Conditions: Paroxysmal Nocturnal Hemoglobinuria
Keywords: Complement alternative pathway paroxysmal nocturnal hemoglobinuria hemolysis LNP023 PNH LDH hemoglobin Iptacopan
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 13
Healthy volunteers: no

Brief summary:
This was a Phase II randomized, open-label, multicenter, efficacy, safety, pharmacokinetic and pharmacodynamic study assessing four iptacopan doses in adult Paroxysmal nocturnal hemoglobinuria (PNH) patients with active hemolysis who were not on eculizumab or any other complement inhibitor less than 3 months prior to first iptacopan dose. Active hemolysis was defined by a lactate dehydrogenase (LDH) value ≥ 1.5 × ULN.

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

The total study duration from Screening until end of study (EOS) was approximately 28 months. This three-period study included:

* Screening phase: of up to 8 weeks
* Period 1: a 4-week treatment period of iptacopan at the first dose in the assigned sequence
* Period 2: an 8-week treatment period at the second dose in the assigned sequence
* Period 3: an approximate 2-year treatment extension period for patients who responded to iptacopan treatment
* Taper down period of 2 weeks was applicable only for patients discontinuing iptacopan treatment (Week 13 for non-responders or Week 109 for responders who did not enter the rollover extension program (REP) (Study CLNP023C12001B / NCT04747613)). During this taper down period, patients were to receive 25 mg qd (once a day) of iptacopan for 7 days, followed by 10 mg qd for 7 additional days.
* An EOS visit that took place 1 week after the last iptacopan administration for patients not joining the REP. For patients joining the REP, the last treatment visit was the EOS visit.
* A safety follow-up call 30 days after the last administration of iptacopan was performed for patients not joining the REP.

Patients were randomized to Sequence 1 or Sequence 2 in a 1:1 ratio. Sequence 1: Four weeks of treatment with iptacopan 25 mg bid (Twice daily) in Period 1 followed by treatment with 100 mg bid in Period 2 and Period 3. If during Period 1, LDH was not reduced by ≥ 40% from the mean of pretreatment values by Week 2 (Day 15 study visit), the iptacopan dose was to be up-titrated to 100 mg bid (starting from Study Day 17). If LDH was not reduced by ≥ 40% from the mean of pretreatment values at Week 4 (Day 29), the iptacopan dose was to be up-titrated to 200 mg bid in Period 2 and Period 3 (starting from Study Day 30). In the approximate 2-year treatment extension (Period 3), patients maintained the same treatment regimen as used in Period 2.

Sequence 2: Four weeks of treatment with iptacopan 50 mg bid in Period 1 followed by treatment with 200 mg bid in Period 2 and Period 3. If during Period 1, LDH was not reduced by ≥ 40% from the mean of pretreatment values by Week 2 (Day 15 study visit), the iptacopan dose was to be up-titrated to 200 mg bid (starting from Study Day 17). In the approximate 2-year treatment extension (Extension Period 3), patients remained on 200 mg bid. No further up-titration was possible

Arms:
arm 1: Four weeks of treatment with iptacopan 25 mg bid in Period 1 followed by treatment with 100 mg bid in Period 2 and Period 3. arm 2: Four weeks of treatment with iptacopan 50 mg bid in Period 1 followed by treatment with 200 mg bid in Period 2 and Period 3.

Interventions: intervention 1: LNP023
Intervention descriptions: intervention 1: approximately 2 year of Treatment with LNP023

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
LNP023
Clinical Trial Protocol CLNP023X2204
A multi-center, randomized, open-label, efficacy, safety, 
pharmacokinetics and pharmacodynamics study, 
assessing multiple LNP023 doses in adult patients with 
paroxysmal nocturnal hemoglobinuria and active 
hemolysis
Document type:
Amended Protocol Version
EUDRACT number:
2018-003357-13
Version number:
v02 (Clean)
Clinical Trial Phase:
II
Release date:
03-Aug-2021
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis/Sponsor
Clinical Trial Protocol Template version 1.0 dated 01-Dec-2017
ClinicalTrials.gov Identifier: NCT03896152


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study procedures. Note: The SOM will not be a part of the Clinical Study Report.


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................19
1.1
Background............................................................................................................19
1.2
Purpose ..................................................................................................................20
2
Objectives and endpoints...................................................................................................20
3
Study design ......................................................................................................................21
4
Rationale............................................................................................................................24
4.1
Rationale for study design .....................................................................................24
4.2
Rationale for dose/regimen and duration of treatment ..........................................25
4.2.1
Dose regimen and dose span.................................................................25
4.2.2
Minimal treatment duration of each dose 
25
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................25
4.4
Purpose and timing of interim analyses/design adaptations..................................25
4.5
Risks and benefits..................................................................................................26
4.5.1
Blood sample volume............................................................................27
4.5.2
Rationale for Public Health Emergency mitigation procedures............27
5
Population..........................................................................................................................27
5.1
Inclusion criteria ....................................................................................................27
5.2
Exclusion criteria...................................................................................................28
6
Treatment...........................................................................................................................30
6.1
Study treatment......................................................................................................30
6.1.1
Investigational and control drugs..........................................................30
6.1.2
Additional study treatments ..................................................................30
6.1.3
Treatment arms/group ...........................................................................30
6.2
Other treatment(s)..................................................................................................31
6.2.1
Concomitant therapy.............................................................................31
6.2.2
Prohibited medication ...........................................................................32
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6.2.3
Rescue medication ................................................................................33
6.2.4
Restriction for study subjects................................................................33
6.3
Subject numbering, treatment assignment, randomization....................................34
6.3.1
Subject numbering ................................................................................34
6.3.2
Treatment assignment, randomization ..................................................34
6.4
Treatment blinding.................................................................................................34
6.6
Additional treatment guidance...............................................................................34
6.6.1
Treatment compliance...........................................................................34
6.6.2
Recommended treatment of adverse events..........................................35
6.6.3
Randomization list ................................................................................35
6.7
Preparation and dispensation.................................................................................35
7
Informed consent procedures ............................................................................................35
8
Visit schedule and assessments .........................................................................................36
8.1
Screening ...............................................................................................................41
8.1.1
Information to be collected on screening failures.................................41
8.2
Subject demographics/other baseline characteristics.............................................41
8.2.1
PNH Clone Size (for patient eligibility)................................................41
8.3
Efficacy/Pharmacodynamics .................................................................................41
8.3.1
LDH measurement ................................................................................41
8.3.2
Hemoglobin and red blood cell.............................................................42
8.3.3
PNH cells (C3 deposition, PNH type III cells and clone size)..............42
8.3.4
Appropriateness of efficacy measurements ..........................................42
8.4
Safety.....................................................................................................................43
8.4.1
Laboratory evaluations..........................................................................43
8.4.2
Incidence of transfusions.......................................................................44
8.4.3
Electrocardiogram (ECG) .....................................................................44
8.4.4
Pregnancy and assessments of fertility .................................................44
8.4.5
Other safety evaluations........................................................................45
8.4.6
Appropriateness of safety measurements..............................................45
8.5
Additional assessments..........................................................................................46
8.5.1
Pharmacokinetics ..................................................................................46
8.5.2
Biomarkers............................................................................................46
8.6
Use of residual biological samples ........................................................................47
9
Study discontinuation and completion ..............................................................................48
9.1
Discontinuation......................................................................................................48
9.1.1
Discontinuation of study treatment .......................................................48
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9.1.2
Withdrawal of informed consent...........................................................49
9.1.3
Lost to follow-up...................................................................................50
9.1.4
Study stopping rules..............................................................................50
9.1.5
Early study termination by the sponsor.................................................50
9.2
Study completion and post-study treatment ..........................................................50
10 Safety monitoring and reporting........................................................................................51
10.1
Definition of adverse events and reporting requirements......................................51
10.1.1
Adverse events ......................................................................................51
10.1.2
Serious adverse events ..........................................................................53
10.1.3
SAE reporting........................................................................................53
10.1.4
Pregnancy reporting ..............................................................................54
10.1.5
Reporting of study treatment errors including misuse/abuse................54
10.2
Additional Safety Monitoring................................................................................55
10.2.1
Liver safety monitoring.........................................................................55
10.2.2
Renal safety monitoring........................................................................55
11 Data Collection and Database management......................................................................55
11.1
Data collection.......................................................................................................55
11.2
Database management and quality control............................................................56
11.3
Site monitoring ......................................................................................................56
12 Data analysis and statistical methods ................................................................................57
12.1
Analysis sets ..........................................................................................................57
12.2
Subject demographics and other baseline characteristics......................................57
12.3
Treatments .............................................................................................................58
12.4
Analysis of the primary endpoint(s) ......................................................................58
12.4.1
Definition of primary endpoint(s).........................................................58
12.4.2
Statistical model, hypothesis, and method of analysis..........................58
12.4.3
Handling of missing values/censoring/discontinuations.......................58
12.5
Analysis of secondary endpoints ...........................................................................58
12.5.1
Handling of missing values/censoring/discontinuations.......................59
12.5.2
Safety endpoints....................................................................................59
12.5.3
Pharmacokinetics ..................................................................................61
12.6
Analysis of exploratory endpoints.........................................................................62
12.7
Interim analyses.....................................................................................................62
12.8
Sample size calculation..........................................................................................63
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12.8.1
Primary endpoint(s)...............................................................................63
13 Ethical considerations and administrative procedures ......................................................63
13.1
Regulatory and ethical compliance........................................................................63
13.2
Responsibilities of the investigator and IRB/IEC..................................................63
13.3
Publication of study protocol and results...............................................................63
13.4
Quality Control and Quality Assurance.................................................................64
14 Protocol adherence ............................................................................................................64
14.1
Protocol Amendments ...........................................................................................64
15 References .........................................................................................................................65
16 Appendices ........................................................................................................................66
16.1
Appendix 1: Clinically notable laboratory values and vital signs .........................66
16.2
Appendix 2: Liver Event Definitions and Follow-up Requirements.....................67
16.3
Appendix 3: Specific Renal Alert Criteria and Actions ........................................69
List of tables
Table 2-1
Objectives and related endpoints ..........................................................20
Table 6-1
Investigational and control drug............................................................30
Table 6-2
Prohibited medication ...........................................................................33
Table 6-3
Blinding and unblinding plan................................................................34
Table 8-1
Assessment Schedule ............................................................................38
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................55
Table 12-1
Non-compartmental pharmacokinetic parameters ................................61
Table 16-1
Liver Event Definitions.........................................................................67
Table 16-2
Actions required for Liver Events.........................................................67
Table 16-3
Exclusion of underlying liver disease ...................................................68
Table 16-4
Specific Renal Alert Criteria and Actions.............................................69
Table 16-5
Follow-up of renal events......................................................................70
List of figures
Figure 3-1
Study design..........................................................................................22


