent term)

Any adverse event potentially indicative of liver toxicity
Table 15-2
Actions required for Liver Events
Criteria
Actions required
Potential Hy’s Law case

Discontinue the study treatment immediately 

Hospitalize, if clinically appropriate

Establish causality

Complete CRFs per liver event guidance*
ALT or AST elevation with 
coagulopathy
ALT or AST elevation accompanied by 
symptoms
Isolated ALT or AST elevation > 8 × 
ULN
Jaundice
Isolated ALT or AST elevation > 5 to ≤ 8 
× ULN

If confirmed, consider interruption or discontinuation 
of study drug 

If elevation persists for more than 2 weeks, 
discontinue the study drug 

Establish causality

Complete CRFs per liver event guidance*
Isolated ALT or AST elevation > 3 to ≤ 5 
× ULN (patient is asymptomatic)

Monitor liver chemistry tests two or three times 
weekly
Isolated ALP elevation

Repeat liver chemistry tests within 48-72 hours

If elevation is confirmed, measure fractionated ALP; if 
>50% is of liver origin, establish hepatic causality

Complete CRFs per liver event guidance*
Any AE potentially indicative of liver 
toxicity

Consider study treatment interruption or 
discontinuation 

Hospitalize if clinically appropriate

Complete CRFs per liver event guidance*
*Liver event guidance for CRF completion is available in the Site Operations Manual


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Protocol No. CLNP023X2201
Table 15-3
Exclusion of underlying liver disease
Disease
Assessment
Hepatitis A, B, C, E

IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-HCV, HCV 
RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV 
infection

IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis

ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis

Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic 
steatohepatitis

Ultrasound or MRI
Hypoxic/ischemic 
hepatopathy

Medical history: acute or chronic CHF, hypotension, hypoxia, 
hepatic venous occlusion. Ultrasound or MRI.
Biliary tract disease

Ultrasound or MRI, ERCP as appropriate.
Wilson disease

Caeruloplasmin
Hemochromatosis

Ferritin, transferrin
Alpha-1-antitrypsin 
deficiency

Alpha-1-antitrypsin


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16
Appendix 2: Specific Renal Alert Criteria and Actions
Table 16-1
Specific Renal Alert Criteria and Actions
Criteria
Action required
Serum creatinine (sCr) increase
25 – 49% compared to baseline

Consider causes and possible interventions

Follow up within 2-5 days
Serum creatinine increase > 50%

Consider causes and possible interventions

Repeat assessment within 24-48h if possible

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected

Consider hospitalization and specialized 
treatment
Protein-creatinine or albumin-creatinine ratio 
increase ≥ 2-fold
or
new onset dipstick proteinuria ≥ 1+
or
Albumin-creatinine ratio (ACR) ≥ 30 mg/g or 
≥ 3 mg/mmol;
or
Protein-creatinine ratio (PCR )≥ 150 mg/g or 
>15 mg/mmol

Consider causes and possible interventions

Assess serum albumin & serum protein

Repeat assessment to confirm

Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected 
New onset glucosuria on urine dipstick 
(unless related to concomitant treatment, 
diabetes)
Assess & document:

Blood glucose (fasting)

Serum creatinine

Urine albumin-creatinine ratio
New hematuria on dipstick
Assess & document:

Urine sediment microscopy

Assess sCr and urine albumin-creatinine ratio

Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation

Consider bleeding disorder
Additional specialized assessments are available to assess renal function or renal pathology. 
(Note: In exceptional cases when a nephrologist considers a renal biopsy, it is strongly 
recommended to make specimen slides available for evaluation by Novartis to potentially 
identify project-wide patterns of nephrotoxicity.)


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Whenever a renal event is identified, a detailed subject history and examination are indicated 
to identify, document and potentially eliminate risk factors that may have initiated or 
contributed to the event:

Blood pressure assessment (after 5 min rest, with an appropriate cuff size)

Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain, 
dysuria, hematuria, dependent or periorbital edema

Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output

Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic 
failure, contrast media or other known nephrotoxin administration, or other potential 
causes of renal dysfunction, e.g., dehydration, hemorrhage, tumor lysis
Table 16-2
Follow-up of renal events
Action
Follow up
Assess*, document and record in the Case Report 
Form (CRF) or via electronic data load. Review and 
record possible contributing factors to the renal event 
(co-medications, other co-morbid conditions) and 
additional diagnostic procedures (MRI etc) in the CRF.

