Conditions: Paroxysmal Nocturnal Hemoglobinuria
Keywords: Paroxysmal Nocturnal Hemoglobinuria (PNH) LFG316 LNP023
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
The purpose of this study was to determine whether LFG316 can induce a hematological response, as measured by reduction in hemolytic activity, in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Detailed description:
The study consisted of a 60-day screening period to assess eligibility and conduct vaccinations if required (for all patients not previously vaccinated at least 2 weeks prior to first dosing or if prior vaccination cannot be confirmed) and 4 treatment periods as follows. During the treatment period 1 (Days 1 to 29), all patients received infusions of LFG316 every 14 days. Following assessment of efficacy (hemolytic activity by serum LDH) at the end of treatment period 1, patients entered the optional 48-week treatment period 2 and continued LFG316 infusions every 14 days. At the end of treatment period 2, LFG316-responsive patients (assessed based on the investigator's judgment) were allowed to enter an additional extension period of up to 260 weeks (treatment period 3) in which they continued to receive LFG316 every 14 days. Period 4, which allowed patients to switch to LNP023, lasted approximately 21 weeks. During the first 4 weeks, patients continued to receive LFG316 in addition to oral administration of LNP023. After 4 weeks, patients discontinued LFG316 and continued with LNP023 monotherapy for approximately 16 weeks (+/- 28 days). Patients who participated in period 4 could join the long-term extension study CLNP023C12001B (NCT04747613) as soon as their eligibility was confirmed and study CLNP023C12001B was open to receive patients. There was no LNP023 treatment gap between the studies.

As per strategic decision, further development of LFG316 was terminated in favor of LNP023, Novartis offered patients enrolled in study CLFG316X2201 a conversion from LFG316 to LNP023, aiming to provide uninterrupted treatment for these PNH patients. The CLFG316X2201 trial was not a terminated study.

Arms:
arm 1: During treatment periods 1 to 3, the regimen included LFG316 at a dosage of 20 mg/kg administered as an intravenous (i.v.) infusion biweekly.

In treatment period 4, the patients were given:

* LFG316 at a dosage of 20 mg/kg as an i.v. infusion every two weeks for four weeks, amounting to two infusions in total.
* LNP023 at a dose of 200 mg administered orally twice daily (b.i.d.) for approximately 20 weeks, with four 50 mg capsules taken at each administration.

Interventions: intervention 1: LFG316 intervention 2: LNP023
Intervention descriptions: intervention 1: LFG316 20 mg/kg was administered to all patients enrolled in the study:

* Treatment Periods 1 to 3: LFG316 20 mg/kg as i.v. infusion every 2 weeks
* Treatment Period 4: LFG316 20 mg/kg as i.v. infusion every 2 weeks for 4 weeks (total 2 infusions). intervention 2: Treatment Period 4: LNP023 200 mg b.i.d. for approximately 20 weeks. Four capsules (each 50 mg) were administered each time study medication was taken.

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
LFG316
Clinical Trial Protocol CLFG316X2201 / NCT02534909
An open-label proof of concept study to assess the 
efficacy, safety and pharmacokinetics of LFG316, an anti-
C5 monoclonal antibody in patients with paroxysmal 
nocturnal hemoglobinuria (PNH)
Document type:
Amended Protocol Version
EUDRACT number:
2014-005338-74
Version number:
v08 (Clean)
Development phase:
II
Release date:
11-Dec-2020
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct.
Notification of serious adverse events
Refer to Section 9.2 of the protocol for definitions and reporting requirements for Serious 
Adverse Events (within 24 hours after awareness of the SAE to the local Novartis Chief Medical 
Office and Patient Safety Department and notify the Clinical Trial Leader).
Contact information is listed in the Site Operations Manual.


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Pharmacokinetic definitions and symbols.........................................................................10
Protocol synopsis...............................................................................................................20
1
Introduction .......................................................................................................................23
1.1
Background............................................................................................................23
1.1.1
Relevant data summary.........................................................................23
1.2
Study purpose ........................................................................................................29
2
Study objectives.................................................................................................................29
2.1
Primary objective(s)...............................................................................................29
2.2
Secondary objective(s)...........................................................................................29
2.3
Exploratory objective(s) ........................................................................................30
3
Investigational plan ...........................................................................................................31
3.1
Study design...........................................................................................................31
3.2
Rationale of study design.......................................................................................33
3.3
Rationale of dose/regimen, duration of treatment .................................................34
3.3.1
LFG316 .................................................................................................34
3.3.2
LNP023 .................................................................................................35
3.4
Rationale for choice of comparator .......................................................................36
3.5
Purpose and timing of interim analyses/design adaptations..................................36
3.6
Risks and benefits..................................................................................................36
3.6.1
Risks and benefits for period 4..............................................................38
4
Population..........................................................................................................................39
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4.1
Inclusion criteria ....................................................................................................40
4.2
Exclusion criteria...................................................................................................41
5
Restrictions for Study Subjects .........................................................................................43
5.1
Contraception requirements...................................................................................43
5.2
Prohibited treatment...............................................................................................43
5.3
Dietary restrictions.................................................................................................44
5.4
General restrictions................................................................................................44
6
Treatment...........................................................................................................................44
6.1
Study treatment......................................................................................................44
6.1.1
Investigational treatment.......................................................................44
6.1.2
Additional study treatment....................................................................45
6.2
Treatment arms......................................................................................................45
6.3
Permitted dose adjustments of study treatment .....................................................45
6.4
Treatment assignment............................................................................................46
6.5
Treatment blinding.................................................................................................46
6.6
Emergency breaking of assigned treatment code ..................................................46
6.7
Treatment exposure and compliance .....................................................................46
6.8
Recommended treatment of adverse events ..........................................................47
6.9
Rescue medication.................................................................................................47
6.10
Concomitant treatment...........................................................................................47
7
Discontinuation and study completion ..............................................................................47
7.1
Discontinuation of study treatment........................................................................47
7.2
Study completion and post-study treatment ..........................................................49
7.2.1
Lost to follow-up...................................................................................49
7.3
Withdrawal of consent...........................................................................................49
7.4
Study stopping rules ..............................................................................................50
7.5
Early study termination..........................................................................................50
8
Procedures and assessments ..............................................................................................50
8.1
Informed consent procedures.................................................................................55
8.2
Subject demographics/other baseline characteristics.............................................55
8.3
Safety.....................................................................................................................56
8.3.1
Physical examination ............................................................................56
8.3.2
Vital signs..............................................................................................56
8.3.3
Height and weight .................................................................................56
8.3.4
Laboratory evaluations..........................................................................56
8.3.5
Electrocardiogram (ECG) .....................................................................57


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8.3.6
Pregnancy and assessments of fertility .................................................57
8.3.7
Vaccination ...........................................................................................57
8.5
Pharmacokinetics...................................................................................................58
9
Safety monitoring..............................................................................................................63
9.1
Adverse events.......................................................................................................63
9.2
Serious adverse event reporting.............................................................................65
9.2.1
Definition of SAE .................................................................................65
9.2.2
SAE reporting........................................................................................66
9.3
Liver safety monitoring .........................................................................................67
9.4
Renal safety monitoring.........................................................................................71
9.5
Pregnancy reporting...............................................................................................72
9.6
Early phase safety monitoring ...............................................................................72
10 Data review and database management.............................................................................72
10.1
Site monitoring ......................................................................................................72
10.2
Data collection.......................................................................................................73
10.3
Data Monitoring Committee..................................................................................74
10.4
Adjudication Committee........................................................................................74
11 Data analysis......................................................................................................................74
11.1
Analysis sets ..........................................................................................................74
11.2
Subject demographics and other baseline characteristics......................................74
11.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................74
11.4
Analysis of the primary variable(s) .......................................................................75
11.4.1
Variable(s).............................................................................................75
11.4.2
Statistical model, hypothesis, and method of analysis..........................75
11.4.3
Handling of missing values/censoring/discontinuations.......................75
11.4.4
Supportive analyses...............................................................................76
11.5
Analysis of secondary 
 variables ..................................................76
11.5.1
Efficacy / 
...............................................................76
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11.5.2
Safety.....................................................................................................77
11.5.3
Pharmacokinetics ..................................................................................77
11.5.5
Other assessments .................................................................................78
11.6
Sample size calculation..........................................................................................78
11.7
Power for analysis of key secondary variables......................................................78
11.8
Interim analyses.....................................................................................................79
12 Ethical considerations........................................................................................................79
12.1
Regulatory and ethical compliance........................................................................79
12.2
Responsibilities of the investigator and IRB/IEC..................................................79
12.3
Publication of study protocol and results...............................................................80
13 Protocol adherence ............................................................................................................80
13.1
Protocol Amendments ...........................................................................................80
14 References .........................................................................................................................81
List of tables
Table 8-1
Assessment schedule.............................................................................51
Table 9-1
Liver event and laboratory trigger definitions ......................................68
Table 9-2
Follow up requirements for liver events and laboratory triggers..........68
Table 9-3
Specific renal alert criteria and actions.................................................71
List of figures
Figure 3-1
Study design..........................................................................................33
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List of abbreviations
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
b.i.d.
twice per day
BMI
Body Mass Index
BUN
blood urea nitrogen
CD-ROM
compact disc – read only memory
CDS
Core Data Sheet (for marketed drugs)
CFR
Code of Federal Regulations
CK
creatinine kinase
CMO&PS
Chief Medical Office and Patient Safety
CRF
Case Report/Record Form (paper or electronic)
CO2
carbon dioxide
CRO
Contract Research Organization
CSR
Clinical Study Report
CTC
Common Toxicity Criteria
CTRD
Clinical Trial Results Database
CV
coefficient of variation
DDI
Drug-drug interaction
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
eGFR
Estimated glomerular filtration rate
ELISA
Enzyme-linked immunosorbent assay
EORTC
European Organization for Research and Treatment of Cancer
FB
Factor B
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FDA
Food and Drug Administration
FIH
First in human
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GPI
glycosylphosphatidylinositol
γ-GT
Gamma-glutamyl transferase
h
hour
HIV
human immunodeficiency virus
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IG
Immonogenicity
IgAN
IgA nephropathy
IgG1
Immunoglobulin G 1
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
intrauterine device
IUS
intrauterine system
i.v.
intravenous
LC/MS
Liquid Chromatography/Mass Spectrometry
LDH
lactate dehydrogenase
LFT
Liver function test
LLN
lower limit of normal
LPS
Lipopolysaccharides
mAb
Monoclonal antibodies
MAC
membrane attack complex
MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
MN
membranous nephropathy
ml
milliliter(s)
NOAEL
no observed adverse effect level
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NOVDD
Novartis Data Dictionary
OC/RDC
Oracle Clinical/Remote Data Capture
PA
posteroanterior
PD
pharmacodynamic(s)
PFT
pulmonary function test(s)
PK
pharmacokinetic(s)
PNH
Paroxysmal nocturnal hemoglobinuria
p.o.
oral(ly)
RBC
red blood cell(s)
REB
Research Ethics Board
SAD
single-ascending dose
SAE
serious adverse event
s.c.
subcutaneous
SCC
squamous cell carcinoma
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SD
standard deviation
SOM
site operations manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
ULN
upper limit of normal
ULQ
upper limit of quantification
WBC
white blood cell(s)
WHO
World Health Organization
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Pharmacokinetic definitions and symbols
AUC0-t
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to time ‘t’ where t is a defined time point after administration [mass 
x time / volume]
AUClast
The area under the plasma (or serum or blood) concentration-time curve from 
time 
zero 
to 
the 
time 
of 
the 
last 
quantifiable 
concentration
[mass x time / volume]
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
Tmax
The time to reach the maximum concentration after drug administration [time]