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List of abbreviations
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AP
complement alternate pathway
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
bid
Bis In Die (Twice daily)
BMI
Body Mass Index
BP
Blood pressure
CFR
U.S. Code of Federal Regulations
CK
creatinine kinase
CMO&PS
Chief Medical Office & Patient Safety
COA
Clinical Outcome Assessments
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-Reactive Protein
CSR
Clinical Study Report
DAR
dose administration record 
DHT
Dihydrotestosterone
CV
coefficient of variation
DNA
Deoxyribonuclein acid
ECG
Electrocardiogram
EDC
Electronic Data Capture
EOS
End of study
EoT
End of treatment
eSource
Electronic Source
FB
Factor B
FDA
Food and Drug Administration
FDP
Fibrinogen degradation products
FAS
Full Analysis Set
FSH
Follicule-Stimulating hormone
GPI
Glycosylphosphatidylinositol
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
h
hour
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
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HV
Healthy volunteers
IA
Interim analysis
IB
Investigator Brochure 
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine device
IUS
Intrauterine system
LDH
lactate dehydrogenase
LH
Luteinizing hormone
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
ng
Nanogram(s)
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PNH
Paroxysmal nocturnal hemoglobinuria
PRO
Patient reported outcome 
PT
prothrombin time
q.d.
Quaque die (once a day)
QTcF
Fridericia QT correction formula
REP
Roll-over extension program
RBC
red blood cell(s)
SAE
serious adverse event
sCR
serum creatinine
SD
standard deviation
SoC
Standard of Care
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TSH
Thyroid stimulating hormone
ULN
upper limit of normal
WBC
white blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent
WOCBP
Women of child bearing potential
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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 
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.
Patient
An individual with the condition of interest
Personal Data
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 
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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 
consent (WoC)
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
CLNP023X2204
Full Title
A multi-center, randomized, open-label, efficacy, safety, pharmacokinetics 
and pharmacodynamics study, assessing multiple LNP023 doses in adult
patients with paroxysmal nocturnal hemoglobinuria and active hemolysis
Brief title
Efficacy study, assessing multiple LNP023 doses in PNH patients
Sponsor and Clinical 
Phase
Novartis
II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The study purpose is to evaluate the efficacy and safety of LNP023 in PNH 
patients with active hemolysis, without concomitant complement inhibition 
(e.g., eculizumab). Blockade of the alternative complement pathway with 
oral LNP023 has the potential to prevent both intra- and extravascular 
hemolysis, and therefore, may offer therapeutic benefits compared with 
eculizumab therapy. Additionally, the oral route of administration offers 
patients an advantage compared to the intravenous administration of 
eculizumab.
Primary Objective(s) 
To assess the effect of LNP023 on the reduction of PNH associated 
hemolysis.
Secondary 
Objectives
To assess the dose-response effect of LNP023 on the reduction of PNH 
associated hemolysis.
To assess the effect of LNP023 on markers of intravascular and 
extravascular hemolysis.
To assess the safety and tolerability of LNP023 in PNH patients.
To assess the plasma pharmacokinetics (PK) of LNP023
To assess the effect of LNP023 on markers associated with risk of 
thrombosis.
Study design
This is a non-confirmatory, randomized, open-label, multicenter, efficacy, 
safety, pharmacokinetic and pharmacodynamic
study assessing 
 
LNP023 doses, in adult PNH patients with active hemolysis.
Total study duration from screening until EOS is approximately 2.5 years. 
This three-period study includes: a screening phase of up to 8 weeks, a 
baseline visit, Day 1 (first day that the investigational drug is given), a 4-week 
treatment period of LNP023 at the first dose in the assigned sequence 
(Period 1), an 8-week treatment period at the second dose in the assigned 
sequence (Period 2), an approximately 2 year extension Period 3. Patients 
joining the roll-over extension program (REP) (Section 9.2) will transition into 
the REP immediately after completion of Period 3. Patients not joining the 
REP after period 3 will undergo a taper down period of 2 weeks, an end of 
study visit one week after last LNP023 administration, and a safety follow up 
call performed 30 days post end of treatment (last LNP023 dose).
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Patient will be randomized to sequence 1 or sequence 2 in ratio 1:1.
Population
Ten adult, male and female PNH patients with active hemolysis, are 
planned to complete the study. Patients who drop out the study for reasons 
other than safety or efficacy can be replaced.
Key Inclusion 
criteria

Male and female patients at least 18 years old at baseline.

Diagnosis of active 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).

LDH values > 1.5 x upper limit of the normal range (ULN) for at least
3 measurements over a maximum of 8 weeks prior to Day 1 (Screening,
baseline or medical history data acceptable).

Hemoglobin level < 10.5 g/dL at Baseline.

For Period 3 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.

Vaccinations against N. meningitidis, S. pneumoniae and H. influenzae
is required at least 4 weeks prior to first dosing with LNP023 (existing
vaccinations should provide effective titers at time of LNP023 treatment
start). If LNP023 treatment has to start earlier than 4 weeks post
vaccination, prophylactic antibiotic treatment must be initiated.
Key Exclusion 
criteria

Patients treated with eculizumab or any other complement inhibitor less
than 3 months prior to study Day 1

Known or suspected hereditary or acquired complement deficiency.

History of currently active primary or secondary immunodeficiency.

History of splenectomy.

History of bone marrow/ hematopoietic stem cell or solid organ
transplants (e.g., heart, lung, kidney, liver).

Evidence of malignant disease, or malignancies diagnosed within the
previous 5 years.

Patients with laboratory evidence of bone marrow failure (reticulocytes
< 60x10E9/L, or platelets < 50x10E9/L, or neutrophils < 1x10E9/L)
verified both at screening and baseline.
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
History of recurrent meningitis, history of meningococcal infections
despite vaccination, as verified at both screening and baseline.

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.

A positive HIV, Hepatitis B (HBV) or Hepatitis C (HCV) test result at
screening.

Patients on immunosuppressive agents such, as but not limited to,
cyclosporine, 
tacrolimus, 
mycophenolate 
or 
mycophenolic
acid, cyclophosphamide, methotrexate or IV immunoglobulins, 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 unless on a stable dose for at least 4 weeks
before randomization. Severe concurrent co-morbidities not amenable
to active treatment; e.g., patients with severe kidney disease (CKD stage
4, dialysis), advanced cardiac disease (NYHA class IV), severe
pulmonary arterial hypertension (WHO class IV), or unstable thrombotic
event, as judged by the investigator, both at screening and 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.

History of hypersensitivity to the study treatment or its excipients or to
drugs of similar chemical classes.

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 during dosing and for 1 week after stopping of
investigational drug.
Study treatment
LNP023
Efficacy 
assessments
Key efficacy assessments:

Serum LDH

Hemoglobin concentration and red blood cell counts
Pharmacodynamic 
assessments
PNH cells:

C3 deposition

PNH type III cells

PNH clone size
Pharmacokinetic 
assessments 
The PK of LNP023 in the treated population will primarily be characterized 
by following parameters: Cmax, Tmax, Ctrough, AUClast and or AUCtau. 
Additional parameters may be calculated
Key safety 
assessments
Adverse event monitoring, physical examinations, ECG, monitoring of 
laboratory markers in blood and urine, number of transfusions, patient diary