Urine dipstick and sediment 
microscopy

Blood pressure and body weight

Serum creatinine, electrolytes 
(sodium, potassium, phosphate, 
calcium), bicarbonate and uric acid

Urine output
Monitor subject regularly (frequency at investigator’s 
discretion) until:

Event resolution: (sCr within 10% of 
baseline or protein-creatinine ratio 
within 50% of baseline)
or

Event stabilization: sCr level with 
±10% variability over last 6 months or 
protein-creatinine ratio stabilization at 
a new level with ±50% variability over 
last 6 months.
*Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very 
sensitive metric for integrated kidney function that requires excellent tubular function. A high 
urinary osmolality in the setting of an increase in sCr will point toward a “pre-renal” cause 
rather than tubular toxicity.

SAP_001.pdf: 
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
LNP023
Clinical Trial Protocol CLNP023X2201 / NCT03439839
An open label, single arm, multiple dose study to assess 
efficacy, safety, pharmacokinetics and pharmacodynamics 
of LNP023 when administered in addition to Standard of 
Care (SoC) in patients with paroxysmal nocturnal 
hemoglobinuria (PNH) with signs of active hemolysis
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR 
Document status:
Final
Release date:
19-May-2022
Number of pages:
17
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For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Protected Data (PPD)


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................4
1
Introduction .........................................................................................................................5
1.1
Scope of document ..................................................................................................5
1.2
Study reference documentation ...............................................................................5
1.3
Study objectives.......................................................................................................5
1.3.1
Primary objective(s)................................................................................5
1.3.2
Secondary objective(s)............................................................................5
1.3.3
Exploratory objective(s)..........................................................................6
1.4
Study design and treatment......................................................................................6
2
First interpretable results (FIR) ...........................................................................................8
3
Interim analyses...................................................................................................................8
4
Statistical methods: Analysis sets........................................................................................8
5
Statistical methods: Group presentations ............................................................................9
6
Statistical methods for Pharmacokinetic (PK) parameters..................................................9
6.1
Variables..................................................................................................................9
6.2
Descriptive analyses ..............................................................................................10
7
Statistical methods for Pharmacodynamic (PD) parameters.............................................10
7.1
Primary objective...................................................................................................10
7.1.1
Variables ...............................................................................................10
7.1.2
Descriptive analyses..............................................................................10
7.1.3
Statistical model, hypothesis, and method of analysis..........................11
7.1.4
Handling of missing values/censoring/discontinuations.......................12
7.1.5
Sensitivity analyses ...............................................................................12
7.2
Secondary objectives .............................................................................................12
7.2.1
Variables ...............................................................................................12
7.2.2
Descriptive analyses..............................................................................12
7.3
Exploratory objectives...........................................................................................13
7.3.1
Variables ...............................................................................................13
7.3.2
Descriptive analyses..............................................................................13
8
Statistical methods for safety and tolerability data............................................................14
8.1
Variables................................................................................................................14
8.2
Descriptive analyses ..............................................................................................14
8.3
Graphical presentation...........................................................................................16
9
Statistical methods for biomarker data..............................................................................16


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List of tables
Table 4-1
Protocol deviation codes and analysis sets..............................................9
Table 9-1
List of Biomarkers.................................................................................16


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1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report for trial “CLNP023X2201”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
Final study protocol v05 is available at the time of finalization of the Statistical Analysis Plan
for CSR.
1.3
Study objectives
1.3.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To assess the effect of LNP023 on the 
reduction of chronic hemolysis in PNH 
patients when administered in addition to 
SoC (monoclonal antibody with anti C5 
activity)

LDH level at study week 13
1.3.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary 
objective(s)

To assess the safety and tolerability of 
LNP023 in patients with PNH when 
administered in addition to SoC 
(monoclonal antibody with anti C5 
activity)

All safety parameters including: blood 
chemistry, hematology, urinalysis, 
ECG evaluation, vital signs, adverse 
events, transfusions, PROs, patient 
diary

To assess the effect of LNP023 on markers 
of intra and extravascular hemolysis when 
administered in addition to SoC 
(monoclonal antibody with anti C5 
activity)

Total and free hemoglobin, 
reticulocytes, LDH, C3 fragment 
deposition, PNH-type red blood cells, 
haptoglobin, bilirubin, red blood cell 
count, freedom from transfusion

To assess the plasma PK of LNP023 in 
PNH patients

Non-compartmental PK parameters of 
LNP023 in plasma, including but not 
limited to Cmax, Tmax and AUC and 
Ctrough.