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Protocol synopsis
Protocol number
CLFG316X2201
Title
An open-label proof of concept study to assess the efficacy, safety and 
pharmacokinetics of LFG316, an anti-C5 monoclonal antibody in patients 
with paroxysmal nocturnal hemoglobinuria (PNH)
Brief title
Proof of concept study to assess the efficacy, safety and pharmacokinetics 
of LFG316 in patients with paroxysmal nocturnal hemoglobinuria (PNH)
Sponsor and 
Clinical Phase
Novartis Pharma Services AG
Phase II
Intervention type
Biologic
Study type
Interventional
Purpose and 
rationale
To determine whether LFG316 administered via i.v. infusion can induce a 
hematological response, as measured by reduction in hemolytic activity, in 
patients with PNH.
Period 4 was implemented to convert PNH patients receiving i.v. infusion of 
LFG316 to oral treatment with LNP023 in order to enable participation in the 
planned LNP023 long-term extension study CLNP023C12001B, and to 
assure continuous treatment of the study patients who otherwise have limited 
treatment options.
Primary 
Objective(s)
To assess the effect of LFG316 on the reduction of intravascular hemolysis 
in PNH patients as determined by measuring changes in serum LDH levels 
within 4 weeks of treatment and over the entire treatment period.
Secondary 
Objectives
To assess the tolerability and pharmacokinetics of LFG316 in patients with 
PNH. Standard safety monitoring with increased vigilance for infections will 
be applied, and measurement of serum concentrations of LFG316.
Study design
Open-label, non-controlled study in patients with PNH. The study will consist 
of a 60-day screening period to assess eligibility and conduct vaccinations if 
required (for all patients not previously vaccinated at least 2 weeks prior to 
first dosing or if prior vaccination cannot be confirmed). During the treatment 
period 1, all patients will receive infusions of LFG316 every 14 days. At the 
end of period 1, efficacy on hemolytic activity by serum LDH will be assessed. 
All patients will be allowed to enter the optional treatment period 2 and 
subsequently period 3, and will undergo all assessments specified by the 
Protocol Assessment Schedule. The extension period 3 will be followed by a 
Study Completion evaluation approximately 8 weeks after the last drug 
administration.
Patients participating in extension period 3 (up to 260 weeks) will roll over
from the last dosing visit of period 2 to the first visit (which includes drug 
administration) of period 3. The same dosing interval applied in period 1 and 
2 needs to be respected between the last dosing visit of period 2 (Week 52 
of treatment) and the first visit of period 3. The LFG316 treatment for all 
patients will be completed by end of 2021 regardless of each individual 
treatment period.
Patients participating in period 3 will have the option to complete the period 
3 Follow up and Study Completion evaluation or to continue with study period 
4 which is a pre-requisite for their eligibility to join the long-term extension 


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study CLNP023C12001B. During period 4, which will last approximately 21 
weeks, treatment will be converted from intravenous LFG316 to oral LNP023. 
During the first 4 weeks patients will continue to receive LFG316 20 mg/kg 
every two weeks (total of two administrations) in addition to oral 
administration of LNP023 200 mg b.i.d. After 4 weeks, patients will 
discontinue LFG316 and will proceed with LNP023 200 mg b.i.d. for
approximately 16 weeks (+/- 28 days).
Population
The study population will be comprised of male and female PNH patients not 
currently receiving eculizumab therapy and who fulfill all other eligibility 
criteria.
Key inclusion 
criteria

Male and female patients ≥18 years old with a diagnosis of PNH prior 
to screening. Based on local requirements (applicable in Czech 
Republic) only patients between the age of 18-65 (inclusive) with a 
diagnosis of PNH prior to screening may be eligible for inclusion in this 
study.

A documented PNH clone size of ≥10% by RBCs and/or granulocytes, 
measured by GPI-deficiency on flow cytometry

Serum LDH levels at least 1.5-fold above the upper limit of normal 
(ULN) at screening 

Negative pregnancy test for women of child bearing potential at screening

Previous vaccination against Neisseria meningitidis types A, C, Y and 
W-135 is required at least 2 weeks prior to first dosing. Vaccination 
against meningitidis type B should be conducted if available and 
acceptable by local regulations, at least 2 weeks prior to first dosing.
Subjects to be included in this study after protocol amendment 6 also have 
to fulfill criterion:

PNH patients that are carriers of the C5 gene minor variants as defined 
by nucleic acid changes that lead to amino acid exchanges in position 
p.Arg885
Inclusion Criteria for period 4:

Patients participating in period 3 of the current study who are willing to 
join long-term extension study with LNP023 (CLNP023C12001B)

Previous vaccination for the prevention of S. pneumoniae and H. 
influenzae at least 2 weeks prior to first dosing with LNP023 if locally 
available. If LNP023 treatment has to start earlier than 2 weeks post 
vaccination, prophylactic antibiotic treatment must be initiated.


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Key exclusion 
criteria

Known or suspected hereditary complement deficiency

History of recurrent meningitis, history of meningococcal meningitis
despite vaccination

Presence or suspicion (based on judgment of the investigator) of active
bacterial infection within 2 weeks prior to first dose of LFG316, or
recurrent bacterial infections

Under active therapy with other agents interfering with the complement
system

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 50 days after the last
dose of LFG316.
Investigational and 
reference therapy
Periods 1 to 3: LFG316 will be administered via i.v. infusion every 14 days to 
all patients participating to the study.
Period 4: During the first 4 weeks patients will continue to receive LFG316 
20 mg/kg every two weeks (total of two administrations) in addition to oral 
administration of LNP023 200 mg b.i.d. After 4 weeks, patients will 
discontinue LFG316 and will proceed with LNP023 200 mg b.i.d. for 
approximately 16 weeks.
Efficacy/PD
assessments
Serum LDH
Safety assessments
Laboratory Evaluations
ECG
Pregnancy
Vital signs / Height and weight
Other assessments
Data analysis
The primary efficacy variable is response rate where a patient will be 
considered a responder if the percentage reduction from baseline in serum 
LDH is at least 60% at any time up to and including week 4 for that patient.
Thorough verification and analysis of the LDH response will be also 
conducted on the overall treatment duration.
Total LFG316 concentrations will be expressed as μg/mL. 
All information obtained on adverse events will be displayed as summary and
by subject.
Key words
PNH, LFG316, C5, LNP023
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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). The deficiency 
in CD55 & CD59 allows for uncontrolled C3 activation & opsonization of RBCs. Subsequently, 
assembly of the membrane attack complex (MAC) from Complement factors C5, C6, C7, C8, 
C9 causes intravascular lysis of RBCs. The resulting paroxysms of hemolysis lead to the release 
of high amounts of free hemoglobin into the circulation, which is reflected by hemoglobinuria
and a drop in circulating haptoglobin. The clinical manifestations of PNH are multifold and 
include fatigue, abdominal pain and smooth muscle dystonias. The highly elevated risk for 
thromboembolic events is the most important cause of mortality. Frequent blood transfusions 
are required to treat anemia in PNH patients experiencing severe episodes of hemolysis.
LFG316 is an anti-C5 antibody that binds to a different, remote epitope on C5 compared with 
eculizumab. 
Beside the well-described intravascular hemolysis, PNH patients frequently present with 
persistent extravascular hemolysis despite blockade of the complement Factor C5 leading to 
continuous red blood cell hemolysis, reactive reticulocytosis, increased bilirubin and LDH 
levels (Hill et al 2010; Risitano et al 2009).
LNP023 is a novel oral small molecular weight compound that reversibly inhibits FB of the 
complement alternative pathway (AP) thereby preventing C3 fragments from opsonizing PNH 
erythrocytes
leading 
to 
less 
extravascular 
and 
intravascular 
hemolysis 
(Risitano and Marotta 2016; Subias Hidalgo et al 2017). It is thought that blockade of the AP 
with oral LNP023 has the potential to prevent both intra- and extravascular hemolysis and 
therefore offer therapeutic superiority to the anti-C5 therapy.
1.1.1
Relevant data summary
The most relevant data for the present study are summarized in the sections below. For detailed 
information, please refer to the respective Investigators Brochures.
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1.1.1.3
Human safety and tolerability data
1.1.1.3.1 LFG316
Eculizumab was approved in 2007 for the treatment of PNH and in 2011 for atypical hemolytic 
uremic syndrome. The most important serious safety finding with eculizumab therapy is the 
increased risk of Neisseria infections. Therefore, patients are vaccinated against N. meningitides
prior to receiving eculizumab. In some countries, the prophylactic administration of antibiotics 
is required. Similar measures will be applied in the present study.
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1.1.1.3.2 LNP023
There are N=29 PNH patients receiving b.i.d dose between 25 and 200 mg LNP023 in 
CLNP023X2201 and CLNP023X2204 studies. The approximately 3 months core parts of both
studies are completed and patients continue to receive LNP023 in an extension phase
(total treatment duration between approximately 10 months and 2.5 years depending on the 
patient).
In addition, there are several ongoing studies in C3 glomerulopathy, IgA nephropathy (IgAN) 
and membranous nephropathy (MN).
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Known potential safety risks of LNP023 based on the mechanism of action (complement FB
inhibition) include susceptibility to infections. Patients with mutations of FB are generally 
healthy, 
but 
have 
impaired 
resistance 
against 
encapsulated 
bacterial 
infections 
(Slade et al 2013).
There have been no serious infections reported in PNH patients treated with LNP023, the most 
significant non-serious infections being recurrent herpes virus infections, bilateral otitis and 
mild acneiform lesions in one patient each.
Of note, a suspected unexpected serious adverse reaction (SUSAR) of pneumococcal 
pneumonia with septic shock and acute respiratory distress syndrome (ARDS) was recently 
reported on the C3 glomerulopathy trial in a multiply immunosuppressed patient with a history 
of renal transplantation. This first report of an infection with encapsulated bacteria was 
considered by the Investigator as suspected to be related to LNP023, but also to the other 
immunosuppressive agents the patient was on concomitantly (i.e., prednisone, cyclosporin, 
mycophenolate mofetil) and triggered the issuance of an Investigator Notification. The patient 
completely recovered.
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1.1.1.4
Human pharmacokinetic data
1.1.1.5
Human pharmacodynamic data
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1.2
Study purpose
The purpose of the study is to determine whether LFG316 administered via i.v. infusion at 
20 mg/kg once every 14 days can induce a hematological response, as measured by reduction 
in hemolytic activity, in patients with PNH. 
Period 3 (extension of treatment duration) was implemented to ensure a seamless continuation 
of treatment for LFG316-responsive patients enrolled in the study.
Period 4 is implemented to convert PNH patients receiving i.v. infusion of LFG316 to oral 
treatment with LNP023, thereby allowing them to be considered for participation in the planned 
long-term extension study CLNP023C12001B. 
2
Study objectives
2.1
Primary objective(s)
Objective
Endpoint

To assess the effect of LFG316 on
the reduction of intravascular
hemolysis in PNH patients

Reduction in serum LDH levels
within the first 4 weeks of treatment

Reduction in serum LDH levels over
the entire treatment period.
2.2
Secondary objective(s)
Objective
Endpoint