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Other assessments 
Data analysis
The primary efficacy variable for assessing the effect of LNP023 is response 
rate; where a patient will be considered a responder if LDH is below ULN or 
the percentage reduction from baseline in serum LDH is at least 60% at any 
time up to and including week 12 for that patient. In a proof of concept 
paradigm, a positive sign of efficacy is when the estimated response rate is 
at least 50%. For example, this criterion will be met when 5 out of 10 patients 
are considered responders.
The same mixed modelling approach will be used for other continuous 
response variables. Skewed data will be transformed in order to meet 
underlying normality and homoscedasticity assumptions. In case early 
escalation gives data only to two weeks for some patients, the modelling will 
be adjusted to suit.
Key words
PNH, hemolysis, LDH, hemoglobin
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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).
Hemolysis in PNH is due to complement-dependent intravascular hemolysis, which normally 
is blocked by CD59 (protectin), preventing the final stage of complement assembly. Without 
the glycosylphosphatidylinositol (GPI) anchor, expression of CD59 on the cell surface is 
reduced allowing for C5b-9 formation and erythrocyte lysis (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.
Eculizumab is an approved anti-C5 antibody therapy that targets intravascular hemolysis, used 
in PNH patients and is considered the standard of care (SoC) where available. However:
a. it is not available for all PNH patients in all countries; furthermore, in those countries
where it is marketed, access to treatment may be limited; and
b. it has been demonstrated that approximately 40% of the patients treated with
eculizumab still exhibit signs of active hemolysis based on consistently elevated
lactate dehydrogenase (LDH) levels (Peffault de Latour et al 2015).
Due to its mode of action, almost no patient treated with eculizumab achieves normal 
hemoglobin 
levels, 
even 
in 
the 
absence 
of 
any 
bone 
marrow 
failure 
(Peffault de Latour et al 2015). The ongoing hemolysis is a burden for the patients leading to 
severe anemia, iron deficiency, and pain due to vasospasm and fatigue.
LNP023 is a novel oral small molecular weight compound that inhibits factor B (FB) of the
complement alternative pathway (AP). Factor B (FB) is a key protease of the complement 
alternative pathway (AP) that can bind to C3b to form C3bB which is further cleaved to C3bBb
representing the active C3 convertase. Blockade of the FB with oral LNP023 has the potential
to prevent both intra- and extravascular hemolysis, and therefore, may offer therapeutic benefits 
compared with eculizumab therapy. Additionally, the oral route of administration may offer 
patients an advantage compared to the intravenous administration of eculizumab.
In preclinical studies, LNP023 has excellent efficacy and a good safety profile. 
For further details, please refer to the Investigator Brochure.
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1.2
Purpose
The study purpose is to evaluate the efficacy and safety of LNP023 in PNH patients with active 
hemolysis, without concomitant complement inhibition (e.g., eculizumab).
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the effect of LNP023 on the 
reduction of PNH associated 
hemolysis.

Percentage of patients with 60% reduction in LDH 
or LDH below upper limit of normal (ULN) up to 12 
weeks of treatment.
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess the dose-response effect of 
LNP023 on the reduction of 
PNH associated hemolysis.

LDH, and other relevant parameters such as but 
not restricted to hemoglobin and red blood cell 
count up to week 4 for each dose.

To assess the effect of LNP023 on 
markers of intravascular and 
extravascular hemolysis.

Potentially all of, but not restricted to,

total and free hemoglobin,

carboxyhemoglobin,

reticulocytes,

C3 fragment deposition,

haptoglobin,

bilirubin,

red blood cell count,

platelet counts,

ferritin,

PNH type III red blood cells (RBC)

PNH clone size

To assess the safety and tolerability of 
LNP023 in PNH patients.

All safety parameters including: blood chemistry, 
hematology, urinalysis, ECG evaluation, vital 
signs, adverse events, transfusions, patient diary.

To assess the plasma 
pharmacokinetics (PK) of LNP023

Non-compartmental analysis of LNP023 PK 
parameters including, but not limited to Cmax, 
AUC, Ctrough and Tmax.

To assess the effect of LNP023 on 
markers associated with risk of 
thrombosis.

Assessments including, but not limited to, 
fibrinogen, prothrombin time, activated partial 
thromboplastin time, thrombin time, fibrin D-dimer 


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Objective(s)
Endpoint(s)
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)
3
Study design
This is a non-confirmatory, randomized,
open-label,
multicenter, efficacy, safety, 
pharmacokinetics and pharmacodynamics study assessing 
 LNP023 doses in adult PNH 
patients with active hemolysis.
At least 10 patients will be included in the study, as replacement can occur if any patient 
withdraws for reasons unrelated to safety or lack of efficacy.
Active hemolysis is defined by an LDH value ≥1.5x ULN. At least 3 pre-treatment LDH 
measurements each separated by at least a week over a maximum of 8 weeks prior to study Day 
1 of the study should be ≥1.5x ULN , in order to include the patients in the study. LDH medical 
history data can be taken into consideration for inclusion purposes but at least one value must
be from the study central laboratory. If medical history data is not available, the screening 
period may consist of several visits for LDH verification.
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Total study duration from screening until EOS is approximately 28 months. This three-period 
study includes:

a screening phase of up to 8 weeks,

a baseline visit,

Day 1 (first day that the investigational drug is given),

a 4-week treatment period of LNP023 at the first dose in the assigned sequence
(Period 1),

an 8-week treatment period at the second dose in the assigned sequence (Period 2),

an approximately 2 year treatment extension period for patients who respond to the
LNP023 treatment (Period 3)

taper down period of 2 weeks applicable only for patients discontinuing LNP023
treatment (Week 13 for non-responders or Week 109 for responders).

an EoS visit that will take place 1 week after the last LNP023 administration for
patients not joining the roll-over extension program (REP). For patients joining the
REP (Section 9.2), the last treatment visit will become the EoS visit.
A safety follow-up call 30 days after the last administration of LNP023 will be performed for 
patients not joining the REP.
Figure 3-1
Study design
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Patients will be randomized to sequence 1 or sequence 2 in ratio 1:1.
Subjects who meet the eligibility criteria at screening will continue to randomization and 
baseline evaluations. All baseline safety evaluation results must be available prior to 
randomization and dosing (note: local LDH levels are acceptable for the purpose of confirming 
eligibility prior to randomization). Local laboratories may be used to confirm eligibility of the 
patient at baseline, however, all baseline samples should also be sent to central laboratory for 
analysis. Baseline visits can be conducted on the same day as the last screening visit, in case 
the last screening visit is not more than 7 days prior to Day 1. All baseline assessments need to 
be performed at this time.
Pharmacokinetic, safety and other study assessments will be conducted according to the study 
schedule (see corresponding sections). Safety assessments will include physical examinations, 
ECGs, vital signs, standard clinical laboratory evaluations (hematology, blood chemistry, and 
urinalysis), adverse event and serious adverse event monitoring.
All patients need to complete vaccinations against N. meningitidis, S. pneumoniae and 
H. influenzae at least 4 weeks prior to starting LNP023 treatment. 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. However, if
LNP023 treatment has to start earlier than 4 weeks post-vaccination, prophylactic antibiotic
treatment must be initiated (Section 6.6.2). In addition, to reduce risk of infection, antibiotics
will be required for patients with any sign of infection.
Body temperature should be measured daily in Period 1 and Period 2 and at minimum at the 
time of symptoms of infection during treatment Period 3. A diary will be completed by the 
patient to record, amongst other data, elevation of body temperature on days when no study 
visit is planned. The investigator shall review diaries at every visit. Patients will be instructed 
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to contact their physician immediately if body temperature rises to >38.3°C. For details, please 
refer to Section 6.6.2.
Please refer to the Assessment Schedule for details regarding assessments to be performed.
4
Rationale
4.1
Rationale for study design
The design of this study addresses the primary objective of assessing the effect of LNP023 on 
PNH associated hemolysis and takes into account the rarity of this disease and the objective 
nature of the measurement.
The main key study design elements are described below:

This is a non-placebo-controlled study since the absence of a placebo response for
LDH in this patient population has been demonstrated (Hillmen et al 2006), and is
expected given the nature of the primary outcome measure (LDH). In addition, when
considering available treatment options, restricting PNH patients to placebo treatment
may be considered unethical.

Treatment extension of approximately 2 years for patients responding to LNP023
treatment was included to assure treatment of the patients who otherwise have limited
treatment options

The taper down period of 2 weeks was included to mitigate potential risk of increased
hemolysis after LNP023 discontinuation

Treatment comparisons within patient are included with the advantage that within
patient variation is assumed to be less than between patients
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4.2
Rationale for dose/regimen and duration of treatment
4.2.1
Dose regimen and dose span
4.2.2
Minimal treatment duration of each dose 
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Not applicable
4.4
Purpose and timing of interim analyses/design adaptations
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4.5
Risks and benefits
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 Investigator’s Brochure. The most relevant risks are described below. A 
complete list of toxicological findings is available in the Investigator’s Brochure. 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 5.2 (Exclusion Criteria).
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4.5.1
Blood sample volume
Less than 500 mL of blood is planned to be collected from each study patient during 19 weeks
of Period 1 and Period 2 of the study. Up to approximately 450 mL is planned to be collected  
from each study patient during approximately 2 years of Extension Period 3. Total maximum 
blood volume collected during the study will not exceed 950 mL.
Additional samples may be required for safety monitoring. Timings of blood sample collection 
are outlined in the Assessment schedule. A summary blood log is provided in the Site 
Operations Manual (SOM). Instructions for all sample collection, processing, storage and 
shipment information are available in laboratory manual.
See the section on the potential use of residual samples.
4.5.2
Rationale for Public Health Emergency mitigation procedures
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate.
5
Population
Ten adult, male and female PNH patients with active hemolysis, are planned to complete the 
study. 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 following 
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.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female patients at least 18 years old at baseline.
3. Diagnosis of active 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).
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4. LDH values > 1.5 x upper limit of the normal range (ULN) for at least 3 measurements
over a maximum of 8 weeks prior to Day 1 (Screening, baseline or medical history data
acceptable).
5. Hemoglobin level < 10.5 g/dL at Baseline.
6. For Period 3 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.
7. Vaccinations against N. meningitidis, S. pneumoniae and H. influenzae is required at least
4 weeks prior to first dosing with LNP023 (existing vaccinations should provide effective
titers at time of LNP023 treatment start). If LNP023 treatment has to start earlier than
4 weeks post vaccination, prophylactic antibiotic treatment must be initiated.
8. Able to communicate well with the investigator, to understand and comply with the
requirements of the study.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study:
1. Participation in any other investigational drug trial or use of other investigational drugs at
the time of enrollment, or within 5 elimination half-lives of enrollment, or within 30 days,
whichever is longer; or longer if required by local regulations.
2. Patients treated with eculizumab or any other complement inhibitor less than 3 months
prior to study Day 1
3. Known or suspected hereditary or acquired complement deficiency.
4. History of currently active primary or secondary immunodeficiency.
5. History of splenectomy.
6. History of bone marrow/ hematopoietic stem cell or solid organ transplants
(e.g. heart, lung, kidney, liver).
7. Evidence of malignant disease, or malignancies diagnosed within the previous 5 years.
8. Patients with laboratory evidence of bone marrow failure (reticulocytes < 60x10E9/L, or
platelets < 50x10E9/L, or neutrophils < 1x10E9/L) verified both at screening and baseline.
9. History of recurrent meningitis, history of meningococcal infections despite vaccination,
as verified at both screening and baseline.
10. 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.
11. A positive HIV, Hepatitis B (HBV) or Hepatitis C (HCV) test result at screening.
12. Patients on immunosuppressive agents such, as but not limited to, cyclosporine,
tacrolimus, mycophenolate or mycophenolic acid, cyclophosphamide, methotrexate or
IV immunoglobulins, 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.
13. Systemic corticosteroids unless on a stable dose for at least 4 weeks before randomization.
14. Severe concurrent co-morbidities not amenable to active treatment; e.g., patients with
severe kidney disease (CKD stage 4, dialysis), advanced cardiac disease (NYHA class
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event, as judged by the investigator, both at screening and baseline (unless baseline was 
skipped).
15. 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.
16. History of hypersensitivity to the study treatment or its excipients or to drugs of similar
chemical classes.
17. Female patients who are pregnant or breastfeeding, or intending to conceive during the
course of the study.
18. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 1 week after stopping of investigational drug.
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.