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1.3.3
Exploratory objective(s)
Exploratory objective(s)
Endpoints related to exploratory objective(s)

To explore mechanism of action and
PK-PD relationship of LNP023 in
PNH patients when administered in
addition to SoC (monoclonal
antibody with anti C5 activity)

Biomarker assessments may include but are
not limited to Wieslab assay, CH50, Bb,
sC5b-9

Population PK and PD model parameters.
Correlation analysis and/or PK-PD
modelling of biomarkers using total and/or
unbound drug levels, as determined by
means of ex-vivo dialysis, may also be
explored

To evaluate if co-treatment with
LNP023 results in sustainable
increases in hemoglobin

Change in total hemoglobin level from
baseline

To assess LNP023-induced changes
in quality of life

Functional Assessment of Chronic Illness
Therapy (FACIT)-Fatigue

To assess the effect of LNP023 on
markers associated with risk of
thrombosis in PNH patients

Assessments may include but are not
limited to prothrombin time, partial
prothrombin time, D-dimer
1.4
Study design and treatment
This is a non-confirmatory, open label, multiple dose study in patients with PNH. Two cohorts 
will be included in the study.
For Cohort 1 (approximately 10 patients) this study includes:

a screening period of up to 68 days,

a baseline visit,

Treatment Part 1: 13 weeks of treatment with 200 mg LNP023 b.i.d. administered orally
in addition to SoC,

Treatment Part 2: treatment extension for approximately 2 to 3 year with the same
treatment regimen as used in Part 1 in patients who benefited from the LNP023
treatment in Part 1. The same treatment regimen will be used as in Part 1, Note that
patients can complete Part 2 any time after a minimal total duration of LNP023
treatment of 2 years (i.e., after V130) without being considered early discontinuations,
for example, to transition to the roll-over extension program (REP),

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
an End of Study (EoS) visit 2 weeks after last LNP023 administration for patients not
joining the REP; for patients joining the REP, the last treatment visit will become the
EoS visit.

a safety follow-up call conducted 30 days after last LNP023 administration on
CLNP023X2201 study (applicable only for patients not joining the REP).
For Cohort 2 (approximately 5 patients) this study includes:

a screening period of up to 68 days,

a baseline visit,

Treatment Part 1: Minimum of 2 weeks of treatment with
LNP023 
administered orally in addition to SoC. 

Treatment Part 2: Treatment extension for approximately 2 to 3 year with the same
treatment regimen as used in Part 1 in patients who benefit from the LNP023 treatment
in Part 1. For patients receiving 
 the dose might be escalated as described
in Part 1. For patients receiving 
 the dose may be escalated as described for
Part 1. Note that patients can complete Part 2 any time after a minimal total duration of
LNP023 treatment of 2 years (i.e., after V130) without being considered early
discontinuations, for example, to transition to the roll-over extension program (REP),


and an End of Study (EoS) visit 2 weeks after last LNP023 administration for patients 
not joining the REP; for patients joining the REP, the last treatment visit will become 
the EoS visit.

a safety follow-up call conducted 30 days after last administration of study treatment
(applicable only for patients not joining the REP).
For all patients:

The baseline visit can be skipped if Screening and Day 1 visit are not more than 7 days
apart (Figure 2-1). If possible also other study visits, should be aligned with SoC
administration. On Day 1 and any other visits when both SoC and LNP023 are
administered, LNP023 is administered prior to SoC. Adjustment of the SoC dose or
regimen are not allowed for the first 6 months of the treatment with LNP023.

The expected study duration is between approximately 2.5 and 3.5 years.
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Figure 1-1
Study design
2
First interpretable results (FIR)
No FIR will be produced for the final analysis.
3
Interim analyses 
4
Statistical methods: Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study drug.
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The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data.
The PD analysis set will include all subjects with any available PD data, who received any study 
drug and experienced no protocol deviations with relevant impact on PD data.
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PK analysis in case of these PDs: 
INCL01
Exclude subject from PK 
analysis set 
Subjects are excluded from PD analysis in case of these PDs:
INCL01
Exclude subject from PD 
analysis set
Subjects are excluded from PK and PD analysis in case of these 
PDs: INCL01
Exclude subject from PK 
and PD analysis sets
5
Statistical methods: Group presentations
For summary statistics, subjects will be summarized as follows, depending on which study Part 
is being assessed, unless stated otherwise:
Part 1:

All patients together, for the assessment of Part 1
Parts 1 and 2:

Patients entering Part 2 alone for the whole duration of the study. So there will be 
assessments repeated for Part 1 which only include those patients who went onto Part 2.
In the event that no patients are lost from Part 1 into Part 2 the above grouping becomes 
unnecessary. 
Individual (spaghetti) plots over time will be performed and will include the whole duration of 
the study.
6
Statistical methods for Pharmacokinetic (PK) parameters
All subjects in the PK analysis set will be included in the PK data analysis.
6.1
Variables 
The following pharmacokinetic parameters of total LNP023 will be determined using the actual 
recorded sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 
8.3 or higher):


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
Plasma: Cmax, Tmax, AUCtau, and Cmin (i.e., Ctrough) at Day 1, 29 and 169 and 337.
Other pharmacokinetic parameters as appropriate.

Trough Plasma concentrations 
6.2
Descriptive analyses
Concentration data will be listed by cohort, dose, patient, and visit/sampling time point
(including Part). Descriptive summary statistics will be provided by cohort, dose, visit/sampling 
time point, including the frequency (n, %) of concentrations below the LLOQ. Summary 
statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and geometric), 
median, minimum and maximum. 
 
 
Graphical methods will be employed to show mean and 
individual concentration-time profiles.
Pharmacokinetic parameters will be listed by cohort, dose, patient and Part, and summarized 
with descriptive statistics as listed above. For Tmax, only median, minimum, and maximum 
will be reported.
 
 
 
All individual concentration-time profiles will be displayed graphically by cohort
visit/sampling time point on linear and semi-log view based on nominal time. In addition, the 
arithmetic mean (+/-SD) concentration-time profiles by cohort, dose and visit over time will be 
displayed graphically on the linear and semi-log view based on nominal time.
7
Statistical methods for Pharmacodynamic (PD) parameters
All subjects in the PD analysis set will be included in the PD data analysis.
7.1
Primary objective
The primary objective of this study is to assess the effect of LNP023 on the reduction of chronic 
hemolysis, as assessed by LDH over time, in PNH patients when LNP023 is administered in 
addition to SoC (monoclonal antibody with anti C5 activity)
7.1.1
Variables 
The primary variable is LDH level and it is measured over time, with week 13 (end of Part 1)
considered the primary timepoint.
Baseline is defined as the mean of the last 3 measurements prior to study drug administration.
7.1.2
Descriptive analyses
The primary variable will be listed by cohort, patient and visit/time including Part, and 
descriptive statistics will be provided, by cohort, visit/time and study Part. Summary statistics 
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will include mean (arithmetic), SD, CV (arithmetic), median, minimum, maximum. Summary 
tables may include a combination of individual subject assessments and summary statistics.
Given the severe nature of the indication and the need for close monitoring it is expected that 
there will be very little truly missing data. 
7.1.3
Statistical model, hypothesis, and method of analysis
The primary variable for assessing the effect of LNP023 (in addition to SoC) is the LDH value 
which is measured at multiple times during the study in both Parts.
A mixed model repeated measures (MMRM) analysis of variance model will be fitted to LDH 
levels over time in Part 1. The model will include timepoint (as study day relative to start of 
study treatment) as a fixed effect, and baseline LDH as a fixed covariate. An unstructured 
variance-covariance matrix will be used, if an unstructured covariance cannot be used simpler 
structures will be investigated such as autoregressive and toeplitz, decision on the optimal 
structure will be done based on information criteria.
Results from this modelling will be presented as the estimated mean value of LDH at week 13 
together with the 95% confidence interval. These results will also be presented graphically in a 
forest plot also showing published data from trials of eculizumab, as shown below in Figure 
7-1. Two of the comparative studies are known to be at the same time point but all comparisons 
to this study’s estimate will be useful given their similarity.
Figure 7-1
Forest plot of LDH final mean estimates at from 6 studies of various 
lengths
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7.1.4
Handling of missing values/censoring/discontinuations
7.1.5
Sensitivity analyses
There is no other obvious sensitivity analysis because with so few subjects, differences in results 
between different analyses are unlikely to be detected. However the effect of different ways of 
handling baseline LDH values, different variance-covariance structures and different fixed 
effect models could be examined to ensure robustness of results.
Patients who took prohibited concomitant medication during the study will be excluded from 
the primary endpoint analysis and the analysis related to IVH & EVH markers as part of a 
sensitivity analysis. Both descriptive and inferential analysis will be repeated with these patients 
excluded.
7.2
Secondary objectives
The secondary objective of the study are,