To assess the tolerability and
pharmacokinetics of LFG316 in
patients with PNH

Standard safety monitoring with
increased vigilance for infections

Measurement of serum
concentrations of LFG316
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2.3
Exploratory objective(s)
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3
Investigational plan
3.1
Study design
This is an open-label, non-controlled study in patients with PNH. Approximately 10 patients 
will be enrolled in the study. At the time that Protocol amendment v07 is effective, no additional 
patients will be enrolled. The study drug will be administered via i.v. infusion at the dose level 
of 20 mg/kg every 14 days. Patients participating in study will have an option to either complete 
period 3 Follow up and Study Completion evaluation or continue in study period 4 that is
pre-requisite to join the long-term extension study CLNP023C12001B, that is separate to this 
study protocol. Patients who are potentially eligible and willing to participate in the LNP023 
long-term extension study will join period 4, where treatment will be converted from LFG316 
to LNP023 200 mg b.i.d.
The study will consist of a 60-day screening period to assess eligibility and conduct vaccinations
if required (for all patients not previously vaccinated at least 2 weeks prior to first dosing or if 
prior vaccination cannot be confirmed). An extensive screening window (up to 60 days) is 
planned in order to comply with local vaccination requirements, if available and deemed 
necessary at the investigator’s discretion. Safety evaluation assessments requiring blood and 
urine samplings, pregnancy test, pulmonary function test, ECG, patient reported outcomes, and 
assessment of number of blood transfusions should be performed no longer than 4 weeks prior 
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to the planned dosing day. Subjects who meet the eligibility criteria at screening will be 
admitted to baseline (Day 1) evaluations. The patients will enter treatment period 1, and will 
receive infusions of LFG316 every 14 days, days 1, 15 and 29 (3 administrations).
At the end of period 1, efficacy on hemolytic activity by serum LDH will be assessed. 
All patients will then be allowed to enter the optional treatment period 2, and will receive 
infusions of LFG316 every 14 days, and undergo the efficacy, PK, 
 and 
safety assessments for additional 48 weeks.
Following the 48-week treatment period 2, LFG316-responsive patients (assessed based on 
investigator’s judgment) will be allowed to enter an additional third extension period of up to 
260 weeks (extension period 3).
The LFG316 treatment for all patients will be completed by end of 2021 regardless of each 
individual treatment period.
Patients participating in extension period 3 will roll over from the last dosing visit of period 2 
to the first visit (which includes drug administration) of period 3. The same dosing interval 
applied in Period 1 and 2 will be applied between the last dosing visit of Period 2 and the first 
visit of Period 3.
Period 4 can be initiated as directed by Sponsor and will last approximately 21 weeks. 
During the first 4 weeks patients will continue to receive LFG316 20 mg/kg every two weeks
(total of two administrations) in addition to oral administration of LNP023 200 mg b.i.d. After 
4 weeks, patients will discontinue LFG316 and will proceed with LNP023 200 mg b.i.d.
monotherapy for approximately 16 weeks (+/- 28 days). Patients who participate in period 4 
can join the long-term extension study CLNP023C12001B as soon as their eligibility is 
confirmed and study CLNP023C12001B is open to receive patients. There should be no 
LNP023 treatment gap between the studies. Please refer to Section 7.1 for guidance regarding 
safety monitoring and LNP023 down-titration in case of LNP023 treatment discontinuation.
For patients not participating in the period 4, the extension period 3 will be followed by a Study 
Completion evaluation approximately 8 weeks after the last drug administration. Patients who
discontinue treatment prematurely during any of the study periods will be followed for 8 weeks
after discontinuation, and will similarly undergo a study completion visit. The 8 weeks follow-
up period will start the day after the last drug administration (both for patients completing 
treatment and patients prematurely discontinuing), and will comprise one visit after 
approximately 4 weeks, and a study completion visit after approximately 8 weeks from the last 
drug administration. Safety assessments will include physical examinations, ECG, vital signs, 
standard clinical laboratory evaluations (hematology, blood chemistry, urinalysis) and adverse 
event monitoring.
Patients participating in period 4, will complete their Study Completion evaluation 
approximately one week after last LNP023 treatment administered as a part of this study.
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Figure 3-1
Study design
*Period 4 is applicable only for the patients who are potentially eligible and wish to participate
in the long-term extension study CLNP023C12001B
**+/-28 days
3.2
Rationale of study design
The design of this study addresses the primary objective of reduction of hemolysis in patients
with PNH and takes into account the rarity of this disease and the objective nature of the 
measurement, i.e. reduction in serum LDH levels.
This non-controlled study was designed as a non-placebo-controlled study since the absence of 
a placebo response in this patient population can be assumed, based on published data and the 
nature of the primary outcome measure, which is a biochemical parameter. This study will be 
limited to patients who require treatment but are currently not treated with eculizumab.
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3.3
Rationale of dose/regimen, duration of treatment
3.3.1
LFG316
LFG316 will be administered at 20 mg/kg as i.v. infusion every 14 days throughout all periods.
Duration of the infusion will vary between 40 minutes and 2 hours as described in provided 
separately pharmacy manual.
The dosing regimen may be adjusted in period 2 to achieve sufficient 
drug exposure to warrant safety of the patient, e.g. in case of breakthrough hemolysis towards 
the end of a dosing interval. In period 1 dosing should not be changed, unless judged 
unavoidable to warrant patient’s safety by the investigator. Details are outlined in Section 6.3.
Considering the favorable safety profile and exposure levels detected at the 20 mg/kg dose, a 
dosing regimen of 20 mg/kg every 14 days (2 weeks) was chosen in the present study. 
The dosing regimen may be adjusted if insufficient duration of benefit is observed, e.g. in case 
of breakthrough hemolysis towards the end of a dosing interval, as measured by LDH levels.
To date patients up to 82 years old were safely treated with LFG316 and considering lack of 
any treatment options it is deemed justified to allow the treatment of older PNH patients.
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3.3.2
LNP023
The dose of 200 mg LNP023 b.i.d. as continuous treatment has been selected for period 4 of 
this study based on the available efficacy and safety data obtained at the time of interim analyses 
from the two ongoing Phase 2 PNH studies and is supported by PKPD modeling results.
In the CLNP023X2201 study in patients with active hemolysis despite treatment with 
eculizumab, LNP023 at a dose of 200 mg b.i.d. was administered to N=10 PNH patients 
(Cohort 1) and at a dose of 50 mg b.i.d. to N=6 PNH patients (Cohort 2). 
In the CLNP023X2204 study, enrolling anti-C5 antibody treatment naive patients, participants
received LNP023 monotherapy with sequential dose increments at Week 4 from LNP023 25 
mg b.i.d. to 100 mg b.i.d (Sequence 1) or LNP023 50 mg b.i.d. to 200 mg b.i.d. (Sequence 2). 
The dose of 200 mg b.i.d. is expected to provide optimal efficacy required for PNH as 
monotherapy with an adequate safety profile 
 
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In summary, LNP023 at a dose of 200 mg b.i.d. was not only safe and well tolerated by patients 
in both studies in PNH but demonstrated convincing efficacy as monotherapy measured as 
efficacious control of both, intra- as well as extravascular hemolysis. The same LNP023 dose 
of 200 mg BID was tested safe, well tolerated and efficacious in patients with IgA nephropathy 
(study CLNP023X2203; NCT04557462) and C3 glomerulopathy (CLNP023X2202; 
NCT03832114), further supporting its use in this study. The taper down of 2 weeks was 
included to mitigate potential risk of increased hemolysis after LNP023 discontinuation. 
This will be only implemented for patients who cannot complete period 4 or continue LNP023 
treatment in long-term extension study.
Four weeks of LFG316 and LNP023 co-exposure in period 4 allows to establish LNP023 steady 
state concentration and efficacious complement Factor B inhibition before discontinuing the 
complement Factor C5 neutralization with LFG316. Based on data from study CLNP023X2201 
(see above), co-exposure of LNP023 and anti-C5 therapy is considered safe and well tolerated.
A treatment duration with LNP023 is thought to fulfill the required minimum of 3 months stable 
conditions under LNP023 monotherapy that allows patients to join the long-term extension 
study CLNP023C12001B.
3.4
Rationale for choice of comparator
Not applicable.
3.5
Purpose and timing of interim analyses/design adaptations
3.6
Risks and benefits
PNH is a hematological disease with various severe morbidities and increased mortality, mostly
due to thromboembolic complications. The only approved and effective therapy is the anti-C5 
antibody eculizumab. 
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. Classical treatment regimens are based on blood transfusion, 
anticoagulation, and support of erythropoiesis. They are poorly efficacious and associated with 
a high burden to the patients.
LFG316 has comparable PK/
properties as eculizumab and is therefore expected to 
effectively inhibit hemolysis and show similar clinical benefit in all PNH patients including 
carriers of the variant described above.
The main risks of anti-C5 therapies are related to infections. To date, no infection has been 
observed in the limited number of subjects who have received intravenous LFG316. The most 
important adverse effect associated with systemic eculizumab, however, is infection by 
Neisseria (N). meningitidis (e.g. meningitis). These infections are consistent with reports of
occasional but recurrent meningococcal infections seen in patients with total hereditary C5 
deficiency (Rosenfeld et al 2006; Haeney et al 1980; Cesbron et al 1985; Sanal et al 1992; 
Delgado-Cerviño et al 2005; 
López-Lera et al 2009; 
Zerzri et al 2010);
pneumococcal 
infections were also reported in hereditary complement deficiency. Where measured, affected 
(homozygous) patients showed no measurable circulating C5 protein or complement-mediated 
hemolytic activity. Importantly, heterozygous C5-deficient relatives have roughly half the 
normal levels of circulating C5 and hemolytic activity but do not appear to be at risk for 
infections, thus suggesting that the risk increases only in cases of >50% inhibition of C5.
The risk to patients in this trial will be minimized by adherence to the eligibility criteria,
counseling, close clinical monitoring, and meningococcal vaccination prior to administration of 
LFG316, due to the risk of infection with encapsulated bacteria.
For patients under treatment with any other immunosuppressive drugs during the study, 
treatment with prophylactic antibiotics is strongly recommended. Overall, the potential benefits 
of anti-C5 therapy outweigh the risks in this population of PNH patients.
The study is divided into 4 parts: treatment period 1 (29 days), during which a total of
approximately 350 mL of blood will be collected, treatment period 2 (335 days), during which 
approximately 700 mL blood will be collected,  treatment period 3 (up to 5 years duration),
during which the maximum collected blood volume will be approximately 1300 mL, and period 
4 (approximately 5 months) when approximately 220 mL of blood will be collected.
The maximum blood volume over any 12 week period will not exceed 450 ml.
Additional samples for monitoring of any safety findings would be in addition to this. This is 
not considered to be a risk for this population.
Women of child bearing potential should be informed that taking the study drug may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration of 
the study. If there is any question that the subject will not reliably comply, they should not be 
entered in the study.
There may be unknown risks of LFG316 which may be serious and unforeseen.
In the absence of any additional anticipated or known risks of complement inhibition in 
relationship with COVID-19, the benefit/risk ratio of this study protocol and of both 
investigational drugs in particular, LFG316 and LNP023, remains unchanged during the 
COVID-19 pandemic.
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3.6.1
Risks and benefits for period 4
The risks associated with the use of LNP023 are those inferred by its mechanism of action as 
well as the findings of preclinical safety studies. The most relevant risks and mitigation 
strategies are described below and a more comprehensive description of safety findings to date 
is available in Section 1.1.1.3.2 and in the IB.
Based on its mechanism of action, the main potential risk of LNP023 is infection-related. 
An intact complement system is particularly important for the defense against encapsulated 
bacteria (e.g., Neisseria meningitidis, Streptococcus pneumoniae, and Hemophilus influenzae). 
Patients with factor B loss-of-function mutations are more susceptible to such infections 
(Slade et al 2013). The mitigation strategy is to vaccinate patients before the first LNP023 
treatment. If LNP023 treatment has to start earlier than 2 weeks post vaccination, prophylactic 
antibiotic treatment must be initiated. Data suggest that the protective effect of vaccination is 
maintained after blockade of the AP, but not after C5 blockade (Konar and Granoff 2017). 
In addition, patients will be instructed to contact the Investigator immediately in case of any 
signs or symptoms of infection (listed on a “Patient Card” for participant awareness), and 
relevant AEs will be reviewed on a regular basis.
Regarding the potential safety risks mentioned above, to date, there have been no serious 
infections reported in PNH patients, although a SUSAR of pneumococcal pneumonia and sepsis 
was recently reported on the C3 glomerulopathy trial in a severely immunosuppressed patient 
with a history of renal transplantation (see Section 1.1.1.3.2). Considering implementation of 
the vaccinations and close monitoring, the risk for serious infection during LNP023 treatment 
is still considered to be low. Finally, there have been no serious adverse events related to the 
other potential risks in any of the clinical studies.
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The risk to subjects in this trial receiving LNP023 will be minimized by adherence to the 
eligibility criteria, close clinical monitoring, pre-defined stopping rules, periodic review of the 
safety data, and guidance for the investigators in the Investigator’s Brochure.
To note, 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 Exclusion Criteria. If there is any question that the 
subject will not reliably comply, they should not be entered or continue in the study.
4
Population
The study population will be comprised of male and female PNH patients not currently 
receiving eculizumab therapy and who fulfill all other eligibility criteria. Previous response or 
failure to respond adequately to eculizumab should be documented in all patients who are
carriers of the 
 Patients must be ≥ 18 years old diagnosed with PNH 
prior to screening; both males and females will be allowed to enter the study and background 
therapy with eculizumab is not permitted (wash-out time required: 8 weeks).
Approximately 10 patients will be enrolled. 
The investigator must ensure that all subjects being considered for the study meet the below 
eligibility criteria. No additional criteria should be applied by the investigator, in order that the 
study population will be representative of all eligible subjects.
Subject selection is to be established by checking through all eligibility criteria at screening. 
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.
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4.1
Inclusion criteria
Subjects eligible for inclusion in this study have to fulfill all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed
2. Male and female patients ≥18 years old with a diagnosis of PNH prior to screening.
Based on local requirements (applicable in Czech Republic) only patients between the age
of 18-65 (inclusive) with a diagnosis of PNH prior to screening may be eligible for
inclusion in this study.
3. A documented PNH clone size of ≥10% by RBCs and/or granulocytes, measured by
GPI-deficiency on flow cytometry
4. Serum LDH levels at least 1.5-fold above the upper limit of normal (ULN) at screening
5. Patients receiving treatment with corticosteroids and/or other immunosuppressive
regimens may continue treatment throughout the study, if indicated for treatment of
autoimmune disease (e.g. aplastic anemia). It is strongly recommended, but is at the
investigator’s discretion, that patients receive appropriate prophylactic antibiotics
(e.g. ciprofloxacin, penicillin, erythromycin) while on treatment with any type of
concomitant immunosuppressive agent other than LFG316 (including corticosteroids).
6. Negative pregnancy test for women of child bearing potential at screening
7. Previous vaccination against Neisseria meningitidis types A, C, Y and W-135 is required
at least 2 weeks prior to first dosing. Vaccination against meningitidis type B should be
conducted if available and acceptable by local regulations, at least 2 weeks prior to first
dosing. Further information available in Section 8.3.7.
8. Able to communicate well with the investigator, to understand and comply with the
requirements of the study.
Subjects to be included in this study after protocol amendment 6 also have to fulfill criterion:
9. PNH patients that are carriers of the C5 gene minor variants as defined by nucleic acid
changes that lead to amino acid exchanges in position p.Arg885
Additional inclusion criteria for period 4
10. Patients participating in period 3 of the current study who are willing to join long term
extension study with LNP023 (CLNP023C12001B)
11. Previous vaccination for the prevention of S. pneumoniae and H. influenzae at least 2
weeks prior to first dosing with LNP023 if locally available. If LNP023 treatment has to
start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment must be
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4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. Known or suspected hereditary complement deficiency.
2. History of hematopoietic stem cell transplantation.
3. Participation in any other investigational drug trial or exposure to other investigational
agent, device, or procedure within 30 days or 5-times the half-life prior to screening. 
Note: clinical trials solely involving over-the-counter vitamins, off label use of drugs 
within published standard of care guidelines, supplements, or diet do not exclude an 
otherwise eligible patient.
4. Female patients who are pregnant or breastfeeding, or intended to conceive during the 
course of the study.
5. History of recurrent meningitis, history of meningococcal meningitis despite vaccination.
6. Presence or suspicion (based on judgment of the investigator) of severe active bacterial 
infection within 2 weeks prior to first dose of LFG316, or severe recurrent bacterial 
infections.
7. A positive HIV test result.
8. Under active therapy with other agents interfering with the complement system 
(e.g. eculizumab) Wash-out time should be at least 5 half-lives, approximately 8 weeks 
for eculizumab.
9. Severe concurrent co-morbidities, e.g. patients with severe kidney disease (dialysis),  
advanced cardiac disease (NYHA class IV), severe pulmonary arterial hypertension 
(WHO class IV), unstable thrombotic event not amenable to active treatment as judged 
by the investigator.
10. Either one of the following laboratory abnormalities at screening:
a. Neutrophils <0.5 x 109/L
b. Platelets <30 x 109/L
11. Co-morbidities that are a likely caused by underlying autoimmune diseases other than 
PNH, e.g. kidney disease in the context of lupus nephritis, ANCA-associated vasculitis.
12. 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.
13. History of hypersensitivity to a drug of the same class (human IgG1 mAb) or any other 
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14. 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 50 days after the last dose of LFG316. Highly effective
contraception methods include:
c.
Total abstinence (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
d. Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment.
In case of oophorectomy alone, only when the reproductive status of the
woman has been confirmed by follow up hormone level assessment
e.
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
f.
Combination of any two of the following (i+ii or i+iii, or ii+iii):
i. Use of oral, injected or implanted hormonal methods of contraception
or other forms of hormonal contraception that have comparable
efficacy (failure rate <1%), for example hormone vaginal ring or
transdermal hormone contraception.
ii. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
iii. Barrier methods of contraception: Condom or Occlusive cap
(diaphragm or cervical/vault caps) with spermicidal
foam/gel/film/cream/vaginal suppository. For UK: with spermicidal
foam/gel/film/cream/vaginal suppository
g. In case of use of oral contraception, women should have been stable on the
same pill for a minimum of 3 months before taking study treatment.
h. 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) or tubal ligation at least six weeks prior to screening. 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. This group does not need to use contraception.
Note: In the case where a safety laboratory assessment at screening is outside of the range, the 
assessment may be repeated once prior to randomization. If the repeat value remains outside of
the specified ranges, the subject is excluded from the study, unless the abnormal value is
attributed to the underlying disease (PNH) by the investigator. Re-screening of patients may be 
permitted but has to be discussed with the Novartis clinical team.
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5
Restrictions for Study Subjects
During recruitment, screening/informed consent review, and baseline visit, the subjects must be 
informed and reminded of the following restrictions:
5.1
Contraception requirements
Please refer to exclusion criteria (Section 4) for details of contraception requirements for the study.
5.2
Prohibited treatment
Use of the treatments displayed in the table below is NOT allowed after start of the study drug:
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5.3
Dietary restrictions
No restrictions.
5.4
General restrictions
No restrictions.
6
Treatment
6.1
Study treatment
Details on the storage and management of study medication and instructions for prescribing and 
taking study treatment are outlined in Section 3 of the Site Operations Manual and in the 
Pharmacy Manual.
For the first dosing with LFG316, weight collected at baseline visit should be used for dose 
calculation. For any subsequent dosing, most recently collected pre-dose weight should be used 
for dose calculation. 
6.1.1
Investigational treatment
The investigational drug, LFG316 100 mg Lyophilisate in Vials or 500 mg Liquid in Vials will 
be provided by Novartis, and supplied to the Investigator.
LNP023 10 and 50 mg hard gelatin capsules will be provided in the open label patient specific 
kits.
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6.1.2
Additional study treatment
Permitted concomitant medications are listed below:

Erythropoietin

Corticosteroids and/or other immunosuppressive regimens may be continued
throughout if warranted for treatment of autoimmune disease (e.g. aplastic anemia).
It is strongly recommended, but is at the investigator’s discretion, that patients receive
appropriate prophylactic antibiotics (e.g. ciprofloxacin, penicillin, erythromycin) while
on treatment with any type of concomitant immunosuppressive agent other than
LFG316 (including corticosteroids)

Anticoagulants, e.g. coumarins, low molecular-weight heparins, factor Xa inhibitors,
Thrombin inhibitors

Iron supplements & folic acid

Iron depletion therapy as required

Blood transfusions as required

Analgesic agents

Antibiotics, antivirals
Any dose adjustments or new concomitant treatments must be recorded in the relevant eCRF page.
6.2
Treatment arms
6.3
Permitted dose adjustments of study treatment
Study drug dose adjustments should generally be avoided, particularly in period 1.
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There is no dose adjustment allowed for LNP023 treatment in period 4 except for down-titration 
in case of LNP023 discontinuation. Down-titration is also recommended for patients who start 
LNP023 treatment in period 4 and do not join long-term extension study (Section 7.1).
6.4
Treatment assignment
Patient numbers will be assigned in ascending, sequential order to eligible subjects 
(see Site Operations Manual for details). The investigator will enter the treatment number on 
the CRF.
6.5
Treatment blinding
Not applicable. This study uses an open-label single treatment design.
6.6
Emergency breaking of assigned treatment code
Not applicable.
6.7
Treatment exposure and compliance
LFG316 will be administered at the dose level of 20 mg/kg via intravenous infusion by the 
Investigator or designated study staff over approximately 2 hours in Period 1 and between 
40 minutes and 2 hours in Periods 2 and 3 (please refer to Pharmacy Manual), and therefore 
compliance with the planned treatment will be assumed since infusions will be carried out under 
close medical supervision at the study sites. Although infusion reactions have not been observed
with LFG316 to date, close medical supervision at the study site is requested during the infusion 
time of LFG316 and up to 2 hours after the end of the infusion during Treatment Period 1.
In case of a suspected infusion reaction (e.g. mild rash, general discomfort) the infusion rate 
should be reduced and vital signs should be monitored continuously. Infusion should be stopped 
in case of severe reactions with need for intervention, as judged by the investigator 
(e.g. treatment with glucocorticoids, histamine antagonists, epinephrine, bronchodilators).
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all subjects 
treated with LFG316, as detailed in Section 8.5.
Applicable for period 4: LNP023 will be administered orally at the patients’ home or at the 
study center (mandatory at days when PK samples are collected). During days 1-28 patients 
will be receiving both LFG316 every 2 weeks and LNP023 every day. On days 29-141 (+/-28 
days), LNP023 will be administered as monotherapy. LNP023 dose diary will be implemented 
to capture information on missing doses. During the COVID-19 pandemic that limits or 
prevents on-site study visits, delivery of LNP023 directly to a patient’s home is generally 
permitted in the event the Investigator has decided that an on-site visit by the patient is no longer 
appropriate or possible, and that it is in the interest of the patient’s health to administer the study 
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treatment even without performing an on-site visit. Implementation will need to be discussed 
with Novartis. The dispatch of IMP from the site to the patient’s home remains under the 
accountability of the Investigator. In this case, regular phone calls or virtual contacts (at the 
frequency matching planned study visit) will occur between the site and the patient for 
instructional purposes, safety monitoring, and discussion of the patient´s health status until the 
patients can again visit the site.
6.8
Recommended treatment of adverse events
Treatment of AEs should follow standard practice. Medication used to treat AEs must be 
recorded on the Concomitant medications/Significant non-drug therapies CRF.
6.9
Rescue medication
Use of rescue medication must be recorded on the Concomitant medications/Significant non-drug 
therapies CRF after start of study drug. Additional doses of LFG316 may be administered in case of 
hemolytic crisis between infusions (as evidenced e.g. by sudden increase in LDH levels, decrease in 
Hb and based on Investigator’s judgment, and can be discussed with Novartis).
Use of eculizumab or other biologics as a rescue medication would lead to treatment 
discontinuation, and subjects entering the 8 week safety follow-up. Blood transfusions and other 
therapeutic measures are permitted, as outlined in Section 6.1.2.
6.10
Concomitant treatment
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the timeframe 
defined in the entry criteria prior to the start of the study and during the study, must be recorded 
on the Concomitant medications/ Significant non-drug therapies section of the CRF.
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy.
7
Discontinuation and study completion
7.1
Discontinuation of study treatment
Subjects may voluntarily discontinue study treatment for any reason at any time.
The investigator must discontinue study treatment for a given subject if, on balance, he/she 
believes that continuation would be detrimental to the subject’s well-being.
Study treatment must be discontinued under the following circumstances:

Subject withdraws consent

Pregnancy

Emergence of the following adverse events:

Evidence for invasive Neisseria infection

In case of other severe systemic or life-threatening infections, treatment
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
Use of prohibited treatment as per Section 5.2.

Any other protocol deviation that results in a significant risk to the subject’s safety
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 7.3). Where possible, they should return for the 8 week safety 
follow-up, which includes monitoring of intravascular hemolysis after drug discontinuation. 
If they fail to return for these assessments for unknown reasons, every effort (e.g. telephone, 
e-mail, letter) should be made to contact them as specified in Section 7.2.1.
If treatment with LNP023 has to be discontinued prematurely and immediately (i.e., because of 
a significant safety risk which warrants immediately stopping LNP023 treatment), it is 
recommended to promptly re-initiate treatment with Standard of Care (SoC), as judged by the 
investigator.
Close monitoring of patients for signs and symptoms of hemolysis should be performed upon 
LNP023 discontinuation. It is recommended to monitor at minimum for: increase in LDH, 
decrease in hemoglobin level and PNH clone size, increase in serum creatinine, thrombosis, and 
change in neurological/mental status. If serious hemolysis occurs, the Investigator should 
consider the following supportive treatments (and recording them in the appropriate CRF 
pages):

Blood transfusion (packed RBCs), or

Exchange transfusion if the PNH RBCs are >50% of the total RBCs by flow
cytometry,

Corticosteroids,

Anticoagulation,

Any other supportive treatment or therapy as judged by the investigator.
An End of Study (EoS) visit one week after permanent discontinuation of LNP023 should occur 
for the assessments as specified in the Assessment schedule.
If treatment with LNP023 has to be discontinued prematurely but it is not warranted to 
immediately discontinue LNP023 treatment (i.e., discontinuation due to patient/guardian 
decision or confirmed pregnancy), it is recommended to promptly initiate the available SoC in 
the country as judged by the investigator. In addition, it should be considered to taper down 
LNP023 over a period of 14 days:
Down-titration is also recommended for patients who start LNP023 treatment in period 4 and 
do not join long-term extension study.
The investigator should consider the proposed monitoring and supportive treatments listed 
above in case serious hemolysis occurs. During LNP023 tapering, weekly visits are 
recommended 
 The following assessments are recommended: 
blood hematology and chemistry for parameters specified in Section 8.3.4.
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All data collected will be entered in the appropriate CRF page as an unscheduled 
visit/assessment.
7.2
Study completion and post-study treatment
Each subject will be asked to complete this study in its entirety (period 1, 2 and 3) and they may
be offered to enter an additional extension trial, provided LFG316 shows benefit as defined by 
the response criteria. Patients willing and eligible to join the extension study
CLNP023C12001B must participate in period 4.
Study completion is defined as when the last subject completes their End of Study visit, and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.
At a minimum, patients ending participation after period 3, will be contacted for safety 
evaluations during the 8 week safety follow-up period in which intravascular hemolysis will be
monitored, and a final Study Completion Visit will be conducted at the conclusion of the safety 
follow-up period. A safety follow-up call should be conducted approximately 30 days after last
LNP023 administration to confirm he patient has not experienced any SAEs during this post-
study period for any patient participating in period 4, who does not roll over into 
CLNP023C12001B. Documentation of attempts to contact the subject should be recorded in 
the source documentation The investigator must provide follow-up medical care for all subjects 
who are prematurely withdrawn from the study, or must refer them for appropriate ongoing care.
7.2.1
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 should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be formally considered lost to follow-up until 
his/her scheduled end of study visit would have occurred.
7.3
Withdrawal of 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.
If a subject withdraws consent, the investigator must make every effort to determine the primary 
reason for this decision 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.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until the time of withdrawal) according to applicable 
law.