Use or oral (estrogene 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 below 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 the 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 Informed Consent Form (ICF).
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential. Refer to Section 8.4.4 (Pregnancy and Assessments of 
Fertility).
No additional exclusions may be applied by the investigator, in order to ensure that the study 
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6
Treatment
6.1
Study treatment
Patients will receive study medication at study center for days when visits are planned and at 
home during remaining study days. 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 SOM.
As per Section 4.5.2, 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, and 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.
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational/ 
Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Design
Sponsor
(global or local)
6.1.2
Additional study treatments
No additional treatment beyond investigational drug are included in this trial.
6.1.3
Treatment arms/group
Subjects will be randomized at baseline to sequence 1 or sequence 2.
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6.2
Other treatment(s)
6.2.1
Concomitant therapy
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 medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
in the specific case report form (CRF) page.
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 the Sponsor medical monitor before 
enrolling a patient or allowing a new medication to be started. If the patient is already enrolled, 
contact the Sponsor to determine if the patient should continue participation in the study.
6.2.1.1
Vaccinations
All patients need to complete vaccinations against N. meningitidis, S. pneumoniae and 
H. influenzae at least 4 weeks prior to starting LNP023 treatment. Vaccinations 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.
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. 
6.2.1.2
Prophylactic antibiotics
In case LNP023 treatment has to start earlier than 4 weeks post-vaccination, prophylactic 
antibiotic treatment must be initiated. In addition, to reduce risk of infection, antibiotics will be 
required for patients with any sign of infection (see Section 6.6.2).
6.2.1.3
Permitted concomitant therapy requiring caution and/or action
LNP023 has been shown to have a weak inhibition potential for the liver uptake transporter 
OATP1B1 and respective calculations revealed that the exposure (AUC) of sensitive substrates 
may be increased by about 1.25 fold. It is therefore recommended to use respective co-
medications with a narrow therapeutic index with caution.
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As LNP023 is also an OATP1B1/3 substrate, co-administration with strong inhibitors may 
potentially lead to minor exposure increase (<1.5 fold) for LNP023.
6.2.2
Prohibited medication
Use of the medications displayed in the table below is NOT allowed.
The investigator should consult with Novartis medical expert prior treating a patient with this 
type of co-medication.
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Table 6-2
Prohibited medication
Medication
Prohibited period
Action to be taken
6.2.3
Rescue medication
If required as per judgment of the Investigator, another medication targeting underlying 
pathophysiology of the disease might be used as a rescue medication. Please refer to 
Section 6.6.2 for recommended handling of adverse events (AE).
6.2.4
Restriction for study subjects
For the duration of the study, the subjects should be informed and reminded of the restrictions 
outlined in this section:

Need to adhere to assessment schedule and visit window

Body temperature measurement

Intake of study medication and recording any missing dosages in the patient diary

Using contraception as specified in Section 5.2
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6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
The subject number assigned to a subject at screening remains the unique identifier for the 
subject throughout the study. For information on subject
numbering, please see 
‘Subject numbering’ section in the Site Operations Manual.
6.3.2
Treatment assignment, randomization
Treatment sequence assignment will be blinded and randomized.  Following randomization of 
the patient, study will be open-labelled. 
6.4
Treatment blinding
Following blinded random assignment of treatment sequence to patient, treatment will be open 
to subjects, investigator staff, persons performing the assessments, and the CTT.
Table 6-3
Blinding and unblinding plan
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
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the validity of the study. The subject must also be instructed to contact the investigator if he/she 
is unable for any reason to take the study treatment as prescribed. Compliance will be assessed 
by the investigator and/or study personnel at each visit using capsule counts and information 
provided by the subject. This information should be captured in the source document at each 
visit. All study treatment dispensed and returned must be recorded in the Drug Accountability 
Log.
6.6.2
Recommended treatment of adverse events
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, nausea, photophobia, 
bone pain) and to measure the body temperature daily in study Period 1 and 2 and at minimum 
at the times of symptoms of infection in Period 3. 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 triage.
In case of a suspected infection, patients should either be admitted for emergency evaluation or 
empirically treated with oral fluoroquinolone plus amoxicillin/clavulanate (or plus clindamycin 
if penicillin allergic), unless fluoroquinolone prophylaxis was used before fever developed 
(Flowers et al 2013).
6.6.3
Randomization list
Randomization list will be provided to relevant study personnel of clinical centers participating 
in the study.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
A unique medication number is printed on the study medication label.
As per the treatment assigned to the subject, investigator staff will select the study treatment to 
dispense to the subject. The study medication has a 2-part label (base plus tear-off label), 
immediately before dispensing the package to the subject, site personnel will detach the outer 
part of the label from the package and affix it to the subject’s source document.
Each study site will be supplied with study drug in packaging as described under the 
investigational and control drugs section.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject's representative(s) 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 agreement by 
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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 in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). 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.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
Male subjects must 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.
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
Refer to the Site Operations Manual for a complete list of ICFs included in this study.
8
Visit schedule and assessments
Assessment schedule lists all of the assessments and indicates with an “X”, the visits when they 
are performed. All data obtained from these assessments must be supported in the subject’s 
source documentation.
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 9.1 for guidance in case of treatment and/or 
study discontinuation.
As per Section 4.5.2, 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, 
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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
Baseline14
Visit Numbers1
1
2
101 102 103 104
106
201 202
204
205 10
8
15
22
36
43
71
85
±1
±1
±1
±1
±1
±2
±2
Time (post-dose)
-
-
-
-
-
-
pre-
dose
0.25h 1h 2h 4h 6h
-
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 
S
Demography
X
Randomization3
X
Pregnancy test 4
X
X
X
X
Study drug5
Physical Examination
S
S
S
S
S
S
S
S
S
S
Body height and weight
X
Vital signs6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG6
X
X
X
X
X
X
X
X
X
Hematology6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis6
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
Hormones6
X
X
X
X
Incidence of transfusion
PK blood collection6
X
X
X
X
X
X
X
X
X
X9
X9
X9
X9
X9
X9
X
X
X
X
X
X
X
X
X
X
PNH clone size7
X
PNH cells6, 12
X
X
X
X
X
Patient temperature and 
dosing diary
Adverse Events
Concomitant medications
Comments
Study completion 
Treatment 2
Treatment
X
X
X
X
X
X
X
29
57
±1
±1
±1
X 
Days
-56 to -4
-3 to -1
1
2
16
Pre-Treatment
Treatment 1
Treatment
105 2
107
203
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EOS
EOS
Visit Numbers1 301 302 303 304 305 306 307 308 309 310 311
312
113 141 169 197 225 253 281 309 337 365 393
421
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Visit Numbers1 313 314 315 316 317 318 319 320 321 322 323 324 13
401
402
499 11
449 477 505 533 561 589 617 645 673 701 729
757
92 or 764 99 or 771
106 or 778 15
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±45
±2
±2
±3
X
X
X
X
X
X
X
X
X
X
X
X
X
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
X 16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 16
X
Epoch
Extension Treatment 3
Visit Name
Treatment
Extension Year 1
Down-titration
Days
Extension Year 2
Days
Informed consent
ECG6
Medical history/current medical 
Vaccinations
Hepatitis and HIV 
Demography
Randomization3
Pregnancy test 4
Study drug5
X
Physical Examination
Body Weight
Vital signs6
Hematology6
Clinical Chemistry6
Urinalysis6
Markers of thrombosis6
Hormones6
Incidence of transfusion
X
PK blood collection6
PNH clone size7
PNH cells6, 12
Patient temperature and dosing diary
X
Adverse Events
X
Concomitant medications
X
Comments
X
Study completion 
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5 LNP023 to be administered daily b.i.d
6 To be completed pre-LNP023 dose, if applicable.
7 Done only if no medical data is available that could be used for inclusion purpose
9 Samples collected only if patient did not complete PK sample collection at day 16
10Start of LNP023 down-titration for patients who do not participate in extension period 3
S Assessment to be recorded in the source documentation only
1 Visit structure given for internal programming purpose only
2 Visit only applicable for Sequence 1 and 2 patients who do not have 40% reduction in LDH level at day 15
3 Randomization should only occur once eligibility is confirmed.
4 Serum pregnancy test required at screening and EOS, urine pregnancy test at further time points.
15 For patients not joining REP
16 Assessments to be performed only for patients joining REP and complete study at EoT visit
12 C3 deposition, clone size, type III PNH cells
13 Start of LNP023 down-titration for patients who discontinue LNP023 treatment. EoS visit for patients joining REP
14 Baseline visits can be conducted on the same day as the last screening visit, if the last screening visit is not more than 7 days prior to Day 1
11 A safety follow-up call 30 days after last treatment administered will be performed for patients not joining REP
X Assessment to be recorded in the clinical database or received electronically from a vendor
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8.1
Screening
In the case where a safety laboratory assessment at screening (and/or baseline) is outside of the 
range specified in the exclusion criteria, the assessment may be repeated twice prior to 
randomization. If the repeat value remains outside of the specified ranges, the subject must be 
excluded from the study. 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.
8.1.1
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on the 
screening phase disposition page. The demographic information, informed consent, and reason 
for screen failure must also be completed for screen failure patients. No other data will be 
entered into the clinical database for patients who are screen failures, unless the patient 
experiences a serious adverse event during the screening phase (see Section 10.1.3 for reporting 
details).
8.2
Subject demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all subjects include: age, 
gender, race, ethnicity, relevant medical history/current medical condition present before 
signing informed consent where possible, diagnoses and not symptoms will be recorded.
Hepatitis and HIV tests will be performed for samples collected at screening.
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
8.2.1
PNH Clone Size (for patient eligibility)
If no historic data is available a flow cytometry assay will be performed at screening 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.
8.3
Efficacy/Pharmacodynamics
8.3.1
LDH measurement
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 measured as a part of the study 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 time points when clinical chemistry is analyzed. 
All the LDH values and local normal ranges collected during screening should be recorded in 