To assess the safety and tolerability of LNP023 in patients with PNH when administered 
in addition to SoC (monoclonal antibody with anti C5 activity)

To assess the effect of LNP023 on markers of intra and extravascular hemolysis when 
administered in addition to SoC (monoclonal antibody with anti C5 activity)

To assess the plasma PK of total LNP023 in PNH patients
Please refer to Section 8 for analysis related to safety and tolerability and Section 6 for PK 
analysis.
7.2.1
Variables 
The secondary variables are markers of disease activity and include: Total and free hemoglobin, 
reticulocytes, C3 fragment deposition, PNH-type red blood cells, PNH clone size, haptoglobin, 
bilirubin, red blood cell count, and freedom from transfusion.
7.2.2
Descriptive analyses
The secondary variables will be listed by cohort, dose, patient and visit/time including Part, and 
descriptive statistics will be provided, by cohort, dose, visit/time and study Part. Summary 
statistics will include mean (arithmetic, geometric), SD, CV (arithmetic, geometric), median, 
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minimum, maximum. Summary tables may include a combination of individual subject 
assessments and summary statistics.
Graphical methods will be employed to show individual overlaid profile plots over time by 
cohort. Summary plots may be provided or overlaid on the individual plots. Percentage change 
from baseline plots may also be provided.
The number and timing of transfusions will be listed and each one shown on plots where 
relevant and relevant descriptive summaries will be formed.
7.3
Exploratory objectives
The exploratory objectives of the study are:

To explore mechanism of action and PK-PD relationship of LNP023 in PNH patients when 
administered in addition to SoC (monoclonal antibody with anti C5 activity)

To evaluate if co-treatment with LNP023 results in sustainable increases in hemoglobin

To assess LNP023-induced changes in quality of life

To assess the effect of LNP023 on markers associated with risk of thrombosis in PNH 
patients
7.3.1
Variables 
Mechanism of action and PK-PD relationship:

Biomarkers (See Section 9) including but are not limited to Wieslab assay, CH50, Bb, 
and sC5b-9. and possibly, depending on assay availability Factor B and Eculizumab 
concentrations

Population PK and PD model parameters. Correlation analysis and/or PK-PD 
modelling of biomarkers using total and/or unbound drug levels, as determined by 
means of ex-vivo dialysis, may also be explored
Co-treatment effect in Hemoglobin:

Hemoglobin level: Change in total hemoglobin level from baseline. Baseline is defined 
as the mean of all measurements prior to randomization.
Genetic research: 

Due to the exploratory nature of this objective endpoints are not predefined
Quality of life:

Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue total score.
Risk of thrombosis markers:

Risk of thrombosis parameters: Assessments may include but are not limited to 
prothrombin time, partial prothrombin time, D-dimer
7.3.2
Descriptive analyses
The exploratory variables will be listed by cohort, patient and visit/time including Part, and 
descriptive statistics will be provided, by cohort, visit/time and study Part. Summary statistics 
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of raw and change from baseline, where relevant, will include mean (arithmetic), SD, CV 
(arithmetic), median, minimum, maximum. Summary tables may include a combination of 
individual subject assessments and summary statistics.
Graphical methods will be employed to show individual overlaid profile plots over the time
course of the whole study by cohort. Summary plots may be provided or overlaid on the 
individual plots. Percentage change from baseline plots may also be provided.
8
Statistical methods for safety and tolerability data
All subjects within the Safety analysis set will be included in the safety data analysis.
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., when change 
from baseline is used). In particular, summary tables for adverse events (AE) will summarize 
only on-treatment events.
The on-treatment period lasts from the date of first administration of study treatment to 7 days 
after the date of the last actual administration of any study treatment.
8.1
Variables
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics, baseline characteristics, exposure
and treatment information.
8.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by subject and cohort. 
Summary statistics will be provided.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by cohort and subject.
Medical treatment
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by cohort, subject and study Part.
Number and percentage of subjects who received the vaccination during Screening period will 
be summarized.
Vital signs
All vital signs data will be listed by cohort, subject, and visit/time including Part and if ranges 
are available abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided by cohort, visit/time and study Part.
Individual and mean values over time will be plotted by cohort, visit/time, and study part.