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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.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
7.4
Study stopping rules
Enrollment will be put on hold pending full safety review if more than one unexpected and 
possibly related SAEs is reported. The study will be stopped if the benefit-risk ratio changes to 
be unacceptable in this indication.
7.5
Early study termination
The study can be terminated at any time by Novartis.
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and
efficacy data

Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider subject welfare and safety.
Should this be necessary, subjects should be seen as soon as possible 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 will be responsible for informing IRBs/IECs of the 
early termination of the trial depending on local regulation.
8
Procedures and assessments
Subjects should be seen for all visits on the designated day, with the assessments performed as 
per schedule, within the allowed “visit/assessment window” specified in the Site Operations 
Manual.
If the COVID-19 pandemic limits or prevents on-site study visits, alternative methods of providing 
continuing care may be implemented. Phone calls, virtual contacts (e.g. teleconsultation) or visits 
by site staff/home nursing service to the patient´s home depending on local regulations and 
capabilities, can replace on-site study visits, for the duration of the pandemic until it is safe for the 
patient to visit the site again. Local laboratory to monitor safety might be implemented if feasible.


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Table 8-1
Assessment schedule
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Study epoch
Study phase
Visit Numbers (internal use only)
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
323
324
325
326
1st Year Extension
V41
V42
V43
V44
V45
V46
V47
V48
V49
V50
V51
V52
V53
V54
V55
V56
V57
V58
V59
V60
V61
V62
V63
V64
V65
V66
Week
54
56
58
60
62
64
66
68
70
72
74
76
78
80
82
84
86
88
90
92
94
96
98
100
102
104
Day
379
393
407
421
435
449
463
477
491
505
519
533
547
561
575
589
603
617
631
645
659
673
687
701
715
729
Visit Numbers (internal use only)
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
424
425
426
2nd Year Extension
V67
V68
V69
V70
V71
V72
V73
V74
V75
V76
V77
V78
V79
V80
V81
V82
V83
V84
V85
V86
V87
V88
V89
V90
V91
V92
Week
106
108
110
112
114
116
118
120
122
124
126
128
130
132
134
136
138
140
142
144
146
148
150
152
154
156
Day
743
757
771
785
799
813
827
841
855
869
883
897
911
925
939
953
967
981
995
1009
1023
1037
1051
1065
1079
1093
Visit Numbers (internal use only)
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
3rd Year Extension
V93
V94
V95
V96
V97
V98
V99
V100
V101
V102
V103
V104
V105
V106
V107
V108
V109
V110
V111
V112
V113
V114
V115
V116
V117
V118
Week
158
160
162
164
166
168
170
172
174
176
178
180
182
184
186
188
190
192
194
196
198
200
202
204
206
208
Day
1107
1121
1135
1149
1163
1177
1191
1205
1219
1233
1247
1261
1275
1289
1303
1317
1331
1345
1359
1373
1387
1401
1415
1429
1443
1457
Inclusion /Exclusion criteria
Relevant med. History/Current conditions
Demography
Physical examination
X
X
X
X
X
X
X
X
X
X
X
X
X
HIV screen
Urine drug screen & alcohol test
X
Pregnancy test (a)
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug administration
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
Adverse Events
Concomitant meds/Therapies
Comments
Vital signs and body measurements
        Body height
        Body weight
X
X
X
X
X
X
X
X
X
X
X
X
X
        Body temperature
X
X
X
X
X
X
X
X
X
X
X
X
X
X
        Blood pressure / Pulse rate
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG evaluation
X
X
X
X
X
X
X
X
X
Safety Laboratory Evaluations: Hematology
(including Reticulocyte counts), Blood chemistry
(free Hbg and haptoglobin)  (b)
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum LDH (pre-dose) (b)
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
Urinalysis (b)
X
X
X
X
X
X
X
X
X
X
X
X
X
Number of blood transfusions
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
PNH type III RBCs by flow cytometry (b)
X
X
X
X
X
X
X
Pulmonary Function Test
PK blood collection (b)
Xc
Xc
a: Serum pregnancy test required at screening of Period 1, urine pregnancy test at further time points. Only for post-menopausal women, the hormone measurement (FSH) to confirm post menopausal status required at screening of Period 1
b: Ad-hoc sampling at unscheduled visits allowed (e.g. safey reasons, loss of efficacy, etc)
c: Samples collected pre- dose
d: If not previously collected in Part 1 and 2 of the study - Samples collected pre- dose, sample collected only one time.
As required
Treatment (continued)
Treatment Period 3 (Extension Period 3) 
As required
As required
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Study epoch
Study phase
Follow-up
Study Completion
Visit Numbers (internal use only)
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
4th Year Extension
V121
V122
V123
V124
V125
V126
V127
V128
V129
V130
V131
V132
V133
V134
V135
V136
V137
V138
V139
V140
V141
V142
V143
V144
V145
V146
Week
210
212
214
216
218
220
222
224
226
228
230
232
234
236
238
240
242
244
246
248
250
252
254
256
258
260
Day 1471
1485
1499
1513
1527
1541
1555
1569
1583
1597
1611
1625
1639
1653
1667
1681
1695
1709
1723
1737
1751
1765
1779
1793
1807
1821
Visit Numbers (internal use only)
557
558
559
560
561
562
563
564
565
566
567
568
569
570
571
572
573
574
575
576
577
578
579
580
581
582
5th Year Extension
V147
V148
V149
V150
V151
V152
V153
V154
V155
V156
V157
V158
V159
V160
V161
V162
V163
V164
V165
V166
V167
V168
V169
V170
V171
V172
Week
262
264
266
268
270
272
274
276
278
280
282
284
286
288
290
292
294
296
298
300
302
304
306
308
310
312
Day 1835
1849
1863
1877
1891
1905
1919
1933
1947
1961
1975
1989
2003
2017
2031
2045
2059
2073
2087
2101
2115
2129
2143
2157
2171
2185
Physical examination
X
X
X
X
X
X
X
X
X
Urine drug screen & alcohol test
X
Pregnancy test (a)
X
X
X
X
X
X
X
X
X
Drug administration
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
Adverse Events
X
Concomitant meds/Therapies
X
Comments
X
Vital signs and body measurements
        Body height
        Body weight
X
X
X
X
X
X
X
X
X
        Body temperature
X
X
X
X
X
X
X
X
X
        Blood pressure / Pulse rate
X
X
X
X
X
X
X
X
X
ECG evaluation
X
X
X
Safety Laboratory Evaluations:
Hematology (including Reticulocyte
counts), Blood chemistry(free Hbg and
haptoglobin), LDH level (b)
X
X
X
X
X
X
X
X
X
Urinalysis (b)
X
X
X
X
X
X
X
X
X
Number of blood transfusions
PNH type III RBCs by flow cytometry (b)
X
X
X
PK blood collection (b)
X
a: Serum pregnancy test required at screening of Period 1, urine pregnancy test at further time points. Only for post-menopausal women, the hormone measurement (FSH) to confirm post menopausal status required at screening of Period 1
b: Ad-hoc sampling at unscheduled visits allowed (e.g. safey reasons, loss of efficacy, etc)
As required
X
Treatment (continued)
Treatment Period 3 (Extension Period 3) 
Visit 173 -
Week 316,
Day 2213
or
4 weeks from
last visit
performed
(Internal visit
583)
Visit 777 -
Week 320,
Day 2241
or
 8 weeks from
last visit
performed (4
weeks after
follow-up)
(Internal visit 599)
As required
As required
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Assessment schedule for patients participating in Period 4
Study epoch
Treatment
Study phase
Treatment Period 4 (Extension Period 4)
Study Completion4
Visit Numbers (internal use only)
601
602
603
604
605
606
607
608
Visit 777
Day 148
(1 week after last LNP023 
dose)
Period 4 visit number
V1001
V1002
V1003
V1004
V1005
V1006
V1007
V1008
Day
1
15
29
36
43
57
85
141
Visit window
-
-
±1
±1
±1
±2
±2
±28
±28
Inclusion/exclusion for period 4*
S1
Physical examination
S1
S
S
S
S
S
S
S
S
Pregnancy test
X1
X
X
X
X
LFG316 administration
X
X
LNP023 administration5
X3
        Body weight
X1
X
        Body temperature
X1
X
X
X
X
X
X
X
X
        Blood pressure / Pulse rate
X1
X
ECG evaluation
X1
X
Hematology and blood chemistry
X1
X
X
X
X
X
X
X
X
Blood hormones 
X1
X
X
X
X
X
Urinalysis
X1
X
Number of blood transfusions
X
LNP023 PK
X2
X2
Adverse Events
As required
X
Concomitant meds/Therapies
As required
X
Comments
As required
X
* Eligibility needs to be confirmed before first dose of LNP023 is administered
S: Captured as Source Data only
1 Pre-LNP023 and LFG316 dose
2 Two time points: pre LNP023 morning dose and 2h post morning LNP023 dose
3 B.i.d. administration
4 Safety follow up call should happen approximately 1 month after last LNP023 dose is administered for patients that do not roll over into CLNP023C12001B
5 Patient diary will be implement to collect information on missing LNP023 doses
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8.1
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
If incapable of doing so, in cases where the subject’s representative gives consent, the subject 
should be informed about the study to the extent possible given his/her understanding. If the 
subject is capable of doing so, he/she should indicate assent by personally signing and dating 
the written informed consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the subject source documents.
The date of signing of informed consent (and withdrawal, if later withdrawn) should be 
documented in the CRF.
Novartis will provide to investigators a proposed informed consent form that complies with the 
ICH GCP guideline and regulatory requirements and is considered appropriate for this study. 
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
Novartis before submission to the IRB/IEC.
If applicable, Pregnancy Outcome Reporting Consent for female patients will be implemented.
In the event that Novartis wants to perform testing on the samples that are not described in this 
protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained.
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects.
Relevant medical history/current medical conditions data includes data until signature of 
informed consent. Where possible, diagnoses and not symptoms will be recorded.
Investigators have the discretion to record abnormal test findings on the medical history section 
of the CRF whenever in their judgment, the test abnormality occurred prior to the informed 
consent signature.
Historical data of serum LDH may be recorded, if available, to help characterize disease status 
and progression.
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8.3
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the Site Operations Manual, with the Assessment schedule detailing when each assessment is 
to be performed.
8.3.1
Physical examination
8.3.2
Vital signs

Body temperature

Blood pressure (BP)

Pulse
Blood pressure and pulse should be collected in a sitting position, after the subject has been 
sitting for 3 minutes.
8.3.3
Height and weight

Height

Body weight (to be used for ongoing dose calculation according to SOM instructions)

Body mass index (BMI) will be calculated (Body weight (kg) / [Height (m)]2)
8.3.4
Laboratory evaluations
Clinically relevant deviations of laboratory test results that are considered unexpected in PNH 
patients, occurring during or at completion of the study must be reported and discussed with 
Novartis personnel. The results should be evaluated for criteria defining an adverse event and 
reported as such if the criteria are met. Repeated evaluations are mandatory until normalization 
of the result(s) or until the change is no longer clinically relevant. In case of doubt, Novartis 
personnel should again be contacted.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential and 
platelet count will be measured.
Clinical chemistry
Sodium, potassium, creatinine, urea, uric acid, chloride, albumin, calcium, alkaline phosphatase, 
total bilirubin, CRP, LDH, GGT, AST, ALT, aPTT, PT/INR, CK, glucose, total cholesterol, 
triglycerides. 