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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.
8.3.2
Hemoglobin and red blood cell
Hemoglobin and red blood count will be assessed as a part of the standard central laboratory 
hematology panel at the timepoints specified in the Assessment Schedule.
8.3.3
PNH cells (C3 deposition, PNH type III cells and clone size)
Accumulation of C3 fragments on red blood cells make them prone to phagocytosis causing 
extravascular hemolysis. Level of C3 deposition on red blood cells will be quantified using flow 
cytometry. In addition both PNH type III cells and clone size will be evaluated. 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 central 
laboratory manual. Detailed descriptions of the assays will be included in the bioanalytical data 
reports.
8.3.4
Appropriateness of efficacy measurements
The pathophysiology of PNH is directly linked to the complement-mediated destruction of the 
susceptible PNH red blood cells, which results in intravascular hemolysis, the primary clinical 
manifestation in all PNH patients. Eligibility for this trial therefore requires both, active 
hemolysis and anemia measured and confirmed by respective laboratory markers (i.e., lactate 
dehydrogenase (LDH) ≥1.5 ULN, hemoglobin < 10.5 g/dL). Treatment with LNP023 is 
expected to mitigate intravascular hemolysis, as measured by LDH, number of red blood cells 
and reticulocytes, level of hemoglobin, bilirubin and haptoglobin. Clinically relevant reduction 
in intravascular hemolysis leads to measurable changes in the parameters mentioned and may 
result in increased transfusion avoidance, a reduced need for RBC transfusion and less anemia 
related symptoms such as fatigue.


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8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to Section 10.1.1.
Assessment
Specification
Physical examination
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, 
heart, abdomen, back, lymph nodes, extremities, vascular, and 
neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
A short physical exam will include the examination of general appearance 
and vital signs.
Complete physical examination should be performed at baseline, EoS 
and any other visit deemed necessary by Physician (triggered by safety 
results).
Short examination will be performed at all the other visit as per 
Assessment Schedule.
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are 
present prior to signing informed consent must be included in the Medical 
History part of the CRF. Significant findings made after first administration 
of investigational drug which meet the definition of an Adverse Event 
must be recorded on the Adverse Event section of the CRF.
Vital signs
Vital signs include blood pressure (BP), pulse measurements, and body 
temperature. After the patient has been sitting for five minutes, with back 
supported and both feet placed on the floor, systolic and diastolic blood 
pressure will be measured three times using an automated validated 
device, with an appropriately sized cuff.
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram 
(kg) in indoor clothing, but without shoes) will be measured.  
8.4.1
Laboratory evaluations
8.4.1.1
Clinical Chemistry
Sodium, potassium, creatinine, urea, uric acid, chloride, albumin, calcium, alkaline phosphatase, 
total bilirubin, ferritin, CRP, LDH, GGT, AST, ALT, CK, glucose, total cholesterol, and 
triglycerides data will be collected at timepoints specified in Assessment Schedule.

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 level will be measure at selected timepoints when blood is collected for clinical
chemistry (see SoM for details): 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.


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8.4.1.2
Blood hormone levels
The hormones analyzed are: T3, T4, TSH, reversed T3, testosterone, FSH, LH and DHT. 
8.4.1.3
Hematology
Total hemoglobin, free hemoglobin (at selected timepoints, please see SoM for details),
carboxyhemoglobin, haptoglobin, hematocrit, red blood cell (RBC) count, reticulocyte count, 
white blood cell (WBC) count with differentials and platelet count will be measured. 
8.4.1.4
Markers of thrombosis
Coagulation testing including prothrombin time (PT), reported as INR, activated partial 
thromboplastin time (aPTT), D-dimer, fibrinogen, and thrombin clotting time (at selected 
timepoints, please see SoM for details)  will be measured.
8.4.1.5
Urinalysis
Dipstick measurements for protein, blood, and WBC/leukocytes will be performed.
If dipstick measurement results are positive (abnormal), results will be captured. Microscopy 
must be assessed following an abnormal dipstick test with results captured and provided by 
central laboratory as per agreed data transfer specifications.
8.4.2
Incidence of transfusions
The number and volume of blood transfusions will be counted and recorded in the eCRF. 
The history of transfusions administered within one year before baseline and the number of 
transfusions until EoS visit will be recorded.
8.4.3
Electrocardiogram (ECG)
Below 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.
8.4.4
Pregnancy and assessments of fertility
Refer to Section 5.2 for criteria to determine women that are not of child bearing potential. 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source document. 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 results should be used to confirm 
reproductive status of female patients.


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8.4.5
Other safety evaluations
8.4.5.1
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 Period 1 and 2 of the study and at minimum at 
the time of symptoms of infection in Period 3 of the study. The investigator shall review the 
diary at every visit. 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 clinically significant abnormal values, these will be recorded in the AE CRF page 
(as per judgement of the investigator).
8.4.5.2
Clinical Outcome Assessments (COAs)
8.4.6
Appropriateness of safety measurements
Complement activation in PNH is manifested as chronic hemolysis that leads to the release of 
free hemoglobin and the subsequent depletion of nitric oxide. Consumption of nitric oxide leads 
to vaso-occlusion and platelet activation and results in the common morbidities seen in PNH, 
such as fatigue, dyspnea, recurrent abdominal pain, dysphagia, chest pain and pulmonary 
hypertension. More importantly, chronic hemolysis renders PNH patients at a greater risk of 
thrombotic events, renal insufficiency and other organ damage, and premature mortality. 
Historically, supportive care measures used in PNH, such as transfusions, anticoagulation or 
long-term use of steroids and pain medication, leave patients with a poor quality of life (QoL) 
and are associated with adverse events.
In preclinical and early clinical studies, LNP023 has excellent efficacy and a good safety profile. 
The important potential risks associated with LNP023 are mainly related to increased risk for 
infections which are mitigated by mandatory vaccinations against N. meningitidis, 
S. pneumoniae, and H. influenzae including recommendations for continued monitoring of
clinical signs and symptoms and respective antibiotic treatment recommendations.
Further information about the investigational drug can be found in the Investigator Brochure.
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8.5
Additional assessments
8.5.1
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.
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,ss, Tmax,ss, AUCtau,ss, Cmin,ss, T1/2 at days defined in the schedule. 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.
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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a patient occurs when study treatment is stopped earlier 
than the protocol planned duration. If possible taper-down should be implemented for patients 
who discontinue study treatment. 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 5.2)

Use of prohibited treatment as outlined in Table 6-2.

If a liver or renal event occurs, follow the Hepatotoxicity Clinical Safety Standard 
Guideline or Renal Toxicity Clinical Safety Guideline, outlined in Appendix 1 and 
Appendix 2 regarding discontinuation of study treatment.

Increases in QTcF to >500 ms or of >60 ms over baseline should be used as thresholds for 
patient discontinuation.

Unsatisfactory therapeutic effect- decision to be taken after consultation with Sponsor.
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 9.1.2, Withdrawal of Informed Consent). Where possible, patients 
who discontinue study treatment only should continue to return for study scheduled assessments.
If any patient discontinues study or study treatment with LNP023 they should be closely 
monitored for signs and symptoms of hemolysis.
The 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.