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ECG evaluations
All ECG data will be listed by cohort, subject and visit/time including Part, abnormalities will 
be flagged. Summary statistics will be provided by cohort, visit/time and study Part.
Clinical laboratory evaluations
All laboratory data will be listed by cohort, subject, and visit/time including Part and if normal 
ranges are available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a subject with any abnormal values. Summary statistics will be provided by cohort, 
visit/time and study Part.
Individual and mean values over time will be plotted by cohort, visit/time and study part.
Adverse events
All information obtained on adverse events will be displayed by subject.
The number and percentage of subjects with treatment-emergent adverse events will be 
tabulated by cohort, Part and overall, body system and preferred term. A subject with multiple 
adverse events within a body system is only counted once towards the total of this body system.
Adverse event reporting for Clinical Trial Safety Disclosure (CTSD)
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
5% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population.
If for the same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
Adverse events are considered treatment-emergent if they occur between the date of first 
administration of study treatment and up to 7 days after the date of the last actual administration 
of any study treatment.
Adverse events of special interest (AESI) definitions are found in the compound electronic Case 
Retrieval Strategy (eCRS). Treatment-emergent AESIs (based on the latest eCRS at the time of 


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DBL) will be summarized by frequency and percentage of patients by risk name, MedDRA 
preferred term and by cohort. A listing of the case retrieval strategy will be presented. 
Exposure
Duration of exposure will be presented graphically, using a horizontal bar chart with subjects 
as the y-axis and the number of days exposed to LNP023 as the x-axis. Exposure data will be
summarized (for SoC, for combination and LNP023 as a monotherapy) and listed by cohort, 
subject and visit/time including Part.
8.3
Graphical presentation 
To visualize trends in longitudinal safety data (vitals, ECG, lab parameter), individual overlaid 
profile plots over time will be created by cohort.
9
Statistical methods for biomarker data
The following biomarkers will be analyzed in this trial and fully reported in the CSR, if the 
data is available.
Table 9-1
List of Biomarkers
Biomarker 
Unit
Description
Read out*
Wieslab Assay
%
Alternative complement pathway activity
Wieslab
Bb
ng/ml
Circulating fragment Bb of Factor B
Bb
sC5b-9
ng/ml
Soluble C5b-9
SC5B-9
CH50
iu**
Classical complement pathway activity
CH50
C3-fragment deposition 
on PNH Type-I red 
blood cells (RBC)
%
Relative percentage (%) of C3d positive PNH Type-I 
RBC out of total PNH Type-I RBC
C3d+Type-I RBC
C3-fragment deposition 
on PNH Type-II RBC
%
Relative percentage (%) of C3d positive PNH Type-II 
RBC out of total PNH Type-II RBC
C3d+Type-II RBC
C3-fragment deposition 
on PNH Type-III RBC
%
Relative percentage (%) of C3d positive PNH Type-III 
RBC out of total PNH Type-III RBC
C3d+Type-III RBC
PNH Type-I RBC
PNH Type-II RBC
PNH Type-III RBC
C3-fragment deposition 
on  PNH RBC
PNH clone size
%
%
%
%
%
Relative percentage (%) of PNH Type-I RBC out of 
total RBC
Relative percentage (%) of PNH Type-II RBC out of 
total RBC
Relative percentage (%) of PNH Type-III RBC out of 
total RBC
Relative percentage (%) of C3d positive PNH RBC out 
of total PNH RBC 
Relative percentage (%) of PNH Type-II and Type-III
RBC out of total RBC
Type-I RBC
Type-II RBC
Type-III RBC
C3d+PNH RBC
PNH clone size
Complement Factor B
Ug/mL
Circulating levels of complement factor B
Complement 
Factor B
GlyA+ RBC
iu*
Relative percentage (%) of GlyA-positive red blood 
cells out of total RBC
GlyA+RBC
RBC
Iu*
Relative percentage (%) of red blood cells out of 
acquired cells
RBC
* Biomarker name exactly as it will appear in the dataset
**For CH50, 1 iu corresponds to 1 CH50 KU Eq/L.
**1iu corresponds to 1%.


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PNH clone size should be calculated as the sum of Type-II RBC and Type-III RBC.
These biomarker data will be listed by cohort, patient, and visit/time including Part. Summary 
statistics will be provided by cohort, visit/time and study Part. They will also be plotted as for 
other variables over time and by cohort.
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