Bilirubin: Bilirubin is released during hemolysis and is frequently increased in PNH
patients. Serum levels will be determined using standard procedures. If the total
bilirubin concentration is increased above 3 times above the baseline value, direct and
indirect reacting bilirubin should be differentiated.

Ferritin: Ferritin levels have been reported to increase during treatment with
eculizumab, and are a measure for iron overload. Serum levels will be determined
using standard procedures.


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
Blood hormones (For period 4 only):
o
Thyroid hormone levels including T3, T4, TSH and reversed T3.
o
Reproductive hormones: Testosterone, Dihydrotestosterone (DHT), Follicle
stimulating hormone (FSH), Luteinizing hormone (LH)
Urinalysis
A semi-quantitative "dipstick" evaluation for the following parameters will be performed: 
specific gravity, pH, glucose, protein, bilirubin, urobilinogen, ketones, nitrite, leukocytes and 
blood/hemoglobin.
If the dipstick result is positive for protein, nitrite, leucocytes and/or blood the sample will be 
sent for microscopic analysis of WBC, RBC and casts.
8.3.5
Electrocardiogram (ECG)
PR interval, QRS duration, heart rate, RR, QT, QTc
The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
8.3.6
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have regular serum pregnancy 
test at screening and urine pregnancy tests at all other time points during the study. A positive 
urine pregnancy test requires immediate interruption of study drug until serum β-hCG is 
performed and found to be negative. Only for post-menopausal women hormone measurement
(FSH) to confirm post-menopausal status is required at screening.
8.3.7
Vaccination
Vaccination will be performed according to local recommendations for patients with 
complement deficiencies, if prior vaccination cannot be confirmed. The choice of vaccine(s) 
should take into account the serotypes prevalent in the geographic areas in which study patients 
will be enrolled.
The meningococcal vaccine(s) should be administered at least two weeks prior to starting 
LFG316 and should be boosted during the study as per recommendation. If LNP023 treatment 
has to start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment must be 
initiated.
For patients participating in period 4, vaccination for the prevention of S. pneumoniae and H. 
influenzae infections should be administered at least 2 weeks prior to first dosing with LNP023, 
as per local guidelines and regulations. If LNP023 treatment has to start earlier than 2 weeks 
post vaccination, prophylactic antibiotic treatment must be initiated. Based on local 
recommendations, revaccination at the start of LFG316 therapy should be considered for 
previously vaccinated subjects as well as during LFG316 and LNP023 therapy for subjects who 
will receive prolonged treatment.
Continuous close monitoring of subjects for early symptoms and signs of meningococcal 
infection is required in order to evaluate subjects immediately if an infection is suspected.


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8.5
Pharmacokinetics
PK samples will be collected at the time points defined in the Assessment schedule.
Further details on sample collection, numbering, processing and shipment can be found in the 
Site Operations Manual.
Determination of the concentration of total LFG316 in serum will be performed using an ELISA 
or LC/MS assay.
A detailed description of the method used to quantify the concentration of total LFG316 will be 
included in the bioanalytical raw data of the study and in the bioanalytical data report.
Pharmacokinetic (PK) samples will be obtained and evaluated in all subjects.
Total LFG316 concentrations will be expressed as μg/mL. 
.
PK samples remaining after completion of the determination of total LFG316 may be used for 
exploratory assessments or other bioanalytical purposes (e.g. cross check between different sites, 
stability assessment). Given the exploratory nature of the work, the analytical method used for 
those assessments will not be validated.
For standard pharmacokinetic abbreviations and definitions see the list provided at the 
beginning of this protocol.
The following pharmacokinetic parameters will be determined (if feasible) using 
non-compartmental method(s) with Phoenix WinNonlin (Version 6.2 or higher): AUC (0-tlast), 
AUC(0-t), Cmax, tmax, Cmax/D, AUC/D. The linear trapezoidal rule will be used for AUC 
calculation.
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For LNP023 a exposure assessment will be done by measuring LNP023 in plasma at predose 
as well as at 2 hr (apparent Cmax). Non-compartimental analysis will not be conducted 
to calculate any other PK parameters. 


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9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject 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 occurrence of adverse events should 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, laboratory test, or other 
assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms, 

they are considered clinically significant, 

they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver related events are included in
Section 9.3.
Adverse events must be recorded on the Adverse Events CRF pages for subjects that pass 
screening and enter into the study. The adverse events should be reported according to the signs, 
symptoms or diagnosis associated with them, and accompanied by the following information:
1. the severity grade

mild:
usually transient in nature and generally not interfering with normal 
activities

moderate: sufficiently discomforting to interfere with normal activities

severe:
prevents normal activities
2. its relationship to the study treatment (no/yes)
3. its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.
4. whether it constitutes a serious adverse event (SAE) See Section 9.2 for definition of SAE


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5. action taken regarding [study/investigational] treatment(select as appropriate). 
All adverse events should be treated appropriately. Treatment may include one or more of 
the following: 

no action taken (i.e. further observation only) 

study treatment dosage adjusted/temporarily interrupted 

study treatment permanently discontinued due to this adverse event 

concomitant medication given 

non-drug therapy given 

subject hospitalized/subject’s hospitalization prolonged 
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or Core Data Sheet (for marketed drugs) or will be 
communicated between IB updates in the form of Investigator Notifications. This information 
will be included in the subject informed consent and should be discussed with the subject during 
the study as needed.
The investigator should also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes might 
reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.


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9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the following 
criteria:

is fatal or life-threatening 

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition and has not worsened 
since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

is medically significant, i.e. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention.
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 more severe.
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.
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 patient or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse.
All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to DS&E as per Section 9.2.2.


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9.2.2
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study drug administration must be 
reported to Novartis within 24 hours of learning of its occurrence as described below. Any SAEs 
experienced after this should only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment.
Recurrent episodes, complications, or progression of the initial SAE must be reported as follow-
up to the original episode, regardless of when the event occurs. This report must be submitted 
within 24 hours of the investigator receiving the follow-up information. An SAE that is 
considered completely unrelated to a previously reported one should be reported separately as 
a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the relationship 
to each specific component of study treatment (if study treatment consists of several drugs)
complete the SAE Report Form in English, and send the completed, signed form by fax within 
24 hours after awareness of the SAE to the local Novartis Drug Safety and Epidemiology 
Department, notifying the Clinical Trial Leader. Contact information is listed in the 
Site Operations Manual.
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with 
the source documentation at the study site. Follow-up information should be provided using a 
new paper SAE Report Form stating that this is a follow-up to a previously reported SAE.
SAEs (initial and follow-up) that are recorded electronically in the Electronic Data Capture 
system should be entered, saved and e-signed within 24 hours of awareness of the SAE or 
changes to an existing SAE. These data will automatically be submitted to Novartis Drug Safety 
& Epidemiology immediately after investigator signature or 24 hours after entry, whichever 
occurs first. Study site personnel must also inform the Clinical Trial Leader.
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the subject
continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety and 
Epidemiology 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 investigational 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.


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9.3
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study:

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and 
completion of the standard base liver CRF pages
Please refer to Table 9-1 and Table 9-2 for complete definitions of liver laboratory triggers and 
liver events.
Every liver laboratory trigger or liver event should be followed up by the investigator or 
designated personal at the trial site, as summarized below and detailed in Table 9-2.
For the liver laboratory trigger:

Repeating the LFT within the next week to confirm elevation
These LFT repeats should be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory should then be performed at central laboratory as soon as possible. 
If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the Liver CRF pages.
For the liver events:

Repeating the LFT to confirm elevation as appropriate

Discontinuation of the investigational drug (refer to Section 7.1, if appropriate

Hospitalization of the subject if appropriate

A causality assessment of the liver event via exclusion of alternative causes 
(e.g. disease, co-medications)

An investigation of the liver event which needs to be followed until resolution


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These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded as appropriate in the CRF, including the liver 
event overview CRF pages.
Table 9-1
Liver event and laboratory trigger definitions
Definition/ threshold
Liver laboratory triggers
3 x ULN < ALT / AST 5 x ULN
1.5 x ULN < TBL 2 x ULN (unless TBL elevation is attributed to 
hemolysis, e.g. unconjugated fraction)
Liver events
ALT or AST > 5 × ULN
ALP > 2 × ULN (in the absence of known bone pathology)
TBL > 2 × ULN (in the absence of known Gilbert syndrome, unless 
elevation attributed to PNH hemolysis, e.g. unconjugated fraction)
ALT or AST > 3 × ULN and INR > 1.5 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable increase 
in ALP to > 2 × ULN)
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia
Any adverse event potentially indicative of a liver toxicity * 
Table 9-2
Follow up requirements for liver events and laboratory triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea

Check if increase in TBL is due 
to rise in conjugated [direct] or 
unconjugated [indirect] fraction

If TBL elevation cannot be 
explained by hemolysis (e.g. 
unconjugated bilirubin, 
reticulocytes, haptoglobin), 
discontinue the study drug 
immediately

Hospitalize, if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)


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Criteria
Actions required
Follow-up monitoring
ALT or AST
> 8 × ULN

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN and INR > 1.5

Discontinue the study drug 
immediately

Hospitalize, if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 5 to ≤ 8 × ULN

Repeat LFT within 48 hours

If elevation persists, continue 
follow-up monitoring

If elevation persists for more than 
2 weeks, discontinue the study 
drug

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN accompanied 
by symptomsb

Discontinue the study drug 
immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
> 3 to ≤ 5 × ULN 
(patient is asymptomatic)

Repeat LFT within the next week

If elevation is confirmed, initiate 
close observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 
ALP (isolated)
> 2 × ULN (in the 
absence of known bone 
pathology)

Repeat LFT within 48 hours

If elevation persists, establish
causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks 
or at next visit


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Criteria
Actions required
Follow-up monitoring
TBL (isolated)
> 3 × ULN or baseline, 
whichever is higher (in 
the absence of known 
Gilbert syndrome)

Repeat LFT within 48 hours

Check if increase is due to rise in 
conjugated [direct] or 
unconjugated [indirect] fraction

If elevation cannot be explained 
by hemolysis (unconjugated 
bilirubin, reticulocytes, 
haptoglobin), discontinue the 
study drug immediately

Hospitalize if clinically appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
Jaundice
Unless attributed to PNH

Discontinue the study drug 
immediately

Hospitalize the patient

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
Any AE potentially 
indicative of a liver 
toxicity*

Consider study drug interruption 
or discontinuation 

Hospitalization if clinically 
appropriate

Establish causality

Complete liver CRF
Investigator discretion
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms
a Elevated ALT/AST > 3 × ULN and TBL > 2 × ULN (if TBL within normal range at baseline) or 
TBL > 2 × baseline (if TBL was elevated at baseline), but without notable increase in ALP to > 2 × 
ULN
b (General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
c Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.


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9.4
Renal safety monitoring
Renal events are defined as one of the following:

confirmed (after ≥ 24h) increase in serum creatinine of ≥ 25% compared to baseline 
during normal hydration status

new onset (≥1+) proteinuria (that is not attributed to underlying disease, as judged by 
the investigator), hematuria or glucosuria; or as a

doubling in the urinary albumin-creatinine ratio (ACR) or urinary protein-creatinine 
ratio (PCR) (if applicable).
The following two categories of abnormalities/adverse events have to be considered during the 
course of the study:

Serum creatinine triggers that will require follow up and repeat assessments of the 
abnormal laboratory parameter

Urine dipstick triggers that will require follow up and repeat assessments of the 
abnormal laboratory parameter
Table 9-3
Specific renal alert criteria and actions
Renal Event
Actions
Serum creatinine increase
25 – 49% compared to baseline
Confirm 25% increase after 24-48h 
Follow up within 2-5 days
Serum creatinine increase  50 % 
compared to baseline 
Follow up within 24-48h if possible
Consider drug interruption 
Consider patient hospitalization /specialized treatment
Albumin- or Protein-creatinine ratio 
increase ≥ 2-fold
Albumin-creatinine ratio (ACR) ≥ 30 
mg/g or ≥ 3 mg/mmol;
New dipstick proteinuria ≥ 1+
Protein-creatinine ratio (PCR )≥ 150 
mg/g or >15 mg/mmol
(unless proteinuria is attributable to 
underlying disease)
Confirm value after 24-48h
Perform urine microscopy
Consider drug interruption / discontinuation 
New dipstick glucosuria ≥ 1+ not due to 
diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR 
New dipstick hematuria not due to 
trauma
Urine sediment microscopy
Perform serum creatinine, ACR 
Document contributing factors: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed in the CRF
Monitor patient regularly (frequency at investigator’s discretion) until one of the following:
Event resolution: (sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline) 
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.