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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.
At a minimum, in abbreviated visits, the following data should be collected at clinic visits or 
via telephone/email contact:

new / concomitant treatments

AE / SAE.
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 9.1.3
(lost to follow-up).
9.1.1.1
Replacement policy
Patients can be replaced based on the case-by case after discussion with Sponsor in case the 
patient discontinued the study for a reason not related to safety or efficacy.
9.1.2
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 participate in the study anymore, 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 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.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed.
9.1.4
Study stopping rules
Novartis will review emergent safety reports on an ongoing basis to react as soon as there is a 
possibility that a stopping rule could apply. The Sponsor will review all SAE as individual cases 
and will also review summaries of non-serious AE for patterns and trends, and will first exclude 
any events determined to be clearly not related to LNP023 (e.g., SAE which occurred during 
the pre-treatment screening period, or disease-related SAE expected in the population under 
study). Enrollment in the study and dosing of affected patient(s) with LNP023 will be paused
pending a full safety review by Novartis Study Team if any of the following occurs during the 
study:

Three or more patients developing the same drug related SAE

OR two or more patients developing any life-threatening drug related SAE

OR one or more patient developing a fatal drug related SAE.
9.1.5
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. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible (provide instruction for contacting the 
subject, when the subject should stop taking drug, when the subject should come for a final 
visit) and treated as a prematurely withdrawn 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 or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Based on the benefit of LNP023 treatment observed in the ongoing phase II studies 
(CLNP023X2201 and CLNP023X2204), a roll-over extension program (REP), study 
CLNP023C12201B, has been implemented to ensure long-term post-trial access for all PNH 
patients completing any of the phase II or phase III studies with LNP023. Study patients who 
completed study treatment and who demonstrated benefit from LNP023 treatment will have the 
option to join this roll-over extension program.


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Study completion is defined as when the last subject finishes their study completion visit (EoT 
for patients joining the REP), 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.
Randomized and/or treated subjects not joining the REP should have a safety follow-up call 
conducted 30 days after last administration of study treatment. The information collected is kept 
as source documentation. All SAEs reported during this time period must be reported as 
described in Section 10.1.3 and the SoM. Documentation of attempts to contact the subject 
should be recorded in the source documentation.
Continuing care should be provided by the investigator and/or referring physician based on 
subject availability for follow-up.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the 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 findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2):
1. its severity grade

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression
of underlying illness (i.e. progression of the study indication) the assessment of causality
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a
lack of efficacy or progression of underlying illness are not caused by the trial drug, they
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underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject
3. its duration (start and end dates) or if the event is ongoing, an outcome of not
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which
seriousness criteria have been met
5. action taken regarding with study treatment. All adverse events must be treated
appropriately. Treatment may include one or more of the following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
6. its outcome:
a. not recovered/not resolved
b. recovered/resolved
c. recovering/resolving
d. recovered/resolved with sequelae
e. fatal, or unknown
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. Continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator Brochure (IB).
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
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10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the 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 the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in PNH

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last administration of study 
treatment must be reported to Novartis safety within 24 hours of learning of its occurrence. 
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investigator folder provided to each site. The 30 day safety follow up will be completed as a 
part of the REP for patients joining roll-over extension.
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 
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.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
10.1.4
Pregnancy reporting
Pregnancies
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 should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the LNP0223 and any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported.
Intact pregnancy should be followed up until 1 month until delivery.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, 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.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 


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collected and reported in the safety database irrespective of it being associated with an AE/SAE
within 24 hours of Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections.
10.2
Additional Safety Monitoring
Not applicable
10.2.1
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 Appendix 2 for complete definitions of liver events, information on required 
follow up and actions required.
Liver chemistry repeats should be performed using the local or central laboratory.
10.2.2
Renal safety monitoring
Please refer to Appendix 3 for complete definitions of renal events, information on required 
follow up and actions required.
Renal chemistry repeats should be performed using the local or central laboratory.
11
Data Collection and Database management
11.1
Data collection
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
Designated investigator staff will enter the data required by the protocol into the Electronic Case 
Report Forms (eCRF). The eCRFs have been built using fully validated secure web-enabled 
software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not be given 
access to the EDC system until they have been trained. Automatic validation programs check 
for data discrepancies in the eCRFs, allow modification and/or verification of the entered data 
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The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
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.
At the conclusion of a non-IRT study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused supplies to Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis or 
delegated CRO representative will review the protocol and data capture requirements 
(i.e. eSource DDE or eCRFs) with the investigators and their staff. During the study, Novartis 
employs several methods of ensuring protocol and GCP compliance and the quality/integrity of 
the sites’ data. The field monitor will visit the site to check the completeness of subject records, 
the accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical 
Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be available 
to assist the field monitor during these visits. Continuous remote monitoring of each site’s data 
may be performed by a centralized Novartis or delegated CRO, CRA organization. Additionally, 
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a central analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each 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 of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.
12
Data analysis and statistical methods
The study analysis will be conducted on all patient data at the time the trial ends. As this is a 
multi-period study, all listings will include both study day and period day, especially when early 
escalation entails moving into a period earlier than on the standard study day. Statistical 
summaries and figures will also be aware of the same distinction where relevant. 
Any data analysis carried out independently by any investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
For all analysis sets, patients will be analyzed according to the study treatments received.
The Full Analysis Set (FAS) comprises all patients that received any study drug.
The safety analysis set will also include all patients that received any study drug and hence is 
not referred to again.
The PK analysis set will include all patients 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.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data, including disease characteristics, will be listed and 
summarized descriptively by treatment sequence for the full analysis set.
Categorical data will be presented as frequencies by treatment sequence. For continuous data, 
mean, standard deviation, median, minimum, and maximum will be presented.
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Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and by preferred term, by treatment sequence for all patients.
12.3
Treatments
The full analysis set will be used for the analyses below. Categorical data will be summarized 
descriptively as frequencies. For description of continuous data, mean, standard deviation, 
median, minimum, and maximum will be presented.
The duration of exposure in days (including half days) to each dose of LNP023 will be 
summarized by means of descriptive statistics.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment sequence group.
12.4
Analysis of the primary endpoint(s)
12.4.1
Definition of primary endpoint(s)
The primary efficacy endpoint for assessing the effect of LNP023 is response rate, where a 
patient will be considered a responder if LDH is below ULN or the percentage reduction from 
baseline in serum LDH is at least 60% at any time up to and including Week 12 for that patient, 
whether or not 
12.4.2
Statistical model, hypothesis, and method of analysis
There is no statistical model for the primary endpoint apart from observing and counting success 
or failure for each patient. For the purposes of this study a positive sign of efficacy is when the 
estimated response rate is at least 50%. For example, this criterion will be met when at least 5 
out of 10 patients in the overall study, or 3 of 5 in one of the two Cohorts are considered 
responders.
12.4.3
Handling of missing values/censoring/discontinuations
For calculation of the success rate for the primary endpoint all patients enrolled in the study 
apart from those who were replaced for reasons other than safety or efficacy will be included 
in the denominator. 
12.5
Analysis of secondary endpoints
Assessment of plasma pharmacokinetics is a secondary endpoint but the analyses for it are 
described below in Section 12.5.3. Assessing the dose-response effect on LDH and other 
parameters associated with PNH associated hemolysis is the first secondary objective.
Mixed effect modelling will be performed for LDH. 
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Baseline LDH will be calculated as the average of the last three screening values prior to 
randomization. The subject term will be considered as random so as to allow recovery of 
between subject information.
The same mixed modelling approach will be used for other key continuous response secondary 
endpoint variables apart from LDH that are markers of intravascular and extravascular 
hemolysis, or are markers of thrombosis, as well as for PK parameters excluding Tmax (see 
Section 12.5.3 ). In these cases, except for PK parameters, the baseline covariate is the average 
of all pre-treatment values. 
Data may be transformed in order to meet underlying normality and homoscedasticity 
assumptions. In case early escalation gives data only to two weeks for some patients, the 
modelling will be adjusted to suit, in the first instance looking only at Week 2 data for all 
patients.
12.5.1
Handling of missing values/censoring/discontinuations
12.5.2
Safety endpoints
For all safety analyses, the full analysis set will be used. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g., when change 
from baseline is used). In addition, a separate summary for any deaths including on treatment 
and post treatment deaths will be provided. 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 30 days 
after the date of the last actual administration of any study treatment.
Adverse events
All information obtained on adverse events will be displayed as described above taking into 
account the study design involving sequences, 
Listings will be down to patient level. The number (and percentage) of patients with treatment 
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emergent adverse events (events starting after the first dose of study medication or events 
present prior to start of double-blind treatment but increased in severity based on preferred term) 
will be summarized in the following ways:

by treatment dose group including split by first and second four weeks in second period,
primary system organ class and preferred term.
Separate summaries will be provided for study 
medication related adverse events, death, serious adverse events, other significant adverse 
events leading to study and/or investigational drug discontinuation and any adverse events 
leading to dose adjustment.
A subject with multiple adverse events within a primary system organ class is only counted
once towards the total of the primary system organ class. Adverse events which will be counted 
for a specific treatment period are those which are treatment-emergent. These events are those 
with an onset after the start of the dose level treatment period, or which were present prior to 
the start of the treatment period but increased in severity, changed from being not suspected to 
being suspected of study drug relationship, or developed into SAEs after the start of the dosing 
period.
Vital signs
All vital signs data will be listed by sequence, treatment dose group, subject, and visit/time and 
if ranges are available, abnormalities (and relevant orthostatic changes) will be flagged. 
Summary statistics will be provided as described above. Individual overlaid profile plots over 
time with current dose level per patient color-coded will be presented.
12-lead ECG
PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead ECGs for each patient 
during the study. ECG data will be read and interpreted locally.
All ECG data will be listed by sequence, treatment dose group, subject and visit/time. 
Abnormalities will be flagged. Summary statistics will be provided as described above. 
Individual overlaid profile plots over time with current dose level per patient color-coded will 
be presented.
Clinical laboratory evaluations
All laboratory data will be listed by sequence, treatment dose group, subject, and visit/time and 
if normal ranges are available abnormalities will be flagged. Summary statistics will be 
provided as described above. Individual overlaid profile plots over time with current dose level 
per patient color-coded will be presented.
Other safety evaluations
All transfusion and patient diary data will be listed by sequence, treatment dose group, subject, 
and visit/time and relevant descriptive summaries will be formed.
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12.5.3
Pharmacokinetics
LNP023 plasma concentration data will be listed by sequence, treatment dose group, subject, 
and visit/sampling time point. 
Pharmacokinetic parameters will be calculated from within four weeks of dosing only and will 
be listed by treatment dose group and subject. Descriptive summary statistics will include mean 
(arithmetic and geometric), SD, and CV (arithmetic and geometric), median, minimum and 
maximum. An exception to this is Tmax, where median, minimum and maximum will be 
presented.
Table 12-1
Non-compartmental pharmacokinetic parameters
AUClast
The AUC from time zero to the last measurable concentration sampling time 
(tlast) (mass x time x volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state 
(amount x time x volume-1)
AUCtau
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]
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass x volume-1)
Cmin
The lowest plasma (or serum or blood) concentration observed during a 
dosing interval at steady state [mass / volume]
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid 
drug concentration after single dose administration (time)
T1/2
The elimination half-life associated with the terminal slope (lz) of a semi 
logarithmic concentration-time curve (time). Use qualifier for other half-lives
A linear mixed effects model will be fitted to the log-transformed PK parameters (AUC0-24h, 
AUCinf, and Cmax) as described for dose-response analysis of LDH. For each PK parameter 
backtransformed estimates and confidence interval will be plotted against dose level.
During modeling of the pharmacokinetics of study treatment, the broad principles outlined in 
the FDA guidance will be followed (Guidance for Industry: Population Pharmacokinetics; 
http//www.fda.gov/cder/guidance/1852fnl.pdf).
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12.6
Analysis of exploratory endpoints
12.7
Interim analyses
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12.8
Sample size calculation
12.8.1
Primary endpoint(s)
With 10 subjects this study has 80% probability to meet the efficacy criteria of 5 or more 
successful patients out of 10 if the true response rate is 58%.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, patient 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.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) .
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings
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13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written 
Standard Operating Procedures as well as applicable global/local GCP regulations and 
ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.
14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
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15
References
References are available upon request
Brodsky RA (2014) Paroxysmal nocturnal hemoglobinuria. Blood p. 2804-11. 
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. p. 794-810.
Hillmen P, Young NS, Schubert J, et al (2006) The complement inhibitor eculizumab in 
paroxysmal nocturnal hemoglobinuria. N. Engl. J. Med. p. 1233-43.
ICH Harmonised Tripartite Guideline (2003). Post-approval safety data management: 
definitions and standards for expedited reporting E2D. 
Konar M, Granoff D (2017) Eculizumab treatment and impaired opsonophagocytic killing of 
meningococci by whole blood from immunized adults. Blood 2017 130, pp. 891-899.
Slade C, Bosco J, Unglik G, et al (2013) Deficiency in Complement factor B. N Engl J Med, 
369(17), pp. 1667-1669.
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Protocol No. CLNP023X2204
16
Appendices
16.1
Appendix 1: Clinically notable laboratory values and vital signs
Alert criteria will be specified in the central laboratory documentation.


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16.2
Appendix 2: Liver Event Definitions and Follow-up Requirements
Table 16-1
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 pathology)
Others

Any clinical event of jaundice (if not clearly PNH disease related)

Any adverse event potentially indicative of liver toxicity
Table 16-2
Actions required for Liver Events
Criteria
Actions required
Potential Hy’s Law case

Discontinue the study treatment immediately (if not 
clearly PNH disease related)

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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Table 16-3
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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16.3
Appendix 3: Specific Renal Alert Criteria and Actions
Table 16-4
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.)
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


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Table 16-5
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
CLNP023X2204
A multi-center, randomized, open-label, efficacy, safety, 
pharmacokinetics and pharmacodynamics study, 
assessing multiple LNP023 doses in adult patients with 
paroxysmal nocturnal hemoglobinuria and active 
hemolysis
Statistical Analysis Plan (SAP)
Author(s):
Document type:
SAP Documentation – NIBR 
Document status:
Final – Amendment 2
Release date:
14-Apr-2022
Number of pages:
19
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
ClinicalTrials.gov Identifier: NCT03896152
Personal Protected Data


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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
General considerations ........................................................................................................8
5
Statistical methods: Analysis sets........................................................................................8
6
Statistical methods for Pharmacokinetic (PK) parameters..................................................9
6.1
Variables..................................................................................................................9
6.2
Descriptive analyses ................................................................................................9
6.3
Statistical model, assumptions and hypotheses .....................................................10
6.3.1
Model checking procedures ..................................................................10
6.3.2
Graphical presentation of results...........................................................10
7
Statistical methods for Pharmacodynamic (PD) parameters.............................................11
7.1
Primary objective...................................................................................................11
7.1.1
Variables ...............................................................................................11
7.1.2
Descriptive analyses..............................................................................11
7.2
Secondary objectives .............................................................................................11
7.2.1
Variables ...............................................................................................12
7.2.2
Descriptive analyses..............................................................................12
7.2.3
Statistical model, assumptions and hypotheses.....................................12
7.3
Exploratory objectives...........................................................................................13
7.3.1
Variables ...............................................................................................13
7.3.2
Descriptive analyses..............................................................................14
7.3.3
Descriptive analyses..............................................................................14
8
Statistical methods for safety and tolerability data............................................................15
8.1
Variables................................................................................................................15
8.2
Descriptive analyses ..............................................................................................15
8.3
Graphical presentation...........................................................................................17


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9
Pharmacokinetic / pharmacodynamic relationships ..........................................................17
List of tables
Figure 1-1 
Study design and dosing schema.............................................................7
Table 5-1
Protocol deviation codes and analysis sets..............................................9
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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 (CSR) for trial “CLNP023X2204”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
This SAP has been developed using the Clinical Trial Protocol version v02 (amended protocol) 
dated 03-Aug-2021.
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 PNH associated hemolysis.

Percentage 
of 
patients 
with 
60%
reduction in LDH or LDH below upper
limit of normal (ULN) up to 12 weeks of
treatment.
1.3.2
Secondary objective(s)
Secondary objective(s)
Endpoints 
related 
to 
secondary 
objective(s)

To assess the dose-response effect of
LNP023 on the reduction of PNH
associated hemolysis

LDH, and other relevant parameters such
as but not restricted to hemoglobin and
red blood cell count up to week 4 for
each dose.

To assess the effect of LNP023 on
markers 
of 
intravascular 
and
extravascular hemolysis.

Potentially all of, but not restricted to,

Total and free hemoglobin,

carboxyhemoglobin,

reticulocytes,

C3 fragment deposition,

haptoglobin,

bilirubin,

red blood cell count,

platelet counts,

ferritin,

PNH type III red blood cells (RBC)

PNH clone size.


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
To assess the safety and tolerability of
LNP023 in PNH patients.

All safety parameters including: blood
chemistry, hematology, urinalysis, ECG
evaluation, vital signs, adverse events,
transfusions, patient diary.

To assess the plasma pharmacokinetics
(PK) of LNP023

Non-compartmental analysis of LNP023
PK parameters including, but not limited
to Cmax, AUC, Ctrough and Tmax.

To assess the effect of LNP023 on
markers 
associated 
with 
risk 
of
thrombosis.

Assessments including, but not limited to,
fibrinogen, prothrombin time, activated
partial thromboplastin time, thrombin
time, fibrin D-dimer and fibrinogen
degradation products for fibrinolysis
activity.
1.3.3
Exploratory objective(s)
Exploratory objective(s)
Endpoints 
related 
to 
exploratory 
objective(s)
1.4
Study design and treatment
This is
a
non-confirmatory, randomized, open-label, multicenter, efficacy, safety, 
pharmacokinetic and pharmacodynamic study assessing 
LNP023 doses, in adult PNH 
patients with active hemolysis.
At least 10 patients will be included in the study, as replacement can occur if any patient 
withdraws for reasons unrelated to safety or lack of efficacy.
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Total study duration from screening until EOS is approximately 2.5 years. This three-period 
study includes: a screening phase of up to 8 weeks, a baseline visit, Day 1 (first day that the 
investigational drug is given), a 4-week treatment period of LNP023 at the first dose in the 
assigned sequence (Period 1), an 8-week treatment period at the second dose in the assigned 
sequence (Period 2), an approximately 2 year extension Period 3, followed by a taper down 
period of 2 weeks, an end of study visit and a safety follow up call performed 30 days post end 
of treatment.
Patient will be randomized to sequence 1 or sequence 2 in ratio 1:1.
Figure 1-1
Study design and dosing schema
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2
First interpretable results (FIR)
No FIR will be produced for the final analysis.
3
Interim analyses
4
General considerations
The final study analysis will be conducted on all patients’ data at the time the trial ends. 
5
Statistical methods: Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received. This 
implies that for subjects for whom the actual treatment received does not match the randomized 
treatment, the treatment actually received will be used for the analysis.
The Full Analysis Set (FAS) comprises all patients that received any study drug.
The Safety analysis set will also include all patients that received any study drug and hence is 
not referred to again.
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, who received any study 
drug and with no protocol deviations with relevant impact on PD data.
The analysis sets and protocol deviation codes are related as follows:
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Table 5-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from all (safety and FAS) analysis in case of 
these protocol deviations:
Exclude subject completely 
from all (safety and FAS)
analysis sets
Subjects are excluded from PK analysis in case of these protocol 
deviations: INCL01
Exclude subject from PK
analysis set
Subjects are excluded from PD analysis in case of these protocol 
deviations: INCL01
Exclude subject from PD 
analysis set
Subjects are excluded from PK and PD analysis in case of these 
protocol deviations: INCL01
Exclude subject from PK 
and PD analysis sets
6
Statistical methods for Pharmacokinetic (PK) parameters
All subjects within the PK analysis set will be included in the PK data analysis.
6.1
Variables 
The following PK parameters will be determined, if data permit, using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 8.0 or 
higher), from the plasma concentration-time data:
AUCtau
The area under the plasma concentration-time curve calculated to the end of the 
dosing interval (tau) at steady-state (h*ng/ml)
AUClast
The area under the plasma concentration-time curve calculated to the last 
measurable concentration sampling time (tlast) (h*ng/ml)
Cmax
The observed maximum plasma concentration (ng/ml)
Ctrough (Cmin)
The concentration observed just prior to the beginning, or at the end, of a dosing 
interval (ng/mL)
Tmax
The time to reach maximum plasma concentration (h)
T1/2 (if feasible)
The elimination half-life associated with the terminal slope (lambda_z) of a semi-
logarithmic concentration-time curve (h)
6.2
Descriptive analyses
LNP023 plasma concentrations will be listed by sequence, treatment dose group, patient, and 
visit/sampling time point. Summary tables will be presented as described in Section 4.
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Pharmacokinetic parameters will be listed by patient and summarized by treatment with 
descriptive statistics as listed above. For Tmax, only median, minimum, and maximum will be 
reported. For T1/2 geometric means will not be calculated.
Graphical methods will be employed to show mean (SD) with time defined as the sampling 
time point by treatment dose group on linear and semi-log view based on nominal time.
Moreover, individual PK values trough levels up to Week 12 will be displayed. In addition, all 
individual concentration-time profiles will be displayed graphically by treatment dose and 
sequence (in separate plots), visit/sampling time point on linear and semi-log view based on 
nominal time.
6.3
Statistical model, assumptions and hypotheses
Modeling techniques will be applied on the PK parameters (AUCtau, AUClast and Cmax) at 
Period Week 4 (i.e. including data from both Period 1 Week 4 and Period 2 Week 4). 
In the first instance a mixed model will be fitted with log transformed PK parameter as the 
dependent variable and dose as a categorical variable, and subject as a random term to give 
predicted estimates per each dose. The subject term will be considered as random so as to allow 
recovery of between subject information. The results of the treatment effects will be presented 
as geometric means by back-transforming estimates from the log scale and will be presented 
along with a 95% confidence interval.
6.3.1
Model checking procedures
6.3.2
Graphical presentation of results
The model predicted relationship curve between dose and PK parameter along with its 
corresponding 95% CI will be presented for the nonlinear model.
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7
Statistical methods for Pharmacodynamic (PD) parameters
All subjects within the PD analysis set will be included in the PD data analysis.
7.1
Primary objective
The primary objective is to assess the effect of LNP023 on the reduction of PNH associated 
hemolysis.
7.1.1
Variables 
The primary variable is treatment response. A responder is defined as a patient with at least 
60% reduction in LDH compared to baseline or LDH below upper limit of normal (ULN) at 
any time up to and including Week 12 for that patient, whether or not 
7.2
Secondary objectives
The secondary objectives of this study are:

To assess the dose-response effect of LNP023 on the reduction of PNH associated
hemolysis.

To assess the effect of LNP023 on markers of intravascular and extravascular hemolysis.

To assess the effect of LNP023 on markers associated with risk of thrombosis
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, and a non-responder anyone who doesn’t meet either of these criteria.
Baseline LDH will be calculated as the average of the last three screening values prior to 
randomization. 
7.1.2 
Descriptive analyses
Frequency tabulations reporting number and percentage of responders by week 12 by 
randomized sequence. Frequency tables will also be summarized by dose over time as described 
in Section 4.
There is no statistical model for the primary endpoint apart from observing and counting success 
or failure for each patient. For the purposes of this study a positive sign of efficacy is when the 
estimated response rate is at least 50%. For example, this criterion will be met when at least 5 
out of 10 patients in the overall study, or 3 of 5 in one of the two Cohorts are considered 
responders.
7.1.2.1 
Handling of missing values/censoring/discontinuations
For calculation of the success rate for the primary endpoint all patients enrolled in the study 
apart from those who were replaced for reasons other than safety or efficacy will be included 
in the denominator.


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7.2.1
Variables 
The secondary variables of this study are:

For dose response: LDH, and other relevant parameters including but not restricted to 
hemoglobin and red blood cell count

Markers of intravascular and extravascular hemolysis
 
Including but not restricted to total and free hemoglobin, carboxyhemoglobin,
reticulocytes, C3 fragment deposition, haptoglobin, bilirubin, red blood cell count, 
platelet counts, ferritin, PNH type III red blood cells (RBC) and PNH clone size

Risk of thrombosis parameters: Including but not limited to, fibrinogen, prothrombin 
time, activated partial thromboplastin time, thrombin time, fibrin D-dimer and 
fibrinogen degradation products for fibrinolysis activity.
Baseline LDH will be calculated as the average of the last three screening values prior to 
randomization. For all parameters except LDH, baseline is the average of all pre-treatment 
values.
Partial exclusion of data
In case of an INCL05 deviation, all total and free hemoglobin records from the patient will be 
excluded from the PD analyses.
7.2.2
Descriptive analyses
7.2.3
Statistical model, assumptions and hypotheses
Dose-response effect
CCI
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7.2.3.1
Model checking procedures
7.2.3.2
Graphical presentation of results
The model predicted relationship curve between dose and PK parameter along with its 
corresponding 95% CI will be presented for any nonlinear models. 
7.3
Exploratory objectives
7.3.1
Variables 
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7.3.2
Descriptive analyses
7.3.3
Descriptive analyses
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8
Statistical methods for safety and tolerability data
All subjects within the full analysis set will be included in the safety data analysis.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g., when change 
from baseline is used). In addition, a separate summary for any deaths including on treatment 
and post treatment deaths will be provided. 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, treatment 
information, transfusion and patient diary data.
8.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment sequence and 
subject. Summary statistics will be provided for all subjects, as well as for each treatment 
sequence. For baseline characteristics the values at the baseline visit will be listed/summarized.
Categorical data will be presented as frequencies by treatment sequence. For continuous data, 
mean, standard deviation, median, minimum, and maximum will be presented.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment sequence and subject.
Relevant medical history and current medical conditions will be summarized by reported term, 
system organ class (SOC) and preferred term (PT), by treatment sequence.
Treatment
Data for a) prior and concomitant medications, b) surgical/medical procedures and 
investigations and c) vaccinations and prophylactic antibiotics will be listed separately by 
treatment sequence and subject.
The duration of exposure in days (including half days) to each dose of LNP023 will be
summarized by means of descriptive statistics.
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Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system, by treatment sequence group. In addition, the incidence of on-study 
medical/surgical procedures and investigations by preferred term will be displayed. A subject 
with multiple medical/surgical procedures and investigations with the same preferred term is 
counted only once for that preferred term and treatment.
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 treatment sequence, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided as described in Section 4.
ECG evaluations
All ECG data will be listed by treatment sequence, subject and visit/time, abnormalities will be 
flagged. Summary statistics will be provided as described in Section 4.
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit/time 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 as described in 
Section 4.
Adverse events
All information obtained on adverse events will be displayed as described in Section 4 taking 
into account the study design involving sequence.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by dose for each period separately. 
An adverse event starting in one period and continuing into the next period is counted only in 
the onset period. A subject with multiple adverse events within a body system and treatment 
period is only counted once towards the total of this body system and treatment.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to study and/or investigational drug 
discontinuation and any adverse events leading to dose adjustment.
Adverse event reporting for Clinical Trial Safety Disclosure (CTSD)
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables, 1) on 
treatment-emergent adverse events which are not serious adverse events with an incidence 
greater than 5% and 2) on treatment-emergent serious adverse events and SAE suspected to be 
related to study treatment, will be provided by SOC and PT on the full analysis set population. 
These tables will be produced by Novartis. The value of the cutoff value X will be decided with 
the team when disclosure tables are prepared.


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The summary will be done by dose and Period as described in Section 4.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1-day gap between the end date of the
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1-day gap between the end date
of the preceding AE and the start date of the consecutive AE.
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non-SAE has to be checked in a block e.g., among AE's in a ≤ 1-day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
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 
DBL) will be summarized by frequency and percentage of patients by risk name, MedDRA 
preferred term and by treatment sequence. 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.
Other safety evaluations
8.3
Graphical presentation 
Individual overlaid profile plots over time will be used to visualize trends in longitudinal safety 
data (vitals, ECG, lab parameters) with current dose level per patient color-coded will be 
presented.
9
Pharmacokinetic / pharmacodynamic relationships
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Commercially Confidential Information


Novartis
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Commercially Confidential Information


Novartis
For business use only
Page 19
SAP Amendment V02 
CLNP023X2204
Commercially Confidential Information