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9.5
Pregnancy reporting
To ensure patient safety, each pregnancy in a subject on study drug 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. The study drug must be discontinued, though the subject may stay in the study, 
if she wishes to do so. All assessments that are considered as a risk during pregnancy must not 
be performed. The subject may continue all other protocol assessments. Pregnancy must be 
recorded on a Pharmacovigilance Pregnancy Form and reported by the investigator to the local 
Novartis Drug Safety and Epidemiology Department. Pregnancy follow-up should be recorded 
on the same form and should include an assessment of the possible relationship to the Novartis 
study drug of any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported on an SAE Report Form.
9.6
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly between 
medically qualified personnel representing the Sponsor and Investigator. Such evaluations may 
occur verbally, but the outcome and key discussion points will be summarized in writing (e-mail) 
and made available to both Sponsor and all Investigator(s). Criteria pertaining to stopping the 
study/treatment or adapting the study design are presented above.
The Sponsor will advise all the participating the Investigators at all sites in writing (e-mail) (and 
by telephone if possible) of any new, clinically relevant safety information reported from 
another site during the conduct of the study in a timely manner.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study Novartis employs several methods of ensuring protocol and GCP compliance 
and the quality/integrity of the sites’ data. The monitor will visit the site to check the 
completeness of subject records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study drug 
is being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the monitor during these visits.
Continuous remote monitoring of each site’s data may be performed by Novartis. Additionally, a 
central analytics organization may analyse 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 


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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 CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the eligibility criteria, documentation of SAEs, and 
the recording of data that will be used for all primary and safety variables. Additional checks 
of the consistency of the source data with the CRFs are performed according to the study-
specific monitoring plan. No information in source documents about the identity of the subjects 
will be disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies and, by 
generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify 
that the data entered into the Electronic Case Report Forms are complete and accurate. 
After database lock, the investigator will receive a CD-ROM or paper copies of the subject data 
for archiving at the investigational site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment schedule and can be recorded directly on the CRFs. All other data captured for this 
study will have an external originating source (either written or electronic) with the CRF not 
being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
CRO staff working on behalf of Novartis review the data entered into the eCRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an electronic 
data query. Designated investigator site staff is required to respond to the query and confirm or 
correct the data. If the electronic query system is not used, a paper Data Query Form will be 
faxed to the site. Site personnel will complete and sign the faxed copy and fax it back to the 
CRO working on behalf of Novartis who will make the correction to the database.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).


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10.3
Data Monitoring Committee
Not required.
10.4
Adjudication Committee
Not required.
11
Data analysis
11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The study has four parts, and the safety and efficacy analysis will be presented for period 1, 
period 2 and period 3 combined, and separately for period 4. 
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with available PK data and no protocol deviations 
with relevant impact on PK data.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by subject. Summary statistics 
will be provided.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed and summarized.
11.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Data for study drug administration, and concomitant therapies will be listed and summarized.
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11.4
Analysis of the primary variable(s)
The primary objective of this study is to assess the effect of LFG316 on the reduction of 
intravascular hemolysis in PNH patients as assessed by reduction in serum LDH levels after the 
first 4 weeks of treatment and during the entire treatment period.
11.4.1
Variable(s)
The primary efficacy variable for assessing the effect of LFG316 over the first 4 weeks of 
treatment is response rate where a patient will be considered a responder if the percentage 
reduction from baseline in serum LDH is at least 60% at any time up to and including week 4
for that patient.
The primary efficacy variable for assessing the effect of LFG316 over the entire treatment 
period is the actual serum LDH value measured at multiple time points during the study.
11.4.2
Statistical model, hypothesis, and method of analysis
Proof of concept will be based on LDH levels during the first four weeks. A positive sign of 
efficacy is when:

The estimated median response rate is at least 50%
For the analysis of serum LDH values from multiple time points, a longitudinal model analysis 
of log-transformed LDH levels over time pre- and post-treatment will also be performed.
Longitudinal modelling will include individual and treatment average graphical presentations 
over time incorporating any historical LDH data collected so as to better put post-treatment 
changes in context. 
11.4.3
Handling of missing values/censoring/discontinuations
The study aims to replace subjects enrolled before protocol amendment 5 who discontinue 
before the end of period 1 for reasons other than safety and the primary responder analysis will 
be based on period 1 completers only, in a per protocol fashion.
Further longitudinal model analyses performed to assess the effect of missing data on the 
conclusions drawn from the primary analysis will include, if available, data from any subjects 
who discontinued early. Lack of efficacy will not be considered a missing value. Even if 
treatment is discontinued, LDH values should still be assessed in the eight-week follow-up 
period.
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11.4.4
Supportive analyses
For comparison with the Bayesian analysis above, supportive analyses are in the frequentist 
paradigm giving the possibility of incorporating meaningful prognostic characteristics, such as 
being carriers or not of the minor allelic variant of C5, in modelling the response rate as binary 
data in logit models.
Alternative longitudinal model analyses of log-transformed LDH levels over time pre- and 
post-treatment may also be performed, to assess the sensitivity of the primary analysis to 
missing data, any deviations from assumptions, and to also assess the impact of prognostic 
factors on conclusions. 
Additionally serum LDH at each timepoint will also be summarized in terms of the number and 
percentage of patients achieving a reduction in LDH to within the normal limits.
11.5
Analysis of secondary 
 variables
The analysis of the two secondary endpoints of standard safety monitoring with increased 
vigilance for infections and measurement of serum concentrations of LFG316 are covered in 
Section 9.1 (adverse events) and Section 8.5 (pharmacokinetics) respectively. There will be no 
adjustment for multiplicity over the three main analyses of efficacy (primary), safety and PK 
(both secondary).
11.5.1
Efficacy / 
The analysis of the primary efficacy endpoint of reduction in LDH is described above in 
Section 11.4.2 and Section 11.4.4.
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11.5.2
Safety
Adverse events
All information obtained on adverse events will be displayed as summary and by subject as per 
the secondary objective.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term. A subject with multiple adverse events within a body system is only counted 
once towards the total of this body system.
As this study has four treatment periods an adverse event starting in period 1 and continuing 
into the next period is counted only in the period 1. 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 period. There will be three summaries of AEs, at the end of treatment 
period 1; periods 2 and 3 combined; and period 4.
Vital signs
All vital signs data will be listed by subject and visit/time and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by visit/time.
ECG evaluations
All ECG data will be listed by subject and visit/time, and abnormalities will be flagged. 
Summary statistics will be provided by visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by subject and visit/time and if normal ranges are available 
abnormalities will be flagged. Summary statistics will be provided by visit/time.
11.5.3
Pharmacokinetics
Total LFG316 concentration data will be listed by subject, and visit/sampling time point. 
Descriptive summary statistics will be provided by visit/sampling time point, 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. An exception to this is Tmax where median, 
minimum and maximum will be presented.
Pharmacokinetic parameters will be calculated as described 
in Section 8.5 and will be listed by subject.
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11.5.5
Other assessments
11.6
Sample size calculation
The sample size text below still applies following amendment 6, as the potential increase in 
number of patients treated is not so much to increase power of the study but to provide a 
treatment option for C5 variant PNH patients without an alternative. Notwithstanding that, if 
further patients are recruited then overall power will increase and the calculations below may 
then also be applicable to C5-variant patients only. If no further patients are recruited, the below 
text remains valid.
11.7
Power for analysis of key secondary variables
Not applicable.
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11.8
Interim analyses
12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment procedures 
(e.g. advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis around the time 
of Last Patient Last Visit to be a reviewer and signatory for the clinical study report.
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12.3
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
(e.g. peer-reviewed journal) and/or posted in a publicly accessible database of clinical trial 
results.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study patients. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research related 
purpose involving any investigational drugs.
Investigators must apply due diligence to avoid protocol deviations. If the 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/REB it cannot be implemented. All significant protocol deviations will be recorded 
and reported in the CSR.
13.1
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 intended to eliminate an apparent immediate hazard to subjects may 
be implemented, provided the Health Authorities and the reviewing IRB/IEC are subsequently
notified by protocol amendment.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the CTL should 
be informed and (serious) adverse event reporting requirements (Section 9) followed as 
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14
References
Available upon request.
Cesbron JY, Maillet F, Valance J et al (1985) Déficit homozygote enC5 révélé par une 
méningite purulente à Neisseria meningitidis. Presse Méd;14(45):2287-9.
Delgado-Cerviño E, Fontán G, López-Trascasa M (2005) C5 complement deficiency in a 
Spanish family. Molecular characterization of the double mutation responsible for the defect. 
Mol Immunol;42(1):105-11.
Haeney MR, Thompson RA, Faulkner J et al (1980) Recurrent bacterial meningitis in patients 
with genetic effects of terminal complement components. Clin Exp Immunol;40(1):16-24.
Hill A, Rother RP, Arnold L, et al (2010) Eculizumab prevents intravascular hemolysis in
patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular
hemolysis occurring through C3 opsonization. Haematologica; 95(4):567-73.
Konar M, Granoff D (2017) Eculizumab treatment and impaired opsonophagocytic killing of
meningococci by whole blood from immunized adults. Blood; 130:891-9.
Levey A, Coresh J, and Balk E (2003) National Kidney Foundation Practice Guidelines for 
Chronic Kidney Disease: Evaluation, Classification, and Stratification. Ann Intern 
Med;139:137-147.
López-Lera A, Garrido S, de la Cruz RM et al (2009) Molecular characterization of three new 
mutations causing C5 deficiency in two non-related families. Mol Immunol;46(11-12):
2340-7.
Risitano AM, Notaro R, Marando L, et al (2009) Complement fraction 3 binding on
erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria
patients treated by eculizumab. Blood; 113(17):4094-100.
Risitano AM, Marotta S (2016) Therapeutic complement inhibition in complement-mediated
hemolytic anemias: Past, present and future. Semin Immunol; 28(3):223-40.
Rosenfeld PJ, Brown DM, Heier JS et al (2006) Ranibizumab for neovascular age-related 
macular degeneration. N Engl J Med;355(14):1419-31.
Sanal O, Loos M, Ersoy F et al (1992) Complement component deficiencies and infection: 
C5, C8 and C3 deficiencies in three families. Eur J Pediatr;151(9):676-9.
Slade C, Bosco J, Unglik G, et al (2013) Deficiency in Complement factor B. N Engl J Med;
369(17):1667-9.
Subias Hidalgo M, Martin Merinero H, López A et al (2017) Extravascular hemolysis and
complement consumption in Paroxysmal Nocturnal Hemoglobinuria patients undergoing
eculizumab treatment. Immunobiology; 222(2):363-71.
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Zerzri Y, Kallel-Sellami M, Abdelmalek R et al (2010) Hereditary complement C5 
deficiency: study of 3 Tunisian adult cases and literature review. Tunis Med;88(4):269-76.

SAP_001.pdf: 
Biostatistics & Statistical Programming /
Novartis Institutes for BioMedical Research
LFG316
Study CLFG316X2201 / NCT02534909
An open-label proof of concept study to assess the 
efficacy, safety and pharmacokinetics of LFG316, an 
anti-C5 monoclonal antibody in patients with paroxysmal 
nocturnal hemoglobinuria (PNH)
RAP Module 3: Detailed Statistical Methodology
Author(s):
Document type:
RAP Module 3: Detailed Statistical Methodology
Document status: 
Final Version 2
Document date: 
  08-Aug-2022
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................3
1
Introduction to RAP documentation....................................................................................4
1.1
Scope........................................................................................................................4
1.2
Changes to RAP documentation (M3).....................................................................4
2
Study objectives and design ................................................................................................5
2.1
Study objectives.......................................................................................................5
2.1.1
Primary objective ....................................................................................5
2.1.2
Secondary objective ................................................................................5
2.1.3
Exploratory objectives ............................................................................5
2.2
Study design and treatment......................................................................................6
3
First interpretable results (FIR) ...........................................................................................7
4
Interim analyses...................................................................................................................8
5
Statistical methods: Analysis sets........................................................................................8
6
Statistical methods for Pharmacokinetic (PK) parameters..................................................9
6.1.1
Variables .................................................................................................9
6.1.2
Descriptive analyses................................................................................9
6.1.3
Model checking procedures ....................................................................9
6.1.4
Graphical presentation of results.............................................................9
6.1.5
Pharmacokinetic / pharmacodynamic interactions..................................9
7
Statistical methods for Pharmacodynamic (PD) parameters.............................................10
7.1
Primary objective...................................................................................................10
7.1.1
Variables ...............................................................................................10
7.1.2
Descriptive analyses..............................................................................10
7.1.3
Statistical model, assumptions and hypotheses.....................................10
7.1.4
Graphical presentation of results...........................................................10
7.1.5
Handling of missing values/censoring/discontinuations.......................11
7.1.6
Supportive analyses...............................................................................11
7.2
Secondary objectives .............................................................................................11
7.3
Exploratory objectives...........................................................................................11
8
Statistical methods for safety and tolerability data............................................................12
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8.1.1
Variables ...............................................................................................12
8.1.2
Descriptive analyses..............................................................................12
8.1.3
Graphical presentation of results...........................................................13
List of tables
No table of contents entries found.
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1
Introduction to RAP documentation
1.1
Scope
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CLFG316X2201”.
Module 3 (M3) provides the description of the statistical methodology used to analyze the 
data, Module 7 (M7) details the presentation of the data, including shells of summary tables, 
figures and listings, and Module 8 (M8) contains programming specifications e.g. for derived 
variables and derived datasets, to support the creation of CSR outputs.
1.2
Changes to RAP documentation (M3)
Refer to corresponding guidances and NIBR RAP Addendum template for detailed information 
on the requirements of documenting changes to RAP documentation.
For the statistical methodology (M3), any major changes to the statistical methodology should 
be reflected in the RAP M3 documentation via version control (M3 amendment) (new document 
version to be approved by the trial team as the original module).
Such major changes could include (but are not limited to):

change in statistical methodology

substantial change in (derivation of) main endpoint

substantial change in study design (e.g. protocol amendment introducing new multiple-
dose cohorts in a so far single-dose trial)
Such changes may also require a protocol amendment to ensure consistency. In addition they 
need to be mentioned (high-level) in the CSR (section for changes to planned analysis).
Minor changes to the RAP M3 documentation can be captured e.g. by a study note to file / note 
in RAP Addendum or within the CSR itself. Minor changes include, but are not limited to, 
changes related to exploratory endpoints, addition of further exploratory analyses, changes to 
the extended scope of interim analyses. Corrections of typographical errors or modification of 
spelling (from English to American, for example) do not need to be incorporated into the RAP 
M3 documentation.
Analyses and outputs related to additional exploratory ad-hoc requests used for reporting are 
regarded minor changes and should be documented in the RAP addendum (no RAP amendment 
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2
Study objectives and design 
2.1
Study objectives
2.1.1
Primary objective

To assess the effect of LFG316 on the reduction of intravascular hemolysis in PNH patients
2.1.2
Secondary objective

To assess the tolerability and pharmacokinetics of LFG316 in patients with PNH
2.1.3
Exploratory objectives
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2.2
Study design and treatment
This is an open-label, non-controlled study in patients with PNH. Approximately 10 patients 
will be enrolled in the study. 
The study drug will be administered via i.v. infusion at the dose level of 20 mg/kg every 14 days.
Patients participating in study will have an option to either complete period 3 Follow up and 
Study Completion evaluation or continue in study period 4 that is pre-requisite to join the long-
term extension study CLNP023C12001B, that is separate to this study protocol. Patients who 
are potentially eligible and willing to participate in the LNP023 long-term extension study will 
join period 4, where treatment will be converted from LFG316 to LNP023 200 mg b.i.d.
The study will consist of a 60-day screening period to assess eligibility and conduct vaccinations 
if required (for all patients not previously vaccinated at least 2 weeks prior to first dosing or if 
prior vaccination cannot be confirmed). An extensive screening window (up to 60 days) is 
planned in order to comply with local vaccination requirements, if available and deemed 
necessary at the investigator’s discretion. Safety evaluation assessments requiring blood and 
urine samplings, pregnancy test, pulmonary function test, ECG, patient reported outcomes, and 
assessment of number of blood transfusions should be performed no longer than 4 weeks prior 
to the planned dosing day. Subjects who meet the eligibility criteria at screening will be 
admitted to baseline (Day 1) evaluations. The patients will enter treatment period 1, and will 
receive infusions of LFG316 every 14 days, days 1, 15 and 29 (3 administrations).
At the end of period 1, efficacy on hemolytic activity by serum LDH will be assessed. 
All patients will then be allowed to enter the optional treatment period 2, and will receive 
infusions of LFG316 every 14 days, and undergo the efficacy, PK, 
 and 
safety assessments for additional 48 weeks.
Following the 48-week treatment period 2, LFG316-responsive patients (assessed based on
investigator’s judgment) will be allowed to enter an additional third extension period of up to
260 weeks (extension period 3).
The LFG316 treatment for all patients will be completed by end of 2021 regardless of each
individual treatment period.
Patients participating in extension period 3 will roll over from the last dosing visit of period 2
to the first visit (which includes drug administration) of period 3. The same dosing interval
applied in Period 1 and 2 will be applied between the last dosing visit of Period 2 and the first
visit of Period 3.
Period 4 can be initiated as directed by Sponsor and will last approximately 21 weeks. During 
the first 4 weeks patients will continue to receive LFG316 20 mg/kg every two weeks (total 
of two administrations) in addition to oral administration of LNP023 200 mg b.i.d. After 4 
weeks, patients will discontinue LFG316 and will proceed with LNP023 200 mg b.i.d. 
monotherapy for approximately 16 weeks (+/- 28 days). Patients who participate in period 4 
can join the long-term extension study CLNP023C12001B as soon as their eligibility is 
confirmed and study CLNP023C12001B is open to receive patients. There should be no 
LNP023 treatment gap between the studies. Please refer to Section 7.1 of the protocol for 
guidance regarding safety monitoring and LNP023 down-titration in case of LNP023 
treatment discontinuation.
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For patients not participating in the period 4, the extension period 3 will be followed by a
Study Completion evaluation approximately 8 weeks after the last drug administration. 
Patients who discontinue treatment prematurely during any of the study periods will be
followed for 8 weeks after discontinuation, and will similarly undergo a study completion
visit. The 8 weeks follow- up period will start the day after the last drug administration (both 
for patients completing treatment and patients prematurely discontinuing), and will comprise
one visit after approximately 4 weeks, and a study completion visit after approximately 8
weeks from the last drug administration. Safety assessments will include physical 
examinations, ECGs, vital signs, standard clinical laboratory evaluations (hematology, blood 
chemistry, urinalysis) and adverse event monitoring.
Patients participating in period 4, will complete their Study Completion evaluation 
approximately one week after last LNP023 treatment administered as a part of this study.
Figure 2-1 
Study design 
*Period 4 is applicable only for the patients who are potentially eligible and wish to participate 
in the long-term extension study CLNP023C12001B
**+/-28 days
3
First interpretable results (FIR)
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4
Interim analyses 
5
Statistical methods: Analysis sets
For subjects for which the actual treatment received does not match the planned treatment the 
treatment actually received will be used for the analysis. The study has four parts, the safety 
and efficacy analysis will be presented for period 1, period 2 and period 3 combined, and 
separately for period 4 unless otherwise stated below/in the output shell.
All subjects that received study drug will be included in the safety analysis set.
The PK analysis set will include all subjects with available PK data and no protocol deviations 
with relevant impact on PK data.
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6
Statistical methods for Pharmacokinetic (PK) parameters
6.1.1
Variables 
The following pharmacokinetic parameters will be determined (if feasible) using 
non-compartmental method(s) with Phoenix WinNonlin (Version 6.2 or higher): AUC(0-tlast), 
AUC(0-t), Cmax, tmax, Cmax/D, AUC/D. The linear trapezoidal rule will be used for AUC 
calculation. For LNP023 only pre-dose and 2 hour concentrations will be determined in period 
4.
6.1.2
Descriptive analyses
Total LFG316 concentration data will be listed by patient, and visit/sampling time point while 
pharmacokinetic parameters will be listed by patient. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. An exception to this is Tmax where median, 
minimum and maximum will be presented. 
6.1.3
Model checking procedures
Not applicable.
6.1.4
Graphical presentation of results
Overlaying individual plasma concentration-time profiles will also be generated.
6.1.5
Pharmacokinetic / pharmacodynamic interactions
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7
Statistical methods for Pharmacodynamic (PD) parameters
7.1
Primary objective
7.1.1
Variables 
The primary efficacy variable is response rate where a patient will be considered a responder 
if the percentage reduction from baseline in serum LDH is at least 60% at any time up to and 
including week 4 for that patient.
The primary efficacy variable for assessing the effect of LFG316 over the entire treatment
period is the actual serum LDH value measured at multiple time points during the study.
7.1.2
Descriptive analyses
Unless stated otherwise, summary statistics for PD variables will include sample size (N), mean 
(arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum and 
maximum. 
For serum LDH baseline will be the average of all pre-dose measurements.
7.1.3
Statistical model, assumptions and hypotheses
Proof of concept will be based on LDH levels during the first four weeks. A positive sign of 
efficacy is when:

The estimated median response rate is at least 50%
7.1.4
Graphical presentation of results
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7.1.5
Handling of missing values/censoring/discontinuations
The study aims to replace patients who discontinue before the end of period 1 for reasons other 
than safety and the primary responder analysis will be based on period 1 completers only, in a 
per protocol fashion. However further analyses will be performed to assess the effect of 
including patients with incomplete data on the conclusions drawn from the primary analysis. 
Lack of efficacy will not be considered a missing value. Even if treatment is discontinued, LDH 
values should still be assessed in the eight-week follow-up period.
7.1.6
Supportive analyses
Longitudinal analysis will firstly include individual and average graphical presentations over 
time incorporating any historical LDH data collected so as to better put post-treatment changes 
in context. If deemed potentially useful, longitudinal statistical modelling will be used to look 
at changes within subjects as well as across subjects.
Additionally serum LDH at each timepoint will also be summarized in terms of the number
and  percentage of patients achieving a reduction in LDH to within the normal limits.
7.2
Secondary objectives
The analysis of the two secondary endpoints of standard safety monitoring with increased 
vigilance for infections and measurement of serum concentrations of LFG316 are covered in 
Section 8.1.2 (adverse events) and Section 6 (pharmacokinetics) respectively. There will be no 
adjustment for multiplicity over the three main analyses of efficacy (primary), safety and PK 
(both secondary).
7.3
Exploratory objectives
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8
Statistical methods for safety and tolerability data
8.1.1
Variables 
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as subject demographics and baseline characteristics will be
listed, summarized and plotted.
8.1.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by ethnicity, C5 variant status 
and patient. Summary statistics will be provided.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by ethnicity and C5 variant status and 
summarized.
Treatment
Data for study drug administration, and concomitant therapies will be listed by ethnicity and 
C5 variant status and summarized.
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Vital signs
All vital signs data will be listed by ethnicity, C5 variant status and patient and visit/time and if 
ranges are available abnormalities (and relevant orthostatic changes) will be flagged. Summary 
statistics will be provided over visit/time.
ECG evaluations
All ECG data will be listed by ethnicity, C5 variant status and patient and visit/time, and 
abnormalities will be flagged. Summary statistics will be provided over visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by ethnicity, C5 variant status and patient and visit/time and if 
normal ranges are available abnormalities will be flagged. A separate listing is provided 
presenting all parameters in a patient with any abnormal values. Summary statistics will be 
provided over visit/time.
Adverse events
All information obtained on adverse events will be listed by ethnicity and C5 variant status and 
displayed summarized as per the secondary objective.
The number and percentage of patients with adverse events will be tabulated by body system 
and preferred term. A patient with multiple adverse events within a body system is only counted 
once towards the total of this body system.
As this study has four treatment periods an adverse event starting in one period and continuing 
into another is counted only in the first period grouping in which it occurs. A patient with 
multiple adverse events within a body system and treatment period is only counted once towards 
the total of this body system and treatment period. There will be three types of summaries of 
AEs, starting in periods 1 to 3, starting in period 4, and overall throughout the study.
Pregnancy test
All pregnancy test results for women will be listed by ethnicity, C5 variant status, patient and 
visit.
Other safety evaluations
All other safety evaluations e.g. physical examination will be listed by ethnicity, C5 variant 
status, patient and visit.
Meningococcal vaccination data will be listed by ethnicity, C5 variant status and patient. 
8.1.3
Graphical presentation of results
Plots of individual data across time to visualize trends in longitudinal safety data (vitals, ECG, 
lab parameters) will be created similarly to those proposed for plots of individual LDH data.
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RAP Module 3
CLFG316X2201
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